Racemization in Prins cyclization reactions

Isotopic labeling experiments were performed to elucidate a new mechanism for racemization in Prins cyclization reactions. The loss in optical activity for these reactions was shown to occur by 2-oxonia-Cope rearrangements by way of a (Z)-oxocarbenium ion intermediate. Reaction conditions such as solvent, temperature, and the nucleophile employed played a critical role in whether an erosion in enantiomeric excess was observed. Additionally, certain structural features of Prins cyclization precursors were also shown to be important for preserving optical purity in these reactions.     

Stereoselectivity and regioselectivity in the segment-coupling Prins cyclization

The scope of the segment-coupling Prins cyclization has been investigated. The method is outlined in Scheme 1 and involves esterification of a homoallylic alcohol (1), reductive acetylation to give the alpha-acetoxy ether (3), and cyclization on treatment with a Lewis acid to produce a tetrahydropyran (4). Alkene geometries dictate the product configurations, with E-alkenes leading to equatorial substituents and Z-alkenes leading to axial substituents (Table 1). Not unexpectedly, applying the method to allylic alcohols leads to fragmentation rather than a disfavored 5-endo-trig cyclization. Dienols in which one alkene is allylic and the other alkene is homoallylic cyclize efficiently and produce the tetrahydropyrans 49-54, Table 3. Dienols with two homoallylic alkenes cyclize with modest to high regioselectively, generating tetrahydropyrans 40-45, Table 2. The relative rates for cyclization decrease in the order of vinyl > Z-alkene > E-alkene > alkyne. The configurations of the products are consistent with cyclization via a chair conformation, Figure 1. The 2-oxonia Cope rearrangement may be a factor in the regioselectivity of diene cyclizations and in the erosion of stereoselectivity with Z-alkenes. This investigation establishes the stereoselectivity and regioselectivity for a number of synthetically useful segment-coupling Prins cyclizations.     

Synthesis of the bis-spiroacetal moiety of the shellfish toxins spirolides B and D using an iterative oxidative radical cyclization strategy

The enantioselective synthesis of the bis-spiroacetal fragment of the shellfish toxins, spirolides B 1 and D 2, is reported. The carbon framework was constructed via a Barbier reaction of dihydropyran 10 with aldehyde 11, followed by two oxidative radical cyclizations to construct the bis-spiroacetal ring system. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor 21. The initial unsaturated bis-spiroacetals 9a-d underwent equilibration during epoxidation to trans-epoxide 24 that was converted to tertiary alcohol 7.     

Axial-selective prins cyclizations by solvolysis of alpha-bromo ethers

Prins cyclizations are intramolecular electrophilic additions of oxocarbenium ions. They lead to tetrahydropyrans with a heteroatom at the 4-position, and usually show moderate-to-high selectivity for equatorial substitution. We have found that Prins cyclizations carried out under specific conditions produce tetrahydropyrans with almost exclusive formation of the axial 4-substituent. TMSBr, AcBr, and TMSI all lead to axial-selective Prins cyclizations with alpha-acetoxy ether substrates in the presence lutidine. The mechanism appears to involve solvolysis of the intermediate alpha-bromo ether rather than specific or Lewis acid-catalyzed rearrangement. The scope of the reaction, the high yields, and the stereoselectivity make this a valuable new method for tetrahydropyran formation.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.     

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.     

Solvolysis of a tetrahydropyranyl mesylate: mechanistic implications for the Prins cyclization, 2-oxonia-cope rearrangement, and Grob fragmentation

[reaction: see text] A solvolysis reaction is used to demonstrate that a tetrahydropyranyl cation is a common intermediate for Prins cyclizations, 2-oxonia-Cope rearrangements, and Grob fragmentations of tetrahydropyran rings.     

Acid-promoted Prins cyclizations of enol ethers to form tetrahydropyrans

Trifluoroacetic acid efficiently catalyzes Prins cyclizations of enol ethers 8 to provide tetrahydropyrans 9 and 10. These tetrahydropyrans are isolated with combined yields of 42-85% and stereoselectivities at C(4) ranging from 95:5 to 50:50 depending on the nature of the substituent R. Unique byproducts of these cyclizations that reveal the presence of underlying equilibria have been isolated and identified. [reaction: see text]     

Construction of the tricyclic furanochroman skeleton of phomactin A via the Prins/Conia-ene cascade cyclization approach

A substrate-controlled asymmetric Prins/Conia-ene cascade cyclization has been developed with In(OTf)(3) in CH(3)CN from 0 to 70 °C. These conditions afforded very good yields of the 1-oxadecalin product in one pot and effectively suppressed the racemization of the 1-oxadecalin product with almost no enantiomeric excess (ee) loss. This cascade cyclization has been successfully employed for the construction of the highly functionalized 1-oxadecalin unit of phomactin A with an acyclic β-keto ester and an alkynal as the substrates via a one-pot operation (66% yield, single diastereomer). The 1-oxadecalin moiety has been readily converted to the tricyclic furanochroman skeleton of phomactin A via the epoxidation/dealkoxycarbonylation protocol under very mild conditions with 52% yield in three steps.     

Prins cyclizations in silyl additives with suppression of epimerization: versatile tool in the synthesis of the tetrahydropyran backbone of natural products

[reactions: see text] A catalytic Prins cyclization reaction has been developed. The involvement of trimethylsilyl halides offers a versatile route to the formation of cis-4-halo-2,6-disubstituted tetrahydropyran rings. The problem of epimerization in Prins cyclization has also been addressed in the total synthesis of (-)-centrolobine using this methodology.     

