N-sulfinyl beta-amino Weinreb amides: synthesis of enantiopure beta-amino carbonyl compounds. Asymmetric synthesis of (+)-sedridine and (-)-allosedridine

[reaction: see text] N-Sulfinyl beta-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide. These new chiral building blocks are useful for the asymmetric synthesis of beta-amino carbonyl compounds, as illustrated here by the concise enantioselective syntheses of sedum alkaloids (+)-sedridine and (-)-allosedridine.     

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

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).     

Asymmetric synthesis of alpha-substituted beta-amino ketones from sulfinimines (N-sulfinyl imines). synthesis of the indolizidine alkaloid (-)-223A

Of the possible four stereoisomers, addition of the lithium enolate of 4-heptanone to sulfinimines resulted in only the syn- and anti-alpha-substituted beta-amino ketones. The formation of the major syn-beta-amino ketone was rationalized in terms of addition of the E-enolate to the C-N double bond of the sulfinimine via a six-member chelated chairlike transition state. The enolates of 4-heptanone were generated using LiHMDS in THF where a 1:2.5 E:Z enolate ratio was noted. In diethyl ether the E:Z ratio was 15:1 in favor of the E-enolate and explained in terms of Ireland's transition state model. Here increased steric interactions between the ethyl group and the carbonyl-LiN(TMS)(2) moiety destabilize the transition state leading to the Z-enolate in the poorly coordinating diethyl ether solvent. This new synthesis of syn-alpha-substituted-beta-amino ketones was applied to the concise enantioselective total synthesis of indolizidine (-)-223A, a 5,6,8-trisubstituted alkaloid isolated from the skin of the dendrobatide frog.     

Asymmetric synthesis of cyclopropylamines starting from N-sulfinyl alpha-chloro ketimines

Treatment of novel chiral N-sulfinyl alpha-chloro ketimines with Grignard reagents resulted in the synthesis of chiral N-(1-substituted cyclopropyl)-tert-butanesulfinamides in acceptable to good yields and diastereoselectivity via 1,3-dehydrohalogenation and subsequent addition of the Grignard reagent to the intermediate cyclopropylideneamine. Only in the case of allylmagnesium chloride did the reaction lead to aziridines in high yield. Further deprotection toward N-unprotected 1-substituted cyclopropylamines was established, and the absolute configuration was determined. [reaction: see text].     

Asymmetric synthesis of acyclic 1,3-amino alcohols by reduction of N-sulfinyl beta-amino ketones. Formal synthesis of (-)-pinidinol and (+)- epipinidinol

Stereoselective reduction of acyclic N-sulfinyl beta-amino ketones with (LiEt(3)BH) and Li(t-BuO)(3)AlH, respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl beta-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.     

Parham-type cycliacylation with Weinreb amides. Application to the synthesis of fused indolizinone systems

[reaction: see text] Weinreb amides behave as efficient internal electrophiles in Parham-type cycliacylation reactions. Thus, aryl- and heteroaryllithiums generated by lithium-halogen exchange undergo intramolecular cyclization to give fused indolizinone systems as pyrrolo[1,2-b]isoquinolines, thieno[2,3-f]indolizinones, and pyrrolo[1,2-b]acridinones in high yields.     

High-yielding synthesis of Weinreb amides via homogeneous catalytic carbonylation of iodoalkenes and iodoarenes

Iodoarenes (iodobenzene and 2-iodothiophene) and iodoalkenes (1-iodocyclohexene, 1-iodo-4-tert-butylcyclohexene, 1-iodo-2-methylcyclohexene and 1-iodo-1-(1-naphthyl)ethene) were used as substrates in palladium-catalysed aminocarbonylation with N,O-dimethylhydroxylamine. The corresponding Weinreb amides were prepared in high isolated yields (up to 87%) when forcing conditions (40-60 bar of CO, 50 °C) were used. The aminocarbonylation provides the Weinreb amides as pure products in a chemoselective reaction. No formation of ketocarboxamides, due to double CO insertion, except for 2-iodothiophene, was observed even at 60 bar of CO pressure.     

Stereoselective synthesis of beta-substituted beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines

[reaction: see text] A highly stereoselective synthesis of beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.     

