Total Syntheses of Carbohydrates: Organocatalyzed Aldol Additions of Dihydroxyacetone

Abstract

The selective total synthesis of carbohydrates with defined configuration has been of great interest for a long time. This field has been the domain of enzymatic methods so far. But now the recent development of several organocatalyzed aldol methodologies has made a selective synthetic approach to configuratively defined carbohydrates possible. This development and different strategies will be discussed in this concept article.

Asymmetric Organocatalysis

“…Functionalized aliphatic ketones, including hydroxyacetone, chloroacetone, and fluoroacetone, are important in the aldol reaction as donors because multiple functionalities present in the aldol products, which found widespread applications in organic synthesis [25]. As a result, aldolization involving these functional ketones has been disclosed.…”

Asymmetric assembly of aldose carbohydrates from formaldehyde and glycolaldehyde by tandem biocatalytic aldol reactions

“…3) led us to consider the substitution of S166 by Gly to alleviate the steric hindrance at that position. Variants FSA A129T/S166G and FSA A129T/A165G/S166G were found to tolerate these aldehydes satisfactorily, producing the synthesis of 6-deoxy-(3d), 6-O-methyl-(3e), 6-O-benzyl-(3f ), 6-(benzylthio)-(3g), 6-O-phenyl (3h), 6-deoxy-6-azido (3i) and 6-deoxy-6-chloro-(3j) D-idose (Table 1, entries [11][12][13][14][15][16][17][18][19][20].…”

“…In this manner, the pertinent choice of FSA variants allows for the preparation of a complete, stereochemically consistent series of three-to six-carbon aldose sugars, namely L-glyceraldehyde (2b), D-threose (2a), L-xylose (3b) and D-idose (3a), from achiral precursors (Table 1, entries 1, 2, 4 and 7). Acetaldehyde (1d) and glycolaldehyde analogues (that is, 1e-j, Table 1) were assayed as acceptors for the double addition of glycolaldehyde (that is, with the C 2 +C 2 +C 2 connection) to generate 6-deoxy-D-idose and 6-substituted D-idose derivatives ( Table 1, entries [11][12][13][14][15][16][17][18][19][20][21][22]. The selectivity of FSA variants towards glycolaldehyde as a donor ensures that the other aldehyde component will invariably act as an acceptor substrate.…”

“…Alternatively, straightforward and efficient bottom-up strategies for the de novo construction of polyoxygenated scaffolds may be devised through the consecutive connection of small building blocks, by C-C bond-forming reactions with the concomitant installation of hydroxylated chiral positions 3,10 . The catalytic asymmetric aldol addition reaction has proved to be an extremely useful carboligation procedure for the generation of polyoxygenated molecules [10][11][12] . When aiming to recreate the prebiotic synthesis of sugars, simple amino acids and inorganic catalysts were found to assemble glycolaldehyde (1a) and formaldehyde (1b) into diverse carbohydrates, thereby offering partial control over the sugar size, configuration and enantiomeric ratio 13,14 .…”

Permanganate Oxidation Revisited: Synthesis of 3‐Deoxy‐2‐uloses via Indium‐Mediated Chain Elongation of Carbohydrates

“…Total synthesis provides these compounds independently from natural sources [7] and is able to produce non-natural analogues. [8] Aldol reactions [9] as well as Grignard type reagents [10] make use of the carbonyl functionality to construct and modify the carbohydrate backbone. The deoxygenation of sugars has been extensively used to synthesize deoxy analogues.…”