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Notes: Electrochemical Oxidation of (S)-Malic-Acid Derivatives: a Route to Enantiomerically Pure Alkylmalonaldehydic EstersThe 3,3-dialkymalic-acid diesters, prepared by the previously described diastereoselective alkylations through dilithium alkoxide enolates, are saponified to the monoesters containing a free α-hydroxycarboxylic-acid moiety(Scheme 3). The monoesters are subjected to electrochemical oxidative decarboxylation in MeOH. If the intermediate monoacids are purified, the malonaldehydic esters (2-formy1-2-alkylcaroxylates) Obtained by this procedure are enantiomerically pure; they have the same structural features, i.e. two enantiotopic functionalized branches on the (persubstituted) stereogenic center, as the well known 3-hydroxy-2-methylpropanoic acid (‘Roche acid’) which was employed frequently as a starting material for the preparation of either enantiomer of various target molecules.

Notes: Furanoid and pyranoid glyconothio-O-lactones were prepared by photolysis of S-phenacyl thioglycosides or by thermolysis of S-glycosyl thiosulfinates, which gave better results than the thionation of glyconolactones with Lawesson's reagent. Thermolysis of the thiosulfinates obtained from the dimannofuranosyl disulfide 7 or the manofuranosyl methly disulfide 8 (Scheme 2) gave low yields of the thio-O-lactone 2. However, photolysis of the S-phenacyl thioglycoside 6 obtained by in situ alkylation of the thiolato anion derived from 5 led in 78-89% to 2. Similarly, the dithiocarbonate 10 was transformed, via 11a, into the ribo-thio-O-lactone 12 (79%). Thermolysis of the peracetylated thiosulfinates 14 (Scheme 3) led to the intermediate thio-O-lactone 15, which underwent facile β-elimination of AcOH (→ 16, 75%) during chromatography. The perbenzylated S-glucopyranosyl dithiocarbonate 18 (Scheme 4) was transformed either into the S-phenacyl thioglucoside 19 or into a mixture of the anomeric methyl disulfides 21a/b. Whereas the photolysis of 19 led in moderate yield to 2-deoxy-thio-O-lactone 20, oxidation of 21b and thermolysis of resulting thiosulfinates gave the thio-O-lactone 4 (79%), which was transformed into 20 (36%) upon photolysis. The pyranoid manno-thio-O-lactone 26 was prepared in the same way and in good yields from 22 via the dithiocarbonate 24b and the disulfide 25. The ring conformations of the δ-thio-O-lactones, flattened 4C1 for 15 and 4 and B2,5 for 26, are similar to the ones of the O-analogous oxo-glyconolactones. The reaction of 2 (Scheme 5) with MeLi and then with MeI gave the thioglycoside 27 (29%) and the dimeric thio-O-lactone 29 (47%). The analogous treatment of 2 with lithium dimethylcuprate (LiCuMe2) and MeI led to a 4:1 mixture (47%) of 31 and 27. The structure of 2 was proven by an X-ray analysis, and the configuration at C(6) and C(5) of 29 was deduced from NOE experiments. Substitution of MeI by CD3I led to the CD3S analogues of 27, 29, and 31, i.e. 28, 30, and 32, respectively, evidencing carbophilic addition and ‘exo’-attack on 2 by MeLi and the enethiolato anion derived from 2. The preferred ‘endo’-attack of LiCuMe2 is rationalized by postulating a single-electron transfer and a diastereoselective pyramidalization of the intermediate radical anion.

