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Sequential Biocatalytic Aldol Reactions in Multistep Asymmetric Synthesis: Pipecolic Acid, Piperidine and Pyrrolidine (Homo)Iminocyclitol Derivatives from Achiral Building Blocks
Author(s) -
Soler Anna,
Garrabou Xavier,
Hernández Karel,
Gutiérrez Mariana L.,
Busto Eduardo,
Bujons Jordi,
Parella Teodor,
Joglar Jesús,
Clapés Pere
Publication year - 2014
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201400453
Subject(s) - aldol reaction , dihydroxyacetone phosphate , chemistry , aldolase a , pyrrolidine , dihydroxyacetone , glycolaldehyde , dhap , stereochemistry , regioselectivity , organic chemistry , catalysis , glycerol , enzyme
A multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine‐dependent aldolases and both D ‐fructose‐6‐phosphate aldolase (FSA) or dihydroxyacetone phosphate (DHAP)‐dependent aldolases is presented. The methodology allowed the preparation of known and innovative imine‐derived molecules with a great structural diversity from simple achiral substrates. The strategy consisted of two key aldol addition steps: a first aldol addition of glycine to dimethoxyacetaldehyde catalyzed by L ‐ and D ‐glycine aldolases and a second aldol addition of DHAP, dihydroxyacetone, hydroxyacetone or glycolaldehyde using FSA or DHAP‐dependent aldolases as catalysts to a conveniently transformed aldol adduct from the first aldol addition. Catalytic reductive amination on the aldol adducts rendered the polyhydroxypipecolic acid analogues, (homo)iminocyclitols and polyhydroxylated pyrrolidine iminocyclitols. The reported strategy is thus designed to create up to five new stereogenic centers in three steps, four of them being controlled in two enzymatic reactions. Moreover, it allowed the installation of diverse functionalities in the molecules. This was possible by taking the full advantage of using aldolases in a multistep approach by virtue of their stereocomplementarity, stereoselectivity and broad substrate tolerance.