2-Acyl-2-alkyl-1,3-dithiane 1-oxides

Preparation of Racemic 2-Acyl-2-alkyl-1,3-dithiane 1-Oxide Systems... 

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. 

Alkylation and acylation of dithiane oxides are highly stereoselective processes. In such transformations, it is noticed that the anti substrate leads to the syn acyldithiane oxide (Scheme 4.55), with the choice of base being pivotal in the process. The use of butyllithium for acylation and sodium t-butoxide/butyllithium mixtures for alkylation with aldehydes tends to give the cleanest and most efficient reactions. Of late, simple 2-substituted dithiane oxides have been prepared with very high enantioselectivity, and such compounds have become the preferred starting materials for the various systems under scrutiny. 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

Diethyl-3,5-octadiene 174 Dithiane oxides alkylation of 84 carbanions of 84 Dithianes alkylation of 76,79 as acyl anion equivalents 75 carbanions of 76,79 cleavage of 14-18.76,79 desulfurization of 78 oxidation of 23... 

Variation of 2-alkyl substituent exerted an effect upon diastereoselectivity. The best diastereoselection was obtained when incorporating a 2-ethyl substituent for acyl dithiane oxides (Table 3.6). The diastereoselectivity and the sense of induced stereochemistry can be rationalized on the basis of a simple chelation control model. 

I -oxo-1,3-dithian-2-y 1)- 1-alkanone 2-acyl- 13-dithiane 1-oxide (alkylation) 1455... 

The chemistry of chiral 1,3-dithiane 1-oxides, in particular their use as chiral auxiliaries, has been reviewed <19980PP145>. Some further developments in this field are the stereoselective a-alkylation with alkyl halides <1997T13149> or a-hydrazination with di-fert-butyl azodicarboxylate (DBAD) <2000T9683>. The carbonyl group of 2-acyl-l,3-dithiane 1-oxides was also used as an electrophile (Scheme 82). Interestingly, acyclic enolates react with these substrates to give a 95 5 mixture of anti- and ry -adduct, whereas cyclic enolates produce a mixture of anti- and ry -adduct in 8 92 ratio <2000JOC6027>. 

From the synthetic point of view, the most important a-sulfinyl carbanions appear to be those derived from dithioacetal S-oxides which are a synthon for acyl anions65. However, the yields of the alkylation reaction were found to be low. In spite of the fact that dithiane S-oxides have been intensively studied66 63, their synthetic applications are limited,... 

Acyl silanes by anodic oxidation of2-alkyl-2-trialkylsilyl-l,3-dithianes... 

The cyclic a-lithio-l,3-dithiane S-oxide 406 was generated from compound 392 with n-BuLi at —10 °C and reacted with deuterium oxide, alkyl halides, carbonyl compounds and esters to afford the corresponding products 407 as mixture of diastereomers (Scheme 106)605 - 607. (V-Acyl imidazoles were better acylating agents than esters608. However, compound 406 has not been employed properly as acyl anion. Intermediate... 

Review. Seebach and Corey have published a general paper on the preparation and metalation of 1,3-dithianes and examples of the reaction of 2-lithio-l,3-dithianes with electrophilic reagents (alkyl halides, carbonyl compounds, acids, and oxides). The value of these sulfur-stabilized anionic reagents is that they are equivalent to acyl anions (a), in which the normal polarity of the carbonyl group is reversed (reversible umpolung). 

High diastereofacial selectivity has been observed in asymmetric Mannich reactions of 2-acyl-2-alkyl-l,3-dithiane 1-oxides, leading to P-amino ketones in good yield [118]. This study is of particular significance since stereoselectiAdty in the Mannich reaction has received relatively little attention [119]. 

Enantiomerically pure DiTOX systems (95) and (96) were used to prepare a-hydroxy acids [132], Page had previously described the stereoselective reduction of 2-acyl-2-alkyl-l,3-dithiane 1-oxides with DIBAL [113], and normally observed [132] a reversal of selectivity upon addition of zinc chloride. In this case (Scheme 4.73), THF solutions of the substrates were treated at -78°C with either DIBAL or DIBAL/ZnCl2 reducing systems. As expected, the DIBAL and DIBAL/ZnClz reducing systems gave products of opposite stereoselectivity in most cases only one product diastereoisomer was observed. 

Keto-esters.—Further examples of alkylations of the acyl anion equivalent (105) have been reported (c/. 2, 226 3, 16). Only in some cases can good yields of a-keto-ester dimethyl acetals be realized. In an extension of earlier work, N-aryl-triflamides have been found to be useful reagents for the overall oxidation of a-bromo-esters to a-keto-esters. Benzoylformates are accessible by carboxylation of anions derived from 2-aryl-l,3-dithians this approach seems to be an improvement on existing methods. 

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." ... 

Oxidative hydrolysis of 2-alkyl- and 2-acyl-l,3-dithians by iV-halogeno-succinimides is recommended as a high-yield method of carbonyl regeneration the combination of iV-chlorosuccinimide and silver(i) ion is suitable for reaction with unsaturated 1,3-dithians. In a related oxidative procedure, ketones and aldehydes can be readily regenerated from their ethylene thio- or hemithio-acetals by treatment with aqueous chloramine-T. 

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