Stereoselective Synthesis of trans-Olefins by the Copper-Mediated S(N)2' Reaction of Vinyl Oxazines with Grignard Reagents. Asymmetric Synthesis of D-threo-Sphingosines

The S_N2′ reaction of 6-vinyl-5,6-dihydro-4H-[1,3]oxazines with Grignard reagents in the presence of CuCN was studied, and high trans selectivity for the formation of double bond was observed with a variety of RMgX. The S_N2′ reaction, coupled with regioselective asymmetric aminohydroxylation reaction, provided a highly efficient route for the asymmetric synthesis of d-threo-N-acetylsphingosine.     

Stereoselective synthesis of an ansa-zirconocene in a spirane scaffold

Methodology is described for the preparation of a rigid C₂-bridged zirconocene catalyst system where the C₂-bridge is embedded in a spirane scaffold. The ligand was prepared from 3,4-dihydro-2H-fluoren-1(9H)-one. Initially, the oxo group was converted into a spirocyclobutanone function. Further conversion to a fulvene was followed by regio- and stereoselective saturation to provide the ligand cis-2-(cyclopentadienyl)-1′,2′,3′,4′-tetrahydro-9H-spiro[cyclobutane-1,1′-fluorene]. The ligand was dilithiated and reacted with zirconium tetrachloride to provide the corresponding (η⁵-cyclopentadienyl)-spiro[cyclobutane-1,1′-(η⁵-fluorenyl)]zirconium dichloride complex. The structure of the zirconocene dichloride has been established by crystal X-ray analysis.     

Highly selective oxidative cross-coupling of 2-naphthol derivatives with chiral copper(I)-bisoxazoline catalysts

The asymmetric oxidative coupling reaction of 3-hydroxy-2-naphthoate and 2-naphthol derivatives with the CuCl-(S)-(−)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) catalyst under an O₂ atmosphere was carried out. The reaction proceeded in a highly cross-coupling selective manner (?99.7%) with a moderate enantioselectivity of up to 65%.     

Asymmetric hydroamination/cyclization catalyzed by group 4 metal complexes with chiral biaryl-based ligands

Group 4 metal complexes based on chiral biaryl ligands are readily prepared by a convenient amine elimination procedure, and they are efficient catalysts for the asymmetric hydroamination/cyclization of aminoalkenes. The biaryl-based ligands are highly modular enabling facile tuning of the catalyst reactivity and selectivity. The corresponding heterocyclic products have been obtained in excellent enantiomeric excesses (up to 93%) using sterically hindered C₂-symmetric titanium and zirconium mesitoylamidate complexes such as [1,1′-(C₁₀H₁₀)₂-2,2′-{NCO(2,4,6-Me₃C₆H₂)}₂]M(NMe₂)₂ (M = Ti, Zr). These results are presented in this short review.     

Solvothermal synthesis of large surface area zirconia

The reaction of zirconium n-propoxide in glycol at 300°C yielded microcrystalline tetragonal zirconia (ZrO₂). The crystallite size of the product depended on the carbon number of the glycol and increased in the following order (carbon number of glycol): 2<6<4, which suggested that the heterolytic cleavage of O-C bond of gylcoxide formed by transesterification is the prime factor for the formation of the product. In toluene, zirconium isopropoxide also gave tetragonal zirconia at 300°C, and zirconium tert-butoxide decomposed at 200°C yielding amorphous zirconia, while zirconium n-propoxide was stable at 300°C. These results suggest that the reaction in toluene depends on the structure of the alkyl group of the alkoxides. Thus-obtained tetragonal zirconias maintained large surface areas (90–160 m²/g) even after calcination at 500°C.     

Enantioselective arylation of aldehydes catalyzed by a soluble optically active polybinaphthols ligand

A soluble chiral polymer ligand was synthesized by the polymerization of (R)-6,6′-dibutyl-3,3′-diformyl-2,2′-binaphthol (R-M-1) with 2,5-diaminopyridine (M-2) via a nucleophilic addition-elimination reaction. While arylboronic acids were used as the source of the transferable aryl group, the chiral polybinaphthols ligand in combination with Et₂Zn without Ti(OⁱPr)₄ exhibited higher enantioselectivity in asymmetric addition to aromatic aldehydes than alphatic aldehydes. When aromatic aldehydes with electron-withdrawing groups were chosen as substrates, the resulting diarylmethanols were produced in higher ee values than those with electron-donating groups as substrates. 2-Naphthaldehyde used as a substrate afforded product in 95% ee, which could be ascribed to the steric effect influence on this asymmetric arylation reaction. Moreover, the chiral polymer was easily recovered and reused, but exhibited a decrease of enantioselectivity in the third recycle.     

