Synthesis of α,α-Disubstituted β-Amino Esters and Peptide Derivatives

Abstract

The synthesis of α,α-disubstituted β-amino esters and peptide derivatives from readily available 4-spiro-β-lactams 1 is described. The geminally disubstituted β-amino esters are obtained from the N-Boc spiro β-lactams 2 by treatment with potassium cyanide in methanol. Alternatively, the use of spiro β-lactams 2 as acylating agents of the amino group of C-protected amino acids, allowed its direct incorporation into a peptidic chain.

amino acids - lactams - peptides - ring opening - spiro compounds

References

1 Koert U. Angew. Chem., Int. Ed. Engl.  1997,  36:  1836 

2 Werder M. Hauser H. Abele S. Seebach D. Helv. Chim. Acta  1999,  82:  1774 

3a Porter EA. Wang X. Lee H. Weisblum B. Gellman SH. Nature  2000,  404:  565 

3b Liu D. DeGrado WF. J. Am. Chem. Soc.  2001,  123:  7553 

3c Hamuro Y. Scheneider JP. DeGrado WF. J. Am. Chem. Soc.  1999,  121:  12200 

4 Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1 

5 Seebach D. Abele S. Sifferlen T. Hänggi M. Gruner S. Seiler P. Helv. Chim. Acta  1998,  81:  2218 

6 Abele S. Seiler P. Seebach D. Helv. Chim. Acta  1999,  82:  1559 

7

Typical experimental procedure for 1: To a solution of the imine (2 mmol) and dry Et₃N (0.41 mL, 3 mmol) in dry refluxing toluene (15 mL) was added dropwise a solution of the corresponding 2- or 3-tetrahydrofuroyl chloride (0.269 g, 2 mmol) in toluene (5 mL). The reaction mixture was refluxed overnight, cooled to r.t., and diluted with CH₂Cl₂ (30 mL). The resultant solution was washed with 5% NaHCO₃(20 mL) and brine (20 mL). The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Flash chromatography over silica gel (EtOAc-hexanes) of the crude reactions afforded the final spiro β-lactams 1.

8 Palomo C. Aizpurua JM. Ganboa I. In Enantioselective Synthesis of β-Amino Acids   Juaristi E. Wiley-VCH.; NY: 1997.  p.280-357  

See:

9a Ikeda M. Uchino T. Ishibashi H. Tamura Y. Kido M. J. Chem. Soc. Chem. Commun.  1984,  758 

9b Le Blanc S. Pete J. Piva O. Tetrahedron Lett.  1992,  33:  1993 

9c Bateson JH. Guest AW. Tetrahedron Lett.  1993,  34:  1799 

9d Anklam S. Liebscher J. Tetrahedron  1998,  54:  6369 

9e Croce PD. Ferraccioli R. La Rosa C. Tetrahedron  1995,  34:  9385 

9f Croce PD. Ferraccioli R. La Rosa C. Tetrahedron  1999,  55:  201 

9g Croce PD. La Rosa C. Tetrahedron Asymmetry  1999,  10:  1193 

10 Croce PD. La Rosa C. Heterocycles  2000,  53:  2653 

11 Palomo C. Oiarbide M. Bindi S. J. Org. Chem.  1998,  63:  2469 

12 Floyd DM. Fritz AW. Plusec J. Weaver ER. Cimarusti CM. J. Org. Chem.  1982,  42:  5160 

13

Typical experimental procedure for 3: To a stirred solution of the N-Boc β-lactam 2 (1 mmol) in MeOH (10 mL) was added a catalytic amount of potassium cyanide (10-15% mol). After the consumption of the starting material (monitored by TLC), the methanol was removed in vacuo, 10 mL of NaHCO₃ (5%) and 10 mL of EtOAc were then added. The aqueous solution was extracted with EtOAc (2 × 15 mL). The mixed organic layers were washed with brine (2 × 25 mL) and dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude oil was submitted to a short silica gel column chromatography (1:1, EtOAc-hexanes) to afford 3a-c. Data for 3a: IR (KBr): 3465, 1736, 1686, 1095 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (s, 9 H), 1.64 (m, 1 H), 1.86 (m, 2 H), 2.08 (m, 1 H), 3.74 (s, 3 H), 3.86 (m, 2 H), 5.04 (d, J = 10.0 Hz, 1 H), 5.79 (broad d, J = 10.0 Hz, 1 H), 7.29 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ 174.2, 154.6, 137.8, 128.2, 127.8, 127.4, 88.2, 79.1, 69.5, 58.6, 52.2, 33.2, 27.9, 24.7. HRMS calcd for C₁₄H₁₆NO₄ 262.1077 (M⁺- C₄H₉), found 262.1079.

14 The Practice of Peptide Synthesis   Bodanszky Bodanszky M. 2nd ed:  Springer Lab Manual; 1994. 

15 Ojima I. Sun CM. Park YH. J. Org. Chem.  1994,  59:  1249 

16 Ojima I. Habus I. Zhao M. Zucco M. Park YH. Sun CM. Brigaud T. Tetrahedron  1992,  48:  6985 

17 Palomo C. Aizpurua JM. Galarza R. Mielgo A. Chem. Commun.  1996,  633 

18

Typical experimental procedure for 7-13: To a solution of the N-Boc β-lactam 2 (1 mmol) in dry DMF (10 mL) at 40 ºC was added 2 mmol of the corresponding amino ester and (77 mg, 1.5 equiv) of KCN. After stirring the solution during 16 h, brine (10 mL) was added. The solution was extracted with EtOAc (2 × 15 mL) and the mixed organic layers were washed with 5% NaHCO₃ (15 mL), 1 N HCl (15 mL) and brine (25 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Flash chromatography over silica gel (EtOAc-hexanes) of the crude reactions afforded the final dipeptides 6-11. Data for 8a: [α]_D ²⁰ = -30.8 (c = 0.76, CHCl₃); IR (KBr): 3323, 1731, 1697, 1646 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ 0.89 (d, J = 6.2 Hz, 6 H), 1.38 (s, 9 H), 1.50 (m, 3 H)1.82 (m, 1 H), 2.24 (m, 1 H), 3.58 (s, 3 H), 3.98 (m, 2 H), 4.45 (m, 1 H), 4.76 (d, J = 9.2 Hz, 1 H), 6.56 (broad d, J = 9 Hz, 1 H), 6.87 (broad d, J = 9.2 Hz, 1 H), 7.27 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ 173.7, 171.7, 155.2, 138.6, 127.6, 127.5, 127.1, 87.6, 79.1, 69.6, 59.4, 52.0, 49.9, 41.3, 34.6, 28.1, 25.4, 24.7, 22.6, 21.5. HRMS calcd for C₁₄H₁₆NO₄ 448.2573 (M⁺), found 448.2576.

19

Compound letter were assigned according to their R_f values in column chromatography (silica gel Merck 230-400 mesh, 1:1, hexane-EtOAc as eluent). R_f 7a<7b; R_f 8a<8b.

See for example:

20a Dale JA. Mosher HS. J. Am. Chem. Soc.  1972,  95:  512 

20b Trost BM. Belletire JL. Godleski S. McDougal PG. Balkovec JM. J. Org. Chem.  1986,  51:  2370 

20c Latypov SK. Seco JM. Quiñoá E. Riguera R. J. Am. Chem. Soc.  1998,  120:  877 

21 Dale JA. Dull DL. Mosher HS. J. Org. Chem.  1969,  34:  2543