Clive M. Raynor

Asymmetric Diels–Alder reactions. Part 1. Diastereofacial reactivity of (E)-3-trimethylsilyloxybuta-1,3-dienyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside towards cyclic dienophiles

The title diene (5a) reacted with p-benzoquinone in benzene at ambient temperature to give an 89 : 11 mixture of (1R,6R,10S)-10-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy]-8-trimethylsilyoxybicyclo[4.4.0]deca-3,8-diene-2,5-dione (9a) and its (1S,6S,10R)-diastereoisomer (10a). The stereostructure of the major cycloadduct was established by its conversion into (1R,6R,10S)-10[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy]bicyclo[4.4.0]decane-2,5,8-trione (12), the structure of which was determined by X-ray crystallography. The diene (5a) showed a similar diastereofacial selectivity in its reactions with 2-methoxycarbonyl-p-benzoquinone [to give an 88 : 12 mixture of the cycloadducts (9b) and (10b)], 2-acetyl-p-benzoquinone [to yield a 75 : 25 mixture of the cycloadducts (9c) and (10c)], N-phenylmaleimide [to afford an 86 : 14 mixture of the cycloadducts (15a) and (16a)], maleimide [to produce an 85 : 15 mixture of the cycloadducts (15b) and (16b)], and malefic anhydride [to furnish mainly the cycloadduct (15c)]. In every instance, the major cycloadduct could be isolated in a pure state by crystallisation. Under mildly acidic conditions, it underwent hydrolysis resulting in the conversion of its O-silyl enol moiety into the ketone function. On the basis of c.d. spectroscopy, the ketones (11a–c)[derived from the respective cycloadducts (9a–c)] possessed the same absolute stereochemistry at positions 1, 6, and 10. The ketone (17c), formed by hydrolysis of the cycloadduct (15c), was transformed by the action of aniline and acetic anhydride into the ketone (17a), which was also obtained from the cycloadduct (15a) by hydrolysis. The conformational properties of the cycloadducts and their hydrolysis products were assessed by 300 MHz 1H n.m.r. spectroscopy.

A stereocontrolled cycloaddition route to β-d-glucopyranosyl (1→4)-linked glycals

The facial reactivity of I towards electron-deficient aldehydes can be controlled by Ln(fod)3 catalyst selection, providing the basis of a route to glycals of type II [using Yb(fod)3] or III [using La(fod)3] where R = 4-nitrophenyl, 5-nitrofur-2-yl, or 5-nitrothien-2-yl and R1 = 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside.

Synthesis and allylic reactivity of α-bromomethyl β-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)oxy α,β-unsaturated carbonyl compounds

Abstract Under radical conditions, N -bromosuccinimide converts α-methyl β-(2,3,4,6-tetra- O -acetyl-β- d -glucopyranosyl)oxy α,β-unsaturated carbonyl compounds into their α-bromomethyl derivatives. The bromides undergo nucleophilic displacement reactions without rearrangement with azide, O -ethyl dithiocarbonate and thiocyanate anions; with acetate anion, there is a preference for the formation of rearranged acetates with reasonable stereoselection.

Studies related to anthracyclines. Part 3. Stereoselective synthesis of (+)-daunomycinone

The title compound 2b was prepared by a seven-step sequence from (±)-4a,9a–epoxy-4a,9adihydro-5-methoxyanthracene-1,4,9,10-tetraone 3b/3c and (E)-1-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-trimethylsilyloxybuta-1,3-diene 4. Acidic hydrolysis of the crude Diels–Alder cycloadducts of compounds 3b/3c and 4 led, after fractional crystallisation, to the isolation of (5aS,6aR,7S,1OaR,11aR)-5a,11a-epoxy-4-methoxy-5a,6a,7,8,9,10,10a,11a-octahydro-7-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)naphthacene-5,6,9,11,12-pentaone 6b. The last-cited compound was transformed into (+)-daunomycinone 2b by reduction, ethynylation, oxidation, hydrolysis and hydration steps.

Asymmetric synthesis of (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylic acid and its methyl ester†

Methyl (2E,4E)-5-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)penta-2,4-dienoate 16a, assembled by a Wittig condensation of tributyl(methoxycarbonylmethylene)phosphorane 19a and (2E)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)propenal 20, displays excellent Re-face reactivity towards diethyl azodicarboxylate 15a, bis(2,2,2-trichloroethyl) azodicarboxylate 15b, dibenzyl azodicarboxylate 15c, diisopropyl azodicarboxylate 15d and di-tert-butyl azodicarboxylate 15e in thermal hetero-Diels–Alder reactions to give the cycloadducts 17a–e. When subjected to the action of hydrogen over palladium–carbon, the cycloadducts 17a, 17b, 17d and 17e undergo hydrogenation of their olefinic bonds to give the dihydro derivatives 18a, 18b, 18d and 18e; in the case of the cycloadduct 17c, hydrogenolysis of the benzyloxycarbonyl group also occurs to give methyl (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylate 1b with an ee of 98% and 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose 22. Compound 1b, with an ee of 98%, is also available from the dihydro derivative 18e by the action of trifluoroacetic acid; however, under the acidic conditions, a condensation reaction between the aglycone 1b and the glycone 22 competes to give methyl (3S)-2,3,4,5-tetrahydro-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)pyridazine-3-carboxylate 25.Sodium (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylate 1c, with an ee of 99%, is available from the ester 1b by a saponification reaction. The trifluoroacetic acid salt 27, with an ee of 95%, is obtained from benzyl (3S,6S)-1,2-bis(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-6-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)pyridazine-3-carboxylate 17g by a hydrogenation–trifluoroacetolysis sequence. A hetero-Diels–Alder reaction involving the benzyl pentadienoate 16c and di-tert-butyl azodicarboxylate 15e provides the cycloadduct 17g.

