474'3 COMMUNICATIONS TO TIIE EDITOR I T d . 76

other sources. Oligo-1,G-glucosidase differs from R-enzyme (plants) in that the latter does not hy- drolyze 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 de- scribed17 which would seem to have an activity similar to oligo-1,6-glucosidase on "branched" oligo- saccharides.

(17) L. .4 Underkofler a n d D. K Rov, r e v e a l Chem , 28, 18 (1951)

DIVISION OF BIOCHEMISTRY NOYES LABORATORY O F CHEMIsTRY UXIVERSITY OF ILLINOIS URRAXA, ILLIKOIS

JOSEPH LARNER C. M. MCNICKLE

RECEIVED JULY 26, 1951

THE SYNTHESIS OF (+)-Lu-LIPOIC ACID AND ITS OPTICAL ANTIPODE

Sir: The racemic form of a compound active as a co-

enzyme in the oxidative decarboxylation of pyru- vate has been synthesized.',? This racemate has been designated DL-a-liPOiC acid' and 6-thioctic acid.* The synthesis of the naturally occurring biologically active isomer, (+)-a-lipoic acid, has not been reported. \$'e wish to report a new synthe- sis which has made possible the preparation of (+)-, (- ) - and DL-a-lipoic acid.

The addition of thioacetic acid to 7-carboethoxy- 2-heptenoic acid (I) yielded 7-carboethoxy-3-ace- tylthioheptanoic acid (11) which was converted to 7-carboethoxy-3-acetylthioheptanoyl chloride (111). The reduction of I11 with sodium borohydride yielded a mixture of ethyl 6-acetylthio-&hydroxy- octanoate (IV) and ethyl 6-thiol-8-hydroxyoctano- ate (V). The mixture was converted by alkaline hydrolysis to 6-thiol-8-hydroxyoctanoic acid (VI), ?Z?~. 'D 1.4989. Iodine oxidation of VI produced bis- r3- (l-hydroxy-7-carboxyheptyl)] disulfide (VII) . The introduction of the thiol group into the S-posi- tion of both VI and VI1 was carried out by refluxing with thiourea in aqueous hydrobromic acid fol- lowed by alkaline hydrolysis. Following the intro- duction of sulfur into VII, the product was reduced with sodium borohydride and reoxidized to yield DLa-lipoic acid (VIII), m.p. 59.5-61.0O (micro- block); 333 m p (E 150); anai. Calcd. for

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, DL-7-carboethoxy-3-acetylthioheptanoic acid (11) was resolved. Treatment of I1 with I-ephedrine yielded the crystalline salt of the levorotatory form, m p . 130.0-134.5'. The dextrorotatory iso- mer was isolated from the residue by precipitation in the form of its benzhydrylamine salt, m.p. 92- 96".

(+ )-7-Carboethoxy-3-acetylthioheptanoic acid,

C R H I ~ O ~ S ~ (206.2): C, 46.60; H, 6.84; S, 31.05.

(1) C. S. Hornberger, Jr., R. F. Heitmiller, I. C. Gunsalus, G. H . F. Schnakenberg and L. J . Reed, THIS JOURAAL, 76, 1273 (1953).

( 2 ) Xl . W. Bullock, J . A. Brockman, Jr . , E. L. Patterson, J. V. Pierce, 31. H. von Saltza. F. Sanders and E. L. R. Stokstad, ibid., 76, 1828 [19.54).

( 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 /wn., l a , 160 (1947).

[aIz4D 4- 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

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 ] ~ ~ D -7.2 (c, 6.91; CH30H), yielded (-)-a- lipoic acid, m p . 45.5-47.5" (micro-block) ; [ C Y ] ~ ~ D

Found: C, 46.65; H, 6.66; S, 31.32; mol. wt. (ebull.), 312 f 3 ; neut. equiv. 208. n'hen equal amounts of (+)- and (-)-a-lipoic acid were mixed and recrystallized from cyclohexane, the racemic compound, DL-a-lipOiC acid, m.p. 60-61 (rnicro- block), was obtained.

the activity of synthetic (+)-a-lipoic acid was double that of DL-a-lipoic acid. The activity of (-)-a-lipoic acid was essentially zero, ca. 1% that of DL-a-lipoic acid. The properties listed above substantiate the iden- tity of our synthetic (+)-a-lipoic acid and the nat- ural a-lipoic a~id.5,~.7 This lends additional sup- port to the structural conclusions advanced5l6 pre- viously.

C8H1402S2 (206.2): C, 46.60; H, 6

- 1 1 3 O (C, 1.88; C&j); 333 mp (E 140).

In the enzymatic POF

(4) I. C. Gunsalus, h3. I. D o h and L. Struglia, J. B i d . Chem., 194, 849 (1952).

( 5 ) L. J. Reed, I. C. Gunsalus, G. H. F. Schnakenberg, Q. F. Soper, H. E. Boaz, S . F. Kern and T. V. Parke, TRIS JOURNAL, 75,1267 (1953).

(6) E. L. Patterson, J. V. Pierce, E. L. R. Stokstad, C. E. Hoffmann, J. -4. Brockman, Jr., F. P. Day, hf. E. RIaccbi a n d T. H . Jukcs. ibid., 76, 1823 (1954).

(7) h.1. Calvin and J. .4. Barltrop, ibid., 74, 6153 (1952).

RESEARCH LABORATORIES EDWARD WALTON CHEMICAL DIVISIOX ARTHUR F. WAGNER MERCK & Co., INC. LOUIS H. PETERSON RAHWAY, SEW JERSEY FREDERICK W. HOLLY

KARL FOLKERS RECEIVED JULY 23, 1954

E2 ELIMINATION REACTIONS IN THE CYCLOHEX- ANE AND CYCLOPENTANE SERIES'

S i r : -4 study of base-catalyzed E2 elimination reac-

tions of trans-2-(p-tolylsulfonyl)-cyclohexyl p-tolu- enesulfonate (I), its cis isomer (11)) the correspond-

I3 SOAC7Hi S02C7H7 1

ing trans and cis isomers (111 and IV) in the cyclo- pentane series, and an open-chain analog, 1-(+ tolylsulfony1)-2-propyl p-toluenesulfonate, C7H7- SO~CH~CH(OTS)CHQ (V), with trimethylamine, triethylamine and hydroxide ion has revealed the information reported below.

(1) Each of these reactions gives an a,p-unsatu- rated sulfone. For I and I11 this corresponds to elimination of a hydrogen cis to the tosylate group in preference to a hydrogen trans to the tosylate

(1) This investigation was supported by the Office of Naval Ke- searrh under Contract h-o. N7unr-45007.