Preparation of 3β-acetoxy-5β-pregnan-20-one from 3α-acetoxy-5β-cholan-24-oic acid aimed at the isotopic labelling of the pregnane side chain

Full text of DOI:10.1515/znb-1984-1125

Preparation of3/?-Acetoxy-5/?-pregnan-20-one from 3a-Acetoxy-5ß-cholan-24-oic
Acid Aimed at the Isotopic Labelling of the Pregnane Side Chain
Monica E. Deluca, Alicia M. Seldes, Hugo M. Garraffo, and Eduardo G.Gros*
Departamento de Qufmica Orgänica y UM YM FOR, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Pab. 2, Ciudad Universitaria, 1428 Buenos Aires, Argentina
Z. Naturforsch. 39b, 1617—1621 (1984); received May 25, 1984
3/3-Acetoxy-5/?-pregnan-20-one, 3a-Acetoxy-5/3-cholan-24-oic Acid, Synthesis,
'H NMR Spectra, 13C NM R Spectra
3a-Acetoxy-5/?-cholan-24-oic acid was transformed into 3/3-acetoxy-5/3-pregnan-20-one by a
sequence of reactions that involves inversion of the configuration at C-3 and degradation of the
side chain of the bile acid. The procedure would allow the introduction of a label at C-21 of the
final compound.
In connection with our research on the biosyn-
thesis of cardiotonic steroids [1] it was required the
preparation of 3/3-hydroxy-5/3-pregnan-20-one label-
led at either C-20 or C-21. The unlabelled compound
have been obtained by different methods such as re-
duction of pregnandione [2], or pregnenolone [3],
and by degradation of smilagenin [4] but these proce-
dures follow unappropriate routes for introducing a
label at the side chain and produce the needed com-
pound in very low yields.
We wish to report that using a low cost compound
commercially available in large quantities as
lithocholic acid, the title compound was prepared
following a procedure that would allow the introduc-
tion of an isotopic carbon-atom at C-21.
cleavage of the side chain giving the etianic acid 6a
which was isolated as its methyl ester.
Inversion of C-3 configuration was performed by
displacement of a tosyloxy group on the etianic ester
6b. This classical method gave in this case better
results than those obtained by the formic acid—
ethyl azodicarboxylate procedure or by oxidation—
reduction of the C-3 hydroxy group. Formylation of
6b yielded the 3/3-formyloxy derivative 7a which was
transformed into the acetyl derivative 7 c by usual
methods.
For construction of the pregnane side chain, the
acid 7c was converted into the acyl chloride deriva-
tive 8 which was subjected to alkylation by an or-
ganometallic reagent. For this step, and considering
the requirements of millimole scale that has to be
used for the introduction of the labelled carbon, the
usual procedures employing a large excess of a Grig-
nard reagent were not suitable. The best results were
obtained using dimethyl cadmium on the acyl
chloride 8 adapting the original technique [9, 10] to
microscale preparation.
Results and Discussion
As it is indicated in the Scheme, copper catalysed
oxidative decarboxylation of 3a-acetoxy-5/3-cholan-
24-oic acid (1) with lead tetraacetate in pyridine-
containing benzene gave 3a-acetoxy-24-nor-5/?-chol-
22-ene (2). Treatment of 2 with N-lithioethylen-
diamine afforded the A 20,22 olefin 3a as the sole reac-
tion product [5] with no traces of the A 17-20 isomer,
the 13C NMR spectrum of 3 a indicated the presence of
just the Z isomer. Acetylation of 3a afforded 3b
which was ozonised giving the ketone 4; compound 4
had been previously obtained from lithocholic acid
but following a different degradation approach [6].
Acetoxylation of compound 4 gave compound 5a [7]
which after hydrolysis [8] afforded the a-ketol 5b.
Treatment of 5b with sodium periodate produced the
Experimental
Melting points are uncorrected. IR spectra were
determined as Nujol dispersions using a Perkin
Elmer 421 spectrophotometer. ]H and 13C FT NMR
spectra were recorded with a Varian XL-100-15, us-
ing TMS as internal standard and solvents indicated
in each case. Mass spectra (MS) were performed at
70 eV (direct inlet) with a Varian-Mat CH7-A spec-
trometer interfased to a Varian-Mat Data System
166 computer.
