The synthesis of N α-protected amino hydroxamic acids from N α-protected amino acids employing versatile chlorinating agent CPI-Cl

Racemization free synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing the versatile chlorinating reagent CPI-Cl has been described in one-pot. The present protocol has shown compability towards urethane protecting groups like Boc, Cbz and Fmoc, and side chain protections of amino acids showed complete tolerance.

][26] However, use of toxic and irritative ethyl chloroformate adds inconvenience, though the synthesis of hydroxamic acid from the corresponding carboxylic acid uses minimum reaction duration.Most of the reactions employed require long reaction durations, especially with the use of ester as precursor.Particularly, solid phase synthesis of hydroxamic acids have major disadvantages like they require profuse use of reagents, longer reaction times, and an additional step to release hydroxamic acid from resins makes solid phase strategy less preferred way to obtain hydroxamic acids.There are reports where hydroxamic acids were prepared from aldehydes; [27][28][29] however, use of catalysts and prolonged reaction durations makes the protocol less attractive.In addition, in amino acid chemistry, carboxylic acids are readily available to obtain hydroxamic acids compared to their aldehyde derivatives.
As aforementioned not many halogenating reagents have been reported to obtain hydroxamic acids from their corresponding carboxylic acids, especially in the synthesis of amino acid derived hydroxamic acids, as it involves acid sensitive Boc group.The halogenating reagents like SOCl2, oxalyl chloride and POCl3 are not suitable for halogenation for Boc-protected amino acids.Therefore, activating carboxylic acids with halogenating reagent having compatibility towards acid sensitive groups to obtain hydroxamic acids can be considered a useful strategy.
3,3-Dichloro-1,2-diphenylcyclopropene (CPI-Cl) has found its use not only as stoichiometric reagent but also as catalyst.As a result, it has been employed in many synthetic processes.CPI-Cl has been converted to cyclopropenylidene carbene complexe catalysts and employed for C-C bond formation reactions. 30,31It was also used to chlorinate carboxylic acids 32 and alcohols. 33It was found to catalyze Beckmann rearrangement to obtain amides/lactams from corresponding oximes. 34,35Recently, Sureshbabu et al. reported N α -protected amino acid azides employing stoichiometric CPI-Cl from N α -protected amino acid without affecting acid sensitive groups. 36n this regard, we herein demonstrate a useful application of CPI-Cl in the preparation of N α -protected amino hydroxamic acids from N α -protected amino acids.

Results and Discussion
In the initial trial reaction, Cbz-Gly (1a, 1.0 mmol) was taken as model substrate in CH2Cl2, and DIPEA (1.1 mmol) and CPI-Cl (generated by the treatment of 2, 3-diphenylcyclopropenone with oxalyl chloride in CH2Cl2, 1.0 mmol) were added at room temperature and stirred at the same temperature for ten minutes.
The reaction mixture was then cooled to -10 o C and treated with deprotonated hydroxylamine hydrochloride (obtained by treating hydroxylamine hydrochloride with methanolic potassium hydroxide) and stirred till the completion of the reaction.After simple aqueous workup and column chromatography, the compound 2a was isolated in good yield.In the next reaction, Boc-Phg was taken and the protocol was found to be compatible towards acid sensitive Boc-group, too.Similarly, Fmoc-amino acid hydroxamic acids were obtained in good yields.During the present study, water miscible solvents like acetonitrile, acetone and N, N'dimethylformamide were also tested and found to give poor yields of products.Scheme 1. Synthesis of N α -protected amino hydroxamic acids using CPI-Cl N α -protected serine, threonine and cystiene when employed in the present protocol, resulted in side reactions and found not suitable to use without their side chain protections.Fortunately, on employing their side chain protected analogues resulted in hydroxamic acids without affecting their side chain protections.Side chains of amino acids protected by benzyl, tertiary butyl and trityl groups were found to be stable towards present approach.Table 1.Library of N α -protected amino hydroxamic acids # β-amino acid Interestingly, 2, 3-diphenylcyclopropenone generated at the end of the reaction can be isolated by column chromatography and reused to prepare CPI-Cl.
Fmoc-D-Phe-NHOH was prepared and compared with Fmoc-L-Phe-NHOH by RP-HPLC studies using chiral column.Retention time (t R ) of Fmoc-L-Phe-NHOH was found to be 8.14 min and of Fmoc-D-Phe-NHOH was 5.51 min (Figures 2 and 3).Further, Fmoc-L-Phg-NHOH and Fmoc-D-Phg-NHOH showed retention times 9.16 min and 7.08 min, respectively, and thier equimolar mixture gave two distinct peaks at 9.77 and 7.56 min.These studies confirmed the present method is racemization free.

Conclusions
We have developed a mild protocol to synthesize N α -protected amino hydroxamic acids from N α -protected amino acids employing CPI-Cl.The reaction found to tolerate commonly employed N-protecting groups such as Boc, Cbz and Fmoc and retain optical purity of amino acids.

Experimental Section
General.All the chemicals were purchased from Sigma Aldrich Company, USA.All the solvents were freshly distilled and dried whenever required.TLC analysis was carried out using Merck aluminium TLC sheets (Silica gel 60 F254), the chromatograms were visualized by UV light and also by exposing in an iodine chamber.Column chromatography using mixtures of ethyl acetate and hexane as eluents through silica gel (100-200 mesh).HRMS spectra were recorded in a XEVO-G2-XS-Q-TOF mass spectrometer. 1H and 13 C NMR were determined in Brucker AV NMR (400 MHz, 100 MHz) spectrometer.Melting points were determined in an open capillary and are uncorrected.Optical rotations were recorded at 25 o C. The RP-HPLC analysis of epimers was carried out using an Agilent instrument (method: gradient 0.1% TFA water-acetonitrile (0-100%) in 20 min; VWD at λ 254 nm; flow rate: 1.0 mL/min; column: Agilent Eclipse, XDB-C18, pore size 5 μm, diameter × length = 4.6 × 150 nm).
General procedure for the synthesis of N α -protected amino hydroxamic acid.To a solution of 3,3-dichloro-1,2-diphenylcyclopropene at -10 o C [1.1 equiv.prepared by adding diphenylcyclopropenone (1.0 equiv.) in DCM and oxalyl chloride (1.0 equiv.) at rt and stirred until the gas evolution has ceased] was added a solution of N α -protected amino acid (1.0 equiv.)and diisopropylethylamine (1.2 equiv.) in dichloromethane and stirred.After 10 min hydroxylamine hydrochloride (NH2OH.HCl, 1.5 equiv.) in methanolic potassium hydroxide was added to the reaction mixture and stirred of another 45 min.The solvent was removed under reduced pressure; the residue obtained was diluted with EtOAc, washed with 10% citric acid solution, water and brine solution.The organic phase was dried over anhydrous Na2SO4 and removed under reduced pressure.The crude residue was purified by column chromatography using n-hexane and ethyl acetate as eluents.