镍催化硅基保护烯丙醇的烯氢化反应:一种合成含有手性季碳中心高烯丙醇的有效方法

报道了一例手性螺环亚磷酰胺配体和镍的络合物催化的硅基保护烯丙醇的不对称烯氢化反应,以较高的收率(最高达97%)和对映选择性(最高达95%ee)合成了一系列含有手性季碳中心的高烯丙醇.该反应为含有手性季碳中心的双官能团化合物的合成提供了新的有效方法.     

A highly selective ferrocene-based planar chiral PIP (Fc-PIP) acyl transfer catalyst for the kinetic resolution of alcohols

Novel planar chiral ferrocene nucleophilic catalysts (Fc-PIP) containing both central and planar chiral elements were designed and synthesized for catalytic enantioselective acyl transfer of secondary alcohols. A remarkably efficient catalyst with high selectivity factors (up to S = 1892) was identified. Comparing the combination of central and planar chirality revealed a strong requirement for the "matched" chiral elements, indicating that the stereogenic center of the imidazole rings should present itself on the same face as the ferrocenyl fragment; otherwise, the catalyst is completely inactive. An exclusively stacked transition state that accounts for the high selectivity of the kinetic resolution of secondary alcohols is proposed. Notably, this newly designed catalyst family is suitable for the catalytic kinetic resolution of bulky arylalkyl carbinols, producing esters with extremely high ee (>99%).     

Syntheses of chiral β- and γ-amino ethers, morpholines, and their homologues via nucleophilic ring-opening of chiral activated aziridines and azetidines

Lewis acid catalyzed quaternary ammonium salt mediated highly regioselective ring-opening of chiral activated aziridines and azetidines with alcohols to nonracemic β- and γ-amino ethers has been developed. The reaction mainly proceeds via an S(N)2 pathway, and the partial racemization of the starting substrate was effectively controlled by using quaternary ammonium salts. β- and γ-amino ethers are obtained with high enantio- and diastereospecificity (ee up to >99%, de up to 99%). The methodology was further extended to synthesize morpholines and their homologues with high enantiospecificity (ee up to 90%) when halo alcohols were employed as the nucleophiles.     

Mandelic acid derived α-aziridinyl alcohols as highly efficient ligands for asymmetric additions of zinc organyls to aldehydes

A straightforward synthesis of a series of new catalysts containing secondary hydroxyl and aziridine moieties as nucleophilic centers built on the chiral scaffold of (S)-(+)-mandelic acid is described. The new compounds have been tested for the enantioselective addition of diethylzinc and phenylethynylzinc to aryl and alkyl aldehydes, which yielded the corresponding chiral alcohols in high chemical yields (up to 95%) and with excellent ee’s of ca. 90%. The strong influence of the stereogenic center located at the aziridine subunit on the stereochemical outcome is also reported on.     

Lactic acid derived aziridinyl alcohols as highly effective catalysts for asymmetric additions of an organozinc species to aldehydes

A straightforward synthetic route to a series of new catalysts bearing secondary hydroxyl and aziridine moieties as nucleophilic centers built on the chiral skeleton of (S)-(+)-lactic acid is described. All of the new compounds have been tested in the enantioselective addition of diethyl- and phenylethynylzinc to aryl and alkyl aldehydes, yielding the corresponding chiral alcohols in high chemical yields (up to 85%) and good ee’s of approximately 85%. The influence of the stereogenic center located at the aziridine subunit on the stereochemical outcome is also discussed.     

Lipase-catalyzed kinetic resolution of aryltrimethylsilyl chiral alcohols

Lipase-catalyzed kinetic resolution of aryltrimethylsilyl chiral alcohols through a transesterification reaction was studied. The optimal conditions found for the kinetic resolution of m- and p-aryltrimethylsilyl chiral alcohols, led to excellent results, high conversions (c = 50%), high enantiomeric ratios (E > 200) and enantiomeric excesses for the remaining (S)-alcohol and (R)-acetylated product (>99%). However, kinetic resolution of o-aryltrimethylsilyl chiral alcohols did not occur under the same conditions applied to the other isomers.     

Asymmetric diethylzinc addition and phenyl transfer to aldehydes using chiral cis-cyclopropane-based amino alcohols

A new series of amino alcohols with a chiral cyclopropane backbone have been developed and used in the catalytic asymmetric diethylzinc addition and phenyl transfer to various types of aldehydes. These cyclopropane-based chiral amino alcohols show high enantioselectivity in the addition of organozincs to aromatic and aliphatic aldehydes. For diethylzinc addition to aromatic and aliphatic aldehydes, up to 97% ee and 93% ee are obtained, respectively. For the phenyl transfer to aromatic aldehydes, the best enantioselectivity was 89% ee.     

