mg mmam: REACHGN <3? THE
wwwwg swag

Thom foe- {fio chm 15 pl». D.
MECHEMN SMTE UNWEESETY
Phillip: LeRoy Mattiwn

£967

LIBRARY

Michigan State
University ‘

 

This is to certify that the
thesis entitled
THE FAVORSKII REACTION OF THE

PULEGONE OX IDES

presented by

Phillip LeRoy Mattison

has been accepted towards fulfillment
of the requirements for

M degree infihemistry

 

71%»? /% fled

Major professor

 

DMeFebruary 3. 1967

0-169

ABSTRACT

THE FAVORSKII REACTION OF THE
PULEGONE OXIDES

by Phillip LeRoy Mattison

The Favorskii reaction of the two isomers of pulegone
oxide is found to proceed stereospecifically and in good yield
to give ring-contracted acids. Isomer I, m. 57°, upon treat-
ment with sodium methoxide in glyme, gives cis— and trans-
S-methylcyclopentane carboxylic acid, trans-pulegenic acid,
and trans,trans puleganolic acid. Isomer II, m. 54°, gives
cis- and trans—S-methylcyclopentane carboxylic acid, cis- and
trans-pulegenic acid, trans,cis-puleganolic acid, and cis,
trans-puleganolide. Cis,trans—puleganolide may arise via an
epimerization of trans,cis-puleganolic acid, indicating that
the rearrangement is stereOSpecific, but that the products
may subsequently lose their stereochemical integrity.

The rearrangement is discussed in terms of a direct dis-
placement of the epoxide oxygen by an asanion, leading to a
cyclopropanone intermediate. Opening of this intermediate
occurs predominantly to give a tertiary anion beta to the
hydroxyl group. Elimination of hydroxide ion then leads to
pulegenic acid, and protonation results in puleganolic acid.

This protonation is also stereOSpecific, and proceeds with

Phillip LeRoy Mattison

retention of configuration, a result consistent with previous
studies of electrophilic carbanion substitution. These re—

sults reverse the previous assignment of pulegone oxide

configurations.
J32” x
I II
'CH3CH3
O:\§; ::: E
O

 

Ia

The conformations of I and II are discussed, and Ia and
IIa appear to predominate at room temperature. Using 50,6ar
and SB,BB-epoxycholestan-4-one as model compounds, the Cotton
effects of Spiro-epoxy ketones are found to be consistent
with a normal application of the Octant Rule. The chemical
shifts of‘the orhydrogens of I and II are rationalized in
terms of conformations Ia and IIa.

The recent literature of the Favorskii reaction is re-

viewed.

THE FAVORSKII REACTION OF THE

PULEGONE OXIDES

BY

Phillip LeRoy Mattison

A THESIS

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1967

To Karen

ii

ACKNOWLEDGMENT

The author expresses his appreciation to Professor

William Reusch for his inspiration and guidance during the
course of this investigation.

Appreciation is also extended to the National Institutes

of Health for a pre-doctoral fellowship from September 1965
to September 1966.

The author also expresses his gratitude to his parents
for their understanding and encouragement.

iii

TABLE OF CONTENTS

INTRODUCTION AND HISTORICAL BACKGROUND . . . . . . . .
RESULTS AND DISCUSSION . . . . . . . . . . . . . . . .
EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . .

Reagents. . . . . . . . . . . . . . . . . . . . .
Pulegone Oxide. . . . . . . . . . . . . . . . . .
Favorskii Reaction of Pulegone Oxide LXIII. . . .
A. Isolation and Structure Proof of Products
1. Methyl 5-methylcyclopentane car-
boxylate . . . . . . . . . . . . . .
2. Methyl trans-pulegenate. . . . . . .
5. Methyl trans,trans-puleganolate. . .
4. Conversion of methyl trans-pule-
genate to Cis,trans-puleganolide . .
5. Conversion of methyl trans,trans-
puleganolate to Cis,trans-pule-
ganolide . . . . . . . . . . . . . .
B. Direct Conversion of Pulegone Oxide LXIII
to Cis,transfipuleganolide . . . . . . . .
Favorskii Reaction of Pulegone Oxide LXIV . . . .
A. Isolation and Structure Proof of Products
1. Methyl cis- and trans-pulegenates. .
2. Methyl trans,cis-puleganolatef . . .
5. Cis,trans-puleganolide . . . . . . .
4. Conversion of methyl cis- and trans-
pulegenates to Cis,trans- and cis,
cis-puleganolide . . . . . . . . . .
5. Conversion of methyl trans,cis-pule-
ganolate to methyl cis-pulegenate
and cis,cis-puleganolide . . . . . .
B. Direct Conversion of Pulegone Oxide LXIV
to Cis,trans- and cis,cis-puleganolide. .
Treatment of Methyl Trans,cis-puleganolate with
Base . . . . . . . . . . . . . . . . . . . .
Treatment of Cis,trans- and Cis,cis-puleganolide
with Base. . . . . . . . . . . . . . . . . .
Deuterium.Exchange of Pulegone Oxide. . . . . . .

iv

Page

30
51
51
51
55
55
55
56
56

56

6O
6O
6O
61
61

61
61

65

65
65
66

66
67

TABLE OF CONTENTS - Continued Page

Conversion of Cholest-S-en-36,4B-diol EB-Tosylate
(XVII) to Cholest-S-en-4orol (XCIII) . . . . 68
Oxidation of Cholest-S—en-4orol to Cholest-S-en-
4-one (XCIV) . . . . . . . . . . . . . . . . 68
Conversion of Cholest-5-en-4-one to 56,66—Epoxy-
cholestan-4-one (LXXXIX) . . . . . . . . . . 68
Conversion of Cholest-S-en-4thl to 5a,60rEpoxy-
cholestan-4-one (LXXXVIII) . . . . . . . . . 69
46,56~Epoxycholestan-3-one (LXXXVI) . . . . . . . 71

LITERATURECITED................... 75

LIST OF TABLES

TABLE Page
1. Geminal Methyl Chemical Shifts. . . . . . . . . 44
2. Infrared and Ultraviolet Spectra. . . . . . . . 47

vi

LIST OF FIGURES

FIGURE Page

1. Nuclear magnetic resonance spectra of the pule-
gone oxide isomers. . . . . . . . . . . . . . . . 49

2. Circular dichroism spectra of pulegone oxide
’ LXIII . . . . . . . . . . . . . . . . . . . . . . 53

5. Circular dichroism spectra of pulegone oxide
HIV. 0 O O O O O O O 0 O O O O O O O O O O O O O 54

4a. Infrared spectrum of methyl trans,trans-pule-
ganolate (LXVIIA) in CC14 . . . . . . . . . . . . 57

4b. Infrared spectrum of methyl trans,trans-pule-
ganolate (LXVIIA) in CC14 . . . . . . . . . . . . 58

5. N.M.R. spectrum of methyl trans,trans—pulegano- _
late (LXVIIA) . . . . . . . . . . . . . . . . . . 59

6a. Infrared Spectrum of methyl trans,cis—pulegano-
late (LXVIIB) in cc14 . . . . . . . . . . . . . . 62

6b. Infrared spectrum of methyl trans,cis-pule-
ganolate (LXVIIB) in cc14 . . . . . . . . . . . . 63

7. N.M.R. spectrum of methyl trans,cis-puleganolate
(LXVIIB). . . . . . . . . . . . . . . . . . . . . 64

8. C.D. spectra of 5a,60repoxycholestan-4-one

(LXXXVIII) and 58,6B—epoxycholestan-4-one
(LXXXIX) in 95% EtOH. . . . . . . . . . . . . . . 7o

vii

INTRODUCTION AND HISTORICAL BACKGROUND

During the evolution of the Favorskii reaction, several
mechanisms have been proposed. Of these, three have re—
tained prominence. A semi-benzylic mechanism (eq. 1) was
put forth by Tchoubar i1);in 1959. According to this proposal,
the a' carbonsatom migrates to the arcarbon with the expulsion

of halide.1 On this basis, one would expect different acids

OR
I g~
R1 - C = 0 R1 - C - 06 on
6
OR c = o
(1) 9 \| 9 I
R2 - CH - x R2 - CH - x R; - CH - R2

to be derived from isomeric orhalo ketones.

However, in an elegant experiment, Loftfield (2) showed
that this was not always the case. 2-Chlorocyclohexane (I),
having C13 equally distributed between C1 and C2, gave an ester
of cyclopentane carboxylic acid (II) when treated with alco-
holic base (eq. 2). Degradation of II showed that 50% of the
C13 was at the carboxylic carbon, 25% at C1, and 25% at C2

of the cyclopentane ring.

 

1Throughout this thesis, "cf shall designate the carbon
atom bearing the leaving group; "cv" shall.indicate the other
carbon adjacent to the carbonyl. '

, O 50% j 02R
(2) 50%- 1 25%-— 25%
a a
I II

Application of the semi-benzylic mechanism to this reaction
would require the C13 to be equally distributed between C1
and the carboxylic carbon. Loftfield proposed the formation
of a cyclopropanone intermediate by intramolecular displace-
ment of the halide by an enolate anion (eq. 3). Opening of
the three membered ring in the correSponding hemiketal conju—
gate base would occur at both sides with equal probability,

leading to the observed product mixture.

0 o~ 090R
6 Cl ::-L.¥ 4:IL.*
m ——>.'—>—>

*COgR *COgR
‘ Q"
+

An alternate rationale, offered by Aston and Newkirk (5)
and later supported by Burr and Dewar (4), involved the manner
of formation of the cyclopropanone. Since the orbital
occupied by the a‘—anion must be parallel to the carbonyl
v-bond (see III), it seemed sterically difficult for it to

attain the necessary geometry for intramolecular expulsion of

OJ

halide. Instead, the enolate species (III) may spontaneously
lose halide ion to form a zwitterionic species which would
have two chief resonance Contributors (IVa and b).' From

LCAO-MO calculations, Burr and Dewar predicted that the

()
G /o 9) /°
()//. .GB () C)
0/920 '—"—> O/C/ocaeQ/C 0
-c./ ,\C, 7C?~0\Q_ 0 N-
/U I \X U ()= 0
III IVa IVb

Substitution Products
0

C/
\. ,/” ~\\\ ,/
/C_—__(f

reaction of III -—9*IV should be accompanied by an increase

Favorskii Products *6----

in resonance energy of ca. 14 kcal/mole. They further pre-
dicted that collapse of the zwitterionic Species to a cyclo-
propanone should be exothermic.

Fort (5) has commented that the zwitterionic species
should lack stability, since all the resonance contributors
have charge separation. To alleviate this alleged instability,
he proposed a stabilization through W-bonding. It should be
noted that in the "cyclopropanone" resonance contributor (IVc)
the two arcarbons are w-bonded; formation of a G-bond would

involve rehybridization of the carbon orbitals and rotation

IVc

about the abbonds. Thus, Loftfield's cyclopropanone is not
merely a resonance contributor to the zwitterionic form.

It might be expected that the zwitterionic intermediate
would be favored by a medium of high solvating power, while
the Loftfield mechanism would be favored by non-polar sol—
vents. If direct cyclopropanone formation occurs the products
should be stereOSpecifically related to the configuration of
the departing halide. On the other hand, one would not ex-
pect this stereospecificity to occur if the reaction proceeds
via the zwitterionic intermediate, since it is planar and may
collapse to either of two epimeric cyclopropanones.

