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COMMUNICATIONS TO TIIE EDITOR
other sources. Oligo-1,G-glucosidase differs from R-enzyme (plants) in that the latter does not hydrolyze the terminal a- 1,6-linked glucose residues of isomaltose or panose (except possibly when acting with a-amylase). 2 X limit dextrinase from Aspergillus oryzae culture filtrate has been described17 which would seem to have an activity similar to oligo-1,6-glucosidase on "branched" oligosaccharides.
I T d . 76
[aIz4D4- 7.1" (c, 6.93; CHSOH), when used in the above sequence yielded (+)-a-lipoic acid, m.p. 46.0-48.0" (micro-block); [ a ] " ~ 104' (c, 0.88; Cdh), 333 m p (E 150). Anal. Calcd. for C8H1402S2 (206.2): C, 46.60; H , 6 Found: C, 46.95; H, 6.85;S,31.00; mol. wt. (ebull.), 194 f 2 ; neut. equiv., 208. In a similar manner ( - ) -7-carboethoxy-3-acetylthioheptanoic acid, [ C Y ] ~-7.2 ~ D (c, 6.91; CH30H), yielded (-)-a(17) L. . 4 Underkofler a n d D. K Rov, r e v e a l Chem , 28, 18 (1951) lipoic acid, m p . 45.5-47.5" (micro-block) ; [ C Y ] ~ ~ D - 1 1 3 O (C, 1.88; C&j); 333 mp (E 140). DIVISIONOF BIOCHEMISTRY NOYES LABORATORY O F CHEMIsTRY JOSEPH LARNER Found: C, 46.65; H, 6.66; S,31.32; mol. wt. UXIVERSITYOF ILLINOIS C. M. MCNICKLE (ebull.), 312 f 3 ; neut. equiv. 208. n'hen equal URRAXA, ILLIKOIS amounts of (+)- and (-)-a-lipoic acid were mixed RECEIVED JULY 26, 1951 and recrystallized from cyclohexane, the racemic compound, DL-a-lipOiC acid, m.p. 60-61 (rnicroTHE SYNTHESIS OF (+)-Lu-LIPOIC ACID AND ITS block), was obtained. OPTICAL ANTIPODE In the enzymatic POF the activity of Sir: synthetic (+)-a-lipoic acid was double that of The racemic form of a compound active as a co- DL-a-lipoic acid. The activity of (-)-a-lipoic acid enzyme in the oxidative decarboxylation of pyru- was essentially zero, ca. 1% that of DL-a-lipoic acid. vate has been synthesized.',? This racemate has The properties listed above substantiate the idenbeen designated DL-a-liPOiC acid' and 6-thioctic tity of our synthetic (+)-a-lipoic acid and the natThis lends additional supacid.* The synthesis of the naturally occurring ural a-lipoic a~id.5,~.7 biologically active isomer, (+)-a-lipoic acid, has port to the structural conclusions advanced5l6prenot been reported. \$'e wish to report a new synthe- viously. sis which has made possible the preparation of (+)-, (4) I. C. Gunsalus, h3. I. D o h a n d L. Struglia, J. B i d . Chem., 194, 849 (1952). (- ) - and DL-a-lipoic acid. 5 ) L. J. Reed, I. C . Gunsalus, G. H. F. Schnakenberg, Q. F. Soper, The addition of thioacetic acid to 7-carboethoxy- H.( E. Boaz, S . F. Kern and T. V. Parke, TRISJ O U R N A L , 75,1267 (1953). 2-heptenoic acid (I) yielded 7-carboethoxy-3-ace(6) E. L. Patterson, J. V. Pierce, E. L. R. Stokstad, C . E. Hoffmann, tylthioheptanoic acid (11) which was converted to J. -4.Brockman, Jr., F. P. Day, hf. E. RIaccbi a n d T.H . Jukcs. ibid., 7-carboethoxy-3-acetylthioheptanoyl chloride (111). 76, 1823 (1954). (7) h.1. Calvin and J. .4.Barltrop, ibid.,74, 6153 (1952). The reduction of I11 with sodium borohydride LABORATORIES EDWARD WALTON yielded a mixture of ethyl 6-acetylthio-&hydroxy- RESEARCH CHEMICAL DIVISIOX ARTHURF. WAGNER octanoate (IV) and ethyl 6-thiol-8-hydroxyoctano-MERCK & Co., INC. LOUISH. PETERSON ate (V). The mixture was converted by alkaline RAHWAY, SEW JERSEY FREDERICK W.HOLLY hydrolysis to 6-thiol-8-hydroxyoctanoic acid (VI), KARLFOLKERS RECEIVED JULY 23, 1954 ?Z?~.'D1.4989. Iodine oxidation of VI produced bisr3- (l-hydroxy-7-carboxyheptyl)] disulfide (VII). The introduction of the thiol group into the S-posiREACTIONS IN THE CYCLOHEXtion of both VI and VI1 was carried out by refluxing E2 ELIMINATION ANE AND CYCLOPENTANE SERIES' with thiourea in aqueous hydrobromic acid followed by alkaline hydrolysis. Following the intro- S i r : -4 study of base-catalyzed E2 elimination reacduction of sulfur into VII, the product was reduced p-toluwith sodium borohydride and reoxidized to yield tions of trans-2-(p-tolylsulfonyl)-cyclohexyl DLa-lipoic acid (VIII), m.p. 59.5-61.0O (micro- enesulfonate (I),its cis isomer (11))the correspondblock); 333 m p (E 150); anai. Calcd. for C R H I ~ O(206.2): ~S~ C, 46.60; H, 6.84; S, 31.05. Found: C, 46.90; H , 6.91; S, 31.34; mol. wt. (ebull.), 212 f 7 ; neut. equiv., 206. For the preparation of (+)- and (-)-a-lipoic acid acid, DL-7-carboethoxy-3-acetylthioheptanoic I3 SOAC7Hi S02C7H7 (11) was resolved. Treatment of I1 with I-ephedrine 1 yielded the crystalline salt of the levorotatory form, m p . 130.0-134.5'. The dextrorotatory iso- ing trans and cis isomers (111 and IV) in the cyclomer was isolated from the residue by precipitation pentane series, and an open-chain analog, 1-(+ in the form of its benzhydrylamine salt, m.p. 92- tolylsulfony1)-2-propyl p-toluenesulfonate, C7H7SO~CH~CH(OTS)CHQ (V), with trimethylamine, 96". (+)-7-Carboethoxy-3-acetylthioheptanoicacid, triethylamine and hydroxide ion has revealed the information reported below. (1) C. S. Hornberger, Jr., R. F. Heitmiller, I. C. Gunsalus, G. H . F. (1) Each of these reactions gives an a,p-unsatuSchnakenberg a n d L. J . Reed, THISJOURAAL, 76, 1273 (1953). rated sulfone. For I and I11 this corresponds to ( 2 ) Xl. W. Bullock, J . A. Brockman, Jr., E. L. Patterson, J. V. Pierce, 31. H. von Saltza. F. Sanders a n d E. L. R. Stokstad, ibid., 76, 1828 elimination of a hydrogen cis to the tosylate group [19.54). in preference to a hydrogen trans to the tosylate ( 3 ) G. B. Brown, hl. D. Armstrong, A . U'. hloyer, IT'. P. Anslow, J r . , B. R . Baker, RI. V Qurrry, S . Bernstein a n d S . R . Snfir, J . Org. C / w n . l,a , 160 (1947).
+
(1) This investigation was supported by the Office of Naval Kesearrh under Contract h-o. N7unr-45007.
