Date

37.. A" ' _‘..- Elfin—J: :33:
Li :1: :t- P Y ”"
Michigan Sate

.. .3; . ’ XL.
)g‘Umvem y

   
 
      

This is to certify that the

thesis entitled
Synthesis and Lithium Ammonia Reduction of

Homoconjugated Dienedione Systems
in Steroids

presented by

Hans R. Taneja

has been accepted towards fulfillment
of the requirements for

Ph.D. degree in Chemistry

Was/74w

Major professor

September 2, 1977

 

0-7 639

0! I‘l“ II} 1| I. 1" ‘3'. U

SYNTHESIS AND LITHIUM-AMMONIA REDUCTION OF

HOMOCONJUGATED DIENEDIONE SYSTEMS IN STEROIDS

by

Hans R. Taneja

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1977

ABSTRACT
SYNTHESIS AND LITHIUM-AMMONIA REDUCTION OF

HOMOCONJUGATED DIENEDIONE SYSTEMS
IN STEROIDS

BY

Hans R. Taneja

The synthesis of dienedione g, which is a bis-vinylog
of cyclohexan-l,3-dione, was achieved by two slightly dif-

ferent methods starting from 7-deoxycholic acid’l.

 

Attempts to oxidize the two hydroxy groups in 1 follow-
ed by a-bromination at the 4- and ll-positions simultaneously
resulted in the formation of tetrabromideig’which on dehydro-

bromination gave 2-bromo trienedione i;

Hans R. Taneja

 

A stepwise introduction of 9,11- and 4,5-double bonds
was a logical alternative. Selective protection of the
3-hydroxy function as a carbonate ester was followed by
oxidation of the lZ-hydroxy group and bromination of the
d-methylene group at C-ll. Dehydrobromination of the result-

ing bromoketone §,gave enone g.

 

 

Hans R. Taneja

Hydrolysis of the 3-carbonate functions in Q’and 2’
followed by oxidation and d-bromination with N-bromoaceta
acetamide in aqueous acid gave bromo steroids 1 and g

respectively.

 

8
N

2x)

Dehydrobromination of”; or EIyielded dienedione inn
moderate yields. Lithium and ammonia reduction of 2’pro—

duced the expected cyclopropane 2;

 

DEDICATION
This dissertation is dedicated to the following:

Madhu, my wife, whose love and encouragement has

made these years good and worthwhile;
My parents, brothers and sisters whose love, under-

standing and moral support over the years have made

this opportunity possible.

ii

ACKN OWLE DGEMENT

The author is deeply greateful to Professor William
H. Reusch for his guidance, for his vigorous intellectual
example and his willingness to listen and to make suggestions
during this endeavor.

Appreciation is also extended to my friends and col-
leagues for stimulating and informative discussions, and
for their friendship and humor.

Finally, the author would like to thank the National
Institute of Health and Michigan State University for

finnancial support.

iii

The chemist who can extract from
his Heart's element compassion,
respect, longing, patience, regret,
surprise and forgiveness and come
pound them into one, can create
that atom which is called Love.

iv

TABLE OF CONTENTS

Page
INTRODUCTION . . . . . . . . . . . . . . . . . . . . 1
RESULTS AND DISCUSSION . . . . . . . . . . . . . . . 9
EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . 27
General . . . . . . . . . . . 27
Preparation of methyl 3,12-diketocholanate $1 . 30
Preparation of methyl 2- bromo-3. 12- diketo-
1 -cholatrienate 33 . . . . . . . . . 31
Oxidation and.d-bromination of methyl
deoxycholateJE'. . . . . . . . . . . . 32
Preparation of methyl 3,12-diketon-A3-
cholenate gg. . . . . . . . . . . . . . 33

Preparation of methyl 3 -ethoxycarbonyloxy,
12— ketocholanate 37 . . . . . . . . . . . 33
Preparation9 of 11methyl 3 -ethoxycarbonyloxy,
lZ-keto-A9( —cholenate 3} .. . . . . . . . . 34
Bromination of methyl 3 -ethoxycarbonyloxy,
12-ketocholante 57. . . . . . . . . . . . . . 35
Epimerization of 11 -bromoketone g; to 11-

bromoketone 41 . . . . . . . . . . . . . . . 36
Zinc and acetic acid debromination of

11 -bromoketone 41 . . . . . . . . . . . . . 37
Zinc and acetic acidadebromination of

11 -bromoketone 42 . . . . . . . . . . . . . 37

Dehydrobromination of 11 -bromoketo e $1 . . . 37
Preparation of methyl 3, 12— —diket01§9 -

cholenate 4 . . . . . . . . . . . 39
Pre aration 0 methyl 3-ethoxycarbonyloxy-

1-cholenate 4]. . . . . . . . . . . . . 40
Addition of hypobromons acid to alkene 41 . . . 41
Preparation of 1L1,12x-epoxide 50 . . . . . . . 43
Preparation of bromohydrin éi. . . 43
Oxidation andobbromination o bromohydrin ;2. . 44
PrepaiaEioE)of methyl 3,12- diketo,

-cholanate ép . . . 45

Homogeneous catalytic reduction ofiifi. 1 . 46
Preparation of methyl 3,12-diketo-A 9 ( 15-

choladienate éfi . . . . . . . . 47
Lithium and ammonia reduction of A4'9(11)-
diene-3,12-dione éé . . . . . . . . . . . . 49

Page

REFERENCES . . . . . . . . . . . . . . . . . . . . . 51

APPENDIX: SPECTRA . . . . . . . . . . . . . . . . . 54

vi

Figure

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93

INTRODUCTION

Reduction of unsaturated carbonyl compounds by alkali
metals in ammonia solutions generates reactive nucleophilic
intermediates which are capable of intra- and inter-molecular
attack on electrophilic centers.1 This was first observed
during lithium and ammonia reduction of 10-hydroxymethyl-

1,9

A ,2-octalone tosylate l,bY Stork and co-workers.2

 

In fact, even relatively reactive compounds such as cyclo-
propanols3 have been prepared by this kind of transformation.
It was recognized that cyclopropane ring formation during
dissolving metal reductions of bi- and polyfunctional com-
pounds is probably a general phenomena. This concept has
been applied to the synthesis of vic.- cyclopropanediols.4
Reduction of 2,2,4,4,6,6-hexamethy1 cyclohexane-l,3,5-trione

‘g,with lithium in liquid ammonia produced the corresponding

cyclopropanediol 4.

A logical extension of this work would be to apply this con-
cept to vinylogs of 1,3-diketones. To this end, Wieland-
Miescher ketone §,was subjected to reduction with lithium in

liquid ammonia and gave the cyclopropanol 6,5

O H
7
CC -+
9
o O [:?::[:::]§O
2

,5. 5

   

Eight alkyl-substituted derivatives of Wieland-Miescher
ketone g’were prepared and subjected to lithium and ammonia
reduction with similar results.6 Other tri-functional com-
pounds examined were the steroids 9,lla- and B-oxido methyl
testosterones 19 and 7b, which upon lithium in ammonia
reduction did not yield the expected products 8; and 89,

but gave only the saturatedscompounds 93 and 29.7

 

a
b=B b=B b=B

A further extension of this work would be to apply this
concept to bis-vinylogs of 1,3-diketones, such as the
Wieland-Miescher ketone derivative 19 or the steroid 11.
On lithium and ammonia reduction these compounds would be

expected to give the cyclopropanes I; and 13 respectively.

 

All attempts to introduce an unsaturated carbonyl func-

tion at C-7 in Wieland-Miescher ketone met with no success,8
probably due to the steric hinderance offered by the C-6
angular methyl group. A major part of this thesis is,
therefore, devoted to work leading to the synthesis of
steroid 11, since no steroid having the functionality shown

in formula 11 has been reported in the literature.

The 5,9-cyclosteroid lg, representative of the cycloreduc-
tion product expected from 11, has been isolated by DJLR.
Barton et a1.9 during the chromous acetate reduction of

9a-bromo,llB-hydroxy-progesterone 14.

 

The synthesis of conjugated enone systems in steroids
is usually accomplished by one of two fundamentally different
strategies:

1) A double bond is introduced adjacent to an existing

carbonyl function.

2) An existing double bond is oxidized at an allylic

site.

Some of the methods available for introducing double
bonds adjacent to carbonyl functions are:

a)<x- halogenation followed by dehydrohalogenation

b)cx- selenation followed by oxidative elimination of

selenium-oxy acids.

c) Dehydrogenation with selenium dioxide.

d) Quinone dehydrogenation with DDQ or chloranil.

