Enantiopure sulfoxides are valuable precursors of organosulfur compounds with a broad application in organic and pharmaceutical chemistry. An unprecedented strategy for obtaining highly enantioenriched sulfoxides based on a hydrogenative kinetic resolution using Rh-complexes of phosphine-phosphites ligands as catalysts is reported. After optimization, highly efficient conditions for the kinetic resolution of racemic sulfoxides have been identified. This methodology has been applied to a set of racemic aralkyl or aryl vinyl sulfoxides and allowed the isolation of both recovered and reduced product in excellent yields and enantioselectivities (up to 99% and 97% ee, respectively; 16 examples).Optically pure sulfoxides are a valuable family of chiral compounds which have proven to be highly efficient chiral ligands 1 as well as useful intermediates in the synthesis of relevant biologically active compounds.1a,2 Among the approaches that asymmetric catalysis offers, kinetic resolution (KR) of racemic sulfoxides 3 should be considered an appealing method for the preparation of two optically pure sulfoxides in only one synthetic step, provided that some requisites are fulfilled. First and foremost, it is necessary that efficient enantioselective catalysts working at low catalyst loadings are available and, second, that starting materials and products can be isolated in good yields and enantiomerically enriched forms. 4Whilst the reported nonenzymatic KRs on racemic sulfoxides are mainly based on oxidative transformations (Scheme 1, (a)), 3,5 nonoxidative KRs, including reductive transformations (Scheme 1, (b)), have received much less attention. Moreover, nonoxidative KRs have normally offered unsatisfactory stereoselectivities, with the exception of enzymatic 6 transformations and hydrogenative dynamic kinetic resolutions (DKR) of allyl sulfoxides. 7 There are a few studies reporting reductive KR of vinyl sulfoxides with optically active reagents, 8 however, to the best of our knowledge, there are no previous reports on the KR of vinyl sulfoxides via asymmetric hydrogenation. 9 Scheme 1. Kinetic resolution strategies for racemic sulfoxidesOur group recently reported the highly enantioselective hydrogenation of a structurally diverse set of substrates mediated by phosphine-phosphite (POP) 10 ligands. The high catalytic activities achieved with our ligands promted us to address the challenge of hydrogenatively resolving racemic vinyl sulfoxides (Scheme 1, (c)), whose resolved products have found broad applicability in catalytic asymmetric synthesis.1,2 Herein we describe our results, which include the catalyst optimization studies and the application of the lead-catalyst to the highly efficient hydrogenative KR of an array of racemic aralkyl or aryl vinyl sulfoxides. At the onset of our study, we chose phenyl vinyl sulfoxide rac-1a as model substrate. The reaction conditions and the results of this initial screening are summarized in Table 1
Herein an overview of reductive catalytic enantioselective desymmetrisation of achiral or meso compounds is provided. The most efficient reductive desymmetrisations described in the literature, which involve the reduction of C=O, C=N, C=C and C-halogen bonds, or reductive ring-opening, are summarised. The structural diversity of the valuable highly enantioenriched intermediates prepared by reductive desymmetrisation is highlighted.
Highly efficient catalytic stereoselective hydrogenative desymmetrization reactions mediated by rhodium complexes derived from enantiopure phosphine-phosphite (POP) ligands are described. The highest performing ligand, which contains a TADDOL-derived phosphite fragment [TADDOL = (2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol)], presented excellent catalytic properties for the desymmetrization of a set of achiral 1,4-dienes, providing access to the selective formation of a variety of enantioenriched secondary and tertiary alcohols (six examples, up to 92% ee).The stereoselective desymmetrization of achiral and meso compounds has proved to be a powerful synthetic entry for the preparation of more elaborate optically enriched molecules. 1This transformation implies breaking the symmetry of the molecule by a synthetic operation, in which two enantiotopic groups of an achiral or meso compound are differentiated: the choice of one enantiotopic group (or face) over the other is provided by a chiral reagent or an enantioselective catalyst. Compared to other asymmetric catalytic methodologies, desymmetrization offers several advantages, 2 such as allowing the concurrent generation of multiple stereogenic centers in a single synthetic step. 3 The potential of this synthetic method has been demonstrated by its application in a wide range of catalytic asymmetric transformations.1 However, catalytic stereoselective desymmetrizations by reductive methods have been less studied 1c and for certain transformations, no satisfactory solution in terms of efficiency or chemo-and stereoselectivity has yet been developed. 4 For instance, the catalytic hydrogenative desymmetrization of achiral 1,4-dienes (Scheme 1) can be considered an example of understudied desymmetrization. Several challenges need to be addressed when developing efficient stereoselective catalysts for this transformation: Scheme 1. Stereoselective Hydrogenative Desymmetrization of a General Achiral 1,4-Diene (i) selectivity control in terms of obtaining the monohydrogenation product of the achiral 1,4-diene and (ii) the ability of the catalyst to differentiate two enantiotopic vinyl groups. Notable progress in this topic was made by Brown et al., who paved the way for desymmetrizing a set of achiral 1,4-dienes through enantioselective hydrogenation. These authors used enantiopure Rh bisphosphine complexes as catalysts and demonstrated the feasibility of this hydrogenative desymmetrization, though without complete control of the chemoselectivity of the reaction and with only moderate enantioselectivities (up to 53% ee). 5Following our efforts in developing highly efficient catalytic systems derived from phosphinephosphite (POP) ligands for asymmetric hydrogenations 6 and kinetic resolutions, 6k we became interested in developing enantioselective catalysts for the hydrogenative desymmetrization of achiral 1,4-dienes (Tables 1 and 3), as the resulting products can be considered versatile building blocks for the construction of more complex mole...
A detailed study is disclosed on the Rh‐mediated hydrogenative kinetic resolution of α,β‐unsaturated sulfoxides with alkyl and aryl substituents at the α‐, E‐ and Z‐positions of the double bond. This stereoselective catalytic methodology has enabled the preparation of highly enantioenriched (or even enantiopure) alkyl and aryl‐substituted (un)saturated sulfoxides via a simple and efficient synthetic operation. Moreover, the application of the hydrogenative KR to the preparation of valuable optically active sulfoxide‐containing building blocks or biologically active intermediates is described.
A new series of narrow-bite-angle phosphine–phosphite (1,1-P–OP) ligands (3a–d) has been efficiently prepared from the enantiopure (S P)-tert-butyl(hydroxymethyl)methylphosphino borane complex 1, a crucial intermediate. The catalytic performance of the ligands in Rh-mediated asymmetric hydrogenations and hydroformylations is described. The corresponding rhodium complexes provided excellent efficiencies (full conversion in all cases) and high enantioselectivities (up to 98% ee) for the asymmetric hydrogenation of structurally diverse functionalized alkenes. Furthermore, rhodium catalysts derived from these 1,1-P–OP ligands were highly active and gave excellent regioselectivities (branched/linear product ratios of up to 97/3) and moderate enantioselectivities in the hydroformylation of different terminal olefins.
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