TY - JOUR

T1 - (Chemo)enzymatic synthesis of dTDP-activated 2,6-dideoxysugars as building blocks of polyketide antibiotics

AU - Amann, Stefan

AU - Dräger, Gerald

AU - Rupprath, Carsten

AU - Kirschning, Andreas

AU - Elling, Lothar

N1 - Funding information: The authors thank Professor Dr W. Piepersberg (BUGH Wuppertal) for providing the recombinant E. coli strains expressing RmlA, RmlB, RmlC and RmlD, Dr J.C. Namyslo (TU Clausthal–Zellerfeld) for his excellent help in NMR analysis, Dr Rettberg (University Göttingen) for ESI–MS analysis. The authors thank Professor Dr P.F. Leadlay (Cambridge University) and Dr Martin Hein for critical reading of the manuscript. Financial supports by EU the grants ‘Hyglide’ (Contract No. ERBBIO 4 CT 960080) and ‘GENOVA’ (Contract No. QLK3-999-00095) to L.E. is gratefully acknowledged.

PY - 2001/9/5

Y1 - 2001/9/5

N2 - The flexible substrate spectrum of the recombinant enzymes from the biosynthetic pathway of dTDP-β-L-rhamnose in Salmonella enterica, serovar typhimurium (LT2), was exploited for the chemoenzymatic synthesis of deoxythymidine diphosphate- (dTDP-) activated 2,6-dideoxyhexoses. The enzymatic synthesis strategy yielded dTDP-2-deoxy-α-D-glucose and dTDP-2,6-dideoxy-4-keto-α-D-glucose (13) in a 40-60 mg scale. The nucleotide deoxysugar 13 was further used for the enzymatic synthesis of dTDP-2,6-dideoxy-β-L-arabino-hexose (dTDP-β-L-olivose) (15) in a 30-mg scale. The chemical reduction of 13 gave dTDP-2,6-dideoxy-α-D-arabino-hexose (dTDP-α-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 glycosyltransferases involved in the biosynthesis of polyketides and other antibiotic/antitumor drugs. Their synthetic access may contribute to the evaluation of the glycosylation potential of bacterial glycosyltransferases to generate hybrid antibiotics.

AB - The flexible substrate spectrum of the recombinant enzymes from the biosynthetic pathway of dTDP-β-L-rhamnose in Salmonella enterica, serovar typhimurium (LT2), was exploited for the chemoenzymatic synthesis of deoxythymidine diphosphate- (dTDP-) activated 2,6-dideoxyhexoses. The enzymatic synthesis strategy yielded dTDP-2-deoxy-α-D-glucose and dTDP-2,6-dideoxy-4-keto-α-D-glucose (13) in a 40-60 mg scale. The nucleotide deoxysugar 13 was further used for the enzymatic synthesis of dTDP-2,6-dideoxy-β-L-arabino-hexose (dTDP-β-L-olivose) (15) in a 30-mg scale. The chemical reduction of 13 gave dTDP-2,6-dideoxy-α-D-arabino-hexose (dTDP-α-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 glycosyltransferases involved in the biosynthesis of polyketides and other antibiotic/antitumor drugs. Their synthetic access may contribute to the evaluation of the glycosylation potential of bacterial glycosyltransferases to generate hybrid antibiotics.

KW - Antibiotics

KW - dTDP-α-D-olivose

KW - dTDP-β-L-olivose

KW - Macrolides

KW - Nucleotide deoxysugars

UR - http://www.scopus.com/inward/record.url?scp=0034856716&partnerID=8YFLogxK

U2 - 10.1016/S0008-6215(01)00195-1

DO - 10.1016/S0008-6215(01)00195-1

M3 - Article

C2 - 11553351

AN - SCOPUS:0034856716

VL - 335

SP - 23

EP - 32

JO - Carbohydrate Research

JF - Carbohydrate Research

SN - 0008-6215

IS - 1

ER -