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Synlett 2011(13): 1888-1894  
DOI: 10.1055/s-0030-1260960
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Studies in the Synthesis and Reactivity of New Chiral 1-[(Trialkylsilyl)-methyl]propenamides

Samir BouzBouz*
C.O.B.R.A, UMR-CNRS 6014, INSA et Université de Rouen, IRCOF, Rue Tesnière, 76183 Mont Saint Aignan Cedex, France
e-Mail: samir.bouzbouz@univ-rouen.fr;
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Publication History

Received 25 February 2011
Publication Date:
21 July 2011 (online)

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Abstract

A very simple sequence of reactions such as cross-­metathesis using two catalysts and allylation to give the chiral hydroxyamide is described.

Key words

amino acids - peptides - cross-metathesis - allylation

    References and Notes

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9

Compounds 1-4, and 4′ were prepared from commercially available chiral l-amino esters and acryloyl chloride in the presence of Et3N at 0 ˚C

10

Two separated spots appear corresponding to the two isomers E and Z. The E/Z ratio is greater than 14:1.

11

Spectroscopic Data for Compound 13
¹H NMR (300 MHz, CDCl3): δ = 6.95 (td, J = 8.8, 15.1 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H, NH), 6.45 (d, J = 7.2 Hz, 1 H, NH), 6.36 (d, J = 16.9 Hz, 1 H), 6.23 (m, 1 H), 5.73 (d, J = 14.9 Hz, 1 H), 5.68 (d, J = 9.8 Hz, 1 H) 4.95 (m, 2 H), 3.72 (s, 6 H), 3.37-3.11 (m, 4 H), 1.70 (d, J = 8.8 Hz, 4 H), 0.01 (s, 9 H). ¹³C NMR (75 MHz, CDCl3): δ = 171.2 (s), 170.9 (s), 165.9 (s), 165.3 (s), 145.1 (d), 130.2 (d), 127.8 (t), 120.6 (d), 52.9 (2 q), 51.8 (d), 51.7 (d), 41.2 (t), 41.0 (t), 24.7 (t), -1.7 (3 q). IR (neat): ν = 3320, 2955, 2890, 1741, 1659, 1214, 1186 cm-¹. MS: m/z = 463 (23)[M+ + 1], 405 (64), 391 (100) [M - SiMe3], 377 (17), 313 (9), 276 (20), 242 (7), 204 (56), 190 (25), 170 (20), 156 (7), 142 (1.6), 86 (2). HRMS: m/z calcd for C18H31N2O6S2Si [M]: 463.1393 [M + H+]; found: 463.1404.

12

Spectroscopic Data for Compound 14 E/E-Isomers: ¹H NMR (300 MHz, CDCl3): δ = 6.92 (td, J = 8.8, 14.9 Hz, 2 H), 6.60 (d, J = 7.5 Hz, 2 H, NH), 5.71 (d, J = 15.0 Hz, 2 H), 4.92 (m, 2 H), 3.71 (s, 6 H), 3.15 (ddd, J = 5.9, 14.1, 21.8 Hz, 4 H), 1.65 (d, J = 8.7 Hz, 4 H), 0.01 (s, 18 H). E/E-Isomers: ¹³C NMR (75 MHz, CDCl3): δ = 171.1 (2 s), 165.8 (2 s), 144.7 (2 d), 120.6 (2 d), 52.7 (2 q), 51.5 (2 d), 41.1 (2 t), 24.5 (2 t), -1.8 (6 q). E/Z-Isomers: ¹H NMR (300 MHz, CDCl3): δ = 6.92 (td, J = 8.7, 15.1 Hz, 1 H E ), 6.51 (d, J = 7.5 Hz, 1 H, NH), 6.49 (d, J = 7.3 Hz, 1 H, NH), 6.26 (dd, J = 9.6, 10.7 Hz, 1 H Z ), 5.70 (d, J = 15.1 Hz, 1 H E ), 5.62 (d, J = 11.3 Hz, 1 H Z ), 3.73 (s, 6 H), 3.15 (m, 4 H), 2.35 (m, 2 H), 1.65 (d, J = 8.8 Hz, 2 H), 0.01 (s, 18 H). E/Z-Isomers: ¹³C NMR (75 MHz, CDCl3): δ = 171.2 (s), 171.1 (s), 166.6 (s), 165.8 (s), 146.2 (d), 144.9 (d), 120.6 (d), 117.7 (d), 120.6 (d), 52.8 (q), 52.7 (q), 51.6 (d), 51.2 (d), 41.1 (2 t), 24.6 (t), 22.7 (t), -1.6 (3 q), -1.7 (3 q). IR (neat): ν = 3320, 2955, 2890, 1745, 1656, 1214, 1186 cm-¹. MS:
m/z = 549 (100)[M+ + 1], 477 (8), 276 (22), 242 (6), 204 (2), 170 (1.6), 142 (3), 73 (3). HRMS: m/z calcd for C22H41N2O6S2Si2 [M]: 549.1945 [M + H+]; found: 549.1976.