Stork and Borowitz (6) reported a stereOSpecific re-
arrangement of orchloroketones Va and Vb in a non-polar solvent
(eq. 4,5). Treatment of epimeric 1-chloro-2-methyl-1-acetyl—
cyclohexanes (Va and b) with sodium benzyloxide in ether,
followed by hydrogenolysis of the resulting esters, gave the
acids (VIa and b) corresponding to inversion at the orcarbon

atom.

Clz’“\ : C02H

(4) ——+

Va VIa

’,C02H

(5)

H
VIb

 

House and Gilmore (7) observed the same stereOSpecificity
when Vb was treated with sodium methoxide in dimethoxyethane,
but obtained a 5:4 ratio of VIa:VIb when Vb was treated with
sodium methoxide in methanol. Similarly, Tchoubar and co-
workers (8), treating Vb with various bases in different polar
solvents, found varying ratios of VIa and b in the product
mixture.

The results in polar solvents are consistent with the
formation of a planar zwitterionic intermediate which as it
collapses to form cycloprOpanones, may experience asymmetric
induction, resulting in a stereoselective production of
products. Furthermore, it is possible that polar solvents
may effect an equilibrium between an already-formed cyclo—

‘propanone and its zwitterion.

The Favorskii rearrangement has been applied to a variety
of steroid substrates. When 2orbromo-Soscholestan-S-one(VII)
was treated with sodium methoxide in a methanol-ether mixture,
a 25% yield of methyl A-nor-SQrcholestane-Zascarboxylate plus
a small amount of methyl A-nor-SQrcholestane-Sarcarboxylate
was obtained (9) (eq. 6) (Pappas and Nace (10) obtained similar
products from Zorbromo-Sorprogestan-S,20-dione). Using any
hydrous ether as a solvent, approximately equal amounts of
the 20+ and Sosmethyl esters were found. Treatment of
4B—bromo-SB-cholestan-S-one (VIII) with sodium methoxide in
methanol-ether gave methyl A-nor-SB—cholestane-ZB-carboxylate
and methyl A-nor-58-cholestane-SB-carboxylate, each in 24%
yield (eq. 7). All of these products (from VII and VIII) are
those predicted on the basis of a stereospecific formation of
a cyclopropanone intermediate. It should also be noted that

in each case the departing halide is equatorial, a situation

 

M802C
2 5% small
amount
MEOZC \
‘ I g.
H

M802C

Br VIII 24%

O

that should be optimal for a stereospecific Favorskii re-

action.

The reaction of 5abbromocholestan-EB-ol-6—one (IX) with
sodium ethoxide in ethanol (11) gave a 56% yield of cholestan-
38,56-diol—6-one (x) instead of B—ring contraction (eq. 8).

While a number of different explanations for the observed

(a) } “\

' - a
AC ' 0 HO

IX X

OH

product have been offered (11,6), the fact that the orhalogen
is axial appears to be significant. As long as the cyclo-
hexane ring remains in a chair conformation, displacement of
an axial ossubstituent by an af-anion would be expected to be
difficult. Further, examples of this phenomenon are found

in the reaction of 9arbromopregn-4-ene-5,11,ZO-trione (XI)
with sodium methoxide in methanol, yielding 12osmethoxypregn—4—
ene—5,11,20-trione (XII) (12) (eq. 9), and in similar trans—
formations with other pregnane and ergostane systems (15).
Again, the axial bromine cannot be easily diSplaced by the
Clg-anion, and a mechanism involving SNg' attack by methoxide

on the enol (partial structure XIII) has been suggested (13).

 

“7W7

XI : XIII XII

House and co-workers (14,15) have studied the reactions
of the trans- and cis—9-chloro-1-decalones (XIV and XV,
respectively) with methoxide ion in two solvents. The ex-
‘clusive formation of solvolysis products in methanol (eq. 10,

11) suggests a zwitterionic intermediate; however, the same

 

— 58% 2% 40%

 

intermediate should be formed from both XIV and XV, leading
to identical product ratios from these isomers. The fact
that different product ratios are found indicates that some

other mechanism is in operation. Explanations of these

results (15) have included the formation of an alkylidene
epoxide (XVI), or an abnormal reaction of a cyclopropanone
hemiketal (XVII). These rationalizations do not overcome

all objections, and must be regarded as tenuous.

}1 H [CH3
. I
CH30\( cnsou'to ’. OH

 

XVI XVII

The Favorskii reactions of XIV and XV were also studied
in dimethoxyethane (DME) (15), and were found to give only
ring contracted esters in a predominantly stereOSpecific re-
arrangement (eq. 12,15). This is a surprising result in
view of the fact that the trans-chlorodecalone (XIV) possesses
a chloride which is rigidly held in an axial position.
However, examination of models shows that a twist-boat con—
formation of the ketone ring permits the af-anion to effect

a rear side displacement of chloride ion.

 

COgMe COgMe COgMe C02Me
Mr Ob 0‘. 0. to
DME ”: ”: :.
H H H
88% 2% A 5% 5%
COzMe PI C02Me Pi C02Me
a e .
——> oo o. a
H
XV XVI

52% 57% 11%

10

The predominant formation of the all-cis methyl hydrindane;
1—carboxylate (XVI) from XV is of interest, since it repre-
sents an abnormal opening of the cyclopropanone ring (see
XVII) to give a tertiary, rather than a secondary anion.

This anion must then be stereospecifically protonated to give
the cis ring system (eq. 14). Alternatively, a discrete
carbanion may not be formed at all, but rather proton trans-

fer may occur as the cyclopropanone hemiketal (XVIII) is opened.

The latter explanation seems more reasonable.

CoaMe 902Me Hfi\0Me

V.

MeO (3
Y? o- 5“ “A
Mae‘s”.
H H H H

XVII XVI XVIII

Another ashalodecalone system has been studied recently
by Smissman and co-workers (16). Treatment of 5—a-bromo-
trans-2-decalone (XIX) with sodium ethoxide in either ethanol
or DME gave no Favorskii acids. Only solvolysis products and
a ring-opened diacid were formed (eq. 15). The isomer having
an equatorial halide, S-e-bromo-trans-Z-decalone (XXa, R=H),
also gave solvolysis products plus a 15% yield of a hydrindane
carboxylic acid (XXIA, R=H) when treated under the same con-
ditions (eq. 16). Deuterium incorporation studies with XX
showed rapid exchange at the arcarbon, implying an epimeri-

zation of the osbromide. It was suggested that the presence

11

(15~ E9229 Solvolysis Products
EtDH

or DME
XIX Br

0
/
Solvolysis
1 NaOEt
( Br WW + .. °°2H

or DME
R
R H
XXa, R = H XXIa, R = H
(XXb, R = CH3 XXIb, R = CH3

of axial halide was responsible for the low yield of XXIa.
Accordingly, 2-e-bromo-9-methyl-trans-3-decalone (XXb, R=CH3)
was synthesized with the expectation that the added axial
methyl group would hinder the formation of the axial bromide,
and thus lead to increased yields of Favorskii products.
Indeed, under the same conditions, XXb gave ca. 40% yields of
XXIb. Smissman conCluded that in this system the Favorskii
reactions proceed by intramolecular displacement of halide
to give a cyclopropanone. If the zwitterion could also lead
to Favorskii products, these would have been expected from
the axial isomer also.

Favorskii-like reactions have been observed with ashalo
ketones having no dF-hydrogen. This type of reaction has been
separately classed as the Quasi~Favorskii reaction, and

requires a pseudo-benzylic mechanism.

12

2-Bromocyclobutanone has been observed to give cyclo-
propane carboxylic acid derivatives under Favorskii conditions
(eq. 17). The mechanism has been shown to be of the semi-
benzylic type by means of stereochemical, kinetic, and
deuterium incorporation studies (17). That a cyclopropanone
intermediate is not formed is not surprising in view of the

strain inherent in the requisite [1.1.0] ring system.

 

 

 

 

 

 

 

 

OH 9
(17) —K§2—81-> I, ———> [>—c02H
\Br Br
x,

The Favorskii reaction has also been used in the synthe-
sis of cubane (18,19). Due to the geometry of this system,
it is probable that this reaction also proceeds by a semi-
benzylic mechanism.

The Favorskii reaction of 17asbromo—Sarpregnan-SB-ol-
11,20-dione (XXII) has been‘extensively studied (20-25).
A stereospecific rearrangement would be expected to give
17fi-methyl-Sorpregnan-SB-ol-ll-one-l?arcarboxylic acid (XXIV);
however, the 17ormethyl isomer (XXIII) is found to predominate
(eq. 18). In the most recent study of this reaction, Deghenghi
et a1. (25) examined the incorporation of solvent deuterium
in the products. A single deuterium was found in both XXIII
and XXIV; undeuterated and polydeuterated species were absent.
It may be concluded from this that no exchange occurs prior to
rearrangement. Furthermore, a semi-benzylic mechanism can be

eliminated, since specific monodeuterium incorporation cannot

13

 

 

coan CH3
,a’CHB ,I‘COQH
(18)
90% 10%
XXII XXIII XXIV

be accommodated by this pathway. The authors favor a modified
cyclopropanone formation in rationalizing their results. In
the first step of this mechanism (eq. 19) an enolate anion is
formed; rotation about the C17-C20 bond places the enolate

oxygen in a position away from the bromine, thus relieving

0
g _. {g _. m

dipole-dipole interaction. .Loss of halide then occurs, with

 

electrostatic attraction (or a type of v-bonding) maintaining

the geometry of the system. This intermediate, which may have

resonance contributors of the type mentioned earlier, collapses

to form a cyclopropanone which reacts further to yield XXIII.
Fort (24) has reported that the 6-tosylate of isophorone

(XXIV) reacts with sodium methoxide in methanol to give

products which are readily explained by a zwitterionic Favorskii

intermediate (eq. 20).

14

O O 0

TS MeO
——-—+> 13"? -—-—-%> +
(20) _

XXV
0
Me COgMe /C02Me
+ +
JVV /\/‘/

In addition, Fort (25) has demonstrated that treatment of

 

 

 

 

orchlorodibenzyl ketone (XXVI) with 2,6-lutidine and furan
in dimethyl formamide (DMF) solution gives an 18% yield of
a bicyclic product (eq. 21). A dipolar intermediate was again

used to explain these results.

 

O "
\\ lutidine\y
4""ll ““ b + I l DMF 7'

XXVI XXVII

 

 

 

Recently, Turro has been able to isolate and characterize
a series of cyclopropanones (26-28). 2,2,5,5-Tetramethyl-
cyclopropanone (XXVIII) reacted with sodium methoxide in
methanol or DME to give a 97% yield of methyl 2,2,3-trimethyl-
butyrate (XXIX), and a 3% yield of tetramethylmethoxyacetone
(XXX) (26) (eq. 23). This was the first direct evidence that
a cyclopropanone reacts with basic nucleophiles to give
Favorskii products. Although the same cyclopropanone could

in principle be formed from tetramethylbromoacetone (XXXI).

15

reaction of XXXI with sodium methoxide gave primarily XXX

0
NaOMe \_
XXIX" XXX

(eq. 22).

