Tandem asymmetric conjugate addition/alpha-alkylation using (S,S)-(+)-pseudoephedrine as chiral auxiliary

Alpha,beta-unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine undergo a very clean and diastereoselective tandem conjugate addition/alpha-alkylation reaction. Excellent results have been achieved using a wide range of differently substituted conjugate acceptors, organolithium reagents, and alkyl halides. The chiral auxiliary could be easily removed from the obtained adducts by reduction, furnishing chiral nonracemic alpha,beta-branched alcohols in a very easy and efficient way. [reaction: see text]     

(S,S)-(+)-pseudoephedrine as chiral auxiliary in asymmetric aza-Michael reactions. Unexpected selectivity change when manipulating the structure of the auxiliary

[reaction: see text] The asymmetric aza-Michael reaction of metal benzylamides to alpha,beta-unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine has been studied in detail. A deep study of the most important experimental parameters (solvent, temperature, nucleophile structure, influence of additives) has been carried out, showing that the reaction usually proceeds with good yields and diastereoselectivities, although the experimental conditions have to be modified depending on the substitution pattern of the conjugate acceptor. Additionally, a very interesting facial selectivity inversion has been observed when manipulating the structure of the chiral auxiliary, which has allowed a diastereodivergent procedure to be set up for performing asymmetric aza-Michael reactions using the same chirality source. Finally, the adducts obtained in the asymmetric aza-Michael reaction have proven to be very versatile synthetic intermediates in the preparation of other interesting compounds such as beta-amino esters, gamma-amino alcohols, and beta-amino ketones in highly enantioenriched form.     

(S,S)-(+)-Pseudoephedrine as chiral auxiliary in asymmetric conjugate addition and tandem conjugate addition/alpha-alkylation reactions

Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseudoephedrine enamides furnishing the corresponding beta-alkyl-substituted adducts in excellent yields and diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition step undergo a highly diastereoselective alkylation reaction, furnishing alpha,beta-dialkyl-substituted amides in high yields. The obtained adducts have been converted into chiral nonracemic beta-alkyl- and alpha,beta-dialkyl-substituted carboxylic acids and gamma-alkyl- and beta,gamma-dialkyl-substituted alcohols using very simple and high-yielding procedures.     

Asymmetric synthesis of beta-amino esters by aza-Michael reaction of alpha,beta-unsaturated amides using (S,S)-(+)-pseudoephedrine as chiral auxiliary

Chiral nonracemic beta-amino esters were prepared in good yields and enantioselectivities using the diastereoselective conjugate addition of nitrogen nucleophiles to alpha,beta-unsaturated amides derived from (S,S)-(+)-pseudoephedrine as the key step. In this way, several beta-amino amide adducts were prepared using different conjugate acceptors and two different lithium benzylamides as nucleophiles. These adducts were easily converted in only one step, into the final, highly enantioenriched beta-amino esters     

Asymmetric aldol reactions using chiral CF3-Oxazolidines (Fox) as chiral auxiliary

The aldol reactions of amide enolates derived from a trifluoromethylated oxazolidine (Fox) chiral auxiliary occur in good yields with a moderate anti diastereoselectivity (Li and Na enolates) to a high syn diastereoselectivity (boron enolate). After removal, the Fox chiral auxiliary is very conveniently and efficiently recovered in basic conditions.     

(S,S)-(+)-pseudoephedrine alpha-iminoglyoxylamide as a chiral glycine cation equivalent: a modular and flexible approach to enantioenriched alpha-amino ketones

We have studied the ability of an alpha-imino glyoxylamide derived from (S, S)-(+)-pseudoephedrine as a valuable chiral electrophile for the preparation of alpha-amino carbonyl compounds. In this context, the addition of Grignard reagents to the azomethine moiety of this chiral electrophile afforded the expected alpha-amino amide adducts in good yields and diastereoselectivities. Moreover, these adducts have been transformed into enantioenriched alpha-amino ketones by exploiting the ability of pseudoephedrine amides to undergo selective monoaddition to the carbamoyl group with organolithium reagents.     

Efficient asymmetric synthesis of (S)- and (R)-N-Fmoc-S-trityl-alpha-methylcysteine using camphorsultam as a chiral auxiliary

(1R)-(+)-2,10- and (1S)-(-)-2,10-camphorsultam were acylated with ethyl 2-phenylthiazoline 4-carboxylate to afford (+)- and (-)-2-phenylthiazolinylcamphorsultam, which were stereoselectively alkylated with MeI in the presence of n-BuLi. Alkylation of these phenylthiazolinylcamphorsultams occurred from the beta-face rather than alpha-face, resulting in the formation of (S)-alpha-methylcysteine from (1R)-(+)-2,10-camphorsultam and (R)-alpha-methylcysteine from (1S)-(-)-2,10-camphorsultam after acidic hydrolysis. Subsequent protection of the side chain thiol group with trityl alcohol and alpha-amine function with Fmoc-OSu furnished fully protected (S)- and (R)-N-Fmoc-S-trityl-alpha-methylcysteine in overall 20% yield.     

Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.     

Indene-based thiazolidinethione chiral auxiliary for propionate and acetate aldol additions

An indene-based thiazolidinethione chiral auxiliary was prepared in two steps from trans-1-amino-2-indanol. Chlorotitanium enolates of this chiral auxiliary delivered excellent diastereoselectivities in propionate and acetate aldol additions. The chiral auxiliary was easily removed to deliver several valuable functionalities.     

