Synthese of key intermediates to 1β-methylcarbapenem antibiotics = 항생제 1β-메틸카바페넴을 위한 중요 중간체의 합성에 관한 연구

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A highly enantioselective synthesis of the key intermediate 8 of 1β-methylcarbapenem antibiotics was accomplished. The retrosynthetic strategy was focused on setting four contiguous chiral centers in the bicyclic isoxazolidine 169, followed by selective N-O bond cleavage and ultimate cyclization to construct the β-lactam ring. The key features of the scheme include the intramolecular 1,3-dipolar cycloaddition of nitrone to a bicyclic isoxazolidine with complete control of stereocenters and β-lactam formation from the β-amino acid 206b with trifluoroacetic anhydride in the presence of triethylamine. The substrate for the 1,3-dipolar cycloaddition, trans-lactol 164a, was prepared in 4 steps in three reaction pots starting from methyl (R)-3-iodo-2-methylpropionate in 76% overall yield. It was subjected to the nitrone formation with N-p-methoxybenzylhydroxylamine followed by the intramolecular 1,3-dipolar cycloaddition to provide the bicyclic isoxazolidine 169 as a single isomer with correct stereochemistry in 89% overall yield. Swern oxidation of 169, enol ether formation and oxidative cleavage followed by Wadsworth-Emmons olefination provided the conjugated ester 204a in 69% overall yield. Reductive N-O bond cleavage of 204a, β-lactam formation, debenzylation, TBS protection and oxidative cleavage in sequence afforded the desired azetidinone 8 in 74% overall yield from 204a. The direct formation of β-keto ester 181 from 209b, d, not via carboxylic acid 8, was attempted by palladium catalyzed oxidation. However, allyl ester 209b and p-methoxybenzyl ester 209d could not be converted into the desired β-keto esters. An alternative route to obtain the β-keto acid 232 from bicyclic ketone 184 was also intended. Ketone 184 was converted into 227b over 9 steps, of which the phenyl substituent was found to be resistant to oxidative degradation into carboxylic acid group.
Advisors
Kang, Sung-Horesearcher강성호researcher
Description
한국과학기술원 : 화학과,
Publisher
한국과학기술원
Issue Date
1996
Identifier
105343/325007 / 000925304
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 화학과, 1996.2, [ iii, 169 p. ]

Keywords

1,3-Dipolar Cycloaddition; β-Methylcarbapenem; β-lactam Antibiotics; β-락탐 항생제; 1,3-이중극성 고리화첨가반응; β-메틸카바페넴

URI
http://hdl.handle.net/10203/31425
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=105343&flag=dissertation
Appears in Collection
CH-Theses_Ph.D.(박사논문)
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