5300
of N",N'-di-t-butoxycarbonyllysyl-y-t-butylglutamyl-mediacy of cyclopropene and addition of phenyllithium across the double bond. While hydrocarbons conthreonylalanylalanylalanyl-W- t - butoxycarbonyllysine l o was coupled with phenylalanylglutamylnitroarginylCHz=CHCH&I 4- C6H5L'i+ CsHs f CH;=CHCHLiCI
glutamine benzyloxycarbonylhydrazide monoacetate -19.2" (c 2.27, 10% acetic acid); amino acid ratios in the AP-M digest4 Phe~.99Glu~,04Nargl,ooGlno.gs. Anal. Found: C, 50.3; H, 6.2; N, 18.2; 0, 24.7) to give N",N'-di-t-butoxycarbonyllysyl-yt-butylglutamylthreonylalanylalanylalanylNet- but oxytaining conjugated double bonds are known to add carbonyllysylphenylalanylglutaniylnitroarginyl g 1ut amorganolithium reagents, the reaction with an isolated ine benzyloxycarbonylhydrazide. Catalytic hydrodouble bond is quite rare.3 In no case has the stereogenolysis converted this material into the hydrazide of N",N'-di-t-butoxycarbonyllysyl-y-t-butylgIu- chemistry of addition been determined. We now report that the addition of phenyllithium to cyclopropene tamylthreonylalanylalanylalanyl-Ne-t-butoxycarb onyldoes, indeed, occur and that the reaction proceeds with lysylphenylalanylglutamylarginylglutamine monoacegreater than 99 stereospecificity to cis-2-phenylcyclotate dihydrate (Anal. Found: C, 52.9; H, 8.0; propyllithium. N, 14.8; 0, 24.3); amino acid ratios in acid hydrolysate Lysz.00Gluz.~jThro.9~Ala~.zoPhel,osArg0.~l. The azide H, , H corresponding to this hydrazide was then coupled with pCsHsLi (pyrazolyl-3)alanylmethionylasparticacid d-sulfoxide H ([o!]*~D $44.9" (c 3.12, water); amino acid ratios H H 0 Cyclopropene gas was generated by the tetramethylt ethylenediamine-promoted reaction of methyllithium in the AP-M digest Pyr(3)Alao .geMetl.ooAspl.04. Anal. with allyl chloride6,' and was bubbled cia a -20' Found: C, 43.2; H, 5.8; N, 16.2; 0, 27.2; S, 7.8), cold trap into a solution of phenyllithium in ether. and the ensuing product was deblocked with trifluoroWhen the reaction mixture was quenched with water, acetic acid to afford the d-sulfoxide of 11, [ C ~ ] * ~D47.1 O the only volatile products formed were phenylcyclo(c 1.31, 10% acetic acid); amino acid ratios in acid propane and allylbenzene in an over-all yield of 2 . 5 z hydrolysate Lys2.0,Glu3.11Thr0,96Ala3 .od'heo .98Arg0.97- (mole ratio of the two products 20:1, respe~tively).~ Pyr(3)Alao.s5Meto,5z12Aspl,03. For conversion into I1 In a separate experiment, the reaction mixture was the sulfoxide was reduced with aqueous thioglycolic poured over freshly crushed Dry Ice; acidification acid;4 amino acid ratios in acid hydrolysate Lysz.04- followed by esterification with diazomethane yielded Glu3.o,Thro ,99Ala3, l ~ P h e l . ~ l A. rdg y~ r(3) Ala 0,94Me t 0 . 9 8 methyl benzoate and cis-1-carbomethoxy-2-phenylAsp,,,86ammoniao .97. l 3 cyclopropane;l0Z1l as little as 0.5% of the trans ester The principles which have led us, by a logical process, would have been detected. The neutral fraction from to the discovery of a potent antagonist to S-peptide (1) R. M. Magid and J. G. Welch, J . Am. Chem. Soc., 88, 5681 (1966). may be useful in development of antagonists to other (2) E. Grovenstein, Jr., and G. Wentworth, ibid., 89, 1852 (1967), and biologically active polypeptides. l 4 references cited therein. (3) P. D. Bartlett, S . Friedman, and M. Stiles, ibid., 75, 1771 (1953). Acknowledgment. The skillful technical assistance of (4) The addition of nucleophiles across the highly strained cycloMiss Judy Montibeller, Mrs. Elaine Gleeson, and Mr. propene double bond to yield a relatively stable cyclopropyl anion is an established process with various nitrogen, oxygen, and sulfur bases;6 Albert Frazier is gratefully acknowledged. ([(rIz4~
AH-!-
(10) I
