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LIBRARY
Michigan State
University

 

 

 

This is to certify that the

dissertation entitled

Studies Toward the Stereoselective Construction of
Steroidal Sidechains Using a Novel Reaction of
Dichloroketene With Epoxy Olefins
Part II: Cyclobutanones as Precursors for

Reactive Dienes
presented by

Usha V. Ramesh

has been accepted towards fulfillment
of the requirements for

Ph . D . degree in (:hemiszrx

‘

WW ~ W
1/ / W W

I Major professor

Date 11/19/87

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

 

 

 

 

 

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PART I

STUDIES TOWARD THE STEREOSELECTIVE SYNTHESIS OF STEROIDAL SIDE CHAINS
BY A NOVEL REACTION OF DICHLOROKET ENE WITH EPOXY OLEFINS.

PART II

STUDIES OF CYCLOBUTANONES AS PRECURSORS FOR REACTIVE DIENES

USHAV. RAMESH

A DISSERTATIION

SLbrmedb
Michigan State University
in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1 988.

ABSTRACT

PART I
STUDIES TOWARD THE STEREOSELECTIVE SYNTHESIS OF STEROIDAL SIDE CHAINS
BY A NOVEL REACTION OF DICHLOROKETENE WITH EPOXY OLEFINS.
PART II
STUDIES OF CYCLOBUTANONES AS PRECURSORS FOR REACTIVE DIENES.

By
USHA v. RAMESH.

16a,17u -epoxypregnenolone acetate gave the corresponding methylene
derivative 4 on Wittig reaction. Reaction of 4 with dichloroketene yielded
(20R) - 23,23 - dichloro - 5- cholen - 24,20 - lactone - 3p - acetate 6, via a novel
and unprecedented rearrangement. Dechlorination of 6 with zinc gave (20R)
— 5 - cholen - 24,20 - lactone - 30 - acetate, 8. Selective dechlorination of 6 with
tributyltin hydride gave (20R) - 23a - chloro - 5 - cholen - 24,20 - lactone - Sp -
acetate.

 

8 4 6

Reaction of 4 with dichloroketene gave the allyl chloride 12 as an early

product. Further reaction of allyl chloride 12 with dichloroketene gave the

five membered lactone 6. The mechanism of this rearrangement reaction was
explored. There is strong evidence of the intermediacy of seven membered
lactone 5 in the conversion of 4 to 6. This unique 1,3-oxygen shift of
lactones such as 5 was confirmed by preparation of a similar compound 20
and study of its behaviour under conditions similar to the conversion of 4 to
6. Compound 20 was prepared from the allyl chloride 12 by an alkylation
with dimethyl malonate. The seven membered lactone of 20 undenNent a
rearrangement via a 1,3-suprafacial oxygen shift on treatment with
dichloroketene. On hydrolysis and decarboxylation of the product 26, the
lactone 28 was obtained. This compound was identical in every respect to

the compound obtained by hydrolysis of 8.

 

PART II

Cyclobutanones were prepared in high yield utilizing the 211 +211

cycloaddition reaction of dichloroketene to olefins. These were converted to

the corresponding silylenol ethers in almost quantitative yields. The silylenol
ethers were isolated and characterized. Thermolysis of silylenol ether 4 was
accomplished and the diene thus generated, was trapped by benzophenone
to yield a Diels Alder adduct. cup - unsaturated ester 9, was prepared in six

steps from 3,3-dimethyl glutaric acid.

4

° MeaSiOW
More 051

9 1 1
a CI
OW 0%
COgEI
\ OEt \
1 e 1 9

Reaction of 9 with dichloroketene yielded the cycloadduct 18. Cyclobutanone
19 was selectively converted to the silylenol ether 11. Thermolysis of 11
failed to yield the expected Diels Alder adduct. Attempted Lewis acid
catalyzed intramolecular Michael reaction of 11 also failed to yield the
expected Michael adduct resulting instead in the recovery of cyclobutanone
19. 11 underwent intermolecular Michael reaction with benzylidene

acetophenone (chalcone) when activated by Lewis acids.

DEDICATION

to

My father, whose love and support made this possible

and

My husband Ramesh, whose love and understanding makes it

all worthwhile

ACKNOWLEDGEMENTS

I wish to express my sincere appreciation to Professor William H. Reusch
for his guidance and encouragement throughout the course of this work.

I am very grateful to my sister Shanta, brother-in-law Raja and nephew
Prakash for their help, support and warm hospitality. They opened their home
to me and made my stay in Lansing an extremely pleasant and happy one.
i could not have made it without their help. I would also like to thank my
parents Lakshmi and RV. lyer for being there. . .. all the time. They gave me
the oppurtunities and freedom that they never had. Special thanks to the
Reusch group, especially Balan and Ed for being good friends and great
coworkers.

My warmest thanks and appreciation to Ramesh, for his endless
patience and understanding over the last two years. Without his love, support
and encouragement, this work would not have been possible. He was
always there to cheer me up and motivate me when things get tough. Finally
I would like to thank Michigan State University for financial assistance

without which my stay in this country would have been impossible.

TABLEOFCONTENTS

Chapter ................................................................... .Page
LIST OF FIGURES ............................................................. vii
PARTI
INTRODUCTION .............................................................. .1
RESULTS AND DISCUSSION .................................................. 15
EXPERIMENTAL .............................................................. 43
General ................................................................... 43
Wrttig reaction of 16a,17a-epoxy-
pregnenolone acetate 3 ............................................ 44
Reaction of epoxyolefin 4 with
dichloroketene ........................................................ 45
Dechlorination of 6 with tn'butyl
tin hydride ............................................................ 46
Dechlorination of 6 with zinc ........................................ 47
Reduction of 8 with Diisobutyl
Aluminum hydride .................................................... 48
Reduction of 8 with LAH ............................................. 49
Preparation of 23 .................................................... 50
Preparation of allyl chloride 12 .................................... 50
Preparation of hydroxy ether 33 .................................. 51
Preparation of the diacetate 10 .................................... 52
Reduction of 12 with LAH ........................................... 53
Hydrolysis of 12 with KOH ......................................... 53
Oxidation of 12 with PCC .......................................... 54

iii

Alkylation of 12 with diethyl

malonate ............................................................ 54
Alkylation of 12 with dimethyl
malonate ............................................................ 55
Rearrangement of 20 to 21 ........................................ 56
Hydrolysis and decarboxylation
of 21 to 23 ........................................................ .57
APPENDIX I : SPECTRA PART I ................................................ 58
REFERENCES ............................................................... 12
PART II
INTRODUCTION .............................................................. 128
RESULTS AND DISCUSSION .................................................. 138
EXPERIMENTAL ............................................................. 151
GENERAL .............................................................. 151
Preparation of 2,2—dichloro-3-methyl
cyclobutanone 2 ................................................... 152
Preparation of 3-hexyl cyclobutanone 3 .......................... 152
Preparation of silyl enol ether 4 .................................. 153
Pyrolysis of 4 and its Diels Alder
reaction ............................................................. 154
Preparation of 5-hydroxy-3,3-Dimethyl
pentanoic acid lactone 14 ........................................ 155
Preparation of 2-hydroxy-4,4-dimethyl
tetrahydropyran 15 ................................................. 155
Preparation of Ethyl 7-hydroxy-5,5-
dimethylhept-Z-enoate 16 ......................................... 156
Preparation of Ethyl-7-oxo-5,5-dimethylhept
-2-enoate 17 ....................................................... 157
Preparation of Ethyl-5,5-dimethyl oct-
2,7-dien-oate 9 .................................................... 157
Addition of dichloroketene to olefin 9 .......................... 158
Preparation of compound 19 .................................... 159

iv

Preparation of silyl enol ether 11 ............................... 160
APPENDIX II : SPECTRA PART II ................................................ 162
REFERENCES ................................................................. 215

LIST OF FIGURES

Figure P899

Figure I - #

1.

95.01998)

10.
11.
12.
13.
14.
15.
16.
17.
18.

19.

IR of 21 .......................................................... 59
Mass spectnrm of 4 ............................................... 60
IR of 4 ............................................................ 61
IR of 6 ............................................................ 62
IR of 6 ........................................................... 63
C- 13 NMR of 6 .................................................. 64
0RD 0-13 of 6 .................................................. 65
Proton NMR of 6 ................................................. 66
Mass spectnim of 6 .............................................. .67
Proton NMR of 4 ................................................. 68
0-13 NMR of 4 .................................................. 69
0RD C-13 NMR of 4 .............................................. 70
C-13 NMR of 8 .................................................. 71
Proton NMR of 8 ................................................ 72
Mass spectrum of 8 .............................................. .73
IR of 8 .......................................................... 74
IR of 8 .......................................................... 75
C—13 NMR of 12 ................................................. 76
Proton NMR of 12 ................................................ 77

vi

20 ORD C-13 NMR of 12 ............................................ .78

21. Mass spectrum of 12 ............................................ .79
22. IR of 12 ....................................................... 80
23. Proton NMR of 7 ................................................ .81
24. 0-13 NMR of 7 .................................................. 82
25. Mass spectrum of 7 .............................................. 83
26. IR of 7 .......................................................... 84
27. 0-13 NMR of 9 .................................................. 85
28. Proton NMR of 9 ................................................. 86
29 Mass spectrum of 9 .............................................. 87
30. IR of 9 .......................................................... 88
31. C-13 NMR of 10 ................................................. 89
32. Proton NMR of 10 ................................................ 90
33. Mass spectmm of 10 ............................................. .91
34. IR of 10 ........................................................ 92
35. Proton NMR of 17 ................................................ 93
36. Proton NMR of 14 ............................................... .94
37. C-13 NMR of 14 ................................................. 95
38. IR of 14 ........................................................ 96
39. Mass spectrum of 14 .............................................. 97
40. Mass spectnrm of 17 ............................................. .98
41. C-13 NMR of 11 ................................................. 99
42. IR of 11 ....................................................... 100

vii

43. Mass spectrum of 11 ............................................. 101
44. Proton NMR of 11 ............................................... 102
45. Proton NMR of 13 ............................................... 103
46. IR of 13 ....................................................... 104
47. Proton NMR of 28 ............................................... 105
48. C-13 NMR of 28 ................................................ 106
49. IR of 28 ................................................. 107
50. Mass spectrum of 28 ............................................. 108
51. Proton NMR of 18 ............................................... 109
52. IR of 18 ....................................................... 110
53. Mass spectmm of 18 ............................................ 111
54. C-13 NMR of 18 ................................................ 112
55. Proton NMR of 19 ............................................... 113
56. Proton NMR of 20 ............................................... 114
57 C-13 NMR of 20 ................................................. 115
58. IR of 20 ....................................................... 116
59. Mass spectrum of 20 ............................................ 117
60. IR of 24 ...................................................... .118
61. Proton NMR of 21 .............................................. 119
62. Mass spectrum of 13 ............................................ 120
63. C-13 NMR of 6 ................................................. 121

viii

PART II

1. IR of 2 ......................................................... 162
2. IR of 2 ........................................................ 163
3. Proton NMR of 2 ................................................ 164
4. 0-13 NMR of 2 ................................................. 165
5. Proton NMR of 11 ............................................... 166
6. Mass spectmm of 3 .............................................. 167
7. Proton NMR of 3 ................................................ 168
8. IR of 3 ........................................................ 169
9. IR of 3 ........................................................ 170
10. Mass spectrum of 3 ............................................. 171
11. 0-13 NMR of 4 ................................................. 172
12. IR of 4 ........................................................ 173
13. IR of 4 ........................................................ 174
14. Proton NMR of 4 ............................................... 175
15. Mass spectrum of 21 ............................................ 176
16. Proton NMR of 21 . . . .‘ .......................................... 177
17. IR of 21 ...................................................... 178
18. IR of 21 ...................................................... 179
19. Mass spectrum of 17 ............................................ 180
20. IR of 17 ...................................................... 181
21. IR of 17 ...................................................... 182
22. Proton NMR of 19 .............................................. 183

ix

23. Proton NMR of 18 .............................................. 184
24. Mass spectmm of 11 ............................................ 185
25. Proton NMR of 9 .............................................. . 186
26. 0-13 NMR of 19 ............................................... 187
27. 0-13 NMR of 18 ............................................... 188
28. 0-13 NMR of 9 ................................................ .189
29. IR of 11 ....................................................... 190
30. IR of 11 ....................................................... 191
31. Mass spectrum of 19 ............................................ 192
32. Mass spectrum of 9 ............................................. 193
33. Proton NMR of 17 .............................................. 194
35. C-13 NMR of 17 ................................................. 196
36. IR of 9 ........................................................ 197
37. IR of 9 ........................................................ 198
38. IR of 19 ....................................................... 199
39. IR of 19 ...................................................... 200
40. IR of 18 ....................................................... 201
41 . IR of 18 ....................................................... 202
42. Proton NMR of 15 ............................................... 203
43. Proton NMR of 16 ............................................... 204
44. Mass spectmm of 7 ............................................. 205
45. IR 0114 ....................................................... 206
46. IR of 14 ....................................................... 207

47. IR of 15 ....................................................... 208
48. IR of 15 ...................................................... 209
49. Proton NMR of 14 .............................................. 210
50. Mass spectrum of TBDMS enol ether of 3 ........................ 211
51. Mass spectrum of 8 .............................................. 212
52. Mass spectrum of 6 .............................................. 213
53. 0-13 NMR of 11 ................................................ 214

xi

W

The total synthesis of steroids has long represented a major
challenge to synthetic chemists, and they have responded with many
elegant and practical approaches to this ring system]. The introduction
of characteristic sidechains, however, has received much less attention
in comparison. Early work on side chain construction focussed on
simple ones, such as the two carbon side chains of the corticosteroids

and pregnanes. (fig 1).

0

A60 . .

Pregnenolone acetate. Cortisone

 

 

Progesterone

Figure 1
This was largely due to the remarkable therapeutic effects of these

steroids. Furthermore, knowledge about the more elaborate side chains

present in other systems was increasing rapidly. With the isolation and
characterization of metabolites of cholesterol and other sterols; insect
hormones; Vitamin D metabolites; brain sterols; fungal sex hormones
and marine sterols, an entirely new era opened up in the steroid
chemistry. There was widespread interest and activity in the study of

more elaborate side chains. (fig 2).

 

Fusidic acid.

 

p - Ecdysone

Figure 2.

In addition to these commonly found 8 carbon steroid side chains,
several other interesting steroids with modified side chains have also
been reported. (fig 3). Some examples are Withaferin A2 and other
Withanolides which have significant antitumor activity3; the plant
growth promoters brassinolide4 and castasterones; the sex stimulating

steroid antheridiol6 of the water mold Achlya and all types of marine

sterols7. This has stimulated the search for stereoselective synthesis of

steroid side chains.

'0.

