Science of Synthesis

Ilari, A.; Bonamore, A.; Boffi, A., Science of Synthesis: Biocatalysis in Organic Synthesis, (2015) 2, 170.

RsSTS-mediated synthesis of novel strictosidine analogues containing the piperazinoindole core instead of the tetrahydro-β-carboline (tryptoline) unit has been reported.[‌31‌] Pyrazino- and piperazino[1,2-a]indole systems deserve a special mention in view of their prominent biological activities linked to advanced pharmaceutical product development.[‌32‌] Current synthetic strategies for this class of compounds, especially for regio- and enantioselective synthesis, require demanding chiral transition-metal catalysts. Thus, the use of enzyme catalysis to gain access to the piperazinoindole scaffold is of high potential interest. 2-(1H-Indol-1-yl)ethanamine (‌15‌, IEA) has been synthesized and tested as a possible substrate.[‌31‌] Incubation of recombinant RsSTS wild-type protein with this indole derivative, under neutral conditions in the presence of the monoterpenoid glucoside secologanin (‌4‌), results in excellent enzyme-dependent conversion (>95%), as shown by HPLC (‌Scheme 8‌). In this transformation, the 3α-(S)-piperazinoindole strictosidine analogue ‌16‌ [3α-(S)-PIS] is formed, in which the typical tetrahydro-β-carboline skeleton is replaced by the unusual piperazino[1,2-a]indole framework, representing the first example of a piperazino monoterpenoid indole alkaloid. As is the case for the natural RsSTS substrate tryptamine (‌6‌), the complete stereoselectivity of RsSTS delivers exclusively 3α-(S)-PIS (‌16‌) by condensation of ‌4‌ and ‌15‌. The use of the enzyme RsSTS presently provides exclusive access to ‌16‌.

‌Meeeee 8‌ Meeeeeeee ee e Meeeeeeeee[8,8-e]eeeeee Meeeeeeeeeeee Meeeeeee[‌88‌]

Meeeeeeeeeee Meeeeeeee

8-(8M-Meeee-8-ee)eeeeeeeeee (‌88‌); Meeeeee Meeeeeeee:[‌88‌]

MMMMMMM: Meeee eeeeeee eeeeeeee eeeeeee eeeeee eeeeeeeeee eeee e eeeeeee ee eeeeeeeeee, eee eee eeeeee ee eeeeeee ee eeeeeeee eeeeeeee.

M eeeeeee ee MeM (88% eeeeeeeeee ee eeeeeee eee; 888 ee, 88 eeee) eee 8M-eeeeee (8.88 e, 88 eeee) ee eee MMM (88 eM) eee eeeeeee ee ee eee 88 eee eeeeee eee eeeeeeee ee eeeeeeeeeeeeeeeee (8.88 eM, 88 eeee) ee eee MMM (8.8 eM). Mee eeeeeee eee eeeeee ee 88 °M eee 88 eee, eeeeeee ee ee eee 8 e, eee eeee eeeeeee eeee eee. Mee eeeeeeeee eeeee eee eeeeeeee eee eee eeeeeeee ee eeeee eeeeeeeeeeeeee ee eeee 8-(8M-eeeee-8-ee)eeeeeeeeeeee (‌88‌). M eeeeeeeeee ee 8-(8M-eeeee-8-ee)eeeeeeeeeeee (‌88‌; 888 ee, 8 eeee) ee eee Me8M (88 eM) eee eeeee eeeeee ee e eeee-eeeeeee eeeeee ee MeMeM8 (888 ee, 88.8 eeee) ee eee Me8M (88 eM). Mee eeeeeee eee eeeeeeee eee 8 e eee eeee eeeeee eeee eee eeeee. 8 M ee MeMM (88 eM) eee eeeee eee eee eeeeeee eeeee eee eeeeeeeee eeee MeMMe (8 × 88 eM). Mee eeeeeeeee eeeeeee eeeeee eeee eeeee eee eeeeeeeeeeee. Mee eeeee eeeeeee eee eeeeeeee; eeeee: 88% (eeeee ee 8M-eeeeee).

[(8M,8M)-8-(Meeeeeeeeeeeeee)-8-{[(M)-8,8,8,8-eeeeeeeeeeeeeeeeee[8,8-e]eeeee-8-ee]eeeeee}-8-eeeee-8,8-eeeeeee-8M-eeeee-8-ee]-e-eeeeeeeeeeeee [‌88‌; 8α-(M)-MMM]:[‌88‌]

Mee eeeeeeeeee eeeeeee (8.8 eM), eeeeeeeeee MeMMM (8.8 ee), 88 eM eeeeeeeeeee (‌8‌), 88 eM 8-(8M-eeeee-8-ee)eeeeeeeeee (‌88‌), eee 88 eM eeeeeeeee eeeeeeeee eeeeee (eM 8.8), eee eeeeeeeee eee 8 e ee 88 °M eeee eeeeeee. Mee eeeeeeee eee eeeeeeeeee ee eeeeeeee ee MeMM (8 eM), eee eee eeeeeee eee eeeeeeeee eeee MeMMe (8 × 88 eM). Mee eeeeeeeee eeeeeee eeeeee eeee eeeee, eeeeeeeeeeee, eee eeeeeeee ee eeeeeeeeeee MMM; eeeee: >88%.

References