Iridium‐Catalyzed Intermolecular Asymmetric Dearomatization of β‐Naphthols with Allyl Alcohols or Allyl Ethers

An Ir‐catalyzed intermolecular asymmetric dearomatization reaction of β‐naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]₂ (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β‐naphthalenone compounds bearing an all‐carbon‐substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee . The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.     

Enantioselective construction of carbobicyclic scaffolds

Allylic and benzylic Grignard reagents smoothly open phenylalkynyl-activated cyclic trisubstituted epoxides at the more substituted carbon atom to give secondary alcohols with a chiral quaternary center. These alcohols are good substrates for the construction of enantiomerically pure carbobicyclic scaffolds through intramolecular alkylation.     

Stereospecific thermal isomerization of 2, 2-dimethylbenzocyclobutenols to 2-isopropenylphenyl alcohols

Thermolysis of the 1-alkyl-2,2-dimethylbenzocyclobutenol 3 at 160 degrees C gave the 2-isopropenylphenyl alcohol 8 through an (E)-dienol intermediate by a 1,5-sigmatropic hydrogen shift from the isopropylidene methyl group to the carbon bearing hydroxy group. In the thermolysis of each of the diastereomeric 2, 2-dimethylbenzocyclobutenols 6 and 7 which have a hydroxy group on the beta-carbon of the quaternary C(1)-alkyl substituent, the isomerization to the 2-isopropenylphenyl alcohols 10 and 11 took place stereospecifically through a twisted (E)-dienol intermediate. The configuration of the newly formed chiral center in 10 and 11 was the same as that of the ring carbon bearing hydroxy group in the starting 6 and 7.     

Catalytic asymmetric generation of (Z)-disubstituted allylic alcohols

A one-pot method for the direct preparation of enantioenriched (Z)-disubstituted allylic alcohols is introduced. Hydroboration of 1-halo-1-alkynes with dicyclohexylborane, reaction with t-BuLi, and transmetalation with dialkylzinc reagents generate (Z)-disubstituted vinylzinc intermediates. In situ reaction of these reagents with aldehydes in the presence of a catalyst derived from (-)-MIB generates (Z)-disubstituted allylic alcohols. It was found that the resulting allylic alcohols were racemic, most likely due to a rapid addition reaction promoted by LiX (X = Br and Cl). To suppress the LiX-promoted reaction, a series of inhibitors were screened. It was found that 20-30 mol % tetraethylethylenediamine inhibited LiCl without inhibiting the chiral zinc-based Lewis acid. In this fashion, (Z)-disubstituted allylic alcohols were obtained with up to 98% ee. The asymmetric (Z)-vinylation could be coupled with tandem diastereoselective epoxidation reactions to provide epoxy alcohols and allylic epoxy alcohols with up to three contiguous stereogenic centers, enabling the rapid construction of complex building blocks with high levels of enantio- and diastereoselectivity.     

Preparative access to medicinal chemistry related chiral alcohols using carbonyl reductase technology

Libraries of highly enantioenriched secondary alcohols in both enantiomeric forms were synthesised by enzymatic reduction of their parent ketones using selectAZyme? carbonyl reductase (CRED) technology. Commercially available CREDs were able to reduce a range of substrate classes efficiently and with very high enantioselectivity. Matching substrate classes to small subsets of CREDs enabled the fast development of preparative bioreductions and the rapid generation of 100–1500 mg samples of chiral alcohols in typically >95% ee and the majority in ?99.0% ee. The conditions for small scale synthesis were then scaled up to 0.5 kg to deliver one of the chiral alcohols, (S)-1-(4-bromophenyl)-2-chloroethanol, in 99.8% ee and 91% isolated yield.     

Highly enantioselective asymmetric reactions involving zinc ions promoted by chiral aziridine alcohols

Enantiomerically pure, chiral secondary and tertiary aziridine alcohols (including the aziridine analogue of ProPhenol—AziPhenol) have proven to be highly effective catalysts for enantioselective asymmetric reactions in the presence of zinc ions, including arylation of aromatic aldehydes, epoxidation of chalcone and addition of diethylzinc to aldehydes, leading to the desired chiral products in high chemical yields (up to 90%) and with ee’s up to 90%. A higher catalytic activity of Prophenol-type bis(aziridine alcohol) in the aforementioned asymmetric transformations has been demonstrated.     

Synthesis and application of chiral spiro phospholane ligand in Pd-catalyzed asymmetric allylation of aldehydes with allylic alcohols

[reaction: see text] A novel chiral monodentate spiro phenylphospholane ligand 4 was prepared from a readily accessible, enantiomerically pure 1,1'-spirobiindane-7,7'-diol in high yield. This ligand has proven to be efficient for Pd-catalyzed enantioselective allylation of aldehydes with allylic alcohols. Aromatic, heteroaromatic, and aliphatic aldehydes gave homoallylic alcohols in good enantioselectivities (up to 83% ee) and excellent anti diastereoselectivities (up to 99:1 dr).     

