Enantioselective synthesis of α-hydroxyketones using the ditox asymmetric building block (original) (raw)
Enzymatic diastereo- and enantioselective synthesis of α-alkyl-α,β-dihydroxyketones
Organic & Biomolecular Chemistry, 2011
An enzymatic strategy for the preparation of optically pure a-alkyl-a,b-dihydroxyketones is reported. Homo-and cross-coupling reactions of a-diketones catalyzed by acetylacetoin synthase (AAS) produce a set of a-alkyl-a-hydroxy-b-diketones (30-60%, ee 67-90%), which in turn are reduced regio-, diastereo-, and enantioselectively to the corresponding chiral a-alkyl-a,b-dihydroxyketones (60-70%, ee >95%) using acetylacetoin reductase (AAR) as catalyst. Both enzymes are obtained from Bacillus licheniformis and used in a crude form. The relative syn stereochemistry of the enantiopure a,b-dihydroxy products is assigned by NOE experiments, whereas their absolute configuration is determined by conversion of the selected 3,4-dihydroxy-3-methyl-pentan-2-one to the natural product (+)-citreodiol.
Cheminform, 2010
Catalytic asymmetric conjugate addition (ACA) reactions of carbon-based nucleophiles to β,β-disubstituted enones present an efficient approach to enantioselective synthesis of allcarbon quaternary stereogenic centers[1] that reside adjacent to synthetically versatile enolates [Eq. ( )]. In spite of recent advances involving catalytic ACA reactions of alkyl metal (mostly dialkyl zinc) reagents,[2-5] a number of critical short-comings remain unaddressed. One noteworthy challenge concerns transformations of β-substituted cyclopentenones, processes that are often less efficient[6,7] (vs. reactions of larger rings) but can deliver products that may be used in enantioselective syntheses of a variety of biologically active natural products.[8] Previously reported approaches, involving zinc-based reagents, are only effective with fivememberedring substrates when the enone bears an additional activating substituent.[4] Additions of trialkyl aluminum reagents to β-substituted cyclopentenones catalyzed by chiral copper phosphoramidites have been shown to proceed in three cases. In only a single instance, however, is high selectivity observed (ACA with Et 3 Al; 96.5:3.5 e.r., 93% ee).[5a] Herein, we disclose an efficient set of protocols for catalytic ACA reactions of alkyl and aryl aluminum reagents with a range of unactivated β-substituted cyclic enones, including cyclopentenones. Reactions, promoted in the presence of a chiral bidentate N-heterocyclic carbene (NHC) copper complex (5 mol%), are efficient (up to 97% yield) and highly selective (up to >99: <1 e.r., greater than 98% ee). In the case of transformations involving additions of aryl units, the requisite aluminum-based reagents are prepared in situ from commercially available dimethylaluminum chloride and the corresponding aryl lithium compounds. ** The NIH (GM-47480) and the NSF (CHE-0715138) provided financial support. T.L.M. is grateful for LaMattina and Novartis graduate fellowships; M.K.B. was the recipient of a Bristol-Myers Squibb graduate fellowship. Mass spectrometry facilities at Boston College are supported by the NSF (CHE-0619576).
Chemical Communications, 2010
Transketolase mutants have been identified that accept aromatic acceptors with good stereoselectivities, in particular benzaldehyde for which the wild type enzyme showed no activity. The advantages of using biocatalysts as a sustainable resource 10 in synthesis are well established and includes their potential to achieve high regio-and stereoselectivities. 1,2 Transketolase (TK) (E.C.2.2.1.1) is a thiamine diphosphate (ThDP) dependent carbon-carbon bond forming enzyme. 3 In vivo it reversibly transfers a two carbon ketol unit to D-erythrose-4-65 Notes and references
Advanced Synthesis & Catalysis, 2009
Regio-and stereoselective reductions of several diketones to afford enantiopure hydroxy ketones or diols were accomplished using isolated alcohol dehydrogenases (ADHs). Results could be rationalised taking into account different (promiscuous) substrate-binding modes in the active site of the enzyme. Furthermore, interesting natural cyclic diketones were also reduced with high regio-and stereoselectivity. Some of the 1,2-and 1,3-diketones used in this study were reduced by employing a low excess of the hydrogen donor (2-propanol) due to the quasi-irreversibility of these ADH-catalysed processes. Thus, using lower quantities of co-substrate, scale-up could be easily achieved.
Journal of Molecular Catalysis B: Enzymatic, 2009
Two different biocatalytic reactions-a C C cleavage and a C C forming reaction-were evaluated concerning their application in a reaction sequence. In the overall reaction, an aromatic alkene was converted to a chiral 2-hydroxy ketone. In the first step, the olefin trans-anethole was converted to para-anisaldehyde and acetaldehyde by an aqueous extract of the white rot fungus Trametes hirsuta G FCC 047. The selective oxidative cleavage of the carbon-carbon double bond was achieved using molecular oxygen as a substrate. In a second step p-anisaldehyde was ligated to acetaldehyde to yield either (R)-or (S)-2-hydroxy-1-(4-methoxyphenyl)-propanone. The reaction was catalyzed by the enantiocomplementary C C bond forming enzymes benzaldehyde lyase and benzoylformate decarboxylase, respectively.
Journal of the American Chemical Society, 2014
Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C−C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Brønsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/ donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo-and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,βunsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.