Chiral N-heterocyclic carbene--Pd(0)-catalyzed asymmetric diamination of conjugated dienes and triene

Studies show that a variety of conjugated dienes and triene can be enantioselectively diaminated using di-tert-butyldiaziridinone as nitrogen source and chiral N-heterocyclic carbene-Pd(0) complex as catalyst in good enantioselectivity (62-91% ee) with high regio- and diastereoselectivity.     

Enantioselective synthesis of 20(S)-camptothecin using an enzyme-catalyzed resolution

The important key intermediate of a 20(S)-camptothecin synthesis was prepared enantioselectively using an enzyme-catalyzed resolution. A commercially available papain was found to exhibit the highest enantioselectivity with moderate activity, and the (S)-enantiomer of 99% ee was obtained as the remaining substrate.     

Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine)

Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseudopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with aldehydes diastereoselectively giving exclusively exo isomers and anti/syn selectivity up to 98:2. Granatanone can be enantioselectively lithiated by chiral lithium amides and the resulting non-racemic enolate can be reacted with aldehydes giving aldols with enantiomeric excess up to 93% (99% ee after recrystallization). The absolute and relative configuration of the aldol products was determined by NMR spectroscopy and X-ray analysis.Granatanone; aldol reaction; asymmetric synthesis; enantioselective deprotonation; chiral lithium amide.     

Enantioselective fluorination mediated by cinchona alkaloids/selectfluor combinations: A catalytic approach

A novel catalytic approach related to the enantioselective fluorination reaction using N-fluoroammonium salts of cinchona alkaloids which produces non-racemic α-fluoroketones is described. Acyl enol ethers of ketones 1 are enantioselectively fluorinated with Selectfluor^® in the presence of a catalytic amount of cinchona alkaloid and 1.2 equivalents of sodium acetate at room temperature for 1–3 days to furnish α-fluoroketones 2 in good yields and moderate enantioselectivity (up to 54% ee).     

Organocatalytic regioselective Michael additions of cyclic enones via asymmetric phase transfer catalysis

Cyclohexanone and cycloheptanone can be enantioselectively functionalized in the 3-position with up to 92% ee and 87% ee, respectively, by the base-promoted dimerization of the corresponding enones using 3,4,5-tribenzyloxybenzyl cinchoninium bromide, as a new effective catalyst.     

Asymmetric synthesis via acetal templates. 9. Further studies of the allylation reaction. Preparation of (−)-dihydromyoporone

A procedure has been developed for the high-yield coupling of chiral acetals 1 with allyltrimethylsilane (2, R′=H) as well as with methallyltrimethylsilane (2,R′=ME) to afford the hydroxy ethers 3 in which the new chiral center is formed highly enantioselectively. Homoallylic alcohols 4 of high ee are produced by removal of the chiral auxiliary.     

Formation and reaction of 2-metalated N-Boc-4,4-dimethyl-1,3-oxazolidines in the presence of (−)-sparteine: new chiral formyl anion equivalents

Lithiation of N-Boc-4,4-dimethyl-1,3-oxazolidine with s-BuLi and the following reaction with benzaldehyde was carried out in the presence of (−)-sparteine. The reaction was not diastereoselective (syn:anti=46:54), but each isomer of the adducts was obtained enantioselectively (syn: 90% ee, anti: 88% ee). Addition of MgBr₂ to the reaction mixture increased the diastereoselectivity to syn:anti=90:10.     

Synthesis of tetrasubstituted alkenes through a palladium-catalyzed domino carbopalladation/C-H-activation reaction

Helical tetrasubstituted alkenes (7) were obtained in a highly efficient way through a palladium-catalyzed domino-carbopalladation/CH-activation reaction of propargylic alcohols 6 in good to excellent yields. Electron-withdrawing- and electron-donating substituents can be introduced onto the upper and lower aromatic rings. The substrates (6) for the domino process were synthesized by addition of the lithiated alkyne (20) to various aldehydes (19); moreover, the substrates were accessible enantioselectively (in 95% ee) by reduction of the corresponding ketone using the Noyori procedure.     

