Synthesis of achiral and chiral N -protected γ -amino- β -ketones and β - ketoesters

Novel chiral N -carbamate-protected γ -amino- β -ketones 3a – c and the known N -carbamate-protected nitroketone 3d were prepared from the corresponding 1-( N -protected α -aminoacyl)benzotriazoles 1 by reaction with nucleophiles 2a–d in the presence of bases under mild conditions. Similarly achiral and chiral N -protected γ -amino- β -ketoesters 3e–l were prepared by reaction with acetoacetates in the presence of sodium hydride.


Introduction
Synthesis and development of N-protected γ-amino β-ketones and β-ketoesters has attracted interest for decades since they afford building blocks for intermediates and bioactive pharmaceuticals.Thus optically active α-amino ketones, which can be prepared via decarboxylation of N-protected γamino-β-ketoesters, are useful chiral building blocks for the preparation of biologically active natural products including polyfunctional amino acids, amino polyols such as amino sugars and peptide mimics which may act as enzyme inhibitors. 1,2enzotriazole has been employed extensively as a synthetic auxiliary. 31-Acylbenzotriazoles are stable, may be prepared directly from carboxylic acids in high yields 4 and have been widely used in N-, 4b,5 C-, 6 O-, 6d,7 and S-acylations. 8cently we prepared β-keto esters and β-diketones by C-acylative/deacetylation of acetoacetic esters and acetonyl ketones with 1-acylbenzotriazoles. 6d We have now extended this methodology to the preparation of achiral and chiral N-protected γ-amino-β-keto esters via C-acylation of acetoacetic esters with achiral and chiral 1-(N-protected α-aminoacyl)benzotriazoles, followed by spontaneous deacetylation.More importantly however, we have used similar benzotriazole technology to prepare the first reported representatives of these new classes of functionalized chiral + 1d 2d 3d (4)   t-BuOK DMSO, rt, 8 h

Scheme 1
All the above reactions gave good yields except reaction 3, which produced several unidentified by-products (Table 1).The structures of chiral N-carbamate-protected γ-amino-β-ketones 3a-d, are supported by spectroscopic data and microanalyses.The 1 H and 13 C NMR spectra in CDCl 3 indicate that 3a exists essentially in the enol form with a trace of the keto form, consistent with previously reported l studies.6d,10 Compound 3c is a mixture of keto and enol forms (10 : 7) and 3b and 3d are fully keto forms.Thus the 1 H NMR spectrum of 3a shows a singlet at 5.57 ppm (enolic methine proton) and a broad singlet at 15.11 ppm (enol hydrogen) and its 13 C NMR spectrum shows a signal at 99.0 ppm (enolic methine carbon).The 1 H spectrum of 3c shows an AB quartet at 3.90 and 4.06 ppm (αmethylene protons of the keto form) and a singlet at 5.26 ppm (enolic methine proton of the enol form), and its 13
+ To obtain optimal yields it was crucial to keep the molar ratio of nucleophiles 2 to acylbenzotriazoles 1 at 3 : 1 and the reaction temperature at 0 ºC for a minimum of three hours.
The yields achieved by the synthetic methodology for 3e-l are comparable or somewhat inferior to those reported in the literature for direct reaction of ethyl acetate anion with N-protected amino esters (89%) 12 or by the reaction of allyl or aralkyl acetates with N-protected amino acids in the presence of N,N'-carbonyldiimidazole (75-87%). 13e structure of the known N-protected γ-amino-β-keto ester 3f is supported by comparison of its melting point and spectroscopic data with a literature report. 11The structures of the novel Nprotected γ-amino-β-keto esters 3e,g-l are supported by spectroscopic data and microanalyses.The 1 H NMR spectra of the achiral 3e-g show new sets of singlets at 3.40-3.59ppm assigned to the αmethylene protons and their 13 C NMR spectra show signals at 46.2-47.9ppm corresponding to the α-methylene carbons.The 1 H NMR spectra of the chiral 3h-j,l show AB quartets at 3.43-3.61and 3.49-3.64ppm, due to the presence of two magnetically non-equivalent α-methylene protons.Chiral 3k is an exception, in which the α-methylene protons are seen as a singlet at 3.58 ppm instead of an AB quartet.The 13 C NMR spectra of the chiral 3h-l contain signals at 46.2-47.1 ppm corresponding to the α-methylene carbons.The 1 H and 13 C spectra of 3e-g in CDCl 3 show only the keto form whereas 1 H and 13 C spectra of chiral 3h-l show mixtures of keto and enol forms with the former predominating.A broad singlet at 12.0-12.13ppm in the 1 H NMR spectra of 3h-l is assigned to the enol hydrogen.The only olefinic carbon signal detected among the enol forms of 3e-l is at 90.0 ppm in chiral β-keto ester 3k.Apparently steric effects in 3e-l play an important role in determining the tautomeric equilibria.Thus γ-di-substituted 3h-l tend to stabilize enol forms, while γ-mono-substituted 3e-g do not.
N-Carbamate-protected α-amino ketones 4a,b 14 were prepared via β-keto esters 3e,h in 85-86% yields following a literature procedure (Scheme 4 and Table 3).13b It should be noted that the method is compatible with a variety of functional groups and carbamate protecting groups.
Scheme 4 In summary, procedures for the preparation of achiral/chiral N-protected γ-amino-β-ketones and β-ketoesters have been developed by treatment of starting nucleophiles or acetoacetates with achiral/chiral 1-(N-carbamate-protected β-amino)acylbenzotriazoles in the presence of a base under mild conditions.The advantages of this method include: (i) most acylbenzotriazoles are stable over months; (ii) the use of acylbenzotriazoles offers mild reaction conditions, operational ease and, importantly, O-acylation is greatly reduced; (iii) achiral/chiral N-protected γ-amino-β-ketoesters and analogues are obtained in good to excellent yields by one-pot methodology with retention of chirality.