O

(22) \W/JL\T<2r

XXXI

O

(25)

XXVIII
HO OMe

XXXII

(24) XXXII

 

NaOMe S_

MeOH or]?
DME

NaOMe _>_
MeOH or /
DME

MeOH

12%

97%

98%

24%

88%

3%

<1%

76%

It may therefore be concluded that the reaction of XXXI

——+-XXX occurs mainly by simple displacement by methoxide or

via a zwitterionic intermediate; only a small amount may be

converted to the cyclopropanone XXVIII.

I

The formation of large

amounts of XXX from the reaction of the hemiketal (XXXII) with

methanol (eq. 24) suggested that in a polar solvent the cyclo-

propanone is in equilibrium with the more reactive zwitterion

(XXXIII) (see eq. 25).

16

O O . HO OMe
(25) Wk ——-> A :22 a

XXVIII

XXXI
NaOMerSNg) NaOME IL \\\\\\\\§Am
Wop/1e9— W >-—-/—-c02Me

XXX XXXIII XXIX

Treatment of 2,2-dimethylcyclopropanone (XXXIV) with
methanolic sodium methoxide gave a‘) 70% yield of methyl
2,2fdimethylpropionate (27) (eq. 26). No methyl 3-methyl-
butanoate was found. Opening of the cyclopropanone ring thus
occurs at the least substituted o+carbon as predicted by
previous meChanistic interpretations of the Favorskii re-
action (29). XXXIV was also observed to react with 2-methyl-
furan to give an isomeric mixture of 1:1 adducts (eq. 27);
the intermediacy of a zwitterionic species analogous to that
proposed by Fort (25) seems doubtful in this case.

0

NaOMe x
(2 6) MeOH j +CO2Me (0 >——O CH2C02M€ >

Z+U:i if

XXXIV

 

17

Base initiated cyclization of a,a'-dihaloketones has
been used with success in the preparation of cyclopropenones
(eq. 28). Yields of 12 to 60% have been reported for the
cases where R = propyl (30), phenyl (31), butyl, and cyclo-

CSHIO (52).

0

o
(28) R ‘1/JL\T—‘R N(Et)3 > ,/::K\
' R R

Br Br

 

These reactions proceed through the dehydrohalogenation of

an akbromocyclopropanone. The base used must be a poor
nucleophile in order to avoid opening the ring, since hydroxide
and alkoxide result in the formation of acrylic acid deriva-
tives.

Favorskii reactions of ketones having more than one
ashalogen have been studied extensively. Woodward and Clifford
(55) found that treatment of the acetate of 5,7-dibromo-
cholestan-SB-ol-6-one (XXXV) with anhydrous pyridine, followed
by aqueous hydrolysis, gave the acetate of B-norcholest-S-en-

58—01-6-carboxylic acid (XXXVI) (eq. 29). This reaction has

7~ go
AcO Br r Aco‘ , C02H

 

18

also been successfully applied to the ring-contraction of
cyclic dibromoketones having eight (54), and twelve (55)
membered rings. Acyclic dihalo ketones have also been studied,
and reveal an interesting geometric specificity in the product.
Treatment of 1,5-dibromobutanone (XXXVII) with aqueous bi-
carbonate gave a 77% yield of isocrotonic acid (XXXVIIIa)(56)
(eq. 50). With stronger bases (K2C03, KOH) the specificity
was retained, but yields were lower. a,akDihalo ketones of
type XXXIX (R = ethyl, n-propyl, and n—pentyl) also gave sub—

stituted cis-acrylic acid derivatives in ca. 75% yields (57).

O R C02H
(50) 12% —> >=< <—— RCHafiCHBRg
Br Br H H
XXXVII ‘ XXXVIII XXXIX
(a, R=CH3)

These results suggest a Concerted formation and cleavage of
cyclopropanone intermediates (eq. 31). An af-anion displaces
bromide in such a manner as to give a cyclopropanone having
the alkyl substituent cis to the remaining halide. Basic
cleavage then occurs with immediate loss of halide; if a
discrete anion were formed it would have time to rotate and
subsequently produce a cis-trans mixture of acrylic acid
derivatives. In addition, a discrete anion should be formed

at the halogen-bearing carbon.

19

:B

HK R
R
(31) H o -————> H B o——> XXXVIII
r
H Br
x/br H

The iodobromoketone XL, upon treatment with methanolic
potassium hydroxide, has been found to give a 70% yield of

a mixture of conjugated acids (58) (eq. 52). In this case,

C
COgH

 

XL XLI

formation of an iodocyclopropanone is followed by collapse
with loss of iodide ion to the observed products. If this
collapse is assumed to be stereospecific, then the stereo—
chemistry of the products is determined in the formation of
the 5-membered ring intermediate. Thus, attack by either of
two epimeric Cal-anions will lead to epimeric iodocyclo-
propanones (XLI), followed by stereOSpecific collapse of each
to give the observed mixture.

Trihaloketones have been investigated by Rappe and co-
workers. 1,1,5-Tribromobutanone and 1,5,5-tribromobutanone

were observed to give similar ratios of acidic products

20

(XLII-XLIV) (59,40) (eq. 55). This would indicate that both

 

?r fi CH H CH3 c02H
+
CH3CH-C-CHBr2 >=< >=<
Br C02H B H
(55) NaHC03\
and H20 " XLII XLIII
Br p 56-47% 58-47%
| I
CH3C-C-CHgBr H COgH
I
Br +
Br CH3
XLIV
15-17%

reactions proceed through a common intermediate which is
probably 2,5-dibromo-2-methylcyclopropanone (XLV). Rappe

(41) suggested that XLV is opened in a non-concerted process
to give a formal anionic species, which could rotate before
eliminating bromide ion, and thus yield a mixture of geometric

isomers (eq. 54). However, no explanation was given as to

CH co H H co H
3\ e / 2 \e / 2
CH3 /c —— c\\Br + /c —— c~ Br
(34) Br Br ——9 Br 1 H Br i CH3
XLV
XLII + XLIII XLIV

why a secondary anion should predominate over a primary in
this system.

Somewhat surprisingly, 1,1,5-tribromo-4,4-dimethyl-2—
pentanone (XLVI), upon treatment with bicarbonate, gave only

one acid, trans-2-bromo-4,4-dimethyl-2-pentenoic acid

21

(XLVII) (42) (eq. 55). Semibenzylic and ketocarbene
mechanisms were discounted, since these would lead to more

than one acid.

0 O
///n\\\ ///JL\\\ /’Br
tBu-TH QE-Br'—->- tBu—CH Ce-———a»
' I
Br Br r Br
XLVI
(55)
O
H COgH
Br -———9» /;>::::<:
tBu tBu Br
Br
XLVII

In the cyclopropanone mechanism which was put forth, an anion
at C1 is formed and displaces the C3—bromine. This specificity
may be due either to the inaccessibility of the Ca—proton,

or to a relatively fast reaction of the Cl-anion, since this
would relieve steric crowding at C3. The manner of opening

of the intermediate is interesting, since it requires a stereo-

specific flow of electrons.

22

Dehmlow has applied the Favorskii reaction to 1,1,5,5—
tetrachloroacetone (45). Treatment with aqueous bicarbonate
gave 2,2-dichloroacrylic acid but none of the 1,2-isomer.
Rappe (44) observed similar results with the tetrabromo com-
pound (XLVIII, R=H) and has extended the method to include

the analogs where R = methyl, ethyl, propyl, and isopropyl.

 

Br 0 Br COgH
| H
R - c - c - CHBrg NZHSOE >
(56) I 2 Br R
Br
XLVIII XLIX
35-79%

With the three higher analogs, a 10-15% yield of the 2,5-
dibromo-ZTalkenoic acids is also obtained.

Several Favorskii reactions have been reported for sub-
strates having an epoxide oxygen as the leaving group. In
a study of the reaction of a,8-unsaturated ketones with
alkaline hydrogen peroxide, Treibs (45) found that piperitone
(L) gave a hydroxy acid in ca. 40% yield (eq. 57). Similarly,

carvenone (LI) gave an isomeric hydroxy acid (46) (eq. 58).

By using milder conditions, Treibs was able to isolate the

OH

. H O
(57) 2 2 ->: III}
0 KOH,Me0H C02H

 

25

COgH

(58) 02 A

I
KOH, MeOH OH

LI

epoxy ketone intermediates. Under basic reaction conditions,
these epoxy ketones were also converted to the same hydroxy
acids. By varying the reaction conditions, other products

were obtained. Thus, the slow addition of methanolic potassium
hydroxide to a refluxing methanol solution of piperitone oxide
(LII) gave a diosphenol methyl ether, while reaction with
hydrogen peroxide and potassium hydroxide in cold methanol

gave an unsaturated tertiary alcohol (47) (eq. 59).

o
OCH3 . OH
éKOH H202,K0H5-
(39) MeOH cold MeOH U
o
A
LII

Treibs (48) also investigated the reactions of several other
a,8-epoxy ketones with potassium hydroxide in refluxing
methanol. The products in most cases were diOSphenols and
diosphenol methyl ethers. With pulegone oxide, an unidenti-
fied mixture of acids was obtained.

House and Gilmore reinvestigated the reactions of
piperitone oxide and isophorone oxide with base (49). Using

methanolic sodium hydroxide or sodium methoxide, piperitone

24

oxide gave a mixture of ring-contracted acids and solvolysis

products (eq. 40). The lack of stereOSpecificity in the

 

,oH
——-)~
(40) c02R
/\
LII 16-55%
Me
+ + -+ III}
0 o COgR
Me -
5—17% 4-17% 2-4%

formation of the acids, as well as the solvolysis products,
was rationalized on the basis of a zwitterionic intermediate.
When the reaction was run in aqueous potassium hydroxide, the
hydroxy piperitone (LIII) was formed in 88% yield as the only
neutral product (eq. 41). Treatment of LII with potassium
tert-butoxide in DME gave the cis-lactone in 70% yield. The

stereOSpecificity of this latter case argues against a zwitter-

ionic intermediate.

0
«o
(41) éXOH t-BuOK
0 H20 0 DME I ’

HO

LIII LII

25

Similar reactions with isophorone oxide (LIV) gave predomi-
nantly solvolysis products (eq. 42). The trace of ring-
contracted acid formed was a mixture of stereoisomers. Again,

these results are consistent with the intermediacy of a

zwitterionic species.

0 ‘OH
NaOMe q;
7.
or NaOH COZR
o MeOH
.CogR ‘H
V

81- 85% 0-5% 0—3%

(42)

 

Treatment of 1a,2crepoxylanost-B-en—5-one with ethanolic
potassium hydroxide gave only solvolysis products (50) (eq.
45). Similar results attended the methoxide ion initiated

reaction of 1a,2anepoxy—Sorcholestan—5-one (51).

Reusch and LeMahieu (52) have also observed that both 48,56-

(45)

 

and 4a,Sarepoxycholestan-5—one react with methanolic sodium

hydroxide to give 5-methoxycholest-4-en-5-one (eq. 44).

NaOH
(44) .. MeOH \’
o

 

OCH3

26

These solvolytic reactions are believed to proceed via
a direct nucleophilic displacement of the epoxide oxygen at
the orcarbon (eq. 45). Subsequent basic elimination of

hydroxide ion would lead to the observed products.

