Dramatic rate enhancement with preservation of stereospecificity in the first metal-catalyzed additions of allylboronates

This communication successfully challenges the perception that the additions of allylbonates to aldehydes cannot be catalyzed effectively by added Lewis acids. Using a novel class of isomerically pure, tetrasubstituted 2-alkoxycarbonyl allylboronates (1), we describe that some metals (for example, Sc(OTf)(3) and Cu(OTf)(2)) allow these reagents to add onto aldehydes to yield gamma-lactone products 2 in good yields at temperatures almost 100 degrees C lower than the corresponding uncatalyzed reactions. The large rate enhancement over the uncatalyzed reaction provides a highly improved practical approach to access aldol-like adducts with a stereogenic quaternary carbon center. The crucial role of the 2-alkoxycarbonyl group on allylboronates 1 was demonstrated with control experiments using a model allylboronate lacking such an ester group. Moreover, the stereospecificity observed in the uncatalyzed allylborations is preserved. These observations raise intriguing mechanistic issues such as the suggestion that type I allylmetal behavior is maintained in this unprecedented catalytic reaction manifold.     

Triflic acid-catalyzed additions of 2-alkoxycarbonyl allylboronates to aldehydes. Study of scope and mechanistic investigation of the reaction stereochemistry

The substrate scope and the effect of substrate on the observed inversion of stereoselectivity in the triflic acid-catalyzed allylboration reaction between 2-alkoxycarbonyl allylboronates and aldehydes are presented. A mechanistic investigation is described so as to confirm the involvement of a carbocation intermediate as the source of stereochemical inversion. This methodology allows a facile access to beta,gamma-disubstituted five-membered ring lactones with an exo-methylene at the alpha-position.     

Allylation Reactions of Aldehydes with Allylboronates in Aqueous Media: Unique Reactivity and Selectivity that are Only Observed in the Presence of Water

Zn(OH)₂‐catalyzed allylation reactions of aldehydes with allylboronates in aqueous media have been developed. In contrast to conventional allylboration reactions of aldehydes in organic solvents, the α‐addition products were obtained exclusively. A catalytic cycle in which the allylzinc species was generated through a B‐to‐Zn exchange process is proposed and kinetic studies were performed. The key intermediate, an allylzinc species, was detected by HRMS (ESI) analysis and by online continuous MS (ESI) analysis. This analysis revealed that, in aqueous media, the allylzinc species competitively reacted with the aldehydes and water. An investigation of the reactivity and selectivity of the allylzinc species by using several typical allylboronates ( 6a , 6b , 6c , 6d ) clarified several important roles of water in this allylation reaction. The allylation reactions of aldehydes with allylboronic acid 2,2‐dimethyl‐1,3‐propanediol esters proceeded smoothly in the presence of catalytic amounts of Zn(OH)₂ and achiral ligand 4d in aqueous media to afford the corresponding syn‐adducts in high yields with high diastereoselectivities. In all cases, the α‐addition products were obtained and a wide substrate scope was tolerated. Furthermore, this reaction was applied to asymmetric catalysis by using chiral ligand 9 . Based on the X‐ray structure of the Zn‐ 9 complex, several nonsymmetrical chiral ligands were also found to be effective. This reaction was further applied to catalytic asymmetric alkylallylation, chloroallylation, and alkoxyallylation processes and the synthetic utility of these reactions has been demonstrated.     

Enantioselective Michael addition of α,α-disubstituted aldehydes to nitroolefins catalyzed by a pyrrolidine-pyrazole

An efficient protocol for the asymmetric catalytic Michael additions of α,α-disubstituted aldehydes to nitroolefins with a pyrrolidine-pyrazole is described. The desired products γ-nitrocarbonyl compounds possessing an all-carbon quaternary center, were obtained in good yields and with high levels of enantioselectivities under solvent-free reaction conditions, employing benzoic acid as an additive.     

Scandium-catalyzed allylboration of aldehydes as a practical method for highly diastereo- and enantioselective construction of homoallylic alcohols

A general approach for the allylation of aldehydes using stable, air-tolerant camphor-based chiral allylboronates under Sc(OTf)3 catalysis is described. This practical methodology provides both syn and anti propionate units and other homoallylic alcohols with very high levels of diastereo- and enantioselectivity for several substrates, including functionalized aliphatic aldehydes useful toward the elaboration of complex natural products.     

Novel functionalized trisubstituted allylboronates via Hosomi-Miyaura borylation of functionalized allyl acetates

[reaction: see text] A series of novel functionalized achiral and chiral allylboronates have been synthesized via the nucleophilic addition of boronates on allyl acetates derived via vinylalumination or Baylis-Hillman reaction of aldehydes. These reagents, upon allylboration with aldehydes, furnish beta-substituted-alpha-methylene-gamma-butyrolactones stereoselectively.     

