Tandem conjugate additions and 3-aza-Cope rearrangements of tertiary allyl amines and cyclic alpha-vinylamines with acetylenic sulfones. Applications to simple and iterative ring expansions leading to medium and large-ring nitrogen heterocycles

Tertiary acyclic allyl amines and tertiary cyclic alpha-vinyl amines undergo conjugate additions to acetylenic sulfones to produce zwitterion intermediates, followed by 3-aza-Cope rearrangements. In the case of cyclic alpha-vinyl amines, the process results in ring-expansion, providing a novel route to 9- to 17-membered cyclic amines. The Hammett plot for the reaction of 8b with 2a- 2f shows rho = +1.19, which is consistent with formation of the proposed zwitterion in the rate-determining step, where electron-withdrawing substituents on the arylsulfonyl moiety stabilize the negative charge and enhance the rate of the reaction. Alternative pathways were observed in methanol in the case of 11, where a methoxy substituent promotes a dissociative mechanism of the corresponding zwitterion via a stabilized allyl cation, whereas the zwitterion derived from amine 12 undergoes ring-opening by direct attack of methanol upon the strained aziridinium moiety instead of by rearrangement. An iterative process was developed, where the product of one ring-expansion is converted into a new cyclic alpha-vinyl amine, followed by a repetition of the conjugate addition and [3,3] rearrangement. This protocol was illustrated by its application to the synthesis of motuporamine A and B.     

Enantioselective conjugate addition of dialkylzinc to cyclic enones catalyzed by chiral binaphthyldiamine-copper(I) complexes

The enantioselective conjugate addition of dialkylzinc (R₂Zn) to cyclic enones was examined using chiral binaphthyldiamine-copper(I) catalysts. Under the present reaction conditions, chiral C₂-symmetric [RZn(II)]₂-diamine-Cu(I) complexes were formed from chiral binaphthyldiamine, R₂Zn, and copper(I or II) chloride in situ. The reaction of 2-cyclohexenone with Et₂Zn proceeded smoothly in the presence of the corresponding chiral copper(I) complex (5 mol %) and achiral 2,6-diphenylaniline (10 mol %), and the desired Et-adduct was obtained with up to 76% ee in 95% yield.     

Beckmann rearrangement of cyclotriveratrylene (CTV) oxime: tandem Beckmann-electrophilic aromatic addition

The Beckmann rearrangement has been performed on the oxime of cyclotriveratrylene (CTV) with thionyl chloride affording the ring-expanded 10-membered ring amide exclusively in high yield. Modified conditions afford a helical pentacycle derived from an unusual tandem Beckmann rearrangement and electrophilic aromatic addition followed by demethylation and tautomerization.     

A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition

A second-generation synthesis of the rearranged spongian diterpene aplyviolene is reported. The key step is the addition of a trialkyl tertiary radical generated by photoredox-mediated fragmentation of a N-(acyloxy)phthalimide to an α-chloropentenone. This process fashioned a quaternary stereocenter while combining two units of significant complexity.     

(S,S)-(+)-Pseudoephedrine as chiral auxiliary in asymmetric conjugate addition and tandem conjugate addition/alpha-alkylation reactions

Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseudoephedrine enamides furnishing the corresponding beta-alkyl-substituted adducts in excellent yields and diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition step undergo a highly diastereoselective alkylation reaction, furnishing alpha,beta-dialkyl-substituted amides in high yields. The obtained adducts have been converted into chiral nonracemic beta-alkyl- and alpha,beta-dialkyl-substituted carboxylic acids and gamma-alkyl- and beta,gamma-dialkyl-substituted alcohols using very simple and high-yielding procedures.     

Direct one-pot introduction of 2-methylpyridines to Baylis-Hillman adducts via base-mediated 3-aza-Cope rearrangement

An efficient and regioselective introduction method of 2-methylpyridines to the secondary position of Baylis-Hillman adducts has been developed. A base treatment of 2-methylpyridinium salt of Baylis-Hillman bromide generated N-allylenamine intermediate which underwent a facile 3-aza-Cope rearrangement under mild conditions to produce the product.     

Enantioselective one-pot conjugate addition of grignard reagents to cyclic enones followed by amidomethylation

Enantioselective conjugate addition of Grignard reagents to enones, catalyzed by Cu-Taniaphos or Josiphos complex, affords chiral enolates. Ensuing one-pot Mannich reaction with TiCl(4)-generated imine leads to aminocarbonyl compounds with benzyloxycarbonyl-protected nitrogen. Both diastereomers of these compounds are isolated in moderate yields but high enantiomeric purities (up to er 97.5:2.5).     

