Determination of the Absolute Configuration of Cycloheximide

Determination of the Absolute Configuration of Cycloheximide

1048 Journal of Pharmaceutical Sciences Determination of the Absolute Configuration of Cycloheximide Sir: Cycloheximide, an antibiotic obtained from...

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1048

Journal of Pharmaceutical Sciences

Determination of the Absolute Configuration of Cycloheximide Sir: Cycloheximide, an antibiotic obtained from Streptomyces griseus, is of particular interest because of its antifungal and anticancer activity. Recently, the absolute configuration of the methyl group gamma to the keto group in cycloheximide (I) was determined by relating this center to D-glyceraldehyde using reactions which could not have caused an isomerization (1).

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Anal.-Calcd. for C15H25N02: C, 71.67; H, 10.0; N,5.57. Found: C,71.90; H,9.84; N, 5.76 Determination of the optical rotation of V gave [o]: -9.07’ (c = 6% in acetone). The observation that V is optically active establishes that the methyl groups are trans, since the corresponding compound with cis methyl groups would be meso due to its plane of symmetry.’ Therefore, the absolute configuration of both methyl groups of cycloheximide is correctly depicted in I. Similar conclusions have recently been obtained by a totally different procedure (3).

OH I

We have now determined the absolute configuration of the methyl group alpha to the keto group of cycloheximide by the following sequence: treatment of cycloheximide (I) with phosphorus pentoxide in benzene gave anhydrocycloheximide (11), which on hydrogenation with a platinum catalyst in acetic acid gave tetrahydroauhydrocycloheximide (111) (2). When tetrahydroanhydrocycloheximide (111) was allowed to react with thionyl chloride in dioxane solution, a good yield of the chloro compound (IV) was obtained (m.p. 136-138”). Ana2.-Calcd. for ClsH24C1N02: C, 63.03; H, 8.46; N, 4.90; C1, 12.40. Found: C, 63.29; H, 8.29; N, 5.05; C1, 12.14. Treatment of compound I V with zinc dust and acetic acid gave dideoxycycloheximide (V) (m.p. 135-136’).

I1

(1) Eisenbraun, E. J., Osiecki, J., and Djerassi. C., J . A m . Chem. Soc., 80, 1261(1958). (2) Kornfeld, E. C . , Jones, R. G., and Park, T. V., ibid., 71. i m i 9 4 9 ) .

?3) Lawe,; B. C ,Abstractsof the 139th meeting, American Chemical Society, St. Louis, Mo., March 1961, p. 33N.

HOWARD J. SCHAEFFER VIJAY K. JAIN Department of Medicinal Chemistry School of Pharmacy The University of Buffalo Buffalo, N. Y. Received October 11, 1961. Accepted for publication October 18, 1961. This investigation was supported by Research Grant C Y 4812 from the National Cancer Institute, National Institutes of Health, Public Health Service.

1 The fact that there was no change in configuration of the methyl groups in this reaction sequence and the description of other stereochemical interrelationships will be the subjects of a future paper.