Thioacetates enones

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

The conjugate additions of thiols to a,p-unsaturated electrophiles was extended by Wang [96]. Catalyst 166 promoted the addition of thioacetic acid to a variety of enones, including aliphatic, aromatic and heteroaromatic substituents (Scheme 42). Wang expanded the scope of the reaction to include asymmetric additions of thioacetic acid to nitro-olefms (Scheme 43) [97]. Thiourea catalyst 166 promoted the addition reactions in high yields and high enantiomeric ratios for a variety of P-substituted nitro-olefms. 

The search for compounds that had improved oral activity led initially to the 7a-thioacetyl derivative (51-2) [48]. Dehydrogenation of the enone function in (50-5) using the now-familiar quinone, chloranU, leads to the dienone (51-1). This undergoes 1,6 conjugate addition on treatment with the sodium salt from thioacetic acid to give the la derivative (51-2) this compound, under the name spironolactone, was the first clinical aldosterone antagonist. Studies on the metabolic disposition of... 

Oxidation of a thioacetal at one of the sulfur atoms offers some useful features. After formation of the carbaniun and addition to an electrophilic partner, the hydrolysis is easier than for dithioacetals and can be made with dilute sulfuric or perchloric acid. Moreover, the addition of a lithiated carbanion derived from these species to enones occurs in a 1,4 rather than a 1,2 manner (the usual way for less stabilized more reactive thiocarbanions). The chemistry of these thioacetal monoxides was developed in the 1970s mainly by Ogura and Tsuchihashi [287-290] and by Schlessinger and co-workers [291-293], Two examples of application are given. 

Most functional groups resist Collins oxidation, including the oxidation-sensitive sulfides106 and thioacetals.103 Although Collins reagent can transform alkenes into enones" and alkynes into inones,107 these reactions are slower than the oxidation of alcohols into aldehydes or ketones. Therefore, alcohols can be usually oxidized with no interference from alkenes108 or alkynes.109... 

Thioacetals, prepared from the corresponding ketones, have also been reduced to alkenes using moderately active Raney nickel as the desulfurization agent (Scheme 37). This form of Raney nickel does not reduce the newly formed alkene or react with other isolated carbon-carbon double bonds. Note that under these conditions the saturated hydrocarbon often observed in Raney nickel desulfurizations is not formed. Similar conditions have been used for the conversion of cyclodecanone to cyclodecene. While thioacetals have also served as intermediates in the analogous conversion of enones into dienes, a mixture of diene products is obtained. For instance, dithiane generation from 17p-hydroxy-A -androsten-3-one, followed by desulfurization affords a 4 1 mixture of 17P-hydroxy-A -androstadiene and 17P-hy-droxy-A -androstadiene, respectively. ... 

Takei and co-workers [35] also reported the copper-catalyzed addition to enones (see Table 4, entry 4), using an R-ethylenethioacetal as the potential building block, with a copper sulfide complex. Addition of the Grignard reagent gave the major product, with a (3S, 4R)-configuration, indicating that the addition occurred primarily syn to the thioacetal... 

The preparation of thioacetals involves treatment of the carbonyl substrate with a dithiol in the presence of an acid catalyst, usually TsOH or Bp3 OEt2. Since thioacetals are quite stable toward hydrolysis, there is no special need to remove the H2O formed during the reaction. Also, since it is more difficult to equilibrate thioacetals than acetals via protonation, double bond migration in thioacetalization of enones is usually not observed. 

Lanthanide triflates and Sc(OTf)3 effectively catalyze conjugate addition of SEE, KSA, and ketene silyl thioacetals under mild conditions (0°C to room temperature, 1-10 mol% catalyst) (Scheme 10.86) [69, 238]. After an aqueous work-up these Lewis acids can be recovered almost quantitatively from the aqueous layer and can be re-used without reduction of fheir catalytic activity. Eu(fod)3 also is effective in not only aldol reactions but also Michael addition of KSA [239]. The Eu(fod)3-catalyzed addition of KSA is highly chemoselective for enones in the presence of ketones. 

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]. 

In 1988, Mukaiyama et al. reported the Sn(OTf)2-50d-catalyzed asymmetric Michael reaction of a trimethylsilyl enethiolate, CH2=C(SMe)SSiMej (up to 70% ee) [243]. It was proposed that the catalytic reaction proceeded via an Sn(II) enethiolate. They also demonstrated that a BINOL-derived oxotitaniurn catalyzes the Michael addition of ketene silyl thioacetals to a-enone with high enantioselectivity (up to 90% ee) [244]. After this pioneering work other research groups developed new reaction systems for enantioselective Mukaiyama-Michael reactions. 

