Enantioselectivity hydroxyalkylation

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

Aggregation between lithiated dipolar entities throughout a catalytic cycle for enantioselective hydroxyalkylation of an aldehyde by cat -RLi has been studied. Up to 90%... 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

Kinetic resolutions by means of the selective formation or hydrolysis of an ester group in enzyme-catalyzed reactions proved to be a successful strategy in the enantioseparation of 1,3-oxazine derivatives. Hydrolysis of the racemic laurate ester 275 in the presence of lipase QL resulted in formation of the enantiomerically pure alcohol derivative 276 besides the (23, 3R)-enantiomer of the unreacted ester 275 (Equation 25) <1996TA1241 >. The porcine pancreatic lipase-catalyzed acylation of 3-(tu-hydroxyalkyl)-4-substituted-3,4-dihydro-2/7-l,3-oxazines with vinyl acetate in tetrahydrofuran (THF) took place in an enantioselective fashion, despite the considerable distance of the acylated hydroxy group and the asymmetric center of the molecule <2001PAC167, 2003IJB1958>. 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

Based on these results, attempts have been made to apply enantioselective dehydrogenations with horse liver alcohol dehydrogenase HLADH, E.C. 1.1.1.1), in the presence of NAD+, for kinetic resolution of the isomeric (hydroxyalkyl)silanes rac-105, rac- 107... 

Based on the previous work of this group on the three-component aza[4+2]/ allylboration strategy to construct polysubstituted piperidines [62], Gao and Hall developed a catalytic enantioselective version [63] of the corresponding oxygeneous process to construct a-hydroxyalkylated pyrans from 3-boronoacrolein [64], This recent variant of a Vaultier-Lallemand one-pot three-component reaction (see Scheme 12.14) was successfully applied to a concise total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide 128 (Scheme 12.20), the oviposition attractant pheromone of the female Culex mosquito [65] capable of transmitting the West Nile virus. 

Shang, C-S. Hsu, C-S. Lipase-catalyzed enantioselective esterification of (S)-naproxen hydroxyalkyl ester in organic media. Biotechnology Letters 2003, 25 413-416. 

Hydroxyalkylphosphonates have been prepared by reduction of the corresponding ketones. These include phosphonomalate esters by highly diastereose-lective reduction of 3-phosphonopyruvates with NHs.BHa and both 2-hydroxyalkyl-phosphonates, e.g. 178, and thiophosphonates by asymmetric hydrogenation using chiral ruthenium catalysts. An enantioselective synthesis, from 179, of both enantiomers of phosphonothrixin 180 and their absolute stereochemistry have been reported.The epoxide 179 was prepared from 2-methy -3-hydroxymethyl-1,3-butadiene via a Sharpless epoxidation. 

The hydroxyalkylation of phenols with chiral glyoxylates, followed by hydrolysis, gives regioselectively 2-hydroxymandelic acids with high enantioselectivity (eqnation 28). The crystal-structure determination of the titanium phenoxide complex shows evidence for chelation-controlled reaction giving the observed high enantioselectivities . ... 

Suginome and Ito have developed a reliable method for the synthesis of highly enantioenriched allyl- and allenylsilanes. The synthetic process involves 1,3-chirality transfer from homochiral allyl and propargyl alcohols through Pd-catalyzed intramolecular bis-silylation and subsequent Peterson-type elimination (Scheme 10.142) [395]. This method provides an efficient route to enantioenriched allylsilanes bearing a hydroxyalkyl group, which are very valuable as synthetic intermediates for diastereo- and enantioselective synthesis of heterocycies and carbocycles [396]. Polymer-supported highly enantioenriched allylsilanes have been prepared from enantioenriched allyl alcohols and a polymer-supported disilanyl chloride [397]. 

The one-step transformation of 2- or 3-(l-hydroxyalkyl)-2,3-dihydrobenzofurans to 2- or 3-acylbenzofurans with A -bromosuccinimide was performed with good yields <97H(45)1657>. The asymmetric reduction of dihydrobenzofuran ketoxime ethers to enantiomerically enriched chiral hydroxylamines with reagents prepared from borane and norephedrine has been investigated <97TA497>. An enzymatic resolution of a 3-hydroxymethylbenzofuran using Candida rugosa lipase provides an enantioselective synthesis of vitamin E related antioxidants <97TA45>. 

For the preparation of the hydroxyalkyl-substituted Cig phenol with (S)-configuration at C(17) (Scheme 40), one variant involving no stereoselection and two using enantioselection have been developed. 

A relatively high energetic difference between epimeric complexes 249 and epi-249, comprised of a-methoxybenzylHthium and (S,S)-Box-i-Pr (248), is the origin of the highly enantioselective carboxylation and hydroxyalkylation reported by Nakai et al. [Eq. (69)] [152,153],... 

A chiral Lewis acid catalyst was prepared between the chiral BINOL-derived phosphoric acid (212) and Et2AlCl. In the presence of a catalytic amount of the A1 complex, the reaction between (i )-isocyanoacetamides (209) and aldehydes (210) afforded the corresponding enantio-enriched 2-(l-hydroxyalkyl)-5-aminooxazoles (211) in good yields and enantioselectivities (Scheme 59). ... 

Different from the hydroxyalkylation reactions using carbonyl compounds as substrates, Nicolaou s and Macmillan s groups developed independently the intramolecular asymmetric Friedel-Crafts-type a-arylation of aldehydes with electron-enriched arenes based on the SOMO activation strategy. Using chiral imidazolidione as catalyst, a series of cyclic aldehydes were obtained in good yields and enantioselectivities with cerium ammonium nitrate (CAN) as single electron transfer oxidant [46]. 

Other functionalised alcohols have been recently submitted to DKR in closely related conditions, such as aryl )S-hydroxyalkyl sulfones, which have been successfully transformed into the corresponding optically active O-acetyl derivatives in high yields and enantioselectivities by using CAL-B combined with Shvo s ruthenium catalyst (Scheme 4.20). ... 

An intermolecular FC hydroxyalkylation on a carboxonium ion is the key step in the enantioselec-tive synthesis of the nenrotrophic lignan (-)-talaumidin (Scheme 2.5) [6]. The carboxonium precursor 36 was prepared from alcohol 33 (obtained in eight steps from aldehyde 32 with high diastereo- and enantioselectivity). The crucial diastereoselective FC step was achieved upon treatment of 36 with 1,2-methylenedioxybenzene (37) and SnCl, which afforded straightforwardly the desired product 39 in 89% yield throngh cation 38. Debenzylation of 39 with Pd(OH)2 fnmished (-)-(2S,3S,4S,5S)-talaumidin (40) in 77% yield. 

T. Yue, M.-X. Wang, D.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2008, 47, 9454—9457. Asymmetric synthesis of 5-(l-hydroxyalkyl)tetrazoles hy catalytic enantioselective Passerini-type reactions. 

In addition, the synthesis of various chiral p-(hydroxyalkyl)-y-butyro-lactones was based on the D-proline-catalysed enantioselective aldolisation between aldehydes and methyl 4-oxobutyrate, followed by a reduction with NaBH4. As shown in Scheme 2.2, a series of lactones could be prepared in moderate yields and diastereoselectivities but with high enantioselectivities of up to 99% ee. 

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