The Total Synthesis of Steroids. Journal of the American Chemical Society. Woodward, Sondheimer, Taub, Heusler, McLamore. 1952 74 (17), pp 4223–4251...
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July, 1931



free hydroxyl band; found: C, 73.24; H, S.SS). The washed with water and with dilute sodium bicarbopresently described procedure is equally applicable nate solution, dried and diluted with petroleum to the steroidal sapogenins as exemplified by the ether to crystallize the product. performic acid oxidation of A7~Q"1)-22-isoallo- Amino acids may be used in this procedure by spirostadien-3P-01 acetate3 to 9a, 11a-oxido-22-iso- preparing a solution in one equivalent of 2 N alkali and adding this to the preformed mixed anhydride. allospirostan-3/3-01-7-one acetate (m.p. 295-297', [aI2OD - 128' (CHC13), X z z 1 1736 and 1718 cm.- ' ; The heterogeneous mixture is then stirred rapidly found: C, 71.74; H, 8.94). Analogous trans- for 1-2 hours and the aqueous phase is separated, formations of this oxidoketone to 11-oxygenated extracted with ether and acidified to precipitate the 22-isoallospirostan-3/3-01~have already been com- formed peptide acid. I n general, s-butylchlorocarbonate gave slightly pleted and will be reported shortly in a detailed higher yields than the isobutyl isomer. Peptide paper. Since the starting diol (I)5has been prepared from ethyl esters prepared using these reagents to form both diosgenin3*4 and A5-pregnen-3P-ol-20-one4the reactive mixed anhydrides include those of (which is also available from stigmasterol), the carbobenzoxyglycyl-L-tyrosinel(68%) ; m.p. 129~ (c = 10, ethanol); dicarabove described experiments constitute the con- 130', [ a I z 4+19.3' version of the two most abundant plant steroids bobenzoxy-L-lysylglycine2 (64%), m.p. 89-90', [ a I z 4-12.0' ~ (c = 4, ethanol); carbobenzoxy-Linto 11-oxygenated pregnane derivatives. RESEARCH LABORATORIES GILBERT STORK' leucyl-~-tyrosine3 (63%), m.p. 116-11So, [ a I z 4 ~ SYNTEX, S. A. J. ROMO - 14.9' (c = 10, ethanol) ; phthalylglycyl-L-leuLAGUNA MAYRAN 413 G. ROSENKRANZcine3 (6l%), m.p. 142-143', [ a ( I 2 * D -23.2' (c = 5, CARLD JERASSI ethanol) ; carbobenzoxyglycyl-DL-phenylalanylgly MEXICOCITY17, D. F. RECEIVED JUNE11, 1951 cine3 (83y0),m.p. 134-133' (from carbobenzoxyglycyl-DL-phenylalanine and ethyl glycinate); (9) Department of Chemistry, Harvard University, Cambridge, Massachusetts. phthalyl - DL - phenylalanylglycylglycine3 (670j0), m.p. 164-165' (from phthalyl-DL-phenylalanine and ethyl glycylglycinate) and carbobenzoxyglyACYLALKYLCARBONATES AS ACYLATING AGENTS cyl-~~-phenylalanyl-~~-phenyla~anylglycylglycine~ FOR THE SYNTHESIS OF PEPTIDES (59%), m.p. 188-193' (from carbobenzoxyglycylSir : DL-phenylalanine and ethyl DL-phenylalanylglycylMixed anhydrides of carbonic with carboxylic glycinate) . acids have been found to be excellent acylating Peptide acids prepared by the free aminoacid proagents for the preparation of amides. I n particu- cedure include carbobenzoxyglycyl-DL-phenylalalar, anhydrides between branched chain alkyl car- nine4 (63%), m.p. 160-162O; carbobenzoxyglycylbonic acids and N-substituted amino acids or pep- ~ ~ - v a l i n e(49%), S m.p. 127-128' and 146-147' and tides react readily a t low temperature with amino carbobenzoxy-~~-alanyl-~L-phenylalanine~ (50%)) acid or peptide esters, or with a salt of a n amino m.p. 145-146'. acid, to give the corresponding peptide or higher ADDEDIN PROOF. We have just received a publication by peptide in good yield. The by-products of the re- R. A. Boissonnas (Helv. Chinz. Acta, 34, 874 (1951)) on this action, carbon dioxide and an alcohol, are readily same general subject matter. removed and the peptide is obtained initially in a (1) M. Bergmannand J. S. Fruton, J . Biol. Chcm., 118,405 (1937). very high state of purity. ( 2 ) M. Bergmann, et al., Z . physiol. Chcm., 224,26 (1934). ( 3 ) Carbon, hydrogen and nitrogen analysis was satisfactory. For peptide synthesis, the over-all reaction is (4) H. Neurath, et al., J . Bioi.Chcm., 170, 221 (1947). given by (5) T. Wielandand R.Sehring, Ann., 519, 122 (1950).





where X is a blocking group, R and R' are aminoacid residues and R" is an esterifying or salt forming group. Best results have been obtained when R"' is a s- or isobutyl radical. The mixed anhydrides are formed by treating s- or isobutylchlorocarbonate with a solution of the triethylamine salt of an N-substituted aminoacid or peptide in an inert solvent as toluene or chloroform The reaction is complete in 25-30 a t 0 to -10'. minutes. A solution of the amino acid or peptide ester to be acylated, also in an inert solvent, is then added and the reaction mixture is allowed to warm to room temperature and stand overnight. Carbon dioxide evolution begins immediately upon addition of the base and is substantially complete after several hours. In some cases, the formed N-substituted peptide ester crystallizes directly from the reaction mixture and is essentially pure after washing with water to remove triethylamine hydrochloride. More generally, the reaction mixture is