Thecx- bromination of cholestan-B-one‘l§,was first described

by Butenandt (1935),10 and later shown by Corey11 to give

the Za-bromocholestan-3-one 13. This bromoketone, on

dehydromination with pyridine, gave Alécholestan-3-one 13.

C8H17

    

16 17 18

.\, ,«;
Recently, Sharpless12 reported the synthesis of Al-cholestan-
3-one 13 by a-selenation of cholestan-B-one 16 with Phenyl
Selenium Chloride to give 20-phenylseleno compound 19,
followed by oxidative elimination to 18 with an alkaline

solution of hydrogen peroxide.

 

Kendall and his co-worker313 introduced a 9,11-double bond

in the lZ-ketocholic acid derivative 29 by treatment with

A9,ll

selenium dioxide to give the ,12-keto steroid 21.

 

20 21

The alternative synthesis of l7B-hydroxy androst-l-en-3-one
12; by DDQ dehydrogenation of l7B-hydroxy androstan-B-onelgg,

was reported by Ringold and Turner.14

 

The allylic oxidation of unsaturated steroids has been
accomplished in several different ways, including:
a) Allylic oxidation with t-butyl chromate, chromium
trioxide or sodium dichromate.
b) Allylic dibromination with N-bromosuccinimide
followed by base hydrolysis.

15

Heusler and Wettstein have used t-butyl chromate for

allylic oxidation of 3B, l7B-diacetoxy androst—S-ene 23, the

7-oxo derivative 25 being the major product.

   

24 25
N ~
Dauben 93,31.16 report that the chromium trioxide-pyridine

complex accomplishes this same allylic oxidation, but in
better yield. In a similar approach, Jones gt 21,17 used
sodium dichromate to effect allylic oxidation of 4,4-dimethyl
cholest-S-ene-B-one‘gg to the corresponding 7-keto steroid

27.
N

 

Allylic dibromination of 26 by irradiation in the Presence
of N-bromosuccinimide gave the 7,7-dibromo compound 28,
which was converted to enone 22 by treatment with aqueous

sodium carbonate.18

 

A similar procedure in which allylic dibromination and
hydrolysis occur in the same step was reported by Thomson
SE 2: 19
Of course, other reaction sequences may be used to pre-
pare enones, but many of these have not been widely used

with steroids. The author intends to explore some of them

in this thesis.

RESULTS AND DI SCUSS ION

Deoxycholic acid is an inexpensive and promising start-
ing material for the synthesis of dienedione ll. Esterifi-
cation of deoxycholic acid 22 followed by Jones oxidationz0
provided the required 3- and lZ-carbonyl functions (Equation

1). The synthesis of I; thus becomes a matter of inserting

double bonds at the 4,5- and 9,11-positions.

(l)

 

One simple method that might be used to introduce the
required double bonds would involve simultaneous a-bromi-
nation of the two carbonyl functions, followed by dehydro-
bromination. A major problem with this approach was lack of
control over bromination at different a-sites. Thus, the
3,12-diketosteroid 35 upon bromination in the Presence of

boron trifluoride etherate21 gave a bromo derivative which

10

was tentatively regarded as methyl-2,2,4,1l-tetrabromo-3,12-
diketo cholanate 33. Field desorption mass spectroscopy of
’32 did not give a parent ion; however, dehydrobromination
with lithium carbonate and dimethylformamide22 gave a tris-

dehydrobrominated product, which was established by proton

magnetic resonance (Pmr) and mass spectra to be methyl-2-
A1,4,9(11)

bromo-3,12-diketo- cholatrienate 2} (Equation 2).

(2)

 

Another procedure, capable of giving oxidation and
d-bromination in the same step involved treatment of methyl
deoxycholate 39 with hydrobromic acid and an excess of
N-bromoacetamidezB. The product obtained in this case was
identified as methyl 4B-bromo-3,12-diketo cholanate 23,
which on treatment with lithium carbonate and dimethyl-

22

formamide gave methyl 3,12-diketo-A4-cholenate 25’

(Equation 3)

ll

(3)

 

A second approach involving his a-selenation of the two

carbonyl functions in 31 with phenyl selenium halideslz,

as a prelude to oxidative elimination, proceeded in very

poor yield. Over 90% of the starting material 21 was re-
covered unchanged from the reaction mixture.

Finally, dehydrogenation of the diketone 31 with
selenium dioxide or DDQ introduced double bonds in rings A
and B only, and not at all in ring C24. The crude product
mixture did not show a signal near 65.6 in prOton magnetic
resonance (Pmr) spectra, a feature which is characteristic
of ring C enone systems. Indeed, Nozoe and co-workers24
have reported that there is no introduction of 9,11-doub1e
bond in diketone gl’under similar conditions.

Since the simultaneous introduction of both double
bonds was not effective, a logical alternative was to study
the stepwise introduction of double bonds at the 9,11- and
4,5-positions.

One of the two approaches employed here was first to

selectively protect the 3—hydroxy group of methyl

12

deoxycholate 29 as the carbonate ester by treatment with
ethyl choloroformate in pyridinezs. Oxidation of the free
lZ-hydroxy group with Jones reagentzo, followed by introduc-
tion of the 9,11-double bond by treatment with selenium

dioxide26 gave enone 38 (Equation 4).

(4)

cozca3

I 1
-———4p -—§'
5

..3~§ ,33 as

. y'\>l

   

9e,--¢- o
cn3cnzoflof

However compound 28 obtained in this way was contamin-
ated with the saturated keto steroid 31, and this mixture
could not be separated by fractional crystallization from
ten different solvents and solvent mixtures. Furthermore,
preparative thin layer chromatography, column chromatography
(silica gel and alumina) and high pressure liquid chroma-
tography (silica gel and C-18 reverse phase columns) failed
to resolve the mixture, as indicated by Pmr, infra-red and
mass spectroscopy. Efforts to separate this sharp melting
mixture (mp 163-4°) of saturated and a,B-unsaturated keto
steroids in subsequent steps of the synthesis also met with
no success. Seebeck and Reichstein27 have reported that

9(11)

3a-hydroxy, lZ-keto-A -cholenic acid does not depress

13

the melting point of 3a-hydroxy,lZ-keto-cholanic acid and
that the melting point of a mixture of the methyl esters of
these two acids is not depressed below that of the lower
melting component. Likewise, E. C. Kendall and co-workers26
were unable to separate a mixture of 3d-hydroxy,12-keto-

9(LU-cholanic acid

cholanic acid and 3d-hydroxy,12-keto,A
by crystallization. A similar lack of mixture melting point
depression was noted in the case of methyl 3a-ethoxycarbonyl-
oxy,12-keto cholonate (mp 158-9°) and methyl 3a-ethoxy-

carbonyloxy,12-keto,A9(11)

-cholenate (mp 167-8°), made in
another reaction sequence discussed later.

A second approach involving the a-bromination of
12-keto steroid 31 followed by dehydrobromination gave
excellent results. Bromination in the presence of boron

21 in glacial acetic acid solution pro-

trifluoride etherate
duced 3-ethoxycarbonyloxy,ll-bromo,12-keto cholanic acid in
nearly quantitative yield (Equation 5). The product was,
however, found to be an epimeric mixture of lh:-bromo,
12-keto steroid 33 (95%) and llB-bromo,12-keto steroid 49
(5%). The corresponding methyl esters 4; and 43,were
separated easily by fractional crystallization, with melting
points of 97-8° and l72-3° and optical rotations of 46.6° and
36.3° (C = .85, CHZClZ) respectively. Mass spectra of 41

and 43 did not show parent ions (P), the fragment ion (P-Br)

being the highest mass fragment in the spectrum.

14

(5)

 

COZR
37 R = H, ll-Br = a
’\-’ 0 \‘ , R = H, 11.81. = B
cn3cazoflo‘ R = CH3,ll-Br = a
R = CH3,11-Br = 8

Infrared spectrosc0py played a key role in establishing the
configurations of the two epimeric ll-bromo,12-keto steroids;
the carbonyl stretching frequencies being 1735 cm—1 and

1710 cm-1 respectively. Jones and co-workers28 have reported
that an a-halogen atom having an axial orientation to the
carbonyl group causes only a slight displacement in the loca-
tion of the carbonyl stretching frequency, but an equitori-
ally oriented bromine atom shifts the carbonyl stretching
frequency to a higher value by about 20 cm-l. This clearly
indicated that the lower melting isomer (smax 1735 cm-1) had
configuration 1; and the higher melting isomer (3fiax 1710
cm-1) configuration 43. The llB-bromo,12-keto steroid 4;
underwent a facile epimerization to llcx-bromo,12-keto
steroid gl'in the presence of hydrobromic acid21. This
isomerization probably proceeds by an enolization of the
bromoketone in which the stereoelectronic effects favoring
axial hydrogen loss is accommodated by bending of ring C.
Thus an apparently equatorial hydrogen atom becomes pseudo-

axial in the flexible or boat configuration of ring C

(Scheme I).

