561

REVIEW

~~~L-~O-KETOPRXI'&\~E. A BBVIE?

Mordecai B. Ftubin

Department of Chemistry, Carnegie Institute of Technology, Pittsburgh 13, Pennsylvania

A wide variety of 2CLketopregnanes , unsubstituted at C-17, some of

considerable biological importance, have been isolated from natural sources

or prepared synthetically. Although the two C-17 epimers of these ketones

are interconvertible through a common enol (or enolate ion), only the 17,7-

isomers are naturally occurring. 2

Occasional reports, increasing in

CH I 3 COH

frequency in recent years, have appeared in the literature describing the

preparation (often accidental , of the unnatural (17~) isomers. This report

is an attempt to summarize the available information on compounds possess-

ing the natural configuration at all centers except C-17. It is hoped that,

in addition to its value as a compilation, this work will serve to emphasisc,

the probability of formation of at least small amounts of 17a-29-k&o-

pregnanes under many of the reaction conditions commonly employed in stero4.d

chemistry. The discussion is Fresented in the following sequence;

562 STEROIDS 2:5

I. X&hods of preparation of 17a-2%ketopregnanes

II. Characterization

III. Relative stabilities of 17a and 17B isomers

IV. Choice of conditions to avoid epimerization at C-17

v. Tables

It might be noted that the unnatural isomers generally do not exhibit

significant biological activity.

I. Methods of Preparaticn of 17u-20-Ketopregnanes

A. Isomerization of 17j3-isomers

The formation of the 17,2O_enol of a 20-ketopregnane followed by

protonation frvrm either the alpha or beta side of the molecule provides a

pathway for equilibration at C-17 and possible isolation of the unnatural

isomer. In an investigation beginning in 1935, Butenandt and 3,4,5 co-workers,

employed 5% potassium hydroxide in refluming methanol followed by fractional

crystallization of the resulting mixtures to obtain a number of 17a-20-

ketopregnanes from their naturally occurring isomers. Although recovered

starting material could be recyclized, the operations were tedious and

inefficient; later work 6,7 established that some of the separations were

incomplete. Some improvement can be effected by the use of column chroma-

tography, the 17a-isomer emerging first from Florisil' or acid-washed

alumina9 columns. In spite of the obvious drawbacks of this method, it has

been used occasionally to obtain small amounts of material. The more common

occurrence, however, has been the accidental isolation of a 17a-20-keto-

pregnane resulting from epimerization during acid- or base-catalyzed reactions

such as hydrolysis, aldol condensation, etc. The improved methods of

analysis available at the present time will undoubtedly reveal many additional

examples of this type.

The principal difficulty in this method arises from the fact thS?t the

usually thermodynamically more stable 17@-isomer predominates in an equili-

brated mixture, thus requiring the separation of the least abundant

component. This situation is coapletely reversed in the presence of a 16P-

substituent, where the 16@,17' interaction results in an equilibrium

markedly favoring the alpha orientation of the acetyl side chain (Vti*i.

Recent interest in the biological activity af substituted steroids has led

to the synthesis of a considerable number of 16p-substituted-23-ketoFreg-

Nov. 1963 STEROIDS 563

nanes, some of which have been isomeril;ed to l&3-l'?a-compounds in yields

ranging from 50$ to almost quantitative. In fact, isolation of 17+isomer

would appear to be the more difficult problem in some instances.

B. Serini-Logemann Reaction

A much more desirable means of synthesis (excepting 16p-substituted

compounds) was provided by the discovery of the Serini-Logemann reaction in

p-)ajfj 1% II, f2,13 . As applied to 17a-ZO-ketopregnanes, this reaction involves

heating a 17~-hydroyy_2eaceto~regnane with zinc in the presence or

absence of solvent. Rearr~g~ent to the 17a-20-ketone proceeds in a stereo-

specific manner. Although

and frequently low yields,

H

zn ..c COCH3

a ’ iti

early reports of this reaction described erratic

recent work* has indicated that choice of the

proper experimental conditions can provide excellent results. Since the

required 37c,-h3Tdro~-20_acetates can usually be prepared from available

materials by stiple inethods, the Serini-Logemann reaction appears to be the

method of choice in the majority of cases. Successful reaction has been re-

ported wi.th 14 ll-oxygenated and 21-oxygenated l&l5 steroids; poor yields are

obtained with 16a- and X$-substituted compounds; 8 the reaction fails

completely with 12a-hydroxylated compounds. 16

It has been re,ported 13 that

zinc can be replaced by benzoyl peroxide.

c. Transfornatinns of 17c-20-KetopreLnanes

Zith a 17c-ZO-ketopregnane at hand, the possibility of conversion to

other 17% compounds is obvious. Oppenauer oxidation of 17a-pregnenolone to

17u-iprogesterone5 and DCQ dehydrogenation of 17cr-progesterone to l-dehydro-

l?u-progesterone 17 may be cited as typical examples. A perhaps less obvious

version cf this method has employed the 17a-isomer of an etiocholanic acid as

the starting point.18 It. is hardly necessary to point out that reaction

conditions which lead to appreciable equilibration of the 17a-20-ketones

564 STEROIDS 25

involved must be avoided.

