Asymmetric Synthesis of 1,3‐Butadienyl‐2‐carbinols by the Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid Catalyst

Asymmetric C(sp)? C(sp²) bond formation to give enantiomerically enriched 1,3‐butadienyl‐2‐carbinols occurred through a homoallenylboration reaction between a 2,3‐dienylboronic ester and aldehydes under the catalysis of a chiral phosphoric acid (CPA). A diverse range of enantiomerically enriched butadiene‐substituted secondary alcohols with aryl, heterocyclic, and aliphatic substituents were synthesized in very high yield with high enantioselectivity. Preliminary density functional theory (DFT) calculations suggest that the reaction proceeds via a cyclic six‐membered chairlike transition state with essential hydrogen‐bond activation in the allene reagent. The catalytic reaction was amenable to the gram‐scale synthesis of a chiral alkyl butadienyl adduct, which was converted into an interesting optically pure compound bearing a benzo‐fused spirocyclic cyclopentenone framework.     

Enantiomerically pure 2-aryl(alkyl)-2-trifluoromethylaziridines: synthesis and ring opening with selected O- and N-nucleophiles

We report herein the synthesis of enantiomerically pure 2-phenyl- and 2-ethyl-2-trifluoromethylaziridines by Mitsunobu-type cyclisation of the corresponding N-protected amino alcohols, and our results regarding their ring opening with selected nucleophiles. Under basic conditions, N-tosyl aziridines have been regioselectively opened at the less hindered carbon. Under acidic conditions, the regioselectivity of the attack depends on the nature of the substituent at C-2 and on the nitrogen protecting group.     

S(N)2 ring opening of beta-lactones: an alternative to catalytic asymmetric conjugate additions

Merging catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions with ensuing Grignard-mediated ring opening of the derived enantiomerically enriched beta-lactones is presented as a generally useful asymmetric synthesis of beta-disubstituted carboxylic acids. Enantiomerically enriched beta-lactones are subject to efficient S(N)2 ring opening with a variety of copper-modified alkyl Grignard reagents, including highly branched nucleophiles. Considerable structural variation in the lactone electrophile is also tolerated. Phenyl- and vinyl-derived organometallics are not efficient nucleophiles for the ring-opening reactions.     

Stereoselective synthesis of optically active cyclopenta[c]pyrans and cyclopenta[c]furans by the intramolecular Pauson–Khand reaction

An intramolecular Pauson–Khand reaction of enynes derived from homoallyl, homopropargyl, and allyl alcohols is described. 2-Heteroaryl-substituted homoallyl, homopropargyl, and allyl alcohols are easily and efficiently resolved through enzymatic resolution in high ee (91–99%) and with a known stereochemistry. Each enantiomerically enriched enyne derived from homoallyl and homopropargyl alcohols affords the conformationally most stable diastereomeric cyclopenta[c]pyran ring system as the sole product, whereas enantiomerically enriched enynes derived from allyl alcohols give a diastereomeric cis:trans mixture of the cyclopenta[c]furan ring system.     

Study of the reaction of bulky aryllithium reagents with 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane derived from ephedrine

The ring opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (1) with a variety of bulky aryllithium reagents was studied. Our results are not in total agreement with those obtained by others. In fact, several 2,6-disubstituted aryl groups were successfully appended to the phosphorus atom, furnishing the corresponding (N-ephedrino)phosphine boranes 2a-g with dr>99:1. However, when the attack on the phosphorus atom is hindered, deprotonation on the benzylic position occurs, leading to the formation of enantiomerically pure trans-(N-methylamino)(phenyl)(1-phenyl-1-propenyloxy)phosphine-P-borane (3). While the attack of 2,2'-dilithio-1,1'-biarenes leads to the corresponding (P-phenyl)phosphole derivatives (4i,j) and to [bis(N-ephedrino)](phenyl)phosphine-P-borane (5), the attack of 1,1'-dilithiometallocenes (M=Fe, Ru) leads to a separable diastereomeric mixture of 1,1'-bis[(N-ephedrino)(phenyl)phosphino-P-borane]metallocenes (2k,l/2k',l') with dr approximately 80:20.     

