in experimental animals. Preliminary pharmacological res~llts have been described (1)and a fill1 paper is in preparation. In this report we describe the synthesis a n d stereochemistry of taclamine hydrochloride.T h e synthesis of taclamine.HC1 1 has been accomplislied through two independent pathways (see Scheme I). In the first, 10,1 I-dihydro-(2) (2) was condensed with 8-valerolactone t o give the hydroxyamide 3, which o n treatment with p h o s p h o r o~~s oxychloride undergoes a double cyclization to afford the pentacyclic pyridoisoquinolini~~m salt 4. R e d~~c t i o n of 4 with hydrogen and platinum, or, with sodium borohydride generates the 4a,13b-cis isomer of taclamine~free base which was converted to the hydrochloride salt 5. O n the other hand, reduction of 4 with zinc and hydrochloric acid affords predominately the 4a, l3b-trans isomer, 1. (See disc~lssion of stereochemistry below.) T h e isomeric nature of the two reduction products was confirmed by the oxidation of each, with 'Nonproprietary name selected by the U.S. Adopted Names Council. This compound has also been designated AY-22,214. (3). A mixt~lre o f the 4a,l3b-trar~s-and 4a, I3b-cis-pentacyclic aniino ketones 7 a and 80, respectively, were formed in a ratio of 6 : 1. The m i x t~~r e was readily separated into its components by column chromatography and the amino ketones 7 a and 8a were converted t o 1 and 5, respectively, through desulfi~rization of the corresponding ethylenethioketal derivatives, 76 and 86. T h e pure ethylenethioketal derivatives, 76 and 86 were also obtained by column chromatographic separation o f the m i x t~~r e o f 76 and 86 obtained by direct treatment of t h e amino ketone mixt~lre (7a a n d 8a) with ethaneditliiol and boron trifluoride etherate.Configurational assignments at the 4a and 13b centers o f 1 and 5 were made by interpretation of their n.m.r. spectra a n d , independently, by a consideration of the stereochemical controls operative in the reductions of the iminium salt 4. Thus, the isomer 5 obtained via catalytic hydrogenation of 4 is assigned a 4a,13b-cis relative configuration since examination of molecular models shows that the substrate for reduction, 4, contains an iminium center, which causes rings C, D, a n d E t o be virtually coplanar while the phenyl ring A is located on the cr-side at the Can. J. Chem. Downloaded from www.nrcresearchpress.com by 54.202.233.140 on 05/12/18For personal use only.