15

Scheme I

a-isomer

   

Enolization

B-isomer

Debromination of the Ila-bromo,12-keto steroid 41 or its
B-isomer 43, by refluxing with zinc dust and glacial acetic

acid29

yielded the lZ-ketosteroid 3] in each case, confirm-
ing that 41 and 42 are epimeric ll-bromo,12-keto steroids.
An attempt to eliminate hydrogen bromide from lla-bromo,
12-keto steroid 4} by refluxing with methanolic potassium
hydroxide gave an unidentified acidic substance that was
clearly not the desired enone 33. The product, however,
showed a parent ion at m/e 406 in its mass spectrum, and on
treatment with diazomethane gave a substance with a parent
ion at m/e 420, indicating the presence of only one carbonyl
group. These facts suggest that in addition to the hydroly-
sis of the 3-carbonate ester and 24-methyl ester groups, an

S 2 substitution of the 11-bromo group by hydroxide ion

N
might have taken place, giving ll-hydroxy,12-keto deoxy-

cholic acid (m.w. 406). However, the hydrolysis

16

of lla-bromo,12-keto steroid 33 with methanolic potassium
hydroxide at room temperature gave 3a-hydroxy,lla-bromo,
12-keto deoxycholic acid.

Reaction of lla—bromo,12—keto steroid 31 with 1,5-
diazabicyclo[5.4.0]undec-5-ene (DBU) and dimethylsulfoxide
(DMSO)30 at room temperature was monitored by thin layer
chromatography. In two weeks, only partial conversion to
enone 33 had occurred, but in six weeks, conversion was com-
plete. Fortunately, a more effective dehydrobromination
procedure was found. Thus treatment of lla-bromo,12-keto
steroid 33 with a refluxing solution of lithium carbonate in
dimethylformamide22 gave enone 33 in almost quantitative
yield in 5.5 hours. A two step conversion of saturated ke-
tone 3} to enone 33 by bromination with boron trifluoride
etherate and dehydrobromination with dimethylformamide and
lithium carbonate was thereby achieved in very high yield
(>95%) .

As expected, enone 33 gave 12-keto,A9(ll)-deoxycholenic
acid 33,0n hydrolysis with methanolic potassium hydroxide.
The Pmr spectra of 53’showed a two proton signal at 66.5.
Since the signal disappeared on treatment with D20, it is
probably the result of a fast exchange between the 3-hydroxy
and the 24-carboxyl protons. Addition of freshly prepared

diazomethane to a suspension of carboxylic acid 33,1n ether

gave the corresponding ester 34, which was oxidized to

17

A9(11)

methyl 3,12-diketo, -deoxycholenate’15 with Jones

reagent20 (Equation 6).

(6)

0 O
a u—I’
—-'>
Ho" 0
45

33' R = a t~/
44 R = CH3
~

Although the bromination-dehydrobromination sequence
9(11)

from 3] is undoubtedly the best route to the A -ene-12-

one functionality, another approach that was studied at the
same time merits discussion because of its unusual chemistry.

This procedure was based on a brief report in the patent

31

literature that aquous hypobromous acid converted ll-dehy-

9(11)-ene-12-ol derivative. Such

9(11)

droprogesterone to its A
an enol could, of course, be oxidized to A -ene-12-one
steroid by any of several oxidizing agents. Since hypo-

bromous acid normally adds to carbon-carbon double bonds to
give bromohydrins, and since in the case of All-steroids the

major bromohydrin is presumed to have the llB-hydroxy-12a-

bromo configuration (structure 39) , the report raised several

18

questions that this study has tried to answer.

Initial efforts to prepare the A11

-steroid 47 by phos-
N
phorous oxychloride dehydration32 of alcohol 33 proceeded
in poor yield (<50%). Consequently, a stepwise reaction
sequence that involved formation of a methanesulfonate 33
from alcohol 3§, followed by thermolytic elimination of
methanesulfonic acid33 was developed, and gave excellent

yields (>908 for two steps) of the desired alkene 31

(Equation 7).

(7)

 

Addition of aquous hypobromous acid to 31 gave the reported
enol 33 (458) along with bromohydrin 33 (39%), the mixture
being easily separable by thin layer chromatography

(Equation 8).

l9

(8)

CH
3

 

Since enol 3§,was converted to enoneJ33 upon Jones oxidation,
the structure of this product is unquestioned. It remained
to be determined whether the assignment of configuration 33
to the bromohydrin product is correct, and whether this
product is an intermediate in the formation of enol 33.
Early studies of hypobromous acid addition to All-steroids
by Reichstein and co-workers34 concluded that ll-hydroxy,
12-bromo steroids were the major products, but noted that
lZ-hydroxy,9,ll-dibromo compounds were by products. The
stereochemistry of the bromohydrin was incorrectly assigned
by Reichstein and was later corrected by Fieser3S in his
monograph "Steroids". Configuration 3; would in fact be
predicted by application of the Ffirst-Plattner rule36 to the

addition of hypobromous acid to 52, According to this rule,

20

addition reactions to double bonds which proceed through
three-membered cyclic intermediates preferentially give
trans-diaxial product537. Formation of.a bromonium ion
intermediate from 32 would undoubtedly occur at the less
hindered a-face of the double bond. This bromonium ion
(Scheme II) would then suffer diaxial ring opening only if
a nucleophile such as water (or hydroxide) attacked C-ll
from the B-side. The result of this reaction would be

bromohydrinlgg.

 

Scheme II

Ho
N

t.

 

Br .

33.,
It is interesting to note that the anti-coplanar transition
states that lead to trans-diaxial products are preferred
even though severe steric hinderance may be present (as in
this case). The Pmr spectrum of bromohydrin 33,agrees with
the predicted structure.

It is informative to compare bromohydrin 32 with the
isomer/31 obtained from epoxide 39 by addition of hydro-

bromic acidzg. Epoxide 39 is prepared from alkene 47 by

reaction with a peracid38 (Equation 9).

21

(9)

  

- I
Vs 0 \ H 3

CH CH 030°“
3 2

50 51

Bromohydrin 3;,was clearly different from bromohydrin 53,as
indicated by thin layer chromatography and Pmr spectra.
Bromohydrin 33 on oxidation with chromium trioxide in glacial
acetic acid29 gave the llB-bromo,12-keto steroid 33, which
on debromination with zinc dust and glacial acetic acid29

gave lZ-keto steroid 31. Oxidation of bromohydrin 33,under

similar conditions gave the lZ-bromo,11-keto steroid 33,

which on debromination gave ll-keto steroid 33 (Equation 10),
39

as reported by Archer gt 3;.

(10)

 

”V S
c He ‘
H3CH20CO

52 53

22

Bromohydrin 33 remained unchanged on treatment with
aqueous hypobromous acid or aqueous bicarbonate.4o Surpris-
ingly, it did not form an epoxide even on heating with
sodium hydroxide solution. All these observations indicated
that enol fig and bromohydrin A; were being formed by two
different reaction paths from the alkene 33.

Once it was recognized that enol 33 was a major product
from the reaction of 42 with hypobromous acid, it was possible
to modify the reaction conditions so as to give enone 38,
directly. Treatment of the alkene 37/ with aqueous perchloric
acid and N-bromoacetamide in dark40 gave a mixture of the
enone 33 and bromohydrin 33, The enone 33 was fractionally
crystallized from acetone in moderate yield ( 40%).

Having independently synthesized the two enedione sys-

tems 3g and 3;, the next step was to put the procedures

together to get the dienedionelgg. This proved to be

 

23

unexpectedly difficult. Efforts to brominate the 11- and
4-positions in 33 and fié’respectively met with no success4o.
Reactions of 33 and 33 with pyrolidone-2 hydrotribromide
(PHT)41 proceeded very poorly and also 33 and AEIremained
largely unchanged on refluxing with ethyl acetate and cupric
bromide42. Reaction of £3 with phenyl selenium halides
followed by oxidative elimination12 proceeded very poorly
and most of the starting material (79%) was recovered un-
changed from the reaction mixture.

