Prins Reaction Stereoselectivity

The stereochemistry of the Prins reaction is complex. In the transformation of cyclohexene and 2-butenes anti stereoselective addition was observed,67-69 whereas syn addition of two formaldehyde units takes place in the formation of 1,3-dioxanes from substituted styrenes.70 Most of the transformations are, however, nonstereo-selective,71 72 accounted for by carbocation 18. 

The stereoselective total synthesis of ( )-isocycloseychellene was achieved by S.C. Welch and co-workers. One of the key ring forming reactions was an oxidative Prins reaction that took place without the need of a catalyst (carbonyl ene reaction) to afford the desired tricyclic ketone. 

Kocovsky, P., Ahmed, G., SrogI, J., Maikov, A. V., Steele, J. New Lewis-Acidic Molybdenum(ll) and Tungsten(ll) Catalysts for Intramolecular Carbonyl Ene and Prins Reactions. Reversal of the Stereoselectivity of Cyclization of Citronellal. J. Org. Chem. 1999, 64, 2765-2775. 

The formation of tetrahydropyrans by the Prins reaction The oxo-ene mechanism Stereoselectivity in the Prins reaction... 

The next step is a simple electrophilic attack by another molecule of formaldehyde on the alkene - in other words a simple Prins reaction 215 - showing the regioselectivity we expect to produce the secondary benzylic cation 216. The second molecule of formaldehyde has added onto the opposite side from the first. The resulting cation is perfectly placed for an intramolecular Friedel-Crafts alkylation 216 of the benzene ring. This is again a stereoselective reaction giving the more stable anti diastereoisomer 214. This sequence involves three successive C-C bondforming reactions and the stereochemistry is simply controlled by the preference for the more stable anti product. 

The Prins reaction with formaldehyde is a well-known route to prostaglandins using bicyclic lactone 3 as a precursor. One synthesis of this lactone14 started this sequence with a Prins reaction. Treatment of norbomadiene with paraformaldehyde in the presence of formic acid produced a mixture of epimeric diformates in 67% yield which were transformed in several steps into lactone 3. A second synthesis starts with the unsaturated bicyclic lactone which undergoes attack by the oxonium ion both regio- and stereoselectively from the less hindered face of the double bond, trims Addition of the nucleophilic acetate generates the lactone 3 as the bisacetate derivative15. 

A stereoselective Prins reaction of the estradiol derivative leads exclusively to the 7 -hydroxy-methyl products36. 

The process from the FMC company involves as the pivotal step an intramolecular stereoselective [2 + 1 [-cycloaddition. In a Prins reaction [94] of chloral and isobutene, followed by an isomerisation, a racemic, trichloromethyl-substituted aUyl alcohol is obtained. Reaction with the isocyanate from (R)-naphthylethyl-amine enables separation ofthe diastereomers by crystallisation. The carbamate is cleaved by trichlorosilane/triethylamine, thus permitting the recycling of the chiral auxiliary. The optically pure (R)-aUyl alcohol is reacted with diketene, to produce the / -keto-ester. After diazo transfer and basic cleavage, the diazoacetate is obtained catalysed by a copper salt, this is converted in a [2 + 1 ]-cyclo-addition into a bicyclic lactone. The Boord reaction (discovered by Cecil E. Boord in 1930) [95] finally gives (IR)-cis-permethric acid. [96]... 

The 2,6-czs-dihydropyran 340 was synthesized by the Panek-modified Prins reaction between the chiral aldehyde 338 and the chiral syn-allylsilane 339 mediated by triflic acid. The key point of the stereoselectivity is the sterically hindered electron-withdrawing mesylsulfonate, which induced the chair-like transition state 341. Cyanation, regioselective oxymercuration, and... 

The implementation of the two mechanisms corresponds to the experimental data on a stereoselective Prins reaction for a series of cycloalkenes [13]. 

The implementation of the two mechanisms corresponds to the experimental data on a stereoselective Prins reaction for a series of cycloalkenes [15], However, the role of formaldehyde oligomers in the Prins reaction and its reactivity in addition to the alkenes with various structures are still poorly described. 

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... 

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>. 

Oxidative cyclization of/1-citronellol leads to isopulegone (12) stereoselectively after attack of the olefin at the least hindered face of the resulting six-membered ring17 where both alkyl substituents are in equatorial positions. (Analogous to oxidative Prins cyclization, Section 1.5.5.2.2.1., or to the carbonyl ene reaction. Section D. 1.6.2.)... 

Highly functionalized tetrahydropyran-4-ones can be obtained through a silyl enol ether Prins cyclization promoted by a condensation reaction of hydroxy silyl enol ethers with Lewis-acid-activated aldehydes, with high diastereoselectivity (14JOC8733). Spirooxindole tetrahydropyran-4-ones are obtained from oxa-DA reaction of acyclic a,P-unsaturated methylke-tones and isatins mediated by a bifunctional enamine-metal Lewis acid catalyst, in good yields and moderate stereoselectivities (14S1339). 

Tosylhydrazones such as (149), containing a suitably disposed olefinic group, cyclize to bicyclic azo-compounds [e.g. (150)] on treatment with boron trifluoride etherate. The allyl silanes (151) and (152) each undergo a highly stereoselective Prins-type reaction on treatment with trifluoroacetic acid, whereas other acid catalysts give mixtures. ... 

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