Notes: Glycosylsulfenyl snf (Glycosylthio) sulfenyl Halides (Halogeno and Halogenothio 1-Thioglycosides, Resp.): Preparation and Reaction with AlkenesThe disulfides 11-17 and 20 were prepared from 7, 9, and 18 via the dithiocarbonates 8, 10, and 19, respectively (Scheme 2). The structure of 11 and of 13 was established by X-ray analysis. Chlorolysis (SO2Cl2) of 11 gave mostly the sulfenyl chloride 24, characterized as the sulfenamide 26, a small amount of 21, characterized as the (glycosylthio)sulfenamide 23, and the glycosyl chloride 27 (Scheme 3). Bromolysis of 11 followed by treatment of the crude with PhNH2 yielded only 28. Chlorolysis of the diglycosyl disulfide 13, however, gave mostly the (glycosylthio)sulfenyl chloride 21 and 27, besides 24. Bromolysis of 13 (→22 and traces of 25) followed by treatment with PhNH2 gave an even higher proportion of 23. Similarly, 20 led to 29 and hence to 30. In solution (CH2Cl2), the sulfenyl chloride 24 decomposes faster than the (thio)sulfenyl chloride 21, and both interconvert. Addition of crude 24 to styrene (-78°) yielded the chloro-sulfide 31 and some 37, both in low yields. The product of the addition of 24 to l-methylcyclohexene was transformed into the triol 32. Silyl ethers of allylic alcohols reacted with 24 only at room temperature, yielding, after desilylation, isomer mixtures 33 and 34, and pure 35. Much higher yields were achieved for the addition of (thio)sulfenyl halides yielding halogeno-disulfides. Good diastereoselctivites were only obtained with 21, its cyclohexylidene-protected analogue, and 22, and this only in the addition to styrene (→36, 37, 38), to (E)-disubstituted alkenes (→46, 48, 49a/b, 50a/b, 53), and to trisubstituted alkenes (→47, 51, 52, 54, 55). Other monosubstituted alkenes (→41-45) and (Z)-hex-2-ene (→49c/d,50c/d) reacted with low diastereoselectivities. Where structurally possible, a stereospecific trans-addition was observed; regioselectivity was observed in the addition to mono- and trisubstituted alkenes and to derivatives of allyl alcohols. The absolute configuration of the 2-chloro-disulfides was either established by X-ray analysis (47a) or determined by transforming (LiAlH4) the chloro-disulfides into known thiiranes (Scheme 5). Thus, 37, 48, and the mixture of 49a/b and 50a/b gave the thiiranes 56, 61, and 64, respectively, in good-to-acceptable yields (Scheme 5). Harsher conditions transformed 56 into the thiols 57 and 58. Similarly, 61 gave 62. The enantiomeric excesses of these thiols were determined by GC analysis of their esters obtained with (-)-camphanoyl chloride. Addition of 21 to {[(E)-hex-2-enyl]oxy}trimethylsilane, followed by LiAlH4 reduction and desilylation, gave the known 66 (63%, e.e. 74%). The diastereoselectivity of the addition of 21 to trans-disubstituted and trisubstituted alkenes is rationalized by assuming a preferred conformation of the (thio)sulfenyl chloride and destabilizing steric interactions with one of the alkene substituents, while the diastereoselectivity of the addition to styrene is explained by postulating a stabilizing interaction between the phenyl ring and the C(1)-S substituent (Fig.4).

Notes: The addition of dienes, diazomethane, and carbenoids to the manno- and ribo-configurated thio-γ-O-lactones 1 and 2 was investigated. Thus, 1 (Scheme 1) reacted with 2,3-dimethylbutadiene (→ 4, 73%), cyclopentadiene (→ 5a/b 1:1, 70%), cyclohexa- 1,3-diene (→ 9a/b 2:3, 92%), and the electron-rich butadiene 6(→7a/b 3:1, 82%). Wheras 5a/b was separated by flash chromatography, 7a/b was desilylated leading to the thiapyranone 8. Selective hydrolysis of one isopropylidene group of 9a/b and flash chromatography gave 10a and 10b. The structures of the adducts were elucidated by X-ray analysis (4), by NOE experiments (4, 5a, 5b, 7a/b, 10a, and 10b), and on the basis of a homoallylic coupling (7a/b). The additions occurred selectively from the ‘exo’ -side of1. Only a weak preference for the ‘endo’-adducts was observed. Hydrogenation of 9a/b with Raney-Ni (EtOH, room temperature) gave the thiabicyclo [2.2.2]octane 11. Under harsher conditions (dioxane, 110°), 9a/b was reduced to the cyclohexyl ß-DC-glycoside 12 which was deprotected to 13. X-Ray analysis of 13 proved that the desulfuration occurred with inversion of the anomeric configuration. The regioselective addition of the dihydropyridine 14 to 1 (Scheme 2) and the methanolysis of the crude adduct 15 gave the lactams 16a (32%) and 16b (38%). Desilylation of 15 with Bu4NF · 3H2O, however, gave the unsaturated piperidinedione 17 (92%) which was deprotected to the tetrol 18 (65%). Similarly, 2 was transformed via 19 (62%) into the triol 20 (74%). The cycloaddition of 1 with CH2N2 (Scheme 3) gave a 35:65 mixture of the 2,5-dihydro- 1,3,4-triazole 21and the crystalline 4,5-dihydro 1,2,3-triazole 22. Treatment of 21 and 22 with base gave the hydroxytriazoles 23 and 24, respectively. The structure of 24 was established by X-ray analysis. The triazole mixture 21/22 was separated by prep. HPLC at 5°. At room temperature, 21 already decomposed (half-life 21.6 h) leading in CDCI3 solution to a complex mixture (containing ca. 20-25% of the spirothiirane 27 and ca. 7-10% of its anomer) and in MeOH solution exclusively to the O,O,S-ortholactone 26. Crystals of 22 proved be stable at 105°. Upon heating in petroleum ether at 100°, 22 was transformed into a ca. 1:1 mixture of 27 and the enol ether 28. The reaction of 1 with ethyl diazoacetate (Scheme 4) in the presence of Rh2(OAc)4. 2H2O gave the unsaturated esters 29 (33%) and 30 (26%), whereas the analogous reaction with diethyl diazomalonate afforded the spirothiirane 31 (68%) and the enol ether 32 (29%). Complete transformation of 31 into 32 was achieved by the treatment with P(NEt2)3. Similary, 33 (69%) was prepared from 2.