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Diastereoselective Alkylation of a Proline‐Derived Bicyclic Lactim Ether
Author(s) -
Hendea Daniela,
Laschat Sabine,
Baro Angelika,
Frey Wolfgang
Publication year - 2006
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200690181
Subject(s) - chemistry , alkylation , ether , electrophile , bicyclic molecule , alkyl , stereochemistry , halide , deprotonation , diketopiperazines , steric effects , hydrolysis , medicinal chemistry , organic chemistry , catalysis , ion
N ‐Boc‐protected L ‐proline ( 6 ) was converted into the bicyclic lactim ether (8a S )‐6,7,8,8a‐tetrahydro‐1‐methoxypyrrolo[1,2‐ a ]pyrazin‐4(3 H )‐one ( 5 ) in four steps ( Scheme 1 ). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis ‐ and trans ‐ 9 . The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis ‐ 9 , sterically more‐demanding alkyl halides resulted in cis / trans mixtures. Electrophiles bearing a π ‐system favored the trans ‐products 9 . Some isolated cis ‐ and trans ‐lactim ethers 9 were converted to the corresponding diketopiperazines cis ‐ and trans ‐ 10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X‐ray crystallography ( Figs. 1–4 ).