Stereoselective Aldol Additions Catalyzed by Dihydroxyacetone Phosphate‐Dependent Aldolases in Emulsion Systems: Preparation and Structural Characterization of Linear and Cyclic Iminopolyols from Aminoaldehydes

Abstract

The potential of dihydroxyacetone phosphate (DHAP)-dependent aldolases to catalyze stereoselective aldol additions is, in many instances, limited by the solubility of the acceptor aldehyde in aqueous/co-solvent mixtures. Herein, we demonstrate the efficiency of emulsion systems as reaction media for the class I fructose-1,6-bisphosphate aldolase (RAMA) and class II recombinant rhamnulose-1-phosphate aldolase from E. coli (RhuA)-catalyzed aldol addition between DHAP and N-benzyloxycarbonyl (N-Cbz) aminoaldehydes. The use of emulsions improved the RAMA-catalyzed aldol conversions by three to tenfold relative to those in conventional DMF/water mixtures. RhuA was more reactive than RAMA towards the N-Cbz aminoaldehydes regardless of the reaction medium. With (S)- or (R)-Cbz-alaninal, RAMA exhibited preference for the R enantiomer, while RhuA had no enantiomeric discrimination. The linear N-Cbz aminopolyols thus obtained were submitted to catalytic intramolecular reductive amination to afford the corresponding iminocyclitols. This reaction was diastereoselective in all cases examined; the face selectivity was controlled by the stereochemistry of the newly formed hydroxyl group originating from the aldehyde. Characterization of the resulting iminocyclitols allowed the assessment of the diastereoselectivity of the enzymatic aldol reactions with respect to the N-protected aminoaldehyde. RAMA formed single diastereoisomers from N-Cbz-glycinal and from both enantiomers of N-Cbz-alaninal, while 14 % of the epimeric product was observed from N-Cbz-3-aminopropanal. Diastereoselectivity from RhuA was lower than that observed from RAMA. Interestingly, a single diastereoisomer was formed from (S)-Cbz-alaninal, whereas only a 34 % diastereomeric excess was observed from its enantiomer (i.e., (R)-Cbz-alaninal).

Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A1 and A2 Stereoisomers

“…Experimental preparations, analytical data, biological data and 1 H, 13 C NMR spectra for all compounds; COSY, HSQC and NOE spectra, are described in detail.…”

“…The synthetic strategy devised is based on the ability of dihydroxyacetone phosphate (DHAP) aldolases to accept NCbz-amino aldehydes as substrates. [12,13] Hence, the key step of our synthetic scheme was the aldol addition of DHAP to either (R)-or (S)-N-Cbz-prolinal, as shown in the retrosynthetic analysis (Scheme 1).…”

“…This reaction is highly stereoselective, the hydrogen being delivered from the face opposite to the hydroxy group at the C-1 position. [13,14] Formally, this strategy might lead to obtain 8 out of 16 possible stereoisomers of hyacinthacines A 1 and A 2 starting from DHAP (4) and either (R)-or (S)-N-Cbz-prolinal (3-R or 3-S). The scope of this synthetic approach was investigated using d-fructose 1,6-bisphosphate aldolase from rabbit muscle (RAMA) as well as lrhamnulose 1-phosphate aldolase (RhuA), and l-fuculose 1-phosphate aldolase (FucA) from E. coli as catalysts for the aldol addition of DHAP to 3-S and 3-R.…”

“…[13] The formation of four diastereoisomers of hyacinthacines A 1 and A 2 (Scheme 2, see experimental details in Supporting Information), namely (À)-hyacinthacine A 2 (6) [the enantiomer of (+)-hyacinthacine A 2 [19] ], 7-deoxy-2-epialexine (7) (the enantiomer of 3-epihyacinthacine A 2 [9] ), ent-7-deoxyalexine (8) (the enantioScheme 1. Retrosynthetic analysis for hyacinthacine stereoisomers.…”

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

“…[24,25] The key step of the strategy devised was the aldol addition of dihydroxyacetone phosphate (DHAP) to N-benzyloxycarbonylaminoaldehydes catalyzed by DHAP aldolases, such as d-fructose-1,6-diphosphate aldolase from rabbit muscle (RAMA), and l-rhamnulose-1-phosphate aldolase (RhuA) and l-fuculose-1-phosphate aldolase (FucA), both from E. coli. This methodology allowed us to prepare a number of iminocyclitols from N-Cbz-3-aminopropanal, N-Cbz-glycinal, and both enantiomers of NCbz-alaninal.…”