Enantioselective synthesis of unsymmetrical benzoins from (S)-mandelic acid enolate and aromatic aldehydes

The reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with aromatic aldehydes proceeds readily to give the corresponding aldol products in good yields and diastereoselectivities. Subsequent hydroxyl protection, basic hydrolysis of the dioxolanone, oxidative decarboxylation of the α-hydroxyacid moiety, and hydroxyl deprotection provides chiral unsymmetrical benzoins with high enantiomeric excesses.     

(S)-Mandelic acid enolate as a chiral benzoyl anion equivalent for the enantioselective synthesis of non-symmetrically substituted benzoins

A strategy for the enantioselective synthesis of non-symmetrically substituted benzoins from (S)-mandelic acid and aromatic aldehydes has been developed. This strategy is based on a diastereoselective aldol reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from (S)-mandelic acid and pivalaldehyde with aromatic aldehydes, which gives the corresponding aldols in good yields. Subsequent hydroxyl group protection as MEM ethers, basic hydrolysis of the dioxolanone ring, oxidative decarboxylation of the α-hydroxy acid moiety, and hydroxyl group deprotection provides chiral non-symmetrically substituted benzoins with high enantiomeric excesses.     

An improved procedure for the asymmetric aldol reaction of the titanium enolate of an N3-propionyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one

The direct formation of the titanium enolate of N₃-propionyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one has been achieved through complexation with titanium tetrachloride at 25°C, followed by deprotonation with triethylamine (−78 to 25°C). The preformed titanium enolate has been reacted with D₂O/DCl to afford deuterated derivative 6 and also reacted with a series of aromatic and aliphatic aldehydes affording aldol adducts 4a–f with crude diastereoselectivities ranging from 8:1 to 38:1.     

Organocatalysis of asymmetric aldol reaction in water: comparison of catalytic properties of (S)-valine and (S)-proline amides

(S)-Valine amides containing (S)- or (R)-α-phenylethyl substituents at N¹ atom efficiently catalyze asymmetric aldol reactions between cyclic (heterocyclic) ketones and aromatic aldehydes in water, predominantly giving rise to the aldol anti-diastereomers in high yields (up to 98%) and enantiomeric excess (up to 94%).     

Lithium enolates from a (−)-quinic acid-derived cyclohexanone with a β-alkoxy leaving group: regioselective preparation and evaluation of enolate stability towards β-elimination

Deprotonation of a (−)-quinic acid-derived ketone {(2S,3S,4aR,8R,8aS)-8-[(tert-butyl(dimethyl)silyl)oxy]-2,3-dimethoxy-2,3-dimethylhexahydro-1,4-benzodioxin-6(5H)-one} using lithium hexamethyldisilazide (LHMDS) at −78 °C gave one regioisomeric enolate. The regiocontrol is governed by the axial β-silyloxy substituent and the resulting lithium enolate is stable towards β-elimination at temperatures up to −40 °C. It was found that the axial β-silyloxy group could be conveniently eliminated using 2.1 equiv of LHMDS at 0 °C for 1 h and that an equatorial β-alkoxy group was much more resistant to β-elimination. A chiral lithium amide base was used to overturn the inherent regioselectivity of ketone deprotonation with LHMDS.     

Investigation of site selectivity of the stereoselective deprotonation of cyclohexene oxide using kinetic resolution of isotopic enantiomers in natural abundance

Stereoselective deprotonation of epoxides with lithium amides can occur by abstraction of protons from more than one site. The site selectivity of the deprotonation of cyclohexene oxide by several chiral and achiral lithium amides has been investigated. ²H NMR has been used to measure the relative abundances of the isotopomers of the epoxide containing one deuterium. An isotopic stereoisomer, with deuterium in the site undergoing abstraction, reacts slower than its enantiomer and other isotopomers having protium in the same site due to a kinetic isotope effect. This results in a kinetic resolution yielding a relative excess of the less reactive isotopic stereoisomer. Thus, the relative abundance of such an enantiomer increases when compared with those having protium at the site in question as the reaction proceeds. It can be concluded that deprotonation of cyclohexene oxide using some chiral- and non-chiral lithium amides occurs by β_syn-deprotonation.     