Chiral ligand-controlled asymmetric conjugate addition of alpha-trimethylsilanylacetate to acyclic and cyclic enones

The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of alpha-trimethylsilanylacetate to acyclic and cyclic alpha,beta-unsaturated ketones was mediated by an external chiral ligand to give the corresponding 1,4-adducts in good enantioselectivity of 74% and good chemoselectivity.     

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.     

Mechanism of the exclusive cyclic 1,3-rearrangement of O-benzoyl-N-(p-toluenesulfonyl)-n-arylhydroxylamines

O-(p-Substituted benzoyl)-N-(p-toluenesulfonyl)-N-arylhydroxylamines (1) were found to rearrange thermally giving o-acyloxy-p-toluenesulfonanilides (2) in quantitative yields. An intramolecular concerted cyclic process is considered to be in operation for the rearrangement on the basis of ¹⁸O tracer and kinetic experiments. The effects of both substituents and solvents on the rate of this novel 1,3-acyloxy migration were also examined. While the effect of solvent was small, the electronic effect of substituents on both N and O atoms plays a significant role in determining the mechanism of the rearrangement, especially the mode of cleavage of the NO bond at the transition state of the 1,3-acyloxy migration.     

Enantioselective formal hydration of alpha,beta-unsaturated imides by Al-catalyzed conjugate addition of oxime nucleophiles

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to alpha,beta-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to alpha,beta-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis.     

Development of a tandem cyclization mediated by samarium(II) iodide: sequential intramolecular conjugate addition/nucleophilic acyl substitution

The development of a one-pot tandem intramolecular conjugate addition/nucleophilic acyl substitution using samarium(II) iodide is reported. The reaction relies on the reagent’s unique ability to mediate both radical and anionic pathways, which are likely integral to the mechanism of this transformation. The tricyclic hemiacetal product was formed in good yield, with excellent diastereoselectivity, and its structure was verified by X-ray crystallographic analysis.     

An approach to serrulatane diterpenes via endo-selective conjugate nucleophilic addition to arene-Cr(CO)3 complexes

[formula: see text] Starting from a nonracemic planar-chiral arene tricarbonyl chromium complex, the serrulatane diterpenoid (+)-20-methoxy-serrulat-14-en-7,8-diol was synthesized in a highly stereoselective fashion. The key step of the synthesis is an endo-selective conjugate nucleophilic addition of lithio-methylphenyl sulfone to a 1-ethylidene-tetralin-Cr(CO)3 derivative. By employing different substrates and nucleophiles it was shown that the surprising and rather general endo selectivity must result from a unique complex induced proximity effect under participation of the Cr(CO)3 moiety.     

Cu-catalyzed enantioselective conjugate addition of alkylzincs to cyclic nitroalkenes: catalytic asymmetric synthesis of cyclic alpha-substituted ketones

An efficient and highly enantioselective (>/=92% ee) catalytic method for conjugate addition of alkylzinc reagents to cyclic nitroalkenes is reported. Reactions are promoted in the presence of 0.5-5 mol % (CuOTf)2.C6H6 and 1-10 mol % of chiral amino acid-based phosphine ligands at 0 degrees C in toluene. The Cu-catalyzed reactions can be effectively carried out with small-, medium-, and large-ring nitroalkenes. Depending on the reaction conditions used, either the nitro or the corresponding alpha-substituted ketone product can be readily accessed by the present protocol.     

Palladium(II)-catalyzed tandem intramolecular aminopalladation of alkynylanilines and conjugate addition for synthesis of 2,3-disubstituted indole derivatives

An efficient method for the synthesis of 2,3-disubstituted indoles with high selectivity from 2-ethynylaniline derivatives and α,β-unsaturated carbonyl compounds was developed. This Pd(II)-catalyzed reaction involves tandem intramolecular aminopalladation, olefin insertion and protonolysis of the carbon-palladium bond with the regeneration of Pd(II) species in the presence of halide ions.     

Medium-sized carbocycles by a zirconocene-catalyzed tandem formal ring expansion-magnesation reaction of alkenyl-substituted cyclic enol ethers

A new regio- and stereoselective zirconocene-catalyzed reaction for the synthesis of medium-sized rings is described. The global reaction supposes a formal ring expansion of a cyclic enol ether to give a functionalized carbocycle.     

A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach

A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters.