COMMUNICATIONS TO THE EDITOR
May 20, 1956
clization are accomplished together in one step and substituted P-naphthols or 4-hydroxy-2-tetralones are isolated.
'(CHz),
' 7 0Y
- HzO> CHiO\ /
cH30\,/J/)//0
p) '(CHz),
I
\/OH
CH30/\
'(CHz),
2341
294 and 340, mp; log E 4.80, 3.57 and 4.00, respectively) and of I11 ( n = 2)"::A:( 235, 291 and 345 mp; log E 4.84, 3.56 and 4.02, respectively) again were typical of naphthalene derivatives. Trihydrogenation of hydroxy ketones I11 ( n = 1 and 2) in the presence of palladium-charcoal in ethyl acetate a t 80" gave diols IV ( n = l ) ,m.p. 171-173" (Anal. Calcd. for C18H2604: C, 70.56; H, 8.55. Found: C, 70.50; H I 8.23) and IV ( n = 2), m.p. 142-144' (Anal. Calcd. for C19H&: c , 71.22; H I 8.81. Found: C, 71.44; H, 8.75), respectively. The infrared spectra of compounds IV ( n = 1 and 2) each had a doublet a t 2.76-2.98 y , and their ultraviolet spectra had A E:" 288 my (log E 3.34) and A=": 291 mp (log e 3.43), respectively. HO COCHI
i
CH3
\ / CH
I1
A mixture of homoveratric anhydride,6 cyclohexanone and boron trifluoride etherate was al1 i lowed to stand for three days, and the boron comIV '(CHZ), plex was decomposed with sodium acetate solution. The synthesis permits variation of the size of Compound I ( n = l), m.p. 140-141" (Anal. Calcd. for CleH2004: C, 69.54; H I 7.30. Found: C, 69.55; ring C and thus will be useful in getting compounds H, 7.34), showing infrared absorption a t 2.8-2.9 related to colchicine7as well as new phenanthrenes. (7) H. Rapoport, e l a l . , THISJOURNAL, 79, 1414 (1951); 77, 670 and 5.79-5.8.5 1.1, was isolated in 68% yield. Dehydration by brief treatment with polyphosphoric (1955). OF CHEMISTRY OF ~YATURAL PRODUCTS acid gave I1 ( n = l ) , m.p. 219-221" (Anal. Calcd. LABORATORY HEARTINSTITUTE for Cl6HI8O3: C, 74.40; H , 7.02. Found: C, KATIONAL ~VATIONAL INSTITUTES OF HEALTH GORDON N.WALKER 74.50; H, 7.09). Similar condensation of homo- DEPARTMENT OF HEALTH, EDUCATION A N D WELFARE veratric anhydride with cycloheptanone gave I1 BETHESDA14, MARYLAND ( n = 2) directly (29%), m.p. 207-208" (Anal. RECEIVED APRIL 2 , 1956 Calcd. for C17H2003: C, 74.97; H I 7.40. Found: C, 74.93; H I 7.45). The infrared spectra of comTHE CONFIGURATION OF (+)-a-LIPOIC ACID pounds I1 each showed a band a t 2.76 y. The Sir: ultraviolet spectra of I1 ( n = 1)": :A( 237, 272, The synthesis of naturally occurring (+)-a282, 293, 322 and 336 mp; log E 4.86, 3.60, 3.59, 3.46, 3.59 and 3.72, respectively) and of I1 (n = 2) lipoic acid' has recently been described.2 We wish on the elucidation of its stereochemistry. (AFZ" 237, 274, 285, 296, 324 and 337 my; log E to (report ) -3-Acetylthio-7-carbethoxyheptanoic acid 4.91, 3.61, 3.61, 3.49, 3.58, and 3.72, respectively) were typical of naphthalene derivatives. O-Ace- (Ia)*e3was treated with cold 10% sodium