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Michigan State
University

 

 

 

This is to certify that the

dissertation entitled

The Aza-Annulation Reaction as a Synthetic Tool
for Asymmetric Synthesis and the Construction of
Potentially Biologically Active Compounds

presented by

Petr Benovsky

has been accepted towards fulfillment
of the requirements for

Ph.D. degreein Organic Chemistry

 

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Major professor

Date July 21. 1997

MS U it an Affirmative Action/Equal Opportunity Institution 0-12771

 

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Wanna-o.-

 

THE AZA-ANNULATION REACTION AS A SYNTHETIC TOOL
FOR ASYMMETRIC SYNTHESIS AND THE CONSTRUCTION OF
POTENTIALLY BIOLOGICALLY ACTIVE COMPOUNDS

Petr Benovsky

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

College of Natural Science
Department of Chemistry

1997

ABSTRACT

THE AZA-ANNULATION REACTION As A SYNTHETIC TOOL
FOR ASYMMETRIC SYNTHESIS AND THE CONSTRUCTION OF
POTENTIALLY BIOLOGICALLY ACTIVE COMPOUNDS
By

Petr Benovsky

The stereoselective formation of six-membered nitrogen heterocycles with an
asymmetric quaternary carbon center could be achieved through aza-annulation of B-
enamino amide substrates, prepared by a condensation of a racemic B-keto amide with an
optically active primary amine, and activated acrylate derivatives. A variety of different
B-enamino amide substrate classes were examined in this reaction. When aza-annulation
reaction was performed with an oc-acetamido substituted acrylate derivative, the
quaternary carbon center was formed stereoselectively, but poor selectivity was observed
for generation of the stereogenic center OI to lactam carbonyl.

The aza-annulation reaction provides an efficient route for the potential
construction of the heterocyclic 2-pyridone framework for complex bioactive
compounds, such as natural product targets or synthetic peptide mimetics. Peptide
analogs could be assembled in three steps and in good overall yield.

The aza-annulation was then shown to constitute a quick and efficient method of
building up isoquinoline derivatives, which might serve as non-benzodiazepine sleep

inducing drugs.

To my family and my parents

iii

ACKNOWLEDGMENTS

I would like to express my great appreciation to Dr.Stille for his dedication to the
field of chemistry and for all he has taught me throughout my graduate career. Without
your "pushing" it would be much more difficult. I would also like to thank Dr.Reusch as
a "foster" advisor, your lectures, Tuesday night meeting problems, and explanations were
perfect. I have to thank Dr.Maleczka for letting me to join his group meetings, and
numerous consultations. Thanks to Drs.Nocera, Rathke, and McCracken for their
enthusiasm.

I would like to extend my appreciation to all those individuals without whom my
graduate career would have been incomprehensibly more difficult: the NMR-staff -
Dr.Long, Kermit Johnson - a software magician, Bev at the Mass Spec Facility, Lisa in
the Graduate Office, Nancy and Diane, Tom in the stockroom.

I would like to thank my family for their support and sacrifices, to my friends
Petr, Jana, Ruda, Honza, Marie, Zdenék, and Wen-Ying, to my labmates Drs.Lars, Paul,
Art, Greg, Nancy, Steve and his wife Beth, to Brian and Ed. Thanks to all students from
the Dr.Maleczka's group.

Without a support of American friends, particularly the Wheelers, the Selle
family, Pastor Dave, the Huffords, the life, especially in the beginning, would be much

more difficult. You all are a part of my success.

iv

TABLE OF CONTENTS

LIST OF TABLES .............................................................................. vii
LIST OF FIGURES ............................................................................ viii
LIST OF SCHEMES ............................................................................. ix

CHAPTER I. ASYMMETRIC SYNTHESIS OF NATURAL PRODUCTS... ......1

CHAPTER II. ASYMMETRIC FORMATION OF QUATERNARY CENTERS
THROUGH AZA-ANNULATION OF CHIRAL B-ENAMINO
AMIDES WITH ACRYLATE DERIVATIVE.

Introduction ................................................................................ 12
Asymmetric Induction in the Aza-Annulation Reactions ...................... 14
RESULTS AND DISCUSSION ........................................................ 24
Aza-annulation reactions with cyclic B-ketoamides ............................ 29
Aza—annulation reactions with acyclic substrates ............................... 42
Selectivity of formation of substituted Ot-amino lactams ....................... 48
Mechanistic Discussion ............................................................. 51
Conclusions ........................................................................... 63
EXPERIMENTAL RESULTS .......................................................... 64
LIST OF REFERENCES ................................................................ 84

CHAPTER III. FORMATION OF DIHYDROPYRIDONE- AND PYRIDONE-
BASED PEPTIDE ANALOGS THROUGH AZA-ANNULATION
OF B-ENAMINO AMIDE SUBSTRATES WITH a-AMIDO

ACRYLATE DERIVATIVES.
Introduction ................................................................................ 87
RESULTS AND DISCUSSION ........................................................ 95
Structural Analysis of IH-23c .................................................... 100
Direct Formation of Pyridones ................................................... 103
Conclusions .............................................................................. 107
EXPERIMENTAL RESULTS ........................................................ 109
LIST OF REFERENCES ............................................................... 121

CHAPTER IV. PREPARATION OF ISOQUINOLINE ALKALOID ANALOGS
THROUGH THE AZA-ANNULATION METHODOLOGY.

Introduction ............................................................................... 123
RESULTS AND DISCUSSION ....................................................... 128
Conclusions ............................................................................... 140
EXPERIMENTAL RESULTS ........................................................ 142
LIST OF REFERENCES ............................................................... 159
APPENDICES
Appendix 1 ORTEP Representation of II-69a ....................................... 161
Appendix 2 ORTEP Representation of III-23 ....................................... 162
Appendix 3 Reprints of Publications ................................................. 163

vi

LIST OF TABLES

Table 11-] Effects of Substrate Variations on Asymmetric Induction .................. 19
Table 11-2 Temperature Effects on Asymmetric Induction and Reaction Yields. . ....20
Table 11-3 Unsuccessful Attempts to Prepare Amide 11-23 ................................ 28
Table 114 Effect of Chiral Amine and Acrylate Derivative on the Asymmetric Aza-

Annulation Reaction ............................................................... 32
Table 11-5 Formation of B-Keto Amides .................................................... 37
Table 11-6 Asymmetric Aza-Annulation with B-Keto Amides ........................... 38
Table 11-7 (Jr-Substituted Lactam Products of Asymmetric Aza-Annulation ........... 50
Table 111-1 Different B-Tum Types ............................................................ 88
Table 111-2 Formation of Peptide Analogs through Aza-Annulation and Pyridone

Formation from B-Keto Amides .................................................. 99
Table III-3 Aza-Annulations with Different OI-Amino Acids ........................... 105
Table IV -1 Examples of Isoquinoline Drugs .............................................. 124
Table IV-2 Preparation of Amide Derivatives ............................................. 132
Table lV-3 Formation of Enamino Esters .................................................. 134

vii

LIST OF FIGURES

Figure I-l Examples of Compounds with a Qutemary Stereogenic Center .............. 3
Figure 11-1 Oligopeptide Analogs with Restricted Conforrnations ....................... 24
Figure 11—2 Matsuyama's Hetero-Diels-Alder Transition State for the Aza-annulation

Reaction ............................................................................. 55
Figure 11—3 "Loose" and "Compact" Complex Approaches ............................... 57
Figure 11-4 Frontier Orbital Interaction ...................................................... 58
Figure III-1 Typical B-Turn Arrangement .................................................... 88
Figure III—2 B-Sheet Arrangements ............................................................ 89
Figure III-3 B-Tum Mimics ..................................................................... 90
Figure III-4 B-Tum Mimics ..................................................................... 91
Figure III-5 B-Turn Mimics ..................................................................... 92
Figure III-6 The Endothelial Cell Integrin act/[33 Antagonist ............................... 93
Figure III-7 Captopril (HI-10) and Enalapril (III-11) ....................................... 94
Figure III-8 Potential Inhibitor of Angiotensin I - Angiotensin II Conversion .......... 95

viii

LIST OF SCHEMES

Scheme I-l Asymmetric Synthesis Using Chromium Carbonyl Derivative ............. 4
Scheme 1-2 Construction of S-Epipumiliotoxin ............................................. 5
Scheme 1-3 Synthesis of 8-Oxocephalotaxine ............................................... 6
Scheme 14 Preparation of (i)-Costaclavine ................................................. 7
Scheme 1-5 Synthesis of (fl-Zl-Epiaspidospermin ......................................... 7
Scheme 1-6 Construction of (_-1-_)-Mannonolactam (LI 1) and (fi-Deoxymannojirimycin

(1-10) ................................................................................ 8
Scheme 1-7 Preparation of (fl-Prosopinine (I-12) .......................................... 9
Scheme 11-1 Use of Proline Esters as Chiral Auxiliaries .................................. 12

Scheme 11-2 Use of a Chiral Auxiliary with a C2 Axis in the Michael Reaction ....... 13
Scheme 11-3 Deracemizing Alkylation of (Jr-Substituted Cyclanones .................... 15

Scheme 11-4 Aza-Annulation as a Synthetic Tool for Preparation of a Selective

Inhibitor of Human Type I Steroid S-a—Reductase .......................... 16
Scheme 11-5 Asymmetric Aza-Annulation with RAMP as a Chiral Auxiliary ......... 17
Scheme 11-6 General Strategy for Asymmetric Aza-Annulation Reactions ............ 18
Scheme 11-7 Asymmetric Aza-Annulation with Ester Derivatives ....................... 20
Scheme 11-8 Concomitant Formation of Two Stereogenic Centers ...................... 22
Scheme 11-9 Preparation of Restricted NMDA Analogs ................................... 23
Scheme 11-10 Asymmetric Aza-Annulation of Ester Derivatives ......................... 24
Scheme 11-11 Formation of Amides from Ester Analogs .................................. 25
Scheme 11-12 Unsuccessful Attempts to Prepare an Amide 11-23 ........................ 26

ix

Scheme 11-13 Curtius Rearrangement ......................................................... 27

Scheme 11-14 Imine-Enamine Tautomerism ................................................. 29
Scheme 11-15 Asymmetric Aza-Annulation with Amide Derivatives .................... 30
Scheme 11-16 Asymmetric Aza-Annulation of b-Enamino Amide Intermediates with
Acrylate Derivatives ............................................................ 31
Scheme 11-17 Possible Transition State of B-Keto Amide Formation .................... 34
Scheme 11-18 Using of 2,2-Dimethyl-l,3-Dioxin-4-One Derivatives for Preparation of
B-Keto Amides ................................................................... 35
Scheme 11-19 Asymmetric Aza-Annulation with Amide Derivatives .................... 36
Scheme 11-20 Asymmetric Aza-Annulation of Cyclopentanone Derived B-Enamino
Amide Intermediates with Acrylate Derivatives ............................ 40
Scheme 11-21 Preparation of an 4-Oxoimidazolidin Derivative ........................... 41
Scheme 11-22 Preparation of Acyclic B-Keto Amides ...................................... 42
Scheme 11-23 Asymmetric Aza-Annulation with Acyclic B-Keto Amides .............. 44
Scheme 11-24 Asymmetric Aza-Annulation with Acyclic B-Keto Amides Derived from
D,L-Threonine - Ester Route .................................................. 46
Scheme II-25 Asymmetric Aza-Annulation with Acyclic B-Keto Amides Derived from
D,L-Threonine - Amide Route ................................................ 47
Scheme 11-26 Asymmetric Aza-Annulation Providing (Jr—Substituted Lactam
Derivative ........................................................................ 49
Scheme 11-27 The Preparation of a 12-Azasteroid Systems ............................... 52

Scheme 11-28 Pandit's Explanation of Stereoselectivity for the Michael Reaction. . ...52
Scheme 11-29 Seebach's Topological Rule. Two Possible Approaches .................. 53
Scheme 11-30 Hickmott's Mechanism of Aza-Annulation ................................. 54

Scheme 11-31 Stereoselective Preparation of 2,2-Disubstituted 3-Cyclopentenone
Derivatives by the Asymmetric Michael Reaction .......................... 55

Scheme 11-32 d'Angelo's Asymmteric Michael Addition Reactions ...................... 56

Scheme 11-33 Transition State Suggested by d'Angelo ..................................... 56
Scheme 11-34 A Key Step in the Total Synthesis of (-_I-_)-Vallesamidine .................. 58
Scheme 11-35 Favored Synclinal Approach in the Total Synthesis of (i)-
Vallesamidine .................................................................... 59
Scheme 11-36 3-Aza-Cope Transition State for Asymmetric Induction in the Aza-
Annulation Reaction ............................................................ 60
Scheme 11-37 Synclinal Approach in Ala-Annulation Reaction .......................... 61
Scheme 11-38 Suggested Mechanism of Ala-Annulation .................................. 62
Scheme III-l Construction of Human Renin Inhibitors .................................... 92
Scheme III-2 An giotensinogen Degradation ................................................. 94
Scheme III-3 Attempts to Prepare Tripeptide Analog Fragment .......................... 97
Scheme 111-4 Formation of Peptide Analogs through Ala-Annulation and Pyridone
Formation from B-Keto Amides ............................................... 98
Scheme 111-5 Determination of Epimerization during the Ala-Annulation ............ 105

Scheme 111-6 Determination of Epimerization during Aza-Annulation and Oxidation
Reaction ......................................................................... 104

Scheme 111-7 Direct Pyridone Formation through Aza-Annulation ..................... 106

Scheme III-8 Determination of Epimerization during Direct Pyridone Formation... 107

Scheme IV -1 1,3-Dipolar Cycloaddition Approach ....................................... 126
Scheme 1V-2 Annulation Approach ......................................................... 127
Scheme IV-3 Retrosynthetic Analysis ...................................................... 128
Scheme IV -4 Preparation of Amide Derivatives ........................................... 129
Scheme 1V -5 6-Chloro-indan-1-one Approach ............................................. 131
Scheme IV-6 Formation of Thiolactams through Isothiocyanates ....................... 133

xi

Scheme IV -7 Preparation of Chloro Substituted Tricyclic Isoquinoline Derivatives. 135
Scheme 1V-8 6,7-Dimethoxy Substituted Tricyclic Isoquinoline Derivatives... ......137
Scheme 1V-9 Unsubstituted Tricyclic Isoquinoline Derivatives ......................... 138
Scheme IV-lO Preparation of Thiophene Analogs of Isoquinoline Derivatives ....... 139
Scheme IV-ll Preparation of Indole Substituted Derivatives ........................... 139

Scheme IV-12 Unsuccessful Preparation of Yohimbine Analog ........................ 140

xii

Ac
AIBN
Arg

A89
(30020
n-Bu
m-CPBA

DBU

DDQ
DMAP
DMF
DMSO
DPPA
dppp
Et
EWG
FAB

Gly

LIST OF ABBREVIATIONS

Acetyl
2,2'-Azobisisobutyronitrile
Arginine
Asparagine
Di-tert-butyldicarbonate
Normal Butyl
m-Chloroperbenzoic Acid
1 ,8-Diazabicyclo[5.4.0]undec-7-ene
1 ,3-Dicyclohexylcarbodiimide
2,3-Dichloro-5,6-dicyano— 1 ,4-benzoquinone
4-Dimethylaminopyridine
N,N-Dimethylformamide
Dimethylsulfoxide
Diphenylphosphoryl azide
1 ,3-Bis(diphenylphosphino)propane
Ethyl
Electron Withdrawing Group
Fast Atom Bombardment

Glycine

xiii

His
HRMS

Ile

NMO
NMR
Ph
Phe
i-Pr
PCC

Ser

TMEDA
TMS
p—TsOH
Tyr

Val

Histidine
High Resolution Mass Spectroscopy
Isoleucine
Leucine
Lithium Diisopropyl Amide
Methyl
N-Bromosuccinimide
4-Methylmorpholine N-oxide
Nuclear Magnetic Resonance
Phenyl
Phenylalanine
Isopropyl
Pyridinium Chloro Chromate
Sefine
Tetrahydrofurane
Thin Layer Chromatography
N ,N,N ',N'-Tetramethylethylenediamine
Tetramethylsilane
p—Toluenesulfonic Acid
Tyrosine

Valine

xiv

CHAPTER I

ASYMMETRIC SYNTHESIS OF NATURAL PRODUCTS

Asymmetry itself brings to any system an element of disorder and, consequently
new and unusual properties and behavior. In chemistry as a discipline, the presence of an
asymmetric center in a compound makes synthesis of the molecule even more difficult.
Construction of a chiral molecule has been always a challenging problem and has
required a lot of effort to build up more complex structures.

Recently, the importance of efficient asymmetric synthesis has soared, and
methods for preparing useful and active chemical substances are in great demand (either
for suitable model compounds in biochemical processes or for new drug substances).
Chemists commonly strive to develop new methods and technologies for the selective
formation of stereogenic centers. Numerous efforts to synthesize compounds that occur
naturally in plants and other organisms, or to make potentially more active analogs, have
been made. A few ingenious syntheses include those of strychnine (I-l), vitamin B12

and brevetoxine B (1.2) by Woodward‘ and Nicolaouz, respectively.

 

HO CHO
Me,
H,0 0
H
Me Me UOH'
Mb MeH ‘0’ 7 0“
-0- ..O
/ ' / H
o O o ,HOH HOMe 1'2

Compounds of biological interest such as natural products, synthetic enzyme
inhibitors, or models of naturally occurring scaffolds may be elaborated by several
different techniques:‘°"4'5
o The reagent or reactant may contain a chiral auxiliary, a group in the vicinity of the

reaction site that controls the stereochemistry of the center(s) to be built, and can be
easily removed afterwards;

o A homochiral catalyst (enzyme or synthetic product) may be employed;

0 A "chiral pool approach", in which readily available homochiral molecules, often
from a natural source, are used as building blocks. Alkaloids, amino acids and
carbohydrates are probably the most important chiral building blocks and tools for the
construction of complicated structures.

In the past, easily available, naturally occurring asymmetric compounds have been
used as chiral auxiliaries for specific or more selective preparation of desired molecules.

Among many examples of chiral compounds, there is a large group of molecules

having a quaternary carbon stereogenic center. Some representatives are presented in

Figure [-1, and include lycopodine (I-3)6, akvammicine (I-4)7, cephalotaxine (I-S)“,

ebumamonine (I-6)9, morphine (I-7)‘°, aspidospermidine (1-8)11 and Ot-obscurine (I-9).12

Figure [-1. Examples of Compounds with a Quaternary Stereogenic Center.

 

LYCOPODINE
I-3

    

O E
\

Me
EBURNAMONINE

[-6

 

AKVAMMICINE
1-4

0 °”
KO 0
M N“\ 9
6’
OH

MORPHINE
1-7

6'0 NH

a-OBSCURINE

[-9

<0 O
N
° O”)
HO
OMe
CEPHALOTAXINE
I-5
/\
_ N
O 9 M,
{“1 H

(+)-ASPIDOSPERMIDINE
[-8

3

Due to the relative difficulty of the construction of quaternary carbon stereogenic

centers, new, highly efficient methods are needed. One of the new interesting solutions is

illustrated in Scheme I-l. Here, the complex of a suitably substituted benzene ring with

chromium carbonyl undergoes nucleophilic addition to an aldehyde functionality only

from one side. Moreover, the rotation of the aldehyde group is restricted by the presence

of an ortho substituent. The result is a significant asymmetric induction.3

Scheme I-l. Asymmetric Synthesis Using Chromium Carbonyl Derivative.

O
I ___+.» I” ——->
’/ 2.H3O OMS OMS

(CO)30r 0M6 (CO)3Cr

A few methods provide a relatively convenient approach to the construction of a
stereogenic quaternary carbon center. The aza-annulation methodology, closely related to
Michael reaction, is one of them.

Aza-annulation methodology meets these two important requirements:

0 Formation of a new carbon-carbon bond.
0 Tandem cyclization with formation of a new heterocyclic ring.

Aza-annulation reactions have been used for the construction of a variety of
structures. The synthesis of (fi-lupininel3 and (fi-S-epipumiliotoxin Cl4 (Scheme 1-2),
(fi-S-oxocephalotaxinels (Scheme 1-3), (fi-costaclavine'6 (Scheme I-4) and 21-
epiaspidosperminel7 (Scheme [-5) serve as illustrative examples.

Aza-annulation reactions have been studied by our group, and several naturally
occurring compounds have been synthesized with this methodology. For example,
syntheses of (_-t;)-mannonolactam (I-ll), (j-J-deoxymannojirimycin (I-10) and (i)-
prosopinine (I-12) have been prepared recently in our group'8 (Scheme 1-6, Scheme [-7).
Aza-annulation reactions have been exhaustively reviewed19 and the background details

will not be discussed in this work.

Now aza-annulation is used even as a powerful and efficient tool for an

asymmetric formation of a quaternary carbon stereogenic center.

Scheme 1-2. Construction of S-Epipumiliotoxin.

o o O
i PhAN ii Ph/‘N
———> ——> H”
O ”H
o

O
1 iii
Me O
N 4 steps N Iv PhA N
l-i: <——— k”, 4———— H],
”H 25% ”H ”H
M9 M3 6H3

 

Reaction Conditions. I) benzylamine, benzene, reflux, then acryloyl chloride,
THF, 75% yield; ii) 1 atm of H2, Pd/C(10%), NazCO3 then (COCl)2. DMSO,
Eth, 85% yield; iii) MeMgBr 68% yield; iv) NaH, C82 then MeI then

Bu3SnH, AIBN, 52% yield.

Scheme 1-3. Synthesis of 8-Oxocephalotaxine.

 

ol‘o O/\o

61>}ij

[62: 38 ratio
1 iii

0 O 7 steps O:©/\ O
N
<0 e ._ <0 ..

HO O
OMe

 

 

Reaction Conditions. I) benzene, p-TsOH, reflux, 2 h; ii) 210° C
96% (2 steps); iii) Pb(OAC)4, benzene, reflux then MeOH, MeONa,

94%.

Scheme [-4. Preparation of w-Costaclavine.

several
fl

steps

   

 

Reaction Conditions. i) methylamine then methacryloyl chloride, 66%.

Scheme I-S. Synthesis of (fl-Zl-Epiaspidospernfin.

 

 

Reaction Conditions. I) acryloyl chloride, pyridine, DMAP, MeCN; ii) TiCl4,

ClCHzCHZCl, 80° C, 63% (2 steps).

Scheme 1-6. Construction of Qa-Mannonolactam (1-11) and (i)'

Deoxymannojirimycin (1-10).

0 o O
i \\\‘ILM
l o —> I o —> °
—> O N OBn
HO O N .
Bn

I
Bn
OH
O N OBn

/ B" \‘1
OH OH

N OH O OH

N
H H
[-10 I-11

 

Reaction Conditions. 1') benzylamine, benzene, reflux then acrylic anhydride, THF,
66° C, 71%; ii) a) CF3CO2H, m-CPBA, 55%; b) KOH, H20, 85%; c) KOH, benzyl
bromide, 84%; d) LDA, PhSeCl, NaIO4, 78% then 0504, NMO, 65%; iii) LiAlI-14,

NaOH, H20, 98% then 1 atm of H2, Pd/C, MeOH, 52%; iv) Li/NH3, 44%.

Scheme [-7. Preparation of (_-_I-)-Prosopinine (I-12).

“\OBD i \\\OBD ii “\080
———> .
OINLOBH EIOzc / OBn Et02C\\\\\(Nl’08n

Bn Bn Bn

11

<—
M e/W=\\\\\ N CB" 0 HC \\\\\ N CB"

0 Bn Bn
[-12

-Z

 

Reaction Conditions. I) a) Lawesson's reagent, 94%; b) EtO2CCH2Br, N33, 81%, ii)

NaBHgCN, pH 4.0, 88% (>90: 10 ratio of diastereomers).

LIST OF REFERENCES

10

LIST OF REFERENCES

1. Woodward, R.B.; Cava, M.P.; Ollis, W.D.; Hunger, A.; Daeniker, H.U.; Schenker, K.
Tetrahedron 1963, 19, 247. ‘

2. a) Nicolaou, K.C.; Sorensen, 13.1. in Classics in Total Synthesis, VCH 1996.
b) Nicolaou, K.C.; Hwang, C.-K.; Guggan, M.E.; Nugiel, D.A.; Abe, Y.; Bal Reddy,
K.; DeFrees, S.A.; Reddy, D.R.; Awartani, R.A.; Conley, S.R.; Rutjes, F.P.J.T.;
Theodorakis, E.A. J. Am. Chem. Soc. 1995, 117, 10227;
c) Nicolaou, K.C.; Theodorakis, E.A.; Rutjes, F.P.J.T.; Sato, M.; Tiebes, 1.; Xiao, X.-
Y.; Hwang, C.-K.; Duggan, M.E.; Yang, 2.; Couladouros, E.A.; Sato, F.; Shin, 1.; He,
H.-M.; Bleckman, T. J. Am. Chem .Soc. 1995, 117, 10239;
d) Nicolaou, K.C.; Rutjes, F.P.J.T.; Theodorakis, E.A.; Tiebes, 1.; Sato, M;
Untersteller, E. J. Am. Chem. Soc. 1995, 117, 10252.

3. Davies, S.G. Chem. Brit. 1989, 268.

4. Brown, J.M.; Davies, S.G. Nature 1989, 342, 631.

5. Davies, S.G.; Brown, J.M.; Pratt, A.1.; Fleet, G. Chem. Brit. 1989, 259.

6. Heathcock, C.H.; Kleinman, E.F.; Binkley, ES. 1. Am. Chem. Soc. 1982, 104, 1054.

7. Edwards, P.N.; Smith, G.F. J. Chem. Soc. 1961, 1458.

8. Dolby, L.1 .; Nelson, S.J.; Senkovich, D. J. Org. Chem. 1972, 37, 3691.

9. Magnus, P.; Pappalardo, P.; Southwell, I. Tetrahedron 1986, 42, 3215.

10. Toth, 1.E.; Hamann, P.R.; Fuchs, P.L. J. Org. Chem. 1988, 53, 4694.

11. Huizenga, R.H.; van Wiltenburg, 1.; Pandit, U.K. Tetrahedron Lett. 1989, 30, 7105.

12. Schumann, D. Liebigs Ann. Chem. 1983, 220.

13. Paulvannan, K.; Schwartz, J.B.; Stille, 1.R. Tetrahedron Lett. 1993, 34, 215.

14. Paulvannan, K,; Stille, 1. R. Tetrahedron Lett. 1993, 34, 6673.

15. a) Vill, 1.1.; Steadman, T.R.; Godfrey, 1.1. J. Org. Chem. 1964, 29, 2780.
b) Kuehne, M.E.; Bornmann, W.G.; Parsons, W.H.; Spitzer, T.D.; Blount, J.F.:

Zubieta, 1 J. Org. Chem. 1988, 53, 3439.
16. Ninomiya, I; Kiguchi, T. J. Chem. Soc. Chem. Commun. 1976, 624.

17. Huizenga, R.B.; van Wiltenburg, 1.; Pandit, U.K. Tetrahedron Lett. 1989, 30, 7105.

11

18. a) Cook, G.R.; Beholz, L.G.; Stille, J.R. J. Org. Chem. 1994, 59, 3575; b) Cook,
G.R.; Beholz, L.G.; Stille, 1.R. Tetrahedron Lett. 1994, 35, 1669.

19. Stille, 1.R; Barta, N.S. Studies in Natural Products Chemistry: Stereoselective

Synthesis, contribution to Studies in Natural Products, Atta—ur—Rahman, Ed., Elsevier,
New York 1996, Volume 18, 315.

CHAPTER II
ASYMMETRIC FORMATION OF QUATERNARY CENTERS THROUGH
AZA-ANNULATION OF CHIRAL B-ENAMINO AMIDES WITH ACRYLATE
DERIVATIVES
Introduction.

Methods of forming new carbon-carbon bonds in a stereospecific or
Stereoselective fashion are copious, e.g. Claisen, Cope rearrangements and their hetero
modifications. Asymmetric variations of classical organic reactions such as the Diels-
Alder, Mannich, aldol and Michael reactions are cited in the literature to an increasing
degree.

One of the first experiments in which enantioselective Michael addition was
examined was carried out by Horeaul and Yamada.2 In the latter paper, the authors
reported the first in a series of investigations of the alkylation of chiral enamines formed

from various proline esters (Scheme II-l).

Scheme II-l. Use of Praline Esters as Chiral Auxiliaries.
R0200 <N)’”cozn

1. RX
2. H30+

55,...

12

13

Of the four possible transition states resulting from the distinct pathways of
approach of the alkylating agent, the ester moiety would be expected to exert a significant
steric interaction in only one of them. Due to rotation around the carbon-nitrogen single
enamine bond, the asymmetric induction in this system is limited to 10-35% ee.

Whitesell3 improved this idea by using a chiral auxiliary having a C2 axis of

symmetry (Scheme 11-2). This alkylation method was much more selective (82-93% ee).

Scheme 11-2. Use of a Chiral Auxiliary with a C2 Axis in the Michael Reaction.

0 R = CH3,
Me N I’Me O CH2CH2CH3,
1- RX CH CH=CH
a 2 2
__, (if x = 1, Br
2. H3O+

Whitesell proposed that both diastereomeric immonium ions are formed in a
relatively nonselective alkylation, with a subsequent, selective hydrolysis providing
enantioselectivity by kinetic resolution. Attempts to construct a quaternary carbon center
by regioselective alkylation of more substituted enamines failed, and the major alkylation
product was the less substituted isomer.

Aza-annulation has been fully developed and studied in our group, and has been
successfully applied to the syntheses of naturally occurring compounds (see selected

examples in Chapter 1). This transformation is one of the simplest ways to construct six

l4

membered nitrogen heterocycles from ketones, amines and activated derivatives of (1,13-

unsaturated acids.

Asymmetric Induction in the Aza-Annulation Reactions. Aza-annulation reactions
with chiral enamines (enamines with a chiral auxiliary attached) provide an efficient
method of stereoselective construction of quaternary carbon centers. In 1988, d’Angelo
used chiral enamines for deracemizing alkylation of Ot-substituted cyclanones4 under
neutral conditions (Scheme II-3). In the following series of papers, d’Angelo and
coworkers introduced a particularly efficient method for regioselective and
stereoselective alkylation of ketones.

Considering the tautomeric equilibrium of chiral imine II-2 with two
corresponding regioisomeric secondary enamines, it is clear that the energetically
preferred conformations of these enamines are those depicted in formulas II-2-a and II-2-
b, in which the main steric interactions are minimized. Indeed, these structures exhibit
two main degrees of freedom. By rotation of 180° around the carbon-nitrogen bond, II-2-
a leads to II-2-e and II-2-b to II-2-c. By rotation of 120° around the carbon-nitrogen
bond, II-2-a and II-Z-b give II-2-f and II-Z-d, respectively. All the conformers II-2-c, II-
2-d, II-2-e and II-2-f suffer from a strong destabilizing steric interactions which is not
encountered in the structures II-2-a and II-2-b.

High regioselectivity is explained by an easy proton transfer in tautomeric
enamine II-2-a and by the additional hyperconjugative interaction of the alkyl group.

Due to restricted rotation around the single carbon-nitrogen bond of an enamine, the

15

bulky substituent efficiently blocks one II-face of the enamine species allowing approach

of the electrophilic alkene only from one side.5

Scheme “-3. Deracemizing Alkylation of Ot-Substituted Cyclanones.

 

 

 

 

fi 1
M6 xph
o lawsv 0
Ar“ 6:: 3 M M
—> I,
R
W VVVV‘
IL] “-2 11-3
L J
Me ph Me \Ph
~ H
H°NXH 'NXH
(5* F‘
W W
II-2-e IIlZ-c
Ph Me Ph (Me Ph (Me
Hath,” HxN HxN,..
e» - «H <— e-
—>
W W W
II-2-b
II-2-a 11-2 t
H \Ph H \Ph
MexN‘H MexN'H
(\r“ 6)”
W W
II-2-f II-2-d

Audia used aza-annulation for the preparation of heterocyclic analogs to steroidal
enzyme substrates as 11-4 (a selective inhibitor of human Type I steroid 5-a—reductase)°

(Scheme 11-4).

Scheme II-4. Aza-Annulation as a Synthetic Tool for Preparation of a Selective

Inhibitor of Human Type I Steroid 5-or-Reductase.

0
Cl M “in Cl l/LC' Cl
9
Ph Me O I Me O

 

Me
——* O t . 9
0 toluene, HN THF. 0 N
reflux + -20° C i‘
Me“ H Me“ H
Ph 70% Ph

96:4 ratio

/ of isomers

17

The same idea was used by Enders and coworkers with a different chiral auxiliary
- (S)-(-)-1-amino-2-(methoxymethy1)pyrrolidine (SAMP) and (R)-(+)-l-amino-2-

(methoxymethyl)pyrrolidine (RAMP)7 (Scheme II-5).

Scheme II-5. Asymmetric Aza-Annulation with RAMP as a Chiral Auxiliary.

 

 

 

o“‘0Me “‘NOMe , \\\‘\oMe
o N. 1. n-Bqu, TMEDA N
f N‘NH2 NH THF, -78° C ‘NH ér OMe
> ; - O
R n 0 ”Q0 2' A; we R o 002Me
n 0 n
Moo 0
-78° C
3. N114C1, -30° C
O
HN Z“, ACOH
Ar ‘
R

 

18

Stille demonstrated the power of asymmetric aza-annulation in a study of
reactions of chiral B-enamino esters with acrylate derivatives yielding 5-lactam

derivativess (Scheme 11-6).

Scheme 11-6. General Strategy for Asymmetric Aza-Annulation Reactions.

0

NH2
1H020 R2 SR“: H 0R1 R2 ")L X COZH‘
R3 —> O l 3 —* ” R2R3
O H. N H O N \
SEN“ H SR“+ H
RL RL
II-5 “-6 “-7

The reaction of various B-keto esters, (R)-phenethylamine, and an acrylate
derivative provided O-lactam products with excellent Stereoselectivity in very good yield
(Table II-l). When the size of the chiral auxiliary substituents at different faces of
diastereotopic system 11-6 was comparable, as in entry 4, diastereoselectivity dropped.

Unlike asymmetric Michael reactions,9 these reactions were affected by reaction
temperature. For example, for reaction in THF the product ratio was 79:21 at 66° C, 93:7
at 0° C and 98:2 at -33° C (Scheme 11-7, Table II-2). In each case, a decrease in reaction
temperature also resulted in increased product yield. In dioxane, the differences were

even more dramatic.

19

Table II-l. Effects of Substrate Variations on Asymmetric Induction.

 

diasterepmer

 

entry substrate product ratio yield°
1 D m >97:3 85%
O o N
Me“+H
Ph
co Et
E102C Me I] 2
2 1 Me 97:3 92%
0 Me 0 N
Me“*‘H
Ph
0
o
O Q )
3 03:) "I 94:6 30%
o N
m Me“+H
Ph
co Et
BO 0
4 2 m 57:43 43%
o N
O MeOzc“+H
i-Pr

 

llDetermined by 1H NMR analysis of the crude reaction mixture.

°Yield of the diastereomeric mixture after chromatography.

20

Scheme II-7. Asymmetric Aza-Annulation with Ester Derivatives.

NH2

Ph\“i‘H
CO2Et
benzene,

E1
EtO2C reflux Q
I) r
o 2. 0 o N

l 0' Ph“+H
0023

11-8 II-9

1.

 

Table 11-2. Temperature Effects on Asymmetric Induction and Reaction Yield

 

 

solvent temp [° C] diasrtgggomera y[i;1d°
0]
THF -33 98:2 77
THF 0 93:7 68
dioxane 0 92:8 24
THF 66 79:21 63
dioxane 66 82: 18 43
dioxane 101 36:64 28

 

aDetermined by 1H NMR of the crude reaction mixture.
bYield of the diastereomeric mixture after chromatography

21

 

Me
/
M M
Me 0 CN GMG 6M9

D ’ 'l' (reaction II-l)

N ’ 40-50% 0 N O N EN
Mo“ H combined yield Me“*‘H Me“ H

Ph Ph Ph

11-10 II-ll II-12

Stille utilized d’Angelo’s pioneering studies4 (reaction II-l) for examination of
the concomitant formation of two new stereogenic centers at OL- or B-positions of
carbonyl group of lactam functionality.8 Due to steric hindrance, reaction with crotonyl
chloride proceeded in much lower yield, and the reaction needed longer reaction time and
higher temperature. With a methyl substituent at the (It-position, the reaction was more
rapid, but complete lack of stereoselectivity at the a—carbon of the lactam moiety was
observed.

Reaction of 11-15 with NaH at ambient temperature in THF increased
diastereomeric ratio to 83:17 (Scheme 11-8). With the use of the mixed anhydride of 2-
acetamidoacrylic acid, a mixture of diastereomers was formed in ratio 64:23:9z4 (i.e.
73:27 at the OI-carbon and incomplete asymmetric induction at the quaternary center

(87: 13)).

22

Scheme II-8. Concomitant Formation of Two Stereogenic Centers.

1. NH2

Me“+H
Ph

E120 ’BF3
5,020 benzene,

 

D reflux
0 Me
/

0 Cl
THF, reflux

43% yield

II-l3

1 . NH2
Me“+H
Ph
Et20 -BF3
benzene,
reflux

 

ll

 

2. Mar
Cl

0
THF, -33° C
69% yield

Me

I COfEt

O N
Me“+H
Ph

II-14

Me COfEt
O N
Me“+H
Ph

52:48 ratio

II-15

NaH, Me CO Et
THF, RT m
——>

o N

Me“+H
Ph

83:17 ratio

23

Agami recently demonstrated the enantioselective synthesis of restricted analogs
of N-methyl-D-aspartic acid (NMDA, receptor involved in neuroexcitatory transmission

effects) based on the same methodology (Scheme II-9).l°

Scheme “-9. Preparation of Restricted NMDA Analogs.

CI
0 o MBA/k0 002”

O O
J: J: _. HN CO2H
Ph N \ Ph N \ °°2M° —'
H
0 Me

002m “'9
II-l6 II-l7 II-IS
002H
H”. CO2H
Me

NMDA

24

RESULTS AND DISCUSSION
The stereoselective aza-annulation reaction provides a very good method for
the synthesis of Oligopeptide analogs having restricted conformations.

Figure II-l. Oligopeptide Analogs with Restricted Conformations.

OMe
0 IL“ 0
x’H-N O N
I ,H

o" , ,
R'HJH Nil-ll O>\ :«H
0
Key structure could be prepared by the stereoselective aza-annulation reaction of suitable
starting material, followed by subsequent transformations into corresponding amide
derivatives (peptide analogs), or by the aza-annulation reaction of amide precursors.

The first approach to the preparation of the starting material for this study seemed
to be straightforward. Ester compound II-19 was readily prepared in 85% yield from
ethyl 2-oxocyclohexane carboxylate, (R)-phenethylamine and acrylic acid mixed
anhydride8 (Scheme II-10).

Scheme II-10. Asymmetric Aza-Annulation of Ester Derivatives.

Me
O O H N‘H o 0 GB
i \ ii
@105: o/koa , Ii]

0 N
Me“+H

II-8 II-8a Ph II-19

 

Reaction Conditions. 1') (R)-phenethylamine, Et2O:BF3, benzene ii)

sodium acrylate, ClCO2Et, THF, 85% yield.

25

All attempts to hydrolyze ethyl ester 11-19 failed. The starting material either
decomposed, or proved resistant to reaction conditions. Steric congestion around the
carboxylate was probably responsible for the lack of reactivity. Carboxylic acid
derivative II-22 was finally prepared from benzyl ester II-21 by catalytic hydrogenation
over palladium to deprotect the acid (Scheme II-ll). All attempts to prepare an amide
11-23 were unsuccessful or gave the desired product in very low yield. Scheme II-12 and

Table II-3 summarize the results obtained.

Scheme II-ll. Formation of Anrides from Ester Analogs.

