Construction of Chiral 2,3‐Allenols through a Copper(I)‐Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

Chiral 2,3‐allenols were constructed through copper(I)‐catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)‐DTBM‐SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but‐2‐yn‐1‐ol as the substrates and (R,R)‐Ph‐BPE as the ligand were found to be crucial to get good to high regio‐ and diastereoselectivity. The produced chiral 2,3‐allenols are easily transformed into synthetically useful 2‐furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.     

Catalytic Sc(OTf)3 mediated direct asymmetric aldol reaction of (−)-menthyl isothiocyanatoacetate with aldehydes by using (−)-menthol as chiral auxiliary

This method involves the direct asymmetric aldol reaction of (−)-menthyl isothiocyanatoacetate 5 with a variety of substituted aromatic aldehydes, which offers a convenient method for the synthesis of intermediate containing biologically relevant α-amino β-hydroxyl groups in oxazolidine ring. In this methodology, the products show remarkable diastereoselectivity using Sc(OTf)₃ as a catalyst and easily accessible (−)-menthol as a chiral auxiliary. This approach includes some important aspects such as mild reaction conditions, high yields, and excellent diastereoselectivity with a number of substituted aromatic aldehydes. The optimization and effect of different catalysts were studied at different reaction conditions and it is found that Sc(OTf)₃ shows excellent diastereoselectivity at −45°C.     

Chiral Allenes via Alkynylogous Mukaiyama Aldol Reaction

Herein we describe the development of a catalytic enantioselective alkynylogous Mukaiyama aldol reaction. The reaction is catalyzed by a newly designed chiral disulfonimide and delivers chiral allenoates in high yields and with excellent regio‐, diastereo‐, and enantioselectivity. Our process tolerates a broad range of aldehydes in combination with diverse alkynyl‐substituted ketene acetals. The reaction products can be readily derivatized to furnish a variety of highly substituted enantiomerically enriched building blocks.     

A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions

A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N¹-n-pentyl, N¹-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-β-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively.     

A Modular Approach for the Synthesis of Natural and Artificial Terpenoids

Many terpenoids with isoprene unit(s) demonstrating critical biological activities have been isolated and characterized. In this study, we have developed a robust chem-stamp strategy for the construction of the key isoprene unit, which consists of two steps: one-carbon extension of aldehydes to the alkenyl boronates by the boron-Wittig reaction and the rhodium-catalyzed reaction of alkenyl boronates with 2,3-allenols to yield enals. This chem-stamp could readily be applied repeatedly and separately, enabling the modular concise synthesis of many natural and pharmaceutically active terpenoids, including retinal, β-carotene, vitamin A, tretinoin, fenretinide, acitretin, ALRT1550, nigerapyrone C, peretinoin, and lycopene. Owing to the diversified availability of the starting materials, aldehydes and 2,3-allenols, creation of new non-natural terpenoids has been realized from four dimensions: the number of isoprene units, the side chain, and the two terminal groups.     

A kinetically controlled direct aldol addition of α-chloro thioesters via soft enolization

Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr₂·OEt₂ and i-Pr₂NEt. At ?78 °C the reaction proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover, excellent stereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based aldol addition.     

Highly efficient and solvent-free direct aldol reaction catalyzed by glucosamine-derived prolinamide

The catalytic activity of novel sugar-based prolinamides in the aldol reaction between ketones and aryl aldehydes has been examined. The prolinamide 1c was found to be an efficient organocatalyst for the asymmetric aldol reaction under solvent-free conditions. A variety of ketones and aldehydes were used as substrates and the corresponding aldol products were obtained in excellent chemical yields with high levels of anti diastereoselectivity (up to 99:1) and enantioselectivity (up to >99%).     

A Highly Stereoselective Synthesis of Tetrahydrofurans

The development of a direct and highly stereoselective synthesis of 2,3,5‐substituted tetrahydrofurans has been accomplished through a combination of batch‐ and microchip‐MS‐experiments. This sequential transformation comprises a Lewis acid‐mediated reaction of bis(silyl) dienediolate 1 and a broad range of aldehydes, furnishing products with three new σ‐bonds and three stereogenic centers in a one‐pot process with typically good yields and excellent stereoselectivity. Key steps which have been elucidated primarily with microchip‐MS‐experiments include a vinylogous aldol reaction and a Prins‐type cyclization. Furthermore, a titanium BINOL complex is a powerful chiral catalyst for this process. The products were further converted into bi‐ and tricylic products by carbonyl–ene reactions, proceeding with excellent yields and diastereoselectivity.     