Lipase catalyzed regio- and stereospecific hydrolysis: chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid

Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)-butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α-thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both (S)- and (R)-enantiomers of α-lipoic acid and their analogues.     

Asymmetric hydrogenation of aromatic ketones using an iridium(I) catalyst containing ferrocene-based P–N–N tridentate ligands

Six ferrocene-based P–N–N tridentate ligands have been synthesized and applied in the Ir-catalyzed asymmetric hydrogenation of aromatic ketones. A wide range of ketones are hydrogenated enantioselectively to afford the corresponding optically active alcohols in the enantioselectivities of up to 86.6% ee. The substituent groups on the P-phenyl and pyridine rings play an important role with regard to the enantioselectivity.     

Asymmetric hydrogenation of di and trisubstituted enol phosphinates with N,P-ligated iridium complexes

The iridium-catalyzed asymmetric hydrogenation of various di- and trisubstituted enol phosphinates has been studied. Excellent enantioselectivities (up to >99% ee) and full conversion were observed for a range of substrates with both aromatic and aliphatic side chains. Enol phosphinates are structural analogues of enol acetates, and the hydrogenated alkyl phosphinate products can easily be transformed into the corresponding alcohols with conservation of stereochemistry. We have also hydrogenated, in excellent ee, several purely alkyl-substituted enol phosphinates, producing chiral alcohols that are difficult to obtain highly enantioselectively from ketone hydrogenations.     

Oxidation of acyclic monoterpenes by P450 BM-3 monooxygenase: influence of the substrate E/Z-isomerism on enzyme chemo- and regioselectivity

Oxidized terpenes and terpenoids are highly valuable compounds for organic chemistry. Cytochrome P450 monooxygenase P450 BM-3 from Bacillus megaterium is able to catalyze oxidation of terpenes with high efficiency. Mutations at the amino acid positions 47, 51, and 87 resulted in significantly enhanced activity and regioselectivity of the enzyme during oxidation of geranylacetone and related compounds. The activity of the mutant R47L/Y51F/F87V was in the order of ketone>alcohol>aldehyde>acid. An effect of the substrate cis/trans-isomerism on the enzyme chemo- and regioselectivity was studied. P450 monooxygenase demonstrated similar NADPH turnovers with cis/trans isomers, nerylacetone/geranylacetone (1.9×10³/2.1×10³ min⁻¹) and nerol/geraniol (5.7×10²/5.9×10² min⁻¹), however, resulted in different number of products and product distribution. The Z-isomers, nerylacetone and nerol, were oxidized resulting in several products (five and three, respectively), including allylic alcohols. In contrast, E-isomers were epoxidized exclusively. Geranylacetone was converted with high activity (2080 min⁻¹) and enantioselectivity (97% ee) to 9,10-epoxygeranylacetone, while geraniol was enantioselectively epoxidized to the 6,7-epoxide (250 min⁻¹, 90% ee) with 90% regioselectivity.     

Enantioselective α-hydroxylation of β-keto esters catalyzed by chiral S-timolol derivatives

A screen of aryloxy aminopropanol organocatalysts derived from the β-blocker inhibitor S-timolol determined the most active catalyst of asymmetric α-hydroxylation of β-keto esters. (R)-1-(tert-butylamino)-3-(3,4,5-trimethoxyphenoxy) propan-2-ol (3k) was the most effective derivative, enantioselectively catalyzing α-hydroxylation of β-keto esters using tert-butyl hydroperoxide as the oxidant in hexane to afford the corresponding products in excellent yield and with good enantioselectivity (up to 96% yield, 88% ee).     

(S)-和(R)-盐酸氟西汀的不对称合成

盐酸氟西汀是一种临床广泛使用的非三环类抗抑郁药, 本工作介绍了一种不对称合成(S)-和(R)-盐酸氟西汀的方法. 以自制的手性噁唑硼烷为催化剂, 将起始原料β-氯苯丙酮不对称催化氢化还原成(S)-或(R)-手性醇, 这一步的化学收率和光学收率都较高. 然后再经两步, (S)-和(R)-手性醇转化为(S)-和(R)-盐酸氟西汀. 整个工艺只需三步, 总收率为66.5%, 盐酸氟西汀对映体的ee值可达98.6%. 还考察了反应温度、溶剂、催化剂的量等因素对β-氯苯丙酮的不对称氢化还原的化学产率和光学收率的影响.     