GB 0 Ph
063 " one
———>
O 0
[LS II-20

o OH O OVPh
I"
11) <—
0 N O N

Me“*‘H Mew“ H
Ph Ph

II-22 II-21

 

Reaction Conditions. i) benzyl alcohol, DMAP, xylene, 68%
yield; ii) (R)-phenethylamine, Et2O:BF3, benzene, reflux then
sodium acrylate, ClCO2Et, THF, 70% yield; iii) PdlC(10%), 1

atm of H2, EtOH, 100% yield.

26

Interestingly, reaction of carboxylic acid derivative and DPPA, followed by an
addition of benzyl amine or ethyl glycine, gave Curtius rearrangement product II-24
rather than desired amide (Scheme II-l3).The difficulties encountered in conversion of
II-22 into II-23 served to reinforce the need to examine methods for aza-annulation with

B-keto amide substrates rather than modification of their ester analogs.

Scheme “-12. Unsuccessful Attempts to Prepare an Amide 11-23.

 

O OH H2N/—R 0 “Va
11) > 1i)
0 N i O N
Me“1‘H Me“ H

Ph Ph

“-22 II-23

 

Reaction Conditions. see Table II-3.

27

Scheme 11-13. Curtius Rearrangement.

OTOEt
HN

OOH . HN/KO
1
JOE) ——- (I)
O N

o N
Me\\i~ H Me\\+ H
Ph Ph
II-22 11-24

 

Reaction Conditions. I) glycine ethyl ester, DPPA,

CH2Cl2, 53% yield.

28

Table 11-3. Unsuccessful Attempts to Prepare Amide 11-23.

 

 

 

 

 

 

 

 

 

 

i R Yields, results
NaH, ClCO2Et -CO2Et 0%
0-15%, 10:1 ratio of
DCC -CO2Et diastereomers
stable DCC derivative
(ClCO)2, THF, pyridine -CO2Et 0%
(ClCO)2, (imid)2CO, THF, -CO2Et Starting material recovered
RT
DPPA, THF, Et3N, 0° C -Ph 6-10%
major product - urea derivative
TsCl, pyridine -Ph 0-10% + recovered starting

material

 

 

29

Aza-annulation reactions with cyclic B-ketoamides. One advantage of cyclic
imines derived from cyclic ketones is that the corresponding enamine has defined Z-
geometry (dictated by the presence of the ring). Moreover, in the presence of B-carbonyl
functionality, the rotation around carbon-nitrogen single bond of enamine is restricted
due to a formation of an intramolecular hydrogen bond (see Scheme II-14) forming thus

a more stable, conjugated tautomeric form of an imine.

Scheme II-l4. Imine-Enamine Tautomerism.

 

 

a star represents a chiral auxiliary

Based on previous studies with achiral imines and B-enamino esters and

1 as well as the use of this methodology in the synthesis of natural products,’2

ketones,l
three different classes of acrylate derivatives have been studied. B-Keto amide 11-25,
prepared from commercially available B-keto ester by several methods,13 was used as a
starting material for the enamine aza-annulation sequence as illustrated in Scheme II-15.
A significant dependence of the aza-annulation reaction outcome on the type of

acrylic derivative employed was observed (Table 114). Unlike the aza-annulation

reactions of B-enamino ester substrates, reactions with acryloyl chloride gave lower

30

yields; the use of acrylic acid anhydride, generated in situ by the reaction of
sodium acrylate with acryloyl chloride, resulted in somewhat improved yields.
However, use of the mixed anhydride, formed by the combination of sodium acrylate
with ethyl chloroforrnate just before reaction, proved to be the optimum reagent for aza-
annulation with B-enamino amide substrates. In each case, the diastereoselectivity of the
quaternary carbon formation from the B-enamino amide substrate was high, and was

independent of the acrylate derivative used for the aza-annulation reaction.

Scheme “-15. Asymmetric Aza-Annulation with Amide Derivatives.

Me
O O 0 0 Ph "
i A ii H7\N.H 0
CB
H25

II-8 - II-26

H
o NVPh
04 :N§ :

Me“+H
Ph

II-27

iii

 

Reaction Conditions. I) benzylamine, DMAP, xylene, reflux, 91% yield; it) (R)-

phenethylamine, toluene, reflux; iii) sodium acrylate, ClCO2Et, THF, 99% yield.

31

Scheme 11-16. Asymmetric Aza-Annulation of B-Enamino Amide Intermediates with

Acrylate Derivatives
RBI
0 ’V‘N'H O OVNV Ph
CW“ "———» Oil“? tidbit-1.173
01R\\§;H ON1R“
R2”
11-25 II-28 II-29-32a II-29-32b

A similar reactivity was observed for the B-enamino amide derived from
condensation of phenyl glycine ethyl ester (II-30) with II-25. The aza-annulation of II-25
was significantly more efficient when acrylic acid anhydride was used instead of acryloyl
chloride, and further increase in yield was obtained through the use of the mixed
anhydride. In each case, stereoselective formation of II-30b occurred to the extent of
>98z2. Use of the valine derived substrate II-3l, which resulted in poor
diastereoselectivity in the case of the B-enamino ester substrate (57:43), gave excellent
stereoselective formation of II-3lb (>98:2) in high yield (90%) for the B-enamino amide.
Interestingly, even the phenylalanine derived compound II-28d was effective at
asymmetric induction (95:5), but the yield of the aza-annulation reaction was low with
this auxiliary. For each example, enamine II-28 was readily generated, and the reaction

products II-29-3Za-b were stable to moderate hydrolysis conditions.

32

Table 114. Effect of Chiral Amine and Acrylate Derivative on the Asymmetric Aza-

Annulation Reaction.‘I

 

 

 

 

 

 

Comp. Amine R‘ RI Method II-29a-32a Yield
#
: II-29b-32b" [%]°
11.29 II-33a Me Ph A >98:2 99
NHz B >98:2 86
Me“*‘H
Ph C >98:2 67
11.30 II-33b Ph c0213: A >2:98 98
NH2 B >2z98 80
Ph‘“ H
COzEt C >2:98 49
II-33c
11-31 NH2 cone "Pr A >98:2 9o
M6020“*‘ H
’9:
II-33d
11.32 NH2 c025: Em A 95:5 46
EtOZC“tH
Ph

 

See Scheme II-l6. ”Reaction conditions: (I) II-33a or II-33b-d0HCl/NaHCO3, toluene,
reflux; (ii) method A: sodium acrylate, ClCOzEt, THF, ~78° C; method B: sodium
acrylate/acryloyl chloride, THF, -78° C; method C: acryloyl chloride, THF, RT.
l’Deterrnined by 1H NMR of the crude reaction mixture. cYield of the diastereomeric

mixture after flash column chromatography.

 

33

The use of a—amino acid derivatives instead of benzyl amine in preparation of B-
ketoamides proved to be much more complicated; direct synthesis using DMAP and
corresponding amine, as in the case of the benzylamides, did not give the desired product.
At this stage of the research, it was decided to explore the interesting formation of B-keto
amides from B-keto esters by reaction with primary or secondary aminesm’ This reaction
is believed to occur via a 4-membered cyclic transition state from the initially formed
intermediate II-34 to a B-ketoamide (Scheme II-l7). This type of mechanism may also
be involved in the reaction of B-ketoesters with amines in the presence of DMAP.
Reaction of ethyl 2-cyclohexanone carboxylate with benzylamine and DMAP provided
the expected product in 91% yield, but reaction with ethyl glycine or N-methyl glycine
(sarcosine) did not give the desired products under the same reaction conditions.
Moreover, in the case of sarcosine, only N ,N-dimethyl amide was isolated, the product of

decarboxylation of the desired product.

34

Scheme II-17. Possible Transition State of B-Keto Amide Formation

 

 

 

F Ph Ph '
[—Ph r r
0 0 H2N '0 NH0 '0‘ J:
OEt > DB ——> 0
xylenes, _ EtOH
reflux
II-8 ‘ 11-34 [1.35 ‘
o o
NAPh
H
II-25

A different method for the preparation of B-keto amides is based on the thermal
instability of 2,2—dimethyl-2H,4H-l,3-dioxin-4-one derivatives.13c Thermolysis in
refluxing xylenes in the presence of an amine resulted in formation of the corresponding
B-ketoamide, via ketene intermediate II-38 (Scheme II-18).

This method was successfully used for the preparation of various B-keto amides
derived from a-amino acids (Table II-S). Aza-annulation products were readily obtained
from chiral amines, and the enamine intermediates were immediately used in the next
step to complete the synthesis (Scheme II-l9, Table II-6). Products of this type may

serve as models of restricted (x-amino acid-B-amino acid sequences.

35

Scheme II-18. Using of 2,2-Dimethyl-l,3-Dioxin-4-One Derivatives for Preparation

 

 

 

of B-Keto Amides.
O O O O O O
.. \
@013 . 0H u GAO
II-8 II-36 J “-37
O 0 ca iii 0 °
(1W * é/
II-39 II-38

Reaction Conditions. i) NaOH, H20; ii) acetone, acetic anhydride, H2804, 54% (2

steps); iii) ethyl glycine, xylene, reflux, l h, 54%.

36

Scheme II-19. Asymmetric Aza-Annulation with Amide Derivatives.

0 02331 0 NH
NXH i
H ———->
o N

 

Reaction Conditions. i) (R)-phenethylamine,

toluene, reflux, then sodium acrylate, ClCOzEt, THF

37

Table II-5. Formation of B-Keto Amides.

 

 

 

 

 

R Product Yield
0 o
A
N Ph
II-25
o o
/\
N
-CH2C02Et b): 0028 54%
II-39
0 dVIe Me
M9020“ H
Me Me {I} con" 75%

 

II-40

 

 

 

Table II-6. Asymmetric Ala-Annulation with B-Keto Amides.

38

 

 

 

 

 

Yield de“
R' R2 Amide Product [%] [%]
Ph
HWH
O NH
0 0 d Ph 1b
NXH o N
Ph H H Me\‘+H 99% >98:2
Ph
11.25 II-29a
Et02C
Her”
NXHO2
COzEt H H 74% >98:2
° 1
11.39 s H
Me Ph
1141
M6020
’Pr\\“’H
o o IP44 002MB 0 NH
1‘ [If H
cone Pr 50% >98:2
o N
11.40 Me\‘+H

 

 

 

 

 

 

aRatio at the quaternary carbon stereogenic center.

 

39

The five-membered substrate II-43, prepared from ethyl cyclopentanone-Z-
carboxylate according to the same reaction scheme as II-25, showed different reactivity
and stability patterns than the analogous six-membered ring substrates (Scheme II-20).
Due to its thermal instability, compound II-43 was used without extensive purification
for subsequent formation of enamines II-44 and 1146. These reactions were slower than
their six-membered ring analogs. Before the aza-annulation step, it was necessary to
purify these enamines by flash column chromatography, thus, the isolated yield
dramatically dropped. Aza-annulation of II-42 led to generation of 1145 in only
moderate yield, but the product was obtained with high diastereoselectivity (>98:2).
Treatment of 1146 with the acrylate mixed anhydride led to a more efficient aza-
annulation than that of [142, but the crude ratio of diastereomers was only 84:16 (based
on 1H NMR measurement), and after purification of Ill-47, a 75:25 ratio of diastereomers
was obtained. The products 1145 and II-47 were resistant to catalytic hydrogenolysis
under an atmospheric pressure of hydrogen.

In an attempt to broaden the spectrum of potential synthetic applications, with the
intention to prepare a spiro compound similar to products prepared by Stille and
coworkers,8 1-tert-Boc-5-acetyl-3-methyl-4-oxoimidazolidin II-50 was synthesized'4

(Scheme II-21).

Unfortunately, reaction of compound II-SO with (R)-phenethylamine gave no
enamine product. Prolonged heating of a toluene solution of these reactants, with or
without the presence of an acid catalyst (p-toluenesulfonic acid or Lewis acids), gave

only starting material or products of decomposition.

40

Scheme II-20. Asymmetric Aza-Annulation of Cyclopentanone Derived B-Enamino

Amide Intermediates with Acrylate Derivatives.

0 o

 

 

cam
H
II-43
Ph
Ph EtOzC =
H’K: .OH 1 HXN H 0
ll
HO/KN AP 4; > \ NAPh
H
II-44 [146
iii iii
0 H
11>V Y v...
0193
oMe“§‘I-l Ph“‘+H
COzEt
1145 1147

 

Reaction Conditions. 1') (R)-phenethylamine, toluene, reflux; if) (R).ethyl
phenylglycine hydrochloride, toluene, NaHC03, reflux; iii) sodium acrylate,

ClCOzEt, THF, 50% for 1145, 67% for 1147 (75:25 ratio of diastereomers).

41

Scheme II-21. Preparation of an 4-Oxoimidazolidin Derivative.

 

 

 

l
HCI.H2NAC02Et __, HCI.H2N/YO
HN
6
ii
v
Me. 0 H
Me NT NWN'MG
Me’M'e <N Me>g' o
H
M M
"-48 ° °
iii
V
M Me
Me Bit/(O i" Me N 0
M6 M6 N Me Me N160
0A0 GAO Me
1149 “-50

 

Reaction Conditions. i) methylamine, MeOI-I; it) pivaloyl aldehyde, Et3N,
CH2C12; iii) (Boc)20, DMAP, acetone, 80% yield; iv) LDA, THF, -78° C

then acetyl chloride, -78° C, 95% yield.

42

Aza-annulation reactions with acyclic substrates. The aza-annulation with
acyclic B-keto amide substrates also resulted in initial ring formation with a high degree
of diastereoselectivity (Scheme II-23). Condensation of (R)—phenethylamine and II-53,
prepared by reaction of diketene with benzyl amine in benzene solution, followed by
routine alkylation of the B-keto amide product II-52 with sodium ethoxide and methyl
iodide in ethyl alcohol (Scheme II-22), efficiently generated the corresponding enamine
as a single geometric isomer. This species had a relatively rigid structure due to an
intramolecular hydrogen bond, confirmed by 1H NMR spectroscopy of the crude reaction
mixture. Subsequent aza—annulation with the mixed anhydride of acrylic acid, made in
situ, generated II-54 with high diastereoselectivity (>98:2). All attempts to isolate and
purify compound II-54 either by flash column chromatography or by crystallization led

to hydrolysis of the product to II-55, the open chain keto diamide.

Scheme II-22. Preparation of Acyclic B-Keto Amides.

i o o i,- o o
o t MeMfiAph MeMflAph

0 Me
II-51 II-52 II-53

 

 

V

 

Reaction Conditions. i) benzylamine, benzene, 0° C, 81%; ii) NaOEt, EtOH, MeI,

100%.

43

In order to obtain an accurate yield for the carbon-carbon bond formation process,
crude II-54 was treated with p-toluenesulfonic acid in wet tetrahydrofuran to promote
complete hydrolysis of the enamide functionality. The product “-55 was obtained in an
overall 82% yield in the three-step process of enamine formation, aza-annulation

reaction, and hydrolysis, with a >98:2 diastereomer ratio.

Reaction of II-53 with a different chiral amine followed by aza-annulation led to
similar results as those obtained for II-SS (Scheme II-23). Thus, condensation of II-53
with (R)-ethyl 2-phenylglycine hydrochloride generated an enamine intermediate as a
single geometric isomer, and the annulation reaction gave 8—lactam II-56 with >98:2
diastereoselectivity. Facile hydrolysis of the disubstituted terminal enamide II-56 was
observed during the purification process. As a result, compound II-56 was subjected to
hydrolysis and the acyclic product “-57 was isolated in 71% overall yield without loss of

stereochemical integrity.

Compound II-59, a benzyloxycarbonyl protected derivative of D,L-threonine II-
58,” was the source of the next B-keto carboxylate species studied (Scheme II-24). In
this case, however, instead of the corresponding amide, the B-keto ester II-6l was
prepared first, oxidation of ester II-60 by PCC giving the desired B-keto ester II-6l in
91% yield for the two-step process. Condensation with (R)-phenethylamine, followed by
treatment with the acrylate mixed anhydride gave the aza-annulation reaction product II-
62. As observed for II-54 and II-56, this terminal enamide was sensitive toward
hydrolysis conditions, and even with aqueous NaHC03 work up, hydrolysis occurred

completely to give II-63 in 45% overall yield.

44

Scheme II-23. Asymmetric Aza-Annulation with Acyclic B-Keto Amides.

 

 

 

o o
MeMNAPh
Me H
11-53
i ii
V V H
M6 o OVNVPh

~ = Me
11$“ 1);
O N Ph 0 N

M6“+ H Ph\\\+ H

Ph 002E!
II-54 II-56
iii iii
Ph Ph
0 HN—l O HN
,Me #4 Me
Me Me
0
O NH O NH O
Me“+H Ph“‘+H
Ph ooze:
II-55 II-57

 

Reaction Conditions. i) (R)-phenethylamine, toluene, reflux then sodium acrylate,
ClCOzEt, THF; ii) (R)-ethyl 2-phenylglycinezHCl, NaHCOg, toluene, reflux; then sodium

acrylate, ClCOzEt, THF; iii) p-TsOH, H20, THF.

45

An analogous amide derivative was prepared by a similar reaction scheme
(Scheme II-25). Enamine formation with (R)-phenethylamine, followed by the aza-
annulation reaction with a mixed anhydride made in situ from sodium acrylate and ethyl
chloroformate at low temperature gave a product II-67 having an exo-double bond. The
open chain structure II-68 was again obtained during the purification of the crude product
on the SiOz column. The yield after column purification was 85%, i.e. higher than for the
ester analog. Aza-annulation with acryloyl chloride yielded the same product II-68 in

73% yield.

In general, a comparison of the reactions of ester derivatives and amide
derivatives, indicate that the latter compounds undergo slower aza-annulation reaction
but in higher yields. The major by-product of the reaction was found to be the
corresponding acrylamide. Independent of the reagent used for this reaction, the chiral a-

amino acid was formed with >98:2 stereoselectivity.

46

Scheme Il-24. Asymmetric Aza-Annulation with Acyclic B-Keto Amides Derived

from D,L-Threonine - Ester Route.

0H 0 OH 0

Me MOH ——> 'Jziigl‘orl —"'—’ MeMOEt .
NH Ph VOT NH
II-58 0 11.59 0 II-60

0 CE! . O O
H W
“N TOV Ph ‘— Me OE!
v
0 N 0 Ph VOT NH
0

Me“+H
Ph

._ II-62 — II-61

 

 

vi

 

Reaction Conditions. 1) PhCHgOCOCl, NaHCO3, H20, 95% yield; ii) EtOH, HCl,
reflux; iii) PCC, Celite (1:1 ratio), CH2C12, 91% yield (2 steps); iv) (R)-phenethylamine,

toluene, reflux; v) sodium acrylate, EtOzCCl, THF; v1) aq.NaHCO3, 45% yield.

47

Scheme II-25. Asymmetric Aza-Annulation with Acyclic B-Keto Amides Derived

from D,L-Threonine - Amide Route.

0“ 0H 0 0'
WM ——> MeMO cn

0 VI Cl
II-59 II-64
ii
0 o
M A iii MN AP
Ph M; NH u Ph PhMgT NH
V T
o o
“-66 II-65

H
O NvPh H _/Ph
N
db“? —*v PhXMeO O H 0 Ph
H o \‘ v
0 N ‘ph T

II-67 II-68

 

 

 

Reaction Conditions. 1) DCC, EtOAc, 60%; ii) benzylamine, Et3N, dioxane, H20,
80%; iii) PCC, Celite (1:1 ratio), CH2Cl2, 56%; iv) (R)-phenethylamine, toluene,

reflux then sodium acrylate, ClCO2Et, THF; v) Si02, H20, 75%.

48

The instability of enamide products having an exo double carbon-carbon bond
such as “-62 and II-67 is noteworthy. Comparing these compounds with relatively stable
structures made by Stille and Barta,8 suggests the possibility of nitrogen participation in

nucleophilic attack of a water molecule to the enamine carbon-carbon double bond.

Several important features of the aza-annulation reaction of acyclic B-keto
carboxylate derivatives are of significance. The unexpected hydrolysis process yielded
acyclic substrates in good yields and high diastereoselectivity. As a result, the 1,4-
asymmetric induction that occurred during the reaction appeared as a 1,6-relationship in
the hydrolysis product. This suggests a relatively rigid transition state with strictly
defined geometry, where the carbarnate nitrogen is a much weaker base for participation

in hydrogen bonding and consequently in the nucleophilic displacement.

Selectivity of formation of substituted or-amino lactams. Reaction of different
B-keto amides II-25, II-39 and 1140 with (R)-phenethylamine, followed by the aza-
annulation with a mixed anhydride, prepared by treatment of 2-acetamido acrylic acid
with ethyl chloroformate at -78° C, resulted in formation of roughly equal amounts of two
diastereomeric a—acetamido 8-lactam products II-69a-c and II-70a-c (Scheme II-26).
Results are summarized in Table II-7, with yields and diastereomeric ratios indicated.
The selectivity in forming a quaternary carbon stereogenic center was still excellent

(>98:2), with no bias for selective generation of the stereoisomers at the a position.

49

Separation of the diastereomers by column chromatography allowed

characterization of each product, with the exception of diastereomers II-69c and II-70c.
Mutual relationship of two stereocenters (a quaternary carbon center and the a-carbon
center of lactam functionality) in compound II-69a was confirmed by X-ray

crystallography (Appendix 1).

Reaction of II-69a with NaH led to epimerization a to the lactam carbonyl that
resulted in a 45:55 ratio of II-69a and II-70a, favoring the more thermodynamically
stable diastereomer. No epimerization was observed with DBU as a base. These results
were in an agreement with the behavior of similar substrates, prepared in different

research projects by our group."5

Scheme 11-26. Asymmetric Ala-Annulation Providing a-Substituted Lactam

Derivative.

o 019 R2 , H 0 NH H 0 NH
Lt ‘ Me N Me N,,
N H —_> '
~ ‘0‘ + r
o N o N

\\‘ H \\‘ H
Me Ph Me Ph
II-69a-c lI-70a-c

 

Reaction Conditions. 1’) (R)-phenethylamine, toluene, reflux, then sodium 2-

acetamidoacrylate, ClCO2Et, THF.

Table II-7. oc-Substituted Lactam Products of Asymmetric Aza-Annulation.

50

 

 

 

 

 

 

 

 

 

R‘ R2 Amide Product Yield Ratio‘
Ph
NY”
0 ° '1 Ph H NH
M N
«S. “or
H Ph H 0 N 67% 50:50
Me“‘PhH
11-25
II-69a, II-70a
Etozc H
H“
O NH
O 0 '1 Cozfit M n
ma 2r
H C02Et 0 79% 65:35
Me“‘ H
11.39 P"
II-69b, II-‘70b
M9026
’Pn\“"H
O NH
0 o 'P H
air-Mo MeTN
it o
iPr C02Me ‘3 15% 50:50
Me“\PhH
11.40
II-69c, II-70c

 

 

 

' diastereomeric ratio at (at-carbon of the lactam ring.

51

Mechanistic Discussion. A detailed mechanism of the aza-annulation reaction is
still not known, and several hypotheses have been suggested. Ala-annulation is closely
related to the Michael addition reaction, in which a carbon-carbon bond formation occurs
between an enamine nucleophile and mB-unsaturated carbonyl system, followed by
acylation at nitrogen atom of an enamine species. In 1967, Panditl7 described reactions of
cyclic tertiary enamines with mB-unsaturated esters (Scheme II-27). To explain
stereoselectivity of the course of the reaction, authors suggested a formation of a dipolar

intermediate II-71 with subsequent intramolecular hydrogen transfer (Scheme II-28).

In 1981, Seebach formulated the general, topological rule18 based on his
experimental results with open-chain nitroolefins and open-chain enamines,’9 and
previous experiments done by Risaliti with enamines prepared from cyclic ketones and

nitroolefins.20

52

Scheme II-27. The Preparation of a 12-Azasteroid Systems.

CC M
2 R61 N 18°C M602C \H R1 (Nj
+ E i ——» a,
Me0H

1130+

 

II-71

Seebach postulated that the approach of the two reactants is in a synclinal
fashion, where :
0 All bonds in the transition state are staggered;

o The donor (C-N bond) and the acceptor C=A and OH bonds are in a synclinal

conformation;

 

53

o A hydrogen atom (the smaller substituent on the donor component) is in an
antiperiplanar position with respect to the C=A bond (Re-Si approach in Scheme II-
29);

o The components, if they can exist in M isomeric forms, orient the actual donor and
acceptor atoms close to each other.

In the cases where very bulky groups R', R2, R3 and R4 were present and/or
the solvent was protic, antiperiplanar rather than synclinal approach, allowing for better

solvation of the donor and acceptor heteroatoms, is kinetically preferred.

Scheme II-29. Seebach's Topological Rule. Two Possible Approaches.

3 4 3
3*... R few"
2R A H A
R5 R5
.129? .125?
H R2
Re-Si approach Re-Re approach

Hickmott proposed a reaction mechanism that involved formation of an amide,
followed by [3,3] sigmatropic rearrangement to a ketene intermediate.21 In the presence
of a base (triethylamine), the positively charged ammonium species II-72 loses a proton
providing only the amide II-73. In the absence of a base, intermediate II-72 undergoes
sigmatropic rearrangements to give the ketene species, which consequently cyclizes to a

lactam compound (Scheme II-30).

54

Scheme II-30. Hickmott's Mechanism of Aza-Annulation.

 

 

 

0
C H e C H s
6 " {q 6 ‘1 NH "/‘LCI C3H11-:?\ COH"‘N
Me \ Me abase Me
“-72 II-73
[3.3]

H O O + 0
06 "‘N CeHnrN ’H+ CSHH‘NH
+— l +—— I
M6 Me Me

Matsuyama and coworkers22 used an asymmetric Michael reaction for the

preparation of (It-disubstituted unsaturated cyclanones, and suggested a hetero-Diels-

Alder transition state (Scheme II-31, Figure II-Z). In support of this hypothesis, they

cited analogous results from acyliminoacetates and chiral enamines, and the isolation and

spectral characterization of a cyclic intermediate.23

55

Scheme II-31. Stereoselective Preparation of 2,2-Disubstituted 3-Cyclopentenone

Derivatives by Asymmetric Michael Reaction.

Me 1’" Me 1’“
x x O
H NH l/‘L H NH 0 0
Me I M6
\ , Me——»_. Me

Figure II-2. Matsuyama's Hetero-Diels-Alder Transition State for the Aza-

Annulation Reaction

 

d'Angelo studied the influence of a chiral enamine intermediate in intramolecular
asymmetric Michael additions (Scheme II-32).24 Based on the experimental results from
their laboratory, they suggested an intramolecular mechanism proceeding via a cyclic
chair-like compact transition state with almost concerted hydrogen transfer from a

nitrogen atom. (Scheme II-33).

56

Scheme II-32. d'Angelo's Asymmetric Michael Addition Reactions.

Mg’ {COZMe
th‘u i = 50% ee
Wow/Ia -—* Q
Me
65% 0
Me
Phi;

N ii
H
MGM/Wows ———> M9020 36% 3°

trans/cis = 4:1

62% 0 M9 (epimerization during
work up process)
Me
P"? N iii
W —" Meo’t’C‘D 62% ee
M6 002““ 61% i
0 Me

Reaction Conditions. i) MgBrz (2 equiv.), EtzO, 0° C, 5 min.; it) benzene, 80° C, 6 h; iii)
12 kbar, THF, 20° C, 60 h.

Scheme II-33. Transition State Suggested by d'Angelo.
— - I

H
H l H {cone

0
I 0
II”
2
J
O
2:».

 

 

57

Figure II-3. "Loose" and "Compact" Complex Approaches.

 

 

 

\
\\
s‘
I
I”
tho
I ‘
\
\\
e‘
a--- 1-------
1”,
0 2 ’
't f-
C
’

\
’0 §
\\
I
”I,
\
s‘
’I
ll”,

 

 

"loose" complex "compact" complex

Pfau and Sevin25 supported the idea of a cyclic transition state by 3-216,
MNDO and ab initio calculations for simpler reactants, and confirmed that the energy of
a "loose" transition state is only slightly lower than that of a "compact" transition state
(Figure II-3). However, in aprotic solvents, the formation of a zwitterionic species would
be very unlikely and energetically demanding. Extra attractive interactions resulting from
HOMO-LUMO interactions between an enamine and an acrylic acceptor (Figure “-4)

shifts the "compact" transition state to almost the same energy level.

58

Figure [14. Frontier Orbital Interaction.

HOMO

LUMO

 

Heathcock utilized an aza-annulation reaction as a key step in the total
synthesis of (_-t;)-vallesamidine26 (Scheme II-34). Even in dioxane at reflux, the less
hindered synclinal complex was favored, giving 20:1 mixture of cis/trans isomers

(Scheme II-35).

Scheme II-34. A Key Step in the Total Synthesis of (fl-Vallesamidine.

dioxane, Ar 0
+ ——> N
B N02 ammonium salt of cis/trans ratio=20:l
. cmnannc ac1d
(125 eqmv.) (1.25 equiv.) E
90 h

42%

59

Scheme “-35. Favored Synclinal Approach in the Total Synthesis of

(fl-Vallesamidine
HO 0'
:0 [$02.4 Ar I Ar 0
Ar N N N
-——-> z —->
Et Et Et

Stille assumes similar factors in the Michael addition reaction and the aza-
annulation reaction, but points out some differences,8 too :

o The lower reactivity of B-enamine esters toward unsaturated esters, sulfonyl and
nitrile derivatives in the Michael reaction is well documented”. Aza-annulation
reactions with the same substrates are fast;

0 Lack of stereoselectivity at a stereogenic center a to the acrylate derivative was
observed for the aza—annulation reactions;

0 Stereoselectivity in carbon-carbon bond formation in aza—annulation depends on
both temperature and the acrylate like reagent (sulfone, methyl, t-butyl esters), but
not for the Michael reaction.

Stille proposed three different pathways likely to be responsible for the
stereochemical course of reaction, with the aza-Cope-like transition state as the most
likely one (Scheme II-36). He assumed that pathways in which equilibration occurs a to
the lactam carbonyl can be used to explain the generation of epimeric products during the

course of a cyclization.

60

Scheme “-36. 3-Aza-Cope Transition State for Asymmetric Induction in the Aza-

Annulation Reaction.

R
18 1
3-Aza-Cope R 7 A
_. -0 l _. -0
H~N H-N“ H-N"

Me\\‘\+H Me““ H ”9““ H
Ph

 

 

Agami and coworkers28 suggested frontier orbitals participation (AMI
calculations), but as an explanation of a possible mechanism considered only Michael
addition of the enamine moiety onto crotonyl chloride in accordance with Seebach's
topological rule (synclinal approach), followed by the formation of the lactam group

(Scheme II-37).

61

Scheme II-37. Synclinal Approach in Aza-Annulation Reaction.

J:0 a O 0
Me —> I
CIOC CO Me
Me 2 O

ltEAe\

90:10 ratio of isomers

All the facts and experimental results cited above form a relative complex
picture of a possible mechanism for the aza-annulation reactions. Although a detailed
mechanism cannot be written, this information allows speculation about the most likely
pathway. Different reaction conditions make a comparison even more difficult due to
strong dependence of reaction pathway on temperature, type of a solvent and the presence
of bulky groups.

The character of a chiral auxiliary, particularly the orientation of the most
bulky group of this auxiliary, influences the interaction of two reagents favoring the less
sterically hindered side. This defines the stereochemistry at the [3 center in the lactam
functionality. Two reactants encounter each other in a chair-like compact cyclic transition
state structure of the 3-aza-Cope type. There is a strong attractive interaction of the
HOMO-LUMO frontier orbitals of the enamine and acrylate species.

After Michael addition step and a selective hydrogen transfer, the better
leaving group X might leave the product, generating a ketene intermediate, which
undergoes an acylation reaction with an imine. Then, the logical result is the

epimerization at the at center of lactam moiety (Scheme II-38).

62

Scheme II-38. Suggested Mechanism of Aza-Annulation.

 

63

Conclusions. The stereoselective formation of six-membered nitrogen
heterocycles having an asymmetric quaternary carbon center can be achieved through
aza-annulation of B—enamino amide substrates with activated acrylate derivatives.
Condensation of a racemic B-keto amide with an optically active primary amine, either
(R)-0t-methylbenzylamine or a-amino esters derived from amino acids, can generate the
corresponding optically active tetrasubstituted secondary enamine, in which the enamine
tautomer is stabilized through conjugation with an amide carbonyl, and by the presence
of a hydrogen bond between the enamine N-H bond and the amide functionality.
Treatment of the intermediate enamine with either acryloyl chloride, acrylic anhydride, or
sodium acrylate/ethyl chloroformate derivatives results in aza-annulation to give the
corresponding 8-lactam with high diastereoselectivity. A variety of different B-enamino
amide substrate classes were examined in this reaction. When the aza-annulation reaction
was performed with an a-acetamido substituted acrylate derivative, the quaternary carbon
center was formed stereoselectively, but poor selectivity was observed the stereogenic

center Otto the lactam carbonyl.

EXPERIMENTAL RESULTS.

General Methods. All reactions were carried out performing standard inert atmosphere
techniques to exclude moisture and oxygen, and reactions were performed under an
atmosphere of nitrogen or argon. Acryloyl chloride and 2-acetamidoacrylic acid were
purchased from Fluka or Aldrich, respectively, and used without purification. Sodium
acrylate was either freshly made before reaction by reaction of acrylic acid and NaH in
dry THF at -78° C or purchased directly from Aldrich. Compound II-53 was prepared by
alkylation of benzylacetoacetamide with MeI in EtOH/EtONa.3’3 Azeotropic removal of
water was assisted by the use of 4-A molecular sieves in the modified Dean-Stark
adapter”. Concentration of solutions after work up was performed by rotary evaporator
Buchi. Flash column chromatography was performed using SiOz of 230-400 mesh.
Reactions were monitored by TLC using Whatman K6F Silica Gel 60A 250 um
thickness plates. Acetyl chloride was distilled from PC15 in the presence of quinoline.

IR spectra were recorded using a Nicolet 42 FT-IR instrument, 1H NMR spectra
are reported as follows : chemical shift relative to residual CHCl3 (7.24 ppm) or TMS
(0.0 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, in = multiplet),
coupling, and integration. 13C NMR data are reported as chemical shifts relative to
CDCI3 (77.00 ppm). High resolution mass spectra were carried out on a JEOL AX-SOS
double-focusing mass spectrometer (E1) or a JEOL HX-l 10 double-focusing mass
spectrometer with helium as the collision gas (FAB). Optical rotation measurement was

performed on the Perkin-Elmer 141 instrument.

65

Preparation of Benzyl 2-Oxocyclohexane Carboxylate II-20.

To a solution of ethyl 2-oxocyclohexyl carboxylate in toluene was added freshly
distilled benzyl alcohol and the mixture was refluxed under nitrogen for 42 hours. The
solution was concentrated under reduced pressure and the residue of the starting material
was removed by the bulb-to-bulb distillation (oven 105° C/l mm). The residual product

was pure enough for using in the next step without further purification. Yield : 68%.

Hydrogenation of II-21.

To a solution of II-21 (1.65 g, 1.27 mmol) in 40 mL of EtOH, 10% Pd/C (0.15 g) was
added, the reaction vessel was flushed 3 times with H2, and the reaction was placed
under a balloon of H2. The reaction mixture was stirred 4 hours at RT, filtered through a
pad of Celite, and concentrated under reduced pressure to give “-22 (0.38 g, 1.27 mmol,
100% yield).

[1.22 : (0.37 g, 1.27 mmol, 100% yield); [a]D24=-116.1 (c=1.73, THF); m.p.=133° c

(decomp.); 1H NMR (300 MHz, DMSO'dé) 5 1.30-1.58 (m, 3 H), 1.50 (m, 1 H), 1.63 (d,
J=7.1 Hz, 3 H), 1.82 (m, 1 H), 2.01 (m, l H), 2.08-2.22 (m, 2 H), 2.38 (m, 1 H), 2.57 (m,
1 H), 4.90 (dd, J=2.6, 4.7 Hz, 1 H), 6.12 (q, J=7.1 Hz, 1 H), 7.12-7.32 (m, 5 H), 12.78
(bs, 1 H); 13C NMR (75 MHz, DMSO-ds) 5 14.8, 18.3, 24.0, 30.2, 34.7, 45.9, 50.1, 55.0,
110.4, 125.4, 128.3, 129.4, 134.6, 142.5, 167.8, 175.6; IR (KBr) 3410, 2920, 1725, 1601,
1449, 1188, 749, 704 cm'l; HRMS calcd for C13H21NO3 m/z 299.1522, obsd m/z

299.1531.

66

Peptide Coupling with DPPA.

To the carboxylic acid II-22 (0.4 g, 1.37 mmol, 1 equiv.) in dry THF (35 mL) was added
DPPA (0.32 mL, 1.50 mmol, 1.12 equiv.) and freshly prepared ethyl glycine (0.16 g,
1.50 mmol, 1.12 equiv.) (from its hydrochloride with Ba(OH)2 in CHC13 (dried over
activated 4-A molecular sieves) under Ar at 0° C. The mixture was stirred for 30 min,
13th (0.22 mL, 1.60 mmol, 1.20 equiv.) was added, and the solution was gradually
warmed to room temperature. After the mixture was stirred for an additional 12 hours,
the mixture was diluted with 30 mL of EtOAc, washed sequentially with 20 mL of 5%
HCl, 2 x 30 mL of H20, 25 mL of saturated aqueous NaHCO3, and 25 mL of brine. The
organic layer was dried (NaZSO4), and then purified by flash column chromatography
(hexane:EtOAc gradient: 65:35 to 50:50 to 0:100) to give II-27 (as a 91:9 mixture of
both diastereomers) (0.05 g, 0.13 mmol, 10% yield) and II-24 (0.28 g, 0.70 mmol, 53%
yield).

II-24: (hexanezethyl acetate=65z35-50:50-ethyl acetate gradient, 0.281 g, 0.70 mmol,

53% yield), m.p.=(85-86)0 c; 1H NMR (300 MHz, CDC13) 5 1.19 (t, J=7.2 Hz, 3 H),
1.29 (m, 1 H), 142-1.52011, 2 H), 1.53 (d, J=6.9 Hz, 3 H), 1.59-1.87 (m, 3 H), 1.97 (m,
1 H), 2.49-2.79 (m, 3 H), 3.72 (dd, J=6.0, 18.0 Hz, 1 H), 3.80 (dd, J=6.0, 18.3 Hz, 1 H),
4.09 (q, J=7.2 Hz, 2 H), 4.87 (dd, J=3.5, 4.7 Hz, 1 H), 5.00 (s, 1 H), 5.56 (dd, J=5.4, 5.4
Hz, 1 H), 6.25 (q, J=6.9 Hz, 1 H), 7.09-7.27 (m, 5 H); 13c NMR (75 MHz, CDC13) a
14.1, 15.4, 17.8, 24.6, 29.3, 30.2, 33.8, 41.8, 50.0, 52.4, 61.2, 113.5, 125.4, 126.5, 128.5,

135.6, 141.7, 156.8, 170.2, 171.2; IR (CHCl3) 3372, 2986, 2938, 1746, 1636, 1617,

67

1559, 1397 cm'l; HRMS (FAB) M+1 calcd for C22H29N304 m/z 400.2236, obsd m/z
400.2242.

II-27: (65:35/hexanezethyl acetate, 0.05g, 0.13 mmol, 9.4% yield, 91:9 ratio of
diastereomers); 1H NMR (300 MHz, CDCl3) (significant peaks) 5 1.22 (t, J=7.2 Hz, 3
H), 1.31-1.66 (m, 4 H), 1.72 (d, J=6.9 Hz, 3 H), 1.82-2.00 (m, 2 H), 2.03-2.17 (m, 2 H),
2.41 (m, 1 H), 2.56 (m, 1 H), 3.87(dd, J=4.8, 18.6 Hz, 1 H), 4.05 (dd, J=5.4, 18.3 Hz, 1
H), 4.15 (q, J=7.2 Hz, 2 H), 5.07 (dd, J=3.0, 4.8 Hz, 1 H), 5.30 (dd, minor), 5.95 (bt,
minor), 6.30 (q, minor), 6.40-6.52 (m. 2 H), 7.11-7.29 (m, 5 H); 13C NMR (75 MHz,

CDCl3) (major isomer) 8 14.1, 14.5, 17.8, 24.3, 30.2, 30.4, 35.5, 41.7, 46.6, 49.4, 61.6,

113.2, 125.3, 126.4, 128.6, 133.3, 141.4, 169.4, 169.5, 173.6; IR (CHC13) 3357, 2940,

1748, 1665, 1636, 1512, 1449, 1397, 1198, 1030, 913, 731 cm'l.