Diastereoselective aldol additions of chiral beta-hydroxy ethyl ketone enolates catalyzed by Lewis bases

The trichlorosilyl enolates derived from chiral ethyl ketones bearing a beta-hydroxyl group and an alpha-stereogenic center were employed in the phosphoramide-catalyzed aldol reaction. The addition of Z-enolates to achiral aldehydes produced aldol products in good yields and high syn relative diastereoselectivities. The internal diastereoselectivity is controlled by the catalyst configuration, allowing for selective formation of either syn diastereomer. [reaction: see text]     

Lewis base activation of lewis acids. Addition of silyl ketene acetals to aldehydes

The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral trichlorosilyl cation which is an extremely effective promoter of aldol addition reactions between aldehydes and silyl ketene acetals. The tert-butyldimethylsilyl ketene acetal of methyl acetate adds nearly instantaneously to aromatic and olefinic aldehydes as well as aliphatic aldehydes (albeit more slowly) with excellent enantioselectivity. The homologous tert-butyldimethylsilyl ketene acetal of tert-butyl propanoate adds with nearly exclusive anti diastereoselectivity to a similar range of aldehydes also with excellent enantioselectivity. The origin of the slower reaction rate with aliphatic aldehydes is revealed to be the formation of chlorosilyl ether adducts.     

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α‐methylbenzyl amine for cis‐aziridines from α‐diazo esters and for trans‐aziridines from α‐diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis‐aziridines involved the (R)‐amine with the (S)‐ligand, but curiously, for trans‐aziridines the matched case involved the (R)‐amine with the (R)‐ligand for imines derived from benzaldehyde and n‐butanal, and the (R)‐amine with the (S)‐ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.     

Chiral thiophosphoramide catalyzed asymmetric aryl transfer reactions for the synthesis of functional diarylmethanols

In this investigation, chiral thiophosphoramide 3d was easily prepared from chiral (1R,2R)-1,2-diphenylethylenediamine and then applied as an efficient chiral ligand in the catalytic asymmetric arylation reactions of various aromatic aldehydes. The corresponding diarylmethanol products were produced with good to excellent yields (up to 98%) and enantioselectivities (up to 94%). The recovery of chiral ligand 3d could be as high as 96%.     

Highly diastereoselective boron and titanium mediated aldol reactions of a mannitol derived 2,3-butanediacetal ethyl ketone

A mannitol derived 2,3-butanediacetal ethyl ketone displays high levels of diastereoselectivity in boron and titanium mediated aldol reactions with a range of aliphatic and aromatic aldehydes to afford syn aldol products in high yield. The stereochemical outcome of the reaction was determined using J-value analysis, NMR analysis of O-acetylmandelate derivatives and X-ray crystallography.     

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.     

Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.     

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.     

Highly Enantioselective Direct Asymmetric Aldol Reaction Catalyzed by 4,5‐Methano‐L‐proline

The 4,5‐methano‐L‐proline was used as chiral organocatalysts in direct asymmetric aldol reactions. Under the optimal conditions, excellent enantioselectivities (up to 99% ee) were obtained with high chemical yields (up to 95%) for a series of aldehydes using only 5 mol% catalyst loading. To show the practicality of the method, the reaction was tested at a large scale. The reaction was complete in 16 h, and the aldol product was obtained in 86% yield and 93% ee.     

Sequential Norrish Type II Photoelimination and Intramolecular Aldol Cyclization of α‐Diketones: Synthesis of Polyhydroxylated Cyclopentitols by Ring Contraction of Hexopyranose Carbohydrate Derivatives

The excitation of the innermost carbonyl of nono‐2,3‐diulose derivatives by irradiation with visible‐light initiates a sequential Norrish type II photoelimination and aldol cyclization process that finally gives polyfunctionalized cyclopentitols. The rearrangement has been confirmed by the isolation of stable acyclic photoenol intermediates that can be independently cyclized by a thermal 5‐(enolexo)‐exo‐trig uncatalyzed aldol reaction with high diastereoselectivity. In this last step, the large deuterium kinetic isotope effect found for the 1,5‐hydrogen atom transfer seems to indicate that the aldol reaction runs through a concerted pericyclic mechanism. Owing to the ready availability of pyranose sugars of various configurations, this protocol has been used to study the influence of pyranose ring‐substituents on the diastereoselectivity of the aldol cyclization reaction. In contrast with other pyranose ring contraction methodologies no transition‐metal reagents are needed and the sequential rearrangement occurs simply by using visible light and moderate heating (0 to 60 °C).     

Chiral ytterbium complex-catalyzed direct asymmetric aldol-Tishchenko reaction: synthesis of anti-1,3-diols

The asymmetric aldol-Tishchenko reaction of aromatic aldehydes with aliphatic and aromatic ketones has been developed as an efficient strategy for the synthesis of anti-1,3-diols in good yield with high diastereocontrol and good levels of enantioselectivity. This domino-type reaction is catalyzed by a chiral ytterbium complex that promotes both the aldol reaction through enolization of the carbonyl compound and the Evans-Tishchenko reduction of the aldol intermediate. The stereochemistry of the resulting diols is also investigated and finally proved by using CD techniques.     

Aldol-additions t0eα- and β-alkoxy aldehydes: The effect of chelation on simple diastereoselectivity

The TiC1₄ or SnCl₄ mediated reaction of enol silanes with chiral α- and β-alkoxy aldehydes constitutes the only presently known, general way to perform aldol additions with chelation-control (asymmetric induction 90%). If the enol silane is prochiral, the additional stereoselection (simple diastereoselectivity) is surprisingly good. This unusual effect has been traced to syn-type of complexation of the aldehyde function.