Facile Syntheses of Enantiopure 3-Hydroxypiperidine Derivatives and 3-Hydroxypipecolic Acids

Abstract

Facile syntheses of enantiopure trans- and cis-3-hydroxypiperidine derivatives and 3-hydroxypipecolic acids are reported, featuring Rh-catalyzed cyclohydrocarbonylation through common intermediates. A diaxial conformation in a 2,3-disubstituted N-Boc-piperidinyl structure is revealed by an X-ray crystallographic analysis.

Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes

“…Benzyl protection of compound 45 and subsequent deprotection of the silyl group furnished alcohol 46 in 94 % yield, which further underwent azoniabicycle formation and ring‐opening with NaOAc to furnish compound 47 in 84 % yield and >9:1 regioselectivity. Removal of the acetyl group under basic hydrolysis, followed by debenzylation in the presence of Boc 2 O, gave known intermediate 48 in 93 % yield …”

“…M.p. 123–125 °C; [ α ] =+30.1 ( c= 1.0, MeOH); lit . [ α ] =+29.8 ( c =0.99, MeOH); 1 H NMR (400 MHz, CDCl 3 ): δ =4.15 (td, J= 7.1, 3.3 Hz, 1 H), 3.97 (d, J= 3.1 Hz, 1 H), 3.91–3.65 (m, 3 H), 2.98 (t, J= 11.3 Hz, 1 H), 2.85 (br s, 2 H), 1.94–1.64 (m, 3 H), 1.46 (s, 9 H), 1.45–1.39 ppm (m, 1 H); 13 C NMR (CDCl 3 , 101 MHz): δ =156.6, 80.1, 64.5, 60.3, 59.8, 40.5, 28.3, 27.0, 19.3 ppm; HRMS (MALDI): m / z calcd for C 22 H 42 N 2 O 8 : 485.2833 [2 M +Na] + ; found: 485.2830.…”

Domino Reactions Triggered by Hydroformylation

“…A quite similar protocol has been used for the synthesis of 3-hydroxypipecolic acid derivatives [37] and homokainoids (Scheme 14) [38]. Mann and Taddei widely explored CHC for stereoselective synthesis of heterocyclic compounds in cascade with other transformations such as: CHC/aza-Sakurai Hosomi, CHC/aza-Sakurai Hosomi/HF, and CHC/Pictect-Spengler [39].…”

Synthesis of (±)-Aphanorphine Using Rh-Catalyzed Cyclohydrocarbonylation

“…As part of our interest in synthesis of medicinal active alkaloids for medicinally purposes, our group has utilized the Rh-catalyzed cyclohydrocarbonylation − strategy as a practical route to construct the piperidines, pyrrolidinoindoline and tetrahydrofuranoindoline alkaloids. , Here we report our progress in using this methodology to construct bridged benzazepine skeleton and its application to the formal syntheses of aphanorphine and its analogue.…”