hydroxide tates of I1 (n = l ) ,m.p. 170-171" (Anal. Calcd. for to give 3-thioloctanedioic acid (IIa), m.p. 114.5C18H2004:C, 71.95; H I 6.71. Found: C, 72.03; H, 115.5", [CU]~'D-7.9" (c 3.4, pyridine); calcd. for 6.69) and of I1 ( n = 2), m.p. 139-141" (Anal. CsH1404S: C, 46.G; HI 6.8; SI 15.6; found: C, Calcd. for C19H2204: C, 72.59; H, 7.06. Found: 46.6; H , 6.6; S, 15.4. Similarly (-)-3-acetylC, 72.84; H, 7.06) had similar ultraviolet spectra thio-7-carbethoxyheptanoic acid (Ib)2*3gave 3and absorbed light a t 5.70 J.L in the infrared region. thioloctanedioic acid (IIb), 1n.p. 115-116°, [ c t ] * ' ~ When boron trifluoride in acetic acid was used in f 7 . 9 " (c2.5, pyridine), calcd. for CgH1404S: C, 46.6; condensation of homoveratric anhydride with cy- H I 6.8; S, 15.6; found, C, 46.8; H , 6.8; SI 15.4. Benzyl hydrogen glutarate was prepared from clohexanone and cycloheptanone, acetylation of the phenolic ring also occurred, probably through Fries glutaric anhydride, benzyl alcohol and pyridine, rearrangement of 0-acetates, giving I11 ( n = l ) , b.p. 153-155" (0.05 mm.), E z 5 D 1.5108; calcd. for imp. 167-168" (Anal. Found: C, 72.01; H, 6.75) C12H1404:C, 64.8; H, 6.4; neut. eq., 222; found: and I11 (n = 2), m.p. 157-158" (Anal. Found: C, 65.0; H, 6.1; neut. eq., 221. Anodic crossC, 72.64; H, 7.06) in yields of 3870 and 1170, re- coupling with (+) -methyl hydrogen ,&methyl(1) L. J. Reed, I. C . Gunsalus, G. H . F. Schnakenberg, Q. F. Soper, spectively. These yellow compounds gave characteristic ferric chloride tests and had infrared H. E. Boaz. S . F . Kern and T.V. Parke, THISJOURNAL,75, 1267 E. L. Patterson, J. V. Pierce, E. L. R . Stokstad, C. E. Hoffspectra similar to that of 1-hydroxy-2-acetonaph- (1053); mann. J. A. Brockman, Jr., F. P. Day, M. E. Macchi and T. H. Jukes. thone, with no hydroxyl or normal carbonyl peaks. ibid., 76, 1823 (1954). (2) E. Walton, A. F. Wagner, F. W. Bachelor, L. H. Peterson, F. W. ": :A( 234, The ultraviolet spectra of I11 (n = 1)
+
(6) Prepared by refluxing homoveratric acid with acetic anhydride in the presence of pyridine; m.p. 83-84O.
Holly and K. Folkers, ibid.. 77, 5144 (1055). (3) A sample was kindly supplied by Dr. F. BI. Robinson, Merck and
co.
fore Ia, have the same configuration. The coiifiguration of (+)-a-lipoic acid, which is prepared' from Ia, is hence correctly represented by V, arid that of ( - )-a-lipoic acid by VI. It is interesting to note t h a t aleprestic acid (( )-3-(2-cyclopenten-l-y1) -pentanoic acid), a chaulnioogra oil acid which differs from a-lipoic acid in having an ethylene function in place of the disulfide linkage, has the same configuration as T'.i
+
SCOCH::
/*\
S€I 1
/'\,
COOCzHj +
i
I
'\,,/
COOH CHa
1 1
I
COD11
(Iai
' 7 ) I;.3Iislorr and I . V, Steinberg, ibid., 77, 3807 (1933!, a n d ]>ul,lishedresults.
COOH (Ira)
CH.
