Synthesis and applications of masked oxo-sulfinamides in asymmetric synthesis

This short perspective reports on the synthesis and applications of a class of chiral amino carbonyl compounds, masked oxo-sulfinamides where the amine is protected with an N-sulfinyl moiety and the carbonyl group is protected as the ketal or 1,3-dithiane. These polyfunctionalized chiral building blocks are prepared by addition of organometallic reagents to masked oxo-sulfinimines (N-sulfinyl imines) or the addition of oxo-organometallic reagents and lithio-1,3-dithianes to sulfinimines. Because unmasking of the amino and carbonyl groups results in cyclic imines, these chiral building blocks are particularly useful for the asymmetric synthesis of functionalized nitrogen heterocycles, including prolines, pipecolic acids, pyrrolidines, homotropinones, tropinones, and tropane alkaloids such as cocaine and C-1 cocaine analogues.     

Asymmetric synthesis of beta-amino carbonyl compounds with N-sulfinyl beta-amino Weinreb amides

[reaction: see text] Diverse organometallic reagents readily add to enantiopure N-sulfinyl beta-amino Weinreb amides providing the corresponding, stable, N-sulfinyl beta-amino carbonyl compounds in good to excellent yields. This new methodology represents a general solution to the problem of beta-amino carbonyl syntheses, which are important chiral building blocks and constituents of natural products. N-Sulfinyl beta-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy N-methylacetamide with sulfinimines (N-sulfinyl imines) or lithium N,O-dimethylhydroxylamine with N-sulfinyl beta-amino esters.     

Asymmetric synthesis of syn-alpha-substituted beta-amino ketones by using sulfinimines and prochiral Weinreb amide enolates

Syn-alpha-substituted beta-amino Weinreb amides are new chiral building blocks for asymmetric synthesis of syn-alpha-substituted beta-amino acids, aldehydes, and ketones and are prepared by addition of prochiral lithium enolates of Weinreb amides to sulfinimines (N-sulfinyl imines).     

Synthesis and biological activity of fluorine-containing amino derivatives based on 4-caranethiol

Fluorine-containing N-substituted sulfinamides were synthesized via 4-caranethiol-based sulfenimines and sulfinimines. Stereochemical features of oxidation of sulfenimines and addition of fluorine-containing reagents to sulfinimines were discussed. Antimicrobial activities of the obtained compounds were screened.     

Asymmetric synthesis of alkaloids using polyfunctionalized chiral building blocks

Enantiopure N‐sulfinyl‐δ‐amino‐β‐ketoesters and isoquinolones, prepared from sulfinimines (N‐sulfinyl imines) are a new class of polyfunctionalized chiral building blocks. These building blocks provide easy access to enantiomerically pure, functionalized piperidines and tetrahydroisoquinolines with a minimum of chemical manipulation and protecting‐group chemistry. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:486–492, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10090     

Asymmetric synthesis of ethoxydienamines in superbasic medium mediated by chiral sulfinyl group

The direct addition of metalated alkoxydiene 2, obtained from α,β-unsaturated acetal 1 through a LIC-KOR-promoted conjugated elimination reaction, to enantiopure sulfinimines 3 (both R and SN-sulfinyl imines) afforded N-sulfinyl alkoxydienyl amines 4 with high diastereoselectivity. Functionalized enantiopure alkoxydienyl amines 5 were then easily obtained upon the selective removal of the chiral auxiliary under mild conditions. Moreover, the further hydrolysis of the alkoxydienyl moiety gave access to protected enantiopure β-keto amines 7.     

Efficient preparation of N-phenylsulfenyl ketimines from oximes or nitro compounds without racemization of alpha-stereocenters

As N-sulfenyl imines (e.g., RR'C=N-SAr) can be readily transformed to their N-sulfinyl imines (RR'C=N-SOAr), N-sulfonyl imines (RR'C=N-SO2Ar), and N-sulfonyl oxaziridines, the very mild procedure developed to convert ketoximes and secondary nitro derivatives to N-arenesulfenyl ketimines constitutes a new and efficient route to all these series of compounds. The configuration of the alpha-stereocenters is retained.     

