Control of up to five stereocenters in a cascade reaction: synthesis of highly functionalized five-membered rings

Mukaiyama-Aldol and Prins reactions have been identified as highly efficient methods in C-C bond formation since they were discovered several decades ago. Since both reactions gave the same common intermediate, oxocarbonium, we intend to combine the two reactions into a domino process, which means the formation of multiple C-C bonds and stereogenic centers in one pot without isolation of any intermediates. We envisage that the domino reactions involving the Mukaiyama-Aldol reaction of silyl enol ether and acetal treated with Lewis acid (TiBr4) will produce an oxonium intermediate which upon trapping by an alkene functionality in an intramolecular Prins cyclization will generate the cyclopentyl ring system.     

Utilization of an oxonia-Cope rearrangement as a mechanistic probe for Prins cyclizations

An oxonia-Cope rearrangement was used as an internal clock reaction to probe the mechanism of the Prins cyclization reaction and the subsequent nucleophilic capture of the resultant tetrahydropyranyl cation. The oxonia-Cope rearrangement was shown to occur rapidly under typical Prins cyclization conditions when the oxocarbenium ion resulting from the rearrangement is similar to or lower in energy than the starting oxocarbenium ion. Oxonia-Cope rearrangements can be disfavored by destabilizing the resultant oxocarbenium ion or by stabilizing an intermediate tetrahydropyranyl cation. Stereoselectivity in the nucleophilic capture was dramatically affected by the reactivity of the nucleophile and electrophile. More reactive partners combined rapidly to give axial-substituted Prins products through a least-motion pathway. High selectivity for the equatorial-substituted tetrahydropyran was observed for less reactive nucleophiles and electrophiles.     

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.     

A modified Prins reaction for the facile synthesis of structurally diverse substituted 5-(2-hydroxyethyl)-3,3-dihydrofurane-2(3H)-ones

Furanones are important synthetic intermediates commonly found in natural products, receptor ligands, and drug molecules. Unacceptable yields of substituted furanones obtained using a previously reported Prins reaction led to the development of a modified approach. Readily prepared substituted allylic esters were reacted under Prins reaction conditions catalyzed by a protic acid to provide structurally diverse substituted furanones in modest to good yields. The reaction goes through a protected caprolactone intermediate that was isolated and characterized for selected compounds. The approach supplies an efficient, versatile, and higher yield method for the synthesis of these important heterocyclic intermediates.     

A Cascade “Prins‐Pinacol‐Type Rearrangement and C4‐OBn Participation” on Carbohydrate Substrates: Synthesis of Bridged Tricyclic Ketals,Annulated Sugars and C2‐Branched Heptoses

A “Prins pinacol type rearrangement followed by C4‐OBn participation” in a cascade manner has been observed while probing the fate of carbocation in some carbohydrate derived homoallylic alcohols in the Prins reaction. This has led to an easy access to tetrahydrofuran‐fused bridged bicyclic ketals (or tetrahydrofuran‐fused 1,6‐anhydro‐heptopyranose frameworks) which are further converted into some annulated sugars and C2‐branched heptoses.     

Competitive Silyl–Prins Cyclization versus Tandem Sakurai–Prins Cyclization: An Interesting Substitution Effect

Two different mechanism pathways are observed for the reaction of allylsilyl alcohols 1 and aldehydes in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). In the case of allylsilyl alcohols without allylic substituents, the reaction gives dioxaspirodecanes, which are the products of a tandem Sakurai–Prins cyclization. In contrast, allylsilyl alcohols with an allylic substituent (R²≠H) selectively provide oxepanes, thus corresponding to a direct silyl–Prins cyclization. Both types of product are obtained with excellent stereoselectivity. Theoretical studies have been performed to obtain some rationalization for the observed stereoselectivity.     

Kinetics of the Reaction of 2-Methylpropene with Formaldehyde in the Presence of Synthetic Zeolites

Kinetics and Catalysis - It is well known that zeolites exhibit catalytic activity in the Prins reaction. It was found that their use makes it possible to increase the selectivity of the Prins...     

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 (-)-centrolobine by Prins cyclizations that avoid racemization

[formula: see text] The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine highlight the utility of Prins cyclizations.     

Studies in sesquiterpenes—XX Acetoxymethylation of longifolene

Longifolene in Prins reaction with formaldehyde yielded the expected ω-acetoxymethyl longifolene, which was transformed into a number of interesting derivatives. Configuration of the Prins product has been arrived at by NMR measurements. The UV absorption of these derivatives show a considerable bathochromic shift with respect to those in the camphene series and this could be attributed to the slight twisting of the ethylenic linkage in longifolene and its derivatives.     

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.     

Transannular Diels-Alder studies on the asymmetric total synthesis of chatancin: the pyranophane approach

[reaction: see text] A pathway is proposed for the biosynthesis of (+)-chatancin and (+)-sarcophytin linking these tetracycles to cembranoids by a pyranophane transannular Diels-Alder reaction. Preliminary synthetic results in this direction to reach macrocyclic dienedione 28 from farnesol are reported. Major synthetic steps include a Prins reaction, two enantioselective hydrogenations, and a macrocyclization via a beta-ketosulfoxide Michael-addition on an enone.     

Synthesis of 1,3-Dioxanes Catalyzed by TsOH-SiO2 Under Solvent-Free Conditions

Silica-supported p-toluene sulfonic acid is found to be an excellent catalyst for the Prins reaction to produce 1,3-dioxanes in good yields from olefins and aliphatic aldehydes in dichloromethane at room temperature and solventless microwave irradiation within a short reaction time.     

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.     

Prins Cyclization of Styrenes or Acetophenone Catalyzed by DBSA in Water

Dodecylbenzenesulfonic acid (DBSA) was proved to be an efficient catalyst for Prins cyclization of styrenes and formaldehyde or acetaldehyde in water. A tandem dehydration/Prins cyclization reaction using a tertiary alcohol and formaldehyde as substrates proceeded very well by using DBSA as catalyst. Acetophenone, which is less reactive compared with styrene, can also react with formaldehyde when catalyzed by DBSA in water to afford 1,3-dioxan-5-ylphenylmethanone in good yield.     

14β-hxdroxy steroids - III. Synthesis of digoxigenin from deoxycholic acid

A new synthetic approach to cardenolides is discussed which employs singlet oxygen addition to dienol ethers and an intramolecular Prins reaction.     

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.     

The "aqueous" Prins reaction

[reaction: see text] In this communication we demonstrate that Prins cyclization reactions occur under very mild conditions when cyclic alpha,beta-unsaturated acetals are employed as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles in water, demonstrating that colloidal suspensions can protect highly electrophilic intermediates from hydrolysis. Reactions are experimentally facile and useful in the preparation of a variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol.     

Bioinspired Total Synthesis of Sespenine

The first total synthesis of sespenine, a rare indole sesquiterpenoid from a mangrove endophyte, has been accomplished. A bioinspired aza‐Prins/Friedel–Crafts/retro Friedel–Crafts cascade reaction assembles the bridged tetrahydroquinoline core. Further investigations on the aza‐Prins cyclization imply that the C3 configuration of the hydroxyindolenine intermediate is crucial to the biosynthesis of sespenine and its congener xiamycin A.     

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.