Organocatalytic Asymmetric Total Synthesis of (R)-Rolipram and Formal Synthesis of (3S,4R)-Paroxetine

Abstract

An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling

“…Because the latter is a known, advanced intermediate to paroxetine 38 , this sequence constitutes a formal synthesis of (þ)-paroxetine that can be accomplished in only seven steps from commercial t-Boc 4-piperidinone. This concise route compares favourably with the most recent enantioselective syntheses [39][40][41][42] , which were achieved, respectively, in 4 (82% ee) 8 (99% ee), 15 (95% ee) and 8 (94% ee) steps. The above-described syntheses of (þ)-anabasine and (þ)-paroxetine highlight how the use of a different catalyst/ ligand in the Suzuki Miyaura cross-coupling provides a regiodivergent access to optically enriched piperidine derivatives of great utility in medicinal chemistry.…”

Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

“…They have been used in the synthesis of many nitrogen containing functional groups including α-amino carbonyls, 2, 3 1,2-diamines, [4][5][6][7] peptidomimetics, 8 natural products [9][10][11][12][13][14][15] and many heterocyclic small molecules. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] To address the paucity of structurally diverse nitroalkanes we have developed conjugate addition nitro-Mannich protocols (Scheme 1). [30][31][32] The use of nitroalkenes (prepared via the Henry reaction) provides easy access to more structurally complex nitro coupling partners, thereby generating β-nitroamines with higher levels of functionality which may be further manipulated to produce a range of useful intermediates.…”

New Multicomponent Reaction for the Direct Synthesis of β-Aryl-γ-nitroesters Promoted by Hydrotalcite-Derived Mixed Oxides as Heterogeneous Catalyst

“…The reduction of the nitro group in the presence of NaBH 4 /NiCl 2 ·6H 2 O in ethanol led directly to the isolation of the lactams 14 and 15 in yields of 82 and 87%, respectively. 42 The transformation of the respective lactams into the GABA-derivatives was achieved in presence of HCl 6 mol L -1 , under reflux for 12 hours. 43 Afterwards, Phenibut was isolated in an 88% yield, and Baclofen was produced in an 89% yield, both in the chloridrate form.…”