Treatment of the enedione 33 with selenium dioxide in

1’4'9(11)-cholat-

t-amyl alcohol43 gave methyl 3,12-diketo,A
rinate 39. Surprisingly, 39 was resistant to reduction by
Wilkinson's catalyst (tris triphenyl chlororhodium) and
hydrogen in contrast to the facile and selective reduction
of the Al-double bond reported for cholesta-1,4-diene-3-
one44 under similar conditions. Even more unexpected was
the finding that a 1:1 mixture of tristriphenyl chlororho-
dium and cyclooctene rhodium complex catalyzed the reduction

1 4 45

of both A- and A -double bonds , reforming enedione 33.

These reactions were repeated several times with identical

results (Equation 11).

(ll)

.45 '

 

24

Efforts to simultaneously oxidize and a-brominate

9(11)

methyl 3a-hydroxy,12-keto,A -cholenate’33 by treatment

with hydrobromic acid and an excess of N-bromoacetamide23
produced a mixture of two compounds. One of them.was estab-
lished to be the expected product/37. And the other product,
whose structure was not established, appeared to have added
a mole of hypobromous acid across the 9,11-double bond of

‘33 in addition to oxidation and bromination in ring A.

This was indicated by Pmr, infra red and mass spectra of the
compound. However, addition of exactly two equivalents of
N-bromoacetamide and hydrobromic acid tolfifi gave only 33,
which on dehydrobromination with a refluxing solution of

lithium carbonate in anhydrous dimethylformamide22 gave

dienedione 55 (Equation 12).
A/

(12)

 

=r 57

/\../

Another approach involved oxidation and d-bromination
of methyl 3a-hydroxy, lla-bromo,12-keto cholanate 33, which
was obtained by hydrolysis of methyl 3a-ethoxycarbonyloxy,
lla-bromo,12-keto cholanate 31 with a 2.5% methanolic

potassium hydroxide solution followed by esterification with

25

diazomethane. Steroid 33 on treatment with two equivalents
of N-bromoacetamide and hydrobromic acid gave dibromide 33,
which on bis dehydrobromination with lithium carbonate and

dimethylformamide22 gave dienedione 33'(Equation 13).

(13)

 

4,9(11)

Synthesis of methyl 3,12-diketo,A -choladienate
‘33by two different approaches had achieved the first goal
of this research. The next step would be to subject
A4'9(11)-dien-3,12-dione 33 to lithium and ammonia reduction
and see if the two ring A and ring C enone systems behave
independently or 33 behaves as a bis-vinylog of cyclohexane-
1,3-dione.

Lithium and ammonia reduction of diendioneygg gave a
product that could not be purified by either crystallization
or chromatography (silica gel or alumina). Further work

needs to be done for characterization of the product.

However, the initial examination of the spectral data on the

26

crude product indicated that 35 behaved as a bis-vinylog of
cyclohexan-l,3-dione. In addition, the C24-ester seemed to
have been reduced to the corresponding alcohol. The product

was tentatively assigned the structure/39.

 

55 —>

"\.t

 

EXPERIMENTAL

General

Except as indicated, all reactions were conducted under
dry nitrogen or Argon, using solvents purified by distilla-
tion from suitable drying agents. Magnetic stirring devices
were used for most small scale reactions and mechanical
stirrers for large scale reactions and lithium and ammonia
reduction. Organic extracts were generally dried over anhy-
drous magnesium sulfate, before being concentrated, unless
otherwise specified. The progress of most reactions was
followed by thin layer chromatography (Tlc) using 30% sul-
furic acid as spray reagent and subsequent heating or ultra-
violet (UV) light.

Preparative Tlc was carried out on a 2 mm silica gel
F-254 adsorbent on 20x20 cm glass plates. Visualization of
preparative Tlc was effected by UV light. Melting points
were determined on either a Hoover-Thomas apparatus (capil-
lary tube) or on a Reichert hot-stage microscope and are
uncorrected. Infrared (ir) spectra were recorded on a
Perkin-Elmer 237B grating spectrophotometer. Proton magnetic
resonance Pmr) spectra were taken in deuterochloroform

(CDC13) or carbon tetrachloride (CC14) solutions with a

27

28

Varian T-60 or Bruker SpectrOSpin (180 MHz) spectrometers

and are calibrated in parts per million (6) downfield from

tetramethylsilane (Tms) as an internal standard. Ultraviolet

spectra were recorded on a unicam SP-800 spectrophotometer.

Mass spectra (ms) were obtained with a Hitachi RMU 6 or

LKB 9000 mass spectrometers. Optical rotations were measur-

ed with a Perkin-Elmer 141 Polarimeter using methylene

chloride solutions with concentrations of 8-10 mg/ml.
Microanalysis were performed by Spang Microanalytical

Labs, Ann Arbor, Michigan.

General procedure for oxidation with
Jone's reagent

 

To a solution of the compound in acetone kept in a water
bath at 30-35°, a solution of 8 N chromium trioxide-sulfuric
in

acid (8 N Cro -HZSO4), made by dissolving 26.72 g Cro

3 3
23 m1 concentrated H SO and diluting to 100 ml with dis-

2 4
tilled water, was added dropwise until yellow color persisted.
Excess of Jone's reagent was destroyed by dropwise addition
of methanol. After concentrating the green solution in
vacuo, water was added and the precipitated product filtered
and air dried.

General procedure for esterification
with diazomethane on .001 M scale

 

In a 500 m1 round bottom flask with side arm condenser

kept in an ice bath was added N,N'-dinitroso-N,N'—dimethyl

29

terephthalamide (0.3 g, Dupont EXR-lOl), 7.5 ml of 30%

sodium hydroxide solution, 2 ml of diethylene glycol mono-
ethyl ether and 25 ml of diethyl ether.. Ice bath was re-
moved, the reaction flask was heated carefully on a steam
bath and a solution of diazomethane in ether was condensed
over a solution or slurry of the carboxylic acid using water
condenser. The reaction mixture was stirred in a hood for
1-4 hour period and then the ether removed. Excess of diazo-
methane precursor was destroyed by dropwise addition of
acetic acid.

General procedure for bromination of
keto steroids using BF3catalyst

 

 

To a solution of the keto steroid in glacial acetic
acid under Argon, bromine was added dropwise followed by
addition of boron trifluoride etherate. The reaction mix-
ture was stirred at room temperature for five days, diluted
with water and sufficient sodium bisulfite was added to
destroy excess bromine. The precipitated product was fil-
tered, washed with water and air dried.

General procedure for oxidation and
o-bromination of hydroxy steroids

 

The starting material was dissolved in t-butyl alcohol
by heating on a steam bath. To this solution at room
temperature, were added 2-3 ml of water, 48% hydrobromic

acid and N-bromoacetamide. After stirring at room

30

temperature for 43 hr, a 5% sodium sulfite solution was
added to the reaction mixture to destroy excess NBA and
extracted with ether. The ether extract was washed sequen-
tially with water, sodium hydrogen carbonate solution and
brine, and then dried. Removal of the solvents gave the
crude product.

General procedure for dehydrobromination

of d—bromo ketones with lithium carbon-
ate afia dimethylformamide

 

 

 

The a-bromo keto steroid was added to a suspension of
lithium carbonate in dimethylformamide under Argon. The
reaction mixture was heated in an oil bath at l60-70° for
5.5 hr using an air condenser. The suspension was cooled,
diluted with ether and lithium carbonate was neutralized by
dropwise addition of 6 N hydrochloric acid. Water was
added and the two layers separated. The ether layer was
successively washed with water, sodium hydrogen carbonate
solution and brine, and then dried. Removal of ether gave

the crude product.

 

Preparation of Methyl 3,12-diketocholanate 31

A solution of 10 g (.0254 M) of deoxycholic acid 33 in
100 ml of methanol containing 1 ml of 37% hydrocholric acid
was refluxed for 45 min. and then condensed in vacuo to a
small volume. The residue was dissolved in ether and the

ether solution was washed sequentially with water, saturated

31

sodium carbonate solution, water, brine and dried over
anhydrous sodium sulfate. After removal of the solvents,
10.29 g (99%) of methyl deoxycholate 39 obtained was pure
enough for further reactions.

A solution of 39 (10.29 g) in 200 ml of acetone was
oxidized to methyl 3,12-diketocholanate’3l using Jone's

reagent (6.4 m1 of 8N CroB-H 804). Recrystallization of the

2

product from ethyl acetate yielded 9.53 g (93%) of pure ;$
0

as prisms, mp l32-3° (lit. 129-30°), [0135 + 90.9° (lit.

+ 90.4° i 4°).

