Efficient Biomimetic Synthesis of Indole Alkaloids of the Vallesiachotamine Group by a Domino Knoevenagel Hetero Diels‐Alder Hydrogenation Sequence

Abstract

An efficient three-step biomimetic synthesis of the four di-spectively, in 74-86% yield, hydrogenation of which gives astereomeric 18,19-dihydroantirhines 4a-d starting from the mainly 15 and 16 with the skeleton of the vallesiachotamine tetrahydrocarboline aldehydes 5a and 5b is described. Do-indole alkaloids (55-86%). In addition, small amounts of 17 mino reaction of the aldehydes 5a and 5b, respectively, with and 18 with the corynanthe skeleton are also formed Meldrum's acid (6) and the enol ethers 8a and 8b in the pres-(10-12%). Reduction of both 15 and 16 with LiAlH, yields ence of catalytic amounts of ethylenediammonium diacetate the diastereomeric rac-l8,19-dihydroantirhines 4a-d in leads to the strictosidine analogues lOa-d and l l a -h , re-78-86'30 yield.In the biosynthesis['l of the over 2000 monoterpenoid indole alkaloids, strictosidine (1 a), formed from secologanin[*] and tryptamine under catalysis by the enzyme strictosidine synthetase"], is the key intermediate. Enzymatic glycoly~is[~] of strictosidine 1 a provides the highly reactive aglucon lb, which reacts in vivo via its open dialdehyde form either by an N-4/C-17 cyclization to the give indole alkaloids of the vallesiachotamine (2) group, or alternatively by a competitive N-4/C-2 1 cyclization with formation of indole alkaloids of the corynanthe group, e.g. geissoschizine. Interestingly, the in vitro treatment of strictosidine 1 a with emulsine (P-glucosidase) gives almost exclusively vallesiachotamine (2) as the thermodynamically more stable product ['].

Meldrum's Acid in Multicomponent Reactions: Applications to Combinatorial and Diversity‐Oriented Synthesis

“…Removal of the Boc-group, condensation with methyl formate, and methylation of the corresponding enol resulted in hirsutine 8 (Scheme 2) [9]. The synthesis of (þ)-dihydrocorinantheine 9 [10], the 3-epimer of hirsutine 8, followed a route similar to the synthesis of hirsutine 8, albeit with a lower diastereoselectivity [11].…”

Multicomponent domino reactions for the synthesis of biologically active natural products and drugs

“…The obtained product contains about 10% of the 20-epimer (Scheme 16). 15 Scheme 14. Synthesis of (À)-hirsutine 22.…”

Domino reactions in the synthesis of heterocyclic natural products and analogs

“…Here, the secondary amine in ent-22 after deprotection by hydrogenolysis attacks the lactone moiety to form 25 containing a lactam and an aldehyde moiety. Reduction of 25 with lithium aluminum hydride group led to the indole alkaloid (−)-dihydroantirhin 26 [13]; the obtained product contains about 10 % of the 20-epimer (Scheme 8) [14].…”