D. Sarett Procedure for Formation of Ring D

In the course of their total synthesis of cortisone, Sarett and co-

worker? developed a method for formation of ring D from tricyclic pre-

cursors which involves intramolecular base-catalyzed cyclization of a keto-

tosylate to a l7-acetyl steroid as illustrated. The initial product of this

CYCki~atiOn is the l’la-epimer which my undergo isomerisation under the basic

conditions of the reaction, Johnson et a1.,2o who used this method in their

total. synthesis of aldosterone, report that best results are obtained using

potassium t-butoxide in t-butyl alcohol, Yields are approximately 50%. No

mechanistic explanation for the stereochemical result of these cyclixationa

has been offered.

E. H.scellaneous Rethods

1. Microbiological Reduction of a l&17-Double Bond. A very

interesting result was obtained by Peterson et al. 21 from the incubation

of l&dehydropregesterone with Rhizopus nigricans. Not only did the

expected llu-hydroxylation occur, but reduction of the l&17-double bond

from the beta side led to formation (25% yield) of lla-hydroxy-17u-

progesterone. Similar incubation of 16-dehydropregnenolone 22 led to

formation of an unidentified product, mop. 195-197’. The recent report*

of isolation of labeled 17a-pregnanolone from human xine after ingestion

of labeled l&dehydroprogesterone provides another example of this type of

reduction.

2. Catalytic Hy~ogenation of a 16,1?-Double Bond, A report has

appeared in the patent literature 23 describing the selective reduction of

the l&,17-double bond of 16-dehydroprogesterone over a palladium catalyst.

It is stated that, in addition to progesterone, ttsome'f f?c-?rcgesterone

was formed in this reaction. $umeroue exvrples of the catalytic hydro-

Nov. 1963 STEROIDS 565

genation of 16-dehydrosteroids have appeared in the literature, but in no

other case has the formation of any l'/a-isomer been reported. In view of

this fact and the paucity of information available, the one exception must

be regarded with skepticism.

3. Nitrous Acid Deamination of a &Homo Steroid. The nitrous acid

deamination of 17a-amino-17aS-hydro~-17a-methyl-D-homopregnenolone has been

reported by Shoppee et al. u, to yield 35% of 17a-pregnenolone as the only

isolable product. Surprisingly, the l'la-epimeric amino alcohol furnished

less than 3% of 17a-pregnenolone , the major product supposedly being the

17a,17aa-epoxy-D-homo compound. The 17a epimers of the 178~amine behaved

normally in deamination reactions.

II. Characterization of 17a-2C-Ketopregnanes

A. Optical Rotation

The standard method for assignment of 17u-configuration to one of

a pair of C-17-epimeric 20-ketones has been based on the fact that the 17~~

ketone is 25 invariably the more levorotatory of the two isomers. k&en

sufficient examples of simple l'la-compounds were available, it became

apparent that the molecular rotation difference (ME - &$) was remarkably

constant for a considerable number of compounds.

of 550 allowed Warshall and Gallagher6

Assignment of a fU$ value

to conclude that some of the 17c-

compounds reported by earlier workers were impure. Shoppee' reached similar

conclusions using a value of 536. From examination of values Fresented in

Tables II and III, it is seen that variations in the ma&nitude of &IQ do

STEROIDS

occur when a conjugated carbcnyl group is present in ring A or when there

are substituents close to C-17 (C-12, C-16, C-21).

The application of optical rotatory dispersion studies to steroids

provided a considerable improvement over measurements at 589 w. Since the

first report by Djerassi26 in 1957, it has been observed in all cases that

the presence of a 17c-acetyl side chain results in a large, negative Cotton

effect curve in contrast to the positive Cotton effect observed with 17p-

isomers. The magnitude of this effect is sufficiently great that it is not

cbFcured by the presence of other groups although variations in amplitude

:\re observed. 27 This has allowed assignment of configuration in a number of

cases where the 17p-isomer was not available for comparison. The relative

constancy of molecular rotation difference observed in measurements at

589 m)l has been found to extend throughout the spectrum. 28

3. Suclear Magnetic Resonance Spectra

ri second method for identification of the 17c-acetyl side chain

has become available from examination of n.m.r. spectra of 2C-ketopregnanes.

In 17;' isomers, the c-18 methyl resonance is observed at about 36-43 cps.

(60 NC.) downfield from tetramethylsilane, while inversion of the side chain

results in a shift to 51-54 cps. I?,29

Careful measurements in the author's

laboratory have given a value of 17.5 + 0.2 cps. for six 17c-compounds

('&10,11,12,14 and I& in which the nature of ring A has been varied. This

effect undoubtedly is due to long range shielding by the 20-ketone; its

magnitude presumably reflects the spatial relationship of the ketone and

methyl groups and might allow calcul.stion of molecular geometry. Kith the

possible exception of special cases where the presence of other methyl

groups might obscure this effect , a seccnd convenient (and possibly quanti-

tative) method for characterization of 17a-23-ketoFregnanes is now available.

c. Chromatograyhic Nethods

:hile chrcmatographic methods do not define C-17 stereochemistry,

they are useful for analysis and may be helpful in assigning configuration.

