Synthesis of 2,6-disubstituted dihydropyrans via an efficient BiBr3-initiated three component, one-pot cascade

The rapid synthesis of cis-2,6-disubstituted dihydropyrans is achieved in a three-component, one-pot cascade reaction. BiBr₃-mediated addition of ketene silyl acetals or silyl enol ethers to β,γ-unsaturated cis-4-trimethylsilyl-3-butenal provides a Mukaiyama aldol adduct containing a vinylsilane moiety tethered to a silyl ether. Addition of a second aldehyde initiates a domino sequence involving intermolecular addition followed by an intramolecular silyl-modified Sakurai (ISMS) reaction. Isolated yields of this one-pot reaction vary from 44 to 80% and all compounds were isolated as the cis-diastereomers (10 examples).     

Cationic iridium complex is a new and efficient Lewis acid catalyst for aldol and Mannich reactions

A cationic iridium complex [Ir(cod)₂]SbF₆ was found to be a new and efficient Lewis acid catalyst for Mukaiyama aldol and Mannich reactions. Aldehydes react smoothly with silyl enol ethers to give β-siloxy ketones in the presence of 0.5 mol % of [Ir(cod)₂]SbF₆. The reaction of N-alkyl arylaldimines with ketene silyl acetals in the presence of 5 mol % [Ir(cod)₂]SbF₆/P(OPh)₃ gave β-amino esters. After Mannich reaction was complete, stirring of the reaction mixture for 24 h led to cyclization to give β-lactam. The reaction of N-aryl benzaldimine with silyl enol ether derived from acetophenone gave a tetrahydroquinoline derivative as a single diastereomer.     

Preparation and application of 2-(arylmethoxy)isopinocampheols for the asymmetric aldol reaction of 3,3,3-trifluoropropionates

The preparation of 2-(arylmethoxy)isopinocampheols from pinanediol via the DIABL-H reduction of the corresponding aryl aldehyde acetals has been described. A systematic examination of the asymmetric aldol reaction of 3,3,3-trifluoropropionates led to the double diastereoselective aldol reaction of 2-(arylmethoxy)isopinocampheyl 3,3,3-trifluoropropionates providing anti-α-trifluoromethyl-β-hydroxy esters in 63-85% yields, ?99% anti-selectivity and 80-96% de for the anti-isomer.     

Unique chemoselective Mukaiyama aldol reaction of silyl enol diazoacetate with aldehydes and acetals catalyzed by MgI2 etherate

Functionalized diazo acetoacetates are prepared by an efficient Mukaiyama aldol reaction between 3-TBSO-2-diazo-3-butenoate with aldehydes and acetals under mild reaction conditions. A variety of substituted aldehydes and the corresponding acetals are both accessible in good to excellent yields through this methodology. MgI₂ etherate (MgI₂·(OEt₂)_n) is the preferred catalyst and, the addition proceeds without decomposition of the diazo moiety. In addition, this MgI₂·(OEt₂)_n-catalyzed Mukaiyama aldol reaction shows unique chemoselectivity towards aldehydes and acetals.     

Platinum(II) complex-catalyzed enantioselective aldol reaction with ketene silyl acetals in DMF at room temperature

[{(R)-binap}Pt(μ-OH)]₂2X is a weak Lewis acid, which can catalyze the enantioselective aldol reaction of aldehydes with ketene silyl acetals in DMF at room temperature. The platinum(II) complex-catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene gave the corresponding aldols in high yields with enantioselectivity up to 92%. With 5 mol % loading of the complexes, the enantioselective aldol reaction of aldehydes with 1-benzyloxy-1-(trimethylsilyloxy)propene smoothly proceeded in DMF containing 10% HMPA as to predominantly give anti-propionates with enantioselectivity up to 89%, irrespective of the silyl nucleophile geometry.     

Chiral 1,2-diaminocyclohexane as organocatalyst for enantioselective aldol reaction

A simple and commercially available chiral 1,2-diaminocyclohexane as catalyst, hexanedioic acid as co-catalyst could efficiently catalyze the asymmetric aldol reaction in MeOH-H₂O. Cyclic ketones as aldol substrates gave the anti-β-hydroxyketone products with moderate to good yields, diastereoselectivity and enantioselectivity (up to 78% yield, >20:1 anti/syn, 94% ee). Hydroxyacetone as aldol substrate afforded the syn-α, β-dihydroxyketones as major products in up to 85% yield with good enantioselectivity (up to >20:1 syn/anti, 93% ee).     

Mechanistic investigations of the ZnCl2-mediated tandem Mukaiyama aldol lactonization: evidence for asynchronous, concerted transition states and discovery of 2-oxopyridyl ketene acetal variants

The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted β-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl(2)-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl(2) and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated β-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to β-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system.     

Synthesis of brasilibactin A and confirmation of absolute configuration of β-hydroxy acid fragment

A synthesis of brasilibactin A, a cytotoxic siderophore from the actinomycete of Nocardia brasiliensis, and three unnatural diastereomers of the natural product is described. Four possible diastereomers of the β-hydroxy acid fragment were prepared via asymmetric aldol reactions and used to synthesize brasilibactin A and its diastereomers. Careful analysis of ¹H NMR data confirmed that brasilibactin A possesses the 17S,18R absolute stereochemistry.     