3 ß-Acetoxy-24-nor-5ß-chol-22-ene (2)
A mixture of 3/3-acetoxy-5/3-cholan-24-oic acid
(800 mg, 1.90 mmoles), cupric acetate (80 mg,
* Reprint requests to Prof. Dr. E. G. Gros.
0340-5087/84/1100-1617/$ 01.00/0
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1618
M. E. Deluca et al. • Preparation of 3ß-Acetoxy-5/3-Pregnan-20-one
3a R =H
3b R-Ac
5a R =Ac
5b R =H
6a R =H
6b R =Ts
0.44 mmoles) and anhydrous pyridine (0.01 ml,
0.12 mmoles) in dry benzene (30 ml) was refluxed
under nitrogen for 4 h while lead tetraacetate (2.4 g,
5.40 mmoles) was added in portions. The solids were
then collected and the filtrate was evaporated to dry-
ness. The residue was dissolved in methylene
chloride, washed with 5% hydrochloric acid, 5%
sodium hydrogen carbonate solution and water,
dried over magnesium sulphate and evaporated. The
crude extract was chromatographed on silica gel G,
elution with toluene afforded compound 2 (450 mg,
63%). It was crystallized from methanol, m.p.
84-85 °C. IR (cm-1) 1730 (C = 0 ), 1630 (C=C).
■H NMR (C13CD)(<5): 0.68 (s, 3H, 18-CH,), 0.94
(s, 3H, 19-CHs), 1.03 (d, 3H. J = 6 Hz, 21-CH3),
2.04 (s, 3H, CH3CO), 4.75 (m. 1H, 3/ff-H), 4.90 (m.
2H , 23-CIL), 5.70 (m, 1H, 22-CH). 13C NMR
(C13CD) (ppm): 35.10 (C-l), 26.39 (C-2), 74.39
(C-3), 32.31 (C-4), 41.94 (C-5), 27.08 (C-6), 26.68
(C-7), 35.85 (C-8), 40.51 (C-9), 35.10 (C-10), 20.90
(C -ll), 40.10 (C-12), 42.71 (C-13), 56.55 (C-14 or
C-17), 24.27 (C-15), 28.51 (C-16), 56.55 (C-17 or
C-14), 12.28 (C-18), 23.40 (C-19), 41.22 (C-20),
20.15 (C-21), 145.14 (C-22), 111.43 (C-23), 21.54
(CH3CO), 170.47 (CH3CO). MS: m/e (%): 372
(M+, 2.4), 357 (M "-C H 3, 4.1), 317 (M+-side
chain, 2.9), 312 (M+-C H 3COOH, 38.4), 297
(M+-C H 3C O O H -C H 3, 12.9), 257
(M- —CH3CO O H —side chain, 100), 215 (28.6).