Aldol addition of lithium and boron enolates of 1,3-dioxan-5-ones to aldehydes. A new entry into monosaccharide derivatives

Methods allowing control of stereoselectivity in aldol reactions of enolates derived from 1,3-dioxan-5-ones (4) are described. Boron enolates, generated in situ, react with benzaldehyde to give the corresponding anti aldol selectively (the anti:syn ratio of up to 96:4) and in high yield. Lithium enolates give high anti selectivity only with aldehydes branched at the alpha-position. Enantioselective deprotonation of C(S) symmetrical dioxanones (e.g., 4b) can be accomplished efficiently, with enantiomeric excess of up to 90%, with chiral lithium amide bases of general structure PhCH(Me)N(Li)R (9, 10) if the R group is sufficiently bulky (e.g, R = adamantyl) or is fluorinated (e.g., R = CH2CF3). Dioxanone boron and lithium enolates react readily with glyceraldehyde derivatives (19), yielding protected ketohexoses (20 and 21).     

Diastereoselective Aldol Reaction with an Acetate Enolate: 2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenol as an Extremely Effective Chiral Auxiliary

A C ₂ -symmetrical phenol was used as a chiral auxiliary in the asymmetric aldol reaction of chiral acetates with various aldehydes [Eq. (a)]. The reaction proceeds readily under mild conditions to provide aldol adducts with high enantioselectivity. LDA=lithium diisopropylamide.     

(4R,5S)-1,5-Dimethyl-4-phenylimidazolidin-2-one as a chiral auxiliary for the diastereoselective alkylation of a new iminic glycine derivative: practical asymmetric synthesis of α-amino acids

The lithium enolate of enantiomerically pure N-[bis(methylthio)methylene] glycinate 11 derived from (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one reacts with alkyl halides giving the alkylated derivatives 12 with a high degree of control of the diastereoselectivity. These alkylated systems are easily hydrolyzed to the corresponding α-amino acids, the chiral auxiliary being recovered.     

Studies on the synthesis of bafilomycin A(1): stereochemical aspects of the fragment assembly aldol reaction for construction of the C(13)-C25) segment

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.     

Enantioselective butylation of aliphatic aldehydes by mixed chiral lithium amide/n-BuLi dimers

The enantioselective butylation of aliphatic aldehydes with mixtures of n-butyllithium and chiral lithium amides in a diethyl ether–dimethoxymethane solvent mixture is described. Enantiomeric excesses ranging from 91 to 98.5% were observed for several aliphatic alcohols. The asymmetric butylation of the prochiral aldehydes proceeds much faster by the mixed lithium amide/n-BuLi complexes than by tetrameric n-BuLi.     

Stereoselective syntheses of substituted succinic acid derivatives of the iron chiral auxiliary [(η-C5H5)Fe(CO)(PPh3)]

A range of alkyl- or aryl-substituted iron succinoyl complexes, incorporating the iron chiral auxiliary [(η⁵-C₅H₅)Fe(CO)(PPh₃)], were prepared in high regio- and diastereoselectivities by employing four successful strategies: (i) the alkylation of chiral enolate equivalents with tert-butyl bromoacetate; (ii) the mutual kinetic resolution of tert-butyl α-bromoacetate with a chiral acetate enolate equivalent; (iii) the alkylation of chiral succinoyl enolate equivalents; (iv) the conjugate addition of organolithium reagents or lithium amide reagents to chiral fumaroyl derivatives. Oxidative cleavage of the iron chiral auxiliary was shown to occur without compromising the stereochemical integrity of the succinoyl fragments.     

Oxazinanones as chiral auxiliaries: synthesis and evaluation in enolate alkylations and aldol reactions

Homochiral beta-amino esters (prepared on multigram scale by lithium amide conjugate addition) are readily transformed into oxazinanones. N-acyl derivatives of oxazinanones undergo stereoselective enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans oxazolidin-2-one. A C(4)-iso-propyl stereodirecting group within the oxazinanone conveys higher stereoselectivity than the analogous C(4)-phenyl substituent. gem-Dimethyl substitution at C(6) within the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish alpha-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity. Hydrolysis of the aldol products affords homochiral alpha-methyl-beta-hydroxy-carboxylic acids.     