Applications of methylsulfonylsulfene in synthesis. Part 1. Conversion of 3,4-dihydro-2H-pyran into cis-2-(C-substituted)tetrahydropyran-3-sulfonates/sulfinates

(1R*,6S*,8R*)-8-Methylsulfonyl-2-oxa-7-thiabicyclo[4.2.0]octane 7,7-dioxide 10a, available from the reaction of 3,4-dihydro-2H-pyran and methylsulfonylsulfene 1(generated in situ from MeSO2Cl and Et3N), underwent alkylation at position 8 in the presence of sodium hydride and alkyl halides. With methyl iodide and chloromethyl methyl ether, mixtures of the endo- and exo-methyl derivatives 10b and 11b(with 10b in predominance) and the endo- and exo-methoxymethyl derivatives 10c and 11c(with 11c in predominance) were produced. With benzyl chloride, tert-butyl bromoacetate and allyl bromide, only the exo-alkyl derivatives 11d-f were isolated, the stereostructure of compound 11f being established by X-ray crystallography.In the presence of sodium thiophenoxide and thiophenol, compound 10a underwent a reductive cleavage of its S(7)–C(8) bond to give, after acidification, the sulfinic acid 9a; the sodium salt of the last-cited acid underwent methylation with methyl iodide to give (2S*,3S*)-3-methylsulfonyl-2-(methylsulfonylmethyl)tetrahydropyran 15d. Under corresponding conditions (and also in the presence of a large excess of Na/Hg in MeOH), compound 11f afforded the sulfinic acid 27c which was transformed into (2R*,3S*)-3-methylsulfonyl-2-[(1′R*)-1′-(methylsulfonyl)but-3′-enyl]-tetrahydropyran 21d; the stereostructure of the last cited compound was determined by X-ray crystallography. The sulfinic acid 27c also underwent reaction with diazomethane to give the methyl sulfinate 27b as a ∼ 1 : 1 mixture of diastereoisomers.In the presence of Raney nickel, compound 10a furnished (2R*)-2-(methylsulfonylmethyl)-tetrahydrofuran 14 whereas compound 11f underwent reduction of its olefinic linkage to give the propyl derivative 11h.Sodium methoxide in methanol (and also Na/Hg in MeOH) induced an overall hydrolytic cleavage of the S(7)–C(8) bonds of compounds 10a and 11f to give, after acidification, the cis-sulfonic acids 15c and 21b(which were isolated as their methyl esters 15a and 21a). In the presence of sodium hydroxide, the cis-sulfonic acid 15c underwent epimerisation at position 2 to give the trans-sulfonic acid 17c(which was isolated as its methyl ester 17a).

Fluoro-olefin chemistry. Part 18. Thermal reaction of hexafluoropropene with diphenylmethane, butylbenzenes, benzyl alcohol, and benzyl methyl ether

The thermal reaction of hexafluoropropene with diphenylmethane gives the 1 : 1 adduct Ph2CHCF2CHFCF3(4a) and the rearranged adduct PhCH2CF2CFPhCF3(5a)via benzylic hydrogen abstraction. Analogous 1 : 1 adducts are formed from benzyl alcohol in low yield, i.e. PhCH(OH)CF2CHFCF3(4e) and HOCH2CF2CFPhCF3(5b), but the reaction is complicated by decomposition of the alcohol to benzaldehyde, toluene, and water followed by the formation of the toluene–hexafluoropropene adduct PhCH2CF2CHFCF3(4c). A similar decomposition is observed with benzyl methyl ether and compound (4c) is the only fluorinated product isolated. With n-butylbenzene the 1 : 1 adduct PhCHPrnCF2CHFCF3 is formed in relatively low yield due to rearrangement of the intermediate radical PhCHPrnCF2ĊFCF3 by a 1,5-hydrogen shift followed by β-scission to give the radical PhĊHCF2CHFCF3 and propene and hence (4c) and the cyclobutane CF3·[graphic omitted]HMe (8a), respectively. With isobutylbenzene the only 1 : 1 adduct isolated is PhCH2CMe2CF2CHFCF3, although benzylic hydrogen abstraction does occur as shown by the formation of compounds (4c) and (8a). 1 : 1 Adducts are not detected in the products from the reaction with S-butylbenzene; the intermediate radical PhCMeEtCF2ĊFCF3 undergoes (i) cyclisation to give the indan (12), (ii) decomposition to give the olefin CF2:CMeEt and the radical PhĊFCF3 and (iii) rearrangement followed by β-scission to give ethylene and the radical PhĊMeCF2CHFCF3.

Fluoro-olefin chemistry. Part 15. Thermal reaction of hexafluoropropene with hydrocarbon olefins

The thermal reaction of hexafluoropropene with hydrocarbon olefins can give three different types of product, 1,1,2-trifluoro-2-trifluoromethylcyclobutanes, hexafluoroalkenes of the type R1R2CCR3·CH2·CHF·CF2·CF3, and 1,1,2-trifluoro-2-trifluoromethylcyclopentanes. The cyclobutanes are formed via diradical intermediates and the cyclopentanes via intermediate allyl-radical attack on the fluoro-olefin, while the hexafluoroalkenes arise via either of these radical intermediates or by the ‘ene’ reaction. With olefins of the type CH2CHR (R = Me or Et), cyclobutanes are formed exclusively, while those such as CH2CMeR (R = Et or Pri) give both cyclobutanes and hexafluoroalkenes. However, the olefins CH2CMe2, CHMeCMe2, and CMe2CMe2 afford all three types of product, but only with the alkene CHMeCMe2 is cyclopentane-formation a major reaction (29% at 270 °C and 35% at 220 °C). Certain of the reactions are complicated by hydrocarbon-olefin isomerisation.