£13 £6 {I}
(45) .__, ___,
o ‘+\+ o g 11 o

CHgOH oCH3 OCH3

One would expect that in an epoxy ketone having a tertiary
orcarbon, the tendency toward simple displacement would be
reduced. Furthermore, since such a substrate has no orhydrogen,
the final elimination could not occur. In this regard,

LeMahieu (51) has examined the reaction of 58,6B-epoxycholestan-
4-one (LV) in methanolic sodium hydroxide. The observed
products were A-norcholest-5-en-5-carboxylic acid (LVI) and
A-nor-5£'-cholestan-6€ -ol-5€ -carboxylic acid (LVII) (eq. 46).
While the stereochemistry of the latter product was not rigor-
ously established, it probably arises from an abnormal opening
of a cyclopropanone intermediate to give a tertiary, rather

than a secondary anion.

(46) NaOH
MeOH

 

LV

Cavill and Achmad (55) have investigated the Favorskii

reaction of pulegone dibromide and pulegone oxide. Reaction

27

of the dibromide with ethanolic sodium ethoxide gave only
trans-pulegenic acid, whereas aqueous potassium hydroxide
gave a 40:60 mixture of trans- and cis-pulegenic acids,

respectively (eq. 47). These results were interpreted in

terms of stereospecific formation and reaction of a

 

cyclopropanone intermediate in ethanol as a solvent, and'
formation of a zwitterionic intermediate in the aqueous sys—
tem. The authors proposed that the dibromide was composed
essentially of one isomer; however, Wolinsky (54,55) asserts
that the dibromide is rather a mixture of isomers, both of
which react stereOSpecifically. The ethyl esters which are
formed ulabsolute ethanol are rapidly isomerized, and are
hydrolyzed to acids at different rates, resulting in the se-
lective formation of trans-pulegenic acid. In the aqueous
system only acids are formed, and since these are not labile,
the stereochemistry is retained.

The pulegone oxide used by Cavill (55) was obtained by
the action of alkaline hydrogen peroxide on pulegone, and was
assumed to be a single stereoisomer, since it melted sharply
at ca. 400, gave one peak on gas chromatography, and showed a

single carbonyl stretching absorption in the infrared. After

28

inspecting models, Cavill assigned configuration LVIII to

this material. Treatment of the epoxide with ethanolic sodium
ethoxide gave a 20% yield of two acidic products which were
shown to be trans, cis-puleganolide (LIX) and trans, trans-

puleganolic acid (LX) (eq. 48). These products would be

   

{
————>N:::;: Q o +
(48) '“iz:
LVIII LIX LX

expected from a stereospecific transformation of isomer LVIII
to the cyclopropanone intermediate LXI. Abnormal opening of
LXI gives a tertiary anion which may be protonated from

either side (eq. 49).

(49) LIX + LX

   

Treatment of LVIII with sodium hydroxide in aqueous ethanol
gave LXII, as an epimeric mixture. This may be formed by a
normal Opening of the cyclopropanone intermediate to give a

secondary anion. To account for the observed mixture of

O

OH
LXII

29

products, Cavill suggested formation of both possible cyclo-
propanone intermediates via an initially formed zwitterionic
species.

Reusch and Johnson (56) have reported that the pulegone
oxide modification having a mp of 400 is actually a mixture
of stereoisomers; and they were able to isolate each of the
pure isomers (mp 590 and 550). On the basis of n.m.r. spectra,
optical rotatory dispersion curves, thermal isomerization,
and a consideration of available conformations, the following

assignments were made:

   

m. 59° m. 550

A Favorskii reaction of these isomers, if stereospecific,
would provide firm chemical evidence for or against this

assignment.

RESULTS AND DISCUSSION

Treatment of pulegone oxide (LXIII, m. 570) with a
4-fold excess of sodium methoxide in boiling glyme gave a 70%
yield of acidic products. The glyme used in this experiment
was found to contain 0.25-0.50% water, roughly 0.6 molar
equivalent of the sodium methoxide used. The remaining neutral
product was analyzed by vapor phase chromatography (v.p.c.),
and contained no starting*material.

The acids were converted to methyl esters by treatment
with excess diazomethane and were separated into three com-
ponents by v.p.c. These were shown to be an epimeric mixture
of methyl 5-methylcyclopentanecarboxylates (LXV, 21%), methyl
trans-pulegenate (LXVIA, 29%), and methyl trans, trans-
puleganolate (LXVIIA, 50%). The infrared and nuclear magnetic

resonance (n.m.r.) spectra were in agreement with the above

,COaMe A C02Me
\
C02Me Y 0H

LXV LXVIA LXVIIA

 

 

 

 

 

structures. LXVIIA, a new compound, showed absorption at
5500 and 1750 cm"1 in the infrared. The n.m.r. spectrum
exhibited a doublet at T 8.98 (J=6c.p.s., area 5), a singlet
at T 8.90 (area 6), a singlet at T 6.57 (area 5), and broad

5O

51

absorption from T 7.5 to 8.8. Upon treatment with methanolic
hydrochloric acid, both LXVIA and LXVIIA were converted to
the known cis, trans-puleganolide (LXVIIIA). No cis, cis-

puleganolide (LXVIIIB) was observed.

0 0

"/<
n K. a o
LXVIIIA LXVIIIB

Reaction of the lower melting pulegone oxide isomer
(LXIV, m.540) under identical conditions gave a mixture of
acids in 85% yield. After esterification with excess diazo-
methane, this mixture was separated by v.p.c. analysis into
five components: the epimeric methyl 5—methylcyclopentane—
carboxylates (LXV, 15%), a mixture of methyl cis- and trans-
pulegenates (LXVIA and B, 25%), methyl trans, cis-puleganolate
(LXVIIB, 55%), Cis,trans-puleganolide (LXVIIIA, 22%), and an

unidentified component (8%).

C02Me C02Me

/,; 'W<6H
LXVIB LXVIIB
These structure assignments are supported by infrared and

n.m.r. spectra. LXVIIB showed absorption at 5500 and 1750

cm“1 in the infrared. The n.m.r. spectrum exhibited a doublet

52

at T 9.12 (J=6.5c.p.s., area 5), a singlet at T 8.98 (area 6),
a singlet at T 6.57 (area 5), and broad absorption from

T 7.1 to 8.4. The methyl pulegenate mixture was converted by
methanolic hydrochloric acid into a mixture of the stereoiso-
meric puleganolides (LXVIIIA and B). In a similar manner,
LXVIIB was converted to cis,cis-puleganolide (LXVIIIB); no
cis, trans-puleganolide was formed. Methyl cis—pulegenate
(LXVIB) was also formed in this reaction.

These results are best explained by a stereospecific
formation and cleavage of a cycloprOpanone intermediate.
According to this mechanism, the epoxide is directly displaced
by an af-anion leading, in the case of isomer LXIII, to inter—

mediate LXXA (eq. 50). A zwitterionic intermediate (LXXI)

.1 63 0
OH

LXIII LXXA LXXI

(50)

 

would be common to both isomeric pulegone oxides, and the
same mixture of products would be expected from each isomer.
The cyclopropanone intermediate may be opened by base in
two ways, one to give a secondary anion, the other to give a
tertiary anion beta to the hydroxyl group (LXXIIA) (eq. 51).

The former mode of opening is apparent in ca. 20% of the

55

 

LXV LXVIA LXVIIA

products. Protonation of the secondary anion, followed by
retroaldolization, would lead to LXV; that this material is

an epimeric mixture is not surprising, since the reverse aldol
reaction would not be stereospecific. The latter mode of
opening (eq. 51) predominates by roughly 4 to 1. Loss of
hydroxide ion from LXXIIA would lead to LXVIA; a stereospecific
protonation with retention of configuration would give LXVIIA.
Competition between these two reactions is reasonable, due to
the small concentration of proton donating species in the sol-
vent. Cavill and Hall (57) have now extended their study of
the reaction of the pulegone oxides in ethanolic sodium
ethoxide, and report that no pulegenic acids are found. In
this proton donating solvent the anionic intermediates would
be immediately protonated, and elimination of hydroxide ion
becomes unlikely. That LXVIA was not formed during the acidic

portion of our work-up was proven by treating pure LXVIIA under

54

the same conditions. Only unchanged starting material was
recovered.

The predominant direction of opening of the cyclopropanone
intermediate is opposite to that found in Favorskii reactions
of orhalo ketones (29). These compounds yield products aris-
ing from the formation of the less substituted anion. (Discrete
carbanions may not be formed in these reactions; however, some
carbanion character must reside on the orcarbon atom.) In
epoxy ketones, however, the anion beta to the hydroxyl group
seems to be preferentially formed. In the case of piperitone
oxide (L)(45,47,49) and carvenone oxide (LI) (46), this anion
is the less substituted of the two possibilities; however, the
Favorskii reaction of 58,68-epoxycholestan-4-one (LV) proceeds
via a tertiary anion at C5 (51). This mode of reaction may be
due to inductive stabilization of the B-anion by the hydroxyl
group. Alternatively, the polar hydroxyl group may orient
solvent molecules closer to the orcarbon, resulting in stabili—
zation of the forming anion by solvation.

An interesting abnormal Favorskii product was observed
by Kunduret al. (58) . a—Chloroketone LXXIII gave only a poor
yield of the expected product (LXXIV), while LXXV was found

to be the major product (eq. 52). If this reaction proceeds

(52) NaOMe +
C02Me
ch 1 COgMe COgMe C02Me

C02Me

LXXIII LXXIV LXXV

55

via a cyclopropanone mechanism, the ring-opening step must
occur predominantly to give the more substituted anion;
however, the carbomethoxy group would not be expected to exert
a significant inductive effect over three carbon atoms.
Alternatively, LXXV may be formed by a competing semi-benzylic
mahhanism.

The stereospecificity of the protonation of LXXIIA is
surprising. Random protonation would result in a mixture of
LXVIIA and LXVIIIA. Since a mixture of puleganolides LXVIIIA
and B was found to be unchanged when submitted to the Favorskii
reaction conditions, the protonation is indeed stereospecific,
and LXVIIIA is never formed. The observed retention of con-
figuration during ring Opening is in accord with the principles
of carbanion substitution as formulated by Cram (59). According
to this study, the stereochemistry of products resulting from
heterolytic carbon-carbon bond cleavage depends on the solvent
and the cation accompanying the base. In solvents of low di-
electric constants and with alkali metal cations a high degree
of retention of configuration was observed. The use of sol-
vents of high dielectric constants, as well as quaternary
ammonium bases in solvents of low dielectric constants, gave
complete racemization. Protic solvents of high dielectric
constants gave moderate inversion of configuration.

An opposite stereochemical result has been reported by
Nickon et al. (60). Treatment of 1-hydroxynortricyclene

(LXXVI) with potassium tert-butoxide in tert-butyl alcohol-O-dl

56

gave > 94.5% 6—exo-d-norbornan-2—one (LXXVII), corresponding

to inversion of configuration at C5 (eq. 55). Similar results

A
(55) A.

H 0H

 

LJQCVI LXXVII

were obtained when LXXVI was treated with potassium methoxide
in methanol-O-dl and in a DMSO-methanol-O-dl mixture, or with
tetramethylammonium deuteroxide in deuterium oxide.

