Samarium diiodide-mediated reductive couplings of chiral nitrones with aldehydes/ketones and acyl chlorides

The SmI₂-mediated and H₂O-promoted reductive cross-coupling reactions of the l-tartaric acid derived nitrone (3S,4S)-8 with aldehydes/ketones, and the l-malic acid derived nitrone (S)-6 with aliphatic acyl chlorides have been investigated, respectively. (2R,3S,4S)-1,3,4-Trihydroxyprolinol derivatives 9a-f were obtained with high C-2/C-3 trans-selectivities, and 72:28-85:15 diastereoselectivities at the carbinol center from aromatic ketones/aldehydes, while low diastereoselectivities for aliphatic aldehydes. Conditions have been established for the syntheses of (2R,3S,4S)-3,4-dihydroxyprolinol derivatives such as 18, by N-O bond cleavage of the corresponding N-hydroxyprolinol derivatives 9b-f, or more conveniently by a one-pot reductive coupling of nitrone 8 and in situ N-O bond cleavage of the resultant coupling product. The 2-acyl-3-benzyloxy-1-hydroxypyrrolidines 10a-f were formed in 48-82% yields, and in 74:26-78:22 diastereoselectivities. It was revealed that the amount of water required for the reaction is substrate-depending.     

Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids

Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective synthesis of α-substituted β-amino acids. Pyrimidinone 1 was prepared from inexpensive β-aminopropanoic acid in 62% overall yield. Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9, (S,S)-10, or (−)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li, that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without racemization to afford α-alkyl-β-amino acids 4 and 5, respectively.     

1,1′-Binaphthyl ligands with bulky 3,3′-tertiaryalkyl substituents for the asymmetric alkyne addition to aromatic aldehydes

The BINOL ligand (R)-2 that contains bulky 3,3′-tertiaryalkyl groups shows improved catalytic properties over the previously reported 3,3′-substituted BINOL ligands in the asymmetric alkyne addition to aromatic aldehydes. It catalyzes the phenylacetylene addition to aromatic aldehydes with high enantioselectivity (86-94% ee) and good yields without using Ti(OⁱPr)₄ and a Lewis base additive. The catalytic properties of several analogs of (R)-2 in the asymmetric alkyne addition to aldehydes have also been studied.     

Enantioselective fluorescent recognition of chiral acids by 3- and 3,3′-aminomethyl substituted BINOLs

Benzylaminomethyl groups are introduced to the 3,3′-positions of BINOL. The resulting compounds can be used to conduct the enantioselective fluorescent recognition of mandelic acid and N-benzyloxycarbonylphenylglycine. In the presence of (S)-mandelic acid, compound (R)-2 showed over 30-fold fluorescence enhancement with the ef [ef=enantiomeric fluorescence difference ratio=(I_S−I₀)/(I_R−I₀)] up to 4.2. In the presence of d-N-benzyloxycarbonylphenylglycine, compound (RR)-4 showed up to 15-fold fluorescence enhancement with the ef up to 5.0. These high fluorescence sensitivity and enantioselectivity make compounds (R)-2 and (RR)-4 practically useful sensors for the recognition of the chiral acids in apolar solvents.     

Synthesis of a C1 symmetric BINOL-terpyridine ligand and highly enantioselective methyl propiolate addition to aromatic aldehydes

A novel C₁ symmetric BINOL-terpyridine ligand (R)-5 is synthesized. This ligand in combination with ZnEt₂ and Ti(OⁱPr)₄ is found to catalyze the highly enantioselective reaction (up to 98% ee) of methyl propiolate with a variety of aromatic aldehydes at 0 °C to give the synthetically useful γ-hydroxy-α,β-acetylenic esters. In comparison with the previously reported BINOL system, the use of (R)-5 requires a reduced amount of the chiral ligand without the addition of a Lewis base. It shows higher enantioselectivity for a number of substrates.     

A BINOL-terpyridine-based multi-task catalyst for a sequential oxidation and asymmetric alkylation of alcohols

Treatment of a BINOL-terpyridine compound with RuCl₃ generates a Ru(II) complex (R)-6. This complex is found to be a novel multi-task catalyst capable of conducting a sequential oxidation and asymmetric alkyl addition to convert primary alcohols to chiral secondary alcohols. The terpyridine-Ru(II) site of (R)-6 catalyzes an efficient oxidation of primary alcohols to aldehydes which then undergo an enantioselective alkylation to generate chiral secondary alcohols when the BINOL site of (R)-6 is combined with ZnEt₂ and Ti(OⁱPr)₄.     