O

Withaferin A

 

HO...
HO" :
H O O
Brassinolide
Figure 3.

An important aspect of side chain synthesis is control of
stereochemistry, especially at C-17 and C-20. Most of the reported
syntheses of steroid side chains start with one of the following
substrates, (fig 4) due to their ready availability from naturally

occurin g compounds.

K ‘N

 

Figure 4.
Compound A is prepared by efficient microbiological methodss, B is the
major product of chromic acid oxidation of cholesterolg, C is derived
from plant sapogenins such as diosgeninlo, and D by degradation of
stigmasterolll. Earlier workers used A and B for the construction of the
pregnane type side chain”. Common reactions at the C-17 carbonyl
function included addition of HCN13, acetylenes”, Wittig reactions”,

and Reformatsky reaction”. (fig 5).

 

P1132: CHMe

 

The 020 acid C may be transformed via its acid chloride12 or by direct

153

addition of Organolithium reagents as shown in fig 6.

COOH M 0
Li
1.5 .. T 1‘ ..

 

 

Figure 6.
Among the commonly used methods beginning with C-20 ketones were
addition reactions of Grignard reagents and Wittig reactions. In the
Grignard reactions, where a chiral center is created at C—ZO, a mixture
of epimers usually resulted, the ratio depending on the structure of the
steroid and the bulkiness of the reagent17’18’l9. (fig 7).

In contrast to Grignard reagents, the addition of dimethyl
Sulphoxoniummethylide, has been reported to proceed with a high
degree of stereoselectivity, to give the 20-R epoxidezo. Koreeda and
coworkers”, have used this selectivity in a synthesis of
20-iso cholesterol. (fig 8). The 20-R epoxide has also been synthesized
by Krief et.al21 via a stereoselective addition of
methylselenomethyllithium. They have utilized this approach in the

synthesis of the side chain of 20S isolanosterol (fig 9), obtaining an

80 : 20 mixture of the 20-S and 20-R stereoisomers.

 

20$ labelled.

Figure 7.

 

 

 

Figure 8.

 

 

 

 

.0 °
.. 1. LICHZSeCHa)
THPO 2. CH3OSOZF ‘1“ 8
3. KOH
1. EtOCE CMgBr
2. LIAIH4
3. st04
V
\ CHO
1.H2/Pd 83804
<
2. Ph3P= C(CH3)2
3. PTSA (cat) M,
Figure 9.

The Grignard reaction is presumed to proceed via an initial Lewis
- acid catalyzed, stereospecific isomerization of the epoxide into the 20-
iso-Zl-aldehyde, followed by stereoselective addition of the Grignard
reagent to the aldehyde.

Wittig reaction of C-20 methyl ketones with non - stabilized
ylides, is noted to give solely the E-isomerzz. Reaction with stabilized
ylides such as diethylcyanomethylene phosphonate is also reported to
give a high yield of the E-isomer23. An interesting example of an
intramolecular Wittig cyclization was reported by Nickisch, Klose and

24

Bohlman , using ketenyliden triphenyl phosphorane. (fig 10).

 

 

Figure 10.

The major disadvantage of the 20-carboxaldehydes (D) is the
isomerization of 02025. Reactions of 20-carboxaldehydes with
Grignard reagents and other Organometallics usually give a

mixture, the ratio depending on the type of reagent”. Wittig

reaction with non stabilized ylides gives E or Z in varying ratios

depending on the reaction conditions”. Reaction with stabilized
ylides yield E-isomer327a. (fig 11).
0H0 o

I a
. I
x

Figure 11.

 

It is well documented that the stereochemistry of the steroid
sidechain is an important factor in determining its physiological
activity”. Many of the methods mentioned earlier give imperfect
stereoselectivity and need to be improved in this respect. In a flexible
sidechain diastereoselectivity will be poor unless one uses reactions
having highly - organized transition states which immobilizes key parts
of the chain. This is the concept behind most recent work.

One of the simplest and most elegant approaches to sidechain
construction was reported by Dauben et.a129“’b and later by Snider and
coworker829c'd. These workers used the known preference for Or-attack
on the C-17(20) double bond and the highly - ordered transition state
of the ene reaction to set the stereochemistry at the C-20 carbon. The
advantage of this methodology is that it permits stereospecific
synthesis of both 20R and 208 steroidal sidechains. Starting with the
(Z)-l7(20)-steroid, reaction with methyl propiolate and
diethylaluminumchloride gave excellent yields of the 20R steroidzga. On
the other hand, under identical conditions, the E-17(20)-steroid gave

exclusively, the 208 steroidng. (Scheme 1).

 

Scheme 1.

An efficient synthesis of Desmosterol was reported by Koreeda,

wherein he acheives stereochemical transmission via the Oxy Cope

rearrangement”. Only the 20R isomer derived from the (Z)-l7(20)
pregnene derivative could be prepared using this methodology. The

related (E)-17(20)-pregnene derivative failed to undergo the

rearrangement, presumably due to the quasi-1,3-diaxial interaction

between the 16-0‘ K+ and the 20-CH3 groups. (Scheme 2).
O'K+

 

Scheme 2.

Several workers have used the Claisen rearrangement to control
stereochemistry at C-2031. Both (E) and (Z)- Ethylidene sidechains
smoothly undergo the Claisen - Carroll rearrangement to yield the 20R
and 20S isomers respectively“? (fig 12). This reaction succeeds
however only with the 16 Or isomer. The 16 p isomer fails to react,
probably due to steric crowding of the [3 face31b. However, by
employing the enol ether variant (the Saucy-Marbet variant”), it has
been reported that the Claisen rearrangement is also feasible on the
sterically crowded p face. Thus starting with a E-l6 [3 alcohol,

rearrangement proceeded smoothly, to yield the 208 epimer31b. (Fig

10

13). The success of this rearrangement is attributed to the lesser steric

demand in the enol ether variant of the Claisen.

 

E:R1=Me,R2=H -002

z : R1 - H, R2 = Me
Ra=CH20HICH3I2

 

 

 

i i M
“M 0
Figure 12.
I M8 __ —
M8 ‘ 7
0:: Me Me; .
1' A ___,. I "
-
H H _
E -l6p /
M9 Me Me
" CHO
fw
208
Figure 13.

In a distinctly different approach, steroid sidechains can be
stereoselectively introduced by alkylation of a 1't-allyl Pd complex”.
Trost used this approach to synthesize both the 20R and the 208

11

31C

1';
Lil I

epimers-13a. Thus attack of a stabilized carbanion on the n-allyl Pd
complex generated from the alkene 1, gives the 20S epimer exclusively.
On the other hand, generation of the 11 -ally1 Pd complex from the allylic
acetate 2, using a catalytic amount of (PPh3)4Pd yields the 20R epimer
exclusively33a. (fig 14). Schwartz33°, has reported that alkenyl
Zirconium species couple with (11 -allyl) palladium chloride complexes to

give high yields of the resultant dienes. (fig 15).

   

"r CM
4’ (PPh3)4Pd

——>
NaCH(COzMe)2

2 20R

 

 

\ 20R

Figure 15 .

12

§g:‘l~\

‘SL‘
“HG

In“.
SQ ’

Regio and stereospecific 1,4-addition of alkyl cyanocuprates to
vinyl epoxides was the key step in a novel synthesis devised by Marine

and coworkersso' (fig 16).

 

 

Figure 16.

This dissertation describes a new method for the construction of
steroidal sidechains with control of stereochemistry at C-20. The
synthesis of the steroidal lactone 8, which is a potential precursor of
steroid sidechain, has been accomplished. The lactone has been
synthesized in a completely stereoselective manner from the epoxy
olefin 4. In the course of this study, we have observed a novel and
unprecedented rearrangement of an epoxy olefin, when reacted with

dichloroketene.

 

AcO

13

Although there have been reports on the reaction of
dichloroketene with allylic ethers and thioethers34, there are no
examples in the literature, concerning its reaction with epoxy olefins.
The unexpected rearrangement observed here, should provide a

fruitful area for further research in the future.

14

W

At the outset, our aim was to synthesize seven membered
lactones such as 5, which we believed could be elaborated with good
configurational control at C - 20. The lactone ring serves two major
purposes. Firstly, due to its presence, the exocyclic double bond in 5 is
constrained to assume the Z geometry. Secondly, the p face of this rigid
ring is more sterically hindered than the or face. We believed these two
factors enhanced considerably our chances of controlling the
stereochemistry at C - 20. Furthermore, 5 would enable us to introduce
a hydroxyl group at C - 16, a feature common in many steroids and
tetracyclic triterpenes. Finally, a Wittig reaction using
isopropyltriphenylphosphonium bromide would allow us to complete
construction of the eight carbon side chain commonly found in most

steroids. (fig 19).

 

Figure 18

15

 

Figure 19.

Our strategy for the synthesis of 5, was developed along the
lines of a rearrangement observed when allyl ethers are reacted with
dichloroketene“. A brief outline of this reaction and our reasoning
behind its use are in order.

In recent years, reactions of dichloroketene have been the
subject of extensive research. Several excellent reviews on this subject
have appeared in the literature”. Undoubtedly, the reaction of
dichloroketene that has attracted the most attention is the 211 + 211
cycloaddition with nucleophilic double bonds“. This reaction gives a
dichloro cyclobutanone as the product and is probably the simplest way

of constructing functionalized four membered rings (fig 20).

16

0|
Pc=c=c °

c
R/\ ,

 

Cl
Cl

Figure 20.
The high yields and the ready availability of starting materials make
this an especially attractive method. There have been several studies
probing the mechanistic details of this reaction”. Recent modifications
in reaction conditions have led to considerable improvement in the
yield of the cycloadduct”.
Normally the reaction proceeds with a high degree of

chemoselectivity and regioselectivity, with no unwanted side reactions.

However, when dichloroketene is reacted with allyl ethers or allyl

sulfides, a competing rearrangement reaction is observed34 (fig 21)

fx/ 0I20=0=O 0| Cl 0
° x/
I

 

CI

 

c.|

Figure 21

17

 

 

/ \ O
x 02 KS' CI R
W \R ——> '57 —->CI x/
x\
q R
\ /
X = S or O. 22
Figure 22

In this case the two nucleophilic sites; viz., the double bond and the
oxygen (or sulfur), compete with each other for the electrophilic
dichloroketene. In the case of allyl ethers (X: 0), this competing reaction
generally predominates and in most instances completely suppresses the 211
+ 211 cycloaddition“. The reaction may proceed through formation of the
1, 3-dipolar intermediate, 22, which then undergoes a 3,3— sigmatropic
rearrangement to yield the rearranged product. It is probable that
nucleophilic attack at the carbonyl of dichloroketene leading to the
1, 3-dipolar intermediate is facilitated by complexation of zinc chloride (which
is formed in the reaction) at the carbonyl carbon.

An important feature of this ”Claisen rearrangement" is that it occurs
under very mild conditions. Claisen rearrangements have been studied quite
extensively and have found several synthetic applications”. A major problem
with this rearrangement has been the need to use rather high temperatures
to achieve the desired transformation. This problem can be remedied by
introducing suitable substituents on the Claisen substrate. It is well
documented that the presence of 11 donor substituents at position 0 - 2

enhances the rate of the Claisen rearrangement significantly“).

18

R

A second factor that facilitates this rearrangement is the presence of a

positively charged hetero atom at position 341

. It is important to note that the
1, 3-dipolar intermediate formed in the "ketene Claisen" incorporates both
these activating factors. It is therefore not surprising that the rearrangement in
this case is extremely facile.

Unlike the 211 +211 cycloaddition reaction of haloketenes, this reaction
has not been studied extensively, nor has it found many synthetic
applications. In fact it is often considered an unwanted side reaction,
competing with 211 +211 cycloaddition reactions of allyl ethers and sulfides. In
a recent synthesis of Lineatin, Oehschlager reported that side reactions
arising due to participation of oxygen in these substrates could be minimized
by using 1, 2-dimethoxy ethane (glyme) as solvent”. He succeeded in
obtaining significantly higher yields of the 211 +211 cycloadduct under these
conditions (fig 23), and proposed that under these conditions, glyme acts as
a sequestering agent for zinc chloride. Consequently the 1,3-dipolar
intermediate 22 is formed at a slower rate and the 211 + 211 adduct is

obtained in a higher yield.

19

 

CCI3000I I C'
> 0 + O
O
Zn-Cu O
Q'yme 0 CI CI
60% 10%
Figure 23

Our interest in this rearrangement was prompted by our expectation
that epoxy olefins such as 23 would react with dichloroketene, yielding

seven membered lactones as products. [Scheme 3].

(‘5‘ ccfl O
DCK TX O/lkccb

o|___, o|__,
A) U
/ _

 

 

\
23
Scheme 3

We also believed that this reaction would provide us with a simple
and direct route to the steroidal seven membered lactone 5, which we set
out to synthesize. To this end, we chose the epoxy olefin 4, as our
substrate. This olefin was easily prepared from commercially available epoxy

ketone 3 by a Wittig reaction with methyltriphenylphosphonium bromide43
(fig 24).

20

 

 

Figure 24.

With the requisite epoxyolefin on hand, we proceeded to react it with
dichloroketene, generated by zinc dehalogenation of trichloroacetyl
chlorideaea. Examination of the product obtained, indicated that addition of
dichloroketene to 4 had indeed occured. However, spectral analysis of the
product revealed it was not the anticipated seven membered lactone. The
13C NMR spectrum of this compound revealed the presence of two ester like
carbonyls and two trisubstituted olefins (off resonance decoupled 13C NMR
spectrum). A vinylic hydrogen signal at 6 5.68 ppm in the 1H NMR spectrum
also confirmed the presence of a second trisubstituted double bond. The
infra- red spectrum of this compound showed two carbonyl absorptions at
1791 cm'1 and 1725 cm". Since the 130 NMR showed two ester carbonyl
signals, we concluded that one of the carbonyl functions was a five
membered lactone. Based on all the evidence, we concluded that the
product from the reaction of 4 with dichloroketene was actually compound 6.

(fig 25)

21

 

5:

 

Zn - Cu couple.

 

con 3 0061

 

Figure 25.

Final confirmation of structure 6 was eventually accomplished by
X- ray analysis of monodechlorinated derivative 7 (vide infra). It must be
added that 6 was the only product obtained whether the reaction was
performed in ether solvent or conducted in glyme/ether as suggested by
Oehschlager“.

 

Figure 26.

An interesting aspect of this reaction is that the oxygen atom of the 16a,17a

-epoxide in the starting material is no longer bonded to either of these

22

carbons (16 or 17) in the product. Furthermore, this oxygen shift is
completely stereoselective, giving only one 0-20 epimer as the product.
Our initial speculation regarding the mechanism of the reaction of
dichloroketene with epoxy olefin 4 centered around the possibility that the
seven membered lactone 5 was formed as an intermediate. Under the
reaction conditions an acid catalyzed suprafacial 1, 3- shift of oxygen from
0-16 to 0-20 would then account for the stereoselective formation of five

membered lactone 6. (scheme 4)

 

 

 

CCI3000I

4 >
Zn-Cu

6 ¢

 

 

 

 

Scheme 4.