16

Spectroscopic Data for Compound 15
Major isomer(syn): ¹H NMR (300 MHz, CDCl3): δ = 7.26-7.08 (m, 10 H), 6.31 (d, J = 7.5 Hz, 1 H, NH amide), 5.90 (m, 1 H), 5.27 (d, J = 10.2 Hz, 1 H), 5.17 (d, J = 17.1 Hz, 1 H), 4.79 (m, 1 H), 4.17-4.10 (m, 3 H), 3.31 (br s, 1 H, OH), 3.15 (m, 2 H), 2.82 (dd, J = 7.5, 3.2 Hz, 1 H), 1.28 (t, J = 7.2 Hz, 1 H), 1.12 (d, J = 6.4 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 171.7 (s), 171.5 (s), 135.9 (s), 132.1 (d), 129.3 (2 d), 128.6 (2 d), 127.2 (d), 121.0 (t), 67.5 (d), 61.7 (q), 57.5 (d), 53.1 (d), 37.8 (t), 19.9 (q),14.2 (q). IR (neat): ν = 3367, 3306, 2978, 2929, 1724, 1632, 1545, 1279, 1180 cm-¹. HRMS: m/z calcd for C17H24NO4 [M]: 306.1705 [M + H+]; found: 306.1711.

17

The identities of the syn and anti products were readily established from their ¹H NMR spectra. The α-products were distinguished by virtue of the larger vicinal coupling constant of the α-methine proton in the anti diastereomer (J = 7-8 Hz) relative to the syn diastereomer (J = 3.2 Hz, Figure  [³] ).

Figure 3

18

Separation of syn and anti isomers was achieved by Supercritical Fluid Chromatography (column: AD-H21 × 250, mobile phase 15% EtOH, parameters: F = 50 mL/min, nozzle pressure: 100 bar).

19

When the reaction is not complete and when the aldehyde contains traces of water, protodesilylation product 23 is formed (Figure  [4] ).

Figure 4

20

General Procedure for the One-Pot Process
To a solution of allyltrimethylsilane (1.1 equiv) and acrylamide 1 (1 mmol) in dry THF (5 mL/mmol) under an argon atmosphere was added Hoveyda-Grubbs catalyst II. After 2 h at r.t. the aldehyde was introduced (1.3 equiv), the temperature reduced to -78 ˚C, and TBAF (1.1 equiv) was added. After 10 min, the reaction mixture was washed with NH4Cl, dried over MgSO4, and concentrated carefully at r.t. under reduced pressure. The residue was purified by a silica gel chromatography to give the desired hydroxyamide.

21

Spectral Data for Compound 24 ¹H NMR (300 MHz, CDCl3): δ = 7.36-6.65 (m, 12 H), 6.07 (d, J = 7.5 Hz, 1 H, NH amide), 5.87 (d, J = 14.9 Hz, 1 H), 4.92 (m, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.77 (s, 3 H), 3.14 (m, 2 H), 1.25 (t, J = 7.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 171.8 (s), 165.8 (s), 160.1 (s), 142.0 (d), 139.3 (d), 136.0 (s), 129.4 (d), 129.0 (s), 128.5 (d), 127.0 (d), 124.1 (d), 122.0 (d), 114.1 (d), 61.5 (t), 55.3 (q), 53.3 (d), 37.9 (t), 14.1 (q). HRMS (EI+): m/z calcd for C23H26NO4 [M]: 380.1862; found: 380.1857.

22

Marimastat is a drug that acts on the Zn²+ ion at the active site of the matrix metalloproteinase (MMP, Figure  [5] ).

Figure 5