Chiral phosphoramide-catalyzed enantioselective addition of allylic trichlorosilanes to aldehydes. Preparative and mechanistic studies with monodentate phosphorus-based amides

The addition of allylic trichlorosilanes to benzaldehyde promoted by chiral phosphoramides to give the enantioenriched homoallylic alcohol has been investigated. In a survey of Lewis bases as activators for the addition of allyltrichlorosilane to benzaldehyde, phosphorus-based amides have been found to be the most effective promoters. To achieve asymmetric induction, chiral phosphoric triamides derived from chiral diamines have been developed and applied in the allylation reaction albeit with modest enantioselectivities. The addition of 2-butenylsilanes was highly diastereoselective, suggesting a closed, chair-like transition structure. A detailed mechanistic study has been carried out to probe into the origin of activation. From a combination of nonlinear effects and kinetics studies, the reaction was found to likely involve two phosphoramides in both the rate and stereochemistry determining steps. These studies provided the background for the development of highly selective and reactive catalysts.     

Enantioselective allylation of α,β-unsaturated aldehydes with allyltrichlorosilane catalyzed by METHOX

α,β-Unsaturated aldehydes 6a-j undergo an enantioselective allylation with allylic trichlorosilanes 2a,b in the presence of METHOX (4) as a Lewis basic catalyst (≤10 mol %) to produce the homoallylic alcohols 7a-l at good to high enantioselectivity (83-96% ee). This study shows that the reactivity scope of METHOX can be extended from aromatic to nonaromatic aldehydes.     

Chiral phosphine-free Pd-mediated asymmetric allylation of prochiral enolate with a chiral phase-transfer catalyst

[reaction: see text]. A chiral phase-transfer catalyst has been applied to the asymmetric allylation of the tert-butyl glycinate-benzophenone Schiff base with various allylic acetates for the first time to give the allylated products in good yields and with comparable to higher enantioselectivity than for asymmetric alkylation at the same temperature (91-96% ee) without any chiral ligands for coordinating to the palladium.     

Palladium-catalyzed allylic transposition of (allyloxy) iminodiazaphospholidines: a formal [3,3]-aza-phospha-oxa-Cope sigmatropic rearrangement for the stereoselective synthesis of allylic amines

The synthesis of N-protected allylic amines has been achieved utilizing a palladium(II)-catalyzed, [3,3]-rearrangement of (allyloxy) iminodiazaphospholidines. This [3,3]-aza-phospha-oxa-Cope sigmatropic rearrangement reaction is thermodynamically driven by a P=N to P=O interconversion and is an alternative to the Overman rearrangement. The overall process involves the nucleophilic displacement of an allylic alcohol onto a P(III) precursor, followed by a Staudinger reaction to generate the (allyloxy) iminodiazaphospholidine precursors. Pd(II)-catalyzed [3,3]-aza-phospha-oxa-Cope rearrangement then gives a phosphoramide, which is readily hydrolyzed under acidic conditions to yield allylic amine derivatives. Pd(II) catalysis is believed to occur in a fashion analogous to that of the rearrangement of allylic imidates. The scope of racemic, diastereoselective, and enantioselective variants of this rearrangement is described. The use of chiral diamine auxiliaries in diastereoselective rearrangements is reported. Rearrangement of chiral N,N'-dimethyl cyclohexanediamine derived diazaphospholidines gives rise to phosphoramides with moderate diastereoselectivities (up to 3.5:1 dr). The same major diastereomeric product in these rearrangements was prepared irrespective of the starting allylic alcohol geometry. An enantioselective variant of the reaction was demonstrated for the rearrangement of cis-(allyloxy) iminodiazaphospholidines with cobalt oxazoline palladacycle (COP-X) catalysts (5 mol %) in high yield and enantioselectivity (up to 96% ee).     

Enantioselective conjugate addition of dialkylzinc and diphenylzinc to enones catalyzed by a chiral copper(I) binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system

The enantioselective conjugate addition of dialkylzinc or diphenylzinc to enones was catalyzed by a copper(I)-axially chiral binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system at room temperature (20 degrees C) or 0 degrees C, affording the Michael adducts in high yields with excellent ee for cyclic and acyclic enones. The enantioselectivity and reaction rate achieved here are one of the best results yet for the Cu-catalyzed conjugate addition to enones. It was revealed that this series of chiral phosphoramides was a novel type of S,N-bidentate ligands on the basis of (31)P NMR and (13)C NMR spectroscopic investigations. The mechanism of this asymmetric conjugate addition system has been investigated as well. We found that the acidic proton of phosphoramide in these chiral ligands play a significant role in the formation of the active species. A bimetallic catalytic process has been proposed on the basis of previous literature. The linear effect of product ee and ligand ee further revealed that the active species is a monomeric Cu(I) complex bearing a single ligand [Cu(I):ligand 1:1].     

Enantioselective synthesis of fluorene derivatives by chiral N-triflyl phosphoramide catalyzed double Friedel-Crafts alkylation reaction

A highly efficient tandem double Friedel-Crafts reaction between indoles and 2-formylbiphenyl derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl) fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products with opposite absolute configuration.     