Preparation of B-Keto Amides.

Method A : The mixture of B-keto ester (1 equiv.) and an amine (2 equiv.) and DMAP
(0.3 equiv.) in toluene was heated to reflux for 24 hours. Then the solution was
concentrated under reduced pressure and the residue purified by a flash column
chromatography (eluent as indicated).

Method B : The mixture of [i-keto ester (1.0 equiv.) and an amine (1.5 equiv.) in xylene
was brought to reflux and kept at this temperature for 24 hours. The solution was
concentrated under reduced pressure and the crude product purified by flash column

chromatography (eluent as indicated).

68

Method C : A solution of II-37 (1.0 equiv.) and a corresponding amine (1.1 equiv.)was
brought to reflux in xylene and kept at this temperature for 2 hours. The solvent was
evaporated under reduced pressure and the crude product purified by flash column
chromatography (eluent as indicated).

II-25 : (80:20/hexanezethyl acetate, 2.5 g, 10.8 mmol, 96% yield); m.p.=(85-86)° C; 1H
NMR (300 MHz, CDCl3) 8 1.54-1.78 (m, 2 H), 1.80-2.00 (m, 2 H), 2.04 (m, 1 H), 2.20
(m, 1 H), 2.22-2.44 (m, 2 H), 3.14 (dd, J=5.5, 10.5 Hz, 1 H), 4.36-4.46 (m, 2 H), 5.63
(bs, 1 H), 7.15-7.31 (m, 5 H); 13C NMR (75 MHz, CDCl3) (mixture of tautomers) 8

21.8, 22.5, 22.6, 24.3, 27.3, 29.2, 31.7, 42.2, 43.1, 43.3, 55.7, 96.8, 127.3, 127.5, 127.6,

127.7, 128.6, 128.7, 138.1, 138.2, 168.9, 170.5, 172.3, 210.6; IR (CHC13) 3389, 3019,

2938, 1640, 1605, 1530 cm'l; HRMS calcd for C14H17N02 m/z 231.1259, obsd m/z
231.1268.

II-39: (hexanezethyl acetate/8:2, 0.16 g, 0.70 mmol, 54% yield based on a recovery of
the starting material); 1H NMR (300 MHz, CDCl3) (mixture of tautomers) 8 1.22 (t,
J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H), 1.58-1.82 (m, 6H), 1.85-2.10 (m, 3H), 2.10-2.23
(m, 4H), 2.24-2.49 (m, 3H), 3.21 (dd, J=5.7, 9.9 Hz, 1H), 3.21 (dd, J=5.7, 9.9 Hz, 1H),
3.90-4.07 (m, 4H), 4.15 (q, J=7.2 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 6.01 (bs, 1H), 7.45
(bs, 1H), 13C NMR (75 MHz, CDC13) 8 14.0, 21.7, 22.3, 23.9, 27.1, 29.1, 31.1, 40.9,
41.2, 41.9, 55.6, 61.2, 61.4, 96.7, 169.2, 169.5, 169.9, 170.6, 172.3, 209.7; IR (CHC13)
3378, 2942, 1750, 1717, 1640, 1538, 1377, 1202, 1026 cm"; HRMS calc. for CanNO4

m/z 227.1158, obsd m/z 227.1160.

69

11-40: (hexanezethyl acetate/8:2, 0.26 g, 1.02 mmol, 75% yield) 'H NMR (300 MHz,
CDC13) (mixture of tautomers) 8 0.84—0.92 (m, 12H), 1.57-1.80 (m, 6H), 1.82-2.02 (m,
3H), 2.02-2.22 (m, 6H), 2.22-2.48 (m, 3H), 3.18 (dd, J=5.4, 10.5 Hz, 1H), 3.66 (s, 3H),
3.69 (s, 3H), 4.44454 (m, 2H), 5.82 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.50 (d,
J=8.1 Hz, 1H); 13C NMR (75 MHz, CDC13) (mixture of tautomers) 5 17.5, 17.6, 18.6,
18.8, 21.6, 22.2, 22.2, 23.8, 24.0, 27.0, 27.1, 29.0, 30.7, 30.9, 31.1, 31.4, 41.9, 41.09,
51.8, 51.9, 55.4, 55.6, 56.3, 56.8, 56.9, 77.2, 96.6, 125.7, 128.6, 168.6, 168.9, 170.6,
171.9, 171.9, 172.1, 172.3, 209.5, 209.9; IR (neat) 3366, 2961, 2874, 1744, 1642, 1526,
1437, 1314, 1212, 1154, 756 cm"; HRMS calc. for C13H21NO4 m/z 255.1471, obsd. m/z

255.1472.

General Procedure for Aza-Annulation of B-Ketoamides and B-Ketoesters:
The primary amine or primary amine salt (0.5-5 mmol, 1.1 equiv.) was taken up in
toluene (0.05 M relative to the amine) and the B-ketoamide or B—ketoester (1.0 equiv.)
was added at room temperature. In the case of amine salt, NaHCO3 ( 1.5 equiv.) was
added, and for condensation that involved B-ketoesters, 0.02 mL of EtzO:BF3 (0.3
equiv.) was added. The flask was fitted with a modified Dean-Stark trap filled with
activated 4-A molecular sieves, and the mixture was heated at reflux until the reaction
was complete as determined by NMR analysis (10-18 hours). Solvent was removed
under reduced pressure. A solution of acrylate derivative was then added to the
intermediate enamine at room temperature and the reaction mixture was allowed to stir at
room temperature for 12-18 hours. [Method A: mixed anhydride of acrylic acid : (freshly

prepared from combination of sodium acrylate (1.3 equiv.) and ethyl chloroformate (1.3

70

equiv.) for 1 hour in dry THF (0.05 M solution); Method B: acrylic acid anhydride:
(freshly prepared from combination of sodium acrylate or the acetamido derivative (1.3
equiv.) and acryloyl chloride (1.3 equiv.) for 1 hour in dry THF (0.05 M solution);
Method C: acryloyl chloride (1.3 equiv.) in dry THF (0.05 M solution). Reactions were
quenched by the addition of H20 (for mixed anhydrides or acrylic anhydride) or
saturated aqueous NaHCO3 (acryloyl chloride), and the mixture was extracted 4 times
with 20 mL of either Et2O or EtOAc. The combined organic fractions were dried
(N a2SO4), filtered, and the solvent evaporated under reduced pressure. The crude product

was purified by flash column chromatography (eluent as indicated).

II-21 : (8:2/hexanezethyl acetate, 1.98 g, 5.08 mmol, 70% yield); [0t]DZO=-93.5 (c=1.7,

CHC13); 1H NMR (300 MHz, CDCl3) 8 1.24-1.56 (m, 2 H), 1.51 (d, J=7.1 Hz, 3 H),

1.69 (ddd, J=6.4, 12.6, 12.8 Hz, 1 H), 1.76-1.92 (m, 2 H), 2.03 (m, 1 H), 2.16 (m, 1 H),
2.27 (ddd, J=1.9, 6.4, 13.1 Hz, 1 H), 2.41 (m, 1 H), 2.58 (ddd, J=2.0, 6.4, 18.0 Hz, 1 H),

4.91 (dd, J=5.3, 3.0 Hz, 1 H), 5.02 (d, J=13.0 Hz, 1 H), 5.09 (d, J=l3.0, 1 H), 6.20 (q,
J=7.2 Hz, 1 H), 7.04-7.30 (m, 10 H); 13C NMR (75 MHz, CDCl3) 8 14.6, 18.5, 24.4,
30.4, 31.0, 35.4, 46.7, 50.6, 67.1, 112.3, 125.6, 126.3, 128.3, 128.4, 128.5, 128.6, 133.6,
135.5, 142.4, 168.7, 174.2; IR (CHC13) 3420, 3060, 3033, 2940, 2869, 1728, 1669, 1638,
1497, 1453, 1393, 1341, 1281, 1237, 1161 cm‘l; HRMS calcd for C25H27NO3 m/z
389.1991, obsd m/z 389.2190.

II-29a : (65:35/hexanezethyl acetate, 0.31 g, 0.80 mmol, 99% yield); m.p.=(126-127)° C;

[a]DZ5= -149.5(c=0.31,CH2C12); 1H NMR (300 MHz, CDCl3) 8 (m, 2 H), 1.39 (d, J

71

:71 Hz, 3 H), 1.47-1.65 (m, 2 H), 1.85 (m, 1 H), 2.10 (m, 1 H), 2.38-2.64 (m, 3 H), 4.32
(dd, J =54, 14.6 Hz, 1 H), 4.41 (dd, J=6.0, 14.6 Hz, 1 H), 4.96 (dd, J =35, 5.3 Hz, 1 H),
6.18 (bt, J = 5.2 Hz, 1 H), 6.33 (q, J :71 Hz, 1 H), 7.06-7.29 (m, 10 H); 13C NMR (75
MHz, CDCl3) 6 14.1, 18.0, 24.3, 30.2, 30.4, 35.3, 44.0, 46.7, 49.4, 112.8, 125.2, 126.4,

127.6, 128.5, 128.8, 133.7, 137.6, 141.2, 169.4, 173.0; IR (CHC13) 3420, 2944, 1665,

1634, 1512, 1451, 1393, 1302 cm '1; HRMS calcd for C25H28N202 m/z 388.2151,
obsd m/z 388.2147.

II-30b : (65:35/hexane:ethyl acetate, 0.36 g, 0.81 mmol, 95% yield); [a]023=+83.3

(c=1.59, CHC13), 1H NMR (300 MHz, CDCl3) d 1.18 (t, J=7.1 Hz, 3 H), 1.30-1.48 (m,
2 H), 1.56-1.76 (m, 2 H), 2.01-2.10 (m, 2 H), 2.38-2.54 (m, 3 H), 2.60 (dd, J=5.0, 16.6
Hz, 1 H), 4.06-4.26 (m, 2 H), 4.41 (dd, J=5.8, 14.8 Hz, 1 H), 4.49 (dd, J=5.8, 14.8 Hz, 1
H), 5.04 (t, J=3.8 Hz, 1 H), 7.07 (s, 1 H), 7.17-7.35 (m, 10 H), 8.04 (t, J=5.8 Hz, 1 H);
13C NMR (75 MHz, CDCl3) 8 13.9, 18.1, 24.2, 29.9, 30.6, 34.9, 43.8, 46.9, 58.2, 62.2,
111.3, 127.0, 127.4, 127.4, 127.6, 128.0, 128.3, 134.0, 135.0, 138.5, 168.8, 169.9, 173.2,
IR (CHC13) 3343, 2984, 2934, 1721, 1665, 1644, 1534, 1497, 1451, 1393, 1384, 1339,
1217, 1200, 1026, 752, 700 cm'l; HRMS calcd for C27H30N204 m/z 446.2206, obsd
m/z 446.2190.

II-3la : (65:35/hexanezethyl acetate, 0.30 g, 0.75 mmol, 90% yield); [a]D23=+121.4

(c=1.34, CHC13); m.p.=(128-129)° C; 1H NMR (300 MHz, CDCl3) 8 0.72 (d, J=7.1 Hz,
3 H), 1.10 (d, J=6.4 Hz, 3 H), 1.16-1.38 (m, 2 H), 1.42-1.68 (m, 2 H), 2.05-2.33 (m, 2
H), 2.36-2.52 (m, 2 H), 2.69 (m, 1 H), 3.49 (s, 3 H), 3.83 (d, J=9.3 Hz, 1 H), 4.19 (dd,

J=5.2, 14.8 H, 1 H), 4.57 (dd, J=6.9, 14.8 Hz, 1 H), 5.22 (t, 3.8 Hz, 1 H), 7.10-7.25 (m, 5

72

H), 7.41 (bt, J=5.8 Hz, 1 H); 13c NMR (75 MHz, CDCl3) 8 18.3, 18.6, 21.8, 24.8, 26.5,
29.5, 30.8, 35.0, 43.8, 47.1, 52.1, 63.6, 108.2, 127.0, 127.4, 128.3, 138.5, 138.5, 168.4,
170.9, 172.9; IR (CHC13) 3413, 2960, 2930, 1717, 1653, 1638, 1522, 1456, 1399 cm'l;
HRMS calcd for C23H30N204 m/z 398.2206, obsd m/z 398.2204.

II-32a: (65:35/hexanezethyl acetate; 0.36g, 0.78 mmol, 46% yield; 95:5 ratio of
diastereomers); m.p.=(144-145)0 C; 1H NMR (300 MHz, CDCl3) 8 1.04-1.46 (m, 3 H),
1.24 (t, J=7.0 Hz, 3 H), 1.55 (m, 1 H), 1.83 (m, 1 H), 2.06 (dt, J=17.9, 4.8 Hz, 1 H),
2.18-2.38 (m, 2 H), 2.39-2.58 (m, 2 H), 3.33 (dd, J=9.1, 14.0 Hz, 1 H), 3.52 (dd, J=5.5,
14.0 Hz, 1 H), 4.17 (q, J=7.0 Hz, 2 H), 4.21 (dd, J=5.2, 7.0 Hz, 1 H), 4.41 (bt, J=3.6 Hz,
minor), 4.52 (dd, J=5.7, 9.0 Hz, 1 H), 4.61 (dd, J=7.0, 14.7 Hz, 1 H), 4.83 (t, J=3.6 Hz, 1
H), 5.11 (bt, J=5.4 Hz, minor), 7.12-7.31 (m, 10 H), 7.44 (bt, J=5.4 Hz, 1 H), 7.8 (bt,
J=5.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 8 14.0, 18.4, 24.8, 29.9, 30.9, 34.4, 35.0,

43.9, 47.0, 59.4, 61.7, 108.0, 108.6 (minor), 126.7, 127.0, 127.6, 128.3, 128.4, 129.4,

135.1 (minor), 137.4, 137.9, 138.7, 168.8, 170.4, 171.1 (minor), 173.0; IR (CHC13)

3359, 3021, 2944, 1740, 1642, 1514, 1455, 1399 cm]; HRMS calcd for C23H32N204
m/z 460.2362, obsd m/z 460.2360.

II-41: (hexanezethyl acetate/65:35, 0.10 g, 0.26 mmol, 74% yield); (98:2 ratio of
diastereomers); 1H NMR (300 MHz, CDC13) 8 1.27 (t, J=7.2 Hz, 3H), 1.36-1.54 (m,
2H), 1.54-1.71 (m, 2H), 1.76 (d, J=6.9 Hz, 3H), 2.02 (m, 1H), 2.08-2.22 (m, 2H), 2.46
(m, 1H), 2.52-2.70 (m, 2H), 3.92 (dd, J=4.5, 18.3 Hz, 1H)), 4.10 (dd, J=5.4, 18.3 Hz,
1H)), 4.20 (q, J=7.2 Hz, 2H), 5.12 (dd, J=3.0, 5.1 Hz, 1H), 6.51 (q, J=6.9 Hz, 1H), 6.51

(bs, 1H), 7.16-7.34 (m, 5H), 13(3 NMR (75 MHz, CDClg.) 5 14.0, 14.5, 17.8, 24.3, 30.2,

73

30.3, 35.4, 41.7, 46.6, 49.4, 61.6, 113.1, 125.2, 126.4, 128.5, 133.3, 141.3, 169.4, 169.4,
173.6; IR (neat) 3359, 2940, 1748, 1660, 1632, 1507, 1397, 1194, 1030, 752 cm";
HRMS calc for C22H23N2O4 m/z 384.2049, obsd m/z 384.2049.

“-42: (hexane:ethyl acetate/2:1, 0.10 g, 0.24 mmol, 50% yield); >98:2 ratio of
diastereomers; 1H NMR (300 MHz, CDCl3) 8 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz,
3H), 1.27-1.68 (m, 4H), 1.73 (d, J=7.2 Hz, 3H), 1.86 (m, 1H), 2.00-2.20 (m, 3H), 2.33-
2.54 (m, 2H), 2.64 (m, 1H), 3.67 (s, 3H), 4.51 (dd, J=5.l, 8.4 Hz, 1H), 5.04 (dd, J=3.3,
5.1 Hz, 1H), 6.53-6.64 (m, 2H), 7.10-7.30 (m, 5H); 13C NMR (75 MHz, CDC13) 6 14.4,
17.7, 18.1, 18.9, 24.2, 30.0, 30.5, 31.2, 25.5, 47.0, 48.8, 52.1, 57.5, 113.2, 125.1, 126.4,
128.5, 132.8, 141.2, 169.3, 172.3, 173.5; IR (CHC13) 3407, 3007, 2963, 1740, 1669,
1636, 1497, 1449, 1393, 1341, 1300, 1273, 1154 cm"; HRMS calc for C24H32N2O4 m/z
412.2362, obsd m/z 412.2382.

II-45: (65:35/hexanezethyl acetate, 0.045 g, 0.12 mmol, 50% yield); m.p.=(57-58)° C;
[a]DZS=-38.2 (c=0.4, CHC13); 1H NMR (300 MHz, CDCl3) 6 1.51 (d, J=7.2 Hz, 3 H),
1.60-1.94 (m, 2 H), 2.07-2.37 (m, 3 H), 2.57-2.78 (m, 3 H), 4.40 (dd, J=5.5, 14.7 Hz, 1
H), 4.46 (dd, J=5.7, 14.6 Hz, 1 H), 4.74 (t, 2.2 Hz, 1 H), 6.22 (q, J=7.2 Hz, 1 H), 6.24
(bt, J=5.5 Hz, 1 H), 7.10-7.30 (m, 10 H); 13c NMR (75 MHz, c0013) 6 14.4, 29.2,
29.3, 30.8, 36.3, 43.9, 49.8, 55.9, 110.2, 126.0, 126.9, 127.5, 127.7, 128.5, 128.9, 137.9,
139.5, 140.2, 169.5, 172.4; IR (CHC13) 3400, 1669, 1628, 1509, 1266, 706, 670 cm’l;
HRMS calcd for C24H26N202 m/z 374.1994, obsd m/z 374.2000.

[147: (65:35/hexanezethyl acetate, 0.20 g, 0.47 mmol, 67% yield, 75:25 ratio of

diastereomers); 1H NMR (300 MHz, CDCl3) characteristic peaks (both isomers) 8 1.16

74

(t, J=7.1 Hz, minor), 1.17 (t, J=7.1 Hz, 3 H), 1.60 (m, 1 H), 1.71 (m, 1 H), 2.05-2.31 (m,
3 H), 2.45 (m, 1 H), 2.53-2.67 (m, 2 H), 4.12 (q, J=7.1 Hz, 2 H), 4.28 (dd, J=5.8, 14.8
Hz, 1 H), 4.42 (dd, J=6.l, 14.8 Hz, 1 H), 4.75 (bt, J=2.6 Hz, 1 H), 4.99 (131, J=2.2 Hz,
minor), 6.08 (8, minor), 6.18 (bt, J=5.4 Hz, minor), 6.78 (s, 1 H), 7.05-7.30 (m, 10 H),
7.83 (bt, J=5.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) (both isomers) 8 14.0, 28.8

(minor), 29.0, 29.6, 30.4, 36.8, 37.2 (minor), 43.6 (minor), 43.7, 55.8 (minor), 56.4, 58.2,
60.3 (minor), 61.8 (minor), 62.2, 62.3 (minor), 109.6 (minor), 110.4, 127.0, 127.2
(minor), 127.4, 127.9 (minor), 127.9, 128.2 (minor), 128.4, 128.5 (minor), 133.8 (minor),

134.1, 138.2 (minor), 138.6, 139.4, 140.7 (minor), 169.1 (minor), 169.4, 169.5, 172.5
(minor), 173.1; IR (CH2C12) 3345, 2934, 1732, 1667, 1638, 1497, 1266, 739, 704 cm‘l;
HRMS calcd for C26H23N204 m/z 432.2049, obsd m/z 432.2025.

II-54 : 1H NMR (300 MHz, CDCl3) 8 1.33 (s, 1 H), 1.42 (d, J=7.1 Hz, 3 H), 1.62 (m, 1

H), 2.15 (s, 3 H), 2.41 (ddd, J=2.2, 6.8, 13.1 Hz, 1 H), 2.57 (ddd, J=2.2, 6.2, 18.5 Hz, 1

H), 2.76 (ddd, J=6.7, 12.2, 18.5 Hz, 1 H), 4.29-4.36 (m, 3 H), 4.45 (d, J=1.9 Hz, 1 H),
6.21 (bt, J=5.3 Hz, 1 H), 6.27 (q, =7.1 Hz, 1 H), 7.10-7.25 (m, 10 H); 13C NMR (75
MHz, c0013) 6 14.0, 25.6, 29.5, 30.2, 43.8, 47.4, 50.2, 98.4, 125.4, 126.6, 127.6, 127.7,
128.5, 128.8, 137.8, 141.1, 145.0, 169.9, 172.5.

11-56 : 1H NMR (300 MHz, CDCl3) 6 1.21 (t, J=7.1 Hz, 3 H), 1.40 (8, minor), 1.50 (s, 3

H), 1.75 (ddd, J=7.5, 11.6, 12.7 Hz, 1 H), 2.48 (m, 1 H), 2.58-2.70 (m, 2 H), 4.18 (q,
J=7.1 Hz, 2 H), 4.31 (dd, J=5.9, 14.9 Hz, 1 H), 4.45 (dd, J=5.9, 14.9 Hz, 1 H), 4.45 (d,

J=3.0 Hz, 1 H), 4.62 (d, J=3.0 Hz, 1 H), 6.86 (s, 1 H), 7.20-7.40 (m, 10 H), 7.69 (bt,

J=5.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3) 8 14.1, 25.5, 30.2, 30.7, 43.8, 47.6, 59.3,

75

62.3, 97.7, 127.2, 127.5, 127.7, 127.9, 128.3, 128.5, 134.1, 138.5, 145.8, 169.5, 169.6,
173.0; IR(CHC13) 3345, 3021, 1727, 1667, 1626, 1516, 669 cm'l.

II-69a: (90:5:5/diethyl etherzmethyl alcohol:petroleum ether, 0.15 g, 0.31 mmol, 34%
yield); [a]D24=-322.8 (c=0.36, CHC13); m.p.=(119-l20)° c (sealed); 1H NMR (300
MHz, CDCl3) 8 1.45-1.72 (m, 3 H), 1.56 (d, J=7.1 Hz, 3 H), 1.80-1.97 (m, 3 H), 1.93 (s,

3 H), 2.03-2.15 (m, 3 H), 2.41 (dd, J=5.6, 13.2 Hz, 1 H), 4.10 (dd, J=4.9, 14.5 Hz, 1 H),
4.28 (td, J=12.0, 5.9 Hz, 1 H), 4.42 (dd, J=6.2, 14.5 Hz, 1 H), 5.39 (t, J=3.9 Hz, 1 H),

5.55 (q, J=7.1 Hz, 1 H), 6.01 (bt, J=5.1 Hz 1 H), 6.53 (d, J=5.8 Hz, 1 H), 7.06-7.29 (m,
10 H); 13C NMR (75 MHz, CDCl3) 8 17.1, 18.0, 23.2, 24.0, 34.8, 36.5, 44.1, 47.8, 48.8,
55.4, 120.6, 126.3, 127.2, 127.7, 127.8, 128.6, 128.8, 135.7, 137.8, 141.3, 169.9, 170.4,
173.7; IR (CHC13) 3400, 3021,2963, 1665, 1509, 1262, 1098, 1015 cm'1;HRMS calcd
for C27H31N3O3 m/z 445.2366, obsd m/z 445.2376.

II-70a: (90:5:5/diethy1 etherzmethyl alcohol:petroleum ether, 0.15 g, 0.31 mmol, 34%
yield); [61025: -1349 (c=0.75, CHC13); m.p.=(116—117)0 c (sealed); 1H NMR (300
MHz, CDCl3) 8 1.30-1.60 (m, 3 H), 1.48 (d, J=6.8 Hz, 3 H), 1.80-2.15 (m, 4 H), 1.92 (s,

3 H), 2.75 (dd, J=6.6, 13.2 Hz, 1 H), 3.97 (ddd, J=6.6, 6.6, 14.4 Hz, 1 H), 4.36 (dd,
J=4.2, 10.2 Hz, 1 H), 4.43 (dd, J=5.7, 16.2 Hz, 1 H), 5.04 (dd, J=4.4, 5.6 Hz, 1 H), 6.14

(q, J=6.8 Hz, 1 H), 6.28 (t, J=6.0, l H), 6.48 (d, J=6.6 Hz, 1 H), 7.05-7.30 (m, 10 H);
13C NMR (75 MHz, CDCl3) 8 14.5, 17.7, 23.2, 24.3, 35.5, 35.9, 44.2, 46.3, 50.3, 51.4,

112.9, 125.5, 126.5, 127.8, 128.6, 128.9, 133.6, 137.8, 141.0, 168.4, 170.3, 172.9; 1R

76

(CHC13) 3420, 3330, 3021, 2963, 1669, 1640, 1511, 1261, 1096, 1019 cm'l; HRMS
calcd for C27H31N303 m/z 445.2366, obsd m/z 445.2327.
II-69b: diethyl etherzpetroleum etherzmethyl alcohol/90:5:5, 0.083 g, 0.144 mmol, 51%
yield); lH NMR (300 MHz, CDC13) 8 1.21 (t, J=7.2 Hz, 3H), 1.56-1.68 (m, 2H), 1.70 ((1,
=7.2 Hz, 3H), 1.81-1.98 (m, 2H), 1.94 (s, 3H), 2.02-2.22 (m, 3H), 2.38 (dd. J=5.4, 13.2
Hz, 1H), 3.68 (dd, J=4.5, 18.3 Hz, 1H), 3.98 (dd, J=6.0, 18.6 Hz, 1H), 4.12 (q, J=7.2 Hz,
2H), 4.31 (ddd, J=6.0, 6.0, 12.3 Hz, 1H), 5.49 (dd, J=3.8, 3.8 Hz, 1H), 5.59 (q, J=7.2 Hz,
1H), 6.33 (bt, J=5.0 Hz, 1H), 6.60 (d, J=6.0 Hz, 1H), 7.13-7.29 (m, 5H); ”C NMR (75
MHz, CDC13) 8 14.0, 17.3, 17.8, 23.1, 23.9, 34.7, 36.3, 41.5, 47.6, 48.6, 55.5, 61.6,
120.8, 126.2, 127.1, 128.5, 135.5, 141.3, 169.6, 169.9, 170.3, 174.0; IR (CHC13) 3335,
3009, 2942, 1744, 1651, 1512, 1449, 1406, 1375, 1240, 1022 cm"; HRMS calc for
C24H31N305 m/z 441.2264, obsd m/z 441.2278.
II-70b: (diethyl etherzpetroleum etherzmethyl alcohol/90:5:5, 0.045 g, 0.10 mmol, 28%
yield); IH NMR (300 MHz, CDCl3) 8 1.28 (t, J=7.2 Hz, 3H), 1.46-1.64 (m, 3H), 1.79 (d,
J=7.2 Hz, 3H), 1.90-2.24 (m, 4H), 2.00 (s, 3H), 2.84 (dd, J=6.0, 12.6 Hz, 1H), 4.00 (dd,
J=5.4, 18.6 Hz, 1H), 4.06 (m, 1H), 4.11 (dd, J=5.4, 18.3 Hz, 1H)), 4.21 (q, J=7.2 Hz,
2H), 5.19 (dd, J=3.0, 5.3 Hz, 1H), 6.32 (q, J=7.2 Hz, 1H), 6.39 (d, J=5.7 Hz, 1H), 6.58
(t, J=5.3 Hz, 1H), 7.17-7.38 (m, 5H); 13C NMR (75 MHz, CDC13) 8 14.1, 14.8, 17.5,
23.2, 24.2, 35.5, 35.9, 41.8, 46.2, 50.2, 51.4, 61.6, 113.2, 125.5, 126.5, 128.6, 133.2,
141.0, 168.4, 169.5, 170.3, 173.3; 1R (CHC13) 3328, 3007, 2942, 1744, 1640, 1518,
1449, 1377, 1267, 1032 cm"; HRMS calc for C24H31N305 m/z 441.2264, obsd m/z

441.2253.

77

II-69c/II-70c (diethyl etherzpetroleum etherzmethyl alcohol/90:5:5, 0.035 g, 0.075 mmol,
15.2% yield), (50:50 ratio of diastereomers); 1H NMR (300 MHz, CDCl3) (both
diastereomers) 6 0.79 (d, J=4.2 Hz, 3H), 0.82 (d, J=4.2 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H),
0.87 (d, J=6.9 Hz, 3H), 1.36-1.66 (m, 8H), 1.72 (d, J=7.2 Hz, 3H), 1.74 (d, J=7.2 Hz,
3H), 1.78-2.29 (m, 8H), 1.95 (s, 6H), 2.48 (dd, J=5.4, 12.9 Hz, 1H), 2.75 (dd, J=5.6, 12.5
Hz, 1H), 3.68 (s, 6H), 3.96 (ddd, J=6.0, 6.0, 12.6 Hz, 1H), 4.29 (ddd, J=5.7, 5.7, 12.3
Hz, 1H), 4.43 (dd, J=4.8, 8.1 Hz, 1H), 4.50 (dd, J=5.1, 8.4 Hz, 1H), 5.11 (dd, J=3.0, 5.1
Hz, 1H), 5.45 (dd, J=3.8 3.8 Hz, 1H), 5.65 (q, J=7.2 Hz, 1H), 6.24 (bd, J=7.8 Hz, 2H),
6.39 (q, J=7.2 Hz, 1H), 6.56 (d, J=6.0, 1H), 6.59 (d, J=8.7 Hz, 1H), 7.12-7.30 (m, 10H);
”C NMR (75 MHz, CDCl3) (both diastereomers) 6 14.1, 14.8, 17.1, 17.4, 17.7, 18.2,
18.7, 19.0, 23.2, 23.8, 24.2, 29.6, 31.2, 31.3, 35.2, 35.6, 35.7, 36.3, 46.4, 47.8, 48.7, 50.2,
50.7, 52.2, 54.7, 57.5, 57.7, 113.6, 120.7, 125.4, 126.1, 126.5, 126.9, 128.5, 128.6, 132.6,
134.9, 140.9, 141.4, 168.5, 170.0, 170.2, 170.4, 172.3, 172.4, 173.2, 174.2; IR (CHC13)
3337, 3011. 2959, 2938, 1738, 1661, 1499, 1373, 1267 cm"; HRMS calc for C26H35N305

m/z 469.2577, obsd m/z 469.2566.

General Procedure for Hydrolysis of Aza-Annulation Enamides.
After aza-annulation, the crude enamide product II-S4 or II-56 was mixed with 5.0 mL
of H20 (280 equiv.) in THF and p-TsOH (0.03 g) was added. The mixture was stirred at
room temperature for 24 hours, washed with an excess of saturated aqueous NaHCO3,
extracted with 15 mL of B20 3 times, and the combined organic layers were dried over

Na2SO4. Products were crystallized from EtOAc/hexanes=l : 1.

78

II-55 : (0.30 g, 0.80 mmol, 82% yield (crystallization from ethyl acetate:hexane=1:1));
[a]020=+58.81 (c=0.7, CHC13); m.p.=(159-160)° c; 1H NMR (300 MHz, CDCl3) 6

1.32 (s, 3 H), 1.38 (d, J=6.9 Hz, 3 H), 1.88-2.22 (m, 4 H), 2.11 (s, 3 H), 4.28 (dd, J=5.6,

14.8 Hz, 1 H), 4.34 (dd, J=5.5, 14.8 Hz, 1 H), 4.98 (m, 1 H), 5.75 (d, J=7.5 Hz, 1 H),
6.69 (bt, 1:49 Hz, 1 H), 7.11-7.29 (m, 10 H); 13c NMR (75 MHz, CDCl3) 6 19.7, 21.8,
26.5, 31.4, 31.8, 43.7, 48.8, 59.0, 126.1,127.3, 127.5, 127.6, 128.6, 128.6, 138.0, 143.0,
171.2, 208.8; IR (CHC13) 3295, 3029, 1717, 1628, 1541, 1456, 1356 cm-1; HRMS

calcd for C23H23N203 m/z 380.2100, obsd m/z 380.2107.

II-57: (0.30 g, 0.68 mmol, 71% yield); 1H NMR (300 MHz, CDCl3) 8 1.14 (t, J=7.1 Hz,

3 H), 1.33 (s, 3 H), 2.02-2.22 (m, 4 H), 2.11 (s, 3 H), 4.01-4.22 (m, 2 H), 4.32 (d, J=5.8
Hz, 2 H), 5.44 (d, J=7.1 Hz, 1 H), 6.41 (bd, J=7.1 Hz, 1 H), 6.52 (bt, J=5.8 Hz, 1 H),
7.10-7.30 (m, 10 H); 13C NMR (75 MHz, CDCl3) 8 14.0, 19.6, 26.6, 31.2, 31.5, 43.9,
56.5, 59.0, 61.9, 127.2, 127.6, 127.7, 128.5, 128.7, 128.9, 136.5, 137.9, 170.8, 170.8,

171.2, 208.9; IR (CHC13) 3324, 3289, 3021, 1746, 1709, 1646, 1532, 1181, 1026, 700,

669 cm'l; HRMS calcd for C25H30N205 m/z 438.2155, obsd m/z 438.2157.

II-63: (50:50/diethyl etherzpetroleum ether, 0.44 g, 0.92 mmol, 60% yield);
[(1.]D26=+27.0 (c=3.6, CHC13); 1H NMR (300 MHz, CDCl3) 6 1.09 (t, J=6.8 Hz, 3 H),

1.33 (d, J=6.9 Hz, 3 H), 1.83-2.26 (m, 2 H), 2.11 (s, 3 H), 2.45-2.68 (m, 2 H), 4.01-4.17

(m, 2 H), 4.88-5.03 (m, 3 H), 5.92 (bd, J=7.6 Hz, 1 H), 6.37 (bs, 1 H), 7.11-7.28 (m, 10
H); 13C NMR (75 MHz, CDCl3) 8 13.7, 21.5, 24.4, 27.7, 30.4, 48.7, 62.6, 66.8, 71.3,

126.0, 127.1, 127.9, 128.1, 128.3, 128.5, 135.9, 142.9, 154.4, 168.1, 170.2, 199.6; IR

79

(neat) 3391, 3305, 3033, 2980,2934, 1709, 1644, 1489, 1455, 1370, 1250, 1055, 756,
698 cm-1; HRMS calcd for C25H30N206 m/z 454.2104, obsd m/z 454.2131.
II-68: (gradient diethyl etherzpetroleum ether/2:1-diethyl ether-ethyl acetate, 0.22 g,
0.427 mmol, 75% yield, >98:2 ratio of diastereomers); m.p. = (49-50)° c; [61023 = 29.1
(c=0.35, EtOH); ‘H NMR (300 MHz, CDCl3) 6 1.42 (d, J=6.9 Hz, 3H), 1.84-2.14 (m,
2H), 2.17 (s, 3H), 2.47-2.66 (m, 2H), 4,204.40 (m, 2H), 4.96-5.16 (m, 3H), 5.79 (d,
:75 Hz, 1H), 6.93 (bs, 1H), 7.05 (bt, J=5.4 Hz, 1H), 7.13-7.40 (m, 15H); 13C NMR (75
MHz, CDCl;) 6 21.6, 25.1, 28.5, 30.6, 44.0, 48.8, 67.1, 71.5, 126.1, 127.3, 127.5, 127.5,
128.1, 128.2, 128.5, 128.6, 128.6, 136.1, 137.4, 143.0, 154.9, 166.5, 170.5, 205.4; IR

(CHC13) 3332, 3033, 2930, 1715, 1669, 1534, 1497, 1455, 1242, 1067, 754 cm"; HRMS

CfllCd for C30H33N305 M/Z 515.2420, ODSd M/Z 515.2402.

Preparation of 2,2-Dimethyl-1,3-Dioxin-4-One Derivatives.30

Concentrated sulfuric acid (0.01 mmol) was added dropwise to a mixture of B-keto acid
(0.05 mmol), acetone (0.1 mmol), and acetic anhydride (0.1 mmol) with stirring at 0° C.
The mixture was stirred under ice-cooling for 3 hours and then was kept in a refrigerator
for 12 hours. Then it was poured into 10% sodium carbonate solution (120 mL) under
ice-cooling. The mixture was stirred at room temperature for 30 minutes to give the

corresponding product.

80

Preparation of 2,4,6-Trichloropheny1 Ester of Carbobenzoxy D,L-Threonine II-
64.3'

To a solution of the carbobenzoxy-D,L-threonine (3.0 g, 11.85 mmol, 1.0 equiv.) in ethyl
acetate (35 mL) was added 2,4,6-trichlorophenol (2,81 g, 14.21 mmol, 1.2 equiv.). N,N'-
Dicyclohexylcarbodiimide (2.44 g, 11.85 mmol, 1.0 equiv.) was added to the solution at
0° C. After 0.5 hour the mixture was allowed to warm up to room temperature and was
kept at ambient temperature for 1 hour. The N ,N '-dicyclohexylurea was filtered off and
washed with ethyl acetate. The combined filtrate and washings were evaporated to
dryness under reduced pressure and the solid residue was recrystallized from ethyl

acetate and petroleum ether. Yield : 3.0 g (60%).

Preparation of Carbobenzoxy D,L-Threonine Benzylamide II-65.32

2,4,6-Trichlor0phenyl ester of carbobenzoxy D,L-threonine (1.50 g, 3.47 mmol, 1.0
equiv.) in a mixture of THF (7.5 mL) and dioxane (4.0 mL) was added to a solution of
benzylamine (0.67 g, 6.24 mmol, 1.8 equiv.) and triethylamine (0.87 mL) in H2O (7.5
mL) and the solution was stirred at room temperature for 28 hours. The solvent was
evaporated under reduced pressure and the residue was dissolved in H20 (40 mL), which
was acidified with 5 M HCl (litmus). The crude product was extracted with ethyl acetate,
organic layers washed with H20 and brine, and dried over Na2SO4, then concentrated

and crystallized from EtOAc and petroleum ether (low boiling) . Yield : 0.95 g (80%).

81

General Oxidation with PCC.

To the stirred suspension of PCC (1.8 equiv.) and Celite (1:1/wzw) in CH2C12 was added
B-hydroxy ester or B-hydroxy amide in CH2C12 dropwise at 0° C and the mixture was
stirred at 0° C for 3 hours. Then it was gradually warmed up and stirred for 10-15
additional hours. Filtered through a pad of neutral alumina:SiO2:Celite=4:4:1 and the
filtrate concentrated. The crude product is pure enough to use without further

purification.

Synthesis of t-Butyl Ester of 3-Methyl-4-oxoimidazolidin-l-carboxy1ic Acid)“

A) Glycine ethyl ester hydrochloride (7.0 g, 50 mmol) was added to a solution of
methylamine in methyl alcohol ( 75 mL of 2.0M solution, 3.0 equiv.) at 0° C (ice-
bath) with stirring. Then reaction mixture was stirred at room temperature for 18
hours, the suspension was concentrated under reduced pressure and a slurry was
dissolved in CH2C12 (15 mL) and concentrated under reduced pressure three times
(overall with 45 mL of CH2C12). The crude product was immediatelly used for the
next step without isolation or purification.

B) The crude product from part A, pivaloyl aldehyde (6.46 g, 8.15 mL, 75 mmol, 1.5
equiv.) and triethylamine (10.45 mL, 1.5 equiv.) in dry CH2C12 (50 mL) was
refluxed with a modified Dean-Stark trap (4A activated molecular sieves) for 15
hours. After cooling the mixture was filtered through a coarse sintered glass filter and
the solid was washed with 25 mL of diethyl ether. The combined filtrates were

concentrated under reduced pressure and dissolved in 15 mL of methyl alcohol. 30

82

mL of 2.0 M solution of HCl in diethyl ether was added to the solution at 0° C, the
mixture stirred for 30 minutes at 0° C and then 6 hours at room temperature. Then
solution was concentrated under reduced pressure, the residue dissolved in 40 mL of
CH2C12 and washed with 40 mL of 3M NaOH. Organic layers were evaporated to
give the crude product, which crystallized upon cooling.Yield : 3.75 g (48%).

