Saturated oxygen heterocycles CHRISTOPHER J. BURNS Pfizer Central Research, Sandwich, Kent CT13 9NJ Reviewing the literature published between January 1992 and March 1993 1 2 3 3.1 3.2 4 4.1 4.2 5 6 T hree-membered rings Four-membered rings Five-membered rings Tetrahydrofurans Dihydrofurans Six-membered rings Tetrahydropyrans Dihydropyrans Medium and large ring ethers References 1 Three-membered rings Significant progress has been made in the synthesis of chiral epoxides from unfunctionalized olefins. Kolb and Sharpless have shown that chiral vicinal diols, prepared by Sharpless' asymmetric dihydroxylation protoco1,l can be efficiently converted into chiral epoxides via a three-step one-pot procedure.2 Thus, the diol 1 yields the epoxide 4 via the intermediate acetoxy bromides 2 and 3 in 83% overall yield.In related work the protected chiral glyceraldehyde epoxide 6 was prepared from the chiral diol5 by mono-tosylation and subsequent base-promoted cy~lization.~ An analogous one-pot procedure has been reported by Rao and co-workers wherein treatment of the diol7 with a mixture of tosyl chloride and sodium hydride affords the enantiomerically pure epoxide 8 in 72% yield.4 5 6 7 8 Of numerous reports detailing the use of molecular oxygen as oxidant in epoxidations, the work of the group of Kaneda is particularly n~teworthy.~ They have shown that a combination of molecular oxygen and an aldehyde, particularly pivalaldehyde, efficiently epoxidizes olefins, as exemplified by the formation of the epoxide 10 from 2-methyl-1-pentene 9.Molecular oxygen has also been used in the synthesis of epoxy-alcohols directly from vinyl silanes.6 Thus, photo-oxygenation of the vinyl silane 11 followed by treatment with titanium tetra-isopropoxide gave the product 12 in 59% overall yield. Caubere and his co-workers have shown that a combination of hydrogen peroxide and sodium tungstate under phase transfer conditions is the method of choice for the epoxidation of olefins containing the sensitive methacrylate m~iety.~ Using this method the epoxide 14, for example, could be generated from ally1 methacrylate 13 in good yield. Cooke and Lindsay Smith have reported the use of polymer bound iron ( 111) tetra( 2,6-dichloro- pheny1)porphyrin (Fe'" TDCPP) as an efficient catalyst in the epoxidation of cyclooctene 15.8 The procedure Burns: Saturated oxygen heterocycles 23uses iodosylbenzene as the oxidant, with a catalyst turnover of 7900, giving the epoxide 16.15 16 2 Four-membered rings Saksena et al. have reported a much improved route to substituted oxetane-2-carboxylic acids.' Thus, they have demonstrated that ring contraction of a furanone bearing a mesylate at the three position can be affected in aqueous base, as shown in the preparation of the oxetane 18 from the glucose-derived lactone 17. The [2 + 21 photocycloaddition between a 2-substituted furan and an aldehyde generally gives a mixture of regioisomeric bicyclic oxetanes. Cartess and Halfhide have now shown, however, that 2-acetylfuran 19 undergoes highly regioselective [ 2 + 21 cycloadditions, with the reactions occurring on the more substituted furan double bond, as exemplified by the reaction of 19 with p-cyanobenzaldehyde 20 leading to the bicycle 2 1.l0 C H ~ O M ~ 18 19 H 21 a,B-Epoxy diazomethylketones have been shown to yield oxetanones on treatment with tin tetrachloride.' The reaction proceeds through a chlorohydrin intermediate 23 (which in certain instances can be isolated) as shown in the transformation of 22 to the product 24.r 1 22 L 23 J 0 24 3 Five-membered rings 3.1 Tetrahydrofurans Progress in the synthesis of natural and unnatural furanosides has been partly covered in a review (3 17 references) entitled 'AIDS-Driven Nucleoside Chemistry',12 while the applications of palladium (11) catalysis in tetrahydrofuran synthesis has been reviewed (54 references) by Hosokawa and Murahashi.13 The use of free-radical chemistry to gain access to substituted tetrahydrofurans continues to be an active area of research.For example, Dalla and Pale, have reported the first synthesis of spiroketals using a free-radical approach, wherein a 2-methylene tetrahydrofuran 25 is converted in two steps via the iodide 26 into the spirocycle 27 in good yield.I4 The addition of tributyltin hydride to carbohydrate derived propargyl ethers has been shown to be an efficient route into fused bicyclic ketals.15 The conversion of 28 into 29 is representative, though in some instances a mixture of E and 2 isomers of the vinyl stannane product results. 