3 a-Hydroxy-24-nor-5ß-chol-20(22)-ene (3a) and
3 a-acetoxy-24-nor-5ß-chol-20(22)-ene (3b)
3a-Acetoxy-24-nor-5/3-chol-22-ene (2) (3.5 g,
9.40 mmoles) was added in one lot to a stirred and
heated solution (125 —130 °C) of 7.8 equivalents of
N-lithioethylene-diamine (234 mg Li added in por-
tions to stirred dry ethylendiamine (7.9 ml) at
90—100 °C bath temperature, under nitrogen and
heating for 2 h to complete the reaction) under nitro-
gen and the mixture refluxed for 15 min. After cool-
ing, water was added and the solution extracted
twice methylene chloride. The organic extracts were
washed with water until neutral reaction, dried over
magnesium sulphate and evaporated under reduced
pressure to afford crude 3a which crystallized from
diluted ethanol; m .p. 114—115 °C (2.8 g, 90%). IR
(cm-1) 3300 (broad, OH), 1650 (C=C). !H NMR
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M. E. Deluca et al. ■Preparation of 3ß-Acetoxy-5/?-Pregnan-20-one
1619
(CI3CD) (6): 0.52 (s, 3H, I8-CH3), 0.93 (s, 3H,
I9-CH3), 1.58 (s, 3H, 23-CH,), 1.62 (s, 3H, 21-CH3),
3.65 (m, 1H, 3/3-H), 5.25 (m, 1H, 22-CH). 13C NMR
(CI3CD) (ppm): 35.42 (C-l), 30.48 (C-2), 71.62
(C-3), 36.42 (C-4), 42.16 (C-5), 27.20 (C-6), 26.44
(C-7), 36.16 (C-8), 40.74 (C-9), 34.63 (C-10), 20.82
(C -ll), 39.05 (C-12), 43.71 (C-13), 55.98 (C-14),
24.21 (C-15), 27.20 (C-16), 59.02 (C-17), 13.40
(C-18), 23.36 (C-19), 135.15 (C-20), 24.78 (C-21),
118.72 (C-22), 17.51 (C-23). MS: m/e (%): 330 (M*,
14.1), 312 (M+- H ,0 , 2.2), 257 (M+-H .O -sid e
chain, 3.9), 215 (3.4).
Acetylation with pyridine—acetic anhydride (1:1)
at room temperature for 18 h afforded 3b as a solid
which crystallized from ethanol; m .p. 104—105 °C.
IR (cm"1) 1740 (C = 0 ), 1650 (C=C). ’H NMR
(CI3CD) (<5): 0.52 (s, 3H, I8-CH3), 0.94 (s, 3H, 19-
CH3), 1.58 (s, 3H, 23-CH3), 1.62 (s, 3H, 21-CH3),
2.04 (s, 3H, CH3CO), 4.75 (m, 1H, 3/8-H), 5.25 (m,
1H, 22-CH). 13C NMR (C13CD) (ppm): 35.11 (C-l),
26.36 (C-2), 74.34 (C-3), 32.30 (C-4), 41.95 (C-5),
27.04 (C-6), 26.65 (C-7), 36.16 (C-8), 40.73 (C-9),
34.69 (C-10), 20.85 (C -ll), 39.05 (C-12), 43.79 (C-13),
56.04(C-14), 24.25 (C-15),26.25 (C-16), 59.10(C-17),
13.48 (C-18), 23.38 (C-19), 135.21 (C-20), 24.80
(C-21), 118.85 (C-22), 17.62 (C-23), 21.47 (CH3CO),
170.40(CH3CO). MS: m/e (%): 372 (M+, 76.5), 357
(M+-C H 3, 3.1), 312 (M+-C H 3COOH, 64.1), 297
(M+-C H 3-C H 3COOH, 26.9), 257
Ja,21-Diacetoxy-5/?-pregnan-20-one (5a) and
3 a,21-dihydroxy-5ß-pregnan-20-one (5b)
Treatment of 3a-acetoxy-5/3-pregnan-20-one (4)
in the conditions described by Cocker et al. [7] for
3/3-acetoxy-pregn-5-en-20-one
afforded
3a,21-
diacetoxy-5/?-pregnan-20-one (5a) (600 mg, 73%) of
m .p. 95-96 °C (Lit. [8] m.p. 97-98 °C). IR (cm-1)
1740 (C = 0 , acetoxy group), 1710 (C = 0 ). ’H NMR
(CI CD) ((3): 0.64 (s, 3H, I8-CH3), 0.94 (s, 3H,
3
I9-CH3), 2.04 (s, 3H, 3-CH3CO), 2.18 (s, 3H,
2I-CH3CO), 4.62 (qAB, 2H, 7 = 6 Hz, 21-CJL),
4.70. (m, 1H, 3ß-H). MS: m/e (%): 358
(M+-C H 3COOH, 4.4) 345 (M+-C H 2OCOCH3,
70.4), 343 (M+-C H 3C O O H -C H 3, 1.4), 257
(M+—CH3COOH—side chain, 93.3), 75 (100).