However, we were concerned about the fact that 5 was never observed or
isolated during the course of this reaction. In our attempts to isolate 5 we

repeated the key reaction while varying the number of equivalents of

23

dichloroketene, the reaction time and the concentration of the reactants.
When 4 was reacted with one equivalent or less of dichloroketene, a new
product was isolated after two to four hours of reaction. If the reaction was
allowed to continue further, 6 was the only product isolated. The amount of
new product isolated depended on the concentration of the reaction mixture.
Under dilute conditions, significant quantities of this compound could be
isolated even after four to five hours of reaction. On the other hand, in a
more concentrated solution, We observed the formation of 6 (thin layer
chromatography) after only 1.5 to 2 hours of reaction. In the course of
identifying this new compound, we relied not only on spectroscopic evidence
but also the chemical reactions it underwent with various reagents.

The new compound was assigned structure 12, based on the following
evidence. The 13C NMR showed no carbonyl signal, other than the acetate
(at C- 3). The oil resonance decoupled 13C NMR spectrum revealed the
presence of one trisubstituted double bond and one tetrasubstituted double
bond. The fact that 12 possesses one chlorine atom was evident from the
mass spectrum. A signal at 3563 cm‘1 in the infra red spectrum of 12 was
indicative of a hydroxyl group.

When epoxy olefin 4 was treated with zinc chloride in ether solution,
12 was obtained, albeit in rather poor yield. This indicated that there could
be no increase in the number of carbons in the going from 4 to 12.
Reaction of 12 with dichloroketene, under the same conditions as with 4,
yielded 6 in good yield. Thus it was clear that 12 is an early product of the

reaction of 4 with dichloroketene.

24

  
 

  
 

coracoci ZI'I/CU
>

 

Of

ZnCI2 A

4 12
Figure 27

. The structure of 12 was later confirmed unambiguously, by
studying its behavior in various chemical reactions. (figs 28 & 29). Thus,
when 12 was reacted with methanolic potassium carbonate solution,
hydroxy ether 13 was obtained. Reduction of 12 with lithium aluminum
hydride gave diol 14, and oxidation of 12 with pyridinium chlorochromate
yielded enone 17. Finally, on refluxing 12 with aqueous potassium hydroxide
in dioxane, the original epoxy olefin, 15, was isolated as the major product,

along with a small amount of 16.

  
 
 

aq. KOH
1 2 dioxangl

Figure 28.

25

 

 

Figure 29

The results of these reactions leave no doubt as to the identity of 12.
The 2 configuration of the double bond in 12 was established by chemical
shift changes on converting 12 to 17. Oxidation of the 16- hydroxyl group
causes the chemical shift of the 21 - methyl hydrogens to shift downfield by
0.1 ppm whereas the hydrogens of the chloromethylene group are shifted
downfield by about 0.55 ppm. This compares well with the data obtained by
Koreeda et 2152. Although we did not isolate the seven membered lactone

5, we continued to believe that it must be formed as an intermediate in the

26

conversion of 4 to 6. There are two possible explanations for the observed
result. The isolation of 12 as an early product may represent an
unproductive detour in the ultimate conversion to 6, or it may reflect a
previously unsuspected path to 5. In other words, one possibility is that 12
might be in equilibrium with 4, which reacts with dichloroketene according to
the mechanism oulined earlier (Schemess and 4). A second possibility is
that under the reaction conditions (viz., presence of Lewis acids), epoxy
olefin 4 may first undergo a 1,4- addition to the allyl chloride 12, which
then may react with dichloroketene to give the seven membered lactone 5.
(Scheme 5). As shown in Scheme 5, the alcoholic oxygen may act as a
nucleophile in the reaction with dichloroketene, similar to reactions of
dichloroketene with allyl ethers. The chlorine atom of the allylic chloride
serves as a nucleofugal leaving group, giving rise to the seven membered
lactone 5, which rearranges to 6 as suggested earlier (Scheme 4).. We
believe the rearrangement of 5 is so fast under the reaction conditions as to
preclude its isolation. This rearrangement is a curious and interesting one,
and we know of no precedence for such a transformation. The most
interesting aspect is, of course, the completely stereoselective nature of this
1, 3-shift. The driving force for the rearrangement is presumably the
increased stability associated with the relief of strain in going from a seven

membered lactone to a five- membered lactone.

27

 

 

 

Scheme 5.

Dechlorination studies of 6 gave some interesting results.
Dechlorination of 6 using zinc and acetic acid44a, resulted in the isolation of
8 as a mixture of C- 20 epimers. The ratio of the two epimers were roughly
1 :1. A doubling of 1H NMR signals from protons on C- 16, C- 18 and
0-21, were indicative of this epimerization, which presumably is due to acid
catalyzed ring opening and reclosure of lactone 6. This undesirable
epimerization can be avoided by conducting the dechlorination reaction In a
methanol solution saturated with ammonium chloride“). In this fashion

lactone 8 was obtained in almost quantitative yield, from 6. (fig 30.)

28

 

Figure 30.

The sensitivity of lactone 8 to acid catalyzed epimerization was
demonstrated by brief exposure to zinc chloride in acetic acid solution,
whereupon a 50 :50 mixture of 0-20 epimers was obtained. This is in good
agreement with the results obtained from a MM247 calculation, according to
which both C - 20 epimers are of approximately equal energy. Lactones such
as 8 are quite rare, the only previous synthesis, by Kocor et. al., being from
3b- methoxy-S- androsten -17-one in four steps with rather poor
stereoselectivity45 (fig 32). The key step in this strategy is the phenyl seleno
Iactonization of 17, 20 - unsaturated acids to the desired lactones. The poor
yield of this reaction and the inability to control the stereochemistry of the
17- 20 double bond are major drawbacks to this method. In another early

report, Sarel et. al.,463 prepared similar lactones by oxidation of cholanol.

29

 

Figure 30.

The sensitivity of lactone 8 to acid catalyzed epimerization was
demonstrated by brief exposure to zinc chloride in acetic acid solution,
whereupon a 50:50 mixture of 0-20 epimers was obtained. This is in good
agreement with the results obtained from a MM247 calculation, according to
which both 0-20 epimers are of approximately equal energy. Lactones such
as 8 are quite rare, the only previous synthesis, by Kocor et. al., being from
3b- methoxy -5- androsten - 17 - one in four steps with rather poor
stereoselectivity“ (fig 32). The key step in this strategy is the phenyl seleno
Iactonization of 17, 20 - unsaturated acids to the desired lactones. The poor
yield of this reaction and the inability to control the stereochemistry of the
17- 20 double bond are major drawbacks to this method. In another early

report, Sarel et. al.,‘sa prepared similar lactones by oxidation of cholanol.

29

However their strategy also lacked stereoselectivity (fig 31). Lactones of this

kind were used in a synthesis of 14a- Bufa-20, 22 -dienolide46b.

 
 

 

 

[—V
O .,
OH ,
” 0
WOM)4+12
>
I D
CHOLAN-24-OL ’
0:03
O
O .,
{3.
Figure 31.

3O

During our study of the dechlorination reactions of 6, we studied its
reaction with tributyltin hydride”. This reduction yielded a mono-
dechlorinated product, 7, (fig 33) as revealed by its mass spectrum and
1H NMR studies. The reduction proceeds by selective dechlorination of the
Q -chIorine, indicating steric hindrance of the 8 -face. Neither treatment with
excess tributyltin hydride nor longer reaction times or higher reaction
temperatures caused further reduction of 7. Compound 7 yielded crystals
suitable for X- ray analysis. Figure 34 displays an ORTEP diagram of 7,
determined in the course of its stnrcture elucidation and refinement. This
diagram clearly discloses the 20- R configuration in 7, and consequently the
corresponding configurations of 6 and 8. Figure 34 also confirms that the
stereoselective dechlorination of 6 proceeds with the loss of the less
hindered chlorine atom. Interestingly, the structure displayed in figure 34
resembles closely the most stable 0-17 : 0-20 rotamer found by MM247

calculations on structure 7.

 

 

Figure 33

32

It“ In 1H-

 

 

 

34

Next we conducted some reactions of 8 with reducing agents.
Reaction of 8 with diisobutylaluminum hydride at -20°C for four hours
resulted in recovery of unchanged starting material. When the reduction was
performed at 0°C using one equivalent of the reducing agent, reduction of
the 0-3 acetate was observed. No reduction of the five membered lactone
was detected. When excess reducing agent (5 equivalents) was used, and
the reaction was performed at room temparature, the tetrahydrofuran 11 was

isolated. (fig 35).

 

 

Figure 35

As can be seen from fig 35, 11 was isolated as a 1:1 mixture of
C-20 epimers. The reason for the slower reduction of the lactone function
compared with the acetate is not entirely clear. It is possible that the Lewis
acidic nature of DIBAL, causes the lactone ring to open up before it gets
reduced. This would account for the epimerization at 0-20. The
tetrahydrofuran itself is formed by dehydration of triol 9, which is the initial
reduction product. (fig 36) This dehydration is no doubt catalyzed by the

Lewis acidic nature of the aluminum in this reducing agent.

35

 

Figure 36

Triol 9 can be isolated by conducting the reduction of 8 with lithium
aluminum hydride. In this manner the stereochemical integrity of 0-20 is
preserved. The acid sensitive nature of triol 9 is demonstrated by the its
facile dehydration to 11 in the presence of mild acids. In fact, a solution of
9 in 0D0I3 was completely converted to 11 over several hours. This
dehydration could be avoided by adding a few drops of pyridine during the
work up. In this fashion 9 remained stable over extended periods of time,

even in solution. (fig 37).

11

 

Figure 37.

Oxidation of trioI 9 using pyridinium chlorochromate yielded enone

24. Understandably, the acidic condition of this oxidizing reagent caused the

36

migration of the double bond from 0-5 to 0-4. Oxidation of 9 using
pyridinium dichromate did not cause migration of the double bond and also
enabled the isolation of the C - 24 aldehyde 25. It also possible to protect
selectively the two hydroxyl groups at C- 3 and C -24 of 9 without affecting
the stereochemistry of 0- 20 in any way. Thus reaction of 9 with acetic

anhydride in pyridine48 yielded diacetate 10. (fig 38).

 

OAc

 

Figure 38.

As described earlier, we believe the conversion of epoxy olefin 4 to
the five membered lactone 6 proceeds through the intermediacy of the

seven membered lactone, 5. We realized that this proposal would remain

37

speculative unless we were able to isolate the seven membered lactone 5
and study its rearrangement. However, all our efforts aimed at its isolation
from the reaction of 4 with dichloroketene had been unsuccessful. Realizing
that compound 5 is probably too unstable under these reaction conditions to
allow its isolation, we turned our attention to other ways of constructing
similar systems. We hoped that from our study of these related systems, we
would be able to support our theories regarding the mechanism of the
reaction of dichloroketene with epoxy olefin 4. If we could prove that seven
membered lactones similar to 5, do indeed rearrange to five membered
lactones as suggested earlier, it would give considerable credence to the
proposed mechanism.

The isolation and characterization of the allyl chloride 12 provided us
with a reasonable pathway for the synthesis of seven membered lactones
similar to 5. Alkylation of 12 with the anion of diethyl malonate, followed by
hydrolysis of the ester and decarboxylation should lead us to the type of

substrate we are interested in. (scheme 6).

38

 
  

0H 2 (COOEt)2
12 ———>
NaI-I

   

H+
<———
\,
Scheme 6

The alkylation of 12 proceeded as anticipated49 and 18 was isolated
in near quantitative yield. However attempts to hydrolyze 18 failed to yield
the expected diacid. The reaction generally resulted in the formation of a
white solid, insoluble in most organic solvents and water. The 1H NMR of this
compound was not very helpful its identification. However there were
indications of some decomposition.

At this point we decided to modify our approach slightly, by using the
anion of dimethyl malonate to alkylate the allyl chloride 12, since methyl
esters can be converted to the corresponding acids by SN2 type
displacements“ Alkylation of 12 using the anion of dimethyl malonate was
performed as described in the experimental section. The product isolated
from this reaction was almost entirely the seven membered lactone 20. Only

a trace (6%) of the expected product 19, was isolated. (fig 39).

39

12

CH 2 (CW9) 2
NaH

 

Figure 39.

The structure of 20 was confirmed beyond any doubt by
spectroscopic evidence. The downfield shift of the proton at C - 16 by
approximately 0.7 ppm (relative to the signal in 18 and 12), and the
presence of only one methoxy group in the 1H NMR spectrum were indicative
of the formation of 20. The carbonyl absorption signal at 1752 cm'1 in the
infrared spectrum of 20 also confirmed the presence of a seven membered

lactone.

4O

The isolation of 20 provided us with a substrate similar to 5, and we
decided to study its behaviour with Lewis acid catalysts. Thus 20 was
reacted with trichloroacetyl chloride and zinc in ether solution, conditions
similar to those under which 6 was formed from 4. The 1H NMR of the
product revealed that the seven membered lactone of 20 had indeed
undergone a rearrangement to the five membered lactone. The appearance
of a new 1H NMR signal at 5 5.68, due to the vinylic hydrogen at
0-16, was an indication of this fact. However this spectrum also revealed
that the product was approximately a 5 :1 mixture of two epimers. The infra
red spectrum of this product showed a carbonyl absorption at 1775 cm",

confirming the presence of a five membered lactone.

COOMe

cor 3 cocr
2 o a

 

 

Figure 40

Hydrolysis of the methyl ester 26 using methanolic potassium
hydroxide gave the acid 27. On refluxing with benzene, 27 decarboxylated
smoothly to yield the lactone 28. The spectra of 28 are identical with those
obtained from the compound produced by hydrolysis of 8 with methanolic
potassium carbonate. (fig 41). The isolation of 28 as a single epimer by the

hydrolysis and decarboxylation of 26 indicates that 26 must be epimeric at

41

C -22. Thus the rearrangement of 20 to 26 is completely stereoselective,
and we have demonstrated that seven membered lactones such as 5

undergo a novel and stereoselective 1, 3 - rearrangement.

 

CCI3000I aq. KOH
20 ————> 26 ———->
Zn CH30H
aq. K2003
8
CH30H

 

Figure 41

With the synthesis of lactone 20, we have achieved one of the
primary objectives of this work. We have also uncovered a new reaction of
epoxy olefins with dichloroketene. This has led to ths synthesis of lactone 8
in a concise and stereoselective fashion. Compound 8 may be very useful

for the elaboration of steroid side chains in a stereoselective manner.

