Thiol addition

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

Dialkyl esters of cystine (39) and lanthionine (40) undergo a surprising thermolysis reaction at between 25 C and 80 °C to afford cis and trans methyl 2-methylthiazolidine-2,4-dicarboxylates (43) in protic solvents. A two stage process is proposed for this transformation. An initial i-elimination reaction gives the thiol (41) and the enamine (42). Thiol addition to the imine tautomer of (42) is then followed by loss of ammonia and an intramolecular cyclisation to give (43) <96CC843>. 

Another advantage to the use of a thiol additive is that the abundance of free thiol groups in the reaction environment will prevent the oxidation of the cysteine thiol at the N-terminal of the other peptide. Without added thiol transesterification catalysts, disulfide formation resulting in dimerization of the Cys-peptide would be a dominant side reaction in aqueous, oxygenated buffer conditions. 

PE Dawson, MJ Churchill, MR Ghadiri, SBH Kent. Modulation of reactivity in native chemical ligation through the use of thiol additives. J Am Chem Soc 119,4325, 1997. 

B. Kinetic Resolution Using the Chiral-Amine-Catalyzed Thiol Addition... 

C. Synthetic Utility of Asymmetrically Catalyzed Thiol Addition Reactions.105... 

Quinine and quinidine, as well as cinchonidine and cinchonine, are diastereo-meric pairs. However, at the critical sites—the P-hydroxyamine portions of the molecules—they are enantiomeric. Thus if quinine is used as the chiral catalyst in an asymmetric transformation (i.e., with one enantiomer being formed in excess), the other enantiomer is formed in excess when quinidine is used. Table 2 gives a representative example, the thiol addition reaction (19). 

Japanese workers (50,51) were the first to observe optical activity in the addition of thiols to electron-poor olefins (eq. [9]) The e.e. was not determined, but these observations led us to attempt using a cinchona alkaloid as the catalyst in the addition of thiophenol to cyclohexenone. The reaction lends itself admirably to a scope, limitations, and mechanism study, and the results have been published in detail (19). An important mechanistic difference between the addition of the dodecanethiol to isopropenyl methyl ketone and the addition of thiophenol to a cyclohexenone (eq. [1]) lies in the sequence of chirality-producing steps. In the former case, chirality is produced when the proton adds to the a-caibon atom of the ketone—after thiol addition has taken place. In the latter... 

Since all of the thiol addition products were unknown compounds, except for racemic 3-phenylthiocyclohexanone, it became necessary to devise a method far determining the absolute configuration without resorting to Bijvoet s method (53) for each new compound (see Table 4). This was accomplished by preparing the thioacetal of the adamantanedione, a model 3-thiosubstituted cyclohexanone of known absolute configuration (54) (eq. [10]). 

The relatively high e.e. s obtained in most of the quinine-catalyzed thiol addition reactions, the wide range of enones and thiols potentially amenable to this reaction, and the versatility of the sulfur (and carbonyl) functionality combine to make this reaction useful in many ways. 

Recently Ikegami used the thiol addition reaction in the preparation of optically pure 4-phenylthioazetidin-2-one, the starting material for an elegant ( + )-thienamycin synthesis (58). When 4-phenylsulfonylazetidin-2-one was treated with cinchonidine and thiophenol, the intermediate azetinone underwent a thiol addition reaction and the 4-phenylthioazetidin-2-one was obtained in 54% optical and 96% chemical yield (eq. [13]). Recrystallization of the optically active aze-tidinone allows isolation of the pure enantiomer from the mother liquor. The phenylthio group is eliminated later in the synthesis of thienamycin. 

The thiol addition reaction discussed in the previous section does not lend itself readily to the preparation of (chiral) mercaptans. 

The example of the thiol addition reaction to a cyclohexadienone indicates that discrimination of this type can be carried out catalytically the proximity of the meso carbon to the reaction center increases the stereoselectivity substantially. 

The 1,4-thiol addition reaction lends itself well to a mechanistic study, for the following reasons ... 

Figur 10. Transition states for 1,4-thiol addition to cycloalkenooes.

The 1,4-addition of selenophenols to cycloalkenones proceeds smoothly under the same conditions used in the thiophenol addition (see Section V) (eq. [18]). Although the e.e. of the products is 40 to 65%, compared with the 60 to 80% achieved in the thiol addition reaction, the solid adducts are readily purified to enantiomeric purity by crystallization (63). 

Although the mechanism of this reaction has not been studied as thoroughly as that of the thiol addition reaction, there appears to be considerable similarity in the main features of the reaction. Thus, although the transition state may well differ in a number of details, the transition state shown earlier (Figure 10) appears to predict the correct configuration for the products of the selenophenol addition as well as of the thiophenol addition to cyclohexenones. 

The first 1,6-addition reactions of thiolates to steroid dienones were examined well before the discovery of the antiestrogenic properties of 7o -substituted steroids. Ralls and coworkers129 and Djerassi and coworkers130 studied thiol additions to A3,5-steroids for example, the reaction of 3,5-cholestadien-7-one with ethanethiol was reported to proceed with high 1,6-regioselectivity and -stereoselectivity (equation 47)129. In a series of papers, Brueggemeier and coworkers131-137 described the synthesis and biochemical evaluation of numerous 7at-sul fur-substituted steroids which were prepared by Michael addition to steroid dienones. Thus, 4,6-androsta-3,17-dienone was treated with various... 

Scheme 77 Ionic liquid catalyzed thiol addition to a, /1-unsaturated ketones...

Racemic thioglycerol (3-sulfanylpropane-l,2-diol) was used for the attachment of two lipid chains via ester bond formation with the hydroxy groups 82 while the free thiol group serves for selective cross-linking to other molecules via disulfide or sulfide bonds utilizing mild thiol-disulfide interchange or thiol addition reactions (Scheme 15).[163,164,167]... 

Where it is possible to distinguish the products, thiol additions show stereospecificity. The products of addition of hydrogen sulfide, thio-phenol, and thiolacetic acid to 1-chlorocyclohexene are to be 75%, 94%, and 66% cis-l, 2-disubstituted cyclohexane, respectively.88 The addition of thiolacetic acid is less stereopecific than the other thiols. The stereospecificity apparently depends upon the ratio of addendum to 1-chlorocyclohexene, Phenylthiyl radical addition to 1-methylcyclo-... 

In this method, the cyclic peptide is generated through cysteine-perthioester cyclization to afford a Xaa-Cys bond whose thiol is then used for the second ligation step to the core through a thiol addition reaction (Scheme 25).[S71 For the perthioester cyclization, the linear precursor 91 consists of an activated N-terminal Cys(Npys) and a C-terminal thiocarboxylic acid which favors cyclization due to intramolecular mixed disulfide formation between them. 

An unusual example of intramolecular thiol addition to double bonds is illustrated in the synthesis of spirothiazines.551 The key step is described as an acid-catalyzed Markovnikov addition of a thiol to a double bond (Scheme 6). 

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