Preparation of Methyl 2-bromo-3,12-diketo-
pmwn)

 

-cholatrienate 33
N

 

A solution 0f,§l (2.01 g, .005 M) in glacial acetic
acid (50 ml) under Argon was brominated by the usual pro-
cedure using 1.06 ml (.OZM) of bromine and boron trifluoride
etherate (5 drops). The crude product upon esterification
with diazomethane by the usual procedure followed by recrys-
tallization from methanol gave pure methyl 2,2,4,ll-tetra-
bromo-3,12-diketo cholanate 33, mp 112-3°, [0135+ 4.6°; ir
(00013) 1730, 1700 cm‘l; Pmr (c0c13) 51.07 (5,3 H), 1.47
(8, 3H), 3.6 (S, 3H), 4.97 (d, J = 10 Hz, 1H), 5.11 (d, J =
12 Hz, 1 a); ms, m/e 558.06970 (14+, calc. for C25H3204Brgl,

corresponding to P-ZHBr) and 557.06647 (M+, calc. for

79 81 .
C25H3304Br Br , correSponding to P-Br-HBr).

32

The tetrabromo steroid 33 (1.44 g, .002 M) was tris-
dehydrobrominated with lithium carbonate (2.0 g) and
dimethylformamide (20 ml) by the usual procedure to give
0.75 g (95%) of the crude product as a light yellow oil.
An analytical sample of methyl 2-bromo-3,12-diketo-Al'4’9(ll)
cholatrienate 33 was obtained as rhombic crystals by crystal-
lization from acetone, mp 168-9° [0135+ 2.1°; ir (CDC13)
1735, 1685, 1665, 1605, 1600 cm'l; Pmr (c0c13) 61.0 (s, 3H),
1.57 (8, 3H), 3.6 (S, 3H), 5.73 (d, J = 2H2, l H), 6.13
(S, In), 7.47 (S, 1H); ms (70 eV) m/e (rel. intensity) 476
(8), 474 (8), 396(17), 241(100), 240(90).

Anal. Calcd. for C H O Br:C, 63.16; H, 6.57;

25 31 4
Found :C, 63.07; H, 6.70.

Oxidation and a-bromination of Methyl
deoxycholate 39

 

Treatment of one gram (.00246 M) of methyl deoxycholate
‘39 with 50 ml of t-butyl alcohol, 3.6 ml of water, 0.6 m1
(.00492 M) of 48% hydrobromic acid and 2.04 g (.0148 M) of
N-bromoacetamide by the usual procedure for oxidation and
a-bromination of hydroxy steroids gave a light yellow solid
which on recrystallization from acetone yielded 0.948 g (80%)
of methyl 4-bromo-3,12-diketocholanate13$ as colorless
needles, mp 121-3°; [a]25°

D
cm71; Pmr (00c13) 60.95 (s, 3H), 1.47 (s, an), 3.5 (s, 3H),

+ 107.6°; ir (CDC13) 1735, 1710

33

5.0 (d, J = 12 Hz, 1H); ms (70 eV) m/e (rel. intensity) 482

(49), 480 (49), 401 (100).

Preparation of Methyl 3,12-diketo-A4-cholenate‘25

0.481 g (.001 M) of methyl 4-bromo-3,12-diketo cholanate
35 was dehydrobrominated using 0.7 g of lithium carbonate
and 10 ml of dimethylformamide by the usual procedure af-
forded 0.395 g (99%) of crude 35, mp 118-20°. Recrystalliza-
tion from acetone gave pure 3; as prisms, mp l45-6°;
[6135 + 116.7°; ir (cc14) 1735, 1710, 1675, 1615 cm’l; Pmr
(CC14) 50.93 (S, 3H),1”]i5(S, 3H), 3.4 (S, 3H), 5.42 (s, 1H);
ms (70 eV) m/e (rel. intensity) 400 (100), 285 (20), 245

(86).

Preparation of Methyl 3a-ethoxygarbonyloxy,
lZ-ketocholanateizl

To a solution of methyl deoxycholate 30,(4.06 g, .01 M)
in dioxane (20 m1) and pyridine (3.2 m1) cooled in an ice-
water bath, ethylcholoroformate (4.0 ml) was added dr0pwise.
The ice water bath was removed and the reaction mixture
stirred at room temperature for 30 min. 50 ml of water con-
taining 2.0 ml of 37% hydrochloric acid was added and the
reaction mixture was heated on a steam bath for 30 min. 250

m1 of ether was added after cooling the reaction mixture and

34

washed sequentially with water, sodium hydrogen carbonate
solution and brine, and then dried. Removal of the solvents
afforded the crude product which was recrystallized from
methanol to give 4.0 g (83%) of methyl Ba-ethoxycarbonyloxy
deoxycholate 36, mp 142-3° (lit. 142-3°); [aJD + 56° (lit.
+ 54° 1 2°).

The diester 36 (2.39 g, .005 M) in 70 ml of acetone
was oxidized to 12-keto steroid 32 with Jones reagent by
the usual procedure. Recrystallization from ethyl acetate
gave 2.26 g (91%) of pure 37, mp 159-60° (lit. 157—9°),

[0135+ 90.6° (lit. + 91° : 1°).

Preparation of Methyl 3a-ethoxycarbonyloxyh

lZ-keto-A9(lly:cholenate 33’

 

 

2.38 g. (.OOSM) of 12-keto steroid gz’was dissolved in
100 m1 of a 4:1 mixture of chlorobenzene and acetic acid.
0.666 g (.006M) of selenium dioxide and a drop of hydrochloric
acid were added and the reaction mixture was refluxed for
72 hr. After cooling, the reaction mixture was filtered
through a short pad of Celite. The filtrate was concentrated
to a small volume in vacuo, diluted with ether (250 ml) and
washed successively with water, sodium hydrogen carbonate
solution and brine and then dried. Removal of the solvents
yielded 2.0 g (84%) of crude product. Recrystallization

from acetone gave a sharp melting (163-4°) mixture of 31

35

(20%) and 38 (80%) as indicated by ir, Pmr and mass spectral
analysis. Identical results were obtained by recrystalliza-
tion from methanol, ethanol, ethyl acetate and various mix-
ture of solvents with ether, benzene and hexanes. Chroma-
tography on alumina or silica gel columns did not improve
the percentage of 38 in the mixture. However, 99.9% pure
}§,(mp 167-8°) was obtained by three different methods as

discussed later.

Bromination of Methyl 3a—ethoxycarbony1oxy,
lZ-keto cholanate 32

 

A solution of 21 (4.74 g, .01 M) in glacial acetic
acid (50 ml) under Argon was brominated by the usual pro-
cedure using 0.8 m1 (.015 M) of bromine and five drops of
boron trifluoride etherate. 5.45 g (99%) of the crude
product was obtained upon addition of sodium sulfite and
water. A 1.20 9 portion of the crude product was chroma-
tographed on silica gel, elution with chloroform gave 0.886
g (73.8%) methyl Ba-ethoxycarbonyloxy, ll-bromo,12-keto
cholanate (A) and 0.291 g (24.2%) 3a-ethoxycarbonyloxy,1l-
bromo,12-keto cholanic acid (Q). Treatment of §,with dizao-
methane in ether by the usual procedure gave A, Recrystal-
lization of combined A’from methanol gave methyl 3a-ethoxy—

/
carbonyloxy,lla-bromo,12-keto cholanate 41,(1.0 g, 90%),

24°

mp 97-8°; [GJD

+ 46.6°; ir (cc14) 1730 cm’l; Pmr (cc14)

36

01.0 (S, 3H), 1.17 (S, 3H), 3.55 (8, 3H), 4.0 (q, J = 7 Hz,
2H), 4.27-4.62 (m, 1H), 4.81 (d, J = 10 Hz, 1H); ms (70 eV)
m/e (rel. intensity) 525 (1), 523 (1), 475 (65), 474 (19),
385 (35).

Anal. Calcd. for C28H43Br O6:C, 60.54; H, 7.80;

Found :C, 60.46; H, 7.80.

The mother liquor from A upon recrystallization from

methanol gave methyl 3a-ethoxycarbonyloxy,llB-bromo,12-keto

O
cholanate 42 (0.059 g, 5%), mp l72-3°; [an4 + 36.3°; ir

(c014) 1730, 1700 cm’l; Pmr (cc14) 61.25 (s, 3H), 1.22 (s,
3H), 3.57 (s, 3H), 4.03 (q, J = 7 Hz, 23), 4.17—4.27 (m, 1H),
4.27-4.70 (m, 1H); ms (70 eV) m/e (rel. intensity) 525 (<1)

523 (<1), 47S (33), 474 (24), 385 (27), 384 (23).

