New, Simple and Versatile Synthesis of Protected α-Alkylidene-β-amino Acids from Activated Vinylphosphonates

Abstract

A two-step route to Boc-protected α-alkylidene-β-amino esters was developed by addition of sodium tert-butylcarbamate to ethyl 2-diethoxyphosphoryl-2-alkenoates followed by the Horner-Wadsworth-Emmons olefination of aldehydes using intermediate 2-diethoxyphosphoryl-3-tert-butoxycarbonylaminoalkanoates.

α-Alkylidene-β-amino acids - Michael addition - vinyl­phosphonates - Wittig-type reaction - tert-butylcarbamate

References and Notes

1 Minachi N. Shibasaki M. J. Org. Chem.  1990,  55:  1975 

2 Perlmutter P. Teo CC. Tetrahedron Lett.  1984,  25:  5951 

3 Genisson Y. Massardier C. Gautier-Lunean I. Greene A. J. Chem. Soc., Perkin Trans. 1  1996,  2869 

4 Kant J. Schwartz WS. Fairchilid C. Gao Q. Huang S. Long BH. Kadow JF. Langley DR. Farina V. Vyas D. Tetrahedron Lett.  1996,  36:  6495 

5a Borrel JI. Teixido J. Matallana JL. Martinez-Teipel B. Conceiro E. Heterocycles  2000,  52:  1207 

5b Huck J. Durn C. Roumestant ML. Martinez J. Synthesis  2003,  2165 

6a Huck J. Receveur JM. Roumestant ML. Martinez J. Synlett  2001,  1467 

6b Kundig EP. Xu L.-H. Romanens P. Tetrahedron Lett.  1995,  36:  4047 

7 Takagi M. Yamamoto K. Tetrahedron  1991,  47:  8869 ; and references cited therein

8 Enantioselective Synthesis of β-Amino Acids   Juaristi E. Soloshonok V. Wiley-Interscience; Hoboken, New Jersey: 2005. 

9 Galeazzi R. Martelli G. Orena M. Rinaldi S. Synthesis  2004,  2560 ; and references cited therein

10 Bertenshaw S. Kahn M. Tetrahedron Lett.  1989,  30:  2731 

11 Kundig EP. Xu LH. Schnell B. Synlett  1994,  413 

12 Buchholz R. Hoffmann HMR. Helv. Chim. Acta  1991,  74:  1213 

13 Rajesh S. Banerji B. Iqbal J. J. Org. Chem.  2002,  67:  7852 

14 Ramachandran PV. Burghardt TE. Reddy MVR. Tetrahedron Lett.  2005,  46:  2121 

15 Ciclosi M. Fava C. Galeazzi R. Orena M. Sepulveda-Arques J. Tetrahedron Lett.  2002,  43:  2199 

16 Li G. Wei H.-X. Whittlesey BR. Batrice NN. J. Org. Chem.  1999,  64:  1061 

17 Wei H.-X. Hook JD. Fitzgerald KA. Li G. Tetrahedron: Asymmetry  1999,  10:  661 

18 Reginato G. Mordini A. Valacchi M. Piccardi R. Tetrahedron: Asymmetry  2002,  13:  595 

19 Gasperi T. Loreto MA. Tardella PA. Gambacorta A. Tetrahedron Lett.  2002,  43:  3017 

20 Adam W. Degen H.-G. Krebs O. Saha-Möller CR. J. Am. Chem. Soc.  2002,  124:  12938 

21 Janecki T. Wąsek T. Różalski M. Krajewska U. Studzian K. Janecka A. Bioorg. Med. Chem. Lett.  2006,  16:  1430 

22a Janecki T. Baszczyk E. Synthesis  2001,  403 

22b Janecki T. Wąsek T. Tetrahedron  2004,  60:  1049 

22c Janecki T. Baszczyk E. Studzian K. Janecka A. Krajewska U. Różalski M. J. Med. Chem.  2005,  48:  3516 