Acetate 5a (400 mg, 0.96 mmoles) was refluxed
with sulphuric acid (0.6 ml) in ethanol (30 ml) for
24 h. The mixture was poured onto ice-water, ex-
tracted twice with ethyl acetate and the combined
organic extracts were washed with water, dried over
magnesium sulphate and evaporated. The crude ex-
tract was chromatographed on silica gel G with mix-
tures of increasing polarity of methylene chloride—
methanol. Elution with 95:5 afforded 5b (230 mg,
72%) of m.p. 130—131 °C (Lit. [8] m.p.
152.5-153.5 °C from acetone). IR (cm“1) 3300
(broad, OH), 1705 (C = 0 ). *H NMR (C13CD) (6):
0.62 (s, 3H, I8-CH3), 0.93 (s, 3H, 19-CH3), 3.65 (m,
1H, 3/3-H), 4.18 (b.s., 2H, CH2OH). MS: m/e (%):
334 (M+, 0.9), 316 (M+- H 20 , 0.8), 303
(M *-O C H 3, 94.9), 301 (M ^-H 20 - C H 3, 2.2), 257
(M~ —H20 —side chain, 100), 215 (5.8).
(M+—CH COOH—side chain, 21.3), 215 (43.1).
3
3 a-Acetoxy-5ß-pregnan-20-one (4)
Ozone was passed through a solution of 3 a-
acetoxy-24-nor-5/3-chol-20(22)-ene
(3b)
(1.0 g,
3 a-Hydroxy-5ß-androstan-17ß-carboxylic acid
methyl ester (6 a) and 3 a-tosyloxy-5ß-androstan-
17ß-carboxylic acid methyl ester (6b)
2.70 mmoles) in methylene chloride (10 ml) at
—10 °C, until the mixture was blue. The mixture was
evaporated under reduced pressure. The residue was
dissolved in acetone (10 ml) and treated with Jones
reactive at 0 °C till the mixture was redish brown. It
was poured onto ice-water and extracted twice with
methylene chloride. The combined organic extracts
were washed with water, dried over magnesium sul-
phate and evaporated under reduced pressure. The
residue was chromatographed on silica gel G. Elu-
tion with toluene — ethyl acetate (90:10) afforded
3a-acetoxy-5/?-pregnan-20-one (4) (770 mg, 80%) of
m.p. 101-102 °C (Lit. [8] m .p. 101-102 °C). IR
(cm-1) 1720 (C = 0 , acetoxy group), 1705 (C = 0 ).
To a solution of 3a,21-dihydroxy-5/?-pregnan-20-
one (5b) (1.0 g, 2.99 mmoles) in methanol (50 ml)
a solution of sodium periodate (2.0 g, 9.30 mmoles)
in water (20 ml) was added. The stirred mixture
was maintained at room temperature for 4 h dur-
ing which a white solid appeared. The mixture
was poured into water and the precipitate formed
was filtered off, washed with water and dried.
The solid was dissolved in methanol and treated with
diazomethane. Evaporation of the solvent afforded
3a-hydroxy-5/3-androstan-17/?-carboxylic acid meth-
yl ester (6a) (913 mg, 91.3%) which crystallized
from methanol; m .p. 142—146 °C (Lit. [11] m.p.
142—146 °C from ether — petroleum ether). IR
(cm-1) 3300 (broad, OH), 1740 (C = 0 ). :H NMR
(CI3CD) ((5): 0.65 (s, 3H, I8-CH3), 0.93 (s, 3H,
I9-CH3), 3.60 (m, 1H, 3/3-H), 3.68 (s, 3H, COOCH3).
*H NMR (CI CD) (<3): 0.61 (s, 3H , I8-CH3), 0.95
3
(s, 3H, I9-CH3), 2.04 (s, 3H, CH3CO), 2.12 (s,
3H , 2I-CH3), 4.65 (m, 1H, 3/3-H). MS: m/e (%):
360 (M+, 1.2), 300 (M+-C H 3COOH, 67.0), 285
(M+-C H 3C O O H -C H 3, 14.2), 257
(M+—CH3COOH—side chain, 10.6), 215 (33.0), 43
( 100).
