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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
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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
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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
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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).