Synthesis of a biphenyl-based axially chiral amino acid as a highly efficient catalyst for the direct asymmetric aldol reaction

A biphenyl-based axially chiral amino acid (S)-2 has been designed and synthesized. The new amino acid (S)-2 has been found to be a more efficient catalyst than (S)-1 in the direct asymmetric aldol reaction of acetone with aldehydes. For instance, the use of only 0.1 mol % of (S)-2 was sufficient to complete the reaction between acetone and 4-nitrobenzaldehyde, giving the corresponding aldol adduct in good yield with an excellent enantioselectivity.     

Dendritic BINOL ligands for asymmetric catalysis: effect of the linking positions and generations of the dendritic wedges on catalyst properties

Three types of new chiral BINOL ligands (2, 3 and 4) bearing dendritic wedges have been synthesized through coupling reaction between 3-hydroxymethyl-2,2′-bis(methoxymethyl)-1,1′-binaphthol (7), 6,6′-dihydroxymethyl-2,2′-bis(methoxymethyl)-1,1′-binaphthol (12), 6-hydroxymethyl-2,2′-bis(methoxymethyl)-1,1′-binaphthol (15) and Fréchet-type polyether dendritic benzyl bromide, followed by deprotection of methoxymethyl groups by ⁱPrOH/HCl, respectively. These new ligands obtained were assessed in enantioselective Lewis acid-catalyzed addition of diethylzinc to benzaldehyde. Compared to the enantioselectivity observed with dendrimer 1 bearing the dendritic wedges at 3,3′-positions of the binaphthyl backbone, higher enantioselectivity for all these ligands was observed. Difference in the effect of linking positions and generations on enantioselectivity and/or activity for all three kinds of dendritic ligand-derived catalysts was observed. Among these dendritic ligands, (R)-3/Ti(IV) catalyst with the dendritic wedges at 6,6′-positions of BINOL gave the highest enantioselectivity (up to 87% ee).     

Protonated chiral prolinamide catalyzed enantioselective direct aldol reaction in water

Protonated chiral prolinamide organocatalysts have been shown to catalyze an enantioselective direct aldol process in water to provide the aldol product in high yield and good enantioselectivity. The two diastereomeric catalysts (S,R)-4b and (S,S)-4c show different reactivity.     

6,6′-Bis-substituted BINOL boronic acids as enantioselective and chemoselective fluorescent chemosensors for d-sorbitol

A new chiral fluorescent BINOL boronic acid 1 has been synthesized. The chiral recognition properties of 1 are drastically different from BINOL boronic acid c. Sensor 1 shows improved enantioselectivity as well as chemoselectivity toward sugar alcohols, such as d-sorbitol and d-mannitol.The enantioselectivity of sensor 1 toward d-sorbitol (K_R/K_S) is 1:35 (pH 9.0), and the chemoselectivity for d-sorbitol/d-mannitol is 20:1.     

Corrigendum to “Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids” [Tetrahedron 59 (2003) 4223]

This paper describes work that corrects the synthetic procedures reported in the title paper for the preparation of novel chiral phenolic acids (S)-11, (S)-13, (S,S)-12 and (S,S)-14. Unlike the results provided in the article being reexamined, protonation of prochiral enolates 2-Li and 3-Li with chiral Brønsted acids 11-14 proceeded with negligible enantioselectivity.     

The enantioselective synthesis of poison-frog alkaloids (−)-203A, (−)-209B, (−)-231C, (−)-233D, and (−)-235B″

The enantioselective synthesis of indolizidines (−)-203A, (−)-209B, (−)-231C, (−)-233D, and (−)-235B″ has been achieved and the absolute stereochemistry of both indolizidines 203A and 233D was established as 5S,8R,9S. The relative stereochemistry of natural 231C was established by the present asymmetric synthesis.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

Asymmetric addition of phenylacetylene to aldehydes catalyzed by soluble optically active polybinaphthols ligand

A chiral polymer ligand was synthesized by the polymerization of (S)-5,5′-dibromo-6,6′-dibutyl-2,2′-binaphthol (S-M-1) with (S)-2,2′-bishexyloxy-1,1′-binaphthyl-6,6′-boronic acid (S-M-2) via Pd-catalyzed Suzuki reaction. The application of the chiral polymer ligand to the asymmetric addition of phenylethynyl zinc to various aldehydes has been studied. The results show that the soluble chiral polybinaphthols ligand in combination with Et₂Zn and Ti(OⁱPr)₄ can exhibit excellent enantioselectivity for phenylacetylene addition to both aromatic and aliphatic aldehydes. The catalytically active center of the repeating unit S-1 used as a catalyst produced the opposite configuration of the propargylic alcohols to that of S-1, on the contrary, the chiral polymer gave the same configuration as the optically active binaphthol moiety of the polybinaphthols ligand. Moreover, the chiral polymer ligand can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity.     