42

GeneraL

Except where indicated, all reactions were conducted under dry nitrogen
or argon, using solvents purified by distillation from suitable drying agents.
Magnetic stirrers were used for small scale reactions; large scale reactions
were agitated using paddle stirrers. Organic extracts were always dried over
anhydrous sodium sulfate or anhydrous magnesium sulfate. The progress of
most reactions were followed by thin layer chromatography and/or gas liquid
chromatography. Visualization of the thin layer chromatograms was effected
by 30% sulfuric acid with subsequent heating.

Analysis by GLPC was conducted with a Varian 1200 gas
chromatograph. Flash chromatography was carried out on flash silica
(37-53 mesh) as suggested by Still et al. Melting points were determined on
a Hoover-Thomas apparatus (capillary tube) and are uncorrected. Infrared
spectra were recorded on a Perkin-Elmer 237B grating spectrophotometer.
Proton magnetic resonance spectra were taken in deuterochloroform solutions
with either a Varian T-60 or a Bruker 250 MHz spectrometer and are
calibrated in most cases in parts per million (5) downfield from
tetramethylsilane as an internal standard. In some cases the chloroform peak
(7.24 ppm) was used as a standard for 1H NMR measurements. Carbon-13
NMR spectra were taken in deuterochloroform solutions with Bruker 250 MHz

spectrometer and are calibrated in parts per million (5) using

43

tetramethylsilane as an intemel standard. Mass spectra were obtained with a
Finnigan 4000 GC/MS spectrometer.

Microanlyses were performed by Spang Microanalytical Laboratories,
Eagle Harbor, MI. High resolution mass spectroscopy were performed by
Mass Spectroscopy Facility, Department of Biochemistry, Michigan State
University, East Lansing, MI.

Wittig Reactlon of 16 or, 17 ct - Epoxypregnenolone Acetate

To a solution of 1.4 mL of diisopropylamine in 7 mL of THF held at 0°C
was added 4 mL of 2.5 M n-Butyl Iithium. The solution was stirred at this
temperature for 20 min. The resulting lithium diisopropylamide solution was
then transferred by a cannula to a suspension of 3.6 g (10 m.mol), of methyl
triphenyl phosphonium bromide in 15 mL of THF (0°C). The yellow colored
ylide was stirred at this temperature for a further 2 h, a solution of 2.97 g
(8 m.mol) of 16a, 17 ct -epoxypregnenolone acetate (3) in 15 mL of
tetrahydrofuran was then added and the resulting mixture was allowed to
warm to room temperature. Following 4 to 5 h. of stirring, the reaction
mixture was quenched by the addition of saturated ammonium chloride
solution and extracted with ether. The combined organic layers were
evaporated and the residue was purified by column chromatography (silica
gel, ethyl acetate/hexane). In this manner pure 4 (2.53 g, 86% yield) was
obtained together with 3 to 4 % of unreacted ketone. Characteristic
properties of 4:

MP. : 129-131°C.

1H NMR (CD0I3). 6 5.34 (d, 1H, J = 4.9 Hz), 5.04 (t, 1H, J = 1.5 Hz),

44

4.98 (br. s, 1H), 4.55 (m, 1H), 3.38 (s, 1H), 2.00 (s, 3H), 1.798 (s, 3H), 1.01 (s,
3H), 0.799 (s, 3H) ppm.

130 NMR (CDCI3) 5: 170.89 (s), 140.37 (s), 122.70 (d), 116.37 (1), 74.29 (d),
73.06 (5), 61.44 ((1), 50.79 ((1), 46.21 ((1), 42.50 (5), 38.56 (I), 37.38 (I), 37.24 (6),
32.91 (t), 31.97 (I), 30.96 ((1), 28.18(q), 27.89 (I), 21.83 (q), 21.42 (t), 21.19(t),
19.71 (q), 16.24 (q) ppm.

IR (CD0I3) : 2950, 2850, 1748 cm"

Mass spectrum (70eV), m/e (rel. intensity): 370 (0.2); 310 (9.5); 242 (7.8); 198
(15» 43(100)

Anal. Calcd. for 024H3403: C, 77.80; H, 9.25.

Found : C, 77.61; H, 9.26.

Reaction of dlchloroketene with Epoxy Olefln 4:

To 1.85 g (5 m.mol) of 4 was added 6 mL of anhydrous 1,2-
dimethoxyethane, 12 mL of diethyl ether and 500 mg of Zinc/copper couple.
This mixture was stirred under nitrogen while 0.67 mL (6 m.mol) of
trichloroacetyl chloride in 1 mL of ether was added dropwise. The resulting
mixture was refluxed for 24 h, additional portions of the reagents (1 g of
fine/copper couple, 5 mL of glyme and 5 mL of ether and 0.8‘mL of
trichloroacetyl chloride) were then added, the latter dropwise. and reflux was
continued for an additional 24 h. The reaction mixture was filtered through
celite, extracted with ether and the ether extracts were washed with saturated
aqueous bicarbonate, brine and dried over anhydrous sodium sulfate. The
solvent was evaporated and the solid residue then purified by column

chromatography (silica gel, 15% ethyl acetate in hexane), giving 1.7 g (71%)

45

r»

of pure 6. In ether solution alone, with excess dichloroketene, yields up to
85% have been obtained. Characteristic properties of 6:

MP. :128-130°C.

1H NMR (CDCI3): 6 5.675 (dd, 1H,J=1.5&3Hz), 5.36 (d,1H,J=4.4Hz),
4.58 (m, 1H), 333-30 (AB quartet, 2H, J: 15 Hz), 2.0 (s, 3H), 1.7 (s, 3H), 1.02
(s, 3H) , 1.0 (s, 3H) ppm.

13ONIvIR (CDCI3): 5 172 (s), 170.6 (s), 155.6 (s), 140.5 (s), 129 (d), 122.2 (d),
85.8 (s), 76.75 (s), 75.1 (d), 59 (d), 56.2 (t), 50.7 (d), 48.2 (s), 38.3 (t), 37.7 (t), 37.6
(s), 36.3 (t), 32.5 (t), 31 (d), 29.1 (q), 28.9 (t), 22 (q), 21.5 (t), 20 (q), 18.5 (q) ppm.
IR (CD0I3) : 2900, 2830, 1791, 1728 cm".

Mass spectrum (70eV): m/e (rel. intensity) 422 (2);.421 (0.7); 420 (3.3)
[M-CHacOzH]; 105 (10); 91 (13); 43 (100).

Anal. Calcd. for 026H3404Cl2: C, 64.86; H, 7.12: CI, 14.73.

Found : C, 64.76; H, 7.15; CI, 14.70.

Dechlorlnatlon of 6 by Trlbutyltln Hydrlde

A solution of 115 mg of 6 (0.24 m. mol) in 3 mL of toluene was cooled to
0°C and maintained under an argon atmosphere while 0.14 mL (0.53 m. mol)
of tributyltin hydride was added. The reaction mixture was then allowed warm
up to room temperature and stirred for 3 h. The reaction was quenched by
the dropwise addition of water. The solution was extracted with ether, the
organic layer dried over anhydrous sodium sulfate and the solvent
evaporated. The solid residue was purified by flash chromatography (elution
with hexane removes all the tin residues and further elution with methylene
chloride gave a white solid). The product proved to be a single isomer, but

one chlorine atom still remained (mass spectroscopy) and the final

46

identification was made by X-rey analysis. Purification gave 85 mg (80%) of
7, which exhibited the following characteristics :

MP. 210- 212°C.

1H NMR (CDCI3) 5 5.67 (dd, 1H, J=1.4&3Hz), 5.36(d,1H,J=5.1 Hz), 4.58
(t overlapping m, 2H, J=9 Hz), 2.72 (two overlapping doublets, 2H), 2.01 (s,
3H), 1.55 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H) ppm.

130 NMR (CDCI3) 5 171.92, 170.62, 155.88, 140.10, 127.23, 122.18, 84.82,
73.83, 57.91, 50.94, 50.11, 47.70, 44.61, 38.07, 36.81, 36.66, 35.54, 31.30, 31.19,
30.23, 27.65, 27.45, 21.38, 20.70, 19.14, 17.53.

IR (CHZCIZ) : 3060,2950, 1785, 1730 cm“

Mass spectrum (70eV) : m/e (rel. intensity) :388 (5); 387 (5); 386 (20) [M-
CH3002H]; 371 (11); 253 (14); 159 (13);), 157(13); 145 (24); 43 (100).

Dechlorlnatlon of 6 by Zlnc In Methanollc Ammonium Chloride

To a solution of 200 mg of 6 in 20 mL of methanol saturated with
ammonium chloride was added 250 mg of zinc. This stirred mixture was
refluxed under an argon atmosphere for 6 h. The reaction mixture was then
cooled and filtered through a celite pad, followed by an ether wash. The
white residue remaining after evaporation of the solvent was treated with
dilute acid (0.5% sulfuric acid) and extracted with ether. The extracts were
washed with brine, dried and the solvent evaporated, yielding 164 mg
(95.5%) of 8. This compound exhibited the following properties.

M.P. : 174-177°C.

1H NMR (cocra) 6 5.63 (dd, 1H, J =1.5 83.2 Hz), 5.43 (d, 1H, J = 4.7 Hz), 4.58
(m, 1H), 2.55 (m, 2H), at 2.01 (s, 3H), 1.545 (s, 3H), 1.027 (s, 3H), 0.979 (s, 3H)
ppm.

47

13C NMR (CDCI3) 5 176.92, 170.62, 156.58, 140.07, 126.24, 122.26, 87.02,
73.85, 58.00, 50.14, 47.28, 38.07, 36.83, 36.66, 35.63, 34.29, 31.33, 31.04, 30.27,
29.04, 27.86, 27.67, 21.35, 20.70, 19.14, 17.35 ppm.

IR (CDCI3) :2970, 1768, 1720 cm".

Mass spectrum (709V) :m/e (rel. intensity): 352 (83) [M-CH3002H];337 (33);
253 (23); 99 (88); 43 (100).

[Ot]D = -58.78° (4.1 mg/ml in CHCI3).

Anal. Calcd. for 026H3504 : C, 75.69; H, 8.80.

Found : C, 74.96; H,8.71.
Reduction of 8 by Diisobutylalumlnum Hydrlde (DIBALH):

A solution of10 mg of the lactone 8 in 5 mL of ether was mixed with 5
equivalents of diisobutylaluminum hydride and the mixture was refluxed for
12 h. It was quenched by the addition of 3 mL of methanol. A 30% sodium -
potassium tartarate solution was added and the mixture stirred for a further
2 h. It was then extracted with ether, the organic layer washed with sodium -
potassium tartarate twice and the ether layers dried over anhydrous sodium
sulfate. Evaporation of solvent yielded 7.1 mg (82%) of a white solid which
proved to be 11. From the 1H NMR it is clear that the acetate group has
been lost in the reduction. Efforts to reduce the lactone selectively without
removing the acetate proved unsuccesful, even when the reduction was
carried out at lower temperatures with one equivalent of diisobutylaluminum
hydride. Furthermore, this reaction appears to cause some epimerization at
0-20. Characteristic properties of 11 :

1H NMR (CDCI3) 5 5.61 (dd, 1H, J = 1.5 & 3.2 Hz), 5.4 (d, 1H, J = 4.92 Hz), 3.95-
3.77 (m, 2H), 3.5 (m, 1H), 1.4 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H).

48

130NMR(0D0I3) 6 159.9, 141, 123.8, 121.7, 83.2, 71.6, 66.2, 581,503, 46.6,
42.3, 37, 36.8, 36.2, 36, 31.9, 31.8, 31, 30.4, 27.8, 25.6, 21.2, 19, 17.3 ppm.

IR (CDCI3) : 3610, 2940. 2860 cm"

Mass spectrum (709V), m/e (rel. intensity) :356 (8); 341 (38); 124

(43); 85 (100).

Reduction of 8 by Lithium Aluminum Hydrlde (LAH):

A solution of 9 mg of lactone 8 in 7 mL of ether, was mixed 8 mg of
lithium aluminum hydride and refluxed for 2 h. The reaction was quenched
by the dropwise addition of aqueous sodium hydroxide and the resulting
suspension was filtered. The residue was extracted with other, the combined
ether portions were dried and the solvent evaporated. The white solid thus
obtained was purified by column chromatography yielding 7 mg (86%) of triol
9. As expected, this compound was polar; furthermore, it slowly decomposed
to tetrahydrofuran 11, especially on exposure to acids (a chloroform solution
of 7 was completely converted to 11 in a few hours). By adding a few
drops of pyridine during workup, this dehydration could be prevented, even
in solution. The triol 9 showed the following properties.

M.P. 129° to 132°C.

1H NMR (CDCI3) 5 5.54 (dd, 1H,J=1.45 & 3.1 Hz), 5.34 (d,1H,J=5Hz),
3.63 (t, 2H,J=6Hz), 3.52 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H) ppm.
130NMR (CDCI3) 6 149.84, 141.125, 124.66, 121.55, 74.68, 71.68, 63.29,
58.17, 50.29, 47.19, 42.25, 38.95, 37.16, 36.65, 36.42, 31.58, 31.47, 30.95, 30.45,
29.09, 27.77, 20.94, 19.29, 17.82 ppm.

IR (CDCI3): 3610, 3420 (br), 2935, 2850 cm".

Mass spectrum (706V): m/e (rel. intensity). 356 (1.7)[M-18], 341 (16), 315(16),
124 (46), 91 (33), 85 (100).

49

Hydrolysis of the acetate group of 8

To 20 mg of the lactone 8, in 2 mL of methanol, was added 6 mg of
potassium carbonate, in 0.6 mL of water. The mixture was stirred for 3 h.
The solvent was evaporated, the residue then extracted with ether. The
combined organic layers were washed with water, dried over anhydrous
sodium sulfate, and the solvent evaporated to yield a white solid. Purification
by column chromatography, using 40% ethyl acetate in hexane as the eluent
yielded 16.4 mg (93.8%) of the alcohol 23. The compound exhibited the
following properties:

M.P. : 159- 162°C.

1H NMR (CD0I3) 6 5.65 (dd, 1H,J=1.45&3.1), 5.33 (d,1H,J=5), 3.56 to
3.46 (m, 1H), methyl signals were at (1 154,101 and 0.97.

13CNIvIR (CDCI3) 6 176.80, 156.46, 141.10, 126.19, 121.23, 87.05, 71.68,
58.09, 50.24, 47.29, 42.24, 37.12, 36.62, 35.74, 34.30, 31.59, 31.38, 31.09, 30.36.
29.09, 27.89, 20.80, 19.26, 17.42.

Mass spectnrm 70eV: m/e, (rel. intensity) :370 (2.7);355(5.59);337(6.1);271
(16.34); 99 (89.64); 55 (53.52); 43 (100).

