Diastereoselective synthesis of 4-hydroxypiperidin-2-ones via Cu(I)-catalyzed reductive aldol cyclization

[chemical reaction: see text]. 4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of alpha,beta-unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric Mannich reactions, this methodology enables the enantioselective synthesis of more highly functionalized piperidin-2-ones and hydroxylated piperidines.     

Spiranes synthesis based on samarium diiodide-mediated reductive cyclization

A general and efficient method for the preparation of spiro compounds is described. Enone–aldehydes were exposed to samarium diiodide under mild conditions and various spirocyclic γ-hydroxyketones were obtained in good yields.     

Diastereoselective reductive nitro-Mannich reactions

A range of nitroalkenes 1 and imines 3 derived from alkyl, aryl, and heteroaryl aldehydes underwent a tandem 1,4-hydride addition nitro-Mannich reaction to afford anti-rich β-nitroamines 4. The crude anti-β-nitroamines 4 could be converted to the corresponding anti-β-nitroacetamides 5 (33 examples) to allow purification in good yield from the parent nitroalkenes (60-87%), and with a high diastereomeric ratio (90:10 to mostly >95:5). A representative selection of anti-β-nitroacetamides 5 (five examples) were reduced to vicinal diamines 7 with zinc hydrochloride; concomitant acyl migration provided differentially protected vicinal diamines 7 in good yield (80-91%).     

Diastereoselective synthesis of tetrahydrofurans via mead reductive cyclization of keto-beta-lactones derived from the tandem Mukaiyama aldol lactonization (TMAL) process

The development of a diastereoselective, three-step strategy for the construction of substituted tetrahydrofurans from alkenyl aldehydes based on the tandem Mukaiyama aldol-lactonization process and Mead reductive cyclization of keto beta-lactones is reported. Stereochemical outcomes of the TMAL process are consistent with models established for Lewis acid-mediated additions to alpha-benzyloxy and beta-silyloxy aldehydes while reductions of the five-membered oxocarbenium ions are consistent with Woerpel's models. Further rationalization for observed high diastereoselectivity in reductions of alpha-silyloxy 5-membered oxocarbenium ions based on stereoelectronic effects are posited. A diagnostic trend for coupling constants of gamma-benzyloxy beta-lactones was observed that should enable assignment of the relative configuration of these systems.     

Diastereoselective synthesis of 4,5'-bis-proline compounds via reductive dimerization of N-acyloxyiminium ions

A short, practical synthesis of novel, unsymmetrical 4,5'-bis-proline compounds has been achieved, highlighted by the application of an unprecedented samarium diiodide-driven regio- and diastereocontrolled reductive dimerization of N-acyloxyiminium ions generated from readily available 2-methoxy-5-silyloxymethyl-N-Boc pyrrolidines. The title proline dimers proved to be pertinent metal-free catalysts in aldol and Mannich reactions.     

Diastereoselective synthesis of substituted tetrahydrothiopyrans via (3,5)-thionium-ene cyclization reaction

Tetrahydrothiopyrans have been efficiently synthesized in good yields with excellent diastereoselectivity from aldehydes and substituted 5-methylhex-4-ene-1-thiol via (3,5)-thionium-ene cyclization reaction mediated by boron trifluoride etherate.     

Diastereoselective synthesis of cyclopentapyridazinones via radical cyclization: synthetic studies toward halichlorine

The pyridazinone ring system serves as an excellent scaffold for the diastereoselective preparation of novel cis-fused cyclopentapyridazinones utilizing the directed 5-exo radical cyclization approach. This overall approach was successfully employed in the preparation of a functionalized aza-spirocycle.     

An unusual reductive cyclization

Li-NH₃ reduction of 1α-Ethynyl-1β-hydroxy-6-oxo-8a-methyl-1,2,3,4,6,7,8,8a octahydronaphthalene 5 furnishes, in addition to reported products, the tricyclic compound $\text{8}$.     