The fact that 17a-compounds emerge first from Florisil and acid-washed

alumina columns has already been noted. Separations of 17~- and 17p-isomers

can sometimes be achieved by gper or thin-layer chromatography. The availa-

bility of techniques for gas chromatograrhjr of steroids holds :Xomise and

two a~;ilications tr: 170-, W-ketopre~~nanea have been reported to date. Wechter

Nov. 1963 STEROIDS 567

and Murray 29 have described the analysis of mixtures of the l?-epimeric ll-

ketopregnenolones ar.d their acetate s on a 25 silicone oil column at about 250'

The compositions obtained by this inethod were in good agreement with those

obtained by n.m.r. analysis. In both cases the 17:-compound had the shorter

retention time. Crabb&27 has chrociatographed a number of 16-substituted

17a- and 17p-compounds under similar conditions and checked the results by

collecting material eluted from the column and determining rotatory disper-

sions. In one case, I&-carbomethoxy-17d-progesterone (s), the rotatory

dispersion curve of the eluted material was identical with that of the 17S-

isomer.

III. Relative Stabilities of 2GKetopregnanes

The large rotational difference between 17u- and 17F-204etopregnanes

allows for reasonably accurate determination of the composition of a mixture

of the two provided that the rotation of each pure isomer is known. This

fact, plus the existence of a facile pathway for equilibration of these

ketones makes the determination of their relative stabilities a comparatively

simple matter. In turn, the examination of the effects of variations in

structure on the relative stabilities of the two isomers allows a convenient

method for quantitative evaluation of a variety of spatial effects. The

available examples of equilibration of 20-ketopregnanes are collected in

Table I. Only those cases have been included which we believe to present

true equilibrium values; that is , cases where reaction of each isomer has led

to a mixture of identical or nearly identical composition or where, from

knowledge of reaction conditions, it seems certain that equilibrium was

attained.

The commonly accepted value3' of 70% beta isomer and 34 alpha isomer

for the composition of mixtures obtained by alkaline isomerization of simple

20-ketopregnanes is based on results of Rutenandt et al. 394 and 1;offett and

Hoehn 31 9 both of whose 17a-isomers were later shown to be impure. "Uaminatior

of cases 1-7 in Table I gives a value of 20-255 of l'j'a-isomer in all cases of

base-catalyzed equilibration. The reasons for the slightly lower values

(cases 3,4) obtained in acid medium are not clear. It might be noted that

these equilibrium compositions corres[lond to a free energy difference of about

one k. cal. per mole. Slightly higher values for percent of 17a-isomer at

equilibrium aJ.pear to obtain in llc-hydroxylated and ll-keto steroids.

568 STEROIDS 2:5

No.

1

2a

b

3

9

10

11

12

13 a

b

14

TABI;E; I

~*~~I~TrO~ OF 2~~0~~~~~

Pregnane-Z-one Conditionsa

%-3a-or Zt5$ KOH, refl., 2 hr

ox3p-01 1 N KOH, 24 hr

HC1 (HOBe)

A5-3P-methoxy 5% p-toluenesulfonic acid, 2.25 hr

5c-3-one 1 N KOH, 24 hr

5P-3-me tt 11

A4-3-one It tt

i&4-3-one II 11

5+3c,llu-diol 0s 5 N NaOH(XtOH), 800, l/2 hr

D,L-A5a3-ethylenedioxy-ll-orie 0.3 FI KOK, refl., 3 hr

D,L-3-ethyfenedioxy-A5-llfi-ol-13- earboxylic acid (11--&3)-la&one

5?-21,21-dimethoxy-3a-ol-11-one 0.4 N KOH, 3 hr 16P-methyl-AT-38-01 lNKOH,24hr

16,R-mathyl-~ior-A9(11)-3~-ol 9.215 N NaO-i-pr., 20 hr

0.1 N HC1 (Chf),O.S hr

16~-methyl-5a-9~,11~- dichloro-3E-ol 11 tt 25 hr

$ 17n Lit.

23 b) 0

21 (17)

18 (37)

15 (38)

23 07)

23 07)

25 (17)

22 (17)

29-34 (c) (6) 22-31 (d,e) (19)

>50 (20, t&f) 3933)

33 (&I) (39)

100 (34)

100 td) (35)

100 (d) (40)

100 (d) (40)

(a) Room temperature and methanol solution unless specified otherwise. (b) Original value (3% 17~) has been corrected. Cf. ref. 6. (c) The range given in this case is due to the different results obtained with the two epimers. (d) Only one isomer equilibrated. (e) Analyzed by column chroma- tography; the composition of one irtermediate fraction was not determined. (f) 8pproximate analyses from both acid- and base-c&alyzed equilibrations. (g) Product mixture analyzed after acetylation.