Chemoenzymatic route to various spirocyclic compounds based on enantiomerically enriched tertiary allylic,homoallylic, and homopropargylic alcohols

A ring closing metathesis (RCM) reaction of dienes and an intramolecular Pauson–Khand (PKR) reaction of enynes derived from tertiary allyl, homoallyl, and homopropargyl alcohol backbones to afford the corresponding spirocyclic dihydrofuran and dihydropyrans and spirocyclic cyclopentenone pyrans, respectively, are described. Cyclopent-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols 1a–c have been efficiently resolved via enzymatic resolution with high ee (up to 90%) with 44%, 40%, and 43% chemical yields, respectively. Moreover, the cyclohex-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols 3a–c have also been resolved in the same manner with high ee (up to 97%) and in 42%, 45%, and 49% chemical yields. Enantiomerically enriched dienes derived from tertiary homoallyl alcohols yield the corresponding enantiomerically enriched spirocyclic dihydropyran derivatives via RCM with 74% and 78% chemical yields and with 90% and 97% ee, respectively. Moreover, enantiomerically enriched enynes derived from tertiary homoallyl alcohols afford the corresponding enantiomerically enriched cyclopentenone pyrans with spirocyclic motifs via PKR with 80% and 81% chemical yields, respectively, and as single diastereomers.     

Conformational control on remote stereochemistry in the intramolecular Pauson–Khand reactions of enynes tethered to homoallyl and homopropargyl alcohols

An intramolecular Pauson–Khand reaction of enynes derived from homoallyl and homopropargyl alcohols is described. 2-Furyl substituted homoallyl and homopropargyl alcohols are easily and efficiently resolved through enzymatic resolution in a high ee (93–99%) with a known stereochemistry. Each enantiomerically enriched enyne affords the conformationally most stable diastereomeric cyclopenta[c]pyran ring system.     

Resolution of secondary arylalkyl alcohols using pentafluorophenyl 2-phenylbutanoate and zinc chloride

The resolution of racemic secondary arylalkyl alcohols using pentafluorophenyl 2-phenylbutanoate and zinc chloride is discussed. The levels of enantiomeric recognition were high leading to enantiomerically enriched alcohols in good yield.     

Density functional study of the insertion and ring-opening mechanism of MCP over Cp2LaH and Cp2LuH catalysts

The insertion and ring opening of methylenecyclopropane (MCP) catalyzed by Cp2LnH (Ln = La and Lu) was investigated using DFT method. Geometries and energies of the reactants, minima, and transition states for this reaction were obtained. The present study indicates the formation of Cp2LaH-MCP complex followed by 1,2-insertion through a tetrahedral transition state with subsequent ring opening at the proximal bond via hydrogen transfer transition state resulting in the formation of the final product.     

Opening of substituted oxetanes with H(2)O(2) and alkyl hydroperoxides: stereoselective approach to 3-peroxyalcohols and 1,2,4-trioxepanes

[reaction: see text] Lewis acid-catalyzed opening of oxetanes by hydrogen peroxide proceeds regioselectively and with good to moderate stereoselectivity to furnish enantiomerically enriched 3-hydroperoxyalkanols. The corresponding opening using alkyl hydroperoxides furnishes 3-peroxyalkanols. The hydroperoxyalkanols are easily converted into enantiomerically enriched 1,2,4-trioxepanes, building blocks for antimalarials.     

Modular amino alcohol ligands containing bulky alkyl groups as chiral controllers for Et2Zn addition to aldehydes: illustration of a design principle

A new family of enantiomerically pure (1S,2R)-1-alkyl-2-(dialkylamino)-3-(R-oxy)-1-propanols containing a very bulky alkyl substituent (tert-butyl or 1-adamantyl) on their hydrocarbon chains has been synthesized from the corresponding enantiopure epoxy alcohols, arising from the catalytic Sharpless epoxidation, by protection of the primary hydroxy group and subsequent regioselective ring opening of the epoxide by a secondary cyclic amine (C-2 attack). The performance of these amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been studied, with enantioselectivities of 92-96% being recorded. The best performing ligands, those with a bulky R-oxy group, also depict a convenient activity and selectivity profile in the addition of Et(2)Zn to a representative family of aldehydes. An anomalous structure/enantioselectivity relationship of some ligands in the tert-butyl series has been studied using PM3 calculations, and conclusions have been drawn on the possible effects of including in modular designs structural fragments giving rise to a variety of rotameric transition states.     

