A-Thioacetal

The synthesis of 11-oxaprostaglandlns from o-glucose uses the typical reactions of gl cofuranose diacetonide outlined on p. 267. Reduction of the hemiacetal group is achieved a thioacetal. The carbon chains are introduced by Wittig reactions on the aldehyde grou] which are liberated by periodate oxidation and laaone reduction (S. Hanessian, 1979 G Lourens, 1975). 

The addition of aromatic and aUphatic thiols, RSH and ArSH, and a thioacetic acid to isoprene yields mainly the trans-l,4-adduct (56). The aromatic thiyl radicals, ArS , add almost entirely to the first carbon atom however, aUphatic thiyl radicals, RS, also add to the fourth C atom in significant amounts. 

NaSMe, MeOH, 23°, 81-95% yield. This procedure is chemoselective for removal of a thioacetate in the presence of an acetate. 

The most common procedure previously employed to effect the elimination of thiols from thioacetals has been heating in the presence of a protic acid. For example, propionaldehyde diethyl thioacetal is converted to 1-ethylthio-l-propene on heating at 175° in the presence of phosphoric acid. The relatively high temperature and acidic conditions of such procedures are, however, distinct disadvantages of this method. Another approach consists of oxidation of a thioacetal to the mono S-oxide and thermal elimination of a sulfenic acid at 140-150°. ... 

Carbonyl compounds react with thiols, RSH, to form hemi-thioacetals and thioacetals, rather more readily than with ROH this reflects the greater nucleophilicity of sulphur compared with similarly situated oxygen. Thioacetals offer, with acetals, differential protection for the C=0 group as they are relatively stable to dilute acid they may, however, be decomposed readily by H20/HgCl2/CdC03. It is possible, using a thioacetal, to reverse the polarity of the carbonyl carbon atom in an aldehyde thereby converting this initially electrophilic centre into a nucleophilic one in the anion (31) ... 

Another synthetic application of olefin metathesis using a thioacetal-titanocene(II) system is the ring-closing olefin metathesis (RCM) of carbene complexes possessing an olefin moiety, e. g. 33 (Scheme 14.17). The success of the RCM apparently depends on the substituents at the carbon—carbon double bond (i. e. the substituent(s) on the resulting carbene complex 34). 

Table 14.8. Carbonyl olefination utilizing a thioacetal-titanocene(l I) system.

Scheme 14.27. Intramolecular carbonyl olefination utilizing a thioacetal-titanocene(ll) system.

Methyl deoxypodocarpate 127 (Scheme 1) 129) represents a simple problem since the ketone 132 is well-known and readily available from Hagemann s ester in three steps. The problem of geminal alkylation of this ketone stems from its existence as an EjZ mixture of ring fusion isomers. Recognizing that decarbonylation of aldehydes occurs readily with Wilkinson s catalyst creates a structural equivalence of an acetaldehyde chain and a methyl group as in 128. This simple relationship immediately establishes several options, a simple one uses a thioacetal such as 129 as a synthon for the aldehyde. The presence of a carbonyl group three carbons away... 

In much the same vein as above, hydrolysis of the enol ether (13-2) with a weak acid gives the unconjugated 5,9 olefin (16-1). This is then successively converted to a thioacetal, desulfurized, oxidized, and ethynylated. There is thus obtained the orally active progestin tigestol (16-2) [18]. 

The Wittig reaction efficiently olefinates aldehydes and ketones, but not esters or amides. Several early-transition-metal approaches have been taken to this problem. Recently, Takeshi Takeda of the Tokyo University of Agriculture and Technology reported (Tetrahedron Lett. 44 5571,2003) that the titanocene reagent can effect the condensation of an amide 10 with a thioacetal 11 to give the enamine 12. On hydrolysis, 12 is converted into the ketone 13. When the reaction is intramolecular, reduction proceeds all the way, to give the pyrrolidine IS. 

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. 

Carboxy terminal amino acid or peptide thiols are prepared from various p-amino alcohols by conversion into a thioacetate (R2NHCHR1CH2SAc) via a tosylate followed by saponification.Several methods have been used to prepare N-terminal peptide thiols, the most common procedure is the coupling of (acetylsulfanyl)- or (benzoylsulfanyl)alkanoic acids or add chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 16 Other synthetic methods include deprotection of (trit-ylsulfanyl)alkanoyl peptides, 1718 alkaline treatment of the thiolactones from protected a-sulfanyl acids, 19 and preparation of P-sulfanylamides (HSCH2CHR1NHCOR2, retro-thior-phan derivatives) from N-protected amino acids by reaction of P-amine disulfides with carboxylic acid derivatives, followed by reduction. 20,21 In many cases, the amino acid or peptide thiols are synthesized as the disulfides and reduced to the corresponding thiols by the addition of dithiothreitol prior to use. 

