Stereoselective synthesis of 2,4,5-trisubstituted tetrahydropyrans using an intramolecular allylation strategy

A highly stereoselective route to 2,4,5-trisubstituted tetrahydropyrans is reported. The key step employs an intramolecular allylation of a (Z)-allylsilane onto an aldehyde under Br?nsted acid activation. Complete 1,4-stereoinduction accounts for the formation of only two out of the possible four THP products. The level of 1,3-stereoinduction is optimal when the reaction is carried out in an apolar solvent, which is in accord with electrostatics being key to controlling this aspect of the stereoselectivity.     

5- And 6-exocyclic products, cis-2,3,5-trisubstituted tetrahydrofurans, and cis-2,3,6-trisubstituted tetrahydropyrans via Prins-type cyclization

Exocyclic products having cis-2,5 and cis-2,6 substitution were synthesized from terminally substituted alkynyl alcohols with various aldehydes via Prins-type cyclization in good yields. It is of interest that synthesized 5- and 6-exocyclic vinyl cations generated as a result of Prins-type cyclization could be trapped as a vinyl triflate in CH2Cl2 to give 3-furanylidenes and 3-pyranylidenes. Those 3-furanylidenes and 3-pyranylidenes underwent hydrolysis to give the corresponding 3-acyl-substituted products having all-cis-configured isomers, such as 2,3,5-trisubstituted tetrahydrofurans and 2,3,6-trisubstituted tetrahydropyrans.     

Stereoselective synthesis of 2,3,4-trisubstituted tetrahydrothiophenes

We describe an efficient new approach for the synthesis of highly substituted chiral tetrahydrothiophenes, based on the oxidation of a chiral furan substrate with singlet oxygen, followed by intramolecular hetero Michael addition.     

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 synthesis of 4-hydroxy-2-phenylproline framework

Highly diastereoselective (>20:1) bromo-lactonization of N-sulfonyl-2-allyl-2-phenylglycine methyl ester (11) was observed. Successive treatment of the chiral lactone with MeONa gave the desired (2S,4R)-4-hydroxy-2-phenylproline derivative in high yield without erosion of the diastereoselectivity. The starting chiral non-racemic compound (5) was prepared from the racemic 2-phenylglycine using a classical kinetic resolution (crystallization), an asymmetric phase transfer alkylation, and an enzyme-catalyzed kinetic resolution.     

Stereoselective approaches to 2,3,6-trisubstituted piperidines. An enantiospecific synthesis of quinolizidine (-)-217A

The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy and a piperidine 2,3-cyclopropanation-ring opening reaction as the key steps.     

Stereoselective synthesis of side chain-functionalized tetrahydropyrans from 5-hexenols

Molecular oxygen stereoselectively converts 5-hexenols into 2,6-trans-, 2,5-trans-, and 2,4-cis-derivatives of 2-methyltetrahydropyran via oxidative cyclization/radical functionalization cascades, when activated by fluoro-substituted cobalt(II) bis-(β-diketonate) complexes in solutions of cyclohexa-1,4-diene (CHD). Aerobic 5-hexenol oxidations in solutions of bromotrichloromethane and CHD furnish products of 6-exo-bromocyclization, as exemplified by synthesis of diastereomerically pure 2,4,6-substituted tetrahydropyrans. The cobalt method extends to intermolecular alkene/alkanol cross-coupling and to multi-component reactions between dimethyl fumarate, CHD, a 5-hexenol, and dioxygen, providing α-tetrahydropyranyl-2-methyl succinates in synthetically useful yields.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines via radical cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.     

Barbier allylation-Prins reaction of PEG-bound aldehydes—soluble polymer-supported synthesis of 2,4,6-trisubstituted tetrahydropyrans

PEG-bound aldehydes undergo zinc-mediated Barbier allylation to form homoallylic alcohols, which on further reaction with various aldehydes in the presence of BF₃·Et₂O through a Prins cyclization afford 4-hydroxytetrahydropyrans and 4-fluorotetrahydropyrans.     