An efficient synthesis of the C27–C45 fragment of lagunamide A,a cyclodepsipeptide with potent cytotoxic and antimalarial properties

An efficient and stereoselective synthesis of the entire C27–C45 moiety of lagunamide A has been achieved from 1-[(4S)-4-benzyl-2-thioxothiazolidin-3-yl]propan-1-one in six steps with 22% overall yield. The key step in the synthesis is an asymmetric acetal aldol reaction featuring the enantioselective addition of a chiral thiazolidinethione-derived titanium enolate to an acetal to establish the stereochemistry at C39.     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.     

Composition of the activated complex in the stereoselective deprotonation of cyclohexene oxide by a chiral lithium amide

Chiral lithium amides are being developed for stereoselective synthesis of chiral allylic alcohols in high yields and with high enantiomeric excess. However, rational design of the amides for improved stereoselectivity by computational methods, for example, has not been possible due to lack of knowledge of the activated complexes involved in the reactions. Kinetic results are presented for the stereoselective deprotonation by lithium (S)-1-(2-pyrrolidinylmethyl)pyrrolidide (1-Li) of cyclohexene oxide 2, in diethyl ether (DEE), to form (S)-2-cyclohexen-1-ol (S)-3 in high enantiomeric excess. The results show that the rate limiting activated complex is composed of one lithium amide monomer and one molecule of 2 and presumably a solvent molecule. The diamine 1 is found to catalyze the deprotonation.     

(2S,5S)-Pyrrolidine-2,5-dicarboxylic acid,an efficient chiral organocatalyst for direct aldol reactions

Enantioselective aldol reaction of ketones with aldehydes catalyzed by (2S,5S)-pyrrolidine-2,5-dicarboxylic acid in the presence of an equal molar amount of Et₃N was described. By using the new chiral organocatalyst, the direct aldol condensation products were obtained in reasonable yields and up to 90% ee.     

Asymmetric aldol reactions using (S,S)-(+)-pseudoephedrine-based amides: stereoselective synthesis of alpha-methyl-beta-hydroxy acids, esters, ketones, and 1,3-Syn and 1,3-anti diols

A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S, S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-alpha-methyl-beta-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as alpha-methyl-beta-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained alpha-methyl-beta-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-alpha-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.     

Studies towards complex bridged alkaloids: regio- and stereocontrolled enolate chemistry of 2,5-diketopiperazines

The substitution of symmetrical N-protected diketopiperazines (DKPs) via enolate intermediates has been studied. The enolate reactions were highly diastereocontrolled, leading to enantiopure DKP products if chiral amino acid precursors were employed, and giving racemic products, starting with centrosymmetric DKPs, even when a chiral lithium amide base was used to generate the lithium enolate. With unsymmetrical DKPs derived from proline and either alanine, phenylalanine or valine, the enolate substitution occurred with high regio- and stereoselectivity on the proline residue. This enabled the synthesis of substituted DKPs that could be cyclised via cationic processes to give the bicyclo[2.2.2]diazaoctane core structure present in paraherquamide and stephacidin natural products.     

A DFT study of the origins of the stereoselectivity in the aldol reaction of bicyclic amino ketones in the presence of water

Experimental diastereoselectivities of the direct solvent-less (neat) aldol reactions of tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) and granatanone (pseudopelletierine, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one) in the presence of catalytic amounts of water are most accurately reproduced by thermodynamic distributions of isomeric products calculated in the gas phase at the B3LYP/6-31g(d) level of theory. Less than 30% systematic errors, on average, exist in the predicted anti/syn-diastereomeric ratio (dr) for the solvent-less reaction of tropinone with several aromatic aldehydes. The CPCM-B3LYP/6-31g(d) method reproduces the anti/syn-diastereomeric ratio of the aqueous aldol reaction of tropinone with several aromatic aldehydes with reasonable deviation (0-88%), excellent (0-10)% agreement was found for the reactions of tropinone and granatanone with benzaldehyde. Qualitatively satisfactory agreement was also found for dr values in different solvents (DMF, THF, and Et₃N). The density functional theory (DFT) results support the notion of the thermodynamic control of the reaction.