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This is to certify that the

dissertation entitled

AZA-ANNULATION :

METHODOLOGY DEVELOPMENT
AND
APPLICATIONS IpNeéIfiMbQID SYNTHESIS

 

Kumarapandian Paulvannan

has been accepted towards fulfillment
of the requirements for

Ph . D . degree in Chemistry

 

l A1421!

Major professor

Date September 15, 1993

 

MSUL: an Affirmative Action/Equal Opportunity Institution 0- 12771

 

 

 

 

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AZA-ANNULATION:

METHODOLOGY DEVELOPMENT
AND
APPLICATIONS IN ALKALOID SYNTHESIS

By

Kumarapandian Paulvannan

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1993

ABSTRACT

AZA-ANNULATION:
METHODOLOGY DEVELOPMENT

AND
APPLICATIONS IN ALKALOID SYNTHESIS

By

Kumarapandian Paulvannan

Aza-annulation is an elegant method for the preparation of six-membered lactams
from the reaction of imine-enamine tautomers with a,B-unsaturated acid derivatives. The
aza-annulation process was systematically studied to define its mechanism and limitations
as well as to apply this methodology in alkaloid synthesis.

Reaction of imines with a,B-unsaturated acid chlorides gave a mixture of acyclic
enamides and six-membered lactams. With triethylamine in the mixture, the reaction of
imines and a,B-unsaturated acid chlorides gave acyclic enamides as the major product.
Changing from acid chlorides to other acid derivatives, such as a,B-unsaturated acid
anhydrides, (MB-unsaturated acids in the presence of diphenylphosphoryl azide or ethyl
chloroformate. predominantly gave lactams as the major product. The presence of a
substituent in the a position of the (LB-unsaturated acid derivatives exhibited a steric effect
during the carbon-carbon bond formation, and gave 36-63% of acyclic enamides along
with lactams. The reaction of a,B-unsaturated acid chlorides and anhydrides with bulky
N-substituted imines predominantly gave six-membered lactams. Acyclic imines were
sensitive to acids and gave a considerable amount of side products during the aza-

annulation. Mechanistic studies of the aza-annulation showed that this annulation took

place via initial Michael addition of the enamine tautomer onto the a,B-unsaturated acid
derivative followed by intramolecular N-acylation.

The aza-annulation was also carried out on enamines conjugated with electron
withdrawing groups. In contrast to the reaction of imines with a,B-unsaturated acid
chlorides, these reactions gave only six-membered lactams and in high yield. Catalytic
hydrogenation of the annulated products obtained from enamino ester and enamino amide
gave excellent cis selectivity (>95:S). Other electron withdrawing groups, such as
phosphate and ketones, gave poor selectivity.

The cis decahydroquinoline alkaloid, (:t)-5-epipumiliotoxin C, was synthesized
from readily available 1,3-cyclohexanedione. The quinolizidine alkaloid (t)-lupinine and
indolizidine alkaloids (i)-tashiromine and (:lz)-5-epitashiromine were synthesized starting
from a common acyclic starting material, ethyl acetoacetate. Aza-annulation was used as
the key reaction for the construction of the octahydroquinolone ring skeleton. Catalytic
hydrogenation was used to establish the cis stereochemistry of (i)-5-epipumiliotoxin C,

(2t)-lupinine and (:t)-5—epitashiromine.

To my wife Susila
and
daughters Devi and Kiruthika

iv

ACKNOWLEDGMENTS

Foremost, I would like to thank my advisor professor John Stille for his guidance,
patience, and understanding during my studies at Michigan State University. Joining his
research group was one of the best decisions I ever made. He allowed me to pursue my
research interests and spent a great deal of time listening to my suggestions and criticisms
and for that I will be forever grateful. I would also like to thank my graduate committee
members, Dr. Eugene Le Goff, Dr. George Leroi, and Dr. John Allison for their help and
understanding.

I would like to thank Art, Greg and Nancy for their help and for being my official
proofreaders throughout my graduate career. I would also like to thank Subramani and
Brian for their help and moral support. I am going to miss my company Greg, Lisa Cook
and Subramani. My thanks to "Big" Dave, Lars, and Steve for all their help. I would also
like to give my appreciation to Petr and Carol. _

I would like to acknowledge professors William Fold (Wright State University) and
T. Rangarajan (Annamali University). They provided me with the incentive and
encouragement to pursue my graduate career.

I would like to acknowledge my parents and Susila's parents for their caring love,
kindness and support. I would also like to extend my acknowledgment to our family
members and friends in India.

Finally, I take this opportunity to thank my wife and my daughters for their love,

understanding, caring and support.

TABLE OF CONTENTS

LIST OF TABLES ...........................................................................
LIST OF SCHEMES ........................................................................
LIST OF FIGURES ..........................................................................
LIST OF ABBREVIATIONS ...............................................................
CHAPTER I. AZA-ANNULATION OF [MINES
INTRODUCTION ...................................................................
a. Reactions of Imines with a,B-unsaturated Acid Chlorides ..................
b. Reactions of Imines with a,B-unsaturated Acids .............................
c. Reactions of Imines with a,B-unsaturated Esters .......................... -
(1. Reactions of Imines with a,B-unsaturated Amides ............................
e. Reactions of Imines with a,B-unsaturated Anhydrides .......................
RESULTS AND DISCUSSION ...................................................
a. Acrylic Acid Derivatives ..........................................................
b. a or B-Substituent Effect .........................................................
c. Methacrylic Acid Derivatives .....................................................
d. Crotonic Acid Derivatives ........................................................
e. Nitrogen Substituents ..............................................................
f. Mechanistic Discussion of Aza-Annulation ......................................
CONCLUSION .......................................................................
EXPERIMENTAL SECTION .......................................................
REFERENCES ........................................................................

E:

2

3

7

9
10
ll
13
l3
19
19
21
23
31
34

36
50

CHAPTER II. AZA-ANNULATION OF ENAMINES

INTRODUCTION ..................................................................... 54
a. Reactions of Enamines with a,B-unsaturated Acid Chlorides ................. 55
b. Reactions of Enamines with a,B-unsaturated Esters ........................... 57
c. Reactions of Enamines with a,B—unsaturated anhydrides ...................... 61
(1. Reactions of Enamines with a,B-unsaturated Acids ............................ 63
RESULTS AND DISCUSSION .................................................... 65
CONCLUSION ......................................................................... 79
EXPERIMENTAL SECTION 80
REFERENCES ......................................................................... 95

CHAPTER III. TOTAL SYNTHESIS OF (i)-5-EPIPUMILIOTOXIN C
195A AND APPROACHES TO THE SYNTHESIS OF
(i)-PUMILIOTOXIN C 195A

INTRODUCTION .................................................................... 98
RESULTS AND DISCUSSION ................................................... 104
a. 8N2 Displacement Reaction Approach .......................................... 105
b. Wittig Reaction Approach ......................................................... 106
c. Radical Deoxygenation Approach ................................................ 109
CONCLUSION ....................................................................... 113
EXPERIMENTAL SECTION ....................................................... 115
REFERENCES ........................................................................ 123
CHAPTER rv.’ TOTAL SYNTHESIS or (:t)-LUPININE AND
(:t)-TASHIROMINE
INTRODUCTION .................................................................... 126
a. Lupinine ............................................................................ 126
b. Tashiromine ....................................................................... 128

RESULTS AND DISCUSSION ..................................................

a. Total Synthesis of (:t)-Lupinine .................................................

b. Total Synthesis of (TD-Tashiromine ............................................

CONCLUSION ......................................................................

EXPERIMENTAL SECTION .....................................................

REFERENCES ......................................................................
REPRINTS OF PUBLICATIONS

Table I.
Table II.
Table III.
Table IV.
Table V.
Table VI.
Table VII.
Table VIII.
Table IX.
Table X.
Table XI.
Table XII.
Table XIII.
Table XIV.
Table XV.
Table XVI.
Table XVII.

Table XVIII.

Table XIX.
Table XX.
Table XXI.
Table XXII.

Table XXIII.

LIST OF TABLES

The Reaction of Imine 52 with Acrylic Acid Derivatives ................. 14
The Reaction of Imine 60 with Acrylic Acid Derivatives ................. 16
The Reaction of Imine 65 with Acrylic Acid Derivatives ........... _. ..... 18
The Reaction of Imine 52 with Methacrylic Acid Derivatives ............ 20
The Reaction of Imine 60 with Methacrylic Acid Derivatives ............. 21
The Reaction of Imine 52 with Crotonic Acid Derivatives ................ 22
The Reaction of Imine 60 with Crotonic Acid Derivatives ................ 23
The Reaction of Hydrazone 76 with Acrylic Acid Derivatives ........... 23
The Reaction of Imine 23 with Acrylic Acid Derivatives ................. 24
The Reaction of Imine 23 with Methacrylic Acid Derivatives ............ 25
The Reaction of Imine 23 with Crotonic Acid Derivatives ................. 26
The Reaction of Imine 83 with Acrylic Acid Derivatives .................. 27
The Reaction of Imine 83 with Methcrylic Acid Derivatives ............. 28
The Reaction of Imine 83 with Crotonic Acid Derivatives ................ 29
The Reaction of Imine 90 with Acrylic Acid Derivatives ........... ..... 30
The Reaction of Imine 90 with Crotonic Acid Derivatives ................ 31

Reaction of Enamino Esters 108 and 109 with a,B—unsaturated

Acid Chlorides and Esters ..................................................... 56
Aza-Annulation of Enamino Ketones ........................................ 69
Aza-Annulation of Acyclic Enamino Esters ................................. 71
Aza-Annulation of Cyclic Enamino Esters .................................. 72
Aza—Annulation of Cyclic Enamino Esters .................................. 75
Aza-Annulation of Enamino Amides ......................................... 76
Aza-Annulation of Various Enamines ....................................... 78

Scheme L
Scheme 11.
Scheme III.
Scheme IV.
Scheme V.
Scheme VI.
Scheme VII.
Scheme VIII.
Scheme D(.
Scheme X.
Scheme XI.
Scheme XII.
Scheme XIII.
Scheme XIV.

LIST OF SCHEMES

Proposed Mechanism for Aza-Annulation .................................. 4
Formation of 1-Aza-1,3-Butadiene From Imine 60 ....................... 17
Reaction of Imine 95 with Dimethyl Maleate ............................... 32
Reaction of Enamino Ketone 160 with Acrylic Acid Derivatives ....... 65
Retrosynthetic Analysis of (:l:)-Pumiliotoxin C ............................ 104
Total Synthesis of (:l:)-S-Epipumiliotoxin C (259) ....................... 113

General Routes for the Establishment of Lupinine Stereochemistry.... 127

Asymmetric Synthesis of (—)-Tashiromine ................................. 129
Retrosynthetic Analysis of (i)-Lupinine (3) .............................. 131
The Total Synthesis of (i)-Lupinine (3) ................................... 133
Retrosynthetic Analysis of (21:)-Tashiromine (269)..................;.... 134
Total Synthesis of (:t)-5-Epitashiromine (270) ........................... 135
Alternate Synthesis of (:t)-5-Epitashimmine (270) ....................... 136
Conversion of (i)-5-Epitashiromine to (i)-Tashiromine ................. 137

LIST OF FIGURES

Figure 1. Structure of Compound 166 ................................................ _ 67

AIBN

Bn

Bu
n-Bu3SnH
n-BuLi
CHzClz
C6H6

DPPA

EtzO

IDA
MCPI

LIST OF ABBREVIATIONS

Azobisisobutyronitrile
Benzyl

Butyl

Tributyan Hydride
n-Butyllithium

Methylene Chloride
Benzene

Carbon disulfide
Dicyclohexylcarbodiimide
Diisobutylaluminum Hydride
4—Dimethylaminopyridine
NJV-Dimethylformamide
Methyl Sulfoxide
Diphenylphosphoryl Azide
Ethyl

Ethyl Alcohol

Diethyl Ether

Lithium Aluminum Hydride
Lithium Diisopropylamide
Methyl-Z-Chloropyridinium Iodide
Methyl

Methyl Alcohol

NaBH4
Ni(acac)2

Methyl Iodide
Methanesulfonyl
Sodium Borohydride
Nickel acetylacetonate
Phenyl

Propyl

prropyl
Tetrabutylammonium Fluoride
ten-Butyldimethylsilyl
Triethylamine
Tetrahydmfuran
p-Toluenesulfonic Acid

CHAPT ER I

AZA-ANNULATION OF IMINES

INTRODUCTION

Saturated six-membered nitrogen heterocycles, such as piperidines,
decahydroquinolines, quinolizidines and indolizidines, occupy a pivotal position in
organic chemistry. A wide range of biologically important alkaloids (e.g. pinidine (l),
pumiliotoxin (2), lupinine (3), swainsonine (4)) possessing these skeletons have been

isolated and have been synthetic targets of organic chemists of several generations.1

OH
Me H H EHQOH HO :1
0 C0 “~60
N
Me“ N ‘A N 3"” Me N
l H l
H H
1 2 3 4'
Pinidine Pumiliotoxin C Lupinine Swainsonine
(Piperidine) (Hydroquinoline) (Quinolizidine) (Indolizidine)

Due to our interest in alkaloid synthesis, we wanted to develop a general
methodology that could be used to prepare a variety of six-membered nitrogen
heterocycles. Numerous methodologies have been reported for the construction of six-
membered nitrogen heterocycles, and these heterocycles have been utilized in natural
product synthesis.2 Among all the reported methodologies, the aza-annulation reaction3
attracted our attention because of its simplicity to make six-membered lactams. Aza-
annulation has been used to prepare six-membered lactams, l,2,3,4-tetrahydro-2-
pyridones (6), from the reaction of imines s with a,B—unsaturated acids (x = 0H),4 and
acid derivatives such as acid chlorides (X = Cl),3 esters (X = OR),5 and amides (X =

NH2)6 («11).

 

RH R‘ t (1’
R4

a) Reactions of Imines with (LB-Unsaturated Acid Chlorides

In 1971, Hickmott reported that reaction of imine ‘7 with acryloyl chloride gave a
1:1 mixture of lactam 8 and enamide 9 in the presence of triethylamine (TEA, eq 2).3a In
this case, TEA was added followed by the addition of acryloyl chloride to imine 7.
Without the addition of TEA to this reaction mixture, a 4:1 mixture of 8 and 9 was
obtained. These conditions produce a very inefficient reaction and caused the very low

yield of lactam 8.

 

CsfirrsN 8 9 - (2)

o
TEA
m Cl/H C696 26% 27%
+ ——'E: 38% 10%
7

Hickmott also studied the reaction of acryloyl chloride with the acyclic ketimine
10. Formation of a 3:1 mixture of cyclic lactam 11 and enamide 12 was observed upon
reaction of imine 10 with acryloyl chloride (eq 3). Lactam 11 was obtained in low yields

as an inseparable 1:3 mixture of exozendo double bond isomers. 3a

 

33 q, 14 %
(azb, 3:1)

Hickmott suggested a mechanism for the formation of lactam 8 and enamide 9
from the reaction of imine 7 with acryloyl chloride (Scheme 0.3a He proposed that N-
acylation of the enamine tautomer 13 gave 14, which after [3,3] sigmatropic
rearrangement, gave ketene 15. The loss of a proton from 14 gives neutral enamide 9,
while attack of nitrogen on the ketene carbon of 15 gives lactam 8. In the presence of

TEA, enamide 9 would be the major product because of the removal of proton from 14.

Scheme I. Proposed Mechanism for Aza-Annulation.

r R2
Rz'conll
R =Me

 

5
Imine 16 is in equilibrium with its enamine tautomer l7 (eq 4). In this case, the
enamine form is not stabilized by further conjugation. As a result, the equilibrium is
predominantly in favor of the imine 16. On the other hand, imine 18 is stabilized by
further conjugation, and the equilibrium lies in favor of the enamine form 19 (eq 5). The
imine-enamine tautomer equilibrium has been confirmed by spectral studies.7

 

 

R‘ R
N ‘NH
- —- (5
16 17
favored
R‘ R‘
N NH
— ~t
o o
18 19
favored

Using Hickmott's conditions, Ninomiya prepared a 4:1 mixture of lactam 21 and
enamide 22 in 66% yield from the reaction of imine 20 and methacryloyl chloride (eq 6).
Even though considerable amount of enamide 22 was isolated along with lactam 21, this
annulation regioselectively gave the six-membered lactam in one step. The lactam 21
was an important intermediate in the synthesis of the alkaloid costaclavine, and this

annulation was used as the key step for construction of the six-membered lactam.8

 

 

20 21 22

Ninomiya prepared lactams 26 and 27 from the reaction of imine 23 with acryloyl
chloride and cinnamoyl chloride, respectively (eq 7).9 On the other hand, enamides 24
and 25 were prepared from the reaction of imine with the corresponding acid chlorides
and TEA. Lactams 26 and 27 were prepared by irradiation of enamides 24 andn25 under
conditions of high dilution (0.02 M). Since photocyclization of enamides into lactams
requires very dilute conditions, this route cannot be used to prepare lactams efficiently in

bulk amounts.

 

(7)

23 58% =I-I 24 61%
R=Ph 25

 

Danieli developed several pathways to prepare lactam 30 from imine 28.4a In one
approach, lactam 30 was prepared in 63% yield by heating imine 28 and acryloyl chloride
in refluxing acetoniuile with a catalytic amount of 4-dimethylaminopyridine (DMAP),

which is known to increase the reactivity of acyl groups (eq 8).10 Danieli demonstrated

7
the use of DMAP in avoiding the formation of enamide during the reaction of imine 28
with acryloyl chloride. Further chemical transformations were canied out to convert the

lactam 30 to the ebumane alkaloid apovincamine.

acrylic acid/p-xylene/9196
(I

r acrylic acid/DPPA/DMFDS‘JE 1

 

 

b) Reactions of Imines with a,B-Unsaturated Acids

In refluxing chlorobenzene, the reaction of acrylic acid with imine 7 produced
lactam s in 28% yield (eq 9).3a The reaction of imine 7 with acrylic acid required higher
temperatures than with acryloyl chloride, and the lactam 8 was isolated in low yield.

   

C6HII\N

O C6H11‘N
‘ Me Ho chlaubemene
+ Jk“ ,
23%
7

 

8

Heathcock used this methodology to prepare a key intermediate in the synthesis of
the alkaloid vallesamidine. A 6:1 stereoisomeric mixture of cyclic lactams 33 and 34 was
obtained in 42% yield from imine 31 and cinnamic acid (32, eq 10).4b Acyclic enamide
was not observed as a product of this reaction. The low yield of the lactams could have
been due to the steric effect of the B—phenyl group during C-C bond formation. Attempts
to cyclize the enamide, prepared from the imine and cinnamoyl chloride in the presence
of TEA, under thermal and acid catalyzed conditions gave only a trace of lactarrls 33 and
34.

N C00“ dioxaneretltut
+
q) ON (42%)
Et
3 l 3 2

 

ii

(10)

   

In Danieli’s second approach to apovincamine, lactam 30 was prepared in 91%
yield by heating acrylic acid and imine 28 to reflux in anhydrous p-xylene (eq 3).4a
Danieli also used acrylic acid in the presence of the acid activating reagent
diphenylphosphoryl azide (DPPA) which resulted in a 95% yield of the lactam 30. He
increased the scope of this annulation reaction by replacing the a,B-unsaturated acid
chloride with an a,B—unsaturated acid and DPPA to prepare lactams in high yields.

9

c) Reactions of Imines with (LB-Unsaturated Esters

Takahashi obtained lactam 38 in 7% yield along with mono and bis-C-alkylated
products 36 and 37 from the reaction of aldimine 35 and methyl acrylate (eq 11).11
Products 36 and 37 result from Michael addition reaction. The lactam 38 was also
prepared separately by heatng 36 in pyridine. Danieli reacted methyl acrylate with the
imine 28 in refluxing 1:1 benzene-methanol solution to give the C—alkylation product 29
(eq 8).4a The ester 29 was converted into lactam 30 in 52% yield by heating in p-xylene
for 96 h. The reaction of an a,B-unsaturated ester with an imine appears to be a two-Step

process requiring longer reaction times and more severe reaction conditions.

 

reflux/pyridine
1i
.. CH3 IN 0
ll
N+ ékmjfim reflux/16h ( )
CH
35 36
6% 366% 7%

R=CH(CH3)2 R1=COOMe

Aza-annulation has also been used to prepare indolizidine skeletons. Hua
prepared indolizidinone 40 in 60% yield from the reaction of methyl acrylate and «-
sulfinyl ketimine 39 (eq 12).5a The 1,4-addition reaction of the chiral a-sulfinyl
ketimine anion, derived from 39 and n-BuLi, with methylacrylate followed by
intramolecular N-acylation gave indolizidinone 40. Since esters are not good acylatin g
agents, n-BuLi was used in this reaction to initiate the intramolecular N-acylation after
the C-C bond formation. Hua also reacted the anion of the a-sulfinyl ketimine 41 with

the a-amidoacrylate 42 to give a 55% yield of indolizidinones 43 and 44 in a ratio of 3:2

10
(eq l3).5b After several reaction sequences, indolizidinone 43 was converted into (-)-
slaframine. Hua also studied this reaction with a variety of substituted acrylate
derivatives5c and applied this methodology in the asymmetric synthesis of various

indolizidine alkaloids such as alloyohimhan,5a elaeokanines Mali” and lupinine.5¢

 

 

O o .‘v
0 ' ' o ‘ e‘
e ,r n-BuLll-78 c s
‘ OMe > ‘ 12
Q’S‘Tol + {k TIE/60% N Tol ( )
o
3 9 4 0
(pram/ls o
‘ 0 i R -BuLi/-78 °c
[k‘s’ + 0M6 " =
N ‘Tol Tar/55%
4 1 4 2 (13)
§OTBDMS ’OTBDMS
0‘ a“ 0‘s;
RsNHCOzt-Bu N ‘T01 + N ‘Tol
O 3 O
R 3 2 R
4 3 4 4

(1) Reactions of Imines with (LB-Unsaturated Amides

Ninomiya prepared lactam 45 in 77% yield from the reaction of imine 23 with
acrylamide in the presence of a catalytic amount of p-toluenesulfonic acid (p-TsOI-I, eq
14).69 Lactam 45 was formed via initial conjugate addition of the enamine tautomer to
acrylamide followed by intramolecular C-N bond formation with elimination of
benzylamine. By refluxing acrylamide and imine 46 in methanol, Hickmott isolated
lactam 45 in 18% yield along with Michael addition products (eq 15).6b

ll

,CHzPh

N
TflH cat)
K + .é’lcm‘... - 04>
0 NH: ' 0/ N

 

 

77% .
H
23 45
NAC2H5
f “6"“ 1?.
+0 = a
o N": 8% o N
H ,
46 45

e) Reactions of Imines with cab-Unsaturated Anhydridas

Kametani attempted to synthesize benzoquinolizines from the reaction of crotonic
anhydride (48) and imine 47 in the presence of pyridine (eq 16). 12 Only enamide 49 was
obtained as the major product. The formation of enamide 49 could be due to the steric
effect exhibited by B-methyl group of the crotonic anhydride. Attempts to cyclize the
enamide 49 using irradiation or treatment with acids, including various Lewis acids,
resulted in failure. He prepared benzoquinolizinone 51 in 56% yield by reacting imine 47
with glutaconic anhydride (50 eq 17). Glutaconic anhydride did not behave as previous
a,B-unsaturated acid derivatives. He proposed that compound 51 could have formed by
nucleophilic attack of the methylene carbon of the anhydride at imine carbon followed by
N-acylation and subsequent decarboxylation.

0 O O .. Mao
to}: W - Jag.
MeO
Me Me CH2
Me
49

47 48

 

 

 

 

50

From the literature survey on aza-annulation, we have found that the aza-
annulation has not been extensively studied and efficiently utilized in organic synthesis.
In order to make this reaction valuable for organic synthesis, especially in alkaloid
synthesis, we decided to re investigate this reaction with the following goals:

1) Selectivity:

To selectively prepare lactams in high yield from the reaction of imines with (1,3-
unsaturated acid derivatives.

2) mB-Unsaturated acid derivatives:

To study the reaction of imines with a variety of a,B—unsaturated acid derivatives,
such as anhydrides and carboxylic acids activated by various acid activating reagents.

3) Substituent effect:

a) To study the effect of a-substituted or B-substituted acid derivatives on the product
distribution and yield of the reaction.

b) To carry out this annulation with different N—substituted imines to gain an insight

on the mechanism of this annulation reaction.

13
RESULTS AND DISCUSSION

a) Acrylic Acid Derivatives

Initial optimization studies were conducted with the reaction of imine 52 and acrylic
acid derivatives (eq 18). Imine 52 was prepared from isobutyl amine and cyclohexanone
in 87% yield by azeotropic removal of H20 via modified Dean-Stark trap designed in our
laboratories. In order to find a suitable solvent to carry out this annulation, the reaction of
imine 52 and acryloyl chloride was performed in a variety of solvents including benzene,
toluene, THF, DMF and CH3CN. The ratio of enamide 53 and lactam 54 was obtained
by gas chromatographic analysis and was found to vary according to solvent. Both THF
and DMF gave predominantly lactam 54. THFS low boiling point and ease of handling

made it a suitable salvent for this reaction.

”if” it Nth ”‘1,”
' (5 '* a

Reagent r

 

52 53 54

The optimized results of the reaction of imine 52 with various acrylic acid
derivatives are given in Table I. In the presence of TEA, reaction of imine 52 with acryloyl
chloride gave enamide 53 as the major product (entry 1). In the absence of TEA, lactam
54 was obtained as the major product (entries 2 and 3). Attempts to cyclize the enamide
53 into lactam 54 using acids, including various Lewis acids and thermal conditions, were
unsuccessful. Similar observations were reported previously by Heathcoclt,”'b

Hickmott,3a and Kametani.12 These observations provided evidence that enamide 53 was

14
not an intermediate in the formation of lactam 54. Only upon irradiation using very dilute

conditions, enamide 53 was converted into lactam 54.

Table I. The Reaction of Imine 52 with Acrylic Acid Derivatives.

 

Em X Reagent W Xilzltlsa 53.2.5.4 (LL11)
1 Cl TEA 66 °C / 7 h 68% 96 : 4 -
2 Cl - 25 °C/ 31 h 16% 23 : 77 (86: 14)
3 CI - 66°C/l7h 32% 13:87 (83: 17)
4 Cl H2CCH002N8 - 45 °C / 3 h 59% o : 100 (26: 74)
5 Cl H20014002Na 25 °C/ 1 h 67% 0 : 100 (45 : 55)
6 Cl H20€H002Na 66 °C/ 15 h 70% 0 : 100 (81 : 19)
7 Cl W 66°C/33h 81% 0:100 (74:26)
8 0H EtOzCCl 25°C/3.5h 77% 4:96 (34:66)
9 0H (PhO)2P(0)N 3 0 °C / 2 h 69% s : 95 (76 : 24)
10 on MCPI/NEt3 66 °c / 2 h 58% 21 : 79 (38 : 62)

 

aValuesrepleaentisolatedyieldsot‘themajorptoduct.

In order to Study the effect of the reaction of imines with various a,B-unsaturated
acid derivatives on product distribution (enamide vs lactam), a variety of acid derivatives
were considered. The order of increasing reactivity of the acylating agents are RCO-NRz <
R-COOH < R-COOR < acoocoa < R-COCI < R-CH=C=O.13 Initially, acrylic
anhydride, a relatively poor acylating agent compared to acryloyl chloride, was chosen.
Acrylic anhydride was prepared from the reaction of sodium acrylate with acryloyl
chloride. The reaction of anhydride with imine 52 gave lactam 54 as the major product
(entries 4 to 6, Table I). Lactam 54 was obtained as an inseparable mixture of double bond
isomers 54a and 54b. At low reaction temperatures, the double bond isomer 54b was the
major product, and at 66 °C, isomer 54a was the rmjor product. Attempts to isomerize the
mixture into a single isomer produced the 81: 19 thermodynamic mixture. In the next series

of experiments, acyl imidazole, another relatively poor acylating agent, was chosen.14 The

15
use of acyl imidazole resulted in the formation of only lactams 54a and 54b (entry 7).
The above results proved that the less reactive acylating agent was more efficient for lactam
formation.

A more efficient approach to activate carboxylic acids would eliminate the need for
acid derivatives such as chlorides and anhydrides. Acid activating agents that meet this
requirement are Mukaiyama’s reagent, Ph3P/Py282 (55),15 dicyclohexylcarbodiimide
(DCC, 56),16 ethyl chloroformate (57),17 diphenylphosphoryl azide (DPPA, 58),18 and
methyl-2-chloropyridinium iodide (MCPI 59).19 The aforementioned activating reagents
have been used by others to activate carboxylic acids to prepare amides, esters, B—lactams

and macrolides under mild conditions.

 

 

 

 

 

 

 

 

 

Imine 52 was reacted with acrylic acid in the presence of various activating agents
55 to 59. Mukaiyama’s reagent, 55 and DCC (56) gave lactam 54 in low yields, and
isolation of product was more difficult. Under mild conditions, acrylic acid, activated by
ethyl chloroformate (57), and DPPA (58) gave lactam 54 as the major product with a
trace of enamide. MCPI (59) gave more enamide 53 compared with activating agents 55
to 58. The formation of more enamide 53 might be due to the better leaving ability of N-

methylpyridininone or due to the presence of two equivalents of TEA.

16

Annulation of acyclic imine 60 with various acrylic acid derivatives was
investigated. Imine 60 was made from the condensation of butyraldeliyde and
isobutylamine in 76% yield. Imine 60 was treated with various acrylic acid derivatives (eq
19) and the results are given in Table II. The reaction of imine 60 with acryloyl chloride
gave enamide 61 as the major product both in the presence or absence of TEA (entries 1
and 2). Lactam 62 was obtained as the major product up on reaction with acrylic
anhydride (entry 3). For ease in the isolation of the lactam, the small amount of enamide
61 produced as a side product was selectively hydrolyzed by stirring with p-TSOH in
methanol at room temperature. Reaction of imine 60 with acrylic acid and ethyl
chloroformate gave enamide 61 as the major product (entry 4) and treatment of imine 60

with acrylic acid in the presence of DPPA provided lactam 62 as the major product in low
yield (entry 5).

O O 0
M’ " "Jl ”‘hNJW ”°Y‘N
Me = Me I + Me (19)
Rmnm
5‘ Et

3

60 61 62

Table II. The Reaction of Imine 60 with Acrylic Acid Derivatives.

 

Enflxmflmmmmafljfl

1 c1 TEA 66°C/55h 84% 100:0
2 C1 - 25°C/11h 1491." 96:4
3 Cl H2CCHC02N8 66°C/12h 47% 15 :85
4 0H 15:020C1 25 °C/7 h 15%c 78: 22
5 0“ mamas 0 °c /2 h 39%c 3: 97

 

IIVrtluetrrepresentisolated yieldsofthemajor product. bMixtme of61 and62.
cGascllrotnatographyyieldsofthemajorprotluct.

17
The consequence of reacting imine 60 with acyl imidazole provided the unexpected
1-aza-1,3-butadiene (63, eq 20). Compound 63 might have arisen from the attack of
enamine tautomer 64 on imine 60 (Scheme 2). A similar result has been reported by
Pfau.20 Compound 63 was also prepared from the imine 60 by stirring with a catalytic
amount of camphorsulfonic acid (CSA) and this clearly shows that the acyclic imine 60 is

more acid sensitive and in the presence of acid source acyclic imine can easily undergo

 

 

 

aldoltypecondensation.
O
”‘Y‘ All M‘Y‘N o
N Me
Me H = Me 'Tfit + \l/\N (20)
THF I Me
Et P, E
60 63 62
X=imidazole
Scheme 11. Formation of 1-Aza-l,3-Butadiene From Imine 60.
R. LN“ R.
Et Et Et
60 64 60
P R.
R NH R N_ N
——> ——-- “\[B'l' R”“2
H
. El .. Pr
R=isobutyl 63

The annulation methodology was extended to imine 65, which was synthesized
from cyclopentanone and isobutylamine in 53% yield. Imine 65 was treated with various

18
acrylic acid derivatives (eq 21) and the results are shown in Table III. In the presence of
TEA, the reaction of acryloyl chloride with imine 65 gave enamide 66 as the major product
(entry 1, Table III). Lactam 67 was obtained as the major product from the reaction of 65
with other acrylic acid derivatives (entries 2 to 5). Lactam 67 was isolated as an
inseparable mixture of double bond isomers 67a and 67 b. Unfortunately, the two isomers
67a and 67b could not be isomerized to a single compound. The ratio of the two isomers
was determined from GC analysis and 1H NMR spectroscopy. From the results of the
reactions of various acrylic acid derivatives with imines 52 and 65, it was obvious that
acrylic anhydride and acrylic acid, activated by either ethyl chloroformate 57 or DPPA 58,

were the better reagents to selectively prepare lactams in high yield.

 

0
Me O O
X
é r Meé + M, . ( )
Reagent
65 66 67

Table III. The Reaction of Imine 65 with Acrylic Acid Derivatives.

 

WXWWWMM

1 c1 TBA 66 °C/7 h 87% 100: 0 -

2 c1 - 66°C/30h 2911," 15:85 (46:54)
3 c1 H20CHC02Na 55 cm 1 h 53% 2 :98 (43:57)
4 OH EtOzCCl 66 0c /4 h 63% 5 :95 (46:54)
5 OH (P110)2P(0)N3 25 °c / 25 h 51% 0 : 100 (54 :46)

 

Walues represent isolated yields of the major product More of 66 and 67.

19

b) a- or B-Substituent Effect

The effect of a- or B—substituted acrylic acid derivatives on this annulation was
studied with methacrylic acid and crotonic acid derivatives. Since the a—substituent on the
methacrylic acid does not provide any significant steric hindrance during the carbon-carbon
bond formation or carbon-nitrogen bond formation, the methacrylic acid derivatives were
expected to show reactivity similar to acrylic acid derivatives. In the case of crotonic acid
derivatives, the presence of a B-methyl group was expected to inhibit carbon-carbon bond
formation, and hence, more uncyclized enamide formation was expected in comparison to

methacrylic and acrylic acid derivatives.

c) Methacrylic Acid Derivatives

In order to study the effect of the a-substituted acrylic acid derivatives on the
annulation product distribution, methacrylic acid derivatives were reacted with imine 52
(eq 22). The results are shown in Table IV. With added TEA, methacryloyl“ chloride
reacted with imine 52 and gave enamide 68 as the major product (entry 1), and in the
absence of TEA, a 39:61 mixture of enamide 68 and lactam 69 was obtained (entry 2).
Lactam 69 was obtained as the major product with other methacrylic acid derivatives
(entries 3-6). The minor product, enamide 68, was selectively hydrolyzed by heating with
0.2 eq of p-TsOH in methanol. The lactam 69 was obtained as inseparable double bond
isomers 69a and 69b. The isomer 69b was obtained as two diastereomers. Under the
isomerization conditions, p-TSOH and methanol, the mixture of isomers 69a and 69b was
isomerized mostly to 6911. The ratio of isomer 69a to diastereomers 69b and 69c was
determined by 1H NMR spectroscopy.