Glycosylation-induced asymmetric synthesis: β-amino acid esters via Mannich reactions

Activation of Schiff bases by N-glycosylation induces asymmetric Mannich reactions with O-silyl ketene acetals to give β-amino acid esters in good yields.     

Trapping enols of esters and lactones with diazomethane

A series of regioisomeric ketene-O,O-dialkyl acetals were prepared from ambident β-dicarbonylfuroindoles by trapping the enol tautomers of esters and lactones with diazomethane. Definitive structural characterization was accomplished by X-ray crystal structure determination on a ketene-O,O-dimethyl acetal (R = Me).     

Dibenzylaminoacetates as useful synthetic equivalents of glycine in the synthesis of α-amino-β-hydroxyacids1

The stereochemical course of three new simple methodologies for the preparation of α-amino-β-hydroxyacids starting from dibenzylaminoacetates as synthetic equivalents of glycine is described. While the aldol-type condensation via lithium enolates gave results highly dependent on the aldehyde employed, producing in some cases diastereoselectivities up to 5:1 for the anti isomers, the acid-catalysed aldol condensation of silyl ketene acetals yielded predominantly syn adducts with selectivities from 5:1 to 32:1. Finally the acylation-reduction procedure gave the best results in terms of yields and stereoselectivities, affording syn isomers with excellent induction (⩾ 13 : 1).     

Improved enantioselective synthesis of anti α-methyl-β-hydroxyesters through TiCl4-PPh3 mediated aldol condensation

The complex between TiCl₄ and PPh effectively catalyses the aldol addition of silyl ketene acetals to aldehydes dramatically improving the anti-syn ratios.     

A flexible route to immunosuppressive agent FR252921. Asymmetric total synthesis of its (13R,14R,19R)-isomer

A flexible route to the proposed structure of FR252921, a novel immunosuppressive agent, is developed. The key elements include the assembly of its two β-hydroxy acid residues via asymmetric aldol condensation of N-acylthiazolidinethinones with aldehydes, and its triene part via a CuI/N,N-dimethylglycine catalyzed Sonogashira coupling and subsequent isomerization. Using this strategy (13R,14R,19R)-FR252921 is elaborated.     

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.     

Three-component condensations of aldehydes with N-methoxycarboxamides

The first condensations of N-methoxycarboxamides (component A) with aliphatic acetals (component B) are described. Depending upon the conditions, the hemiaminal type products (AB) can usually be isolated. Conducting the condensations with 2 equiv of acetal affords β-(N-methoxy)amido aldehydes (type ABB products). A condensation using anisole (component C) afforded a product of type ABC.     

High diastereoselectivity in lewis acid mediated aldol condensations using thioester silyl ketene acetals.

BF₃ OEt₂ mediated aldol condensations of thioester silyl ketene acetals are stereoconvergent, and exhibit high internal (anti) and relative (Cram) diastereoselectivity.     

Aza variant of intramolecular nucleophile-catalyzed aldol lactonization (NCAL): formal synthesis of (3S,4R) and (3R,4S) 4-(hydroxymethyl)pyrrolidin-3-ol

Aza variant of intramolecular catalytic, asymmetric nucleophile-catalyzed, aldol lactonization (NCAL) reaction has been explored to synthesize β-lactone fused nitrogen heterocycles as aza sugars’ precursors by employing achiral amino acids. The utility of these bicyclic β-lactones is presented by the formal synthesis of aza sugars, (3S,4R) and (3R,4S) 4-(hydroxymethyl)pyrrolidin-3-ol.     

Asymmetric synthesis of β-substituted Baylis-Hillman products via lithium amide conjugate addition

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis-Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium (R)-N-methyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester to generate an N-protected β-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with B(OMe)₃ and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to homogeneity followed by tandem N-oxidation and Cope elimination gives the desired β-substituted Baylis-Hillman products in good yield and high de and ee.     

β-Ferrocenyl-α,β-unsaturated phosphonates and sulfones

Ferrocene reacts with β-ketophosphonates and β-ketosulfones (or acetals of formylphosphonates and sulfones) in the presence of a strong acid (triflic or methanesulfonic) to afford β-ferrocenyl-α,β-unsaturated phosphonates and β-ferrocenyl-α,β-unsaturated sulfones in good yield. The (E)-stereochemistry of these compounds was confirmed by spectral and analytical data, as well as by X-ray diffraction.     

Syntheses of chiral hybrid O,N-donor ligands for the investigation of lanthanide complex reactivities in direct aldol condensations

A method for the synthesis of new chiral α/β-dimethylamino esters and β-amino ethers from (S,S)-hydrobenzoin is described. These new O,N-donor ligands are expected to prove a useful platform for exploring the relationship between the ligand structure and stereoselective direct aldol condensation catalyzed by their lanthanide complexes. The initial survey of the catalytic utility of newly synthesized complexes in the unique aldol-Tishchenko reaction of aldehydes and aliphatic ketones is also presented.