Syn-aldol Products Research Articles

C2-Symmetric Amino Acid Amide-Derived Organocatalysts

N-alkylated C2-symmetric amino acid amide derivatives were shown to catalyse the Michael addition of 2-hydroxy-1,4-napthoquinone to β-nitrostyrene, achieving a maximum ee of 44%. The corresponding trifluoroacetic acid salts also catalysed the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone, leading to the formation of predominantly syn-aldol products in up to 55% ee. Aspects of the solvent dependence of the aldol reaction and the H-bonding of the catalyst were investigated.

Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products. Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities. Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98 % ee. Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

Highly diastereoselective asymmetric syn-aldol reactions of (R)-(N-tosyl)phenylalaninol propionate-derived titanium enolate and bidentate aromatic and aliphatic aldehydes

Asymmetric aldol reactions of ester-derived titanium enolates of (R)-(N-tosyl)phenylalaninol propionate and bidentate aromatic aldehydes has been investigated. Substrate scope of this aldol reaction was examined with a variety of bidentate aromatic aldehydes to provide syn-aldol products with high diastereoselectivity and isolated yields. Both enantiomers of N-(tosyl)phenylalaninol are readily prepared from commercially available and optically active phenylalaninol. Mild saponification removed the chiral auxiliary and furnished optically active β-hydroxy carboxylic acids.

Photocontrolled Cobalt Catalysis for Selective Hydroboration of α,β-Unsaturated Ketones.

Selectivity between 1,2 and 1,4 addition of a nucleophile to an α,β‐unsaturated carbonyl compound has classically been modified by the addition of stoichiometric additives to the substrate or reagent to increase their “hard” or “soft” character. Here, we demonstrate a conceptually distinct approach that instead relies on controlling the coordination sphere of a catalyst with visible light. In this way, we bias the reaction down two divergent pathways, giving contrasting products in the catalytic hydroboration of α,β‐unsaturated ketones. This includes direct access to previously elusive cyclic enolborates, via 1,4‐selective hydroboration, providing a straightforward and stereoselective route to rare syn‐aldol products in one‐pot. DFT calculations and mechanistic experiments confirm two different mechanisms are operative, underpinning this unusual photocontrolled selectivity switch.

Stereoselective aldol reactions of dihydroxyacetone derivatives catalyzed by chiral Zn2+ complexes

The direct aldol reaction between a protected dihydroxyacetone derivative and 4-nitrobenzaldehyde catalyzed by chiral Zn2+ complexes of 1-(n-carboxylalkyl)-7-aminoacyl-1,4,7,10-tetraazacyclododecane is reported. New Zn2+ complexes containing l-histidine and carboxylalkyl chains that mimic a class II aldolase, carboxypeptidase A and a serine protease were designed and synthesized. Syn-aldol products were mainly formed by an aldol reaction of acetonide-protected dihydroxyacetone with benzaldehydes and other benzaldehydes in N-methylpyrrolidone (NMP)/alcohol (MeOH, EtOH or 2-PrOH) in good yields with a high degree of diastereo- and enantioselectivity (56%∼quant., 57∼>99% ee). Mechanistic aspect based on ESI-HRMS, elemental analysis and pH titrations of model ligands is also discussed.

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.

A chiral pool approach for asymmetric syntheses of both antipodes of equol and sativan

For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98% ee with good overall yields starting from readily available starting materials. The chiral isoflavan, (−)-equol is produced from soy isoflavones, formonentin and daidzein by the action of intestinal bacteria in certain groups of population and other chiral isoflavans are reported from various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans' enantioselective aldol condensation was used as a chiral-inducing step to introduce the required chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity. Functional group transformations followed by intramolecular Mitsunobu reaction and deprotection steps resulted the target compounds, S-(−)-equol and S-(+)-sativan, with high degree of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and following the same synthetic sequence the antipodes, R-(+)-equol and R-(−)-sativan were achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. This flexible synthetic process lends itself quite readily to the enantioselective syntheses of other biologically active C-3 chiral isoflavans.

Completely Stereocontrolled Aldol Reaction of Chiral β-Amino Acids

A general protocol to independently access stereoisomerically pure β'-hydroxy-β-amino acid derivatives that is based on dibutylboron triflate-mediated aldol reaction of suitably protected β-amino acids bearing chiral oxazolidinone auxiliary is reported. The method smoothly afforded syn-aldol (α,β'-syn) products in pure form and excellent isolated yield. Both α,β-syn and α,β-anti isomers are readily accessible solely through the choice of the oxazolidinone chirality. This method allows for the preparation of stereoisomeric β'-hydroxy-β-amino acid derivatives that were previously unreported.