20

 

Table IV. The Reaction of Imine 52 with Methacrylic Acid Derivatives.

 

E1111! X
1 c1
2 c1
3 c1
4 on
s 0H
6 0H

Emmi WWW
96:4

TEA
H2CCCH3C02N8
EtOzCC I
(P110)2P(O)N3

MCPI/N513

66°Cl8h
66°C/24h
66°C/1h
66°C/1h
25°C/40min
66°C/2.5h

67%
54%
69%
87%
64%
82%

b

b

39:
2:
:99
0:
24:

1

61
98

100
76

(40:53z7)
(92:6 :2)
(95:4 :1)

 

Wattles represent isolated yields of the major product. lMixture of 68 and 69.

The acyclic imine 60 was also treated with methacrylic acid derivatives (eq 23),

and the results are shown in Table V. Comparable to our earlier results, enamide 70 was

obtained as the major product from the reaction of imine 60 with methacryloyl chloride in
the presence of TEA (entry 1). Lactam 71 was produced as the major product from the

reaction of methacrylic anhydride and imine 60 (entry 2). The lactam 71 was separated

from the mixture by selectively hydrolyzing the enamide using p-TsOH in methanol. The

reaction of imine 60 with methacrylic acid in the presence of acid activating reagents 57 -

59 gave compound 63. In order to avoid the formation of compound 63 in the presence
of free acid, sodium salt of the methacrylic acid was reacted with imine 60 in the presence

of activating reagent 57 or 58. Only a trace of the lactam 71 was observed even after

longer reaction times, however, the aldol-type reaction was prevented.

21

0 o 0
Me M“ Me Me Me Me
x
Mo K‘ Ream = M, K] + M, (23)
Et Et

 

Et
60 70 71

Table V. The Reaction of Imine 60 with Methacrylic Acid Derivatives.

 

E11111 X Reagent W W 19.11
1 Cl TEA 66°C/8h 62% 100:0
2 Cl H2CCCH3C02Na 66 °C/ 16 h 25% 11 : 89

 

aValuer: represent isolated yields ofthe majorproduct.

d) Crotonoic Acid Derivatives

Imine 52 was reacted with various crotonic acid derivatives and the results are
given in Table VI (eq 24). AS expected, the methyl group in the B position had an
influence on this reaction. The reaction of imine 52 with crotonic acid derivatives required
more vigorous conditions and longer reaction times than the reaction of imine 52 with
acrylic or methacrylic acid derivatives. Both in the presence and absence of TEA in the
reaction mixture, the reaction of crotonoyl chloride with imine 52 gave enamide 72 as the
major product (entries 1 and 2). The reaction of 52 with crotonic anhydride and crotonic
acid in the presence of ethyl chloroformate gave lactam 73 as the major product with 30-
40% of enamide 72 (entries 3 and 4). Imine 52 reacted with crotonic acid, activated by
MCPI, and gave enamide 72 as the major product (entry 5). Isolation of lactam 73 was
made easier by selectively hydrolyzing enamide 72. Lactam 73 was obtained as a mixture
of double bond isomers 73a and 7 3b. The isomer 73b was obtained as two
diastereomers. Under isomerization conditions, compound 73a was isolated as the major

product. The ratio of isomer 73a to diastereomers 73b and 73c was determined by 1H

NMR spectroscopy.

22

s» ”1,4
We

52 73

 

°= Me YESWW - (24)

Table VI. The Reaction of Imine 52 with Crotonic Acid Derivatives.

 

WK WWWMW

1 Cl TEA 66°C/4h 76% 100:4 -
2 Cl - 66°C/20h 34%b 82: 18 -
3 Cl Hsfi‘CIHCHCOzl‘ia 66 °c / 5 h 33% 36: 64 (81:15:4)
4 on E102CC1 66 .C / 15 h 799;," 45 : 55 (79: 14:7)
5 OH MCPI/N313 66 °c / 3 h 50%b 62 : 38 -

 

avarice represent isolated yields of the major product. bMixture of 72 and 73.

The reaction of imine 60 with crotonic acid derivatives showed the influence B—
methyl group during the carbon-carbon bond formation, and the results are given in Table
VII (eq 25). Only enamide 74 was obtained as the major product from the reaction of
imine 60 with either crotonoyl chloride or crotonic anhydride (entries 1 and 2). Treatment
of imine 60 with crotonic acid, in the presence of acid activating reagents such ”as DPPA

and ethyl chloroformate, provided only a trace of lactam 75.

rtrr.-\llv:\lii\I 1::LUYwNjLLM: 11er SELMC (25)

 

E1

50 74

23
Table VII. The Reaction of Imine 60 with Crotonic Acid Derivatives.

 

Em X Reagent W Yieldsa 14.3.1.5
1 c1 TEA 66 °c / 8 h 62% 96: 4
2 c1 H3CCHCHC02Na 66 °C/ 16 h 18% 63 : 37

 

aValues represent isolated yields of the major product.

e) Nitrogen Substituents

In order to expand the scope of this annulation and to study the product distribution

with other substituents on the nitrogen, both -CH2Ph and -NMe2 were chosen as N-
substituents. Since both -CH2,Ph and -NMe2 can be readily removed after annulation, the
annulated product can be modified for use in organic synthesis.

 

 

76 77

Table VIII. The Reaction of Hydrazone 76 with Acrylic Acid Derivatives.

 

EntDLX WWWMW

1 Cl TEA 66°C/21h 77% 96:1 -
2 Cl - 66°C/22h - 64:36 -
3 Cl H2CCHCOzNa 66°C/18 h 70% 1 :99 (83:17)

 

Wellies represent isolated yields of the major product.

Hydrazone 76, prepared from cyclohexanone and 1,1-dimethylhydrazine in 72%
yield, was treated with acrylic acid derivatives (eq 26), and the results are given in Table
VIII. In the presence or absence of TEA in the reaction mixture, acryloyl chloride reacted
with hydrazone 76 to give enamide 77 as the major product (entries 1 and 2). However,

24

lactam 78 was obtained as the major product upon treatment of hydrazone 76 with acrylic
anhydride (entry 3). Reaction of hydrazone 76 with acrylic anhydride required longer
reaction times as compared with the reaction of acrylic anhydride with imine 52. The slow
reactivity of hydrazone 76 could be due to the inductive effect from -NMe2 substituent.
The reaction of hydrazone 76 with both methacrylic anhydride and crotonic anhydride did
not provide any product. Hence, further studies were not pursued with this hydrazone.

Further investigation into this methodology, annulation of imine 23 was
investigated. Imine 23 was made from cyclohexanone and benzylamine in 85% yield.
Benzylamine derivatives have been widely used in organic synthesis because of the ease
with which benzyl group can be removed fi'om nitrogen. Imine 23 was expected to behave
similarly to isobutyl imine 52. The imine 23 was reacted with acrylic acid derivatives,
methacrylic acid derivatives and crotonic acid derivatives (eq 27, 28 and 29), and the

results are given in Tables lX-XI, respectively.

0 O

l g I +
. Reagent l.

23 24 26

(27)

 

Table IX. The Reaction of Imine 23 with Acrylic Acid Derivatives.

 

EnlDLX WWWMM

1 c1 TEA 66°C/3h 70% 99:1 -
2 c1 - 66°C/12h 6096b 15:85 -

3 c1 cnzcncooNa 66°C/2h 70% 0: 100 (33:67)
4 OH EtOzCCl 66°C/2h 7711: 0:100 (76:24)
5 0H (PhO)2P(O)N3 0°C/2h 71% 3:97 (77:23)

 

avttluet represent isolated yields of the major product. bMixtm'e of 24 and 26.

25

With added TEA, reaction of imine 23 with acryloyl chloride gave enamide 24 as
the major product (entry 1, Table IX). Lactam 26 was isolated as the major product from
the reaction of imine 23 with other acrylic acid derivatives (entries 2-5). As before, the
lactam was obtained as a mixture of two double bond isomers 26a and 26b, and the ratio
of isomers 26a and 26b was determined by 1H NMR spectroscopy.

Treatment of methacryloyl chloride with imine 23 provided enamide 79 as the
major product (entries 1 and 2, Table X). Reaction of other methacrylic acid derivatives
with imine 23 gave lactam 80 as the major product (entries 3-5). Again, lactam 80 was
obtained as a mixture of isomers 80a and 80b. Under isomerization condition, 8011 was

obtained as the major isomer.

0 o
/\ Me Me
"I N x’kfl’ PhANJk" Ph/‘N
W ’ as + ‘

23 79 80

   

Table X. The Reaction of Imine 23 with Methacrylic Acid Derivatives.

 

me mm WWMW

1 Cl TEA 66 °C [4 h 80% 98 : 2 -
2 Cl - 66°C/22h 39%b 52:48 -

3 Cl HchCI-I3002Na 66 °C / 2.5 h 81% 0: 100 (>95:<5)
4 0H W1 66 °c / 2 h 81% 1 : 99 (>95:<5)
5 011 (momma 25 °c / 2 h 63% 0 : 100 (>95:<5)

 

'Values represent isolated yields of the major product. bMixture of 79 and 80.

In the presence or absence of TEA, reaction of imine 23 with crotonyl c‘hloride gave
enamide 81 as the major product (entries 1 and 2). Reaction of other crotonic acid derivatives

with imine 23 gave lactam 82 as the major product (entries 3 and 4, Table XI). In order to

26
isolate lactam 82 from the mixture of enamide and lactam, enamide 81 was selectively
hydrolyzed using p-TSOH and methanol. As before, the lactam 82 was obtained as a mixture
of isomers 82a and 82b, and the mixture was isomerized to 823. The ratio of isomer 82a and

the diastereomers 82b and 82c could not be determined by 1H NMR spectroscopy.

0

O
X
Pit/\N H‘ PIT/\N Ph
' Me = I +
O W“ M:
23 81

   

AN

 

Me (29)

Table XI. The Reaction of Imine 23 with Crotonic Acid Derivatives.

 

EDIDLX WWWMW"

1 Cl TEA 66 °C / 4 h 55% 100: 0 -
2 Cl - 66 °C I 20 h 73%0 91 : 9 -
3 Cl H3CCHCHC02Na 66 °C I 12 h 62%c 36 : 64 -
4 OH EtOzCCl 66 °C / 24 h 65%6 44 : 56 -

 

aValuesrejxesentisolatedyieldsofthenlajorproduct. l’Isornerratiocouldnothedeterrnirled.
“Mixture of81 and82.

In order to study the effect of bulky groups on the nitrogen, as well as to gain more
insight into the mechanism of this reaction, imine 83 was treated with acrylic, methacrylic
and crotonic acid derivatives. In the annulation reactions, the presence of a bulky isopropyl
group on the nitrogen was expected to Show a steric effect during the C-N bond formation
compared to imines 23 or 52, and this effect was expected to change the product
distribution.

Imine 83, prepared from the condensation of isopropyl amine and cyclohexanone
in 79% yield, was reacted with acrylic acid derivatives and the results are given in Table
XII (eq 30). Enamide 84 was obtained as the major product from the reaction of imine 83

27
with acryloyl chloride and TEA (entry 1). Lactam 85 was obtained as a single product
with other acrylic acid derivatives (entries 2 to 5). The reaction of imine 83 with acryloyl
chloride gave more lactam 85 (84:85, 5:95, entry 2, Table XII) than the reaction of imine
52 with acryloyl chloride (53:54, 13:87, entry 2, Table I). The slight enhancement of
lactam 85 formation shows the influence isopropyl group on this annulation. Lactam 85
was obtained as double bond isomers 85a and 85b. The ratio of isomers 85a and 85b

was determined by 1H NMR spectroscopy.

 

W 0 Me 0

Me/kN x"\“ MCANJH Mc/k
W > o +
83 84

 

Table XII. The Reaction of Imine 83 with Acrylic Acid Derivatives.

 

EDIIIX Rm WWMM)

1 Cl TEA 66 °C / 2 h 87% 100 : 0 -

2 Cl - 66 °C/ 10 h 32% 5 : 95 (81:19)
3 Cl HZCCH002Na 66 °C / 2 h 67% 0 : 100 (81:19)
4 OH E102CC1 66 °C / 2 h 77%9 0 : 100 (84:19)
5 OH (P110)2P(O)N3 25 °C [4 h 53% 0 : 100 (91:9)

 

aValuesrepresentisohtetlyieldsofthetrllijtrproduct.

The result of the reaction of imine 83 with methacrylic acid derivatives are shown
in Table xm (eq 31). In the presence of TEA, enamide 86 was produced as the major
product with methacryloyl chloride (entry 1). Without the addition of TEA, the reaction of
imine 83 with methacryloyl chloride gave lactam 87 as the major product (86:87, 3:97,
entry 2). In contrast to this result, the reaction of imine 52 with methacryloyl chloride gave
enamide 68 as the major product (68:69, 61: 39, entry 2, Table IV). The increase in
considerable amount of lactam 87 formation showed that the bulky N -isopropyl group

28
substituent favored the lactam formation. Only lactam 87 was isolated in moderate to high
yields from the reaction of imine 83 with other methacrylic acid derivatives (entries 3 to 5).
The isomer 87a was obtained as the major product with a small trace of isomer 87b. The

ratio of the isomer 87a and the diastereomers 87b and 87c was determined by 1H NMR

spectroscopy.

M“ 0 MeO

 

(31)

 

Table XIII. The Reaction of Imine 83 with Methacrylic Acid Derivatives.

 

Ennx Reagent Wmmm

1 Cl TBA 66 °C I 4 h 86% 95 : 5 -

2 Cl - 66°C/th 50% 3:97 (93:2:5)
3 Cl HZCCCH3C02Na 66 °C I 2 h 82% 0 : 100 (93:3:4)
4 0H EtOzCCl 66 °C I 3 h 62% 0 : 100 (>95:5)
5 0H (PhO)2P(O)N3 25 °C I 4 h 47% 0 : 100 (>95:5)

 

Walues representisolatedyieldsofthemajaproduct.

The reaction of imine 83 with crotonic acid derivatives gave unexpected results (eq
32). The reaction of the imine with crotonoyl chloride and TEA gave several products.
The formation of unwanted products could be due to the competition between N-acylation
and removal of a proton from the B-methyl group to form a vinyl ketene. The formed vinyl
ketene can give rise to various products. Vinyl ketene formation from crotonoyl chloride in
the presence of TEA has been previously reported by Hickmott.21 Use of a weaker base
was expected to inhibit the formation of vinyl ketene. By using pyridine instead of TEA,
enamide 88 was obtained in 25% yield (entry 1, Table XIV). The reaction of imine 83

29
with crotonyl chloride gave enamide 88 as the major product (entry 2). Surprisingly, the
reaction of imine 83 with crotonic anhydride gave only lactam 89 in 77% yield (entry 3).
In the case of imine 52, reaction of crotonic anhydride gave considerable amount of
enamide (72:73, 36:64, entry 3, Table VI). The increase in amount of lactam 89
formation clearly indicated that the bulky N—isopropyl substituent favored the lactam
formation over the formation of enamide 88. The reaction of imine 83 with crotonic acid,

activated by ethyl chloroformate, also gave lactam 89 as the major product (entry 4).

0

Me Me O
X
Me/kN Me/LN Me
I Me: J\'L +
‘ Reagent l :| Me
83 88

Table XIV. The Reaction of Imine 83 with Crotonic Acid Derivatives.

MeO

 

 

 

me WWWMM

1 Cl Pyndrnc 66 °C / 4 h 25% 100 : 0 -

2 Cl - 66 °C /10 h 69 : 31

3 Cl H3CHCXIHC02Na 66 °C /10 h 77% 0 : 100 (>95:5)
4 0H EtOzCCl 66 °C /12 h 66% 4 : 96 (89:11)

;-

 

aValuesrepr'errerrtiaolatedyieldsofthemajorproduct.

In order to study the ability of sterically hindered acych imine in controlling the
formation of lactam vs enamide, annulation of imine 90 was carried out with acrylic and
crotonic acid derivatives. Imine 90 was prepared from the condensation of butyraldehyde
and isopropylamine in 68%. The results of the reaction of imine 90 with acrylic and
crotonic acid derivatives (eq 33 and 34) are given in Tables XV and XVI, respectively.

Enamides 91 and 93 were obtained as the major products from the reactions of imine 90

30
with the corresponding acid chlorides and TEA (entry 1, Tables XV and XVI). In the
absence of TEA, the reaction of imine 90 with acryloyl chloride gave a 65:35 ratio of 91 to
92 (entry 2, Table XV). This product distribution clearly shows the formation of more
lactam as compared to that of the reaction of acryloyl chloride and imine 60 (61:62, 96:4,
entry 2, Table II). Without the addition of TEA, reaction of crotonyl chloride with 90 gave
a 30:70 ratio of 93 to 94 (entry 2, Table XVI). The formation of more lactam 94 clearly
shows the influence of bulky substituent on the imine 90. The reaction of acrylic
anhydride with imine 90 gave a 7:93 mixture of 91 to 92 in 27% yield, which shows an
increase in lactam formation over the reaction of 60 with acrylic anhydride (61:62 15:85,
entry 3, Table II). Treatment of crotonic anhydride with 90 gave a 6:94 mixture of 93 to
94 in 47% yield which shows a tremendous increase in lactam formation over the ratio of
63:37 (entry 2, Table VII) obtained from the reaction of imine 60 and crotonic anhydride.
These results clearly show the presence of a bulky isopropyl substituent on the nitrogen

influenced the formation of lactam over the formation of enamide.

 

0
Me Me 0 Me 0
Me/kN XJ\“ Me/LNJH Me/kN
u\‘ = H l + (33)
Reagent _
E! Et Et
90 911 9 2

Table XV. The Reaction of Imine 90 with Acrylic Acid Derivatives.

 

WXWWWM

1 Cl TEA 66°C / 5 h 49% 100 : 0
2 Cl - 66°C I12 h - 65 : 35
3 Cl HzmI-ICO2N8 66°C / 2 h 27% 7 : 93

 

aValues representiaolatedyieldsofthemaja'product.

31

e Me N

 

(34)

o
1‘“ ka Me 0 M o
I e
MA M : WAN I + A
“W Reagent Me Me

’5‘ Et
90 93 9 4

Table XVI. The Reaction of Imine 90 with Crotonic Derivatives.

 

WXWWM‘M

1 Cl TEA 66°C/6h 37% 100:01
2 C1 - 66 °C /12 h - 30 : 70
3 C1 H3CHCCHC02Na 66 °C /1 2 h 47% 6 : 94

 

aValues represent isolated yields ofthe majaproduct.

f) Mechanistic Discussion of Aza-Annulation

The mechanism of the aza-annulation reaction has not been fully investigated, and
there are number of pathways possible for this annulation process. In general, options can
be divided into two different pathways, those that acylate first at nitrogen, N—acylation, and
those that undergo initial conjugate addition to form the carbon-carbon bond, initial C-
alkylation. Hickmott proposed a mechanism for the formation of lactam 8 and enamide 9
from imine 7 with acryloyl chloride (Scheme I). According to Hickmott, the enamine
tautomer l3 undergoes N-acylation to give the intermediate 14 which, after [3,3]
sigmatropic rearrangement, gives ketene 15. The loss of proton from 14 gives neutral
enamide 9. Attack of nitrogen on the ketene carbon of 15 gives lactam 8. Both are
competitive processes. In the presence of TEA, enamide 9 would be the major product
because of the removal of proton from 14 by TEA. Since enamide 9 cannot be converted
into lactam 8 under thermal, protic and Lewis acidic conditions, enamide 9 is not likely to
be intermediate in lactam formation.

32

On the other hand, initial Michael type adduct formation from the enamine tautomer
and (LB-unsaturated derivatives can undergo intramolecular N—acylation to give lactams.
In the reaction of imine 35 with methyl acrylate,11 Takahashi observed an initial Michael
type addition, C-alkylation, followed by N-acylation to give lactam 33 (eq 11). The mono
and his Michael addition products 36 and 37 were isolated as the major products, and 36
was converted to lactam 38 upon heating. Pfau22 reported that the reaction of imine 95
with dimethyl maleate (97) gave lactam 100 via the enamine tautomer 96 (Scheme III).
The intermediates 98 and 99 were not isolated. Both Takahashi and Pfau did not observe
any N-acylated amide products. The C-alkylation of the imine in the form of the enamine

tautomer with a,B-unsaturated esters has been confirmed by the isolation of the mono and

his C-alkylation products.1 1

Scheme III. Reaction of Imine 95 with Dimethyl Maleate.

 

 

 

 

R1 R1 1}!
N’ HN’ N
C02Me R,
O— +[ —> O
C02Me d
95 96 97 98 99
Rl'C6H11
R2=COOMe

100

During our investigation on aza-annulation of imines, we observed that the reaction

of imines with aficunsaturated acid chlorides and TEA gave only enamides (except the

33

reaction of imine 83 with crotonoyl chloride and TEA ). In the absence of TEA, the
reaction of imines with (LB-unsaturated acid chlorides gave a mixture of enamide and
lactam, and the enamide to lactam ratio varied with imines and a,B-unsaturated acid
chlorides. These results show a competition between initial N-acylation and C-alkylation.
The presence of TEA favors the initial N-acylation to give an intermediate similar to 14,
and removal of the proton by TEA gives enamide which cannot not be converted into
lactam. In the absence of TEA, the initial C-alkylation occurs faster than N-acylation to
give lactam as the major product after intramolecular N-acylation.

The reaction of imine 35 with methyl acrylate gave C-alkylated Michael adduct
products 36 and 37 and lactam 38. No enamide was observed. The difference between
(LB-unsaturated acid chloride and a methyl acrylate is their reactivity towards N-acylation.
The acid chloride is a better acylating agent than the ester. Since the better acylating agent
(a,B-unsaturated acid chloride) gives a mixture of lactam and enamide and the poorer
acylating agent (methyl acrylate) gives a mixture of Michael adduct and lactam, the products
distribution could be controlled by adjusting the acylating ability of the (LB-unsaturated
acid derivatives. As expected from these arguments, the reaction of imine with relatively
poor acylating agents such as anhydrides and acids, in the presence of acid activating
reagents, gave lactams as the major product. However, from these results, we could not
rmke any conclusion about initial N—acylation versus C-alkylation.

Further, steric effects due to the substituents on the nitrogen and substituents on the
acylating agent (eg. fl-methyl group in crotonic acid derivatives) could be used to control
both N-acylation or C-alkylation. Bulky groups on the nitrogen would be expected to
disfavor the N-acylation and substituents on the B-position of the cab-unsaturated acid
derivatives would be expected to disfavor the C-alkylation. The reaction of imine 83,
having a sterically hindered isopropyl group on the nitrogen, provided us with some insight
into the mechanism. The reaction of imine 83 with both acrylic and methacrylic acid

derivatives gave >95% of the lactams (85 and 87). Unexpectedly, crotonic anhydride

34

gave only lactam 89 from the reaction with imine 83. Usually crotonic anhydride gave
roughly a 60:40 mixture of uncyclized enamide and lactam. The formation of lactam as the
major product clearly indicates that the lactam is formed from the initial C-alkylation
followed by intramolecular N-acylation. In the reaction of crotonic anhydride with imine
83, C-alkylation is more favorable than N-acylation because of the steric hinderance due to
the bulky isopropyl group on the nitrogen. The effect of the bulky N-isopropyl group on
the lactam formation was further confirmed from the reaction of imine 90 with crotonic
anhydride. Treatment of imine 90 with crotonic anhydride gave a 6:94 mixture of enamide
to lactam in 47% yield and demonstrated significant improvement over the 63:37 formation
of the analogous 74:75. Since the reaction of crotonic anhydride with other imines (23
and 52) did not favor either C-alkylation or N-acylation due to the 8 methyl group, nearly
equal amounts of lactams and enamides were obtained. In the case of crotonoyl chloride,
N-acylation was faster than C-alkylation because of the steric effect due to the B-methyl
group; hence, the enamide was the major product.

From the above results, it can be concluded that the lactam was formed by initial C-
alkylation followed by intramolecular N-acylation.

CONCLUSION

Lactams or enamides were selectively prepared in high yields by reaction of the
imine made from cyclohexanone and acrylic or methacrylic acid derivatives. Acid
activating reagents DPPA and ethyl chloroformate with a,B-unsaturated acids were better
alternatives to the anhydrides and acid chlorides. Treatment of imines with crotonic acid
derivatives produced more enamides. Enamides were selectively hydrolysed from a

mixture of enamide and lactam. Annulation of the acyclic imine, made fiom butyraldehyde,

with a,B-unsaturated anhydrides gave lactams in moderate yields. The acyclic imine was
sensitive to carboxylic acids and gave aldol type condensation products. Reaction of afi-

unsaturated derivatives with bulky N -isopropyl group substituted imine favored the C-

35

alkylation and gave more lactams. In most of the cases, the B-substituted «MS-unsaturated

acid derivative favored the N-acylation and gave more uncyclized enamides.

36
EXPERIMENTAL SECTION

General Methods. All reactions were carried out performing standard inert atmosphere
techniques to exclude moisture and oxygen. Acrylic acid, methacrylic acid, methacrylic
anhydride, crotonic anhydride, methacryloyl chloride, and crotonoyl chloride were
purchased from Aldrich Chemical Co., and distilled before use. Acryloyl chloride was
purchased from Fluka and used without purification. Aldrithiol-Z (2,2’-dipyridyl
disulfide), and 2-chloro—l-methylpyridinium iodide were purchased fiom Aldrich Chemical
Co. and used without purification. Diphenylphosphoryl azide (DPPA) was prepared
according to a literature procedure.23 Unless specified, concentration of mixtures was
performed using a Buchii rotary evaporator.

General Procedure for the Preparation of Ketimines: A mixture of the
primary amine (313 mmol) and ketone (250 mmol) in 750 mL of benzene was heated at
reflux until >90% of the H20 had been azeotropically removed from the reaction mixture
with a Dean-Stark trap. After draining the H20 from the Dean-Stark apparatus, the trap
was filled with 411 molecular sieves, and the reaction was heated for up to an additional 24
h to produce complete imine formation. The solution was then cooled to ambient
temperature, concentrated, and distilled under vacuum using a vigereux column to give the
corresponding imine. A

23: (bp 92 °C, <1 mmI-Ig): 1H NMR (300 MHz, 0303) 8 1.59-1.83 (m, 6H),
2.34 (t, 411, J = 5.8 Hz), 4.50 (s, 2H), 7.15-7.30 (m, 5H); 13c NMR (75.5 MHz,
CDC13) 5 25.6, 26.5, 27.3, 28.7, 39.6, 53.6, 126.1; IR (neat) 3085, 3062, 3028, 1660,
1495, 1452, 1346 cm-1.

52: (bp 75 °C, 6 mmHg): 1H NMR (300 MHz, CDC13) 5 0.87 (d, 6H. J = 6.7
Hz), 1.59 (m, 4H), 1.68 (m, 2H), 1.85 (m, 1H), 2.24 (m, 4H), 3.06 (d, 2H, J = 6.7 Hz);
13c NMR (75.5 MHz. coc13) 5 19.9, 25.2, 26.1, 27.0, 27.9, 28.9, 39.2, 57.5, 171.9;
IR (neat) 2930, 2862, 1660, 1469, 1449 cm-1.

37

65: (bp 77 °C, 15 mmHg): 1H NMR (300 MHz, CDC13) 5 0.90 (d. 6H, J = 6.7
Hz), 1.71 (m, 2H), 1.77 (m, 2H), 1.92 (m, 1H), 2.12 (m, 2H), 2.31 (m, 2H), 2.97 (m,
2H); 13C NMR (75.5 MHz, CDC13) 5 20.5, 23.9, 24.6, 28.7, 29.4, 36.0, 61.7, 179.9;
IR (neat) 2958, 2858, 1678, 1466 cm-1.

76: (hp 66 °C, 14 mmHg): 1H NMR (300 MHz, CDC13) 5 1.55-1.72 (m, 6H),
2.21 (t, 2H, J = 6.2 Hz), 2.40 (s, 6H), 2.47 (t, 2H, J = 6.2 Hz); 13C NMR (75.5 MHz,
CDC13) 5 25.9, 26.5, 27.4, 28.6, 35.9, 47.5, 170.1; IR (neat) 2858, 2815, 2771, 1635,
1468, 1449 cm-1.

83: (bp 68 °C, 20 mmHg): 1H NMR (300 MHz, CDC13) 5 1.09 (d, 611,1 = 6.3
Hz), 1.58-1.66 (m, 4H), 1.66-1.75 (m, 2H), 2.20230 (m, 4H), 3.68 (sept, 1H, J =6.3
Hz); 13C NMR (75.5 MHz, CDC13) 5 23.9, 26.1, 27.4, 27.8, 28.8, 40.1, 48.8, 170.4;
IR (neat) 1660, 1450, 1377 cm-1.

General Procedure for the Preparation of Aldimines: A mixture of amine
(137 mmol), butyraldehyde (9.86 g, 137 mmol), and potassium carbonate (37.90 g, 274
mmol) in 200 mL EtzO was stirred for 12 h at ambient temperature. The solution was then
removed floor the insoluble material via cannula and distilled using a vigereux to give the
corresponding imine.

60: (78% yield hp 53 °C, 25 mmHg): 1H NMR (300 MHz, CDC13) 5 0.81 (d,
6H, J = 6.4 Hz), 0.87 (t, 3H, J = 7.4 Hz), 1.48 (sext, 2H, J = 7.4 Hz), 1.82 (non, 1H, J
= 7.4 Hz), 2.14 (td, 2H. J = 7.4, 5.0 Hz), 3.10 (d, 2H, J = 6.7 Hz), 7.5 (t, 1H, J = 5.0
Hz); 13C NMR (75.5 MHz, CDC13) 5 12.8, 18.6, 19.6, 28.3, 36.9, 68.9, 164.4; IR
(neat) 2958, 2875, 2828, 1674, 1469 cm-1.

90: (68% yield, hp 108°C): 1H NMR (300 MHz, CDC13) 5 0.91 (t. 3H, J = 7.4
Hz), 1.11 (d, 6H, J = 6.4 Hz), 1.51 (sext, 2H, J = 7.4 Hz), 2.6 (dt, 2H, J = 5.2.7.4
Hz), 3.23 (sept, 1H, J = 6.4 Hz), 7.61 (t, 1H, J = 5.2 Hz); 13C NMR (75.5 MHz,
CDC13) 5 13.1, 19.1, 23.7, 37.1, 60.7, 161.6; IR (neat) 2969, 2935, 2874, 2830, 1669,
1466 cm'l.

38

General Procedure for the Preparation of Enamides: To 40 mL of dry
THF were added the imine (8.0 mmol) and NEt3 (1.21 g, 12.0 mol) at 0 °C. The
appropriate a,B-unsaturated acid chloride (9.6 mmol) was added slowly to this solution at
0 °C. After the addition was complete, the reaction was carried out under the conditions
listed in the Tables. Solids were removed from the mixture by filtration, and were then
washed thoroughly with EtZO. The combined filtrate was concentrated, and the
corresponding enamide was isolated by Kugelrohr distillation.

53: (hp 70-80 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.89 (d, 6H, J =
6.9 Hz), 1.60 (m, 2H), 1.72 (m, 2H), 1.87 (m, 1H), 2.06 (m, 2H), 2.13 (m, 2H), 3.32
(bd, 2H, J = 7.2 Hz), 5.51-5.59 (m, 2H), 6.30 (dd, 1H, J = 16.9, 2.4 Hz), 6.46 (dd,
1H, J -- 16.9, 10.0 Hz); 13C NMR (75.5 MHz, CDC13) 8 20.2, 21.7, 22.9, 24.9, 27.3,
28.3, 52.4, 127.3, 128.3, 129.4, 138.7, 166.1; IR (neat) 2961, 2934, 1651, 1618 cm'l;
HRMS calcd for C13H21NO m/z 207.1623, found m/z 207.1629.

24: (mp 67-68 °C): 1H NMR (300 MHz, CDC13) 5 1.52 (m, 2H), 1.64 (m, 2H),
1.94-2.06 (m, 4H), 4.67 (s, 2H), 5.39 (m, 1H), 5.61 (dd, 1H, J = 9.7, 2.7 Hz), 6.38
(dd, 1H, J = 16.9, 2.7 Hz), 6.49 (dd, 1H, J = 16.9, 9.7 Hz), 7.20-7.28 (m, 5H); 13C
NMR (75.5 MHz, CDC13) 8 21.5, 22.7, 24.7, 28.7, 49.7, 127.1, 127.3, 128.2, 128.5,
128.6, 128.7, 137.9, 165.2; IR (KBr) 3068, 3030, 2940, 2855, 1645, 1611, 1414 cm'l;
HRMS calcd for C15H19NO m/z 241.1466, found m/z 241.1475.

84: (hp 70-80 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 1.15, (d, 6H, J =
6.8 Hz), 1.62 (m, 2H), 1.71 (m, 2H), 2.06 (m, 2H), 2.16 (m, 2H), 4.66 (sept, 1H, J =
6.8 Hz), 5.55 (dd, 1H, J = 3.3, 9.2 Hz), 5.59 (m, 1H), 6.31 (dd, 1H, J = 16.8, 3.3
Hz), 6.40 (dd, 1H, J = 16.8, 9.2 Hz); 13C NMR (75.5 MHz, CDC13) 5 20.8, 21.4,
22.8, 25.0, 31.8, 46.4, 126.6, 129.5, 129.7, 136.0, 164.7; IR (neat) 2975, 2936, 2881,
2860, 1652, 1614, 1448, 1438 cm-1; HRMS calcd for C12H19NO m/z 193.1466, found

m/z 193.1467.

