Acyl dithiane oxide

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. 

As with our other acyl dithiane oxide systems, the thioacetal moiety can be readily removed by hydrolysis, in this case without affecting the dihydroisoxazoline ring (Scheme 11). 

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... 

Since 1987 our group has been concerned with the design, synthesis, development, and more recently the application of dithiane 1-oxide derivatives as asymmetric building blocks for organic synthesis. This review focuses on the development of highly diastereoselective reactions, principally carried out at the acyl side chain of 2-acyl dithiane 1-oxide derivatives (1). 

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... 

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. 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

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... 

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

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,... 

The l,3-dithiane-l,3-dioxides can also be prepared by sodium periodate oxidation of the 1,3-dithiane, and the irons isomer was thus obtained in a 58% recrystallized yield [81]. Chiral molecules of this type (C2 symmetry ) are particularly suitable for use as chiral acyl anion equivalents [11,82]. 

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)). 

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

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

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

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

While such transition-state models have helped us to rationalize the patterns of selectivity observed in other reactions of 2-acyl- 1,3-dithiane 1-oxide substrates, such clear trends are not found in conjugate addition reactions (Table 3). One simple explanation for the poorer levels of stereoselectivity may be bond rotation within the acyl substituent, allowing the enone moiety to attain conformations other than those shown in 17 and 18. 

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. 

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