Additions of enantiopure alpha-sulfinyl carbanions to (S)-N-sulfinimines: asymmetric synthesis of beta-amino sulfoxides and beta-alphamino alcohols

The addition of the lithium anions derived from (R)- and (S)-methyl and -ethyl p-tolyl sulfoxides to (S)-N-benzylidene-p-toluenesulfinamide provides an easy access route to enantiomerically pure beta-(N-sulfinyl)amino sulfoxides. Stereoselectivity can be achieved when the configurations at the sulfur atoms of the two reagents are opposite (matched pair), thus resulting in only one diastereoisomer, even for the case in which two new chiral centers are created. The N-sulfinyl group primarily controls the configuration of the carbon bonded to the nitrogen, whereas the configuration of the alpha-sulfinyl carbanion seems to be responsible for the level of asymmetric induction, as well as for the configuration of the new stereogenic C-SO carbon in the reactions with ethyl p-tolyl sulfoxides. An efficient method for transforming the obtained beta-(N-sulfinyl)amino sulfoxides into optically pure beta-amino alcohols, based on the stereoselective non-oxidative Pummerer reaction, is also reported.     

Use of alpha-chlorinated N-(tert-butanesulfinyl)imines in the synthesis of chiral aziridines

[reaction: see text] Reaction of chiral alpha-chloro tert-butanesulfinyl aldimines with Grignard reagents efficiently afforded beta-chloro N-sulfinamides in high diastereomeric excess. The latter compounds were cyclized toward the corresponding chiral aziridines in a high-yielding one-pot reaction or after separate treatment with base. The diastereoselectivity obtained in the newly synthesized beta-chloro sulfinamides is explained via the coordinating ability of the alpha-chloro atom with magnesium resulting in the opposite stereochemical outcome as generally observed for nonfunctionalized N-sulfinyl imines.     

Asymmetric synthesis of alpha-amino 1,3-dithioketals from sulfinimines (N-sulfinyl imines). Synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline

[reaction: see text] N-Sulfinyl alpha-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups affords stable alpha-amino 1,3-dithioketals and N-sulfinyl alpha-amino ketones, respectively. This new sulfinimine-derived chiral building block is employed in the asymmetric synthesis of polyoxypeptin amino acid (2S,3R)-(-)-3-hydroxy-3-methylproline.     

Stereoselective cyanation of 4-formyl and 4-imino-β-lactams: application to the synthesis of polyfunctionalized γ-lactams

The stereoselective reaction of 4-oxoazetidine-2-carbaldehydes and their corresponding imines with cyanide-based reagents give β-lactam α-aminonitriles, which are chameleonic building blocks for the controlled synthesis of a variety of new compounds including functionalized γ-lactams, succinimide derivatives, and diamino-lactams derivatives in optically pure form.     

Fluorinated Imines in Tandem and Cycloaddition Reactions

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.     

Highly stereoselective addition of organometallic reagents to N-tert-butanesulfinyl imines derived from 3- and 4-substituted cyclohexanones

Addition of alkyl or aryl Grignard reagents to N-sulfinyl imines derived from 3- and 4-substituted cyclohexanones proceeds with good yields and with excellent diasteroselectivity. The selectivity of the reaction is controlled by the ring substituent rather than the sulfinyl group stereochemistry, and therefore racemic tert-butanesulfinamide can be employed.     

Recent applications of N-sulfonyloxaziridines (Davis oxaziridines) in organic synthesis

N-Sulfonyloxaziridines are the most commonly used oxaziridines in organic synthesis. Most applications of these stable, commercially available reagents involve the stereo- and regioselective oxidation of nucleophiles which have found many applications in the synthesis of architecturally complex molecules. In addition, these oxaziridines have been used in cycloaddition reactions (oxyamination), epoxidation of alkenes, silyl enol ethers and enamines, as well as C-H oxidation and amination reactions. The object of this review is to highlight recent applications of N-sulfonyloxaziridines in organic synthesis.     

