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Synlett 2009(10): 1562-1566  
DOI: 10.1055/s-0029-1217340
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Transformation of Glutamic Acid into (S)-Benzyl 2-(dibenzylamino)-6-(dimethoxyphosphoryl)-5-oxohexanoate for a Convenient Access to 5-Substituted Prolines

Elena Cinia, Gianluca Giorgib, Manuela Rodriquezc, Maurizio Taddei*a
a Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Fax: +39(0577)234333; e-Mail: taddei.m@unisi.it;
b Dipartimento di Chimica, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
c Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte don Melillo, 84084 Fisciano, Salerno, Italy
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Publication History

Received 02 September 2008
Publication Date:
02 June 2009 (online)

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Abstract

l-Glutamic acid was transformed into β-keto-phosphonate in two steps. This compound was employed in the stereocontrolled synthesis of cis-5-substituted prolines through a Woodward-Horner-Emmons (WHE) reaction with different aldehydes followed by hydrogenolysis/hydrogenation-mediated ring closure. We found also that a one-pot sequential hydroformylation-WHE reaction was possible with cis-5-substituted prolines. In addition to differently functionalised prolines, an indolizidine amino acid with a structure related to constrained peptidomimetics was obtained.

Key words

amimo acids - hydrogenation - peptidomimetics - microwaves

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For example, search for ‘proline’ in ISI Web of KnowledgeTM of Thomson Reuters) gives more than 200 reviews in ‘chemistry’ between 2000 and 2008.

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( S )-2-Dibenzylamino-6-(dimethoxyphosphoryl)-5-oxohexanoic Acid Benzyl Ester (5) To a soln of dimethyl methylphosphonate (0.191 g, 1.54 mmol) in dry THF (17 mL) cooled at -78 ˚C, BuLi (0.62 mL of a 2.5 M soln in hexane) was added dropwise. After 40 min, a soln of 4 (0.390 g, 7.7 mmol) in dry THF (14 mL) was added. After stirring for 4 h at -78 ˚C, a sat. soln of NH4Cl (6 mL) was added followed by EtOAc (30 mL). After warming to r.t., the organic phase was separated. The aqueous phase was extracted with EtOAc, all the organic fractions were collected and dried over Na2SO4. The solvent was removed in vacuo, and the crude material was purified by column chromatography (PE-EtOAc, 1:3) to give compound 5 as colourless oil (0.26 g, 65% yield). ¹H NMR (400 MHz, CDCl3): δ = 1.95-2.02 (m, 2 H, H-3), 2.41-2.78 (m, 2 H, H-4), 2.79-2.97 (m, 2 H, H-6), 3.29 (t, J = 6.8 Hz, 1 H, H-2), 3.67 (AB system, 4 H, NCH2Ph), 3.68 (d, J = 2.8 Hz, 3 H, OCH3), 3.71 (d, J = 2.8 Hz, 3 H, OCH3), 5.19 (AB system, 2 H, OCH2Ph), 7.19-7.36 (m, 15 H, ArH). ¹³C NMR (50 MHz, CDCl3): δ = 22.6, 40.0, 40.4, 42.5, 52.8, 53.0, 54.4, 59.8, 66.1, 127.1 54.5, 59.8, 66.2, 127,1, 128.2, 128.3, 128.5, 128.6, 128.9, 135.9 (2 C), 139.21, 172.13, 200.7, 200.8. HRMS (ES): m/z calcd for C29H35NO6P [M + H]+: 524.2202; found: 524.2180.

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( S , E ) 2-Dibenzylamino-5-oxoicos-6-enoic Acid Benzyl Ester (11) - General Procedure To a soln of 5 (0.900 g, 1.7 mmol) in dry MeCN (18 mL), dry LiCl (72.0 mg, 1.7 mmol) was added followed by DIPEA (180 mg, 239 µL, 1.4 mmol). After stirring for 2 h at r.t., tetradecanal (0.276 g, 1.3 mmol) in MeCN was added and the mixture stirred at r.t. for 72 h. Brine was added
and the organic layer separated. The aqueous phase was extracted with EtOAc, all the organic fractions were collected and dried over Na2SO4. The solvent was removed under vacuum and the crude mixture was purified by column chromatography (PE-EtOAc, 5:1) to give compound 11 as a colourless oil (0.673 g, 85% yield); [α]D ²5 -55.5 (c 0.1, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 6.6 Hz, 3 H), 1.24-1.47 (m, 20 H), 1.45 (m, 2 H), 2.07-2.19 (m, 4 H), 2.41-2.69 (m, 2 H), 3.39 (dd, J = 8.4, 6.2 Hz, 1 H), 3.73 (AB system, 4 H), 5.23 (AB system, 2 H), 6.00 (d, J = 15.6 Hz, 1 H), 6.71 (dt, J = 15.6, 7.0 Hz, 1 H), 7.22-7.43 (m, 15 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.0, 20.8, 22.6, 23.3, 28.0, 29.1, 29.2, 29.3 (3 C), 29.4, 29.5, 31.8 (2 C), 32.3, 36.3, 54.4, 60.1, 65.9, 126.9 (3 C), 128.1 (4 C), 128.2 (2 C), 128.4 (4 C), 128.7 (2 C), 130.1, 135.9, 139.2 (2 C), 147.2, 172.2, 199.3. MS (ES): m/z = 632 [M + Na]+.
(2 S ,5 R )-5-Pentadecylpyrrolidine-1,2-dicarboxylic Acid 1- tert -Butyl Ester (21) - General Procedure To a soln of 11 (100 mg, 0.16 mmol) in CH2Cl2-MeOH (1:9, 5 mL) placed in the bottle connected with a Parr apparatus, Boc2O (54 mg, 0.25 mmol) and Pd(OH)2/C (20%, 9 mg, 0.012 mmol) were added. The bottle was filled with H2 at 4.8 bar and shaken at r.t. for 8 h. The bottle was degassed, the catalyst filtered (attention: the residue Pd may be pyrophoric) and washed several times with MeOH. The solvent was removed under vacuum and the crude mixture was purified by column chromatography (CHCl3-MeOH, 98:2) to give compound 21 as white gel (51 mg, 75% yield); [α]D ²5 -20.7 (c 0.1, CDCl3). ¹H NMR (400 MHz, CHCl3):
δ = 0.84 (t, J = 7.2 Hz, 3 H), 1.09-1.43 (m, 26 H), 1.47 (s, 9 H), 1.59-1.67 (m, 2 H), 1.82-1.94 (m, 2 H), 1.95-2.28 (m, 2 H), 3.71-3.83 (m, 1 H), 4.18-4.26 (m, 1 H), 9.91 (br s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.0, 22.7, 26.6, 28.3 (3 C), 29.3 (2 C), 29.7 (10 C), 31.9, 34.3, 58.9, 60.0, 67.0, 173.7, 179.4. MS (ES): m/z = 424 [M - H]-.

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Crystallographic data (excluding structure factors) for X-ray crystal structure of 18 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 710555. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].