Synthesis of the C22-C26 tetrahydropyran segment of phorboxazole by a stereoselective prins cyclization

[formula: see text] Tetrahydropyran rings are found in many complex natural products, and the segment-coupling Prins cyclization is an effective strategy for their synthesis. We report a four-step, stereoselective synthesis of the C20-C27 tetrahydropyran segment of phorboxazole. The key step is a Prins cyclization induced by catalytic BF3.OEt2.     

A concise stereoselective formal total synthesis of the cytotoxic macrolide (+)-Neopeltolide via Prins cyclization

A convergent and highly stereoselective formal total synthesis of the naturally occurring, cytotoxic 14-membered macrolide neopeltolide has been achieved via two Prins cyclizations.     

The silylalkyne-Prins cyclization: stereoselective synthesis of tetra- and pentasubstituted halodihydropyrans

[reaction: see text] A new type of Prins cyclization using silylated secondary homopropargylic alcohols and aldehydes yielding tetra- and pentasubstituted dihydropyrans is described. The presence of the trimethylsilyl group in the triple bond favors the Prins cyclization and minimizes the 2-oxonia-[3,3]-sigmatropic rearrangement as a competitive alternative pathway. Ab initio theoretical calculations of the species involved in the rearrangements support the proposed mechanism. The process is highly stereoselective, affording cis-dihydropyran as the only isomer.     

Unprecedented synergistic effects between weak Lewis and Brønsted acids in Prins cyclization

Novel synergistic effects between Lewis and Br?nsted acids in Prins cyclization are reported. Non-reactive Lewis acids and non-reactive Br?nsted acids, which failed to perform Prins cyclization when used alone, have shown remarkable synergistic effects when used in combination to perform the reaction successfully.     

Cellulose-SO3H as a recyclable catalyst for the synthesis of tetrahydropyranols via Prins cyclization

Tetrahydropyranols are prepared in good yields and with high cis-selectivity by means of the Prins cyclization using cellulose-sulfonic acid under mild reaction conditions. This is the first report on the preparation of tetrahydropyranols using epoxides and homoallylic alcohols via Prins cyclization.     

o-Benzenedisulfonimide as a Recyclable Homogeneous Organocatalyst for an Efficient and Facile Synthesis of 4-Amidotetrahydropyran Derivatives Through Prins–Ritter Reaction

A highly diastereoselective synthesis of 4-amidotetrahydropyran derivatives has been achieved using a catalytic amount of o-benzenedisulfonimide under mild conditions involving sequential allylation and Prins–Ritter amidation. The oxo-carbenium ion formed in Prins cyclization could be successfully trapped with nitriles through Ritter amidation. The catalyst is highly efficient in promoting both allylation and Prins cyclization with a net addition of nitrile. The catalyst can be easily recovered and reused in subsequent reactions.     

Tandem Prins/Friedel–Crafts cyclization for stereoselective synthesis of heterotricyclic systems

Homoallylic substrates such as (E)-6-arylhex-3-enyl alcohols, N-tosylamides, and thiols undergo smooth cross-coupling with various aldehydes in the presence of 10 mol % Sc(OTf)(3) and 30 mol % TsOH to afford the trans-fused hexahydro-1H-benzo[f]isochromenes, N-tosyloctahydrobenzo[f]isoquinolines, and hexahydro-1H-benzo[f]isothiochromenes, respectively. However, the cross-coupling of (Z)-olefins such as 6-arylhex-3-enyl alcohols, N-tosylamides, and thiols with aldehydes affords the corresponding hexahydro-1H-benzo[f]isochromenes, N-tosyloctahydrobenzo[f]isoquinolines, and hexahydro-1H-benzo[f]isothiochromenes with complete cis selectivity via intramolecular Prins-, aza-Prins-, and thia-Prins/Friedel-Crafts cyclizations, respectively. Though the Prins cyclization proceeds smoothly under the influence of Sc(OTf)(3), high conversions and enhanced reaction rates are achieved using a mixture of Sc(OTf)(3) and TsOH (1:3).     

Indium trichloride mediated intramolecular Prins-type cyclization

[reaction: see text] Intramolecular Prins-type reactions of compounds having both functionalities of homoallyl alcohol and acetal moiety are described. The intramolecular Prins cyclizations were performed using indium trichloride in chloroform or 25% aqueous THF. Both 9-oxabicyclo[3.3.1]nonane and 3,9-dioxabicyclo[3.3.1]nonane compounds were successfully obtained in moderate yields.     

Total synthesis of 7-desmethoxyfusarentin and its methyl ether

A concise total synthesis of 7-desmethoxyfusarentin and its methyl ether has been accomplished involving a sequence of reactions such as Prins cyclization, ring opening of tetrahydropyran ring and Alder-Rickerts reaction as key steps. This is the first report on the construction of anti-1,3-diol unit of 7-desmethoxyfusarentin by means of Prins cyclization.     

Rhenium(VII) catalysis of Prins cyclization reactions

The rhenium(VII) complex O3ReOSiPh3 is a particularly effective catalyst for Prins cyclizations using aromatic and alpha,beta-unsaturated aldehydes. The reaction conditions are mild, and the highly substituted 4-hydroxytetrahydropyran products are formed stereoselectively. Rhenium(VII) complexes appear to spontaneously form esters with alcohols and to directly activate electron-rich alcohols for solvolysis. Re2O7 and perrhenic acid are equally effective in catalyzing these cyclizations.