1.3- Dithiane moiety

The pivotal step in this sequence is an electrophilic substitution on indole. Although the use of l,3-dithian-2-yl carbanions is well documented, it has been shown only recently that 1,3-dithian-2-yl carbenium ions can be used in a Priedel-Crafts type reaction. This was accomplished initially using 2-methoxy-l,3-dithiane [1,3-Dithiane, 2-methoxy-] or 2-metlioxy-l,3-dithiolane [1,3-Dithiolane, 2-methoxy-] and titanium tetrachloride [Titanate(l —), tetrachloro-] as the Lewis acid catalyst.9 2-Substituted lysergic acid derivatives and 3-substituted indoles have been prepared under these conditions, but the method is limited in scope by the difficulties of preparing substituted 2-methoxy-1,3-dithianes. l,3-Dithian-2-yl carbenium ions have also been prepared by protonation of ketene dithioacetals with trifluoroacetic acid,10 but this reaction cannot be used to introduce 1,3-dithiane moieties into indole. 

In this chapter, the structures and chemistries of 1,3-dioxins, 1,3-oxathiins, and 1,3-dithiins are described, including both their fully saturated forms (1, 7, and 13) as well as their benzo analogs (6, 11, 12, and 17). The formally fully unsaturated monocyclic structures (4, 9, 10, and 16) contain only one endocyclic double bond with further unsaturation being accomodated by exocyclic double bonds (2, 3, 5, 8, 14, and 15), for example, by the introduction of a carbonyl group. Well known and intensively studied are the Meldrum s acid derivatives 18 and 19. In addition, 1,3-dioxane, 1,3-oxathiane, and 1,3-dithiane moieties can be part of spiro structures as well as hi- and tricyclic analogs. And finally, both the structures and chemistries of the corresponding sulfoxides and sulfones are also reported. 

Table 7 Conformations and selected bond lengths (A) for the 1,3-dithiane moiety in different soiid-state structures...

CEJ1358> and the ruthenium mediated isomerization of double bonds (cf. Scheme 89, Section 8.11.7) <2007TL137> are recent examples of transition metal catalyzed manipulations at the side chain carbon atoms of 1,3-heterocycles. A novel side-chain addition reaction of aldehydes to 6-alkylidene-l,3-dioxin-4-ones was used for the construction of intermediates of lophotoxin <2006CJC1226>. An acid-catalyzed intramolecular cycloaddition of a hydroxy group to an alkene has been effected by the presence of an adjacent 1,3-dithiane moiety <2006TL4549>. 

Another convenient method for the preparation of functionalized cyclobutanol derivatives is by treatment of 1,2-diphenylethylene acetals containing a 1,3-dithiane moiety in the y-position, e.g. 14c. with butyllithium. The isolation of 2,2-(propane-l,3-diyldisulfanyl)cyclobutanol (15c) together with benzyl phenyl ketone in 90 and 92 % yield, respectively, indicates that the reaction mechanism should involve the intramolecular attack of the metalated dithiane on the acetal carbon atom with concomitant hydride shift at the acetal group.15... 

The liquid-phase oxidation of 1,3-dithian, and oxidation of alcoholic functional groups in the presence of the 1,3-dithian moiety by the Pfitzner-Moffatt reagent, has been studied. Both cis- and 1,3-dithian 1-A -arylimides (167) were prepared and they rearranged with high stereospecificity. 1,3-Dithian 1-imide 1,3,3-trioxide (168) has been obtained, in excellent yield, by the cleavage of the corresponding A-tosyl compound with Na and... 

Even if the mechanistic details of the 1,4-addition to 7 were unclear, we were glad to validate the concept with the versatile 1,3-dithiane moiety. Indeed, the corresponding carboxaldehyde 15 was unmasked in 73% yield (gram scale) upon treatment of 12 with PhI(OCOCF3)2 (PIFA), while treatment of 12 with Raney nickel delivered 16 in 95% yield (Scheme 10). 

Initial attempts to convert the 2,3-tra J-2,6-tran5-tetrahydropyran aldehyde 2.197a to the epoxide 2.198 through asymmetric allylation and subsequent epoxidation were made (Scheme 2.41). Towards this end, aldehyde 2.198 was transformed to the homoaUyl alcohol 2.201 via Brown asymmetric allylation [95], was in turn exposed to a variety of epoxidation conditions, including Sharpless asymmetric epoxidation [146] as well as achiral reagents such as VO(acac)2/t-BuOOH [147, 148] and m-CPBA. Unfortunately, aU attempts were not effective for the installation of the epoxide. Instead, the former two reactions yielded three side products which were the results of the oxidation of the 1,3-dithiane moiety under oxidation reaction conditions. The latter resulted in the epoxide, but the poor diastereoselectivity (dr = 1 1) as well as significant loss of the PMB group were observed. 

Further study has been made of the use of the methylthiomethyl group for protection of alcohols in synthesis. Primary and secondary alcohols and tertiary alcohols are converted into methylthiomethyl ethers using dimethyl sulphoxide and AcgO, and de-protection is brought about under neutral conditions with a mercury(n) salt. Under these conditions, a 1,3-dithian moiety or a silyl ether grouping in the same molecule are unaffected. Protection of alcohols as 2-phenylselenoethyl ethers and their de-protection by oxidation has been proposed. ... 

A modihcation on verapamil uses a spiro-dithiane moiety to supply the quaternary center. Reaction of veratraldehyde (64-1) with propane 1,3-dithiol leads to dithiane (64-2). Reaction with hydrogen peroxide oxidizes the ring sulfur atoms to... 