25 26 Bu3SnH 1 27 ACO e b 0 PhH 75% H Bu3SnH I BuBSn 28 29 A highly regioselective [ 3 + 41 annulation reaction for the synthesis of bridged cyclic ethers has been reported by Molander and Cameron.16 Thus, the bis(trimethylsily1) enol ether 30 adds to the diketones 3 1 under Lewis acid catalysis to give the product ethers 32 in fair to excellent yields. 32 Wender et al.have extended their work on [ 5 + 21 cycloaddition reactions and shown that the pyrylium salt 33 reacts with dimethyl acetylenedicarboxylate, in 24 Contemporary Organic Syntheskthe presence of base, to provide the cyclic ether 34.17 The aqueous Diels-Alder reaction between the arylfuran 35 and dimethyl acetylenedicarboxylate offers a highly efficient route to the cyclic ether 36 which has then been converted in several steps into the unusual antifungal agent 37.'* 33 73% 0 I CI 35 CI / CI 36 Iodoetherifications and related processes continue to offer efficient routes to tetrahydrofuran derivatives. Thus, Knight and his group have shown that E-homoallylic alcohols readily cyclize to trans- iodotetrahydrofurans in anhydrous acetonitrile, as exemplified by the formation of 39 from 38; the corresponding 2-homoallylic alcohols furnish the cis products.' Interestingly, the 2-hydroxyalkenoates 40 cyclize under identical conditions to give the hydroxytetrahydrofurans 42, presumably via the intermediate orthoester 4 1 .20 38 39 r 1 40 L 41 1 RH& C02Me 42 Beebe et al.have shown that the polymer-bound isoxazole 44 liberates the tetrahydrofuran 45 upon treatment with iodine monochloride, regenerating in the process the starting aldehyde 43.21 Treatment of y-silyloxyallenes 4 6 with N-iodosuccinimide has been shown to efficiently generate iodovinyl tetrahydrofuran derivatives 47, with the cis isomer predominating by greater than nine to one.22 0 TMSO II I p--- 43 44 N C y J - 1 45 Acetone > 8796 46 47 In a synthetic process related to iodoetherification, Mikami and Shimizu have shown that the bis-homoallylic silyl ether 48 undergoes an intramolecular cyclization on treatment with methyl glyoxylate and tin tetrachloride to provide the substituted tetrahydrofuran 49.23 Another interesting route to highly functionalized tetrahydrofurans, e.g.5 1, involves the treatment of the protected polyol benzyl ether 50 bearing a leaving group at the y-carbon with very mild acid.24 40 O x b ' O x 0 50 Kennedy and Tang have shown that treatment of 5-hydroxyalkenes with rhenium (WI) oxide is an efficient route to 2-hydro~ymethyl-tetrahydrofurans.~~ Thus, for example, the tetrahydrofuran 53 is formed in 86% yield from the hydroxyalkene 52, with oxidative cyclization occurring stereospecifically syn to the double bond.26 .. 53 88% 52 Burns: Saturated oxygen heterocycles 25A novel three component palladium catalysed process for the synthesis of 2-alkylidene-tetrahydrofurans has been reported by Luo and a~sociates.~~ The reaction presumably proceeds through the vinylpalladium intermediate 55, as shown for the synthesis of 56 from the hydroxy acetylene 54. 54 Ph 55 of the protected oxazine 62 with lithium diisopropylamide generates the dihydrofuran 63 in 63% yield.62 63 The tungsten 11 '-propynyl compound 64 has been shown to react with a range of aldehydes leading to the cyclized intermediates 65, which can then be demetallated in reasonable yields to provide the corresponding dihydrofurans 66.31 r 56 Clark has shown that copper acetylacetonate is the catalyst of choice for the conversion of the a-diazo ketone 57 into the trans-furanone 59, a reaction which appears to proceed through the metal-bound ylide 58.28 Crandall et al. have extended their earlier work on the epoxidation of allenes and demonstrated that the hydroxy-allene 60 can be converted into the hydroxyfuranone 6 1 on treatment with dimethyldioxirane.2Y \ 66 Ozaki and co-workers have demonstrated that the nickel (11) catalyst 68 can induce intramolecular free-radical cyclization reactions under electrochemical condition^;^^ the synthesis of the dihydrobenzofuran 69 from the ally1 ether 67 in 75% yield is representative of the procedure.0 60 61 3.2 Dihydrofurans Desai and co-workers have uncovered an interesting base-induced rearrangement reaction of 3,6-dihydro- 1,2-0xazines which provides an efficent route to 2-amin0-2,5-dihydrofurans.