Tetmhcdron Lmers. Vol. 33, No. 33, pp. 4721-4724.1992 hinted in Great Britain 0040~4039,92 $5.00 + .tl Pergamon Press Ltd MECHANISM DRIVEN TRANS STEREOSPECIFICITY IN THE PICTET-SPENGLER REACTION. STEREOSPECIFIC FORMATION OF TRANS-1,2,3-TRISUBSTITUTED--RO p- CARBOLINES BY CONDENSATION OF Nb-DIPHENYLMETHYL TRYPTOPHAN ISOPROPYL ESTERS WITH ALDEHYDES Kevin M. Czerwinski, Li Deng and James M. Cook* Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201 USA Summary: Stereoelectronic control in the Pictet- Spengler condensation of Nb-alkylsubstituted tryptophan alkyl esters has been employed to promote 100% stereoselectivity in this process. The reaction of Nb- dipheny lmethy l tryptophan isopropyl ester 8 with acetaidehyde in benzene at refIux y ielded the trans- diastereomer 1Od to the complete exclusion of the corresponding cis isomer. This trans stereospecificity was also observed for butyraldehyde and cy clohexy lcarboxaldehy de. The Pictet-Spengler condensation has served as an important ring forming reaction in the synthesis of indole alkaloids for many years. 1,2 More recently it has been employed to prepare alkaloids of important pharmacological significance including P-carboline-3-alkyl esters,3 canthin-&ones,4 eudistomins,5 and fumertrimorgens.6 as well as permitting entry into new ring systems.7 In keeping with our interest in controlling the chirality in the Pictet-Spengler reaction for the enantiospecific synthesis of indole alkaloids,8 new results were recently reported which indicated that attack on intermediate 1 Figure 1 &?$t &!!J:o $jj$it Figu$q.I.I ri H’ 4 1 I’ Ii I’ 4 2 b tram spiroindolenine cis spiroindolenine intermediate intermediate (Figure 1) was favored over attack via 2. This resulted in trans stereospecificity in the condensation when benzaldehyde was employed and was shown to increase in the case of butyraldehyde when the methyl ester function in 1 was replaced with an isopropyl ester group.9 Presumably, the steric interactions between the imine substituent in 1 and the ester functions not only favors the intermediacy of the E isomer (1) over the Z isomer (2, not favored) during the cyclization but facilitate attack from the face opposite the ester group.9 This is also consonant with the trans stereospecificity observed in the cyclization of 1 rather than conversion of 2 into the cis diastereomer; the latter is not favored in the case of Nb-benzyl tryptophan alkyl esters.10 It is clear that the size of the ester substituent in the tryptophan alkyl ester and of the aldehyde influences the however, until carboline with trans stereospecificity when Nb-benzyl tryptophans are involved in the cyclization;9 now the Pictet-Spengler reaction had never provided the 1,3_disubstituted tetrahydro-p- 100% stereoselectivity when acetaldehyde was employed as the substrate. Examination 4721