A Practical and Enantiospecific Synthesis of (−)‐(R)‐ and (+)‐(S)‐Piperidin‐3‐ols

Abstract

A highly enantiospecific, azide-free synthesis of (À)-(R)-and (þ)-(S)-piperidin-3-ol in excellent yield was developed. The key step of the synthesis involves the enantiospecific ring openings of enantiomerically pure (R)-and (S)-2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-diones with the diethyl malonate anion and subsequent decarboxylation.

Characterization of a Carbonyl Reductase from Rhodococcus erythropolis WZ010 and Its Variant Y54F for Asymmetric Synthesis of (S)-N-Boc-3-Hydroxypiperidine

“…Many natural products and active pharmaceutical ingredients share a common piperidine core, and the introduction of a chiral hydroxyl group on the C3-position of the piperidine ring may alter the bioactivity of the molecule [1,2,3]. ( S )- N -Boc-3-hydroxypiperidine (( S )-NBHP) is a key chiral intermediate in the synthesis of ibrutinib as the inhibitor of Bruton’s tyrosine kinase [4].…”

“…In the chemical synthesis of ( S )-NBHP, employed strategies include the synthesis of racemic 3-hydroxypiperidine followed by chiral resolution and the enantiospecific synthesis of ( S )-NBHP from chiral precursors. The former only achieves a maximum yield of 50%, making the process economically unviable, while the latter appears to be limited because of the lengthy procedure, rather poor yields of the products, and the use of potentially hazardous reagents [1,5,6]. Alternatively, the carbonyl-reductase-catalyzed asymmetric reduction of N -Boc-3-piperidone (NBPO) has gained increasing focus due to its mild reaction conditions, high yield, and remarkable enantioselectivity [4,7,8,9].…”

Phenylphenothiazine-Based Porous Organic Polymers as Visible-Light Heterogeneous Photocatalysts for Switchable Bromoalkylation and Cyclopropanation of Unactivated Terminal Alkenes

“…When 3b was treated with silver acetate in acetic acid, lactonization occurred smoothly to yield 6 along with 7 , which was formed followed by a spontaneous decarboxylation (eq 2). By using stoichiometric amounts of LiCl at elevated temperature, 6 could be further converted into 7 , which has been identified as a key intermediate for the synthesis of piperidone and related analogues (65% yield, eq 3) . Notably, 5 could be alternatively delivered starting from 4b under identical conditions with that of eq 1 (44% yield, eq 4).…”