MS: m/e (%): 316 (M+- H 20 ,
1.5), 302
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M. E. Deluca et al. ■Preparation of 3/3-Acetoxy-5/3-Pregnan-20-one
1620
(M+-C H
3
OH, 100), 287 (M --C H
3
O H -C H
3
, 70),
was refluxed for 2 h. The mixture was poured onto
ice —water, acidified with hydrochloric acid and ex-
tracted twice with ethyl acetate. The combined or-
ganic extracts were washed with water until neutral
reaction, dried over magnesium sulphate and evapo-
rated under reduced pressure. Crystallization from
ethanol afforded 3/3-hydroxy-5/3-androstan-17/3-car-
boxylic acid (7b) (82 mg, 93%) m .p. 239—241 °C
(Lit. [12] m .p. 226-228 °C). IR (cm-1) 3350 (broad,
275 (M*—side chain, 4.1), 257 (M+—side
chain —H20 , 3.6), 230 (21.1), 215 (59.3).
To a solution of 6a (140 mg, 0.42 mmoles) in dry
pyridine (5 ml) a solution of p-toluenesulphonyl
chloride (280 mg, 1.47 mmoles) in dry pyridine
(5 ml) was added. The mixture was maintained at
room temperature for 20 h and poured into dilute
hydrochloric acid—ice. It was extracted twice with
methylene chloride and the combined organic ex- OH), 3500-2700 (broad, COOH), 1700 (C = 0 ).
tracts were washed with water, dried over mag- !H NMR (CI3C D -C H 3OD 1:1) (d): 0.88 (s, 3H,
nesium sulphate and evaporated under reduced
pressure. Crystallization from methanol afforded 3a-
tosyloxy-5/3-androstan-17/?-carboxylic acid methyl
ester (6b) (194 mg, 95%) of m.p. 120-121 °C. IR
(cm-1) 1735 (C = 0 ), 1300, 1170 and 1000-750 (tosy-
I8-CH3), 1.02 (s, 3H , I9-CH3), 4.30 (m, 1H, 3a-H).
MS: m/e (%): 302 (M+- H 20 , 4.7), 287
(M +- H 20 - C H 3, 2.7), 215 (1.0), 45 (100).
Acetylation of 7b (100 mg, 0.31 mmoles) with gla-
cial acetic acid at reflux for 2 d afforded 7 c as a solid
loxy group). !H NMR (C13CD) (d): 0.64 (s, 3H, 18- which was purified by column chromatography on
CH3), 0.91 (s, 3H, I9-CH3), 2.46 (s, 3H,
H 3C -C 6H4- S 0 2), 3.68 (s, 3H, COOCH3), 4.45 (m,
1H, 3/3-H), 7.55 (dd, 4H , H 3C -C 6H4- S 0 2). MS:
m/e (%): 316 (M+- H 3CC6H4S 0 3H, 100’), 301
(M+- H 3CC6H4S 0 3H -C H 3, 87.6), 284
silica gel G using methylene chloride as eluent and
crystallized from ethanol; m.p. 170—172 °C.
*H NMR (CI3CD) (d): 0.73 (s, 3H, I8-CH3), 0.95 (s,
3H , I9-CH3), 2.07 (s, 3H, CH3CO), 5.10 (m, 1H,
3a-H ).
(M+- H 3CC6H4S 0 3H -C H 30 H , 4.1), 257
(M+—H 3CC6H4S 0 3H —side chain, 37.1), 230 (11.6),
215 (52.5), 172 (88.0).
