Keto lactones, enantioselective

Availability. Although commercially available via the degradation of pantothenic acid, (i )-pantolactone is also conveniently prepared by enantioselective reduction of its corresponding keto lactone employing homogeneous catalysis," " or by microbial methods. The (5)-enantiomer has been prepared by inversion of the natural product in 90% yield and 97% ee via triflate activation, acetate displacement, and Lithium Hydroxide hydrolysis. The enantiomers were also prepared by resolution of the race-mate with (R)- and (5)-phenethylamine. A gas chromatographic method exists for ee determination. ... 

There are many classes of substrate structures involved in heterogeneous enantioselective hydrogenation on modified metal catalysts. They consist of 2-oxocarboxylic acids and their esters, ketones, diketones, keto lactones, imsaturated acids, oximes, and amides. Enantioselectivities of heterogeneous chirally modified metal catalysts are determined in an important way by the matched interactions between die functional groups of the substrate and the modifier. 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

A BINAP-Ru catalyzed asymmetric hydrogenation ofy-keto esters and o-acylbenzoic esters gives y-lactones and o-phthalides, respectively, with an excellent enantioselectivity (Scheme 1.36) [190,191], The sense of enantioselection is the same as that in the hydrogenation of a-and (3-keto esters. 

The product is the lactone derived from the hydroxy acid that would result from a normal Cannizzaro reaction. Chiral additives have been used, but with bis(oxazo-lidine) derivatives the reaction proceeded with poor enantioselectivity. ° a-Keto aldehydes give internal Cannizzaro reactions ... 

Asymmetric hydroxylation of etiolates. Davis and Chen1 have reviewed this reaction using in particular (R,R)- and (S,S)-2-phenylsulfonyl)-3-phcnyloxaziridene (1) and (camphorylsulfonyl)oxaziridine (2). Of these reagents, 1 and ( + )- and (—)-2, derived from (lR)-lO-camphorsulfonic acid, provide highest enantioselectivity and in addition are easy to prepare. They are effective for hydroxylatation of ketones, esters, /2-keto esters, amides, lactones, and lactams. 

If the reactivity of the substrate in the shielded [substrate-modifier] complexes is higher than that of the free keto ester, enantioselectivity can occur. According to Margitfalvi the quinuclidine N, which aims towards the keto carbonyl group in the keto ester, provides the increased reactivity of the keto carbonyl group. This shielding model, can e q)lain enantioselectivity and rate acceleration effects for almost all substrates used in many examples, for example, hydrogenation of MePy, MBf, ketopanto-lactone, and trifluoroacetophenone over Pt-alumina-Cnd catalysts. 

Moving to a related type of [2 + 2] cycloaddition, not involving aldehydes or imines as partners, Calter and coworkers reported Cinchona alkaloid (TMSO-QN) catalysed asymmetric dimerisation of ketenes, generated in situ from the corresponding acid chlorides, yielding (3-lactones via a formal Claisen condensation (Scheme 14.29). The unstable ketene dimers were trapped with an alko>yamine to afford p-keto amides i.e. Weinreb amides) with variable yields and excellent enantioselectivities. 

The 2b-catalyzed reduction of j or 8-keto esters provided the corresponding hydroxy esters with high enantioselectivity (Scheme 11.9) [5b], while the reduction of a-keto esters was less effective [6b, 44b, 59]. Desymmetrization of meso-imides 31 via stereoselective reduction is one of the most powerful transformations to provide products with three new chiral centers. Such transformations with good enantioselectivities were achieved by OABs-catalyzed reductions (Scheme 11.10) [60-62], The hydroxy lactams 32 obtained were easily converted into ethoxy lactams 33 by acidic ethanoly-sis, and were transformed into chiral lactones 34 by sodium borohydride reduction. 

Following this pioneering work, other metals with various chiral ligands were added to the list of successful systems able to catalyze electrophilic fluorination on a wide range of substrates in particular, this includes Pd, Ni, Cu, Zn, and Ru catalysts. Indeed, efficient enantioselective fluo-rinations of various p-keto esters, oxindoles, rcrt-butoxy-carbonyl lactones and lactams, and p-keto phosphonates... 

In these cases, NFSI was preferred to Selectfluor and the reactions were performed either in alcohol or in ionic liquids in which the palladium complexes can be immobilized and reused with excellent reproducibility even after 10 consecutive cycles. For example, the enantioselective electrophilic fluorination of 2-methyl-3-oxo-3-phenylpro-pionic acid tert-butyl ester in [hmim] [BF4] gives the corresponding fluorinated product in 93% yield with 92% ee, and still in 67% yield with 91% ee after 10 cycles. The fluorination of various cyclic and acyclic (3-keto esters was carried out with NFSI in ethanol in the presence of 2.5 mol% of catalyst, leading to excellent ee-values up to 94%. The reaction is not sensitive to water, can be run on a 1-g scale, and proceeds via a palladium enolate complex as for the titanium-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyl-dioxolane (TADDOL) catalyst. The reaction was extended to tert-butoxycarbonyl lactones and lactams. Reactions with lactones proceeded smoothly in an alcoholic solvent with 2.5 mol% of catalyst and NFSI, while the less acidic lactam substrates required concurrent use of the Pd complex and 2,6-lutidine as a co-catalyst. Under the reaction conditions, the fluorinated lactones and lactams were obtained in good yields with excellent enantioselectivities (up to 99%... 

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