Synthesis of oxapenem derivatives by novel reductive cyclization

Several 6-ethyl-substituted l-oxapenem derivatives were synthesized by the application of the established method. Furthermore novel and effective synthesis of oxapenems $\text{via}$ reductive cyclization of 2-chloro-2-(4-chloro-3-ethyl-2-oxo-l-azetidinyl) acetoacetates ($\text{1}$$\text{0}$) using sodium thiolates is reported.     

A convenient synthesis of 1,2,4-trisubstituted azetidines by reductive cyclization of aza-Michael adducts of chalcones

Aza-Michael adducts of chalcones and diethyl N-arylphosphoramidates undergo reductive cyclization with sodium borohydride followed by sodium hydride to afford 1,2,4-trisubstituted azetidines diastereoselectively in a one-pot procedure and excellent yields.     

Catalytic enantioselective synthesis of chiral phthalides by SmI2-mediated reductive cyclization of 2-acylarylcarboxylates

A significant new and efficient catalytic asymmetric approach for the highly enantioselective synthesis of chiral phthalides by SmI2-induced reductive cyclization of 2-acylarylcarbonylates was developed. The combination of (4S,5R)-4,5-diphenyloxazolidin-2-one and 2,2,6,6-tetramethylpiperidine was found to be a very effective catalyst system in the reaction. This method provides a ready access to a broad range of enantiomerically enriched phthalides (up to 99% ee).     

Nickel-catalyzed reductive cyclization of organohalides

A mild and convenient nickel-catalyzed method for free-radical cyclization of organohalides is described. The use of a NiCl(2)?DME/Pybox complex as the catalyst and zinc powder in methanol efficiently promotes the reductive cyclization of various unsaturated alkyl halides to give carbo-, oxa-, and azacycles as products in high yields.     

Double reductive cyclization: a facile synthesis of the indoloquinoline alkaloid cryptotackieine

A new synthesis of the indoloquinoline alkaloid cryptotackieine, isolated from Cryptolepis sanguinolenta, is described which involves a Perkin reaction, a tandem double reduction-double cyclization reaction followed by regioselective methylation at the quinoline nitrogen.     

Efficient synthesis of the 3-benzazepine framework via intramolecular Heck reductive cyclization

A microwave-assisted protocol based on reductive Heck reaction was developed for regio- and stereoselective construction of the 3-benzazepine core.     

Diastereoselective reductive amination of pyrazolidinyl alkyl ketones

Reductive amination of pyrazolidinyl alkyl ketones with sodium triacetoxyborohydride or sodium tripivaloyloxyborohydride takes place diastereoselectively with the formation of aminoalkylpyrazolidines of trans structure. The volume of the substituent in the borohydrides does not affect the ratio of stereoisomers. Dedicated to the memory of A. A. Potekhin, renowned teacher, scientist, and editor of journal “Chemistry of Heterocyclic Compounds” __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 691–698, May, 2008.     

Catalytic asymmetric reductive Michael cyclization

A highly efficient and chemo-, regio-, diastereo-, and enantioselective organocatalytic tandem conjugate reduction-Michael cyclization of enal enones has been developed. Accordingly, treating the enal enone with a Hantzsch dihydropyridine in the presence of a catalytic amount of an imidazolidinone organocatalyst provides cyclic keto aldehydes in high yields and enantiomeric excesses. The reaction works well with aliphatic and aromatic substrates in the synthesis of five- and six-membered carbacyclic derivatives.     

A palladium mediated reductive cyclization

α,ω-bis(Allylic acetates) undergo regioselective intramolecular reductive coupling with hexamethyldistannane catalyzed by pd(O).     

Asymmetric synthesis of dibenzo[b,d]azepines by Cu-catalyzed reductive or borylative cyclization

A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d]azepines is described. Use of 2′-vinyl-biaryl-2-imines as substrates and in situ formed [Cu^I/(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereo- and enantioselectivities (>20 : 1 d.r., up to 99% ee). Moreover, the same catalyst was found to facilitate a related borylative cyclization to afford versatile boronic ester derivatives. Both reactions proceed under mild conditions (rt) and are applicable to a variety of substituted aromatic and heterocyclic derivatives.

Dibenzo[b,d]azepines featuring axially chiral 7-member-bridged biaryls have been prepared by asymmetric reductive or borylative cyclizations using copper catalysis.