Lewis acids catalyze the addition of allylboronates to aldehydes by electrophilic activation of the dioxaborolane in a closed transition structure

This study addressed the mechanism of the recently reported Lewis acid-catalyzed manifold for additions of allylboronates to aldehydes. A series of control experiments using various reagents and conditions, and kinetic studies by low-temperature NMR spectroscopy, were performed to investigate the origin of the activation provided by the best catalyst, Sc(OTf)3. The results obtained are strongly supportive of a mechanism involving electrophilic boron activation by coordination of the metal ion to one of the boronate oxygens in a closed bimolecular transition state.     

One-pot enol silane formation-Mukaiyama aldol reactions: Crossed aldehyde-aldehyde coupling,thioester substrates,and reactions in ester solvents

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a trialkylamine base promote both in situ enol silane/silyl ketene acetal formation and Mukaiyama aldol addition reactions between a variety of reaction partners in a single reaction flask. Isolation of the required enol silane or silyl ketene acetal is not necessary. For example, crossed aldol reactions between α-disubstituted aldehydes and non-enolizable aldehydes yield β-hydroxy aldehydes in good yield. In a related reaction, the common laboratory solvent ethyl acetate functions as both an enolate precursor and a green reaction solvent. When thioesters are employed as enolate precursors, high yields for additions to non-enolizable aldehydes are routinely observed.     

Enantioselective additions of diethylzinc and diphenylzinc to aldehydes using 2-dialkyl-aminomethyl-2'-hydroxy- 1,1'-binaphthyls

[reaction: see text] A set of 2-dialkylaminomethyl-2'-hydroxy-1,1'-binaphthyls was prepared and used in the catalytic asymmetric additions of diethylzinc and diphenylzinc to various types of aldehydes. These binaphthyl-based axially chiral amino alcohols show high enantioselectivity in the addition of organozincs to aromatic and aliphatic aldehydes.     

Palladium-catalyzed diastereoselective synthesis of homoaldol equivalent products

A palladium-catalyzed reaction of easily accessible 3-(pinacolatoboryl)allyl acetates and aldehydes provides facile access to synthetically useful homoaldol equivalent products with high diastereoselectivity. The reaction presumably proceeds via allylation of aldehydes with α-acetoxy allylboronates that produced in situ by reductive elimination from allylic gem-palladium/boryl intermediates.     

Catalytic asymmetric assembly of stereodefined propionate units: an enantioselective total synthesis of (-)-pironetin

Double diastereoselection in alkaloid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions provides a strategy for realizing syn- or anti-selective propionate aldol additions from a common reaction manifold. Matched AAC homologation of enantioenriched aldehydes afford cis-disubstituted beta-lactones as surrogates for syn aldols; the mismatched AAC reactions provide anti-selective aldols in the form of trans-disubstituted 2-oxetanones. The utility of this reaction technology in synthesis activities is exemplified in a catalytic asymmetric total synthesis of (-)-pironetin.     

Pd-catalyzed cross-coupling of Baylis-Hillman acetate adducts with bis(pinacolato)diboron: an efficient route to functionalized allyl borates

The cross-coupling of Baylis-Hillman acetate adducts and bis(pinacolato)diboron proceeds readily in high yields in the presence of palladium catalyst to produce 3-substituted-2-alkoxycarbonyl allylboronates. These allylboronates can be transformed to stable allyl trifluoroborate salts by addition of excess aqueous KHF2. Both the allylboronate and allyltrifluoroborate derivatives react with aldehydes to afford functionalized homoallylic alcohols stereoselectively.     

Efficient two-step conversion of alpha,beta-unsaturated aldehydes to optically active gamma-oxy-alpha,beta-unsaturated nitriles and its application to the total synthesis of (+)-patulolide C

[reaction: see text] An efficient two-step conversion of alpha,beta-unsaturated aldehydes into optically active gamma-oxy-alpha,beta-unsaturated nitriles is described. First, catalytic asymmetric cyanation-ethoxycarbonylation using (S)-YLi(3)tris(binaphthoxide) (YLB) afforded chiral allylic cyanohydrin carbonate. Second, a [3,3]-sigmatropic rearrangement proceeded without racemization under thermal conditions to give gamma-oxy-alpha,beta-unsaturated nitriles. Lewis acids were also effective for the rearrangement, and the reaction proceeded smoothly under mild conditions. To demonstrate the utility of the conversion, concise catalytic enantioselective total synthesis of (+)-patulolide C was performed.     

alpha-Aminoallylation of aldehydes with ammonia: stereoselective synthesis of homoallylic primary amines

Three-component reactions of aldehydes, ammonia, and allylboronates were found to provide homoallylic primary amines in high yields with high chemo- and stereoselectivities. A two-step, one-pot, stereoselective synthesis of an uncommon alpha-amino acid, alloisoleucine, was achieved utilizing this reaction.     