The presence of an XL+13 lactone or la&o1 bridge (case Ici) ccnfers

considerably enhanced stability on the 17o-isomer. ' SIrlee the compounds

investigated in these series have been racemic products of total synthesis,

quantitative measurements Wenot been applied in most cases. However, it

is abundantly clear from numerous experiments 2'3,32 that the usual greater

Nov. 1963 STEROIDS 569

stability of the beta side chain does not apply. Two possible explanations

for this effect may be considered; the conformations of the two bonds at C-17

may be appreciably changed by distortions caused by the two-atom bridge, or

the presence of a carbonyl or hydroxyl group at C-18 may destabilize the 17j+

isomer. qualitative support for the view that a substituent larger than

hydrogen may have an effect on the equilibrium at C-17 is provided by the re-

sults obtained by Schmidlin and brettstein 33 with the 3,20-bis-ketal of

11,18&iketoprogesterone. Attempted ketalization of this compound resulted

in intramolecular ketal exchange to yield ll$ of the 17fi-3,18-bis-ketal and

H~H2CH2~H

H+ P

+ 170 isomer

l

The facile synthesis of l&?-substituted-17a-2Gketopregnanes by

isomerization of the 17fi-isomers has been noted earlier. The last three cases

in Table I establish that the 16@,17p-interaction COnferS COI@ete Speci-

ficity, no detectable amount of 17@-isomer being present at equilibrium.

Although exactly the opposite effect would be predicted in the case of

l&cr-substituted compounds, quantitative measurement has not been possible. 34

While l&-methylpregnenolone is unchanged after 24 hours standing in 1 N

methanolic potassium hydroxide, its 17a-isomer is similarly unaffected,

presumably because of an extremely slow rate of enolization. The marked 35 inhibition of enolization in such compounds has been noted by other workers.

Derivatives of the four possible 16-carboxspregnenolones have been

synthesized (v.i.). The most stable isomer is the one possessing the all-

trans configuration, l@-carbow-17o-pregnenolone. 36 The 16$-carboxamido

compound appears to be an exception; 36 the 168,178 isomer is reportedly

most stable, possibly due to hydrogen bonding.

XV. Choice of Conditions to Avoid Epimerization at C-17

The considerable ease with which appreciable isomerization at C-17 may

570 STEROIDS 2:5

occur has often been ignored. Probably the most striking example of this

facility is provided by experiments of Wettstein 32 and Johnson" with aldo-

sterone and 17o-aldosterone. In both cases, sufficient isomerization had

occurred after ten minutes at room temperature in 0.1 N potassium carbonate

solution (80% methanol) to allow isolation of epimerized product. The

practice of hydrolyzing ester groups by refluxing for one hour in al.coho1j.c

potassium hydroxide undoubtedly leads to complete equilibration of the side

chain in most cases.

The equilibration experiments described in Table I provide a selection

of reaction conditions under which rapid isomerization may occur, The

rapidity of reaction in acid medium (nos. 2b, 3, 13b and lf+), where two and

one-half hours or less in dilute mineral. acid suffices for equilibration, is

especially striking. Organic acids, particularly acetic acid, have been

employed in many instances without appreciable isomerization.

The rate of reaction in basic solution is somewhat slower. In the

author's laboratory, 1 N methanolic potassium hydroxide solutions have been

used routinely for equilibration studies at room temperature. Under these

conditions, complete equilibration required 12 to 24 hours in all instances

(except 16a-methylpregnenolone); half-lives were about two hours. Similar

reaction times have been observed by Barton et al. 35 who reported no ap

preciable difference in reaction rate with sodium methoxide, sodium iso-

propoxide or sodium t-butoxide in the appropriate alcohol as solvent.

Johnson et aL2' state that the use of basic reagents in the aprotic solvent,

dimethyl sulfoxidep results in marked increase in the rate of isomerization in

the case of an 11413 bridged compound.

The temptation at this point to accept iSOmeriZatiOn at C-17 as an

unavoidable fact of life with 20-ketosteroids is not justified. Although

occasional exceptions have been reported, the following will generally not

result in appreciable isomerization: hydrolysis with bicarbonate or carbon-

ate in alcohol or aqueous alcohol at room temperature; acetylation with

acetic anhydride-pyridine or hot acetic anhydride; dehydrogenation with

chloranil or dichlorodicyanoquinone; oxidations with chromium trioxide in

acetic acid, in pyridine (Sarett reagent), or in aqueous, acidic acetone

(Jones reagent); Oppenauer oxidation; catalytic hydrogenation. Shoppee I.4 and Beichstein have reported that the diacetate (2) of 5n,l7a-Pregnane-

Nov. 1963 STEROIDS 571

3p,21-dial-ll,2O-dione is unchanged after eight hours in pyridine at ll5'

or after 24 hours in nitromethane at 100".

Enolization of the 20lketone toward C-17 is, of course, required in

order for epimerization to occur. Attenburrow et aL4' have reported isola-

tion of an enol, l&methyl-%-A 901),17 -pregnadiene-3j3,20-dial-3-acetate,

in 27% yield by catalytic hydrogenation of the corresponding l&dehydro-20-

ketone. They report that the preponderant product formed by brief treatment

kc0

of this en01 in ,001 N nethanolic sodium hydroxide or .001 N hydrochloric

acid in THF solution is the 17p isomer (the less stable product, cf.

Table I, no. 13). A similar result was observed with 14% triethylamine in

THF. Complete specificity has been observed in the hydrolysis of a 17,20-

enol acetate with potassium carbonate 62 or bicarbonate,34 only the 17F-2Q

ketone being formed.