39

77: (hp 50-60 °C, <1 mmI-Ig): 1H NMR (300 MHz, CDC13, Mixture of rotational
isomers, -30°C) 5 1.50-1.64 (m, 2H), 1.64-1.75 (m, 2H), 2.04-2.23 (m, 4H), 2.47 (s,
3H), 2.84 (hs, 3H), 5.46-5.64 (m, 2H), 6.25-6.36 (m), 7.14 (dd, J = 17.3, 10.3 Hz);
13C NMR (75.5 MHz, CDC13) 5 21.2, 21.3, 22.2, 22.3, 24.52, 24.53, 27.5, 29.1, 43.2,
45.0, 126.4, 127.2, 127.4, 127.7, 128.9, 129.5, 132.3, 136.9, 164.6, 166.6. IR (neat)
2979, 2939, 2885, 2860, 1661, 1618, 1448, 1437 cm-1; HRMS calcd for C11H13N20
m/z 194.1419, found mIz 194.1425.

68: (hp 6545 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.88 (d, 6H J =
6.7 Hz), 1.55 (m, 2H), 1.66 (m, 2H), 1.85 (m, 1H), 1.90 (t, 3H, J=1.4 Hz), 2.06 (m,
4H), 3.28 (d, 2H, J = 7.5 Hz), 5.00-5.08 (m, 2H), 5.50 (m, 1H): 13C NMR (75.5 MHz,
CDC13) 5 20.1, 20.6, 21.5, 22.7, 24.8, 26.9, 27.9, 52.1, 115.1, 125.6, 138.6, 142.3,
171.9; IR (neat) 3009, 2872, 2842, 1645, 1615 cm-1; HRMS calcd for C14H23NO m/z
221.1779, found m/z 221.1785.

79: (hp 110-120 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 1.45 (m, 2H),
1.56 (m, 2H), 1.92-1.99 (m, 7H), 4.65 (s, 2H), 5.08 (m, 1H), 5.17 (m. 1H), 5.33 (m,
1H), 7.22-7.28 (m, 5H); 13C NMR (75.5 MHz, CDC13) 5 20.5, 21.4, 22.6, 24.7, 28.4,
49.8, 116.0, 126.3, 127.1, 128.2, 128.4, 137.9, 138.7, 141.7, 171.6; IR (neat) 3088,
3066, 3008, 2935, 1648, 1619, 1496, 1453 cm-1; HRMS calcd for C17H21NO m/z
255.1612, found m/z 255.1615.

86: (hp 60-70 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 1.14 (d, 6H, J =
6.8 Hz), 1.53 (m, 2H), 1.61 (m, 2H), 1.89 (t, 3H, J=l.3 Hz), 1.99-2.12 (m, 4H), 4.52
(m, 1H), 4.87-5.00 (m, 2H), 5.49 (m, 1H); 13C NMR (75.5 MHz, CDC13) 5 20.8, 21.3,
22.7, 24.8, 31.3, 46.3, 114.1, 128.3, 136.5, 142.6, 171.3; IR (neat) 2974, 2934,2882,
2860, 1649, 1628, 1450, 1408 cm-1; HRMS calcd for C13H21NO m/z 207.1623, found
m/z 207.1625.

72: (hp 65-75 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.87 (d, 6H J =
6.7 Hz), 1.60 (m, 2H), 1.71 (m, 2H), 1.82 (dd, 3H, J = 1.7, 6.9 Hz), 1.85 (m, 1H),

40

2.05 (m, 2H), 2.13 (m, 2H), 3.28 (m, 2H), 5.58 (m, 1H), 6.14 (dq, 1H, J =15.1, 1.7
Hz), 6.87 (dq, 1H, J = 15.1, 6.9 Hz): 13C NMR (75.5 MHz, CDC13) 5 18.1, 20.1,
21.6, 22.8, 24.8, 27.2, 28.2, 52.2, 123.0, 127.4, 138.4, 140.4, 165.8; IR (neat) 2874,
1670, 1649, 1446 cm-1. Anal. Calcd for C14H23NO: C, 75.97; H, 10.47; N, 6.33.
Found: C, 76.62; H, 10.26; N, 6.34.

81: (mp 7071 °C): 1H NMR (300 MHz, CDC13) 5 1.53 (m, 2H), 1.64 (m, 2H),
1.83 (dd, 3H, J = 6.9, 1.7 Hz), 1.96 (m, 2H), 2.02 (m, 2H), 4.65 (s, 2H), 5.38 (m,
1H), 6.15 (dq, 1H, J = 15.1, 1.7 Hz), 6.94 (dq, 1H, J = 15.1, 6.9 Hz), 7.17-7.28 (m,
5H); 13C NMR (75.5 MHz. CDC13) 5 17.7, 21.1, 22.3, 24.3, 28.3, 49.5, 122.3, 126.6,
127.8, 127.9, 128.2, 137.8, 140.6, 165.1; IR (KBr) 3046, 3032, 2858, 1661, 1615,
1494 cm-1; HRMS calcd for C17H21NO m/z 255.1612, found mIz 255.1623.

88: (hp 65-75 °C, <1 mmHg): 1H NMR (300 MHz, CDCl3) 5 1.13 (d, 6H, J =
6.9 Hz), 1.61 (m, 2H), 1.71 (m, 2H), 1.82 (dd, 3H, J = 6.9, 1.8 Hz), 2.04 (m, 2H),
2.16 (m, 2H), 4.66 (sept, 1H, J=6.9 Hz), 5.57 (m, 1H), 6.05 (dd, 1H, J = 15.1, 1.6
Hz), 6.87 (dq, 1H, J =15.1, 6.9 Hz); 13C NMR (75.5 MHz, CDC13) 5 18.0, 21.0, 21.5,
22.9, 25.0, 31.8, 46.1, 123.6, 129.4, 136.1, 140.1, 165.0; IR (neat) 2973,2935, 2841,
1662, 1626, 1477 cm-1: HRMS calcd for C13H21NO m/z 207.1623, found m/z
207.1625.

66: (hp 6070 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.89 (d, 6H, J =
6.7 Hz), 1.86 (m, 1H), 1.90 - 2.05 (m, 2H), 2.39 (m, 4H), 3.35 (d, 2H, J =‘7.5 Hz),
5.49 (m. 1H), 5.57 (dd, 1H, J = 10.2, 2.2 Hz), 6.33 (dd. 1H, J = 16.9.2.2 Hz), 6.52
(dd, 1H, J a 10.2, 16.9 Hz); 13C NMR (75.5 MHz, CDC13) 5 20.0, 22.3, 27.4, 30.3,
32.6, 52.2, 126.9, 129.1, 142.4, 165.6; IR (neat) 3020, 2965, 2931, 1644, 1611 cm-1;
HRMS calcd for C12H19NO m/z 193.1466, found m/z 193.1469.

61: (hp 5555 °C, <1 mmHg): 1H NMR (300 MHz, CDC13, 2:1 82 mixture of
isomers) 5 0.86 (d, 6H, J = 6.4 Hz, hoth isomers), 0.99 (t, 3H, J = 7.4 Hz, both), 2.05
(m, 2H, both), 3.36 (bd, 2H, J =7.3 Hz, minor), 3.44 (bd, 2H, J = 7.3 Hz, major),

41
5.00-5.22 (m, 1H, both), 5.63-5.70 (m, 1H, both), 6.25 (d, 1H, J = 17.0 Hz, major),
6.37 (m, 1H, minor), 6.39 (d, 1H, J = 12.9 Hz, major), 6.62 (dd, 1H, J = 16.8, 10.3
Hz, both), 7.24 (bd, 1H, J = 14.8 Hz, minor); 13C NMR (75.5 MHz, CDC13 (major)) 5
13.8, 19.7, 23.1 26.0, 50.9, 119.4 126.7, 127.1 128.3, 165.2. (minor) 14.1, 19.7,
23.3, 26.8, 51.4, 114.5, 125.0, 127.5, 128.3, 164.4; IR (neat) 2964, 2930, 2875, 1646,
1612 cm-1; HRMS calcd for C11H19NO mIz 181.1467, found m/z 181.1473.

70: (hp 5060 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.88 (d, 6H, J =
6.8 Hz), 0.98 (t, 3H, J = 7.4 Hz), 1.96 (dd, 3H, J = 1.1, 1.6 Hz), 1.97-2.14 (m, 3H),
3.48 (d, 2H, J = 7.5 Hz), 5.01 (m, 1H), 5.08 (t, 1H, J =1.1 Hz), 5.25 (t, 1H, J = 1.4
Hz), 6.60 (bd, 1H, J =12.6 Hz); 13C NMR (75.5 MHz, CDC13) 5 14.6, 20.1, 20.4,
23.6, 26.0, 49.2, 113.2, 116.9, 128.1, 140.8, 171.5; IR (neat) 2963, 2932, 2874, 1670,
1649, 1454 cm-1; HRMS calcd for C12H21NO m/z 195.1623, found m/z 195.1629.

74: (hp 5060 °C, <1 mmHg): 1H NMR (300 MHz, CDC13, 2:1 E:Z mixture of
isomers) 5 0.86 (d. 6H. J = 6.3 Hz, major), 0.88 (d, 6H, J = 6.3 Hz, minor), 1.00 (t, 3H,
J=7.3 Hz, both), 1.86 (dd. 3H, J =1.6, 6.8 Hz, both), 1.93-2.12 (m, 3H, both), 3.35
(bd, 2H, J=5.3 Hz, minor), 3.44 (d, 2H, J = 7.8 Hz, major), 4.98-5.20 (m, 1H, both),
6.24-6.56 (m, 111, both), 6.74-7.00 (m, 1H, both), 7.24 (hd, 1H, J = 14.2 Hz, minor);
13c NMR (75.5 MHz, CDC13) 5 14.5, 18.2, 20.1, 23.7, 26.4, 51.0, 118.5, 122.6,
127.3, 141.6, 165.8; IR (neat) 3031,2963, 2874, 1653, 1628, 1448 cm-1; HRMS calcd
for C12H21NO mIz 195.1623, found m/z 195.1627. ‘

91: (hp 75-85 °C, 10 mmHg): 1H NMR (300 MHz. CDCl3, 93:7 ratio of £2
isomers) 5 1.05 (t. 3H, J =7.5 Hz), 1.11 (d, 6H, J = 6.8 Hz), 2.14 (m, 2H), 4.77 (sept,
1H, J =- 6.8 Hz), 5.47 (dt, 1H, J = 13.7, 6.9 Hz), 5.55 (dd, 1H, J = 10.3, 2.2 Hz), 5.93
(bd, 1H, J = 13.7 Hz), 6.28 (dd, 1H, J = 16.9, 2.2 Hz), 6.55 (dd. 1H, J = 16.9, 10.3
Hz) ; 13C NMR (75.5 MHz, CDC13) 5 13.6, 19.9, 23.3, 45.4, 123.1, 126.2, 129.9,
135.9, 165.1; IR (neat) 2972, 2934, 2876, 1651, 1614, 1462, 1414 cm'1;HRMS calcd
for CloHl7NO m/z 167.1310, found m/z 167.1309.

42

93: (hp 90100 °C, 7 mmHg): 1H NMR (300 MHz, CDC13, 93:7 ratio of 8:2
isomers) 5 1.02 (t, 3H, J = 7.5 Hz), 1.07 (d. 6H. J = 7.4 Hz), 1.79 (dd, 3H, J = 6.9, 1.5
Hz), 2.12 (m, 2H), 4.74 (sept, 1H, J = 6.9 Hz), 5.46 (dt, 1H, J = 13.7, 6.9 Hz), 5.90
(bd, 1H, J = 13.7 Hz), 6.22 (dq, 1H, J = 15.1, 1.5 Hz), 6.81 (dq, 1H, J = 15.1, 6.9 Hz);
13C NMR (75.5 MHz, CDC13) 5 13.3, 17.5, 19.6, 22.9, 44.9, 123.0, 123.7, 135.0,
139.5, 165.2; IR (neat) 2971, 2935, 2875, 2855, 1667, 1626, 1448 cm'l; HRMS calcd
for C11H19NO m/z 181.1466, found m/z 181.1460.

General Procedure for the Reaction of Imines with Acid Chloride:
The (1.8-unsaturated acid chloride (8.8 mmol) in 15 mL of dry THF was slowly added to
the imine (6.8 mmol) in THF (30 mL) at reflux and the mixture was maintained at reflux

for the required reaction time (see Tables). After the reaction was complete, the solution

was washed with 25 mL of satln'ated aqueous N aHCO3 solution. The aqueous layer was
then extracted with 4 x 40 mL of EtzO, and the organic fractions were combined and dried
over NazSO4, Following removal of solvents, the residue was purified by flash column
chromatography (eluent: 20:80 EtzO:petroleum ether, 40:60 Et20:peuoleum ether, or 50:50

EtzO:petroleum ether). The solvents were removed, and the residue was distilled under

vacuum to give lactam or a mixture of enamide and lactam.

General Procedure for the Reaction of Imines with Acrylic
Anhydride: To a suspension of NaH (0.43 g, 17.9 mmol) in 35 mL of THF at -78 °C
was slowly added acrylic acid (0.87 g, 12.1 mmol). The mixture was warmed to ambient
temperature and then stirred for 1 h. Acryloyl chloride (0.84 g, 9.3 mmol) was then added
to the solution of sodium acrylate, and the reaction mixture was stirred for an additional 1 h
at ambient temperature. The resulting solution of acrylic anhydride was transferred to a
100 ml. flask containing the imine (7.2 mmol), and the original flask was rinsed with an
additional 25 mL of 1111:.24 After the reaction was carried out under the conditions listed
in the Tables, the solution was washed with 30 mL of saturated NaHCO3 solution. The

aqueous layer was then extracted with 4 x 50 mL of Et20, and the organic fractions were

43
combined and dried over N82804. After removal of solvents, the residue was purified by
flash column chromatography (eluent: 50:50 Et20:petroleum ether), and the resulting
lactam was distilled under vacuum.
General Procedure for the Reaction of Imines with Methacrylic
Anhydride or Crotonic Anhydride: To a solution of imine (6.5 mmol) in 44 mL of
THF was added methacrylic anhydride or crotonic anhydride (8.5 mmol), and the mixture

was heated at reflux for the required reaction time (see Tables). After the reaction was
complete, the solution was washed with 25 mL of saturated aqueous NaHCO3 solution.

The aqueous layer was then extracted with 4 x 40 mL of EtZO, and the organic fractions
were combined and dried over NazS 04. Following removal of solvents, the residue was
purified by flash column chromatography (eluent: 20:80 Et20:petroleum ether, or 40:60
Et20:petroleum ether). The solvents were evaporated and the residue was distilled under

vacuum to give the lactam.

General Procedure for the Reaction of Imines with Acrylate

Derivatives Activated by EtOzCCl (The Mixed Anhydride Method): To a
cooled solution (-30°C to -25°C) of (1.8-unsaturated acid (8.5 mmol) in 43 mL of THF
were added TEA (0.9 g, 8.5 mmol) and ethyl chloroformate (0.92 g, 8.5 mmol). After the
mixture was stirred for 1 h at this temperature, the imine (6.5 mmol) was added and stirred
for an additional 1 h. The reaction mixture was then stirred at the appropriate temperature

for the required time. After the reaction was complete, the solution was washed with 25
ml. of saturated aqueous NaHC03 solution. The aqueous layer was extracted with 4 x 40

mL of Et20, and the organic fractions were combined and dried over NazSO4. Eollowing

concentration of the solution, the residue was purified by flash column chromatography
(eluent: 20:80 EtzO:pet1o1eum ether, 40:60 Et20:peuoleum ether, or 50:50 EtzOzpetroleum

ether). The solvents were evaporated and the residue was distilled under vacuum to give

lactam.

44

General Procedure for the Reaction of Imines with Acrylate
Derivatives Activated by DPPA: To a solution of imine (6.5 mmol) in 30 mL THF
at 0 °C were added TEA (0.86 g, 8.5 mmol) and DPPA (2.34 g, 8.5 mmol) and the mixture
was stirred for 30 min. The a,B-unsaturated acid (8.5 mmol) was added slowly and the
reaction mixture was stirred for 30 min at 0 °C, followed by stirring under the conditions
listed in the Tables. After the reaction was complete, the solution was concentrated and the
residue was extracted with 50 mL of CHC13 and the organic layer was washed with 30 mL
of 10% H0. The resulting aqueous layer was further extracted with 3 x 25 mL of CHC13,
and the combined organic layers were subsequently washed with 35 mL of saturated
aqueous NaHC03 solution. The aqueous layer was extracted with 4 x 25 mL of CHC13.
The combined organic layers were washed with 50 mL of H20, and this aqueous layer was
then extracted with 4 x 25 mL of CHC13. The combined organic layers were dried
(NazSO4), filtered, and concentrated to give a crude residue. The crude residue was
purified by flash column chromatography (eluent: 20:80 Et20:petroleum ether, 40:60
Et20:petroleum ether, or 50:50 Et20:petroleum ether). The solvents were evapdrated and
the residue was distilled under vacuum to give the corresponding lactam.

General Procedure for the Reaction of Imines with Acrylate
Derivatives Activated by MCPI: To 75 mL of dry THF were added MCPI (3.0 g,
11.7 mmol), imine (9.8 mmol), a,B-unsat11rated acid (11.7 mmol), and TEA (2.4 g, 23.5
mmol). The solution was heated to reflux for the corresponding reaction time (see Tables).

After the reaction was complete, the solution was concentrated and the crude product was
purified by flash column chromatography (eluent: 20:80 E120:petroleum ether, 40:60

E120:petroleum ether, or 50:50 E120:petroleum ether). The solvents were evaporated and
the residue was distilled under vacuum to give the lactam or a mixture of enamide and

lactam.

General Procedure for the Reaction of Imines with Acyl Intidazole:

To a solution of acryloyl chloride ( 0.77 g, 8.5 mmol) in 20 mL of dry THF was slowly

45
added imidazole (1.2 g, 17.0 mmol) in 30 mL THF and the resulting solution was stirred
for 1 h at ambient temperature. Imine (6.5 mmol) was added into the reaction mixture and

heated at reflux for the corresponding reaction time (see Table 1). After the reaction was
complete, the solution was washed with 30 mL of saturated aqueous NaHC03‘so1ution.

The aqueous layer was extracted with 4 x 30 mL of Et20 and the organic fractions were
dried over Na2SO4. Following concentration of the solution, the residue was purified by
flash column chromatography (eluent 50:50 Et20:petroleum ether). The solvents were
evaporated and the residue was distilled under vacuum to give lactam.

54: (hp 75-85 °C. <1 mmHg): 1H NMR (300 MHz, CDC13, mixture of isomers)
5 0.83 (d, 3H, J = 6.7 Hz, 54b), 0.84 (d, 6H, J = 6.7 Hz, 54a), 0.85 (d, 3H, J = 6.7
Hz, 54b), 1.20-2.20 (to, both), 2.42 (dd, 2H, J = 6.5, 8.4 Hz, 548), 2.48 (dd, 1H, J =
6.0, 12.8 Hz, 54b), 2.58 (ddd, 1H, J = 17.7, 5.6, 2.0 Hz, 54b), 3.40 (d, 2H, J = 7.4
Hz, 54a), 3.55 (d, 2H, J = 7.4 Hz, 54b), 5.03 (m, 1H, 54b); 13C NMR (75.5 MHz,
CDC13, major) 5 19.8, 22.0, 22.8, 25.2, 25.4, 28.3, 29.0, 32.0, 46.7, 116.3, 131.8,
170.9, (minor) d 20.0, 20.2, 21.4, 24.5, 26.1, 27.4, 30.6, 32.9, 35.1, 48.5, 104.4,
138.6,169.3; IR (neat) 3014, 2875, 1634, 1405 cm-1. Anal. Calcd for C13H21NO: C,
75.31; H, 10.21; N, 6.76. Found: C, 75.18; H, 10.04; N, 6.74.

26: (hp 120130 °C, <1 mmHg): 1H NMR (300 MHz. CDC13) 5 1.401.50 (m,
2H, 26a), 1.50-1.60 (m, 2H, 26a), 1.60-1.75 (m, 26b), 1.80-2.00 (m, 26b), 2.03 (m,
4H, both), 2.14 (t. 2H. J = 7.8 Hz, 26a), 2.55-2.80 (m, 2H, both), 4.61 (d, 1H, J =
16.0 Hz, 26b), 4.84 (s, 2H, 26a), 4.96 (m, 1H, 26b), 5.21 (d, 1H, J = 16.0 Hz, 26b),
7.05-7.30 (m, 5H); 13C NMR (75.5 MHz, CDC13, both isomers) 5 21.3, 21.9, 22.8,
24.4, 25.3, 25.4, 27.5, 29.0, 30.4, 31.7, 32.9, 35.0, 43.7, 46.4, 105.4, 115.3, 126.2,
126.3, 126.6, 126.7, 128.4, 128.5, 131.4, 137.7, 138.6, 138.7, 169.3, 170.4; IR (neat)
3087, 3064, 3030, 2932, 2858, 2839, 1669, 1641, 1496, 1454 cm'l; HRMS calcd for
C13H21NO m/z 241.1466, found m/z 241.1473.

46

85: (hp 7080 °C, <1 mmHg): 1H NMR (300 MHz. CDC13, major isomer) 5 1.40
(d, 6H, J = 6.9 Hz), 1.50-1.70 (m, 4H), 1.93-2.09 (m, 4H), 2.09-2.18 (m, 2H), 2.33
(m, 2H), 3.97 (sept, 1H, J = 6.9 Hz); 13C NMR (75.5 MHz, CDC13 mixture of isomers)
5 20.5, 22.2, 23.2, 25.2, 26.3, 29.1, 33.2, 46.8, 116.4, 132.3, 171.1; IR (neat) 3019,
2972, 2937, 1639, 1428, 1419 cm-1; HRMS calcd for C12H19NO m/z 193.1466, found
m/z 193.1464.

78: (hp 55-65 °C, <1 mmHg): 1H NMR (300 MHz, CDCl3, major isomer) 5
1.501.69 (m, 4H), 1.95-2.08 (m, 4H), 2.13-2.23 (m, 2H), 2.41 (m, 2H), 2.81 (s, 6H);
13C NMR (75.5 MHz, CDC13) 5 22.3, 23.0, 24.7, 25.3, 28.8, 33.0, 43.3, 112.4, 134.1,
169.4; IR (neat) 2935, 2888, 1685, 1651, 1441 cm-1; HRMS calcd for C11H13N20 m/z
194.1419, found m/z 194.1415.

69a: (hp 75-85 °C, <1 mmHg): 1H NMR (300 MHz. CDC13) 5 0.84 (d, 3H, J =
6.7 Hz), 0.85 (d, 3H, J = 6.7 Hz), 1.15 (d, 3H, J = 6.9 Hz), 1.45-2.22 (m, 11H), 2.43
(m, 1H), 3.19 (dd, 1H, J = 13.8, 6.9 Hz), 3.60 (dd, 1H, J = 13.8, 7.9 Hz); 13C NMR
(75.5 MHz, CDC13) 5 15.5, 19.9, 20.0, 22.2, 23.0, 25.5, 28.4, 29.3, 33.5, 35.6, 47.1,
115.0, 131.0, 173.3; IR (neat) 2959, 2934,2870, 2831, 1668, 1458 cm-1; HRMS calcd
for C14Hz3NO m/z 221.1779, found m/z 221.1777.

80: (hp 120130 °C, <1 mmHg): 1H NMR (300 MHz, CDC13, major isomer) 5
1.23 (d, 3H, J = 6.9 Hz), 1.42-1.66 (m, 4H), 1.94-2.10 (m, 4H), 2.15 (dd, 1H, J =16.0,
6.5 Hz), 2.59 (m, 1H), 4.73 (d, 1H, J = 16.2 Hz), 4.97 (d, 1H, J = 16.2 Hz), 7.107.32
(m. 5H); 13C NMR (75.5 MHz, CDC13, mixture of isomers) 5 15.2, 21.6, 22.4, 25.0.
28.7, 33.2, 35.0, 43.6, 114.0, 125.8, 126.2, 128.1, 130.5, 138.3, 173.1; IR (neat)
3087, 3062, 3032, 2931. 2867, 2832, 1665, 1495, 1453 cm-1; HRMS calcd for
C17H21NO m/z 255.1612, found m/z 255.1619.

87: (mp 56-57 °C): 1H NMR (300 MHz, CDC13, major isomer) 5 1.08 (d, 3H, J
=6.9 Hz), 1.37 (d, 3H, J = 6.9 Hz), 1.39 (d, 3H, J= 6.9 Hz), 1.44 - 2.22 (m, 1011), 2.32
(m, 1H), 3.95 (sept, 1H, J = 6.9 Hz); 13C NMR (75.5 MHz, CDC13) 5 15.1, 20.5, 20.6,

47

22.3, 23.3, 26.4, 29.5, 33.4, 36.3, 46.9, 115.6, 131.8, 173.7; IR (KBr) 2966, 2931,
1664, 1451, 1418 cm-1; HRMS calcd for C13H21NO m/z 207.1623, found m/z
207.1630.

73a: (hp 75-85 °C, <1 mmI-lg): 1H NMR (300 MHz, CDC13) 5 0.87 (d, 3H, J =
6.8 Hz), 0.88 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J = 7.1 Hz), 1.35 - 1.90 (m, 5H) 1.95
2.20 (m, 5H), 2.26 (dd, 1H, J = 15.6.4.2 Hz), 2.56 (dd, 1H, J = 15.6, 6.4 Hz), 3.09
(dd, 1H, J = 13.9, 7.0 Hz), 3.71 (dd, 1H, J = 13.9, 7.5); 13C NMR (75.5 MHz, CDC13)
5 16.8, 20.1, 20.4, 22.2, 23.0, 25.6, 27.3, 28.6, 30.6, 39.2, 46.9, 120.0, 130.3, 169.7;
IR (neat) 2957, 2870, 2837, 1670, 1639, 1466, 1435 cm-1. Anal. Calcd for
C14H23NO: C, 75.97; H. 10.47; N, 6.33. Found: C, 75.97; H, 10.30, N, 6.40.

82: (hp 120130 °C, <1 mmHg): 1H NMR (300 MHz, CDC13, major isomer) 5
1.00 (d, 3H, J = 7.1 Hz), 1.30 - 2.30 (m, 9H), 2.39 (dd, 1H, J = 15.6, 4.3 Hz), 2.70
(dd, 1H, J = 15.6, 6.5 Hz), 4.70 (d, 1H, J = 16.0 Hz), 5.03 (d, 1H, 16.0 Hz), 7.107.32
(m, 5H); 13C NMR (75.5 MHz, CDC13) 5 16.7, 21.7, 22.4, 25.0, 26.7, 30.4, 38.6,
43.4, 119.2, 126.2, 126.3, 128.0, 129.7, 138.4, 169.5; IR (near) 3087, 3062, 3031,
2932, 2862, 2836, 1665, 1641, 1496 cm-1; HRMS calcd for C17H21NO m/z 255.1612,
found m/z 255.1622.

89: (bp 70-80 °C, <1 mmHg): 1H NMR (300 MHz, CDC13, major isomer) 5 0.92
(d, 3H, J = 7.1 Hz), 1.38 (d, 3H, J = 6.9 Hz), 1.40 (d, 3H, J= 6.9 Hz), 1.302.20 (m,
9H), 2.15 (dd, 1H, J=3.5, 15.4 Hz), 2.51 (dd, 1H, J =15.4, 6.2 Hz), 3.95 (sept, 1H, J =
6.9 Hz): 13C NMR (75.5 MHz, CDC13) 5 16.5, 20.0. 20.5, 22.3, 23.2, 26.4, 27.4,
30.5, 40.2, 46.7, 121.1, 130.9, 170.2; IR (neat) 2960,2933, 2866, 1666, 1418 cm-1;
HRMs calcd for C13H21NO m/z 207.1623, found m/z 207.1627.

67: (hp 65-75 °C, <1 mmHg): 1H NMR (300 MHz, CDC13, mixture of isomers)
5 0.83-0.89 (m, 6H), 1.37-1.53 (m, 1H), 1.73-2.24 (m), 2.302.82 (m), 3.29 (d, 2H, J
=7.6 Hz, 36a), 3.38 (dd, 1H, J = 7.0, 13.4 Hz, 36b), 3.56 (dd, 1H, J = 8.2.13.4 Hz,
36h), 4.78 (m, 1H, 36h). 13C NMR (75.5 MHz, CDC13) 5 20.0, 20.1, 20.2, 21.0,

48
21.7, 26.2, 27.1, 28.4, 29.9, 30.4, 31.2, 32.0, 32.8, 33.2, 41.9, 50.1, 102.9, 115.6.
137.0, 144.1, 169.4, 170.1; IR (neat) 3010, 2963, 2934, 2903, 2872, 2849, 1688, 1660,
1633, 1466, 1406 cm-1. Anal. Calcd for C12H19NO: C, 74.57; H, 9.91; N, 7.25.
Found: C, 74.13; H, 9.95; N, 7.19. I-

62: (hp 5565 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.84 (d, 6H, J =
6.7 Hz), 0.98 (t, 3H, J = 7.4 Hz), 1.88 (m, 1H), 2.00 (m, 2H), 2.14 (t, 2H, J = 7.9 Hz),
2.44 (t. 2H. J = 7.9 Hz), 3.20 (d, 2H, J = 7.5 Hz), 5.68 (m, 1H); 13C NMR (75.5 MHz.
CDC13) 5 12.5, 20.0, 24.2, 26.9, 27.9, 31.6, 53.4, 121.5, 124.4, 169.5; IR (neat) 2964,
2842, 1639 cm-1. Anal. Calcd for C11H19NO: C, 72.88; H, 10.56; N, 7.72. Found:
C, 72.85; H. 9.87; N, 7.72.

71: (hp 55-65 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.86 (d, 6H, J .-
6.7 Hz), 1.01 (t, 3H, J = 7.4 Hz), 1.18 (d, 3H, J = 7.0 Hz), 1.83 - 2.08 (m, 4H), 2.26
(ddd, 1H, J = 6.7, 16.4, 1.0 Hz), 2.48 (d quint, 1H, J = 10.4, 7.0 Hz), 3.15 (dd, 1H, J =
13.4, 7.4 Hz), 3.30 (dd, 1H, J = 13.4, 7.6 Hz), 5.70 (s, 1H); 13C NMR (75.5 MHz,
CDC13) 5 12.4, 15.9, 19.9, 20.0, 26.9, 27.8, 32.1, 35.3, 53.4, 120.1, 123.6, 172.6. IR
(neat) 2964, 2932, 2872, 1662, 1458 cm-1; HRMS calcd for CleleO m/z 195.1623,
found m/z 195.1623.

75: (hp 55-65 °C. <1 mmHg): 1H NMR (300 MHz, CDC13) 5 0.87 (d, 6H, J =
6.7 Hz), 1.02 (m, 6H), 1.92 (m, 1H), 2.04 (m, 2H), 2.23-2.36 (m, 2H), 2.58 (m, 1H),
3.01 (dd, 1H, J = 13.4, 7.1 Hz), 3.46 (dd, 1H, 1 = 13.4, 7.7 Hz), 5.63 (t, 1H, J = 0.8
Hz); 13C NMR (75.5 MHz, CDC13) 5 12.7, 17.7, 19.9, 20.0, 24.8, 27.9, 29.8, 39.1,
53.2, 122.9, 125.9, 168.4; IR (neat) 2964, 2930, 2873, 1679, 1467, 1456, 1414 cm-1;
HRMS calcd for C12H21NO m/z 195.1623, found m/z 195.1630.

92: (hp 85-95 °C, 3 mmHg): 1H NMR (300 MHz, CDC13) 5 1.03 (t, 3H, J = 7.4
Hz), 1.13 (d, 6H, J = 6.8 Hz), 2.07 (bq, 2H, J = 7.4 Hz), 2.18 (bt, 2H, J = 8.1 Hz),
2.48 (dd, 2H, J = 7.3, 8.7 Hz), 4.87 (sept, 1H, J = 6.8 Hz), 5.85 (quint, 1H. J = 1.2
Hz); 13C NMR (75.5 MHz, CDC13) 5 12.4, 20.4, 23.5, 27.1, 31.6, 42.9, 117.7, 122.0,

49

168.1; IR (neat) 2968, 2934, 2898, 2877, 2842, 1657, 1463, 1437, 1410 cm'l; HRMS
calcd for C10H17NO m/z 167.1310, found m/z 167.1309.

94: (hp 95-105 °C, 3 mmHg): 1H NMR (300 MHz, CDC13) 5 0.97 (d, 3H, J =
6.9 Hz), 1.04 (t, 3H, J = 7.4 Hz), 1.10 (d, 3H, J = 6.9 Hz), 1.13 (d, 3H, J = 6.9 Hz),
2.02-2.11 (m, 2H), 2.26 (m, 1H), 2.26 (dd, 1H, J = 3.8, 16.6 Hz), 2.57 (dd, 1H, J =
16.6, 7.4 Hz), 4.87 (sept, 1H, J = 6.9 Hz), 5.76 (t, 1H, J = 1.4 Hz); 13C NMR (75.5
MHz, CDC13) 5 12.7, 17.5, 20.0, 20.6, 25.2, 29.1, 39.3, 42.8, 116.5, 127.3, 167.6; IR
(neat) 2965, 2932, 2876, 1671, 1463, 1410 cm‘l; HRMS calcd for C10H19NO mIz
181.1466, found m/z 181.1462.

General Procedure for the Isomerization of Double Bonds and
Hydrolysis of Enamides: To a solution containing a mixture of enamide and lactam or
mixture of double bond isomers (1 mmol in 10 mL of methanol) was added p-
toluenesulfonic acid (0.2 mmol) and the reaction mixture was heated at reflux or stirred at
ambient temperature until either the enamide was hydrolyzed or isomerization demonstrated
no further change.

50

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51

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Bernasconi, S.; Comini, A.; Corbella, A.; Gariboldi, P.; Sisti, M. Synthesis 1980,
385.

Holzapfel, C.; Pettit, G. J. Org. Chem. 1985, 50, 2323.

(a) Shiori, T.; Ninomiya, K.; Yamada, S. J. J. Am. Chem. Soc. 1972, 94, 6203. (b)
Danieli, B.; Lesma, G.; Palmisano, G.; Tollari, S. Synthesis 1984, 353.

(19)
(20)
(21)

(22)
(23)
(24)

52
Bald, B.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163'.
Pfau, M.; Monfrin, J. U. Tetrahedron 1979, 35, 1899.
Hickmott, P. W.; Miles, G. J.; Sheppard, G.; Urbani, R.; Yoxall, C. T. J. Chem.
Soc., Perkin Trans.) 1973, 1514.
Pfau, M.; Ribiere, C. J. Chem. Soc., Chem. Commun. 1970, 66.
Shiori, T.; Yamada, S. Org. Synth. 1984, 62, 187.
In order to avoid aldol type condensation products in the reaction with aldimine
62, acrylic anhydride was first transferred to a schlenk flask followed by addition
of the imine to the acrylic anhydride solution.