C) The mixture of di-t-butyl-dicarbonate (0.89 g, 4.1 mmol), DMAP (0.04 g, 0.31
mmol) in 30 mL of acetone was added to the crude product (0.5 g, 3.2 mmol) from
part B by a cannula at 0° C. After stirring at ambient temperature for 8 hours, 0.5 mL
(3.1 mmol) of triethylamine was added, the mixture stirred for 1 hour, 5.0 mL of H20
added and the solution stirred for 1 additional hour. Then it was concentrated at
reduced pressure and the residue extracted with diethyl ether. Combined organic
layers were washed with 15 mL of 1M HCl and with 15 mL of saturated NaHCO3,
and dried over MgSOa. The solution was filtered and concentrated under reduced

pressure to give yellowish oil. Yield :0.66 g (80%).

Preparation of t-Butyl Ester of 5-Acetyl-3-Methyl-4-Oxoimidazolidin-l-Carboxylic
Acid)“

Hexane solution of n-butyllithium (0.30 mL of 2.5 M solution in hexane, 2.15 mmol, 1.1
equiv.) was added dr0pwise to freshly distilled diisopropylamine (0.86 mL, 1.1 equiv.) in
the flame dried flask at 0° C. The mixture was stirred for 30 minutes, cooled to -78° C
and “-49 (0.5 g, 1.95 mmol) in dry THF (20 mL) was added dropwise by a cannula. The
mixture was stirred for 30 minutes at -78° C and then freshly distilled acetyl chloride was

added dropwise at -78° C and the mixture was stirred for 1 hour. Then it was slowly

83

quenched at -78° C with 7.0 mL of phosphate buffer (pH=7.0; 50 mL of 0.1 M
NaH2P04:H2O, 29.1 mL of 0.1 M solution of NaOH), 15 mL of the mixture
HzO/Et2O=l :1 was added, water layer was extracted 3 times with 30 mL of diethyl ether,
combined organic layers washed with 30 mL of brine and dried over MgSO4. The crude

product crystallized from hexane. Yield : 0.55 g (95 %).

Preparation of B-Keto Amides from 2,2-Dimethyl-l,3-Dioxin-4-One Derivatives and
a-Amino Acids. W
A solution of 2,2-dimethyl-1,3-dioxin-4-one derivative (10 mmol) and an a-amino acid

(10 mmol) in xylene (20 mL) was heated to reflux for 1-2 hours. The solvent was

evaporated in vacuo and the residue was either crystallized or purified as indicated.

LIST OF REFERENCES

84

LIST OF REFERENCES

1. Mea-Jacheet, D; Horeau, A. Bull. Soc. Chim. Fr. 1968, 4571.

2. Yamada, S.; Hiroi, K.; Achiwa, K. Tetrahedron Lett. 1969, 4233.

3. Whitesell, J.K.; Felman, S.W. J. Org. Chem. 1977, 42, 1663.

4. d’Angelo, J.; Guingant, A.; Ricke, C.; Chiaroni Tetrahedron Lett. 1988, 29 2667.

5. a) Dumas, F.; d'Angelo, J. Tetrahedron: Asymm. 1990, I, 167; b) d'Angelo, J.;
Desmaele, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymm. 1992, 3, 459; c)
Desmaele, D.; d'Angelo, J. J. Org. Chem. 1994, 59, 2292; d) Mekouar, K.; Ambroise,
L.; Desmaele,D.; d'Angelo, J. Synlett 1995, 529; d) Cave, C.; Desmaele, D.;
d'Angelo, J. J. Org. Chem. 1996, 61, 4361.

6. Audia, J.B.; Lawhom, D.E.; Deeter, J .B., Tetrahedron Lett. 1993, 34, 7001.

7. Enders, D.; Demir, A.S.; Puff, H.; Franken, S., Tetrahedron Lett. 1987, 28, 3795.

8. Barta, N.S.; Brode, A.; Stille, J.R., J. Am. Chem. Soc. 1994 116, 6201.

9. a) d'Angelo, J.; Revial, 6.; Costa, P.R.R.; Castro, R.N.; Antunes, O.A.C.
Tetrahedron: Asymm. 1991, 2, 199; b) Costa, P.R.R.; Castro, R.N.; Farias, F.M.C.;
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10. Agami, C.; Hamon, L.; Kadouri-Puchot, C.; LeGuen, V., J. Org. Chem. 1996, 61 ,
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11. Paulvannan, K.; Stille, J.R. J. Org. Chem. 1992, 57, 5319.

12. Cook, G.R.; Beholz, L.G.; Stille, J.R. Tetrahedron Lett. 1994, 35, 1669.

13. a) Cossy, J ., Thellend, A., Synthesis 1989, 753; b) Labelle, M.; Gravel, D. J. Chem.
Soc. Chem. Comm. 1985, 105.; c) Sato, M.; Ogasawa, H.; Komatsu, S.; Kato, T.
Chem. Pharm. Bull. 1984, 32, 3848.

14. a) Fitzi, R.; Seebach, D. Angew. Chem. Int. Ed. Engl. 1986, 25, 345; b) Fitzi, R.;
Seebach, D. Tetrahedron 1988, 44, 5277; c) Blank, S.; Seebach, D. Liebigs Ann.
Chem. 1993, 889.

15. Greenstein, J.P.; Winitz, M. Chemistry of the Amino Acids, Vol 2, 1961,
J.Wiley&Sons, p. 895.

16. Beholz, L.G.; Benovsky, P.; Ward, D.L.; Barta, N.S.; Stille, J.R. J. Org. Chem. 1997,
62, 1033.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

85

Pandit, V.K.; Huisman, H.O. Tetrahedron Lett. 1967, No.40, 3901.
Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.

a)Seebach, D,; Colvin, E.W.; Lehr, F.; Weller, T. Chimia 1979, 33, 1; b) Seebach,
D.; Leitz, H.F.; Ehrig, V. Chem. Ber. 1975, 108, 1924; c) Zuger, M.; Weller, T.;
Seebach, D. Helv. Chim. Acta 1980, 63, 2005.

a) Risaliti, A.; Forchiassin, M.; Valentin, E. Tetrahedron 1968,24, 1889;

b) Colonna, F.P.; Valentin, E.; Pitacco, G.; Risaliti,A. Tetrahedron 1973, 29, 3011;
c) Valentin, E.; Pitacco, G.; Colonna, F.P.; Risaliti, A. Tetrahedron 1974, 30, 2741;
d) Calligaris, M.; Manzini, G.; Pitacco, G.; Valentin, E. Tetrahedron 1975, 31, 1501;
e) Fabrissin, S.; Fatutta, S.; Malusa, N.; Risaliti, A. J. Chem. Soc. Perkin Trans.1
1980, 686; t) Fabrissin, S.; Fatutta, S.; Risaliti, A. J. Chem. Soc. Perkin Trans]
1981, 109.

Hickmott, P.W.; Sheppard, G. J. Chem. Soc.( C) 1971, 1358.
Matsuyama, H.; Ebisawa, Y.; Kobayashi, M. Heterocycles 1989,29, 449.

a) Kober, R.; Hammes, W.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1982, 21, 203;
b) Hall, H.K., Jr.; Miniutti, D.L. Tetrahedron Lett. 1984, 25, 943; c) Kober, R.;
Papadopoulos, K.; Miltz, W.; Enders, D.; Steglich, W.; Reuter, H.; Puff, H.
Tetrahedron Lett. 1985, 41, 1693.

Dumas, F.; d'Angelo, J. Tetrahedron: Asymm. 1990, I, 167.

a) Sevin, A.; Tortajada, J.; Pfau, M. J. Org. Chem. 1986, 51, 2671; b) Sevin, A.;
Masure, D.; Giessner-Prettre, C; Pfau, M. Helv. Chim. Acta 1990, 73, 552; c) Sevin,
A.; Giessner-Prettre, C. Tetrahedron 1994, 50, 5387; d) Pfau, M.; Tomas, A.; Lim,
S.; Revial, G. J. Org. Chem. 1995, 60, 1143.

a) Dickman, D.A.; Heathcock, C.H. J. Am. Chem. Soc. 1989, III, 1528; b)
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a) Tomioka, K; Ando, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986, 27, 715; b)
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86

29. Barta, N.S.; Paulvannan, K.; Schwartz, J.B.; Stille, J.R. Synth. Commun. 1994,
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CHAPTER III
FORMATION OF DIHYDROPYRIDONE- AND PYRIDONE-BASED PEPTIDE
ANALOGS THROUGH AZA-ANNULATION OF B-ENAMINO AMIDE
SUBSTRATES WITH a-AMIDO ACRYLATE DERIVATIVES
Introduction.

Biological processes are extremally important and scientists have made an effort
to understand these systems in details. Recently, the secondary structure of biologically
active peptides, i.e. the conformation of succesive adjacent amino acid residues in peptide
chains, was shown to be crucial to the efficiency and selectivity of recognition processes.
The secondary structure of peptides, one of the most important groups of biological
active compounds, can be determined and potentially modified by an interaction of
different parts of a molecule, by steric repulsions, hydrogen bonding, and electrostatic
attractions, just to name a few. The most common secondary peptide and protein structure
types are a-helix, B-sheet and reverse turn conformations, which include such varieties as
the B- and 'y-tums (Figure III-1).

A mimic of a B-tum should meet the following criteria.1 It should :

Reproduce the spatial area of a B-tum;

Contain the side chains of the amino acid residues i+1 and i+2 in the correct

stereochemistry;

Minimize steric interactions beyond the peptide backbone;

Contain the N- and C-terminal ends.

87

88

Figure III-1. Typical B-Turn Arrangement.

Thirteen types of B-tums that vary in their dihedral angles (112, ‘1’2, (1);; and ‘1’3 ' can be
distinguished (Table 111-1).

Table HI-l. Different B-Turn Types.

 

Helix and sheet

 

 

 

 

 

structures (1) \p
a-Helix -57 -47
Parallel chain -1 19 +113
Antiparallel chain -139 +135
Reverse (13) turns $141 ‘1’.“ <I>t+2 ‘I’m
Type 1 -60 -30 -90 0
Type F +60 +30 +90 0
Type 11 -60 +120 +80 0
Type 11' +60 -120 -80 0
'y-Turn ‘1': (pm ‘Pm ‘Pm

 

+120 -65 +80 - 120

 

 

89

Potential drug candidates often do not meet demanding requirements due to

unfavorable solubility, biodegradation, bioavalibility and bioselectivity properties.

Conformationally restricted amino acids and oligopeptides, as well as peptide

mimetics, can be employed to address these disadvantages and to improve the biological

activity.

Figure III-2. B-Sheet Arrangements.

H H o H H ('3 F1 H o R
evNN¥LNJTN9NHN¥LsHN
H o it H o H H o H H o
anti-parallel B-sheet

z-I---
Z-I---

o H 13
= \l‘
R o H R H R H

parallel B-sheet

90

B-Sheets are a dominant structural motif characterizing the V" and VL domains
in antibodies (Figure III-2).2 [3- And y-turns are often involved in diverse biochemical
recognition mechanisms. In many cases, recognition is the first step in a cascade of
events leading to the biological effect. Turns are important in the recognition necessary
for post-translation modification of proteins by phosphorylation and glycosylation.
Interestingly, it has been noted that B-turns play an important role even in the
construction of spider webs. 3

Because of the flexibility of peptide molecules, the desired biologically active
conformations are hidden in a population of many other conformers. To attain the best
conformation leading to an optimal biological effect, it would be desirable to rule out
unfavorable conformations by fixing the molecule structure, and decreasing the flexibility
of the backbone.

To illustrate these features, several examples of the structures known as enzyme
inhibitors have been chosen. Ripka described benzodiazepine derivatives III-1 able to
mimic cyclic peptides having a B-tum.4 Houpis and coworkers constructed a similar 2-

pyridone skeleton III-2, which showed activity against HIV-reverse transcriptase.s

Figure III-3. B-Turn Mimics.

R2
N’ N 0
3am ‘ NH
1
N R O \ / M6

0 4R)-002H NHz Me

III-1 III-2

91

Smith introduced the idea that hydrogen bonding involving the amide backbone
plays a critical role in the binding of peptide inhibitors to proteolytic enzymes. With help
of interactive computer modeling, he suggested that the series of 3,5-linked pyrroline-4-
ones would adopt a backbone conformation mimicking a B-strand III-3.° Structure III-3
mimics a Leu-Leu-Val-Phe fragment in a peptide backbone. Freidinger proposed that
lactam-constrained dipeptide analogs III-4 could behave as enzyme inhibitors.7
Zydowsky constructed chymotrypsin inhibitors, designed as dipeptide isosters for the

Phe-His portion 111-5.8

Figure III-4. B-Turn Mimics.

 

III-3 III-4 III-5

Kempf and Condon, from the Abbott Laboratories, prepared human renin
inhibitors having the rigid a—amino lactam feature III-6.9 Genin developed spirolactams
111-7 and III-8 as B-tum mimics (Figure 111-5).10 The cyclopentapeptide cyclo(Arg-Gly-
Asp-D-Phe-Val) III-9 was tested as a selective endothelial cell integrin owl}; antagonist

(Figure 111-6).“

92

These examples of active structures were carefully chosen to show a common
structural feature - amine functionality at the (it-position to a lactam group. This skeletal

feature may also be prepared through aza—annulation methodology.

Scheme III-l. Construction of Human Renin Inhibitors.

H I H
g
0 R 0

5°“ 1
W ’R O
\
+— CO H
N O mar—,5 2
H H

will

I

R

III-6

Figure III-5. B-Turn Mimics.

"N'> “Q15

0

k k

002MB C02Me
III-7 III-8

93

Figure 111-6. The Endothelial Cell Integrin avB3 Antagonist.

Ph "N4/(:—ivye Me

Hozc\_2= OH

III-9

Initially, this work focused on the preparation of potential angiotensin converting
enzyme (ACE) inhibitors through the aza-annulation reaction. ACE facilitates the
removal of dipeptide or in some cases tripeptide fragments from the C-terminus of the
angiotensin 1 molecule. The enzyme is a glycoprotein, with a molecular weight between
130 and 160 kDa. The whole cascade degradation of angiotensinogen into angiotensin II
is illustrated in Scheme III-2.12

The enzyme has low requirements for substrate specificity :

o A free carboxylic acid group at the C-terminus

0 Absence of a proline unit in the penultimate position of the peptide chain.

ACE appears to have a high affinity for peptide substrates having an aromatic
amino acid in the antepenultimate position. Although the mechanism of its action is still
not fully understood, efforts to prepare inhibitors of ACE have culminated in the

development of captopril 111-10 and enalale III-ll (Figure II-7).

94

Scheme III-2. Angiotensinogen Degradation.

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr—Ser Angiotensinogen
1 Renin

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Ieu Angiotensin I
1 1....

Asp-Arg-Val-Tyr—Ile-His-Pro-Phe Angiotensin H

Figure III-7. Captopril (III-10) and Enalapril (III-11).

BO 0
HS Me Me
L3— Ph HN-Sr

O O

O
O 0" O-

III-10 III-11

In order to mimic the cleavage site of the natural substrate, it was suggested that

bicyclic system III-12 could successfully play the role of a phenylalanine-histidine

95

fragment mimic, thus providing an inhibitor of angiotensin I - angiotensin 11 conversion
(Figure III-8).

Figure III-8. Potential Inhibitor of Angiotensin I - Angiotensin II Conversion.

P“: o H HNS"
o "' N
TH: Y: -Pro-Phe-His-Leu
O N OMB Me
(’ l
N
H
H
P1; 0 N‘(Me
E10 OY‘N OO
O N In?
NH 11 = 0,1
11
(
Ph
III-12
RESULTS AND DISCUSSION

The initial formation of the aza-annulation benzyl ester amide product III-16
proceeded smoothly in 69% yield. Hydrogenolysis of III-l6 on Pd under atmospheric
pressure of hydrogen gave a near quantitative yield of the corresponding acid III-17,
but many attempts to extend the side chain by peptide coupling gave the product 111-
18 in very low yield (Scheme III-3). For the construction of even more complex
systems with an amino substituent at carbon or of lactam system III-l9, problems with

inseparable mixtures of diastereomeric products added to the above-mentioned

complications.

III-19

After a series of unsuccessful reactions with disappointing yields and poor
stereoselectivity, it was decided to change direction in the research. The new approach to
the construction of peptide mimetics has involved the preparation of 0t- and/or B-amino
acid-substituted 8-lactams that restrict the conformation of the ‘1’ dihedral angle. Typical
approaches, and examples of products of this type, have been mentioned in the
introduction part of this chapter.

A synthetic strategy using suitably substituted amides instead of B-enamino esters
introduces another amino acid unit into a peptide mimetic, thus building the complex

synthetic target in several steps.

97

Scheme III-3. Attempts to Prepare a Tripeptide Analog Fragment.

ph\\gBHH + MOMOEI PNVO
2 Ph 0
III-l3 111-14
1 ii
H
OvaPh 0 Ph
: /\ =
Ph o’gk .H
O N NAPh
Ph‘iH H
o 0
111-16 K,Ph III-15
liv
H
OvaPh OvaPh
= V =
II) —- .03
o N o N
Ph‘“ H Ph‘il‘l
0 OH 0 D
111-17 (5,020 III-18

 

Reaction Conditions. i) KOH, benzyl chloride, MeOH, DMF, 69%; ii) 2-
oxo-cyclohexane carboxylate benzylamide, toluene, reflux; iii) sodium
acrylate, ClCO2Et, THF, 69%; iv) Pd/C, 1 atm of H2, EtOH, 99%; v) L-

ethyl proline, DCC, CH2C12, 1%.

98

Scheme III-4. Formation of Peptide Analogs through Aza-Annulation and

Pyridone Formation from B-Keto Amides.

H , H
‘HVN Me ’ ‘H VNWMe
2
o o o H.NTH
III-21a,c Ph III-22a-d
ii a R'=Ph, R2=H
b R‘=Ph, R2=C02Et
‘n \| in c R1=C02Et, R2=H
HN 0 H74 0 d R‘=Cozlat, R2=C02Et
0 l \ M9 iii 0 \ Me
<—-—
Mo’u‘N NYRZ M, N N F12
H H T
0 Ph 0 Ph
III-24a-d III-23a-d

 

Reaction Conditions. i) PhCH(R2)NH2, BF3:OEt2, benzene, reflux; ii) sodium 2-

acetarnidoacrylate, ClCO2Et, THF; iii) DDQ, toluene, reflux

The aza—annulation reaction of the mixed anhydride, made from 01-
acetarnidoacrylic acid and ethyl chloroformate in THF in situ, with intermediate [3-
enamino amide III-22a, generated from B-keto amide III-21a, resulted in efficient
formation of the dihydropyridone product III-23 (Scheme III-4). Even more complex
systems were accessed through condensation of 111-21 with ethyl (R)-pheny1glycine

(Scheme III-4, Table III-2). Aza-annulation of the intermediate B-enamino amide

99

Table 111-2. Formation of Peptide Analogs through Aza-Annulation and Pyridone

Formation from B-Keto Amides.

 

 

 

Isolated yield
Product R; R2 III-22 to III-23 III-23 to III-24
a Ph H 90 76
b Ph C023 87" 55
c CO2Et H 95 78
(1 C023 CO2Et 86" 60

 

"51:49 ratio of diastereomers.

III-22b with the corresponding mixed anhydride, resulted in the formation of III-23b as
an equal mixture of diastereomers. This two-step procedure provides a rapid and efficient
way of preparing complex heterocyclic products from simple components.

DDQ oxidation of III-23b generated the amide-substituted 2-pyridone derivative
III-24b in 55% yield. Attempts to oxidize III-23b with MnO2 in xylene at reflux resulted
in even lower yield (50%).13

For preparation of the pyridone system III-24c, compound III-21c, readily
obtained by the reaction of diketene with ethyl glycine, was used in a condensation with
benzylamine, followed by aza-annulation, giving the tripeptide analog III-23c in 95%
yield for the two-step process. Oxidation of III-23c proceeded in a fashion similar to that
of III-23b, additional treatment with DDQ was necessary to achieve a yield of 78%.
Condensation of the amide III-21c with (R)-pheny1 glycine ethyl ester provided III-22d,
which gave III-23d as an equal mixture of diastereomers (Table 111-2) upon aza-

annulation with the mixed anhydride. Oxidation of the product III-23d with DDQ in

 

100

refluxing toluene generated the pyridone derivative III-24d with amino acid
functionality radiating from the 1,3, and 5 positions.

The substituted 2-pyridone products III-24a and III-24b represent an interesting
class of conforrnationally restricted peptide-like molecules. Peptide functional groups,
both amino and carboxylate functionalities, radiate from the 1,3, and 5 positions of the
pyridone hub. The lactam functionality of the pyridone heterocycle mimics a peptide
amide bond. Combination of the 1 and 5 substituents reflects the structural features of a
linear dipeptide, while the 3 and 5 positions are similar to those found in
confonnationally restricted peptide chains. For compounds III-24b the relationship
between the 1 and 5 positions is one in which both an or and B-amino acid radiate from a
common nitrogen atom.

The drawback of the use of amide substrates is the substantially more sluggish

DDQ oxidation than that of the related ester substrates13b

. The dehydrogenation reaction
of III-23b and III-23d with approximately one equivalent of DDQ was incomplete and
required prolonged reaction times with additional DDQ to increase yields of the desired
products. The use of a higher boiling solvent (xylene) in place of benzene or toluene, or
the initial use of an increased amount of oxidation agent, did not improve yields of the
products. Application of a recently published catalytic DDQ oxidation procedure failed to
improve the yield.14

Structural Analysis of III-23c. oc-Amido lactam III-23c was obtained as a
crystalline solid, which permitted a the single crystal X-ray analysis of this molecule.
Appendix 2 shows the ORTEP representation of this molecule. In addition to structure

confirmation, the orientation and interactions of the peptide-like chains at the 3 and 5

positions of the 2-pyridone derivative are interesting.

101

Although intramolecular hydrogen bonding in solution cannot be ruled out, the
ORTEP representation of this molecule clearly illustrates an absence of intramolecular
hydrogen bonding in the solid state. However, several intermolecular hydrogen bonding
interactions were observed in this crystal lattice between the amide substituent at the 3
and 5 positions of the lactam heterocycle. As a result of these interactions, a “ladder" type
structural arrangement was observed.

In order to test compatibility of the aza-annulation reaction conditions with the
stereochemical integrity of the amino acid components, lactam and pyridone products
that contain two separate sites of asymmetry were constructed. Condensation of III-25
with either valine- or (R)-phenylglycine-derived esters was performed in toluene to give
III-27 and III-30, respectively (Scheme III-6). In each case, examination of the
intermediate enamine III-26 or III-29 by 1H NMR analysis revealed the presence of a
single diastereomer. Aza-annulation with sodium acrylate and ethyl chloroformate under
established standard reaction conditions led to the conversion of 111-27 to III-28a as a
single diastereomer (>98:2 by NMR analysis of the crude reaction mixture).

Similarly, treatment with sodium 2-acetamidoacrylate and ethyl chloroformate led
to an 89% yield of III-27b, which was a 50:50 mixture of diastereomers at C-3 of the

lactam, but did not result in epimerization of the amino acid side chains.

102

Scheme III-5. Determination of Epimerization during the Aza-Annulation.

OMe Me
oéfiwk Me

M 60,111 flMe 1' MeoJiNo WI: ii HN o

Meo'NH \

 

Reaction Conditions. 1') H2NR’, toluene, reflux; ii) CH2=CH(R2)C02Na,

ClCO2Et, THF.

Conversion of 111-29 to III-30 also proceeded to a single stereoisomer. Based on
these observations, epimerization of the stereocenters in amino acid side chains did not
occur under the aza-annulation conditions. A summary of results and reaction conditions
is shown in Scheme 111-5 and Table III-3.

The yields and general efficiency of the oxidation of lactam compounds III-27a-b
and III-30 was dependent on the nature of the susbtituent at C-3 of the lactam ring. When
R2=H (Scheme III-5), treatment of III-27a or III-30 with DDQ led to a mixture of side-
products containing no significant quantity of the desired pyridone products. However,
when R2=2-acetamido substituent (III-27b), oxidation gave III-28 as a single
diastereomer. This reaction could not be driven to complete conversion without
significant degradation of the desired product. After two sequential treatments with DDQ,
the product was isolated in only 40% yield, which represented a 59% yield based on
recovered III-27b.

The generation of a single stereoisomer demonstrated that the stereochemical

integrity of the amino acid groups was maintained even during the oxidation process.

103

Direct Formation of Pyridones. 2-Phenyl-4-(ethoxymethylene)oxazolone III-
33 was explored as an alternative reagent for the direct formation of pyridone products in
the aza-annulation reaction (Scheme III-7). Reagent III-33 was readily prepared from
hippuric acid with ethyl orthoforrnate in acetic anhydride, as previously reported.”

Although aza-annulation of enamino esters and amides with this reagent had been
reported to proceed in dioxane with triethylamine as a base at 85° C,15 analogous reaction
of enamino amide III-32 with III-33, with or without triethylamine, resulted primarily in
the formation of III-34. Cyclization of 111-34 to III-35 was effected eventually by
heating a solution of 111-34 in refluxing DMF. This aza-annulation process was
accomplished in a one-pot procedure by treatment of 111-32 with III-33 in DMF followed
by reflux of the reaction mixture. The low isolated yields obtained for III-35, especially
when compared to yields obtained for other similar reaction of 111-33 (Scheme III-8),
were a consequence of the generation of reaction byproducts and their difficult
separation.

Aza-annulation of 111-36, derived from III-25, resulted in more efficient ring
formation to give III-37 (Scheme III-8). Isolation and analysis of III-37 led to some
interesting properties of these molecules in solution. Initial 1H NMR analysis of III-37 in
CDC]; revealed a 70:30 ratio of two sets of resonances. However, systematic dilution of
III-37 resulted in conversion of this mixture into predominantly one set of peaks (90: 10).
This concentration dependent phenomena has been observed before with peptides, and
has been attributed to intermolecular hydrogen bonding of these molecules, which

becomes less prevalent upon increased dilution.1°

104

Scheme III-6. Determination of Epimerization during the Aza-Annulation and

/M80J:IEGO fl Me
\d‘o
III-25

1vleo':IN‘g/\rhi Meo’uIHO W3
Mao H‘N j’u‘orst
h

Oxidation Reactions.

M90 HN OMe
III-26 M.;/1 M, 111-29 P
l 111 1 iii
OMe Me OMe Me
O \\‘ M O \\‘\ M
HN O HN O
\ Moo \ Moo
R N‘E/ILOMe N1/ll‘OEt
qweAMe 0 Ph
III-27a-b III-30

in

OMe Me

O)\l‘“\l\ Me
HN O

o | \ M°o
Mel“ N\=)LOMe

(he/{Me 111-28

 

Reaction Conditions. i) (S)-methyl valinezHCI, toluene, NaHC03, reflux; i1) (R)-ethyl
phenylglycinezHCl, toluene, NaHCO3, reflux; iii) sodium acrylate or sodium 2-

acetamidoacrylate, ClCO2Et, THF; iv) DDQ, toluene, reflux, 40 h.

105

Table 111-3. Aza-Annulations with Different a-Amino Acids.

 

 

Amine Product Yield dea
M6020 ‘9‘in
9.. o
NHQ'HCI 60% >98:2
Meozc“ H \ Me
Me Me NY002M8
O TPr
III-27a
Maozc‘ws'br >98:2
HN o in amino
NHz'HCI 89% acid side
M6020“ H ° \ M° chainS'
Me Me Me a NYCQMO 50:50
0 'Pr mixture
of
111-271) diastereo
mers at
C-3
M9020 “o'Pr
.1. o
NHz'HCl 49% >98:2
Ph“ H \ ”‘3
002*?t N 00221
T
0 Ph
III-30

 

 

 

“The ratio was determined by 1H NMR analysis of the crude reaction mixture.

106

Scheme III-7. Direct Pyridone Formation through Aza-Annulation.

H
Ph N Me
H . v \
PhVN Me 1 w 0
——> o .N
O O H E OMe
3
111-31 0 o ”'9‘” W 111-32
EtO / N

   

III-33
O 0 Ph
/)—Ph
/ N HN O
H iii
PhVN \ MeO 0 | \ M90
0 H'NQLOMe Phlfi ”\E’kom
MeAMe cillle/\Me
III-34 III-35

 

Reaction Conditions. 1) (S)-Valine methyl esterzHCl, NaHCOg,
toluene, reflux; ii) III-33, dioxane, reflux; ii1) DMF, reflux; iv) III-33,

DMF, reflux.

Enamine III-26, formed as a single diastereomer as determined by 1H NMR, was
used to determine the extent to which epimerization occurred in the aza-annulation of III-
33 (Scheme III-8). The reaction of 111-33 with III-26, generated by condensation of (S)-
valine methyl ester with III-25, resulted in an 81% yield of 111-38 for the two-step
condensation/aza-annulation process. Although this procedure provided an efficient route
for the rapid construction of a complex molecules from readily available starting
materials, the diastereomer ratio from this reaction sequence was only 86:14. During this
aza-annulation process, some epimerization had occurred at the site of asymmetry due to

the high temperature required for heterocycle formation.

107

Scheme III-8. Determination of Epimerization during Direct Pyridone

0 t'
MeOJ'INflMe
Me M90 0
,7 111-25 \:

MeOfiNO WWW} Meofizo Wmo

Formation.

Mao HN Mao H'N E OMe
‘ iii 111.36111-26 Me AMe
OMe Me OMe Me i "'
oé\r¢\k Me 0%“fik Me
HN o HN o
o | \ ”‘3 o l \ M(’0
phi” ”VP“ Phi” N‘E/ILOMe
o A
III-37 III-38 g“ N“

 

Reaction Conditions. i) benzylamine, toluene, reflux; ii) (S)-valine methyl ester :HCl,

toluene, NaHCO3, reflux; iii) III-33, DMF, reflux.

Conclusions. Attempts to prepare the inhibitors of the ACE cascade, mimicking
the Phe-His fragment were not successful due to low yields and inseparable mixtures of

diastereomers. The aza-annulation reaction provides an efficient route for the potential

108

construction of the heterocyclic 2-pyridone framework for complex bioactive
compounds such as natural product targets or synthetic peptide mimetics. With this
method, peptide analogs as III-24b and III-24d can be assembled in three steps and in
good overall yield. The resulting compounds contain 5-lactam peptide-like bonds, which
exhibit restricted rotation of both ‘I’ and 0) dihedral angles. These angles can be altered by
oxidation of the dihydropyridone (‘i’=166°) to the 2-pyridone (‘I’=l80°). However, the
oxidation process using DDQ gave lower yields due to a loss of the product during the
course of the reaction. 2-Pyridone peptide analogs are inert to typical conditions for
peptide hydrolysis. As possible peptide mimics, these compounds have the potential to

interfere with biochemical events, and may exhibit significant biological effects.

109

EXPERIMENTAL RESULTS.

General Methods. Unless otherwise noted, all reactions were carried out using
standard inert atmosphere techniques to exclude moisture and oxygen, and reactions were
performed under an atmosphere of either nitrogen or argon. Benzene, toluene,
tetrahydrofuran (THF), dichloromethane and diethyl ether were distilled from
sodium/benzophenone immediately prior to use. Unless specified, concentration of
solutions after workup was performed on a Buchi rotary evaporator. Oven temperature
ranges are reported for bulb to bulb (Kugelrohr) distillations.

NMR spectra were obtained on Varian Gemini 300 or VXR-300 spectrometers
with CDC13, and acetone-d6 as solvents. 1H NMR spectra are reported as follows :
chemical shift relative to residual CHC13 (7.24 ppm) or TMS (0.0 ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling, and integration. '3 C
NMR data are reported as chemical shifts relative to CDC]; (77.00 ppm). Flash column
chromatography was performed using SiOz of 230-400 mesh. Reactions were monitored
by TLC using Whatman K6F Silica Gel 60A 250 um thickness plates. High resolution
mass spectra were carried out on a JEOL AX-SOS double-focusing mass spectrometer
(EI) or a JEOL HX-l 10 double-focusing mass spectrometer with helium as the collision
gas (FAB). Optical rotation measurement was performed on the Perkin-Elmer 141
instrument, the instrument Siemens (Nicolet) PRV has been used for X-ray measurement.
Dehydration of condensation reactions was performed with the use of a modified Dean-

Stark apparatus in which the cooled distillate was passed through 4—A molecular sieves

110

rior to return of the solvent to the reaction mixture.” The sieves were chan ed durin
P g g

reactions in which additional reagent was added after reaction had progressed.

Preparation of Benzyl (R)-Phenyl Glycine 111-13.18

KOH (1.85 g, 33 mmol, 1.0 equiv.) was dissolved in methyl alcohol (66 mL), phenyl
glycine (5.00 g, 33.1 mmol, 1.0 equiv.) was added and dissolved by gentle heating. Ethyl
acetoacetate (4.73 g, 36.4 mmol, 1.1 equiv.) was added and the mixture was brought to
reflux for 10 minutes, then the solvent was removed under reduced pressure to yield a
solid cake. The cake was dissolved in DMF (33 mL) and benzyl chloride (4.19 g, 33.1
mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 20 hours.
The resulting suspension was diluted with 1M NaHC03 (150 mL) and ethyl acetate (150
mL), washed with water. Combined organic layers were dried over Na2804. After
concentration, to the crude oil 1M EtZO solution of HCl was added and after 10 minutes,
the solution was concentrated under reduced pressure. The oil solidified after addition of
Et20. The product was pure enough to be used in the next step without further

purification. Yield : 6.34 g (69%).

Hydrogenolysis of 111-16.

To a solution of III-16 (0.25 g, 0.49 mmol) in 15 mL of EtOH, 10% Pd/C (0.06 g) was
added, the reaction vessel was flushed 3 times with H2, and the reaction was placed under
a balloon of H2. The reaction mixture was stirred 4 hours at RT, filtered through a pad of
Celite, and concentrated under reduced pressure to give III-17 (0.20 g, 0.48 mmol, 99%

yield).

111

III-17: (0.20 g, 0.48 mmol, 99% yield); m.p. = (l 14-115)° C (sealed); [01]];22 = +22.9; 1H
NMR (300 MHz, CDCl3) 8 1.10-1.36 (m, 2H), 1.40-1.63 (m, 2H), l.80-1.98 (m, 2H),
2.18-2.38 (m, 3H), 2.51 (m, 1H), 4.24 (d, J=5.1 Hz, 2H), 5.04 (m, 1H), 6.99 (s, 1H),
7.03-7.14 (m, 5H), 7.14-7.28 (m, 5H), 8.41 (bt, J=5.1 Hz, 1H), 1020 (bs, 1H); 13C NMR
(75 MHz, CDC13) 8 18.0, 24.3, 29.7, 30.3, 34.7, 43.8, 46.9, 58.1, 112.6, 127.3, 127.5,
127.6, 128.1, 128.4, 133.8, 134.4, 138.2, 169.5, 171.5, 174.2; IR (CHC13) 3306, 3015,
2934, 1715, 1671, 1644, 1619, 1541, 1453, 1364, 1283 cm'l; HRMS m/z calcd for

C25H26N204 418.1893, obsd 418.1887.

Peptide Coupling Reaction of 111-17 with Ethyl Proline.

To III-17 (0.20 g, 0.48 mmol, 1.0 equiv.) in 10 mL of dichloromethane was added
triethylamine (0.07 mL, 0.48 mmol, 1.0 equiv.) and L-ethyl proline hydrochloride (0.085
g, 0.48 mmol, 1.0 equiv), the mixture cooled to 0° C and DCC (0.1 g, 0,48 mmol, 1.0
equiv.) was added at once. The mixture was stirred for 1 hour at 0° C and then 18 hours at
room temperature. N,N'-dicyclohexylurea was filtered off on the pad of Celite, washed
with dichloromethane, extracted with 0.1 M HCl, saturated NaHCOg, brine and water.
Organic layers were dried over Na2804. The crude product purified by flash column
chromatography (diethyl etherzpetroleum etherzmethyl alcohol/48:48z4). Yield of III-18 :

0.003 g (1%).

112

General Method for the Formation of B-Keto Amides.

Diketene (5.0-30.0 mmol, 1.0 equiv), benzylamine, HCl-(R)-ethy1 phenylglycine or
HCl-(S)-methyl valine (1.0 equiv), and NaHCO3 (2.0 equiv) were combined in
benzene (0.5 M solution of amine) at 0° C. The mixture was slowly warmed to room
temperature, stirred for 10-15 hours, and then filtered. Removal of solvent under
reduced pressure gave the product pure enough to use it for the next step without
further purification.

III-21a: (3.60 g, 18.8 mmol, 81% yield; m.p.=(100-101)° C; lH NMR (300 MHz,
CDC13) 5 2.24 (s, 3H), 3.42 (s, 2H), 4.44 (d, J=6.0 Hz, 2H), 7.25-7.400 (m, 6H); 13C
NMR (75 MHz, CDC13) 8 30.9, 43.5, 49.6, 127.4, 127.6, 128.6, 137.9, 165.4, 204.4;
IR(KBr) 3249, 3085, 1715, 1640, 1443, 1410, 1190, 1163 cm"; HRMS calcd for
CuH13N02 m/z 191.0146, obsd m/z 191.0982.

III-21c: (1.74 g, 9.35 mmol, 99% yield); m.p. = (52-53)° C; lH NMR (300 MHz, CDC13)
5 1.28 (t, J=7.1 Hz, 3H), 2.28 (s, 3H), 3.50 (s, 2H), 4.04 (d, J=5.4 Hz, 2H), 4.20 (q, J=7.2
Hz, 2H), 7.61 (bs, 1H); l3C NMR (75 MHz, CDC13) 5 13.8, 30.4, 41.1, 49.6, 61.1, 166.2,
169.4, 203.5; IR (KBr) 3353, 2986, 1754, 1715, 1673, 1543, 1418, 1401, 1321, 1175
cm"; HRMS calcd for C3H13NO4 m/z 187.0845, obsd m/z 187.0844.

III-25: Noncrystalline, purified by column chromatography, eluent : 50:50/diethyl
etherzpetroleum ether, 3.27 g, 15.2 mmol, 85% yield; 1H NMR (300 MHz, CDC13) 5 0.85
(d, J=7.2 Hz, 3H), 0.89 (d, J=7.2 Hz, 3H), 2.12 (m, 1H), 2.21 (s, 3H)), 3.43 (s, 2H), 3.66
(s, 3H), 4.46 (dd, J=5.0, 8.6 Hz, 1H), 7.48 (bd, J=8.6 Hz, 1H); l3c NMR (75 MHz,

CDCl3) 5 17.5, 18.8, 30.5, 30.8, 49.5, 51.9, 57.1, 165.8, 172.0, 203.9; IR (neat) 3320,

113

2967, 2878, 1746, 1653, 1541, 1437, 1360, 1267, 1156 cm"; HRMS calcd for C10H17NO4

m/z 215.1158, obsd m/z 215.1149.

General Method for the Aza-Annulation of B-Keto Amides and B-Keto Esters.

A mixture of the benzylamine, (R)-pheny1glycine ethyl ester hydrochloride or (S)-valine
methyl ester hydrochloride (0.5-5.0 mmol, 1.0 equiv) and the B-keto amide (1.0 equiv)
and in the case of hydrochloride salts sodium bicarbonate (1.5 equiv) were taken up in
toluene (0.5 M relative to the substrate). The reaction vessel vas fitted with a modified
distillation apparatus for azeotropic removal of 11120,17 and the reaction was heated at
reflux until complete as determined by NMR analysis (10-18 hours). The solvent was
then removed under reduced pressure, and the crude enamine product was brought up in
THF (0.1 M). To the mixture mixed anhydride made freshly before reaction by reaction
of NaH, appropriate acid (acrylic acid derivatives) and ethyl chloroformate in THF at -
78° C. The reaction mixture was stirred at room temperature for 10-20 hours. The mixture
was then washed with water and extracted with ethyl acetate or dichloromethane. The
combined organic fractions were dried over anhydrous N a2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash column chromatography

(eluent as indicated).

