Electroreductive intramolecular coupling of chiral alpha-imino esters: stereoselective synthesis of mixed ketals of cis-2,4-disubstituted azetidine-3-ones

The electroreduction of chiral aromatic alpha-imino esters prepared from (S)-alpha-amino acids, such as (S)-valine, (S)-leucine, and (S)-phenylalanine, in the presence of chlorotrimethylsilane and triethylamine afforded four-membered cyclized products, mixed ketals of cis-2,4-disubstituted azetidine-3-ones, stereospecifically (>99% de, 85-99% ee). The best result of the electroreductive cyclization was obtained using Bu(4)NClO(4) as a supporting electrolyte and a Pt cathode. The absolute stereochemistry of the obtained single stereoisomers was confirmed to be 2R,3R,4S by X-ray crystallography. Calculations for the transition states of the cyclization support the stereospecific formation of the (2R,3R,4S)-isomers.     

Catalytic enantioselective amination of silyl enol ethers using chiral dirhodium(II) carboxylates: asymmetric formal synthesis of (-)-metazocine

Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, is an exceptionally efficient catalyst for enantioselective aminations of silyl enol ethers derived from acyclic ketones or alpha,beta-enones with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh), providing N-(2-nitrophenylsulfonyl)-alpha-amino ketones in high yields and with enantioselectivities of up to 95% ee. The effectiveness of the present catalytic protocol has been demonstrated by an asymmetric formal synthesis of (-)-metazocine.     

Practical and convenient enzymatic synthesis of enantiopure alpha-amino acids and amides

Catalyzed by the nitrile hydratase and the amidease in Rhodococcus sp. AJ270 cells under very mild conditions, a number of alpha-aryl- and alpha-alkyl-substituted DL-glycine nitriles 1 rapidly underwent a highly enantioselective hydrolysis to afford D-(-)-alpha-amino acid amides 2 and L-(+)-alpha-amino acids 3 in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of a high L-enantioselective amidase and a low enantioselective nitrile hydratase. The influence of the substrates on both reaction efficiency and enantioselectivity was also discussed in terms of steric and electronic effects. Coupled with chemical hydrolysis of D-(-)-alpha-phenylglycine amide, biotransformation of DL-phenylglycine nitrile was applied in practical scale to produce both D- and L-phenylglycines in high optical purity.     

Unusual resolution of N-(3,5-dinitrobenzoyl)-alpha-amino acids on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

While HPLC chiral stationary phases (CSPs) based on chiral crown ethers have been known useful for the resolution of only racemic primary amino compounds or some secondary amino compounds, in this study, we first demonstrated that the CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid is also useful for the resolution of N-benzoyl-alpha-amino acids, which do not contain a primary or secondary amino group. Especially, N-(3,5-dinitrobenzoyl)-alpha-amino acids were resolved better than corresponding N-(3-nitrobenzoyl)- or N-benzoyl-alpha-amino acids, the separation (alpha) and the resolution factors (R(S)) for the resolution of eight N-(3,5-dinitrobenzoyl)-alpha-amino acids being in the range of 1.06-1.81 and 0.54-2.81, respectively. The optimum mobile phase condition was the mixture of acetic acid-triethylamine-acetonitrile with the ratio of 0.05/0.25/100 (v/v/v).     

Convenient synthesis of N-methylamino acids compatible with Fmoc solid-phase peptide synthesis

N(alpha)-Methylamino acid containing peptides exhibit interesting therapeutic profiles and are increasingly recognized as potentially useful therapeutics. Unfortunately, their synthesis is hampered by the high price and unavaibility of many N(alpha)-methylamino acids. An efficient and practical preparation of N(alpha)-methyl-N(alpha)-(o-nitrobenzenesulfonyl)-alpha-amino acids without extensive purification is described. The procedure is based on the well-known N-alkylation of N(alpha)-arylsulfonylamino esters which was improved by using dimethyl sulfate and DBU as base. Ester cleavage is efficiently achieved by using an S(N)2-type saponification with lithium iodide, avoiding racemization observed with lithium hydroxide hydrolysis. Compatibility of the synthesized N(alpha)-methylamino acids with Fmoc solid-phase peptide synthesis is demonstrated by using normal coupling conditions to efficiently prepare N-methyl dipeptides. The described procedure allows the preparation of N(alpha)-methylamino acids in a very short period of time and a rapid synthesis of N-methyl peptides using Fmoc solid-phase peptide synthesis.     

