Catalytic Enantioselective Nazarov Cyclization

Abstract

A detailed account of an asymmetric Nazarov cyclization that leads to α‐hydroxycyclopentenones bearing either vicinal, all‐carbon quaternary centers, or vicinal quaternary and tertiary centers is given. The all‐aliphatic examples represent the greatest challenge, as the dienone starting materials are not activated toward cyclization by an aryl group. The rational design and optimization of the substrates in parallel with optimization of the chiral Brønsted acid catalyst is also described, as well as a series of diastereoselective transformations of a fully substituted cyclopentenone product.

Direct construction of vicinal all-carbon quaternary stereocenters in natural product synthesis

“…5 In 2004, Overman and Peterson presented a perspective on the direct asymmetrical formation of vicinal all-carbon quaternary stereogenic centers in natural product synthesis .6 Since then, many elegant methodologies have been developed, [7][8][9][10][11][12][13][14][15] and methods for the catalytic asymmetric construction of vicinal all-carbon quaternary stereogenic centers have been reported. [16][17][18][19][20][21][22][23][24][25][26][27][28] Although a comprehensive review of the synthesis of vicinal 50 all-carbon quaternary stereogenic centers is beyond the scope of this review, we herein report the powerful reactions that can form this challenging motif in "a single operation" and that have been successfully applied to the total synthesis of complex natural products. This review has been organized based on reaction types, 55 and highlights their usefulness in the construction of structurally diverse vicinal all-carbon quaternary centers.…”

Asymmetric synthesis of multiple quaternary stereocentre-containing cyclopentyls by oxazolidinone-promoted Nazarov cyclizations

“…Careful design of the divinyl ketone 1 with dual-activating electron donor (OCHPh 2 ) and acceptor (CO 2 R) elements was key to attaining efficient cyclization. 6 Electrofugal release of Ph 2 HC + from the intermediate oxyallyl cation 2 further promoted the cyclization and suppressed competing Wagner–Meerwein rearrangements ([1,2]-sigmatropic shifts of R 1–3 within 2 ). Herein, we report that highly substituted aryl vinyl and divinyl ketones 5 can be readily accessed through carbometalations of oxazolidinone ( Ox )-substituted ynamides 4 ( Scheme 1b ).…”

“…3 However, the potential of the Nazarov cyclization for 4°-stereocentre formation has not yet been fully realized due to two significant challenges: (i) stereoselective access to highly substituted divinyl (and aryl vinyl) ketone substrates 4 and (ii) torquoselective 5 ring closure. In a landmark study, Tius and co-workers 6 reported chiral Brønsted acid-catalyzed Nazarov cyclizations of divinyl ketones 1 ( Scheme 1a ) leading to cyclopentenols 3 containing two new vicinal 4°-stereocentres (R 1–3 ≠ H) with high enantioselectivities (often er > 97 : 3). Careful design of the divinyl ketone 1 with dual-activating electron donor (OCHPh 2 ) and acceptor (CO 2 R) elements was key to attaining efficient cyclization.…”

Optimization of Nazarov Cyclization of 2,4-Dimethyl-1,5-diphenylpenta-1,4-dien-3-one in Deep Eutectic Solvents by a Design of Experiments Approach

“…The Nazarov reaction consists in the electrocyclization of divinyl ketones to cyclopentenones through a 4π conrotatory mechanism promoted by Bronsted (BA) or Lewis acids (LA). Many versions of such protocol have been recently developed, both in terms of substrates suitable for cyclization [6] and promoters, including transition metals catalysts [7][8][9][10][11], organocatalysts [12][13][14][15], and UV irradiation (photo-Nazarov reaction) [16].…”