Sir: We have resolved methyl dl-3-ketoetiocholatrienatel by the following method. Reduction of the keto-ester with sodium borohydride in ethanol gave a mixture of the corresponding 3-CY and 3-&hydroxy-esters. Treatment with excess digitonin,a followed b y decomposition of the precipitated complex, gave material enriched in the desired d - 3 - /3 - hydroxy-ester. Further resolution was achieved by two repetitions of this procedure, and A4jg(11)916-

(1) Woodward, Sondheimer, Taub, Heusler and McLamore, THIS

73, 2403 (1951). (2) Cf. Windaus, KlLnhardt and Weinhold, Z. physiol. Chem., 136, 308 (1923). JOURNAL,



Vol. 73

Ifethyl 3-ketoetioallocholanate (I) has been obthe product was oxidized by the Oppenauer method. Chromatographic purification oi the resulting h i - tained previously by total synthesis.' I n view of pure keto-ester, followed by several crystallizations, conversions already described,2 essentially the only then furnished pure methyl d-3-keto- A4t9(11),16remaining stage in a synthetic route from (I) to etiocholatrienate, m.p. 188-19lo, [cY]D lS2O * S o cholesterol is the homologation of 3-6-acetoxynor(CHC13). This keto-ester has been obtained by A5-cholenic acid to 3-0-acetoxy- A5-cholenic acid. the degradation of Compound F', and had m.p. The rather cumbersome nature of this scheme 187-191', [a]= 4-17'7 *.io (CHCL); mixed m.p. however led us t o employ a more direct approach. showed no depression. Reduction of (I) with sodium borohydride in Hydrogenation of the d-keto-ester with platinuiii ethanol gave crude methyl 3-/3-hydroxyetioalloin acetic acid, and oxidation of the resulting satu- cholanate, purified through the digitonide. The rated product with chromium trioxide in acetic pure ester, 111.p. 16s-170' (undepressed on adacid, gave a mixture from which methyl 3-ketoetio- mixture with an authentic sample), was hydrolyzed allocholanate (I), 1n.p. 1i7-1SO0, was isolated after to the corresponding hydroxy-acid, m .p. 249-251 O, chromatography and crystallization. -in authen- which was then acetylated. Treatment with tic sample of ( 1 ) 3 2 4 had n1.p. li'S-lSOo, a n d there thionyl chloride gave the acid chloride, m.p. 134was no depression in map. on admixture. The in- 136') which with excess cadmium-methyl yielded frared spectra of the two samples were also identical. crude 3-0-acetoxyallopregnanone-20,m.p. 139The saturated keto-ester (I) has previously been 144'. The latter reacted with excess isohexylconverted t o the A4-compound14which we have now magnesium bromide, and the gummy product, hydrolyzed to the free acid, 3-keto- A*-etiocholenic containing 20-hydroxycholestanol-3 and probably acid, m.p. 240-243'. I n view of the conversion of the C-20 epimer, was dehydrated (at C-20) and the latter to desoxycorti~osterone,~ and progester- acetylated (at C-3) by boiling with acetic acid and one,6 this reaction sequence constitutes a total syn- then with acetic acid-acetic a n h ~ d r i d e . ~The rethesis of these hormones. action mixture was hydrogenated in the presence Alkaline hydrolysis of the keto-ester (I) has given of a platinum catalyst. Chromatographic purius the corresponding acid, 3-ketoetioallocholanic fication of the saturated material gave crude acid, m.p. 256-259', which has previously been cholestanol-8 acetate, which on crystallization transformed into methyl 3-a-acetoxyetiallocholan- readily yielded the pure ester, 111.1). 109-110°,4 :Lte.' This compound has been converted to an- undepressed on admixture with an authentic clrosterone,s which in turn has been transformed via sample (1n.p. 110'). The infrared spectra of the :tndrostanedioneg into androstenedione, lo and two samples were also identical. Alkaline hythence into testosterone.ll The conversion of pro- drolysis of the synthetic acetate furnished cholesgesterone to androstanedione has also been de- tanol-3, m. p. l~I2-142.5',~ undepressed on adscribed,I3 and this constitutes another route to tes- mixture with an authentic specimen (m.p. 142tosterone. 143'). Cholestanol-3 has already been oxidized to (3) Steiger and Reichstein, tlcl:.. C h i m At-Lu, 80, 1040 (1937). cholestanone-315which in turn has been converted (4) Djerassi and Scholz, THISJ O I T R N A L , 69, 2404 (1047). VL'L A4-cholestenone-36into cholesterol*; the total (5) Wilds and Shunk, ibid., 70, 2127 (l(l48j. synthesis of the latter is therefore complete. (6) Riegel and Prout, J . O r g . C h r m . , 13, 'I:::: 1 1 9 i X ) ; lieichstein and ITnchs, N e l s . Chiiiz. A d a , 23, OR4 I l!ltO'. Cholesterol has previously been converted into a ( 7 ) Plattner and Fiirst, rbid , 26, 22lX ( l ! l is3). number of other compounds of interest, the most I S ) Dalinrr, \ ~ . IYerder, Ilotiijimann and IIe!.ili. Lir:.., 68, 1814 iniportant of which perhaps is vitamin DS. (1935).


(9) Ilutenandt and Tscherning, Z . piivsiol. Chtiri., 889, 185 (143.1). (10) Djerassi and Scholz, .T. Org. Cheni., 13, tiV7 (1448): Rosenkranz, Mancera, Gatica and Djerassi, THISJ O U R S . ~ L , 78, 4077 (1950) I ' X s A I . , 69, ( j l 4


(1) Woodward. Sondheimer and Taub, THISJOURNAL,75, 3547 (1961). CONVERSE MEMORIAL LABORATORY I