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.

Key words

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

References

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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.

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.

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.