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Synlett 2002(1): 0069-0072
DOI: 10.1055/s-2002-19326
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Eduardo Alonso, Carlos del Pozo, Javier González*
Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, 33071 Oviedo, Spain
Fax: +34(985)103446; e-Mail: FJGF@sauron.quimica.uniovi.es;
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Publication History

Received 9 October 2001
Publication Date:
01 February 2007 (online)

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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

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 Rf values in column chromatography (silica gel Merck 230-400 mesh, 1:1, hexane-EtOAc as eluent). Rf 7a<7b; Rf 8a<8b.