Enantioselective synthesis of a GPR40 agonist AMG 837 via catalytic asymmetric conjugate addition of terminal alkyne to α,β-unsaturated thioamide

Organic Letters

Volumn 13, Issue 5, 2011, Pages 952-955

  Yazaki, Ryo ^a,b   Kumagai, Naoya ^a   Shibasaki, Masakatsu ^a  

^a INSTITUTE OF MICROBIAL CHEMISTRY   (Japan)

^b UNIVERSITY OF TOKYO   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYNE; AMG 837; BIPHENYL DERIVATIVE; FFAR1 PROTEIN, HUMAN; G PROTEIN COUPLED RECEPTOR; THIOAMIDE;

ARTICLE; CATALYSIS; CHEMICAL STRUCTURE; CHEMISTRY; COMBINATORIAL CHEMISTRY; DRUG POTENTIATION; HUMAN; STEREOISOMERISM; SYNTHESIS;

ALKYNES; BIPHENYL COMPOUNDS; CATALYSIS; COMBINATORIAL CHEMISTRY TECHNIQUES; HUMANS; MOLECULAR STRUCTURE; RECEPTORS, G-PROTEIN-COUPLED; STEREOISOMERISM; THIOAMIDES;

EID: 79952122636     PISSN: 15237060     EISSN: 15237052     Source Type: Journal    
DOI: 10.1021/ol102998w     Document Type: Article

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30. nBuLi did not afford 4a in the absence of a Cu complex even at 50 °C, suggesting that transmetalation to Cu acetylide is likely involved. Indeed, the reaction proceeded smoothly with 5 mol % of a mesitylcopper/(R)-DTBM-Segphos catalyst, where only the Cu acetylide of 3a can be formed, affording 4a in 91% yield and 90% ee under otherwise identical conditions.
31. The possibility that H-HMDS was deprotonated by intermediate C and the resultant Cu-HMDS functions as a Brønsted base for the next catalytic cycle cannot be ruled out. Considering the proximity of 3a and Cu thioamide enolate in intermediate C, the direct deprotonation as depicted in Figure 1 is more likely.
32. 4-p -OMe, leading to low catalytic performance. The higher catalytic efficiency by using KHMDS is not clear at this stage.
33. Sterically bulkier TES acetylene instead of TMS acetylene gave an inferior result (63% yield, 92% ee). Even bulkier TBS or TIPS acetylenes did not afford any product presumably due to considerable steric repulsion in the transition state. The reaction using propyne was not reproducible and is under investigation.
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38. No racemization was observed at this stage as confirmed by chiral-stationary-phase HPLC analysis.