DePuy and co-workers (61) have examined the reaction of
1-methyl-trans-2-phenylcyclopropanol (LXXVIII) with sodium
deuteroxide in a 50:50 mixture of deuterium oxide and dioxane,
and report complete inversion of configuration in the product

(eq. 54). These results are in qualitative agreement with the

H
. x0
(54) ¢ 3AMOH ——> D ~C/\C/

\CHg / ‘CH3
‘1’

LXXVIII

studies of Cram (59), in which the use of a protic solvent
of high dielectric constant is predicted to result in sub-
stantial inversion.

The base-catalyzed opening of endo- (LXXIXa) and exo-Z—
hydroxy-1,6-dimethyl[4.1.0]bicycloheptane (LXXIXb) has been
examined by Wharton and Bair (62). Treatment of either LXXIXa

or b with potassium tert-butoxide in tert-butyl alcohol gave

57

1,2-dimethylcyclohexanecarboxaldehyde (LXXX) having > 90%

retention of configuration at the C2-carbon.

With ethylene

'glycol and its sodium salt, LXXIXa gave a cis-trans mixture

of LXXX corresponding to 40% inversion, while LXXIXb gave

70% inversion (eq. 55). Again,
CH3

(55) OH ——->-
CH3

LXXIX

theSe results are consistent

 

CHO
: CH3
+
: CH3
H
Retention Inversion
Product Product
LXXX

with the observations of Cram, with the exception of the de-

pendence of the product ratio on the configuration of the

leaving group. Cram et al.(65)
results from the basic cleavage
1,2-diphenyl-2-methyl-1-butanol
butanol. Wharton and Bair (62)

in product ratios is due to the

found identical stereochemical
of two pairs of diastereomers,
and 2,5-diphenyl-5-methoxy-2-
suggested that the difference

formation of conformationally

different cyclohexane chairs from the isomeric starting

materials.

Thus,

it may be concluded that there is no evidence for

a novel mechanism due to the unusual properties of the cyclo-

propane ring.

based on Cram‘s suggestions.

The mechanism presented in eq.

56 for LXIII is

The neighboring hydroxyl group

is a factor which was not present in any of Cram's examples.

58

OH

OH
(56) ff”
0
H ----- Q (-)
B ----- pi

 

It is improbable that this group exerts a significant influ-
ence on the direction of protonation, since it can orient
solvent molecules toward either side of the incipient car—
banion. In this regard, predominant retention of configura-
tion is also observed when the reaction is effected in ethanol
(57) .

While the products obtained from LXIII are exclusively
those which would be predicted from a stereospecific Favorskii
reaction, the products obtained from LXIV are not. Cavill (57)
has shown that treatment of LXVIIB with ethanolic sodium
ethoxide results in incomplete conversion to cis, trans-
puleganolide (LXVIIIA). Thus, the hydroxy acid initially
formed in the reaction is epimerized to the observed "non—
stereospecific" product. It is believed that trans-pulegenic
acid arises from the cis—isomer by a similar pathway.

The absence of cis-pulegenic acid from the rearrangement
of LXIII is somewhat surprising, since Wolinsky (64) has
shown that methyl trans-pulegenate (LXVIA) is epimerized by
methanolic sodium methoxide to give a 25:77 ratio of cis and
trans methyl pulegenates, respectively. Either opening of

the cyclopropanone is effected by hydroxide ion, leading to

59

an acid which is resistant to epimerization or the ester is
hydrolyzed much faster than it is epimerized.

The stereospecific Favorskii reaction of the pulegone
oxide isomers permits the unambiguous assignment of their
configurations. In isomer LXIII, m. 570, the Cl-methyl and
the epoxide oxygen bear a trans-relationship, and in isomer
LXIV, m. 540, they bear a cis-relationship. This assignment
is the reverse of that previously made (56). These assign-
ments have recently been confirmed by Katsuhara (65).
Lithium aluminum hydride reduction of LXIV gave a mixture of
(+)-trans-4-hydroxyneomenthol (LXXXI) and (+)—cis+4-hydroxy-
menthol (LXXXII), both known compounds (eq. 57). Reduction
of LXIII gave only (—)-trans-4-hydroxyneoisomenthol (LXXXIII)
(eq. 58).

+
“ 0H

:\ HO : OH HO :

//*\\ ,/*\\
LXXXI LXXXII

——->-
, OH
HO’

LXIII LXXXIII

(58)

 

While the configurations of the pulegone oxide isomers
have now been established, the problem of a conformational

analysis consistent with the Spectral data remains.

40

The interpretation of the optical rotatory dispersion
(O.R.D.) and circular dichroism (C.D.) spectra of a,8-epoxy
ketones is complicated by two factors. First it must be
determined whether the conjugated epoxy ketone system is an
inherently dissymmetric chromophore (as is the case with cer-
tain enones). Such chromophores are usually characterized
by relatively large rotational strengths. Second, the sign
of the rotatory contribution of a chiral epoxy ketone system
must be resolved. In this regard, Djerassi and co-workers
(66) have presented extensive evidence for a reversal of the
Octant Rule in its application to epoxy ketones and cyclo-
propyl ketones having fused rings of type LXXXIV. Here, it

appears that the epoxy ketone acts as a single, integrated

Z = 0, CH2.

LXXXIV LXXXV

chromophore having inherent dissymmetry, this condition being
reflected in increased amplitudes and a reversal of the Cotton
effect sign. An example of this phenomenon is found in the
comparison of 4B,58—epoxycholestan-5-one (LXXXVI) with 58-
cholestan-5-one (LXXXVII). LXXXVII exhibits a molecular
ellipticity of [e] = -1,500 (67), while LXXXVI has [9] =

+12,400 (Ro=12.5 x 10’40c.g.s.). In this case, introduction

41

 

LXXXVI LXXXVII

of a fused epoxide ring has resulted in a change in sign of
the Cotton effect with an attendant increase in magnitude.
Extension of this reversal to compounds having the 5-membered
ring spiro to the carbonyl-carrying ring (type LXXXV) was
based on only a few examples, and must be regarded as tenuous.
In systems of this type, substituents on the epoxide ring may
occupy a near octant, thus reversing the sign of their contri-
bution to the rotational strength of the chromophore.

Since the pulegone oxides are of the spiran type, the sign
of the Cotton effect for a given conformation is difficult to
predict. In order to provide rigid models for this system,
5a,6arepoxycholestan—4-one (LXXXVIII) and 58,6B-epoxycholestan-

4-one (LXXXIX) were synthesized, and their O.R.D. and C.D.

\\

 

O
LXXXIX LXXXVIII

 

spectra were taken. Examination of Drieding models indicates
that in LXXXVIII, the epoxy ketone is locked in conformation
LXXXVIIIa. Application of the Octant Rule in a normal fashion

predicts a moderate negative Cotton effect for this conformation,

42

since the steroid residue occupies a negative octant, while

the epoxide oxygen lies in a positive octant. The only sub-
stituent which lies in or near a front octant is the C6~hydro—
gen; and no significant contribution to the rotational strength

is expected. An inspection of models discloses that LXXXIX

CH. % }
r052

LXXXVIIIa LXXXIXa

 

 

 

 

 

 

 

 

CH3
CH3 CH3 / CH3

0 “/2 L_.o__J z/I

 

 

 

LXXXIXb LXXXIXC

is more flexible than LXXXVIII. Three conformations involving
changes in ring A configuration are easily discerned. One

is a chair (LXXXIXC) and two are twist boat forms (LXXXIXa

and b). On the basis of nonsbonded interaction measurements
with Dreiding models, LXXXIXa is predicted to be the most
stable conformation. In this case, the Octant Rule would pre-
dict a moderate positive Cotton effect, the steroid residue

lying in a positive octant, and the epoxide oxygen occupying

45

a negative octant. The other conformations would, by a similar
analysis, have a predicted negative Cotton effect. Calculated
(68a) rotational strengths were in accord with the above pre-
dictions: LXXXIX, R0: 2.02 x 10‘40c.g.s. (95% EtOH), R0:

2.51 x 10'40c.g.s. (cyclohexane); LXXXVIII, Ro= -2.58 x 10-40
c.g.s. (95% EtOH), Ro= -2.55 x 10‘40c.g.s. (cyclohexane).
Application of the reversed Octant Rule would predict an in-
tense Cotton effect of reversed sign for each of these com-
pounds. For comparison the rotational strength of Sascholestan—
4-one (XC) (Ro= -4.15 x 10’4oc.g.s.) (69) is of the same sign
as, and larger than that of the corresponding epoxide (LXXXVIII).
Thus, the abnormal behaviour of fused epoxy ketones is not ob—
served in these spiran-type compounds.

It is known that the chemical shifts of the protons in a
ketone vary upon changing the solvent from CCl4 to benzene.
Recently, an empirical rule has been formulated which corre-
lates the direction of this variation with the location of the
substituent relative to the carbonyl group (70-72). The

chemical shift difference (A) is defined in eq. 59.

(59) A = (TpH —TCC14) p.p.m.

Those substituents located behind a plane perpendicular to
the carbonyl bond and passing through the carbonyl carbon
will exhibit a positive A; those located in front of the plane
will exhibit a negative A. The chemical shifts of the geminal

methyls of the pulegone oxide isomers and those of nor-pulegone

44

oxide (XCI) in benzene and CCl4 are summarized in Table 1.

XCI

It may be concluded from this data that in all cases the
methyls lie on or behind the reference plane. Since this plane
in turn lies behind the plane separating near and far octants
in the Octant Rule (68b), the Cotton effect of the pulegone
oxides must be explained solely in terms of contributions from

the far octants.

Table 1. Geminal Methyl Chemical Shiftsa

 

 

Compound Benzene(T) CC14(T) (p.p.m.)
LXIII 8.90 8.88 +0.02
8.78 8.85 +0.15
LXIV 8.88 8.84 +0.04
8.79 8.64 +0.15
XCI 8.96 8.88 +0.08
8.87 8.64 +0.25

 

aSee reference 75.

An examination of Dreiding models indicates that chair

conformations of the pulegone oxides are probably favored over

boat and twist-boat conformations.

melting isomer these are LXIVa and LXIVb,

In the case of the lower

and in the higher

45

melting isomer they are LXIIIa and LXIIIb. Application of the
Octant Rule in a normal manner would predict LXIVa and LXIIIb
to be positive, and LXIIIa and LXIVb to be negative. The

O.R.D. and C.D. spectra of LXIII exhibit a positive Cotton

0
CH3-..
CH3 .
H3
0

LXIVa (+)

 

CH3

 

I
V

LXIIIb (+)

LXIIIa (

effect of rotational strength 2.64 x 10‘40c.g.s. (95% EtOH),
1.97 x 10-40c.g.s. (cyclohexane). In addition, LXIII exhibits
a temperature dependence in EPA (5:5:2 etherzisopentane:

25°_ -74°_ -192°
alcohol) (74). [91505— 5257, [91304 — 2442, [@1505

Two explanations are consistent with these results. Either

= 2155.

an equilibrium is occurring between LXIIIb and some solvated
species which has a smaller positive rotational strength (a
decrease in temperature favors the more weakly rotating sol-

vated Species, resulting in a net decrease of rotational

46

strength), or LXIIIb may be in equilibrium with another con-
formation which has a greater, positive rotational strength
but which is less stable. A lowering of the temperature in
the latter case would favor LXIIIb and result in a decrease
of the rotational strength. While a choice between these two
explanations is not possible, it appears that LXIIIb is the
predominant conformer at room temperature.