Synthesis, structure, and catalytic activity of titanium(IV) and zirconium(IV) amides with chiral biphenyldiamine-based ligands

A new series of titanium(IV) and zirconium(IV) amides have been prepared from the reaction between M(NMe₂)₄ (M = Ti, Zr) and C₂-symmetric ligands, (R)-2,2′-bis(pyridin-2-ylmethylamino)-6,6′-dimethyl-1,1′-biphenyl (2H₂), (R)-2,2′-bis(pyrrol-2-ylmethyleneamino)-6,6′-dimethyl-1,1′-biphenyl (3H₂), (R)-2,2′-bis(diphenylphosphinoylamino)-6,6′-dimethyl-1,1′-biphenyl (4H₂), (R)-2,2′-bis(methanesulphonylamino)-6,6′-dimethyl-1,1′-biphenyl (5H₂), (R)-2,2′-bis(p-toluenesulphonylamino)-6,6′-dimethyl-1,1′-biphenyl (6H₂), and C₁-symmetric ligands, (R)-2-(diphenylthiophosphoramino)-2′-(dimethylamino)-6,6′-dimethyl-1,1′-biphenyl (7H) and (R)-2-(pyridin-2-ylamino)-2′-(dimethylamino)-6,6′-dimethyl-1,1′-biphenyl (8H), which are derived from (R)-2,2′-diamino-6,6′-dimethyl-1,1′-biphenyl. Treatment of M(NMe₂)₄ with 1 equiv. of N₄-ligand, 2H₂ or 3H₂ gives, after recrystallization from an n-hexane solution, the chiral zirconium amides (2)Zr(NMe₂)₂ (9), (3)Zr(NMe₂)₂ (11), and titanium amide (3)Ti(NMe₂)₂ (10), respectively, in good yields. Reaction of Zr(NMe₂)₄ with 1 equiv of diphenylphosphoramide 4H₂ affords the chiral zirconium amide (4)Zr(NMe₂)₂ (12) in 85% yield. Under similar reaction conditions, treatment of Ti(NMe₂)₄ with 1 equiv. of sulphonylamide ligand, 5H₂ or 6H₂ gives, after recrystallization from a toluene solution, the chiral titanium amides (5)Ti(NMe₂)₂·0.5C₇H₈ (13·0.5C₇H₈) and (6)Ti(NMe₂)₂ (15), respectively, in good yields, while reaction of Zr(NMe₂)₄ with 1 equiv. of 5H₂ or 6H₂ gives the bis-ligated complexes, (5)₂Zr (14) and (6)₂Zr (16). Treatment of M(NMe₂)₄ with 2 equiv. of diphenylthiophosphoramide ligand 7H or N₃-ligand 8H gives, after recrystallization from a benzene solution, the bis-ligated chiral zirconium amides (7)₂Zr(NMe₂)₂ (17) and (8)₂Zr(NMe₂)₂ (19), and bis-ligated chiral titanium amide (8)₂Ti(NMe₂)₂ (18), respectively, in good yields. All new compounds have been characterized by various spectroscopic techniques, and elemental analyses. The solid-state structures of complexes 10, 12, 13, and 17-19 have further been confirmed by X-ray diffraction analyses. The zirconium amides are active catalysts for the asymmetric hydroamination/cyclization of aminoalkenes, affording cyclic amines in good to excellent yields with moderate ee values, while the titanium amides are not.     

Stereoselective SN2′ alkylation reaction sequence of the γ,δ-epoxy α,β-unsaturated ester system via γ,δ-chlorohydrin intermediates by the use of a R3Al-CuCN reagent

A novel stereoselective S_N2′ alkylation reaction sequence of the γ,δ-epoxy α,β-unsaturated ester system has been developed which involves a regioselective substitution reaction with chloride ions at the γ-position and a subsequent S_N2′ alkylation reaction of the resulting γ-chloro-δ-hydroxy derivatives with a R₃Al-CuCN reagent. The new methodology was demonstrated to be applicable to a variety of substrates and to provide various δ-hydroxy-α-alkyl-β,γ-unsaturated esters including those bearing a quaternary asymmetric carbon atom at the α-position in a highly stereoselective manner and high yields.     

