Stereoselective synthesis of cembranolides via conjugate addition to cycloalkynones

Addition of lithium dimethylcuprate to the conjugated cycloalkynone 8 yielded, after equilibration, a single (E)-enone 10 which was converted via acidic hydrolysis, oxidation, and reduction to the cis lactone 14. α-Methylenation afforded the natural cembranolide 16.     

Stereoselective synthesis of highly functionalized nitrocyclopropanes via organocatalyic conjugate addition to nitroalkenes

A convenient and novel one-pot organocatalytic methodology for the stereoselective synthesis of highly functionalized nitrocyclopropanes is reported. The addition of dimethyl chloromalonate to a variety of nitroolefins catalyzed by tertiary amines leads to a Michael adduct which cyclizes to form the cyclopropane in the presence of DBU under carefully controlled reaction conditions with outstanding diastereoselectivity.     

Stereoselective gamma-lactam synthesis via palladium-catalysed intramolecular allylation

A novel route to the synthesis of 3-(tolylsulfonyl)-4,5-cis-disubstituted gamma-lactams using a diastereoselective palladium-catalysed intramolecular allylation of amino acid-derived allylic carbonates has been developed.     

Synthesis of aziridinomitosenes through base-catalyzed conjugate addition

Synthesis of an aziridinomitosene core structure that relies on a facile tertiary-amine base-catalyzed azide conjugate addition is reported. Straightforward derivatization of the conjugate addition product affords the desired mitomycin ring system. Initial catalyst screens have identified peptides that afford the product with modest enantioselectivities.     

Stereoselective synthesis of versatile 2-chloromercurium-3,5-syn-dihydroxy esters via intramolecular oxymercuration

Regio- and stereocontrolled alkoxy mercuration of α,β-unsaturated esters allows direct access to 1,3-syn diols in good yields. Demercuration of adducts leads to 1,3 skipped dihydroxy esters, alcohols, and α-halo esters. The deprotection of acetonide with Amberlyst 15 on 1,3-syn-dihydroxy esters gives the corresponding δ-lactones.     

Stereoselective synthesis of densely functionalized pyrrolidin-2-ones by a conjugate addition/nitro-Mannich/lactamization reaction

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield). An enantioselective copper-catalyzed conjugate addition of diethylzinc led to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks for further organic synthesis.     

Concise total synthesis of antiarrhythmic drug dronedarone via a conjugate addition followed intramolecular heck cyclization

A concise, scalable, and an efficient total synthesis for dronedarone ( 2 ) was described using conjugate addition followed by intramolecular Heck cyclization. The other key reaction includes selective reduction of nitro functionality and addition of lithiated terminal alkyne to the aldehyde. The overall yield of this approach is 44% in six steps.     

Stereoselective conjugate addition of lactams to nitroalkenes and formal total synthesis of indolizidine 167B

Optically active 5-substituted pyrrolidin-2-ones underwent conjugate addition to nitroalkenes to give the corresponding adducts in a diastereoselective manner. The presence of 18-crown-6 was crucial to achieve good stereoselective addition. Addition of 6-substituted piperidin-2-ones also gave the corresponding adduct in a stereoselective manner. The adduct was readily converted into a bicyclic lactam through intramolecular nitroaldol reaction, and the formal synthesis of indolizidine 167B was achieved.     

Convergent synthesis of panclicin-D via intramolecular SN2 displacement approach

A convergent enantioselective synthesis of panclicin-D has been reported from simple octanal using syn aldol reaction via intramolecular S_N2 displacement reaction for the first time towards the construction of anti-β-lactones in panclicin-D. The key steps involved are C-allylation, asymmetric aldolization under Crimmins condition, intramolecular S_N2 displacement, and Mitsunobu esterification reaction.     

Access to 2-alkyl chromanones via a conjugate addition approach

The introduction of alkyl substituents at C-2 of chromanones via conjugate addition of silyl enol ethers to a variety of chromenones is reported. In most cases racemic 2-alkyl chromanones were obtained in good yield in the presence of TMSOTf. The copper(II)-promoted conjugate addition of silyl enol ethers to chromenones was also carried out, albeit in low yields and no selectivity. Reliable syntheses of the chromenones via acylation of the corresponding β-diketo-compounds are also described.     

Stereoselective synthesis of azepines through the conjugate addition of formamides to nitroalkenes and subsequent intramolecular nitrile oxide cycloaddition reaction

A concise and stereoselective formation of azepines is achieved through the conjugate addition of formamides to nitroalkenes and the subsequent intramolecular nitrile oxide cycloaddition (INOC) reaction. High cis-selectivity was observed. The one-pot modification of the two reactions provides direct preparation of azepines from nitroalkenes and formamides in moderate yields. The formyl group was readily removed by an acidic treatment without significant epimerization.     