III-16: (diethyl etherzpetroleum ether/ 1:1, 0.63 g, 1.24 mmol, 69%); mp. = (46—47)° C
(sealed); [01].,” = + 28 (c=2.7, c1103); 'H NMR (300 MHz, CDCl3) 5 1.08-1.37 (m, 2H),
1.40-1.64 (m, 3H), 1.84 (m, 1H), 2.27-2.60 (m, 4H), 4.29 (dd, J=5.8, 14.8 Hz, 1H), 4.37

(dd, J=6.1, 14.6 Hz, 1H), 4.82 (dd, J=2.8, 4.9 Hz, 1H), 5.01 (d, J=12.2 Hz, 1H), 5.02 (d,

 

114

J=13.8, 1H), 7.00 (s, 1H), 7.10-727 (m, 15H), 7.82 (1, J=5.8 Hz, 1H); l3c NMR (75
MHz, CDC13) 8 18.0, 24.0, 30.0, 30.6, 34.9, 43.8, 46.9, 58.4, 67.9, 111.6, 127.1, 127.5,
127.6, 127.7, 128.1, 128.4, 128.5, 128.6, 128.7, 133.8, 134.6, 134.9, 138.5, 168.9, 170.0,
173.2; IR (CHC13) 3345, 3033, 3011, 2932, 1721, 1661, 1644, 1532, 1497, 1451, 1341,

1277, 1286, 698 cm";

III-23a: 0.78 g, 2.06 mmol, 90% yield; m.p. = (82-85)° C; 1H NMR (300 MHz, CDC13) 5
1.92 (s, 3H), 2.07 (d, J=2.3 Hz, 3H), 2.41 (btd, J=15.3, 2.3 Hz, 1H), 2.93 (dd, J=15.5, 6.4
Hz, 1H), 4.35 (dd, J=14.7, 5.5 Hz, 1H), 4.43 (dd, J=l4.7, 5.5 Hz, 1H), 4.54 (dt, J=15.0,
6.4 Hz, 1H), 4.63 (d, J=16.4 Hz, 1H), 5.05 (d, J=16.4 Hz, 1H), 6.80 (bt, J=5.7 Hz, 1H),
6.98 (bd, J=6.3 Hz, 1H), 7.07 (d, J=6.6 Hz, 2H), 7.16-7.30 (m, 8H); 13C NMR (75 MHZ,
CDCl3) 5 15.9, 22.8, 28.5, 43.4, 45.5, 48.8, 112.5, 125.9, 127.2, 127.6, 128.4, 128.6,
136.8, 138.0, 139.1, 167.8, 169.3, 170.2; IR (KBr) 3289, 3002, 1734, 1659, 1584, 1543,

1321, 1248 cm'l; HRMS calcd for C23H25N303 m/z 391.1896, obsd m/z 391.1895.

III-23b: (diethyl etherzpetroleum ether2methyl alcohol/905:5, mixture of diastereomers,
ratio 49:51; 0.36 g, 0.80 mmol, 87% yield); m.p. = (83-85)° C (mixture); 1H NMR (300
MHz, CDC13) (characteristic peaks) 5 (major isomer) 2.01 (s, 3H), 2.22 (d, J=1.2 Hz,
3H), 2.30 (bdt, J=9.2, 1.5 Hz, 1H), 5.67 (s, 1H), 5.92 (m, 1H), (minor isomer) 2.02 (s,
3H), 2.10 (d, J=1.2 Hz, 3H), 2.43 (btd, J=9.2, 1.5 Hz, 1H), 5.59 (s, 1H), 5.95 (m, 1H);
13C NMR (75 MHz, CDCl3) 5 13.9, 16.2, 16.5, 20.9, 22.8, 28.2, 28.3, 40.4, 43.5, 46.5,
48.9, 59.8, 61.7, 111.1, 113.6, 114.0, 117.3, 126.0, 127.1, 127.2, 127.5, 127.6, 127.7,

128.0, 128.2, 128.4, 128.4, 128.5, 134.3, 134.4, 137.9, 138.0, 138.5, 139.4, 167.5, 167.6,

115

168.0, 168.4, 169.2, 169.6, 170.1, 170.2; IR (KBr) 3297, 3007, 1742, 1651, 1532, 1217

cm“; HRMS calcd for C26H29N305 m/z 463.2107, obsd m/z 463.2150.

III-23c: (diethyl ether:petroleum etherzmethyl alcohol/90:5:5, 1.06 g, 2.74 mmol, 95%
yield); m.p. = (71—74)° C; 1H NMR (300 MHz, CDCl3) 5 1.25 (t, J=7.1 Hz, 3H), 2.00 (s,
3H), 2.16 (d, J=2.2 Hz, 3H), 2.46 (btd (J=15.3, 2.2 Hz, 1H), 2.96 (dd, J=15.3, 6.5 Hz,
1H), 3.95 (dd, J=18.1, 5.6 Hz, 1H), 4.04 (dd, J=18.1, 5.6 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H),
4.59 (dt, J=15.3, 6.5 Hz, 1H), 4.67 (d, J=16.7, 1H), 5.13 (d, J=16.7 Hz, 1H), 6.91 (t,
J=5.6 Hz, 1H), 7.05-7.13 (m, 3H), 7.19-7.34 (m, 3H); l3C NMR (75 MHz, CDC13) 5 13.8,
15.8, 22.8, 28.3, 41.2, 45.4, 48.7, 61.1, 112.0, 125.8, 127.1, 128.6, 136.8, 139.7, 168.1,
169.3, 169.7, 170.3; IR (KBr) 3285, 2984, 1744, 1657, 1584, 1543, 1319, 1190 cm";

HRMS calcd for C20H25N305 m/z 387.1794, obsd m/z 387.1789.

III-23d: (diethyl ether:petroleum etherzmethyl alcohol/90:5:5, mixture of diastereomers,
ratio 49:51; 0.52 g, 1.13 mmol, 86% yield); m.p. = (77-80)° C (mixture); 1H NMR (300
MHz, CDCl3), characteristic peaks) 5 (major isomer) 2.03 (s, 3H), 2.12 (d, J=1.5 Hz,
3H), 2.45 (btq, J=9.0, 1.5 Hz, 1H), 2.77 (ddd, J=7.8, 3.3, 1.5 Hz, 1H), 5.62 (s, 1H), 6.17
(bt, J=2.9 Hz, 1H), (minor isomer) 2.02 (s, 3H), 2.24 (d, J=1.5 Hz, 3H), 2.33 (btq, J=9.0,
1.5 Hz, 1H), 3.10 (ddd, J=9.0, 3.3, 1.5 Hz, 1H), 5.68 (s, 1H), 6.13 (bt, J=2.9 Hz, 1H); ”C
NMR (75 MHz, CDC13) 5 14.0, 16.3, 16.6, 22.8, 23.0, 28.2, 28.3, 41.4, 41.4, 46.4, 49.0.
59.7, 59.9, 60.8, 61.3, 61.8, 62.4, 100.4, 113.2, 113.5, 113.5, 167.7, 127.7, 127.8, 128.0,
128.0, 128.1, 128.2, 128.3, 133.3, 134.2, 134.4, 139.5, 139.5, 140.4, 167.2, 168.0, 168.5,
169.0, 169.3, 169.4, 169.4, 169.7, 169.8, 170.2, 170.3, 171.1; IR (KBr) 3277, 2986, 1744,

1655, 1541, 1204 cm"; HRMS calcd for C23H29N307 m/z 459.2006, obsd m/z 459.2011.

116

III-27a: (48:48:4/diethyl ether:petroleum etherzmethyl alcohol; 0.53 g, 1.39 mmol, 60%
yield);1H NMR (300 MHz, CDC13) 5 0.74 (d, J=7.1 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H)),
0.90 (d, J=6.9 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H), 2.14 (s, 3H), 2.16 (m, 1H), 2.38-2.53 (m,
4H), 2.61 (m, 1H), 3.60 (s, 3H), 3.69 (s, 3H), 4.03 (bd, J=8.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) 5 16.5, 17.9, 18.9, 19.1, 22.0, 22.2, 28.0, 31.2, 52.0, 52.1, 57.0, 61.2,
113.2, 140.5, 168.8, 170.2, 170.6, 172.5; IR (CHC13) 3316, 2969, 2876, 1746, 1657,
1524, 1437, 1399, 1304, 1267 cm"; HRMS calcd for C19H30N205 m/z 382.2104, obsd m/z

382.2098.

III-27b: (90:5:5/diethyl ether:petroleum etherzmethyl alcohol; 2.73 g, 6.21 mmol, 89%
yield); (50:50 mixture of diastereomers; m.p. = (69-70)° C sealed, dec); 1H NMR (300
MHz, CDC13) 5 0.74 (d, J=7.2 Hz, 3H), 0.75 (d, J=7.2 Hz, 3H), 0.85-0.94 (m, 12H), 1.09
(d, J=7.2 Hz, 3H), 1.11 (d, J=7.2 Hz, 3H), 1.96 (s, 3H), 1.97 (s, 3H), 2.06 (d, J=1.8 Hz,
3H), 2.09-2.20 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 2.24-2.42 (m, 2H), 2.48-2.68 (m, 2H),
2.91 (dd, J=6.3, 15.3 Hz, 1H), 2.99 (dd, J=6.3, 15.3 Hz, 1H), 3.61 (s, 3H), 3.64 (s, 3H),
3.69 (s, 6H), 3.95 (d, J=8.7 Hz, 1H), 4.26 (bs, 1H), 4.35-4.57 (m, 4H), 6.19 (d, J=8.7 Hz,
1H), 6.42 (d, J=8.4 Hz, 1H), 6.56 (d, J=5.7 Hz, 1H), 6.61 (D, J=5.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 11.5, 11.7, 13.2, 13.2, 14.2, 14.4, 17.0, 17.4, 18.2, 22.9, 23.5, 23.6,
23.8, 26.1, 26.4, 44.0, 44.3, 47.3, 47.4, 47.5, 52.5, 52.6, 56.9, 57.4, 107.9, 108.7, 134.0,
136.1, 162.8, 163.3, 164.4, 164.5, 164.8, 165.4, 165.5, 165.9, 167.5, 167.6; IR (CHC13)
3308, 2969, 1742, 1653, 1534, 1437, 1269, 1244 cm"; HRMS calcd for C21H33N307 m/z

439.2319, obsd m/z 439.2285.

117

III-30: (48:48:4/diethyl ether:petroleum ether:methyl alcohol, 0.29 g, 0.68 mmol, 49%
yield); m.p. = (44-45)° C; 1H NMR (300 MHz, CDC13) 5 0.85 (d, J=6.9 Hz, 3H), 0.90 (d,
J=6.8 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 2.06 (s, 3H), 2.12 (m, 1H), 2.40-2.55 (m, 2H),
2.55-2.66 (m, 2H), 3.69 (s, 3H), 4.18 (q, J=7.1 Hz, 2H), 4.55 (dd, J=4.8, 8.6 Hz, 1H),
5.60 (s, 1H), 5.84 (bd, J=8.6 Hz, 1H), 7.05-7.33 (m, 5H); 13C NMR (75 MHz, CDCl3) 5
14.1, 16.8, 17.9, 22.2, 31.2, 31.4, 52.2, 57.1, 59.8, 61.7, 114.1, 126.1, 128.0, 128.4, 128.7,
135.0, 140.1, 168.7, 168.8, 170.6, 172.5; IR (CHC13) 3324, 2967, 1744, 1659, 1522,
1395, 1374, 1302, 1262, 1156, 1028 cm"; HRMS calcd for C23H30N206 m/z 430.2104,

obsd m/z 430.2105.
Direct Method for the DDQ Oxidation of Aza-Annulation Products.

A mixture of the aza-annulation product (0.5-20.0 mmol, 1.0 equiv) and DDQ (1.5
equiv.) was taken up in toluene (0.1 M with respect to the aza-annulation product). After
heating at reflux for 10-18 hours, the solvent was removed under reduced pressure, the
residue dissolved in dichloromethane, filtered through a pad of Celite and the crude
product was purified by flash column chromatography (eluent as indicated). The

oxidation was repeated to acquire the indicated yields.

III-24a: (diethyl etherzethyl acetate/2:1, 0.21 g, 0.59 mmol, 71% yield); m.p. = (180-
181)° C; 1H NMR (300 MHz, acetone-d6) 5 2.10 (s, 3H), 2.42 (s, 3H), 4.55 (d, J=6.0 Hz,
2H), 5.51 (s, 2H), 7.12-7.16 (m, 2H), 7.19-7.56 (m, 8H), 8.18 (t, J=6.0 Hz, 1H), 8.54 (s,
1H), 8.96 (s, 1H); 13C NMR (75 MHz, acetone-d6) d 12.3, 24.4, 44.2, 48.8, 108.5, 122.4,

127.3, 127.8, 128.1, 128.5, 129.2, 129.5, 129.6, 137.0, 137.3, 145.4, 158.6, 168.5, 170.0;

118

IR (KBr) 3299, 3067, 3034, 2880, 1705, 1634, 1507, 1476, 1248, 1003 cm"; HRMS

calcd for C23H23N303 m/z 389.1739, obsd m/z 389.1762.

III-24b: (diethyl etherzethyl acetate/2:1, 0.16 g, 0.35 mmol, 55% yield); m.p. = (155-
156)° C; 1H NMR (300 MHz, CDCl3) 5 1.24 (t, J=7.2 Hz, 3H), 2.18 (s, 3H), 2.50 (s, 3H),
4.26 (q, J=7.2 Hz, 2H), 4.57 (dd, J=5.6, 1.7 Hz, 2H), 6.12 (s, 1H), 6.19 (m, 1H), 7.19-
7.43 (m, 10H), 8.27 (s, 1H), 8.53 (s, 1H); 13C NMR (75 MHz, CDCl3) 5 14.1, 17.5, 24.7,
44.3, 62.1, 62.7, 116.2, 120.7, 126.9, 127.7, 127.9, 128.2, 128.5, 128.6, 128.9, 133.0,
137.7, 139.8, 140.5, 167.2, 167.4, 169.3; IR (KBr) 3280, 2960, 2920, 1736, 1647, 1516,

1455, 1217 cm"; HRMS calcd for 96112719305 m/z 461.1951, obsd m/z 461.1901.

III-28: (90:5:5/diethyl ether:petroleum etherzmethyl alcohol, 0.20 g, 0.46 mmol, 40%
yield); m.p. = (90-91)° C (sealed), dec.; lH NMR (300 MHz, CDC13) 5 0.63 (d, J=6.9 Hz,
3H), 0.97 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 1.24 (d, J=6.9 Hz, 3H), 2.13 (s, 3H),
2.19-2.32 (m, 2H), 2.49 (bs, 3H), 3.60 (s, 3H), 3.76 (s, 3H), 4.32 (bs, 1H), 4.65 (dd,
J=4.5, 8.7 Hz, 1H), 6.45 (d, J=8.7 Hz, 1H), 8.19 (bs, 1H), 8.53 (s, 1H); 13C NMR (75
MHz, CDC13) 5 17.6, 17.8, 18.9, 19.1, 22.2, 24.4, 26.8, 31.2, 52.2, 52.3, 57.6, 64.9,
115.5, 120.8. 126.3, 139.6, 157.2, 167.5, 168.9, 169.1, 172.1; IR (CHC13) 3305, 3015,
2971, 2876, 1748, 1653, 1611, 1522, 1215 cm"; HRMS calcd for C21H31N307 m/z

437.2162, obsd m/z 437.2158.

119

General Method for Aza-Annulation with III-33 (2-PhenyI-4-

(ethoxymethylene)oxazolone).

The corresponding enamine (0.78-2.6 mmol) was dissolved in anhydrous DMF (0.26 M)
and III-33 (1.0 equiv) was added. After the reaction mixture was heated to reflux for 2
hours, the dark brown solution was concentrated to an oil (boiling water bath), dissolved
in dichloromethane, filtered through a pad of Celite/SiOZ=l :1 (w/w) and purified by flash

column chromatography (eluent as indicated).

III-3S: (90:5:5/diethy1 ether:petroleum etherzmethyl alcohol, 0.18 g, 0.38 mmol, 49%);
1H NMR (300 MHz, CDC13) 5 0.57 (d, J=6.9 Hz, 3H), 1.20 (d, J=6.3 Hz, 3H), 2.50 (s,
3H), 2.93 (m, 1H), 3.61 (s, 3H), 4.32 (m, 1H), 4.49 (dd, J=14.7, 5.7 Hz, 1H), 4.54 (dd,
J=15.6, 5.7 Hz, 1H), 6.67 (bt, J=5.1 Hz, 1H), 7.16-7.32 (m, 5H), 7.32-7.41 (m, 2H)), 7.46
(m, 1H), 7.74-7.81 (m, 2H)), 8.59 (s, 1H), 8.95 (bs, 1H); l3C NR (75 MHz, CDC13) 5
17.8, 18.9, 22.2, 26.8, 44.2, 52.4, 65.0, 115.9, 121.0, 126.2, 127.0, 127.6, 127.9, 128.7,
132.3, 133.6, 137.8, 140.0, 157.5, 165.8, 167.4, 169.0; IR (CHC13) 3372, 3015, 2971,
1750, 1638, 1611, 1582, 1520, 1491, 1389, 1275, 1215, 1024 cm"; HRMS calcd for

C27H29N305 m/z 475.2107, obsd (M+l) m/z 476.2174.

III-37: (90:5:5/diethyl ether:petroleum etherzmethyl alcohol, 0.62 g, 1.31 mmol, 71%
yield); 1H NMR (300 MHz, CDCl3) 5 0.85 (d, J=6.9 Hz, dimer), 0.89 (d, J=6.9 Hz,
dimer), 1.00 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3 H), 2.08 (m, dimer), 2.17 (s, dimer),
2.20 (s, 3H), 2.24 (m, 1H), 3.63 (s, dimer), 3.70 (s, 3H), 4.44 (dd, J=8.5, 5.1 Hz, dimer),
4.56 (dd, J=8.5, 5.2 Hz, 1H), 5.03 (bd, J=15.7 Hz, 1H), 5.31 (bd, J=15.7 Hz, 1H), 6.99

(d, J=6.6 Hz, 2H), 7.12-7.24 (m, 3H), 7.34-7.52 (m, 3H), 7.82 (d, J=7.8 Hz, 2H), 8.63 (s,

120

1H), 9.09 (s, 1H); 13C NMR (75 MHz, CDCl3) 5 16.6, 17.6, 18.1, 18.9, 19.1, 30.8, 48.3,
52.0, 52.1, 57.00, 57.9, 58.0, 115.7, 115.7, 121.0, 121.1, 125.8, 125.9, 126.2, 127.0,
127.2, 127.6, 128.6, 128.8, 132.1, 133.4, 133.5, 135.0, 140.0, 158.0, 158.1, 165.6, 165.6,
167.7, 167.8, 171.9, 172.1; IR (neat) 3306, 2967, 1744, 1646, 1522, 1210, 1154 cm"‘;

HRMS calcd for C27H29N305 m/z 475.2107, obsd (M+l) m/z 476.2172.

III-38: (90:5:5/diethyl ether:petroleum etherzmethyl alcohol, 0.75 g, 1.50 mmol, 81%
yield); lH NMR (300 MHz, CDC13) 5 0.50 (d, J=6.6 Hz, 3H), 0.80-0.90 (m, minor), 0.94
(d, J=7.9 Hz, 3H), 0.98 (d, J=7.9 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H), 2.008 (m, minor), 2.21
(m, 1H), 2.43 (s, 3H), 4.29 (bd, J=6.3 Hz, 1H), 4.43 (dd, J=8.3, 5.0 Hz, minor), 4.58 (dd,
J=8.3, 5.0 Hz, 1H), 6.89 (bd, J=6.6 Hz, 1H), 7.30-7.50 (m, 3H)), 7.80 (d, J=7.1 Hz, 2H),
8.49 (8, minor). 8.66 (s, 1H), 8.95 (bs, 1H), 9.67 (bs, minor); 13C NMR (75 MHz, CDC13)
5 17.6 (minor), 18.0, 18.8 (minor), 19.0, 22.0 (minor), 300.8 (minor), 31.0, 49.3 (minor),
51.9 (minor), 52.1, 52.3, 57.1 (minor), 57.8, 115.7, 121.0, 126.2, 127.0, 127.3 (minor),
128.4 (minor), 128.6, 128.8 (minor), 132.1, 133.6, 139.6, 165.6, 167.6, 172.1; IR (neat)
3366, 3305, 2969, 1742, 1640, 1613, 1516, 1389, 1380, 1271, 1210 cm"; HRMS calcd

for C26H33N307 m/z 499.2319, obsd m/z 499.2323.

LIST OF REFERENCES

10.

11.

12.

13.

121

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Amzel, L.M.; Poljak, R.J. Ann. Rev. Biochem. 1979, 48, 961.
Schulz, S. Angew. Chem. Int. Ed. Engl. 1997, 36, 314.
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Tetrahedron 1993, 49, 3593; b) Ripka, W.C.; DeLucca, G.V.; Bach II, A.C.;
Pottorf, R.S.; Blaney, J .M. Tetrahedron 1993, 49, 3609.

. Houpis, I.N.; Molina, A.; Lynch, J.; Reamer, R.A; Volante, R.P.; Reider, PJ.

J. Org. Chem. 1993,58, 3176.

Smith 1H, A.B.; Keenan, T.P.; Holcomb, R.C.; Sprengeler, P.A.; Guzman,
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a) Pfaff, M.; Tangermann, K.; Muller, B.; Gurrath, M.; Muller, G.; Kessler,
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a) Smeby, R.R. Chemistry and Biochemistry of Amino Acids, Peptides, and
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Chemtracts 1993, 6, 263.

a) Bonnaud, B.; Bigg, D.C.H. Synthesis 1994, 465; b) Beholz, L.G.;
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CHAPTER IV
PREPARATION OF ISOQUINOLINE ALKALOID ANALOGS THROUGH

THE AZA-ANNULATION METHODOLOGY

Introduction

The broad variety of potential applications of isoquinoline alkaloids, or their
analogs, emphasizes the importance of this class of compounds. The isoquinoline moiety
represents a valuable template which has led to the discovery of many quite different
drugs.

On the one side of the spectrum is morphine (IV-1), one of the major opium
alkaloids, still indispensable in modern medical practice on account of its analgesic,
hypnotic, and sedative activity. On the other side, there is a class of new isoquinoline

derivatives having very different properties. Some examples are shown in Table IV-l.l

 

123

124

Table IV-1.Examples of Isoquinoline Drugs.

 

 

 

 

 

 

 

 

 

Name Structure Activity
OMe
Codeine antitussive
”8° O \
. / N .
Papaverme MeO spasmolytrc
O OMe
OMe
Nomifensin antidepressant
O N.Me
NH2
. N 0 . .
Prazrquantel H T anthelnnntrc
N
0%

 

 

125

Because of their broad physiological applications, new isoquinoline derivatives
are prepared as potential drugs. Recently, the novel tricyclic isoquinoline drug IV-2 was
prepared and evaluated for its activity as a central benzodiazepine receptor agent, acting

thus as a potential sleep inducer.2’3

c1 IN 0
R / Ph
IV-2

Interestingly, this compound does not have typical hydroxy or alkoxy substituents
in the positions 6 and 7 of isoquinoline system. The chlorine atom at carbon 7 is crucial
for the induction and maintenance of the effective non-sedative hypnotic activity.

There are two reported syntheses of compound IV-2. One, developed by Widmer2
(R=C02Me), proceeds by 1,3-dipolar cycloaddition reaction of compound IV-3 with
methyl prop-2-ynoate to give, after extrusion of sulfur from the primary adduct under the
reaction conditions, a mixture of regioisomeric pyridones IV-4 and IV-S, where the

former one is the major product (Scheme IV-l).

126

Scheme IV-l. 1,3-Dipolar Cycloaddition Approach.

Br 0
Ph: :CI 0::
’ N+
NH , .
CI DMF, then 0' f0

 

 

 

S 2 eq. of TEA S [V 3
Ph -
H 2 002MB
Cl | N O + Cl | N O
MeOzc / Ph MeOZC /
Ph
IV'4 [98 : 2 ratio] IV-S

 

A more recent synthesis has been developed by Spurr,3 from the Hoffmann La-
Roche company. The compound IV-2 (R=Me) was prepared by annulation of a suitable
enamine substrate with ethyl 3-dimethylamino-2-phenylacrylate (Scheme IV-2).

The enamine compound was constructed by a novel variation on the Bischler-
Napieralski procedure,4 using the chlorooxazolidinedione intermediate, which behaved in
the presence of FeC13 as a superior acylating agent to produce the oxalyl-adduct IV-6 in
good yield. Methanolysis of the crude product in MeOH/HzSO4 solution released the
cyclic oxalyl-protecting group and provided the corresponding enamino compound IV-7.
Compound IV-7 on annulation with ethyl 3-dimethylamino-2-phenylacrylate gave the

product IV-2 (R=Me) in 70-75% yield.

127

Scheme IV-2. Annulation Approach.

H

NH
UV 2 .- (:rww
——>
Cl Cl 0
iii

N O
N
CVEEE: O ‘— /©/\ICI><Me

0 Cl
0
IV-6 1,,
v
—>
or NH Cl IN 0
/ Ph
IV-7 IV-2 (R=Me)
vi
er I N o
O / Ph
L"?
1515
R0 41-3696

 

Reaction Conditions. 1') Aczo, toluene, 100%; ii) (COC1)2, CH2C12; ii1)
FeCl3, 85% (2 steps); iv) H2804, MeOH, 80%; v) ethyl 3-dimethylamino-
2-phenyl acrylate, AcOH, 70%; vi) NBS, AcOH, 75% then (S)-3-ethoxy

pyrrolidine, Pd(OAC)2. dppp, KHCO3, MeCN, 20 bar CO, 85%.

128

RESULTS AND DISCUSSION

Compound IV-8 (R=C02Et) was chosen as a synthetic target. Retrosynthetic
analysis shows that ring C can be made by the aza-annulation reaction (Scheme IV-3). In
order to demonstrate the utility of the aza-annulation reaction in this class of molecules,

transformations suggested by this scheme were explored.

Scheme IV-3. Retrosynthetic Analysis.

Cl N O 1:9 Cl N O
I / I
E1020 Ph E1020 Ph

IV-8 IV-9

..cN. W <= .cc;

fl IV-ll [v.10 002Et

Cl

IV-12

Preparation of the amide IV-ll proceeded smoothly, using commercially
available 4-chlorophenethylamine IV-12 and ethyl malonyl chloride. However, attempts
to successfully cyclize the amide substrate into an enamine derivative IV-10 left either

uncyclized starting material or gave undesired side-products. Many experimental

129

procedures mentioned in the literature were tried for Bischler cyclization, for example
cyclization in polyphosphoric acid (PPA)° or polyphosphate ester (PPE),° activation with
triflic anhydride,7 or classical cyclization in the presence of POC13 or PC15,° but none of
them gave the desired product. In this case, the presence of the halogen atom caused
deactivation of aromatic ring toward electrophilic attack. The attempts to cyclize the
appropriate amide under Bischler conditions failed even for other substrates, including
heterocycle IV-l8 (Table IV-2). Cyclization of an unsubstituted amide IV-lS gave the
enamino product only in very low yield, and the same type of cyclization either with an
amino group (IV-17), or protected amino group as a substituent generated insoluble
polymeric products. Even Bischler cyclization of the 4-methoxy substituted amide did not

generate the desired product (Scheme IV-4 and Table IV-2).

Scheme IV-4. Preparation of Amide Derivatives.

NH i B
Q 2 _' CD/V rec...
0

Reaction Conditions. 1) ClCOCHZCOZEt, CH2C12 or EtZO,

 

K2CO3 01‘ E13N.

This complication initiated an effort to construct the enamine molecule in another
way, shown in Scheme IV-S. 4-Chloro substituted benzaldehyde IV-l9 served as a
starting material, and gave 6-chloro-1-indanone IV-22 as the desired product via Perkin

reaction,9 catalytic hydrogenation and cyclization in hot concentrated sulfuric acid.lo This

130

product was then transformed then into lactam IV-23 by Schmidt rearrangement with
sodium azide in trichloroacetic acid.” This procedure also provided the undesired
regioisomer IV-24 in significant amount (15% yield), and generation of this byproduct
was a major drawback of this approach (74:26 crude ratio). Interestingly, the
intramolecular Friedel-Crafts cyclization of a chloride of the corresponding acid,
mentioned in the literature, did not give the desired indanone derivative.‘s Lactam
product IV-23 was transformed with Lawesson's reagent into thiolactam IV-2512 and this
product was used for the construction of an enamine product IV-10 using Eschenmoser
sulfide extrusion.l3

To avoid the time consuming separation of two lactam regioisomers, it was
decided to look for a different and better way for enamine IV-10 preparation. Finally, a
relatively simple and efficient procedure was found, using the corresponding
isothiocyanate made from an amine, carbon disulfide and ethyl chloroformate in the
presence of triethylamine. Cyclization of the crude product was achieved, using either
polyphosphoric acid, or AlC13 in 1,1,2,2-tetrachloroethane.l4 This approach has been
chosen as the best way of making different thiolactams. The products were usually pure
enough to use in the next step without further purification (Scheme IV-6). They have

been subsequently used for the preparation of all enamino derivatives by Eschenmoser

sulfide extrusion without difficulty.

131

Scheme IV-S. 6-Chloro-indan-l-one Approach.

c” ,c~%» —"»" ."cN"

 

 

[v.19 IV 20 1v-21
«W1 iii
IV 24 O1v-23 IV-22
HO£26 : 74 mi; Cl: v
Iv-25S 1v-10 ICOZEt

 

Reaction Conditions. 1) CH2(C02H)2. DMSO, piperidine, 90° C, 10 h, 87%; ii) Pd/C,
2 atm of H2, dioxan, 14 h, 98%; iii) conc.H2SO4, 175° C, 30 s, 64%; iv) NaNg,
C13CC02H, 65° C, 4 h, 85% overall yield; v) Lawesson's reagent, toluene, reflux, 45

min., 98%; vi) BrCH2COzEt, PPh3, Et3N, MeCN, 68 h, 78%.

132

Table IV-2. Preparation of Amide Derivatives.

 

 

 

 

 

 

 

 

 

Amine Product Product Yield
# [%]
NH2 n
c“ cmm.
c: C, 0 IV-ll 66
MeOD/V NH2 MeO N
*n/‘coza
Meo [MD/V ° 1v-13 49
NH2 H
c” ccw-
MeO M90 0 1v-14 58
NH2 n
UV recast
O IV-15 36
NH2 H
UV 0pm....
ozN 0,... ° IV-l6 43
11
c“ W
' HzN O IV-l7 100‘
0151
N IV-18 29
H

 

HN-<_(O
w 0

N

H

 

 

 

8Prepared by reduction of the corresponding nitro derivative.

 

133

Scheme IV-6. Formation of Thiolactams through Isothiocyanates.

NH2 i NOS 8
NH

Reaction Conditions. 1) C82, CH2C12, Et3N, ClCOzEt; i1) PPA or ClzCHCHClz, A1C13.

 

With the successful synthesis of enamino substrates in hand, the aza-annulation
with different derivatives of acrylic acid was explored. Chloro substituted enamine IV-10
was treated with either the unsubstituted mixed anhydride of acrylic acid in THF,
generating thus IV-26 in 68% yield, or with mixed anhydrides of 2-substituted
derivatives of acrylic acid. 2-Phenyl acrylic acid, made from or-bromo styrene with n-
BuLi and carbon dioxide,16 generated mixed anhydride in situ with NaH and ethyl
chloroformate, and the reaction of this compound and IV-10 provided the desired
synthetic target IV-9 in 81% yield (Scheme IV-7). Analogous reactions with 2-
acetamido substituted acrylic mixed anhydride with IV-IO gave the product IV-27
in 84% yield. The oxidation of IV-9 with DDQ in toluene at reflux provided the 2-
pyridone derivative IV-8 in 81% yield. The alternative direct preparation of IV-8 from
IV-10 and ethyl 3-dimethylamino-2-phenyl acrylate IV-28 in hot glacial acetic acid,

generated the product IV-8 in only 17% yield (Scheme IV-7).

134

Table IV-3. Formation of Enamino Esters.

 

 

 

 

 

 

 

Thiolactam Enamino Ester Product Yield
# [%]
NH NH
S 00251
MeO MeO
Meoj£>\j/;IWi M90 1 NH IV-29 77°
S 00.5:
I IV-35 10
S 00251
S S S \ COzEt IV-38 91
NH NH
N s N 0023 “7'41 77
H H

 

 

 

 

aPrepared directly from the corresponding amide by Bischler cyclization.

 

135

Scheme IV-7. Preparation of Chloro Substituted Tricyclic Isoquinoline Derivatives.

 

 

 

 

c1 IN 0
51020 Ph
1
IV-26 \
c: |N Oi cu IN 0
EtOzc ” Me EtOzc / Pb
IV-27 Iv-s

 

Reaction Conditions. 1') sodium acrylate, ClCOZEt, THF, 68%; 11) sodium 2-phenyl
acrylate, C1COzEt, THF, 81%; iii) IV-28, glacial HOAc, 95° C, 17%; iv) sodium 2-

acetarnidoacrylate, C1C02Et, THF, 84%; v) DDQ, toluene, reflux, 81%.

Preparation of dimethoxy enamino substrate IV-29 by Bischler reaction
proceeded smoothly due to the presence of two activating substituents on the aromatic
ring, and the product IV-29 was made from IV-13 in 77% yield. The same derivatives of

acrylic acid as for chloro substituted analogs have been used for aza-annulation reactions

136

of IV-29 and the products and yields are shown in Scheme IV-8. The compound IV-31
was prepared either by DDQ dehydrogenation of IV-30 in 81% yield, or directly by
reaction of IV-29 with IV-28. Preparation of IV-32 using 2-acetamidoacrylic mixed
anhydride as an active aza-annulation component was not complete and gave the product
in only 29% yield. The compound IV-33 was made by direct cyclization with 2-pheny1-4-
(ethoxymethylene)oxazolone IV-34 in DMF in 25% yield.

The unsubstituted derivative IV-35 was prepared in much lower yield through the
amide derivative via Bischler reaction. The product with an unsubstituted aromatic ring
IV-36 was prepared in 69% yield by reaction of enamine IV-35 in 69% yield with 2-
phenyl acrylic mixed anhydride, and subsequently oxidized with DDQ according to the
common protocol into IV-37 in 79% yield (Scheme IV-9).

At this stage of research it was decided to prepare heterocyclic analogs as
promising biologically active compounds.” As starting materials, tryptamine and 2-
thiophen-3-yl-ethylamine (prepared by hydrogenolysis of 3-thiopheneacetonitrile in the
presence of Raney-nickel) were chosen. The corresponding thiolactams were generated
via the corresponding isothiocyanates without problems.

Eschenmoser sulfide extrusion gave enamine IV-38 which was used in aza-
annulation reactions with either 2-phenylacrylic acid or 2-acetamidoacry1ic acid mixed
anhydrides. The results and yields are shown in Scheme IV-10. This type of product is a
thiophene isostere of the isoquinoline alkaloids, and might have potentially new and

important properties.

137

Scheme IV-8. 6,7-Dimethoxy Substituted Tricyclic Isoquinoline Derivatives.

M90 M60

N 0 iii
M90 1 : Meo IN 0

EtOzc Ph E1020 ’ Ph

1v-30 \ / IV-3l

 

 

 

 

M 0
9 M90

N 0
M00 1 )3 M60 IN 0 O
N M
Et02C H e Et020 / 11 JL
IV-32 IV-33

 

Reaction Conditions. 1) sodium 2-phenylacrylate, ClCOzEt, THF, 76%; i1) IV-28,

glacial HOAc, 95° C, 55%; iii) DDQ, toluene, reflux, 81%; iv) sodium acetamido

acrylate, C1COzEt, THF, 29%; v) IV-34, DMF, reflux, 25%.

The analogous aza-annulation reaction of enamino compound IV-41, derived

from tryptamine, with the same reagents used in previous schemes, provided interesting

products IV-42, IV-43, and IV-44 in 89%, 58%, and 48% yields, respectively (Scheme

IV-ll).

A11 attempts to prepare the yohimbine—like compound IV-45 either via the mixed

anhydride of 1-cyclohexene-1-carboxylic acid IV-46 or directly with DPPA17° and IV-46

have been unsuccessful (Scheme IV-12). An important factor in this failure is probably

the steric congestion at the B—carbon of the acrylic species.

138

Scheme IV-9. Unsubstituted Tricyclic Isoquinoline Derivatives.

i ii

NH —-"> N o ——’ N o
I I I /
COgEt 151020 Ph Et02C Ph
IV-35 IV-36 IV-37

 

Reaction Conditions. 1) sodium 2-phenylacrylate, ClCOzEt, THF, 69%, i1) DDQ,

toluene, reflux, 79%.

Scheme IV-10. Preparation of Thiophene Analogs of Isoquinoline Derivatives.

l 0 ii 0
/ \ NH —_> / \ N Ph _.. / \ N Ph
8 c0251 3 \ S \ /
E102C Et02C
IV-38 IV-39 IV-40

 

Reaction Conditions. 1) Sodium 2-phenylacrylate, ClCOzEt, THF, 64%; i1) DDQ,

toluene, reflux, 97%.

139

Scheme IV-ll. Preparation of Indole Substituted Derivatives.

N \ C02E1
H
/ ”'41 iii

 

 

 

Reaction Conditions. 1) Sodium 2-phenylacrylate, ClCOzEt, THF,
89%; it) sodium 2-acetamidoacrylate, ClCOZEt, THF, 58% , iii) IV-

28, glacial HOAc, 95° C, 48%.

140

Scheme IV-12. Unsuccessful Preparation of a Yohimbine Analog.

o
\ NH 1 \ N
------ ->
N \ C02Et O N \ .
Ho
0151
IV-41 IV-45

 

Reaction Conditions. 1) l-cyclohexen-l-carboxylic acid, DPPA,
MeCN, 24 h or sodium 1-cyclohexen-1-carboxylate, C1C02Et,

THF, 24 h.

Conclusions.

Comparing with previously reported methods, 2'3 a broad variety of substrates has
been constructed using the aza-annulation methodology. Enamino esters have been
prepared as the starting materials for the aza-annulation reaction. Bischler cyclization
proceeded well only with sufficiently activating substituents on the aromatic ring.
Unsubstituted aromatic B-ester amides generated enamino ester products only in low
yields. The presence of a halogen substituent on the aromatic ring caused deactivation
of the system to the electrophilic aromatic substitution, and alternative methods for the
preparation of the desired substrates had to be sought. A chloro substituted ester
enamine was prepared from 6-chloro-1-indanone derivative, and was then transformed
into the desired product by Schmidt rearrangement, formation of a thiolactam, and

Eschenmoser sulfide extrusion. The best method for the synthesis of enamino esters

141

has been found to be via preparation of a thiolactam intermediate directly from the
corresponding amine compound and its isothiocyanate derivative.

The enamino esters have been used in aza-annulation reactions, generating a wide
variety of the products, and thus providing more evidence for the versatility of this

methodology.

142

EXPERIMENTAL RESULTS.

General Methods. All reactions were carried out performing standard inert atmosphere
techniques to exclude moisture and oxygen, and reactions were performed under an
atmosphere of nitrogen or argon. 2-acetamidoacrylic acid was purchased from Aldrich,
and used without purification. Sodium acrylate was either freshly made before reaction
by reaction of acrylic acid and NaH in dry THF at -78° C or purchased directly from
Aldrich. Azeotropic removal of water was assisted by the use of 4—A molecular sieves in
the modified Dean-Stark adapter.18 Concentration of solutions after work up was
performed by rotary evaporator Buchi. Flash column chromatography was performed
using Si02 of 230-400 mesh. Reactions were monitored by TLC using Whatman K6F
Silica Gel 60A 250 um thickness plates.