Chiral metallacyclophanes: self-assembly, characterization, and application in asymmetric catalysis

[structure: see text] A family of chiral metallacyclophanes has been readily assembled based on robust Pt-acetylide linkage and characterized by a variety of spectroscopic techniques and X-ray crystallography. The steric congestion around the chiral dihydroxy groups in rigid metallacyclophane 4 prevents their reactions with Ti(O(i)()Pr)(4) to form active catalysts for enantioselective diethylzinc additions to aromatic aldehydes. In contrast, chiral dihydroxy groups in more flexible unclosed metallacyclophane 5 are effective ligands for enantioselective catalytic diethylzinc additions to aromatic aldehydes.     

联萘衍生物作为手性配体在二烷基锌和醛不对称加成反应中的应用

光学活性的联萘衍生物作为优异的手性配体应用到不对称催化中已取得了巨大进展,显示出广阔的应用前景,综述了近年来联萘衍生物小分子、树枝状大分子和高分子作为手性配体和其金属络合物作为手性催化剂在二烷基锌和醛不对称加成反应中的应用.     

Me2Zn mediated, tert-butylhydroperoxide promoted, catalytic enantioselective Reformatsky reaction with aldehydes

A practical and highly enantioselective catalytic Reformatsky reaction with aldehydes using a cheap, commercially available aminoalcohol as ligand is described.     

Baylis-Hillman chemistry: a one pot cross-coupling/allylboration reaction

A one pot sequential cross-coupling/allylboration is described. Baylis-Hillman acetate adducts couple with bis(pinacolato)diboron to form substituted allylboronates, which react with aldehydes in the presence of a silica supported BF₃ catalyst to form highly functionalized homoallylic alcohols in excellent yields.     

Mechanism of Ketone Allylation with Allylboronates as Catalyzed by Zinc Compounds: A DFT Study

The mechanism of the allylation reaction between 4‐chloroacetophenone and pinacol allylboronates catalyzed by ZnEt₂ with alcohols was investigated using density functional theory (DFT) at the M05‐2X/6‐311++G(d,p) level. The calculations reveal that the reaction prefers to proceed through a double γ‐addition stepwise reaction mechanism rather than a Lewis acid‐catalyzed concerted one. The intermediate with a four‐coordinated boron center, which is formed through proton transfer from EtOH to the ethyl group of ZnEt₂ mediated by the boron center, is the active species and an entrance for the catalytic cycle. The latter is composed of three elementary steps: 1) boron to zinc transmetalation leading to the formation of allylzincate species, 2) electrophilic addition of ketone to allylzincate species, and 3) generation of the final product with recovery of the catalyst. The boron to zinc transmetalation step has the largest energy barrier of 61.0 kJ mol^?1 and is predicted to be the rate‐determining step. The calculations indicate that the additive EtOH plays important roles both in lowering the activation free energy for the formation of the four‐coordinated boron active intermediate and in transforming the low catalytic activity ZnEt₂ into high activity zinc alkoxide species. The alcohols with a less sterically encumbering R group might be the effective additives. The substituted groups on the allylboronates might primarily affect the boron to zinc transmetalation, and the allylboronates with substituents on the C_γ atom is poor in reactivity. The comparison of the catalytic effect between the zinc compounds investigated suggest that Zn(OEt)₂, Zn(OH)₂, and ZnF₂ exhibit higher catalytic efficiency for the boron to zinc transmetalation due to the activation of the B? C_α bond through orbital interactions between the p orbitals of the EtO, OH, F groups and the empty p orbital of the boron center.     

(E)-alpha-substituted gamma-alkoxyallylboronic esters as new reagents: synthesis and reactivity toward aldehydes

We have developed a synthesis of new allylboration reagents based on an allylic rearrangement. This approach led to the alpha-substituted gamma-alkoxyallylboronates 2 with a high stereoselectivity in favor of the E-isomer, independent of the organometallic used. We have also studied the reactivity of these reagents toward aldehydes, showing that the allylboration reaction occurs with an excellent diastereoselectivity to give the anti-diol derivatives 5. Moreover, the sequence can be carried out in a "one-pot" procedure avoiding the purification of allylboronates.