Wechter and Murray 29 have established that eptierication occurs under

the usual conditions for converting ketones to cycloethylene ketals. The

identical 20-ketal was obtained from 11-ketopregnenolone (64% yield) and

from 17a-ll-ketopregnenolone (6%). It was further established that

hydrolysis of this ketal in deuterioacetic acid-deuterium oxide solution

led to ll-ketopregnenolone, uncontaminated by the 17a epimer, which

contained no dueterium at C-17.

HOCH2CH2CBi

H+, >

c6H6

0

0 d 1 i

572 STEROIDS 25

V. Tables

The listing of 17c-20-ketopregnanes has been divided into three Tables:

Table II includes all optically active compounds except those substituted

at C-16, Table III lists &-substituted and l&e-substituted compounds

separately, and Table IV includes racemic products of total synthesis. Com-

pounds are arranged within each table in order of increasing oxidation state.

Literature coverage is believed to be complete through 1962 and to include

the major journals through June 1963. rjhere more than one value for a

physical constant appears in the literature, we have chosen the value which

we beJ..ieve to be most reliable. irptical rotation values for chloroform

solutions have been used where available, otherwise the solvent has been in-

dicated in parentheses. The values for specific rotations of 17p-isomers used

to calculate AMD values have been taken from "Pouvoir". In some cases

specific rotations of the two C-17 epimers are not available in the same

solvent; this has been indicated in the tables.

Most of the compounds listed, with the exceptions noted below, deserve

no special comment in the light of the preceding discussion.

Al1

The structures of the last two compounds listed in Table II, 5a,l7a-

-pregnene-3B,21-diol-2O-one diacetate (s) and 5c,l7a-a 14-*regnene i -3 - 3 20

dione (z), are in some doubt. Compound '& was obtaineda by acid-catalyzed

dehydration of the corresponding Up-alcohol; the position of the double

bond was not established nor was any other evidence presented in support of

the structure assigned.

CH20Ac

?

AcO

A mixture of 21 and its 178 isomer was obtained by Tsuda et al. 42 from

acid-catalysed dehydration of the lSj+hydroxy compound. Acid-catalyzed

equilibration of the 176 isomer also furnished 2. As will be noted from the

table, this is the only purported 17a-204etopregnane which is mere dextro-

Nov. 1963 STEROIDS 573

rotatory than its 178 isomer. The possibility that double bond migration

occurred during the acid-catalyzed reaction was ruled out by base-catalyzed

equilibration of 21 to a mixture from which the 178 isomer was isolated.

CoCH3

ib =D +73O

=D +125’

The 16-carboxypregnenolones and their derivatives described in Table

III merit comment since their configurations have been subject to some

confusion. The starting material for preparation of these compounds was 16u-

cyanopregnenolone obtained by addition of cyanide ion to &dehydropregneno-

lone.43r44 The 16a configuration was assigned to the cyano compound on the

basis of the well-known stereochemistry of addition reactions at c-16 and was

later confirmed by rotatory dispersion measurements. 27 Alkaline hydrolysis

of the nitrile was originally assumed to yield 16a-carboxypregnenolone. 3cw-

ever, Mazur and Cella45 suggested, on the basis of the negative specific

rotation, that the C-17 configuration was 17a and that the hydrolysis Troduct

was* in fact, lb@-carboxy-17o-pregnenolone (z). Chemical evidence and

CN-

rotatory dispersion studies

I - U-J

/27 by Crabbe supported this view and final con-

firmation af its correctness was prcvided by 46 L'orochts unequivocal synthesis

OH- _

of 16a-carboyy,?regnenolone. Thus the 16a,17~ config~ations assigned by

Ro:rlo43 and by Fetrow et al. lc4 must be corrected to l@,17a (compounds 70, 75,

574 STEROIDS 2:5

With the exception of 16o-methyl-17a-progesterone (2) obtained by

Serini-Logemahn reactionJ8 all of the 16o-substituted-li'c.-2%ketopregmnes

have been prepared by CrabbLand co-workers. 36,55 Entry into this series was

provided by the observation that reaction of 16fi-carbow-17c-pregnenolone

acetate with acetic anhydride and p&dine on the steam bath afforded the

160,17a-A20-enol lactone shown below whose stereochemistry was assigned on

the basis of ~d~genation to the known 16u,l7a-saturated lactone. Hy-

drolysis of the enol lactone under mild conditions (potassium bicarbonate,

aqueous dioxane) afforded 16a-carboxy-17a-pregnenolone acetate (a) thus

providing a means for synthesis of a number of compounds (jl-55) which

would otherwise have been available only with considerable difficulty.

Nov. 1963 STEROIDS

17a-pregnam-20-one Xethod of Synthesis" *3’9$‘17

,7s 17,3

A3W

c20

Cl?

B17 A4(.J5’ 17$4

,5,17,4,24

A38 ,3,?,17,47

P ,m 48,5

c49

Cl'7

Cl6

A6

A6

M.p. aD "MD --

139O - 75 535

119 - 75 540

145 - 50 515

159 - 28 553

155, 171b - 70 545

I.23 - 78 580

172 - I-49 560

170 - 120 538

132 - 154 569

149 - 44 543

107 - 65 563

145 + 10 580

105 + 36 467

147 - 63 635

151 - 80 812

123 - 69 550

168,182b - 41 465

O.R.D. ref.