IR (CDCI3) cm": 3600, 2940,1770.

Preparation of the allyl chloride 12:

To 2 g (5.4 m.mol) of epoxyolefin 4 in 100 mL of ether, was added 0.5 g
(7.5 m.mol) of fine-Copper couple. This mixture was refluxed under an
argon atmosphere, and to the refluxing mixture was added dropwise, a
solution of 0.77 mL (7 m.mol) of trichloro acetylchloride in 50 mL of ether.

Reflux was continued for 6 h; the mixture was then filtered through celite,

50

washed with saturated sodium bicarbonate solution and brine, dried and
evaporated to yield 1.13 g (51.6%) of 7, 0.68 g (34%) of unreacted starting
material and a small amount of dichloroadduct 6. Trace amounts (~1%) of
17-chloro,16- hydroxy compound is also obtained. Compound 12 exhibited
the following properties:

M.P. : 120 to 122°C.

1H NMR (CDCI3) 6 5.37 (d, 1H,J=5Hz), 4.72 (d, 1H,J=4.7 Hz), 4.15(AB
quartet, 2H, J = 10.6 Hz), 2.01 (s, 3H), 1.86 (s, 3H), 1.01(s, 3H), 0.86 (s, 3H) ppm.
136 NMR 6 170.5 (s), 153.2 (s), 139.8 (s), 129.4 (s), 122.3 (d), 73.8 (d), 71.9 (d),
52.5 (dd), 49.8 (d), 49.0 (t), 44.5 (s), 38.0 (1), 371,369, 36.6, 35.4 (t), 31.6 (t),
30.5 (d), 27.7 (q), 21.4 (q), 21.1 (t), 19.2 (q), 16.5 (q) ppm.

IR (00I4) : 3563,2935,1721cm'1.

Mass spectrum (70eV) : m/e, (rel. intensity) : 348 (1.9), 346 (5.9) [M-
CH3000H], 328 (1.1), 310(13.14), 43(100).

Preparation of hydroxy ether 13:

To 40 mg of the compound 12 In 10 mL of methanol, was added, a
solution of 50 mg of potassium carbonate in 0.5 mL of water. This mixture
was stirred at room temperature for 3 h. The solvent was then evaporated,
the residue dissolved in ether and washed twice with water. The combined
organic layers were dried over anhydrous sodium sulfate and the solvent
evaporated to yield 34 mg of a white solid which proved to be 13 (yield
96%). This compound exhibited the following characteristics :

M. P. : 69 to 71°C.

51

1H NMR (CDCI3) 6 5.34(d,1H,J=5.1 Hz); 4.65 (d, 1H,J=5.3 Hz); 4.18 to
3.67 (AB quartet, 2H,J = 10.4 Hz); 3.5 (m, 1H); 3.3 (s, 3H); 1.84 (s, 3H); 0.99 (s,
3H); 0.86 (s, 3H) ppm.

IR (CDCI3) : 3610, 3450 (br), 2940, 2862 cm".

Mass spectrum (70eV); m/e, (rel. intensity) : 342 (40.2) [M18], 328 (8.9), 157
(30.3),145(4o), 105 (81.7), 91 (100).

Preparation of the diacetate 10:

To 10 mg of the triol 9 in 4 mL of benzene, was added 0.2 mL of pyridine
and 0.1 mL of acetic anhydride. The mixture was maintained under an argon
atmosphere and stirred overnight. It was then poured into water and
extracted several times with ether. The combined organic layers were dried
over anhydrous sodium sulfate and the solvent evaporated, to yield the
diacetate 10, as a white solid. Purification by column chromatography (silica
gel/25% ethyl acetate in heXane) yielded 13 mg (94% yield) of the
diacetate 10, which exhibited the following characteristics.

1H NMR(CDCI3) 5 5.52 (dd, 1H,J=1.5&3Hz); 5.36 (d, 1H,J=4.5 Hz); 4.03 (t,
2H,J=6 Hz); 2.02 (s, 3H); 2.01 (s,3H); 1.35 (s,3H); 1.03 (s,3H); 0.96 (s, 3H)
ppm.

13CNMR (CDCI3) 6 171.33, 170.71, 159.91, 140.07, 124.88, 122.47, 74.67,
73.96, 64.83, 58.06, 50.22, 47.23, 38.43, 38.14, 36.93, 36.75, 36.28, 31.46, 30.98,
30.41, 28.99, 27.75, 24.01, 21.42, 21, 20.89, 19.21, 17.82 ppm.

IR (00013) : 3600, 2975, 2940, 2860, 1728 cm“.

Mass spectrum (259V); m/e, (rel. intensity) : 398 (1.2) [M—CH3000H], 380
(13.83), 357 (37.03), 297 (90.3), 107 (34.75), 85 (100).

52

Reduction of 12 with LItthm Aluminum Hydrlde:

To 40 mg (0.098 m.mol) of 12 in 3 mL of ether, was added 11.34 mg

(0.3 m.mol) of Lithium Aluminum Hydride. The mixture was stirred for 4 h.
under an argon atmosphere. The reaction was quenched by the dropwise
addition of 5% sodium hydroxide solution. The reaction mixture was filtered
through a celite pad, the filtrate extracted with ether, and the combined ether
extracts dried over anhydrous sodium sulfate. Evaporation of solvent yielded
30 mg (91.5% yield), of 14, which exhibited the following properties:

M.P. : 154 to 155°C.

1H NMR (CDCI3) : 6 5.34(d,1H, J=5Hz), 4.6 (d, 1H, J=4.76 Hz), 3.45 to
3.61 (m, 1H), 1.79 (s,3H), 1.74 (s, 3H), 0.99(s,3H), 0.84 (s, 3H) ppm.

138 NMR (CDCI3) : 6 147.3, 140.81, 129.63, 121.54, 72.65, 71.70, 53.07,
50.06, 43.95, 42.25, 37.83, 37.13, 36.57, 35.12, 31.68, 31.59, 30.57, 23,
21.31, 20.13, 19.31, 17.07 ppm.

IR (CDCI3) : 3610, 2940, 2865 cm".

Mass spectrum (70 eV); m/e, (rel. intensity) : 330 (7), 315 (18.8), 312 (33),297
(37.6), 159 (50.87), 99 (88), 91 (100).

Hydrolysis of 12 with potassium hydroxide

To 40 mg of 12 in 5 mL of dioxane, was added 1 mL of 5% aqueous
potassium hydroxide solution. After refluxing for 2.5 h, the reaction mixture
was cooled, the solvent evaporated and the residue extracted with ether. The
combined ether extracts were dried over anhydrous sodium sulfate and the
solvent evaporated to yield a white solid. Purification by column
chromatography (silica gel/20% ethyl acetate in hexane), yielded 22 mg
(80%) of 15 and 1.8 mg (5%) of 16.

S3

Oxidation of 12 with pyridinium chlorochromate (P00)

To 18 mg of 12 in 3 mL of methylene chloride, was added 0.5 gm of celite
and 40 mg (4 equivalents) of pyridinium chlorochromate added to it. After
stirring for 6 h under an argon atmosphere, the reaction mixture was filtered
through a celite pad, extracted several times with ether and the combined
organic layers dried over anhydrous sodium sulfate. Evaporation of the
solvent followed by purification of the residue by column chromatography
(silica 96V 30% ethyl acetate in hexane), gave 16 mg (89%), of 17. 17
exhibited the following characteristics :

M.P. : 45 to 48°C.

1H NMR (CDCI3) : 5 5.35 (d, 1H, J=5Hz), 4.68 (s, 2H), 4.67 to 4.5 (m,1H),
2.0 (s, 3H), 1.99 (s, 3H), 1.04 (s, 6H).

IR (opera) : 2951, 2863, 1725, 1714, 1625 cm".

Mass spectnrm (706V) : m/e, (rel. intensIIY): 362, (3.85); 360, (10.94) [M-
CH3CHO]; 346, (11.77); 344, (33.81)[M-CH3COOH]; 331, (31.53); 329 (100);
295, (15.43); 293, (40.31); 129, (54.75).

Preparation of compound 18

Sodium hydride (1.2 mg, 0.05 m.mol); was added to 2 mL of tetrahydrofuran,
followed by the addition of 7.6 mL (0.05 m.mol) of diethyl malonate. After
stirring for 45 mins under an argon atmosphere, a solution of 15 mg

(0.04 m.mol) of 12 in 2 mL of tetrahydrofuran is added to it. The mixture
was stirred at room temperature for 5 h. It was then quenched by the
addition of saturated ammonium chloride and extracted with ether. The

combined organic layers were dried and the solvent evaporated to give a

54

white solid. Purification by column chromatography yields 14 mg (71.5%) of
18, and 3 mg (20%) of recovered 12. Compound 18 exhibited the following
properties:

M. P. : 168 to 169°C.

1H NMR (CDCI3) : 6 5.36(d,1H, J=4Hz), 4.66 (d, 1H, J=5Hz), 4.57 to 4.64
(m, 1H), 4.22 to 4.1 (two overlapping quartets, 4H,

J=7Hz), 3.64 (dd, 1H, J=6& 10 Hz), 3.08 (br. s, 1H), 2.92 (dd, 1H,

J=10&14 Hz), 2.55 (dd, 1H,J=6814 Hz), 1.99(s,3H), 1.68 (s, 3H), 1.23 (t,
6H, J=7Hz), 0.99 (s,3H), 0.84 (s, 3H) ppm.

13C NMR (CDCI3) : 6 170.51, 170.07, 169.19, 151.34, 127.11, 122.61,
73.88, 71.29, 61.83, 61.59, 52.53, 49.82, 49.78, 44.18, 38.07, 37.51, 36.87,
36.63, 35.59, 34.62, 31.58, 30.45, 27.72, 21.4, 21.22, 19.21, 16.81, 16.48,
14.06, 14.02 ppm.

IR (CDCI3) : 3480 (br), 2970, 2945, 2910, 1738, 1725 cm".

Mass spectrum (256V) : m/e, (rel. intensity) : 515, (6.64) [M- 15]; 452 (23.86)
[M-CH3000H & H20]; 437, (22.77); 310, (30.61); 173, (75.27); 160, (100).

Alkylation of 12 with dimethyl malonate

To a suspension of 12 mg (0.5 m.mol) of sodium hydride in 2 mL of
tetrahydrofuran was added 0.06 mL (0.5 m.mol) of dimethyl malonate in 2 mL
of tetrahydrofuran. After stirring for 1 h under an argon atmosphere, a
solution of 81 mg (0.2 m.mol) of 12 in 1 mL of tetrahydrofuran was added.
The mixture was stirred for a further 10 h. The reaction was then quenched
by the addition of water. Extraction with ether and evaporation of solvent
gave a white solid which was purified by column chromatography (silica-gel;
30% ethyl acetate in hexane) to yield 70.5 (75% yield) of 20 and 6 mg
(6%) of 19. The compound 20 exhibited the following properties.

55

(It:

NH

M.P. : 185 to 187°C.

1H NMR (CDCI3) : 5 5.35 (two overlapping doublets, 2H); 4.6 (m, 1H); 4.29
(dd, 1H, J=6.3&13Hz); 3.76 (s, 3H); 2.75 (dd, 1H, J: 138 18 Hz); 2.49 (dd,
1H, J=6.3&18Hz); 1.99 (s, 3H); 1.74 (s, 3H); 0.99 (s, 3H); 0.86 (s, 3H)
ppm- '

13C NMR (CDCI3) : 6 170.62,170.41,169.04,143.19,139.64,128.96,122.1,

78.53, 73.71, 52.62, 51.59, 49.4, 46.71, 45.95, 37.98, 37.42, 36.75, 34.69, 32.57,
31.24, 30.79, 27.63, 21.36, 21.07, 19.65, 19.19, 16.88 ppm.

IR (CDCI3) : 2950, 1752, 1737, 1726, 1440 cm".

Mass spectmm (70eV); m/e(rel. intensity) : 410 (75) [M-CH3000H]

395 (21), 370 (8.7), 355 (10.4), 295 (46), 157 (67.4), 135 (100).
Rearrangement Of 20 IO 21 2

To 50 mg (0.1 m.mole) of 20, in 3 mL of diethyl ether, was added 9 mg of
Zinc - Copper couple. The mixture was stirred under an argon atmosphere
while a solution of 0.013 mL of trichloroacetyl chloride in 3 mL of ether, was
added dropwise. After refluxing for 4 h. the reaction mixture was filtered
through a celite pad and washed successively with saturated aqueous
bicarbonate and brine solution. The combined organic layers were dried over
anhydrous sodium sulfate and the solvent evaporated to yield 43.5 mg (87%)
of 21. The product appeared to be a mixture of epimers (4:1) from the

1H NMR. The compound 21 exhibited the following characteristics.

1H NMR (CDClg) : 6 5.68 (dd, 1H,J= 1.5 ast); 5.34(d,1H,J=4Hz); 4.6
(m, 1H); 3.75 (s, 3H); 3.6 (dd, 1H,J=6818 Hz); 2.02(s,3H); 1.67 (s, 3H); 1.03
(s, 3H); 0.97 (s, 3H).

IR (CDCI3) : 2950, 1775, 1735, 1720 cm".

56

Hydrolli

I147 ms
3110I I
6510' reflux
raid an!
IRWIN;
ted to ‘
~30. alm<
her em a
re Mia
titrated
it comm

tired as

Hydrolysis and decarboxylation of 21

To 47 mg (0.1 m. mol.) of 21 in 3 mL of methanol, was added 3 mL of
0.1M of methanolic potassium hydroxide solution. This mixture was stirred
and refluxed for 3 h. under an argon atmosphere. The mixture was then
cooled and acidified to pH 5 by the dropwise addition of cold 0.1N
hydrochloric acid. The solvent was then evaporated and 5 mL of benzene
added to the white residue. The benzene solution was refluxed under an
argon atmosphere, for 1 h. It was then cooled and extracted with ether. The
ether extracts were washed successively with water and brine. The combined
ether extracts were dried over anhydrous sodium sulfate and the solvent
evaporated to yield 32 mg of a white solid. Examination of the spectra of
this compound revealed that it was identical to 23. This compound was

obtained as a single isomer.

57

Hydrolysis and decarboxylation of 21

To 47 mg (0.1 m. mol.) of 21 in 3 mL of methanol, was added 3 mL of
0.1M of methanolic potassium hydroxide solution. This mixture was stirred
and refluxed for 3 h. under an argon atmosphere. The mixture was then
cooled and acidified to pH 5 by the dropwise addition of cold 0.1N
hydrochloric acid. The solvent was then evaporated and 5 mL of benzene
added to the white residue. The benzene solution was refluxed under an
argon atmosphere, for 1 h. It was then cooled and extracted with ether. The
ether extracts were washed successively with water and brine. The combined
ether extracts were dried over anhydrous sodium sulfate and the solvent
evaporated to yield 32 mg of a white solid. Examination of the spectre of
this compound revealed that it was identical to 23. This compound was

obtained as a single isomer.

