Synthesis of highly functionalized β-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines

A rapid and simple procedure was devised for the synthesis of multifunctionalized cyclic β-amino esters and γ-amino alcohols via the 1,3-dipolar cycloaddition of nitrile oxides to β-aminocyclopentenecarboxylates. The opening of the isoxazoline reductive ring to the corresponding highly functionalized 2-aminocyclopentanecarboxylates occurred stereoselectively with good yields.


Results and Discussion
We recently reported a regio-and stereoselective procedure for the formation of a series of isoxazoline-fused cispentacin and transpentacin regio-and stereoisomers (2-6) from bicyclic β-lactam 1 [48,49] (Scheme 1). The syntheses consisted of a dipolar cycloaddition of nitrile oxide (generated with Boc 2 O, Et 3 N and DMAP) to the olefinic bond of cis-ethyl 2-aminocyclopent-3-enecarboxylate derived from 1, during which the isoxazoline-fused amino ester regio-and stereoisomers (2 and
Since isoxazoline-functionalized molecules are excellent precursors for the construction of different functional groups through reductive ring cleavage, our recent aim was to synthesize highly functionalized β-aminocyclopentanecarboxylate regio-and stereoisomers from the earlier prepared isoxazolinefused cispentacin and transpentacin derivatives.
For the reduction, we selected model compound 2 from earlier prepared isoxazoline-fused cispentacin stereoisomers to execute the reduction under different conditions. The isoxazoline-fused derivative was treated with the above-mentioned reducing agents. Unfortunately, neither transformation nor isoxazoline opening with ester reduction was observed. When the reduction was carried out with NaBH 4 in EtOH, three products were obtained: The epimerized isoxazoline-fused amino carboxylate 7 and amino alcohols 8 and 9 which were separated by chromatography and isolated (Scheme 2).
Thus, this reaction did not lead to the formation of highly functionalized isoxazoline ring-opened β-amino ester either. When ammonium formate in EtOH in the presence of Pd/C was investigated for the reduction of 2, the ring opening resulted in carbonyl compound 10 in rather low yield through the corresponding hydroxyimine intermediate, followed by elimination and saturation (Scheme 3).
Combinations of NaBH 4 (as a mild and selective reducing agent) with cobalt, nickel, iridium or rhodium halide have previously been employed for cleavage of the isoxazoline ring system, which is otherwise inert to NaBH 4 without such metal halide additives [50]. Accordingly, we investigated the reduc- tion of isoxazoline-fused amino ester stereoisomers 2 [48,49] with NaBH 4 in the presence of NiCl 2 (Scheme 4), which was found to be a suitable reducing system. The reduction carried out by adding NaBH 4 to a mixture of NiCl 2 and isoxazoline derivative 2 in EtOH/H 2 O, followed by amino group protection with Boc 2 O, selectively afforded only isoxazoline-opened product 12 as a single diastereomer in good yield. The reaction was exothermic and deposited a black granular precipitate, reflecting the presence of metal boride. The product was purified by column chromatography and the structure of 12 was certified by X-ray analysis ( Figure 2).
The isoxazoline opening occurred with the formation of a new stereocenter at a one-carbon distance from C-3. In accordance with earlier results [39][40][41][42][43][44][45][46][47], the hydrogenation of the isoxazoline proceeded through hydrogen attack from the carbamate side (cis to -NHBoc) of the cyclopentane skeleton. This was confirmed by X-ray analysis of 12.
In order to increase the number of multifunctionalized amino ester stereoisomers, we next examined the reductions of isoxazoline-fused cispentacin and transpentacin stereoisomers (3-6) The thermal ellipsoids are drawn at the 20% probability level. [49]. Reactions were carried out similarly with NaBH 4 in the presence of NiCl 2 in EtOH/H 2 O and led selectively to the corresponding multifunctionalized amino esters 13-16 in good yields (Scheme 5) as single diastereoisomers.

Conclusion
The present work has furnished a facile and efficient stereoselective reduction of isoxazoline-fused cyclic β-amino esters to multifunctionalized 2-aminocyclopentanecarboxylates through the use of NaBH 4 /NiCl 2 as reducing agent. As Peramivir related derivatives, highly functionalized cyclic amino esters may be regarded as promising bioactive compounds.

Experimental
The chemicals were purchased from Aldrich. The solvents were used as received from the supplier. Melting points were determined with a Kofler apparatus. NMR spectra were recorded on a Bruker DRX 400 MHz spectrometer in deuterated DMSO or CDCl 3 . Chemical shifts are expressed in ppm (δ) from the signal of internal tetramethylsilane. Mass spectra were recorded on a Finnigan MAT 95S spectrometer. Elemental analyses were recorded on a Perkin-Elmer CHNS-2400 Ser II Elemental Analyzer. FTIR spectra were recorded on a Perkin-Elmer Spectrum 100 instrument. Cycloadducts 2-6 were synthesized according to previously published procedures [8].
General procedure for the synthesis of compounds 8 and 9 To a solution of izoxazoline-fused β-aminocyclopentanecarboxylate 2 (0.96 mmol) in dry EtOH (15 mL) NaBH 4 (2.88 mmol) was added and the reaction mixture was stirred under reflux for 16 h. The reaction was quenched by the addition of H 2 O (10 mL) and then, the mixture was concentrated under reduced pressure. The reaction mixture was diluted with H 2 O (20 mL), washed with EtOAc (3 × 15 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (n-hexane/EtOAc) giving 8 and 9.
General procedure for the synthesis of 10 To a stirred solution of isoxazoline-fused β-aminocyclopentanecarboxylate 2 (1.6 mmol) in dry EtOH (15 mL), HCOONH 4 (3.2 mmol) and Pd/C (0.10 g) were added and the reaction mixture was stirred under reflux for 24 h. The mixture was filtered through a celite pad and the filtrate was evaporated in vacuo. The crude residue was diluted with EtOAc (30 mL), washed with H 2 O (3 × 15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/EtOAc), giving 10.