Epimerization of 118-bromo ketone 13
to lla-bromo ketone 41

 

A mixture of 50 mg of llB-bromo ketone 43 and a 10%
hydrobromic acid solution in acetic acid (10 ml) was stirred
at room temperature under Argon for two days. The reaction
mixture was diluted with 100 m1 of water and extracted with
chloroform. Removal of the solvents and recrystallization
of the residue from methanol afforded a crystalline product

identical in all respects with Ila-bromo ketone 41.

37

Zinc and Acetic Acid Debromination of
Ila-bromo ketone 41

 

A solution of 50 mg of 41 in 2 ml of glacial acetic
acid was refluxed with 50 mg of zinc dust under Argon for
one hour. After filtration the solution was diluted with
100 ml of ether and washed successively with water, sodium
carbonate solution and brine, and then dried. Removal of
the solvent and recrystallization of the residue from ethyl

acetate gave 38 mg (88%) of crystalline product identical

in all respects with 33.

Zinc and Acetic Acid Debromination of
118-bromo ketone {a

 

 

Treatment of 30 mg of 53,1“ 2 m1 of glacial acetic acid
with 30 mg of zinc dust under similar conditions as for 41/
gave 20 mg (87%) of product, after recrystallization from
ethyl acetate, that was also identical in all respects with

370
”V

Dehydrobromination of 110-bromo ketone 41/

A. With DBU and DMSO

 

To a solution of lla-bromo ketone 41/(0.555 g, .001 M)
in dry DMSO (10 ml), 0.25 g (.002 M) of DBU was added and

the reaction mixture stirred under Argon at room temperature.

38

In six weeks, all the starting material had disappeared as
indicated by thin layer chromatography on a small scale

ether extract of reaction mixture. 200 m1 of water was

added to the reaction mixture and extracted with three 100

ml portions of methylene chloride. The combined extracts
were washed sequentially with five 200 ml portions of water
and once with brine, and then dried. Removal of methylene
chloride gave enone 38 (0.45 g, 95%) which was recrystallized

from acetone, mp l67-8°.

B. With Lithium Carbonate and Dimethylformamide

118-bromo ketone 41 (0.555 g, .001 M) was dehydro-
brominated by the usual procedure using 0.833 g of lithium
carbonate and 10 m1 of dimethylformamide to give 0.47g;(99%)
of enone 38. Recrystallization from acetone gave pure 38,
mp 167-8° (lit. 158-60°), [6135+ 109° (lit. 92 1 2°): ir
(KBr) 1735, 1675, 1605 cm’l; Pmr (coc13) 60.88 (s, 3H),
1.17 (S, 3H), 3.6 (S, 3H), 4.09(q, J = 7 Hz, 2H), 4.3-4.8
(m, 1H), 5.6 (d, J = 2 Hz, 1H); ms (70 eV) m/e (rel. intens-
ity) 474 (92), 385 (38), 384 (100), 229 (97).

Anal. calcd. for C :C, 70.86; H, 8.92;

28H4206
Found :C, 70.91; H, 8.89.

39

Preparation of Methyl 3,12-diketo-
A9(11)

 

-cholenate 4;

 

A 2.37 g (.005 M) solution of enone 38 in 40 m1 of
methanol containing 20 m1 of 10% potassium hydroxide was
refluxed for 90 min. under Argon. Methanol was removed in
vacuo, the residue dissolved in water and acidified with 6N
hydrochloric acid. The precipitated product was filtered,
washed with water and air dried to give 30-hydroxy,12-keto,
A9(ll)-cholenic acid 43’(1.89 g, 98%) which was recrystal-
lized from methanol, mp. 177-8°; [010 + 87°; ir (CDC13) 3575,
3490, 1700, 1670, 1600 cm’lz Pmr (cc14) 60.9 (s, 3H), 1.0
(d, J = 4 Hz, 3H), 1.17 (8, 3H), 3.3-3.9 (m, 1H), 5.65 (d,

J = 2H2, 1H), 5.97 (bs, 24).

A suspension of 1.89 g (.0049 M) of 43,1n 100 m1 of
ether was esterified with diazomethane by the usual pro-
cedure to give 1.94 g (99%) of the methyl ester 43. A solu-
tion of this methyl ester in 50 m1 of acetone was oxidized
with Jones reagent by the usual procedure to give 1.90 g
(98%) of the crude product, which was recrystallized from
ethyl acetate to give enedione 45, mp 13l-2°; [a]§5+ 69.3°
(lit. 71.6 : 2°); ir (KBr) 1730, 1710, 1680, 1605 cm—1; Pmr
(CC14) 60.9 (S, 3H), 1.25 (8, 3H), 3.53 (S, 3H), 5.63 (d,

J = 2H2, 1H) ms (70 EV) m/e (rel. intensity) 400 (22), 369

(5), 245 (31), 121 (100).

40

Preparation of Methyl 3 ~ethoxycarbony10xy,

All—cholenate 41

 

A. Dehydration of 39

A 4.78 g (.01 M) solution of 36 in 50 m1 of pyridine
and phosphorous oxychloride (23 g, .15 M) was stirred under
nitrogen at 50° for 24 hr. After cooling, the reaction
mixture was diluted with ice water and extracted with three
100 m1 portions of ether. The combined ether extracts were
washed sequentially with water, 1N hydrochloric acid and
brine, and then dried. Removal of ether gave an oil that
crystallized out from dioxane to yield 42 (2.3 g, 50%), mp
135—6°.

B. Via Mesylate 49

 

Methanesulfonyl chloride (1.6 g, .014 M) was added
dropwise to an ice cooled solution of gé,(4.78 g, .01 M) in
50 ml of dry pyridine. The reaction mixture was stirred
under Argon at room temperature for 24 hr, poured into ice
cooled brine (100 m1) and extracted with three 100 m1 por-
tions of ether. The combined ether extracts were washed
sequentially with water, 1N hydrochloric acid and brine,
and then dried. Removal of ether gave mesylate 46 (5.50 g,
99%), mp 154° (d); [61D + 69.2°, ir (cc14) 1735 cm'l; Pmr
(CC14) 60.75 (S, 3H), 0.91 (S, 3H), 2.97 (5, 3H), 3.53 (8,

3H), 4.03 (q, J = 7 Hz, 2H), 4.2-4.66 (m, 1H), 4.93 (bs, 1H);

41

ms (70 eV) m/e (rel. intensity) 460 (<1), 371 (67), 370 (96),
256 (49), 255 (100).
Agel. Calcd. for C29H48083:C, 62.56; H, 8.69;
Found :C, 62.47; H, 8.70.
A mixture of 50 ml of hexamethylphosphoric triamide
(distilled over CaHZ), 4 g (.04 M) of potassium acetate and

5.0 g (.009 M) of mesylate 49 was stirred under N at 100°

2
for two days. After cooling, the reaction mixture was

poured into 500 ml of ice water. The precipitated product
was filtered, washed with water and air dried. Recrystal-
lization from dioxane afforded 47 (3.93 g, 95%), mp 135-6°;

[01D + 39.5°; ir (KBr) 1735, 1615 cm”1

, Pmr (c014) 60.7 (s,
3H), 0.87 (s, 3H), 3.53 (s, 3H), 4.0 (q. J = 7 Hz, 2H);
4.27-4.63 (m, 1H), 5.25 (d, J = 10 Hz, 1H), 5.97 (dd, J =
10 Hz, 3 Hz, 1H); ms (70 eV) m/e (rel. intensity) 460 (<1),
370 (100). 255 (85).

Anal. Calcd. for C :C, 73.01; H, 9.63;

28H4405
Found :C, 73.06, H, 9.67.

Addition of Hypobromous Acid to Alkene 41,

To a mixture of alkene 41,(0.46 g, .001 M) and N-bromo-
acetamide (0.276 g, .002 M) in 50 ml of dioxane under Argon,
27.5 ml of 0.16N perchloric acid was added dropwise. After
stirring for 20 min. at room temperature, excess N-bromo-

acetamide was destroyed by adding a 10% sodium sulfite

42

solution and the reaction mixture extracted with chloroform.
The chloroform extract was washed sequentially with water,
sodium hydrogen carbonate solution and brine, and then dried.
Removal of solvents gave 0.56 g of an oil. Thin layer
chromatography indicated it to be a mixture of two different
compounds. Addition of ether to the oil gave 100 mg of a
white solid which was recrystallized from methanol to give

bromohydrin 43,mp 179-80°; [a] + 51°; ir (KBr) 3400, 1735

D
cm'l; Pmr (cc14) 61.18 (s, 3H), 1.22 (s, 3H), 3.57 (s, 3H),
4.06 (q, J = 7 Hz, 2H), 4.3-4.63 (m, 1H), 4.7 «iai,J’= 2 Hz
and 3 Hz, 1H), 4.97 (d, J = 2 Hz, 1H); ms (70 eV) m/e (rel.
intensity) 541 (2.5), 539 (2.5), 458 (31), 270 (56), 369
(100).