57

APPENDIX - I

58

 

 

 

 

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ELL
amp

_ . a: _ hit-4 «r . 3

 

 

 

 

 

 

 

 

 

 

 

 

 

C-13 NMR of 11

 

 

99

 

. I . .O—‘I-QO

 

. .3
.1: ..3—

 

 

 

.I- ...: :3.

...I II . 80:...2388m
. al.-nannuv. . .....zrxx.

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of 11

‘100

33v :ww ::~ 3mm :3» . om~ oo_ m 2

ma“ «m

 

 

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(A

 

 

wmq

.. r .H. .3

 

 

 

 

Mass spectrum of 11
101

 

 

 

 

 

 

 

 

 

 

 

 

M. J. i WMW‘LL

 

 

 

_...;

i Proton NMR of 11

102

0.9

. f3

1

2.9

. f2

. ['3

S

8.0

. B

7
/

8.8 8.8 8.N 8.n

ELL

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#:q_J41:4qq:4424a3qfiT.n:411

 

 

 

 

:qAA: H

 

 

 

“11:44:.Iqu—IIIZT—iil:

 

1J7

 

 

Proton NMR of 13

I ()3

 

 

 

 

 

 

 

_
51.2.3 ..3. ... I.:¢o- . . . 3.3.3 . I.I -.. I .r .. Ir .. l .r .--
...: .2313; u I. .. II-.. I ..3 . IIII . . \.P.|.I.n
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co: 002 002 00-. ooofi co: oOOn can

 

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06

.. — ...—Irv“ .

 

104

 

 

 

 

 

Proton NMR of

[05

28

 

 

 

fiv—

 

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ELL
.8.\. Sr 88 Sm

1.r1_ 1.1141111 _IIIfiII1.IJ4I_.I-E—II1I._T1JIWIIJWIIJII

H.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

8m: 8

$32.}... . . ...-......

r #

4.144142

 

0-13 NMR of 28

«m

 

I a... Ev.
. 10:12:??-

 

 

IR of 28

107

 

 

 

 

_ _ . _ .— . . . _ . . ..... . Li. .I. —1m . a _ . . . ._‘m.d. .1- «u A.
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. nmm ~00 mmN .
. «mm . t
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.. 1
._ r
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th
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Mass spectrum of 23

l08

.®.8 .E.~
,Prrprphrrpppppp—P—PPPPPP—pp :prrpb: FPPPCPPF—_PPPPPPP——PpprrP—~PF~__

8.N

8.8

rear

8.m

8.m

8.h

 

bp—
4

I]:

 

 

 

 

 

 

.3.

 

 

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8

Proton NMR of 18

109

 

. I... Ir I.I II .. 2.1. 3:.

. u 1 89:22.33:
. .
a .3 n d .530:

coma

IR of 18

PF—II. v.

110

 

 

 

mhgo: zomHQMJm mN

on. so“ on

. com
5 __ -.N _. ___ a; _ . a
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C-13 NMR of 18

112

8

. 8

8.8 E

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“III| \o

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Proton NMR of 19
113

02000
m.2000

 

 

 

ELL

 

I I I “lb
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8 y. 8 N 13.1 - 1 1:2: .1:qu
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Proton NMR of 21

119

 

 

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350

 

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C-13 NMR of 6

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10.

11.

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45.

46.

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126

47.

48.

49.

50.

51.

(a) MM2 calculations were run on an IBM - AT computer
using programs distributed by Serena Software, Box 3076,
Bloomington, IN 47402. These programs were adapted from
the original MM programs of Allinger47b by J. J. Gajewski
and K. E. Gilbert.; (b) Burkert, U.; Allinger, N. L. Molecular
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Washington, 1982).

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McMurry, J. E. Org. React. 1976, 24, 187.

127

W

Among carbon-carbon bond forming reactions, cycloaddition reactions
occupy a position of particular significance. An attractive feature of these
reactions is the ”simultaneous” formation of two bonds with the generation of
up to four chiral centers‘. The most prominent of the cycloaddition reactions
is, undoubtedly the 411 +211 cycloaddition reaction. Since its discovery nearly
sixty years agoz, the reaction has found extensive application in the
synthesis of a wide array of complex organic moleculesa. The high yields,
mild reaction conditions, high stereoselectivity and regioselectivify of this
reaction make it an invaluable tool to the synthetic organic chemist.
Furthermore, the mechanism of the bimolecular Diels Alder reaction is
sufficiently well understood, that the outcome of the reaction can be predicted
with a high degree of accuracy‘.

The intramolecular version of the Diels Alder reaction has added an
entirely new dimension to this already versatile synthetic method. This
reaction has made it possible to create complex multicyclic arrays in a single
step. Due to the entropic advantage of the intramolecular process, even
relatively unreactive dienes and dienophiles undergo cycloaddition reactions
in a facile manner. (fig 1). These factors have led to a tremendous growth in
the field of intramolecular Diels Alder reaction, as evidenced by the number

of reviews published on this topic in the recent pasts.

128

 

Figure 1

A major challenge in any synthetic strategy using the Diels Alder
reaction is construction of the appropriate diene and dienophile moieties. The
elegance of a synthetic strategy involving an intramolecular Diels Alder
reaction depends to a great extent on facile construction of the requisite
diene and dienophile moities. Furthermore, it is often difficult to carry a
reactive diene or dienophile through various steps of a synthetic sequence.
One way of overcoming this problem is to use latent dienes and dienophiles
which may be unmasked at a convenient stage of the synthesis. This
strategy has been used to advantage by many workers.

An interesting example of an intramolecular Diels Alder
strategy using a latent diene and a latent dienophile is, lchihara's synthesis
of Coronafacic acids. In this synthesis a single thermolysis unmasked the
diene and dienophile and also accomplished an intramolecular Diels Alder
reaction. (fig 2). A conrotatory ring opening of cyclobutene unmasked the
diene, whereas a retro Diels Alder reaction with the elimination of fulvene,
uncovered the dienophile. The intramolecular Diels Alder reaction between
these two reactive species afforded a single product in 92% yield. This

control of stereochemistry is an attractive feature of this strategy.

129

 

 

Figure 2.

As can be seen in fig 2, steric requirements in the transition state
favor the exo arrangement more than the endo arrangement, which has a
severe nonbonded interaction between 2 - H and the acetal oxygens.
Latent dienophiles have proven especially useful in alkaloid
syntheses, due to the inherently unstable nature of many of the dienophiles

used in hetero Diels Alder reactions. Acylimines, which are dienophiles in

130

imino Diels Alder reactions, are invariably generated in_si1u from the
corresponding acetates and trapped by a suitable diene7. (fig 3). This
technique has been used in the syntheses of several indolizidine alkaloids.
An example is the synthesis of Elaeokanine A73, wherein Weinreb used an
intramolecular imino Diels Alder reaction as the key step. The diene was
generated from a dihydro thiophene dioxide, and the acyl imine dienophile

was generated from the corresponding acetate. (fig 4).

OrAcO O

 

 

 

Figure 3.
o H / \
N o
OTMS > OTMS
OAc Ill
-——>
302 C“?
CH CH3 \
3 /
\
OTMS /
N 0
CH3
Figure 4

131

Complementing the work on the use of acyl imines as dienophiles,
there have also been reports of reactions of N -acyl- 1 -aza-1,3-dienes in
Diels Alder reactionss.(fig 5). Although these species have not been directly
observed, even when the N- acyl function does not contain a dienophile,

there is strong evidence for their existence in these thermal reactions.

 

 

n=10r2.

Figure 5.

The acyl nitroso group is another reactive but unstable dienophile. In
the synthesis of Pyrrolizidine alkaloids, using an acyl nitroso group as the
dienophile, Gary Keck9 generated the dienophile Mu via a retro Diels
Alder reaction with the elimination of 9,10-dimethylanthracene. (fig 6). Thus
reactive species with only a brief lifetime may be efficiently employed in

Diels Alder reactions by generation from a latent or protected precursor.

TBDMSO

 

Diene moities are commonly masked as dihydrothiophene dioxide. lts
ease of preparation and thermolysis make it highly useful in synthesis of
reactive dienes. Martin10 has used this masked diene in several alkaloid

syntheses for intramolecular 4 + 2 cycloadditions of enamides. (fig 7).

 

 

S
02
O‘VK 0 r
< O '
O C6H4OM8 CsH4OMe

Figure 7.

Our work is aimed at using cyclobutanones as precursors for
reactive dienes. We proposed to generate reactive dienes by thermolysis of

cyclobutanone silyl enolethers and use these in Diels Alder reactions. (fig 8).

 

o oms oms
fl _. [1’ _...
R n
R
Figure 8.

The ring strain inherent in cyclobutene systems make appropriately
derivatized cyclobutanones suitable candidates for further elaboration by
thermal bond cleavage. Cyclobutene is known to undergo facile ring opening

to butadiene. The thermolysis of benzocyclobutenes11 and their use as

133

dienes in intramolecular Diels Alder reactions have been studied extensively.
(fig 9)

 

Figure 9

In contrast, however, thermolysis of cyclobutanone derivatives have not been
examined in detail. One noteworthy example in this direction is Trost's use of

2- methoxy-3- phenylthio buta-1,3-diene as a latent diene‘z. (fig 10)

 

O SPh SPh
Ct ——»_. ——»
o
CH3° Methyl vinyl ketone. PhS
‘
PhS CH30
Figure 10

It is interesting to note here that phenyl thio rather than the methoxy group

is controlling the regiochemistry in the thermal process where as methoxy

134

group plays a greater role in the catalyzed reaction. This approach permits
the obtention of a regiochemistry that complements that obtained with usual
dienes such as 2 - methoxy butadiene.

We proposed to study the synthesis and thermolysis of cyclobutanone
silylenolethers, and their use in Diels Alder reactions. An attractive feature of
this strategy is that the expected Diels Alder adducts incorporate potentially

useful functional groups (fig 11).

 

 

/ \ E R
OSJMO3 r E
OSiMeg I
A f< _1
———>
M63310
R \ /
Figure 11

Although cyclobutanones are potentially very useful intermediates in
organic synthesis, their application has been limited by the methods available
for their construction. The 211 +211 cycloaddition reaction provides a simple
and direct route to this system. The ready availability and inexpensive nature
of the reagents used, mild experimental conditions and good yields are some
attractive features of this reaction‘3a. Furthermore the reaction is regiospecific.
In the favored adducts, the most nucleophilic carbon of the olefin is always
bonded to the sp-hybridized carbon atom of the ketone. The reaction is also
chemoselective. Addition occurs preferentially to the most nucleophilic and
the least hindered double bond“.

135

Dichloroketene is an extremely reactive species and is commonly
generated in situ and trapped by olefins. It is usually generated either by
dehydrohalogenation of dichloacetyl chloride, using triethyl amine,15a or by
zinc dehalogenation of trichloroacetyl chloride‘5b‘d. Early researchers
encountered several problems with both methods. Triethyl amine catalyzed
the decomposition of dichloroketene. Zinc chloride, formed in the
dehalogenation reaction, catalyzed polymerization of several olefins.
Furthermore, dichloroketene itself was prone to polymerization under these
conditions.

Recently, several methods have been developed to minimize side
reactions catalyzed by the acidic zinc salts formed during dehalogenation of
the acid chloride. Brady and Bak15b noted that high dilution conditions
helped overcome the problem of ketene polymerization. Hassner reported that
use of phosphorous oxy chloride improved the yield of cycloadducts and
minimized unwanted side reactions‘5c. He proposed that phosphorous oxy
chloride complexes the zinc cation formed in the reaction, thereby
deactivating it. In the reaction of dichloroketene with allyl ethers, higher
yields of cycloadducts were obtained by using glyme as a cosolvent with
ether15d.

The dehalogenation synthesis of dichloroketene initially called for the
use of activated zinc. Mehta has reported that commercial zinc can be used
for this reaction provided the reaction mixture was agitated by ultrasonic
energy”. The yields compared favorably with those reported for other
methods and the reaction times were considerably shorter.

Here we describe our attempts at synthesizing various cyclobutanone

derivatives and converting them to their silylenolethers. We also describe the

136

results of our attempts at using these silylenolethers in Diels Alder reactions,

both intramolecular and intermolecular.

137

In our study of 3- substituted cyclobutanones as precursors to 1 - alkyl -
3- siloxy - substituted 1, 3 - butadienes, we chose n - octene (1) as our initial
substrate. In our hands, the zinc dehalogenation method of generating
dichloroketene gave the best results. Using Brady's high dilution

procedure15b

, we isolated 2,2-dichloro-3-hexyl cyclobutanone (2) in
excellent yield (> 86%). All the spectroscopic evidence were in agreement
with this structure. Dehalogenation of the on,0l -dichloro cyclobutanone 2,
was accomplished by treatment with zinc and acetic acid”. The reduction
proceeded smoothly to give 3- hexyl -cyclobutanone (3), in near quantitative

yield from 2 (fig 12).

Cl n-CsH 3
ccgcom 0' Zn 1
—__> ——>
Zn - Cu HOAC
O O
l 2 3

Figure 12

Having synthesized the requisite cyclobutanone precursor we

proceeded to generate the corresponding silyl enol ether. This proved to be

138

a much tougher task than we had earlier anticipated. Treatment of 3 with

triethyl amine in dimethyl formamide1861

and trapping the enolate with
chlorotrimethyl silane followed by the usual aqueous work up resulted in
complete recovery of starting material. Use of lithium diisopropyl amide as a
base gave identical results‘ab. Several other methods were also attempted
but without any success”. Since it is known that ten-butyl dimethyl silyl
enolethers are much more stable compared with trimethyl silyl enolethers, we
modified our approach slightly and attempted the synthesis of tert-butyl
dimethyl silyl enolether of 3. The lithium enolate of 3, generated by its
reaction with lithium diisopropyl amide, was treated with hexamethyl
phosphoramide and tert- butyl dimethyl silyl chloride‘ec. However after the
usual aqueous work up only the starting material was recovered.

In all the above experiments, a GC trace of the reaction mixture before
work up indicated probable formation of the desired silylenolether (GC - Mass
spectrum). Hence we concluded that the enolether was sensitive to aqueous
work up and was easily hydrolyzed to the ketone. We decided therefore to
avoid the aqueous work up and attempted to isolate the enol ether by
distillation. However, on evaporation of the solvent (tetrahydrofuran),
substantial quantities of lithium chloride precipitated, making the distillation of
product very difficult.

