Chiral N-phosphonyl imine chemistry: asymmetric additions of malonate-derived enolates to chiral N-phosphonyl imines for the synthesis of β-aminomalonates

Chiral N-phosphonyl imines attached by 1-naphthyl group were found to react with lithium malonate enolates smoothly to give chiral β-aminomalonates. Good yields and excellent diastereoselectivity were achieved for sixteen examples. The chiral auxiliary can be readily removed by treating with trifluoroacetic acid (TFA) to give free amino malonates. The absolute structure has been unambiguously determined by converting one of the products into an authentic sample.     

Synthesis of a new chiral oxazolidinone auxiliary based on d-xylose and its application to the Staudinger reaction

The synthesis of a new chiral oxazolidinone auxiliary based on d-xylose is described which is employed in diastereoselective Staudinger-type β-lactam syntheses. Using 2-chloro-1-methylpyridinium iodide as the dehydrating reagent, the reaction of auxiliary tethered acetic acid with acyclic or cyclic imines gave the desired β-lactams in good yields with excellent cis- or trans-selectivity depending on the geometry of the imine. X-Ray structure determination of one of the obtained compounds corroborated the absolute configuration for all cis products.     

Orthoacylimines: a new class of chiral auxiliaries for nucleophilic addition of organolithium reagents to imines

A new class of orthoacylimine-derived chiral auxiliaries has been synthesized and tested in the nucleophilic addition of organolithium reagents to imines. The precursors can be prepared by an aza-Wittig reaction between the corresponding orthoacyl azide and a variety of aldehydes in the presence of trialkylphosphines. The nucleophilic addition of organolithium reagents led to the addition products in good yields and with good to excellent diastereoselectivities (from 85:15 to 99:1). The chiral, nonracemic secondary amines could be readily obtained under mild hydrolytic condition. Furthermore, the chiral auxiliary can be recovered in quantitative yield and reconverted to the starting orthoacyl azide precursor. This method was applied to the synthesis of (S)-t-leucine.     

Asymmetric catalytic aza-Morita-Baylis-Hillman reaction using chiral bifunctional phosphine amides as catalysts

The asymmetric catalytic aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with α,β-unsaturated ketones has been successfully conducted by using chiral bifunctional phosphine amides as catalysts. A series of new chiral bifunctional phosphine amides were designed, synthesized, and systematically studied for this asymmetric reaction. The corresponding aza-MBH adducts were obtained in good yields (75-99%) and up to very good enantiomeric excesses (51-95% ee) under mild conditions.     

Enantioselective direct Mannich reactions of 3-substituted oxindoles catalyzed by chiral phosphine via dual-reagent catalysis

A combination of an amino acid-derived chiral phosphine catalyst and methyl acrylate to catalyze the direct Mannich reaction of 3-substituted oxindoles and imines has been reported to afford 3-tetrasubstituted oxindole derivatives which are key structures for biological activities. The products are formed with a quaternary carbon and featured with two adjacent chiral centers. Various N-EDG(electron-donating group) and N-EWG(electron-withdrawing group) protected oxindoles, including 3-aryl and 3-alkyl substituted ones, have been evaluated with aromatic and aliphatic imines under this catalytic system, smoothly giving desired products in good yields as well as excellent diastereo- and enantioselectivities.     

Enantioselective aza-Henry reaction using cinchona organocatalysts

The aza-Henry reaction of imines with nitromethane was promoted by cinchona alkaloids and modified cinchona bases to give optically active β-nitroamines. Various N-protected imines were examined as substrates. N-Boc, N-Cbz, and N-Fmoc protected imines gave the best results in terms of chemical yields and enantioselectivities. After a careful screening of a series of chiral bases, very good enantioselectivities up to 94% ee were obtained using a cinchona-based thiourea organocatalyst under the optimized reaction conditions.     