Stereoselective aldol additions of achiral ethyl ketone-derived trichlorosilyl enolates

Methods for the preparation of geometrically defined enoxy(trichlorosilanes) derived from ethyl ketone enolates have been developed. The addition of enoxy(trichlorosilanes) (trichlorosilyl enolates) to aldehydes proceeds with good yields in the presence of catalytic amounts of chiral phosphoramides. The reaction of Z-trichlorosilyl enolates to aryl aldehydes affords aldol products with good to excellent diastereo- and enantioselectivities. Phosphoramide-catalyzed aldol additions lacked substrate generality providing modest selectivities with unsaturated and aliphatic aldehydes. In all cases, the phosphoramide-catalyzed aldol addition of E-trichlorosilyl enolates to aldehydes provided good yields with moderate to good stereoselectivities.     

Synthesis of novel N,P chiral ligands for palladium-catalyzed asymmetric allylations: the effect of binaphthyl backbone on the enantioselectivity

A series of novel chiral aminophosphine ligands with a 5,5,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl backbone (H₈-MAPs) have been synthesized. The application of these ligands in asymmetric allylic substitutions was examined and higher enantioselectivity was observed than that by using the parent ligand (MAP). Under the optimized conditions, the allylation product can be obtained in up to 90.9% ee with H₈-MAP having 3,5-xylyls as chiral inducer. The dramatic effect of the binaphthyl backbone on the enantioselectivity of the reaction can be attributed to the change of the bite angle in H₈-MAPs/Pd complexes.     

Catalytic asymmetric hydroboration of heterofunctional allylic substrates: an efficient heterogenized version

The hydroboration of heterofunctional allylic systems with catecholborane (HBcat) using neutral and cationic rhodium complexes modified with P–P and P–N bidentate chiral ligands has been described in order to produce the secondary heteroorganoboronate ester as a major product with moderate enantioselectivity. The immobilization of cationic chiral rhodium complexes onto clays has beneficial effects on the recyclability and reuse of the catalytic system in particular for the hydroboration of allyl aryl sulfones.     

Palladium-catalyzed asymmetric umpolung allylation of imines with allylic alcohols

A palladium-catalyzed asymmetric umpolung allylation reaction of imines with allylic alcohols has been developed. In the presence of chiral spiro phosphoramidite ligand 4, the allylation was accomplished with high yields and good enantioselectivities. The use of highly stable and easily available allylic alcohols instead of allylic metal reagents facilitated the preparation of chiral homoallylic amines.     

Synthesis of beta-substituted alpha-amino acids with use of iridium-catalyzed asymmetric allylic substitution

The asymmetric synthesis of beta-substituted alpha-amino acids with use of iridium-catalyzed allylic substitution was described. The Ir-catalyzed allylic substitution of diphenylimino glycinate with allylic phosphates proceeded smoothly even at 0 degrees C and gave branch products with high enantioselectivity (up to 97% ee), when chiral bidentate phosphite bearing the 2-ethylthioethyl group was employed. In addition, both diastereomers of the branch products were synthesized stereoselectively by simply switching the base employed. These methods were also applied to the asymmetric synthesis of quaternary alpha-amino acids.     

Tin powder‐promoted diastereoselective allylation of chiral acylhydrazones

An efficient method for the allylation of chiral acylhydrazones derived from aldehydes has been developed to give the corresponding allylic hydrazides in good yields and diastereoselectivities. The method uses a combination of tin powder and allylic bromide as allylation system, which avoids the use of toxic allylic stannanes while retaining their merits.     

Selective mono- and di-allylation and allenylation of chlorosilanes using indium

Allyl and allenyl groups have been introduced into silicon systems by the allylation and allenylation of chlorosilanes using allyl bromide or propargyl bromide with indium. The allylation of chlorosilanes afforded a variety of aryl, aralkyl, and alkenyl substituted allylsilanes. By applying this method, the reactions of 1-bromo-3-methylbut-2-ene, 3-bromo-2-methylprop-1-ene and 3-bromobut-1-ene with chlorosilanes also proceed smoothly to give regioselectively allylic rearrangement products in good yields. Mediated by indium, dichlorosilanes (R₂SiCl₂) and trichlorosilanes (RSiCl₃) can either afford monoallylated silanes or diallylated silanes depending on the amount of allyl bromide and indium used.     

Asymmetric allylation of unsymmetrical 1,3-diketones using a BINAP-palladium catalyst

[reaction: see text] The chiral palladium complex generated in situ from [Pd(eta(3)-allyl)Cl](2) and (R)-BINAP is a good catalyst for the catalytic asymmetric allylation of 1,3-diketones. The reaction provided chiral 2,2-dialkyl-1,3-diketones with 64-89% ee in high yields (13 examples). Enantiomeric excesses are strongly affected by the gamma-substituent of the allylic substrates. A variety of unsymmetrical 1,3-diketones were alkylated with cinnamyl acetate in good enantioselectivities via use of the BINAP-palladium catalyst (77-89% ee).     

