Ketene thioacetals, synthesis

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

Ketene thioacetals 619 a-Ketoacylamides, synthesis of 615 a-Ketocarbothioates 635 a-Ketocycloalkyl sulphoxides, synthesis of 261... 

Thiol esters RC(0)SR are stronger acylating agents than simple alkyl esters, and have been prepared on solid phase mainly as synthetic intermediates. The preparation of thiol esters as intermediates for the synthesis of support-bound thiols is discussed in Section 8.1. Further examples of the preparation of thiol esters on insoluble supports include the aldol addition of ketene thioacetals to polystyrene-bound aldehydes... 

Ketene thioacetals. Two laboratories2,3 have reported a useful, general synthesis of ketene thioacetals (2) by the reaction of (1) in THF with aldehydes or ketones at... 

Some thermally forbidden [2 + 2]-cycloaddition reactions can be promoted by Lewis acids1-6. With chirally modified Lewis acids, the opportunity for application in asymmetric synthesis of chiral cyclobutanes arises (for a detailed description of these methods see Sections D.l. 6.1.3.. D.l. 61.4. and references 7, 28-30). Thus, a chiral titanium reagent, generated in situ from dichloro(diisopropoxy)titanium and a chiral diol 3, derived from tartaric acid, catalyzes the [2 + 2]-cycloaddition reaction of 2-oxazolidinone derivatives of a,/ -unsalurated acids 1 and the ketene thioacetal 2 in the presence of molecular sieves 4 A with up to 96 % yield and 98% ee. Fumaric acid substrates give higher yields and enantiomeric excesses than acrylic acid derivatives8. Michael additions are almost completely suppressed under these reaction... 

The syntheses by Ban and co-workers of both Na-acetylaspidospermidine (180) and deoxylimapodine (181) (Scheme 32) utilize the important pentacyclic ketone (182), prepared earlier. The critical stage in both syntheses is a Michael reaction, apparently stereospecific, of (182) with methyl vinyl sulphone [-> (180)] and keten thioacetal monoxide [—>(181)], respectively. The later stages in the synthesis are unexceptional. Mercuric acetate oxidation of deoxylimapodine enabled the first synthesis of iVa-acetylaspidoalbidine (183) to be completed. ... 

Ketene thioacetals. This reagent reacts with various methyl esters to form ketene acetals (2) in 50-85% yield. The products (2) are useful for synthesis... 

Note that the Wittig synthesis of ketene thioacetals can only be used with aldehydes. Of course, the reaction can be used for preparation of other thioacetals. ... 

The first examples of the use of the Knoevanagel-type condensation for the synthesis of a,p-unsaturated sulfoxides were made by Ogura and Tsuchihashi, who prepared racemic ketene thioacetal monoxides by the condensation of methyl... 

Thiophilic addition to dithioesters followed by capture of the thioacetal anion with an electrophile provides a useful approach to the formation of carbonyl compounds such as (42) and (43), and has been elegantly employed in the total synthesis of the macrocycles ( )-maysine and ( )-4,5-deoxymaysine. Trimethyl borate has been used to convert bis(phenylthio)methyl-lithium into the keten thioacetal (45) via the boron-containing carbanion (44), as shown in Scheme 4. Bis(phenylthio)methyl-lithium and related compounds are also the key reagents in the preparation of 2-(phenylthio)-enones, 2-(phenylthio)-butadienes, a-(phenyl-... 

Aluminium thiophenoxide reacts readily with carboxylic esters to form keten thioacetals. A most important reaction of keten thioacetals has been reported by Cohen. Reduction of keten thioacetals with lithium naphthalide gives the sulphur-stabilized vinyl anions, powerful reagents for ketone synthesis. This type... 

TMAL) reaction sequence for the synthesis of P-lactones. Despite the relatively high diastereoselectivity, the ZnCb mediated aldol reaction was only optimized when smaller silyl and thiol groups of the ketene acetyl were employed for the improved efficiency of the subsequent lactonization. The methodology was utilized in the synthesis of (-)-panicilin D, a pancreatic lipase inhibitor, where the ketene thioacetal 60 was added to aldehyde 59, upon which lactonization followed by deprotection yielded the 3-lactone 61 as a diastereomeric mixture (9.3 1) in modest yield. 

Earlier work has demonstrated that pyridinium 7V-ylides and keten thioacetals and related compounds yield allyl ylides and indolizines/ " The extension of this reaction to pyridinium JV-imines provides a useful synthesis of pyrazolo-[l,5-a]pyridines (95), as shown in Scheme 21. ... 