Efficient ball-mill procedure in the ‘green’ asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides in the presence of water

The organocatalytic activity of (S)-proline-based dipeptides 1a-c has been evaluated in the asymmetric aldol reaction between representative ketones with various aromatic aldehydes under solvent-free conditions in a ball mill. In particular, the methyl ester of (S)-proline-(S)-tryptophan, (S,S)-1c, proved to be an efficient organocatalyst, and the aldol reaction proceeded with good chemical yields and excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 98% ee), in the presence of water, and 5 mol % of benzoic acid as additive.     

δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (−)-tetra-O-acetylosmundalin

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerization. This δ-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (−)-(4R,5S)-7 from the chiral starting material (+)-(4S,5R)-6 or (−)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (−)-(4R,5S)-7 by the AlCl₃/m-xylene system gave the natural osmundalactone (+)-(4S,5R)-5 or (−)-(4R,5S)-5 in good yield, respectively. Condensation of (−)-(4R,5S)-5 and tetraacetyl-β-d-glucosyltrichloroimidate 22 in the presence of BF₃·Et₂O afforded the condensation product (−)-8 (97% yield), which was identical to tetra-O-acetylosmundalin (−)-8 derived from natural osmundalin 9.     

Nickel-catalyzed multi-component connection reaction of isoprene, aldimines (lactamines), and diphenylzinc

Ni(acac)₂ catalyzes the four-component connection reaction of diphenylzinc, isoprene, aromatic aldehydes, and aromatic amines in this order and provides stereochemically homogeneous (E)-1-arylamino-1-aryl-3-methyl-5-phenyl-3-pentenes (1) in excellent yields. Aliphatic aldehydes react similarly and give (E)-1-arylamino-1-alkyl-3-methyl-5-phenyl-3-pentenes (1) in slightly reduced yields. When the alkyl groups are bulky, in addition to 1 are formed (E)-1-arylamino-1-alkyl-4-methyl-5-phenyl-3-pentenes (1′) as the minor products. Lactamines prepared in situ from five- and six-membered lactols and aromatic amines are more reactive than alkyl aldehyde aldimines and furnish (E)-4-arylamino-6-methyl-8-phenyl-6-octen-1-ols (4) and (E)-5-arylamino-7-methyl-9- phenyl-7-nonen-1-ols (5), respectively, in good yields with excellent E-stereoselectivity.     

Practical asymmetric synthesis of α-methylserine derivatives under mild phase-transfer conditions

The enantioselective methylation reaction of phenyloxazoline tert-butyl ester 5 using (R)-4b as a catalyst under mild phase-transfer conditions provides optically active α-methylserine derivatives in moderate yields with high enantioselectivity. Other α-alkylated serine derivatives are also achievable in high yields with high enantioselectivity by using catalytic amount of (R)-4b.     

Chiral binuclear copper(II) catalyzed nitroaldol reaction: scope and mechanism

Chiral binuclear copper(II) Schiff base complexes 4a-g have been prepared from aldehydes 1a,b, (S)-amino alcohols 2a-f, and Cu(OAc)₂·1H₂O in high yield. Their catalysis is studied for the addition of nitroalkanes to aldehydes at ambient conditions with 76:24 er.     

Enantioselective protonation of prochiral enolates in the asymmetric synthesis of (S)-naproxen

Racemic methyl, iso-propyl, and tert-butyl ester derivatives of naproxen were treated with achiral LDA base to give the corresponding prochiral enolates 2-Li, 3-Li, and 4-Li. Protonation of these enolates with novel chiral proton sources (S)-10 and (S,S)-11, containing the α-phenylethylamino group, proceeded in a highly enantioselective manner. Saponification of enantioenriched ester derivatives 2-4 afforded naproxen, (S)-1, with no loss of enantiopurity.