Conjugate additions of thiols or thioacetates to a-enones, a,P-unsaturated esters or nitrostyrenes are catalyzed by cinchona alkaloids [173, 1058]. Even under pressure [1388], the adducts are obtained with an enantioselectivity lower than 75%. However, the use of 7.41 as catalyst induces higher selectivities [173] (Figure 7.36). 

Few examples have been reported for the organocatalytic asymmetric conjugate addition of sulfur nucleophiles other than thiols. The reaction of thiocarboxylic acids to cyclohex-2-enones [390] and a,p-nnsatnrated esters [391] was initially studied by Wynberg et al. employing Cinchona alkaloid catalysts with limited success in terms of selectivity (up to 54% ee). Slightly better enantioselectivities have been recently obtained by Wang et al. in the 1,4-addition of thioacetic acid to P-nitrostyrenes (up to 78% ee) [392] and trani-chalcones (up to 65% ee) [393], using Takemoto s thiourea 142 as catalyst (2-10 mol%). 

Hoechst workers [140] used steps similar to those employed in the (128) to (129) transformation to convert the enone (130), prepared from the hemiacetal (131) by thioacetal formation, Moffat oxidation and olefln bond migration, to the aldehyde (132) which was then elaborated to afford ( )-l l-deoxy-PGE2. 

Hydrolysis of Vinylogous Thioacetals. Carbanions prepared by lithiation of y-phenylthioallyl phenyl thioethers can serve as synthetic equivalents of /3-acyl vinyl anions. Umpolung of the usual electrophilic reactivity of 2-cyclohexenone is achieved by a sequence exploiting electrophilic capture of a hthiated vinylogous thioacetal and subsequent CuOTf-assisted hydrolysis (eq 57). Otherwise unfunctionalized vinylogous thioacetals can be hydrolyzed to enones by mercury(II) chloride in wet acetonitrile. However, the keto-substituted derivative in eq 57 gave only a 25% yield of enone by this method. A superior yield was obtained by CuOTf-assisted hydrolysis. ... 

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-... 

Michael addition of thioacetic acid to a series of a-substituted (V-acryloyloxazolidin-2-ones, followed by enantioselective protonation, catalysed by the cinchonidine-derived thiourea (288a), has been reported to proceed with <97% ee The pseudo-enantiomeric, cinchonine-derived thiourea (289a) can catalyse the Michael addition of dimedone to enone RCH=CHCO( -Py) with <98% ee The isosteviol-derived thiourea (290) represents yet another variation this organocatalyst has been reported to facilitate the Michael addition of a-substituted cyanoacetates NCCH(Ar)C02R and maleimides in toluene at -30 °C (with <93% ee and <98 2 dr) as a method for the construction of quaternary chiral centres " ... 

Dicarbonyl compounds continue to attract attention as precursors to unsaturated ketones. Readily prepared trimethylsilyl enol ethers react well with alkyl-lithiums, but poorly with Grignard or dialkylcopper-lithium reagents, to give enones [equation (23)]. a-Oxoketene thioacetals undergo chemoselective... 

Hydroxy-a-phenylthio-acids and their methyl esters can be prepared by condensations between carbonyls and the bis-anionic species (13) from phenyl-thioacetic acid or the monoanion (14) from methyl phenylthioacetate respectively. Yields are often excellent although the bis-anion (13) is less reactive, failing to condense with 2-methylcyclohexanone or acetophenone. With enones, (13) undergoes [1,2] addition by contrast the monanion (14) adds in a Michael fashion. 

The Takemoto s catalyst (9) was extensively employed for the enantioselective addition of arylthiols to a,P-unsaturated carbonyl compounds and P-arylthio ketones were obtained in good ees [90]. Conjugate addition of thioacetic acid to nitroalkene and to enone have been also reported by Wang [91]. 

In 2006, Wang and coworkers reported the use of chiral bifunctional amine thiourea catalysts for the Michael reaction between thioacetic acid and different enones, affording products in excellent yields but moderate enantioselectivities (up to 63% ee) [117]. 

Asymmetric chiral (thio)urea-catalyzed sulfa-Michael reactions have been extended to thioacetic acid and nitroal-kenes (Scheme 46.33). In 2006, Wang and co-workers used Takemoto s chiral thiourea 272 in the addition reaction of thioacetic acid 271 to acyclic enones 270 with modest enan-tioselectivities ranging from 20% to 1Q%P The use of... 

Li H, Zu L, Wang J, Wang W. Organocatalytic enantioselec-tive Michael addition of thioacetic acid to enones. Tetrahe-dronLett. 2006 47 3145-3148. 

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