While orthoesters do not react with trifluoroacetic anhydride, aryltrithio-orthoacetates (ArS)3CMe give keten thioacetals (ArS)2C=CHC(0)CF3, by way of the parent keten dithioacetal (ArS)aC=CH2 acetic anhydride does not react. Aryl trithio-orthoacetates readily exchange with CFsCOa H as a consequence of the reversible loss of ArSH, and this can be exploited in the synthesis of deuteriated hydrocarbons, e.g. (ArS)2CArC H3 -> ArCHaC Hs (after treatment with Raney nickel). ... 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

The reaction of Cjq with silylated nucleophiles [47] requires compounds such as silyl ketene acetals, silylketene thioacetals or silyl enol ethers. It proceeds smoothly and in good yields in the presence of fluoride ions (KF/18-crown-6) (Scheme 3.10). The advantage of the latter synthesis is the realization of the cyclopropanation under nearly neutral conditions, which complements the basic conditions that are mandatory for Bingel reactions. Reaction with similar silyl ketene acetals under photochemical conditions and without the use of F does not lead to methanofullerenes but to dihydrofullerene acetate [48]. 

Ketene acetals and thioacetals can be used as ketene equivalents in cyclobutanone synthesis in situations where ketene to alkene cycloadditions are inefficient such as in the case of electron-deficient alkenes.14 Although thermal cycloadditions of ketene acetals and thioacetals with electron-deficient alkenes have been observed (see Section 1,3.2.1.), such cycloadditions proceed more efficiently and under milder conditions with metal catalysts. Efficient cycloadditions between ketene dimethyl acetal and alkenes substituted by a single electron-withdrawing group have been reported.15... 

Schlessinger has shown that the addition of ester enolates to sulfur stabilized acceptors, e.g. ketene di-thioacetal monoxide (151) and methyl a-(methylthio)acrylate (187), is highly efficient for the synthesis of Y-ketoesters.148 Similarly, Ahlbrecht and Seebach have reported that amide and ester enolate additions to nitrogen stabilized acceptors, e.g. nitroalkenes (40) and 2-(/V-methylanilino)acrylonitrile (59 Scheme 72), are highly efficient.149... 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

A simple synthesis of symetrically functionalized dithiosalicylides 77a-d from the 377-1,2-benzodithiol-3-ones 75 and triphenylphosphine was described (Scheme 6) <1997JOC9361>. As indicated, the preparation of precursors 75 was based on a known transformation of the substituted anthranilic acid derivatives 73 to the thiosalicylic acid derivatives <1943OSC580>. Upon treatment with thioacetic acid in sulfuric acid, cyclization <1990JOC4693> afforded products 75 in 38-64% yield. Dimerization of a benzothietan-2-one 78a or ketene 78b <1987JOC3838>, arising presumably from initially formed intermediate 76, was proposed to account for the product formation. As revealed... 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

Mikolajczyk, M.. Grzejszczak, S., Zatorski, A., Mlotkowska, B., Gross, H., and Costisella, B., Orga-nosulphur compounds. Part 18. A new and general synthesis of ketene S,S- and O,S-thioacetals based on the Homer-Wittig reaction. Tetrahedron. 34. 3081, 1978. 

This reaction provides a synthesis of r/oos-calamene (7) from the ketene di-thioacetal (5) of /-menthonc. 

Although the thio-Claisen transposition affords various possibilities of synthesis with stereocontrol, few examples of natural product synthesis have been described. Takano s group was a pioneer in this field with the synthesis of nine-membered indole alkaloids (Scheme9.32) related to deavamine [152] and velbana-mine [153]. The key step involved the transformation of a sulfonium salt into a corresponding ketene amino thioacetal, which underwent the thio-Claisen transposition. A similar strategy was used for the synthesis of the strychnos alkaloid framework [154]. 

The cleavage of ketene dithioacetals and the action of P2I4 on thioacetals, as just described, provides vinyl sulphides in good yield but of course there are many alternative methods for preparing these versatile compounds. This is evident in the reaction of the methoxycarbonylketene equivalent (251) with dienes to give vinyl sulphides (252). These latter compounds can then be converted by standard methods into p-keto-esters (253). Another synthesis which culminates in the conversion of a vinyl sulphide into a carbonyl group is... 

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