Facile synthesis of versatile functionalized amino caprolactams using RCM reactions of α-amino acrylamide

We report an efficient synthetic methodology allowing access to functionalized α-amino caprolactams using ring-closing metathesis (RCM). A very high tolerance of α-amino acrylamide RCM precursors toward functional groups is demonstrated. The synthetic pathway is facile, and can be extended to prepare a variety of substituted amino caprolactams in good to excellent yields. These compounds serve as versatile building blocks for the synthesis of some important natural products and their analogues.     

Synthesis of 3-oxooxa- and 3-oxoazacycloalk-4-enes by ring-closing metathesis. Application to the synthesis of an inhibitor of cathepsin K

3-Oxooxa- and 3-oxoazacycloalk-4-enes were obtained with good yield from 1-(ω-alkenyloxy)- and 1-(ω-alkenylamino)-but-3-en-2-ones by using a ring-closing metathesis. This methodology has been used to synthesize an inhibitor of cathepsin K.     

Asymmetric synthesis of α-amino aldehydes from sulfinimine (N-sulfinyl imine)-derived α-amino 1,3-dithianes. Formal synthesis of (−)-2,3-trans-3,4-cis-dihydroxyproline

Hydrolysis of sulfinimine-derived N-sulfinyl α-amino 1,3-dithianes with aqueous 1,3-dibromo-5,5-dimethylhydantoin affords the corresponding N-tosyl α-amino aldehydes in good yield and high enantiomeric purity. These aldehydes can be reduced to amino alcohols and undergo the Wittig reaction to give allylic amines without epimerization. The utility of this methodology is illustrated in a formal synthesis of (−)-2,3-trans-3,4-cis-dihydroxyproline.     

A stereodivergent route to epimeric 2-piperidinylglycines: application to the synthesis of carbocyclic β-lactam derivatives

A route to two epimeric hitherto unknown 2-piperidinylglycine derivatives, as precursors of carbocyclic β-lactam derivatives, has been developed, which features diastereoselective addition of allyl metal reagents to an N-allylimine derivative of Garner’s aldehyde and ring-closing metathesis as key steps.     

A synthesis of optically active α-quaternary α-amino acids and esters by assembling three components, ketones, (R)-chloromethyl p-tolyl sulfoxide, and sodium azide, via sulfinyloxiranes

Treatment of lithium α-sulfinyl carbanion of chloromethyl p-tolyl sulfoxides with ketones at low temperature afforded adducts in almost quantitative yields, which were exposed to t-BuOK to give sulfinyloxiranes in high yields. The sulfinyloxirane was reacted with benzylamine to give α-amino aldehyde, which was oxidized with iodine in methanol to afford α-amino carboxylic ester in moderate yield. The sulfinyloxiranes were treated with sodium azide to afford α-azido aldehydes in good yields. Oxidation with NaClO₂ followed by catalytic hydrogenation of the azido group of the α-azido aldehydes gave α-quaternary α-amino acids in good overall yields. The oxidation of the azido aldehydes with iodine in methanol in the presence of KOH followed by the catalytic hydrogenation resulted in α-quaternary α-amino acid methyl esters in good yields. When these reactions were carried out starting from unsymmetrical ketones and optically pure (R)-chloromethyl p-tolyl sulfoxide, a new method for a synthesis of optically active α-quaternary α-amino acids and esters in good overall yields was realized.     

Stereoselective synthesis of the cyclic ether core of (+)-laurenyne

A concise enantioselective synthesis of the cyclic ether core of the marine natural product (+)-laurenyne has been accomplished using ring-closing metathesis for medium-ring construction.     

A new synthesis of enantiomerically pure α- and β-amino acid derivatives using aziridinyl anions

Optically active sulfinylaziridines having a 4-methoxyphenyl group on their nitrogen atom were synthesized from optically active 1-chloroalkyl p-tolyl sulfoxide and an imine derived from benzaldehyde and p-anisidine stereoselectively in good overall yields. The sulfinylaziridines were treated with ethylmagnesium bromide or tert-butyllithium to afford aziridinylmagnesiums or aziridinyllithiums, respectively, in quantitative yields. Cross-coupling of the aziridinylmagnesiums with iodoalkanes in the presence of Cu(I) iodide gave tri-substituted aziridines in high yields from which enantiomerically pure β,β-disubstituted β-amino acid derivatives were synthesized. A β-amino acid derivative having deuterium at the stereogenic center was also realized by this method. On the other hand, from the aziridinyllithium, enantiomerically pure quaternary phenylalanine and quaternary aspartic acid derivatives were synthesized.     