In another experiment, 100 mg of the crude product was
separated by preparative thin layer chromatography on a 2 mm
silica gel plate to give 39 mg of bromohydrin 42 and 45 mg
of enol 4g, mp 145° (a); ir (c014) 3460, 1735, 1600 cm‘l;
Pmr (CC14) 00.83 (S, 3H), 1.17 (S, 3H), 3.53 (S, 3H), 4.06
(q, J = 7 Hz, 2H), 4.23-4.80 (m, 2H), 5.57 (d, J = 2 Hz, 1H);
ms (70 eV) m/e (rel. intensity) 476 (16), 386 (60), 231 (100).

Enol 4§,on oxidation with Jones reagent by the usual

procedure gave enone 45.
M

43

Preparation of 110,1Za-epoxide‘53

 

To a solution of alkene 41 (0.46 g, .001M) in 20 ml of
chloroform, 0.25 g (.0011 M) of 75% m-chloroperbenzoic acid
was added and the reaction mixture stirred under N2 at room
temperature for 4 hr. After diluting with 200 m1 of chloro-
form, the reaction mixture was washed successively with
water, sodium carbonate solution and brine, and then dried.
Recrystallization from methanol gave 11 ,12 -epoxide 59
(0.45 g, 95%), mp 147.5-8°; [6135+ 34°; ir (cc14) 1735, 1260
cm‘l; Pmr (cc14) 60.67 (s, 3H), 0.9 (s, 3H), 2.67 (d, J =
4 Hz, 1H), 2.86 (d, J = 4 Hz, 1H), 3.5 (S, 3H), 4.0 (q, J =
7 Hz, 2H), 4.2-4.7 (m, 1H); ms (70 eV) m/e (rel. intensity)
476 (6), 386 (45), 271 (49), 253 (100).

5331. Calcd. for C H O :C, 70.56; H, 9.30;

28 44 6
Found :C, 70.53; H, 9.39.

Preparation of Bromohydrinegl

To a solution of epoxide 50,(0.238 g, .0005 M) in 20
m1 of acetone, 1 m1 of 48% hydrobromic acid was added drop-
wise. After stirring under nitrogen for 2 hr. at room
temperature, acetone was removed under vacuo, the residue
diluted with water and extracted with ether. The ether ex-
tract was washed successively with water, sodium hydrogen

carbonate solution and brine, and then dried. An excess

44

diazomethane in ether was added and the solvent removed after
stirring for 1 hr. at room temperature to give bromohydrin
51 (0.25 g, 90%) as an oil. A 139 mg portion of the crude
product was separated on a silica gel column by high pres-
sure liquid chromatography (25% ethyl acetate in hexane
elutant) to give 111 mg (80%) of bromohydrin 51 as an oil
which could not be crystallized, ir (CC14) 3600, 3480, 1735
cm’l; Pmr (cc14) 61.0 (s, 3H), 1.17 (s, 3H), 2.57-3.07 (m,
1H), 3.52 (s, 3H), 4.0 (q, J = 7 Hz, 2H), 4.2-4.7 (m, 3H),
ms (70 eV) m/e (rel. intensity) 509 (<1), 507 (<1), 459 (61)
458 (30), 370 (64), 369 (100), 253 (96).

However, bromohydrin 51 on oxidation with chromium

trioxide and glacial acetic acid gave llB-bromo,12-ketone

42.
N

Oxidation and Debromination of Bromohydrin 49

To a solution of 50 mg of bromohydrin 42 in 5 m1 of
glacial acetic acid, 1.0 ml of 0.56 N chromium troxide in
acetic acid was added. The reaction mixture was stirred
overnight at room temperature and then excess chromium tri-
oxide destroyed by addition of methanol. water was added
to the reaction mixture and extracted with two 100 m1 por-
tions of ether. The combined ether extracts were washed
successively with water, sodium carbonate solution and brine,

and then dried. Removal of the solvents and recrystallization

45

of the residue from methanol gave 38 mg of l2-bromo,11-

ketone 53, mp 168-9°; ir (CC14) 1735 cm-1, Pmr (CC14) 61.23

(S, 3H), 1.33 (S, 3H), 3.55 (S, 3H), 4.0 (q, J = 7 Hz, 2H),
4.2—4.7 (m, 2H).

Treatment oflgg with zinc and acetic acid gave ll-keto
steroid 53, which was recrystallized from acetone, mp 145-6°

(lit.39 146-147.5°).

Preparation of Methyl 3,12—diketo,
A1,4,9(11)

 

-cholatrienate 56
N

A 0.4 g (.001 M) solution of enedione 45 in 100 m1 of
t-amyl alcohol was refluxed with 0.22 g of selenium dioxide
under nitrogen. After 4.5 hr, more selenium dioxide (0.2 g)
was added and the solution was refluxed for a further 18 hr.
The volume of the solution was then reduced to 10 m1 under
vacuo, the residue dissolved in chloroform and washed
successively with water, sodium carbonate solution and brine,
and then dried. Removal of the solvents and chromatography
of the crude product on alumina (chloroform elutant) afforded
0.22 g (55%) of trienedione 56, which was recrystallized from
methanol, mp 132-4°; [6135+ 88.5°; ir (cc14) 1735, 1685,
1670, 1640, 1600 cm'l; Pmr (cc14) 60.93 (s, 3H), 1.25 (s,
3H), 3.52 (S, 3H), 5.57 (8, 1H), 5.90 (S, 1H), 6.07 (d.d,

J = 10 Hz and 2H2, 1H), 7.0 (d, J = 10 Hz, 1H); ms (70 eV)

m/e (rel intensity) 396 (95), 365 (24), 242 (84), 241 (100).

46

Anal. Calcd. for C25H3204zc, 75.73; H, 8.13,

Found :C, 75.63; H, 8.21.

Homogeneous Catalytic Reduction 0f,2§

A 50 ml pear shaped flask containing 5 m1 of dry ben-
zene was cooled to 0°, evacuated and filled with hydrogen.
10 mg of Tris triphenylphosphine chlororhodium (Wilkinson's
catalyst) was added and the process of freezing, evacuating
and refilling with hydrogen repeated three times. A 50 mg
solution of 59 in 5 ml of dry benzene, after freezing,
evacuating and refilling with hydrogen, was added to the
above solution. The reaction mixture was stirred at room
temperature for 4 hr under hydrogen at atmospheric pressure.
Filtration through a short path alumina column followed by
elution with chloroform gave 45 mg of unreacted 59.

In another experiment under similar conditions, reduc-
tion of 45 mg of 56 with Wilkinson's catalyst (10 mg),
cyclooctene rhodium chloride complex (10 mg) and hydrogen
gave a product which after recrystallization from acetone

was found to be identical in all respects to 13'

47

Preparation of Methyl 3,12-diketo-
A4,9(11);

choladienate 55
N

 

A. Oxidation and a—bromination of 44 and
dehydrobromination of 5]

 

0.2 g (.0005 M) of gglwas oxidized and brominated in
ring A with 0.138 g (.001 M) of N-bromoacetamide and 0.1 m1
of 48% hydrobromic acid (.0006 M) by the usual procedure to
give 0.28 g of crude §Z,as an oil, ir (CDC13) 1735, 1675,
1600 cm'l; Emr (c0013) 60.9 (s, 3H), 1.3 (s, 3H), 3.55 (s,
3H), 4.23 (d, J = 12 Hz, 1H), 5.68 (d, J = 2 Hz, 1H).

Without further purification, 0.28 g of 53 was dehydro-
brominated with 0.42 g of lithium carbonate and 10 m1 of
dimethylformamide by the usual procedure yielding 0.18 g of
the crude product. Preparative thin layer chromatography on
a 2 mm silica gel plate (2% methanol in chloroform elutant)

4,9(11)

gave 0.10 g (51%) of methyl 3,12-diketo-A -choladienate

55, which was recrystallized from acetone, mp 116-8°;

[0135+ 105.7; ir (cc14) 1735, 1675, 1620, 1600 cm'l; Pmr

(CDCl , 180 M Hz) 61.44 (8, 3H), 1.53 (S, 3H), 3.58 (S, 3H),

3
5.65 (d, J = 2 Hz, 1H), 5.68 (d, J = 2 Hz, 1H); ms (70 eV)

m/e (rel. intensity) 398 (56), 243 (100), 241 (48).
Anal. Calcd. for C25H34O4
Found :C, 75.11; H, 8.54.