53

CHAPTER 2

AZA-ANNULATION OF ENAMINES

54
INTRODUCTION

In contrast to the isolation of a mixture of enamide and lactam from the reaction
of an imine and acryloyl chloride,1 Hickmott isolated only the six-membered lactam 102
in 47% yield from the reaction of enamino ester 101 and crotonyl chloride (eq 1).2
Under the same reaction conditions,.enamino ketone 103 also gave only bicyclic lactam

104 in 47% yield (eq 2).

 

 

0 Me
3w crotonoyl chloride E10 Xi
benzene/48 h -
(1)
Me 0151 47% Me If 0
Bn
101 102
0
M. e
Me
103

 

The absence of uncyclized enamide in the reaction of enamino ester 101 or
enamino ketone 103 with (1.8-unsaturated acid chlorides could be explained on the basis
of the stable enamine tautomer. In the case of the imine 105 with an electron
withdrawing group (B) in the B-position, the equilibrium favors the enamine tautomer
106 because of the conjugation of the enamine double bond with electron withdrawing
group (B) (eq 3). Since the B-carbon of the enamine is more nucleophilic than the
nitrogen as shown in 107, initial C-alkylation occurs faster than the N-acylation during
the annulation reaction. Hence the initial C-alkylation followed by intramolecular N-

acylation would give only lactam.

55

+

NI-IR
R1 ’(EW- (3)

E

 

NR NHR

""31 .=.._._____ ('4
Rd Rla
B

E E

imine enamine

105 106 107

Following Hickmott's earlier reports, several research groups have investigated
the reactions of enamines with a variety of a,B-unsaturated acid derivatives. These
results help us to understand the limitation and usefulness of this annulation. Selected

examples of the reactions of enamines with various acid derivatives are discussed.

11) Reaction of Enamines with cab-Unsaturated Acid Chlorides

Lhommet studied the reaction of cyclic enamino esters 108 and 109 with various
a,B-unsaturated acid chlorides (eq 4) and the results are shown in Table XV 11.3 The
reaction of acryloyl chloride with enamino ester 108 gave only lactam 110 (entry 1) and
the reaction methacrolyl chloride and crotonyl chloride with 108 gave the corresponding
enamides 114 and 115 as the major product (entry 2 and 3). The formation of uncyclized
enamides 114 and 115 as the major product could be due the presence of pyridine in the
reaction mixture. The reaction of enamino ester 109 with acryloyl chloride, methacryloyl
chloride and crotonyl chloride gave the corresponding lactams 116 to 118 (entries 4 to 6),
and the lactams were isolated as a mixture of double bond isomers. Lhommet increased
the scope of this methodology by preparing several valuable substituted indolizidinone
and quinolizidinone skeletons in a simple and elegant manner. These indolizidinone and
quinolizidinone compounds could be used to synthesise various biologically active

alkaloids.

56

 

 

( 11 N‘
H
1121 108 n=1, R1: H R2 = H 110 113
n=2 109 n=1, R1: Me R2 a H 111 114
n=1, R1211 R2=Me 112 115
n=2, R1: H R2 = H 116 119
n=2, R1= Me R2 = H 117 120
n=2, R1: H R2 = Me 118 121

Table XVII. Reaction of Enamino Esters 108 and 109 with (LB-Unsaturated Acid

 

Chlorides and Esters.

Earn a 81 82 21 min Command: Ratio 01:40
1 1 H H Cl 72% 110: 113 100: 00 0: 100
2 1 Me H Cl 64% 111: 114 3 0:70 0: 1(1)
3 1 H Me Cl 72% 112: 115 0: 100 0: 100
4 2 H H Cl 82% 116: 119 100:00 70:30
5 2 Me H C1 68% 117: 120 100:00 80:20
6 2 H Me Cl 68% 118:121 100:00 60:40
7 1 H H OEt 75% 110: 113 100: 00 0: 1(1)
8 1 Me H OEt 72% 111: 114 100:00 0: 100
9 1 H Me OEt 63% 112: 115 100: 00 0: 1(1)

10 2 H H OEt 82% 116: 119 100: 00 65 :35
11 2 Me H OEt 68% 117: 120 100:00 92 :08
12 2 H Me OEt 68% 118: 121 100: 00 52 :48

 

Treatment of the enamino ester 122 with acid chloride of 2-phthalimidoacrylic
acid (123a) gave the bicyclic lactam 124 in 30% yield.4 Lactam 124 is analogous to a B-

lactam antibiotics. The yield of this reaction was improved to 92% by refluxing 122 with

57
123b and PC13 (eq 5). Isolation of compound 124 shows the use of the aza-annulation
reaction to prepare six-membered lactams with an amino group a to the amide carbonyl
group in a single step from the corresponding enamino ester. Under the above reaction

conditions, reaction of enamino ester 125 with acrylic acid in the presence of PC13 gave

 

 

 

lactam 126 in 45% yield (eq 6).4
H COan
5 0 X=CVIEAICHC13 s
0023“ + R reflux/30% 5
NH x a > N ( )
Me X=OHIPC13IC6H¢ Me R
C0213n reflux/92% gnozc o
122 1238 X=C1 123b X=0H 124
COzMe
S acrylic a‘cioidIPClg S
xane
wire. .. Wm - N
p; H stozc“ H
o
125 126

b) Reaction of Enamines with (LB-Unsaturated Esters

Lhommet studied the reaction of enamino esters 108 and 109 with various 01,8-
unsaturated esters (eq 4) and the results are shown in Table XVII.3 In the reaction of
enamino esters 108 and 109 with a,B-unsaturated esters, NaH was used as a base to favor
the intramolecular N-acylation. Only bicych lactams 110 to 112 and 116 to 118 were
obtained in moderate to good yield from the reaction of enamino esters 108 and 109 with

all (1.8-Unsaturated esters (entries 7 to 12). Lactams 116 to 118 were isolated as a

58

mixture of double bond isomers. Since the preparation of (LB-unsaturated esters are
easier than the corresponding acid chlorides, use of (LB-unsaturated esters is an
alternative to carry out annulation reactions.

Singh and his co-workers isolated lactam 128 in 60% yield from the reaction of
enamino nitrile 127 with methyl methacrylate (eq 7).5 Treatment of 127 with methyl
propiolate gave pyridinone 129 in 38% yield (eq 8). Lactams 128 and 129 were formed
via initial C-alkylation followed by intramolecular N-acylation. Even though the yield of
the formation of compound 129 was low, use of methyl propiolate in this annulation
opened a new door to prepare various substituted aromatic nitrogen heterocycles in a

single step from the corresponding acyclic enamines.

 

 

NC 0 l. NaH/dioxane NC Me
100 °C.35 h
l + Mam/k0” 2. AcOH ’ n (7)
Me NH, 60% Me 1:1 0
H
127 128
NC NC
DMF/72 h
| + > I (8)
Me NH“ C°2M° 38% 1‘“ If 0
H
127 129

The Maccioni group reported the isolation of the intermediate dienamino ester
130 from the reaction of 127 and ethyl propiolate (eq 9).6 Dienamino ester 130 was a
stable compound, did not undergo cyclization under normal conditions, and was cyclized
into 132 by heating with sodium ethoxide in ethanol. On the other hand, reaction of
diethyl acetylenedicarboxylate with 127 gave compound 131 without isolation of any C-
alkylation product. As mentioned in the previous example, use of methyl propiolate and

59
diethyl acetylenedicarboxylate as acylating agents provided substituted aromatic nitrogen

heterocycles in good yields and increased the usefulness of this annulation reaction.

NC NC El
I + C0215: WM h CO:
i 65-91% I (9)

 

X NH, X NH,
1 2 7 l 3 0
Et02C—-—cozgr 1. NaOBt/EtOH
r.t.I30 min 2. AcOH
65-85% 86-95%
V
C0281
NC NC
I MO I1
X N O X 1:1 0
r': u
13 l 132

Danishefsky used this annulation as one of the key steps in the synthesis of the
anti tumor alkaloid camptothecin.7 Enamino ester 108 was reacted with enol phosphate
133 to give pyridone 134 (eq 10). The yield of this reaction has been increased from 54%
to 92% by using readily available dimethyl-3-chloroglutoconate (135) in the presence of
triethylamine (eq 11).8 Compounds 133 and 135 are precursors of allene functionality

and generate allene in situ with TEA.

I cone
CCH =CH El C0251
OACOZMG + BO: 23 C02 H ’- CH2 (10)
N ‘ r.tJ48 hIS4% N I

 

,H /P(01~:t),
° 0

108 133 134

60
TEA/EtOI-I

 

l :-

08 + Me02CCH¢C CHC02Me mosh/92%" 134 (11)
C1
135

Huang prepared lactam 137 in 53% yield from the annulation of heterocyclic
ketene N,O-acetal 136 with ethyl propiolate.9 Only the more reactive 4-methoxy benzoyl
substituted ketene N,O-acetal 136 reacted with ethyl propiolate to give the lactam 137 in
moderate yield (eq 12). Reaction of other benzoyl substituted ketene N,O-acetals with
ethyl propiolate gave only a trace of products. On the other hand, other benzoyl
substituted ketene N,O-acetals such as p-methyl benzoyl substituted ketene N,O-acetal
138 gave 139 in 83% yield with diethyl acetylenedicarboxylate (eq 13). The rate of the

reaction was very slow and the yields were moderate to high.

 

 

COZE‘ . 0 CO-Ph-OMe
[EH EIOH E _ ( 12)
H 53%
O
136 137
1:1: Lcorn-Mt: + + reflux/1 days’ [Egcozm (13)
H €023 83%
138 139

Huang also investigated the annulation of ketene aminals with ethyl propiolate (eq
14).10 Compound 141 (R=Me) failed to react with ethyl propiolate, and resulted in the
recovery of starting material. On the other hand, reaction of compound 140 (R=H) with
ethyl propiolate readily gave the C-alkylated product 142, which was cyclized in
refluxing ethanol to give lactam 143. The lactam 143 was also directly prepared in one

61
step by refluxing 140 with ethyl propiolate in ethanol. Polar protic solvents gave the

cyclized product directly without the isolation of any intermediate.

 

 

 

’1‘
N
diR=Me
ENH:Ph HC 'C "C0251 xane/r. t. »no reaction
I
140R R2 H
141 R = Me
R=H
dioxane (14)
.L/4 days
96%
R ‘1‘
I
N 00.11:; N CO-Ph
E H EIOH E —
'
N reflux/20 h N
1': 82%
H COZEI 0
142 143

c) Reaction of Enamines with (LB-Unsaturated Anhydrides

Nagasaka and his coworkers used the enamino ester 108 as an useful precursor to
prepare a variety of fused heterocyclic compounds (eq 15).11 Lactam 146 was prepared
in 97% yield from the reaction of 108 and maleic anhydride (144) in refluxing benzene.
In the case of 2-substituted maleic anhydride 145, the annulation reactions required
longer reaction times and gave lactams in low yield as a mixture of regioisomers 147a
and 147b. The low reactivity could be due to the steric effect of the methyl group during
the initial C-C bond formation. Annulation of 108 with itaconic anhydride (148) gave

lactam 149 in 92% yield (eq 16). These reactions demonstrate the use of cyclic (1,8—

62

unsaturated anhydrides as annulating agent in aza-annulation to prepare six-membered

 

 

lactams in high yield.
o (30:131 C0213:
R cozH co,H
N N
R
0 o o
R=H 144 R=H 146 R=H 146
R=Mel45 R=Mel47a R=Me147b
COzEt
11
108 + o C6333”; “" 0 N (16)
0 CH,C0,H
o
148 149

In extension of the use of cyclic anhydrides as the annulating agent, Danishefsky
reacted a-methyleneglutaric anhydride (151) with enamino ester 150, prepared from D,L-
pyroglutamic acid, to give compound 152 in 95% yield. The compound 152 was used to
the total synthesis of the enzyme inhibitor A58365A (eq 17).12

 

COan
C112
Colic/mam:
Woman + 0mg 95% , N R (17)
Moo2 H
1:2
15 0 l 5 l l 52

R=-CH2CH;C02H

63

d) Reaction of Enamines with a,B-Unsaturated Acids

“Wrestler used the aza-annulation reaction as the key step toward the synthesis of
lycopodium alkaloid annotinine. The key intermediate 154 was obtained in quantitative
yield by heating the enamino ketone 153 with a 15% excess of acrylic acid at 135 °C (eq
18).13 The use of acrylic acid as the annulating agent required higher temperature and

solvent was not used. However these conditions cannot be used in the presence of other

 

 

sensitive functional groups.
0
153 154

Young prepared bicych lactams 156 and 158 in 63 and 27% yields respectively
from the annulation of the cyclic enamino esters 155 and 157 respectively with propiolic
acid in the presence of acid activating reagent DCC (eq 19 and 20).4 Young showed the
use of acid activating reagent DCC in this annulation. Use of acid in the presence of acid
activating agents eliminates the conversion of acids to the corresponding acid chlorides,

esters or anhydrides.

 

Me 8N7“ ‘ cont. ”“1““ (19)“
c DCC/CHzCl
502 H N” r. Ll63% 2 more

155 156

COan

5
o o . s
7" ‘co,an Wm” 3°“ : I (20)
MOOZC 0.. N‘ DCC/CH2C12 N
H H

ILL/27% Meozc

 

H

157 158

Even though several reactions of enamines with various (1.8-unsaturated acid
derivatives have been reported, no one has systematically investigated the aza-annulation
of enamines. Hence, we wanted to thoroughly study this reaction with the following
aims:

1) To optimize the reaction conditions of the annulation to prepare lactam in high yield
under mild conditions and to extend this annulation methodology to various enamines
conjugated with a variety of electron withdrawing groups.

2) To study the cis and trans selectivity of catalytic hydrogenation of the double bond
of the lactams prepared from the reaction of enamines and acryloyl chloride. Since
numerous alkaloids have saturated six-membered nitrogen heterocycles, hydrogenation
of the annulated lactam would show the importance of this methodology in alkaloid

synthesis.

65
RESULTS AND DISCUSSION

In order to study the aza-annulation of enamines conjugated with electron
withdrawing groups, enamino ketone 160 was chosen for our initial studies. Enamino
ketone 160 was prepared in 89% yield from the condensation of 1,3-cyclohexanedione
159 and benzylamine. 14 Purified enamino ketone 160 was reacted with various acrylic
acid derivatives and the results are given in Scheme IV. Reaction of 160 with acrylic
acid derivatives (acryloyl chloride, acrylic anhydride and acrylic acid in the presence of
ethyl chloroformate) gave only bicyclic lactam 161 in moderate yields (52-62%).

Scheme IV. Reaction of Enamino Ketone 160 with Acrylic Acid Derivatives.

o o 0 o
l
I x 1
“W O '9
’ >
reflux/89% .
o NHCH21>h N ‘
159

 

 

 

 

 

 

 

 

 

' o
160 161 Bn
1)PhCH2NHz/CoHo - -
”flu/24h X Irma Kelli
2) removalofsolvent C1 10 h “62%
o CH2=CHC02 13h 5295
KL EtOCOz 24h 54%
x o
3) I THF/reflux
+ ~ e
X lime Xirld N 1 0
1
C1 24 h 75% 3“
CHz-CHCO; 13h 72% 161

 

Since the enamine formation is an efficient process, the crude enamino ketone 160
obtained after the removal of the solvent was directly treated with acrylic acid derivatives

without further purification. For the two-step process, both acryloyl chloride and acrylic

66

anhydride gave lactam 161 in good yields (75 and 72% respectively). Since the two-step
one pot reaction (enamine formation and annulation) was efficient and gave lactams in
good yield, these conditions were used as the general annulation procedure to prepare six-
membered lactams directly from the corresponding ketones. Further, acryloyl chloride is
a readily available inexpensive reagent which serves as the annulating agent for the
annulation process. This two-step one-pot annulation procedure using acryloyl chloride
as the annulating reagent was employed in most of the annulation reactions unless
otherwise noted.

Having optimized the aza—annulation conditions, attention was then focused on
finding suitable conditions for the stereoselective reduction of the tetra substituted
emamine double bond to either cis or trans lactams. The cis or trans lactam lends itself
nicely as a precursor in organic synthesis. Reaction of lactam 161 with NaBH4 did not

reduce the enamine double bond, but reduced the ketone and gave alcohol 162 in 77%
yield (eq 21).

 

 

OH O (:)H
‘ NaBHdBtOH Pd/C/Hz/45 psi- (21)
1:1 . O r.L/10 h/77% If \0 Nmfl N g 0
Bn Bn Bn
162 161 163
(85:5:10)

Catalytic hydrogenation of the lactam 161 over 10% Pd on carbon gave a
considerable amount of unwanted side products. Hydrogenation of compound 161 in
ethanol in the presence of 3.5 equivalent of N 82CO3 under 45 psi of H2 atmosphere gave
cis fused hydroxy lactam 163 as the major product along with a trace of its hydroxyl
epimer (5%) and trans isomer (10%) in 91% yield15 The stereochemistry of alcohol 163

was confirmed both by comparison with similar reactions in the literature and by

67
chemical transformations. Haberrnehl reported isolation of alcohol 165 from the catalytic
hydrogenation of enamino ketone 164 with P1 in acetic acid (eq 22).16

0 HO
g H
If C3H7 H If C3H7
H H
164 165

In order to confirm the configuration of alcohol 163 by chemical transformations,
compound 163 was oxidized to a 90: 10 mixture of cis and trans ketone 166 in 93% yield
using Swem oxidation (eq 23).17 The ketone 166 was then reacted with NaBH4 to give
alcohol 163 along with a trace of its epimer (3%) and trans isomer (12%) in 92% yield.
Attack of the hydride ion would be expected from the least hindered side, top side, of the
cis fused ring to avoid steric hindrance as shown in Fig 1. As expected, during NaBH4
reduction of 166, the hydride ion was delivered from the sterically unhindered top side of
the ring to give the alcohol 163 as the major product along with a small amount of its

epimer.

 

(23)

 

 

68

The isomer and epimer ratios of the compounds 163 and 166 were determined by
the 1H NMR spectroscopy. Since both alcohol 163 and ketone 166 have asymmetric
centers, the benzylic methylene protons are non-equivalent and give an AB pattern in the
1H NMR spectrum. The AB pattern due to the benzylic methylene protons was used to
determine isomer and epimer ratio of the compounds. A similar observation was also
reported by Hickmott.2

Having optimized the aza-annulation and hydrogenation conditions, this
methodology was extended to a variety of enamines. Initially, acyclic symmetrical
ketone 167, non symmetrical ketone 170, and cyclic enamino ketone 173 were chosen,
and the results of annulation and hydrogenation are shown in Table XVIII. Aza-
annulation of acetylacetone (167) gave lactam 168 in 84% yield (entry 2). On catalytic
hydrogenation, lactam 168 gave a 65:35 mixture of cis and trans lactams 169 in 87%

yield. The poor selectivity was believed to arise from the epimerization of the

asymmetric center, a to the keto group, by NazCO3 present in the reaction‘mixture.
However, hydrogenation of lactam 168 in the absence of NazCO3, also gave similar
selectivity. Annulation of the unsymmetrical 1,3-diketone, benzoylacetone (170)
regiospecifically gave lactam 171 in 79% yield (entry 3). Absence of the regioisomer
could be explained on the basis of steric effects due to the phenyl group in the starting
ketone. Unfortunately, the hydrogenation of the lactam 171 gave a mixture of products.
The cyclic enamino ketone 173 was prepared using Meyer's procedure from the
corresponding imine, 2,4,4-trimethy1-2-oxazoline (172), and ethyl acetate. 18 Reaction of
173 with acryloyl chloride gave lactam 174 in 64% yield (entry 4). Hydrogenation of the
lactam 174 gave a 61:39 mixture of cis and trans lactam 175 in 34% yield. Aza-
annulation of enamino ketones gave lactams in moderate to high yield, but the catalytic

hydrogenation of the lactams 168, 171 and 174 gave poor selectivity.

69

Table XVIII. Aza-Annulation of Enamino Ketones.

 

 

 

 

 

 

 

 

 

 

172

 

Me

I
H

173

. Annulated . 11)er ‘1' 1d
5“” W product “8“ product (cis'tians)
0 Ho
0 g H
, 91%
1 75% (85:10:5)
N o N o
O I H I
Bn Bn
159 161 163
o o o H
Me Me 87%
Me N 0 Men N 0
Me 0 Ba Bn
167 168 169
o
0
Ph
3 Ill/.1 JIl 79% Mixuneofproducts —-
Me N 0
Me 0 I
Bn
170 171
COMe COMe 34%
4 mfi& Mg U 64% Me U (61239)
H com o o
173 174 175 P
0 "1° 0
Me A 1.8-3111.1 f (24)
N Me zethyltwate’ N
“'3 CDCH

70

In developing this methodology, the annulation was extended to various enamino
esters which were prepared from B-keto esters and a primary amines. The results of the
annulation of various acych D-keto esters and hydrogenation of the lactams are shown in
Table XIX. Annulation of ethyl acetoacetate (176) gave lactam 177 in 94% yield (entry
1). Catalytic hydrogenation of 177 gave a >98z<2 mixture of cis and trans lactams 178 in
91% yield. Lactam 180 was obtained in 91% yield from the annulation of benzyl
acetoacetate (179) and hydrogenation of lactam 180 gave a 96:4 mixture of cis and trans
acids 181 in 91% yield (entry 2). In order to avoid the formation of sodium salt of acid
181, hydrogenation was carried out without the addition of Na2C03. High cis
stereoselectivity upon hydrogenation of lactams 178 and 181 encouraged us to extend
these annulation and hydrogenation processes to other B-keto esters. The intermediate
crude enamino ester 102, derived from 176 and benzylamine, was treated with crotonyl
chloride to give the lactam 103 in 75% yield (entry 3). Hydrogenation of lactam 103 was
sluggish and gave a 86:14 mixture of diastereomers 182 in 53% yield. The enamino ester
183, prepared from the reaction of dimethyl acetylenedicarboxylate and benzylamine,
was treated with acryloyl chloride to give lactam 134 in 34% yield (entry 4).19
Hydrogenation of lactam 184 stereospecifically gave only cis lactam 185 in 80% yield.
Changing from benzylamine to NN-dimediylhydrazine did not affect either the yield of
the annulation product or selectivity of hydrogenation. The crude enamino ester prepared
from 176 and N ,N-dimethylhydrazine was treated with acryloyl chloride to provide
lactam 186 in 75% yield (entry 5). Catalytic hydrogenation of lactam 186 was highly
stereoselective and gave a >98:d mixture of cis and trans lactam 187 in 87% yield. In
this methodology, annulation of acyclic enamino esters gave lactams in high yield and
hydrogenation of the lactams stereoselectively gave cis lactams as the major product.

This procedure is one of the simplest ways to prepare cis substituted piperidine skeletons.

Table XIX. Aza-Annulation of Acyclic Enamino Esters.

71

 

 

 

 

 

 

 

Annulated . °
Entry B-Ketoester product Yield WWI [($9.1ng
O O 0 H
BIO EtO 9l%
1 BIO )‘Il 94% (>98:<4)
Me 0 Me If 0 Me 1:1 0
En Bn
176 177 178
O 0 O H
. 3110 H0 91%
2 300i lino 91% mo (96:4)
Me 0 I H I
Bn Bn
179 180 181
0 0 Me O H Me
BIO BIO 53%
3 Bto’ul | 75% (86:14)
M. o M. t 0 M. 1? 0
En Bn
176 103 182
O i O O H
b MeO MeO 80%
4 m MeO I 84% mom (lOlhO)
NHBn If 0 H I 0
O O Bn 0 Ba
183 184 185
O 0 O H
F40 BIO 87%
Me O I H I -
NW2
176 186 187

 

 

 

a) Hydrogenation wascaniedoutwithoutNazCO3. b) Hydrogemtionwascaniedoutin methanol
without Na2C03,

72

The results obtained from the annulation of B-keto esters prompted us to carry out
aza-annulation on various cyclic B—keto esters 188, 191, 194. The results of annulation of

fl-keto esters and hydrogenation of the annulated products are shown in Table XX.

Table XX. Aza-Annulation of Cych Enamino Esters.

 

 

Annulated . Hydrogenated Yield
Entry Km 1mm,“ Y3“ Mic! (ciszuans)
0 00,3 00,3
1.:‘Loa .. .232,
g N O N O
0 r'an H 8n
188 189 190
o 0 0 O O O
83%
2 Q0 34% (91.9)
Me If 0 M‘ II If 0
En Bn
191 192 193
0
83%
3 0 I 43% 0 .
0d If 0 H If 0 (95.5)
on Bn Bn
194 195 196

 

 

 

 

 

 

 

Annulation of ethyl 2-cyclohexanone carboxylate (188) gave lactam 189 with an
angular quaternary ester group in 89% yield (entry 1). Catalytic hydrogenation of lactam
189 was not very selective and gave lactam 190 as a 56:44 mixture of two diastereomers

in 85% yield. The spiro lactam 192 was obtained in 84% yield from the annulation of 2-

 

73

acetyl butyrolactone (191) (entry 2). The enamine double bond was exo cyclic, and
hydrogenation of the lactam 192 gave a 91:9 mixture of two diastereomers of 193 in 83%
yield. The absolute configuration of the major and minor diastereomers was not
determined. Annulation of tetronic acid (194) gave lactam 195 in 43% yield (entry 3).
The isolation of the lactam 195 in low yield was due to the formation of a side product.
Attempts to avoid the formation of the side product or to increase the yield of the reaction
were not made. Hydrogenation of the lactam 195 gave a 95:5 mixture of cis and trans
compounds 196 in 83% yield. Even though the lactams 190, 193 and 196 were obtained
from moderate to high yield, the hydrogenation of lactams 189 and 192 was not selective
as expected.

The aza-annulation was extended to prepare various indolizidinone derivatives
from the corresponding cyclic enamino esters. Cyclic enamino esters 108 and 200 were

chosen for aza-annulation. Enamino ester 108 was prepared using Lhommet's procedure

as shown in eq 25.20
0 O
0 ME Numb 0 MO
Q + _. (25)
N 0M6 0X Me GIGS/reflux If OxMc
o H o _
197 198 199
NaOEl/EIOH
12 h/leflux

108

74

The results of the annulation of enamino esters 108 and 200 are given in Table
XXI. The reaction of 108 with acryloyl chloride gave lactam 110 in 87% yield (entry 1).
Hydrogenation of the lactam 110 gave a 95:5 mixture of cis and trans lactam 201 in 95%
yield. This sequence of annulation of enamino ester 108 followed by hydrogenation of
the lactam provided the thermodynamically less stable cis fused indolizidinone skeleton.

Lhommet's inability to prepare lactam 113 from the reaction of enamino ”ester 108
and crotonoyl chloride prompted us to re investigate the same reaction using our
annulation conditions. Under our annulation conditions, the reaction of crotonyl chloride
with 108 gave a mixture of products with bicyclic lactam 112 as the major product in
45% yield. A 90:10 mixture of diastereoisomers 202 was obtained in 28% yield upon
hydrogenation of the lactam 112. Isolation of only enamide 115 by Lhommet could be
due to the presence of pyridine in the reaction mixture. Presence of pyridine probably
initiated the initial N-acylation over C-alkylation to avoid the steric hindrance due to the
B-methyl group in crotonyl chloride. In the absence of base, C-alkylation is faster than
N-acylation and gives the lactam as the major product.

The enamino diester 200 was prepared from the condensation of lactim-ether 197
and diethyl malonate in the presence of catalytic amount of Ni(acac)2 (eq 26).21
Reaction of enamino ester 200 with acryloyl chloride gave indolizidinone 203 with a
quaternary carbon in 75% yield. Hydrogenation of lactam 203 gave compound 204 in
85% yield. Since the enamino diester 200 gave lactam 203, the structurally similar
enamino diester 199 was expected to give a spiro compound after annulation. Treatment

of 199 with acryloyl chloride did not give any expected product, and only starting

 

material was recovered.
C02Et
U + < Ni(w)z > [DI—xrcozrat (26)
N OMe €025, 110 °C In{ C023

75

Table XXI. Aza-Annulation of Cyclic Enamino Esters.

 

 

. Annulated . Hydrogenated Yield
Entry Enamrnoecter 1 I Yield 1 (cis:trans)
r'i C0251 0 °
108 l 10 20 1
2 (Nk N C025! 45% N COZEI 28%
I (90:10)
H (3025‘ 0 Me 0 Me
108 1 12 202
C02Et C0251
3 1:; 0025‘ N 0021-1 75% N CozEt 35%
I-l C0215; 0 0
200 203 204

 

 

 

 

 

 

 

 

Annulation was also carried out with B-keto amides (Table XXII). Annulation of
keto amide 205 gave lactam 206 in 53% yield (entry 1). The low yield of the lactam was
due to the formation of a side product. Hydrogenation of 206 gave a 95:5 mixture of cis
and trans lactam 207 in 56% yield. Excellent cis stereoselectivity on hydrogenation
prompted us to carry out the annulation on an enamine conjugated with a chiral amide,
and to study the diastereoselectivity of hydrogenation of the annulated product. Evan's
chiral oxazolidone imide, commonly used in organic synthesis, was employed as the
chiral auxiliary. Preparation of the required B—keto oxazolidone imide 209 is shown in

equation 27.22

76
Table XXII. Aza-Annulation of Enamino Amides.

 

 

Em Annulated Yield Hymumd ( €13;ng )
0 0 OH
1 PhNH’ul m'HJjL/l 53% m" (33:)
Me 0 Me III 0 Me H If 0
En Bn
205 206 207
o
o
2 “'1 “II 9”"
Me 0 Me If 0
En
209 210
o
Xc'OJLN—
~iPr
O O
”“ J1 ”“10
3 I I m
o‘J‘N M12 OJWN N o 9
Me Me H
211 212

 

 

 

 

 

 

 

 

Compound 208 was prepared from valinol using Evan's procedure.23 The enolate
generated from 208 using LDA was treated with acetyl chloride to give 209 in 44% yield
(eq 27).24 Under annulation conditions, lactam 210 was isolated in 93% yield from 209.
Lactam 210 was hydrogenated under the optimized conditions. The hydrogenation was

77

very slow, and even after 48 h, only a trace of the reduced product was observed by 1H
NMR spectroscopy. Since lactam 210 was almost inert to hydrogenation, further studies
on this compound 210 were not pursued.

O 0 1 LDA O O 0
oJkNJLcu3 £132.02. OJLNMma (27)

‘—k.

r-Pr i-Pr
208 209

Reaction of the commercially available 1.6-dimethyl 2-amino uracil (211) with
acryloyl chloride gave lactam 212 in 79% yield. Since the enamine functionality
possesses a primary amine, formation of uncyclized enamide was also expected.
However, only lactam 212 was isolated without any trace of uncyclized enamide. In
compound 211, the enamine carbon is more nucleophilic than the corresponding nitrogen,
and favors the C-alkylation followed by intramolecular N-acylation.

Aza-annulation methodology was also extended to other ketones with electron
withdrawing groups such as a phosphate, sulfone, nitrile or nitro group in the B position.
The results are given in the Table XXIII. Lactam 214 was obtained in 72% yield from
diethyl-(2-oxopropyl)-phosphate (213). Hydrogenation of the lactam 214 gave a 78:22
mixture of cis and trans compounds 215 in 67% yield. Under the annulation conditions,
B-keto sulfone 216 gave lactam 217 in 69% yield and only starting material was
recovered when reduction of the double bond was attempted. Reaction of the
commercially available enamino nitrile 127 with acryloyl chloride gave only lactam 218
in 82% yield. Hydrogenation of lactam 218 gave only a trace of reduced product even
after extended exposure to the hydrogenation conditions. The cyclic enamino nitro
compound 219 was prepared from the condensation of lactim-ether 197 and nitromethane
in the presence of catalytic amount of Ni(acac)2 (eq 28).25 After the removal of the

78

methanol by product, the crude compound 219 was treated with acryloyl chloride to give

lactam 220 in 38% yield (from the starting lactim-ether 197). The presence of Ni(acac)2

catalyst did not affect the annulation. Catalytic hydrogenation of lactam 220 gave a

mixture of cis and trans of amino compounds and the ratio could not be determined.

Table XXIII. Aza-Annulation of Various Enamines.

 

 

 

 

 

 

 

 

Annulated . H Yield
Entry W p'oduct Ye“ Wmm (cisztrans)
o 9 (I? a
II
(50),? (50),? (1540),? 67%
1 l I 72* (78:22)
Me N OI Me N
Me 0 | H I
Bn Bn
2 l 3 2 l 4 2 l 5
o (I?
phi: Phi
2 gl on 69% Noreaction
Me N 0
Me 0 I
Bn
2 l 6 2 l 7
NC NC |
3 1 Me N O 32% Time of [lodmt
Me NH2 1
, H
l 2 7 2 l 8
N
4 [1% E7 0’ 38%' N NH“
I
H N02 0 o
2 l 9 2 2 0 2 2 l

 

a)yieldfromthestartinglactirn-ether197.

 

79

NO
( 3‘ + Cl-IsNOz “mach ; (X (28)
110°C _

N OMe 1:1
H N02

 

197 219

CONCLUSION

As planned, annulation reaction conditions were optimized to prepare six-
membered lactams in high yield under mild conditions from the corresponding ketones.
Preparation of lactams in high yield under mild conditions involving two steps one pot
reaction shows the superiority of this methodology compared to other previously reported
annulation conditions. Annulation was carried out on enamines conjugated with many
electron withdrawing groups such as ester, ketone, amide, nitrile, sulfone, phosphate and
nitro compounds. In general, the aza-annulation reaction can be performed on any
enamine conjugated with an electron withdrawing group to give a six-membered lactam
without any uncyclized enamide.

The stereoselectivity of the catalytic hydrogenation of the carbon-carbon double
bond in lactams were studied. Catalytic hydrogenation gave a mixture of cis and trans
lactams and the cis to trans selectivity depended on the nature of the electron withdrawing
groups present in the lactam. Both ester and amide gave excellent cis selectivity. Other
electron withdrawing groups, such as phosphate and ketones, gave poor selectivity. Aza-
annulation, followed by hydrogenation of the annulated lactam, is one of the simplest
ways to prepare cis substituted piperidine compounds and thermodynamically less stable
5,6-cis indolizidinones from readily available starting materials. Because of its simple
and elegant nature, this methodology is expected to play a major role in_ alkaloid

synthesis.