The problem of isolating the silyl enol ether was finally overcome in the
following fashion. The enolate of 3 was generated using lithium diisopropyl
amide and trapped with trimethyl silyl chloride. After the reaction was
complete, an excess of dry pentane was added to the reaction mixture
resulting in precipitation of lithium chloride. The mixture was allowed to stand
until precipitation of lithium chloride was complete. The solution was then

filtered under an argon atmosphere. The clear solution was evaporated under

139

vacuum to remove the solvent and the residue purified by bulb to bulb
distillation. The colorless oil obtained possessed all the spectral features
expected for silyl enolether 4. Table 1 shows some important 1H NMR, 13C
NMR and IR values of compound 4 and those reported in the literature19 for

cyclobutanone silyl enolether.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O OSiMe
Jj LDA, -78°C 3
b
4
Figure 13.
I l 5 (130) sletny. IR;vC=5 cm"
r 1 C(1) C(2) CH3
'epwed 148.48 102.15 0.10 4.52 1615 - 40
observed 147.96 107.58 0.88 4.64 1617 - 40
for 4.
Table l.

A survey of the chemical literature reveals very little information
regarding the preparation and isolation of cyclobutanone silyl enolethers. 1,2-
Bis (trimethylsiloxy) cyclobutene has been synthesized by an acyloin
condensation”. Clark et.al have reported generation of the enolate of
cyclobutanone by the reaction of the corresponding a-chloro compound with
dimethyl copper lithiumz‘. They have used these enolates in aldol

condensations. Although they refer to the reaction of this enolate with

140

trimethyl silylchloride, it is not entirely clear whether they have isolated the
silyl enolether (fig 14). They also report that reaction of 20 with lithium

diisopropyl amide failed to generate the desired enolate.

 

0 0
/° /
<———— ———>
, I C. I H
Me Me Cl Me CI
20
/ \
LDA

 

 

 

Figure 14.

The silyl enolether 4 was stored under an argon atmosphere, and in
this fashion it could be used over extended periods of time. However,
exposure to moisture causes rapid hydrolysis to the cyclobutanone 3.
Thermolysis of 4, at 230°C generated the corresponding diene, which was
trapped by benzoquinone to give the expected Diels Alder adduct. (fig 15).
The thermolysis was conducted by passing a solution of the silyl enolether
in tetrahydrofuran, through a pre- heated vertical column packed with glass
beads. The hot vapors were collected in a receiver cooled with liquid
nitrogen. This flask also contained a solution of the dienophile in
tetrahydrofuran. The thermolysis was conducted under an argon atmosphere

and the entire reaction was completed in less than five minutes.

141

O

(3 °
M83310

0

——>

A 00

06m, 0
21

Figure 15.

Encouraged by these results, we attempted to synthesize other
reactive dienes by the same procedure. Our next substrate was the
methylene derivative of p-cyclocitral (fig 16). This olefin 5 was prepared in
good yield from tB-ionone22 (fig 16).

As expected, on reaction of 5 with dichloroketene addition occurred
exclusively at the less hindered double bond to give 6. Dehalogenation of 6
with zinc and acetic acid gave the cyclobutanone derivative 7. Reaction of 7
with lithium diisopropyl amide followed by trapping of the enolate with
trimethyl silyl chloride as described earlier, gave the expected silyl enolether
8. Attempts to achieve a cleavage of the four membered ring of 8 followed
by an electrocyclic ring closure did not succeed. This thermolysis was
complicated by a methyl rearrangement, and resulted in a complex mixture of

products (fig 17).

142

NaOCl
O ——’
OH

O o
Cu20
Quinoline
A
CH;- PPha
—._.>
CHO
5
Figure 1 6

 

CCISCOCI
—_>
Zn/Cu
5
LDA ,-78°C
TMSCl

9+ .

Figure 17.

  

OSiMea

Realizing that 8 was perhaps an anomalous case, we continued to

explore this strategy further with other substrates. We decided to attempt an

143

intramolecular Diels Alder reaction and chose the olefin 9 (fig 18) as our

substrate.

0

W OEt

Figure 18.

We anticipated that the 211 +211 cycloaddition of 9 with
dichloroketene would occur preferentially at the terminal double bond. Further
elaboration of the cyclobutanone as described earlier would lead ultimately to
diene 10 (fig 19). Compound 10 possesses both a reactive diene and a
reactive dienophile, and is therefore a suitable substrate for an intramolecular
Diels Alder reaction. The chain length connecting the diene and the

dienophile in 10 is also appropriate for an intramolecular Diels Alder

reaction.

Measio
M
\ CB
1 0
Figure 19.

Another attractive feature of this study was the possibility that the
cyclobutanone silylenol ether 11, might undergo a Lewis acid - catalyzed

intramolecular Michael reaction23 (fig 20). The substituted bicyclo [4.2.0]

144

octanone expected from such a reaction would offer a number of subsequent

transformations, having potential synthetic applications.

MeaSiOW Lewis acid
------ -> l
051

1 1 E10

 

Figure 20.

Olefin 9 was synthesized, starting from 3, 3 -dimethy| glutaric acid, in
six steps“. 3, 3-dimethyl glutaric acid 12, was converted to 3, 3-dimethyl
glutaric anhydride 13, by refluxing in acetic anhydride. Reduction of
anhydride 13, using sodium borohydrlde gave the 5 -lactone 14, in near
quantitative yield. Lactone 14, was then reduced with diisobutyl aluminum

hydride to the lactol 15 (fig 21).

 

 

o O O
HO OH acetic anhydride
—->
O O
1 2 1 3
NaBH,,
4— ‘—
1 5 1 4
Figure 2 1 .

145

Wittig reaction of lactol 15, using carboethoxy methylene triphenyl
phosphorane, yielded alcohol 16 as a 6 :1 mixture of E and Z isomers
(1H NMR). This mixture was oxidized to the aldehyde 17 (E to Z ratio 6 :1)
by the action of pyridinium chlorochromatezs. The isomeric aldehydes were
easily separated by flash column chromatography; and the E isomer was
converted to the corresponding methylene derivative, 9 by a Wittig reaction

using methylene triphenyl phosphorane (fig 22).

O

 

 

O OH
EtOOCCH = Pen3
> HO 0E!

16

15 6 : 1 ; E : 2

FCC
0
NW CHE: ”“3 H O
f
05' W
9 O \ 0E1

17

Figure 22.

On reaction with dichloroketene, olefin 9 yielded 18 via a 211 +211
addition to the terminal double bond. The internal double bond in 9 is not
only more sterically hindered but also less nucleophilic compared to the
terminal double bond. The cycloadduct 18 on treatment with zinc and acetic

acid was reduced to the dehalogenated compound 19 (fig 23).

146

:1:

O

MOB

 

9
colacOCI
Zn — Cu
Cl
0 CI o o
‘ . \ Zn/HOAc \ COzEt
OEt ’
1 8 1 9
Figure 23.

Our next step was to generate the silyl enolether of 19. We were
aware of the presence of more than one acidic hydrogen in 19. Since
hydrogens 0: to a ketone are generally more acidic than hydrogens Y to the
carbonyl of an 6,8 - unsaturated ester, we believed we could achieve
selective deprotonation of the former. Furthermore, the Y -carbon atom of 19
is neopentyl in nature, and hence abstraction of a y - hydrogen would be
further disfavored. We were concerned however, that 19 might undergo an
intramolecular Michael reaction on treatment with a strong base as shown in

(fig 24).

 

Figure 24.

147

1“;

When 19 was reacted with one equivalent of lithium diisopropylamide
at -78°C, an orange red color ensued. The mixture was warmed up slowly to
0°C and quenched by the addition of trimethyl silyl chloride. The red
coloration disappeared as soon as trimethyl silyl chloride was added to the
reaction mixture. Addition of pentane to the reaction mixture caused
precipitation of lithium chloride, which was filtered off under argon.

Evaporation of the solvent yielded 11 as a colorless oil (fig 25).

O
M83310
W002 Et _MM 002121

TMSCl

11
Figure 25.

The structure of 11 was evident from its spectral features. A signal at
6 4.58 in the 1H NMR of 11, and an infrared absorption at 1618 cm"1
indicated the presence of the silyl enol ether moiety. The 13C NMR showed
no signal for the carbonyl of a cyclobutanone, instead signals at 6 147.95,
107.58 and 0.89 confirmed the presence of cyclobutanone silyl enolether.
The NMR data of 11 also indicated that the unsaturated ester was
unaffected in this transformation. The 1H NMR of 11 showed signals at
6 6.95 (dt), 5.81 (dt), 4.05 (q) and 1.3 (t) ppm corresponding to the
unsaturated ester. 130 NMR showed signals at 166.49, 146.64 and 123.38
corresponding to the 0t,p-unsaturated ester. Compound 11 was highly

sensitive to acidic conditions and was stored and handled under an argon

atmosphere.

148

Thermolysis of 11 at 200°C yielded a single product (by thin layer
chromatography). However the spectroscopic characten’stic of this compound
indicated that it was not the expected intra molecular Diels Alder product.
We were unable to determine the actual structure of this new compound.
The identity of this compound and also the course of the thermolysis of 11
are still under investigation in our laboratory.

We also explored the reaction of 11 with Lewis acids. We expected
that 11 would undergo an intramolecular Michael reaction, as suggested
earlier (fig 20). However, treatment of 11 with various Lewis acids resulted
in the complete recovery of the corresponding cyclobutanone 19.
Presumably, Lewis acids cleave the silyl group first, causing regeneration of
the cyclobutanone. Compound 11 undergoes intermolecular Michael reaction
with other Michael acceptors when activated by titanium tetrachloride. Thus
when a solution of benzylidine acetophenone (chalcone) in methylene
chloride at -78°C, is treated with 0.3 equivalents of titanium tetrachloride and
0.2 equivalents of titanium tetraisopropoxide, followed by addition of a
solution (1 equivalent) of the silyl enol ether 11 in methylene chloride, the
Michael adduct 22 is isolated along with some cyclobutanone 19.

(fig 26).

149

llt

O

.1.
0E!

Tic:4

“(0 -< )4

l -78°c

 

 

Figure 26

In summary it may be said that we have achieved some degree of
success in our strategy of synthesizing reactive dienes from cyclobutanones.
We can now synthesize and isolate cyclobutanone silyl enol ethers in good
yields from the corresponding ketones. We also have learnt that these silyl
enolethers can be converted to reactive dienes by thermolysis. However the
thermolysis reaction needs to be studied in much greater detail and its
reaction conditions optimized. This should make this approach a useful

synthetic method.

150

:s' arg
llag'le
were i

* ljbt

738‘. l

 

fieneLaL

Except where indicated, all reactions were conducted under dry nitrogen
or argon, using solvents purified by distillation from suitable drying agents.
Magnetic stirrers were used for small scale reactions; large scale reactions
were agitated using paddle stirrers. Organic extracts were always dried over
anhydrous sodium sulfate or anhydrous magnesium sulfate. The progress of
most reactions were followed by thin layer chromatography and/or gas liquid
chromatography. Visualization of the thin layer chromatograms was effected
by 30% sulfuric acid with subsequent heating.

Analysis by GLPC was conducted with a Varian 1200 gas
chromatograph. Flash chromatography was carried out on flash silica
(37-53 mesh) as suggested by Still et al. Melting points were determined on
a Hoover-Thomas apparatus (capillary tube) and are uncorrected. Infrared
spectra were recorded on a Perkin-Elmer 237B grating spectrophotometer.
Proton magnetic resonance spectra were taken in deuterochloroform solutions
with either a Varian T-60 or a Bruker 250 MHz spectrometer and are
calibrated in most cases in parts per million (6) downfield from
tetramethylsilane as an internal standard. In some cases the chloroform peak
(7.24 ppm) was used as a standard for 1H NMR measurements. Carbon-13
NMR spectra were taken in deuterochloroform solutions with Bruker 250 MHz

spectrometer and are calibrated in parts per million (6) using

151

aided

in .

cit

"0b! P1
..lyt‘léoll

tetramethylsilane as an internal standard. Mass spectra were obtained with a

Finnigan 4000 GC/MS spectrometer.

Preparation of 2,2-dlchloro-3-methyl cyclobutanone 2:

To a solution of 1.56 mL (10 m. mol.) of n-octene in 100 mL of ether, was
added 920 mg (14 m. mol.) of zinc-copper couple. The mixture was refluxed
under an argon atmosphere and a solution of 1.32 mL (12 rn. mol.) of
trichloroacetyl chloride in 100 mL of ether was added dropwise over a
period of three hours. The mixture was refluxed for an additional 16 h,
filtered through a celite pad and washed twice with saturated sodium
bicarbonate solution. The organic layer was then washed with brine and
dried over anhydrous sodium sulfate. Evaporation of the solvent followed by
distillation of the residue (bulb to bulb distillation) gave 1.93 g. (86.9%) of 2
as a pale yellow oil. Compound 2 exhibited the following characteristics.

‘H NMR (CDCI3). 5 3.4 to 3.2 (m, 1H), 3.0 to 2.77 (m, 1H), 1.97 to1.82 (m, 1H)
Plim-

13c NMR (c0013) 5: 195, 88, 47.5, 45, 32, 31.8, 29.5, 27.5, 22.5, 14 ppm.

lR (CDCI3) : 2910, 2840, 1808 cm"

Mass spectrum (708V), m/e (rel. intensity): 222(1.8);224(1.1);182(15.4);
180(24.9); 109(55.3); 69(53.5); 56(78): 43(100).

Preparatlon of 3-hexyl cyclobutanone 3:

1.1 g. (5 m. mol.) of 1,1-dichloro-3-hexyl cyclobutanone 2, was dissolved in
10 mL. of glacial acetic acid and 1.32 g. of zinc added to it. The mixture
was refluxed at 90°C for five hours. The solution was cooled, filtered through

a celite pad and 300 mL of ether added to it. The other solution was

152

135.5%
mm
atrium

itsiu

washed with 10% aqueous sodium hydroxide solution, to a pH of 10. The
combined organic layers were washed with brine and dried over anhydrous
sodium sulfate. Evaporation of the solvent yielded a pale yellow oil which
was further purified by Kugel rohr distillation. The distillation yielded 730 mg.
of 3, (96% yield) as a colorless liquid with a strong odour. 3 exhibited the
following characteristic properties:

1H NMR (CDCl3): 6 3.2 to 3.07 (m, 2H); 2.72 to 2.6 (m, 2H); 2.45 to 2.27 (m, 1H)
Plim-

lR (CDCI3) :2929, 1775 cm".

