Stereoselective tetrahydropyrans

Scheme 14.3 Stereoselective tetrahydropyran synthesis by a domino oxa-Michael-Tsuji-Trost reaction, (a) Substrate scope, (b) Generation of tetrasubstituted carbon...

In order to overcome the special problems posed by brevetoxin B s tetrahydropyran systems, the decision was made to develop and test regio- and stereoselective ring closures employing two types of substrates hydroxy epoxides and hydroxy a,/ -unsaturated esters. The basic concepts of these reactions are shown in Schemes 1 and 2, respectively. 

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

Loh and coworkers used a combination of a carbonyl-ene and an oxenium-ene reaction for the synthesis of annulated tetrahydropyrans 1-61, using methylenecyclo-hexane 1-60 as substrates (Scheme 1.16) [15]. The most appropriate catalyst for this reaction with the aldehydes 1-59 turned out to be In(OTf)3, which furnished the desired products in good to excellent yields and high stereoselectivity [16]. 

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. 

If the side chain with the nucleophile is situated in the 1-position of the conjugated diene, a palladium-catalyzed spirocyclization occurs. In this case stereoselective oxa-spirocyclizations were obtained from the diene alcohols 59 and 60 (equation 23 -25)58. The reaction worked well for the formation of a tetrahydrofuran and tetrahydropyran in the spirocyclization. In the absence of chloride ions 59 gave high yields of the acetoxy oxaspirocyclic compound 61 via a 1,4-anti addition across the diene (equation 23). In the presence of stoichiometric amounts of LiCl a 1,4-syn oxychlorination took place and allylic chloride 62 was obtained (equation 24). Under chloride-free conditions, cyclohep-tadiene alcohol 60 afforded oxaspirocyclic acetate 63 (equation 25). 

The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) , whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the ci s-2,6-disubstituted tetrahydropyran (Scheme 16) . 

Several recent reviews have included specific types of electrophilic cyclofunctionalization reactions.1 Important areas covered in these reviews are halolactonization u cyclofunctionalization of unsaturated hydroxy compounds to form tetrahydrofurans and tetrahydropyrans lb cyclofunctionalization of unsaturated amino compounds lc cyclofunctionalization of unsaturated sulfur and phosphorus compounds ld lf electrophilic heterocyclization of unconjugated dienes 1 synthesis of y-butyrolactones 1 h synthesis of functionalized dihydro- and tetrahydro-furans lj cyclofunctionalization using selenium reagents lk lm stereocontrol in synthesis of acyclic systems 1" stereoselectivity in cyclofunctionalizations lP and cyclofunctionalizations in the synthesis of a-methylenelactones.lq Previous reference works have also addressed this topic.2... 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

The effect of the nature of the electrophile on the stereoselectivity of reactions with substrates containing a terminal alkene and an allylic substituent is dramatically illustrated by some recent results with palladium electrophiles.124 Cyclizations of 3-methyl- or 3-phenyl-5-hydroxyalkenes with palladium catalysts proceed with high selectivity (>9 1) for the 2,3-trans isomer (equation 41).50-124 It is suggested that the steric interactions of the palladium-alkene complex affects the stereochemistry of these cyclizations. In some related cyclizations to form tetrahydropyran products (equation 42 and Table 10), reaction with iodine in the presence of sodium bicarbonate gives a different major diastereomer from cyclization with mercury(II) trifluoroacetate or palladium chloride.123... 

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

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... 

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. 

Closer examination of tetrahydropyrans 173 clearly reveals that two molecules of aldehyde 174 have been appended onto allylsilane 171 via a novel three-component coupling reaction. Marko et al. proposed the mechanism depicted in Scheme 13.61 [65], Formation of heterocycles 173 is described as a sequence of two processes an initial ene-type reaction [80] which leads to alcohol 177 via the chair-like transition state 176, in which both the aldehydic R-group and the OTMS substituent assume an equatorial position. The high regio- and stereoselectivity observed in this ene-reaction can be nicely explained by considering the stabilizing /(-silicon effect and the repulsive 1,3-diaxial interactions. Transition state 176 contains no 1,3-diaxial interactions and benefits fully from the stabilizing /(-silicon effect [81, 82] (for more detailed transition-state discussion see ref. [63]). 

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. 

The stereoselective formation of spiroketals 242 can be explained in terms of the thermodynamic stability of the three possible products. Oxonium cation 245, formed by the condensation of ortholactone 244b and allylsilyl ether 106a, is in equilibrium with the starting materials. Spiroketal 242 also equilibrates under the reaction conditions with the other anomers. The thermodynamically more stable product 242b, stabilized by a double anomeric effect, is obtained as the only product of the reaction (Scheme 13.89) as the substituents attempt to occupy equatorial positions in the newly generated tetrahydropyran ring. 

A Lewis-acid-mediated intramolecular cyclization of allenyl stannane 344 furnishes 2,6- //-tetrahydropyran as the major product, the stereochemistry of which can be switched to syn with moderate effect if a propargylstannane 345 is used as a substrate (Equation 147, Table 16) <1996TL3059>. The stereoselectivity observed in an analogous system, the intramolecular cyclization of y-alkoxyallyl stannanes 346 with a tethered aldehyde, can be controlled by changing the geometry of the alkene (Scheme 83) <1997JOC7439>. y-Alkoxyallyl stannanes are also known to cyclize both diastereoselectively and enantioselectivity, by incorporation of both a chiral auxiliary and a chiral catalyst respectively into the reaction <1999JOC4901>. 

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>. 

Treatment of (Z)-A-(4-nitrobenzyl)benzimidoyl chloride with base generates the nitrile ylide 1018, which undergoes a 1,3-dipolar cycloaddition with 5,6-dihydropyran-2-one to afford the exo-adduct tetrahydropyran-2-one 1019 as the exclusive product (Scheme 264) <1998T11613>. A 1,3-dipolar cycloaddition of a chiral cyclic nitrone with 5,6-dihydropyran-2-one proceeds with high stereoselectivity to the co-tetrahydropyran-2-one <2000TA2015, 2001TA3163>. 

The reductive lithiation of substituted tetrahydropyrans such as 82 is stereoselective, producing principally the axial organolithium at -78 °C.81 Since reductive lithiation proceeds by fast reduction of a more slowly formed radical, the stereochemical outcome of the reaction... 

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