2.3.4- trisubstituted tetrahydropyrans

Interesting intramolecular cyclization of 1-nitroalkyl radicals generated by one-electron oxidation of aci-nitro anions with CAN is reported. As shown in Eq. 5.44, stereoselective formation of 3,4-functionalized tetrahydrofurans is observed.62 l-Nitro-6-heptenyl radicals generated by one electron oxidation of aci-nitroanions with CAN afford 2,3,4-trisubstituted tetrahydropyrans.63 The requisite nitro compounds are prepared by the Michael addition of 3-buten-l-al to nitroalkenes. 

Table 10 Stereoselectivity in Cyclizations to 2,3,5-Trisubstituted Tetrahydropyrans (Equation 42)...

Siloxyallyl)silane 24, acting as a synthetic equivalent of acetone a,a -dianion, readily undergoes double alkylation (equation 15)60. An acid-catalyzed transacetalization-ring closure reaction occurs in the reaction of 6-hydroxy substituted allylsilanes 25 with acetals to afford the corresponding trisubstituted tetrahydropyrans in moderate to good yield with high diastereoselectivity (equation 16)61. 

Triflic acid has been successfully used in the stereocontrolled synthesis of substituted tetrahydropyrans. 2,4,6-Trisubstituted tetrahydropyrans have been synthesized by an intramolecular Prins reaction-pinacol sequence694 [Eq. (5.250)]. 

When Mohr [69] initially published the synthesis of vinyltetrahydropyrans 160 in 1995, the reaction conditions required four to five equivalents of starting acetal 159 per equivalent of allylsilane 158. The condensation was catalyzed by the Bnansted acid p-TSA (Scheme 13.54). The reaction proceeded with excellent stereoselectivity and generally the syw-awh-trisubstituted tetrahydropyran 160 was formed with overwhelming preference. However, 160 proved to be very difficult to purify and was always contaminated by 5% or less of the other three stereoisomers. The yields of the reaction varied from moderate to good. 

Another elegant way leading to tetrahydropyrans 20S was described by Overman et al. [93] In this case, homoallylic alcohol 206 was reacted with various aldehydes in the presence of TfOH to furnish the carbonyl-substituted tetrahydropyrans 205 along with its C4 stereoisomer 207 (Scheme 13.74). The reaction is highly stereoselective and the xyu-2,4,6-trisubstituted tetrahydropyrans 205 were obtained as the major products in good yields. 

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>. 

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>. 

A ceric ammonium nitrate (CAN) mediated stereoselective cyclization of epoxypropyl cinnamyl ethers 352 provides a facile route to 3,4,5-trisubstituted tetrahydropyran derivatives 353 (Equation 149) <2004TL2413>. 

Intramolecular cyclization of the chiral oxime ether 993 in the presence of isopropyl iodide and triethylborane affords the 3,4,5-trisubstituted tetrahydropyran-2-one 994 in poor yield but with good diastereoselectivity (Equation 388) <2003JOG5618>. Similarly, a triethylborane-induced atom transfer radical cyclization of 3-butenyl 2-iodoacetate leads to 4-(iodomethyl)tetrahydropyran-2-one. Higher yields are achieved when conducting the reaction at lower concentrations (Equation 389) <2000JA11041 >. 

Cyclizations. A stereocontrolled synthesis of trisubstituted tetrahydropyrans by condensation of homoallylic alcohols with aldehydes is developed. Treatment of THP ethers derived from unsaturated alcohols with triflic acid leads to oxygen heterocycles. ... 

Lewis acid-catalysed cleavage of the bicyclic acetal (8) with allyltrimethylsilane occurs with 1,3- and 1,6- asymmetric induction arising from the chiral sulfinyl group. The resulting chiral 2,2,5-trisubstituted tetrahydropyran was used to synthesise (-) malyngolide, a marine antibiotic <97CC1755>. 

Triethylsilane can also facilitate the high yielding reductive formation of dialkyl ethers from carbonyls and silyl ethers. For example, the combination of 4-bromobenzaldehyde, trimethylsi-lyl protected benzyl alcohol, and EtsSiH in the presence of catalytic amounts of FeCls will result in the reduction and benzylation of the carbonyl group (eq 32). Similarly, Cu(OTf)2 has been shown to aid EtsSiH in the reductive etherification of variety of carbonyl compounds with w-octyl trimethylsilyl ether to give the alkyl ethers in moderate to good yields. Likewise, TMSOTf catalyzes the conversion of tetrahydrop)ranyl ethers to benzyl ethers with Ets SiH and benzaldehyde, and diphenylmethyl ethers with EtsSiH and diphenylmethyl formate. Symmetrical and unsymmetrical ethers are afforded in good yield from carbonyl compounds with silyl ethers (or alcohols) and EtsSiH catalyzed by bismuth trihalide salts. An intramolecular version of this procedure has been nicely applied to the construction of cA-2,6-di- and trisubstituted tetrahydropyrans. ... 

Waldmann and coworkers " (Scheme 7.12) described the enantioselective synthesis of a library of 2,4,6-trisubstituted tetrahydropyrans by an oxa-Diels-Alder reaction. The corresponding pyrane ring is prevalent in a number of natural products. To access it stereoselectively with a solid-phase synthesis strategy, cycloaddition reaction of Danishefsky s diene 59 with resin-bound aldehydes 58 was carried out in the presence of 5 mol% of the chromium catalyst 63. After the release of resin, the product (61) was... 

As the reaction passes through a six-membered transition state with an equatorial orientation of both substituents, the syn-1,3-configuration is formed with high selectivity. If an a-substituted homoallylalcohol is employed, the all-syn trisubstituted tetrahydropyran is obtained in good yield. 

The first report was ROCM of oxabicycles with styrene (one example of aUyl TBS ether was also reported) to yield the trisubstituted tetrahydropyran products in high enantioselectivities, and, more importantly, up to >98% Z-selectivity (Fig. 25) [58]. It is noteworthy that when a closely related catalyst supported by a more bulky 2,6-diisopropylphenyl imido group (instead of the smaller adamantyl imido as in the catalyst shown) was used, no product was obtained. 

Maezaki, N., Matsumori, Y, Shogaki, T, Soejima, M., Ohishi, H., Tanaka, T, and Iwata, C. (1998) Stereoselective synthesis of a 2,2,5-trisubstituted tetrahydropyran chiron via 1,3- and 1,6-asymmetric induction a total synthesis of (—)-malyngolide. Tetrahedron, 54, 13087-13104. 

Preparation of 2,3-r <.v-2,5-rran.v-trisubstituted ictrahydrofurancs by this methodology is possible, but presents some problems. Cyclization is not stercospccific or results only in tetrahydropyranes because of unfavorable 1,3-inii ractions. Moreover, ring contraction can result in the undesired 2,5-c(.v-diastereomer, even as the major product. 

Rapamycin (sirolimus 2), isolated from Streptomyces hygroscopicus, is a highly functionalized 31-membered macrolide that exhibits potent antibiotic, cytotoxic, and immunosuppressive activity. FK506 (1) and rapamycin (2) are the structurally related macrolides (Fig. 1) thus, rapamycin possesses an a,p-diketoamide hemi-ketal system, a pipecolic acid moiety, 1,2,4-trisubstituted cyclohexane, and trisub-stituted tetrahydropyran rings, which are similar to those of FK506. In addition to these units, rapamycin (2) includes an ( , , )-triene moiety, two stereochemically complex aldol units, and 15 chiral centers beyond those found in FK506. 

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