The C.D. spectrum of LXIV in 95% ethanol exhibits a nega-
tive Cotton effect at 505 mu (R0 = -0.597 x 10‘40c.g.s.) and
a weakly positive Cotton effect at 270 mu (R0= 0.141 x 10"40
c.g.s.). In cyclohexane the C.D. shows some fine structure,
the rotational strengths being -0.422 x 10‘40c.g.s. and +0.056

x 10‘40c.g.s., respectively. A temperature dependence is also

observed in EPA (74): [BJZSO = -965 [9]250 = +252 [e]"740 =
° 508 ' 275-7 ' 508-10
-74° -192° —192°
-1104, [9]278 = +559, [G]512 = -455, [G]285 = +1411.

Djerassi and co-workers have shown that "a C.D. curve with two
oppositely signed extrema separated by ca. 50 mu will arise
whenever two Cotton effects of similar amplitudes, but opposite
sign, are superimposed with their individual maxima separated
by 1 to 20 mp“ (75). Furthermore, the rotational strengths

of the resulting Cotton effects are diminished in comparison

to their individual rotational strengths. It is also known
that a solvated ketone will usually exhibit an n-9w* absorption
at shorter wavelengths than the corresponding unsolvated Species.
Thus, in LXIV the positive band at the shorter wavelength is

probably due to a solvated species, since it increases upon

47

lowering the temperature. It should also be noted that this
band decreases markedly on going from 95% ethanol to cyclo-
hexane. The negative extremum shows an abnormal temperature
dependence, the rotational strength increasing from 250 to -740
and decreasing from -740 to -1920. The simplest explanation
of this phenomenon involves an equilibrium between LXIVb and
some other less negative conformation at 250. Lowering the
temperature to -740 favors the more stable conformation
(LXIVb), resulting in a net increase in rotational strength.
A further decrease in temperature to -1920 results in extensive
conversion of LXIVb to the solvated Species. Thus, at room
temperature, the predominant conformation is probably LXIVb.
The ultraviolet absorption maxima and carbonyl stretching

frequencies of a number of epoxy ketones are listed in Table 2.

Table 2. Infrared and Ultraviolet Spectra

 

 

Compound v ggé4(cm‘l) A fiyilohexane mu(€)
LXXXVIII 1711 504 (44.5)
LXXXIX 1725 297 (57.7)
LXXXVI 1710 504 (52.1)

515 (51.7)
LXIII 1725 502 (55.8)
LXIV a 1726 505.5 (51.4)
Isophorone Oxide 1717 505 (24.5)

—J::io a 1720 502.5 (19.9)

o
[710 a 1747 505.5 (25.0)
(:1; a 1750 505 (25.0)

aSample furnished by Mr. Charles Markos, Mich. State Univ.

48

Little can be concluded from the ultraviolet maxima, since

the relative configuration of the ketone and epoxide functions
has no apparent effect on either the wavelength or the ex-
tinction coefficient. Similarly, no correlation can be made
for the carbonyl stretching frequencies, since some similar
configurations have different frequencies, and different con-
figurations have similar frequencies.

The pulegone oxides exhibit significant differences in
the n.m.r. spectrum, especially the low field portion (see
Figure 1). Isomer LXIV displays a broad two proton doublet
at T 7.68, while LXIII shows a single proton multiplet
centered at T 7.51 that appears to be the low field portion
of an ABC spectrum. The previous assignment of these low
field resonance signals to the C-2 hydrogen atoms (56) has
now been confirmed by deuterium exchange in mild alkaline
solution.

Eliel and co-workers (76) have examined the effect of
methyl substituents on the chemical shift of the orhydrogen
in various cyclohexanols. The introduction of an axial methyl
at C-2 deshielded an axial ahhydrogen by 11.5 c.p.s., while
an equatorial orhydrogen was shielded by 24 c.p.s. An equa-
torial methyl at C-2 shielded an axial abhydrogen by 28 c.p.s.,
while an equatorial Okhydrogen was shielded by 17 c.p.s.

If these substituent values are applied to the pulegone oxide

conformers LXIVb and LXIIIb, the position of He in LXIII Can

be calculated from the observed methylene resonance in LXIV.

Both hydrogens in LXIV appear at 140 c.p.s. (56) (Chemical

49

 

 

 

 

 

 

 

 

 

 

 

 

 

 

umumEomH mUHXO maommasm osu mo mnuommm .m.2.z .H .mflm
.E.m.m 05Hm> P 05Hm> H
o.oa o.o o.o o.a .5.o.o o.ofi o.o o.o owe
_ _ _ _ q _ _
_
_ 8.4
3;. no o 1
mm.b }
am.m
HHHxA >HNA
/ mm.m
mm.M\ mm.m

 

 

 

50

shifts measured from TMS at 60 Mc). Application of Eliel's
shielding factors to a change of the methyl from axial to
equatorial (LXIV to LXIII) predicts He of LXIII to appear at
147 c.p.s. and Ha at ca. 100 c.p.s. In qualitative agree-
ment with these predictions, He is observed as a pair of
doublets at 145 and 154 c.p.s., and Ha is obscured by the
remaining methylene absorptions (< 150 c.p.s.) (56). XCI is
conformationally similar to the pulegone oxides, and similar
calculations would predict He to appear at 167 c.p.s. and Ha
at 128 c.p.s. Experimentally, single protons appear at
155 and 145 c.p.s. (75), representing a deviation of 14 and
17 c.p.s., respectively. This discrepancy may be due to the
complex Splitting of what would be an ABCD system, since
the observed values fall between and about the same distance
from the predicted values. Thus, while the n.m.r. does not
provide firm evidence for conformations LXIIIb and LXIVb,
it is not inconsistent with them.

Finally, it should be noted that the thermal isomeriza-
tion of pulegone oxide favors LXIII over LXIV by a factor
of 5:1 (56). This is consistent with the conformational

assignments made here, since LXIVb is destabilized by an

axial methyl group.

EXPERIMENTAL

Vapor phase chromatographic analyses (v.p.c.) were made
with an Aerograph A-90-P instrument. Infrared spectra were
determined with a Perkin Elmer 257B spectrophotometer.
Nuclear magnetic resonance (n.m.r.) spectra were determined
with a Varian associates A-60 high resolution spectrometer,
using tetramethylsilane as an internal standard. Ultraviolet
spectra were determined with a Carey Model 11 spectropho-

tometer.

Reagents

Dimethoxyethane (glyme) was obtained from Aldrich Chemi-
cal Company. The amount of water present in this solvent was
determined by reaction with sodium hydride, the hydrogen
evolved being measured by a gas buret. Values from 0.25 to
0.50% were obtained.

Commercial sodium methoxide (Matheson, Coleman and Bell)

was used.

Pulegone Oxide

Pulegone Ox'ide isomers LXIII and LXIV were prepared accord-
ing to the procedure of Reusch and Johnson (56), substituting
m-chloroperbenzoic acid for perbenzoic acid. The following

spectral properties of LXIII, m. 570, were obtained:

51

52

VCCl4 1725 cm'l; Acyclohexane
max max

EtOH (c, 0.047). [¢]317 +22600, [¢]soo £00. [¢]27a -27800;

502 mu(€ 55.8); O.R.D. in 95%

O.R.D. in cyclohexane (c, 0.050), [01326 +1956O, [¢]317 +9250,
[¢]310 40°, I¢1290 -2080°, [¢]285 -2105°; C.D. in 95% EtOH

(C, 0.047), [¢]333 10, [¢]298 +5570, [¢]254 i0 (Ro=2.84 X 1.0"40
c.g.s.); C.D. in cyclohexane (c, 0.050), [¢]345 i0, [¢]320 +1990,
[4]313 +2480, [M309 +2560, [¢]211 :0 (R0: 1.97 x‘10‘4oc.g.s.);

O _.
C.D. in EPA (74) (c, 0.177), [¢]25 +5257, [¢] 74°
305 30

+2442,
5

[¢];ég?5 +2155 (see Fig. 2). The following spectral properties

vCCl4 1726 cm‘l; xcyclohexane

of LXIV, m. 540, were obtained:
max max

505.5 mu(e 51.4); O.R.D. in 95% EtOH (c, 0.049), [41321 -492°,
[¢]308 40°, [41289 +1044O; O.R.D. in cyclohexane (c, 0.048),
[¢]328 -2970: [$1320 100: [91303 +7320: (9)295 +8540: [¢]287
+7550; C.D. in 95% EtOH (c, 0.049), [41330 :0, [¢]305 -984,
[¢]284 :0, [¢]270 +247, [¢]235 10 (R0: -0.597 X 10-40 and
+0.141 x 10'40 c.g.s.); C.D. in cyclohexane (c, 0.048),

[¢]348 i0: [91312-7 ‘508: (¢]307 -645, [$1298 ‘545: [¢]287 i0.
[91275-80 +78: [¢[272 +95: [¢]288-9 +70: [¢]256 i0 (R0:
-0.422 x 10"40 and +0.056 x 10‘40c.g.s.); C.D. in EPA (74)

o o o
(C. 0-180)) [¢]558 “965) [91575-7 +252, [¢]808—10 “1104.

_ O _ 0 _ o
[.1253 +559, [o13132 -455, [¢]ag§2 +1411 (see Fig. 5).

+5

55

 

 

 

 

r
4250
£7740
+2 - if, \\ i‘.
J ‘
0' \ .‘
"q a" O] \ l
[9] X 10 7 ”-192 \ t.
7 l
.'l \ ‘
:7 ‘
+1 4 ,‘I \ '
."I \ .
07 ‘ \ . ‘t
I \ 1
."l \i :
.r,’ l
,1, \ z
X") \ ‘\
0 . ’4 \C .
1 1
250 500 550
Wavelength (mu)
Fig. 2.

C.D.

spectra of LXIII in EPA.

 

+16

+12

+8

-12

54

 

 

 

 

 

 

J l
250 500
Wavelength (mu)
Fig. 5. C.D. spectra of LXIV in EPA.

550

55

Favorskii Reaction of Pulegone Oxide LXIII

A. Isolation and Structure Proof of Products

A solution of LXIII (500 mg., 1.8 mmoles) and sodium
methoxide (455 mg., 8.0 mmoles) in glyme (50 ml.) was refluxed
for 19 hours. After cooling, the mixture was taken up in
ether and extracted three times with 10% sodium hydroxide.

The combined aqueous portions were acidified with hydrochloric
acid (pH < 1), and then extracted with ether. The combined
ether extracts, after being washed, dried and evaporated,
yielded 210 mg of an oily acidic material.

The original organic layer was washed, dried and evapoe
rated, yielding 115 mg of a light oil. Analysis of this
material by v.p.c. (4% QF-1 on 60/80 Chromosorb G at 1400)
disclosed that the major component was glyme (ca. 80%); the
remaining neutral products (retention times 5.5 and 4.4 min.)
exhibited hydroxyl absorption but no carbonyl absorption in
the infrared.

The crude acid products were methylated with diazomethane,
and analysis (v.p.c. — same conditions) showed three components
having retention times of 1.5, 2.5 and 6.5 min. These were
identified as LXV, LXVIA and LXVIIA (integrated areas 5:4:7
respectively), by a combination of spectroscopic and chemical
evidence.