Disulfides, diselenides, and ditellurides can be oxidized by hypervalent iodine compounds quite easily. Depending on the reaction conditions disulfides can be oxidized to sulfinic esters [59] or thiosulfonic S-esters [60,61]. Diselenides can be transformed into selenosulfonates [62]. Arenetellurinic mixed anhydrides are mild oxidants and can be obtained by oxidation of the corresponding ditellurides as shown in Scheme 9 [63]. Recently it was shown that a thioacetal based linker for solid-phase synthesis can be cleaved oxidatively using [bis(trifluoro-acetoxy)iodo]benzene 4 [64]. 

The reduction of azetidin-2-one 302 containing a thioacetal moiety at C-4 to the corresponding acetal azetidine, followed by diethylaluminium chloride promoted C(2)-N(l) bond cleavage, afforded bicyclic pyrrolidines 303 and pyrroles 304 (Equation 98) <1999JOC9596, 1998TL467>. 

Merckl6 et al. <2001JOC5058> proposed a mechanism for the formation of taxol-thietanes 57 and 33 from spiro taxol-oxiranes 118 and 122. According to these authors, the reaction starts with the attack of the sulfur atom from a thioacetate anion on an oxirane carbon atom to form the intermediate A. Then, an acetyl group migrates from sulfur to oxygen to form the intermediate B, and the X group leaves with simultaneous formation of a fused thietane product G (Scheme 19). 

Other thioacetal-type functional groups are good starting materials for reductive lithiation for example, a-lithioether 79 is readily made by oxidation of a sulfide to a thioacetal 78 followed by reductive lithiation.87... 

Reductive lithiation of a thioacetal provided the first method for the synthesis of 2-lithiotetrahydropyran. The scheme below shows a lithiated dihydropyran 80 being used in an efficient synthesis of two diastereoisomers of the insect pheromone brevicomin 81.87... 

Another simple elimination reaction on the thiosulfinate ester makes another molecule of the sulfenic acid and a highly unstable unsaturated thioaldehyde, which promptly dimerizes to give a thioacetal found in garlic as a potent platelet aggregation inhibitor. 

Stereoselective synthesis of the C11-C16 fragment of the polyene macro-lide antibiotic, pentamycin, has also been accomplished under the aldolase protocol.45 A formyl and benzyl protected aldehyde, available from D-glucose by chemical methods, reacts with DHAP under the influence of FDP aldolase. After phosphatase hydrolysis the essential C11-C16 skeleton of pentamycin is generated. Removal of an additional hydroxyl group at position 1 and isolation of the C11-C16 fragment as a thioacetal, is accomplished in several steps (Scheme 5.23). 

Oxa-thiacrown ethers 11 and 12 possessing a thioacetal unit have been prepared by Llorca et al. <1997AXC816>, and Romanski and Marchand <2004PJC223>, respectively. The X-ray structure of 11 showed that the S and O atoms were located at side positions of the quadrilateral. 

Reduction of carbonyl group to methylene via thioacetals In contrast to the Clemmensen reduction (section 6.4.3) and Wolff-Kishner reduction (section 6.4.4), this method does avoid treatment with strong acid or base but requires two separate steps. The first step is to convert the aldehyde or ketone into a thioacetal. The second step involves refluxing an acetone solution of the thioacetal over a Raney nickel. This reduction method is known as Mozingo reduction. Hydrazine can also be used in the second step. 

As shown in Scheme 8.31, ketone 115 was further homologated to carbacyclic analogs of L-idose and D-glucose. As illustrated, temporary protection of the ketone through a thioacetal was followed by the removal of the benzoyl groups. Protection with acetonides, and cleavage of the thioacetal, afforded the ketone 116. This intermediate was transformed into carba-idopyranose by... 

Importantly, with a-silyloxy acetaldehyde, the syn aldol is the major dimer (threose derivative). Thus, applying Mukaiyama condensations with 27 (see O Scheme 23), hexoses such as idose, gulose, and galactose can be prepared. A highly stereoselective protocol for the cross coupling of aldehydes and ketones with a-thioacetal aldehydes has been developed... 

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