80
EXPERIMENTAL SECTION

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 either nitrogen or argon. Benzene, toluene, and tetrahydrofuran (THF)
were distilled from sodium/benzophenone immediately prior to use. Triethylamine,
dichloromethane and pyridine were heated at reflux over calcium hydride for a minimum
of 12 h, and then distilled immediately prior to use. 1,3-Cyclohexanedione was obtained
from Aldrich Chemical Co., and recrystallized from benzene prior to use. Benzylamine,
acetoacetanilide and acryloyl chloride were obtained from Fluka and used without further
purification. Acrylic acid, crotonyl chloride, diethyl-(2-oxopropyl)-phosphonate, benzyl
acetoacetate, N ,N-dimethyl hydrazine, ethyl 2-cyclohexanonecarboxylate and 2-
acetylbutyrolactone were obtained from Aldrich Chemical Co., and used without further
purification. n-Butyllithium (2.5 M in hexane) was purchased from Aldrich Chemical
Co. Benzoyl acetone, tetronic acid, 3-aminocrotonitrile, 2,4,4—trimethyl-2-oxazolone,
phenyl sulfonyl acetone and 6-amino-1,3-dimethyluracil were purchased from Lancaster
and used without further purification.

NMR Spectra were obtained on a Varian Gemini 300 instrument with CDC13 as
the solvent. 1H NMR spectral data are reported as follows: chemical shifts relative to
residual CHC13 (7.24 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, sext = sextet, sept = septet, b = broad), coupling, and integration. l3C
signals are reported in ppm relative to the residual CHC13 (77.0 ppm). Infrared spectra
were recorded on a Nicolet 42 FT-IR instrument.

Preparation Enamino ketone 160. A mixture of benzylamine (19.11 g, 178.4
mmol) and 1,3-cyclohexanedione (159) (20.0 g, 178.4 mmol) in 1600 mL of benzene was
heated at reflux for 24 h. The water generated during the condensation was

azeotropically removed from the reaction mixture using a molecular sieves (4—A) filled

81

modified Dean-Stark trap, developed in this laboratory. The reaction mixture was then
cooled to room temperature, and concentrated to give the crude product. This crude
product was crystallized from ethyl acetate to give enamino ketone 160 in 89% yield.

Reaction of Enamino Ketone 160 with a Mixed Anhydride. To a cooled
solution (-30 °C to -25 °C ) of acrylic acid (0.47g, 6.5 mmol) in 35 mL of THF were
added TEA (0.65 g, 6.46 mmol) and ethyl chloroformate (0.69 g, 6.5 mmol). After the
mixture was stirred for 1 h at this temperature, the enamino ketone 160 (1.00 g, 5.0
mmol) was added and stirred for an additional 30 min. The reaction mixture was then
heated at reflux for 24 h. Then the solution was washed with 25 mL of saturated aqueous
NaHCO3 solution. The aqueous layer was extracted with 4 x 40 mL of methylene
chloride, and the organic fractions were combined and dried over NazSO4. Following
concentration of the solution, the residue was purified by flash column chromatography
(eluent: 75:25 CH2C12-EtOAc). The solvents were removed, and the residue was
distilled under vacuum to give lactam 161 in 54% yield.

Reaction of Enamino Ketone 160 with Acrylic Anhydride. To a suspension of
NaH (0.30 g, 12.6 mmol) in 30 mL of THF at -78 °C was slowly added acrylic acid (0.61
g, 8.4 mmol). The mixture was warmed to ambient temperature, and stirred for 1h.
Acryloyl chloride (0.59 g, 6.5 mmol) was then added to the solution of sodium acrylate,
and the reaction mixture was stirred for an additional 1 h at ambient temperature. The
resulting solution of acrylic anhydride was transferred via cannula to a 100 mL flask
containing the enamino ketone 160 (1.00 g, 5.0 mmol) in 10 mL of THF. The flask was
and then rinsed with an additional 15 mL of THF. The reaction mixture was heated at
reflux for 13 h, cooled to room temperature and then washed with 30 mL of saturated
aqueous NaHCO3 solution. The aqueous layer was extracted with 4 x 50 mL of CHzClz,
and the organic fractions were combined and dried over Na2S04. After filtration and

removal of solvents, the residue was purified by flash column chromatography (eluent:

82
70:30 CHzClz-EtOAc). The solvents were removed, and the residue was distilled under
vacuum to give lactam 161 in 52% yield.

Preparation of Lactam 161 from Cyclohexanedione (159) Using Acrylic
Anhydride. A mixture of ketone (159) (0.64 g, 5.7 mmol) and benzylamine (0.58 g, 5.4
mmol) was taken up in 35 mL of benzene and heated at reflux for 24 h. The water
generated was azeotropically removed from the reaction mixture using a modified Dean-
Stark trap filled with 4-A molecular sieves. The reaction mixture was then cooled to
room temperature, and concentrated to give crude enamino ketone 160. The yellow solid
was placed in a 100 mL flask and dissolved in 10 mL of THF. The acrylic anhydride
(7.04 mmol), prepared using the above procedure, was transferred into the flask and then
was washed over with an additional 15 mL of THF. The reaction mixture was heated at
reflux for 13 h, cooled to room temperature and washed with 25 mL of saturated
NaHCO3. The aqueous layer was then extracted with 4 x 50 mL of CHzClz. The
organic fractions were combined and dried over Na2SO4. After removal of solvents, the
residue was purified by flash column chromatography (eluent: 70:30 CH2C12-EtOAc).
The solvents were removed, and the residue was distilled under vacuum to give lactam
161 in 72 % yield.

Reaction of Enamino Ketone 160 with Acryloyl Chloride. To a solution of
enamino ketone 160 (2.0 g, 9.9 mmol) in 70 mL of THF was added acryloyl chloride
(1.18 g, 12.9 mmol), and the reaction mixture was heated at reflux for 10 h. The reaction
mixture was cooled to room temperature and washed with 50 mL of saturated aqueous
NaHCO3 solution. The aqueous layer was then extracted with 4 x 100 mL of CHzClz,
and the organic fractions were combined and dried over NazSO4. After removal of
solvents, the residue was purified by flash column chromatography (eluent: 80:20
CI-12C12:EtOAc). The solvents were removed, and the residue was distilled under

vacuum to give lactam 161 in 62% yield.

83

Preparation of Lactam 161 from 1,3-Cyclohexanedione (159) Using Acryloyl
Chloride. A mixture of benzylamine (25.2 g, 235.2 mmol) and ketone 159 (27.7 g, 247.0
mmol) was taken in 1500 mL of benzene and heated at reflux for 24 h. The water
generated was azeotr'Opically removed from the reaction mixture using a modified Dean-
Stark trap filled with 4—A molecular sieves. The reaction mixture was then cooled to
room temperature, concentrated to give crude enamino ketone 160. The crude enamino
ketone was redissolved in 1570 mL of THF, and acryloyl chloride (27.7 g, 306.0 mmol)
was slowly added to the reaction mixture. The reaction mixture was then heated at reflux
for 24 h. Solvent was removed, and the residue was taken up in 400 mL of CH2C12 and

washed with 100 mL of saturated NaHCO3. The aqueous layer was extracted with 4 x
100 mL CHzClz. The organic fractions were combined and dried over NazSO4. After
removal of solvents, the residue was purified by flash column chromatography (eluent:
80:20 CH2C12-EtOAc). The solvents were removed, and the residue was distilled under
vacuum to give lactam in 76% yield. ~

Hydrogenation of Lactam 161. A mixture of Lactam 161 (1.06 g, 4.2 mmol)
and sodium carbonate (1.53 g, 14.5 mmol) in 70 mL of absolute ethanol was
hydrogenated (45 psi) over 10% Pd on carbon for 18 h. The catalyst and sodium
carbonate were removed by filtration. The solid was washed several times with CH2C12,
and the washings and filtrates were combined, and solvent was removed to give a viscous
crude residue. The crude residue was transferred to a silica gel column. The less polar
impurities were removed by flushing the column with a 80:20 mixture of CH2C12-
EtOAc. Elution of the column with a 1:1 mixture of CH2C12:MeOH followed by
removal of solvents gave alcohol 163 as a white gummy solid in 91% yield. Compound
163 was solidified by triturating with a minimum amount of Et20.

Reduction or Lactam with NaBH4. To a solution of lactam 161 (0(72 g, 2.8
mmol) in 20 mL of EtOH and 5 ml. of MeOH at 0 °C was slowly added NaBH4 (1.1 g,

28.2 mmol). The reaction mixture was warmed to room temperature, and stirred for 10 h.

84
Water (25 mL) was added to the reaction mixture and stirred for 30 min. The reaction
mixture was extracted with 5 x 50 mL of 01202, and the combined organic layers were
dried (Na2S04), filtered, and concentrated to give a crude residue. The crude residue
was purified by flash column chromatography (eluent: 60:40 Et0Ac-CH2C12). The
solvents were evaporated to give alcohol 162 in 77 % yield.

Oxidation of Alcohol 163. To a cooled solution (-70 to -60 °C) of oxalyl
chloride (5.8 g, 45.7 mmol) in 85 mL of CH2C12 was slowly added DMSO (7.14 g, 91.3
mmol) in 19 mL of CH2C12 and stirred at this temp for 10 min. To this reaction mixture
was slowly added alcohol (7.90 g, 30.4 mmol) in 77 mL of CI-12C12 and stirred at -60 °C
for 45 minutes. TEA (18.5 g, 182.7 mmol) was added and stirred for 20 min at this

temperature, and the reaction was warmed to room temperature over a period of 30 min
and stirred for an additional 30 min. Then 180 mL of H20 was added and stirred for 1 h.

The aqueous layer was extracted with 5 x 100 mL of CI-12C12. The combined organic
layers were washed with 200 mL of H20. The organics were dried (Na2S04), filtered,
and concentrated to give a crude residue, which was purified by flash column
chromatography (eluent 75:25 CH2C12-Et0Ac). The solvents were evaporated to give
ketone 166 as a viscous product in 93% yield. This ketone 166 was solidified by
triturating with a minimum amount of Et20.

Reduction of Ketone 166 with NaBH4. To a solution of the ketone 166 (0.66 g,
2.6 mmol) in 21 mL of MeOH at 0 °C was added NaBH4 ( 0.97 g, 25.63 mmol). The
reaction mixture was stirred for 12 h at room temperature. Solvent was removed to give a
solid which was taken up in 30 mL of CH2C12 and 20 mL of H20 and stirred for 2 h.
The aqueous layer was then extracted with 4 x 30 mL of CI-12C12. The combined organic
layers were dried (MgSO4), filtered, and concentrated to give a crude residue, which was
purified by column chromatography (eluent: first 20:80 Et0Ac-CH2C12. second, 1:1
MeOH-CHzClz). The solvents were removed to give the alcohol 163 in 92% yield.

85

General Procedure for Aza-Annulation. A mixture of the primary amine (12
mmol), ketone (10 mmol) and p-TSOH (0.01 g, 0.05 mmol) in 66 mL of benzene was
heated at reflux for 12 to 24 h. The water generated during the condensation was
azeotropically removed from the reaction mixture using a modified Dean-Stark trap filled
with 4—A molecular sieves. The reaction progress was monitored by 1H NMR
spectroscopy. After enamine formation was complete, the reaction mixture was cooled to
room temperature, and concentrated to give the corresponding crude enamine. The crude
enamine was taken up in 66 mL of THF and the appropriate (1.8-unsaturated acid chloride
(13 mmol) was added slowly at room temperature. The reaction mixture was heated at
reflux until the disappearance of starting materials was complete (6-24 h). Disappearance
of starting material was monitored by 1H NMR spectroscopy. The reaction mixture was

washed with 25 mL of saturated aqueous NaHC03 solution, and the aqueous layer was
extracted with 4 x 40 mL of CHzCl2. The organic fractions were combined and dried
over N a2S04. Following concentration of the solution, the residue was purified by flash
column chromatography. The solvents were evaporated to give the corresponding
lactam.

General Procedure for Hydrogenation of the Annulation Products. In most
of the hydrogenation reactions, this general procedure was used unless otherwise noted.
A mixture of lactam (2.00 mmol) and sodium carbonate (0.74 g, 7.0 mmol) in 27 mL of
absolute EtOH was hydrogenated (45 psi) over 10% Pd on carbon (0.2 g ) for 12-48 h.
The catalyst and sodium carbonate were removed by filtration. The solid was washed

several times with CH2C12, and the washings were combined, and solvents were
removed to give a viscous residue. The crude residue was redissolved in CHsz and
refiltered. Concentration of the filtrate and washings gave the corresponding lactam.
Preparation of Enamino Ester 183. To a cooled solution (05 °C) of dimethyl
acetylenedicarboxylate (1.42 g, 10.0 mmol) in 50 mL of benzene was slowly added

benzylamine (1.1 g, 10 mmol). The reaction mixtme was stirred at room temperature for

86
12 h. The removal of solvent gave the crude enamino ester which was carried on to the
annulation reaction without further purification.

Preparation of Enamino Nitro Compound 219. A mixture of lactim-ether 197
(6.5 g, 65.7 mmol), nitromethane (4.8 g, 78.8 mmol), and Ni(acac)2 (0.1 g, 0.4 mmol)
was heated at 110 °C for 48 h. Removal of the solvent gave the crude cyclic‘enamino
nitro compound which was used for annulation without further purification.

General Procedure for the Reaction of Enamines 108, 200, 219 with or,B-
Unsaturated Acid Chlorides. To a solution of enamine (10 mmol) in 66 mL of THF
was added the appropriate (1.8-unsaturated acid chloride (13 mmol). The reaction
mixture was heated at reflux until complete disappearence of starting materials (6-24 h),
as monitored by 1H NMR spectroscopy. The reaction mixture was washed with 25 mL
of saturated aqueous NaHC03 solution. The aqueous layer was extracted with 4 x 40 mL
of CI-12C12, and the organic fractions were combined and dried over Na2$04. Following
concentration of the solution, the residue was purified by flash column chromatography.
The solvents were evaporated to give the corresponding lactam.

102: (mp 84-85 °C) 1H NMR (300 MHz, CDC13) 5 1.06 (d, J = 7.1 Hz, 3 H),
1.27 (t, J = 7.1 Hz, 3 H), 2.34 (s, 3 H), 2.48 (dd, J= 15.7, 2.2 Hz, 1 H), 2.71 (dd,J= 15.7,
6.6 Hz, 1 H), 3. 01(dquint, J = 6.9, 1.8 Hz, 1 H), 4.16 (q, I = 7.1 Hz, 2 H), 4.78 (d, J =
16.2 Hz, 1 H), 5.22 (d, J = 16. 2 Hz, 1 H), 7.13-7.33 (m, 5 H); 13C NMR (75.5 MHz,
CDC13) 8 13.8, 16.2, 17.6, 26.6, 37.8, 44.6, 59.8, 113.5, 126.1, 126.8, 128.3, 137.3,
146.6, 167.1, 170.0: IR (KBr) 3034, 2980, 2959, 1678, 1615, 1383, 1124 cm‘l; HRMS
calcd for C17H21N03 m/z 287.1520, found m/z 287.1521.

110: (mp 4547 °C) 1H NMR (300 MHz, CDC13) 5 1.29 (t, J = 7.1 Hz, 3 H), 1.97
(quint, J -- 7.6 Hz, 2H), 2.51 (m, 2 H), 2.65 (m, 2H), 3.14 (tt, .1 = 15.4, 1.8 Hz, 2 H), 3.72
(t, J = 7.2 Hz, 2 H), 4.19 (q, I = 7.1 Hz, 2 H); 13C NMR (75.5 MHz, CDC13) 5 13.9,
20.7, 20.9, 30.4, 31.2, 45.4, 59.5, 100.4, 1525, 166.5, 168.9; IR (KBr) 2980, 1689, 1634,

87

1385, 1294, 1265, 1200, 1129 em-l; HRMS calcd for C11H15N03 m/z 209.1051, found
m/z 209.1068.

112:1H NMR (300 MHz. CDC13)81.04(d, J = 7.1 Hz, 3 H), 1.30 (t, J = 7.1 Hz,
3 H), 1.98 (quint. J = 7.5 Hz, 2 H), 2.39 (dd, J = 16.4, 1.7 Hz, 1 H), 2.62 (dd, J = 16.4,
7.1 Hz, 1 H), 3.04 (m, 1 H), 3.14 (td, J = 7.7, 3.3 Hz, 2 H), 3.63-3.83 (m, 2 H), 4.20 (m, 2
H); 13c NMR (75.5 MHz, CDC13) 5 14.3, 19.1, 21.2, 27.3, 31.6, 38.2, 45.6, 59.7, 106.2,
151.7, 166.6, 168.7; IR (KBr) 2967, 1676, 1626, 1383, 1300, 1237, 1116 cm-1.

161: (bp 190-200 °C, <1mm Hg): 1H NMR (300 MHz, CDC13) 5 1.93 (quint, J =
6.4 Hz, 2 H), 2.33 (t, J = 6.5 Hz, 2 H), 2.46 (t, J = 6.5 Hz, 2H), 2.63 (s, 4 H), 5.0 (s, 2 H),
7.08-7.35 (m, 5 H); 13C NMR (75.5 MHz. @013) 5 16.7, 21.3, 26.0, 30.6, 35.5, 44.4,
116.1, 125.5, 127.0, 128.5, 136.6, 154.6, 170.6, 195.8; IR (neat) 3063, 3032, 2953, 1690,
1649, 1615,1389, 1296, 1177,1130em-1.

163: 1H NMR (300 MHz, @013) 5 1.15 (qt. J = 13.4, 3.6 Hz, 1 H), 1.38 (dquint
J = 12.9, 3.8 Hz, 2 H), 1.56—2.05 (m, 6 H), 2.22 (m, 1 H), 2.49 (ddd, J = 18.3, 11.6, 7.5
Hz, 1 H), 2.67 (dd, J = 18.3, 5.6 Hz, 1 H), 3.17 (dt, J = 11.8, 4.4 Hz, 1 H), 3.73 (dt, J =
11.8.4.7 Hz. 1 H), 3.96 (d, J = 15.1 Hz, 1 H), 5.34 (d, J =15.1Hz, 1 H), 7207.35 (m, 5
H); 13c NMR (75.5 MHz. c1303) 5 14.6, 20.9, 25.5, 28.4, 30.8, 40.3, 47.4, 56.3, 70.3,
126.8, 127.1, 128.2, 137.1, 169.7; IR (KBr) 3397, 3055, 2942, 1622, 1476, 1454,1265
cm-l.

166; 1H NMR (300 MHz, CDC13) 5 1.51 (m, 1 H), 1.77-1.89 (m, 2 H), 1.89-2.05
(m, 1 H), 2.07-2.52 (m, 4 H), 2.57 (dd, J = 10.4, 7.1 Hz, 1 H), 2.63-2.76 (m, 2 H), 3.56
(ddd, J=10, 5, 5 Hz, 1 H), 4.03 (d, J = 15.1 Hz, 1 H), 5.39 (d, J= 15.1 Hz, 1H), 7.19-7.33
(m, 5 H); 13c NMR (75.5 MHz. c1303) 5 20.7, 21.1, 25.8, 30.3, 37.6, 47.1, 49.6, 56.7,
127.0, 127.1, 128.3, 136.6, 168.7, 209.9; IR (KBr) 3056, 2955, 1711, 1638, 1472, 1453,
1420, 1265 em-l.

168: 1H NMR (300 MHz, CDC13) 5 2.26 (s, 6 H), 2.65 (s, 4H), 5.02 (s, 2 H),
7.12-7.35 (m, 5 H); 13c NMR (75.5 MHz, coc13) 5 15.8, 21.8, 29.4, 30.9, 44.3, 117.0,

88

125.7, 126.8,128.3,137.0, 145.9, 170.3, 198.6; IR (neat) 3030, 1690, 1669, 1591,1383,
1186 cm-1; HRMS calcd for C15H17N02 m/z 243.1259, found m/z 243.1260.

169: 1H NMR (300 MHz, CDC13, mixture of isomers) 5 1.09 (d, J = 6.5 H, 1.2 H,
minor), 1.24 (d, J = 6.5 Hz, 1.8 Hz, major), 1.93 (s, 1.8 H, major), 1.96-2.16 (m, 2.0 H,
both), 2.08 (s, 1.2 H, minor), 2.39-2.70 (m, 2.6 H, both), 2.79 (dt, J = 12.6, 4.1 Hz, 0.4 H,
minor), 3.78-3.88 (m, 1 H, both), 3.94 (d, J = 15.1 Hz, 0.4 H, minor), 4.03 (d, 15.1 Hz,
0.6 H, major), 5.28 (d, J = 15.1 Hz, 0.6 H, major), 5.36 (d, J = 15.1 Hz, 0.4 H, minor),
7.207.39 (m, 5 H, both); 13C NMR (75.5 MHz, CDC13) 5 14.4, 17.2, 19.5, 19.8, 27.5.
28.1, 29.3, 29.9, 46.9, 47.7, 51.0, 52.2, 126.9, 127.0, 127.3, 127.7, 128.1, 128.2, 136.8,
136.9, 168.7, 168.9, 206.3, 207.1; IR (neat) 2975, 1711, 1638, 1474, 1453, 1161 em-l;
HRMS calcd for C15H19N02 m/z 245.1415, found m/z 245.1422.

171: (mp 7072 °C) 1H NMR (300 MHz, CDC13) 5 1.92 (t, J = 1.4 Hz, 3 H), 2.62
(m, 2 H), 2.72 (m, 2 H), 5.04 (s, 2 H), 7.16-7.73 (m, 10 H); 13C NMR (75.5 MHz,
CDC13) 5 17.0, 23.1, 31.2, 44.2, 117.4, 125.8, 126.8, 128.2, 128.3, 128.4, 132.3, 137.2,
138.1, 142.8, 170.3, 196.7; IR (KBr) 3029, 2967, 1682, 1655,1605,1576, 1451, 1385,
1364 em-1;HRMs calcd for C20H19N02 m/z 305.1415, found m/z 305.1402. ‘

174: (mp 94-96 °C) 1H NMR (300 MHz, CDC13) 5 1.61 (s, 6 H), 2.37 (s, 3 H),
2.49 (m, 2 H), 2.61 (m 2 H) 4.20 (s, 2 H); 13C NMR (75.5 MHz. CDC13) 5 19.0, 24.0,
30.2, 32.2, 60.1, 80.3, 91.3, 158.3, 169.6, 194.1; IR (KBr) 2978, 2853, 1707, 1645, 1605,
1402, 1350, 1151 cm-1

175; 511H NMR (300 MHz, 'CDC13, cis) 5 1.50 (s, 3 H), 1.51 (s, 3 H), 1.81 (m,
1 H), 1.96 (m, 1 H), 2.29 (s, 3 H), 2.32-2.51 (m, 2 H), 2.71 (ddd, J = 12.4, 8.8, 3.9 Hz, 1
H), 3.56 (dd. J = 8.8, 0.7 Hz, 1 H), 3.84 (d, J = 8.8 Hz, 1 H), 4.79 (d, J = 8.8 Hz, 1 H);
13C NMR (75.5 MHz, CDC13) 5 20.9, 23.1, 24.1, 30.3, 31.0, 51.8, 59.4, 78.6, 88.5,
166.2, 206.8; IR (neat) 2969,2874, 1717, 1651, 1464, 1443, 1363 om-l.

89

Diagnostic Peaks for trans Isomer: 1H NMR (300 MHz, CDC13, trans) 5 2.24 (s, 3
H), 3.37 (q, J = 4.67 H, 1 H), 5.0 (d, J = 4.67 Hz, 1 H); 13C NMR (75.5 MHz, CDC13) 5
19.6, 23.2, 23.6, 29.1, 32.3, 46.0, 53.0, 59.2, 785, 88.0, 167.2, 206.7.

177: (mp 75-77 °C) 1H NMR (300 MHz, CDC13) 5 1.29 (t, J = 7.1 Hz, 3 H), 2.35
(t, J = 1.4 Hz, 3 H), 2.57-2.71 (m, 4 H), 4.18 (q, J = 7.1 Hz, 2 H), 5.03 (s, 2 H), 7.107.35
(m, 5 H); 13C NMR (75.5 MHz, CDC13) 5 13.8, 16.0, 20.8, 30.9, 44.4, 59.9, 109.0,
125.7, 126.7, 128.3, 137.1, 148.0, 167.0, 171.0; IR (KBr) 2984, 2959, 2845, 1684,1617,
1377, 1269, 1184, 1120 em-l; HRMS calcd for C15H19N03 m/z 273.1364, found m/z
273.1363.

178: (mp 51-53 °C) 1H NMR (300 MHz, CDC13) 5 1.14 (d, J = 6.5 Hz, 3 H),
1.23 (t, J = 7.1 Hz, 3 H), 2.02-2.20 (m, 2 H), 2.50 (ddd, J = 18.3, 10.5, 8.5 Hz, 1 H), 2.63
(ddd, J = 18.3, 6.6, 3.0 Hz, 1 H), 2.81 (dt, J = 12.0, 4.8 Hz, 1 H), 3.82 (m, 1 H), 3.99 (d, J
= 15.1 Hz, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 5. 28 (d,J = 15.1 Hz, 1 H), 7.23-7.37 (m, 5 H);
13C NMR (75.5 MHz, CDC13) 5 13.7, 14.6, 17.7, 30.0, 43.4, 47.8, 51.7, 60.4, 126.9,
127.3, 128.2, 136.9, 168.6, 171.0; IR (KBr) 3032,2978, l732,1643,1497, 1474, 1453
(ml; HRMS calcd for C15H21N03 m/z 275.1521 found m/z 275.1508. ‘

180: (mp 64-66 °C) 1H NMR (300 MHz, CDC13) 5 2.25 (t, J = 1.4 Hz, 3 H), 2.49
(m, 2 H), 2.59 (m, 2 H), 4.91 (s, 2 H), 5.05 (s, 2 H), 6.99-7.28 (m, 10 H); 13C NMR (75.5
MHz, CDC13) 5 16.1, 20.8, 30.9, 44.5, 65.7, 108.5, 125.7, 126.8, 127.7, 127.8, 128.2,
128.4, 135.8, 137.1, 148.9, 166.7, 170.6; IR (KBr) 3034, 2953, 1703, 1682, 1618, 1387.
1368, 1269 em-l; HRMS calcd for C21H21N03 m/z 335.1521, found m/z 335.1533.

181 (mp 134-136 °C): 1H NMR (300 MHz, CDC13) 5 1.18 (d, J = 6.6 Hz, 3 H),
2.01-2.19 (m, 2 H), 2.55 (td, J = 18.5, 9.8 Hz, 1 H), 2.67 (m, 1 H), 2.80 (m, 1 H), 3. 84
(m, 1 H), 3.97 (d, J =15.1 Hz, 1 H), 5.29 (d, J = 15.1 Hz, 1 H), 7.207.35 (m, 5 H), 10.19
(bs, 1 H); 13C NMR (75.5 MHz, CDC13) 5 14.6, 17.3, 29.5, 43.1, 48.1, 51.7, 127.2,
127.4,128.3, 136.2, 170.2, 174.0; IR (KBr) 3034,2971, 1736,1601, 1489, 1453, 1437,
1233, 1167 em-l; HRMS calcd for C14H17N03 m/z 247.1208, found m/z 247.1299.

90

182:1H NMR (300 MHz, CDC13) 5 1.05 (d, J = 6.9 Hz, 3 H), 1.20 (d, J 4 6.7 Hz,
3 H), 1.27 (t, J = 7.1 Hz, 3 H), 2.27 (m, 1 H), 2.49-2.68 (m, 2 H), 2.77 (t, J = 4.7 Hz, 1
H), 3.67 (m, 1 H), 4.19 (q, J = 7.1 Hz. 2 H), 4.40 (d, J = 15.7 Hz, 1 H), 5.10 (d, J =15.7
Hz, 1 H), 7,207.34 (m, 5 H); 13C NMR (75.5 MHz, CDC13) 5 13.9, 17.6, 18.5, 28.4,
36.2, 45.6, 50.1, 52.5, 60.0, 126.4, 126.7, 128.0, 137.4, 170.1, 170.4; IR (neat) 3063,
3028, 2978, 2934, 1728, 1644,1497, 1449, 1412, 1292cm-1.

184: (mp 86-88 °C) 1H NMR (300 MHz, CDC13) 5 2.502.62 (m, 4 H), 3.52 (s, 3
H), 3.60 (s, 3H), 4.67 (s, 2 H), 7.05-7.21 (m, 5 H); 13C NMR (75.5 MHz, CDC13) 5 19.6,
29.9, 46.4, 51.7, 52.3, 108.3, 126.7, 127.1, 128.0,136.1, 142.6, 1635, 165.1, 169.3; IR
(KBr) 3038, 2955, 1736, 1692, 1628, 1458, 1441, 1381, 1300 (ml; HRMS calcd for
C15H17N05 m/z 303.1106, found m/z 303.1120.

185: 1H NMR (300 MHz, CDC13) 5 1.98-2.22 (ddd, J = 8.1, 10.7, 15.5 Hz, 2 H),
2.49 (m, 1 H), 2.67 (ddd, J = 18.2, 6.9, 2.2 Hz, 1 H), 2.90 (dt, J = 12.9, 4.7 Hz, 1 H), 3.62
(s, 3 H), 3.65 (s, 3 H), 3.91 (d, J = 15.0 Hz, 1 H), 4.32 (dd, J = 4.1, 1.3 Hz, 1 H), 5.28 (d,
J a 15.0 Hz, 1 H), 7.19-7.33 (m, 5 H); 13C NMR (75.5 MHz, CDC13) 5 195, 29.9, 42.0,
49.2, 51.8, 52.2, 59.1, 127.3, 127.9, 128.2, 135.7, 169.0, 1695, 170.3; IR (neat) 3011,
2955, 1748, 1655, 1414, 1311, 1209 cm-1; HRMS calcd for C15H19N05 m/z 305.1262,
found m/z 303.1210.

186: (bp 95-105 °C, <1 mm Hg) 1H NMR (300 MHz, CDC13) 5 1.30 (t, J = 7.1
Hz, 3 H), 2.41 (t, J = 1.5 Hz, 3 H), 2.42-2.48 (m, 2 H), 2.51-2.58 (m, 2 H), 2.85 (s, 6 H),
4.19 (q, J = 7.1 Hz. 2 H); 13C NMR (75.5 MHz. CDC13) 5 13.8, 15.0, 20.6, 32.0, 43.0,
56.6, 106.4, 151.3, 167.0, 169.8; IR (neat) 2980, 2896, 1696, 1620, 1541, 1379, 1273 cm-
1, '

187: (mp 4042 °C) 1H NMR (300 MHz, CDC13) 5 1.15 (d, J = 6.4 Hz, 3 H),
1.26 (t, J = 7.1 Hz, 3 H), 1.85-1.95 (m, 2 H), 2.28 (ddd, J = 18.1, 10.2.9.1 Hz, 1 H), 2.43
(ddd, J = 18.1, 5.1, 4.9 Hz, 1 H), 2.78 (m, 1 H), 2.84 (s, 6 H), 3.89 (quint, J = 6.1 Hz, 1
H), 4.08-4.25 (m, 2 H); 13C NMR (75.5 MHz. CDC13) 5 13.7, 14.7, 17.1, 31.5, 43.2 (b),

91
44.2, 56.3, 60.4. 168.2, 170.8; IR (KBr) 2977. 2951, 1734, 1649, 1404, 1233, 1169 em-l;
HRMS calcd for C11H20N203 m/z 228.1473, found m/z 228.1480.

189: (mp 72-74 °C): 1H NMR (300 MHz, CDC13) 5 1.25 (t, J = 7.15 Hz, 3 H),
1.37 (m, 1 H), 1.49 (ddd, J = 13.8, 13.0.2.5 Hz, 1 H), 1.66 (m, 1 H), 1.78 (td, J = 13.3,
5.7 Hz, 1 H), 2.03 (dddd, J = 17.9, 9.3, 6.3, 3.0 Hz, 1 H), 2.16 (m, 1 H), 2.25-2.38 (m, 2
H), 2.49 (ddd, J = 6.1, 12.8, 18.4 Hz, 1 H), 2.70 (ddd, J = 18.4, 5.8, 1.5 Hz, 1 H), 4.18 (q,
J = 7.1Hz. 2 H), 4.63 (d, J = 15.9 Hz, 1 H), 5.18 (dd. J = 5.1, 3.0 Hz, 1 H), 5.33 (d, J
=15.9 Hz. 1 H), 7.207.34 (m, 5 H); 13C NMR (75.5 MHz. CDC13) 5 13.8, 18.1. 23.8,
29.6, 30.3. 34.4, 46.0, 47.3, 60.8, 107.6, 125.9, 126.2, 127.9. 136.5, 137.2, 167.8, 173.6;
IR (KBr) 3063, 2980. 1719, 1669, 1644, 1451, 1404. 1373 cm' 1; HRMS calcd for
C19H23N03 m/z 313.1677, found m/z 313.1692.

190: 1H NMR (300 MHz. CDC13, mixture of isomers) 5 1.25 (t, J = 7.1 Hz, 3 H,
major) 1.27 (t. J = 7.1 Hz, 3 H minor), 1.33-1.59 (m, 1 H, both), 1.60-1.84 (m, 2 H, both),
1.85-2.1 (m, 2 H, both), 2.1-2.37 (m, 2 H, both), 2.38-2.56 (m, 1 H, both), 2.58-2.75 (m, 1
H, both), 3.26 (dd, J = 12.1 Hz, 0.56 H, major), 4.12-4.26 (m, 2 H, both), 4.47 (d, J =-
15.9 Hz. 0.56 H, major), 4.63 (d, J = 15.9 Hz, 0.44 H, minor), 5.08-5.20 (m, 1 H minor),
5.32 (d, J = 15.9 Hz, 0.56 H. major), 7.18-7.35 (m, 5 H, both); 13C NMR (75.5 MHz,
CDC13) 5 13.8, 18.2, 21.8, 23.8, 24.5, 25.7, 29.7, 30.4, 32.3, 345, 35.9, 45.0, 46.0, 47.4,
47.5. 60.2, 60.9, 62.1, 107.8, 125.9, 126.2, 126.4, 128.0, 136.6, 137.2, 137.8, 168.0,
169.8, 172.7, 173.8.

