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Chapter 1
Asymmetric Synthesis of Axially Chiral Biaryls and Heterobiaryls
Abel Ros∗,†, ‡, Pedro Ramírez-López∗,§, Rosario Fernández†,¶,
and José María Lassaletta,∗,||
∗Instituto Investigaciones Químicas (CSIC-US),
C/Américo Vespucio, 49, 41092 Sevilla, Spain
†Departamento de Química Orgánica, Universidad de Sevilla,
C/Prof. García González, 1, 41012 Sevilla, Spain
1.Introduction
Obviously, the most straightforward approach to synthesize axially chiral biaryls is by coupling two aromatic reaction partners to generate the stereogenic axis as a new bond. Transition metal-catalyzed crosscoupling reactions constitute a broad family of methodologies for the formation of new C–C bonds. The number of such methodologies has exponentially increased over the last 20 years, constituting a breakthrough in the field of organic synthesis.1 This significance was recognized in 2010 with the Nobel Prize in Chemistry being awarded to Eichi Negishi, Akira Suzuki, and Richard Heck “for palladium-catalyzed cross-couplings in organic synthesis.” Using a variety of chiral ligands, these reactions have been widely explored for the synthesis of axially chiral biaryls, with varying degrees of success. Oxidative homo- and cross-couplings have also been used to achieve this aim. A handful of methods based on [2+2+2] cycloadditions, dynamic kinetic resolution (DKR) techniques, and central-to-axial chirality transfer complement the available alternatives.
2.Direct construction of the stereogenic axis
2.1.Atroposelective cross-coupling reactions
The introduction of at least three ortho substituents around a CAr–CAr bond is required, in general, to provide a configurationally stable stereogenic axis. Considering the huge diversity of available ortho-substituted aryl electrophiles and nucleophiles that can be used as coupling partners, the direct formation of the stereogenic axis by asymmetric cross-coupling reactions can be regarded as an elegant and efficient strategy for the asymmetric synthesis of chiral biaryls. Extremely efficient and selective catalytic systems for the direct formation of the CAr–CAr bonds have recently been developed, resulting in an exponential increase in the number of metal-catalyzed cross-coupling methodologies (mainly of the Suzuki-Miyaura type) for the asymmetric synthesis of axially chiral biaryl systems2,3 (Scheme 1).
Scheme 1.Asymmetric cross-coupling reactions.
Scheme 2.First examples of Ni-catalyzed asymmetric Kumada–Tamao–Corriu reactions.
2.1.1.Kumada and Negishi-type reactions
The first catalytic asymmetric version of a CAr–CAr cross-coupling reaction was described in 1975 by Kumada and co-workers.4,5 It consisted of a Kumada–Tamao–Corriu reaction between 1-bromo-2-methylnaphthalene 1a and 2-methyl-l-naphthylmagnesium bromide 2a using a Ni-based catalyst and a planar-chiral aminophosphine (PPFA) or an axially chiral diphosphine (NAPHOS) as the chiral ligand (Scheme 2). The reaction took place at room temperature, affording the desired product 3a with very low enantioselectivities of 4.5% and 12.5% ee, respectively. A few years later, Hayashi, Ito, and co-workers6 described a more efficient catalytic system based on monodentate phosphine ligands with planar chirality, which could be extended to non-functionalized Grignard reagents 1 and 1-bromonaphthalenes 2 to afford the desired binaphthyls 3 in moderate to excellent yields and enantioselectivities up to 95%.
As Pd-based catalytic systems usually exhibit better robustness, activity, and selectivity than their Ni counterparts,7 the groups of Frejd8 and Dorta9 decided to explore the use of Pd-based catalysts based on BINAP and chiral N-heterocyclic carbenes (NHCs) in the asymmetric Kumada reaction; however, only moderate enantioselectivities (up to 48%) were obtained in both cases. Aiming to exploit the higher functional group compatibilities of organozinc reagents, Espinet and co-workers10,11 developed an asymmetric Negishi coupling reaction for the synthesis of chiral biaryl systems. Thus, using different Pd(0) and Pd(II) sources and (R)-(pS)-PPFA as the chiral ligand, different ZnAr2 reagents were successfully coupled to afford binaphthyl products 3 with 60–95% yields and up to 85% ee. These Negishi reactions could be accelerated using of microwave techniques; however, there was a significant drop in the enantioselectivity. In contrast with the asymmetric Kumada reaction, the Negishi coupling methodology works with more valuable substrates such as ether derivatives 1 (R=OMe, OBn) to give the corresponding binaphthyl products 3 with moderate enantioselectivities (49–66%).
2.1.2.Suzuki-type reactions
Owing to the air and moisture sensitivity of Grignard and organozinc reagents, as well as their limited functional group tolerance, the asymmetric versions of the Kumada and Negishi reactions for asymmetric synthesis of axially chiral biaryl products have been less explored than the Suzuki–Miyaura reaction. The first Suzuki–Miyaura reactions for the asymmetric synthesis of axially chiral biaryl systems were described in mid-1990s and were based on diastereoselective coupling reactions using aryl halides with chiral auxiliaries.3 In 2000, Cammidge12 and Buchwald13 independently described the first catalytic asymmetric versions of the Pd-catalyzed Suzuki–Miyaura reaction using planar and axially chiral aminophosphine ligands (Scheme 3). In Cammidge’s approach, products 6 could be obtained in moderate yields of 44–50% and good enantioselectivities of up to 85%. However, this method was limited to non-functionalized substrates and only aryl iodides 4 could be used as the electrophilic coupling partner. On the other hand, Buchwald’s methodology showed higher versatility and the asymmetric coupling methodology could be extended to the synthesis of biaryls 10 containing –P(O)(OR)2, –NO2, and OMe substituents. Using KenPhos/Pd2(dba)3 (1.2:1, 1–4 mol%) as the catalyst, biaryl phosphonates 10 could b...