Asymmetric synthesis of fluorinated cyclic beta-amino acid derivatives through cross metathesis

The asymmetric synthesis of several fluorinated cis-2-aminocycloalkane carboxylic acids (cis-2-ACACs) with a cross metathesis (CM) reaction as the key step has been carried out, constituting the first time a metathesis protocol has been undertaken with fluorinated imidoyl chlorides. Subsequent chemoselective hydrogenation of the olefin moiety, Dieckmann condensation, and stereoselective reduction of the iminic double bond afforded the corresponding beta-amino esters with several ring sizes. The asymmetric version of the process was achieved by using (-)-8-phenylmenthol as a chiral auxiliary.     

Asymmetric synthesis of cyclic alpha-amino phosphonates using masked oxo sulfinimines (N-sulfinyl imines)

Five-, six-, and seven-membered cyclic alpha-amino phosphonates, amino acid surrogates, are prepared in enantiomerically pure form via the highly diastereomeric addition of metal phosphonates to masked oxo sulfinimines. Hydrolysis of the resulting masked oxo alpha-amino phosphonates followed by reduction of the intermediate cyclic imino phosphonates affords the title compounds in good yield.     

Asymmetric synthesis of beta-amino alcohols by reductive cross-coupling of benzylideneamine with planar chiral benzaldehydes

[reaction: see text] Samarium iodide mediated reductive cross-coupling of N-tosyl benzylideneamine with benzaldehydes or the corresponding chromium complexes gave syn-beta-amino alcohol derivatives. A dynamic kinetic resolution of a configurationally equilibrated reactive species occurred in the cross-coupling with planar chiral benzaldehyde chromium complexes.     

A new synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation

Lithium α-sulfinyl carbanions of 1-chloroalkyl p-tolyl sulfoxides were reacted with carbonyl compounds to afford adducts in high to quantitative yields. The adducts were treated with t-BuMgCl or LDA to give magnesium or lithium alkoxides, which were treated with i-PrMgCl or t-BuLi to afford the enolate with one-carbon elongation through β-oxido carbenoids. The enolate intermediates were found to be able to be trapped with electrophiles to give α,α-disubstituted carbonyl compounds in moderate to good yields. As a whole, this procedure offers a new and good method for synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation in only two synthetic steps.     

Asymmetric addition of chiral triquinphosphoranes on activated carbonyl compounds

Chiral triquinphosphoranes react with trifluoroacetophenone, ketopantolactone and aromatic aldehydes affording pairs of hydroxyphosphoranes diastereomers with a diastereoselectivity up to 90% depending on the nature of the electrophile. In the case of ketopantolactone, hydroxyphosphorane diastereomers are quantitatively converted to alkoxyphosphoranes with a decreasing of diastereomeric excesses. The major alkoxyphosphorane diastereomer exhibits a close SP structure determined by x-ray diffraction analysis.     

Regiocontrolled synthesis of pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones from pyrrole Weinreb amides

A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-carboxaldehydes was completed in two steps from acyclic starting materials. A Barton-Zard pyrrole synthesis between N-methoxy-N-methyl-2-isocyanoacetamide and alpha-nitroalkenes or beta-nitroacetates provided N-methoxy-N-methyl pyrrole-2-carboxamides (pyrrole Weinreb amides), which were converted into the corresponding pyrrole-2-carboxaldehydes by treatment with lithium aluminum hydride. A regioselective oxidation of the pyrrole-2-carboxaldehydes gave the corresponding 3,4-disubstituted 3-pyrrolin-2-ones.     

Synthesis of Weinreb amides via Pd-catalyzed aminocarbonylation of heterocyclic-derived triflates

The direct transformation of lactam-, lactone-, and thiolactone-derived triflates into N-methoxy-N-methyl or morpholine Weinreb amides has been realized using Pd-catalyzed aminocarbonylation under CO atmospheric pressure and at room temperature. The carbonylative coupling can be efficiently carried out with 2% of catalyst in the presence of Xantphos as a ligand. The amides smoothly react with nucleophiles to afford acylated aza-, oxa-, and thio-heterocycles. The proposed methodology could be advantageously exploited for the synthesis of dienones in which one of the double bonds is embedded in a heterocyclic moiety, as useful substrates for Nazarov cyclization.     

A one-flask synthesis of Weinreb amides from chiral and achiral carboxylic acids using the deoxo-fluor fluorinating reagent

[structure] The reagent [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor reagent) converts carboxylic acids to the corresponding acid fluorides, which then react with N,N-dimethylhydroxylamine to give the corresponding Weinreb amides in high yields. The reaction proceeds without racemization when optically active acids are used as the starting material. This method is operationally simple and provides the products in high purity.