β -Lithiation of oxazolinyloxiranes: synthetic utility

β− Lithiated oxazolinyloxirane 13a , generated by deprotonation of ( R *, R *) trisubstituted oxazolinyloxirane 12a with s -BuLi/TMEDA in Et 2 O at –100 °C, was found to be chemically and configurationally stable for at least 1 h at this temperature and reacted stereospecifically with electrophiles to give the corresponding tetrasubstituted derivatives 14a–j with complete retention of configuration at the β− carbon


Introduction
Over the past fifteen years the oxiranyl anion-based methodology, a useful synthetic route to functionalized epoxides, 1 has been addressed a considerable interest due to the contribution of numerous research groups, 2 our research group included.In previous papers we demonstrated that α-lithiated oxazolinyloxiranes are sufficiently stable to be trapped with electrophiles. 3 In particular, we could prove that lithiation of cis and trans oxazolinyloxiranes of the kind of 1 followed by the reaction with electrophiles proceeded stereospecifically with retention of configuration under proper conditions to give α-substituted oxazolinyloxiranes 2 (Scheme 1). 4 O R R 1 Li However, oxiranyllithiums generated by lithiation of optically enriched oxazolinyloxiranes 3 underwent deuteration, alkylation and hydroxyalkylation (addition to carbonyl compounds) to give the corresponding α-substituted derivatives 4 in a poor diastereoselective manner (Scheme 2). 4,5 Base E dr: 50/50 -90:10

Scheme 3
This observation led us to develop a strategy for the synthesis of α-epoxy-β-amino acids 7 (Scheme 4). 7 Counting on the configurational stability of aryl-substituted lithiated oxiranes which allowed us to synthesize styrene oxide derivatives and an optically active oral antifungal agent of industrial interest, 8 we have also reported 9 that oxazolinyl α-β−aryltrisubstituted oxiranes can be β-lithiated and trapped with electrophiles.In particular, the reaction of (R*, S*) configured lithiated isomers 8 with carbonyl compounds allowed the development of a synthetic procedure to α,β-epoxy-γ-butyrolactones 9, which are a recurrent structural motif in many natural products of interest in medicinal chemistry (Scheme 5).
In connection with a research project mainly based on the use of this oxiranyl anion-based methodology for synthetic purposes we report herein on the β-lithiation of (R*, R*) configured α,β−disubstituted oxazolinyloxiranes.One example of β-lithiation in substituted oxiranes has been recently reported. 10

Results and Discussion
(1R*, 2R*)-and (1R*, 2S*)-1,2-Epoxy-2-(4,4-dimethyl-2-oxazolin-2-yl)-1-p-tolylpropanes 12a,b were synthesized by the Darzens reaction 11 of lithiated 2-(1-chloroethyl)-4,4-dimethyl-2oxazoline 10 with 4-methylbenzaldehyde according to a reported general procedure. 12The addition of 4-methylbenzaldehyde to a precooled THF solution of 10 at -98 °C furnished a diastereomeric mixture (syn + anti) of the chlorohydrins 11, which, without separation, were cyclized to the epoxides 12 upon treatment with NaOH/i-PrOH. 12Column chromatography separation (petroleum ether/AcOEt 7/3) gave pure 1,2-epoxy-2-(4,4-dimethyl-2-oxazolin-2-yl)-1-p-tolylpropanes 12a and 12b (overall yield 71 %, 1R*, 2S*/1R*, 2R* ratio = 1.3/1) whose configuration was established by 13 C NMR, as reported (Scheme 6). 9,13 N Li Then, pure (1R*, 2R*)-12a was subjected to lithiation.Treatment of 12a with s-BuLi (1.2 equiv) in the presence of TMEDA (1.2 equiv) in Et 2 O at -100 °C produced a red solution of 13a, which proved to be chemically and configurationally stable at this temperature for at least 1 h.Indeed, the deuterium quenching of the warmed up solution of 13a gave the corresponding βdeuterated starting epoxide 14a (> 98 % D) in excellent yield (> 98 %).Such a configurational stability is not unexpected if we just consider that lithiated styrene oxides (and 13a is a lithiated substituted styrene oxide) are configurationally stable. 8,9The stabilizing assistance in this case should be likely provided only by the aryl group.The configurational stability of 13a was also confirmed by its reactions with other electrophiles: methylation, trimethylsilylation and allylation took place stereospecifically with complete retention of configuration at the β-carbon to give trisubstituted epoxides 14b-d (Table 1).Oxiranes 14b-d were assigned the same R*, R* configuration of the starting epoxide 12a on the basis of the opposite stereochemistry found in the reaction of lithiated 12b with the same electrophiles. 9The reaction of 13a with symmetrical aliphatic, aromatic and alicyclic ketones similarly occurred with retention of configuration providing in good yields the corresponding oxazolinyl-β-epoxy alcohols 14e-i (Table 2).The reaction of 13a with benzaldehyde furnished a mixture of syn and anti oxazolinyl epoxy alcohols 14j 14 with no stereoselectivity with reference to the newly created stereogenic center.These stereoisomers could be easily separated by column chromatography even if in a low overall yield as, in consequence of a prolonged contact on silica gel, they tended to revert to the starting epoxide and the corresponding carbonyl compound (retroaldol reaction) (Table 2).The assignment of syn (or anti) stereochemistry was made on the basis of the characteristic resonance of the carbinol hydrogen (H A ) that in the case of the anti isomer was shifted downfield compared to that of the syn isomer, as reported for similar oxazolinyl epoxy alcohols. 4