Experimental Section
General Procedures and Materials.Melting points were determined on a hot-stage apparatus and are uncorrected.Optical rotations were measured on a PERKIN-ELMER 241 polarimeter.NMR spectra were recorded in CDCl 3 with TMS as the internal standard for 1 H (300 MHz) and CDCl 3 as the internal standard for 13 C (75 MHz), unless otherwise specified.All reactions were carried out under an atmosphere of nitrogen unless otherwise specified.Anhydrous THF was obtained by distillation immediately prior to use, from sodium/benzophenone ketyl.Column chromatography was carried out on silica gel S733-1 (200−425 mesh).

Procedure for the preparation of benzyl N-{(1S,2S)-2-methyl-1-[2-(phenylsulfonyl)acetyl] butyl}carbamate (3b).
To a solution of methyl phenyl sulfone (0.78 g, 5 mmol) in THF (37 mL) was added BuLi (1.6 M, 6.25 mL, 10 mmol) at -78 ºC and stirring was continued for 1 h under nitrogen.A solution of Z-L-ILE-Bt (1.83 g, 5 mmol) in THF (20 mL) was added by syringe.The resulting mixture was stirred at -78 ºC and the temperature was allowed to rise to rt during 8 h.The mixture was quenched with a solution of saturated aqueous ammonium chloride and extracted with ethyl acetate (150 mL).The extract was washed with aqueous sodium carbonate (1M, 2 x 100 mL), dried over anhydrous magnesium sulfate and solvents removed under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixture of hexanes/ethyl acetate as eluant (4-3/1, v/v) to give an impure oily product, which was dissolved in a mixture of ether and hexanes and cooled in the freezer (twice) to give the pure product benzyl

General procedure for the preparation of achiral and chiral N-protected γ-amino-β-keto esters 3e-l
To a solution of an acetoacetate ester (2a-h, 15 mmol) in THF (60 mL) was added NaH (60%, 0.70 g, 17.5 mmol) at room temperature and stirring was continued for 30 min under nitrogen.The reaction mixture was cooled to 0 ºC for 10 min before a solution of an acylbenzotriazole (1a-h, 5 mmol) in THF (40 mL) was added by syringe.The resulting mixture was stirred at 0 ºC for 3 h and rt for 1 h.A small amount of silica gel was added and THF was removed under reduced pressure.The residue was purified by column chromatography on silica gel using a mixture of hexanes/ethyl acetate as eluant to give the corresponding achiral and chiral N-protected γ-amino-β-keto esters.

General procedure for the preparation of N-carbamate-protected α-amino ketones 4a,b
To a stirred solution of palladium acetate (20.74 mg, 0.092 mmol), PPh 3 (49.44mg, 0.189 mmol), formic acid (0.29 mL, 7.25 mmol), and Et 3 N (1.31 mL, 9.4 mmol) in dry THF (15 mL) was added dropwise a solution of the corresponding allyl esters 3a or 3d (3.77 mmol) in THF (29 mL) at room temperature under nitrogen.The mixture was stirred for 8 h for 6a and 45 h for 6b.After the filtrate was concentrated, the residue was purified by column chromatography on silica gel using a mixture of hexanes/ethyl acetate as eluant to give the corresponding N-carbamate-protected α-amino ketones.