Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue

Alberto Oddo; Ralph Holl

doi:10.1016/j.carres.2012.06.006

Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue

Alberto Oddo, Ralph Holl

21 Citations (Scopus)

Abstract

The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with D-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et(3)SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO(3) oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H(2)NOH into the hydroxamic acid 3.

Original language	English
Journal	Carbohydrate Research
Volume	359
Pages (from-to)	59-64
Number of pages	6
ISSN	0008-6215
DOIs	https://doi.org/10.1016/j.carres.2012.06.006
Publication status	Published - 1 Oct 2012

Keywords

Amidohydrolases
Carbohydrate Conformation
Chemistry Techniques, Synthetic
Drug Design
Enzyme Inhibitors
Glycosides
Hydroxamic Acids
Stereoisomerism
Substrate Specificity
Threonine

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10.1016/j.carres.2012.06.006

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title = "Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue",

abstract = "The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with D-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et(3)SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO(3) oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H(2)NOH into the hydroxamic acid 3.",

keywords = "Amidohydrolases, Carbohydrate Conformation, Chemistry Techniques, Synthetic, Drug Design, Enzyme Inhibitors, Glycosides, Hydroxamic Acids, Stereoisomerism, Substrate Specificity, Threonine",

author = "Alberto Oddo and Ralph Holl",

year = "2012",

month = oct,

day = "1",

doi = "10.1016/j.carres.2012.06.006",

language = "English",

volume = "359",

pages = "59--64",

journal = "Carbohydrate Research",

issn = "0008-6215",

publisher = "Pergamon Press",

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TY - JOUR

T1 - Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue

AU - Oddo, Alberto

AU - Holl, Ralph

PY - 2012/10/1

Y1 - 2012/10/1

N2 - The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with D-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et(3)SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO(3) oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H(2)NOH into the hydroxamic acid 3.

AB - The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with D-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et(3)SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO(3) oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H(2)NOH into the hydroxamic acid 3.

KW - Amidohydrolases

KW - Carbohydrate Conformation

KW - Chemistry Techniques, Synthetic

KW - Drug Design

KW - Enzyme Inhibitors

KW - Glycosides

KW - Hydroxamic Acids

KW - Stereoisomerism

KW - Substrate Specificity

KW - Threonine

U2 - 10.1016/j.carres.2012.06.006

DO - 10.1016/j.carres.2012.06.006

M3 - Journal article

C2 - 22925765

SN - 0008-6215

VL - 359

SP - 59

EP - 64

JO - Carbohydrate Research

JF - Carbohydrate Research

ER -

Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue

Abstract

Keywords

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