Modi®ed Pictet±Spengler reaction. A highly diastereoselective approach to 1,2,3-trisubstituted-1,2,3,4-tetrahydro-b-carbolines using perhydro-1,3-heterocycles Kamaljit Singh, a,p Prasant K. Deb a and P. Venugopalan b a Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143-005, India b Department of Chemistry, Panjab University, Chandigarh, India Dedicated to the loving memory of the late) Maninder Kaur Chawla Received 26 March 2001; revised 21 June 2001; accepted 19 July 2001 Abstract ÐA¯exiblevariantofthePictet±Spenglerreactionemployingoxazinanesassyntheticequivalentsofseveralcarbonylcompounds has been developed. Using acid catalyzed one pot condensation of perhydro-1,3-heterocycles various 1,3-disubstituted and 1,2,3-trisubsti- tuted-1,2,3,4-tetrahydro-b-carbolines THBCs) have been synthesized diastereoselectively. q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The interest in the synthesis of indole alkaloids stems from their intricate cyclic frame-work and diverse medicinal properties such as anti-tumor 1 and cardiovascular effects. 2 Many 1,2,3-trisubstituted-1,2,3,4-tetrahydro-b-carbolines THBC) alkaloids 2,3 in their skeleton embody l-tryptophan unit pointing to its use in their synthesis as an enantio- merically pure starting material for control of the stereo- chemistry at C-1 and C-3 in the Pictet±Spengler reaction withaldehydes,whichhaslongbeeninuseforthesynthesis of THBCs and other related systems. 4 Out of a variety of reaction conditions employed, the use of non-acidic aprotic media becomes more obvious when acid-labile aldehydes are used, 5 and aqueous-acidic conditions 6 result in con- siderably lower yields of the THBCs in comparison to non-acidic or acidic±aprotic reaction conditions. 7±10 A few variant approaches involving combinatorial chemistry, 11 solid phase synthesis, 12 and alternatives for aldehydes such as conjugated alkynoates, 13 azalactones, 14 D 1 -piperidines, 15 acetals, 16 active methylene compounds 17 etc. have also appeared. Most of these methods exhibit good to excellent asymmetric control 10b,18 and several elegant routes leading to enantioselective and/or diastereo- selective preparation of the title compounds using chiral auxiliaries such as carbohydrates, 19 amino acid esters, 20 R) and S)- glyceraldehydes, 21 2)-8-phenylmethylcarba- mates, 22 chiral acetylenic sulfoxides 23 or chemoselective and asymmetric reductions of corresponding dihydro b-carbolines 24 etc have also been developed. Wehaveforquitesometimebeenengagedindevelopingan alternate synthetic strategy using the `Folate model approach', 25 wherein variously C-2 substituted perhydro 1,3-heterocycles have been convincingly employed 26 as carbonyl equivalents for obtaining a variety of useful synthetic targets through a single pot, acid catalyzed C-2 unit transfer reaction of these reagents to various nucleo- philes, thus avoiding the direct use of aldehydes. Owing to the ease in synthesis, proven carbonyl resource and ef®cacious elaboration at C-2 of oxazinanes 27 and oxazoli- dines, 28 a conspicuous merit of these reactions has been diversi®cation of the transferred carbon unitÐan attribute of potential utility in the synthesis of lead compounds for a variety of pharmacologically interesting 26d,e events. Herein we report on the synthetic usefulness of this modi®ed Pictet±Spengler reaction, 26a wherein stable oxazinanes and oxazolidines are reacted with l-tryptophan derivatives to obtain the title compounds diastereoselectively as in the conventional Pictet±Spengler reaction. 4,5a,10,29 2. Results and discussion 2.1. Synthesis of oxazinanes and oxazolidines Oxazinanes 1a ± e and g used in this study are obtained by condensing g-hydroxypropyl amine with aldehydes and 1f, h ± m were synthesized through borohydride reductions of correspondingly 2-substituted-4,4,6-trimethyl-5,6-dihydro- 4H)-1,3-oxazines 2a ± f obtained by condensation of Tetrahedron 57 2001) 7939±7949 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-402001)00763-3 Keywords: oxazinane; oxazolidine; tetrahydro-b-carboline; Pictet± Spengler reaction; diastereoselectivity; carbonyl equivalent. p Corresponding author. Tel.: 191-0183-258853; fax: 191-0183-258819/ 20; e-mail: kamal_deb@yahoo.com