Asymmetric synthesis of anti-α-substituted β-amino ketones from sulfinimines

Previously unknown, enantiopure, β-amino ketones were prepared in modest yield by addition of lithium reagents to N-sulfinyl anti-α-substituted β-amino Weinreb amides. Grignard reagents failed to add to these Weinreb amides in contrast to the syn-α-substituted isomers which did. The anti-α-substituted β-amino Weinreb amides were prepared by addition of LiN(OMe)Me to the corresponding N-sulfinyl anti-α-substituted β-amino esters because α-alkylation of N-sulfinyl β-amino Weinreb amide enolates resulted in poor diastereoselectivities.     

Applications of the sulfinimine-mediated asymmetric strecker synthesis to the synthesis of alpha-alkyl alpha-amino acids

Addition of Et(2)AlCN and i-PrOH to ketosulfinimines (N-sulfinyl imines) affords corresponding alpha-alkyl alpha-amino nitriles in moderate to good yields. The diastereoselectivity is largely dependent on the E/Z isomer ratio of the ketosulfinimine. Hydrolysis of the diastereomerically pure amino nitriles affords enantiopure alpha-alkyl alpha-amino acids in moderate to good yields.     

Development and application of a new general method for the asymmetric synthesis of syn- and anti-1,3-amino alcohols

A general method is described for asymmetric synthesis of both syn- and anti-1,3-amino alcohols. The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes. The reduction of the product beta-hydroxy N-sulfinyl imines 2 with catecholborane and LiBHEt(3) provides syn- and anti-1,3-amino alcohols with very high diastereomeric ratios. This method was found to be effective for a variety of substrates incorporating either aromatic or various aliphatic substituents. The convergent and efficient asymmetric syntheses of the two natural products, (-)-8-epihalosaline and (-)-halosaline, were also accomplished.     

配体参与的有机金属化合物对亚胺的不对称加成反应

手性胺类化合物是一类重要的有机化合物,在生物化学及药物合成中有广泛应用.有机金属化合物对亚胺的不对称加成反应是合成手性胺类化合物的重要方法之一.本文对近年来外加配体参与的有机金属化合物对亚胺的不对称加成反应,特别是催化合成手性胺类化合物的研究进展作一概述.     

Asymmetric synthesis of aziridine 2-phosphonates from enantiopure sulfinimines (N-sulfinyl imines). Synthesis of alpha-amino phosphonates

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best results involve cyclization of the syn and anti diastereomerically pure alpha-chloro-beta-amino phosphonates to cis- and trans-N-sulfinyl aziridine 2-phosphonates, respectively, with n-BuLi. A transition-state hypothesis is proposed wherein the chloromethylphosphonate anion adds to the C-N bond on the side that is opposite the bulky p-tolyl sulfinyl group. The N-sulfinyl group is easily removed by treatment with MeMgBr or TFA/MeOH, which affords the NH-aziridines in good yield. Using transfer hydrogenation conditions, the NH-aziridines were regioselectively opened to the corresponding enantiopure alpha-amino phosphonates without N-activation and in excellent yield.     

Unlocking Hydrogenation for C-C Bond Formation: A Brief Overview of Enantioselective Methods

Hydrogenation of π-unsaturated reactants in the presence of carbonyl compounds or imines promotes reductive C-C coupling, providing a byproduct-free alternative to stoichiometric organometallic reagents in an ever-increasing range of C=X (X = O, NR) additions. Under transfer hydrogenation conditions, hydrogen exchange between alcohols and π-unsaturated reactants triggers generation of electrophile-nucleophile pairs, enabling carbonyl addition directly from the alcohol oxidation level, bypassing discrete alcohol oxidation and generation of stoichiometric byproducts.