Asymmetric Methods for the Synthesis of Flavanones, Chromanones, and Azaflavanones

Abstract

Flavanones, chromanones, and related structures are privileged natural products that display a wide variety of biological activities. Although flavanoids are abundant in nature, there are a limited number of available general and efficient synthetic methods for accessing molecules of this class in a stereoselective manner. Their structurally simple architectures belie the difficulties involved in installation and maintenance of the stereogenic configuration at the C2 position, which can be sensitive and can undergo epimerization under mildly acidic, basic, and thermal reaction conditions. This review presents the methods currently used to access these related structures. The synthetic methods include manipulation of the flavone/flavanone core, carbon-carbon bond formation, and carbon-heteroatom bond formation.

Figure 1

Flavanoid nomenclature.

Figure 2

Representative biologically active flavanoid natural products.

Figure 3

General methods for accessing enantio-enriched flavanoids.

Scheme 1

Base-promoted racemization of enantio-enriched flavanones.

Scheme 2

Asymmetric hydrogenation of 4-chromone 1.

Scheme 3

Asymmetric hydrogenation of 4-chromone 3.

Scheme 4

Resolution of (±)-flavanone (5) through the synthesis of ketals 6a and 6b.

Scheme 5

Resolution of (±)-flavanone (5) through conversion into cis-amines 7a and 7b.

Scheme 6

Enzymatic kinetic resolution of racemic flavanol acetate 9.

Scheme 7

Enzymatic kinetic resolution of racemic flavanone oxime acetate 10.

Scheme 8

Lipase-catalyzed kinetic resolution of racemic flavanol 8.

Scheme 9

Enzymatic resolution of flavanones via Mitsunobu construction of α-phenoxyester 14.

Scheme 10

Kinetic resolution of 2-substituted 2,3-dihydro-4-quinolones 17 through palladium-catalyzed asymmetric allylic alkylation.

Scheme 11

Diastereoselective cojugate addition to sulfinylchromone 20.

Scheme 12

Total synthesis of the originally proposed structure of leridol (25).

Scheme 13

Highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to 4-chromanone (26).

Scheme 14

Asymmetric synthesis of 2-aryl-2,3-dihydro-4-quinolones 32 by rhodium-catalyzed 1,4-addition of arylzinc reagents in the presence of chlorotrimethylsilane.

Scheme 15

Rhodium-catalyzed asymmetric 1,4-additions of sodium tetraarylborates to 4-chromones 33 in the presence of a C₂-symmetric chiral bis-sulfoxide ligand.

Scheme 16

Enantioselective synthesis of flavanones 34 through rhodium-catalyzed 1,4-additions of phenylboronic acid derivatives.

Scheme 17

Enantioselective synthesis of (S)-pinostrobin (38) through a rhodium-catalyzed 1,4-addition of phenylboronic acid.

Scheme 18

Quinine-catalyzed stereoselective cyclization of o-tigloylphenol 39.

Scheme 19

Quinine-catalyzed asymmetric cyclization of 2′,6′-dihydroxychalcone 42.

Scheme 20

Catalytic enantioselective synthesis of flavanones and chromanones 45 from alkylidenes 44.

Scheme 21

Total synthesis of flindersiachromanone (47) through a single-flask Knoevenagel condensation/cyclization/decarboxylation sequence.

Scheme 22

Ni^II-catalyzed cyclization of alkylidenes 44.

Scheme 23

Cyclization of alkylidenes 44 catalyzed by chiral N-triflyl phosphoramides.

Scheme 24

Asymmetric synthesis of 2-aryl-2,3-dihydro-4-quinolones 49 catalyzed by bifunctional thioureas.

Scheme 25

Tandem intramolecular conjugate addition/decarboxylation reaction sequences from alkylidenes 50.

Scheme 26

Synthesis of chiral 2-methylchromanone 54.

Scheme 27

First total synthesis of (–)-pinostrobin (38).

Scheme 28

Synthesis of (2R)-flavanone (5) through a dithiane addition/intramolecular Mitsunobu inversion sequence.

Scheme 29

Tandem cyclization/fluorination sequences starting from alkylidenes 61.

Scheme 30

Tandem intramolecular conjugate addition/Michael addition or halogenation sequences.

Scheme 31

Oxidative cyclization of 2-(1-hydroxybut-3-en-1-yl)-phenol.