L-Glutamic acid and L-alanine derivatives as building blocks for the synthesis of a chiral monomer precursor of AABB-type polyamide

The chiral monomer N -(1´-amino-2´-( S )-propyl)-5-oxo-2-( S )-tetrahydrofurancarboxy-amide hydrochloride ( 11 ), a precursor of a AABB-type stereoregular polyamide, has been synthesized from pentachlorophenyl 5-oxo-2-( S )-tetrahydrofurancarboxylate ( 2 ) and 2-( S )-amino-1-propanol ( 3 ). Compounds 2 and 3 are derivatives of the natural amino acids L -glutamic acid and L -alanine, respectively. The regioselective attack of the amino group of 3 to the ester function of 2 led to N - (1´-hydroxy-2´-( S )-propyl)-5-oxo-tetrahydrofurancarboxyamide ( 4 ) in 80% yield. However, the tosylation of the primary hydroxyl group of 4 , and the subsequent substitution by azide to give 6 , took place with low yields. Therefore, an alternative route was conducted starting from 3 , which was selectively N -protected as the tert -butyloxycarbonyl derivative ( N -Boc), O -tosylated and substituted by azide to afford 1-azido-2-( S )- N -( tert -butyloxycarbonyl)aminopropane ( 9 ) in 41% yield from 3 . The amino group of 9 was deprotected by acid hydrolysis and the resulting amine 10 was regioselectively condensed with 2 to give the azide derivative 6 . Hydrogenolysis of 6 afforded the desired monomer 11 in 69% yield from 2 and 10 .


Introduction
Common polyamides are a source of environmental pollution as they are resistant to chemical and enzymatic degradation.The highly ordered structures of polyamides, due to strong intramolecular interactions caused by hydrogen bonding, are responsible for their low biodegradability.Such polyamides are based on petroleum, a non-renewable resource, which is expected to become difficult to obtain in the near future.One strategy to solve the problems of fossil resources and environment relies upon the utilization of natural regrowing products for the chemical synthesis of polymers.2][3][4] For example, the amide linkages of polyamides formed by sebacic acid and L-phenylalanine itself, or together with L-valine, were cleavable by chymotrypsin. 5Also, copolyamides of caprolactam and L-phenylalanine were susceptible to biodegradation. 6In our laboratory, we have employed common monosacharides [7][8][9] and amino acids [10][11][12] for the synthesis of potentially biodegradable, stereoregular polyamides.In particular, the synthesis of stereoregular polyamides of AABB-type is difficult when the monomers derived from carbohydrates or amino acids possesses one or more stereocenters in their structures. 1,12,13he requirement for the construction of a stereoregular polymer is the existence of a 2-fold axis of symmetry in the precursor monomer.Otherwise, regioisomerism occurs during the polycondensation leading to a non-stereoregular polyamide with the building blocks radomly oriented along the polymer chain.Therefore, stereocontrol in the polymerization is needed when non-symmetric monomers are employed. 11,12,14n the present work we wish to report the synthesis of a monomer precursor of a nonpolypeptidic stereoregular AABB-type polyamide.For the preparation of such a monomer we employed a diacid derived from L-glutamic acid and a diamine derived from L-alanine.The resulting polyamide will possess in both, the diamine and diacid units, a stereocenter having the S-configuration.It has been reported [1][2][3] that analogous materials could be employed as chiral matrices in asymmetric synthesis.

Results and Discussion
The diacid derivative 2 was prepared by deamination of L-glutamic acid (1) with nitrous acid 15 followed by activation of the carboxylic acid function with pentachlorophenol. 11Compound 2 reacted with L-alaninol (2-(S)-amino-1-propanol, 3), the commercially available product of reduction of L-alanine (Scheme 1).The reaction was highly chemo-and regio-selective to give the single regioisomer 4 from the four theoretically possible.Compound 4 was obtained crystalline from the reaction mixture in 80% yield.The high selectivity for the addition through the amino group of 3 should be expected as the amine function is a better nucleophile than the alcohol.The higher reactivity of the pentachlorophenyl ester of 2 with respect to the lactone group may be attributed to the fact that the pentachlorophenolate is a weaker base (a better leaving group) than the alkoxide, and also because the ester group possesses a hydroxy substituent on the α-carbon, which increases the rate of aminolysis. 16The structure of 4 was confirmed by NMR spectroscopy.Thus, the 13 C NMR spectrum of 4 showed the signals for the amido and lactone carbonyl carbons, the carbon bonded to oxygen (C-1´, 65.8 ppm) and to nitrogen (C-2´, 47.4 ppm) and the aliphatic carbons (C-3, 4, and C-3´).Furthermore, the low field resonances for C-2 (77.5 ppm) and H-2 (4.86 ppm, in the 1 H NMR spectrum of 4) indicated that the lactone ring remained intact, as those signals appear more shielded on opening of the lactone.

Scheme 1
To convert the free hydroxyl group of 4 into amine, the sequence of sulfonylation and subsequent substitution by azide was followed.The tosylation afforded 5 in low yield, under the various reaction conditions employed.A yield somewhat better (34%) was obtained when the sulfonylation was conducted by a modification of the procedure described by Kabalka et al., 17 using as solvent dichloromethane containing three molar equivalents of pyridine.However, 5 was also rather unstable to the various conditions employed for the substitution by azide, and decomposition ocurred in all the cases attempted.Therefore, the azide derivative 6 was obtained in low yields.Since compound 6 is the immediate precursor of the desired "amino acid" 11, an alternative route was designed for the synthesis of 6 (Scheme 2) starting from L-alaninol (3).Protection of the amino group of 3 with di-tert-butyldicarbonate afforded the N-Boc derivative 7 (97% yield).The primary hydroxyl group of 7 was converted into the tosylate 8 (70% yield) by the procedure mentioned above. 17The substitution of the sulfonyloxy group by azide was conducted in DMF at 70 ºC for 5 h.The azide derivative 9 was isolated as a colorless oil by column chromatography.Finally, the N-protecting tert-butyloxycarbonyl group was removed by treatment of 9 with a solution of hydrogen chloride in ethyl acetate.The hydrochoride derivative 10 was obtained in crystalline form (90% yield).The structures of compounds 7-10 were confirmed by NMR spectroscopy.
The condensation of 2 with 10 was conducted in DMF and in the presence of N,Ndiisopropylethylamine, which formed the free amino group from the hydrochloride salt (Scheme 3).The hydrogenolysis of the azide function of 6 with 10% Pd/C in hydrochloric acid solution or in hydrogen chloride in methanol led to a low yield of the amine hydrochloride 11, because the lactone ring underwent partial opening by hydrolysis or alcoholysis.However, the hydrogenolysis of the azide group of 6 could be conducted without affecting the lactone by using the same catalyst and a 10:1:2 mixture of EtOAc-EtOH-CHCl 3 as solvent.In this way, hydrogen chloride was smoothly generated by hydrogenation of chloroform to give the hydrochloride of the amino group formed in the same reaction. 18The hydrochloride derivative 11 was thus obtained as a crystalline product in 86% yield.As described for 4, compound 11 exhibited in its 13 C NMR spectrum the resonances due to the amide and lactone carbonyl carbons.The low field signals for C-2 (76.9 ppm) and for H-2 (4.89 ppm), in the respective 13 C and 1 H NMR spectra of 11 indicated the presence of the lactone ring.Furthermore, the amino acid 11 gave a satisfactory elemental analysis.The polymerization of 11 under various reaction conditions is being studied.

Scheme 3
In summary, the synthesis of 11 was successfully accomplished starting from readily accessible derivatives of L-glutamic acid and L-alanine.The carboxylic acid of 11 is activated for the homopolycondensation, as lactones readily undergo aminolysis reactions.The polymerization of 11 will yield a stereoregular AABB-type polyamide having S-configuration for both stereocenters of the repeating unit.

Experimental Section
General Procedures.Solvents were dried and purified by appropiate standard procedures.Melting points were determined with a Fisher-Johns apparatus and are uncorrected.Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel 60 F 254 (Merck) aluminum supported plates.Detection was effected by exposure to UV light or charring with 5% H 2 SO 4 (v/v) in EtOH containing 0.5% p-anisaldehyde.Column chromatography was performed with silica gel 60 (230-400 mesh, Merck).Optical rotations were measured with a Perkin-Elmer 343 digital polarimeter at 25 ºC.Nuclear magnetic resonance (NMR) were recorded on a Brucker AC 200 spectometer at 200 MHz ( 1 H) and 50.3 MHz ( 13 C) in CDCl 3 solutions (unless otherwise indicated) with TMS as an internal standard.