Practical asymmetric synthesis of a γ-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition

Journal of Organic Chemistry

Volumn 71, Issue 8, 2006, Pages 3086-3092

  Scott, Jeremy P ^a   Oliver, Steven F ^a   Brands, Karel M J ^a   Brewer, Sarah E ^a   Davies, Antony J ^a   Gibb, Andrew D ^a   Hands, David ^a   Keen, Stephen P ^a   Sheen, Faye J ^a   Reamer, Robert A ^b   Wilson, Robert D ^a   Dolling, Ulf H ^b  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIASTEREOSELECTIVITY; HEXAHYDROBENZISOXAZOLE; SECRETASE INHIBITOR; SUBSTRATE-CONTROLLED INTRAMOLECULAR NITRILE OXIDE-OLEFIN CYCLOADDITION;

ADDITION REACTIONS; ALCOHOLS; ALKYLATION; CHROMATOGRAPHY; ENZYMES; STEREOCHEMISTRY; SUBSTRATES;

ENZYME INHIBITION;

ALKENE; GAMMA SECRETASE INHIBITOR; NITRIC OXIDE;

ALKYLATION; ARTICLE; ASYMMETRIC SYNTHESIS; CYCLIZATION; CYCLOADDITION; REDUCTION; STEREOCHEMISTRY;

ALKENES; AMINO ALCOHOLS; AMYLOID PRECURSOR PROTEIN SECRETASES; ENZYME INHIBITORS; MOLECULAR STRUCTURE; NITRILES; OXIDES; STEREOISOMERISM; TARTRATES;

EID: 33645781012     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo060033i     Document Type: Article

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41. Azetidine 20 can be readily prepared by the cyclization of 16 with KOt-Bu in THF at 40 °C.
42. An attempted direct ethylation of sultam 15 was thwarted by our inability to prepare the N,C-dianion, as indicated by deuterium incorporation studies. Profiles of deprotonations were also unsatisfactory at higher temperatures, presumably a result of competing aryl C-H abstraction.
43. The observed diastereoselection is kinetic in origin under the conditions used, as prolonged aging in the presence of the 0.4 equiv of excess LHMDS or NaHMDS employed does not lead to any change in the ratio of 24:25. In addition, under conditions of thermodynamic equilibration (KOt-Bu/t-BuOH, 80 °C), a 1:1 mixture of 24 and 25 afforded only a 97:3 ratio favoring 24.
44. Other trapping agents evaluated were thiourea, thiosemicarbazide, 2-thiobenzoic acid, L-methionine, and thioanisole. The use of protic solvents EtOH or IPA with 6 or 12 M HCl afforded high assay yields of 1, however, impurity profiles were unsatisfactory.
45. 2O catalyst (70 psi, MeOH/ AcOH, 10% w/t dry basis relative to 24).
46. The absolute stereochemistry of (-)-1 was confirmed by X-ray crystallography. See Supporting Information.