Chiral N-phosphonyl imine chemistry: new reagents and their applications for asymmetric reactions

Novel chiral N-phosphonyl imines 2 have been designed and synthesized using chiral N-phosphoramide 1. These N-phosphonyl imines have been successfully utilized for asymmetric aza-Darzens reaction and asymmetric aza-Henry reaction. The C₂-symmetric chiral auxiliary tolerates oxidation, is not sensitive to racemization and can be recycled for large scale synthesis.     

Catalytic,asymmetric aza-Baylis–Hillman reaction of N-sulfonated imines with 2-cyclohexen-1-one and 2-cyclopenten-1-one in the presence of a chiral phosphine Lewis base

In the aza-Baylis–Hillman reaction of N-sulfonated imines with 2-cyclohexen-1-one or 2-cyclopenten-1-one, we found that by using (R)-2′-dimethylphosphanyl-[1,1′]binaphthalenyl-2-ol LB1 as a chiral phosphine Lewis base, the corresponding Baylis–Hillman adducts 2 or 3 can be obtained in good yields and moderate enantiomeric excess. The structure of this chiral phosphine Lewis base on chiral induction in this reaction has also been discussed.     

N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).     

Diastereoselective alkynylation of glucose-modified imines with terminal alkynes

The copper(I)-catalyzed enantioselective alkynylation of aldimines incorporating a 2,3,4,6-tetrakis-O-pivaloyl-d-glucopyranosyl (Piv₄Glc) chiral auxiliary with terminal alkynes is reported. The present system provides a versatile tool for the construction of optically active propargylamine derivatives. Good yields and enantiomeric excess values were achieved with an array of imines and biologically active, propargylamine derivatives.     

Asymmetric synthesis of α-amino-1,3-dithianes via chiral N-phosphonyl imine-based Umpolung reaction without using chromatography and recrystallization

A series of α-amino-1,3-dithianes have been synthesized via the asymmetric Umpolung reaction of 2-lithio-1,3-dithianes with chiral N-phosphonyl imines in good chemical yields (up to 82%) and good to excellent diastereoselectivities (>99:1). The manner by which chiral N-phosphonyl imines are slowly added into the solution of 2-lithio-1,3-dithiane was found to be crucial for achieving excellent diastereoselectivity. The current synthesis was proven to follow the GAP chemistry (group-assistant-purification chemistry) process, which avoids traditional purification techniques of chromatography or recrystallization, i.e., the pure chiral α-amino-1,3-dithianes attached with the chiral N-phosphonyl group were readily obtained by washing the solid crude products with hexane or a mixture of hexane-ethyl acetate.     

A practical diastereoselective synthesis of β-hydroxy-β-trifluoromethyl imines

The asymmetric carbon-carbon bond formation reaction affording chiral β-hydroxy-β-trifluoromethyl imines is reported involving the nucleophilic addition of sulfinimine anions derived from chiral N-(tert-butanesulfinyl) ketimines to trifluoromethyl ketones. The reaction tolerates a wide range of nucleophiles, giving the condensation products in good to excellent total yields with good diastereoselectivities (up to 85:15 dr).     

Novel Method for the Enantioselective Synthesis of β-Lactams

A novel method for the enantioselective synthesis of β-lactams is described in this study. 2,3-Dihydrobenzooxazin-4-one derived from salicylamide and L-menthone was used as the chiral auxiliary, which reacted with a-bromo-acyl bromides in the presence of pyridine to give carboximides 2. The stereo-controlled Reformatsky-type reactions of carboximides with imines yielded the corresponding trans β-lactams with high enantioselectivities（e.e. 75%-86%） and high chemical yields（63%-85%）, meanwhile, the chiral auxiliary dihydrobenzooxazin-4-one was released and recovered.     

Synthesis of chiral isoindolinones via asymmetric propargylation/lactamization cascade

A Zn-mediated propargylation/lactamization cascade reaction with chiral 2-formylbenzoate derived N-tert-butanesulfinyl imines was realized, which provided a practical and efficient method for the synthesis of chiral isoindolinones. High diastereoselectivities (up to 97:3 dr) and good reaction yields were observed for most examined cases.     