Supramolecular helical architecture assembled by double-helical [Ag2L2] units

A series of new sterically hindered bridged ligand 4,4^′-methylene-N,N^′-bis(phenyl-2-pyridylmethylene)-bis(2,6-dialkylanil)s was efficiently synthesized by the condensation reaction of 4,4^′-methylene-bis(2,6-disubstituted aniline) and benzoyl pyridine. They easily coordinated with Ag(I) to form Ag(I) complexes. The structure of complex [Ag₂L⁴₂][ClO₄]₂ was determined by the single X-ray crystallographic analysis, and the double-helical asymmetric unit containing two [Ag₂L⁴₂] moieties was interconnected with the adjacent unit through hydrogen bonds to form a helical supramolecular architecture.     

One catalyst for two distinct reactions: sequential asymmetric hetero Diels-Alder reaction and diethylzinc addition

This paper describes the successful development of a series of chiral zinc catalysts containing (R)-3,3′-Br₂-BINOL ligand and various diimine activators for enantioselective HDA reaction of Danishefsky's diene with aldehydes through a combinatorial approach, affording the corresponding 2,3-dihydro-4H-pyran-4-one derivatives in excellent yields and enantioselectivities. The application of this type of catalysts was also extended to the diethylzinc addition to the benzaldehyde, affording the corresponding secondary alcohol with up to 94.5% ee under optimized conditions. On the basis of these facts, the integration of two distinct enantioselective reactions, HDA and diethylzinc addition reactions, has been realized in one-pot with the promotion of a single chiral zinc catalyst in a sequential manner. The impact of diimine additive on the catalytic system of HDA reaction was also investigated by probing the nonlinear effect of reaction system. The positive nonlinear effect exhibited in the catalytic system could be attributed to the poor solubility of the heterochiral zinc species. On the basis of various experimental findings disclosed in this research, a possible mechanism for the asymmetric induction in the 3,3′-Br₂-BINOL/Zn/diimine catalyzed enantioselective HDA reaction of Danishefsky's diene with aldehydes was outlined.     

Chiral hetero Diels-Alder products by enantioselective and diastereoselective zirconium catalysis. Scope,limitation, mechanism,and application to the concise synthesis of (+)-Prelactone C and (+)-9-deoxygoniopypyrone

Catalytic asymmetric hetero Diels-Alder (HDA) reactions using a chiral zirconium complex have been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the corresponding pyranone derivatives in high yields with high diastereo- and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide, (R)-3,3'-diiodobinaphthol or its derivative, a primary alcohol, and a small amount of water. It is noted that 2,3-trans-pyranone derivatives were obtained with remarkably high diastereo- and enantioselectivities in the reaction with 4-methyl Danishefsky's diene. This is the first example of catalytic asymmetric trans-selective hetero Diels-Alder reactions of aldehydes. Furthermore, asymmetric HDA reactions with 4-benzyloxy Danishefsky's dienes were conducted to afford 2,3-cis-pyranone derivatives in high selectivities. Isolation of an intermediate of this asymmetric hetero Diels-Alder reaction indicated that the reaction proceeded in a stepwise cycloaddition pathway. Finally, these catalytic, asymmetric hetero Diels-Alder reactions were successfully applied to concise syntheses of biologically important natural pyranone derivatives, (+)-Prelactone C and (+)-9-deoxygoniopypyrone.     

Enantioselective synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone

A concise enantioselective total synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone is described. Key feature of this protocol is a catalytic asymmetric hydrogenation and a prophenol-zinc-catalyzed diazo addition to imine reaction as genesis of chirality. Moreover, flexibility is built in the synthesis to generate enantioenriched analogs using catalytic amount of enantioenriched C₂-symmetric ligands.     

γ-Selective allylic substitution reaction with Grignard reagents catalyzed by copper N-heterocyclic carbene complexes and its application to enantioselective synthesis

The reaction of allylic compounds with alkyl Grignard reagents in the presence of a catalytic amount of copper N-heterocyclic carbene (NHC) complexes proceeded predominantly in an S_N2′ reaction pathway to give γ-substituted product in excellent yield. The method was applied to asymmetric reaction by using optically active NHC ligands.     

Synthesis and X-ray crystal structure analysis of the first nickel bisoxazoline pincer complex

The reaction in toluene between 2-iodo-1,3-bis(4′,4′-dimethyl-2′-oxazolinyl)benzene and Ni(COD)₂ gave [2,6-bis(4′,4′-dimethyl-2′-oxazolinyl)phenyl-N,C¹,N′]iodonickle(II) isolated in 69% yield. The structure of this novel nickel bisoxazoline pincer complex was confirmed by a X-ray crystal structure analysis.     

