Aldol Prins reactions

S.2 Domino Processes with the Aldol Reaction as First Step 271 Table 8.2 Domino aldol/Prins reaction toward tetrahydropyran synthesis [7]. 

Scheme 8.5 Domino aldol/Prins reaction of unsaturated enol ethers [8].

Scheme 8.6 Domino Mukaiyama-aldol-Prins reaction of silyl enol ethers and unsaturated acetals [9].

The synthetic strategy is based on Yamaguchi macrolactonization, metal alkynylide addition at C17, Mukaiyama-aldol Prins reaction of vinyl ether 219 with aldehyde 218 forming 2,6-d5-tetrahydropyran, Hosomi-Sakurai reaction giving 2,6-tran5-tetrahydropyran, asymmetric center formation via Myers alkylation at C12 and Noyori reduction at C15 and C3 (Scheme 47). 

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>. 

The transformation of VIII/3 to VIII/4 is called a fragmentation1 [3] [4]. As in the aldol reaction the reverse version of the fragmentation also is known (VIII/4 — VIII/3). An example of this reaction type is the so-called Prins reaction the acid catalyzed (base catalysis is also possible) addition of an olefin to formaldehyde in order to get a 1,3-diol. Further examples are known in the field of transannular reactions in medium-sized rings [5],... 

In the Cannizzaro reaction (62), which involves self-condensation of aldehydes that have no a-hydrogen atoms, the nucleophile is represented best as a hydride ion in the Prins reaction (26), the nucleophile is an olefin in the aldol condensation (63) and reaction of methyl acetate with formaldehyde (62), the nucleophile is a methylene group a- to a... 

Kopecky, D. J., Rychnovsky, S. D. Mukaiyama Aldol-Prins Cyclization Cascade Reaction A Eormal Total Synthesis of Leucascandrolide A. J. Am. Chem. Soc. 2001, 123, 8420-8421. 

The carbon-carbon bond forming step of the Prins reaction, the reaction of an alkene with a carbonyl group (1) - (2), is, in one sense, the most fundamental reaction of synthetic organic chemistry at one extreme it is the base-catalyzed aldol reaction, where the alkene component is an enolate ion and the carbonyl group is unprotonated, and at the other extreme it is the Friedel-Crafts reaction. It is a paradigm for a fast organic reaction both bonds involved in the key step are iT-bonds, which are simultaneously more reactive than o-bonds and more susceptible to modification in reactivity by the presence or absence of substituents on either or both components. It is no wonder that, in one form or another, it is the most frequently used of all carbon-carbon bond forming reactions. 

Rychnovsky reported synthesis of Leighton s macrolide 201 of leucascandrolide A, wherein the key reaction is the Mukaiyama aldol-Prins cascade reaction (Sect. 2.4). In this cascade reaction, oxonium cation, required for the Prins reaction, is prepared by a Lewis acid-mediated Mukaiyama aldol reaction of alkyl vinyl ether with aldehyde. Usually, alkyl vinyl ethers are not suitable for Mukaiyama-aldol, because of oligomerization of the resulting oxonium cation. Rychnovsky resolved this issue by trapping the cation with an intramolecular nucleophile, which resulted in Prins cyclization. 

Mukaiyama-Aldol-Prins (MAP) reaction of silyl enol ethers and aeetals leads to the formation of five-membered ring systems with up to five new chiral centers in a one-pot operation in high yields (Scheme 6.2) [4],... 

In 2001, Rychnovsky and co-workers completed the synthesis of the leucascandrolide macrolactone. The key features of the Rychnovsky s synthesis are the Mukayama aldol-Prins cascade reaction of alkyl enol ether with the aldehyde forming 2,6-cij-tetrahydropyran, and Hosomi-Sakurai allysilane addition to generate 2,6-tranj-tetrahydropyran (Schemes 2.12, 2.13). 

Kopecky and Rychnovsky also targeted leucascandrolide A to demonstrate their Mukaiyama Aldol-Prins (MAP) method (Scheme 38) [78]. The MAP reaction generates an oxocarbenium intermediate from an enol ether and an aldehyde, which is capable of imdergoing a Prins cyclization with the pendant allylsilane. Aldehyde 278 (from Scheme 73, Eq. 1) in the presence of enol ether 142 and boron trifluoride etherate underwent the MAP cascade without incident. The reaction mixture was treated with sodium borohydride to reduce any of the unreacted aldehyde and simplify purification. Desired alcohol 143 was then isolated in 78 % yield as a 5.5 1 mixture of diastereomers. 

Diethyl 3-oxoheptanedioate, for example, is clearly derived from giutaryl and acetic acid synthons (e.g. acetoacetic ester M. Guha, 1973 disconnection 1). Disconnection 2 leads to acrylic and acetoacetic esters as reagents. The dianion of acetoacetic ester could, in prin-ciple,be used as described for acetylacetone (p. 9f.), but the reaction with acrylic ester would inevitably yield by-products from aldol-type side-reactions. 

Another attractive domino approach starts with an aldol reaction of preformed enol ethers and carbonyl compounds as the first step. Rychnovsky and coworkers have found that unsaturated enol ethers such as 2-237 react with different aldehydes 2-238 in the presence of TiBr4. The process consists of an aldol and a Prins-type reaction to give 4-bromotetrahydropyrans 2-239 in good yields, and allows the formation of two new C-C-bonds, one ring and three new stereogenic centers (Scheme 2.56) [131]. In the reaction, only two diastereomers out of eight possible isomers were formed whereby the intermediate carbocation is quenched with a bromide. 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

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