Enantiospecific Total Synthesis of (−)-(E)16-Epiaffinisine, (+)-(E)16-Epinormacusine B, and (+)-Dehydro-16-epiaffinisine as well as the Stereocontrolled Total Synthesis of Alkaloid G

Abstract

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.

Recent advances in the chemistry of macroline, sarpagine and ajmaline-related indole alkaloids

“…Shortly after the reports summarised in Section 2.3.1, Cook's group published improved syntheses of (-)ajmaline 23 and alkaloid G. 23,24 The improvements address the issue of stereocontrol in the organometallic addition and oxyanion-Cope steps. Using methodology due to Yamamoto, 25 Cook and co-workers treated N1unsubstituted α,β-unsaturated aldehyde 61 with an organobarium reagent derived from (E)-pent-2-enyl bromide 62.…”

“…A slightly different approach was used to access sarpagine alkaloids possessing the opposite configuration at C16 (ajmaline configuration). From sarpagan C16 ketone 88, Wittig methylenation and selective hydroboration of the disubstituted olefin from the less hindered face gave 16epi-normacusine B 24,46 99 (26% from D-tryptophan methyl ester). In the N1-methyl series, from sarpagan C16 ketone 100, the same Wittig methylenation and selective hydroboration gave 16-epi-affinisine 24,46 101 (25% from Dtryptophan methyl ester).…”

“…From sarpagan C16 ketone 88, Wittig methylenation and selective hydroboration of the disubstituted olefin from the less hindered face gave 16epi-normacusine B 24,46 99 (26% from D-tryptophan methyl ester). In the N1-methyl series, from sarpagan C16 ketone 100, the same Wittig methylenation and selective hydroboration gave 16-epi-affinisine 24,46 101 (25% from Dtryptophan methyl ester). DDQ-mediated α-aryl oxidation gave dehydro-16-epi-affinisine 24,46 102 (24% from Dtryptophan methyl ester), as shown in Scheme 34.…”

Sarpagine and Related Alkaloids

“…134,135 Later Zhou et al published the synthesis of gardnerine ( 202 ) and gardnutine ( 205 ). 136 These alkaloids have the C-16 hydroxymethyl group present in the S configuration.…”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…However, under these conditions the racemization of the products was possible [22]. By this methodology, besides the application of Cook's group to the preparation of natural products [18,[23][24][25][26][27][28], a new class of inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B was synthesized by Waldmann and co-workers [29].…”