(Chemo)enzymatic synthesis of dTDP-activated 2,6-dideoxysugars as buildingblocks of polyketide antibiotics

The flexible substrate spectrum of the recombinant enzymes from the biosynt hetic pathway of dTDP-beta -L-rhamnose in Salmonella enterica, serovar typh imurium (LT2), was exploited for the chemoenzymatic synthesis of deoxythymi dine diphosphate- (dTDP-) activated 2,6-dideoxyhexoses. The enzymatic synth esis strategy yielded dTDP-2-deoxy-alpha -D-glucose and dTDP-2,6-dideoxy-4- keto-alpha -D-glucose (13) in a 40-60 mg scale. The nucleotide deoxysugar 1 3 was further used for the enzymatic synthesis of dTDP-2,6-dideoxy-beta -L- arabino-hexose (dTDP-beta -L-olivose) (15) in a 30-mg scale. The chemical r eduction of 13 gave dTDP-2,6-dideoxy-alpha -D-arabino-hexose (dTDP-alpha -D -olivose) (1) as the main isomer after product isolation in a 10-mg scale. With 13 as an important key intermediate, the in vitro characterization of enzymes involved in the biosynthesis of dTDP-activated 2,6-dideoxy-, 2,3,6- trideoxy-D- and L-hexoses can now be addressed. Most importantly, compounds 1 and 15 are donor substrates for the in vitro characterization of glycosy ltransferases involved in the biosynthesis of polyketides and other antibio tic/antitumor drugs. Their synthetic access may contribute to the evaluatio n of the glycosylation potential of bacterial glycosyltransferases to gener ate hybrid antibiotics. (C) 2001 Elsevier Science Ltd. All rights reserved.