Enantioselective functionalisation of the C-2' position of 1,2,3,4,5-pentamethylazaferrocene via sparteine mediated lithiation: potential new ligands for asymmetric catalysis

The s-BuLi-sparteine base combination deprotonated the C-2' position of 1,2,3,4,5-pentamethylazaferrocene and subsequent reaction with a range of electrophiles gave C-2 substituted products in 76-93% yield and approximately 80% ee. The products could be recrystallised to enrich ee's to >90%. Resubjection of the initial addition products ( approximately 80% ee) to the deprotonation conditions led to a kinetic resolution to give products with >90% ee and superior overall yields compared to recrystallisation for the cases where the electrophiles were Ph2CO, MeI and Ph2S2. Transmetallation of the 2-lithiopentamethylazaferrocene ( approximately 80% ee) with ZnCl2 allowed palladium catalysed cross coupling with a variety of C-2 haloaryl, heteroaryl and vinyl groups to give some novel C-2' substituted pentamethylazaferrocene derivatives in 61-77% yield in 80% ee. Potential N,N-chelate ligands were recrystallised to >95% ee. A novel C2-symmetric bis-pentamethylazaferrocene could be synthesised by an iron catalysed oxidative coupling of the enatioenriched C-2 lithio derivative and in the presence of a PhMe-Et2O solvent mixture proceeded in 97% ee.     

A novel stereocontrolled synthesis of 1,2-trans cyclopropyl ketones via suzuki-type coupling of acid chlorides with cyclopropylboronic acids

[reaction: see text] The palladium-catalyzed cross-coupling reaction of cyclopropylboronic acids with acyl chlorides was achieved by the combination of Ag(2)O and K(2)CO(3) as the base. Highly enantiomerically enriched cyclopropyl ketones (ee >90%) were also obtained by the reaction of corresponding chiral cyclopropylboronic acids.     

Rhodium(I)-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated amides.

The conjugate addition of arylboronic acids to alpha,beta-unsaturated amides was carried out in the presence of a chiral rhodium catalyst and an aqueous base. The catalyst prepared in situ from Rh(acac)(CH(2)=CH(2))(2) and (S)-binap provided (R)-N-benzyl-3-phenylbutanamide with 93% ee in the addition of phenylboronic acid to N-benzyl crotonamide. The reaction suffered from incomplete conversion resulting in moderate yields, but addition of an aqueous base, such as K(2)CO(3) (10-50 mol%) was found to be highly effective to improve the chemical yields. The role of the base giving a RhOH species active for transmetalation with arylboronic acids was discussed.     

Preparation and application of HPLC chiral stationary phases based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

Preparation of liquid chromatographic chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid and their application are reviewed. The various methods of connecting (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid to silica gel covalently or dynamically are demonstrated. The CSPs based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid have been very successful for the resolution of various primary amino compounds with the use of an aqueous mobile phase containing organic and acidic modifiers. In addition, the resolution of secondary amino compounds including beta-blockers and N-(3,5-dinitrobenzoyl)-alpha-amino acids has been demonstrated on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid with a non-aqueous mobile phase.     

Chiral phosphine Lewis base catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone and phenyl acrylate

In the aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone (MVK) promoted by chiral phosphine Lewis base: (R)-2'-diphenylphosphanyl-[1,1']binaphthalenyl-2-ol (10 mol%), the aza-Baylis-Hillman adducts 1 were obtained in good yields with high ee (70-94% ee) at -30 degrees C in THF. In CH2Cl2 upon heating at 40 degrees C, the aza-Baylis-Hillman reaction of N-sulfonated imines with phenyl acrylate gave the adducts 2 in high yields (60-97%) with moderate ee (52-77%).     

