Sulfoxides, alkyl reduction

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

However, the 0-alkyl derivatives are potentially unstable with respect to thermal elimination of a carbonyl compound and consequent reduction to the corresponding lactam. A combination of steric and electronic factors may permit this decomposition, i.e., 133 -a- 134, to occur at quite moderate temperatures. The 0-methyl derivative of the benzalphthalimidine (132) undergoes slow loss of formaldehyde at 177° (Ti/a in dimethyl sulfoxide 40 minutes), but this elimination is much faster in certain thiohydroxamic acid derivatives, e.g., 135, which lose benzaldehyde readily at 139° in dimethyl sulfoxide (T1/2 6 minutes). The outstanding example of this decomposition, however,... 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

The seleno derivative 1374, which can be readily prepared by reduction of di-phenyldiselenide with sodium borohydride then alkylation with chloromethyltri-methylsilane, is alkylated to 1375 to give, on oxidative hydrolysis, aldehydes 1376 in high yields, PhSe02H-H20 1377 [104], and 7 (Scheme 8.44). Alkylation of the commercially available methyl thiomethyl sulfoxide 1378 leads to mono- or dialkyl... 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

The (3-keto sulfoxides can be alkylated via their anions. Inclusion of an alkylation step prior to the reduction provides a route to ketones with longer chains. 

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. 

Oxidation of alkenes, sulfides, sulfoxides and amines by alkyl hydroperoxides (ROOH) is catalyzed by [VO(acac)2] (equations 39-42),552 and mechanisms involving association of ROOH with [VO(acac)2] forming Vv compounds have been suggested.552 The reactions of phenoxyl, iminoxyl, nitroxyl, peroxyl and alkoxyl radicals with [VO(acac)2] in solution were studied by kinetic ESR spectroscopy552 and the net reaction was found to be catalytic reduction of the radical, probably also involving initial formation of a Vv compound. 

Dioxo-l,4,7,10-tetrahydro-l,10-phenanthroline (72) with dimethyl sulfate gives l,4-dihydro-7-methoxy-l-methyl-4-oxo- 1,10-phenanthroline (73) rather than a quaternary salt, steric hindrance presumably preventing alkylation of both nitrogens.203 A related alkylation has also been reported.295 1,2,3,4-Tetrahydro-1,10-phenanthrolines similarly form 1-alkyl derivatives rather than 10-alkyl quaternary salts with alkyl halides.38 The rate of methylation of 1,10-phenanthroline with methyl iodide in dimethyl sulfoxide has been studied,296 and the polaro-graphic reduction of 1 -methyl- 1,10-phenanthrolinium iodide was reported.286... 

Sulfonium salts of thiepanes are readily formed by electrophilic attack of alkyl halides on the cyclic thioether. Thus, thiepane (35) was found to yield a sulfonium iodide (123), which at elevated temperatures and in the presence of excess methyl iodide underwent ring cleavage to yield 1,6-diiodohexane (isolated as the 1,6-diphenoxy derivative Scheme 24) (53M1206). The alkoxysulfonium salt (124) formed by reaction of (35) with t-butyl hypochlorite (equation 23) was characterized as a stable hexachloroantimonate (67JOC2014). Reduction of thiepane 1-oxide (115) to thiepane has been achieved using an aqueous solution of NaHSC>3 (72JOC919). A hydroxysulfonium salt intermediate (125) has been proposed in the latter reduction reaction which provides a general method for sulfoxide reductions under mild conditions (equation 24). 

Chiral a-methylene-y-lactones.1 (R)-( + )-Alkyl p-tolyl sulfoxides (2), readily obtainable in almost quantitative yield from (l),2 on lithiation (LiTMP) and reaction with lithium a-bromomethylacrylate (3) are converted into a-methylene-y-sulfinyl carboxylic acids (4), which can be separated by chromatography or crystallization. Reduction of optically pure 4 provides y-tolylthio acids [(S)-5], which on methylation and treatment with potassium f-butoxide are converted into (4R)-a-methylene-y-lactones (6), with inversion of chirality. 

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