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).