A Short, Stereocontrolled Synthesis of (—)-Detoxinine

Abstrsct -An improved synthesis of (-)-detoxinine is described. ... In 1968, s group of antagonists were found to negate the toxic eida effects of blasticidin S agsinet Be&L1?!s-c_8_r~g& This group of antasonista, termed the detoxin complex, was produced by the organism S t r e p b g c ~s caes~itosus vsr.d .& s & 7072 GCI.The complex contained several components of varying detoxifying activity.Bhsticidin S inhibits the virulent fungus Piriculuria og.-which causes rice blast disease in Japan.'The curative effect of blasticidin S --on rice plant-required dosages which also caused phytotoxicity.This phytotoxicity was greatly reduoed when the detoxin complex was administered with blesticidin S, without diminishing the effectiveness of the drug against Piriculuria oryz*.Degradation of detoxin Dz &forded the amino acida L-vsline, L-phenylalanine and the previouely unknown debxinine (l).'A detoxinine All detoxins contain detoxinine, except dahxins BI and Ba whrch lack the 3-hydroxyl group in the proline ring.Detoxine B, and B a have been previously synthesieed in our laboratory.6Debxinine possesses several unusual structural features.Known hydraxylated amino acide may be divided into two categories.There are Shydroxy-a-amino scida such a s BMT," h~droxyhomotyrosine,' or hydroxymethylproline,~ in which the hydmxyl group is contained in the side chain.The other category contains such amino acids as slatine,.dohiaoleuine,g or d o l a ~r o i n e , ~ in which the urrboxylic acid group is r e p k e d by a 8-hydrory acid unit.The amino acid detoxinine wntaina both of these structural features.The synthesis of de4Axinine hae been reported by our groupro a s well se by other investigators."J'Our original synthesim" represented the shortest route to this molecule.This synthesis, however, had some shortfomings in that the proline ring syetem was racsmic and required rssolution & an eldol condensation employing a ohiral snolate.Herein, we report the ensntioselective synthesis of the pyrrolidine moiety, end the stereocontrolled eyntheais of (-1detoxinine.The aynthesis begins with D-serine as the source of chirality (Scheme 1).Scheme 1 b -87% BocNH 0SiMe2tBu 41% BocNH OSiMe,tBu a 99% 0 OSiMe,tBu Boc Boc ( 3 ) ( 4 ) OSiMe,tBu 0SiMe2tBu C -6 d 74% Boc Boc (5) ( 6 ) a. 1. tBUMezSiCi, DMF, imldazole, 2. K,CO,; b. 1. lsopropenyl chloroformate, DMAP, Meldrum's add, 2. EtOAc, reflux, 3. NaBH,, AcOH, CH,CI,; c. BHiSMe,, THF, reflux; d