Tetrahydropyrans synthesis processes

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

Metal-activated alkene additions can be classified as stoichiometric or catalytic processes. Stoichiometric processes for THP synthesis typically involve the use of mercury(II) salts and to a lesser extent iodo and seleno reagents. The progress of intramolecular oxymercuration is determined by the stabiUty of the cationic intermediates. Product stereochemistry is under substrate control and usually leads to the thermodynamically more stable THP product. Catalytic variations generally involve palladium complexes [44], but other transition metals are becoming more common (e.g., Pt [45], Ag [46], Sn [47], Ce [48]). The oxidation state of Pd determines the catalyst reactivity. Palladium(O) complexes are nucleophilic and participate in tetrahydropyran synthesis through jt-allyl cation intermediates, whereas Pd(II) complexes possess electrophilic character and progress through a reversible t-complex. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Tetrahydropyrans 182, formed by this process, proved to be highly valuable intermediates for the synthesis of 2,3,4,6-tetrasubstituted tetrahydropyrans. Indeed, the exo-methylene double bond can be easily transformed, with high stereocontrol, into a variety of useful functionalities. For example, Marko et al. used this approach during the total synthesis of pseudomonic acid analogue (Scheme 13.65) [49]. 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

The natural insect poison (+)-pederine (14) continues to attract interest. One useful intermediate in its synthesis, pederol dibenzoate (12), has been synthesized in several steps from (SH-)-malic acid,30 while the tetrahydropyran-2-acetamide part of pederine has been synthesized in a multistage process reduction... 

Another natural product synthesis features that of a key domino ene-yne coupling/Michael reaction to a tetrahydropyran ring (Scheme 7.29) [22]. An in-depth Trost domino ene-yne/oxa-Michael reaction methodology process was first carried out prior to using the key substrates 143 and 144, with [CpRu(MeCN)3]PFg 145 as the catalyst The product 146 contained almost all the carbons of the natural product target (—)-exiguolide as well as most of its asymmetric centers. 

Of the numerous coimections for the construction of THP rings, 01-C2 bond formation has proven to be an efficient, stereochemically predictable, and reliable approach. Such methods encompass Sn2 and SnI nucleophilic addition, conjugate addition, metal-promoted, and dehydrative cyclizations as represented in Scheme 1. This section will only cover those processes that produce tetrahydropyrans (Scheme 1, Eqs. 1 ). As such, the common 01-C2 closure by dehydration of 5-hydroxy ketones to give dihydropyrans will not be discussed (Scheme 1, Eq. 5). The goal of this section is to highlight methods used for the stereoselective construction of tetrahydropyrans in the context of complex natural product synthesis. 

Kopach M.E., Murray M.E., Braden T.M., Kobierski M.E., Williams O.L. Rractical synthesis of chiral 2-morpholine (4-benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl)methanone mesylate, a useful pharmaceutical intermediate. Org. Process Res. Dev. 2009 13(2) 152-160. 

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