Diastereoselective synthesis of 2,3,6-trisubstituted tetrahydropyran-4-ones via Prins cyclizations of enecarbamates: a formal synthesis of (+)-ratjadone A

Enecarbamates are shown to be excellent terminating groups for Prins cyclizations. A noteworthy feature of this methodology is the easy, stereoselective construction of the cyclization precursors by alkylation of metalated (E)-enecarbamates with epoxides. The stereochemistry of the resultant trisubstituted (E)-enecarbamates is then transferred with high fidelity to afford the frequently observed and biologically significant all-cis-2,3,6-trisubstituted tetrahydropyran substructures of naturally occurring compounds. Other substituted tetrahydropyrans, including 2,3,5,6-tetrasubstituted, cis-2,3-disubstituted, and cis-2,6-disubstituted, are also accessible. This methodology facilitated an exceptionally concise formal total synthesis of the nuclear export inhibitor (+)-ratjadone A.     

Stereocontrolled synthesis of 2-alkenyl-4-methylene tetrahydropyrans

A variety of 2-alkenyl-4-methylene tetrahydropyrans were synthesized via consecutive transition metal-catalyzed bond forming processes. In this approach, ruthenium-catalyzed coupling of homoallylic carbonates and homopropargylic alcohols generates substrates containing the requisite functionality for a palladium-mediated cyclization, thereby providing concise access to the target structures. The installation of a trisubstituted alkene at the C-2 position was achieved using an olefin cross metathesis process.     

Stereoselective synthesis of tetrahydropyrans via formal [4 + 2]-cycloaddition: a comparison of allylsilane and crotylsilane

The reaction of a series of beta-(triethylsilyloxy)aldehydes with several allylsilanes and crotyldimethylphenylsilane is described. Aldehydes possessing an alpha-stereocenter afforded tetrahydropyrans as mixtures of two diastereomers with allylsilane, but only a single diastereomer was observed in the case of crotylsilanes. The reaction time for crotylsilanes was longer than that for allylsilanes likely due to the increased steric hindrance. Allylsilanes afforded tetrahydropyrans in 34-67% yields, and crotylsilanes provided products in 0-62% yields.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

Cyclisation of aldehydes 3-e catalysed by concentrated hydrochloric acid affords predominantly the all cis 2,4,5-trisubstituted piperidines 4a-ewhen the 2-substituent is small, while catalysis by MeAlCl2 in refluxing chloroform gives the trans piperidines 5a-e with diastereomeric ratios of up to 99:1.     

Stereoselective synthesis of chiral 3,4,5-trisubstituted 1,5-dihydropyrrol-2-ones from azadienes

A new access to enantiopure 3-phthalimido-4-amino-5-(1-hydroxyalkyl) 1,5-dihydropyrrol-2-ones has been developed from 1,3-azadienes. Stereoselective Lewis acid catalyzed addition of a cyano group to an azadiene, followed by intramolecular ring closure, in a four-step one-pot synthesis, results in the formation of γ-lactams in satisfactory yields.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH(2)Cl(2) at -78 degrees C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94:6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl(2) in CH(2)Cl(2) or CHCl(3) at temperatures of between 20-60 degrees C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99:1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl(2) proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.     

Stereoselective synthesis of optically active 3-hydroxy-7,8-dihydro-beta-ionol-glucosides

A stereocontrolled synthesis of optically active beta-D-glucopyronosides 6a, b and 11a, b was accomplished via the 7,8-saturated alcohols 4a, b, efficiently prepared by an asymmetric transfer hydrogenation of the alpha,beta-acetylenic ketone 1 and subsequent catalytic hydrogenation. Simultaneous separation of these four glucosides by HPLC was also performed. This work is useful not only in order to confirm the stereochemistries of the trace amount of glucosides in plants but also to clarify their biosynthesis.     

Solid-phase synthesis of 1,2,5-trisubstituted 4-imidazolidinones

An efficient method for the preparation of 1,2,5-trisubstituted 4-imidazolidinones is presented. The synthetic approach is based on the formation of an N-[1-(benzotriazol-1-yl)alkyl] moiety on the amino group of a MBHA resin-bound amino acid. The nucleophilic substitution of the benzotriazole group with an amidic nitrogen results in the formation of a five-membered imidazolidinone ring. The reaction is nonstereospecific and produces diastereomers in ratios that vary depending on the substituents on the ring. A variety of N-alpha-alkylated amino acids were cyclized with aromatic, aliphatic, and heterocyclic aldehydes to determine optimal reaction conditions and to select building blocks for the future preparation of a large, diverse range of individual trisubstituted imidazolidinones as well as a mixture-based combinatorial library.