Efficient crystallization-induced dynamic resolution of alpha-substituted carboxylic acids

Herein we present a novel route to enantiomerically enriched chiral alpha-substituted carboxylic acids by crystallization-induced dynamic resolution (CIDR) of their diastereomeric salts with chiral amines. Thus, the racemic alpha-bromo acid 3 is converted reliably with (1R,2S)-2-amino-1,2-diphenylethanol in the presence of a catalytic amount of tetrabutylammonium bromide into its R-enantiomer 4 in 90% yield with 88% ee. Similarly, the racemic alpha-thiobenzoyl acid 5 could be resolved to 90% ee in 74% yield. Further enrichment to enantiomeric homogeneity could be achieved in both cases by crystallization. In a telescoped, two-step process, S-alpha-thiobenzoyl acid 6 (>or=99.6% ee) was prepared from the racemic bromide 3 in 63% yield. State-of-the-art parallel experimentation enabled rapid screening for suitable dynamic resolution conditions. Kinetic studies defined the influence of temperature, tetrabutylammonium bromide concentration, molarity, and solvent polarity on the resolution rate, product yield, and enantiomeric excess.     

Synthesis of optically active 2-hydroxy monoesters via-kinetic resolution and asymmetric cyclization catalyzed by heterometallic chiral (salen) Co complex

The binuclear chiral (salen) Co complexes bearing Lewis acids of Al and Ga catalyze regio- and enantioselective ring opening of terminal epoxides with carboxylic acids. The ring opened product of epichlorohydrin with carboxylic acids followed by cyclization step in the presence of catalyst and base represent straightforward, efficient methods for the synthesis of enatiomerically enriched (>99% ee) valuable terminal epoxides. Strong synergistic effects of different Lewis acid of Co-Al and Co-Ga were exhibited in the catalytic process.     

Chiral phosphine lewis bases catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with activated olefins

In the aza-Baylis-Hillman reaction of N-sulfonated imines (N-arylmethylidene-4-methylbenzenesulfonamides and others) with methyl vinyl ketone, ethyl vinyl ketone, and acrolein, we found that, in the presence of a catalytic amount of chiral phosphine Lewis base such as (R)-2'-diphenylphosphanyl-[1,1']binaphthalenyl-2-ol LB1 (10 mol %) and molecular sieve 4A, the corresponding aza-Baylis-Hillman adducts could be obtained in good yields with good to high ee (70-95% ee) at low temperature (approximately -30 to -20 degrees C) or at room temperature in THF, respectively. In CH2Cl2 upon heating at 40 degrees C, the aza-Baylis-Hillman reaction of N-sulfonated imines with phenyl acrylate or naphthyl acrylate gave the adducts in good to high yields (60-97%) with moderate ee (52-77%). The mechanistic insight has been investigated by 31P and 1H NMR spectroscopic measurements. The key enolate intermediate, which has been stabilized by intramolecular hydrogen bonding, has been observed by 31P and 1H NMR spectroscopy. An effective bifunctional Lewis base and Bronsted acid phosphine Lewis base system has been disclosed in this catalytic, asymmetric aza-Baylis-Hillman reaction.     

Synthesis of the anti-influenza agent (-)-oseltamivir free base and (-)-methyl 3-epi-shikimate

A new enantioselective synthesis of the anti-influenza agent (-)-oseltamivir free base (7.1% overall yield; 98% ee) and (-)-methyl 3-epi-shikimate (16% overall yield; 98% ee) has been described from readily available raw materials. Sharpless asymmetric epoxidation and diastereoselective Barbier allylation of an aldehyde are the key reactions employed in the incorporation of chirality, while the cyclohexene carboxylic ester core was constructed through a ring closing metathesis reaction.     

Extended application of a chiral stationary phase based on (+)-(1 8-crown-6)-2,3,11,12-tetracarboxylic acid to the resolution of N-(substituted benzoyl)-alpha-amino acid amides

A chiral stationary phase (CSP 1) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was applied to the resolution of N-(substituted benzoyl)-alpha-amino acid amides and esters. N-(Substituted benzoyl)-alpha-amino acid amides were well resolved using a mixture of acetic acid-triethylamine-acetonitrile (0.01:0.05:100, v/v/v) as an optimum mobile phase while N-(substituted benzoyl)-alpha-amino acid esters were not resolved at all. In contrast, both N-(substituted benzoyl)-alpha-amino acid amides and esters were not resolved at all or resolved very poorly on another CSP (CSP 2), which lacks the two N-H hydrogens of the amide tethers of CSP 1. Among the substituents on the benzoyl group of analytes, the nitro group was the best for good resolution of analytes on CSP 1. From these results, the two N-H hydrogens of the amide tethers of CSP 1, the carbonyl oxygen of the amide group of analytes, and the nitro group on the benzoyl group of analytes were concluded to play significant roles in chiral recognition. In addition, various N-(3,5-dinitrobenzoyl)leucine amides with different lengths of N-alkylamide chains were resolved on CSP 1 and N-(3,5-dinitrobenzoyl) leucine N-propylamide was found to show the best chiral recognition in terms of the separation (alpha = 1.30) and the resolution factor (Rs= 3.17).     