Highly active asymmetric Diels-Alder reactions catalyzed by C2-symmetric bipyrrolidines: catalyst recycling in water medium and insight into the catalytic mode

A new class of C₂-symmetric 3,3′-dialkoxy-2,2′-bipyrrolidines have been designed and synthesized for asymmetric organocatalytic Diels-Alder reactions of α,β-unsaturated aldehydes. The remarkable rate-accelerating effect for the cycloaddition reaction has been observed in aqueous medium. The catalyst 1c·2HClO₄ can be recovered and reused several times by simple extraction without significant loss of catalytic activity and stereoselectivity. The catalytic mode has been demonstrated by DFT calculation, NMR, and X-ray crystallographic studies for diiminium intermediate.     

Solid-phase mechanochemical synthesis of zirconium tetracarboxylates

The solid-phase synthesis of zirconium carboxylates Zr(OOCR)₄ (R = Alk) by reactions of zirconium tetrachloride with metal carboxylates (isobutyrate, pivalate, and palmitate) (the molar ratio ZrCl₄: RCOOM is 1: (4–5)) under mechanical activation is developed. Further thermal treatment of the reaction mixture and extraction with an organic solvent afford zirconium carboxylates.     

2,2′-Bis(diarylstibano)-1,1′-binaphthyls (BINASbs); a useful chiral ligand for palladium-catalyzed asymmetric allylic alkylation, and the structure of a BINASbPdCl2 complex

The first attempt to use enantiopure antimony ligands 1-4 as a chiral auxiliary was successfully accomplished in a palladium-catalyzed asymmetric alkylation of 1,3-diphenylprop-2-ene-1-yl acetate with dimethyl malonate. Under the optimized conditions, the allylation product can be obtained with up to 96% ee in 84% chemical yield by use of enantiopure C₂-symmetric 2,2′-bis[di(p-tolyl)stibano]-1,1′-binaphthyl [BINASb(p-Tol)] 4a as a chiral ligand with O-bis(trimethylsilyl)acetamide (BSA) and potassium acetate. The structure of the intermediary BINASb-PdCl₂ complex was elucidated by single crystal X-ray analysis, implying that the BINASb should work as a bidentate chiral ligand in the reaction.     

Fluorination in superacids: a novel access to biologically active compounds

In HF-SbF₅, reaction of various alkaloids with NBS, NCS, H₂O₂ yields fluoroderivatives: anti-addition is observed at the C6C7 double bond with tabersonine, but a more complex reaction is operative with vindoline, leading to 7-substituted (Br, Cl, OH)-20-fluoro derivatives. A completely different reaction pathway is observed with bis indole alkaloids (vinblastine, anhydrovinblastine, vinorelbine) in HF-SbF₅. In the presence of NBS (or better of CCl₄ or CHCl₃), 20′,20′-difluoroderivatives are obtained. Vinflunine (20′,20′-difluoro-3′,4′-dihydrovinorelbine) has been selected for its promising antitumor activity.     

Oxidation of sulfides to sulfoxides by optically active phosphite ozonides

A study was carried out on the oxidation of dialkyl and aryl alkyl sulfides by optically active phosphite ozonides in the case of the oxidation of methyl phenyl sulfide, methyl decyl sulfide, and benzyl octyl sulfide by the ozonides of L-(-)-menthyl o-phenylene phosphite, L-(-)-menthyl (2,2 -methylene-bis(4-methyl-6-tert-butylphenyl) phosphite, and L-(-)-bornyl (2,2 -methylene-bis(4-methyl-6-tert-butylphenyl) phosphite. These ozonides oxidize the indicated sulfides to the corresponding sulfoxides at –80°C. Partial asymmetric oxidation is possible. The addition of Ti(OC₃H₇-i)₄ increases the asymmetric control of the reaction.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2133–2135, September, 1990.     

Facile synthesis of 2′-O-cyanoethyluridine by ring-opening reaction of 2,2′-anhydrouridine with cyanoethyl trimethylsilyl ether in the presence of BF3·Et2O

In this Letter, a facile method for the synthesis of 2′-O-cyanoethyluridine, which is a key intermediate in the synthesis of fully and partially 2′-O-cyanoethylated oligoribonucleotides as well as unmodified oligoribonucleotides, was developed by the ring-opening reaction of 2,2′-anhydrouridine with 2-cyanoethyl trimethylsilyl ether in the presence of BF₃·Et₂O in dimethylacetamide. The 2′-O-cyanoethyluridine 3′-phosphoramidite derivative was converted into the 2′-O-cyanoethyl-4-N-acetylcytidine 3′-phosphoramidite derivative by a series of reactions involving displacement of the 4-(1H-1,2,4-triazol-1-yl)uridine derivative with ammonia followed by acetylation.