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.     

Catalytic asymmetric synthesis of β-triazolyl amino alcohols by asymmetric transfer hydrogenation of α-triazolyl amino alkanones

The synthesis of optically active β-triazolyl amino alcohols was carried out via ruthenium catalyzed asymmetric transfer hydrogenation of α-triazolyl amino alkanones. This reaction proceeds under mild reaction conditions with up to 99% yield and 99.9% enantiomeric excess (ee). This protocol was applied to the synthesis of an enantiopure antitubercular agent and its arylated product with retention in enantiomeric purity. The absolute configuration at the stereogenic center of the chiral product as found to be (S).     

Asymmetric reductions using the chiral boronic ester TarB-H: a practical and inexpensive procedure for synthesizing chiral alcohols

Chiral alcohols are prepared in high enantiomeric excesses using an inexpensive and easily synthesized tartaric acid derived boronic ester (TarB-H) with sodium borohydride. The phenylboronic acid could be recovered quantitatively using a simple extraction with sodium hydroxide and diethyl ether. The optimized TarB-H system was used to reduce aromatic and aliphatic ketones in an open flask to chiral alcohols with enantiomeric excesses up to 99%.     

Aluminum-catalyzed asymmetric alkylations of pyridyl-substituted alkynyl ketones with dialkylzinc reagents

Alkylations of pyridyl-substituted ynones with Et2Zn and Me2Zn, promoted by amino acid-based chiral ligands in the presence of Al-based alkoxides, afford tertiary propargyl alcohols efficiently in 57% to >98% ee. Two easily accessible chiral ligands are identified as optimal for reactions of the two dialkylzinc reagents. Catalytic alkylations with Et2Zn require a chiral ligand carrying two amino acid moieties (valine and phenylalanine) along with a p-trifluoromethylphenylamide C-terminus. In contrast, reactions with Me2Zn are most effectively promoted in the presence of a chiral ligand containing a single amino acid (benzyl cysteine), capped by an n-butylamide. Enantiomerically enriched tertiary alcohols bearing a pyridyl and an alkyne substituent can be functionalized in a variety of manners to furnish a wide range of difficult-to-access acyclic and heterocyclic structures; two noteworthy examples are Cu-catalyzed protocols for conversion of tertiary propargyl alcohols to enantiomerically enriched tetrasubstituted allenes and bicyclic amides that bear an N-substituted quaternary carbon stereogenic center. Mechanistic models that account for the trends and enantioselectivity levels are provided.     

Reduction of carbonyl compounds via hydrosilylation: V. Synthesis of optically active allylic alcohols via regioselective asymmetric hydrosilylation

Regioselective asymmetric reduction of prochiral α,β-unsaturated ketones to optically active allylic alcohols was performed via hydrosilylation catalyzed by a rhodium(I) complex with (+)-BMPP, (+)-DIOP and (?)-DIOP as chiral ligands. The allylic alcohols with optical purity up to 69% e.e. were obtained in good yields. The extent of asymmetric induction was found to depend on the stereo-electronic matching of the chiral ligand, ketone and hydrosilane employed. In the asymmetric reduction of (R)-carvone, leading to carveol, the extent of asymmetric induction was found to depend markedly on the ligand/rhodium ratio. Either trans-(5R,1S)-carveol or cis-(5R,1R)-carveol was obtained with good stereoselectivity by using (?)-DIOP or (+)-DIOP as chiral ligand, and it turned out that the chiral center present in carvone had only a slight influence on the asymmetric induction by the chiral catalysts.     

Asymmetric addition of alkylzinc reagents to cyclic alpha,beta-unsaturated ketones and a tandem enantioselective addition/diastereoselective epoxidation with dioxygen

Although over 100 catalysts have been reported to catalyze the asymmetric addition of alkyl groups to aldehydes, these catalysts fail to promote additions to ketones with >90% enantioselectivity. This paper describes the asymmetric 1,2-addition of alkyl groups to conjugated cyclic enones to give allylic alcohols with chiral quaternary centers. The resultant allylic alcohols are converted into epoxy alcohols with excellent diastereoselectivities. Treatment of the epoxy alcohols with BF3.OEt2 induces a semipinacol rearrangement to provide alpha,alpha-dialkyl-beta-hydroxy ketones with all-carbon chiral quaternary centers. We also report a one-pot procedure for the asymmetric addition/diastereoselective epoxidation reaction. Simply exposing the reaction mixture to dioxygen after the asymmetric addition reaction is complete results in epoxidation of the allylic alcohol with high diastereoselectivity.