192: 1H NMR (300 MHz, CDC13) 5 1.85 (ddd, J = 13.4, 6.3, 3.1 Hz, 1 H), 2.22
(ddd, J = 12.8, 9.8, 8.2 Hz. 1 H), 2.34 (ddd, J = 12.8, 6.5. 2.5 Hz, 1 H), 2.43 (ddd, J =
12.0. 13.5, 6.0 Hz. 1 H). 2.63 (ddd, 18.1, 12.0, 6.2 Hz, 1 H), 2.93 (ddd, J = 18.1, 6.0, 3.3
Hz, 1 H), 4.16 (dt, J = 9.8, 6.6 Hz, 1 H), 4.24 (d, 3.1 Hz, 1 H), 4.38 (ddd, J = 9.2. 8.2, 2.6
Hz, 1 H), 4.54 (d,J = 3.1 Hz, 1 H), 4.93 (d,J =15.7 Hz. 1 H), 5.03 (d, J: 15.7 Hz, 1 H,
7.15-7.34 (m, 5 H); 13C NMR (75.5 MHz. CDC13) 5 27.3, 28.5, 33.8, 46.3, 47.3, 64.9,

92

94.2, 126.1, 126.7, 128.2, 136.1, 142.4, 167.7, 176.7; IR (neat) 3032, 2942, 1775, 1673.
1620, 1456. 1186, 1028 cm-1.

193: 1H NMR (300 MHz, CDC13, major isomer) 5 1.25 (d, J = 6.6 Hz. 3 H), 1.49
(m, 1 H), 1.67 (ddd, J = 13.0, 6.8, 2.8 Hz, 1 H), 1.87 (ddd, J = 12.9, 9.6, 8.7 Hz, 1H),
2.25-2.42 (m, 2H), 2.54 (m, 1H). 3.19 (qd. J = 6.6, 1.6 Hz, 1 H), 3.44-3.60 (m, 2H), 3.99
(td, J = 9.2, 2.8 Hz. 1 H), 5.48 (d, J = 14.3 Hz, 1 H), 7.12-7.26 (m, 5 H); 13C NMR (75.5
MHz, CDC13) 5 15.2, 23.7, 27.5, 32.4, 45.6, 47.2, 52.4, 64.1, 127.6, 128.3, 128.6, 136.3,
167.6, 176.9; IR (KBr) 2973, 2946, 1763, 1644, 1495, 1472, 1455, 1219 cm-i; HRMS
calcd for C16H19N03 m/z 273.1364, found m/z 273.1374.

195: (mp 115-117 °C) 1H NMR (300 MHz, CDC13) 5 2.64 (m, 2 H), 2.85 (td, J =
8.0, 1.1 Hz, 2 H). 4.65 (t, J = 2.0 Hz, 2 H), 4.81 (s, 2H), 7.16-7.40 (m, 5 H); 13C NMR
(75.5 MHz, CDC13) 5 15.5, 30.2, 45.6, 64.9, 102.4, 126.5, 127.9, 128.8, 135.0, 159.7,
169.1, 170.8; IR (KBr) 3038, 2982, 2959, 1746, 1695, 1664, 1435, 1275, 1196 cm-1;
HRMS calcd for C14H13N03 m/z 243.0895. found m/z 243.0896.

196 : 1H NMR (300 MHz, CDC13) 5 2.01 (m, 1 H). 2.31 (m, 1 H), 2.41 (m, 1 H),
2.47-2.59 (m, 1 H), 2.97 (m, 1 H), 4.18-4.26 (m, 4 H), 5.13 (d, J = 15.1 Hz, 1 H), 7.19-
7.39 (m. 5 H); 13C NMR (75.5 MHz. CDC13) 5 19.2, 29.1, 37.4, 47.4, 55.0, 70.8, 127.3,
127.4, 128.5, 135.8, 169.1, 176.0, IR (KBr) 3032,2959, 2946, 2922, 1788, 1644, 1470,
1451, 1362, 1163 cm" 1; HRMS calcd for C14H15N03 m/z 245.1051, found m/z
245.1050.

201: 1H NMR (300 MHz, CDC13) 5 1.23 (t, J = 7.1 Hz, 3 H), 1.63-1.85 (m, 2 H),
1.87-2.05 (m, 3 H), 2.16 (m, 1 H), 2.37 (ddd, J = 17.9, 7.6, 2.6 Hz. 1 H), 2.52 (ddd, J =
17.9, 10.8, 7.4 Hz, 1 H), 2.96 (q, J = 4.2 Hz, 1 H), 3.47-3.54 (m, 2 H), 3.66 (quint, J = 5.3
Hz, 1 H), 4.12 (qd. J = 7.1, 1.4 Hz, 2 H); 13C NMR (75.5 MHz, CDC13) 5 13.7, 21.6,
23.4, 27.8, 29.2, 40.0, 44.6, 58.5. 59.9, 168.1, 171.1; IR (neat) 2977, 2880, 1730, 1640,
1460, 1414, 1327. 1302, 1177 om-l.

93

202: 1H NMR (300 MHz, CDC13, major isomer) 5 1.13 (d, J = 6.51 Hz, 3 H).
1.25 (t, J = 7.1 Hz. 3 H). 1.43-2.54 (m, 7 H), 2.87 (t. J = 4.0 Hz, 1 H), 3.43-3.61 (m, 2 H),
3.70 (dt, J = 5.8.5.2 Hz. 1 H), 4.16 (qd. J = 7.1. 1.8 Hz, 2 H); 13C NMR (75.5 MHz,
CDC13) 5 13.9, 18.6, 21.7, 29.5, 30.3, 35.8, 44.6, 46.8. 59.2, 59.8, 168.4, 170.2; IR (neat)
2964, 2878, 1728, 1628, 1458,1412. 1387, 1302, 1175 (ml.

203: 1H NMR (300 MHz, CDC13)81.27(t,J = 7.1Hz, 6 H), 2.34-2.40 (m, 4 H),
2.62 (m, 2 H), 3.91 (dd, J = 9.2, 8.6 Hz, 2 H), 4.25 (q, J = 7.1Hz, 4 H), 5.25 (t. J = 2.7
Hz, 1 H); 13C NMR (75.5 MHz. CDC13) 5 13.4, 26.2, 26.4, 28.2, 44.2, 54.4, 61.8, 109.6,
135.6, 164.9, 167.6; IR (neat) 2982, 2869, 1736, 1667. 1647, 1439, 1414, 1372 em-l.

204: 1H NMR (300 MHz, CDC13) 5 ); 1.24 (t. J = 7.1 Hz, 3 H). 1.26 (t, J = 7.1
Hz. 3 H), 1.65-1.98 (m, 2 H), 2.02-2.29 (m, 3 H), 2.42-2.60 (m, 3 H), 3.45-3.55 (m, 2 H),
3.85 (dd, J = 9.7, 6.8 Hz, 1 H), 4.14-4.26 (m, 4 H); 13C NMR (75.5 MHz, CDC13) 5
13.3. 13.4, 21.5, 28.1, 28.2, 28.4, 44.9, 54.9, 60.9, 61.2, 167.3. 167.6, 169.0; IR (neat)
2980, 2883, 1734. 1649, 1460,1414, 1370, 1252 (ml.

206: 1H NMR (300 MHz, CDC13) 5 1.92 (1,! = 1.5 Hz, 3 H), 2.62 (m, 2 H), 2.72
(m, 2 H), 5.04 (s, 2 H), 7.19-7.71 (m, 10 H); 13C NMR (75.5 MHz, CDC13) 5 16.0, 22.0,
30.9,-14.4, 113.3, 119.8, 124.1, 125.7, 126.9, 128.4, 128.6. 137.1, 137.4, 1403,1670,
170.1; IR (KBr) 3029,2969, 1680, 1655, 1605, 1385, 1364, 1281 em-l; HRMS calcd for
C20H20N20 m/z 304.1575, found m/z 304.1530. ‘

207: 1H NMR (300 MHz, CDC13) 5 1.25 (d, J = 6.5 Hz. 3 H), 2.00 (m, 1 H),
2.31 (m, 1 H), 2.52 (ddd, J = 18.2, 10.9, 7.7 Hz. 1 H), 2.68 (ddd, J = 18.2, 7.7, 1.6 Hz, 1
H), 2.80 (ddd, J = 12.7, 4.5, 3.7 Hz, 1 H), 3.82 (quint, J = 6.1 Hz, 1 H), 4.01 (d, J = 15.1
Hz, 1 H), 5.29 (d. J = 15.1 Hz, 1 H), 7.08-7.49 (m, 10 H); 13C NMR (75.5 MHz, CDC13)
514.7, 18.1, 29.9, 45.4, 48.1, 52.9. 119.6, 124.2. 127.3, 127.4, 128.3, 128.6, 136.9, 137.1,
168.8, 168.9; IR (KBr) 3298, 3132, 3065, 2980. 1661, 1645, 1599, 1541, 1497, 1443

1240 cm‘l.

94

212: (mp 222-225 °C) 1H NMR (300 MHz, CDC13) 5 2.62 (m, 2 H), 2.80 (m, 2
H), 3.37 (s, 3 H), 3.54 (s, 3 H), 9.29 (bs, 1 H); 13C NMR (75.5 MHz. CDC13) 5 16.8,
27.9. 29.4, 29.9, 88.7, 144.0, 150.7, 161.1, 172.6; IR (KBr) 3289, 3048,2957, 1715.
1667. 1634, 1507 cm-1; HRMS calcd for C9H11N303 m/z 209.0800, found 209.0803
III/z 303.1120.

214:1H NMR (300 MHz, CDC13)81.29(dt, J= 7.1.0.6 Hz, 6 H), 2.30 (m, 3 H),
2.51 (m, 2 H), 2.60 (m, 2 H), 4.03 (m, 4 H), 5.00 (s, 2 H), 7.09-7.33 (m. 5 H); 13C NMR
(75.5 MHz, CDC13, includes C-P coupling) 515.8, 15.9, 16.9, 17.0. 21.3. 21.4, 31.0,
31.1, 44.2, 61.0, 61.1, 102.3, 104.9, 125.6, 126.7, 128.3, 137.0, 149.2, 149.5. 170.4; IR
(neat) 3065, 3033, 2982, 2938, 2905. 1688, 1624, 1389, 1366, 1252, 1233, 1024 cm-1;
HRMS calcd for C17H24N04P m/z 337.1443, found m/z 337.1443.

215: 1H NMR (300 MHz. CDC13, mixture of isomers) 5 1.14 -1.34 (m, 9 H),
1.90 2.72 (m, 5 H), 3.68 (m, 1 H), 3.85-4.15 (m, 5 H), 5.14 (d, J = 14.8 Hz. 0.24 H.
minor isomer), 5.31 (d, J = 14.8 Hz. 0.76 H. major isomer), 7.19-7.33 (m, 5 H); 13C
NMR (755 MHz, CDC13, mixture of isomers ) 5 15.7, 16.2, 16.3, 16.9, 17.0, 18.7, 18.8,
21.7, 21.8, 30.4, 30.5, 30.6, 30.9. 36.3, 37.2, 38.3, 39.1, 47.8, 47.9. 50.6, 50.9, 51.0, 61.7,
61.8, 61.9, 62.0, 127.2, 127.3, 127.8, 128.3, 128.4, 1285, 137.2, 168.6, 169.8.

217: (mp 110112 °C) 1H NMR (300 MHz, CDC13) 5 2.36 (t, J = 1.6 Hz, 3 H),
2.60 (m, 2 H). 2.74 (m, 2 H), 4.98 (s, 2H), 7.04-7.83 (m, 10 H); 13C NMR (75.5 MHz,
CDC13)815.6,21.3,30.8,44.6, 117.6, 125.5, 126.1, 127.0, 128.4, 128.8, 132.6, 1365,
141.8, 147.6, 169.4; IR (KBr) 3061, 3032, 2957. 1688, 1622, 1449, 1360, 1302, 1173 cm-
1: HRMS calcd for C19H19N038 m/z 341.1086, found m/z 341.1060.

218: (mp 211-213 °C) 1H NMR (300 MHz. CDC13) 5 2.17 (s, 3 H), 2.57 (s, 4 H),
7.96 (m, 1 H); 13C NMR (75.5 MHz, CDC13) 5 18.6, 21.9, 29.4, 84.6, 118.5, 148.4,
170.9; IR (KBr) 3212, 3139. 2205. 1690, 1653, 1373, 1327 cm-1; HRMS calcd for
C7H3N20 m/z 136.0636 found m/z 136.0645.

95

220: (mp 98-100 °C) 1H NMR (300 MHz, CDC13) 5 2.10 (quint, J = 7.7 Hz, 2 H),
2.73 (t. J = 8.4 Hz, 2 H), 3.06 (tt, J = 8.4, 1.7 Hz, 2 H) 3.46 (tt, J = 7.7,1.8 Hz, 2 H), 3.83
(t. J = 7.5 Hz. 2 H); 13C NMR (75.5 MHz, CDC13) 5 20.4, 21.3, 30.1, 33.0, 46.6, 124.3.
153.2, 167.7; IR (KBr) 2968,2907, 1688, 1640, 1474, 1339. 1302, 1258 cm-1;HRMS
calcd for C3H10N203 m/z 182.0691, found m/z 182.0715.

96

REFERENCES

(1) Hickmott. P. W.; Sheppard, G. J. Chem. Soc. (C), 1971, 1358.

(2) Hickmott, P. W.; Sheppard. G. J. Chem. Soc. (C), 1971, 2112.

(3) Brunerie, P.; Celerier, J. P.; Huche, M.: Lhommet, G. Synthesis 1985, 735.

(4) Capps, N. K.; Davies, G. M.; Loakes, D.; McCabe, R. W.; Young, D. W. J. Chem.
Soc. Perkin Trans. 1 1991, 3077.

(5) Singh, B.; Lesher, G. Y.; Brundage, R. P.; Synthesis 1991, 894.

(6) Coco, M.T.; Congiu, C.; Maccioni, A.; Onnis, V. Synthesis 1992, 371.

(7) Danishefsky, S.; Etheredge, S. J. J. Org. Chem. 1974, 39, 3430.

(8) Shell, W.; Coburn, C. A.; Bornmann, W. G.; Danishiefsky, S. J. Org. Chem.
1993, 58, 611.

(9) Huang, Z. T.; Zhang, P. C. Chem. Ber. 1989, 122, 2011.

(10) Huang, 2. T.; Zhang, P. C. J. Chem. Soc. Perkin Trans. 1 1993, 1085.

(11) Nagasaka, T.; Inoue, H.; Ichimura, M. Synthesis 1982, 848.

(12) Fang, G. F.; Danishefsky, S. J. Tetrahedron Lett. 1989, 28, 3621.

(13) Wiesner, K.; Jirkovsky, 1.; Fishman, M,; Williams, C. A. Tetrahedron Lett.
1967, 1523.

(14) Jirkovsky, I. Can. J. Chem. 1974, 52, 55

(15) (a) Barth, W.; Paquette, L. J. Org. Chem. 1985, 50, 2438. (b) Kazmierezak, F.;
Helquist, P. J. Org. Chem. 1989, 54, 3988.

(16) (a) Haberrnehl, G.; Kibing, W. Chem. Ber. 1974, 107, 2326. (b) Capt‘athe, B. W.;
Jaen, J. C.; Wise, L. W.; Heffner, T. G.; Pugsley, T. A.; Meltzer, L. T.; Parvez, M.
J. Med. Chem. 1991, 34, 2736.

(17) (a) Tidwell, T. T. Synthesis 1990, 857. (b) 0mura, K.; Swem, D. Tetrahedron
1978, 34, 1651.

(18) Meyers, A. 1.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. J. Org. Chem. 1974,

39, 2778.

(19)

(20)

(21)

(22)

(23)
(24)

(25)

97
Ramaiah, D.; Ashok, K.; Barik, R.; Venugopal. D.; Rath, N. P.; Bhattacharya, K.;
Das, P. K.; George, M. V. J. Org. Chem. 1992, 57, 6032
Celerier, J. P.; Marchalant, E. D.; Lhommet, G.; Maitte, P. Org. Synth. 1988, 67,
170.
Brunerie, P.; Celerier, J. P.; Petit, H.; Lhommet, G. J. Heterocyclic Chem. 1986,
23, 1 183.
Evans, D. A.; Takacs, J. M.; Mc Gee, L. R.; Ennis, M. D.; Mathre, D. J .; Bartroli,
Pure & Appl. Chem. 1981, 53, 1109.
Gage, J. R.; Evans, D. A.; Org. Synth. 1989, 68, 77.
Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am. Chem. Soc.
1984, 106, 1154.
Alternative way to prepare enamino nitrocompounds, see. Lyubchanskaya, V.M.;
Sarkisova, V. M.; Alelseeva, L. M.; Granik, V. G. Chem. Heterocyclic
compounds 1992, 299.

CHAPTER III

TOTAL SYNTHESIS OF (i)-5-EPIPUMILIOTOXIN C 195A
AND APPROACHES TO THE SYNTHESIS OF
(:t)-PUMILIOTOXIN C 195A

98
INTRODUCTION

In order to demonstrate the use of the recently developed aza-annulation
methodology in alkaloid synthesis, we targeted the total synthesis of several simple
alkaloids. Since octahydroquinolone skeletons can be readily prepared in high yield
using the aza-annulation methodology pumiliotoxin C 195A (2), a cis decahydroquinoline
alkaloid, was selected as our target alkaloid.

Pumiliotoxin C 195A is one of the physiologically active alkaloids belonging to
the family Dendrobatidae, and was isolated from the skin extracts of Dendrobates
pumilio, a strikingly colored Panamanian frog.1 The absolute stereochemistry of
pumiliotoxin C 195A, ([2S, 4aS, 5R, 8aR] 5-methy1-2-n—propyl-cis decahydroquinoline)
was determined by a single crystal X-ray analysis of its hydrochloride salt.2

0.11:

 

(21:) Pumiliotoxin C 195A

Pumiliotoxin C is a relatively non-toxic compound. Higher concentrations of this
alkaloid are required to have pharmacological effects on biological systems. "At higher
concentrations of 80-320 11M, dl-pumiliotoxin C initially potentiated and then blocked
indirect elicited twitch of the rat striated muscle preparations".3 The impossibility of
isolation of more than milligram quantities of this alkaloid (16 mg from 250 frogs),
together with the pharmacological activity makes this alkaloid an attractive target for a
total synthesis.

99

A successful syntheses of pumiliotoxin C 195A deals with the construction of the
cis-decahydroquinoline ring system and elaboration of the correctly oriented side chains
at carbons C-2 and C-5. In pumiliotoxin C 195A (2), the two side chains are equatorially
oriented in the most stable cis-decahydroquinoline conformation. Further, the cis fused
hydroquinoline intermediates are expected to show great stereoselective nucleophilic
additions or catalytic hydrogenations because of the approach of reagents being restricted
exclusively to the convex face of the molecule. .

Several total synthesis of pumiliotoxin C have been reported,4 and these routes
have been reviewed}: 5 Most of the synthetic routes provided racemic pumiliotoxin C,
but some asymmetric synthesis have also been reported. One of the first syntheses of (i)-
pumiliotoxin C was reported by Inubushi in 1975.“ The cis fused decahydroquinolone
ring 223 was prepared through the Beckmann rearrangement of cis tetrahydroindenone
222 (eq 1). After a series of chemical transformations, 223 was converted into 2. This

method required sixteen steps to prepare 2 from 222.

 

H 1.NH HHCI/NaOAc/MeOH H
on - o
5391. N o
H 0 H 111
222 223

Yamamoto synthesized 2 to demonstrate the ability of organoaluminum reagents
to induce the Beckmann rearrangement of oxime derivatives, as well as, to capture the
well known intermediate iminocarbocation by the nucleophile, which was originally
attached to aluminum.“ The precursor for Beckmann rearrangement (225) was prepared
from 224 in three steps (eq 2). Catalytic hydrogenation of the tetrasubstituted C=C was
used to obtain the cis fused ring. In the presence of 3 equivalents of tri-n-

propylaluminum compound 225 was subjected to the Beckmann rearrangement

100
conditions to give imine 226 which upon reduction with DIBAL' gave 2 in 60% yield.

This methodology is an excellent way to prepare 02 alkyl substituted cyclic amines.

(2)
N n-prwyl

 

 

224 225 226

The Diels-Alder reaction has been used as a popular route for constructing the
required cis ring junction of the decahydroquinoline system. 0ppolzer used an
intramolecular Diels-Alder reaction to establish the four stereocenters in a single step.4a
Heating triene amide 227, prepared from chiral (S)-norvaline, gave 228 in 60% yield,
which after hydrogenation and deprotection, gave natural 2-(S) pumiliotoxin C (eq 3).
This route was efficient, and afforded 97 % enantiomerically pure (-)-pumiliotoxin C.

M, sealedtube230°C
.-

U-N "n'ml toluene/16 h
66%

O

(3)

 

227

Overman generated the cis ring fusion and the C-5 methyl stereochemistry
through an intermolecular Diels-Alder reaction.4c Heating the protected aminobutadiene
229 with crotonal at 110 °C gave the endo adduct 230 in 61% yield (eq 4). Further
elaboration of 230 gave (113-pumiliotoxin C. This short and convenient route provided
racemic 2 in 56% overall yield from the diene 229.

101

 

 

MeH
I T; CHO 110 :13/160 min ; (4‘)
[\"‘\hflKXth
229 230

Brandi used the thermal rearrangement of 5-spirocyclopropane isooxazoline as the
key reaction to establish both the cis fusion and the C-5 methyl stereochemistry.4f
Heating compound 231 at 140 °C in xylene gave a 1:1 mixture of regioisomers 232 and
233 (eq 5). After tedious time consuming separations, 232 was isolated from the other

stereo-and regioisomers and carried on to 2.

140 W h
xylene

a::b7l a::bll

 

231 232 233

Polniaszek used an anionic oxy-cope rearrangement to prepare the cis fused
hydroquioline skeleton.“ The anionic oxy-cope rearrangement of the alcohol 234 in
DME gave 235 in 79% yield (eq 6). An assumption was made that the presence of the
bulky phenyldimethylsilyl group influenced the C-2 stereochemistry. Compound 235
was converted into 236 in two steps, which after conjugate addition and further

transformations yielded 2.

 

 

R1
H
2 steps
NB R2 110 °C/8.5h 4., 2 —’73%
0 H II R
Bn
234 235 236
R1: PhMe28i R2=n-propy1

The synthesis of 2 by LaBel involved the intramolecular cycloaddition of a
niuone.4h The nitrone obtained from the reaction of hydroxl amine 237 and aldehyde
238 underwent intramolecular cycloaddition to give 239, which upon reduction with zinc
dust gave the cis 2,3,6-trisubstituted piperidine structure (eq 7). Conversion of alcohol
240 into the tosylate followed by intramolecular alkylation gave 241. After removal of
the sulfone group, 241 was converted to 2.

 

 

 

2:7 10 °C __ Me 1 Zn dust, Horse/8771.
2. WM h ,N
P1150: /\/\ CH0 74% o 2 géaoztaumrlr
238
2 39 Me
(7)
Ho
J." .. ”a
" 1 TsCl/pyrldlne/92% 502
4.-
PhSOz\/\ e '0, 2. n-BuLl . '0
‘. H 11‘ "'9' “p" -78 °C to r.t./2 h H N “'n-propyl
Doc 83% Bee
2 40 2 4 1

From this literature survey, it can be seen that a variety of methodologies have

been used to prepare the cis fused decahydroquinoline skeleton. Since we demonstrated

103
the use of aza-annulation in preparing octahydroquinolones in reasonably high yields, we
undertook the tow] synthesis of (219-pumiliotoxin C with the following goals: -
1) To utilize the aza-annulation methodology as the key reaction for the
preparation of a suitable octahydroquinolone skeleton.

2) To functionalize the octahydroquinolone for further elaboration .

 

104

RESULTS AND DISCUSSION

The planned retrosynthetic analysis of (:t)-pumiliotoxin C is shown in Scheme V.
(:t)-Pumiliotoxin C (2) should be readily available from 242 after functionalization of the
amide carbonyl group using 0ppolzer’s procedure.4111 The lactam 242 could be prepared
from 161 after stereoselective reduction of the enamine double bond and transformation
of the ketone functionality into the C-5 methyl group with correct stereochemistry
followed by debenzylation. The keto lactam 161 is a typical aza-annulation product
which had been prepared from readily available diketone 159.

Scheme V. Retrosynthetic Analysis of (1)-Pumiliotoxin C.

 

105
As previously reported,6 compound 161 was prepared in good yields from
diketone 159 (eq 8). Under the established conditions, catalytic hydrogenation of 161
stereoselectively gave the cis alcohol 163 in 91% yield with a trace of its hydroxyl epimer
and trans isomer.6 With cis alcohol 163 in hand, possible pathways for the introduction

of the methyl group at C-5 with correct stereochemistry were explored.

0
1.1hmflhJCdH5
PdIC/l-l2/45 psi
, OiLaaykwldwuuk: INCHflfluCCQMSh’
THF/24 h N O 91%
Bn

75%

"to

 

 

159 161 163

a) 8142 Displacement Reaction Approach

Based on literature precedent, the transformation of alcohol 163 into a better
leaving group would facilitate 8N2 displacement with a methyl nucleophile to introduce
the C-5 methyl group with correct stereochemistry.7 Better leaving groups such as a
mesylate and a tosylate were selected. Both mesylate 243 and tosylate 244 wereprepared
in 90% and 70% yields respectively from alcohol 163 (eq 9).

 

H R
‘r’ 5°13
RS 1
(I). :0 -
PI! 0 1:1 0
Ba Bn
163 243 R-CH3

244 R=p-CH3C5H4

Both mesylate 243 and tosylate 244 were treated with a variety of methyl copper
and methyl Grignard reagents (eq 10). Unfortunately, the desired product (245a) was not
obtained, and either starting material or the elimination product 246 was recovered. Even

106
though several 8N2 displacement reactions of simple secondary tosylates with various
copper reagents have been reported, both 243 and 244 failed to undergo SN2
displacement possibly due to the steric hindrance exhibited in the cis decahydroquinolone

system.7

Methyl

Nucleophiles (10)

 

 

b) Wittig Reaction Approach

Since alcohol 163 could not be transformed into 245 via 8N2 displacement of
mesylate 243 or tosylate 244 with methyl nucleophiles, different approaches were
examined. Next, our attention was focused on a Wittig reaction to introduce the C-5
methyl group. In order to carry out the Wittig reaction, alcohol 163 was converted into
ketone 166 in 91% yield using the Swern oxidation (eq 11).

 

9H 0
i
(COClhIDMSO 11
2C1 p ( )
N 0 91% 2 If 0
85:10:5 2., 90:10 Bn -

163 166

107
Reaction of the ylide, prepared from (methoxymethyl)triphenylphosphonium
chloride and sodium hydride in dimethyl sulfoxide, with ketone 166 gave the enol ether
of trans lactam 247a in low yields (eq 12).8 Under the reaction conditions, the cis lactam
was isomerized to the trans lactam. In order to avoid this isomerization, the ylide was
prepared using n-BuLi and reacted with ketone 166 at -78 °C. Under these modified

conditions the formation of enol ether 247a was avoided to a larger extent, and 247b was

 

 

obtained as the major product.
OMe OMe
H
2 + - + -
‘CH30CH2PPh3Cl l 6 6 CH30CH2PPh3Cl > (12)
NaHJDMSO n-BuLI/I'HF
N 0 -78 °C to r.t. N 0
H l I
Ba Ba
247a 247b

Without further purification, crude enol ether 247b was submitted to hydrolysis
under acidic conditions to give an aldehyde. Since the C-5 substituent in pumiliotoxin C
is equatorially oriented, the hydrolysis of the enol ether 247b was expected to give the
desired aldehyde 248a as the major product along with a trace of the undesired epimer.
In order to find suitable conditions that enhance the formation of the desired aldehyde
248a the enol ether was submitted to different hydrolysis conditions (eq 13).9
Unfortunately, the optimum condition for the hydrolysis of enol ether 247b with p-Ts0H
in refluxing aqueous dioxane gave a 1:1 mixture of the aldehydes 248a and 248b (eq
13).9a When the mixture of aldehydes 248a and 248b was submitted to epimerization
conditions using sodium carbonate in methanol, significant change in the epimer ratio

was not observed.

108

 

CHO CHO
O r— 0 + a»
1:1 0 1:1 0 1:1 0

Ba Bn Bn

247 b 248a 248b
H20/I-1280fl1-1F 45 55
HCl/I'HF 38 62
HzOII-ICOOH 42 58
H20/p-TsOI-l/Dioxane 47 53

Since a single aldehyde could not be obtained from the hydrolysis of e‘nol ether
247b, the mixture of crude aldehydes 248a and 248b was carried on to the next reaction.

In order to reduce the aldehydes to the corresponding methyl groups, aldehydes 248a and
248b were reacted with ethanedithiol in the presence of BF3:Et20 to give dithianes,

which upon desulfurization with Raney nickel, gave a 42:58 mixture of methyl lactams
245a and 245b in 47% yield from ketone 166 (eq 14).

R1 R2
1) RSI—I SH ’
2)RaneyNi N (14)

 

o
I
Bn
24811 Rl-CHo R2-H 245a Rl-CH3 112-H
2486 112-H 112-CH0 2450 R2=H R7—CH3

In another approach, ketone 166 was reacted with the ylide prepared from
methyltriphenylphoshonium iodide to give 249 in 46% yield. The trans lactam obtained
along with crude 249 were separated by column chromatography. Catalytic
hydrogenation of 249 over Pd/C gave 245 in 84% yield with a 24:76 mixture of epimers

 

109
245a and 245b (eq 15). As expected from the model studies, the hydrogen was delivered
from sterically less hindered t0p face of the decahydroquinoline system to give lactam
245b as the major product. Since 245a could not be obtained as a single epimer with

nucleophilic displacement reaction or Wittig reaction approach, other methods were

 

 

investigated.
R2 R1
166
n-Buli/I'HF -’hopm NECK/452 Psi 1““ij (15)
12 W% 'n
2498“ azb 24:76

245a R‘scug stH A
24511 R‘-H R2-CH3

c) Radical Deoxygenation Approach

In the process of finding various approaches to introduce the C-5 methyl group,
replacement of an -OH group by a hydrogen using deoxygenation of an alcohol attracted
our attention. Several methods have been reported for the deoxygenating of alcohols. 10
Among the possible methods, deoxygenation of tertiary alcohol xanthatesll and
deoxygenation of the diethyl phosphate of 3° alcohols12 were simple and efficient.
Kochetkov examined the deoxygenation of various tertiary alcohol xanthates, and
observed inversion of stereochemistry (50% to 98%) in the deoxygenated products.11
Ireland reported that the deoxygenation of diethyl phosphates of 8 3° alcohol by a lithium
ethylamine solution gave the deoxygenated product in good yield with retention of
configuration. 12

In order to examine the stereochemical outcome of the deoxygenation of 8 3°
alcohol in a cis decahydroquinolone system, 250 was prepared in 68% yield from the

reaction of ketone 166 and methyl magnesium bromide (eq 16). The minor epimer was

1 10
separated by column chromatography. Initial attempts to make the phosphate from
alcohol 250 and diethylchlorophosphate using Ireland’s procedure provided a mixture of
products, and reduction of the crude reaction mixture with lithium in liquid ammonia did
not give the desired product 245a. Next, deoxygenation of the 3° alcohol xanthate was
examined Xanthate 251 was prepared using Kochetkov's procedure (eq 17).11 During
the xanthate preparation, the temperature of the reaction mixture had to remain below 5
°C to avoid undesired side reactions. When the temperature was increased above 10°C

prior to addition of C82, dixanthate 252 was obtained as a single product (eq 18).

Me OH
-78 °C% to r. t. N 0

 

 

 

166 250
Me .OcszMe L4‘"
1. NaH/[HF ‘
0 °C-5 °C n-BugsmI/AIBN
25” T" ........... " ‘1— “7’
3. Mel/I'HF N O 93% N 0
5 °C to r.t. Bn Bn
251 245b
m CH Me OCSZMG
l. NaH/[HF/IO °C
18
2. cs; 4. ( )
N 0 3. Met N 0C82Me
Ba Ba

250 252

 

1 1 1

The xanthate at C-2 in 252 could have formed from the reaction of the amide
enolate, generated during the reaction, with C82 and Mel. Dixanthate formation was
closely examined through a comparative experiment. Alcohol 163 was treated with NaH,
C82 and Mel both at 5 °C and at room temperature (eq 19). Only the mono xanthate 253
was isolated at both temperatures. The only difference between these two alcohols is the
fact that one is 8 3° alcohol and other is a 2° alcohol. From the above experiment, it was
evident that the 3° alkoxide formed at higher temperatures was basic enough to. generate
the amide enolate which reacted with C82 and Mel to give xanthate 252. However, in
the case of the 2° alcohol, the 2° alkoxide formed was not basic enough to generate an

amide enolate, and hence, only the mono xanthate was observed.

 

H .011 H 90112181c
;. 2:1/1min. _ (19)
If 0 3: Mel N 0
Bn Bn
163 253

Deoxygenation was carried out by heating xanthate 251 at reflux in toluene with
tributyltin hydride and a catalytic amount of the radical initiator AIBN -(eq 17).
Surprisingly, deoxygenation of xanthate 251 gave the undesired epimer 245b as the major
product (>95%) in 93% yield. The ease of hydrogen radical approach, the themodynamic
stability of the intermediate radical and other stereoelectronic factors had an appreciable
influence in the stereoselective formation of 245b.

The stereoselectivity observed during the deoxygenation of xanthate 251
prompted us for the preparation of lactam 245a. Deoxygenation of 3° alcohol 254 via
xanthate 255 was expected to give lactam 245a which could be transformed into (21:)-
pumiliotoxin C. Based on this assumption, alcohol 254 was prepared in 55% yield from

112
oxymercuration of 249 (eq 20). Attempts to prepare xanthate 255 were unsuccessful, and
as a result, pure 245a could not be prepared (eq 21).

l. HgSOflI-IF/Hzo ‘

2. NaBHdNaOH 7
55%

 

 

249

l. NaH/IIIF/S °C

2. C82
3. Mel

 

(21)

   

Since lactam 245a could not be prepared as a single compound, we decided to
transform lactam 245b into (i)-5-epipumiliotoxin C (259). The total synthesis of (i)-5-
epipumiliotoxin C (259) from compound 245b is shown in Scheme VI. Reductive
debenzylation of lactam 245b in liquid ammonia with lithium metal at -33 °C gave
decahydroquinolone 256 in 74% yield. Lactam 256 was converted to imine 258 using
0ppolzer's conditions.“m Treatment of lactam 256 with trimethyloxonium
tetrafluoroborate in the presence of a catalytic amount of Hunig’s base gave lactim-ether
257. Without purification, crude 257 was treated with propylmagnesium chloride in
refluxing benzene to give imine 258. Catalytic hydrogenation of imine 258 gave a
mixture of products, but the reduction of crude imine 258 with DIBALH using
Yamamoto’s procedure4e gave (:t)-5-epipumiliotoxin C (259) in 33% yield from lactam
245b. Even though all of the attempts to introduce 8 C-5 methyl group with the correct

113
stereochemistry failed, the unexpected stereoselective formation of 245b by the radical
deoxygenation method allowed us to complete the total synthesis of unnatural (11:)-5-
epipumiliotoxin C. (i)-5-Epipumiliotoxin C was obtained in 7 .3 overall yield from
readily available diketone 159.