1. Methyl 5-methylcyclopentane carboxylate. The infrared

 

spectrum of LXV showed carbonyl absorption at 1750 cm’l, but

no hydroxyl bands. Only end absorption was observed in the

56

ultraviolet. The n.m.r. spectrum exhibited a pair of doub-
lets at T 9.05 and 8.97. (J:: 7 cps, area 5), a singlet at
T 6.41 (area 5) and broad absorption from T 7.0 to 8.9 (area
8.5).

2. Methyl trans—pulegenate. The infrared spectrum of
LXVIA was identical with that of an authentic sample of methyl
trans-pulegenate (77). The n.m.r. spectrum exhibited a doublet
at T 8.99 (J=7 c.p.s., area 5), a pair of methyl singlets
centered at T 8.40 and separated by 5 c.p.s. (area 6), a sing-
let at T 6.42 (area 5) and broad absorption from T 7.0 to 8.5
(area 6).

5. Methyl trans,transapuleganolate. The infrared spectrum
of LXVIIA showed hydroxyl absorption at 5500 cm‘1 and carbonyl
absorption at 1750 cm'1 (see Fig. 4). The n.m.r. spectrum
exhibited a doublet at T 8.98 (J8 6 c.p.s., area 5), a singlet
at T 8.90 (area 6), a singlet at T 6.57 (area 5) and broad
absorption from T 7.5 to 8.8 (see Fig. 5).

4. Conversion of methyl transjpulegenate to Cis,trans-
puleganolide. A solution of LXVIA (60 mg.) in 2 ml.
methanol containing 0.5 ml. conc. hydrochloric acid was re-
fluxed for 7 hours. The reaction mixture was dissolved in
ether, washed, dried and concentrated. The oily residue (40
mg.) was analyzed by v.p.c. (5% FFAP on 60/80 Chromosorb G at
1500); the most readily eluted component was unreacted LXVIA
(19%), a minor unidentified material (7%) followed and the

major product (74%), which was the last to appear, was

57

oomd
_

 

 

 

 

 

 

.4HUU CH A<HH>xqv mumHocmmmasmlmcmuu.mcmuu axzuma m0 Enhuommm UmumumcH

ooom
_

 

 

 

 

Aalsov mosmskum

00mm
_

 

 

 

 

ooom
L

 

00mm

(I!

_

.mw .mflm

Ooov

 

ON

ow,

om

om

00a

.4
H00 SH AdHH>XAV onwaosmmmasmlmcmuu.mamuu Hwnuma m0 Esuuommm UmumumcH .Q¢ .mam

AHIEUV wocmsvmum

 

 

 

 

 

 

 

 

 

 

 

oom oooa OONH oowd oomd oomfi ooo

_ _ _ 4 _ _ w
.lom
.105
.10m
.lom

)\

[Goa

 

 

 

 

.A<HH>xAV mumHocmmmHsmumsmuu.mcmuu Hmzuws mo Esuuomdm .m.z.z .m .mflm
.E.m.m
msam> e
o o8 o.m o6 og
W, _ _ _
mm.m

9

5

 

 

 

 

 

om.m

 

 

mm.w//

 

 

 

60

identified as cis, trans-puleganolide (LXVIIIA). The infra-
red and n.m.r. spectra of the LXVIIIA isolated here were
identical with those reported by Wolinsky (77).

5. Conversion of methyl trans,trans-puleganolate to
Cis,trans-puleganolide. A solution of LXVIIA (65 mg) in
5 ml. methanol containing 1 ml. conc. hydrochloric acid was
refluxed for 5 hours and worked up by the previous procedure.
The oil thus obtained (52 mg) was analyzed by v.p.c. and
proved to be a mixture of LXVIA (27%), LXVIIIA (50%), unre-
acted LXVIIA (22%) and an unidentified component (22%) ex—

1 in the infrared. This com-

hibiting absorption at 1750 cm‘
pound may be a 7,0-unsaturated isomer of LXVIA.

B. Direct Conversion of Pulegone Oxide LXIII to
Cis,trans-puleganolide

A solution of LXIII (100 mg) and sodium methoxide (145
mg) in glyme (10 ml.) was refluxed 19 hours followed by a
work-up procedure similar to that used above. The acidic
product (75 mg.) was dissolved in 2 ml. methanol containing
0.8 ml. conc. hydrochloric acid, and this solution was refluxed
1 hour followed by the usual work-up. The resulting oil (52
mg.) was analyzed by v.p.c. and infrared spectroscopy and

proved to be 90% LXVIIIA.

Favorskii Reaction of Pulegone Oxide LXIV
A solution of LXIV (600 mg, 519 mmoles) and sodium
methoxide (870 mg) in glyme (69 ml.) was refluxed for 19 hours

and subjected to the same work-up procedure employed with

61

isomer LXIII. The neutral product (41 mg) showed three
components on v.p.c. analysis, and infrared spectra of these
disclosed no carbonyl absorption. Analysis of the acidic
product mixture (501 mg), after methylation with diazomethane,
demonstrated the presence of five components: LXV (15%), an
equimolar mixture of LXVIA and LXVIB which was not resolved
by the v.p.c. technique used here (25%), LXVIIB (55%), LXVIIIA
(22%) and an unidentified component (8%). The proof for these
structures rested on spectrosc0pic and chemical correlations.

A. Isolation and Structure Proof of Products

1. Methyl cis- and trans-pulegenates. The mixture of
LXVIA and LXVIB exhibited an infrared spectrum consistent with
a mixture of methyl cis- and trans-methylpulegenates. The
n.m.r. spectrum showed a pair of doublets at T 9.05 and 8.98
(J: 6.5 c.p.s.) (area 5.2), a broad singlet at T 8.57 (area
6.1), a pair of singlets centered at T 6.41 and separated by
1 c.p.s. (area 5), and a broad absorption from T 8.5 to 6.7.

2. Methyl trans,cis-puleganolate. The infrared spectrum
of LXVIIB showed hydroxyl absorption at 5500 cm":L and carbonyl
absorption at 1750 cm"1 (see Fig. 6). The n.m.r. spectrum
exhibited a doublet at T 9.12 (J= 6.5 c.p.s.) (area 5), a
singlet at T 8.98 (area 6), a singlet at T 6.57 (area 5), and
broad absorption from T 8.4 to 7.1 (see Fig. 7).

5. Cis,trans-puleganolide. The infrared and n.m.r. spectra
of LXVIIIA from this reaction were identical to corresponding

spectra of authentic Cis,trans—puleganolide (77).

.+HUU CH AmHH>xHV mumHocmmmasmlmflo.mcmuu Hmnume mo Ednuommm pmnmnmsH .mm .mHm

AHIEUV mucmswmum

 

62

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ooma ooom oomm ooom oomm ooo4
_ 7 _ _ q. o

. om
- o4

A
- oo

‘
.. om
r r

l ooa

 

.+HUU :H AmHH>NAV mumHocmmmHsmamH0.mcmuu Hanume mo Eduuommm UmumuwcH .Qm .mHm

AHJEUV mocmdvmnm
oom OOOH OONH oo¢H oomH OOmH ooom

 

65

_ _ _ _ 5 _ o

 

 

 

 

 

 

 

 

 

 

 

 

 

I.OOL

 

64

.AmHH>qu mumHocmmmasmlmHo.mcmuu Hanumfi m0 Eduuommm .m.2.z .5 .mam

05Hm> B

O.m o.m o.>

 

 

 

 

 

 

 

 

 

 

md.m

_ H H1

 

 

 

 

mm.m

 

 

“Kn. av fi"

 

mm.w

 

 

 

65

4. Conversion of methyl cis- and transzpulegenates
to Cis,trans- and cis,cisjpuleganolide. A 50 mg-,sample of
the.LXVIA plus LXVIBJmIXEHre'WaSVdISSOlved in 2 ml. methanol
containing 0.8 ml. conc. hydrochloric acid and refluxed for
5 hours. The usual work-up gave 20 mg. of an oil which
v.p.c. analysis showed to consist of at least four components.
These were identified as starting material (21%), LXVIIIA
(40%), LXVIIIB (55%) and an unidentified material (6%). The
stereoisomeric puleganolides LXVIIIA and LXVIIIB were
characterized by v.p.c. retention times and infrared spectra.

5. Conversion of methyl trans,cis—puleganolate to methyl
cis-pulegenate and cis,cis-puleganolide. A solution of 48
mg. LXVIIB in 5 ml. methanol containing 1 ml. conc. hydro-
chloric acid was refluxed for 5 hours and subjected to the
usual work-up procedure. At least three components were dis-
closed by v.p.c. analysis of the crude product (57 mg.). The
first to be eluted (52%) was identified as LXVIB by comparison
with authentic methyl cis-pulegenate (77). The next com-
ponent (15%) was not identified. The major component (55%)
proved to be LXVIIIB by comparison of its infrared spectrum
with that of authentic cis,cis-puleganolide (77).

B. Direct Conversion of Pulegone Oxide LXIV to cis,
trans- and cis,cis-puleganolide

A solution of LXIV (600 mg.) and sodium methoxide (870
mg.) in 60 ml. glyme was refluxed for 1 hour and worked up by

the procedure used for the previous Favorskii reactions.

66

The neutral product (219’ mg.) was analyzed by v.p.c. and
proved to be largely (90%) recovered LXIV. The remaining
neutral materialwfinshomogeneous to v.p.c. and exhibited an
infrared spectrum similar to that found for a mixture of
LXVIA and LXVIB.

The acidic product (285 mg.) was treated with diazo-
methane and analyzed by v.p.c. The major products were LXV
(19%), LXVIA plus LXVIB (50%), LXVIIB (20%) and LXVIIIA (21%).
Identification was based on v.p.c. retention times and infra-

red spectra.

Treatment of Methyl Trans,cis:puleganolate with Base

A 47 mg. sample of LXVIIB was mixed with 20 ml. of 10%
sodium hydroxide solution, heated with vigorous stirring to
600, and allowed to stand for 14 hours. Acidification to
pH < 1 followed by ether extraction yielded 59 mg. of crude
product. This was treated with diazomethane and analyzed by

v.p.c. and infrared spectroscopy. Only recovered LXVIIB was

observed.

Treatment of Cis,trans- and Cichis-puleganolide with Base

A solution of LXVIIIA (50 mg.) LXVIIIB (15 mg.) and
sodium methoxide (87 mg.) in 6 ml. glyme was refluxed for 19
hours. A work—up similar to that used previously gave 48 mg.
of crude material (both neutral and acidic) which was treated
with diazomethane (no apparent reaction) and analyzed by

v.p.c. Only recovered starting material was detected.