3 ß-Acetoxy-5ß-pregnan-20-one (9)
a) Preparation of 3 ß-acetoxy-5ß-androstan-17ß-
carboxylie acid chloride (8): To a solution of 3ß-
3 ß-Formyloxy-5ß-androstan-17ß-carboxylic acid
methyl ester (7a), 3ß-\iydroxy-5ß-androstan-
17ß-carboxylic acid (7b) and 3ß-acetoxy-
5ß-androstan-17ß-carboxylic acid (7 c)
acetoxy-5/?-androstan-17/3-carboxylic
acid
(7 c)
(100 mg, 0.28 mmoles) in dry benzene (1 ml), oxalyl
chloride (1 ml) was added. The mixture was stirred
and maintained at room temperature for 2 h after
which the solvents were evaporated at reduced
pressure to afford a crude product which was iden-
tified as 3/3-acetoxy-5/3-androstan-17/?-carboxylic
acid chloride (8) and used without further purifica-
tion. IR (cm-1) 1800 (C1C = Q ), 1730 (C = 0 , acetoxy
group).
A solution of 3a-tosyloxy-5/3-androstan-17/3-car-
boxylic
acid
methyl
ester
(6b)
(100 mg,
0.20 mmoles) in dry N,N-dimethylformamide
(4.0 ml, 52.00 mmoles) was stirred under nitrogen at
80 °C for 50 h. It was then poured onto ice-water and
the mixture extracted twice with methylene chloride.
The combined organic extracts were washed with wa-
ter several times, dried over magnesium sulphate and
b) Preparation of dimethyl cadmium and reaction
with acid chloride 8: To magnesium turnings (8 mg)
evaporated under reduced pressure. The crude ex- contained in an evacuated tube, dry ether (1 ml) and
tract was chromatographed on silica gel G. Elution
with toluene afforded 5/3-androst-3-en-17/?-carboxy-
lic acid methyl ester (22 mg, 34%). Further elution
with toluene—ethyl acetate 95:5 afforded 3/3-formyl-
oxy-5/3-androstan-17/3-carboxylic acid methyl ester
(7a) (45 mg, 61%) which crystallized from ethanol;
m .p. 95-96 °C. ’H NMR (CI3CD) (6): 0.66 (s, 3H,
I8-CH3), 0.99 (s, 3H , 19-CH3), 3.68 (s, 3H,
COOCH3), 5.20 (m, 1H, 3a-H), 8.08 (s, 1H,
HCOO). MS: mte (%): 316 (M — HCOOH, 100),
303 (M+—side chain, 4.1), 301
methyl iodide (0.018 ml) dried over phosphorous
pentoxide were added. The mixture was stirred at
room temperature until most of the magnesium dis-
appeared (1 h). Then cadmium chloride (122 mg)
was added under nitrogen atmosphere. The mixture
was stirred at room temperature for 2 h followed by
the addition of the solution of acid chloride 8
(105 mg) in benzene (2 ml). After 18 h in the same
conditions the mixture was warmed to 50 °C and
further stirred for 1 h. The reaction was quenched by
addition of IN hydrochloric acid, decanted and ex-
tracted twice with methylene chloride. The com-
bined organic extracts were washed with water, dried
over magnesium sulphate and the solvents evapo-
rated under reduced pressure. Chromatography on
(M+-H C O O H -C H 3, 40.5), 257
(M+—HCOOH —side chain, 12.3), 215 (19.9).
A solution of 7a (100 mg, 0.28 mmoles) in 2%
sodium hydroxyde hydroalcoholic solution (10 ml)
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M. E. Deluca et al. • Preparation of 3/3-Acetoxy-5/3-Pregnan-20-one
1621
silica gel
G
using as solvent methylene
3H , CH3CO), 2.12 (s, 3H, 21-CH3), 5.10 (m, 1H,
3a-H ). MS: mle (%): 360 (M+, 1.1), 300
(M+-C H 3COOH, 100), 285
(M+-C H 3C O O H -C H 3, 21.9), 257
(M+—side chain—CH3COOH, 10.6), 215 (31.8).
chloride —methanol 98:2 afforded 3/3-acetoxy-5/3-
pregnan-20-one (9) (37 mg, 38%) m.p. 120—121 °C
(Lit. [2] m.p. 121 °C). IR (cm-1) 1740 (C = 0 ,
acetoxy group), 1700 (C = 0). ‘H NMR (C13CD) ((3):
0.62 (s, 3H, I8-CH3), 0.98 (s, 3H , 19-CH3), 2.06 (s,
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