Scheme VI. Total Synthesis of (i)-5-Epipumiliotoxin C.

 

 

 

 

 

 

 

 

Li/NH3 __ Mejo*ar=,' _
74% 0120ij h '
If 0 If 0 0 °C to r.t. N 0MB
Bn H
24 5 b 2 5 6 2 5 7
n-PtMgCl
Email!!!
6 h
I? 1:16 v
I 0 °C to r.t./8 h
If /\M° 33% yield from 256 N Me
H H
259 258

CONCLUSION

Application of the aza-annulation methodology in alkaloid synthesis has been
demonstrated by the total synthesis of (i)-5-epipumi1iotoxin C. Aza-annulation was used
as the key reaction for construction of the octahydroquinolone ring skeleton, and the
octahydroquinolone was transformed into unnatural (21:) 5-epipumiliotoxin C after several
transformations. Catalytic hydrogenation of the octahydroquinolone was used to

stereoselectively establish the cis ring fusion. The use of radical deoxygenation for stereo

 

1 14
chemical inversion has been utilized for the introduction of the C-5 methyl group. In
general, aza-annulation of 1,3—cyclohexanedione followed by catalytic hydrogenation of
the annulated lactam is one of the simplest and more economical methods for the
construction of a cis—decahydroquinolone skeleton, which can be used as a common
precursor for the preparation of several other cis-decahydroquinoline alkaloids.- Further
studies are required to prepare (i)-pumiliotoxin C from the octahydroquinolone skeleton.

1 15
EXPERIMENTAL SECTION

General Methods. All reactions were carried out under an atmosphere of either nitrogen
or argon. Benzene, toluene, tetrahydrofuran (THF), and Et2O were distilled from
sodium/benzophenone immediately prior to use. Triethylamine, dichloromethane and
pyridine were heated at reflux over calcium hydride for a minimum of 12 h, and then
distilled immediately prior to use. 1.3-Cyclohexanedione was obtained from Aldrich
Chemical Co. and recrystallized from benzene prior to use. Benzylamine and acryloyl
chloride were obtained from Fluka, and used without further pmification. A solution of
DIBALH (1.0 M in hexane) was prepared from neat DIBALH obtained from Aldrich
Chemical Co. Methylmagnesium bromide (3.0 M in Et20), propylmagnesium chloride
(2.0 M in Et20), BF3:Et20 and trimethyloxonium tetrafluoroborate were purchased from
Aldrich Chemical Co. Acrylic acid, methanesulfonyl chloride, and ethyl chloroformate
were purchased from Aldrich Chemical Co. and distilled before use. Compounds 161,
163 and 166 were prepared as described in Chapter II.

NMR Spectra were obtained on a Varian Gemini 300 instrument with CDCl3 as
the solvent. lH spectral data are reported as follows: chemical shifts relative to residual
CHC13 (7 .24 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint =
quintet, sext = sextet, sept = septet, b = broad), coupling, and integration. 13C chemical
shifts are reported relative to residual CHC13 (77.0 ppm). Infrared spectra were recorded
on a Nicolet 42 FT-IR instrument.

Preparation of Maylate (243). To a solution of alcohol (1.26 g, 4.8 mmol) and
TEA (0.98 g, 9.7 mmM) in 45 mL of CH2C12 at 0 °C was added freshly distilled
methanesulfonyl chloride (1.66 g, 14.5 mmol) and stirred for 3 h at this temperature. The
temperature was raised to ambient temperature and stirred for an additional 3 h.
Saturated NaHCO3 (60 mL) was added and stirred for 30 min. The aqueous layer was
then extracted with 4 x 50 mL of C112C12, and the combined organic fractions were dried

 

1 16

over Na2804. After removal of solvents, the residue was purified by flash column
chromatography (eluent: 80:20 CH2C12-EtOAc). The solvents were removed to give
mesylate 243 in 82% yield. The mesylate was directly used for subsequent reactions
without further characterization.

Preparation of Tosylate (244). To a solution of alcohol (0.9 g 3.47 mmol) in 13
mL of pyridine at 0 °C was added p-toluenesulfonyl chloride (0.99 g, 5.2 mmol) . The
reaction mixture was stirred at 25 °C for 24 h. The solvent was removed, and the residue
was taken in 40 mL of CH2C12 and washed successively with 25 mL of 10% aqueous
HCl solution, 25 mL of saturated NaHCO3. and 25 mL of brine. The organic layer was
dried (N a2804), filtered, and concentrated to give a crude residue, which was purified by
flash column chromatography (eluent 15:85 EtOAc-CH2C12). The solvents were
evaporated to give tosylate 244 in 77% yield: 1H NMR (300 MHz, CDC13) 5 1.10 (qt, J
= 13.5, 3.7 Hz, 1 H), 1.33 (dq, J = 3.7, 13.4 Hz, 1 H), 1.55 (dq,J = 4.0, 12.6 Hz, 1 H),
1.58-1.79 (m, 2 H), 1.79-1.93 (m, 3 H), 2.25 (m, 1 H), 2.36 (dd, J = 18.1, 9.5 Hz, 1 H),
2.46 (s, 3 H), 2.58 (ddd, J = 17.9, 4.1, 3.9 Hz, 1 H), 3.13 (dt, J = 11.9, 4.3 Hz, 1H), 3.94
(d,J = 15.3 Hz, 1 H), 4.53 (dt, J=11.9, 5.0 Hz, 1H), 5.28(d,J=15.3 Hz, 1 H), 7.15 (m.
2 H), 7.24-7.38 (m, 5 H), 7.77 (d, J = 8.2 Hz, 2 H); 13C NMR (75.5 MHz CDC13) 5
15.2, 20.5, 21.2, 25.1, 25.9, 30.3, 38.4, 47.5, 55.8, 80.4, 127.0, 127.1, 128.2, 129:4, 133.8,
136.8, 144.5, 168.9; IR (KBr) 3088, 3067, 3032, 2953, 2245, 1632, 1497, 1474, 1453,
1362, 1227, 1190,1177, 1098 cm-1.

Preparation of Compound 246 from Tosylate (244). To a solution of t-BuOK
(0.11 g, 0.9 mmol) in 4 mL of DMSO was added the tosylate 244 (0.3g, 0.7 mmol) The
reaction mixture was heated at 70 °C for 8 h. H20 (10 mL) was added to the reaction
mixture which was stirred for an additional 15 min. The reaction mixture was extracted
with 4 x 20 mL of Et20, and the combined organic layers were washed with 2 x 20 mL
of H20. The combined organic layers were dried (N a2804), filtered, and concentrated to
give a crude residue. The crude residue was purified by flash column chromatography

1 17

(eluent 50:50 Et20~Petro1eum ether). The solvents were evaporated to give 246 in 72%
yield: 1H NMR (300 MHz. CDC13) 5 1.17-1.34 (m. 1 H), 1.39 (m, 1 H), 1.78 (m, 1 H),
1.99 (m, 2 H), 2.19 (m, 1 H), 2.26-2.45 (m, 3 H), 2.64 (m, 1 H), 3.78 (m, 1 H), 4.28 (d, J
= 15.3 Hz, 1 H), 5.20 (d, J = 15.3 Hz, 1 H). 5.55 (m, 1 H): 13C NMR (75.5 MHz CDC13)
8 20.6, 24.2, 29.0, 33.6, 45.7, 45.8, 55.5, 55.6, 123.2, 126.6, 127.1, 128.1, 132.9, 137.2,
170.4; IR (KBr) 3087, 3061, 3029, 2946, 2861, 2840, 1646, 1495, 1449, 1420, 1358,
1279, 1196, 1157 cm-1,

Preparation of Alcohol (250). To a solution of ketone 166 ( 1.42 g, 5.5 mmol) in
45 mL of THF at ~78 °C was added dropwise 3.0 M solution of methylmagnesium
bromide (3.70 mL, 11.07 mmol) and stirred at ~78 °C for 1 h and at 0 °C for 5 h. The
reaction mixture was then quenched with 25 mL of saturated NH4C1 solution and stirred
for 15 min. The aqueous layer was then extracted with 4 x 50 of CI-12C12, and the
organic fractions were combined and dried (N 82804). After removal of solvents, the
residue was purified by flash column chromatography (eluent 40:60 CH2C12-Et0Ac).
The solvents were evaporated to give alcohol 250 in 71% yield: 1H NMR (300 MHz,
CDC13)51.21 (s, 3 H), 1.26 (m, 1 H), 1.32-1.49 (m, 2 H), 1.54 (dd, J = 13.1, 4.2 Hz, 1
H), 1.65-1.96 (m, 4 H), 2.06 (m, 1 H), 2.46 (m, 1 H), 2.64 (dd, J = 18.1, 5.8 Hz, 1 H),
3.30 (dt, J = 12.0, 4.2 Hz, 1 H), 4.05 (d, J = 15.2 Hz, 1 H), 5.12 (d, J = 15.2 Hz, 1 H),
7.16—7.36 (m, 5 H); 13C NMR (75.5 MHz. CDC13) 5 16.6, 20.7. 26.0, 27.2, 30.9, 33.6,
45.2, 48.0, 56.1, 71.2, 126.7, 126.9, 128.1, 137.1, 169.7; IR (KBr) 3392, 3088, 3063,
3030. 2938,2868, 1620, 1496, 1453. 1416, 1359,1129, 1123 cm-1,

Preparation of Compounds 245a and 245b from Ketone (166): To a
suspension of (methoxymethyl)t1iphenylphosphonium chloride (5.0 g, 14.6 mmol) in 55
mL of THF at ~78 °C was added a 2.5 M solution of n-BuLi (5.85 mL, 14.6 mmol). The
reaction was stirred at this temperature for 15 min, and then warmed to 0 °C for an
additional hour. The reaction mixture was then cooled to ~78 °C, and the ketone 166

(2.05 g, 9.7 mmol) in 7 mL of THF was added and stirred at ~78 °C for 2 h, at ~45 °C for

 

1 18

7 h , at ~20 °C for 2 h, at 0 °C for 2 h and at room temperature for 4 h. The reaction
mixture was then quenched with 35 mL of saturated NH4C1 solution, and the aqueous
layer was extracted with 4 x 50 mL of CH2C12. The combined organic layers were dried
(Na2804), filtered, and concentrated to give crude enol ether 247. The crude enol ether
247 was added to a solution of 96 mL of dioxane, 27 mL of H20 and p-TsOH (0.46 g,
2.4 mmol). The reaction mixture was heated at reflux for 12 h, cooled, and saturated
NaHC03 was added and stirred for another 30 minutes. The aqueous layer was extracted
with 4 x 25 mL of CHzCl2. The combined organic layers were dried (Na2804), filtered,
and concentrated to give a mixture of crude aldehydes 248a and 248b. The crude
aldehydes were filtered through a silica gel column (eluent 80:20 CHzClz-EtOAc). After
removal of the solvents, the crude aldehydes were used for further reaction. To a solution
of ethanedithiol (2.75 g, 29.2 mmol) and aldehydes 248a and 248b (9.7 mmol) in 190 mL
of CHC13 at 0 °C was slowly added BF3:0Et2 (0.69 g, 4.9 mmol). The reaction mixture
was stirred for 12 h at room temperature, 100 mL of 5% NaI-IC03 was added and the
reaction mixture was stirred for 20 min. The organic layer was washed with 50 ml. of
H20 and the combined aqueous layers were washed with 2 x 50 mL of CHC13. The
combined organic layers were dried (Na2804), filtered, and concentrated to give the
crude dithiane. The crude dithiane was added to a suspension of 48.8 g of Raney nickel
in 240 mL of EIOH, and heated at reflux for 12 h. The reaction mixture was cooled,
filtered, and concentrated to give a crude residue. The residue was purified by flash
column chromatography (eluent 55:45 Et20~petroleum ether). The solvents were
evaporated to give a mixture of 245a and 245b in 47% yield from ketone 266.

Preparation of Compound 249. To a suspension of
methyltriphenylphosphonium iodide (4.04 g, 10 mmol) in 35 mL of THF at ~78 °C was
added a 2.5 M solution of n~BuLi (4.00 mL, 10 mmol) and stirred at this temperatme for
15 min and stirred at room temperature for 1 h. The reaction mixture was then Cooled to

~78 °C, and ketone 166 (1.71 g, 6.7 mmol) in 6 mL of THF was added slowly and stirred

i ”I.

 

I?!“ I '

1 19

at ~78 °C for 8 h, at -45 °C for 2 h, at 0 °C for 2 h and at room temperature for 4 h.
Saturated ammonium chloride (25 mL) was added, and the mixture was stirred for 20
min. The aqueous layer was extracted with 4 x 40 mL of methylene chloride. The
combined organic layers were dried (MgSO4), filtered, and concentrated to give a crude
residue. This residue was purified by flash column chromatography (eluent 60:40 Et20~
Petroleum ether). The solvents were evaporated to give 249 as a viscous liquid in 46%
yield: 1H NMR (300 MHz, CDC13) 5 1.17 (m, 1 H), 1.45-1.65 (m, 2 H), 1.82 (dq, J =
13.2, 3.5 Hz, 1 H), 2.01 (dq, J = 13.2, 3.4 Hz, 1 H), 2.07-2.14 (m, 2 H), 2.16-2.29 (m, 1
H), 2.44-2.59 (m, 2 H), 2.64 (dt, J = 13.0, 4.5 Hz, 1 H), 3.21 (dt, J = 12.1, 4.4 Hz, 1 H),
3.98 (d,J= 15.2Hz, 1 H), 4.68 (d,J= 1.5Hz. 1 H),4.74 (d,J= 1.5 Hz,1H), 5.29 (d,J=
15.2 Hz, 1 H), 7.19-7.34 (m, 5 H); 13C NMR (75.5 MHz. CDC13) 8 22.7, 24.7, 26.4,
29.8, 31.1, 43.5, 47.4, 57.9, 109.6, 126.7, 127.2, 128.1, 137.3, 149.0, 168.9; IR (KBr)
3067, 2940, 2882, 2861, 1640, 1495. 1468, 1453, 1418, 1360 cm-1. .

Hydrogenation of Compound 249. Compound 249 (0.59 g, 2.3 mmol) was
taken up in 60 mL of MeOH and was hydrogenated at 45 psi over 10% palladium on
carbon (0.2 g) for 12 h. Removal of the catalyst by filtration followed by concentration
gave a 26:74 mixture of 245a and 245b in 84% yield.
Preparation of Xanthate (251). To a suspension of NaH (1.13 g, 47.2 mmol) in 22 mL
of THF at 0 °C was slowly added tertiary alcohol 250 (2.58 g, 9.4 mmol) in 27 mL of
THF. The flask was washed with additional 3 mL of THF, and the washing was added to
the reaction mixture, which was stirred at 03 °C for 30 min. Then carbon disulfide (3.59
g, 47.2 mmol) was slowly added, and the reaction was stirred at 0-3 °C for 45 min. To
this reaction mixture was slowly added methyl iodide (6.7 g, 47 .2 mmol), and the
macdonmixnnewassdnedthistemperanneforwnfinandatmomtemperaturefor 12
h. The reaction mixture was then cooled to 0 °C and quenched by slow addition of water.
The aqueous layer was extracted with 4 x 30 mL of EtOAc. The combined organic layers

were dried (Na2804), filtered, and concentrated to give a crude residue, which was

 

120
purified by flash column chromatography using Et20 as the eluent. The solvent was
evaporated to give xanthate 251 in 76% yield. The xanthate was directly used for
deoxygenation without further characterization.

Deoxygenation of Xanthate (251). A mixture of xanthate 251 (2.47 g, 6.8
mmol), tributyltin hydride (3.95 g, 13.6 mmol) and AIBN (0.223 g 1.36 mmol) in 27 mL
of toluene was heated at reflux for 5 h. The reaction mixture was cooled to room
temperature, and poured out on a silica gel column. The mixture was first eluted with
petroleum ether and then 70:30 petroleum etherzEt20 and finally flushed with Et20.
Evaporation of the ether fractions gave the crude deoxygenated product. The crude was
purified by flash column chromatography (eluent 90:10 Et20~petroleum ether). The
solvents were evaporated to give 245b as a viscous liquid in 93% yield: 1H NMR (300
MHz, CDC13) 8 0.88 (d, J = 6.9 Hz, 3 H), 1.01-1.25 (m, 2 I1), 1.26-1.43 (m, 2 H), 1.52~
1.95 (m, 6 H), 2.42 (ddd, J = 18.2, 10.9, 8.1 Hz, 1 II), 2.59 (ddd, J -- 18.2, 6.1, 1.9 Hz, 1
H), 3.12 (ddt, J = 11.3, 0.7, 3.6 Hz, III), 3.92 (d, J= 15.1 Hz, 1 H), 5.31(d,J = 15.1 Hz,
1 H). 7.13-7.33 (m, 5 H); 13C NMR (75.5 MHz. CDC13) 5 15.0, 18.7. 24.1, 26.0, 27.8.
30.8, 33.9, 39.2, 47.2, 58.1, 126.6, 127.1, 128.1, 137.4, 169.5; IR (KBr) 3063, 3029,
2930, 2861, 1638, 1453, 1358. 1227 cm-1.

Preparation of Lactam (256). Compound 245b (1.89 g 7.3 mmol) in 20 mL of
TIIF was added to liquid ammonia (150. 200 mL) at ~78 °C. Small pieces of lithium rod
were added slowly to generate a dark blue color. The dry ice bath was removed, and the
reaction mixture was stirred for 2 h at ~33 °C. The reaction mixture was then cooled to
~78 °C and quenched by adding solid NH4C1. Ammonia was evaporated overnight to
give a white solid. The white solid was dissolved in methanol and transferred into a
round bottom flask. The solvent was removed to give a residue, and the residue was
redissolved in CH2C12 and filtered to remove the insoluble inorganic salts. The filtrate
was evaporated to give crude lactam 256 which was purified by flash column

chromatography (eluent ethyl acetate). The solvent was evaporated to give 256 in 74%

 

121

yield: lHNMR (300MHz. CDCl 3) 5 0.95 (d,J = 6.9 Hz, 3 H), 1.03(m, 1H), 1.17-1.50
(m, 3 Il), 1.61-1.76 (m, 5 II), 1.94 (m, 1 H), 2.28 (ddd, J = 18.1, 10.4, 8.2 Hz, 1 H), 2.44
(ddd, J = 17.9, 4.2, 3.5 Hz, 1 H), 3.30 (dq, J = 11.5, 4.1 Hz, 1 H), 6.21 (bs, 1H); 13C
NMR (75.5 MHz. CDC13) 8 14.6, 18.9, 23.9, 27.8, 30.1, 30.8, 33.8, 38.0, 53.7, 171.8; IR
(KBr) 3193. 3087,2926, 2877, 2855, 1653, 1495, 1416, 1302, 1227 cm-1.

Preparation of (i)~5~Epipumiliotoxin C (259). To a solution of
trimethyloxonium tetrafluoroborate (0.613 g, 4.1 mmol) and N~ethyl~diisopropylamine (2
drops) in 3 mL of CH2C12 at 0 °C was added lactam (0.35 g, 2.1 mmol) in 1 mL of
CI-12C12. The the reaction mixture was stirred at room temperature for 2 h, cooled to 0
°C, and 5 mL of saturated NaHCO3 was added. The reaction mixture was stirred at 0 °C
for 10 min and the aqueous layer was extracted with 3 x 10 mL of CH2C12. The
combined organic layers were dried (N 82804) and filtered. The solvent was removed to
give crude lactim-ether 257. Without further purification, 257 was immediately
transformed into (:i:)~5~epipumi1iotoxin C. '

To a 1M solution of propylmagnesium chloride in Et20 (8.3 mL, 8.3 mmol) was
added 6.5 mL of dry benzene. The Et20 was removed by heating the reaction mixture at
80 °C under a stream of nitrogen. After the removal of Et20, the reaction mixture was
cooled to 45 °C, and 257 in 2 mL of benzene was added slowly. The flask was washed
with an additional 2 mL of benzene and the washing was added to the reaction flask. The
reaction mixture was heated at reflux for 6 h, cooled to 0 °C, and then 10 mL of saturated
aqueous NaHCO3 was added. The aqueous layer was extracted with 3 x 10 mL of
CHzClz. The combined organic layers were dried (N 82804), filtered, and concentrated
to give crude imine 258.

To a solution of crude 258 in 21 mL of CI-12C12 at 0 °C was added a 1 M solution
of DIBALH (10 mL, 10 mmol) in hexane and stirred at 0 °C for 2 h and- at room
temperature for 6 h. The reaction mixture was then cooled to 0 °C and quenched with 30
mL of MeOH and 15 mL of 15 % aq NaOH and stirred at room temperature for 30 min.

 

1r

122

The aqueous layer was then extracted with 3 x 20 ml. of CHzClz. The combined organic
layers were dried (Na2804), filtered, and concentrated to give a crude residue, which
was purified by flash column chromatography (eluent 80:20:2 Et20-Me0H-NH40H).
The solvents were evaporated to give (:t)~5-epipumiliotoxin C (259) as a viscous liquid in
33% yield for the three step-sequence. 1H NMR (300 MHz, CDC13) 5 0.88 (t. J = 6.9
Hz, 3 II), 0.98 (d, J = 6.9 Hz, 3 H), 1.14-1.76 (m, 17 II), 2.74 (m, 1 H), 2.84 (m, 1 II);
13C NMR (75.5 MHz. CDC13) 8 13.8, 19.1, 19.5, 21.3, 29.2, 30.9, 32.2, 34.1, 38.6, 39.6.
52.7, 55.2, 55.3; IR (neat) 2953, 2930, 2870, 1456, 1377, 1137.

 

 

123

REFERENCES

(1) (a) Daly, J. W.; Myers, C. E. Science 1967, 156, 970. (b) Daly, J. W.; Witkop, B.;
Tokuyama, T.; Nishikawa, T.; Karle, I. L. Helv. Chim Acta 1977, 60, 1128.

(2) Daly, J. W.; Tokuyama, T.; Haberrnehl, G.; Karle, I. L.; Witkop, B.; Ann. Chem.
1969, 729, 128.

(3) Daly, J. w. Fortschr. Chem. Org. Naturst. 1982,41, 206.

(4) (a) 0ppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60 204. (b) Schultz, A.

G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493. (c)
Overman, L. B.; Jessup, P. J. Am. Chem. Soc. 1978, 100, 5179. (d) Ibuka, T.;
Masaki, N.; Saji, 1.; Tanaka, K.; Inubushi, Y. Chem. Pharm. Bull. 1975, 23, 2779.
(e) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.;
Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 2831. (1') Brandi, A.; Cordero, F.
M.; Goti, A.; Guarna, A. Tetrahedron Lett. 1992, 33, 6697. (g) Polniaszek, R. P.;
Dillard, L. W. J. Org. Chem. 1992, 57, 4103. (h) LeBel, N. A.; Balasubramanian,
N. J. Am. Chem. Soc. 1989, III, 3363. (i) Abe, K.; Tsugoshi, T.; Nakamura, N.
Bull. Chem. Soc. Jpn. 1984, 57, 3351. (i) 0ppolzer, W.; Frostl, W.; Weber, H. P.
Helv. Chim. Acta. 1975,58, 593. (k) Murahashi, S.; Sasao, S.; Saito, B.; Naota, T.
J. Org. Chem. 1992, 57, 2521. (l) Haberrnehl, G.; Andres, H.; Miyahara, K.;
Witkop, B.; Daly, J. W. Ann. Chem. 1976, 1577. (m) 0ppolzer, W.; Fehr, C.;
Warneke, J. Helv. Chim. Acta 1977, 60 48. (n) Masamune, s.; Reed, L. 11.; Davis,
J. T.; Choy, W. J. Org. Chem. 1983, 48, 4441. (o) Bonin, M.; Besselievre, R.;
Grierson, D. S.; Husson, II. P. Tetrahedron Lett. 1983, 24, 1493. (p) Bonin, M.;
Royer, J.; Grierson, D. S.; Husson, H. P. Tetrahedron Lett. 1986, 27, 1569. (q)
Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1991, 32, 5697.

111-mam“...- '1

 

(5)

(6)
(7)

(8)

(9)

(10)
(11)

(12)

124

(a) Inubushi, V.; Ibuka, T. Heterocycles 1977 , 8, 633. (b) Daly, J. W.; Spande, F.
in Alkaloids; Chemical and Biological Perspectives; Pelletier, S. W.; Ed., Wiely:
New York, 1986, Vol 4, Chapter 1.

Chapter II, this thesis.
a) Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7777. b) Johnson, C.

R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7783. c) Lipshutz, B. H.; Wilhelm,
R. S. J. Am. Chem. Soc. 1981, 103, 7672. (d) Mori, K.; Sugai, T. Synthesis 1982,
752. (e) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.; Tetrahedron 1984,
40, 5005. (f) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.; Parker, D. J.
Org. Chem. 1984, 49, 3928. (g) Lipshutz, B. H.; Kozlowski, J.; Parker, D.;
Nguyen, S. L.; McCarthy, K. E. J. Organomet Chem. 1985, 285, 437. (h)
Lipshutz, B. H. Synthesis 1987, 325.

(a) Danishefsky, S.; Nagasawa, K.; Wang, N. J. Org. Chem. 1975, 40, 1989. (b)
Greenwald, R.; Chaykovsky, M.: Corey, E. J. J. Org. Chem. 1963, 28, 1128.

(a) Novak, J.; Salemink, C. A. Tetrahedron Lett. 1981, 22, 1063. (b) Magnus, P.;
Roy, G. Organometallics, 1982, I, 553. (c) Kende, A. S.; Blacklock, T. J.
Tetrahedron Lett. 1980, 21, 3119.

Hartwig, W. Tetrahedron 1983, 39, 2609.

Kochetkov, N. K.; Sviridov, A.F.; Yashunskii, D. V.; Ermolenko, M. S.;
Borodkin, V.S. Bull.Acad. Sci. USSR. 1986, 35, 408.

Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J. Am. Chem. Soc. 1972, 94,
5098

 

 

125

CHAPT ER IV

TOTAL SYNTHESIS OF
(i)~LUPDIINE AND (:t)~TASHIROMINE

 

‘F -. :1.
\

126
INTRODUCTION

a) Lupinine

Lupinine (3), one of the simplest lupin alkaloids, was initially isolated from
yellow lupin seeds by Cassolal in 1835, and was obtained in pure form by Baumert2 in
1881. Lupinine is present in numerous plants of the Lupinus family such as Lupinus
luteus, Lupinus niger and Lupinus palmeri.3 The absolute configuration of (~)~lupinine
(5R, 6R)~1~hydroxymethquuinolizidine was established by a number of methods. 1)
Degradation of (~)~lupinine to the optically active 4~methylnonane has the same sign of
rotation as the optically active 4~methylnonane obtained from natural sources.4 2)
During the chemical synthesis of dl-lupinine, establishment of asymmetric centers at GS
and C~6 by catalytic hydrogenation using platinum showed the cis relationship of the GS
and C~6 asymmetric centers.5 3) Spectroscopic methods have also been used to confirm
the absolute configuration of (~)~lupinine.6 Lupinine has little medicinal value, however
the p-aminobenzoate derivative has been shown to possess a marked local anesthetic

action.7

 

Since lupinine (3) is a simple quinolizidine alkaloid. This has been a target of
choice for demonstrating the applicability of developed methodology. Lupinine has been
prepared through several routes, and in most of the syntheses, the relative stereochemistry
of the two asymmetric centers has been established by reduction of either 260 or 261 to
give 262 (Scheme VII).8 Subsequent reduction of 262 with LiAlI-I4 was then used to
prepare lupinine (3). Alternatively, epimerization of 262 to 263, the more

thermodynamically stable isomer, followed by reduction to 264 provided a route to

 

127
epilupinine (264). In most of the reported total synthesis of lupinine, at least one of the

two heterocycle rings was already present in the starting material.

Scheme VII. General Routes for the Establishment of Lupinine (3) Stereochemistry.

 

 

 

00,13t CHZOH
6.3”“ 03 m CO
I ..
H29 Pt()2 EtOH N805!
00,10 CH,0H
CS5 C5 W“ 05
Epiupinine

In some cases, the two asymmetric centers were established, as in 265, prior to the
second ring formation which was then cyclized from the intermediate amino alcohol (eq
1).9

“g

 

CHQOH
! l. EtzNSIMeg
2. Me38il
NH 3. azMe,N*I= (1)
.OH
265 3

An intramolecular immonium ion based Diels-Alder reaction has also been used

to establish b0th stereocenters and quinolizidinine rings from the corresponding

 

 

128

immonium salt (eq 2).10 Compound 266 readily gave a separable mixture of Diels-Alder
adducts 267 and 268 in 82% yield in a ratio Of 1:1.6. -

 

(31120311 gnzoan CHZOBn
. 2 @305
¢ + N N
266 267 268
F
b) Tashiromine I

Tashiromine (269), an indolizidine alkaloid, was isolated along with

ammodendrine and seven other lupin alkaloids from the Maackia species, I

 

Maackia.tashiroi. Maackia.tashiroi is a deciduous shrub distributed widely in
subtropical Asia. 11 _

The stereochemistry of tashiromine was assigned by comparing 1H NMR and
13C NMR chemical shifts with epilupinine (3) and its cis diastereomer, lupinine (264)11
Synthetic samples of (i)~tashiromine (269) and its diastereomer, (1)-epitashiromine
(270), were prepared by catalytic hydrogenation of cyclohexapyrrole 271 (eq 3). The

synthetic and natural alkaloids were chromatographically and spectroscopically

indistinguishable.
CHQOH CH,0H (£11,011
HyPtoglACOH
———> 3
N 8 h N + CO ( )
45% 31%
271 269 270

An asymmetric synthesis of (~)~tashiromine has been reported by Nagao and
coworkers. 12 The synthesis of 269 involves a highly diastereoselective alkylation of

cyclic acyl imine 274 with a chiral tin (II) enolate 273, prepared from 272, to give 275

129
(Scheme VIII). Reduction of 275, followed by intramolecular annulation gave a mixture
of 276 and (~)~tashiromine (269). This is a short and comparatively efficient synthesis

and can be used to prepare various bicyclic alkaloids.

Scheme VIII. Asymmetric Synthesis of (~)~Tashiromine.

FCQfiO
3 \n

o 8 /Ҥ
Jk 0
GWLNL/s Sn(0802CF3)2 > C1 W14 $8

.\

 

ire
272 273
(Mm
274 NH
0
I
H CHRHI rayon

not:

 

%"
+
Z

22% 41%
276 269

 

In order to demonstrate the use of our aza—annulation methodology in indolizidine
and quinolizidine alkaloids synthesis, total synthesis of both (219-lupinine and (21:)-
tashiromine were undertaken with the following goals:

130
1) To utilize the aza-annulation methodology as the key step to prepare six-membered
lactams in high yield.
2) To utilize catalytic hydrogenation to generate cis stereocenters from the annulated

product.

131

RESULTS AND DISCUSSION

a) Total Synthesis of (2)-Lupinine (3)

The retrosynthetic analysis of (i)~lupinine is shown in Scheme IX. We hoped to
prepare 3 from the amino alcohol 277 via formation of a C~N bond followed by
desilylation. Compound 277 could be synthesized from 278 after reduction of the
enamine double bond, reduction of amide and ester functionality, protection of primary
alcohol and debenzylation. Lactam 278 could be readily obtained from aza-annulation of
the suitably tethered B-keto ester 279. B—Keto ester 279 should be readily prepared from
ethyl acetoacetate (176) and iodide 280. The retrosynthetic analysis of 3 shows the
importance of aza-annualtion methodology in the preparation of six-membered lactams
from acyclic substrates.

Scheme IX. Retrosynthetic Analysis of (:t)~Lupinine (3).

 

 

 

 

 

 

 

$H¢0II CirzorBDMs co,r~:t
05:) " GINO 3 BnN
3 on 27 7 03,, 2 78
o o L
mum core
176
+ c: O
Bn0/\/\1
280 OBn

279

 

132

The total synthesis of (1)-lupinine is shown in Scheme X. The required iodide
was prepared according to commonly used procedures (eq 4). The monoptotected
alcohol 284 was prepared from the corresponding diol 282 using Takano’s procedure.13
The alcohol 284 was converted into iodide 280 through the formation of a mesylate.14

 

 

l) PhCHO/p-TsOH 1) I
2) DIBAI/I‘oluene refl
ux
281 n=1 283 n=1 285 n=1
282 n=2 284 n=2 280 ll:

Alkylation of the dianion of ethyl acetoacetate (176) with iodide 280 at room
temperature gave the B—keto ester 279 in 66% yield. 15 Condensation of B—keto ester 279
with BnNH2 in benzene with a catalytic amount of p-TsOH, assisted by the azeotropic
removal of H20, gave the enamino ester 286. After removal of benzene, crude enamino
ester 286 was taken up in THF and treated with acryloyl chloride to give the annulated
product 278 in 86% yield in two-step procedure from B-keto ester 279. Catalytic
hydrogenation of 278 in the presence of N82C03 stereoselectively reduced the double
bond to give lactam 287 (cis:trans, >95:<5) in 92% yield. The presence of Na2CO3 is
crucial during the catalytic hydrogenation to avoid loss of O~benzyl protecting group.
Both the amide and the ester of 287 were reduced with excess LiAlH4 to give alcohol
288, which was protected as TBDMS ether 289 in 76% yield for the two step sequence.
Catalytic hydrogenation of 289 deprotected only the N~benzyl group to give 290. Even
after the addition of formic acid,16 hydrogenation for several days, and increasing the
amount Pd/C, the O-benzyl group was still present. The O-benzyl group was finally
removed using liquid NH3 and lithium metal at ~33 °C to give the amino alcohol 277.

