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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Carbohydrate Research
Vol/bind	359
Sider (fra-til)	59-64
Antal sider	6
ISSN	0008-6215
DOI	https://doi.org/10.1016/j.carres.2012.06.006
Status	Udgivet - 1 okt. 2012

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10.1016/j.carres.2012.06.006

Citationsformater

@article{627bd1b791d7482db62ffb9c6888b011,

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",

}

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

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