A considerable number of electrophiles were used, and the dithiane route found great utility for the syntheses of simple monofunctional compounds as well as for polyfunctional molecules, for which the dithiane moiety affords an invaluable temporary protection of a future carbonyl group. Some experimental procedures published in Organic Syntheses — cyclobutanone [277] and 3-hydroxy-l-cyclohexene-l-carboxaldehyde [278] — are illustrative. A similar route to aldehydes [279] makes use of sym-trithiane as a formyl anion equivalent. 

The synthesis of the coupling partner (enone 124) began in the manner reported by Noda [70] (Scheme 30). Thus, starting with commercially available acetylacetaldehyde dimethylacetal (125), the dithiane protection of both the ketone and the dimethyl acetal units under acidic conditions afforded compound 131 in 86% yield as a white crystalline solid. Deprotonation with n-BuLi, followed by the addition of / -benzyl glycidyl ether (132) provided an 80% yield of the hydroxyl ether 133. Deprotection of the dithiane moiety with HgCb in acetonitrile and water revealed the two carbonyl units, which underwent spontaneous cyclization to the enone 124. Spectroscopic data for this compound were in complete agreement with the published data [70]. 

The stereocontrolled enantioselective synthesis of an advanced B-ring synthon of bryostatin 1 was achieved in the laboratory of K.J. Hale. " The key step was a Smith-Tietze coupling of 2-lithio-2-TBS-1,3-dithiane with a homochiral epoxide in the presence of HMPA. The resulting dithiane alkoxide was trapped with TBSCI in situ followed by deprotection of the dithiane moiety to give a Crsymmetrical ketone. This ketone was then further elaborated into the target B-ring synthon. 

Danishefsky et al. (33) reported a method of one-carbon chain incorporation necessary for the elaboration to the five-membered D-ring of cephalo-taxine (Scheme 39). (See also Scheme 9, Section III, for the formal total synthesis of cephalotaxine by this method.) Reaction of dihydroisoquinoline 219 with acid chlorides 220 or 221 followed by the addition of aqueous sodium bicarbonate gave carbinolamides 222 or 223, respectively, which, on treatment with 1,3-propanedithiol and boron trifluoride etherate, yielded the ring-opened dithiane 224 or 225. These dithianes were converted by treatment with sodium hydride or potassium rert-butoxide to 226 or 227, respectively. Removal of the dithiane moiety in 226 or 227 by iV-bromosuc-cinimide gave the a-keto esters 228 or 229, which on treatment with Lawes-... 

Acyldithianes were reduced asymmetrically to give the enantio-enriched alcohols. As shown in Scheme 10 the obtained alcohols containing a dithiane moiety can be subsequently transformed into useful chiral alcohols in high enanti-opurity, compounds that would be inaccessible via direct reduction [91]. 

The reaction of 1,3-dithienum tetrafluoroborate with 1,3-dienes was among the first to be studied with this reagent and was found to follow a path which initially produced a bicyclic sulfonium salt (eq 9). Deprotonation of this salt with / butyllithium led to a vinylcyclopropane which rearranged under thermal conditions to a spirodithiane. Hydrolysis of the dithiane moiety gave a cyclopent-3-enone in an overall sequence that is formally equivalent to the addition of carbon monoxide across the terminal carbons of a 1,3-diene. 

Alkylations. Treatment of 1 with various primary alkyl halides provides the corresponding substituted dithianes (eqs 3-5 ). Removal of the dithiane under the Lewis acid conditions, illustrated in eqs 3-5, unmasks the acyl silane for subsequent transformations such as photolysis, radical reactions, and heterocyclic synthesis. Other conditions for removing the dithiane moiety of 2-substituted-2-f-butyldimethylsilyl-l,3-dithianes include anodic oxidation, ceric ammonium nitrate (CAN)/NaHC03 in CH3CN/H2O, iodomethane/CaC03 in THF/H20, 8 and l2/CaC03 in THF/H2O. The formyl sUane of 2-t-butyl-dimethylsilyl-l,3-dithiane has also been reported." ... 

One involves the simultaneous encapsulation of the diene and dienophile components within the cyclodextrin cavity, overcoming the intrinsic entropic barrier associated with bringing these two reactive centers together. This was, in fact, the same argument put forth by Breslow to explain the effect of cyclodextrins on analogous intermolecular Diels-Alder reactions. Alternatively, one could also imagine encapsulation of the dithiane moiety by the cyclodextrin. Such complexation might also accelerate the reaction by... 

Yu and coworkers presented an elegant approach to (-)-hyacinthacine C5 164 (Scheme 33). It was based on the nucleophilic addition of 2-lithio-l,3-dithiane derivative (-E/ )-157 to cyclic, sugar-derived nitrone 156, followed by a Cope-House cyclization, which provided derivatives 158 and 159 as a separable mixture of diastereoisomers dr=l 1). Their reduction (performed independently for each isomer) with Zn/AcOH gave thioacetals 160 and 161. Subsequent removal of the dithiane moiety in 160, followed by a highly stereoselective reduction of the carbonyl group... 

Besides 1,3-oxathianes, the 1,3-dithiane 1-oxide moiety can be used for directing the nucleophilic addition of an organometallic reagent to a carbonyl group in a diastereoselective manner. The addition of methylmagnesium iodide to the 2-acyl-l,3-dithiane 1-oxide 23A leads exclusively to the diastereomer which is formed by Re-side attack. On the other hand, addition... 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

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