Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly Efficient Construction Method of Three Stereogenic Centers

Abstract

An improved asymmetric synthesis of renin inhibitor DS-8108b (1) is described. This compound consists of three intermediates: 4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contains three stereogenic centers. Especially, the chiral lactone is a key intermediate, and development of a scalable synthetic method was required, considering the quality, speed, and manufacturing cost. We established a scalable synthetic method of 1 from 4,6-O-benzylidene-d-glucose for early clinical studies. Furthermore, a highly efficient synthetic route of the chiral lactone for manufacturing was also successfully developed from n-butyryl chloride via Evans stereoselective alkylation, followed by stereoselective bromolactonization. In addition, a unique and highly efficient conversion protocol was developed from α-bromo-N-(2-nitrobenzenesulfonyl)amide to apparent rearranged diamine derivatives with a sequential aziridination–substitution reaction in one-pot.

Minimális fázisjelölés terc-butil csoporttal és alkalmazása Mitsunobu-, és Wittig-reakcióban

“…[58], [59], [60], [61], [62], [63], [64], [65], [66] Mindenképpen érdemes azonban megje- [69], [70], [71] Savas vagy bázikus funkciós csoportot tartalmazó olefinek esetében sóképzés [72] és/vagy pH változtatással járó extrakció alkalmazható a termék tisztítására. [73], [74], [75], [76], [77] Néhány esetben a Wittig reakció után a nyersterméket tisztítás nélkül alakítják tovább, majd egy későbbi lépésben, mikor a termék könnyebben elválasztható a foszfin-oxidtól végzik el a tisztítást. [78], [79] Fontos megjegyezni, hogy a fent említett példák csak különleges esetekben alkalmasak egyszerűsített tisztítási procedúra alkalmazására, ezért nagy jelentősége van a módosított foszfin reagensek fejlesztésének is.…”

Divergent Synthesis of α,γ-Disubstituted γ-Butyrolactones through Diastereoselective Bromolactonization with Alkali Metal Bromide: Asymmetric Total Synthesis of (+)-Dubiusamine C

“…In 1984, Yoshida and co-workers reported the 1,3- trans -selective halolactonization of α-alkyl- N , N -dimethyl-4-pentenamide with N -halosuccinimide (NXS) as the halogen reagent. Since then, the 1,3- trans -selective halolactonization of chiral α-alkyl-1-oxo-4-pentenyl carbonyl compounds bearing a chiral 2-oxazolidinone framework, derived from the method of Evans et al, has been extensively utilized for the asymmetric synthesis of biological products . We have developed various oxidative transformations via umpolung of bromide from alkali metal bromide instead of organic bromo reagents, and our approach has shown that alkali metal halides, one of the most abundant natural resources on earth, are stable in air, easy to handle, neutral, and nontoxic.…”

Catalyst- and solvent-free aminolysis of the asymmetric derivatives of Evans’ chiral N-acyloxazolidinones: enantioselective synthesis of chiral amides and its applications

“…The pioneering work of Evans on the use of chiral N -acyloxazolidinones 1A as chiral templates for diverse asymmetric C–C bond forming reactions 1 has forged a powerful asymmetric methodology (Scheme 1), 2 which is still widely used nowadays in the total synthesis of structurally complex natural products 2,3 and medicinal agents. 4 Significantly, the 1,3-dicarbonyl nature of the imides renders the achiral N -acyloxazolidinone auxiliaries 1B as valuable bidentate substrates for catalytic asymmetric reactions. 5…”