Ring transformation of 2-(haloalkyl)azetidines into 3,4-disubstituted pyrrolidines and piperidines

[reaction: see text] Reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane (AlH(2)Cl) afforded new 2-(haloalkyl)azetidines in high yields. The latter compounds proved to be very useful starting materials for rearrangements toward stereospecifically defined five- and six-membered azaheterocycles, such as 3,4-cis-disubstituted pyrrolidines and piperidines. During these reactions, bicyclic azetidinium intermediates were formed which were ring opened by a variety of nucleophiles. Hereby, reactions proceeding via 1-azoniabicyclo[2.2.0]hexanes are reported for the first time.     

Stereoselective synthesis of 3,4-disubstituted pyroglutamates by ring transformation of 5-ylidene-1,3-dioxan-4-ones with N-(diphenylmethylene)-glycinate

N-(Diphenylmethylene)-glycinate gives stereoselective conjugate addition to readily available (E) and (Z)-5-ylidene-1,3-dioxan-4-ones. Hydrolytic cleavage of the imine functionality of the resulting Michael-adducts causes ring transformation to new, optically active 3,4-disubstituted pyroglutamates.     

Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine

Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity. The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.     

A novel synthesis of cis-3,4-disubstituted cyclopentanones

A new method for the stereospecific synthesis of cis-3,4-disubstituted cyclopentanones is described.     

Stereoselective synthesis of cis-1,3-disubstituted cyclobutyl kinase inhibitors

Two synthetic routes to a series of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane are described. The first route utilized addition of 3-aminocyclobutanol to 1,4-dinitroimidazole 5 as the crucial step in preparing 1, whereas the second route employed a novel 1,4-addition of 4-nitroimidazole 18 to in situ generated cyclobutenone 17 as the key reaction. This allowed for a stereoselective and shorter synthesis that eliminated the use of potentially explosive 1,4-dinitroimidazole 5. [structure: see text]     

Conjugate addition of organocuprates to chiral bicyclic delta-lactams. Enantioselective synthesis of cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines

[reaction: see text] Chiral nonracemic bicyclic lactam 3, easily accessible by cyclodehydration of (R)-phenylglycinol and racemic methyl 4-formylhexanoate, was converted to the unsaturated lactams 5, which undergo the stereoselective conjugate addition of lower order cyanocuprates to ultimately lead to enantiopure cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines.     

Stereoselective synthesis of 3,4-disubstituted and 3,4,5-trisubstituted piperidines by Lewis acid-catalysed ene cyclisation of 4-aza-1,7-dienes

The thermal or Lewis acid-catalysed ene cyclisation of a variety of 4-aza-1,7-dienes afforded 3,4-disubstituted or 3,4,5-trisubstituted piperidines. Activation of the enophile with a single ester facilitated a thermal ene cyclisation, although the reaction was not amenable to Lewis acid catalysis. With other activating groups on the enophile it was found that Lewis acid catalysis was facile, although there was a fine balance between the desired ene cyclisation and the competing hetero-Diels-Alder reaction, with the product distribution being influenced by the activating group on the enophile, the nature of the ene component, and the Lewis acid used. Activation of the enophile with an oxazolidinone function facilitated Lewis acid-catalysed cyclisation to afford mixtures of ene and hetero-Diels-Alder products. Activating the enophile with two ester groups gave a substrate that underwent a very facile ene cyclisation catalysed by MeAlCl(2) to give the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200 : 1.     

Asymmetric synthesis of ring functionalized trans-2,6-disubstituted piperidines from N-sulfinyl delta-amino beta-keto phosphonates. total synthesis of (-)-myrtine

Sulfinimine-derived N-sulfinyl delta-amino beta-ketophosphonates are transformed via the enaminones to the phosphoryl dihydropyridones that selectively give trans-2,6-disubstituted 1,2,5,6-tetrahydropyridines on organocuprate addition and dephosphorylation.     

Asymmetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines

A convenient and practical method for the preparation of chiral 4-aryl-2-piperidinone from 3-arylglutaric anhydride and (S)-methylbenzylamine is described. Acylation or alkylation at the α-carbon of the chiral 4-aryl-2-piperidinone product afforded chiral trans-3,4-disubstituted 2-piperidinone derivatives and reduction of the chiral 2-piperidinones with lithium aluminum hydride provided the corresponding enantiomerically pure trans-3,4-disubstituted piperidines. This methodology has been successfully applied to the synthesis of the anti-depressant paroxetine.     