Stereoselective routes to 3-hydroxy and 3,4-dihydroxy derivatives of 2-aminocyclohexanecarboxylic acid

The Diels-Alder adduct of ethyl (E)-3-nitroacrylate and furan provides a versatile template for the stereoselective synthesis of mono and dihydroxylated derivatives of 2-aminocyclohexanecarboxylic acid (ACHC). The hydroxylated ACHC derivatives can be considered to be useful building blocks for β-peptides.     

A mild and efficient synthesis of α-tosylamino ketones from aryl aziridines in the presence of β-cyclodextrin and NBS in water

NBS has been utilized for the first time for the oxidative cleavage of aryl aziridines involving β-cyclodextrin-aziridine complexes in water to give the corresponding α-amino ketones in high yields.     

Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

Regioselective acylation of carbohydrate derivatives using lipases leading to a facile two-step procedure for the separation of some α- and β-glucopyranosides and galactopyranosides

The resolution of α- and β-anomers of glucopyranosides and galactopyranosides was achieved via enzyme-catalysed regioselective acylation. This two-step procedure to prepare pure α- and β-anomers of glycopyranosides would be most useful for the cases where glycosidases are not available or expensive to purchase. From a synthetic viewpoint, the regioselective acylation of glycopyranosides provides access to mono- and di-esters with well-defined substitution patterns.     

A new synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine as the key reaction

A new synthesis of pipecolic acid and homopipecolic acid derivative was accomplished from 1-chloroalkyl p-tolyl sulfoxides having a 2-aminophenyl group at the ω-position by treatment with i-PrMgCl via the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine. In a similar way, proline and pipecolic acid derivatives were synthesized from 1-chloroalkyl p-tolyl sulfoxides having an arylamino group at the ω-position.     

[Bmim]BF4 ionic liquid: a novel reaction medium for the synthesis of β-amino alcohols

Epoxides undergo smooth ring-opening with aryl amines in 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) or 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF₆) ionic liquids under mild and neutral conditions to afford the corresponding β-amino alcohols in excellent yields with high regioselectivity.     

Aspartyl methyl ester formation via aspartimide ring opening: a proposed modification of the protocols used in Boc- and Fmoc-based solid-phase peptide synthesis

Aspartimide formation is still an unresolved problem in the solid-phase peptide synthesis of aspartic acid-containing peptides, following either Boc- or Fmoc-based synthetic strategies. α-Aspartyl peptides of high purity can be obtained, despite aspartimide formation, by incorporating an additional step in the Boc- and Fmoc-based solid-phase peptide synthesis protocols, consisting of treatment of the peptide-resin with methanol in the presence of 2% DIEA (v/v) for 15 min immediately after completion of the peptide chain elongation.     

A concise and enantioselective approach to the total synthesis of (−)-lasubine I

An efficient, enantioselective total synthesis of (−)-lasubine I (1) has been achieved in an overall 8.8% yield from readily available starting materials. The important features of this approach include the creation of stereogenic centers through two sequential highly stereoselective Roush allylborations and the use of S_N2 cyclization and ring-closing metathesis reactions for the construction of the quinolizidine skeleton.     

Tandem Claisen rearrangement and ruthenium catalyzed enyne bond reorganization as a route to the synthesis of tricyclic 1,8-naphthyridinones

A novel procedure for the synthesis of substituted 1,8-naphthyridinones via tandem Claisen rearrangement and ring-closing enyne metathesis is reported.     

New synthesis of carbazole-1,4-quinone using a tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere, and its application to the synthesis of murrayaquinone A

A tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere was newly developed to the synthesis of carbazole-1,4-quinones. This new tandem reaction was applied to the synthesis of murrayaquinone A in four steps.     

Diels-Alder cycloadditions of 3-phenylamino-5-bromo-2-pyrone for the synthesis of constrained α-amino acid derivatives

3-Phenylamino-5-bromo-2-pyrone undergoes facile Diels-Alder cycloadditions with various electron deficient dienophiles to afford an array of functionally rich and stereochemically defined cycloadducts in good to excellent isolated yields. Due to the electron donacity of the amine group, it only proceeds in normal electron demand D-A cycloadditions. Subsequent ring openings with NaOMe provided constrained α-amino acid derivatives.     

Concise syntheses of stereoisomeric hexahydroazepine derivatives related to the protein kinase inhibitor balanol

A stereodivergent route to four stereoisomeric azepane derivatives related to the important protein kinase inhibitor balanol is developed which utilises (−)- or (+)-serine as starting material, and a ring-closing metathesis as the key ring forming step.