The asymmetric gold(I)-catalyzed ring expansion of 1-allenylcyclopropanols is described. The method provides synthetically valuable cyclobutanones with a vinyl-substituted quaternary stereogenic center in high enantioselectivities and yields. The method shows a broad substrate scope, tolerating protected alcohols and amines, alkenes, unsaturated esters and acetals. The reaction is easily adjustable to large scale synthesis, leading to product formation without significant loss of selectivity or yield with only 0.5 mol% catalyst loading.
Dichloroiodo)toluene ( dichloro(4-methylphenyl)iodine; 2) was found to be a suitable chlorinating agent in the catalytic asymmetric chlorination of b-keto esters 3 catalyzed by the [Ti(TADDOLato)] complex 1 ( bis(acetonitrile)dichloro[(4R,5R)-2,2-dimethyl-a,a,a',a'-tetra(naphthalen-1-yl)-1,3-dioxolane-4,5-dimethanolato(2 À)-kO,kO']titanium), whereby a-chlorinated products were obtained in moderate to good yields and enantioselectivities of up to 71% (Scheme 2, Table 2). The enantioselectivity of the reaction shows a remarkable temperature dependence, the maximum selectivity being obtained at ca. 508.
An amine transaminase
was engineered for the efficient production
of a chiral precursor to sacubitril, (2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic
acid, a key component in the blockbuster heart failure drug Entresto.
Starting from an enzyme with trace activity and preference for the
undesired diastereoisomer, 11 rounds of enzyme evolution were performed.
The resultant variant, CDX-043, showed high productivity giving 90%
conversion at 75 g/L substrate concentration with 1% enzyme loading
with respect to the substrate in 24 h and without the use of an organic
cosolvent. The product diastereomeric purity toward the desired (2R,4S)-stereoisomer was >99.9:0.1 d.r. This variant also exhibited high process robustness
and could tolerate reaction temperatures up to 65 °C, isopropylamine
concentrations of at least 2 M, and reaction times of at least 5 days.
A structural analysis of the enzyme variants gave insight into how
the mutations affected activity and selectivity. This enzyme variant
allows for the efficient and cost-effective production of sacubitril
at large scale.
[chemical reaction: see text]. We report the reduction of 2,3-dihydroisoxazoles to beta-amino ketones and beta-amino alcohols. The latter are obtained in high diastereoselectivity with preference for the syn isomer.
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