Stereoselective alkenylation of a 1,3-disubstituted pyrazol-5-one through ring transformation of 2H-pyran-2-ones

A one-pot stereoselective alkenylation of 1-(3-chlorophenyl)-3-methyl-1,4-dihydro-5-pyrazolone 2 by 2H-pyran-2-ones 1 to give (E,E)-5-aryl-5-[1-(3-chlorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4- ylidene]-3-methylsulfanyl-pent-3-en-carbonitrile/methyl carboxylate 3 has been delineated through ring transformation in moderate yields.     

Synthesis of enantiopure cis- and trans-2,3-disubstituted piperidines

The synthesis of enantiopure cis- and trans-2,3-disubstituted piperidines 4 is described. The key step of the synthesis involves the stereoselective reduction of chiral nonracemic lactams 2 by using BH3.Me2S. A rationalization of the stereoselectivity is presented.     

Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates

Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from L-phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl substituent proceed smoothly to form the N-sulfamate intermediates which on acidic hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity (98%?≥?d.e.) with good chemical yields (68–86%). The present approach provides a novel route for the stereoselective synthesis of cis-2,6-disubstituted piperidines.     

Stereoselective synthesis of cis- or trans-2,4-disubstituted butyrolactones from Wynberg lactone

(R)-Wynberg lactone was used to prepare various asymmetric 2,4-disubstituted butyrolactones in three to four steps. Attainment of any possible stereoisomer, based upon commencement from (R)- or (S)-4-trichloromethyl-2-oxetanone, and the capacity to install disparate substituents at C₂ make this approach particularly versatile.     

A new route to 3,4-disubstituted piperidines: formal synthesis of (−)-paroxetine and (+)-femoxetine

A new route to 3,4-disubstituted piperidines was developed using chiral 1,4-dihydropyridines as key intermediates, the synthetic utility of which was demonstrated by formal synthesis of (−)-paroxetine and (+)-femoxetine.     

Highly selective Syn acyclic homoaldol chemistry synthesis of cis-3,4-disubstituted butyrolactones

Syn acyclic homoaldol products have been prepared by the conjugate addition reaction of α-alkoxyorganocuprates to enals. Selectivities of up to >250:1 have been obtained.     

Stereoselective synthesis of 2,5,6-trisubstituted piperidines

[reaction: see text] A short and efficient synthesis of 2,5,6-trisubstituted piperidines was achieved by a combination of an aza-Achmatowicz oxidation of a furyl benzenesulfonamide, conjugate addition to the resulting 2H-pyridinone, and subsequent addition of various nucleophiles to a transient N-sulfonyliminium ion. The steric bulk of the tosyl group directs attack of the nucleophile from its opposite side, thereby leading to the formation of cis-substituted products.     

Stereoselective construction of cis-2,6-disubstituted tetrahydropyrans via the reductive etherification of delta-trialkylsilyloxy substituted ketones: total synthesis of (-)-centrolobine

[reaction: see text] The stereoselective intramolecular reductive etherification of delta-trialkylsilyloxy substituted ketones with catalytic bismuth tribromide and triethylsilane provides a convenient method for the construction of cis-2,6-disubstituted tetrahydropyrans. This method was highlighted in the key step of an expeditious total synthesis of the antibiotic, (-)-centrolobine.     

Stereocontrolled chemoenzymatic synthesis of 2,3-disubstituted piperidines

(R,R)-2,3-Disubstituted piperidines were readily synthesized starting from (R)-(+)-5-bromo-2-hydroxypentanenitrile (R)-2. An enantioselective (R)-oxynitrilase-catalyzed transcyanation was used to prepare the starting cyanohydrin (R)-2.     

Divergent asymmetric synthesis of 3,5-disubstituted piperidines

A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently obtained from N-benzylglycinate in five steps by the use of chemoenzymatic methods. In the subsequent enzyme- and Ru-catalyzed reaction, the rac/meso diol mixture was efficiently transformed to the cis-(3R,5S)-diacetate with excellent diastereoselectivity and in high yield. Further transformations of the cis-diacetate selectively delivered the cis-piperidine diol and the cis-(3R,5S)-hydroxy acetate. Alternatively, the DYKAT could be stopped at the monoacetate stage to give the trans-(3R,5R)-hydroxy acetate.