New methods for the synthesis of spirocyclic cephalosporin analogues

Alan X. Zhao; Louise E. Horsfall; Alison N. Hulme

doi:10.3390/molecules26196035

New methods for the synthesis of spirocyclic cephalosporin analogues

Alan X. Zhao, Louise E. Horsfall, Alison N. Hulme^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Spiro compounds provide attractive targets in drug discovery due to their inherent threedimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).

Original language	English
Article number	6035
Journal	Molecules
Volume	26
Issue number	19
Early online date	5 Oct 2021
DOIs	https://doi.org/10.3390/molecules26196035
Publication status	E-pub ahead of print - 5 Oct 2021

Keywords / Materials (for Non-textual outputs)

Michael-type reaction
Spiro-cephalosporin
Spiro-cyclisation

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10.3390/molecules26196035

20211029_Hulme_molecules-26-06035-v2_VoRFinal published version, 17.7 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.mdpi.com/1420-3049/26/19/6035

Cite this

@article{e600ed49767f471e8874dcffdaacced9,

title = "New methods for the synthesis of spirocyclic cephalosporin analogues",

abstract = "Spiro compounds provide attractive targets in drug discovery due to their inherent threedimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).",

keywords = "Michael-type reaction, Spiro-cephalosporin, Spiro-cyclisation",

author = "Zhao, {Alan X.} and Horsfall, {Louise E.} and Hulme, {Alison N.}",

note = "Funding Information: Funding: We thank the EPSRC (Grant Refs: EP/M506515/1 and EP/N509644/1) and IBioIC (Innovation Centre Programme funded by SFC, SE and HIE) for funding (studentship to AZ). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = oct,

day = "5",

doi = "10.3390/molecules26196035",

language = "English",

volume = "26",

journal = "Molecules",

issn = "1420-3049",

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TY - JOUR

T1 - New methods for the synthesis of spirocyclic cephalosporin analogues

AU - Zhao, Alan X.

AU - Horsfall, Louise E.

AU - Hulme, Alison N.

N1 - Funding Information: Funding: We thank the EPSRC (Grant Refs: EP/M506515/1 and EP/N509644/1) and IBioIC (Innovation Centre Programme funded by SFC, SE and HIE) for funding (studentship to AZ). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10/5

Y1 - 2021/10/5

N2 - Spiro compounds provide attractive targets in drug discovery due to their inherent threedimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).

AB - Spiro compounds provide attractive targets in drug discovery due to their inherent threedimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).

KW - Michael-type reaction

KW - Spiro-cephalosporin

KW - Spiro-cyclisation

U2 - 10.3390/molecules26196035

DO - 10.3390/molecules26196035

M3 - Article

AN - SCOPUS:85116545917

SN - 1420-3049

VL - 26

JO - Molecules

JF - Molecules

IS - 19

M1 - 6035

ER -

New methods for the synthesis of spirocyclic cephalosporin analogues

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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