Of dithioesters

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

Scheme 8. Oxepane synthesis by photo-induced ring closure of dithioesters. The term dithioester is used in this chapter to describe compounds of type 39 even though such systems are sometimes referred to as dithionoesters or dithioxoesters.

Scheme 20 Preparation of Dithioester-Modified Peptides via the HF Method1 1...

Table 3 Examples of Dithioesters Incorporated in Peptide Struc-...

Dithioacids themselves (R CSSH) could be prepared in about a 40-50% yield by addition of Grignard reagents to caibon disulfide in THF as the solvent, followed by acidification in the presence of ether or pentane [143], Hartke has reported that the yields of dithioacids could be improved by reverse addition of the Grignard reagent to carbon disulfide [144], a protocol previously used by Julia [145] in the preparation of dithioesters from allylic organometallics. A 70-80% yield of dithioacetic acid was thus achieved on a molar scale. 

Alkylation in situ of the above magnesium salts yielded the dithioesters in good yields [143, 146], providing the most convenient laboratory preparation, and a wide range of dithioesters are thus simply and readily available (Table 2.4) [147]. 

An indirect method makes possible the general use of lithium as well as magnesium organometallic reagents for the synthesis of dithioesters their addition to phenylisothiocyanate followed by alkylation gives A-phenylimidothioesters (themselves valuable intermediates), which are readily sulfhydrolysed [151,152],... 

The sequence, addition of one equivalent of MeLi to a solution of dithioester (1) and (2) in THF at -78°C, led, after allowing the temperature to rise slowly to 20°C and the usual work up, to dithioacetal (3) in a 79% yield [333]. Dithioacetalization and a Wittig reaction yielded dehydro-ar-curcumene (4). 

Davy reagents 32,38 decarboxylation 64,67 Dehydrogenation of ketones 55 Dehydrohalogenation 57 Deracemization 68 Desulfurization 75 of dithioacetals 78,100 of dithioesters 69... 

Synthesis of dithioesters from 5-thioesters and La wesson s reagent... 

General procedure for the preparation of dithioesters from CS2 and Grignard reagents... 

Under copper(l) catalysis, excellent yields of dithioesters were obtained at -50°C, and t-alkyl magnesium halides, which led mainly to polymeric products without catalysis, gave yields above 90% in the presence of a catalytic amount (5-10 mol%) of copper(i) bromide [148]. 

The conversion of dithioesters into aldehydes is also easily realized through reduction to a mixed dithioacetal by tributyltin hydride [264]. 

A few a-acylamino dithioesters were successfully synthesized by the Pinner reaction in the early 1970s. 6 9 However, many amino acid and peptide dithioesters have now been prepared by this procedure and used for the synthesis of endothiopeptides 10 and spectroscopic studies of dithioesters. 1 ... 

An improved procedure for condensation of dithioesters with a-amino groups of amino acids has been used to prepare several peptide thioamidesJ8 The N-protected amino acid dithioesters condense with alkali salts of a-amino acids, catalyzed by alkali fluoride in EtOH, to give the endothiopeptides within 60 minutes. Under these conditions, the thioamides are obtained without racemization. 

Metzner reports that lithium dithioenolates, which are softer nucleophiles than the corresponding carbonyl enolates, add kinetically in a 1,4-mode exclusively to ot, 3-enones and the diastereoselectivity preferences are similar to that for ester enolate additions.l43a d Typically, kinetic deprotonation of dithioesters affords predominantly the (Z)-enethiolate (170) which is opposite to that for esters 139 thus, with ( )-enones, anti adducts (172) are obtained. In contrast, the addition of methyl dithioacetate to ot,P-disubstituted enones affords predominantly syn adducts (174 and 175) which is a consequence of intramolecular protonation of the resultant enolate (Scheme 68).143e... 

The high electrophilicity of dithioesters towards amines was applied to the synthesis of phosphonothioamides [35, 36] and thiohydroxamic acids [37]. Dithioacid salts may also be used as starting materials for this thio-acylation with catalysis by boron trichloride [38]... 

As classical routes (using CS2, H2S or LR) work efficiently [3, 54-56], the attention in this field has concentrated on the synthesis of dithioesters bearing complementary functional groups. 

The aldol reaction of dithioester enethiolates has been used for the synthesis of dithiolactones [123], chiral substrates for the Claisen rearrangement [124, 125], and oxathianes [126]. Thioamide enethiolates may be employed in this reaction as well as shown with /Tthiolactams [26], or with a precursor of the antitumour agent vinblastine [127]. 

An attempted synthesis of dithioesters 220 by stepwise treatment of enolates from cyclopropanes 97 with carbon disulfide and methyl iodide lead to an unexpected new product without a cyclopropane ring. By spectroscopic means and study of the reactions dihydrothiophene structure 222 has been established 98). 

The reaction of dithioesters with Grignard reagents is even more remarkable. Because sulfur and carbon have about the same electronegativity, the Grignard reagent may add to either end of the ji bond. If it adds to sulfur, the resulting anion is stabilized by two sulfur atoms, rather like the dithiane anions we have seen earlier in this chapter, and can be used as a d1 reagent. 

Syntheses of dithioesters by the reaction of Grignard reagents with dithiochloroformates have been reported, but the yields were at best modest [5] ... 

Alvarez-Builla and co-workers synthesized several examples of N-benzimidazolylmethylpyridinium salts of type 41 by cyclization of new dithioesters with 1,2-arylenediamines 92 (88H1233 89H57) [Eq.(20)], in the course of an investigation on the chemistry of dithioesters and highly stabilized ylides (90T6033). For other examples of pyridinium salts 41 see Tables II and III. 

On the other hand, reaction of dithioester 16 with diazomethane leads to a single diastereomer of 1,4-dithiane 17146,... 

Base-induced S-allylation of dithioesters [17,18], thionoselenoesters [19] as well as tertiary thioamides [20-23] with allylic halides and alcohols [24] have been commonly used to generate S-allyl ketene-S,W-acetals (W = S,Se, N), which are prone for a thio-Claisen rearrangement. In fact, the marked trend of the starting thiocarbonyl compounds to render the cis-... 

Since 1926, it has been known that thiols could be formed by reaction of 2 mol of RMgX with 1 mol of dithioester [31] ... 

Carbophilic addition of prenylmagnesium bromide and other allylic Grignard reagents to the thiocarbonyl group of dithioesters occurs exclusively with rearrangement of the allylic... 

The reactive species in these additions has not been fully elucidated. It is likely that considerations similar to those involved in the addition of dithioester enethiolates to enones are involved (vide supra). 

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