67

Deuterium Exchange of Pulegone Oxide

A mixture of 1.0 g LXIII in 5 ml cyclohexane (reagent
grade) and 0.50 g anhydrous potassium carbonate in 5 ml
deuterium oxide was refluxed with stirring for 72 hours.
The mixture was taken up in ether, washed twice with 5% sodium
hydroxide, twice with water, dried, and evaporated. The white
crystalline product (710 mg) was recrystallized from pentane,
giving 589 mg of needles, m. 57-80. The infrared spectrum
showed(}{>stretch at 2100 and 2215 cm‘l. In the mass spectrum,
LXIII displayed a parent peak at m/e=168 (relative intensity =
1.00) and P+1 and P+2 peaks of relative intensities 0.118 and
0.010, respectively. Corresponding peaks from the deuterated
product showed relative intensities of 2.5, 15.5, 57.5, 9.0,
and 1.0, for m/e 168 through 172, respectively. Calculations
indicate 5.4% undeuterated product, 17.9% d1, 75.7% d2, and
5.1% d3.. The intensity of the peaks at T 7.58 and T 7.45 in
the n.m.r. was decreased to ca. 10% of that in undeuterated

LXIII.
An identical procedure, using 1.00 g LXIV, gave 425 mg

colorless needles, m. 54-50. Infrared analysis showed C-D
stretch at 2215 and 2090 cm‘l. In the mass Spectrum, LXIV
displayed a parent peak at 168 (relative intensity = 1.00),
and P+1 and P+2 peaks of relative intensities 0.12 and 0.10,
respectively. Corresponding peaks of the deuterated product
showed m/e 168 through 172 peaks with relative intensities of

5.5, 18.0, 62.0, 8.0, and 1.0, respectively. Values of 6.6%

68

undeuterated, 20.8%,d1, 71.9% d2, and 0.7% d3 product were
obtained. The intensity of the peak at T 7.68 in the n.m.r.
was decreased to ca. 50% of that in undeuterated LXIV.
Conversion of Cholest-S-en-5B,48-diol 56-Tosylate

(XCII) to Cholest-S-en-4orol(XCIII)

To a solution of 58.2 g XCII (0.069 mole) in 500 ml re—
agent benzene and 500 ml absolute ether was added 4.0 g lithium
aluminum hydride (0.105 mole). After stirring at room
temperature for 24 hours, the mixture was cooled, and ethyl
acetate was added, followed by water. The mixture was filtered
and the residue was washed with ether. The organic layer was
washed with water, saturated sodium chloride solution, dried,
decolorized, and evaporated. The residue was recrystallized
from hexane and then from methanol—chloroform, giving 16.9 g
XCIII (64% of theoretical), m. 125-5O (lit. (78): m. 145-4°

from acetone-hexane).

Oxidation of Cholest-S—en-4orol to Cholest-
5-en-4-one (XCIV)

The oxidation of XCIII was carried out using aluminum
isopropoxide and cycloheXanone, following a procedure adapted
from the oxidation of cholesterol (79). A 15% yield of XCIV

was obtained, m. 112°, ”$244 1685, 1627 cm-1.

Conversion of Cholest-S-en14-one to 58,68-
Epoxycholestanr4—one‘(Lxxx1X)

 

Treatment of XCIV with sodium hydroxide and hydrogen
peroxide in methanol according to the procedure of R. LeMahieu

(51) gave LXXXIX in 65% yield, m. 105-6O (lit.: m. 98-1000 (51),

69

102-40 (78). The spectral properties were: vigi4 1711 cm‘l;

cyclohexane
max

[@1325 +1925°, [¢]306 40°, [41280 -1955°; O.R.D. in cyclo—

A 504 mu(€ 44.5); O.R.D. in 95% EtOH (c, 0.077),
hexane (c,0.079), [41337 +2220°, [cu]316 40°, [41295 -2020°;
C.D. in 95 EtOH (c, 0.077), [¢]307 +2650 (Ro= 2.02 x 10-40
c.g.s.)(see Fig. 8); C.D. in cyclohexane (c, 0.079), [¢]318
+2780 (Ro= 2.51 x 10-40).

Conversion of Cholest-S-en-4orol to 50,60r
Epoxycholestan-4-one (LXXXVIII)

A solution of 6.8 g XCIII (17.6 mmole) and 4.9 g 85%
m—chloroperbenzoic acid (50 mmoles) in 275 ml thiophene-free
benzene was stirred at room temperature for 19 hours. A 10%
sodium sulfite solution was added until a negative test with
sodium iodide-starch paper was attained. The benzene layer
was extracted with 5% sodium hydroxide solution, washed with
water and saturated sodium chloride solution, dried and the
benzene was evaporated. The residue was a gum which dould not
be crystallized.

Seven g chromium trioxide (70 mmole) was added in small
portions to 120 ml cold, well-stirred pyridine. Then the
crude product from above in 25 ml pyridine was added in one
portion and the mixture was stirred at room temperature for
5 days. After addition of ethyl acetate and filtration, as
much pyridine as possible was evaporated at reduced pressure.
The residue was taken up in ether and washed with 5% hydro-

chloric acid, water, saturated sodium chloride solution, dried,

+5

+2

+1

[8] x 10'3

Fig.

70

 

 

” LXXXVIII

 

I l 1

 

250 500 550
Wavelength (mu)

8. C.D. spectra of 50,605epoxycholestan-4-one
(LXXXVIII) and 58,68-epoxycholestan-4-one
(LXXXIX) in 95% EtOH.

 

71

decolorized, and the ether evaporated, leaving a green oil.
Chromatography on 70 gm silica gel and elution with 1:7
chloroformzbenzene gave 1.4 g of a non-recrystallizable solid.
This material was purified by preparative thin layer chroma-
tography using a 1 mm layer of silica gel PF254 (Brinkmann
Instruments, Inc.), and eluting with chloroform. The band

of Rf = 0.17-0.49 was recovered and recrystallized twice from
methanol, yielding 500 mg LXXXVIII, m. 84-6O (lit. (78): 86-70).
The spectral properties were: v:::4 1725 cm'l; xgyilohexane
297 mu(€ 57.7); O.R.D. in 95% EtOH (c, 0.058), [41328 -1748°,
[4132, -187o°, [41303 10°, [41279 +1665°; O.R.D. in cyclo-
hexane (c, 0.075), [41329 -1900°, [41324 —1620°, [41319 -1860°,
I¢1311 -725°, [41305 r0°, [4123l +1618O; C.D. in 95% EtOH
(c,0.058), [¢]300 -2560 (R0: -2.58 x 10‘4oc.g.s.) (see Fig.
8); C.D. in cyclohexane (c, 0.075), [¢]324 -1160, [0J313 -2510,
[¢]310 -2240, [41304 -2,640, [41296-8 -2,540 (R0: -255 x 10‘40

c.g.s.).

4515 -Epoxycholestan-5-one (LXXXVI)

 

LXXXVI, prepared by the method of Shaw and Stevenson

vCC14

(80) exhibited the following spectral properties: max

1710 cm‘l; kCyClohexane
max

O.R.D. in 95% EtOH (c, 0.081), [@1328 +8920°, [¢]307 too,

504 mu(€ 52.1) and 515 mu (6 51.7):

[41282 -808o°; O.R.D. in cyclohexane (c, 0.081), [41342 +91oo°,
[4(336 +7720°, [91329 +9500°, [@1318 +5715°, [41313 40°,
[41280 -8080°; C.D. in 95% EtOH (c, 0.081),[¢]306 +12,400

(Ro= 12.5 x 10-4oc.g.s.); C.D. in cyclohexane (c, 0.081),

72

[¢]334 +4580: [¢]323 +10,200, [@1321 +9950. [91313 +12 100

[¢]3o4 +10,47O (R0: 11.6 X 10-40 c.g.s.).

10.
11.
12.
15.
14.
15.

16.

17.
18.

19.

20.

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75

21.

22.
25.

24.
25.
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27.
28.

29.

50.

51.

52.

55.

54.
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57.

58.
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41.

74
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R. Deghenghi, G. Schilling, and G. Papieneau-Conture,
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A. Fort, J. Am. Chem. Soc. 84, 2625 (1962).

Ibid., 84, 4979 (1962).

N. Turro and W. Hammond, J. Am. Chem. Soc. 81, 5258 (1965).
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Ibid., 88, 5672 (1966).

A. Kende, "Organic Reactions," Wiley, New York, 1960,
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R. Breslow, L. Altman, A. Krebs, E. Mohacsi, I. Murata,
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R. Woodward and A. Clifford, J. Am. Chem. Soc. 65, 2727
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G. Hess and F. Urbanek, Ber. 91, 2755 (1958).
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J. Kennedy, N. McCorkindale, R. Raphael, W. Scott, B.
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J. Romo and R. deVivar, J. Am. Chem. Soc. 19, 1118 (1957).
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C. Rappe, Arkiv Kemi. 24, 515 (1965).

42.
45.
44.
45.
46.
47.
48.
49.

50.

51.

52.

55.

54.

55.
56.
57.

58.

59.

60.

61.

62.

65.

75-

C. Rappe, Acta Chem. Scand. 20, 862 (1966).

E. Dehmlow, Z. Naturforsch, Pt. B, 20, 1128 (1965).

C. Rappe and K. Andersson, Arkiv Kemi. 24, 505 (1965).
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Ibid., 65, 165 (1952).

Ibid., 66, 610 (1955).

Ibid., 66, 1485 (1955).

H. House and F. Gilmore, J. Am. Chem. Soc. 85, 5972 (1961).

J. McGhie, P. Palmer, M. Rosenberger, J. Birchenough, and
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R. LeMahieu, Ph. D. Thesis, Michigan State University,
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W. Reusch and R. LeMahieu, J. Am. Chem. Soc. 85, 1669
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G. Cavill and S. Achmad, Aust. J. Chem. 16, 858 (1965).

J. Wolinsky, H. Wolf, and T. Gibson, J. Org. Chem. 28,
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J. Wolinsky and D. Cahn, J. Org. Chem. 59, 41 (1965).
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G. Cavill and C. Hall, Personal Communication.

N. Kundu, S. Mukherjee, and P. Dutta, Tet. Letters,
627 (1962).

D. Cram, "Fundamentals of Carbanion Chemistry,"
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A. Nickon, J. Lambert, R. Williams, N. Werstiuk,
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C. DePuy, F. Breitbeil, and K. DeBruin, J. Am. Chem. Soc.
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P. Wharton and T. Bair, J. Org. Chem. 51, 2480 (1966).

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64.
65.

66.

67.

68a.

68b.

69.

70.
71.
72.

75.

74.

75.

76.

77.

78.

79.

80.

76

J. Wolinsky and D. Cahn, J. Org. Chem. 59, 41 (1965).
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C. Djerassi, W. Klyne, T. Norin, G. Ohloff, and E. Klein,
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M. Ligrand, R. Viennet, and J. Coumartin, Compt. rend
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C. Djerassi, "Optical Rotatory Dispersion," McGraw-Hill
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Ibid., p. 178.

K. Wellman, R. Records, E. Bunnenberg, and C. Djerassi,
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D. Williams and N. Bacca, Tetrahedron 21, 2021 (1965).

J. Connolly and R. McCrindle, Chem. and Ind., 579 (1965).
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N.M.R. measurements were made by Dr. Lois Durham and her
staff, Dept. of Chemistry, Stanford University, Stanford,
California.

Low temperature C. D. measurements were made by Mrs. Ruth
Records through the courtesy of Prof. Carl Djerassi, Dept.

of Chemistry, Stanford University, Stanford, California.

K. Wellman, P. Laur, W. Briggs, A. Moscowitz, and C.
Djerassi, J. Am. Chem. Soc. 81, 66 (1965).

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Kindly provided by Prof. J. Wolinsky.

D. Lavie, Y. Kashman, and E. Glatter, Tetrahedron 22,
1105 (1966).

"Organic Syntheses," Coll. Vol. IV, Wiley, New York,
1965, p. 192.

J. Shaw and R. Stevenson, J. Chem. Soc. 5549 (1955).

IIIHIIHIH

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