Al III -Calix[4]arene Catalysts for Asymmetric Meerwein-Ponndorf- Verley Reduction Partha Nandi,* ,† Andrew Solovyov, Alexander Okrut, and Alexander Katz* ,† † Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States * S Supporting Information ABSTRACT: Chiral Al III -calixarene complexes were inves- tigated as catalysts for the asymmetric Meerwein-Ponndorf- Verley (MPV) reduction reaction when using chiral and achiral secondary alcohols as reductants. The most enantioselective catalyst consisted of a new axially chiral vaulted-hemispherical calix[4]arene phosphite ligand, which attained an enantiose- lective excess of 99%. This ligand consists of two lower-rim hydroxyl groups, with the remaining two lower-rim oxygens directly connected to the phosphorus of the phosphite, which is derived from a chiral diol. The results emphasize the importance of the rigid calix[4]arene lower-rim substituents and point to a possible role of a lower-rim chiral pocket and Lewis-basic phosphorus lone pairs in enhancing asymmetric hydride transfer. KEYWORDS: MPV reduction, chiral, asymmetric hydride transfer, Lewis-acid catalysis, calixarene complexes, phosphite ligand ■ INTRODUCTION The Meerwein-Ponndorf-Verley (MPV) reaction is a mild reduction method for ketones, which is catalyzed using nontoxic and earth-abundant main group elementsin this case, Lewis acidic Al(III) 1-4 and can be directed to introduce asymmetric carbons in prochiral ketones. There are several applications of this reaction, including a stereoselective variant that has been recently used for the synthesis of pharmaceutical building blocks for anti-HIV therapeutics. 3 In general, asymmetric MPV reduction can be tuned by using either a chiral alcohol as a sacrificial reductant or a chiral Lewis acid complex as a catalyst. Here, in this article, we investigate the essential catalyst structural features for asymmetric MPV reduction using Al(III)-calixarene complexes, in which the metal is placed in a chiral oxo environment. Our results demonstrate enantioselective Al-based catalysts for MPV reduction, which are among the few that accomplish this in the absence of chiral alcohol. 5,6 Our approach leverages lower-rim-substituted cone Al(III)- tert-butylcalix[4]arene complexes, which are tunable. We recently demonstrated these complexes as highly active homogeneous-catalyst sites for MPV reduction. 7,8 The Al- (III)-calixarene complex remained intact as observed using 1 H NMR spectroscopy during catalysis. The crucial role of the calixarene is to enforce active-site isolation in these catalysts, thereby avoiding aggregation of Al-alkoxide-type species, 7 which leads to coordinatively saturated hexacoordinate Lewis acid sites, which are catalytically inactive. This class of catalyst is 2-fold more active per Al site compared with freshly prepared aluminum isopropoxide, and active-site isolation was charac- terized previously using 27 Al NMR spectroscopy both in homogeneous as well as in grafted Al(III)-calixarene sites on silica. 7,8 This class of catalyst bridges the homogeneous- heterogeneous gap in that both homogeneous and grafted Al(III)-calixarene-on-silica variants of this molecular catalyst have the same per-site MPV activity. Also, in the case of the homogeneous catalyst, we demonstrated that the calixarene enabled synthesis of a molecular pocket, which affected accessibility and catalytic rate at the Al center. 7,8 Here, we build on the tunability of calixarene-based catalysts, with the synthesis of chiral 1,3-disubstituted lower-rim calixarene ligands, including new axially vaulted chiral hemispherical calixarene catalysts based on phosphite substituents, and demonstrate their catalytic utility for MPV reduction. ■ RESULTS AND DISCUSSION Our investigation of asymmetric MPV reduction used previously reported enantiopure chiral hemispherical calix[4]- arene ligands 1a-1c, shown in Table 1, 9 in which the asymmetric carbon is directly attached to the calixarene lower rim. We synthesized Al(III) complexes 2a-2c using these ligands (Table 1). This was accomplished by treating 1a-2c with 1 equivalent (with respect to calix[4]arene diol) of trimethylaluminum in toluene at room temperature for 3 min, followed by the addition of 4 equivalents (with respect to ketone substrate) of secondary alcohol as MPV reductant. Table 1 lists yields and enantioselectivity as measured by chiral gas chromatography for MPV reduction of 2-chloroacetophe- Received: February 13, 2014 Revised: May 6, 2014 Research Article pubs.acs.org/acscatalysis © XXXX American Chemical Society 2492 dx.doi.org/10.1021/cs5001976 | ACS Catal. 2014, 4, 2492-2495