Catalytic Enantioselective Nazarov Cyclization: Construction of Vicinal All‐Carbon‐Atom Quaternary Stereocenters

Abstract

Abstract:The diastereoselective asymmetric synthesis of vicinal all-carbon-atom quaternary stereocenters is a challenging problem in organic synthesis for which only few solutions have been described. A catalytic asymmetric Nazarov cyclization of fully substituted dienones that provides cyclopentenone derivatives with vicinal quaternary stereocenters in high optical purity and as single diastereoisomers is now reported.The catalytic asymmetric synthesis of vicinal, all-carbonatom quaternary stereocenters presents a difficult challenge for which only a small number of solutions, none of which are completely general, have been described to date.[1] The enantioselective version of the reaction that is shown in Equation (1) would constitute a new solution to this problem. None of the asymmetric Nazarov cyclizations that have been described thus far [2] form vicinal quaternary stereocenters. At best, vicinal quaternary and tertiary stereocenters could be generated. [3] Polarization of the acyclic dienone precursor [4] accelerates the Nazarov cyclization.[5] We have previously disclosed the highly diastereoselective triflimide-catalyzed cyclization that converts dienone 1 into cyclopentenone 2 in 80 % yield [Eq. (1)].[6] The stereochemistry of 2 reveals that a conrotatory process, which is required to conserve orbital symmetry, has occurred. The polarization of "push-pull" dienone 1 and the rapid termination process that is enabled through loss of the 2-(trimethylsilyl)ethoxymethyl (SEM) group contribute to the success of this cyclization, which results in the formation of vicinal all-carbon-atom quaternary stereocenters. Rapid termination is especially important in the case of Nazarov cyclizations that lead to sterically congested products as Wagner-Meerwein rearrangements of the intermediate cyclic cation, which would be driven by relief of steric compression, have to be suppressed.[7] Herein, we report the first catalytic asymmetric Nazarov cyclization of fully substituted dienones for the construction of vicinal all-carbon-atom stereocenters.We had confidence that an asymmetric version of the cyclization that is shown in Equation (1) could be developed through systematic variation of the enol ether and ester groups, which could serve as recognition elements for a catalyst. The process could be optimized through iterative changes in catalyst, solvent, and additive(s). As the enol ether moiety must depart as a stable cation following the cyclization, its choice does not restrict the structural types of cyclopentenones that might be accessed by this reaction.We chose the (R)-BINOL scaffold for our screen of chiral Brønsted acids.[8] The broad utility of this class of compounds for a variety of catalytic asymmetric reactions is related to the ease with which substituents at the C3 and C3' positions can be introduced to quickly assemble a library of catalysts. [9] Catalyst optimization is summarized in Table 1. The phenyl ester group in 3 strongly influenced the enantioselectivity of the reaction. The ethyl ester analo...

Experimental and Computational Study of the Catalytic Asymmetric 4π‐Electrocyclization of N‐Heterocycles

“…[1] In general, the reaction can be carried out using Brønsted or Lewis acid catalysis; however, only few asymmetric versions have been developed. [2][3][4][5] With regard to the asymmetric versions, the Nazarov cyclization of aromatic and heteroaromatic substrates presents a major challenge. [4][5][6][7] To our knowledge, an asymmetric 4p-electrocyclization of N-heterocycles has not been described so far.…”

Pentanidium-Catalyzed Direct Assembly of Vicinal All-Carbon Quaternary Stereocenters through C(sp3)-C(sp3) Bond Formation

“…5,6 Amongst the limited number of strategies, for the formation of this highly congested moiety, double Heck coupling, 7,8 double Aldol reaction, 9 and double allylation 10 have been reported to be useful (Figure 1a). Separately, the use of multi-substituted alkenes in [3+2] annulation, 11,12 Diels-Alder [13][14][15] and other cycloadditions 16,17 is another common approach (Figure 1a). Recent advances include dearomatization addition of b-naphthols on 3bromooxindoles, 18 Claisen rearrangement of g,d-unsaturated carbonyl compounds, 19 dialkylation of bisoxindoles, 20 phosphine-catalyzed cyclization of allenes 21 and a nucleophilic substitution at a quaternary carbon center with concomitant opening of a cyclopropane ring.…”