5a-38-01 II II acetate

SB-3a-ol 11 n acetate

58-38-03 tt ‘t acetate

L5-3$3-01

II II acetate It 1' methyl ether

Sa-3-one

5f3-3-one 4 A -3-one

&-methyl-A'-3-one

1L1~~-3-one

&4*6-3-me

5$-3a, lla-diol tt ft 21-benzal

~\~-12u-ol-3,2O-dione acetate

5+3u, 12$-diol

5a-3pJ21-diOl 214Uethyl ether

21-diazo-5a-3fl-01

A5-3B-ol-Xl-one

3B-chloro-A'-ll-one

A4-lla-ol-3-one

tt 11 acetate

(1'~Zl-ol-3-one

It If acetate

5fi-3,X&dione

A&-'?, U-dime

26

17

38

17

17

17,28

17

AS0

A51

Cl8

Clg

A29

A29

E21

C21

cl5

B15 A52c51

246 + 126 332

233 - 46

I.23 - 58 467

1-46 - 90 755

167 -- --

128 -- ."_

21.1. - 12 602

133 - 27 615e

181 - 6' 608

172 - ~6~ 755

153 + 58 4@7

__ cs2 203 + 45 634 28

575

576 STEROIDS 2:5

TABIS II (cant)

17a-pregnane-20-one Method of Synthesisa

5a-3~,11~,21-triol 3,21-diacetate Bl4&3

5a-3$,21-diol-ll-one diacetate Bl4,22

A4_6a, lla-diol-3-one A53

5$-3a-ol-ll,21-dione 3-acetate-21-hydrate C54

A&k,lla-diol-3-one-2l- dimethyl acetal A54

21-bromo-5f3-3a,21-diol- ll-one 3-acetate-21- methyl ether ,54

5a-A11-3p,21-diol

diacetate CO

5a-&-g-one A25

#.p.

148

132

188

ll9

138

180

142

142

TABLE III

A. &-substituted compounds

l&P Sub&.

-cH 3

-COOH

-ccwF13

I1

II

II

17a-pregnane- 2O-one

A4-_7-one

.b5-3fi-ol-acetate

5a-3F-01 acetate

u5-3@-01

II acetate

G4-);-one

B. l&substituted compounds

Cpd. uip- l?c-pregnane- No. subst. 20-one - P

60 -CH3 A5-38-01 -

61 II II acetate

Wthod ofs 1t.p. ;y-khesis 140

C36 224

C55 205

G6 193

C36 221

P 206

Method ofa PT.p. 5 thesis *

.- - *5 157 228

C56B8 175, 199

aD -

- 60"

-Wed

- 10

- 11

-6

+ 36

+ 33g

+ 125

aD -

677

480

407

--

600

--

_-

- 165

&D

+ 13 478

- 121e

- 79

- 150

- 146

- 3se

"D % - - 117 346

- 126 380

O.R.D. ref.

C.R.D. Ref.

27

27

27

27

O.R.D. Ref.

27

27

Nov. 1963 STEROIDS

TABLE III (cent)

577

Cpd. lb@- _ Subst. No.

l?a-pregnane- 2i\-one

5&9~llL3S.-ol

5&9(%3@-of acetate

l&-3-one

6zaethyL-h4-3-one

A3-OW-21-d acetate

5a-9G,ll$-dichloro- 3j3-ol-acetate

A4-3-one

tt

5C-3js-01

If acetate

A-3+01

II acetate

ti4-3-one

3x, 5-cycle-68-03

t1 -6-one

A3+o1

11 acetate

tt tosylate

Afi-3+Tfuoro 4 ii -%one

50-3u-ol-U-one

A4-3,11-dime 5 L -3+fluoro

G-3$-ol

II acetate

.b4-3-one 5 i: -j?-ol acetate

--

A@ 121 - 43. 294

P 166 +27 3118

A5VG 154 -+ 16 336

A60 162 + 20 545

A40 174 -4 235

$3 168 + 77

G36 169 - 18

AS5 222 - 38e

e55 198 - 51

,36'43r4'4 235 - 115 ?94f

cwr 210 - 95 ,36,43

c4?,44 254 + 15

$5 192 - 36

c55 154 - 25

,36,43,44 208 c36A4

- u5 630f

157 - XL0 600f

CT5 149 - 86

e55 146 - 116

$+3&+ 154 + 12 4d

200 - 115

268 -@ye

212 -llo

261 f 12

136 - 72

2i34 * 90 560

O.R.D. ref.

28

28

27

27

55.