Catalytic syn‐Selective Direct Aldol Reactions of Benzophenone Glycine Imine with Aromatic, Heteroaromatic and Aliphatic Aldehydes

AbstractWe have developed highly diastereoselective silver‐catalyzed direct aldol reactions of benzophenone glycine imines with aromatic, heteroaromatic and aliphatic aldehydes. Protection of the secondary alcohol in the aldol product in situ with di‐tert‐butyl dicarbonate was applied to effectively circumvent the retro‐aldol process resulting in improved yields of the aldol products. Only a catalytic amount of base, lithium tert‐butoxide, is required since tert‐butoxide is regenerated during the Boc protection. Computational studies support a stereochemical model in which the axially‐oriented nitrogen atom of the imino (Z)‐enolates coordinates the silver center in a boat conformation. The highly‐ordered transition states favor the formation of the syn aldol products due to the destabilizing interaction between the 1,3‐pseudoaxial alkoxyl group and the aldehyde substituent in the anti isomer.magnified image

Formal Total Synthesis of Stevastelins B and B3

AbstractThe formal total synthesis of stevastelins B and B3 (2 and 4, resp.) have been accomplished employing a highly enantiomerically controlled Lewis acid catalyzed non‐aldol approach to obtain the syn aldol product and temperature controlled hydroboration oxidation reaction to construct four consecutive stereogenic centers. The other key reactions include Sharpless asymmetric epoxidation, macrolactonization, and macrolactamization towards building the core skeleton 2 and 4.

ChemInform Abstract: An Uncatalyzed Aldol Reaction of Thiazolidinediones.

Thiazolidinediones have been used as aldol donors with aromatic aldehydes “on water” and in DMSO without using any catalyst to give the corresponding β-hydroxy carbonyl compounds in high yield and purity. The p-cyano and p-nitro substituted aldol products undergo syn/anti isomerization via an enolization mechanism providing an “on water” diastereoselectivity switch. Water molecules play a significant role in stabilizing the syn aldol products of pyridine and thiazole containing aldehydes.

Noninnocent Role of N-Methyl Pyrrolidinone in Thiazolidinethione-Promoted Asymmetric Aldol Reactions

The origin of stereoselectivity in the reaction between α-azido titanium enolate derived from chiral auxiliary N-acyl thiazolidinethione and benzaldehyde is established using the DFT(B3LYP) method. A nonchelated transition state with N-methyl-2-pyrrolidinone (NMP) bound to a TiCl(3) enolate is found to be energetically the most preferred model responsible for the formation of an Evans syn aldol product. The TS model devoid of NMP, although of higher energy, is found to be successful in predicting the right stereochemical outcome.

An uncatalyzed aldol reaction of thiazolidinediones

Thiazolidinediones have been used as aldol donors with aromatic aldehydes “on water” and in DMSO without using any catalyst to give the corresponding β-hydroxy carbonyl compounds in high yield and purity. The p-cyano and p-nitro substituted aldol products undergo syn/anti isomerization via an enolization mechanism providing an “on water” diastereoselectivity switch. Water molecules play a significant role in stabilizing the syn aldol products of pyridine and thiazole containing aldehydes.

Cysteine-Based Organocatalysts for the Highly Efficient Direct Stoichiometric anti- and syn-Aldol Reactions

A series of cysteine-based organocatalysts have been designed and synthesized from a simple step. The anti-aldol and syn-aldol products could be obtained with up to 98:2 anti/syn and 99% ee; the st...

Highly enantioselective aldol reactions using a tropos dibenz[ c, e]azepine organocatalyst

The four-step synthesis of a chiral primary tertiary diamine salt, possessing a tropos dibenz[ c, e]azepine ring is described. It is shown that 3.5–5 mol % of this salt is capable of promoting highly enantioselective crossed-aldol reactions between cyclohexanone and a series of aromatic aldehydes. In all cases, the aldol reactions proceed with high diastereoselectivity for the anti-aldol product. The outcome of crossed-aldol reactions involving other cyclic ketones and acyclic ketones are also described. All examples involving cyclic ketones result in selectivity for the anti-aldol products, whereas acyclic ketones were found to favour the syn-aldol products. A discussion on the role of the chiral primary tertiary diamine salt in the catalysis of the aldol reactions is also presented.

Simple and inexpensive threonine-based organocatalysts for the highly diastereo- and enantioselective direct large-scale syn-aldol and anti-Mannich reactions of α-hydroxyacetone

Simple and inexpensive threonine-based organocatalysts that promote syn-aldol reactions and three-component asymmetric anti-Mannich reactions of α-hydroxyacetone achieving a respectable level of enantioselectivities are reported. The syn-aldol products could be obtained with up to a 99:1 syn/ anti ratio and >99% ee while the anti-Mannich products could be obtained with up to a 96:4 anti/ syn ratio and >99% ee. Catalyst 1c can be used efficiently on a large-scale with the enantioselectivities of the syn-aldol and anti-Mannich reactions being maintained at the same level, which offers a great possibility for application in industry.