Regio- and enantioselective alkane hydroxylation with engineered cytochromes P450 BM-3

Cytochrome P450 BM-3 from Bacillus megaterium was engineered using a combination of directed evolution and site-directed mutagenesis to hydroxylate linear alkanes regio- and enantioselectively using atmospheric dioxygen as an oxidant. BM-3 variant 9-10A-A328V hydroxylates octane at the 2-position to form S-2-octanol (40% ee). Another variant, 1-12G, also hydroxylates alkanes larger than hexane primarily at the 2-position but forms R-2-alcohols (40-55% ee). These biocatalysts are highly active (rates up to 400 min(-1)) and support thousands of product turnovers. The regio- and enantioselectivities are retained in whole-cell biotransformations with Escherichia coli, where the engineered P450s can be expressed at high levels and the cofactor is supplied endogenously.     

Enantioselective arylation of 2-methylacetoacetates catalyzed by CuI/trans-4-hydroxy-L-proline at low reaction temperatures

CuI/trans-4-hydroxy-l-proline-catalyzed coupling reaction of 2-iodotrifluoroacetanilides with 2-methylacetoacetates took place at -45 degrees C to create alpha-aryl all-carbon quaternary centers enantioselectively. Up to 93% ee was achieved when tert-butyl ester was used. The combination of ligand, ortho substituent (participation of NHCOCF3), and solvent effects was shown to account for these unprecedentedly mild reaction conditions.     

Optically-active dihydropyridines via lipase-catalyzed enantioselective hydrolysis

Several prochiral esters of 1,4-dihydropyridines were enantioselectively hydrolyzed by Pseudomonas lipases (AK, P-30, and K-10) and Candida cylindracea lipase (OF-360). The stereochemical preferences of the lipases P-30 and K-10 were found to be always 4-Pro R and that of OF-360 to be 4-Pro S. In contrast, the prochiral preference of the lipase AK varied depending on the substitution on the dihydropyridine ring. The N-methoxymethyl derivatives afforded the 4S isomers (95% ee) whereas the N-unsubstituted compounds yielded the 4R isomers (50–70% ee).     

The highly enantioselective 1,3-dipolar cycloaddition of alkyl glyoxylate-derived nitrones to E-crotonaldehyde catalyzed by hybrid diamines

1,3-Dipolar cycloaddition of alkyl glyoxylate-derived nitrones to E-crotonaldehyde can be catalyzed by hybrid diamines, obtained from (S)-BINAM and l-α-amino acids. The hybrid of (S)-BINAM and l-Phe was found to be the best organocatalyst. Products were obtained in good yield and diastereoselectivity as well as high enantioselectivity (82-91% ee). Subsequent transformations into functionalized pyrrolidinones have been demonstrated.     

Highly stereoselective direct aldol reactions catalyzed by (S)-NOBIN-l-prolinamide

(S)-NOBIN-l-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic aldehydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cyclic ketones furnished the anti-aldols in moderate to high yield, excellent diastereoselectivity (up to >99/<1 anti/syn ratio) and high ee (up to 95%).     

Highly enantioselective reduction of the C–C double bond of N-phenyl-2-methyl- and N-phenyl-2,3-dimethyl- maleimides by fungal strains

The CC double bond of non-substituted and substituted maleimides were hydrogenated to the corresponding succinimides by fungal strains. 2- and 2,3-methylated-phenyl-maleimides were enantioselectively reduced to (R)-N-phenyl-3-methylsuccinimide and to trans-(R,R)-N-phenyl-2,3-dimethylsuccinimide respectively by Aspergillus niger, A. flavus and A. fumigatus (conversion 96 to 99%), Fusarium graminearum and Penicillium sp (conversion: 37 and 39%), with 99% ee.