β-Amino Amides from β-Lactams: Application to the Formal Synthesis of a Peptide-Deformylase Inhibitor

Abstract

A facile and a practical synthesis of peptide-deformylase inhibitor 1 is described using an acid-catalyzed aminolysis of β-lactam 12 with pyrrolidine 6 as the key transformation. In addition, simplified conditions for the conversion of a β-hydroxy acid to a β-lactam are reported.

Key Words

β-amino amides - β-lactams - peptide-deformylase inhibitor

References and Notes

• 1a

  Lopez, S.; Wu, C.; Blais, J.; Hackbarth, C.; Gomez, M.; Kubo, A.; Jain, R.; Sundaram, A.; Alvarez, S.; Bracken, K.; Dean, K.; Weidmann, B.; Patel, D.; Trias, J.; White, R.; Yuan, Z. 44 ^th Annual Interscience Conference on Microbial Agents and Chemotherapy; Washington, D.C., 2004; October 20 - November 2, Poster No. F1959.

• 1b Patel DV, Yuan Z, Jain RK, Garcia Alvarez S, and Jacobs J. inventors; WO  2002102790. 
• 1c Jones RN. Sader HS. Fritsche TR. Diagn. Microbiol. Infect. Dis.  2005,  51:  139 
• 2 Slade J. Parker DJ. Girgis M. Mueller M. Vivelo J. Liu H. Bajwa JS. Chen G.-P. Carosi J. Lee P. Chaudhary A. Wambser D. Prasad K. Bracken K. Dean K. Boehnke H. Repič O. Blacklock TJ. Org. Process Res. Dev.  2006,  10:  78 
• 3 Xu Y. Miller MJ. J. Org. Chem.  1998,  63:  4314 
• 4 Jin Y. Kim DH. Bioorg. Med. Chem. Lett.  1998,  8:  3515 
• 5 Jin Y. Kim DH. Synlett  1998,  1189 
• 7a

  In the literature, acetone in combination with potassium carbonate was typically used for the formation of these type of β-lactams, see ref. 7b. For practical reasons we preferred THF as the solvent and this necessitated the use of a phase-transfer catalyst.

• 7b Floyd DM. Fritz AW. Pluscec J. Weaver ER. Cimarusti CM. J. Org. Chem.  1982,  47:  5160 

6

Spectral data on new compounds are as follows.
Compound 10: ¹H NMR (CDCl₃): δ = 0.85 (t, J = 4.12 Hz, 3 H), 1.18-1.26 (m, 5 H), 1.50-1.53 (m, 1 H), 2.10-2.23 (m, 1 H), 3.56-3.57 (s, 1 H), 3.60-3.62 (m, 2 H), 4.81-4.88 (m, 2 H), 7.31-7.37 (m, 5 H), 9.47 (s, 1 H). ¹³C NMR (CDCl₃): δ = 14.29, 23.01, 28.41, 29.73, 46.88, 63.96, 79.02, 128.70, 128.99, 129.60, 135.70, 173.56; [α]_D ²⁵ +0.556 (c 1.05, MeOH).
Compound 11: ¹H NMR (CDCl₃): δ = 0.87 (t, J = 6.78 Hz, 3 H), 1.30-1.40 (m, 5 H), 1.58-1.60 (m, 1 H), 2.41-2.43 (m, 1 H), 2.97 (s, 3 H), 4.26-4.28 (m, 2 H), 4.93 (s, 2 H), 7.30-7.40 (m, 5 H), 8.52 (s, 1 H). ¹³C (CDCl₃): δ = 13.78, 22.47, 28.02, 29.10, 37.23, 43.98, 70.21, 78.43, 128.66, 128.87, 129.31, 135.03, 170.06; [α]_D ²⁵ +5.901 (c 1.06, MeOH).
Compound 12: ¹H NMR (CDCl₃): δ = 0.87 (t, J = 7.14 Hz, 3 H), 1.27-1.29 (m, 4 H), 1.43-1.48 (m, 1 H), 1.65-1.67 (m, 1 H), 2.81-2.83 (m, 1 H), 2.90 (dd, J = 2.46, 3.88 Hz, 1 H), 3.34 (dd, J = 2.46, 4.89 Hz, 1 H), 4.93 (s, 2 H), 7.35-7.39 (m, 5 H). ¹³C NMR (CDCl₃): d = 13.85, 22.42, 28.49, 29.25, 45.11, 51.46, 77.94, 128.32, 128.69, 129.85, 135.31, 166.99; [α]_D ²⁵ +24.63 (c 1.02, MeOH).
Compound 13: ¹H NMR (CDCl₃): δ = 0.78 (t, J = 6.90 Hz, 3 H), 0.82-0.90 (m, 1 H), 1.08-1.28 (m, 4 H), 1.31-1.38 (m, 1 H), 1.51-1.68 (m, 1 H), 1.69-1.73 (m, 1 H), 1.82-2.10 (m, 2 H), 2.32-2.42 (m, 1 H), 2.86-3.05 (m, 2 H), 3.20-3.31 (m, 1 H), 3.42-3.56 (m, 2 H), 4.68 (s, 2 H), 4.72-4.76 (m, 1 H), 7.20-7.42 (m, 6 H), 8.10-8.20 (m, 2 H), 9.75 (s, 1 H). ¹³C (CDCl₃): δ = 13.91, 22.79, 24.33, 24.95, 29.60, 31.03, 42.36, 47.54, 53.83, 60.40, 75.85, 114.45, 114.50, 124.63, 124.89, 127.98, 128.45, 135.35, 135.69, 137.61, 147.72, 147.75, 154.58, 157.90, 169.53, 176.32; [α]_D ²⁵ -74.43 (c 1.01, MeOH).