One pot synthesis of amino acid derived chiral disubstituted morpholines and 1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences

A new one-pot synthetic strategy is described for the synthesis of enantiomerically pure cis-3,5-disubstituted morpholines and 3,6-disubstituted 1,4-oxazepanes via tandem aziridine/epoxide ring opening sequences. This new strategy describes how epoxy alcohols could act as both a nucleophile and an electrophile in a tandem fashion and undergo intermolecular regioselective ring opening of chiral aziridines for the first time.     

A cross-metathesis route to the 5-F(2)-isoprostanes

A library of eight 5-F(2)-isoprostanes was prepared through a ring-opening metathesis/cross-metathesis protocol between functionalized bicyclo[3.2.0]heptenes, ethylene, and alpha,beta-unsaturated ketones. This sequence provided racemic enones in a regio- and stereoselective fashion that could be converted to enantiomerically enriched allylic alcohols through a catalyst-controlled asymmetric reduction. Completion of the sidechains, followed by global deprotection, resulted in a stereodivergent route to eight enantiomerically enriched 5-F(2)-isoprostanes. Overall, the synthesis of this library of known and anticipated lipid oxidation metabolites was achieved in 10 steps from commercially available 4-hydroxy-2-cyclopentenone.     

Catalytic Asymmetric Propionate Aldol Reactions via Acyl Halide-Aldehyde Cyclocondensations

Catalyzed asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions afford highly enantiomerically enriched 3,4-disubstituted-2-oxetanones. These reactions constitute catalytic asymmetric propionate aldol additions. An optically active Al(III)-triamine complex (10 mol %) catalyzes the di(isopropyl)ethylamine-mediated cyclocondensation of propionyl bromide and a variety of aldehydes to afford beta-lactone adducts with uniformly high enantioselection (90 --> 98% ee), diastereoselection (74 --> 98% de), and chemical yields (78-90%). Lactone ring opening reveals that the enantiomerically enriched beta-lactones act as surrogates for syn propionate aldol adducts.     

Development of Enantioselective Palladium‐Catalyzed Alkene Carboalkoxylation Reactions for the Synthesis of Tetrahydrofurans

The Pd‐catalyzed coupling of γ‐hydroxyalkenes with aryl bromides affords enantiomerically enriched 2‐(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2‐arylcyclohexanol‐derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.     

An efficient synthesis of enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols with quaternary stereocenters by diastereoselective addition of TMSCF3 to chiral 2-acyl-1,3-perhydrobenzoxazines

TMSCF3 adds to chiral 2-acyl-1,3-perhydrobenzoxazines with total diastereoselectivity leading to quaternary trifluoromethyl alcohols. Further transformation of the addition products yields enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols.     

Synthesis of 1-alkyl-2-(trifluoromethyl)azetidines and their regiospecific ring opening toward diverse α-(trifluoromethyl)amines via intermediate azetidinium salts

A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF(3)-azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2.     

Access to enantiomerically enriched cis-2,3-disubstituted azetidines via diastereoselective hydrozirconation

An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.     

Synthesis of sterically controlled chiral β-amino alcohols and their application to the catalytic asymmetric sulfoxidation of sulfides

Sterically hindered and enantiomerically pure β-amino alcohols 8a and 8b were prepared from the enantiomerically pure aziridine-2-carboxylic acid menthol ester 13. Vanadium complexes of the chiral Schiff-base ligands prepared from the β-amino alcohols catalyze an efficient enantioselective sulfoxidation of alkyl aryl sulfides, while enantioselectivities as high as 96% ee can be observed in the sulfoxidation of benzyl aryl sulfides.     

Cu(I)-catalyzed enantioselective [2 + 2] cycloaddition of 1-methoxyallenylsilane with alpha-imino ester: chiral synthesis of alpha,beta-unsaturated acylsilanes

[reaction: see text] The catalytic, enantioselective [2 + 2] cycloaddition reaction of 1-methoxyallenylsilanes with alpha-imino ester has been achieved by means of the [Cu(MeCN)(4)]BF(4)/(R)-Tol-BINAP catalyst to afford 3-methylene-azetidine 2-carboxylates in good yields and with excellent enantiomeric excesses. The acid-catalyzed ring opening of the azetidines afforded chiral acylsilanes quantitatively.