Non-cross-linked Polystyrene Supported Cyclosulfamide:A New Chiral Auxiliary for Highly Stereoselective Alkylation Reactions

The asymmetric alkylation reactions induced by non-cross-linked polystyrene supported cyclosulfamide chiral auxiliary occurred in moderate to good yields with a very high stereoselectivity（e.e.〉99%）. Compared to non-supported cyclosulfamide chiral auxiliary, this chiral auxiliary can be recovered by simple precipitation and filtration, and could be reused at least four cycles without appreciable reduction in the yield or stereoselectivity.     

Asymmetric synthesis of aziridines by reduction of N-tert-butanesulfinyl alpha-chloro imines

Reduction of (RS)-N-tert-butanesulfinyl alpha-halo imines afforded chiral aziridines in good to excellent yields. Upon reduction of (RS)-N-tert-butanesulfinyl alpha-halo imines with NaBH4 in THF, in the presence of 10 equiv of MeOH, (RS,S)-beta-halo sulfinamides were formed in excellent yield (up to 98%) with very good stereoselectivity (>98:2). Simple treatment of the latter (RS,S)-beta-halo-tert-butanesulfinamides with KOH afforded the corresponding (RS,S)-N-(tert-butylsulfinyl)aziridines in quantitative yields. On the contrary, its epimer, (RS,R)-N-(tert-butylsulfinyl)aziridine was synthesized by switchover of the reducing agent from NaBH4 to LiBHEt3. (RS,R)-N-(tert-Butylsulfinyl)aziridines were synthesized in good yields (up to 85%) and diastereoselectivity (up to 92:8) by reduction of (RS)-N-tert-butanesulfinyl alpha-halo imines with LiBHEt3 in dry THF and subsequent treatment with KOH. All chiral aziridines were obtained as a single diastereomer after recrystallization (overall yield up to 91%) or after flash chromatography.     

Organocatalytic asymmetric [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with enals: Efficient approach to functionalized spiro N-heterocyclic oxindoles

An unprecedented chiral secondary amine-catalyzed [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with α,β-unsaturated aldehydes was developed. This strategy allowed the construction of structurally novel spiro N-heterocyclic oxindole derivatives in good yields (up to 91%) and good to excellent enantioselectivities (up to >99% ee), albeit with modest diastereoselectivities (up to 3.1:1 dr).     

Chiral imines prepared from 1-(2-aminoalkyl)aziridines as novel chiral shifts reagents for efficient recognition of acids

Optically pure, chiral imines synthesized from the corresponding aldehydes and 1-(2-aminoalkyl)aziridines in good chemical yields, have been assessed as an NMR chiral shift reagents for effective discrimination of the signals of some acids (mandelic acid and its derivatives and N-protected amino acid). The title compounds have proven to be very useful for the determination of enantiomeric purity and absolute configuration of the aforementioned acid derivatives.     

A new approach to enantioselective cyanation of imines with Et2AlCN

An enantioselective Strecker-type reaction of imines with Et₂AlCN in the presence of chiral additives has been examined. The enantioselectivity varied depending on the substituents of the imino group as well as the chiral additives used. Thus, α-aminonitriles were obtained in good yields with good enantioselectivities in the reaction of N-benzylidenebenzhydrylamine with Et₂AlCN and BINOL. The reaction with excess BINOL gave the aminonitrile with reversed configuration.     

Asymmetric synthesis of multifunctionalized pyrrolines by a ruthenium porphyrin-catalyzed three-component coupling reaction

[reaction: see text] Chiral multifunctionalized pyrrolines have been synthesized by a ruthenium porphyrin catalyzed three-component coupling reaction. In a one-pot reaction, ruthenium porphyrins catalyzed in situ generation of chiral azomethine ylides from chiral diazo esters and imines. Asymmetric 1,3-dipolar cycloaddition reactions of the chiral azomethine ylides with dipolarophiles afforded the corresponding pyrrolines in good yields and high diastereoselectivity (up to 92% de).