Prins Cyclization Reaction

Prins cyclization reaction of scalemic homoallylic alcohols (26) with aldehydes (R CIIO), carried out in the presence of an acid catalyst (HX), affords tetrasub-stituted tetrahydropyrans (27) (99% ee) with high stereoselectively in good yields... 

A novel and rapid synthesis of tetrahydropyran derivatives through the Prins cyclization reaction of homoallyl alcohols with aldehydes in the presence of bismuth trichloride was described. The reaction proceeded rapidly under microwave irradiation in solvent-free conditions. The conversions were clean and the products were obtained in excellent yield with high diastereoselectivity (Equation 24) [43a]. 

There are several natural product syntheses which utilize the Prins cyclization reaction as a key step to construct substituted tetrahydropyrans [13—17]. For example, the Loh group has nicely employed the Prins cyclization to furnish the two tetrahydropyranic subunits of (+)-SCH 351448 (Scheme 1.2) [18]. 

Li et al. reported an early use of the mild InC to promote the tandem carbonyl allylation and Prins cyclization reaction to give symmetrical tetrahydropyran rings [199]. Ally lie tin compounds were used for the allylation of aldehydes, and the resulting allylic alcohols proceeded to react with excess aldehydes to form either... 

Aubele DL, Wan S, Floreancig PE. Total synthesis of (+)-dac-tylolide through an efficient sequential Peterson olefination and Prins cyclization reaction. Angew. Chem. Int. Ed. Engl. 2005 44(22) 3483-3488. 

The synthesis of different substituted finans by cyclization of 4-pentynones using potassium tert-butoxide in DMF was reported <96TL3387>. Dihydrofuran 32 can be prepared by a destannylative acylation of l-[(2-methoxyethoxy)methoxy]-2-(phenylsulfonyl)-2-(tributylstannyl)-cyclopropane. Treatment of 32 with BFj-EtjO yields 3-acyUurans via an intramolecular Prins-type reaction of the resulting oxonium ion intermediate <96TL4585>. 

In furtherance of these smdies, the reaction scope was broadened by employing homopropargylic amines to give the corresponding aza-cycles (Scheme 26) [39, 40]. Hence, the alkyne aza-Prins cyclization between homopropargyl tosyl amines... 

A plausible mechanism for this new alkyne aza-Prins cyclization is outlined in Scheme 27. Thus, reaction of the homopropargyl tosyl amine with an aldehyde promoted by ferric halide generates the W-sulfonyl iminium ion. This intermediate evolves to the corresponding piperidine, via the vinyl carbocation. Ah initio theoretical calculations support the proposed mechanism. 

FeX3 was also found to be an excellent promoter in the classical Prins cycliza-tion (Scheme 10, route H), with the observation of a satisfactory reaction between 3-buten-l-ol and several aldehydes, affording the corresponding c/s-4-halo-2-alkyl tetrahydrop3Tans in good yields [Eq. (1) in Scheme 32] [35], In a similar manner, the methodology can be extended to the piperidine synthesis through an aza-Prins cyclization [Eq. (2), Scheme 32] [41],... 

The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acid-catalyzed) and a closely related Prins cyclization (B, Brpnsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 <06JOC2460 06OBC51>. Of note, in the formation of di-substituted derivatives, R1 = H and R2 = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R1 = f-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. 

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

Tetrahydropyrans hydroxylated at the 4-position have good synthetic value [113]. Although many synthetic methods have been reported [17-23,114,115], the search for potential alternate approaches and the development of eco-friendly and high-yielding reactions resulted in the development of a method that poses less problems for the environment. Synthesis of tetrahydropyranol derivatives can be achieved through the Prins-type cyclization reaction of homoallylic alcohols with aldehydes using bismuth triflate as catalyst in [bmim]PF6 solvent system [108] (Fig. 22). 

New hydrophobic Brpnsted acidic ionic liquids (HBAILs) have been prepared and used as organic catalysts of dehydration reactions in water, e.g. Prins cyclization of styrene derivatives with aqueous formaldehyde, to give 1,3-dioxanes.183... 

The silyl-modified Prins reaction and the silyl-modified Sakurai reaction are common methods employed for dihydropyran (and tetrahydropyran) synthesis, and are in fact the same reaction. For the sake of clarity, the term silyl-Prins cyclization is adopted herein. A review of the use of silicon containing compounds in reactions of this type is available <1995CRV1375>. 

Prins cyclization of the acetal 327 can be conducted in the presence of a Lewis acid surfactant catalyst in water to afford 2,4,6-trisubstituted tetrahydropyrans. The reaction proceeds via ionization of the crji-iinsatuiated acetal and subsequent reaction with the tethered electron-rich alkene, proving that the interior of micelles are sufficiently anhydrous to protect Prins cyclization intermediates (Equation 138) <20030L4521>. 

Aldehydes undergo a Mukaiyama-aldol reaction followed by a Prins cyclization with the highly reactive allylsilane 329 to afford jy -2,6-tetrahydropyrans 330 that feature an oeo-methylene group at C-4 (Equation 140, Table 12). This Mukaiyama-aldol-Prins (MAP) cascade cyclization has been used to form a key bis-tetrahydropyran intermediate during the total synthesis of leucascandrolide A <2001JA8420>. Similarly, titanium tetrabromide mediated MAP reactions afford 4-bromo tetrahydropyrans <20030L3163>. 

A stereocontrolled synthesis of 2,4,5-trisubstituted tetrahydropyrans 331 can be achieved via a Lewis-acid-catalyzed intramolecular Prins cyclization of homoallylic acetals 332. Incorporation of a variety of substituents at C-4 of the resulting tetrahydropyrans is possible by simple variation of the reaction conditions (Equation 141, Table 13) <2001CC835>. 

The intermolecular Prins cyclization between ketones and homoallylic alcohols can be catalyzed by mercuric triflate <1999TL1153>. TMSNTf2 is an effective catalyst for the reaction between aldehydes and homoallylic alcohols <2002AGE161>. 

Cyclization of allo-ocimene, using alkali metal amines, may give cycloheptadienes or acyclic dienes depending upon the conditions used 1,2,4-trimethylcyclohepta-1,3-diene may be obtained exclusively with sodium-piperidine, and 2,6-dimethylocta-2,4-diene (predominantly trans) is the major product using sodium-morpholine.129 The Prins formaldehyde reaction on myrcene (12), on the chelo-tropic adduct (42), and on the Diels-Alder adduct (43), has been investigated 130... 

Overman and Pennington have developed a versatile methodology for stereoselective tetrahydrofuran synthesis based on pinacol terminated Prins cyclizations. The general reaction is outlined in Scheme 63. A review on the strategic use of these cascade reactions in natural product synthesis has been published <2003JOC7143>. 

A Prins cyclization is also involved in the reaction of the cyclopropylenynes in equation (72) with AuCl or cationic Au(I) complexes to give tricyclic derivatives with an octahydrocyclobuta[a]pentalene skeleton. The formation of stereoisomers was unexpected and suggests the involvement of cationic intermediates (equation 72). 

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