Divergent Asymmetric Synthesis of 3,5-Disubstituted Piperidines

Abstract

A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently obtained from N-benzylglycinate in five steps by the use of chemoenzymatic methods. In the subsequent enzyme- and Ru-catalyzed reaction, the rac/meso diol mixture was efficiently transformed to the cis-(3R,5S)-diacetate with excellent diastereoselectivity and in high yield. Further transformations of the cis-diacetate selectively delivered the cis-piperidine diol and the cis-(3R,5S)-hydroxy acetate. Alternatively, the DYKAT could be stopped at the monoacetate stage to give the trans-(3R,5R)-hydroxy acetate.

Shvo’s Catalyst in Hydrogen Transfer Reactions

“…The Shvo catalyst 1 was successfully used in the transfer hydrogenation of 1,3-diones to the corresponding 1,3-diols with isopropanol as the hydrogen donor (2) [36,37]. This reaction is synthetically useful for the reduction of cyclic diones since reduction of these diketones by LiAlH 4 preferentially gives the allylic alcohol [36].…”

“…This reaction is synthetically useful for the reduction of cyclic diones since reduction of these diketones by LiAlH 4 preferentially gives the allylic alcohol [36]. Also piperidine-3,5-diones were efficiently reduced to the corresponding diols by isopropanol using 1 as catalyst [37], and these diols were subsequently used in dynamic kinetic asymmetric transformations (DYKATs) to provide stereodefined 3,5-disubstituted piperidines [36,37]. 88 M.C.…”

Synthesis of cyclic 1,3-diols as scaffolds for spatially directed libraries

“…In 2006, Cossy reported a synthesis of enantioenriched 3,5-dihydroxy piperidine via ring-expansion of 4-hydroxyproline, 13 and Bäckvall reported a combined enzymatic/metallocatalysis route to related materials. 14 …”

Structure–Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio Hartree–Fock Calculations

“…Diketone 19, also decomposed on silica gel, 18 thus crude 19 was converted directly into 7-N-benzyl analogue 9 in 57% yield (Scheme 2).…”

“…This afforded the title compound as a pale-yellow oil (1.45 g, 7.50 mmol, 90% yield); R f 0.26 (EtOAc/heptane 1:1). 1 Ethyl 2-(Benzyl(2-oxopropyl)amino)acetate (18). Ethyl 2-(benzylamino)acetate (17) (165 mg, 853 μmol) and NaHCO 3 (72 mg, 853 μmol) were stirred in abs EtOH (3 mL) at 60°C under a N 2 atmosphere.…”