Mass spectrum (709V):m/e (rel. intensity) 154(17):147(6.4);126(13);98(100).
Preparation of silyl enol ether 4:

To a solution of 3.1 mL. of diisopropyl amine in 20 mL. of tetrahydrofuran
was added, 11 mL of 2.2M n-butyl lithium. The solution was maintained at
0°C and stirred for fifteen minutes under an argon atmosphere. The mixture
was then cooled to -78°C, and a solution of 2.7 g. (18 m. mol.) of ketone 3
in 15 mL of tetrahydrofuran was added. The mixture was stirred for 30
minutes at this temparature and then warmed up to 0°C. A solution of 5.6
mL (44 m. mol.) of trimethyl silyl chloride in 3 mL of tetrahydrofuran was
added to it. The mixture was stirred for 2 h. and 100 mL of dry pentane
added to it. This caused the precipitation of lithium chloride. The mixture was
allowed to stand for an additional 0.5 h. to allow precipitation to be
complete. The solution was filtered under an argon atmosphere and the clear
filtrate evaporated in a rotary evaporator to yield 3.85 g. (98% yield) of 4 as
a colorless liquid. Compound 4 exhibited the following properties:

153

 

1H NMR (coca) 6 4.66(s,1H):2.64(dd,1H,J=4&14Hz):2.25(m,1H):2.0(d,
1H, J=14 Hz); 0.12(s, 9H) ppm.

130 NMR (CDCI3) 6 149, 107.6, 40, 35.8, 33, 32, 29.8, 28.3, 22.6, 14, 0.88 ppm.
IR (CDCI3): 2950,2910,1615 cm"

Mass spectrum (709V) :m/e (rel. intensity) :226(2.4); 211(2.0); 197(52): 141(100);
73(89.2).

Pyrolysis of 4 and its reaction with benzoquinone:

A vertical glass column was filled with glass beads and heated to 240°C
using a heating jacket. The temparature was monitored using a
thermocouple. A solution of silyl enol ether 4 (500 1.1L in 25 mL of THF)
was added dropwise to the hot column. The system was continually flushed
with argon and maintained under an argon atmosphere. The vapors
emerging from the hot column were collected in a receiver containing a
solution of benzoquinone in THF and cooled by liquid nitrogen. After the
thermolysis was complete, the liquid in the receiver was refluxed for one
hour and the compound purified by column chromatography. The cycloadduct
21 was obtained in 83% isolated yield. The adduct was the quinone rather
than the enone presumably due to oxidation of the initial product by excess
benzoquinone. The adduct 21 possessed the following properties.

1H NMR (CDCI3) 6 6.7(s,2H);4.9(d,1H):3.5(m,1H):3(m,2H;0.2(s,9H) ppm.
IR (coma) : 2900,2840,1685 cm".

Mass spectmm (709V) :m/e (rel. intensity): 332 (1.38);247(60.9);85(100);
73(39).[

154

IL‘ I

as.
J

‘sl
‘ :

r

at

Preparatlon of 5-Hydroxy-3,3-Dlmethylpentanolc acld lactone 14:

To a suspension of sodium borohydride (1.42 g) in 7 mL of tetrahydrofuran
at 0°C, was added over a half hour period, a solution of 3.7 g. of 3,3-
dimethylglutaric anhydride, in 18 mL of tetrahydrofuran. The resulting solution
was allowed to warm up to room temparature and stirred at this temparature
for four hours. The solution was then cooled to 0°C and was quenched by
careful addition of 12 mL of 1:1 hydrochloric acid solution. The addition of
the acid caused considerable effervescence. The solution was then washed
with brine and extracted with ether. The ether extracts were dried over
anhydrous sodium sulfate and the solvent evaporated. The resulting oil was
purified by column chromatography on 15 g 091 silica gel. Elution with 70%
ether in pentane gave 2.95 g. (88%) of 5-hydroxy-3,3-dimethylpentanoic acid
lactone 14. Compound 14 exhibited the following characteristics:

1H NMR(CDCI3) 5 4.35(t,2H,J=6), 2.30(s,2H), 1.70(t,2H,J=6), 1.10(s,6H).
lR (CDCI3) : 1740 cm"

Preparation of 2-hydroxy-4,4-dlmethyltetrahydropyran 15:

To a stirred solution of 5-hydroxy-3,3-dimethylpentanoic acid lactone (2.6 g.)
in 60 mL. of other at 20°C was added dropwise, over one hour., a solution
of diisobutyl aluminum hydride (22 mL of 1M solution in hexane). The

resulting solution was stirred for an additional hour and then quenched by
the addition of 17 mL of methanol. The solution was then allowed to warm
up to room temparature and stirred overnight. The resulting suspension was
diluted with 30 mL of 30% sodium potassium tartarate (3 x 30 mL). The

combined aqueous layers were then extracted with ether and the combined

155

organic layers dried over anhydrous sodium sulfate. Evaporation of the
solvent and purification of the resulting liquid by column chromatography
(silica-gel: 70% ether in pentane) yielded 2.426 g. (92%) of 15. Compond
15 exhibited the following properties:

1H NMR (CDCI3) 5 4.96(m, 1H0, 4.8(d, 1H,J=4), 4.18to 3.37(m, 2H); 1.95 to
1.10(m, 4H), 1.05(s, 6H).

IR (CDCI3): 3575; 3300 (broad) cm“.

Preparation of Etyhl 7-Hydroxy-5,5-dlmethylhept-2-enoate 16:

A stirred solution of 9.318 9 (26.588 m.mol) of Carboethoxy methylene
triphenylphosphorane and 22.3 g (17.8 m.mol) of the pyran in 70 mL of
acetonitrile was refluxed for 34.5 h. Most of the solvent was removed in
vacuo, 100 mL of ether added, and the mixture stirred for 2 h. The white
solid formed was filtered off and washed thrice with cold ether. The solvent
was again removed in vacuo and 50 mL of 70% ether in pentane was
added. After half hour of stirring, the solid formed was once again filtered off
and the filter cake washed with 70% ether in pentane. The solvents were
removed in vacuo and the resulting material was purified by column
chromatography. Elution with 70% ether in pentane gave 3.35 g. (95% yield)
of cis and trans (1:6 respectively) unsaturated hydroxy ester 16. The E-
isomer exhibited the following properties.

1H NMR (CDCI3) 6 6.87(overlapping dt, 1H, J=16 & 8 Hz), 5.72(dt, 1H, J=16&1
Hz), 4.07(q, 2H, J=7 Hz), 3.56(t, 2H, J=8 Hz), 2.90(br s, 1H), 2.0(dd, 2H, J=8 &1 Hz),
1.42(t, 2H, J=8 Hz), 1.17(t, 3H, J=7 Hz), 0.98(br. s, 6H) ppm.

156

Preparation of Ethyl (Z) and (E) - 7 - Oxo - 5,5 - dimethylhept - 2 -

9110816 17:

To a stirred suspension of 5.2 g. of pyridinium chlorochromate in 24.2 mL of
methylene chloride and 5.2 g. of celite at room temparature was added 3 g.
of the alcohol 16, in 6 mL of methylene chloride. The solution turned dark
brown and almost black. After stirring for 3.5 h. the suspension was diluted
with ether andfiltered through flourosil. The filter cake was washed several
times with ether and the solvent evaporated to yield a colorless oil.
Purification of this oil by flash chromatography (15% ethyl acetate in hexane)
gave 2.2 g. (74%0 of the (E) isomer and 0.37 g. (12.5%) of the (Z) isomer
of 17. The E -isomer of 17 exhibited the following characteristics:

1H NMR (CDCl3) 6 9.89(t, 1H,J=3 Hz), 6.90(overlapping dt,1H,J=16&8Hz),
5.78(dt, 1H, J=16&1 Hz), 4.05(q, 2H, J=7 Hz), 2.27(d, 2H, J=3 Hz), 2.30(dd, 2H, J=8
81 Hz), 1.17(t, 3H, J=7 Hz),1.15(s,6H) ppm.

130 NMR 5 203, 166, 145, 125, 60.1,55, 46, 36, 28, 14 ppm.

IR (CDCla) : 2788,1784,172acm".

Mass spectrum (709V) : m/e, (rel. intensity) : 198(1.35),183(0.52),168(3.97),
153(17.24), 139(8.14), 114(55.82), 86(66.38), 81 (36.58), 68(35.61), 57(52.42),

41 (100).

Preparation of Ethyl - (E) - 5,5 - dimethyl oct - 2,7 - dien - cafe 9:

Asolution of potassium tert-butoxide (294 mg. 2.6 m. mol) and methyl
triphenyl phosphonium bromide (937 mg. 2.6 m. mol), in 10 mL of toluene
was stirred for 20 minutes at -20°C. To the yellow ylide formed, was added
a solution of 400 mg. (2 m. mol) of the aldehyde 17 in 5 mL. of toluene.

The solution was stirred at -20°C for an additional 1.5 h., allowed to warm

157

1"“.
>4.

81‘

id

 

up to room temparature and stirred for further 3 h. The mixture was then
poured into cold water, and extracted several times with ether. The ether
extracts were dried over anhydrous sodium sulfate and the solvent
evaporated to yield an oil. Purification by chromatography using 20% other in
hexane as eluent, gave 331 mg. (83.6%) of the compound 9. Compound 9
exhibited the following properties :.

1H NMR (CDCI3) 5 7.02(overlapping dt, 1H, J=16 & 8 Hz), 5.75(dt & m, 2H),
5.05(m, 2H0, 4.07(q, 2H, J=7 Hz), 1.17(t, 3H, J=7 Hz), 2.1 (dd, 2H, J=1 & 8 Hz),
1.96(d, 2H, J=7 Hz), 1.17(t, 3H, J=7 Hz), 0.9(s, 6H) ppm.

lR (00013) : 1710,1650 cm“.

Mass spectrum (706V): m/e, (rel. intensity) : 196(0.52),181(1.0),167(20.99),
149(58.32), 114(17.79), 83(21.66), 71 (28.77), 5507.99), 41 (100).

Addition of dlchloroketene to olefln 9:

A 200 mL three necked flask equipped with a condenser, addition funnel,
magnetic stirrer and nitrogen inlet was flame dried while purged with
nitrogen. When cool, it was charged with 210 mg. of olefin 9, 100 mg. of
zinc-copper couple and 50 mL of dry ether. The mixture was heated to reflux
and to this refluxing mixture was added dropwise over a period of 2 hours,
a solution of 0.2 mL trichloro acetyl chloride in. 30 mL of ether. The mixture
was refluxed for 16 h. It was cooled, filtered through a celite pad, extracted
with ether and the ether extracts were washed with saturated aqueous

sodium bicarbonate solution. The combined organic layers were dried over
anhydrous sodium sulfate and the solvent evaporated to yield a pale yellow

oil. Purification by chromatography (20% ethyl acetate in hexane) gave

158

215 mg. (66% yield) of compound 18. 18 exhibited the following
characteristics:

1H NMR (CDCI3) 5 6.95(overlapping dt,1H,J=16&8Hz),5.85(dt,1H,J=16&1
Hz), 4.18(q, 2H, J=7 Hz), 3.2 to 2.8(m, 2H), 2.18(dd, 2H, J=8 & 1 Hz), 1.9(dd, 2H,
J=4 & 14 Hz), 1.26(t, 3H, J=7 Hz), 0.98(s, 3H), 0.95(s, 3H) ppm.

13CNMR (00013) 5 192.41, 166, 144.82, 1241.89.86, 59.98, 49.28, 44.91,

42.87, 42.29, 33.52, 26.88, 26.8, 13.91 ppm.
IR (CDCI3) : 1708, 1799 cm".

Preparation of compound 19:

A mixture of 153 mg of 18, 2 mL of glacial acetic acid and 352 mg of zinc
was stirred under nitrogen for 5 h. The mixture was cooled, filtered through
celite and extracted with ether. The ether extracts were washed with 10%
sodium hydroxide solution to a pH of 10. The ether layer was washed with
brine, dried over anhydrous sodium sulfate and the solvent evaporated to
yield a pale yellow oil. Purification by chromatography (20% ethyl acetate in
hexane) gave 106 mg. (88.5% yield) of 19. 19 exhibited the following
characteristics:

1H NMR (CDCI3) : 6 6.92(overlapping dt,1H,J=16&8Hz),5.78(dt,1H,J=16&
1 Hz), 4.02(q, 2H, J=7 Hz), 3.25 to 2.6(m, 4H0, 2.2(m, 1H0, 2.08(dd, 2H, J=1 & 8
Hz), 1.58(d, 2H, J=7 Hz), 0.98(s, 6H) ppm.

130 NMR (coma) : 5 208.07, 166.34, 145.69, 123.79, 60.23, 54.21,48.75,
45.32, 34.67, 29.64, 26.99, 20.25, 14.21 ppm.

IR (CDCl3) : 1775, 1710 cm".

Mass spectrum (70 eV); m/e, (rel. intensity) : 238(1.0),155(14.17),114(34.63),
83(40.74), 69(42.5), 55(100), 41 (81 .94).

159

Preparatlon of silyl enol ether 11:

0.92 m. mol of lithium diisopropylamide was generated by the reaction of
0.13 mL of diisopropyl amine in 7 mL of tetrahydrofuran, with 0.42 mL of n-
butyl lithium (2.2M in hexane) at 0°C. The solution was cooled to -78°C and
200 mg of 19 (0.84 m.mol) in 5 mL of tetrahydrofuran was added to it. The
solution instantly acqquired an orange -red color. It was stirred at -78°C for
another 40 minutes. The mixture was warmed up to 0°C and 0.43 mL (3.36
m.mol) of chlorotrimethyl silane was added to it. The red color disappeared
on the addition of trimethyl chloro silane. The mixture was allowed to warm
up to room temparature and stirred for four hours. It was then transferred
using a cannula to a 250 mL. round bottomed flask containing 150 mL of
dry pentane. The mixture was allowed to stand under nitrogen for fifteen
minutes. The white precipitate formed was filtered under nitrogen. The clear
filtrate was evaporated in vacuo, to remove the solvent. Nitrogen was
introduced into the system when the vacuum was broken. Extreme
precautions were taken at all stages of the reaction, to not expose the
compound to air and moisture. The yield of silyl enol ether 11, was nearly
quantitative. Compound 11 exhibited the following characteristic spectral
features:

1H NMR (CDCI3) : 5 6.95(overlapping dt,1H,J=16 &8 Hz),5.81(dt,1H,J=16 &
1 Hz), 4.58(s, 1H0, 4.05(q, 2H, J=7 Hz), 2.65(dd, 1H, J=4 & 13 Hz), 2.3(q, 1H, J=4
Hz), 2.05(m, 3H), 1.4(dd, 2H, J: Hz), 1.3(t, 3H, J=7 Hz), 0.98(s, 3H0, 0.97(s, 3H),
0.3(s,9H) ppm

13c NMR (CDCI3) : 5 166.49,147.95,146.64,123.38,107.58,60.01,47.39,
45.35, 41.65, 34.60, 28.96, 27.12, 14.17, 0.89 ppm.

160

IR (CDCI3) : 1618,1703 cm".
Mass spectrum (709V) : m/e, (rel. intensity) : 310(1.94),295(3.36),265(2.36),
237(2.94), 73(100).

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