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

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

• For recent reviews, see:
• 1a Trnka TM. Grubbs RH. Acc. Chem. Res.  2001,  34:  18 
• 1b Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 
• 1c Grubbs RH. Chang S. Tetrahedron  1998,  54:  4413 
• 1d Armstrong SK. J. Chem. Soc., Perkin Trans. 1  1998,  317 
• 1e Fürstner A. Top. Organomet. Chem.  1998,  1:  37 
• 1f Schuster M. Blechert S. Angew. Chem., Int. Ed. Engl.  1997,  36:  2036 
• 1g Connon SJ. Blechert S. Angew. Chem. Int. Ed.  2003,  42:  1900 
• 1h Hoveyda AH. Gillingham DG. Van Veldhuizen JJ. Kataoka O. Garber SB. Kingsbury JS. Harrity JPA. Org. Biomol. Chem.  2004,  2:  8 
• 1i Brümmer O. Rückert A. Blechert S. Chem. Eur. J.  1997,  3:  441 
• 1j Vernall AJ. Abell AD. Aldrichimica Acta  2003,  36:  93 
• 1k Chatterjee AK. Choi T.-L. Sanders DP. Grubbs RH. J. Am. Chem. Soc.  2003,  125:  11360 
• 2 Kingsbury JS. Harrity JPA. Bonitatebus PJ. Hoveyda AH. J. Am. Chem. Soc.  1999,  121:  791 
• 3 Garber SB. Kingsbury JS. Gray BL. Hoveyda AH. J. Am. Chem. Soc.  2000,  122:  8168 
• 4 Gessler S. Randl S. Blechert S. Tetrahedron Lett.  2000,  41:  9973 
• 5 Rothman JH. J. Org. Chem.  2009,  74:  925 
• 6 Wipf P. Henninger TC. Geib SJ. J. Org. Chem.  1998,  63:  6088 
• 7 Choi T.-L. Chatterjee AK. Grubbs RH. Angew. Chem. Int. Ed.  2001,  40:  1277 
• 8 Streuff J. Nieger M. Muñiz K. Chem. Eur. J.  2006,  12:  4362 
• 13a Majewski M. Mpango GB. Thomas MT. Wu A. Snieckus V. J. Org. Chem.  1981,  46:  2029 
• 13b Green JR. Snieckus V. Tetrahedron Lett.  1986,  27:  535 
• 13c Green JR. Alo BI. Majewski M. Snieckus V. Can. J. Chem.  2009,  87:  745 ; and references cited therein
• 14a Sakurai H. Hosomi A. Saito M. Sasaki K. Iguck H. Sasata J. Araki Y. Tetrahedron  1983,  39:  883 
• 14b Hosomi A. Shirahata A. Sakurai H. Tetrahedron Lett.  1978,  19:  3043 
• 14c Sarker TK. Andersen NH. Tetrahedron Lett.  1978,  19:  3513 
• 14d Deleris G. Dunogues J. Calas R. Pisciotti F. J. Organomet. Chem.  1974,  69:  C15 
• 14e Deleris G. Dunogues J. Calas R. Pisciotti F. J. Organomet. Chem.  1975,  93:  43 
• 14f Able EW. Rowley RJ. J. Organomet. Chem.  1975,  84:  199 
• 14g Hosomi A. Sakurai H. Tetrahedron Lett.  1976,  1295 
• 15 Katritzky AR. Piffl M. Lang H. Anders E. Chem Rev  1999,  99:  665 

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 Zn^²+ ion at the active site of the matrix metalloproteinase (MMP, Figure  [5] ).

Figure 5