3540
COMMUNICATIONS TO THE
Val. 73
EDITOR
same boundaries was obtained with the 105 filter
and 103F date and Dermits the observation of the
globulin i n d 6-bouidaries in the cell. However,
since hemoglobin refracts as well as absorbs light its
quantitative effect upon the globulin components
with which i t is associated must not be overlooked
i n analyzing the pattern. The same light source,
filter and photographic d a t e combination has been
used to obtain continndus scanning records' of the
chromatographic resolution of artificial mixtures of
proteins Goniaining hemoglobin as a curnponent,?*a
and also to obtain cylindrical lens schlieren diagrams in the ultracentrifuges with purified human
carbon monoxide hemoglobin solutions up t u 2c/,
concentration.
(F) G. Kegele. and H. A. Sober. Abstracts 01 119th National Meetihs, American Chemical Society. April, 1951.
17) H. A Sober. G. Kezeles and F. T. Gutter. Abstracts 01 I l 7 t h
National Meeting, American Chemieal Society, April, 1950.
(8) H . A. Soher and G. Kegeles, Fed. Pror., 10, 299 (19511.
(9) G. Kegcles and F . J. Gutter, T HJ o~u s a ~ ~
in.preea.
SATIONAL
CANCER
Ih-snrms
SATIONAI.
I~s-rr~o-rss
OP HEALTU
11.
PUBLIC HF-AI.1." SeRvrcE
s.
R e r ~ s s ~MI,.
a,
STEROIDS.
GERSONKEGELIS
FREDERICK
J. GUTTER
Kectirv~oMAY9. 1951
XMI. THB SYNTHESIS OF 19-NORPROGESTERONE
Fig. 1
is relatively low. For this reason, special infrared
sources have been employed,' and special adaptersi
have been designed,* to permit the interchangeable
use of overvoltage tungsten filaments illuminating a
slit in the correct focal plane for the schlieren optical system. I n an extended study of the sera of a
leukemia ~ a t i e n t the
, ~ critical demand for the analysis of a serum sample which was irreplaceable,
but had been hemolyzed when drawn led ns to the
accidental discovery of a very simple technique for
photography, in the absence of a specially designed
source of red light. We found that with a Wratten
No. 105 (hemoglobin analysis) filter to reduce contrast, Eastman Spectroscopic Type 103F plates are
sufficientlysensitive to the mercury red lines to permit satisfactory schlieren scanning photographs'
in the normal exposure range. Moreover, the lens
svstem used5 is sufficientlv achromatic that satisfactory longitudinal focn&g is obtained without
shifting the source slit. In the accompanying figure, the upper schlieren scanning photograph of a
badly hemolyzed samde was made. after 7200 seconds electrophoresis at 6.29 volts/cm. in 0.1 molar
sodium diethylbarbiturate buffer at p H 8.60, by use
of a Wratten No. 77A (monochromat green) filter
and a Kodaline CTC photomaphic plate. At the
position conjugate t u 'the incidence bf hemoglobin
in the cell, the pattern of the rising boundaries vanishcs. The lower schlieren scanning diagram of the
(1) If. P. TrcRern and D. H. Moore, Scirnrr. 93, 240 (1941).
En& C h m . , A n d . E d . , 18. 219 (1946).
(3) F. J. Gutter. J. Krevans, G. A. Moulfon and G. Kegeles. J . No1
Cancer IIIIt.. in pres.
(4) L. G. Lonseworth. Trrr l o u a l i ~61,
~ 529 (19391.
(6) Klctt Mix: CO.. N e w Yoik. N . Y.
(2) L. G. Longsworth, Ind.
Sir:
I n 1944, Ehrensteinl reported the twelve-step
degradation of strophanthidine in 0.07'% yield to a
resin, [a]D +89", believed to be 19-norprogesterone
(IIIb). The material represented a mixture of
stereoisomers, most likely possessing the "unnatural'' configuration2 at C-14(@) and C-l7(a) and
was reported3 to exhibit the same biological activity as progesterone. Subsequent work4 has shown
that the "unnatural" configuration at C-14 and
C-17 per se does not confer progestational activity
and it remained, therefore, t o be seen whether the
lack of an angular methyl group at C-10 in I I I b was
responsible for this pronounced biological effect, so
surprising in view of the extreme specificity of this
type of hormonal activity.2a
A modified5 Birch reduction6 on 3-methoxy-17acetyl-1,3,5-estratriene (I)7 produced A*,5(10)-19nor-3-methoxy-20-hydroxypregnadiene(II), (m.p.