Tandem reactions to construct heterocycles via phosphine-catalyzed umpolung addition and intramolecular conjugate addition

[reaction: see text] A highly efficient method for constructing heterocycles was achieved by phosphine-catalyzed tandem umpolung addition and intramolecular conjugate addition. This strategy offers a simple and promising method for constructing synthetically useful heterocycles under neutral conditions with high atom economy.     

Asymmetric total synthesis of sperabillins B and D via lithium amide conjugate addition

Diastereoselective conjugate addition of homochiral lithium (R)-N-allyl-N-alpha-methylbenzylamide to methyl (2E,5E)-hepatadienoate, followed by protecting group manipulation and subsequent iodocyclocarbamation allows a concise route to the core fragment, methyl (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoate, of sperabillins B and D. Differentiation between the C-3 and C-6 primary amino groups of this core amino acid was readily achieved by treatment with acetone, giving the 5,6-isopropylidene and C-3-imine protected diamine, with subsequent regioselective acylation of the C-6-nitrogen facilitating the total synthesis of sperabillin D in 10.8% overall yield, and the first asymmetric synthesis of sperabillin B in 5.8% overall yield.     

Enantioselective synthesis of 2-aryl-4-piperidones via rhodium/phosphoramidite-catalyzed conjugate addition of arylboroxines

[reaction: see text] The highly enantioselective synthesis of 2-aryl-4-piperidones by rhodium/phosphoramidite-catalyzed conjugate addition of arylboroxines to 2,3-dihydro-4-pyridones is described. Both enantiomers of a variety of products with sterically and electronically different R substituents were obtained in high isolated yield and with excellent enantioselectivity up to 99%.     

Asymmetric synthesis of Sedum alkaloids via lithium amide conjugate addition

Conjugate addition of lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-but-3-enyl-N-(α-methylbenzyl)amide to an alkyl hexa-2,4-dienoate or alkyl hepta-2,6-dienoate, followed by ring-closing metathesis of the olefin functionalities within the resultant β-amino ester, generates a range of diastereoisomerically pure azacycles in good yield. These homochiral templates are readily transformed to a range of piperidine alkaloids of the Sedum family, and the corresponding five-, seven- and eight-membered ring homologues.     

Stereoselective synthesis of novel glyco-pyrano pyrrolidines/pyrrolizidines/indolizidines through intramolecular [3+2] cycloaddition approach

An efficient and stereoselective synthesis of novel furo-pyrano pyrrolidine/pyrrolizidine/indolizidine derivatives has been achieved by intramolecular [3+2] cycloaddition reaction of azomethine ylide generated in situ from O-allyl sugar-derived aldehyde and different secondary amino acids.     

Copper-catalyzed enantioselective intramolecular conjugate addition/trapping reactions: synthesis of cyclic compounds with multichiral centers

The Cu-catalyzed enantioselective conjugate addition of dialkylzinc to bis-alpha,beta-unsaturated carbonyl compounds followed by the intramolecular trapping of the zinc enolate in the presence of chiral phosphoramidite ligands was investigated. Cyclic and heterocyclic compounds with multichiral centers were formed as a mixture of two diastereomers with excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to 94 % ee, ee=enantiomeric excess). The stereochemistry was determined to be trans,trans for the major products and trans,cis for the minor products. The absolute configuration of the cyclic compounds was assigned by comparison with the analogous adduct derived from trans-3-nonen-2-one and Et(2)Zn or the adduct obtained through conjugate addition of Me(2)Zn to trans-1-phenyl-non-2-en-1-one. Further transformation of these cyclic products into more complex compounds is under investigation in our laboratory.     

Stereoselective synthesis of simplactone B via Prins cyclisation

The synthesis of simplactone B has been achieved through a series of nine steps in 85% overall yield using Prins cyclisation as the key step with high stereochemical control.     

Generation of N-acyliminium ions via intramolecular conjugate addition reactions: a strategy for the total synthesis of nakadomarin A

[reaction: see text] The rapid construction of the tetracyclic core ring system of nakadomarin A via a tandem enecarbamate Michael addition/N-acyliminium ion cyclization is described.     

Stereoselective construction of cis-2,6-disubstituted tetrahydropyrans via an intramolecular bismuth-mediated oxa-conjugate addition reaction

The intramolecular oxa-conjugate addition of tethered triethylsilyloxy substituted α,β-unsaturated ketones mediated by bismuth(III) nitrate pentahydrate provides a mild and efficient method for the stereoselective construction of cis-2,6-disubstituted tetrahydropyrans.