A Novel Strategy towards the Asymmetric Synthesis of Orthogonally Funtionalised 2-n-benzyl-n-α-methylbenzyl- Amino-5-carboxymethyl-cyclopentane-1-carboxylic Acid

The asymmetric synthesis of the orthogonally funtionalised compounds tert-butyl


Results and Discussion
We have obtained dimethyl and di-(1-ethylpropyl)(E,E)-octa-2,6-diendioate on a multigram scale using the method published by Scheffer et al. [10].Treatment of sebacic acid with thionyl chloride followed by bromine, while irradiating the entire apparatus with a 300-W sunlamp and then the addition of alcohol (methanol or 1-ethylpropanol) produces the appropriate dibromodiester, which yields the required diendioate upon refluxing with DMF.It was not possible to obtain the convenient di-tert-butyl diester using this procedure and we used the methodology developed by Mestres et al. [11][12][13][14] (Scheme 2) to obtain diunsaturated dicarboxylic acids by oxidative coupling of the dianions of unsaturated carboxylic acids.
The oxidative coupling of the dianion derived from crotonic acid (8), as shown in Scheme 3, afforded a 70% yield of a 2:1 mixture of (E,E)-octa-2,6-diendioic and (E)-5-vinyl-hex-2-endioic acids (9 and 10) that could be easily separated by crystallization of 9 [13].Methylation of these diacids using diazomethane or methanol in acid media is quantitative.The di-tert-butyldiester 13 is obtained (67% after CC) by reaction of diacid 10 with trifluoroacetic anhydride and tert-butanol, but under the same conditions diacid 9 afforded an easily separable mixture of di-tert-butyl ester 14 (42%) and monoester 15 (57%) which upon further treatment with diazomethane produced the orthogonally protected tertbutyl methyl (E,E)-octa-2,6-diendioate 16.Compound 14 has been used to synthesize the aforementioned β-aminocyclopentanoic acid [9] and 16 provided two differentiated Michael acceptors to be tested with the homochiral lithium amide.The X-ray structure of 19 [9] shows the carbonyl on C-1 almost perpendicular to the ring plane, consequently very shielded by the adjacent groups at C-2 and C-5.So the 18/19 mixture could be easily resolved upon treatment with trifluoroacetic acid in a short period of time, as only the lateral tert-butyl ester at C-5 is hydrolyzed, giving rise to the straightforwardly separable unreacted diester 18 (21%) and the acid compound 20 (61%) from which 19 is obtained as well by methylation with diazomethane.
All the spectroscopic assignments of 20 and 19 have been unambiguously established by 1 H-NMR techniques, including 2-dimensional homonuclear COSY, heteronuclear HMQC and HMBC (noteworthy signals are shown in Figure 2, each methyl group is clearly differentiated), nOe and ROESY experiments. . .
Here we demonstrate an efficient strategy towards the synthesis of a cyclopentane β-aminodiester with three different orthogonal protecting groups on each functionality, which can then submitted to appropriate modifications for use in β-peptide synthesis.The extension of this strategy to the preparation of a range of different orthogonally substituted cyclopentane and cyclohexane derived βamino acids is currently under investigation in our laboratory.

Experimental
General 1 H-NMR and 13 C-NMR spectra were recorded in CDCl 3 at 200 and 400 MHz ( 1 H) or 50 and 100 MHz ( 13 C) on Varian 200 VX and BRUKER DRX 400 instruments, respectively.Multiplicities were determined by DEPT experiments.IR spectra were registered using a BOMEM 100 FTIR spectrophotometer.Optical rotations were determined using a Perkin-Elmer 241 polarimeter in a 1 dm cell and are given in units of 10 -1 deg cm 2 g -1 .Concentrations are quoted in g per 100mL.The electron impact (EI) mass spectra were run on a VG-TS 250 spectrometer using a 70 eV ionising voltage.HRMS were recorded using a VG Platform (Fisons) spectrometer using Chemical Ionisation (ammonia as gas) or Fast Atom Bombardment (FAB) techniques.Thin layer chromatography (tlc) was performed on aluminium sheets coated with 60 F 254 silica.Sheets were visualised using iodine, UV light or 1% aqueous KMnO 4 solution.Column chromatography (CC) was performed with Merck silica gel 60 (70-230 mesh).Solvents and reagents were generally distilled prior to use: THF from sodium benzophenone ketyl and dichloromethane (DCM) from KOH. Compounds 9-12 were prepared according to the published procedures [13][14].
The 17/18 mixture (58 mg, 0.13 mmol) was dissolved in TFA (0.5 mL) and stirred for 2 hours at rt before concentration in vacuo to give 40 mg of product, which upon treatment with a solution of gaseous CH 2 N 2 in ether gave 19 (49 mg, 95%) after concentration in vacuo (yield 72% after crystallization from 7:3 hexane-Et