From allylic alcohols to chiral tertiary homoallylic alcohol: palladium-catalyzed asymmetric allylation of isatins

A palladium-catalyzed asymmetric allylation of isatins with allylic alcohols as an allyl donor was developed by using chiral spiro phosphoramidite ligands. A variety of chiral tertiary homoallylic alcohols 3-allyl-3-hydroxy-2-oxindoles were prepared directly from allylic alcohols in one step with excellent yields and moderate enantioselectivities. This represents the first catalytic asymmetric allylation of ketones with allylic alcohol as the allylating agent.     

New types of soluble polymer-supported bisphosphine ligands with a cyclobutane backbone for Pd-catalyzed enantioselective allylic substitution reactions

A highly efficient and practical optical resolution of anti head-to-head racemic coumarin dimer 7 has been achieved by molecular complexation with TADDOL, (-)-8, through a hydrogen bonding interaction to afford the corresponding two enantiomers, (-)- and (+)-7, in 70 and 75 % yields, respectively, with >99 % ee. Starting from enantiopure (-)-7, a new type of C2-symmetric bisphosphine ligand (S,S,S,S)-3 with a cyclobutane backbone has been synthesized in good yield by facile transformations. The asymmetric induction efficiency of these chiral bisphosphine ligands in Pd-catalyzed asymmetric allylic substitution reactions was evaluated. Under the experimental conditions, the allylic substitution products could be obtained in excellent yields (up to 99 %) and enantioselectivities (up to 98.9 % ee). By taking advantage of the high enantioselectivity of this catalytic reaction and the easily derivable carboxylate groups on the cyclobutane backbone of ligand (S,S,S,S)-3, a new type of analogous ligand (S,S,S,S)-4 as well as the MeO-PEG-supported soluble ligand (S,S,S,S)-5 (PEG=polyethylene glycol) have also been synthesized and utilized in asymmetric allylic substitution reactions. In particular, the MeO-PEG supported (S,S,S,S)-5 b had a synergistic effect on the enantioselectivity of the reaction compared with its nonsupported precursor (S,S,S,S)-4 c, affording the corresponding allylation products 14 a and 14 b with excellent enantioselectivities (94.6 and 97.2 % ee, respectively). Moreover, the Pd complex of (S,S,S,S)-5 b could easily be recovered and recycled several times without significant loss of enantioselectivity and activity in the allylic substitution reactions.     

Complexing and catalytic properties of easily available chiral iminophosphite based on biphenyl-2,2"-diol

A chiral iminophosphite ligand based on biphenyl-2,2"-diol and its chelates with rhodium(i) and palladium(ii) were synthesized for the first time. Successful use of these compounds in asymmetric allylic substitution was demonstrated. The enantioselectivity of palladium-catalyzed alkylation of methyl pent-3-en-2-yl carbonate with dimethyl malonate reached 70%, that in the alkylation of 1,3-diphenylallyl acetate with dimethyl malonate was 88%. In the rhodium-catalyzed sulfonylation of 1,3-diphenylallyl acetate with sodium p-toluenesulfinite, the enantioselectivity was 56%.     

Lewis base activation of grignard reagents with N-heterocyclic carbenes. Cu-free catalytic enantioselective additions to gamma-chloro-alpha,beta-unsaturated esters

Direct activation of alkylmagnesium halides with a chiral bidentate N-hetrocyclic carbene (NHC), formed in situ from the imidazolinium chloride precursor, is reported. The Cu-free catalytic asymmetric allylic alkylation (AAA) of alpha-alkyl-gamma-chloro-alpha,beta-unsaturated esters with alkyl-based Grignard reagents is promoted in the presence of 5-10 mol % of the chiral imidazolinium salt to afford synthetically versatile beta,gamma-unsaturated esters. Products bear all-carbon quaternary sterogenic centers generated in 3.5-13.3:1 regioselectivity, 63-98% ee, and in up to 80% isolated yield of the SN2' product. The in-situ-generated chiral NHC promotes enantioselectivity while altering the reactivity of the Grignard reagents: there is only approximately 30% conversion and <2% allylic alkylation in the absence of chiral carbene.     

Heterofunctional control of regio- and enantioselectivity in rhodium-catalysed hydroboration of allylic systems

Aryl allylic sulfones were reacted with catecholborane (HBcat) in the presence of neutral and cationic Rh complexes modified with bidentate chiral ligands, to produce the branched heteroorganoboronate ester, as the main isomer with moderate enantioselectivity. The relative rate of the formation of the secondary regioisomer seems to be sensitive to the nature of the catalytic system and the electronic effects of the substrate.     

Asymmetric allylic oxidation reactions catalyzed by a chiral nonracemic and C2-symmetric 2,2'-bipyridyl copper(I) complex

The evaluation of a chiral, nonracemic and C2-symmetric 2,2'-bipyridyl ligand in copper(I)-catalyzed asymmetric allylic oxidation reactions of a series of cyclic alkenes with tert-butyl peroxybenzoate is reported (up to 91% ee, the highest reported enantioselectivity for a bipyridyl ligand copper(I) complex to date).