135-138', [ U ] ~ D+88" (all rotations in chloroform),
no selective absorption in the ultraviolet, free hydroxyl band in infrared. Calcd. for CllHJ202:
C, 79.69; H, 10.19; methoxy, 9.80. Found: C,
79.33; H, 10.47; methoxyl, 9.15). which without
isolation upon boiling with alcoholic hydrochloric
acid yielded Al-19-norpregnen-20-ol-3-oiie(IIIa),
(1) M. Ehrcnstcin. 3. Ow. Chsm.. 9. 435 (1944).
(2) (a) M. Bhrenafein. Chcm. e a . , 11,457 (1948); (b) J . Olg. Chrni.
16.. 355 11851).
.
(3) W. M. Allen and M. Ehrenstein, Sricncc. 100, 251 (19441.
(41 PI. A. Phttoer, H. Heuser and A. Segre, Hcla. Chirn. A d o , SI,
249 (1048).
(5) A. L. Wilda and N. Nelson, to be published. We are greatly
indebted to Pmf. A. L. Wilds. University of Wisconsin, loorndvaoee in^
formation on this mcdified procedure.
(6) A. I. Birch, Qunn. Rra.. 1, 69 (1950); 3. Cham. Soc.. 2531
.
.
119491.
(7) C . Djerassi, G. Rorenkmnz. I. Iriarte. 1. Berlin and 1. Romo,
Tsis l a u a a ~ 'IS,
~ , 1523 l I 9 i l ) .
COMMUNICATIONS
TO THE EDITOR
July, 1951
3541
CRYSTALLINE ALLETHRIN ISOMER
probably representing a mixture of 20-epimers;
~
hEZx 240 mp (4.35), Sir :
m.p. 174-177', [ a ] 2 "+42',
The insecticide known as allethrin, now being
infrared bands (CS2) a t 3617 cm.-' (hydroxyl) and
1678 ern.-' ( A4-3-ketone). Calcd. for C20H3002: produced commercially, is obtained by acylation
C, 79.42; H, 10.00. Found: C, 79.45; H, 10.24. of dl-2-allyl-4-hydroxy-3-methyl-2-cyclopenten-1Chromium trioxide oxidation of I I I a in acetic acid one1 (dl-allethrolone) with a mixture of dl-cis- and
solution afforded in 55% over-all yield (based on I) dl-trans-chrysanthemum monocarboxylic acid chlopure 19-norprogesterone (IIIb), m.p. 144-145',
rides.
[CX]~'D +147', A$,
240 mp (4.36), infrared bands
Allethrin may be considered a mixture of four
(CS2) a t 1706 ern.-' (20-ketone) and 1674 ern.-' racemic forms (or eight individual optical and geo( A4-3-ketone). Calcd. for CZOHZ~OZ:
C, 79.95; metric isomers). Two racemic forms are esters of
H, 9.39. Found: C, 80.07; H, 9.28. The red- the cis acid and two of the trans acid.
dish-orange
3,20-bis-2,4-dinitrophenylhydrazone When a sample of molecularly distilled allethrin
possessed m.p. 278-279', XEFF'' 380 mp (4.78).8 was cooled to a low temperature, i t crystallized in
Calcd. for C32H3608N8: c , 58.17; H, 5.49; N, part, as likewise did samples of commercial
16.95. Found: C,58.28; H,5.37; N, 16.57.
allethrin kept a t about 4'. Cold filtration and
recrystallization from isoCHz
CH3
octane or pentane gave
I
I
&Rz colorless crystals,
h.p.
CH,I
50.5-51'.
A n d 2 Calcd. for C19HZ6O3:C, 75.46; H, 8.67.
Found: C, 75.41; H, 8.67.
