Traditionally, ligands used in asymmetric catalysis have contained either stereogenic atoms or hindered single bonds (atropisomerism), or both. Here we demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of aryl boronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals generating bi- and tri-dentate ligands.
Abstract1-Deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase (DXR, also known as methyl-D-erythritol 4-phosphate (MEP) synthase) is a NADPH-dependent enzyme, which catalyzes the conversion of DXP to MEP in the non-mevalonate pathway of isoprene biosynthesis. Two mechanisms have been proposed for the DXR-catalyzed reaction. In the α-ketol rearrangement mechanism, the reaction begins with deprotonation of the C-3 hydroxyl group followed by a 1,2-migration to give methylerythrose phosphate, which is then reduced to MEP by NADPH. In the retroaldol/aldol rearrangement mechanism, DXR first cleaves the C3-C4 bond of DXP in a retroaldol manner to generate a three-carbon and a two-carbon phosphate bimolecular intermediate. These two species are then reunited by an aldol reaction to form a new C-C bond, yielding an aldehyde intermediate. Subsequent reduction by NADPH affords MEP. To differentiate these mechanisms, we have prepared [3-2 H]-and [4-2 H]-DXP and carried out a competitive secondary kinetic isotope effect (KIE) study of the DXR reaction. The normal 2° KIEs observed for [3-2 H]-and [4-2 H]-DXP provide compelling evidence supporting a retroaldol/aldol mechanism for the rearrangement catalyzed by DXR, with the rate-limiting step being cleavage of the C3-C4 bond of DXP.Terpenoids are a large family of secondary metabolites, consisting of more than 55,000 members, that are widely distributed in nature and rich in biological activities. 1,2 Terpenoids are biosynthesized starting with two 5-carbon isoprene units, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which have long been established to be derived from acetate in a pathway involving mevalonic acid as the key intermediate. 3 However, a new mevalonate-independent isoprene source has recently been discovered in eubacteria, archeabacteria, algae, and in the plastids of plants. [4][5][6] Since this pathway is absent in mammals but is essential for many pathogens, including Plasmodium falciparum 7 and Mycobacterium tuberculosis ,8 all enzymes in this pathway are potential antibacterial targets. 9The first committed step of this non-mevalonate pathway is the conversion of 1-deoxy-Dxylulose 5-phosphate (DXP, 1) to methyl-D-erythritol 4-phosphate (MEP, 2), catalyzed by the NADPH-dependent enzyme, DXP reductoisomerase (DXR, also known as MEP synthase, see Scheme 1). 10 Since MEP is the first metabolite specific to this pathway, this biosynthetic route is commonly referred to as the MEP pathway. Two mechanisms have been proposed for the Email: h.w.liu@mail.utexas.edu . DXR-catalyzed reaction (Scheme 1). In the α-ketol rearrangement mechanism (route A), the reaction begins with deprotonation of the C-3 hydroxyl group followed by a 1,2-(C4-to-C2)-migration to give methylerythrose phosphate (3), which is then reduced to MEP (2) by NADPH. NIH Public AccessIn the retroaldol/aldol mechanism (route B), DXR first cleaves the C3-C4 bond of 1 in a retroaldol manner to generate a three-carbon (4) and a two-carbon phosphate (5) Figure S1). 17 This phenomen...
Unsymmetrically substituted allenes (1,2 dienes) are inherently chiral and can be prepared in optically pure form. Nonetheless, to date the allene framework has not been incorporated into ligands for asymmetric catalysis. Since allenes project functionality differently than either tetrahedral carbon or chiral biaryls, they may create complementary chiral environments. This study demonstrates that optically active C 2 symmetric allene-containing bisphosphine oxides can catalyze the addition of SiCl 4 to meso epoxides with high enantioselectivity. The epoxide-opening likely involves generation of a Lewis acidic, cationic (bisphosphine oxide)SiCl 3 complex. The fact that high asymmetric induction is observed suggests that allenes may represent a new platform for the development of ligands and catalysts for asymmetric synthesis.Asymmetric catalysis has revolutionized the synthesis of chiral, non-racemic materials. It has been the subject of academic inquiry and industrial implementation. The last several decades have witnessed continued introduction and development of chiral organic catalysts and ligands for transition and main-group metals. 1 Most existing ligands and organic catalysts are characterized by either of two types of chirality: some species owe their chirality to stereogenic atoms, usually tetrahedral carbon or phosphorus. Many others are chiral by virtue of hindered rotation around a carbon-carbon single bond, the exemplar of which is the binaphthyl backbone. Some of the most successful catalysts combine the elements of both central and axial chirality. 2,3 Allenes can be chiral but have made only limited contributions to asymmetric catalysis to date. They were predicted to display chirality by van't Hoff over a century ago, 4 but, to the best of our knowledge, allenes have been used only once in catalytic quantities to control the stereochemical outcome of a reaction. In that report, Soai and coworkers demonstrated that optically active disubstituted allenes induced asymmetry in the addition of diisopropyl zinc to a pyrimidine carboxaldehyde. 5 The actual effectiveness of the allene as a chiral modulator was difficult to gauge because other experiments with the same system indicate that a strong nonlinear effect coupled with auto-catalysis conspire to amplify even unmeasurable enantiomeric excesses. 6 We hypothesized that allenes of the general structure A or B might represent attractive frameworks for developing ligands for asymmetric catalysis. 7 The unique architecture of the joseph.ready@utsouthwestern.edu. Supporting Information Available. Complete experimental details and characterization data including cif files. This material is available free of charge via the Internet at http://pubs.acs.org. Since phosphine oxides have shown promise as chiral Lewis bases, 8 we prepared a series of optically active mono-and bisphosphine oxides that contain an allene backbone (Scheme 1). Thus, proparygylic acetates 1 were prepared from the corresponding alcohols which, in turn, were generated in optica...
L(2)Pd(0) and L(2)Pd(II) complexes, where L= t-Bu(2)(p-NMe(2)C(6)H(4))P, have been identified as efficient catalyst systems for the Heck alkynylation of a variety of aryl bromides (17 examples) and aryl/heteroaryl chlorides (31 examples) with a range of aryl- and alkyl-acetylenes in excellent yields, under relatively low Pd loadings. The single-crystal X-ray structure determination of the presumably active catalytic species, L(2)Pd(0), was carried out in this study to better understand the superior activity of the current catalyst system from a structure-activity relationship point of view. The P-Pd-P bond angle indicates that the complex is bent (174.7°) in comparison to the perfectly linear (180.0°) structure of the analogous Pd(t-Bu(3)P)(2). Preliminary mechanistic studies on the negative copper effect and substrate effect of aryl acetylenes were conducted to better understand the cross-coupling pathway of Heck alkynylation.
Allenes can be synthesized via the direct SN2′ addition of hydride to propargylic alcohols. Previous examples of this approach, however, have involved harsh reaction conditions and have suffered from incomplete transfer of central chirality to axial chirality. Here we show that Cp2Zr(H)Cl can react with the zinc or magnesium alkoxides of propargylic alcohols to generate allenes in good yield and in high optical purity. Dialkyl-, alkyl-aryl-, and diaryl-allenes are accessible by this method. Furthermore, the reaction can provide silyl-substituted allenes, trisubstituted allenes, and terminal allenes.
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