55

27,s

27

55

27

28

28

53

27

27

27

27

5 S -3b-ol acetate

578 STEROIDS 2:5

TABLE IV

oP!?IcALLY INACTIVE 17a-2O-I!ETOPF@ZNAN OBTAI?h%D BY TOTAL SYNTHESIS

A. General Kethod of

No. D,L-17a-pregnane-20-one Synthesisa &

100 3-ethylenedioxy-A5-ll-one C,D19 214-16

101 tl II -A5-lla-ol D19 200-2

102

Gj

11 11 -A5-118-01 D19 m-w

A4-3,11,18-trione ,33 213-16

104 U-ethylenedioxy-A4-3,11,18-trione A33 170-2

3 3,18-bis-ethylenediow-A5-3,11,18-trione A33 195-200

B. D,L-17a-pregnane-ll~-ol-20-one-18-carboxylic acid (11+13)-lactones

106 5fb3-one lOJ 3-ethylenedioxy-A5

108 A4-3-one

E 3-ethylenedioxy-A'-2l-ol

110 @4-3-one-21-al

J&& 3-ethylenedioxy-A5-21-01 acetate

112 A4-3-one-21-01 acetate

D20 186-8

A32D2o 134-9, 195-9b

C20,32 224-7

C32 179-82

C32 213-18 A32c32 214-20

C32 171-6

I,. CoGpounds Related to Aldosterone (A4 P. -pregnene-3-one-l&21-diol- 18-carboxaldehyde (11313) hemi acetal)

113 D,L-llla-aldosterone

l.lJ D,L-17a-aldosterone-21-acetate

I& D,L-17c-aldosterone-18,21_diacetate

A32 C20,32

C32

199-201

166-9

Nov. 1963 STEROIDS 579

TABLE IV (cant)

ll.6 D,L-21-desoxy-17a-aldosterone C33 176-205

117 D,L-21-desoxy-17a-aldosterone-18-methyl ether C2' 166-8

118 D,L-17a-aldosterone-18-methyl ether-21-acetate C 20 129-34

Footnotes to Tables II, III, IV

(a) The methods of synthesis refer to the discussion in Part I: A, isomer- isation of 170 isomer; 5, Serini-Logemann reaction; C, transformation of a 17a Compound; D, Sarett ring closure; E, special methods. (b) This compound exhibits a double melting point. (c) Alcohol solution. (d) Acetone solu- tion. (e) Methanol solution. (f) Rotations of 17a and 178 isomers in different solvents. (g) Impure sample.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Financial support by the Public Health Service (grant A-3943) is grate- fully acknowledged.

H. I. Calvin and S. Lieberman, BIOCiIEMISTRY, 1, 639 (1962) have isolated 17a-pregnanedione from human urine as a metabolite of l&dehydrogester- one. Cf. also reference 21.

A. Butenandt and L. Mamoli, BER., 68, 1847 (1935).

A. Butenandt and G. Fleischer, BER., 70, 96 (1937).

A. Butenandt, J. Schmidt-Thorn&and H. Paul, BER., 72, 1112 (1939).

C. W. Marshall and T. F. Gallagher, J. BIOL. CHUM., 179,1265 (1949).

C. W. Shoppee, J. CHm. SOC., 1671 (1949).

M. B. Rubin and E. C. Blossey, STEROIDS, 1, 453 (1963).

D. M. Click and H. Hirschmann, J. ORG. CHEN., 27, 3212 (1962).

A. Serini, Tq. Logemann and W. Hildebrand, BER., 72, 391 (1939).

L. F. Fieser ard M. Fieser, STEROIDS, Reinhold Publishing Corp., New York, 1959, pp. 628-631. For recent investigations on the mechanism of this reaction see references 12 and 13.

580 STEROIDS 2:5

12. N. L. Wendler, PRCC. CHEM. SOC., 422 (1960).

13. T. Gd.0, J. CHEM. SOC. JAPAN, 83, 1137 (1962); T. Goto and L. F. Fieser, J. AM. CHEM. SOC., 83, 251 (1961)

14. C. W. Shoppee and T. Reichstein. HELV. CHIM. ACTA, 23, 729 (1940)

15. C. W. Shoppee, HELV. CHIM. ACTA, 23, 925 (1940).

16. M. B. Rubin and J. E. Vaux, Jr., unpublished results.

17. PI. B. Rubin and E. C. Blossey, submitted for publication.

18. R. Casanova and T. Reichstein, HELV. CHIM. ACTA, 33, 4l7 (1950).

19. W. F. Johns, R. M. Lukes and L. H. Sarett, J. AM. Cm. SOC., 76, 5027 (1954).

20. W. S. Johnson, J. C. Collins, Jr., R. Pappo, M. B. Rubin, P. J. W. F. Johns, J. E. Pike and W. Bar-, J. AM. CHEM. SOC., 85, (1963).

21. P. D. Meister, D. H. Peterson, H. C. Murray, S. H. Eppstein, L. A. Weintraub and H. M. Leigh, J. AM. CHEM. SOC., 75, 55 (1953).

22. H. C. Murray and D. H. Peterson, U.S. Patent 2,602,769, July 8, CHEM. ABSTR., 46, 8334b (1952).

23. H. H. Inhoffen and 0. &ss, Ger. Patent 876,407, May ll, 1953. ABSTR., 52, 8221~ (1958).

KNAPP, 1409

M. Reineke,

1952.