:C, 75.39; H, 8.60;

48

B. Oxidation and a-bromination of 59 and
his dehydrobromination of 59

 

A mixture of Ila-bromo ketone 41 (0.555 g, .001 M) and
50 m1 of 2.5% methanolic potassium hydroxide solution was
stirred overnight under Argon at room temperature. Methanol
was removed under vacuo, the residue dissolved in water and
neutralized with 6N hydrochloric acid. The precipitated
product was filtered, washed with water, air dried and
treated with an excess of diazomethane in ether. Removal of
ether followed by oxidation and a-bromination in ring A with
N-bromoacetamide (0.276 g, .002 M) and 0.2 m1 of 48% hydro-
bromic acid (.0012 M) by the usual procedure gave 0.54 g

(83%) of the crude product. Recrystallization from carbon

25
D

(c0c13) 1730 cm’l; Pmr (cnc13) 61.07 (s, 3H), 1.32 (s, 3H),

tetrachloride gave dibromide 59, mp 79-80°; [a] + 34.9°; ir
3.6 (S, 3H), 4.57-5.13 (m, 2H).

0.18 9 (.00033 M) of dibromide 52 was bis dehydro-
brominated with 0.5 g of lithium carbonate and 10 ml of
dimethylformamide by the usual procedure to give 96 mg of
crude product. Preparative thin layer chromatography on a
2 mm silica gel plate (2% methanol in chloroform elutant)
gave 80 mg (60%) of product which was identical in all

reSpects to 55.

49

Lithium and Ammonia Reduction of
4,8(11) - -
A -d1ene-3,12-dione 55

 

 

In a 100 ml three neck round bottom flask, flame dried
under nitrogen, 50 m1 of ammonia was condensed over a small
lump of sodium. The ammonia was then distilled through
Tygon tubing into another 100 ml three neck round bottom
flask under nitrogen, fitted with a dry ice condenser and a
mechanical stirrer, and cooled by a dry ice-iSOpropanol bath.
0.07 g of lithium (.01 M) was added to the reaction flask
and upon completion of condensation of ammonia, dienedione
55 (0.1 9, .00025 M) dissolved in 10 ml of dry THF was
added dropwise over a one hr period. The blue color of the
reaction was discharged by dropwise addition of ethylene
dibromide, following which 1 g of finely ground ammonium
carbonate was added in one portion. The dry ice-isopropanol
bath and dry ice condenser were removed and ammonia was
evaporated into the hood under a stream of nitrogen. The
residue was taken up in 100 m1 of water and extracted with
three 100 m1 portions of ether. The combined ether extracts
were washed sequentially with water and brine, and then
dried. Removal of the solvents gave 85 mg of crude product
which could not be recrystallized. The product did not
separate very well on silica gel or alumina Tlc slides in
various different solvents, so no attempts were made to

purify it by column chromatography. The crude product was

50

tentatively assigned structure 60 on the strength of ir

1

(cc14) 3600, 3375, 1705 cm’ , Pmr (cc14) 62.9-3.15 (m, 1H,

D20 exchangeable), 3.15-3.9 (m, 2H) and mass spectra (70 eV)

m/e (rel. intensity) 372 (40), 207 (38), 149 (77).

REFERENCES

9.
10.
11.
12.
13.
14.

15.

16.
17.

REFERENCES

a) M. Smith in "Reduction", R. L. Augustine, Ed., Marcel
Dekker, New York, N. Y., 1968.

b) G. Stork and S. D. Darling, J. Amer. Chem. Soc., 86,
1761 (1964). .—

G. Stork, P. Rosen, N. Goldman, R. Coombs and J. Tsuji,
ibid., 5;, 275 (1965).

P. S. Venkataramani and W. Reusch, Tet. Lett., 5283
(1968).

 

William Reusch and D. B. Pridday, J. Amer. Chem. Soc.,
5;, 3677 (1969).

 

P. S. Venkataramani, J. E. Karoglan and W. Reusch,
J. Amer. Chem. Soc., 25, 269 (1971).

W. Reusch et al., J. Amer. Chem. Soc., 22, 1953 (1977).

 

D. B. Priddy, unpublished results from this lab.

a) J. Martin, Ph.D. dissertation, M.S.U.
b) H. R. Taneja, Unpublished results.

 

DHR Barton et al., J. Amer. Chem. Soc., 55! 3016 (1966).
A. Butenandt et al., Chem. Ber., 55, 2091 (1935).

E. J. Corey, J. Amer. Chem. Soc., l5, 4832 (1953).

K. B. Sharpless, J. Amer. Chem. Soc., 55, 6137 (1973).
E. C. Kendall et al., J. Biol. Chem., iii, 271 (1948).

H. J. Ringold and A. Turner, Chem. & Ind., 211 (1962).

 

Von K. Heusler and A. Wettstein, Helv. Chim. Acta, 55,
284 (1952). "

 

W. G. Dauben et al., J. Org. Chem., 55, 3587 (1969).

W. R. Jones et al., J. Chem. Soc. (c), 1444 (1966).

51

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.
34.

52

W. N. Speckamp et al., J.C.S. Chem. Comm., 350 (1972).

B. W. Finucane and J. B. Thomson, J.C.S. Chem. Comm.,
1220 (1969).

 

K. Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L.
Weedon, J. Chem. Soc., 39 (1946).

 

Yehuda Yanuka and Gideon Halperin, J. Org. Chem., 55,
2587 (1973). “‘

 

M. P. Hartshorn and E. R. H. Jones, J. Chem. Soc., 1312,
(1962).

 

A. R. Hanze, G. S. Fonken, A. V. McIntosh, Jr., A. M.
Searcy and R. H. Levin, J. Am. Chem. Soc., 15, 3179
(1954). “

 

Kyosuke Tsuda, Shigeo Nozoe and Kazuhiko Ohata, Chem.
Pharm. Bull., ll, 1265 (1963).

Louis F. Fieser and Srinivasa Rajagopalan, J. Am. Chem.
Soc., 13, 5530 (1950).

 

B. F. McKenzie, V. R. Mattox, L. L. Engel and E. C.
Kendall, J. Biol. Chem., 173, 271 (1948).

E. Seebeck and T. Reichstein, Helv. Chim. Acta, 55, 536
(1943). "'

 

R. Norman Jones, D. A. Ramsay, F. Herling and Konrad
Dobriner, J. Am. Chem. Soc., 11, 2828 (1952).

T. F. Gallagher and William P. Long, J. Biol. Chem.,
162, 495 (1946).

 

T. R. Kowar and E. MGoff, J. Org. Chem., 41, 3760 (1976)
cf. H. Oediger and F. Moller, Angew. Chem. ‘I. E., 6, 76
(1967)

 

 

Josef Fried and Josef E. Herz, Chem. Abs., 52, 5491
(1958); 0.8. 2, 814, 629, Nov. 26,1957.

Daniel Levy and Robert Stevenson, J. Org: Chem., 5_
2804 (1968). "‘

 

C. H. Chen, Synthesis, 125 (1976).

 

H. Reich and T. Reichstein, Helv. Chim. Acta, £5, 562
(1943). “'

 

35.

36.

37.

38.

39.

4o.

41.

42.

43.

44.

45.

53

L. F. Fieser and M. Fieser, "Steroids", Reinhold Pub.
Co., New York, N. Y., 1959, pages 634-9.

A. Ffirst and P. A. Plattner, Abstr. Papers 12th Int.
Congress Pure and Appl. Chem., New York, 1951, p. 409.

G. H. Alt and D. H. R. Barton, J. Chem. Soc., 4284
(1954).

J. Fried, J. W. Brown and M. Applebaum, Tet. Lett., 849
(1965).

 

S. Archer, T. R. Lewis, C. M. Martini and Mary Jackman,
J. Am. Chem. Soc., 15, 4915 (1954).

 

Hans R. Taneja, Unpublished results from this lab.

 

D. V. C. Awang and S. Wolfe, Canad. J. Chem., 11, 706
(1969). ‘“

P. B. Sollman and R. M. Dodson, J. Org. Chem., 25, 4180
(1961). “'

M. M. Coombs and H. R. Roderick, J. Chem. Soc. (c),
1819 (1967).

 

Carl Djerassi and J. Gutzwiller, J. Am. Chem. Soc., 55,
4537 (1966). ‘ "’

Hans R. Taneja and Ed Sweet, Unpublished results from
Chemistry Department Michigan State University.

APPENDIX

SPECTRA

54

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Figure 42. Pmr spectrum of £9-

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