1142 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
The results showed the 1,4-diazabicyclo[2.2.l]heptane structure proposed by Pettite2S3 Two cycles of isotropic least squares for all atoms reduced the R factor to 18% and one cycle of full-matrix anisotropic least squares gave an R value of 14.6%.
NEWCOMPOUNDS
Bond distances and angles are given in Figure 1 (a second set of data taken with Ni-filtered Cu radiation gave an R factor of 13.1% after one c*yclc of anisotropic least squares). h list of atomic coordinates for this structure is given in Table I.
New Compounds Synthesis of Enantiomeric Chloroacetylcarnitine Chlorides RAVINDRA C. V~s.4v.mI AND JOSEPH G. TURCOTTE*
Department of Medicinal Chemistry, College of Pharmacy, Unzverszty of Rhode Island, Kingston, Rhode Island 02881 Received N a y 1, 1971
Convincing experimental evidence exists for the role of (R)-(- )-carnitine in enzyme-mediated transport of
activated acyl groups across mitochondrial and possibly other membranes.'-6 Further, the structural similarit,y of carnitine (1) arid acetylcarnitine (2) to choline and acetylcholine, respect'ively, t'he possible biotransformaand the use of 1 in tion of 1 and 2 to p-methyl~holjne,~ the clinic,s point to possible therapeutic potentialg and/ or pharmacologic utility of these types of biological molecules or related derivatives. We report a convenient synthesis of (22)-( -)-, (A')-(+)-, and racemic chloroacetylcarnitine chlorides (3),lo which have been investigated for cholinergic activity,'"I3 and in tissue culture. l 4 (CH3)3N+CH&HO-X
I
CHzCOO-
l,X = H 2 , X = COCH, 3, HCI, S = COCHrCl ..
. . -. ._
(1) G . Wolf, Ed., "Recent Research on Carnitine," hI.1.T. Press, Cambridge, Mass., 1965, P a r t s I 1 and 111, and ref cited therein. (2) I . 13. Fritz and N . R. Marquis, Proc. .Vat. i l c a d . Sci. [.. S . , 64, 1226 (1965). ( 3 ) I-ield,18 mp 179". Anal. C, R, N, C1.
+
Acknowledgment.-The authors wish to express their appreciation t'o Drs. Glen A. Fischer and MingYu Chu, Department of 1\ledicine, Roger Williams General Hospital, Providence, R . Is., for testing these compounds in tissue culture. (16) (R)-(-)-Carnitine chloride, [ a l Z 2-21.7'' ~ (1it.l' -23.7"), (s)-(+)carnitine chloride, [a]*2n +23.1° (lit.l7 +23.6'), and (8s)-carnitine chloride Tvere obtd from Xutritional Biochemicals Co., Cleveland, Ohio 44128. ( R ) ( - ) - 3 , (S)-(+)-S, and ( R S ) - 3 were prepd using t h e same method and only details of t h e synthesis of ( R ) - (-1-3 are given. Optically active precursors and products were found t o be extremely hygroscopic, and i t was necessary to use anhyd p-TsOH as catalyst and t o scrupulously exclude moisture in order t o obtain cryst products-operations requiring moisture-free conditions were carried out in a Labconco controlled a t m glove box. T h e ir and p m r spectra of each compd were consistent n-itli t h e expected structure and are reported for (I?)-( -)-3. Melting points were detd with a Thomas-Hoover r n i - M e l t capillary melting point apparatus and are uncorrected. Where analyses are indicated only by t h e ss-rnhols of the elements, anal. results obtained for those elements were within =t0.4Y0of the theor values: analyses 1)y Xicro-i\nalysis, Inc., Msraliallton. Wilmington, Del. (17) G. K a t 0 and E. ,\. Hosein. C a n . .I. Chem., 47, 1177 (1969). (18) Yields by this method approach those reported19 using three different methods designed t o improve yields of 0-acylation of (RS)-carnitine chloride. (19) H. J. Ziegler, P , Druckner. and F. ninon, , I . Org. Chem., 32, 3989 (1967). .
~
~~~~
.
3-Amino-4-hydroxy-~(-)-butyramide Hydrochloride JOHX
C. KI:RDSZ'II:SY, JR., ARTHURJ. ZAMBITO,* .INI) I?OBERT I). BARSON
Merck Sharp & Dohme Research Laboratories, Co., Inc., Rahway, New Jerseu 07066 Division of M e r c k Rereii~etl .4pril 16, 1971
I n the current investigation of compounds related to asparagine for antitumor nctivity, 3-amino-4-hydrox~~(1) This investigation \vas supported b y Contract PH43-62-4i9 with Chemotherapy, National Cancer Institute, National Institutes of Health.