Acyclic stereoselective boron alkylation reactions for the asymmetric synthesis of beta-substituted alpha-amino acid derivatives

Optically active syn- or anti-beta-substituted-alpha-amino acid derivatives are prepared in 94 to >/=99% ee and 66-98% ds by reaction of the Schiff base acetate of glycine tert-butyl ester with chiral, nonracemic B-alkyl-9-BBN derivatives in the presence of the Cinchona alkaloid, cinchonidine (CdOH) or cinchonine (CnOH), base, and lithium chloride.     

Asymmetric hetero-Diels-Alder reactions of N-sulfinyl dienophiles using chiral bis(oxazoline)-copper(II) and -zinc(II) triflates

Asymmetric hetero-Diels-Alder (HDA) reactions of N-sulfinyl dienophiles using bis(oxazoline)-copper(II) and -zinc(II) triflates are described. The cycloadditions with cyclic and acyclic 1,3-dienes have been studied. In most cases, good enantioselectivities (70-98% ee) and yields (60-85%) were obtained with stoichiometric amounts of the Lewis acids. Cyclic dienes gave the endo adducts as major products, while acyclic dienes provided cis adducts. The HDA adducts have been transformed into N-protected alpha-amino acid methyl esters, amino alcohols, and homoallylic amines. A stereochemical model, which accounts for the enantiofacial selectivity of the HDA reaction by a tetrahedral metal center, has been proposed. Mechanistic studies revealed positive nonlinear effects, assumed to arise from the formation of less-reactive heterochiral complexes. Investigation of the temperature dependence of the enantioselectivity indicated that at least two selective reaction steps exist in the zinc-catalyzed reaction. Reactions run with 10 mol % chiral Lewis acid gave poor yields and selectivities. However, in combination with TMSOTf (100 mol %), high yields (68-86%) and enantioselectivities (97-98% ee) were obtained.     

B-allenyl- and B-(gamma-trimethylsilylpropargyl)-10-phenyl-9-borabicyclo[3.3.2]decanes: asymmetric synthesis of propargyl and alpha-allenyl 3-degree-carbinols from ketones

Simple and efficient Grignard procedures are reported for the syntheses of B-allenyl-10-(phenyl)-9-borabicyclo[3.3.2]decane (1) and its B-(gamma-trimethylsilylpropargyl) counterpart (2) in both enantiomeric forms. Both add selectively to ketones, providing propargyl- and alpha-silylallenyl 3-degree-carbinols, respectively (i.e., 6 (61-93% ee) and 9 (64-98% ee)). The air-stable boron byproduct is efficiently recovered and recycled back to either 1 or 2. The ozonolysis and bromination of 9 provide nonracemic alpha-hydroxy acids and gamma-bromopropynyl carbinols, respectively.     

Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketones with DIFLUORPHOS and SYNPHOS analogues

Applications of electron-deficient DIFLUORPHOS and SYNPHOS analogues in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to α,β-unsaturated ketones afford the 1,4-addition adducts in yields up to 92% and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to nonsubstituted maleimide substrates using the (R)-3,5-diCF(3)-SYNPHOS ligand is also reported. This protocol provides access to various enantioenriched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be upgraded up to 99% ee, after a single crystallization.     

Brønsted acid catalyzed enantioselective α-amidoalkylation in the synthesis of isoindoloisoquinolines

The Parham cyclization-intermolecular α-amidoalkylation sequence results in the facile enantioselective synthesis of 12b-substituted isoindoloisoquinolines (ee up to 95%) using BINOL-derived Br?nsted acids. α-Amidoalkylation of indole occurs through the formation of a chiral conjugate base/bicyclic quaternary N-acyliminium ion pair.