Oxazoline-N-oxide mediated asymmetric cycloadditions. Recent progress in the stereo- selective syntheses of β-lactones and β-lactams*

Camphor-derived oxazoline-N-oxides are versatile dipoles in a new kind of asymmetric [2+3] cycloadditions. Recent applications of this methodology allowed the stereoselective syntheses of several β-lactones natural products such as 1233A and tetrahydrolipstatine. Two formal syntheses of β-lactams antibiotics, β-methyl thienamycin and carpetimycin A, have also been achieved using this type of cycloaddition. Cycloaddition reactions are one of the most important tools for the straightforward construction of complex molecules. Some years, ago we described a new type of asymmetric [2+3] cycloaddition using camphor-derived oxazoline-N-oxides as dipoles. It was anticipated according to Scheme 1 that cycloadditions between dipole 1 and an appropriate dipolarophile should give to adduct 2 in which latent carbonyl and alcohol functional groups are inherently protected. This particular feature should allow functional group transformation on substituents R2 and R3. Final hydrolysis and hydrogenolysis should give rise to anti aldol 3 and the whole process could be considered as an asymmetric hydroxyacylation of alkenes. This type of cycloaddition can also be compared with [2+3] cycloadditions with nitrile oxides, but the control of the asymmetric induction should be much easier in the case of rigid tricyclic dipoles, such as 1, than with a linear functional group as nitrile oxide. Camphor-derived oxazoline-N-oxides 1 are easily prepared from camphorquinone 4 according to Scheme 2. Oximation of the less indered ketone in 4 gave rise to oximino camphor 5 which was sequentially reduced into hydroxylamino iso borneol 6 [1,2]. According to a process described by Coates [3] in achiral series, condensation of 6 with trimethoxy orthoesters in the presence of 4 Å molecular sieves as methanol scavenger afforded the anticipated dipole 1. These compounds proved to be rather unstable, and purification induced loss of material. However, direct cycloaddition with a reactive dipo*Lecture presented at the 13 International Conference on Organic Synthesis (ICOS-13), Warsaw, Poland, 1–5 July 2000. Other presentations are published in this issue, pp. 1577–1797. †Corresponding author Scheme 1 larophile such as phenyl isocyanate afforded in very good yield the anticipated adduct 7. This experiment is an indirect proof of the efficiency of condensation reaction betweeen 6 and orthoesters [1]. Dipoles 1 reacted smoothly with various β-substituted α,β-unsaturated esters in dichloromethane or toluene as solvents. These cycloadditions are highly regio, endo, and diastereoselective, and single cycloadducts 8 were isolated in good yields. However, selectivities are not so good with acrylic esters, a small amount of regio and exo isomers being also obtained in these cases (Scheme 3) [1]. These cycloadditions are the result of highest occupied molecular orbital (HOMO) dipole and lowest unoccupied molecular orbital (LUMO) dipolarophile interaction. Semi-empirical calculations revealed that the presence of an endocyclic oxygen atom in oxazoline-N-oxides reduces the frontier orbital separation compared to the corresponding nitrones: it shifts the HOMO to higher energy and LUMO to a lower energy. This allows for a stronger interaction between the dipole HOMO and dipolarophile LUMO [4]. The presence of syn methyl group in the camphor bicyclic framework precludes any approach by the β face of the dipole as indicated in the proposed transition state. O. DIRAT et al. © 2000 IUPAC, Pure and Applied Chemistry 72, 1721–1737 1722