IR spectra were recorded using a Nicolet 42 FT-IR instrument, 1H NMR spectra
are reported as follows : chemical shift relative to residual CHC13 (7.24 ppm) or TMS
(0.0 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling, and integration. 13C NMR data are reported as chemical shifts relative to CDC13
(77.00 ppm). High resolution mass spectra were carried out on a JEOL AX-505 double-

focusing mass spectrometer (BI).

Preparation of 4-Chlorocinnamic Acid IV-20 :

To a mixture of 20.0 g (142.3 mmol) of 4-chlorobenzaldehyde and 16.4 g (157.9 mmol)
of malonic acid dissolved in 50 mL of DMSO was added 2.0 mL of piperidine. After an
initial exothermic reaction subsided, the mixture was heated at (85-90)° C for 10 hours.

The mixture was then poured on 500 g of ice and the resulting slurry was acidified with 5

143

M HCl (indicated by a litmus paper). After the ice melted, the mixture was filtered and
the solid was washed repeatedly with water. The product was recrystallized from ethyl

alcohol. Yield: 22.8 g (87%).

Preparation of 6-Chloroindan-l-one IV-22:

a) 4-Chlorocinnamic acid (25.0 g, 136.9 mmol) was shaken under 75-80 psi of hydrogen
over 10% Pd/C (1.95 g) in 150 mL of dioxan for 14 hours. The filtered solution was
evaporated and the residue was crystallized from ethyl alcohol to yield [34-
chloropropionic acid. Yield : 24.8 g (98.1%).

b) B-4-Ch10ropropionic acid (20.0 g, 108.3 mmol) was rapidly added to well stirred
sulfuric acid (375 . g, 200 mL) at (175-180)° C, after 30 seconds the solution was
poured onto ice (150 g). The precipitated product was crystallized from ethyl alcohol.
Yield : 11.5 g (64%).

IV-22: ( 2.89 g, 17.32 mmol, 64% yield) 1H NMR (300 MHz, CDC13) 5 2.68-2.74 (m,

2H), 3.07-3.13 (m, 2H), 7.41 (d, J=8.2 Hz, 1H), 7.52 (dd, J=2.0, 8.2 Hz, 1H), 7.68 (d,

J=2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) 5 25.4, 36.6, 123.4, 127.8, 133.6, 134.5,

138.5, 153.1, 205.4; IR (CHC13) 3393, 3052, 3021, 2965, 2936, 1709, 1597, 1466, 1443,

1258,1194, 1115, 1038 cm".

Preparation of 7-Chloro-3,4-Dihydro-2H-Isoquinolin-l-one IV-23 - Schmidt
rearrangement:
Sodium azide (1.28 g, 19.7 mmol, 1.1 equiv.) was added to a mixture of 6-chloroindan-1-

one (2.98 g, 17.9 mmol) and molten trichloroacetic acid (29.2 g, 178.9 mmol, 10 equiv.)

144

at 65° C and stirring was continued for 4 hours. The solution was then cooled, diluted
with ice water, neutralized with sodium bicarbonate, and extracted with chloroform.
Organic layers dried over sodium sulfate, filtered, concentrated and purified by flash
column chromatography (gradient diethyl ether:petroleum ether/ 1:1-diethyl ether-diethyl
ether:petroleum etherzmethyl alcohol/90:5:5). Yield : 1.38 g (43%) (70% based on the

recovery of the starting material). Yield of lactam regioisomer : 15%.

IV-23: (gradient diethyl ether:petroleum ether/ 1:1-diethyl ether:petroleum ether:methyl
alcohol/90:5:5, 0.54 g, 2.97 mmol, 62% yield based on recovery of 1.46 g of the starting
material); m.p. = (151-152)° c; 1H NMR (300 MHz, CDCl3) d 2.96 (1, J=6.6 Hz, 2H),
3.56 (dd, J=1.8, 6.6 Hz, 1H), 3.58 (dd, J=1.8, 6.6 Hz, 1H), 7.15 (bs, 1H), 7.40 (dd, J=2.4,
8.1 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 25.3, 36.5, 123.4,

127.8, 133.6, 134.5, 138.4, 153.1, 205.4.

General Procedure for Preparation of Thiolactams with Lawesson's Reagent :

The mixture of 1.5 equiv. of a lactam and 1.0 equiv. of 2,4—bis(4-methoxyphenyl)-1,3-
dithia-2,4-diphosphetane—2,4-disulfide (Lawesson's reagent) in toluene ( 0.1 M) was
heated to reflux for 1 hour, concentrated under reduced pressure and purified by flash

column chromatography if necessary.

General Method for Eschenmoser Sulfide Contraction:
The thiolactam (1.0 equiv.) and ethylbromoacetate (1.2 equiv.) were stirred in diethyl

ether ( 0.3 M) for 24-36 hours. The solvent was evaporated and the thionium salt was

145

dissolved in acetonitrile ( 0.3 M). Triethylamine (1.5 equiv.) was added and the mixture
was stirred at room temperature for 15 minutes. Triphenylphosphine (1.2 equiv.) was
added and the mixture was allowed to stir for 15 minutes. Triethylamine (1.5 equiv.) was
added again and the solution was heated to reflux for 40-70 hours. Dark brown mixture
was concentrated and the crude product was purified by flash column chromatography
(eluent as indicated).

IV-10: ( 0.80 g, 3.18 mmol, 78% yield) 1H NMR (300 MHz, CDCl3) 5 1.22 (t, J=7.2 Hz,
3H), 2.78 (t, J=6.3 Hz, 2H), 3.32 (dd, J=3.3, 6.3 Hz, 1H), 3.34 (dd, J=3.00, 6.0 Hz, 1H),
4.08 (q, =7.2 Hz, 2H), 5.04 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.22 (m, 1H), 7.56 (d, J=2.4
Hz, 1H), 8.91 (bs, 1H); 13C NMR (75 MHz, CDC13) 5 14.5, 28.5, 38.6, 58.7, 78.9, 125.2,
154.6, 171.0; IR (CHC13) 3299, 2979, 1649, 1609, 1560, 1480, 1300, 1266, 1177, 1038
cm". HRMS calcd for C13H14N02C1 m/z 251.0713, obsd m/z 251.0709 .

IV-29: (ethyl acetate:hexane/2:l, 0.29 g, 1.05 mmol, 77% yield); lH NMR (300 MHz,
CDCl3) 5 1.26 (t, J=7.2 Hz, 3H), 2.78 (t, J=6.5 Hz, 2H), 3.38 (dt, J=3.0, 6.00 Hz, 2H),
3.84 (s, 3H), 3.86 (s, 3H), 4.12 (q, J=7.2 Hz, 2H), 5.01 (s, 1H), 6.61 (s, 1H), 7.08 (s, 1H),
9.00 (bs, 111)); 13c NMR (75 MHz, CDC13) 8 14.6, 28.4, 38.8, 55.8, 58.4, 76.8, 107.9,
110.5, 121.4, 129.8, 147.6, 150.9, 156.2, 171.0; IR (CHC13) 3299, 3019, 2977, 2940,
2838, 1647, 1601, 1572, 1499, 1464, 1341, 1281, 1262, 1177, 1121, 1057 cm"; HRMS
calcd for C15H19N04 m/z 277.1314, obsd m/z 277.1317.

IV-35: (diethyl ether:petroleum ether/ 1:2, 0.10 g, 0.46 mmol, 10% yield); lH NMR (300
MHz, CDCl3) 5 1.30 (t, J=7.2 Hz, 3H), 2.90 (t, J=6.3 Hz, 2H), 3.42 (dd, J=3.5, 6.5 Hz,
1H), 3.44 (dd, J=3.5, 6.2 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 5.16 (s, 1H), 7.15—7.39 (m,

3H), 7.66 (d, J=8.1 Hz, 1H), 9.05 (bs, 1H); '3 C NMR (75 MHz, CDC13) 5 14.6, 29.0,

146

38.7, 58.6, 78.1, 125.2, 126.9, 128.2, 129.5, 130.3, 136.4, 156.1, 171.2; IR 3299, 2979,
2953, 1710, 1648, 1602, 1484, 1305, 1266, 1178, 1034 cm"; HRMS calcd for C13H15N02
m/z 217.1103, obsd (M+1) m/z 218.1182.

IV-4l: (diethyl ether:petroleum ether/ 1:2, 1.70 g, 6.63 mmol, 77% yield); 1H NMR (300
MHz, CDC13) 5 1.22 (t, J=7.2 Hz, 3H), 2.87-2.96 (m, 2H), 3.44-3.53 (m, 2H), 4.11 (q,
J=7.2 Hz, 2H), 4.84 (s, 1H), 7.03-7.11 (m, 1H), 7.17-7.24 (m, 1H), 7.27-7.33 (m, 1H),
7.47-7.53 (m, 1H), 8.13 (bs, 1H), 8.22 (bs, 1H); 13(2 NMR (75 MHz, CDCl3) 8 14.6, 20.7,
40.5, 58.8, 77.6, 111.6, 116.1, 119.5, 120.3, 124.6, 126.2, 127.7, 137.1, 150.5, 170.6; 1R
(CHC13) 3328, 2930, 1640, 1605, 1538, 1273, 1175, 1132, 1038 cm'l; HRMS calcd for
ClsHmNzOz m/z 256.1212, obsd m/z 256.1220.

IV-38: (diethyl ether:petroleum ether/ 1:2, 0.12 g, 0.54 mmol, 91% yield); 1H NMR (300
MHz, CDCl3) 5 1.22 (t, J=7.2 Hz, 3H), 2.76-2.83 (m, 2H), 3.38-3.45 (m, 2H), 4.08 (q,
J=7.2 Hz, 2H), 4.89 (s, 1H), 6.82 (d, J=5.1 Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 8.39 (bs,
1H); 13C NMR (75 MHz, CDCl3) 5 14.6, 25.0, 39.9, 58.7, 79.3, 127.4, 127.5, 130.9,
140.2, 152.6, 170.7; IR (CHC13) 3314, 2979, 2938, 2901, 2857, 1734, 1649, 1603, 1530,
1495, 1439, 1368, 1285, 1167, 1129, 1051 cm"; HRMS calcd for C11H13N02S m/z

223.0667, obsd m/z 223.0658.

Hydrogenolysis of 3-Thiopheneacetonitrile:

The slurry of 3-thiopheneacetonitrile (3.0 g, 24.35 mmol), 2.2 g of 50% suspension of
Ra—Ni in water in methyl alcohol with 10 drops of saturated solution of ammonium
hydroxide was kept in atmospheric pressure of hydrogen for 24-30 hours at room

temperature. Then the mixture was carefully filtered and concentrated under reduced

147

pressure. The crude product was purified by flash column chromatography (diethyl
ether:petroleum ether/2:1). Yield : 2.0 g (65%). The crude product was pure enough to be

used for the next step without further purification.

Preparation of 2-Phenylacrylic acid:

a-Bromostyrene (1.0 g, 5.46 mmol) was added dropwise to the mixture of n-BuLi in
diethyl ether at -(35-40)° C. After 10 minutes a solution was poured onto an excess of dry
ice and warmed to room temperature. 100 mL of water was added and an emulsion was
acidified by diluted HCl to pH 2-3 (indicated by a litmus paper). Recrystallized from 80%
ethyl alcohol or purified by flash column chromatography (diethyl ether:petroleum

ether/1:1). Yield : 0.65 g (80%).

General Procedure for Aza-Annulation Reactions of Enanrino Esters :

A solution of mixed anhydride of a corresponding derivative of acrylic acid (freshly
prepared from a corresponding acrylic acid, NaH and ethyl chloroformate in THF at -78°
C) was added to the enamine solution in THF at room temperature and the reaction
mixture was allowed to stir at room temperature for 12-18 hours. Reactions were
quenched by the addition of H20, and the mixture was extracted 4 times with 20 mL of
either 320 or EtOAc. The combined organic fractions were dried (Na2804), filtered, and
the solvent evaporated under reduced pressure. The crude product was purified by flash
column chromatography (eluent as indicated). (The concentrated crude product may be

purified directly by flash column chromatography).

148

IV-26: ( diethyl ether:petroleum ether/ 1:1, 0.045 g, 0.15 mmol, 68% yield); 1H NMR
(300 MHz, CDCl3) 5 1.06 (t, J=7.2 Hz, 3H), 2.52-2.60 (m, 2H), 2.65-2.74 (m, 2H), 2.78
(t, J=6.2 Hz, 2H), 3.67 (t, J=5.9 Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.23 (m, 1H), 7.29 (d,
J=1.8 Hz, 1H); 13(3 NMR (75 MHz, CDC13) 5 13.7, 21.7, 28.3, 307,400, 61.0, 110.5.
128.1, 129.5, 129.5, 131.4, 131.9, 135.4, 140.8, 168.1, 169.8; IR 3416, 2980, 2882, 1671
(broad), 1613, 1372, 1300, 1188 cm"; HRMS calcd for CI6H16NO3C1 m/z 305.0819,
obsd m/z 305.0776 .

IV-9: (diethyl ether:petroleum ether/1:1, 0.12 g, 0.32 mmol, 81% yield) m.p. = (189-
190)° C; 1H NMR (300 MHz, CDC13) 5 1.05 (t, J=7.2 Hz, 3H), 2.78-2.85 (m, 2H), 2.98
(dd, J=8.9, 17.7 Hz, 1H), 3.06 (dd, J=7.1, 17.7 Hz, 1H), 3.63-3.80 (m, 3H), 4.06 (q, J=7.2
Hz, 2H), 7.06-7.32 (m, 8H); 13C NMR (75 MHz, CDC13) 5 13.7, 28.4, 28.9, 40.2, 45.6.
61.1, 109.9, 127.3, 127.9, 128.0, 128.6, 129.5, 129.6, 131.4, 131.8, 135.4, 137.4, 140.7,
167.8, 170.3; IR (CHC13) 3019, 1690, 1671, 1377 cm"; HRMS calcd for C22H20N03 m/z
381.1132, obsd m/z 381.1111.

IV-8: ( 0.08 g, 0.20 mmol, 81% yield) 1H NMR (300 MHz, CDC13) d 1.16 (t, J=7.2 Hz,
3H), 2.89-2.97 (m, 2H), 4.21 (q, J=7.2 Hz, 2H), 4.15-4.24 (m, 2H), 7.18-7.40 (m, 6H),
7.64-7.70 (m, 2H), 7.85 (s, 1H); 13C NMR (75 MHz, CDCl3) d 13.8, 28.0, 40.8, 61.7,
110.8, 128.2, 128.5, 128.6, 129.2, 129.7, 130.1, 130.7, 131.9, 135.8, 135.9, 137.6, 143.8,
160.7, 167.6; IR (CHC13) 2928, 1711, 1647, 1534, 1250, 1109 cm"; HRMS calcd for
C22H13N03 m/z 379.0975, obsd m/z 379.0978.

IV-27: ( 0.09 g, 0.25 mmol, 84% yield based on recovery of the 0.126 g of the starting
ester enamine) 1H NMR (300 MHz, CDC13) 5 1.10 (t, J=7.2 Hz, 3H), 2.02 (s, 3H, 2.28

(dd, J=15.3, 16.5 Hz, 1H), 2.75-2.85 (m, 2H), 3.08 (m, 1H), 3.48 (dd, J=6.9, 17.1 Hz,

149

1H), 3.97-4.16 (m, 2H), 4.32 (ddd, J=3.8, 3.8, 12.6 Hz, 1H), 4.50 (ddd, J=6.6, 6.6, 14.7
Hz, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.24 (dd, J=1.8, 8.1 Hz, 1H),
7.37 (d, J=1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) 5 13.7, 23.2, 28.1, 28.1, 40.3, 48.5,
61.2, 110.2, 128.0, 129.9, 129.9, 131.3, 131.5, 135.1, 140.4, 166.6, 168.3, 170.3; IR
(CHC13) 3341, 3017, 1686 (broad), 1543, 1387, 1312, 1258 cm"; HRMS calcd for
C13H19C1N204 m/z 362.1033, obsd m/z 362.1033 .

1V-30: (diethyl ether:petroleum ether/1:1, 0.25 g, 0.61 mmol, 76% yield); ‘H NMR (300
MHz, CDC13) 5 1.12 (t, J=7.2 Hz, 3H), 2.83 (m, 2H), 2.99 (dd, J=10.2, 17.1 Hz, 1H),
3.10 (dd, J=6.6, 17.4 Hz, 1H), 3.66 (m, 1H), 3.76-3.93 (m, 2H), 3.80 (s, 3H), 3.90 (s,
3H), 4.10 (q, J=7.2 Hz, 2H), 6.69 (s, 1H), 6.88 (s, 1H), 7.21-7.38 (m, 5H); l3C NMR (75
MHz, CDC13) 5 13.9, 28.3, 29.3, 40.0, 45.8, 55.8, 56.0, 60.6, 107.2, 109.4, 113.0, 122.2,
127.1, 128.0, 128.4, 130.4, 137.9, 142.0, 146.6, 150.4, 168.3, 170.5; 1R (CHC13) 3031,
3006, 2977, 2940, 1690, 1661, 1605, 1512, 1486, 1377, 1347, 1279, 1242, 1134, 1044
cm"; HRMS calcd for C24H25N05 m/z 407.1733, obsd m/z 407.1727.

IV-3l: ( diethyl ether:petroleum ether/4:1, 0.08 g, 0.20 mmol, 81% yield) ‘H NMR (300
MHz, CDC13) 5 1.23 (t, J=7.2 Hz, 3H), 2.85-3.00 (m, 2H), 3.84 (s, 3H), 3.96 (s, 3H),
4.18-4.30 (m, 2H), 4.25 (q, J=7.2 Hz, 2H), 6.79 (s, 1H), 6.94 (s, 1H), 7.30-7.46 (m, 3H),
7.69-7.75 (m, 2H), 7.89 (s, 1H); 13C NMR (75 MHz, CDC13) 5 14.0, 28.0, 40.6, 56.0,
56.1, 61.3, 109.3, 109.7, 112.9, 120.6, 127.4, 127.8, 128.1, 128.6, 131.3, 136.3, 127.7,
145.4, 147.2, 151.6, 160.8, 168.1; IR (CHC13) 3019, 1703, 1640, 1507 cm"; HRMS calcd
for C24H23N05 m/z 405.1577, obsd m/z 405.1584.

IV-33: (diethyl ether:petroleum ether/4:1, 0.04 g, 0.09 mmol, 25% yield); m.p. = (195-

196)° C (sealed), (decomp.); 1H NMR (300 MHz, CDC13) 5 1.22 (t, J=7.2 Hz, 3H), 2.85-

150

2.92 (m, 2H), 3.77 (s, 3H), 3.88 (s, 3H), 4.15424 (m, 2H), 4.22 (q, J=7.2 Hz, 2H), 6.70
(s, 1H), 6.87 (s, 1H), 7.38-7.44 (m, 3H), 7.84-7.92 (m, 2H), 8.83 (s, 1H), 9.11 (s, 1H); 13C
NMR (75 MHz, CDCl3) 5 14.1, 27.9, 41.2, 56.1, 61.6, 109.9, 110.4, 112.3, 120.4, 122.4,
126.1, 127.2, 128.8, 130.2, 132.1, 134.1, 138.5, 147.4, 151.1, 157.1, 165.7, 168.1; IR
(CHC13) 3376, 3019, 2957, 1722, 1707, 1646, 1609, 1505, 1489, 1300, 1279, 1239 cm";
HRMS calcd for C25H24N205 m/z 448.1634, obsd m/z 448.1628.

IV-32: (diethyl ether:petroleum etherzmethyl alcohol/90:5:5, 0.09 g, 0.23 mmol, 29%
yield); m.p. = (189-190)° C; 1H NMR (300 MHz, CDC13) 5 1.15 (t, J=7.2 Hz, 3H), 2.06
(s, 3H), 2.30 (dd, J=15.0, 16.5 Hz, 1H), 2.71-2.93 (m, 2H), 3.16 (ddd, J=4.8, 11.6, 11.9
Hz, 1H), 3.49 (dd, J=6.9, 16.8 Hz, 1H), 3.81 (s, 3H), 3.88 (s, 3H), 4.00-4.16 (m, 2H),
4.30 (ddd, J=4.2, 4.2, 12.6 Hz, 1H), 4.54 (ddd, J=6.3, 6.3, 15.3 Hz, 1H), 6.58 (d, J=5.4
Hz, 1H), 6.66 (s, 1H), 6.96 (s, 1H); 13C NMR (75 MHz, CDC13) 5 13.9, 23.1, 28.0, 28.1,
40.1, 48.6, 55.8, 55.9, 60.7, 107.5, 1092,1132, 121.7, 129.9, 141.9, 146.6, 150.5, 167.0,
168.6, 170.3; IR 3320, 3017,2940, 1676 (broad), 1512, 1385, 1277, 1258, 1115 cm";
HRMS calcd for C20H24N206 m/z 388.1635, obsd (M+l) m/z 389.1713.

IV-36: (diethyl ether:petroleum ether/ 1:1, 0.06 g, 0.18 mmol, 69% yield); 1H NMR (300
MHz, CDCl3) 5 1.01 (t, J=7.2 Hz, 3H), 2.80-2.87 (m, 2H), 2.98 (dd, J=9.3, 17.4 Hz, 1H),
3.05 (dd, J=6.9, 17.4 Hz, 1H), 3.62-3.82 (m, 3H), 4.01 (q, J=7.2 Hz, 2H), 7.08-7.31 (m,
9H); 13C NMR (75 MHz, CDC13) 5 13.7, 28.8, 28.9, 40.2, 45.7, 60.8, 108.9, 125.8, 126.7,
127.2, 128.0, 128.5, 129.6, 129.8, 130.3, 137.0, 137.7, 142.1, 168.2, 170.5;1R(CHC13)
3017, 1674 (broad), 1381, 1306, 1237, 1169 cm"; HRMS calcd for C22H21N03 m/z

347.1522, obsd m/z 347.1525.

151

IV-37: (diethyl ether:petroleum ether/ 1:1, 0.04 g, 0.13 mmol, 79% yield); m.p. = (145-
146)° C, (sealed); 1H NMR (300 MHz, CDCl3) 5 1.18 (t, J=7.2 Hz, 3H), 2.99 (m, 2H),
4.23 (q, J=7.2 Hz, 2H), 4.21-4.30 (m, 2H), 7.24-7.48 (m, 7H), 7.72-7.77 (m, 2H), 7.92 (s,
1H); 13C NMR (75 MHz, CDC13) 5 13.8, 28.4, 40.7, 61.4, 110.3, 126.2, 127.2, 127.9,
128.2, 128.3, 128.5, 128.6, 129.8, 131.0, 136.2, 137.4, 137.7, 145.4, 160.8, 168.0; IR
(CHC13) 3007, 1709, 1647, 1534, 1298, 1252, 1107 cm"; HRMS calcd for C22H19N03
m/z 345.1365, obsd m/z 345.1359.

IV-42: (diethyl ether:petroleum ether/1:2, 0.4 g, 1.04 mmol, 89%); mp. = (145-146)° C
(sealed) (decomp.); 1H NMR (300 MHz, CDCl3) 5 1.26 ( t, J=7.2 Hz, 3H), 2.89-2.96 (m,
2H), 3.02-3.09 (m, 2H), 3.67 (m, 1H), 4.00 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.53 (m,
1H), 7.04 (m, 1H), 7.13-7.29 (m, 7H), 7.36 (d, J=8.1 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H),
12.16 (bs, 1H); 13C NMR (75 MHz, CDC13) 5 14.2, 21.1, 29.5, 41.7, 46.4, 61.4, 105.8,
112.2, 119.4, 120.0, 124.9, 125.1, 126.1, 127.3, 128.0, 128.6, 136.7, 137.5, 141.0, 168.6,
171.4; IR (CHC13) 3247, 3015, 2932, 1671, 1576, 1368, 1283, 1167, 1130, 1034 cm";
HRMS calcd for C24H22N203 m/z 386.1631, obsd m/z 386.1636 .

IV-43: (gradient diethyl ether:petroleum ether/1:2-diethyl ether-ethyl acetate; 0.25 g,
0.68 mmol, 58% yield), lH NMR (300 MHz, CDCl3) 5 1.37 (t, J=7.2 Hz, 3H), 2.08 (s,
3H), 2.38 (dd, J=15.6 Hz, 1H), 2.90-3.03 (m, 2H), 3.30 (m, 1H), 3.60 (dd, J=5.7, 16.2
Hz, 1H), 4.23-4.38 (m, 2H), 4.45 (ddd, J=5.7, 5.7, 14.7 Hz, 1H), 5.23 (ddd, J=3.3, 3.3,
11.7 Hz, 1H), 6.67 (d, J=5.4 Hz, 1H), 7.12 (m, 1H), 7.29 (m, 1H), 7.43 (d, J=8.1 Hz, 1H),
7.54 (d, J=7.8 Hz, 1H), 12.20 (s, 111); 13.c NMR (75 MHz, CDCl3) 5 14.1, 21.0, 23.2,

28.6, 42.1, 48.8, 61.6, 105.4, 112.2, 117.9, 119.4, 120.0, 124.7, 125.2, 125.6, 136.7,

152

139.9, 168.3, 169.5, 170.2; IR (CHC13) 3283, 3011, 1667, 1574, 1516, 1391, 1256, 1169,

1109, 1034 cm'l; HRMS calcd for C20H21N3O4 m/z 367.1532, obsd m/z 367.1590 .

IV-44: (diethyl ether:petroleum ether/1:2, 0.29 g, 0.75 mmol, 48% yield); m.p. = (165-
166)° C (sealed) (decomp.); 1H NMR (300 MHz, CDC13) 5 1.44 (t, J=7.2 Hz, 3H), 3.07
(m, 2H), 4.45 (q, J=7.2 Hz, 2H), 4.60—4.67 (m, 2H), 7.18 (m, 1H), 7.30-7.51 (m, 5H),
7.63 (d, J=7.8 Hz, 1H), 7.73-7.79 (m, 2H), 8.13 (s, 1H), 11.75 (s, 1H); I3C NMR (75
MHz, CDC13) 5 14.2, 19.4, 42.5, 62.1, 106.0, 112.3, 118.9, 119.6, 120.3, 124.3, 125.5,
126.2, 127.2, 127.8, 128.1, 128.5, 136.4, 137.3, 138.3, 142.0, 161.2, 168.1; IR (CHC13)
3297, 3011, 1696, 1644, 1541, 1495, 1447, 1372, 1339, 1264, 1233, 1188, 1164, 1119
cm"; HRMS calcd for C24H20N203 m/z 384.1474, obsd m/z 384.1485.

IV-39: (diethyl ether:petroleum ether/ 1:2, 0.03 g, 0.09 mmol, 64%); 1H NMR (300 MHz,
CDCl3) 5 1.25 (t, J=7.2 Hz, 3H), 2.75-2.82 (m, 2H), 2.94 (d, J=8.4 Hz, 2H), 3.70 (dd,
J=8.7, 8.7 Hz, 1H), 3.79 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.26 (m, 1H), 6.78 (d, J=5.4
Hz, 1H), 7.16-7.31 (m, 6H); 13C NMR (75 MHz, CDC13) 5 14.1, 25.7, 29.9, 40.1, 46.3,
61.2, 107.0, 126.2, 127.3, 127.7, 128.1, 128.6, 129.0, 1137.4, 137.7, 141.5, 167.9, 170.9;
IR (CHC13) 3013, 2932, 1706, 1680, 1377, 1239, 1153, 1129 cm"; HRMS calcd for
C20H19N038 m/z 353.1086, obsd 353.1096.

IV-40: (gradient diethyl ether:petroleum ether/ 1: l-2:1-diethyl ether-ethyl acetate, 0.026
g, 0.074 mmol, 97% yield) 1H NMR (300 MHz, CDCl3) 5 1.30 (t, J=7.2 Hz, 3H), 2.90-
2.97 (m, 2H), 4.32 (q, J=7.2 Hz, 2H), 4.32-4.40 (m, 2H), 6.90 (d, J=5.4 Hz, 1H), 7.24-
7.39 (m, 3H), 7.43 (d, J=5.4 Hz, 1H), 7.61-7.70 (m, 2H), 7.72 (s, 1H); l3’c NMR (75

MHz, CDC13) 5 14.1, 24.0, 41.2, 61.8, 77.2, 108.6, 125.9, 127.9, 128.0, 128.2, 128.6,

153

130.7, 136.2, 137.1, 140.5, 142.6, 160.9, 167.1; IR (CHC13) 3013, 2930, 1713, 1644,

1538, 1240, 1132 cm'l; HRMS calcd for C20H17NO3S m/z 351.0929, obsd m/z 353.0925.

Preparation of Ethyl 3-(N,N-Dimethylamino)-2-pheny1propenoate :19

A mixture of 1.04 g (6.3 mmol) of ethyl phenyl acetate and 1.29 g (9.75 mmol, 1.6
equiv.) of bis(methoxy)dimethylaminomethane was stirred at 60° C for 48 hours. The
reaction mixture was concentrated under reduced pressure and then bulb-to-bulb distilled
(oven: (80-85)° C, pressure: 1mm of Hg) to afford 0.71 g of the product as a residue

(51%).

Preparation of Ethyl Potassium Malonate :20

KOH (5.6 g, 100 mmol) was dissolved in 100 mL of absolute ethyl alcohol and the
solution was added dropwise to a stirred solution of diethylmalonate (20.23 g, 100 mmol)
in 100 mL of absolute ethyl alcohol, at 0° C during 1 hour. The reaction mixture was then
allowed to warm up to room temperature and the stirring was continued for an additional
1 hour. The white crystals of the salt were separated by filtration and dried under vacuum.

Yield: 11.4 g (67%).

Preparation of Ethyl Malonyl Chloride :2°

Oxaloyl chloride (3.2 g, 25 mmol) in 10 mL of dry benzene was added dropwise to a
stirred suspension of ethyl potassium malonate (2.42 g, 20 mmol) in 50 mL of dried
benzene at 0° C during 1 hour. After the solution had been stirred at room temperature for

1 hour, the solid residue was removed by filtration and the filtrate was concentrated under

154

reduced pressure, diluted with dry dichloromethane and concentrated again. The product

used immediately for the next step without further purification.

General Procedure for the Preparation of Ester Amides.

To suspension of ethyl potassium malonate (1.65 equiv.) in dry benzene was added
oxalyl chloride (2.1 equiv.) in benzene dropwise at 0° C during a period 50 minutes
and the mixture was stirred for 1 hour at 0° C. Then the mixture was gradually
warmed to the room temperature mand stirring was continued for 1 additional hour.
The solution was filtered and concentrated under reduced pressure, diluted with
CH2C12 and concentrated again. The residue was dissolved in CH2C12 and added by a
cannula to a solution of a primary amine (1.0 equiv.) and triethylamine (1 equiv., in
the case of hydrochloride 2 equiv.) in CH2C12 at 0° C. The mixture was stirred for 12-

20 hours at the room temperature, then neutralized with 3M HCl, extracted with
CH2C12, organic layers dried over Na2804. Concentrated and the crude product
crystallized or purified by the flash column chromatography.

IV-ll: (6.2 g, 28.8 mmol, 66% yield); 1H NMR (300 MHz, CDCl3) 5 1.13 (t, J=7.2 Hz,
3H), 2.67 (t, J=7.1 Hz, 2H), 3.12 (s, 2H), 3.32 ( d, J=7.2 Hz, 1H), 3.37 (d, J=7.2 Hz, 1H),
4.03 (q, J=7.2 Hz, 2H), 6.98-7.04 (m, 2H), 7.09-7.15 (m, 2H), 7.33 (bt, J=7.1 Hz, 1H);
13C NMR (75 MHz, CDC13) 5 13.7, 34.4, 40.3, 41.3, 61.0, 128.2, 129.8, 131.7, 137.1,
165.1, 168.5; IR (CHC13) 3291, 2984, 2940, 1740, 1651, 1555, 1493, 1370, 1339, 1196,
1157, 1092,1032, 1017 cm".

IV-l3: (ethyl acetate:hexanel4zl, 2.40 g, 8.13 mmol, 49% yield); 1H NMR (300 MHz,

CDCl3) 5 1.18 (t, J=7.2 Hz, 3H), 2.71 (m, 2H), 3.19 (s, 2H), 3.39-3.44 (m, 2H), 3.77 (s,

155

3H), 3.79 (s, 3H), 4.08 (q, J=7.2 Hz, 2H), 6.63-6.76 (m, 3H), 7.15 (bt, J=7.2 Hz, 1H); ”C
NMR (75 MHz, CDCl3) 5 13.7, 34.8, 40.7, 41.1, 55.5, 55.6, 61.2, 111.1, 111.7, 120.3,
131.1, 147.3, 148.7, 164.8, 169.0; IR (CHC13) 3312, 2938, 1740, 1655, 1516, 1264, 1239,
1157, 1144, 1028 cm".

IV-lS: (3.5 g, 14.9 mmol, 36% yield); 1H NMR (300 MHz, CDC13) 5 1.17 (t, J=7.2 Hz,
3H), 2.75 (m, 2H), 3.17 (s, 2H), 3.42 (m, 2H), 4.06 (q, J=7.2 Hz, 2H), 7.08-7.24 (m, 5H),
7.41 (bt, J-5.7 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 13.5, 35.0, 40.5, 41.3, 60.8, 125.9,
128.0, 128.2, 138.4, 165.1, 168.3; IR (CHC13) 3299, 2982,2938, 1740, 1653, 1555, 1370,
1337, 1192, 1157 cm"; HRMS calcd for C13H17NO3 m/z 235.1209, obsd m/z 235.1214.
IV-l6: (ethyl acetatezpetroleum ether/6:1, 2.52 g, 9.0 mmol, 43% yield); 1H NMR (300
MHz, CDC13) 5 1.19 (t, J=7.2 Hz, 3H), 2.86-2.93 (m, 2H), 3.22 (s, 2H), 3.51 (dd, J=7.1,
13.1, 2H), 4.10 (q, J=7.2 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H), 7.32 (bs, 1H), 8.06 (d, J=8.7
Hz, 2H); 13C NMR (75 MHz, CDCl3) 5 13.8, 35.2, 40.0, 40.9, 61.4, 123.5, 129.5, 146.4,
146.6, 165.4, 169.0; IR (CHC13) 3264, 2986, 1744, 1638, 1559, 1520, 1372, 1347, 1194
cm"; HRMS calcd for C13H16N205 m/z 280.1059, obsd m/z 280.1053.

IV-l7: (1.72 g, 6.87 mmol, 100% yield) II-I NMR (300 MHz, CDCl3) 5 1.25 (t, J=7.2
Hz, 3H), 2.70 (t, J=7.1 Hz, 2H), 3.24 (s, 2H), 3.44 (d, J=7.2 Hz, 1H), 3.48 (d, J=7.2
Hz, 1H), 3.55 (bs, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.61 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4
Hz, 2H), 7.03 (bs, 1H); l3C NMR (75 MHz, CDC13) 5 13.9, 34.5, 41.0, 41.3, 61.4,
115.2, 128.4, 129.4, 144.8, 164.8, 169.2.

IV-l4: (ethyl acetate:hexane/2zl, 2.23 g, 8.39 mmol, 58% yield); m.p. = (53-54)° C; IH
NMR (300 MHz, CDC13) 5 1.13 (t, J=7.2 Hz, 3H), 2.61-2.70 (m, 2H), 3.13 (s, 2H), 3.30-

3.40 (m, 2H), 3.63 (s, 3H), 4.03 (q, J=7.2 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4

156

Hz, 2H), 7.27 (bt, 1H); 13C NMR (75 MHz, CDCl3) 5 13.6, 34.1, 40.7, 41.3, 54.7, 60.9,
113.4, 129.2, 130.4, 157.7, 165.0, 168.5; IR (CHC13) 3316, 3009, 2938, 1738, 1659,
1514, 1248, 1179, 1034 cm]; HRMS calcd for C14H19N04 m/z 265.1314, obsd m/z
265.1315.

IV-18: (diethyl ether:petroleum ether/3:1, 1.0 g, 3.65 mmol, 29% yield) 1H NMR (300
MHz, CDCl3) 5 1.23 (t, J=7.2 Hz, 3H), 2.98 (t, J=7.1 Hz, 2H), 3.23 (s, 2H), 3.58 (d,
J=6.6 Hz, 1H), 3.62 (d, J=6.6 Hz, 1H), 4.13 (q, =7.2 Hz, 2H), 6.98 (s, 1H), 7.08-7.27
(m, 3H), 7.35 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 8.94 (s, 1H); 13C NMR (75
MHz, CDCl3) 5 13.7, 24.8, 39.8, 41.4, 61.2, 111.2, 111.9, 118.2, 118.8, 121.5, 122.2,
126.9, 136.2, 165.3, 168.7; IR 3397, 3316, 3007, 1732, 1659, 1545, 1458, 1389, 1194,

1159, 1030 cm".

Preparation of the Corresponding (3,4-Dihydro-2H-isoquinolin-1-ylidene) Acetic
Acid Ethyl Ester Derivatives (Bischler-Napieralski Reaction) :

The mixture of the corresponding N-phenethyl-malonamic acid ethyl ester derivative (1.0
equiv.) in acetonitrile (0.14 M) was taken up to reflux and POC13 (6.5 equiv.) was added
at once. The mixture was then heated to reflux for 1-2 hours and then concentrated,
diluted with ethyl acetate and concentrated again. Then diluted with ethyl acetate, washed
with saturated NaHCO3, water layer extracted with ethyl acetate and combined organic
layers were washed with water and dried over Na2804. The crude product was purified by

flash column chromatography (an eluent as indicated).

157

Direct Method for the DDQ Oxidation of Aza-Annulation Products.

A mixture of the aza-annulation product (0.5-20.0 mmol, 1.0 equiv) was taken up in
toluene (0.1 M with respect to the aza—annulation product). After heating at reflux for 10-
18 hours, the solvent was removed under reduced pressure, the residue dissolved in
dichloromethane, filtered through a pad of Celite and the crude product was purified by

flash column chromatography (an eluent as indicated).

General Procedure of Preparation of Isothiocyanates :

A solution of carbon disulfide (1.0 equiv.) in dichloromethane was added dropwise
during 15 minutes to a stirred mixture of an appropriate amine (1.0 equiv.), triethylamine
(1.0 equiv.) and dichloromethane (2.76 M) at 0° C, and the resulting mixture was
allowed to warm slowly to room temperature. The mixture was then cooled to 0° C again,
and ethyl chloroformate (1.0 equiv.) was added dropwise during 15 minutes at this
temperature and the mixture was allowed to warm up slowly to ambient temperature.
Triethylamine (1.0 equiv.) was added and the mixture was stirred for a further 1.5 hour at
room temperature, and finally heated under reflux for 15 minutes. An excess of water was
added and the mixture was made alkaline with 2M NaOH. Extraction with diethyl ether
and concentration under reduced pressure gave the product pure enough to use it without

further purification for the next step.

Cyclization of Isothiocyanates with Polyphosphoric Acid :
The isothiocyanate was stirred with polyphosphoric acid (10 times excess) at 150° C for

1-4 hours and the resultant blood-red mixture was poured into an excess of water. The

158

solution was neutralized with saturated NaHCO3 and extraction with dichloromethane
gave the corresponding product. It was purified by flash column chromatography (an

eluent as indicated).

Cyclization of 2-(4-Chlorophenyl)ethyl Isothiocyanate with Aluminium Chloride :

The 2-(4-chlorophenyl)ethyl isothiocyanate (0.99 g, 5.0 mmol, 1 equiv.) was added
dropwise to a stirred suspension of powdered A1C13 (1.5 g, 11.2 mmol, 2.24 equiv.) in
tetrachloroethane (7.0 mL) at (10-20)° C. The mixture was heated at 110° C for 15-20
minutes and then poured onto a mixture of ice and 5M HCl (5.0 mL). The residue was
filtered off and washed with tetrachloroethane, the combined organic layers were dried
over Nasta, concentrated under reduced pressure, and the product purified by flash
column chromatography (diethyl ether:petroleum ether/2:1). Yield : 2.29 g (58% in 2

steps). (m.p. = (189-190)° C).

General Method for Aza-Annulation with 2-Phenyl-4-(ethoxymethylene)oxazolone.

