1.3- Dithianes metallated

Dithiane metallate alkylation was introduced by Corey and Seebach in 1965 and has served well as a method for forging carbon-carbon bonds at a masked carbonyl group by nucleophilic displacement. The method, an example of an umpolung process, has found extensive use for advanced fragment assembly in target-directed synthesis. Contributions from the Smith research group at the University of Pennsylvania, in particular, have served to demonstrate the power of this... 

Scheme 8.31 Smith Ill s three- and multicomponent linchpin coupling of metalated silyl dithiane 109 with epoxides.

The ligand properties of a cyclic dithioether, 1,4-dithiane monosulphoxide (DTMSO), have been studied by physical measurements . The infrared spectra indicate that the metal cation coordinates to the oxygen lone pair electrons of DTMSO. Both infrared and ligand-field spectra show the presence of octahedral ions MfDTMSO) in the compounds M(DTMS0)g(C104) and M(DTMSO)g(BF4) . In the case of M = Cu these ions are distorted from the regular octahedral structure. 

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 most important use of 1,3-dithianes (792) stems from their ability to function as acyl anion equivalents (794 Scheme 184). Metallation of this heterocycle followed by alkylation of the anion and cleavage of the dithiane group produces a carbonyl compound. Since such aspects of dithiane chemistry have been extensively documented (69S17 75JOC231), only a few of the more current applications of these heterocycles are highlighted. We again note here that the application of heterocycles to the synthesis of carbonyl compounds has been the sole subject of an extensive review (77H(6)73l). 

Dithioacetals (see also dithianes and dithiolanes) alkylation of 98 as acyl anion equivalents 75 carbanions of 87,97-102 cleavage of 14-18,98,102 desulfurization of 78 metal-catalysed coupling 127 reaction with Grignard reagents 127 reductive lithiation of 89 synthesis of 12-19,97-102 Dithioacids synthesis of 40... 

Metallation of (4) followed by protonation gave (5), and (6) was obtained by hydrolysis of the dithiane. 

Halo-1,3-dithiane trans-l,3-dioxides (80 X = Cl, Br) act as diastereoselective carbonyl anion equivalents in reactions with aldehydes.117 The scope of the reaction has been explored by varying the temperature, the aldehyde, and the metal used as counterion. Similarly, metal 1,3-dithianides (81 M = Li, Cu1) can be added diastereoselec-tively to chiral aldehydes subsequent hydrolysis yields an a-hydroxyaldehydc.118... 

The scope and limitations of the metal anions of 2-halo-l,3-dithiane trans-1,3-dioxide as diastereoselective carbonyl anion equivalents has been explored with regard to reaction with aldehydes.79 Reactions of metallated trans-, 3-dithiolanc 1,3-dioxide (five-membered ring) with aldehydes under kinetic and thermodynamic control have also been studied and contrasted with those of the metallated monooxide, parent sulfide, and 1,3-dithiane 1,3-dioxide (six-membered ring).80... 

Metalation of 2-substituted 1,3-dithianes.1 This combination (1 1) is more efficient than BuLi/TMEDA for this metalation at —78°. The active species may be BuNa. Moreover, the resulting anion undergoes facile reaction with various electrophiles, even epoxides. 

In the early stages of the project, we reasoned that the sulfoxide unit might be expected to influence the transition state geometry of the 2-acyl side chain, perhaps by chelation to a metal counterion, and hence control the stereochemistry of a wide range of functional group transformations. Indeed, a chelation control model of the reactivity of the 2-acyl dithiane 1-oxide systems has allowed us to rationalize, and predict, the stereochemical outcome of most of the reactions studied so far. These predictions have, in many cases, been confirmed by X-ray structure determination of the relative stereochemistries within product structures.1-4... 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

All types of electrophiles have been used with 2-lithio-l,3-dithiane derivatives, including alkyl halides, sulfonates, sulfates, allylic alcohols, arene-metal complexes, epoxides, aziridines, carbonyl compounds, imines, Michael-acceptors, carbon dioxide, acyl chlorides, esters and lactones, amides, nitriles, isocyanates, disulfides and chlorotrialkylsilanes or stannanes. The final deprotection of the dithioacetal moiety can be carried out by means of different types of reagents in order to regenerate the carbonyl group by heavy metal coordination, alkylation and oxidation184 or it can be reduced to a methylene group with Raney-nickel, sodium or LiAIII4. 

For the fast ge/w-dialkylation of 1,3-dithiane dianion, tin-lithium transmetallation at the 2-position of dithiane is a much faster process than the corresponding deprotonation. 2,2-Bis[tri(n-butyl)stannyl]dithiane (175)223 can be alkylated sequentially it was trans-metallated with n-BuLi at —78 °C, after 5 minutes treated with the first alkyl halide and after 10 more minutes the process was repeated providing dialkylated products224. This strategy has been used in the total synthesis of (—)-perhydrohistrionicotoxin, namely preparing the key compound 178 employing successively iodides 176 and 177 as electrophiles (Scheme 50)224. 

Activation of aromatic compounds by transition-metal complexes was initially studied with Cr(CO)3 complexes. Nucleophilic addition of 2-lithio-l,3-dithianes to arene-chromium(O) complexes 185 followed usually by iodine-promoted decomplexation affords the corresponding 2-arylated 1,3-dithianes 186. The reaction of //-(toluene)- and (anisole)tricarbonylchromium (185) with compound 161 gave mixtures (52 46 and 10 90, respectively) of ortho and meta substituted derivatives (186) (Scheme 54)244. The meta directing effect was also observed (mainly better than 95%) with amino and fluoro substituted complexes245. 

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