Diastereo-and enantioselective syntheses of heteroaryloxiranes

α -Chloroheteroarylalkyllithiums generated by deprotonation of 2-(1-chloroalkyl)-heterocycles with n -BuLi in THF at –78 °C, were found to react as Darzens-type reagents with racemic and optically pure 2-and 3-methylcyclohexanones. Heteroaryloxiranes containing new stereocentres were isolated in a diastereo-and enantioselective manner


Introduction
The deprotonation of α-chloroheteroarylalkanes with n-butyllithium (n-BuLi) or lithium diisopropylamide (LDA) at -78 °C in THF, provides carbanions relatively stable due to the presence, in their framework, of an aza heterocycle in α position and an adjacent electronegative chlorine atom, which add a further electron-withdrawing effect. 1 An interesting diastereoselectivity has been observed in the coupling reaction of the above carbanions with carbonyl or iminic compounds affording oxiranes and aziridines, respectively. 2The option of deblocking the oxiranyl ring 3,4 as well as the potential elaboration of the aza heterocycle to a carbonylic function, make these compounds extremely useful intermediates in the organic synthesis of biologically active compounds. 5It has been reported that the coupling reaction of lithium azaenolates of chiral oxazolines with carbonyl compounds 6 produces asymmetric induction leading to chiral oxiranes.Moreover, the deprotonation of substituted oxazolinyloxiranes with strong bases has been reported, affording oxiranyl anions chemically and configurationally stable to react stereospecifically with electrophiles; 7 recently the coupling The coupling reaction can occur by two possible attacks of the carbanion to the electrophile affording four possible diastereoisomers.According to the route α, a carbanion attack of anti type towards the cyclohexanic CH 3 should take place leading to the diastereomers a (trans configuration) and b (cis configuration).An attack of syn type, as showen by the route β, should produce diastereoisomers c (trans configuration) and d (cis configuration).
b] Diastereomeric ratio (dr) determined by GC and 1 H NMR spectroscopy.
The results reported in Table 1 could be explained by the following considerations.When 3methylcyclohexanone is used as electrophile (Scheme 1) the steric hindrance exerted by the cyclohexanic CH 3 is not significant, consequently the carbanion's attack seems to take place on either of the faces (route α and β) with equal probability.The diastereomeric ratios measured (Table 1, entries 1-7) therefore, showed a predominance of a and c structures generated by an anti and a syn attack of the α-chloroheteroarylalkyllithiums to the 3-methylcyclohexanone, respectively.As these structures are both of trans configuration, we presume that the stereoselective determining step is a transition state energetically favoured, which evolves to the final oxiranic structure.The Scheme 2 shows, as previously reported, 10 that the stable azaenolate reacts with the ketone affording two possible transition states TS 1 and TS 2 .The probable internal coordination of lithium by the nitrogen and the oxygen atoms generates TS 1 energetically more favoured than TS 2 because of the different interaction between the heterocyclic moiety and the methyl-substituted branch of the ketone.
These considerations might explain the trans diastereoselection of a and c structures compared with the cis diastereoisomers b and d which should be generated by the TS 2 transition state.Exceptionally, the substrates 3 and 6 gave four diastereomers in a unitary ratio (entries 3 and 6).
With the 2-methylcyclohexanone, having the CH 3 group closer to the reaction centre the carbanions attack seems to follow preferably the less steric hindered route α (Scheme 1) of anti type towards the cyclohexanic methyl.The sole diastereoisomers isolated were predominantly of a and b structures (Table 1, entries 8-14) afforded by an anti attack of the carbanion to the electrophile (route α).Among a and b structures, the diastereoisomer a, of trans configuration, was mostly obtained, which should be generated by the less hindered TS 1 transition state.Only the substrate 5 produced also a small amount of the diastereoisomer c (entry 12), while the carbanion 6 gave, together with a and b, the structures c and d but in much lower yields (entry 13).The heteroarylalkyllithium 1, instead, showed a complete diastereoselectivity (entry 8): the sole product 2a of trans configuration was isolated, clearly generated by the α route through the TS 1 transition state.The different isomeric distribution could be justified by a different internal coordination of lithium by the nitrogen and the oxygen atoms, depending on the various heterocyclic moiety among the transition states.
In order to extend the above results, a few coupling reactions, leading to a sole diastereoisomer or to a diastereoisomeric mixture separable by chromatography, were carried out also with the enantiopure (R)-3-methylcyclohexanone, (R)-2-methylcyclohexanone, and (S)-2methylcyclohexanone affording heteroaryloxiranes optically pure.The results and the optical rotation measurements are reported in Table 2.
The trans and cis relative configurations for all the above compounds were assigned in comparison with the structure (+)-2a, which was assigned by X-ray measurements, and considering also the oxiranic oxygen atom and the heterocycle influence on the chemical shift of the cyclohexanic CH 3 .An heteroatom having a lone pair deshields the protons lying in the Van der Waals radius, therefore the δ CH3 of the structures a and b is always bigger than that showed by the structures c and d, having, these latter, the farthest oxygen atom.Moreover, the differences between the structures a and b, and c and d were ascribed to the anisotropic effect exerted by the different positions of the heterocycles.

Conclusions
α-Chloroheteroarylalkyllithiums 1-7, easily available by lithiation of chloroheteroarylalkanes, react as Darzens-type reagents with racemic and enantiomerically pure methylcyclohexanones to form substituted heteroaryloxiranes in a stereoselective way.The structures of the various diastereoisomers and enantiomers isolated were supported by a reliable mechanism.The option of freeing the masked acyl group of the heterocyclic moieties, together with the presence of an oxiranic ring give a remarkable synthetic interest to the isolated compounds, which are useful intermediates for more complicated organic syntheses.

Table 1 .
Summary of coupling reactions between α-chloroheteroarylalkyllithiums and carbonyl compounds affording heteroaryloxiranes

General procedure for the preparation of heteroarylalkyloxiranes Method
13MHz and 100.62MHz, for 1 H and13C, respectively) and a Bruker AC200 apparatus (200 MHz and 50.3 MHz, for 1 H and 13 C, respectively); with CDCl 3 as solvent and TMS as internal standard (δ = 7.24 for 1 H spectra; δ = 77.0 for 13 C spectra).The IR spectra were recorded on a Perkin Elmer spectrometer Model 283.GC-MS analyses were performed with a Shimadzu GC-17A gas chromatograph (5% diphenyl / 95% dimethylpolysiloxane capillary column, 30 m, 0.25 mm i.-or 3-methylcyclohexanone in THF (10 mL) was added dropwise.The reaction mixtures were kept at -78 °C for 30 min, and then warmed up and kept at room temperature for 4h.The mixtures were then quenched with 10 mL of a saturated aqueous NH 4 Cl solution, and extracted with Et 2 O (3 × 20 mL).The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuum.The crude products were purified by column chromatography (silica gel, petroleum ether/Et 2 O, 7:3) to afford the pure oxazolinyloxiranes (oils), yields: 65-80%.