Conclusions
In conclusion, we have applied the oxiranyl anion-based methodology for the β-functionalization of trisubstituted β-aryloxazolinyloxiranes (R*, R*) configured obtaining the corresponding stereodefined tetrasubstituted derivatives that seem to be promising in synthetic organic chemistry for the possible elaboration of one or both the oxazolinyl and the oxiranyl ring.The βdeprotonation occurred with complete retention of configuration at the β-carbon.It is worth noting that there is no influence of steric effects on the configurational stability of such lithiated styrene oxide derivatives.The chiral version of the above-described deprotonation-trapping sequence of oxazolinyl aryl oxiranes is under way in our lab and results will be reported in due course.

Experimental Section
General Procedures.Tetrahydrofuran (THF) and diethyl ether (Et 2 O) were freshly distilled under a nitrogen atmosphere over sodium/benzophenone ketyl.N, N, N', N'-Tetramethylethylenediamine (TMEDA) was distilled over finely powdered calcium hydride.All other chemicals were of commercial grade and used without further purification.Petroleum ether refers to the 40-60 °C boiling fraction.Commercial solutions of n-BuLi (2.5 M solution in hexanes) and s-BuLi (1.3 M solution in cyclohexane) were titrated by using N-pivaloyl-o-toluidine prior to use. 15For the 1 H and 13 C NMR spectra ( 1 H NMR 300, 500 MHz; 13 C NMR 75.4,125 MHz), CDCl 3 was used as the solvent.GC-MS spectrometry analyses were performed on a gas chromatograph HP 5890 II (dimethylsilicon capillary column, 30 m, 0.25 mm i.d.) equipped with a mass selective detector operating at 70 eV (EI).Melting points were uncorrected.TLC was performed on Merck silica gel plates with F-254 indicator; visualization was accomplished by UV light (254 nm) or by exposing to I 2 vapour.All reactions involving air-sensitive reagents were performed under nitrogen in oven-dried glassware using syringe-septum cap technique.

General procedure for preparation of β-substituted oxazolinyl p-tolyloxiranes 14a-j
A solution of 12a (100 mg, 0.41 mmol) and TMEDA (0.074 mL, 0.50 mmol) in 5 mL of dry Et 2 O at -98 °C (methanol/liquid nitrogen bath) and under N 2 was treated with s-BuLi (0.42 mL, 0.50 mmol, 1.2 M), and the resulting orange mixture was stirred for 1 h at -98 °C.Then, the electrophile (1.2 mmol) was added at once at this temperature, as pure liquid or as a solution in 1 mL of Et 2 O if solid.The resulting reaction mixture was allowed to warm up to room temperature, and quenched with sat.aq.NH 4 Cl.Then it was poured into saturated brine (20 mL), extracted with Et 2 O (3 × 10 mL), dried (Na 2 SO 4 ), and evaporated under reduced pressure.The crude mixture was flash-chromatographed (silica gel; petroleum ether/AcOEt 8-7/2-3) to give the corresponding β-substituted epoxides, which showed the following data:

Table 1 .
Reaction of 13a with electrophiles a Isolated yield by column chromatography.b Diastereomeric ratio determined by 1 H NMR spectroscopy; only one diastereomer in the 1 H NMR spectrum of the crude product.

Table 2 .
Reaction of 13a with carbonyl compounds a Isolated yield by column chromatography.b Diastereomeric ratio determined by 1 H NMR spectroscopy; only one diastereomer in the 1 H NMR spectrum of the crude product.c Overall isolated yield in both syn and anti stereoisomers (syn/anti = 1.2/1) separable by column chromatography (silica gel, AcOEt/petroleum ether 8/2).