~~ Thus, treatment L 65 64 57 59 67 75% 69 4 Six-membered rings 4.1 Tetrahydropyrans A highly stereoselective route to cis-2,6-disubstituted tetrahydropyrans has been reported by Mandai and co-workers, whereby intramolecular addition of an hydroxyl to an a,#?-unsaturated sulfoxide proceeds under thermodynamic c0nditions.3~ The product sulfoxide 7 1 can then be converted into the corresponding alcohol, as shown in the overall transformation of 70 into the pyran 72.26 Contemporary Organic Synthesis70 n NaOAc 83% overall 72 Mark6 et al. have developed an efficient one-pot synthesis of tetrahydropyrans based on an intramolecular Sakurai reaction.34 Thus, reaction of the allylsilane 73 with ketones (or aldehydes) 74 leads to the pyrans 76 presumably via the oxonium cation 75. The isomeric 3-methylene-tetrahydropyrans can be prepared in a two-step, one-pot reaction sequence reported by Klumpp and his Addition of the ally1 Grignard reagent 77 to cyclopentene oxide 78 first affords the intermediate 79 which then undergoes palladium catalysed cyclization to the desired pyran 80. THF 77 7s 1 R b 76 H 80 4.2 Dihydropyrans The syntheses of dihydropyrans via hetero Diels-Alder reactions offers a rapid entry into this ring system. Dujardin, Molato, and Brown have undertaken a systematic investigation of the europium catalysed Diels-Alder reaction of the pyruvate 8 1 with numerous chiral enol ethers, and have shown that use of the chiral en01 ether 82 gives the best asymmetric induction (d.e.72%) affording the endo-product 83 in a highly endo selective reaction.36 Tietze and 81 8 3 0 Schneider have demonstrated that reaction of the en01 ether 84 with the heterodiene 85 can be controlled to give either the ex0 or endo product.37 Thus, the reaction catalysed by the strong Lewis acid tin tetrachloride gives the ex0 product 86 in 86% yield, whereas trimethylsilyl triflate as catalyst affords the corresponding endo adduct. Phenylboric acid has been shown to catalyse the hetero Diels-Alder reaction of citronellal88 with activated phenols.38 The reaction is presumed to proceed through a quinone methide intermediate such as 89, as shown in the synthesis of 90 from the phenol 87.0 a4 71% 87 6Et 86 89 The use of molybdenum carbene complexes in the synthesis of dihydropyrans has been reported by Harvey and Brown,39 as exemplified in the synthesis of the dihydropyran 93 via the intermediate 92, on thermolysis of the Fischer carbene complex 9 1. Bums: Saturated oxygen heterocycles 27r 1 91 L 92 J 1 ola 93 Tsai and his co-workers have reported a novel cyclization process using acylsilanes to generate 2-~ilyldihydropyrans.4~ Thus, simply heating the 6-bromo acylsilane 94 in N-methylpyrrolidine yields the dihydropyran 95 in 83% yield.0 I 95 5 Medium and large ring ethers Berger and Overman have reported a simple route to oxepenes bearing an halogenated side chain at the two position, via a Prins-type cyclization.4l The reaction yields only the czk-2,7-disubstituted oxepene, as a mixture of stereoisomers at the halogen bearing carbon, as shown for the synthesis of 97 from the mixed ketal96. Boeckman and his co-workers have described an elegant entry into seven- and eight-membered cyclic ethers based on an intramolecular retro-Claisen rearrangement of substituted cycl~propanes.~~ Thus, oxidation of the cyclopropane diols 98 with Dess-Martin reagent provided the desired products 99 in fair to excellent yield. 98 99 An interesting free-radical ring-expansion approach to oxepenes has been reported by Marples et al.whereby treatment of the thiocarbonylimidazolide 100 with tributyltin hydride gives the ring expanded product 102 via the oxiranyl radical 101.43 Moody et al. have shown that the intramolecular Wadsworth-Emmons reaction of the ketone phosphonate 103 affords the cyclic en01 ether 104 in 47% yieid.44 Ph 102 6 References 1 K.B. Sharpless, W. Amberg, Y.L. Bennani, G.A. Crkpho, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.M. Wang, D. Xu, and X.-L. Zhang, J. 0%. Chem., 1992,57, 2768. 2 H.C. Kolb and K.B. Sharpless, Tetrahedron, 1992,48, 10515. 3 R. Oi and K.B. 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