133
Scheme X. The Total Synthesis of (:t)~l.upinine (3).

 

 

 

 

 

 

 

 

 

 

C0210 " 00,131”
C0 E 1) 1 eq. NaH
Me ‘ 2) 1 eq. n~BuLi_ BnNHyC6l-16_
\jH 3) I 7 o "flux/12 1| 7 NIan
0
l 7 6 OBn b OBn
OBn (66%)
280 27 9 286
co,lat co,1~:t F
45 psi H2 1 1) 8- LiAlHt
Acryloyl chloride: Pd/C/EIOH __ ____£_,b- WOW" 1
THF/66 °C/86% BnN Nazcosm h BnN 2) TBDMSCI
92% Imidazole
OBn O OBn O 68%
27 8 287
91120111 CH,OI'BDMs
1) Pd/C/Hp/MeOH : Ph3P/CBr4/NEt3 __

BnN 2) Li/NH3/66% RN 0 °C to r.t./63%

OBn OR2

288 R‘=H 290 R2=Bn

289 R‘srBDMs 277 stH

CHZOTBDMS 932011
i 8
Bu,N*1=‘/1Hr= ’
N 24 N63% N
291 ' (i)~L;pinine

Using Kibayashis’s coupling procedure, compound 277 was converted to 291 in
63% yield 17 Deprotection of 291 with TBAF gave (:t)~lupinine (3) in 63 71: yield. The
overall yield for this synthesis was 9.3%. The spectral data of 3 was consistent with
published In and 13C spectral data18

134

b) Total Synthesis of (1)-Tashiromine

The retrosynthetic analysis of (2)-tashiromine (269) is shown in Scheme X1.
According to the retrosynthetic scheme, thermodynamically more stable 269 should be
available from epitashiromine (270) after epimerization of the C~5 stereocenter.
Epitashiromine (270) could be obtained from 292 via C~N bond formation and
deprotection. Compound 292 could be synthesized from 293 after reduction of the
enamine double bond, ester and amide groups, protection of the primary alcohol and
debenzylation. Lactam 293 could be readily obtained after aza-annulation of suitably
tethered B-keto ester 294. The B~keto ester 294 should be readily prepared from ethyl
acetoacetate (176) and iodide 285.

Scheme XI. Retrosynthetic Analysis of (:t)~Tashiromine (269).

CH,0H €11,011 (impraDMs
Ci) = CO = ($3
(1)-Tashiromine (DJ-Epitashiromine 292
2 6 9 2 7 0

CHMOEI C0213! 00251

285 29‘ 293

 

135
Scheme XII. Total Synthesis of (i)~5~Epitashiromine

 

 

 

 

 

 

C Et C0281
C0251 1) 1 911- Na“ 02 1) BnNH2/C6116
MK") :) 1 “1 “3““ reflux/12 h _
o 2) Acryloyl chloride 7 BnN
”E OBn THF/66 °C/12 h 03"
OBn 75% 82% O
1 7 6 2 8 5 2 9 4 2 9 3
9021a OR1
45 psi H2 3 l) 11. 1.1.4111, €11,
PdlC/EIOH b. NaOH/II20 1) Pd/C/Hs/MeOH
——> p ’
Nazcojm h BnN 2) TBDMSCI BnN 2) 1.1/er3
90% 0311 lmidazole 0311 66%
o 68% -
296 R‘=H
295 297 1:1-moms
911201” c_:rl,0Rl
Pth/CBn/NEI3_ n13u,N*l='/rrll= _ _ . . .
(:90 CH2C12/55% ' C10 60% ' (i) S'Eplmhmm
0R2

298 112-Bu R‘sraDMs 299 R‘ar'aDMs

292 stH R‘ara DMs

According to the retrosynthetic analysis, (i)~5~epitashiromine was initially
prepared. The total synthesis (:t)~5~epitashiromine is shown in Scheme XII. The iodide
285 was prepared from ethylene glycol as shown in eq 4. Alkylation of the dianion of
176 with iodide 285 gave B-keto ester 294 in 75% yield. Aza-annulation of the B—keto
ester gave lactam 293 in 82% yield. Catalytic hydrogenation of 293 in the presence of
Na2CO3 stereoselectively reduced the double bond to give 295 (cis:trans, >98:2) in 90%
yield. Reduction of both amide and ester functional groups in 295 with excess LiAlH4
gave the corresponding amino alcohol 296, which was protected as the TBDMS ether 297
in 68% yield for the two-step sequence. Catalytic hydrogenation followed by Li/NHB

reduction gave amino alcohol 292 in 66% yield. Compound 292 was converted to 299

 

 

136
through the use of PPh3/CBr4/NEI3. Final removal of the TBDMS group on 299 gave
(jg-epitashiromine in 60% yield. The Spectral data of epitashiromine was consistent with
published In and 13C spectral data.“

The synthesis of (i)~epitashiromine was also approached through a simpler and
more efficient route (Scheme XIII). Instead of the aza-annulation of an acyclic enamino
ester, annulation was carried out on cyclic enamino ester 108 to give indolizidinone 110
in 87% yield. Catalytic hydrogenation 110 stereoselectively gave 201 (cis:trans, 95:5) in
95% yield. 19 Reduction of 201 with excess of LiAlI-I4 gave (1)-epitashiromine in 91%
yield. In this process, epitashiromine could be prepared on a large scale with a minimal
number of steps. The overall for the synthesis of (i)~5~epitashiromine from- 108 was
75%.

Scheme XIII. Alternate Synthesis of (:t)~5~Epitashiromine.
COzEt 90,13

04\ t Acryloyl chlaide’ I’d/112145 psi/EIOIL c?
N‘ C 0’5 THF/66 °C/12 h N Nazooam 1119591 N
H

87%

 

 

O O
108 110 201

LiAlI-IJI'HF
66 °C/6 h
91%

911,011

270

Once epitashiromine was prepared, attention was focussed on possible ways to

convert (2t)~5~epitashiromine (270) to (i)~tashiromine (269). In the case of 270, the 5-

 

137
hydroxymethyl is in a less stable axial position, and in 269 the S-hydroxymethyl is in a
more stable equatorial position. The transformation of 270 to tashiromine (269) is

shown in Scheme XIV.

Scheme XIV. Conversion of (134-Epitashiromine to (1)-Tashiromine.

O

 

 

 

 

 

912011 f 9H0
CO Swern oxidation 0:) PipcridineleHo
N ’ "
N N
(i)-S-Epitashirunine 300 301~
95:5 :53” Oxalicacid
' H20
Four steps
58% cnzon CHO
, ‘ LiAlHJI’I-IF
Clj r.t./10 h N
(:l:)-Tashiromine 302
cis:trans
>95:<5

In order to epimerize the 05 position in 270, the axial hydroxymethyl group to
equatorial hydroxymethyl, compound 270 was submitted to Swern oxidation conditions
to give aldehyde 300. Under the oxidation conditions, a considerable amount of the cis
aldehyde was epimerized giving a 60:40 mixture of cis and trans isomers. Enamine 301
was prepared from the condensation of crude 300 and piperidine in benzene assisted by

the azeotropic removal of H20. After removal of benzene, the crude enamine 301 was
hydrolyzed using oxalic acid and H20 to give trans aldehyde 302 as the major product
along with a trace of cis aldehyde.20 Reduction of the aldehyde with LiAlH4 gave (1:)
tashiromine in 58% overall yield from (:l:)-5-epitashiromine.

138

CONCLUSION

Total synthesis of (i)-lupinine, (1)-5-epitashiromine and (i)-tashiromine
demonstrated the efficiency of the aza-annulation for the transformation of suitably
tethered acyclic B—keto esters to bicyclic indolizidine or quinolizidine compounds. This
is one of the few approaches to prepare (:l:)-lupinine from an acyclic precursor. The key
transformations were the high yielding condensation and subsequent aza—annulation of
the resulting B-enamino ester. The less stable cis stereocenters were selectively
established by catalytic hydrogenation of the annulated lactams. Formation of the second
ring by making C-N bond from an alcohol and an amine using Ph3P/l'EA/CBr4 showed
the effectiveness of this reaction. This methodology opens a new door for the preparation

of a variety of alkaloids with different ring sizes.

139
EXPERIMENTAL SECTION

General Methods. All reactions were carried out under an atmosphere of either nitrogen
or argon. Toluene and tetrahydrofuran (DIP) were distilled from sodium/benzophenone
immediately prior to use. Triethylamine and dichloromethane were heated at reflux over
calcium hydride for a minimum of 12 h, and then distilled immediately prior to use.
Benzylamine and acryloyl chloride were obtained from Fluka and used without further
purification. TBDMSCl was obtained from Huls Co. Solutions of DIBALH (1.0 M in
hexane), and DIBALH (1.0 M in toluene) were prepared from neat DIBALH obtained
from Aldrich Chemical Co. n—Butyllithium (2.5 M in hexane) and LiAlH4 (1 M in THF)
were purchased from Aldrich Chemical Co. Methanesulfonyl chloride was purchased
from Aldrich Chemical Co., and distilled before use.

NMR Spectra were obtained on Varian Gemini 300 instrument with CDCl3 as the
solvent. Data are reported as follows: chemical shifts relative to residual CHC13 (7 .24
ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext =
sextet, sept = septet, b = broad), integration, and coupling. Infrared spectra were recorded
on a Nicolet 42 FI-IR instrument.

General Procedure for the Preparation of Monoprotected Aleohoh (283 and
284): A mixture of the desired diol (150 mmol), benzaldehyde (17.51 g, 165.0 mmol),
and p-TsOH (0.144 g, 0.8 mmol) was taken up in 90 mL of toluene, and heated at reflux
for 12 h using a modified Dean-Stark trap apparatus to azeotropically remove H20. The
reaction mixture was then cooled to 0 °C, and an additional 135 mL of toluene was
added. To the cooled reaction mixture was slowly added 3 M solution of DIBALH (62.5
mL, 187.5 mmol) in toluene and stirred at room temperature for 24 h. The reaction was
cooled to 0 °C and quenched with dropwise addition of 90 mL of MeOI-I followed by 90
ml. of 15% NaOH solution, and the solution was stirred for 1.5 h at room temperatm'e.
The aqueous layer was extracted with 5 x 200 mL of Et20, dried (Na2804), filtered,

 

 

 

140

concentrated, and distilled under vacuum to give the corresponding monoprotected
alcohol.
General Procedure for the Conversion of Alcohols to Iodides (285 and 280): To a
cooled (0 °C) solution of alcohol (124.20 mmol) and TEA (52.40 g, 496.7 mmol) in 1250
mL of BtzO was added methanesulfonyl chloride (42.70 g, 372.6 mmol) and stirred at 0
°C for 2 h and then at room temperature for 10 h. The reaction mixture was then washed
with 500 mL of saturated aqueous NH4C1 solution, and the aqueous layer was extracted
with 3 x 500 mL of Et20. The combined organic layers were washed with 1000 mL of
H20, dried (MgSO4), filtered, and the solvent was removed to give crude mesylate
which was used without further purification.

The crude mesylate and sodium iodide (83.8 g, 559.00 mmol) were taken up in
620 mL of acetone and heated at reflux for 24 h. The reaction was cooled to ambient
temperature, and 500 mL of Et20 and 500 mL of H20 were added. The aqueous layer
was extracted with 2 x 500 mL of Et20, and the combined organic layer was washed with
500 mL of satrnated Nazs 203 and 500 mL of saturated NaCl solution. The organic layer
was dried (Na2804), filtered, concentrated and distilled under vacuum to give the
corresponding iodides.
General Procedure for the Alkylation of Ethyl Acetoacetate (176): To a cooled (~
-20 °C) suspension of NaH (0.67 g, 28.0 mmol) in 28 mL of THF was dropwise added a
solution of ethyl acetoacetate (3.65 g, 28.0 mmol) in 6 mL of THF. The reaction mixture
was stirred at this temperature until all of the sodium hydride was consumed (~15 min).
To this clear solution was slowly added 2.5 M n-BuLi solution (11.20 mL, 28.0 mmol) in
hexane to give an orange solution which was stirred at 0 °C for 15 min. A solution of the
iodide (23.34 mmol) in 6 mL of THF was added dropwise, and the flask was rinsed with
an additional 1 mL of THF. The solution was stirred at 0 °C for 1.5 h, and the
temperature was allowed to warm to room temperature and stirred for an additional 12 h.

The reaction mixture was quenched with 30 mL of saturated aqueous NH4C1 solution and

 

 

141
the aqueous layer was extracted with 4 x 50 mL of Et20. The combined organic layers
were dried (Na2804), filtered and concentrated to give a crude residue. The crude
residue was purified by flash column chromatography (eluent: 80:20 hexane-Et20 or
85:15 petroleum ether-Et20).

279: 1H NMR (300 MHz. CDC13) 8 1.28 (t, J = 7.1 Hz, 3 H),1.56-1.77(m, 4 H), 2.57 (t,
J = 7.1 Hz, 2 H), 3.42 (s, 2 H), 3.48 (t, J = 6.1Hz. 2 H), 4.19 (q, I = 7.1 Hz, 2 H), 4.49 (s,
2 H), 7.26-7.35 (m, 5 H); 13c NMR (75.5 MHz. CDC13) 5 14.1, 20.3, 29.0, 42.6, 49.2,
61.3, 69.9, 72.9, 127.5, 127.6, 128.4, 138.5, 167.3, 202.7; IR (neat) 3065, 3032,2982,
2940, 2863, 1746, 1717, 1647, 1455, 1412, 1368, 1316, 1028 can-1; HRMS calcd for
C15H22NO4 m/z 278.1517, found m/z 278.1512.

294: 1H NMR (300 MHz. CDC13)81.27(t, J = 7.1 Hz, 3 H), 1.92 (quint, J = 6.1 Hz, 2
H), 2.67 (t,J=7.1 Hz,2H), 3.44 (s,2H), 3.50 (t,J=6.l 112,211), 4.19 (q,J=7.1 Hz,2
H), 4.48 (s, 2 H), 7.27-7.39 (m, 5 H); 13c NMR (75.5 MHz. coc13) 8 13.6, 23.2, 39.3,
48.9, 60.9, 68.6, 72.4, 127.1, 127.2, 127.9, 137.9, 166.8, 202.2; IR (neat) 3065, 3032,
2982, 2936, 2865, 1743, 1715, 1647, 1455, 1368, 1314 cm-1.

General Procedure for Ant-Annulation: A mixture of benzylamine (1.90 g, 17.7
mmol), the corresponding B-keto ester (16.07 mmol) and p-TsOH (0.152 g, 0.80 mmol)

in 107 mL of benzene was heated at reflux for 12 h. The generated H20 was
azeotropically removed from the reaction mixture using modified Dean-Stark trap
apparatus filled with 4—A molecular sieves. The reaction mixture was then cooled to
room temperature and concentrated to give the crude enamino ester which was used for
annulation without flu'ther purification. Acryloyl chloride (1.89 g, 20.9 mmol) was added
to a solution of the crude enamino ester in 107 m1. of THF, and the reaction mixture was
heated at reflux for 12 h. After the reaction was complete, the solution was washed with
40 mL of saturated aqueous N aHCO3 solution. The aqueous layer was extracted with 4 x
30 mL of CH2C12, and the combined organic layers were dried (Na2SO4), filtered and

concentrated to give the crude residue. The crude residue was purified by flash column

 

 

 

142
chromatography (eluent: 65:35 hexane-Et20 or 60:40 petroleum ether-Et20). The
solvents were evaporated to give the corresponding lactam.

278: 1H NMR (300 MHz. CDC13)51.29(t, J = 7.1 Hz, 3 H), 1.50-1.70011, 4 H),
2.54270 ([11, 4 H), 2.77 (bt, J = 7.5 Hz, 2 H), 3.46 (t, J =6.2 Hz, 2 H), 4.18 (q, J = 7.1
Hz, 2 H), 4.50 (s, 2 H), 5.10 (bs, 2 H), 7.10 (bd, J= 7.1Hz. 2 H), 7.20-7.38 (m, 8 H); 13c
NMR (75.5 MHz. CDC13) 5 13.9, 20.8, 25.4, 28.1, 28.9, 31.1, 44.0, 59.9, 69.3, 72.5,
109.4, 125.7, 126.7, 127.1, 127.2, 127.9, 128.3, 137.3, 138.0, 152.0, 166.7, 171.2; IR
(neat) 3088, 3063, 3031, 2978,2938, 2861, 1688, 1617, 1497, 1455, 1372, 1271, 1119
om-l; HRMS calcd for C25H31NO4 m/z 421.2252, found m/z 421.2262.

293: 1H NMR (300 MHz. CDC13)51.28(t, J= 7.1 Hz. 3 H),1.81 (m, 2 H), 2.57

(m, 2 H), 2.66 (m, 2 H), 2.86 (m, 2 10.3.55 (t, J= 5.9 Hz, 2 H), 4.16 (q,J a 7.1Hz, 2 H),
4.49 (s, 2 H), 5.06 (s, 2 H), 7.07 (bd, J = 8.1 Hz, 2 H), 7.18—7.38 (m, 8 H); 13c NMR
(75.5 MHz. CDC13) 5 13.8, 20.8, 25.6, 28.8, 31.1, 43.7, 59.9, 69.1, 72.6, 109.3. 125.8,
126.6, 127.2, 127.3, 127.9, 128.2, 137.4, 138.0, 151.9, 166.8, 171.2; IR (neat) 3088,
3063, 3032, 2978,2855, 1688, 1617,1497, 1455, 1372, 1271 cut-1.
General procedure for the Hydrogenation of Lactams: A solution of the lactam (6.2
g, 14.72 mmol), and Na2CO3 (5.42 g, 51.51 mmol) in 196 mL of BtOI-I was
hydrogenated at 45 psi over 10% Pd/C (1.5 g) for 24 h. The catalyst and Na2CO3 were
removed by filtration, and the residue was washed with 01202. The combined filtrate
and washings were concentrated to give a crude residue, which was redissolved in
CI-12C12 and filtered. Concentration of the filtrate and washings gave the corresponding
reduced lactam as a viscous liquid.

287: 1H NMR (300 MHz. CDC13) 5 1.20 (t, J = 7.2 Hz, 3 H), 130171 (m, 6H),
2.00-2.24 (m, 2 H), 2.46-2.68 (m, 2H), 2.75 (dt, J = 12.6, 4.6 Hz. 1 H), 3.43 (t, J = 6.2
Hz, 2 H), 3.71 (q, J = 5.2 Hz, 1 H), 3.90 (d. J = 15.1 Hz, 1 H), 3.98-4.18 (m, 2 H), 4.49
(s, 2 H), 5.41 (d, J = 15.1 Hz, 1 H), 7.22-7.40 (m, 10 H); 13C NMR (75.5 MHz, CDC13)
5 13.6, 18.2, 24.0, 29.4, 29.5, 31.4, 43.6, 49.3, 56.4, 60.5, 69.3, 72.5, 127.0, 127.1, 127.2,

143
127.4 127.9, 128.2, 136.8, 138.0, 169.1, 171.2; IR (neat) 3088, 3063, 3030, 2940, 2865,
1732, 1646, 1497, 1452, 1234, 1163 cm-l; HRMS calcd for C25H33NO4 m/z 423.2409,
found m/z 423.2446.

295: 1H NMR (300 MHz. @013) 5 1.20 (t. J = 7.1 Hz, 3 H), 1.55-1.74 (m, 4 H),

2.00-2.24 (m, 2 H), 2.53 (dd, J = 18.4, 8.8 Hz, 1 H), 2.64 (ddd, J = 18.4, 8.3, 3.3 Hz, 1
H), 2.76 (dt, J = 12.4, 4.6 Hz, 1 H), 3.38-3.43 (m, 2 H), 3.75 (bq, J = 4.5 Hz, 1- H), 3.91
(d, J: 15.1 Hz, 1 H), 4.04415 (m, 2 H), 4.48 (s, 2 H), 5.40 (d, J =15.1Hz,1H), 7.20-
7.39 (m, 10 H); 13c NMR (75.5 MHz. CDC13) 5 13.6, 18.3, 27.3, 28.1, 29.4, 43.6, 49.2,
56.3, 60.5, 69.4, 72.5, 126.9, 127.2, 127.4, 127.9, 128.2, 136.8, 137.9, 169.1, 171.1; IR
(neat) 3031, 2955, 1732, 1644, 1468, 1453, 1237 cm-1.
General Procedure for the Preparation of Silyl Ethers: To a solution of the lactam
(14.81 mmol) in 59 mL of THF at 0 °C was slowly added 1.0 M solution of LiAlH4
solution (59.25 mL, 59.25 mmol) in THF, and the reaction mixture was heated at reflux
for 12 h. The solution was cooled to 0 °C and quenched by the sequential addition of 2.3
mL of H20, 2.3 ml. of 15% w/v aqueous NaOH, and 6.9 mL of H20. After stirring for 1
h at room temperature, the aluminum salts were removed by filtration, and the combined
filtrate and washings were dried (N a2804), filtered and concentrated to give the crude
alcohol, which was used without pm'ification.

A mixture of the crude alcohol (14.81 mmol), imidazole (2.52 g, 37.03 mmol) and
tert-butyldimethylsilyl chloride (2.68 g, 17.77 mmol) in 23 mL of DMF was stirred at
room temperature for 12 h. The reaction mixture was washed with 25 mL of saturated
aqueous NaHCO3 solution. The aqueous layer was extracted with 4 x 30 mL of Et20,
and the organic fractions were washed with 50 m1. of H20 and dried over MgSO4.
Following concentration of the solution, the residue was purified by flash column
chromatography (eluent: 40:60 Et20-hexane or 200:800:13 Et20-petroleum ether-
NH40H). The solvents were evaporated to give the corresponding silyl ether.

 

144

289: 1H NMR (300 MHz. CDC13) 5 0.03 (s, 3 H), 0.04 (s, 3 H), 0.87 (s, 9 H),
1.01-1.42 (m, 4 H), 1.43-1.69 (m, 6 H), 2.09 (m, l H), 2.43 (dt, J = 13.2, 3.3 Hz, 1 H),
2.62 (td, J = 12.6, 3.3 Hz, 1 H), 2.74 (m, 1 H), 3.40-3.50 (m, 2 H), 3.73 (s, 2 H), 4.51 (s, 2
H), 7.20-7.37 (m, 10 H); 13C NMR (75.5 MHz. CDC13) 8 -5.8, -5.7, 17.8, 21.7, 22.9,
23.6, 24.1, 25.5, 29.7, 38.6, 45.5, 57.8, 58.6, 64.6, 70.2, 72.5, 126.1, 127.0, 127.2, 127.6,
127.9, 128.2, 138.3, 140.3; IR (neat) 3087, 3063, 3029, 2932, 2857, 2795, 1495, 1472,
1360, 1256, 1103 om-l; HRMS calcd for C3()H47N028i m/z 481.3376, found m/z
481.3351.

297: 1H NMR (300 MHz. CDC13)8-0.1 (s, 3 H), 0.1 (s, 3 H), 0.84 (s, 9 H), 1.10

1.42 (m, 2 H), 1.46-1.80 (m, 6 H), 2.07 (m, 1 H), 2.36-2.50 (m, 1 H), 2.56-2.78 (m, 2 H),
3.41 (m, 4 H), 3.72 (s, 2 H), 4.46 (s, 2 H), 7.22-7.34 (m, 10 H); 13c NMR (75.5 MHz.
CDC13) 8 -5.8, -5.7, 17.8, 20.2, 21.4, 22.8, 25.5, 27.4, 38.3, 45.3, 57.7, 58.1, 64.7, 70.3,
72.3, 126.2, 127.0, 127.2, 127.6, 127.9, 128.3, 138.4, 140.2; IR (neat) 3087, 3063, 3029,
2928,2857, 1495. 1472, 1362, 1256, 1101 cm-1.
General Procedure for the Preparation of Amino Alcohols: A solution of silyl ether
(5.874 g, 11.81 mmol) in 120 mL of MeOH was hydrogenated at 45 psi over 10% Pd-C
(2.3 g), for 24 h. The catalyst was removed by filtration, and the combined filtrate and
washings were concentrated to give the crude deprotected amine, which was used for
Li/NH3 reduction with out further purification.

Thecrudeaminein35 mLof'I'HFwasaddedtoliquid ammonia(300-350mL)at
-78 °C. Small pieces of lithium rod were added slowly to generate a dark blue color. The
dry ice bath was removed, and the reaction mixture was stirred for 2 h at -33 °C. The
reaction mixture was then cooled to -78 °C and quenched by adding solid NH4C1.
Ammonia was evaporated overnight to give a white solid. The white solid was dissolved
in MeOH and transferred into a round bottom flask. The solvent was removed to give a
residue, and the residue was re dissolved in CHsz and filtered to remove the insoluble

inorganic salts. The filtrate was evaporated to give the crude amino alcohol which was

 

145
purified by flash column chromatography (eluent: 15:85 MeOH-CHzClz or 10:90
MeOH-CHzClz). The solvent was evaporated to give amino alcohol.

277: 1H NMR (300 MHz. CDC13) 5 0.07 (s, 3 H), 0.08 (s, 3 H), 0.89 (s, 9 H),
1.48-1.81 (m, 6 H), 1.82-1.98 (m, 2 H), 2.20-2.50 (m, 3 H), 3.10-3.20 (m, 2 H), 3.48 (m,
1 H), 3.59-3.80 (m, 4 H), 8.44 (bs, 1 H), 9.64 (bs, 1 H); 13C NMR (75.5 MHz. CD03) 5
-6.0, -5.9, 17.6, 19.6, 21.8, 22.0, 25.4, 25.5, 31.2, 37.2, 41.0, 55.6, 61.0, 61.7; IR (neat)
3357, 2934, 2858, 2812, 1584, 1472, 1258, 1094 cm-1; HRMS calcd for C15H37N02Si
m/z 303.2593, found m/z 303.2523.

292: 1H NMR (300 MHz. CDC13) 5 0.05 (s, 3 H), 0.07 (s, 3 H), 0.87 (s, 9 H),

1.51-1.62 (m, 2 H), 1.68-2.0 (m, 5 H), 2.26-2.38 (m, 1 H), 3.06-3.22 (m, 2 H), 3.53-3.83
(m, 6 H), 8.73 (bs, 1 H), 9.60 (bs, 1 H); 13C NMR (75.5 MHz. CD03) 5 -6.0, -5.9, 17.6,
19.8, 21.7, 23.2, 25.4, 28.4, 37.5, 40.6, 55.3, 61.1, 61.9; IR (KBr) 3449, 3248, 2955.
2856, 2804, 1584, 1471, 1258, 1092 out-1-
General Procedure for the Preparation of Bicyclic Compounds (291 and 299): To a
solution of amino alcohol (0.614 mmol), and CBr4 (0.255 g, 0.768 mmol) in 2.5 mL of
CHzClz at 0 °C was added Ph3P (0.242 g, 0.921 mmol), and the reaction mixture was
stirred at this temperature for 1 h. TEA (1.043 g, 9.824 mmol) was then added at 0 °C
and stirred for 30 min and the reaction was allowed to warm to room temperature and
stirred for an additional 30 min. The solvent was then removed to give a crude solid,
which was washed with 5 x 25 mL of petroleum ether. Following concentration of the
petroleum ether washings, the residue was purified by flash column chromatography
(eluent: 100:1.5 Et20-NH40H or 20:80:].3 petroleum ether-Etzo-NH40H). The
solvents were evaporated to give the corresponding bicyclic compounds.

291: 1H NMR (300 MHz. CDC13) 50.05 (s, 6 H), 0.89 (s, 9 H), 1.15-1.35 (m, 2
H), 1.36-1.59 (m, 4 H), 1.65-1.81 (m, 3 H), 1.87-2.04 (m, 3 H), 2.76-2.86 (m, 2 H), 3.71
(t, J = 9.8 Hz, 1 H), 3.82 (dd, J = 9.8, 5.2 Hz, 1 H); 13C NMR (75.5 MHz. CD03) 5 -5.7,

 

146
17.8, 20.6, 24.8, 25.1, 25.5, 25.6, 29.2, 40.7, 56.6, 57.2, 60.5, 64.3; IR (neat) 2932, 2857,
2803,2759, 1472, 1464, 1445, 1256 cm-l.

299: 1H NMR (300 MHz. CDC13) 5 0.04 (s, 6 H), 0.88 (s, 9 H), 1.162.26 (m, 12

H), 2.93-3.03 (m, 2 H), 3.64 (dd J = 10.0, 8.2 Hz, 1 H), 3.78 (dd, J = 10.0, 5.4 Hz, 1 H);
13C NMR (75.5 MHz. CDC13) 8 -5.8, 17.8, 20.2, 21.1, 24.8, 25.2, 25.5, 37.9, 52.9, 54.5,
60.8, 65.2.
General Procedure for the Deprotection of Silyl Ethers (291 and 299): To a solution
of silyl ether (0.335 g, 1.112 mmol) in 4 mL of THF was added 2.2 ml of 1 M solution of
TBAF (2.2 mmol) in THF, and stirred at room temperature for 24 h. The reaction
mixture was then washed with 5 mL of 10% aqueous NaOH. The aqueous layer was
extracted with 4 x 15 mL of EtOAc,. and the combined organic layers were dried over
(Na2804), filtered, and concentrated to give a crude residue. The crude residue was
purified by flash column chromatography (eluent: 90:10:15 Et20-MeOH-NH40H or
80:20:1.5 Et20-MeOH-NH40H) to give the corresponding alcohol.

3; 1H NMR (300 MHz. CD03) 5 1.25 (tn, 1 H), l.46-1.64(m,6 H), 1.66-1.94
(m, 4 H), 1.95-2.22 (m, 3 H), 2.78-2.85 (m, 2 H), 3.67 (d, J = 10.9 Hz, 1 H), 4.11 (ddd, J
= 10.9, 3.7, 1.7 Hz, 1 H); 13C NMR (75.5 MHz. CD03) 5 22.8, 24.6, 25.5, 29.6, 31.1,
38.3, 57.1, 65.0, 65.6: IR (neat) 3370, 2934, 2859, 2807, 2764, 1445, 1352 cm'l.

270: 1H NMR (300 MHz. CD03) 5 1.45-1.63 (m, 2 H), 1.64-1.91 (m, 6 H),
1.92-2.13 (m, 3 H), 2.21-2.32 (m, 1 H), 2.94-3.03 (m, 1 H), 3.05-3.13 (m, 1 H), 3. 71 (dd,
J = 10.8, 1.2 Hz, 1 H), 4.14 (ddd, J = 10.8, 4.2, 1.2 Hz, 1 H); 13C NMR (75.5 MHz.
CDC13) 8 20.7, 22.9, 25.6, 29.6, 35.7, 53.4, 54.4, 64.5, 66.5; IR (neat) 3370, 2934, 2787,
2730, 1447, 1379, 1327 cm-1.

Preparation of (:t)-5-Epitashiromine (270) from Lactam (201): To a solution of
lactam 201 (1.11 g, 5.23 mmol) in 26 mL ofTHF at 0 °C was slowly added 1 M solution
of LiAlH4 (13.10 mL, 13.10 mmol) and the solution was heated at reflux for 6 h. The

reaction mixture was cooled to 0 °C, and quenched by the sequential addition of 0.5 mL

 

147

of H20, 0.5 ml. of 15% w/v aqueous NaOH. and 1.5 ml. of H20. After stirring for l h at
room temperature, the aluminum salts were removed by filtration, and the combined
filtrate and washings were dried (Na2SO4), filtered and concentrated to give (i)-5-
epitashiromine (292) in 91% yield.

Conversion of (i)-5-Epitashiromine (292) to Tashiromine (269): To a cooled (-65 to
—70 °C) solution of oxalyl chloride (0.9105 g, 7.173 mmol) in 13 ml. of CH2C12 was
slowly added a solution of DMSO (1.821 g, 14.35 mmol) in 3 ml. of CI-12C12. The
reaction mixture was stirred at this temperature for 10 min. A solution of the alcohol in
12 mL of CHsz was added slowly, and the reaction was stirred for 45 min at -50 to -60
°C. TEA (2.90 g, 28.69 mmol) was added to the reaction mixture and stirred at 50 to -60
°C for 20 min, and the temperature was allowed to warm to room temperature, and stirred
at this temperature for an additional 1 h. At this point, 30 mL of H20 was added and
stirred for l h. The aqueous layer was extracted with 4 x 25 mL of CI-12C12 and the
combined organic layers were dried (Na2804), filtered, and concentrated to give the
crude aldehyde. A mixture of crude aldehyde (4.78 mmol), piperidine (0.45 g, 5.26
mmol) and p-TsOH (0.005 g, 0.024 mmol) in 32 mL of benzene was heated at reflux for
10 h using a modified Dean-Stark trap filled with 4eA molecular sieves to azeotropically
remove H20. The solution was then cooled to room temperature and concentrated to give
the crude enamine 301. To a solution of 301 in 8 ml. of CHzClz was added a solution of
oxalic acid dihydrate (0.63 g) in 5 ml. of H20. The reaction mixture was stirred at room
temperature for 4 h and heated at reflux for 1 h. The reaction was cooled to room
temperature, and 10 ml. of H20, 15 m1. of CH2C12 and 10 m1. of 15% aq NaOH were
added and stirred for 30 min. The aqueous layer was extracted with 4 x 20 mL of
CHzClz, and the combined organic layers were dried (Na2SO4), filtered, and
concentrated to give the crude aldehyde. To a solution of the crude aldehyde (4.78
mmol) in 19 mL of THF at 0 °C, was slowly added 1 M solution of LiAlH4 (7.20 mL,

7.20 mmol) in THF and the solution was stirred at room temperature for 6 h. The solution

 

148

was cooled to 0 °C and quenched by the sequential addition of 0.27 mL of H20, 0.27 mL
of 15% w/v aqueous NaOH, and 0.82 mL of H20. After stirring for l h at room
temperature, the aluminum salts were removed by filtration, and the combined filtrate and
washings were dried (Na2S O4), filtered, and concentrated to give a crude residue, which
was purified by flash column chromatography (eluent: 85:15:2 Et20-MeOH-NH40H).
The solvents were evaporated to give (:t)-tashiromine (269) in 58% yield from (1)-5-
epitashiromine (292).

269: 1H NMR (300 MHz. CD03) 5 1.01 (qd. J = 12.7, 4.7 Hz, 1 H), 1.36-1.97
(m, 10 H), 2.03 (q, J = 9.0 Hz, 1 H), 2.98-3.10 (m, 2 H), 3.44 (dd, J = 10.8, 6.3 Hz, 1 H),
3.67 (dd, J = 10.8, 4.6 Hz, 1 H); 13C NMR (75.5 MHz. CDC13) 5 20.2, 24.6, 27.2, 28.5,
44.1, 52.2, 53.7, 64.6, 66.0; IR (neat) 3374, 2932, 2793, 1462, 1445, 1385, 1331, 1279

cm'l.

 

149

 

 

 

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