Diastereoconvergent Synthesis of (–)‐Paroxetine

Abstract

A diastereoconvergent approach to (–)‐paroxetine from diastereomeric 3,4‐epoxy‐2‐piperidones is reported. For this synthesis, a regioselective and stereodivergent CuI‐catalyzed epoxide‐ring‐opening reaction of epoxyamide precursors to give the 4‐(4‐fluorophenyl)‐2‐piperidone skeleton with the correct absolute configuration is crucial. Using CuBr·SMe2 as a catalyst, the epoxide‐ring‐opening reaction takes place with inversion of configuration; the configuration is retained when CuI is used.

Studies towards the Total Synthesis of Aspergillide‐B

“…Accordingly, regio‐ and stereoselective Pd (0)‐Triphenylborate catalyzed opening of α,β‐unsaturated‐γ,δ‐epoxyester 9 with benzyl alcohol afforded syn ‐ 10 as a single stereoisomer in 52% yield . Reaction involves, rapid in situ formation of tribenzyl borate (PhCH 2 O) 3 B occur through alcohol‐phenol exchange reaction between (PhO) 3 B and BnOH, and the π‐allyl palladium species 9 a smoothly undergoes a benzyloxy substitution involving double inversion of configuration . The selective reduction of olefin 10 by using Mg in MeOH .…”

Stereoselective Synthesis and Antiallodynic Activity of 3‐Hydroxylated Paroxetines

“…With this structural modification, we anticipated effective biological activity either by increasing the solubility of the analogues in aqueous media or by means of an effective hydrogen bond interaction with the receptor [20,21] . To this end, we designed the synthesis of four 3‐hydroxylated paroxetines (3HPX) from chiral dehydropiperidine ( S )‐ 1 [22] (Scheme 1).…”

“…Regio‐ and stereoselective ring‐opening of glycidic amides 2 a and 2 b with the corresponding Grignard reagent ( p ‐F‐C 6 H 4 MgBr) via a S N 2 displacement to tertiary alcohols 3 a and 4 bb , respectively, was achieved by employing CuBr•SMe 2 as catalyst (e. g., 2 a to 3 a via A ; see Scheme 3). [22] On the other hand, ring‐opening of epoxyamides 2 a and 2 b with retention of the configuration to 3 aa and 4 b , respectively, was achieved by using the same Grignard reagent but different cupper catalyst (CuI). The retention of the configuration at C4 can be explained in terms of an initial S N 2 epoxide‐ring‐opening reaction mediated by CuI to give a transient trans ‐halohydrin followed by a subsequent S N 2 substitution with the aryl cuprate to give the corresponding alcohols 3 aa from 2 a and 4 b from 2 b (e. g., 2 a to 3 aa via B ; see Scheme 3).…”

“…The retention of the configuration at C4 can be explained in terms of an initial S N 2 epoxide‐ring‐opening reaction mediated by CuI to give a transient trans ‐halohydrin followed by a subsequent S N 2 substitution with the aryl cuprate to give the corresponding alcohols 3 aa from 2 a and 4 b from 2 b (e. g., 2 a to 3 aa via B ; see Scheme 3). [22] The four tertiary alcohols 3 a , 3 aa , 4 b and 4 bb were subjected to carbonyl reduction with LiAlH 4 to give 5 a , 5 aa , 6 b and 6 bb , respectively, in high chemical yields. Finally, removal of benzyl group of each 3‐hydoxy piperidines 5 a , 5 aa , 6 b and 6 bb with H 2 and Pd(OH) 2 under acidic media (4 M, HCl), provided the target products ( R , R )‐ 3HPX , ( R , S )‐ 3HPX , ( S , R )‐ 3HPX , and ( S , S )‐ 3HPX , respectively, in their hydrochloride forms (Scheme 2).…”

Transition‐Metal‐Free Deconstructive Lactamization of Piperidines

“…[6][7][8][9][10] In recent years,o ur research group has developed efficient, accessible,e conomic,a nd environmentally friendly protocols for the functionalization of simple N-heterocycle substrates to give relevant bioactive precursors. [11] Thesuccess of this direct functionalization of pre-existing N-heterocycles lies in the highly selective CÀHo xidation at the a position mediated by cheap and environmentally friendly reagents such as NaClO 2 ,N aOCl, and 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO), in which, under modulated conditions,t he C À Hoxidation at the b position can be achieved, even under catalytic conditions. [11a] In this work, we introduce asimple protocol that permits the transformation of piperidines to 2-pyrrolidinones via the deconstructive functionalization of ap iperidinesC (sp 3 )-C(sp 3 )single bond to pyrrolidinonesC(sp 2 )-N "single" bond.…”