The corresponding enamine (0.78-2.6 mmol) was dissolved in anhydrous DMF (0.26 M)
and 2-phenyl-4-(ethoxymethylene)oxazolone (1.0 equiv) was added. After the reaction
mixture was heated to reflux for 2 hours, the dark brown solution was concentrated to an
oil (boiling water bath), dissolved in dichloromethane, filtered through a pad of
Celite/S102=1:l (w/w) and purified by flash column chromatography (eluent as

indicated).

LIST OF REFERENCES

10.

11.

12.

13.

14.

15.

16.

159

LIST OF REFERENCES

. Brossi, A. Heterocycles 1978, II, 521.

Fischer, U.; Mohler, H.; Schneider, R; Widmer, U. Helv. Chim. Acta 1990,
73. 763.

Spurr, P.R. Tetrahedron Lett. 1995, 36, 2745.

Larsen, R.D.; Reamer, R.A.; Corley, E.G.; Davis, R; Grabowski, E.J.J.;
Reider, P.J.; Shinkai, I. J. Org. Chem. 1991, 56, 6034.

Kwiecien, H.; Nowicki, R.; Jalowiczor, J.; Bogdal, M.; Krzywosinski, L.;
Przemyk, B. Polish J. Chem. 1991, 65, 2057.

Encyclopedia of Reagents for Organic Synthesis, L.A. Paquette Ed.,
J .Wiley&Sons, 1996, 4166.

Martinez, A.G.; Alvarez, R.M.; Barcina, J.O.; Cerero, S.M.; Vilar, E.T.;
Fraile, A.G.; Hanack, M.; Subramanian, L.R. J. Chem. Soc., Chem. Commun.
1990, 1571.

Jeganathan, S.; Kuila, D.; Srinivasan, M. Synthesis 1980, 469.

Kingsbury, C.A.; Max, G. J. Org. Chem. 1978, 43, 3131.

Bobbitt, J.M.; Katritzky, A.R.; Kennewell, P.D.; Snarey, M. J. Chem. Soc. (B)
1968, 550.

Tomita, M.; Minarni, S.; Uyeo, S. J. Chem. Soc. (C) 1969, 183.
Cava, M.P.; Levinson, M.I. Tetrahedron 1985, 41, 5061.

a) Hart, D.J.; Kanai, K. J. Am. Chem. Soc. 1983, 105, 1255; b) Hart, D.J.;
Hong, W.-P.; Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665.

a) Gittos, M.W.; Robinson, M.R.; Verge, J.P.; Davies, R.V.; Iddon, B.;
Suschitzky, H. J. Chem. Soc. Perkin Trans. 1 1976, 33; b) Davies, R.V.;
Iddon, B.; Paterson, T.McC.; Pickering, M.W.; Suschitzky, H; Gittos, M.W. J.
Chem. Soc. Perkin Trans. 1 1976, 138.

a) Smonou, I; Orfanopoulos, M. Synth. Commun. 1990, 20, 1387; b) Poras, H.;
Stephan, E.; Pourcelot, G.; Cresson, P. Chem. Ind. 1993, 206.

Curtin, D.Y.; Harris, E.E. J. Am. Chem. Soc. 1951, 73,4519.

160

17. a) Lal, B.; Krishnan, L.; deSouza, NJ. Heterocycles 1986, 24, 1977; b)
Danieli, B.; Lesma, G.; Palmisano, G,; Tollari, S. Synthesis 1984, 353.

18. Barta, N.S.; Paulvannan, K.; Schwartz, J.B.; Stille, J .R. Synth. Commun. 1994,
24, 853.

19. Wasserman, H.H.; Ives, J.L. J. Org. Chem. 1985, 50, 3573.

20. Box, V.G.S.; Marinovic, N.; Yiannikouros, G.P. Heterocycles 1991, 32,
245.

APPENDICES

APPENDIX 1

161

Appendix 1. ORTEP Representation of II-69a.

 

APPENDIX 2

162

Appendix 2. ORTEP Representation of III-23c.

C26
C25»)
.-
c24‘~s
C
<19
0 C21 m N
C6 \
020
. O
14.3.. 9, cs,
'2 /
9 i‘ N N” {€12
, C15 c14 C4
C17\’ \3 . Q .
016 019
C1341 C18
. a.)
Et02C\l
HN o
0 \ Me
Me N N
H W
0 Ph

III-23c

APPENDIX 3

163

J. Org. Chem. 1907, Q, 1033-1042 1088

Formation of Dihydropyridone- and Pyridone-Based Peptide
Analogs through Asa-Annulation of fi-Enamino Ester and Amide
Substrates with a-Amido Acrylate Derivatives

Lars G. Beholz, Petr Benovsky, Donald L. Ward, Nancy S. Barta,l and John R. Stille“
WofChsmisuy, Michigan Sam Uniw'sity, EastLansing, Michigan 48824-1322
Rained January 8, 1996 (Revised Hanmipt Ruined November 11, 1996’)

hemmulahonofflananunoutuandanudembehuuswiththemixsdmbydfideof
z-acsumidoamyficaddwuuasdfwtheafidmtcmshmhmofhighlyauhhmuduautamdo
d-lactam products. With the 1).-acetamido subetituent, lactam functionality, and y-carbmlate m,
these d-lsctam products represent an interesting class of conformationally resh'icted dipeptide
analog. Thefiamewmkoftbishctamhubisshuctmllyrdatedmthatofmumaddwuplsd
withafl-aminoacid. Whenu-aminoeetersderivedfimnahirallyoccmingaminoacidswm
medmthemammefinmahonsupmubsequmtmmdahmlsdmbmnchedpephdesum
with two C-tsrmini thatextendedfromacommon N-terminus. Oxidation of the ass-annulation
mdudsmfltedmthegenmhonofaplmsystmwithpephdefimchmhtymdiahngfim
the1,3,and6poeitions.ofthepy1idonebub. Alternahvely,pyridoneproductscouldbeficrmsd
directly fi-om the enamino amides by reaction with 2-pheny1-4—(ethosymsthy1enebxaaolone.
Subsequent hydrolysis of the acetamido and cater substituents of the N-benzylpyridones was
aalsctivelyperfor'medtoaccessuniqueB-aminoacidpmducts. Formationofthemixedanhydride
ofthisaddfoflwedbyanddebmdfmmahmwithtbesduofmuamimadiaflwdutenfion
ofthepeptidechainfi'omthsdihydropyridoneshucture.

Inh-ohehon

Inhibitionofsnsymahcpsthwaysisoneofthsmost
eficientmathodsernployedforthealtsratinnofphysi—
ologicalprocesseswiththeuseofminimalamountsof
pharmacologicalagents. Formanyenzymahcpr'ocesses,
derivativesofaminoacidsareeitherthesubeh-atesor
regulatory molecqu for the catalytic action of the
enzyme. Complexah'on of these amino acid-derived
moleculeswithenzymesisgover-nedbyaspecificcom-
Ia'nationofhydrogenbondeandhydmphobicintemcfions.
Asamulhmolecularrecognitionishighlydspendent
onbotbthstypeoffunctionalgroupspresentandthe
topologyofthepeptide. Animportantclassofsecondary
eh'uctunsofieninvolvedineubeh'aterecognitionand
bindingaretherevsrseturnconformations (1), which
includesuchvar'ietiesarlthefi-andy-tur'ns.1

3..-...)- Ii 1' ’1‘-
HM

Ari-25° retainers;
. . r . I. ll
Reversal-n

Theimportanceofsecondarypephdesh'uctm'einthe
processofmolecularrscognitionbasledtotbash-ategic
design and subsequent synthesis offi-turn mimics.1
These synthetic analogs can be used to examine peptide
fieldingpreceaseeandtoprobepeptideactivityasa
functionofconfilrmahon. Inmcases,thesefragments
can exhibit equivalent or even greater biological activity

 

'DivisinnofOrganicChemishyoftbeAmuicanChemicalSociety
Graduate Peflowahiprsdpienhspcnsorsdbyl’fiaer, Inc., 1998-1994.
address: CbemicalProcs- Prose-ResearchandDevaloprnent.
Elih'llyandCompauy, Indianapolis,lN48285-4813.
'AbshactpubliahsdinAdrmACSAbamJanuaryl,19_97.
(1)Forreviswsonconformahonally

restricted
ase(a)Den‘as, J. S.AminoAa‘dsPept. 1001.22, 145. (b) Liskamp,
REJ.R¢LW.Chi1n.qus-anlm113.1.

thantbenaturalpsphdesubetrate. Anappr'oaebtothe
ccnshuctionofpeptidemimicshaainvolvsdtheprspars—
tion of a-aminosubstitutsd y-, 6-, and e-lactams that

'reshicttheconformationofthewdihedralanglefl, N.

C.—C.--N(.-+n) and apply further constraints on the w
W angle (2, Cg’Cg-N(g+1)-C(¢+1)).u The cyclic

structure provides aframework from which avarietyof

fimch'onal youpscanrsdiate,andspeptide-likeamide
functionalityisanintsgralpartoftheheterocyclethat

‘ contains the peptide B-turn conformation mimic.

Fmtherdevelopmentintheuseofd-lactamsasan
approachtopeptidemimicshasledtotheineor'poration
of conformationally resh'icted dipeptide 6—1actams into
longer peptide sequences. Kemp st 01., were able to
modelthefi-tmntopologythroughtheuaeofatether

.betweentheC. mdQ.+nawmsanddemmshatedthe

presence offurther conformahonal controlthroughin-
h'amolecular hydrogen bonding (8). 3 An alternative
approachwasdevelopedbyheidingeretal,‘who
tetheredtheC.andNu+natomsofdipeptide analogsto
give 4, and a number of confirrmationally restricted
Fmidingerstypeu-aminolactamshavebeenprepaMFor
example,51saninhibitorofangiotensinconverting
snayme(ACE).‘ Thistypeofsh-ucturehasalsobeen

 

(2)Forarsesntrenew of,fi-turntopcgnp1uass:.:3all,JB.
HWRA;Aleweod.P..;P MPWRWMQ

(3)(a)Ksmp,D. 8.; Sun, E. '1‘. mm 1”,”,37594b)
amara,P. WM 14?”, 3761. (c) Kanp,

WW7 000: $14.00 0 1997 American Chemical Society

164

1034 J. Org. Chm, Vol. Q, No. 4, 1997

 

incorporatedintotheframeworkforananalogofPio-
Leu—Gly-Nfig, which serves to modulate the dopaminergic
receptorsinthecentrelnervoussystem,‘andasa
dipeptide isostere for the Phe-His section of aspartic
proteinase substrates. 7

Bicyclic indolizidine structures have been used to
consh-uct conformationally restricted dipeptide models
that contain Pro residues. This conceptual appioach has
been incorporated into the D-Phe-Pio mimic B, which has
been used to examine the peptide folding ofthe type II’
,8-turns present in luteinizing hormone-releasing factor,
human growth hormone-releasing factor, gramicidin S,
Leu-enkephalinamide, and a cyclic somatostatin analog.a
The syntheses of potential Pro-Phe and Ala-Pro type II
fl-turnmimics,’ aswellasthetypeVIturnGif-Pio"
analog7, whichliasbeenincorporatedintobradykinin,m
have also been reported.

43%. @

Similar heterocyclic strategies have hen applied to the
synthesis of mono- and bicyclic pyridone derivatives,
which have played an important role in the development
of bioactive compounds for the inhibition of enzymatic
processes.11 Anumberofrepresentativepyridmederiva-
hves,8,areefl’ecfiveinhibitorsofHIVmerseti-an-
scriptase. 1"“ PyridoneDisapotent(4.6nM), reversible
nonpeptidic inhibitor of human leukocyte elastase

(10), which is an ACE inhibitor for the treatment of

hypertension.“
Ourappioachtotheconsh'uctionofconformationally

reshictedpeptideanalogsandhomologshasutilisedthe

 

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ass-annulation reaction offl-enamino carbonyl substrate
11 with acrylate derivative 12, formed in situ by the
treatment of sodium 2-acetamidoacrylate with IBM

(Scheme 1). Thismethodologyhasbeenaneficienttool
for the formation ofo-lactams” and has been applied to

incm-porationofo-orfi-aniinoacids,andthediioction-
ality of the peptide constituents." Oxidation of these

'epecieslesdstotheformationofbighlysubstituted

pyridoneproductssuchasu. Anappioacbtodii'ect

 

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165

 

pyridone formation, which involves the use of 2-phenyl-
4—(ethoxymethylsne)oxasolone.' rs also described.

Results and Discussion
Asa-Annulation with fi-Enarnino Esters. 'lbe syn-
thesis and oxidation of a-amido lactams was initially
investigaud for the fl-amino acid homolog of alanine.
Condensation of 15 with BHNH: (benzylamine) generated
the intermediate fl-enamino ester 16a. which was taken
on to the next step without isolation (Scheme 2). Treat-
mentoflfiawithm. themixedanhydrideon—acetami—
doacrylicacid, generatedinsitubythereactionof
ClCO;Et with sodium 2-acetamidoacrylate. resulted in
the formation of 17a. This axe-annulation procedure
provided an aficient route for the rapid construction of
conformationally restricted dipeptide 17a. wiflr structural
features resembling those of a-Ala-fl-Ala.
Dehydrogenation of 17a was performed by two difl'er-
ent methods (Scheme 2). Transformation of 17a to 18a
was accomplished by beefing the substrate with DDQ in
toluene at reflux.“ Alternatively, MnO; could be em-

ployed to afixt the same transformation at reflux in_

xylenes.” Inthelattcrcase,ac1eanerreactionwas
observed with significantly higher yield.
Further modification of the dipeptide analog was

accomplished through standard procedures. Hydrolysis .

ofboth the ester and amide carboxylates provided the
amino acid product 19a (Scheme 2). Pyridone 19a bears
thefeatures ofbothay-aminoacidgroupcili substituent
pattern) and the conformationally restricted dipeptide
a—Ala-fl-Ala. Selective hydrolysis of 18a was performed
to give the N-protected dipeptide surrogate 20a. Exten-
aionofthepeptidechainwiththeethylesterofm)
phenylglycine was accomplished through established pep-
tide coupling protocol to give the tripeptide analog 21.

Thecyclicfl-enaminoester 16b.”relatedinstructure
to proline, was also an efi‘ective substrate for asa-
annulation with the mixed anhydride of acrylic acid
(Scheme 2)!1 Oxidation of the resulting fi-enamido ester
17h resulted in eficient aromatization to give 181).
Hydrolytic removal of functional group protection gave
the corresponding amino acid of the a-Ala-B-Pro dipeptide
analoglObandcouldnotbeperfior-medselectivelytogive
the interrnediate 2%.

 

OI

(IDFwtheimpa-tanceo! fl-aminoaddsnee: (a)hibsll.W. D.
Kihrnura,

;M.l_‘loyori.R. WWINIW2W®M

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(18)(a)Meyers.A.l.; l‘l;olen.B.LCol]ington.E.W.. Narwid,’l‘.
A.;Su'rcklandk. lOrgWChanlmssw1974(b)Sano..;T
Y;'huda,Y ;Itatani,Y.HasrocycIesMB,9..161
(19qu Dru.D.C.H.SynthaielM
(2mm synthesisof lflbwasaccornplishedthroudi
daecribedin Celuiar,J..P;Deloisy-.Marchalant.E;Lhommet.G.;
mp.031...83n¢hrsss,e7,17o

methods ‘

J. Org. Chem, Vol. &. No. 4, 1997 1085

Scheme: FormationofDipeptideAnalop
drreugbAamAnnulationotfi-Enaninobters‘

1
”W“ _..' m‘r‘r“ ——.°

15 to (Forum
a- m
I:
3° 0 733m 0
1
o 52‘ some 0 a
l N ' N.
m ‘R’ o: u- n’
u o "m4 a. o

 

 

 

 

an
a. a: shuns-an
° 0 s: flak-(cm.-
o | m
.23 ..
H O 31

mm (o R’mBWCJ-knflm;

(b) Warez-WWW; (c)DDQ.lolneuc.
reflux: (d) MnOz Hume) 30%“202 KOH: (O KOH.
H20. (g)i.NsH.Er01CCL ii.(R)-phany|s!ycimahyiw.

Genuefionoftheintermediatefi-enaminoestu'through
conjugateadditionoanNfiatoallrynoate substrates
provided an alternative method for ass—annulation

' (Scheme 3). Conjugate addition of BnNH, to 22a. fol-

lowed by aza-annulation with 12. generated 24s.. a
conformationally restricted dipeptide of a-Ala-u-Asp.
TreatmentwithDDQintolueneatrefluxresultedin
aficient oxidation of 24a to 26.

ConiugateadditionoanNH,to22band22cprovided
aroutetoPheandSeranalogs(Scheme3). When
initiated from 22b, the two-step ass-annulation proce-
dure resulted in the formation of 24b, the protected
derivative of the a-Ala-fi-Ser dipeptide, in a fashion
analogous to the formation of 17a hour 15. However.
similar reaction of 22c with BnNHg resulted in divergent
product formation. While the expected tetrasubstituted
enamidoesterflccomprisedonlyB‘bofthe product
W.Bneficdepreunafionoftheintarmediateatthe
benzylic position generated the exocyclic enamide 25 as
a 92:8 ratio of products.22

 

(21)meapplimu'onsoflflrandrelated for-asa-
annula .

. . ' W. .;
m.fl.61L&)mllc.fh)mlfia.

166

10” J. Org. Chm, Vol. 62. No. 4. I”?

Sohmes. Formafionotquh-fi-Phgu-Als-APAsp,
Mammwammmm

n‘oWn'

° H’N‘Bn
a 23
ms (emu) 0 em
on (From as) " mass)
n' o o m
o n' e
mi. this an
H H o
u 26 (921‘)

 

 

Ph
0
a. . an
n o
'7 (96:4)
a: Huey-co.“-
o: s‘-a. rm
1:: n'-a. W

 

 

 

‘Reactiouctmditicms: (a) m. 35.0mm. 25°C;
(b) WZWWW;
(c) DDQ Mica-x; (d) Huismmm

Opportunitiesforfurthermodificatiouoffleand”
weresomewhatlimited(Scheme3). 'l‘reatmentofthese
productsunderthesame conditionsusedtooxidisel’l
tolsdidnotresultinoxidafionofthesesubstratesto

the corresponding pyridone products. Instead, reaction ‘

offlbvrithDDQunderstandardconditionaeveufor
extendedperiodsoffime,resultedoulyintherecovery
ofunreactedflb. Similarreactionofflunderthe
established DDQ oxidation conditions resulted only in
alkeneisomerixationtoproduceanfiOflOmixtureofw:
26. while only a trace of the corresponding pyridone
product was observed.” Isolation and subsequent treat-
mentofflcwithDDQunderstandardconditiousstill
did not result in pyridone formation. An alternative
means of product modification. hydrogenation of 26.
produced27asa96z4ratioofonlytwodiastereoniers,
forwhichrigorousstereochemicalasaignmentwasnot
made. Presumably, hydrogen added to the double bond
fi'omtheaideoppositethatoftheesterfunctionality.
whichprovided27withacisrelatioushipbetweenthe
groupsatC-SandC-G. 'lhe94:6ratioreflectsamixture
ofisomersatC-B.

 

(22)Nuclaar Omhsuscmhsnoammtmomstudiaaonflwere
usadtooonfirmthatthestereochemisu'yofthehublsboudmr
mmorisomerwasE. Irradiationofthevinylprotouresultedin
enhancementoftheN-benzylwotousof3.3%and1.6fi. Therelstion-
ah'qidtheminwandmaiormwhethsrisomanc
Mccialtruusdisstarunernwasnetastabl'nbad.

Beholsetal.

Schmuck FormstionofPeptideAnslogathrough
Asa-AmulationandPyrldoneFor-mationm
p-KetoAmidea‘

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mmmmmnoom.
demeanor.
Tablelul'ormsflrmdlkpfldeAnalogsW
andPyridoneFes-sfirmtnmp-Ieto
Amides‘
isolatsdyield
product I!1 - R’ ”to” ”coal
a Ph 1! 90 76
b ' Ph GOsEt 87’ 66
e MIC H 95 78
d W M 80’ 60

‘Tabulstsdraulhforfidiemet‘swratiodw

Asa-annulation with fi-Ensmino Amides. The sea-
annulationreactionofmwithintermediatefl-enamino
amide 29a. generated from fi-keto amide 28a (R1 = Ph),
resulted in eficient formation of the heterocyclic product
90a (Scheme 4). The corresponding oxidation of the
enamide amide derivatives was substantially more slug-
gishthanthatoftherelated estersubstrates.” Infiet,
dehydrogenation was typically incomplete and required
a second treatment with DDQ to increase conversion to
product. The use of xylenes as the solvent in place of
toluene, or the use of increased equivalents of DDQ or
Mnog. did not provide an increased yield of product
(Table 1). Deepitethelowerreactivityofflhtoward
oxidation, the dipeptide analog alawas still obtained in
respectable yield.

Ahigherlevelofcomplexityinthesesystemswas
accessed through condensation of 29s with the ethyl ester
(fail-phenylglycine (Scheme 4, Table 1). Asa-annulation
of the intermediate fi-enamino amide 29h with 12
resultedintheformationofSObasanequalmixtureof
diastereomers (61:49). This two-step procedure served
to rapidly construct a complex heterocyclic product in
87% yield from the three basic components 28b. 2-ac-
etamidoacrylic acid. and (R)-phenylglycine ethyl ester.
Aswasohser'vedfm'mDDQoxidationofsobgener-ated
the amide-substituted pyridone system 81b, but the
reactionwasnotasfadleasthatoftherelatedeeter

 

(23)The80:20oompoaitionofthereacfimmixmrewas
by BMChsr-actsristicpaahofmwerethafollowing: 2.49mi.
J=16.9.3.0Hx.IH).8.55(&l.J-15.9. 638x13).t68(dt.l=
15.1.6.33g1m.

167

substrates. Oxidationwitthogresultedinoulym
conversion ofaob to 31b after 48 h at reflux in xylenes.”

Compounds 31a and 31b represent an interesting class
of conformationally restricted peptide-like molecules.
Peptide functional groups, both amino and carboxylate
functionality. radiate from the 1. 3, and 5 positions of
the pyridone hub. The amide functionality of the pyri-
done heterocycle displays structural features present in
peptide derived molecules. Combination of the 1 and 5
substituents reflect the structural features of a linear
dipeptide.whilethe3 and5 positionsare aimilartothose
found in conformationally bent peptide chains. Interest-
ingly, the relationship between the 1 and 5 positions is
oneinwhichbothanaandafiaminoacidradiatefrom
a common nitrogen atom.

Eficient axe-annulation was observed with substrate
28c (R1 = CO,Et), which was readily obtained by the
reaction of diketene with glycine ethyl ester (Scheme 4.
Table 1). Formation of fl-enamino amide 29c, followed
by ass-annulation, gave the tripeptide analog 30c in 95%
yieldforthetwo—stepprocessfi'omflc. Oxidation ofwc
proosededinafashionsimilartothatofflbmndtwo
treatments with DDQ were required to accumulate a
yield of 78% Condensation of 26c with (ID-phenylglycine
ethylestergenerated29d,whichgave80dasanequsl
mixture of diastereomers (51: 49) upon axe-annulation
with12. OxidationofflOdwithDDQintolueneatreflux
generatedthepyridonehubwithaminoacidfuncfionslity
radiatingfnomthe 1.3,and5positions.

In order to probe the compatibility of the ass-annula-
tionreaction conditionswiththe stereochemicalintsgrity
of the amino acid components. lactam and pyridone
products that contained two separate sites of asymmetry
wereformed. Condensationof82wasperformedsepe—
rataly with valine- and phenylglycine-derived caters to
give 83 and 86. respectively (Scheme 5). In each case.
examination ofthe intermediate enamine showed the

presence of a single diastereomer. Asa-annulation with ,

sodiumacrylate/ClcogEtunderstandardreactionotmdi-
tionsledtotheconvsrsionof83t084aasasingle
diastereomer (>98:2 by NMR analysis of the crude
reaction mixture). Similarly. treatment with sodium
2-acetamidoacrylate/Clcant led to an 89% yield of 84b
whichwasa50z50mixtureofdiastereomersatthe3
podfionofthehctambutdiduetmsultinepimerisation
oftheaminoacidgroups. Conversionof86t037also
wasaccornplisbedasasingle diastereomer. Basedon
these observau'ons. epimerization of the amino acid
stereocenters didnotoccurundertheasa—annulation

Oxidationoffiwasdependentonthenatureofthe
substituentattheSposifionofthelactam. WhenR=
H,treatmentof84aor87withDDQledtoamixtureof
products which did not contain significant quantities of
the dsdred pyridone products. However. when a 2-ac-
etamidosubsfituentwaspresent(34b),oxidationrssulted
intheformationof85basasinglediastereomer. How-
ever, this reaction could not be driven to complete
conversion without significant degradation of the desired
product. AficrtwossquenfialheahnentswithDDche
poductwasisolatsdinMyield,whichrepresentsda
59%yieldbasedonrscovered84b. Thegenerationofs
singlestueoisomademonstretedthatthestereochemhl
intagrityoftheaminoacidgrmpswasmaintainedduring
theoridationprocsss.

Bh'uchiralAnalysis 0120c. Duringthecourseof
these studies. u-amido lactam 90c was obtained as a

J. Org. Chara. Vol. 62, No. 4, 1997 I”?

8cherrse5. Detaminationot
duringAss-AnnulstionandOddationReaetions‘

a \o‘
:/
o 0 '.‘
I
u.
.... . ”WW
0
'3 /\ " '“
gamma!) 49$
‘lumrmm ‘lmsn

‘Rcsctioooondtioos: (a) (SD-valine methyl will.
Mflmm (b) (Mlglyciriesnrylcu-HCL
toluene.NaHCO;.rctlux; (c)sodimiiacrylneasodiu
Z—nctlnidocrylate. ClCOfit. THF. 25 'C; (d) DDQ. m
macs .

crystalline solid, which allowed for the single crystal
X-ray analysis of this molecule.” The ORTEP represen-
tstionofthismoleculeisshowninFigurel. Thereaie
severalfeaturesofthisstrncturethatareworthcom-
merit. Inaddifiontosu-uctureconfirmation,theorienta-
fion and interactions of the peptide-like chains at the 3
and5positionsofthelactamring.andtheefi‘ectsthat
theN-benzyl substitutenthasonthepackingofthis
moleculeareinteresting.
Althoughinu-amelecularhydrogsnbondinginsolufion
cannot be ruled out, the ORTEP representation ofthis
molecule clearly illustrates an absence of intramolecular
hydrogenbondinginthesolid state. However,several
intermolecularhydrogenbondingintaractiouswereob-
servedinthiscrystallatticebetweentheamidesubstit-
uents atthe3and5positiousofthelactamheterocycle.
As a result of these interactions, a ‘ladder" type struc-
turslfeaturewasobservedfli‘igureZ). Theperspecu've
inFigureZcontainsfourmoleculesofSOc.andthe
N—benzyl substituents have been omitted for clarity.
From this representation. the alternating orientations of

168

1038 J. Org. Charm, Vol. 62, No. 4. 1997

 

Figure 1. ORTEP. line representations. and numbering
schsmsofsu-ucuiraldatsobtainedformc.

 

Figure2. Intermolecularhydregenbmdingobservedfirrmc.
N—Benxyl groups have been omitted for clarity.

theringsystemnecessarytoadoptthislatticeisappar-
snt,asisthedirectionalityoftheladder.

These intermolecular hydrogen bond interactions were
found between 000) and H(13)-N(13). with distances
of 1.794 and 1.045 A for the 0-I-I and H—N bonds,
respectively. The O—H-N angle observed for this
interaction was 158.5°. which is typical for hydrogen
bonding geometry. Similarly, 0(19) and H(8)-N(8)
interactions were evident between two molecules of 30c.
withdistancesof1.951 and0.919Aforthe O—Hand

H-Nbondarespectively. Avalueof161.6°wasobserved‘

fortheO—H-N angleofthishydrogeubond.

Baholsetal.
8eheme6. DirecthridonsFos-mstionthrough
Ass
*9 5'
WW“ ——‘—. I=I""Y‘r“'°
° ° ° on.
i
"' fl /\
° 0
Ph
will). a

 

41
‘Rmuoacouditioas: (s) (finhcmdryleumm

mlumcrcflux: (U39.diosmc.reflax.2b: (c) DllF.reflux.2h:
(d) ”,DMPJefllih.

 

DirectFormstiononyridones. Theuseon-phsn-
yl-4-(ethoxymethylene)oxasolone (39). an alternative re-
agent for axe-annulation, was explored for the direct
formation of pyridone products (Scheme 6). Reagent 39
wasreadilypreparedOfi-omhippm-icacidbyreactionwith
ethyl orthoformate in acetic anhydride as previously
reported.“ Although ass-annulation of enamino esters
andamideswiththisreagenthadbeenreportedto
proceedindioxanewithaddedNEtoat85°C."analogous
reaction of enamino amide 38 with 39. with or without
NEtg.resultedprimarilyintheformationof40. Cycliza-
tionof40to41wasafi‘ectedeventuallybyanina'ease
inreactiontsrnperatme;whenasolutionof40was
heatedtorefluxinDMF, complete conversionto41was
achieved. Thisasa-annulationprocesswasperformedin
asingleprocedurebytrestmentofflwithflinDMF
followed by reflux of the reaction mixture. The low
isolatedyieldsobtainsdfor41,eapeciallywhencomparsd
to yields obtained for similar reaction of 39 with either
330r42,wsreacaisequeuceofthegensretionofresctiou
byproductsthatweredificulttoremoveduringisolation
J41.

Axe-annulationof42,derivedflom32,resultedinmore
eficientringformationtogivefl (Scheme 7). Isolation
andanalysisof431edtosomeintsrestingpropertiesof
these molecules in solution. Initial 1H m analysis of
43inCDClarevealeda70:30ratiooftwoseteof
resonances. However, systematic dilution of 43 resulted
in conversion ofthis mixture into predominantly one set
of peaks (90:10). This concentration dependent phenom-
enahasbeenobservedbeforewithpeptides,andhasbeen
attributed to intermolecular hydrogen bonding of these
molecules. whichbscomeslsss prevalent uponincreased
dilution."

Enamine 33. formed as a single diammer as
determined by 1H NMR. was used to determine the
extenttowhichepimerizationoccurredasaresultofthe

 

(24)Behringsr.H.;Taul.H.Chsm.Ber.1957.,90 13$.

(25)(s)Dobashi.A.;Saito Saito..;N WY; Bare.8.J.Arn.arsm.
Salm.108..307(b)Jursic.B..S;Goldbsrg.SLJOrgChesi.
182.57. 7172.

169

o 1;: o a
u. Ila
“.0er use 0
0 (“an o “Ki/KO“.
‘3 3' /\
ms at am
(From 32) (Hana)

 

‘Rcctionoonditions: (a) BMMW;
(b) (vaflhcmylmHQMNfilCO’m
(c)39.DW.rcnux.2h.

asa-annulationprocesswith39(Scheme 7). 'l‘heroaction
of43with39,generatedbycondensationof(S)-valine
methylesterwith33,resultedinan81%yieldof44for
the two-step cmdemafion/aumulafion process. Al-
though this procedure provided an eficient route the
rapid construction of a complex molecule from readily

available starting materials, the diastereomer ratio that .

was produced in this roacu'on sequence was only 86:14.
During this ass-annulation process, some epimerization
hsdoccurredatthesitesofasymmetryduetothebidr
temperature (154 °C) required for heterocycle formation.

Summary. The axe-annulation reaction provides an
efiu'snt route for the potential construction of the
heterocyclic homework for complex bioactive compounds
such as natural product targets or synthetic peptide
mimetics. With this method, peptide analogs as complex
as31dcanbeassernbledintbrsestepsin529boverall
yield, and the ass-annulation process with acrylate
derivatives did not pmed with epimerization. The
resulting compounds contain 6-lsctam pepu'de-like bonds,
whichuhilfitr'estrictedrotationofbothrpandwdihedral
angles. These angles can be altered by oxidation of the
dihydropyridone ('1’ = 166°) to the pyridone (V’ = 180°).
However, dming the oxidation process, significant epimer-
ization of the u-amino acid derivatives (20%) was ob-
served. The pyridone substituents can be completely
deprotected to give the corresponding amino acid, or can
beselectivelyhydrolyzedtogsneratethea-amidocsr-
boxylic acid.

As potential bioprocess substrates, these conforma-
tionslly restricted heterocyclic peptide analogs would be
expected to show unique properties at the active site of
enzymatic reactions. Hydrolysis of the enamides would
leadtothegenerationofanucleopbilicenamine,but
would not result in the Mutation of the substrate”

J. Org. Chars, Vol. 62, No. 4, 1997 1039

chain. Theenamineproductcouldtheneitherreactin
an intermolecular manner with an electrophile at the
active site or intramolecularly revert to the lactam.
Synthetic oxidafion of the 6-lactams leads to pyridone
peptide analogs, which would be inert to typical condi-
tions for peptide hydrolysis. As possible peptide mimet-
ics, these compounds have the potential to interfere with
biochemicalevents thatwouldleadtoaignificantbiologi-
calm Thebiologcel activityofthesemoleculesis

cmrentlybeingexaminedsndwillbereportedseperately.

ExperimentalSection

Gena-elm Unlessotherwisenoted,allreaotions
werecarriedoutusingstandardinertatmospheretechniques
toaxcludemoisuneandcxygen,andreactionswereperformsd
underanatmosphereofnitrogen. Xylenesanddscalinwere
heatedovercalciumhydrideforaminimumofnhandthsn
distilledpriortouse. liAlH.(1MinTHF')wasobtsinedfrom
AldrichChemicalCo. MnOa wasundwithout purification
(FisherScicntific).

Dahydrationofccndcnsationreactionswasparformedwith
theuseofamodifiedDean-Starka tueinwhichthe
cooleddistillatewaspassedtbrough4- molecularsievesprior
toreturnofthesolventtothereactionmixture.” Thesievss

mund-

Gerraral Method tor the Formation off-Kate Amides.
Metals (5.0-30.0 mmol, 1.0 equiv), BnNH; or HCl-HaNCHr
COaEt (1.0 equiv), and NaHCO; (2.0 equiv) were combined in
bmsene(0.5Msolutionofamine)at0°C. Themixhrrewas
warmedtoroomtemperatm'e,stirredfor14h,andthen
filtered. Removalofsolventunderreduoedpressuregavethe
product as a solid, and crysmllintim from Eth/CHCI; yielded

as white leaflets.

th.Ifla:3.59g, 18.8mmol,81%yield;mp 100-102‘C;1HNMR
(300 MHz, CDCla) d 2.24 (s, 3 H), 3.42 (s, 2 H), 4.44 (d, J -
6.0 Hz, 2 H), 7.25-7.40 (m, 6 H); 1’C NMR (75 MHz, CDCI.)
d 30.90, 43.46, 49.56, 127.42, 127.62, 128.62, 137.88, 165.38,
204.35; IR (KBr) 3249, 3085, 1715, 1640, 1443, 1410, 1190,
1163 cm"; HRMS calcd for CanNOa ru/z 191.0146, obsd
Ila/z 191.0982.

88c: 1.74 g, 9.35 mmol, 99% yield; mp 52-53 °C; 1H NMR
(300MHz,CDCl;)6 1.28(t,J=7.1Hz,3H),2.28(s,3H),
3.50(s,2H),4.04(d,J=5.4Hr,2H),4.20(q,J=7.2Hs,2
H), 7.61 (be, 1 H); ”C NMR (75 MHz, CD01.) 6 13.84, 30.36,
41.11, 49.63, 61.13, 166.16, 169.41, 203.54; IR (KBr) 3353,
2986,1754, 1715,1673,1543,1418, 1401, 1321,1175 cm";
HRMS mlcdforCsHuNO4 m/z 187. 0845, obsdm/z 187. 0844.

83: N , purified by column chromatography,
eluent: 50:50/diethyl ether, 3.27 g, 15.2 mmol,
85%yreld,‘HNMR(300m1r.,CDCh)6085(d.J7.2Hs,
3H), 0.89(d,J= 7.2Hz,3H), 2.,12(m,1H) 2.21“, 3H).
3.43 (s, 2 H), 3.66 (s, 3 H), 4.46 (dd, J = 5.0, 8.6 Hz, 1 H), 7.48
(bd, J = 8.6 Hz, 1 H); uC NMR (75 MHz, CDCh) 6 17.5, 18.8,
30.5, 30.8, 49.5, 51.9, 57.1, 165.8, 172.0, 203.9; IR (neat) 3320,
2967, 2878, 1746, 1653, 1541, 1437, 1360, 1267, 1156 cm“;
HRMS calcd for CmHuNO‘ m/z 215.1158, obsd m/z 215.1149.

General Method for the Asa-Annulation of fl-Keto
Amides andfi-Keto Estes-s. (ID-Phenylglycine ethyl ester

'de saltwassuspcndedinbensene(1.5mI/mmol
of substrate) and washed with saturated aqueous NaHOO;
AfiartbeaqueouslayerwaswashedwithbenseneflOmL),
the benzene layers were combined, washed with saturated
aqueous NaCl, and dried (Mg‘SOd. 'lhe banana solution was
then used without further manipulation.

AmixtureoftheBnNflaorphenylglydne ethylestsr(0.5-
5.0 mmol, 1.0 equiv) and the fl-keto amide orfi—keto ester (1.0
equiv)weretakenupinbensens(0.5dlrelativetotbe

 

(26)Barts.N.S.;Paulvannan,K.;8cbwan,J.B.;Mls,J.R.SyntlL
Commun. 1'4, 34, 853.
(27)’1'heauthorhasdepositedatomrc atomiceoor-dinatest'orthisstructure
withtbeCamhridge phicDataCentre. 'lhseoordinates
mmfiomdrebhm, CambridgeCrystal-
logrsphicDamCentre, l2UnionRoad,Cambridgs,CB21£z,UK.

170

1040 J. 011. Chem, Vol. 62, No. 4, 1997

substrate), and BFs-OEt; (0.5 equiv) was added. The reaction
vessel was fitted with a modified distillation apparatus for
azeotropic removal oszO,” and the reaction was heated at
reflux until complete as determined by NMR analysis (6- 18
h). Thesolventwasthenremvedunderreducedpressure,
andthecrudeenaminewasbroughtupin'l'HF(0.1M).'lhe
mixturewascooledto-78°C, sndthesodiumsaltot
2-acetamidoacrylic acid (1. 3 equiv) was added. WC1(1.3
equiv)wasthsnadded,andthereacu'onmixturewaswarmed
to room temperature and stirred until complete (814 h)
SatuutedaqueousNaHCO;wasthensdded,andthemizture
was extracted with EtOAc. The combined organic fractions
weredriedovcs'Nagsor, filtered,andconcentratedundsr
reducedpressure. Thecrudeproductwaspurifiedbyflash
column chromafosflphy (EthIEtOAc/MeOH).

17a: 0.56 g, 1.70 mmol, 74% yield; mp 132-135 °C; 1H NMR
(300MHz,CDCl;)6 128(t,J=7.2Hz,3H),2.06(s,3H),
2.27 (tq, J = 15.9, 2.6 Hz, 1 H), 2.37 (d, J = 2.1 Hz, 3 H), 3.40
(dd. J = 15.9, 6.3 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.55 (dt,
J= 14.7, 6.0 Hz. 1 H), 4.78 (d,J= 16.1 Hz, 1 H), 6.22 (d,J=
16.1 Hz, 1 H), 6.61 (bd, J= 5.1 Hz, 1 H), 7.11 (d, J = 6.9 Hz,
2 H), 7.22—7.36 (m, 3 H); “C NMR (75 MHz, CD04) 6 14.14,
16.11, 23.15, 27.69, 45.80, 48.96, 60.51, 109.12, 126.04, 127.41,
127.63, 128.83, 136.73, 147.35, 166.68, 170.12; IR (KBr) 3299,
m, 1686, 1389, 1248, 1163 cm“; HRMS calcd for CnHaNrOo
m/z 330.1580, obsd m/z 330.1572.