,
/*\
ylOH
/\,
->
(1111
1111-
JVM. H. XICTTOLS CHEMICAL LABORATORY SEI\, YORKCSIVERSITY K G R T XfISI,O\l' ATE\!' Y O K K ,;:j, 1 ' .Y. \I-ILLIAM C. ~ZELCCH RECEIVED APRIL 3, 1936
(.IV) A NEW SYNTHETIC ANALGESIC
!~
Sir: COOCHi COOH COOH Efforts begun here some years ago had as their glutarate (III)a yielded benzyl 6-methyl-7-carbo- most stiiiiulating result the recognition of phenmethoxyheptanoate, b.p. 136-157" (0.23 mm.), ethyl as a potentiating group when substituted for v Z 5 D 1.4886,d2j41.046, [ c v ] ' ~ D f4.6" (c 6.7, pyridine); methyl on the nitrogen atom of certain analgesic calcd. for CliH,,OI: C, GO.(;; H,8.2; MD, SO.:'; compounds. Thus X-phenethylnormorphine' is fouiid: C , Kl.0; H, i . 9 ; M D S0.3. Catalytic hydro- eight times as putent as morphine though also genolysis over jr;. Pd,iC gal-e 6-methyl-/-carbo- inuch inore toxic.? This is a somewhat surprising niethoxyheptanoic acid, b .p. 141-1 43' (0.3mm.) ,n 2 5 ~ finding since heretofore all the evidence has sup1.4444, d"4 1.045,[ a I z 7f5.5" ~ (c 6.4,pyridine); ported the belief that the methyl radical is optimal calcd. for ClaHls04: C, 39.4; H, 9.0; XD 51.6; for the production of significant analgesic a c t i ~ n . ~ found: C, 39.9; H, S.0; MD 31.5. Saponification In fact diminished activity or even antagonism to yielded X-methyloctariedioic acid (II'), r1i.p. 07-9So, analgesia have been by far the iiiore frequent re[ o ] ? * D i- (5.9' (c 3.1, pyridine) ; calcd. for C~H1604: sults of modification of the methyl group on the C, 3 7 . 3 ; H, 8.6; found: C, 37.9; H , 8.3.The con- tertiary nitrogen of analgesic s ~ b s t a n c e s . ~How,~ figuration of I11 has been elucidated5; consequently ever, while S-substituents which on normorphine that of IT' is now established. produce antagonism frequently fail t o produce I t was found (Fig. I) that IT' and IIa form a. con- similar results when substituted for the K-methyl of tinuous series of solid solutions, while 11: and IIb vther types of analgesic agent, our studies arid those are immiscible in the solid state. These results of Perrine and Eddyi suggest that the beneficial permit the conclusion6 that 11: and Ila, and there- effect of phenethyl is more generally obtained. We 7 have found a,lsn that further substitution, now on the aromatic ring of the phenethyl radical, produces still further benefits. ;in extensive program based o i l these findings has led to selcctioii of ethyl 1-(4~rniiriopheneth~-lj-4-phe1~ylisonipecotate (I) most promising candidate for further study.
,.:,
-
92
'2 i ,
*, .~.
88
s4
-
--
L~. ~
~
.>--0, 3-o,o-c7. ,. L.
-1~ ~~-
.
0
10
20
.
30
40
~
0
50
&
-
_i
~
GO
~
70
,
. , ,
..
80
90
100
n-t.yo (+)-3-iiietliq-loctsnedioic acid. 1;ig. l,-MeItiiig poiiit-coinposition diagrams for the >)-stems ( !-3-meth~-loctariedioic acid-( )-3-thioloctanedioic acid (circles, dashed line), and (t)-3-1netliylocta1iedioic acid-( - )-a-thioloctaxledioic acid (triangles, solid line).
+
+
(4) R. P Linstead, J . C. Lunt a n d €3. C. 1- TVeedon. J Chrir!. 3333 (1960) ( 9 ) S S t a l l b e r g - s t e n h ~ ~ e.n , (101Rj.
\'OC,
as
;L
LThen 9-aniinophenethyl chloride hydrochloride6 was allowed to react with ethyl 4-phenylisonipecotate "carbonate"7 in alcohol with added sodium bicarbonate there was formed a base which could be precipitated from ether solution as a dihydrochlo$ 1 ) R . L. Clark, el al , THISJ O V R K A I , , 75, 4!10? (1953). ( 2 ) T v e are indebted t o Dr C . A . IVinter f o r this o h s c r v a t i o n . flcnilh (:3) 0. J . Braenden, S . B Eddy and H. I-Ialbach, A i ~ i l LVovlii Oii: , 13, R:37 ( 1 9 2 5 ) ; A. Rurger. l l e d i ' i n l l Cheiniilry, VoI I , p . 17'1 (19.51); 0. Schaumann, .lrcIz p x b Pnlizol Phnrmnhol , 196, 109 (I$i4(11 See. however, R . X Millar a n d R. P. Stephenson, J3,.ll J . P h n v r n n c d Ciierrrolherapy, 11, 27 ( 1 9 3 ) w h i c h appeared xfter subrnissiov of thls
communication. ( 4 ) 6 .Unna. J P h o ~ w ~ ~ c IoLl p. . Thri rip , 79, 27 (1943); A. 1'. Green, G E;. Ruffell and E. K'aIton, J Pitsii m i i c y owii P h a i n r i r c o l . . 6 , 390 (19.74) Sohc>tka, f b r , 62, 2 l ! J l I 1