cm.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35a

36.

R. J. X. Cremlyn, D. L. Garmaise and C. W. Shoppee, J. CHEM. XX., 1847 (1953).

The single exception to this generalization, reported by H. Hasegawa, Y. Sato, T. Tanaka and K. Tsuda, CHEM. PHARM. BULL. (TOKYC), 9, 740 Q961), is compound 22 in Table II (5o,1'7a-&-preenene-3,2O-dione), for which aD +125 is reported (178 isomer, aD +73).

C. Djerassi, BULL. SCC. CHIM. FRANCE, 74l (1957); cf. also C. Djerassi, OPTICAL ROTATCRY DISPERSION, McGraw-Hill, New York, 1960.

P. Crab&, TETRAHEDRON, 19, 51 (1963).

W. A. Struck and R. L. Houtman, J. ORG. CHEM., 26, 3883 (1961).

lni. J. Wechter and H. C. Murray, J. ORG. CHEM., 28, 755 (1963).

Ref. 11, pp. 566, 567.

?,. B. Moffett and W. K. Hoehn, J. AM. CHEM. SOC., 66, 2098 (1944).

J. Schmidlin, G. Anner, J.-R.Billeter, K. Heusler, H. Ueberwasser, P. Wieland and A. Wettstein, HELV. CHEM. ACTA, 40, 2291 (1957).

J. Schmidlin and A. Wettstein, %LV. CHIM. ACTA, 45, 331 (1962).

W. B. Rubin and E. C. Blossey, unpublished results.

E. J. Bailey, D. H. R. Barton, J. Elks and J. F. Templeton, J. CHIQ4. SOC., 1578 (1962).

P. Crabbe; L. M. Guerrero, J. Romo and F. Sanchez-Viesca, TETXAHEDRGN, 19, 25 (1963).

Nov. 1963 STEROIDS 581

37.

38.

39.

LO.

w. 42.

43.

44.

45.

46.

47.

48,

J.-F. Biellman, D. Kucan and C. @urisson.: BULL. SOC. CHIM. FRANCE, 337 (1962) l

0. R. Rodig, P. Brown and P. Zaffaroni, J. ORG. C.HEM., 26, 2431 (1961).

V. R. Mattox, J. AM. CHEX. SOC., 74, 4340 (1952).

J. Attenburrow, J. E. Connett, W. Graham, J. F. Oughton, A. C. Ritchie and P. A. Wilkinson, J. CHEX. XX., 4547 (1961).

C. W. Shoppee, HE&V. CHIM. ACTA, 23, 740 (1940).

H. Hasegawa, Y. Sato, T. Tanaka and K. Tsuda, Cm. PHARM. BULL. (TCKYO), 9, 740 (1961).

J. Rome, TETRAHEDRON, 3, 37 (1958).

B. Ellis, V. Petrow and D. Wedlake, J. CHEM. SCC., 3748 (1958).

R. H. Mazur and J. A. Cella, TETRAHEDRON, 7, 130 (1959).

E. L. Woroch, J. ORG. CHEM., 28, 855 (1963).

R. E. Marker, E. L. Wittle and L. Plambeck, Jr., J. AM. CHEM. SCC., 61, 1333 (1939).

Swiss Pat. 241,645. Aug. 1, 1946. CHEM. ABSTR., 43, 7978f (1949).

49. D. J.

50. P.

51. Ic.

52. H.

53. K.

54. v.

55. P.

56. J. 4,

57. p.

Burn, B. Ellis, V. Petrow, I. A. Stuart-Webb and D. M. Williamson, CHEM. SOC., 4092 (1957).

Diassi, personal communication.

Sorkin and T. Reichstein, HELV. CHIM. ACTA, 28, 875 (1945).

C. Murray and D. H. Peterson. U.S. Pat. 2,659,74l. Nov. 17, 1953.

Florey and M. Ehrenstein, J. ORG. CHFX., 19, 1331 (1954).

R. Mattox, J. AM. CHEM. SGC., 74, 4340 (1952).

Crabbk, M. Perez and G. Vera, CAN. J. CHEH., 4l, 156 (1963).

Romo, M. Lepe and M. Romero, BOL. INST. @JIM. UNIV. NACL. AUTON. MEX., 125 (1952). CHEM. ABSTR., 48, 9399i (1954).

de Ruggieri, C. Ferrari and C. Gandolphi, GAZZ. CHIM. ITAL., 91, 672 _._. (1961).

58. B. Ellis, S. P. Hall, V. Petrow and D. M. Williamson, J. CHEM. SGC., 22 (1962).

60. 0. G. Nathansohn, F. Donadelli, E. Testa and G. F. Odaeso, J. ORG. CHEM., 27, 3677 (1962).

61. S. Lieberman, K. Dobriner, B. R. Hill, L. F. Fieser and C. P. Rhoads, J. BICX. CHEM., 172, 263 (1948). Cf. also G. Birke, C. A. Gemsell, L. 0. Plantin and H. Robbe, ACTA ENDCCRINOL., 27, 389 (1958).

62. L. F. Fieser and Huang Minlon, J. AM. CHEM. SOC., 71, 1840 (1949).