17b: 1.27 g, 4.77 mmol, 74% yield; mp 150-151 °C; 1H NMR
(300MHz,CDCl.)6 1.29(t,J=7.2Hz,3H),2.03(quint,J=
7.3 Hz, 2 H), 2.07 (s, 3 H), 2.29 (tt, J = 15.6, 2.9 Hz, 1 H), 3.16
(td,J= 7.7, 2.1 Hz, 2 H), 3.40 (dd,J= 16.2, 7.5 Hz, 1 H), 3.68
(dt,J= 11.4, 7.3Hz, 1 H), 3.79(dt,J= 11.4, 72Hz, 1H),
4.19 (q, J = 7.2 Hz, 2 H), 4.54 (dt, J = 14.4, 7.2, 1 H), 6.39“.
J = 5.7 Hz, 1 H); 1’C NMR (75 MHz, CD014) 6 14.33, 21.59,
23.17, 27.99, 31.20, 46.17, 49.60, 60.15, 100.82, 152.30, 166.41,
167.89, 170.23; IR (KBr) 3281, 2984, 2849, 1690, 1642, 1545,
1399, 1248, 1173, 1109 cm"; HRMS mlcd for assume, ru/z
266.1267, obsd ru/z 266.1260.

”a: 0.78 g, 2.06 mmol, 90% yield; mp 82-85 °C; 1H NMR
(300M11z,CDCh)61.92(s,3H),2.07(d,J-2.3Hz,3H),
2.41 (btd, J = 15.3, 2.3 Hz. 1 H), 2.93 (dd, J = 15.5, 6.4 Hz, 1
H), 4.35 (dd, J = 14.7, 5.5 Hz, 1 H), 4.43 (dd, J = 14.7, 5.5 Hz,
1 H), 4.54 (dt, J = 15.0, 6.4 Hz, 1 H), 4.63 (d, J= 16.4 Hz, 1
H), 5.05 (d, J = 16.4 Hz, 1 H), 6.80 (ht, J = 5.7 Hz, 1 H), 6.98
(bd, J = 6.3 Hz, 1 H), 7.07 (d, J = 6.6 Hz, 2 H), 7.16-7.30 (m,
8 H); “C NMR (75 MHz, CD03) 6 15.87, 22.79, 28.51, 43.44,
45.45, 48.78, 112.45, 125.86, 127.15, 127.57, 128.39, 128.61,
136.82, 138.02, 139.12, 167.80, 169.27, 170.21; IR (KBr) 3289,
3002, 1734, 1659, 1584, 1543, 1321, 1248 crn’1;HRMB calcd
for W303 m/z 391.1896, obsd m/z 391.1895. '

”bamixtureofdiastereomers, ratio49251; 0.36g,0.80
mmol, 87% yield; mp 83-85 °C (mixture); lH NMR (300 MHz,
CDChcharaeteristicpeaks)6(maiorisomer)2.01(s,3I-I),
222(d,J= 1.2Hz,3H),2.=30(bdt,J 9.2,1.,5Hz 1H), 6.67
(s, 1 H), 5.92 (m, 1 H), (minor isomer) 2.02 (s, 3 H), 2.10 (d, J
=L2Hz,3H),2.43(btd,J=9.2, 1.5Hz, 1H),5.59(s, 1H),
5.95 (m, 1 H); 1’C NMR (75 MHz, CD01.) 6 13.87, 16.22, 16.50,
H186, 22.78, 28.17, 28.33, 40.42, 43.46, 46.47, 48.94, 59.82,
61.67, 111.05, 113.61, 114.01, 117.30, 126.02, 127.06, 127.17,
127.50, 127.55, 127.71, 127.95, 128.21, 128.37, 128.41, 128.52,
134.26, 134.42, 137.88, 137.95, 138.52, 139.39, 167.46, 167.64,
168.02, 168.43, 169.22, 169.61, 170.13, 170.18; IR (KBr) 3297,
3007, 1742, 1651, 1532, 1217 cm“; HRMS calcd forC‘asHstOs
m/z 463.2107, obsd m/z 463.2150.

”c: 1.06 g, 2.74 mmol, 95% yield; mp 71-74 °C; 1H NMR
(300MHz,CDCla)6 125(;,J= 7.1Hz,3H),2.00(s,3H),
216(d,J=2.2Hz,3H),2 “(btd.J815.3,2.2Hz,1H),
296(de=15.3,6.15Hz, H).,395(dd,J=18.1,5.6Hz,1
H),4.04(dd.J= 18.1,5.Hz6 , 1H),4.14(q,J=7.2Hz,2H),
4.59(dt,J= 15.3, 6.5112,1H). 4.67(d,J= 16.7 Hz, 1H),
5.13(d,J=16.7Hz, 1H),6. 91( J=5.6Hz, 1H),7.05-7.13
(m,3H), 7..19-734(m,3H);”CNMR(75MHz.CDCla)6
13.84, 15.79, 22.78, 28.31, 41.18, 45.42, 48.74, 61.09, 111.95,
125.82, 127.12, 128.58, 136.78, 139.74, 168.09, 169.34, 169.69,
170.25; IR (KBr) 3285, 2984, 1744, 1657, 1584, 1543, 1319,
1190 cm“; HRMS calcd for W915 Ill/z 387.1794, obsd
rulz 387.1789.

Beholzetal.

30drmixturecfdiastsrsomers,ratio49:51;0.52g, 1.13
mmol, 86% yield; mp 77-80 °C (mixture); 1H NMR (300 MHz,
CDCh, characteristic peaks) 6 (major isomer) 2.03 (s, 3 H),
2.12 (d, J = 1.5 Hz, 3 H), 2.45 (btq, J = 9.0, 1.5 Hz, 1 H), 2.77
(ddd, J = 7.8, 3.3, 1.5 Hz, 1 H), 5.62 (s, 1 H), 6.17 (ht, J = 2.9
Hz, 1H),(minorisomer)2.02 (s, 3 H),2.24(d,J= 1.5Hz,3
H), 2.33 (btq, J = 9.0, 1.5 Hz, 1 H), 3.10 (ddd, J = 9.0. 3.3, 1.5
Hz, 1 H), 5.68“, 1H), 6.13(bt,J=2.9Hz, 1H); ”CNMR(75
MHz, CDCl;) 6 13.97, 16.29, 16.56, 22.75, 22.98, 28.16, 28.26,
41.35, 41.42, 46.44, 49.04, 59.71, 59.91, 60.78, 61.32, 61.80,
62.35, 100.38, 113.15, 113.52, 167.73, 127.71, 127.77, 127.99,
128.04, 128.09, 128.20, 128.34, 133.26, 134.22, 134.44, 139.46,
139.49, 140.42, 167.92, 168.04, 168.47, 169.04, 169.30, 169.35,
169.40, 169.74, 169.79, 170.22, 170.30, 171.05; IR (KBr) 3277,
2&6, 1744, 1655, 1541, 1204 an“; HRMS calcdforCafigNgm
m/z 459.2006, obsd m/z 459.2011.

34a: 48:48:4/diethyl ether:petroleum ether-methyl alcohol;
0.53 g, 1.39 mmol, 60% yield; 1H NMR (300 MHz, CDC1.)6
0.74 (d, J= 7.1 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 0.90 (d, J
= 6.9 Hz, 3 H), 1.08 (d, J= 6.4 Hz, 3 H), 2.16 (m, 1 H), 2.14
(s, 3 H), 2.38-2.53 (m, 4 H), 2.61 (m, 1 H), 3.60 (s, 3 H), 3.69
(s,3H),4.03(bd,J=8.5Hz, 1H),4.55(dd,J=4.9,8.5Hz,
1H),5.93(d,J=8.5Hz, 1H); ”CNMR(75MH1,CDC].)6
16.5, 17.9, 18.9, 19.1, 22.0, 22.2, 28.0, 31.2, 52.0, 52.1, 57.0,
61.2, 113.2, 140.5, 168.8, 170.2, 170.6, 172.5; IR (CHCh) 3316,
2969, 2876, 1746, 1657, 1524, 1437, 1399, 1804, 1267 cm'l;
HRMScalcdbrClgHgoNgogm/z 382.2104,obsdm/z 382m

34h: 90:5:5; EtaOIpetroleum sthem/MeOH; 2.73 g, 6.21 mmol,
89%yield,50:50minureofdiastereomers;mp=69-70'C
sealed, deq‘HNMR(300m-Iz,CDCl.)60.74(d,J=7.2 Hz,
3 H), 0.75 (d, J = 7.2 Hz, 3 H), 0.86—0.94 (m, 12 H), 1.09 (d,
J=7.2Hz,3H), 1.11(d,J=7.2Hz,3H), 1.96(s,3H), 1.97
(s, 3 H), 2.06 (d, J = 1.8 Hz, 3 H), 2.09-220 (m, 2 H), 2.20 (d,
J = 1.8 Hz, 3 H), 2.24-2.42 (m, 2 H), 2.48-2.68011. 2 H), 2.91
(dd, J = 6.3, 15.3 Hz, 1 H), 2.99 (dd, J = 6.3, 15.3 Hz, 1 H),
3.61(s, 3 H), 3.64 (s, 3 H), 3.69 (s, 6 H), 3.95 (d, J = 8.7 Hz, 1
H), 4.26 (be, 1 H), 4.35-4.57 (m, 4 H), 6.19 (d, J = 8.7 Hz, 1
H), 6.42 (d,J= 8.4Hz, 1 H), 6.56 (d,J=5.7Hz, 1H),6.61(d,
J = 5.7 Hz, 1 H); “C NMR (75 MHz, CD01.) 6 11.5, 11.7, 13.16,
13.24, 14.2, 14.4, 17.0, 17.4, 18.2, 22.9, 23.5, 23.6, 23.8, 26.1,
26.4, 44.0, 44.3, 47.3, 47.4, 47.5, 52.5, 52.6, 56.9, 57.4, 107.9,
108.7, 134.0, 136.1, 162.8, 163.3, 164.4, 164.5, 164.8, 165.4,

165.5, 165.9, 167 .5, 167 .6; IR (CHC13) 3308, 3011, 2969, 1742,

1653, 1534, 1437, 1269, 1244 cm"; HRMS calcdforCmHuNgOy
m/z 439.2319, obsd m/z 439.2285.

37: 48:48:4/diethyl ether:petroleum etherzmethyl alcohol,
0.29 g, 0.68 mmol, 49% yield; mp = 44-45 °C; 1H NMR (300
MHz, CDClg)60.85(d,J= 6.9 Hz, 3 H), 0.90(d,J=6.8Hz,
3 H), 1.21(t, J= 7.1 Hz, 3 H), 2.06 (s, 3 H), 2.12 (m, 1 H),
2.40-2.55 (m, 2 H), 2.55-2.66 (m, 2 H), 3.69 (s, 3 H), 4.18 (q,
J= 7.1 Hz, 2 H), 4.55 (dd, J = 4.8, 8.6 Hz, 1 H), 5.60 (s, 1 H),
5.84 (bd, J= 8.6 Hz, 1 H), 7.05-7.33 (m, 5 H); 1'C NMR (75
MHz, CDCh) 6 14.1, 16.8, 17.9, 22.2, 31.2, 31.4, 52.2, 57.1,
59.8, 61.7, 114.1, 126.1, 128.0, 128.4, 128.7, 135.0, 140.1, 168.7,
168.8, 170.6, 172.5;111(CHC1;)3324, 2967, 1744, 1659, 1522,
1395, 1374, 1302, 1262, 1156, 1028 cm“; HRMS calcd for
W104 m/z 430.2104, obsd m/z 430.2105.

General Method for the Formation of Aoetylerric
Esters. To 3-(benzylcxy)propyne or 3-phenylpropyne (10-50
mmol, 1.0 equiv, 0.5 M in THF) at -78 °C was added n-BuLi
(1.0squiv,2.5Minhanne).Aiter10min,EtOchl(1.5equiv)
wasaddeddropwise. 'Ihereactionmixtureconmining3-phe-
nylpropynewasslowlywarmedtoroomtemperature,andthe
mixtm'ewassfirredforuh. Inthecaseof3-(benzyloxy)-
propyne, the reaction was promptly as soon as a deep
redcolorbegantoforminthesolution. Eachresctionwas
quenchedbyaddifionostO, theorganiclayerwasremoved.
andthesolventwasremovedunderreducedpressure.’l‘he
crudeoilswerepurifiedbyflashcolumnchromatogrsphy
(petroleum ether).

22h: 1.61 g, 7.45 mmol, 91% yield; 1H NMR (300 MHz,
CDCla)6129(t,J=7.2Hz,3H),4.22(q.J=7.2Hz,2H),
4.25 (s, 2 H), 4.59 (s, 2 H), 7.22-7.40 (m, 5 H); “C NMR (75
MHz, CDCL) 6 13.78, 56.53, 61.90, 71.81, 78.07, 82.94, 127.87,
127.90, 128.29, 136.59, 152.87; IR (oil/NaCl) 3032, 2984, 2872,
2236, 1713, 1248 cm“.

171

Dihydropyr'idone- and Pyridone-Based Peptide Analogs

”or 3.06 g, 16.28 mmol, 94% yield; 1H NMR (300 MHz,
0DC1;)6 1.30(t.,J=7.1Hz, 3H),3.73(s,2H),4.23 (Q.J==
7.1 Hz, 2 H), 7.25-7.40 (m, 5 H); 1'C NMR (75 MHz, CD01.)
6 14.00, 24.97, 61.87, 74.84, 86.20, 127.16, 127.99, 128.69,
134.07, 153.67; IR (oil/NaCl) 2984, 2238, 1709, 1255 cm“.

General Method for the Asa-Annulation otAcetylsnic
Esters. A mixture of BM: (0.5—5.0 mmol, 1.0 equiv) and
acetylenic ester (1.0 equiv) was taken up in THF (0.5 M
relative to the amine), and BFa-OEtg (0.5 equiv) was added.
Themixturewasstirredatambienttemperaurreunfilthe
reactionhadgonetocompletimasmdicatedbyIHNmm
solvent was removed under reduced pressure, and the crude
enaminewastalrenupinTHF(0.1M).'l'hemixtm-ewas
cooledto-78°C, sndthesodiumsaltof2-acetamidoacrylic
acid (1.3 equiv) was added to the enamine. EthCCl (1.3
equiv)wasthenadded,andthereactionmizturewaswarmed
to room temperature and stirred until complete (~14 h).
SatmutedaqueousNaHCOawuaddedandthemixturewas
extracted with EtOAc. The combined organic fractions were
driedoverNafiO‘andfilteredandthesolvcntwasevaporated
underreducedpressure. Thecrudeproductwaspurifiedby
flash column chromatography (EtrO/EtOAc/MeOH).

24a: 3.60 g, 10.0 mmol, 71% yield; mp 151-154 °C; 1H NMR
(300 MHz, CD013) 6 2.05 (s, 8 H), 2.34 (dd, J = 16.3, 15.6 Hz,
1 H), 3.42 (dd, J = 16.3, 7.0 Hz, 1 H), 3.67 (s, 3 H), 3.73 (s, 3
H), 4.63 (ddd, J = 15.6, 7.0, 5.6 Hz, 1 H), 4.65 (d, J = 15.6 Hz,
1H),4.94(d,J= 15.6Hz, 1H),6.51(bd,J=5.6Hz, 1H),
7.16—722 (m, 2 H), 7.25-7.36 (m, 3 H); 1’0 NMR (75 MHz,
CD013) 6 23.07, 26.41, 47.81, 48.43, 52.24, 52.90, 108.95,
127.13, 127.79, 128.56, 135.77, 141.88, 163.32, 165.05, 169.21,
170.14; IR (KBr) 3306, 2953, 1742, 1705, 1634, 1534, 1437,
1248 cm“; HRMS calcd for CMgOg m/z 360.1322, obsd
m/z 360.1308.

2411: 3.32 g, 7.61 mmol, 83% yield; mp 97—99 °C; 1H NMR
(300MHz,0D01;)6 1.26(t,J=7.2Hz,3H),2.03(s,
229(td,J= 16.0 2.0Hz, 1H), 3.39(dd.J= 16.,0 6.6Hz,
H),4.16(q,J= 7.2Hz,2H), 4.31(dd,J= 12.9, 2.0Hz,
445(dt,J= 15.,0 6.0Hr. 1H), 4.=54(d,J 12.0Hz,
4.60(d,J=12.0Hz, 1H), 4.80(d,J= 1651141315.
J= 12.9Hz, 1H), 5.41 (d,J= 16.5Hz, 1H),6.37 (bd,J
Hz, 1 H), 6.98-7.02 (m, 2 H), 7.17-7.38 (m, 8 H); 1’C
(75.5 MHz, CD013) 6 13.97, 22.99, 28.00, 45.62, 48. 50, 60. 90,
63.07, 72.50, 112.97, 125.91, 127.16, 127.87, 128.32, 128.64,
137.12, 137.39, 145.35, 165.91, 170.07; IR (KBr) 3310, 3011,
2936, 1673, 1632, 1497, 1392, 1372, 1217 cm“; HRMS calcd
for W110; m/z 436.1998, obsd m/z 436.2064.

25: mixture of isomer-s, ratio 92:8; 2.64 g, 6.5 mmol, 61%
yield;’HNMR(300MI-Iz,CD01.)6 1.14(t,J=7.1Hz,3H),
1.79 (ddd, J = 13.1, 11.1, 6.6 Hz, 1 H), 2.03 (s, 3 H), 2.80 (ddd,
J 8 13.1, 9.4, 7.0 Hz, 1 H), 3.85-4.87 (m, 3 H), 4.47 (dt, J =
11.1, 6.3 Hz, 1 H), 4.77 (d, J = 15.4 Hz, 1 H), 5.23 (d, J = 15.4
Hz, 1 H), 6.46 (s, 1 H), 6.84 (d, J = 5.8 Hz, 1 H), 7.13—7.38
(m, 5 H); 1"C NMR (75.5 MHz, CD01.) 6 13.84, 23.00, 29.05,
40.78, 48.71, 51.43, 61.38, 121.37, 127.32, 127.47, 128.40,
126.51, 128.90, 134.38, 135.82, 137.00, 169.53, 170.00, 171.91;
IR (KBr) 3330, 2982, 1734, 1671, 1496, 1410, 1244, 1184 cm”;
HRMScalcdforCuHaNrO4m/z 406.1893,obsdm/z 406.1920.

General Method for the DDQ Oxidation oananArmu-
latlon Products. A mixture of the aza-annulation product
(0.5-50.0 mmol, 1.0 equiv) and DDQ (1.5 equiv) was taken
upintoluene (0.1Mwith totheaza-annulau'on
product). Atterheatingatrefluxfor14h,thesolventwas
removedunderreducedpressure, andthecrude productwas
purified by flash column chromatography (Em/EtOAc) or
crystallized (CHCIJEtOAc). For compounds derived from
fi-ketoamides,theoxidafionwasrepeatedtoaoquirethe
indicated yields.

18a: 0.029 g, 0.088 mmol, 58% yield; mp 176-178 °C; 1H
NMB(300MHz,0D0h)6 1.37(t,J=7.1Hz,3H),2.19(s,3
H), 2.68 (s, 3 H), 4.30 (q, J = 7.1 Hz, 2 H), 5.47 (s, 2 H), 7.09
(d, J = 6.7 Hz, 2 H), 7.26-7.35 (m, 3 H), 8.30 (bs, 1 H), 8.91
(s, 1 H); nC NMR (75 MHz, CD01.) 6 14.19, 16.91, 24.63, 48.33,
61.15, 110.44, 122.64, 125.77, 126.05, 127.64, 128.94, 135.22,
145.30, 158.40, 165.88, 169.02; IR (KBr) 3308, 2982, 1713,
1638, 1516, 1192 cm“; HRMS calcd for CuHaoNgo. m/z
328.1423, obsd m/z 328.1411.

33)
1
1H).
1H).
00(d.
NMR

J. Org. Chem, Vol. 62, No.4, 1997 1041

181): 0.039 g, 0.150 mmol, 78% yield; mp 225-226 °C; 1H
NMR(300MHz,CDCh)6 1.33(t,J=7.1Hz,3H),2.18(s,3
H), 221(quint, J = 7.7 Hz, 2 H), 3.50 (t, J= 7.7 Hz, 2 H),
4.16 (t, J= 7.7 Hz, 2 H), 4.28 (q, J = 7.1 Hz, 2 H), 8.14 (bs, 1
H), 8.85 (s, 1 H); 1‘C NMR (75 MHz, CDCh) 6 14.31, 20.99,
24.63, 33.04, 49.43, 60.78, 106.11, 122.55, 126.13, 149.57
156.83, 164.86, 168.80; IR (KBr) 3297, 2982, 2936, 1715, 1684,
1636, 1532, 1196, 1100 cm"; HRMS calcd for CnHuNgO, ru/z
264.1110, obsd m/z 264.1108.

fl: 0.21 g, 0.59 mmol, 71% yield; mp = 128—129 ’C; 1H
NMR (300 Hz, CD015) 6 2.19 (s, 3 H), 3.79 (s, 3 H), 3.85 (s, 3
H), 5.26 (s, 2 H), 7.19—7.32 (m, 5 H), 8.34 (be, 1 H), 8.84 (s, 1
H); 1’C NMR (75 MHz, CD013) 6 24.67, 50.44, 52.62, 53.41,
109.06, 120.06, 127.36, 128.04, 128.61, 128.83, 134.77, 138.14,
157.02, 163.12, 164.18, 169.23; IR (KBr) 3374, 3021, 2955,
1728, 1691, 1645, 1516, 1437, 1215 cm"; HRMS calcd for
CuH15N30. m/z 358.1165, obsd m/z 358.1153.

31a: 0.21 g, 0.56 mmol, 76% yield; mp 180-181 °C; 1H NMR
(300 MHz, acetone-414M 2.10 (s, 3 H), 2.42 (s, 3 H), 4.55 (d, J
= 6.0 Hz, 2 H), 5.51 (s, 2 H), 7.12-7.16 (m, 2 H), 7.19-7.56
(m, 8 H), 8.18 (t, J = 6.0 Hz, 1 H), 8.54“, 1 H), 8.96 (s, 1 H);
”C NMR (75 MHz, acetone-ck) 6 17.28, 24.36, 44.20, 48.79,
108.50, 122.42, 127.30, 127.83, 128.13, 128.45, 129.21, 129.51,
129.60, 136.99, 137.25, 145.43, 158.59, 168.47, 169.97; IR (KBr)
3299, 3067, 3034, 2880, 1705, 1634, 1507, 1476, 1248, 1003
cm“; HRMS calcd for W301 m/z 389.1739, obsd m/z
389.1762.

31h: 0.16 g, 0.35 mmol, 55% yield; mp = 155-156 °C; 1H
NMR(300MHz,CDCh)6 124(t,J=7.2Hz,3H),2.18(s,3
H), 2.50 (a, 3 H), 4.260], J = 7.2 Hz, 2 H), 4.57 (dd, J = 5.6,
1.7 Hz, 2 H), 6.12 (s, 1 H), 6.19 (m, 1 H), 7.19—7.43 (m, 10 H),
8.27 (s, 1 H), 8.53 (s, 1 H); “C NMR (75 MHz, CDCh) 6 14.10,
17.52, 24.67, 44.28, 62.11, 62.69, 116.21, 120.69, 126.86,
127.73, 127.85, 128.15, 128.54, 128.62, 128.85, 133.01, 137.69,
139.77, 140.51, 167.20, 167.38, 169.27; IR (KBr) 3280, 2960,
2920, 1736, 1647, 1516, 1455, 1217 cm"; HRMS mld fir
ammo. m/z 461.1951, obsd m/z 461.1901.

31c: 0.31 g, 0.15 mmol, 80% yield; mp = 177-180 'C; 1H
NMR(300MHz,acetone-d¢)6 1.21(t,J=7.1Hz,3H),2.11
(s, 3 H), 2.48 (s, 3 H), 4.10 (d, J = 6.0 Hz, 2 H), 4.13 (q, J= 7.1

- Hz, 2 H), 5.54 (s, 2 H), 7.14-7.17 (m, 2 H), 7.24-7.56 (m, 3

H), 8.01 (t, J = 6.0 Hz, 1 H), 8.54 (s, 1 H), 9.04 (s, 1 H); rec
NMR (75 MHz, acetone-dc) 6 14.42, 17.22, 24.38, 42.21, 48.85,
61.,47 108.,55 122.56,127.3,0 129.21,129.52,129.,62 137.19,
145. 59, 158.,65 168.80,170.10,170.28;IR (KBr) 3277, 3032,
1748,1671,1644,1512, 1210,1003 cm"; HRMS caldfor
CsersNrOs m/z 385.1638, obsd m/z 385.1623.

31d: 0.32 g, 0.70 mmol, 60% yield; mp = 204-205 °C; IH
NMR(300MHz,0D01;)6 1.24(t,J=7.2Hz,3H), 1.28(t,J
= 7.2 Hz, 3 H), 2.17 (s, 3 H), 2.49 (s, 3 H), 4.13-4.29 (m, 6 H),

- 6.14 (s, 1 H), 6.55 (ha, 1 H), 7.26—7.48 (m, 5 H), 8.32 (s, 1 H),

8.55 (s, 1 H); ”C NMR (75 MHz, CDCh) 6 14.08, 17.53, 24.54,
41.88, 61.74, 62.17, 62.65, 112.68, 115.71, 121.15, 126.60,
128.08, 128.59, 128.92, 132.86, 134.72, 140.19, 157.78, 167.40,
167.67, 169.65; IR (KBr) 3314, 2986, 1744, 1645, 1524, 1217,
1082, 1003 cm"; HRMS calcd for 03111711307 m/z 457.1849,
obsd m/z 457.1853.

35b: 90:5:5; EtsOIpetroleum ether/MeOH; 0.20 g, 0.46 mmol,
40% yield; mp = 90-91 °C sealed, dec.; 1H NMR (300 MHz,
CDCla)60.63(d,J=6.9Hz, 3H),0.97(d,J=6.9Hz,3H),
1.01(d,J=6.9Hz,3H), 1.24(d,J=6.9 Hz,3H),2.13(s, 3
H), 2.19-2.32 (m, 2 H), 2.49 (ha, 3 H), 3.60 (s, 3 H), 3.76 (s, 3
H), 4.32 (bs, 1 H), 4.65 (dd, J = 4.5, 8.7 Hz, 1 H), 6.45 (d, J =
8.7Hz, 1H),8.19(bs, 1H),8.53 (s, 1H); “CNMR(75MHz,
CD01;) 6 17.6, 17.8, 18.9, 19.1, 22.2, 24.4, 26.8, 31.2, 52.2, 52.3,
57.6, 64.9, 115.5, 120.8, 126.3, 139.6, 157.2, 167.5, 168.9, 169.1,
172.1; IR (CHCh) 3305, 3015, 2971, 2876, 1748, 1653, 1611,
1522, 1215 cm”; ms calcd for Gamma, m/z 437.2162,
obsd m/z 437.2158.

Oxidation of 17a with MnOa Compound 17a (028g, 0.89
mmol) and Moo. (0.46g, 5.3 mmol) were combined and
suspendedinzylenes(20mL). Themixurrewasheatedunder
anairatmospherewithazsotr-opicrernovalofHaofor16h.fl
Afierthereacfionmixturewascooledtorcomtemperature,
thesolutionwasfilteredtbroughCeliteandconcentr-atedin
mo. Purificationwasaccomplishedviaflashcolumncbro-

172

1042 J. Org. Chart, Val. Q, No. 4, 1997

matography (80:20 EtOArJ‘petI-oleum other) to give 18a (0.25
g, 0.80 mmol) in 90% yield.

GeneralMethodfortheHydrelyaiaofEstes-sand
Amides. A mixture of the pyridone (0.5—2.0 ml. 1.0 equiv)
and KOH (20.0 equiv) was taken up in H20 (for hydrolysis of
esters) or 30% H202 (for hydrolysis of amides) (0.1 M with
respecttothepyridone). Afier14to38h,thereactionwas
extracted with CHCh, filtered, and neutralized with H01.
Compoundfihwas collectedbyfilu’ation, andtheunprotected
amino acids (19a and 1911) were collected by solvent removal
underreducedpressurefollowedbyextractionwithMeOHor
acetone. The products were then crystallized (MeOH/CHCI;
or MeOH/EtaO).

19a: 0.047 g, 0.183 mmol, 61% yield; mp 205-206 °C; 1H
NMR (300 MHz, DMSO-d.) 6 2.46 (s, 3 H), 5.46 (s, 2 H), 7.07—
7.54 (m, 5 H), 8.02 (s, 1 H); nC NMR (75 MHz, DMSO-d.) 6
16.83, 30.74, 115.41, 127.05, 128.34, 129.37, 129.86, 133.98,
135.86, 137.69, 160.60, 169.74; IR (KBr) 2928, 1709, 1640,
1549, 1455, 1256, 1024 cm“; HRMS alcdforCuHuNgOa m/z
258.1004, obsd m/z 258.0967.

”a: 0.48 g, 2.03 mmol, 61% yield; mp >260 °C; xH NMR
(300 MHz, acetone-(lg) 6 2.07 (s, 3 H), 2.70 (s, 3 H), 5.55 (s, 2
H), 7.17 (d, J = 6.9 Hz, 1 H), 7.26-7.35 (m, 4 H), 8.98 (s, 1 H);
1’C NMR (75 MHz, acetone-d.) 6 17.09, 24.32, 48.52, 106.25,
123.00, 127.10, 128.14, 129.62, 130.55, 133.29, 137.24, 158.84,
167.42, 171.53; IR (KBr) 3277, 3031, 1692, 1622, 1603, 1553,
1387, 1190 cm"; HRMS ulcd for CufiszaO. m/z 300.1110,
obsd m/z 300.1096.

191): 0.061 g, 0.314 mmol, 82% yield; 1H NMR (300 MHz,
DMSO-d.)62.03(quint,J= 7.6Hz, 2H), 325(t,J= 7.6Hz,
2H),3.95(t,J=7.6Hz,2H), 6.91(s, 1H);“CNMR(75
MHz, DMSO-d.) 6 21.09, 32.45, 48.73, 111.03, 128.51, 129.14,
135.41, 143.12, 156.81; IR (KBr) 3364, 1698, 1615, 1536, 1117
cm"; HRMS calcd for CgHmNzO; m/z 194.0692, obsd m/z
194.0681.

Formation o! 21a. To a solution offla (0.20 g, 0.85 mmol)
in THF (8.5 mL) was added NaH (0.92 g, 0.85 mmol) at -78
IC. Et03001 (0.081 m1, 0.85 mmol) was added to the martian
miztme followed by (thhsnylglycine ethyl ester (0.183 g, 0.85
mmol). Thereactionwaswarmedtoroomtemperatureand
wasstirredfor2h. Saturated aqueousNaHCOs(ezcess)was
added,andthemixtmewasextractedwithEt0Ac. The
combinsdorganicfi'actionsweredriedoverNaasoiand
filteredandthesolventwasevaporatedunderreducedpres-
sure. 'lhecrudeproduetwaspurifiedbyflashcolumnchro—
matography (EhO/EtOAc/MeOI-I) to give 21a (0.29 g, 0.66
mmol, 78% yield): mp 209—210 °C; 1H NMR (300 MHz, CDCh)
6 1.22 (t, J= 7.1 Hz, 3 H), 2.17 (s, 3 H), 2.42 (s, 3 H), 4.17 (dq,
J = 10.7, 7.1 Hz, 1 H), 4.25 (dq, J = 10.7, 7.1 Hz, 1 H), 5.38 (s,
2H),5.63(d,J=7.1Hz, 1H),6.98(d,J=7.1Hz, 1H), 7.09

(d, J = 6.5 Hz, 2 H), 7.25-7.44 (m, 8 H), 8.37 (s, 1 H), 8.55 (s, .

1 H); 1’C NMR (75 MHz, CD013) 6 13.90, 16.88, 24.43, 48.53,
57.22, 61.99, 126.20, 126.31, 127.33, 127.63, 128.49, 128.57,
128.84, 128.96, 135.02, 135.89, 140.32, 157.95, 166.84, 169.61,
170.58; IR (KBr) 3324, 3019, 1736, 1636, 1514, 1217 cm“;
HRMS calcd for CssHs'leOs m/z 461.1951, obsd m/z 461.1939.

Formation M27. Enamine 25 (0.24 g, 1.05 mmol) was
dissolved in EtOH (10.5 mL), and New, (0.39 g, 3.67 mmol)
anle%Pd/C(0.10g)wereadded. Thereactionmixturewas
placednnderanaunosphereong. Afterstirringfor 16h,
thereactionmixtmewasfiltered, andtheaolventwasremoved
underreducedpreuure. Theresultingcrudeoilwasptn'ified
by flash column chromatography (EMU). Removal of solvent
pnewhiunfidwhiehmaystdhzedfiommAetogive
fluamiztmeofdiastereomers(96:4productratio,0.23g,
0.99 mmol, 94% yield): mp 202—205 °C; 1H NMR (300 MHz,
CD014.) (major diastereomer) 6 1.16 (t, J = 7.2 Hz, 3 H), 2.00
(s, 3 H), 2.32 (q. J = 13.7 Hz, 1 H), 2.55 (m, 1 H), 2.93 (dt, J
= 13.7, 4.4 Hz, 1 H), 3.21 (dd, J = 13.7, 7.4 Hz, 1 H), 3.29 (d,
J = 15.2 Hz, 1 H), 3.90 (dq, J = 10.8, 7.1 Hz, 1 H), 4.01(dq, J
= 10.8, 7.1 Hz, 1 H), 4.07 (m, 2 H), 5.24 (d, J = 15.2 Hz, 1 H),
7.00 (dd, J= 7.5, 1.9 Hz, 2 H), 7.12 (d, J= 6.4 Hz, 1 H), 7.21-
7.34(m, 8H); uCNMR(75MHz,CD013)(majordiastereome'r)
6 13.92, 22.87, 25.69, 37.30, 42.80, 49.65, 50.81, 58.76, 60.95,
126.77, 127.37, 127.47, 128.51, 128.57, 129.34, 136.80, 138.09,
169.14, 170.45, 170.52; IR (solid/NaCl) 3297, 3067, 3009, 1732,

Beholzetal.

1642, 1541, 1455, 1217 cm“; HRMS calcd for Wroc ml:
408.2049, obsd m/z 408.2075.

General Method flor- Aza-Amlatlen with 39. The
corresponding enamine (0.78—2.6 mmol) was dissolved in
anhydrous DMF (0.26 M) and 39 (1.0 equiv) was added. After
thereactionmizturewasheatedtorefluxfor2h,thedark
hrownsolutionwasconcentratedtoanoilmoilingwaterbath),
andthecrudeproductwaspurifiedbyflashcolumnchroma-
tography (310,, 230—400 mesh, EEO/petroleum ether/MeOH
= 48:48z4).

41:0.18g,0.38mmol, 49%yield;1HNMR(300MHz,CDCh)
60.57 (d,J=6.9Hz,3H), 120(d,J=6.3Hz,3H),2.50(s,
3 H), 2.93 (m, 1 H), 3.61 (s, 3 H), 4.32 (m, 1 H), 4.49 (dd, J =
14.7, 5.7 Hz, 1 H). 4.54 (dd, J = 15.6, 5.7 Hz, 1 H), 6.67 (ht, J
= 5.1 Hz, 1 H), 7.16-7.32 (m, 5 H), 7.32-7.41 (m, 2 H), 7.46
(m, 1 H), 7.74-7.81 (m, 2 H), 8.59 (s, 1 H), 8.95 (bs, 1 H); 1"C
NMR (75 MHz, CDCI.) 6 17.8, 18.9, 22.2, 26.8, 44.2, 52.4, 65.0,
115.9, 121.0, 126.2, 127.0, 127.6, 127.9, 128.7, 132.3, 133.6,
137.8, 140.0, 157.5, 165.8, 167.4, 169.0; IR (CHCh) 3372, 3015,
2971, 1750, 1638, 1611, 1582, 1520, 1491, 1389, 1275, 1215,
1024 cm"; HRMS calcd for Crimson m/z 475.2107, obsd
(M + 1) m/z 476.2174.

4&0.62g, 1.31mmol, 71%yield; 1HNMRGiOOMHz,CD01.)
60.85 (d,J=6.9Hz, dimer), 0.89(d,J= 6.9Hz, dimer), 1.00
(d,J= 6.8Hz, 3 H), 1.01 (d, J= 6.8 Hz, 3 H), 2.08011, dimer),
2.17 (s, dimer), 2.20 (s, 3 H), 2.24 (m, 1 H), 3.63 (a, M),
3.70 (s, 3 H), 4.44 (dd, J = 8.5, 5.1 Hz, dimer), 4.56““, J =
8.5,5.2Hz, 1H).5.03(bd,J= 15.7Hz, 1H),5.31(bd,J=
15.7 Hz, 1 H), 6.99 (d, J = 6.6 Hz, 2 H), 7.12-7.24 (m, 3 H),
7.34-7.52 (m, 3 H), 7.82 (d, J = 7.8 Hz, 2 H), 8.63 (s, 1 H),
9.09 (s, 1 H); “C NMR (75 MHz, CDCla) 6 16.6, 17.6, 18.1,
18.9, 19.1, 30.8, 48.3, 52.0, 52.1, 57.0, 57.9, 58.0, 115.65, 115.70,
121.0, 121.1, 125.8, 125.9, 126.2, 127.0, 127.2, 127.6, 128.6,
128.8, 132.1, 133.4, 133.5, 135.0, 140.0, 158.0, 158.1, 165.55,
165.63, 167.7, 167.8, 171.9, 172. 1; IR (neat) 3306, 2967, 1744,
1646, 1522, 1210, 1154 cm"; HRMS calcdforCaszsNrOsm/z
475.2107, obsd (M + 1) m/z 476.2172.

44:0.75g, 1.50mmol, 81%yield: 1HNMR(300MIHzJIDCl.)
6 0.50 (d, J = 6.6 Hz, 3 H), 0.80—0.90 (m, minor), 0.94 (d, J '
7.9Hz,3H),0.98(d,J=7.9Hz,3H), 1.17(d,J= 6.3Hz,3
H), 2.08 (m, minor), 2.21 (m, 1 H), 2.43 (s, 3 H), 2.88 (m, 1 H),
3.60 (s, 3 H), 3.62 (s, minor), 3.70 (s, 3 H), 4.29 (bd, J = 6.3
Hz, 1 H), 4.43 (dd, J = 8.3, 5.0 Hz, minor), 4.58 (dd, J = 8.3,
5.0 Hz, 1 H), 6.89 (bd, J = 6.6 Hz, 1 H), 7.30-7.50 (m, 3 H),
7.80 (d, J = 7.1 Hz, 2 H), 8.49 (s, minor), 8.66 (s, 1 H), 8.95
(ha, 1 H), 9.67 (ha, minor); 1’0 NMR (75 MHz, CD00 6 17.6
(minor), 18.0,.18.8 (minor), 19.0, 22.0 (miner), 30.8 (minor),
31.0, 49.3 (minor), 51.9 (minor), 52.1, 52.3, 57.1(minor), 57.8,
115.7, 121.0, 126.2, 127.0, 127.3 (minor), 128.4 (minor), 128.6,
128.8 (minor), 132.1, 133.6, 139.6, 165.6, 167.6, 172.1; IR (neat)
3366, 3305, 2969, 1742, 1640, 1613, 1516, 1389, 1380, 1271,
1210 cm"; HRMS calcd fior CasHaNaO‘: m/z 499.2319, obsd
m/z 499.2323.

Aetnow t. Support from the National In-
stitutes of Health (GM44163) is gratefully acknowl-

edged. Spectrelproductcharactmizationwasperformed

onNMRinstrumentationpurchasedinpartwithfunds
from NIH grant 1-SlO-RR04750 and from NSF grant
CI-IE-88-00770. The assistance of Susan Reutzel and
Victoria Russell was invaluable for the structural
analysis of 30c. N.S.B. wishes to thank the Organic
Division ofthe American Chemical Society and Pfizer,
Inc., for a Division ofOrganic Chemistry Graduate
Fellowship, andtheGeneralElectrieCo.foranAca-
demic Incentive Fellowship.

Supper-“MAW X-raydatalhrstruc-
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