Simple and practical asymmetric synthesis of functionally differentiated aminoindanol based endo-N-sulfonyl 1,2,3-oxathiazolidine-2-oxide as sulfinyl transfer agents are developed. The importance of these new and unique sulfinyl transfer reagents are exemplified by the expedient production of several sulfinamide ligands, including either enantiomer of (R)-tert-butanesulfinamide in excellent yields and enantiopurities.
The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO activity. We used computational tools to design a focused, purchasable library of compounds. After screening this library for hDAAO inhibition, we identified the structurally novel compound, ‘compound 2’ [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to enrich for compounds that were competitive for both D-serine and FAD, compound 2 actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as benzoic acid. Compound 2 and an analog were independently co-crystalized with hDAAO. These compounds stabilized a novel conformation of hDAAO in which the active-site lid was in an open position. These results confirm previous hypotheses regarding active-site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors.
(R,R)-Formoterol (1) is a
long-acting, very potent β2-agonist,
which is used as a bronchodilator in the therapy of asthma
and
chronic bronchitis. Highly convergent synthesis of enantio-
and
diastereomerically pure (R,R)-formoterol fumarate
is achieved
by a chromatography-free process with an overall yield of
44%.
Asymmetric catalytic reduction of bromoketone 4 using
as
catalyst oxazaborolidine derived from (1R,
2S)-1-amino-2-indanol and resolution of chiral amine 3 are the origins
of
chirality in this process. Further enrichment of enantio-
and
diastereomeric purity is accomplished by crystallizations of
the
isolated intermediates throughout the process to give
(R,R)-formoterol (1) as the pure stereoisomer (ee, de
>99.5%).
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