New glyco-oxazolidin-2-ones as chiral auxiliaries in boron-mediated asymmetric aldol reactions

Two new chiral glyco-oxazolidin-2-one auxiliaries based on d-glucose are described. Some N-acyl derivatives were synthesized and used in dialkylboron-mediated asymmetric aldol reactions. All reactions delivered as the major diastereomer those predicted by the Zimmerman–Traxler model and were separated by column chromatography and mostly isolated in moderate to good yields.     

Synthesis and evaluation of a new non-cross-linked polystyrene supported hydantoin chiral auxiliary for asymmetric aldol reactions

A new non-cross-linked polystyrene supported chiral hydantoin was prepared and it was shown to be a particularly effective chiral auxiliary for asymmetric aldol reactions, affording high yields and excellent diastereoselectivity. Furthermore, the recovery and recycling of the polymer-supported chiral auxiliary have been successfully achieved without an appreciable reduction in the yield or diastereoselectivity.     

An air-stable,storable chiral zirconium catalyst for asymmetric aldol reactions

Asymmetric aldol reactions of ketene silyl acetals with aldehydes using an air-stable, storable chiral zirconium catalyst, which could be stored for at least 13 weeks at room temperature, proceeded smoothly to afford the desired adducts in high yields with high selectivity.     

Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin: asymmetric glycolate aldol reactions and biological evaluation

The total synthesis of (+)-geldanamycin (GA), following a linear route, has been completed using a demethylative quinone-forming reaction as the last step. Key steps include the use of two new asymmetric boron glycolate aldol reactions. To set the anti-C11,12 hydroxymethoxy functionality, (S,S)-5,6-bis-4-methoxyphenyldioxanone 8 was used. Methylglycolate derived from norephedrine 5 set the C6,7 methoxyurethane stereochemistry. The quinone formation step using nitric acid gave the non-natural o-quino-GA product 55 10:1 over geldanamycin. Other known oxidants gave an unusual azaquinone product 49. o-Quino-GA 55 binds Hsp90 with good affinity but is less cytotoxic compared to GA.     

Synthesis of (−)-(5R,6S)-6-acetoxyhexadecanolide based on l-proline-catalyzed asymmetric aldol reactions

A convenient method for proline-catalyzed asymmetric aldol reactions using synthons of straight-chain aliphatic aldehydes, and aldehydes bearing a 1,3-dithiane moiety at the β-position, has been developed. This method was successfully applied to the synthesis of (−)-(5R,6S)-6-acetoxyhexadecanolide, an oviposition attractant pheromone of the female Culex mosquito.     

Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin with use of asymmetric anti- and syn-glycolate aldol reactions

Geldanamycin (GA), an antitumor Hsp90 inhibitor, was made for the first time by using an oxidative demethylation reaction as the final step. A biaryldioxanone auxiliary set the anti C11-12 hydroxy-methoxy functionality and a methylglycolate auxiliary based on norephedrine was used for the syn C6-7 methoxy-urethane. p-Quinone-forming oxidants, CAN and AgO, produced an unusual aza-quinone product. Nitric acid gave GA from a trimethoxy precursor in 55% yield as a 1:10 mixture with nonnatural o-quino-GA. [structure: see text]     

Synthesis of (−)-(5R,6S)-6-acetoxyhexadecan-5-olide by l-proline-catalyzed asymmetric aldol reactions

The natural mosquito attractant pheromone, (−)-(5R,6S)-6-acetoxyhexadecan-5-olide 1, was synthesized from readily available aldehyde 3 and cyclopentanone 4 using l-proline catalyzed asymmetric aldol reactions as the key step.     

Boron enolates of a hydantoin chiral auxiliary derived from l-phenylalanine: a versatile tool for asymmetric aldol reactions

The aldol reactions of boron enolates derived from a hydantoin chiral auxiliary derived from l-phenylalanine occur in good yields with high syn diastereoselectivity. Aldol adduct 4a is readily cleaved by hydrolysis to afford (2S,3S)-3-hydroxy-2-methyl-3-phenylpropionic acid 5a in good yield and in almost enantiomerically pure form.     

Double diastereoselective acetate aldol reactions with chiral N-acetyl thiazolidinethione reagents

Double diastereoselective acetate aldol reactions using the N-acetyl thiazolidinethione-based chiral auxiliaries 1 and 2 and chiral aldehydes are described. Aldehydes that bear alpha-alkyl stereocenters exhibit moderate levels of double diastereoselection, while those that bear alpha- or beta-alkoxy substitution exhibit little to no double diastereoselection. In all cases studied, the stereoselectivity of the reaction is dictated by the reagent, not the substrate.     

Storable, powdered chiral zirconium complex for asymmetric aldol and hetero Diels-Alder reactions

A storable, powdered chiral zirconium catalyst for asymmetric aldol and hetero Diels-Alder reactions has been developed. The catalyst has the same activity as that prepared in situ even after being stored for 3 months. Moreover, this chiral Zr catalyst worked efficiently not only for asymmetric aldol reactions but also for asymmetric hetero Diels-Alder reactions affording the corresponding addition products with high enantioselectivities.