Upon saponification of
the
crystalline product, dl+ o//
trans - chrysanthemum
H
I
I1
IIIa RZ = (OH
monocarboxylic acid was
bRz=O
obtained, which, after recrystallization from pen19-Norprogesterone (IIIb) exhibits approxi- tane or nitromethane, melted a t 55-56' and gave
mately the same activity as natural progesterone no depression in a mixture melting-point determinain rabbits. Since the mode of synthesis automati- tion with the authentic acid.3
dl-Allethrolone when acylated with dl-cis-chryscally establishes the 'Inatural" configuration for all
asymmetric centers with the possible exception of anthemum monocarboxylic acid chloride furnished
C-lO,Qthe replacement of the angular methyl group an ester mixture, b.p. 146-149' (0.4 mm.), n26D
a t C-10 by hydrogen in progesterone does not reduce 1.5070,4which, on being cooled and seeded with the
biological activity.1° This observation is of consid- above-mentioned crystalline compound, could not
erable importance since if i t should also apply to the be induced to crystallize. Acylation of dl-allethrocortical hormones, notably cortisone, i t would con- lone with dl-trans-chrysanthemum monocarboxylic
siderably simplify the total synthesis of anti-ar- acid chloride furnished a n ester mixture, b.p. 147thritic substances. In fact, the present preparation 150' (0.4 mm.), n26D 1.5047,4which crystallized in
of 19-norprogesterone (IIIb) constitutes the first part on being cooled and seeded. When 8.4 g. of
total synthesis of a potent progestational hormone, this ester mixture was dissolved in 12.6 ml. of isosince the starting methyl ether I7has been obtained" octane, cooled, and filtered on a cold-jacketed filter
from estrone which has already been synthesized kept a t about -30°, about half was obtained as the
totally. l 2
crystalline form. Removal of solvent from the
Further work on 19-norsteroids, particularly of filtrate in vacuo left 4.4 g. of oil, n26D 1,5050. The
the cortical hormone series, is in progress.
crystalline portion, when recrystallized from isooctane, melted a t 50.5-51' and did not depress the
JOINT CONTRIBUTION
FROM THE
melting point of the crystalline compound obtained
RESEARCH
LABORATORIES
OF SYNTEX,
S. A.
LAGUNA
MAYRAN
413
L. MIRAMONTESfrom allethrin. The crystalline isomer will be
MEXICOCITY17, D. F., AND
G. ROSENKRANZcalled the a-dl-trans isomer, and the other isomer
CARLDJERASSI
INSTITUTO DE QUfMICA
found concentrated in the filtrate, the 0-dl-trans
UNIVERSIDAD NACIONAL
AUT6NOMA DE MBXICO
TACUBA,
D. F.
isomer of allethrin. Based on the yield, the conRECEIVED
MAY21, 1951
centrate of P-dl-trans isomer contained about 5%
.of dissolved a-dl-trans isomer.
(8) Progesterone bis-dinitrophenylhydrazone shows
' ' : : :A
383 mr
The crystalline a-dl-trans isomer must consist of
4 72) (C Djerassi. Anal. Chcm., 10, 880 (1948)).
19) The hydrogen atom at C-10 most likely assumed the more stable
one of the racemic ester pairs, d-trans acid with
natural" &configuration during the acid hydrolysis of 11.
d-allethrolone plus 1-trans acid with I-allethrolone,
110) The reason for the high biological activity of Ehrenstein's
/HA="
o.!?
'
(ref 1) mixture of 19-norprogesterones is still obscure since the presently described isomer IIIb could have been at best only a minor constituent of that mixture.
(11) L. Velluz and G. Muller, Bull. Soc. Chim. France, 166 (1950).
(12) G. Anner and K. Miescher, Hclu. Chim. Acta, 81, 2173 (1948);
W. S. Johnson, D. K.Banerjee, W. P. Schneider and C. D. Gutache,
THIS
JOURNAL, 72, 1426 (1950).
(1) M. S. Schechter, N. Green, and F. B. LaForge, THIS
JOURNAL,
71, 1517 (1949); 71, 3165 (1949); Agr. Chemic&, 4 (e), 57 (1949).
(2) J. S. Ard, Bureau of Agricultural and Industrial Chemistry,
U. S. Department of Agriculture.
(3) I. G. M. Campbell and S. H. Harper, J . Chcm. Soc., 283 (1945).
Harper,
I.
M. W.
(4) Compare, L. Crombie, A. J. B. Edgar, S. €
Lowe, and D. Thompson, J . Chem. Soc., 3553 (1950).