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DOI: 10.1055/s-0030-1260960
Studies in the Synthesis and Reactivity of New Chiral 1-[(Trialkylsilyl)-methyl]propenamides
Publication History
Publication Date:
21 July 2011 (online)
![](https://www.thieme-connect.de/media/synlett/201113/lookinside/thumbnails/10.1055-s-0030-1260960-1.jpg)
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
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References and Notes
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
10Two 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.
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.
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.
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] ).
![](https://www.thieme-connect.de/media/synlett/201113/d064_f3.gif)
Figure 3
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).
19When the reaction is not complete and when the aldehyde contains traces of water, protodesilylation product 23 is formed (Figure [4] ).
![](https://www.thieme-connect.de/media/synlett/201113/d064_f4.gif)
Figure 4
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.
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.
22Marimastat is a drug that acts on the Zn²+ ion at the active site of the matrix metalloproteinase (MMP, Figure [5] ).
![](https://www.thieme-connect.de/media/synlett/201113/d064_f5.gif)
Figure 5