Direct Catalytic Enantio- and Diastereoselective Aldol Reaction of Thioamides

A direct catalytic asymmetric aldol reaction of thioamides using a soft Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH(3)CN)(4)]PF(6)/LiOAr is described. Exclusive enolate generation from thioacetamides through a soft-soft interaction with the soft Lewis acid allowed for a direct aldol reaction to α-nonbranched aliphatic aldehydes, which are usually susceptible to self-condensation under conventional basic conditions. A hard Lewis basic phosphine oxide has emerged as an effective additive to constitute a highly active ternary soft Lewis acid/hard Brønsted base/hard Lewis base cooperative catalyst, enabling a direct enantio- and diastereoselective aldol reaction of thiopropionamides. Strict control of the amount of the hard Lewis base was essential to drive the catalytic cycle efficiently with a minimized retro-aldol pathway, affording syn-aldol products with high stereoselectivity. Divergent transformation of the thioamide functionality is an obvious merit of the present aldol methodology, allowing for a facile transformation of the aldol product into the corresponding aldehyde, ketone, amide, amine, and ketoester. An aldehyde derived from the direct aldol reaction was subjected to a second direct aldol reaction, which proceeded in a catalyst-controlled manner to provide 1,3-diols with high stereoselectivity.

Asymmetric Total Synthesis and Structural Elucidation of NFAT-68

Total synthesis of NFAT-68 (7) has been achieved and its relative stereochemistry has been determined. A key step thereof is the utilization of the chelation-controlled vinylogous Mukaiyama aldol reaction (VMAR) to stereoselectively synthesize the syn-aldol product 8. This developed chemistry is anticipated to have wider application in total syntheses of many other natural products.

ChemInform Abstract: syn-Selective Aldol Reaction of Propynal-Hexacarbonylcobalt Complexes with Ketene Silyl Acetals.

3-Phenylpropynal–hexacarbonylcobalt complex, prepared from 3-phenylpropynal with octacarbonyl-cobalt, afforded on treatment with the seven-membered ketene trimethylsilyl acetal the syn-aldol product in a highly stereoselective manner. Similar exposure of the above complex to the six- and five-membered ketene trimethylsilyl acetal gave the corresponding syn-aldol products predominantly. The aldol reaction of the cobalt complexes derived from 3-trimethylsilyl- and 3-butyl-propynal with those cyclic ketene silyl acetals proceeded syn-selectively to provide the syn-aldol products. The preferential formation of the syn- over the anti-isomers was also achieved in the reaction of the cobalt complexed 3-trimethylsilylpropynal with acyclic ketene trimethylsilyl acetals, derived from methyl or tert-butyl propionate. In contrast, uncomplexed 3-phenyl-, 3-trimethylsilyl- and 3-butylpropynal furnished the corresponding aldol products nonselectively or anti-isomers predominantly depending on the structure of the starting ketene trimethylsilyl acetal.

Transition State Models for Probing Stereoinduction in Evans Chiral Auxiliary-Based Asymmetric Aldol Reactions

The use of chiral auxiliaries is one of the most fundamental protocols employed in asymmetric synthesis. In the present study, stereoselectivity-determining factors in a chiral auxiliary-based asymmetric aldol reaction promoted by TiCl(4) are investigated by using density functional theory methods. The aldol reaction between chiral titanium enolate [derived from Evans propionyl oxazolidinone (1a) and its variants oxazolidinethione (1b) and thiazolidinethione (1c)] and benzaldehyde is examined by using transition-state modeling. Different stereochemical possibilities for the addition of titanium enolates to aldehyde are compared. On the basis of the coordination of the carbonyl/thiocarbonyl group of the chiral auxiliary with titanium, both pathways involving nonchelated and chelated transition states (TSs) are considered. The computed relative energies of the stereoselectivity-determining C-C bond formation TSs in the nonchelated pathway, for both 1a and 1c, indicate a preference toward Evans syn aldol product. The presence of a ring carbonyl or thiocarbonyl group in the chiral auxiliary renders the formation of neutral TiCl(3)-enolate, which otherwise is energetically less favored as compared to the anionic TiCl(4)-enolate. Hence, under suitable conditions, the reaction between titanium enolate and aldehyde is expected to be viable through chelated TSs leading to the selective formation of non-Evans syn aldol product. Experimentally known high stereoselectivity toward Evans syn aldol product is effectively rationalized by using the larger energy differences between the corresponding diastereomeric TSs. In both chelated and nonchelated pathways, the attack by the less hindered face of the enolate on aldehyde through a chair-like TS with an equatorial disposition of the aldehydic substituent is identified as the preferred mode. The steric hindrance offered by the isopropyl group and the possible chelation are identified as the key reasons behind the interesting stereodivergence between Evans and non-Evans products normally reported for the title reaction. The application of an activation strain model on the critical TSs has been effective toward rationalizing the origin of stereoselectivity. Improved interaction energy between the reactants is found to be the key stabilizing factor for the lowest energy TS in both chelated and nonchelated pathways. The present study provides newer insights on the role of titanium(IV) toward modulating stereoselectivity in aldol reactions.