22d Albrecht A. Kūdzia J. Koszuk JF. Warzycha E. Janecki T. Tetrahedron Lett.  2006,  47:  2353 

23 Janecki T. Kuś A. Krawczyk H. Baszczyk E. Synlett  2000,  611 

24

Typical Experimental Procedure for Ethyl 3- tert -Butoxycarbonylamino-2-diethoxyphosphoryl-3-phenylpropionate ( 4d).
A solution of BocNH₂ (0.225 g, 1.92 mmol) in THF (3 mL) was added dropwise to a stirred suspension of NaH (84.5 mg, 3.52 mmol) in THF (6 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and a solution of ethyl 2-(diethoxyphosphoryl)-3-phenylacrylate (2d, 0.50 g, 1.6 mmol) in THF (5 mL) was added. The mixture was then warmed to r.t. and stirred for 24 h. After this time the reaction mixture was quenched with H₂O (5 mL), acidified to pH ca. 4.5 with 3 M HCl and extracted with CHCl₃ (3 × 15 mL). The organic extracts were dried (MgSO₄) and evaporated to give crude 4d, which was purified by column chromatography (EtOAc-hexane, 7:3). A 55:45 mixture of diastereoisomers was obtained. IR (film): 3344, 1736, 1708, 1240, 1056 cm^-1. ¹H NMR (250 MHz, CDCl₃): d (major isomer) = 1.10 (t, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH₂OC), 1.18-1.37 [m, 6 H, (CH ₃ CH₂O)₂], 1.38 [s, 9 H, (CH ₃ )₃C], 3.37-3.50 (m, 1 H, PCHCH), 3.98-4.30 [m, 6 H, (CH₃CH ₂ O)₂, CHCH ₂ OC], 5.19-5.46 (m, 1 H, PCHCH), 6.04 (br s, 1 H, NHCO), 7.20-7.56 (m, 5 H, C₆ H ₅ ); d (minor isomer) = 1.08 (t, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH₂O), 1.18-1.37 [m, 6 H, (CH ₃ CH₂O)₂], 1.42 [s, 9 H, (CH ₃ )₃C], 3.37-3.50 (m, 1 H, PCHCH), 3.98-4.30 [m, 6 H, (CH₃CH ₂ O)₂, CH₃CH ₂ O], 5.19-5.45 (m, 1 H, PCHCH), 6.43 (d, ^³ J _HH = 7.50 Hz, 1 H, NHCO), 7.20-7.56 (m, 5 H, C₆ H ₅ ). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.60 (s), 13.67 (s), 15.95 (2d, ^³ J _CP = 6.2 Hz), 16.15 (2d, ^³ J _CP = 6.2 Hz), 28.11 (s), 28.16 (s), 50.90 (d, ^¹ J _CP = 130.25 Hz), 51.84 (d, ^¹ J _CP = 132.14 Hz), 51.93 (s), 53.50 (s), 61.35 (s), 61.50 (s), 62.63 (d, ^² J _CP = 6.64 Hz), 62.79 (d, ^² J _CP = 6.40 Hz), 62.99 (d, ^² J _CP = 6.70 Hz), 63.21 (d, ^² J _CP = 6.94 Hz), 79.26 (s), 79.48 (s), 125.92 (s), 126.68 (s), 127.30 (s), 127.49 (s), 128.20 (s), 128.30 (s), 140.18 (s)140.23 (s), 154.63 (s), 154.68 (s), 166.50 (d, ^² J _PC = 4.50 Hz), 167.86 (s). ³¹P NMR (101 MHz, CDCl₃): δ = 18.97 (major), 20.09 (minor).

25

General Experimental Procedure.
A mixture of alkanoate 4 (0.815 mmol), t-BuOK (0.10 g, 0.896 mmol) and paraformaldehyde (0.122 g, 4.07 mmol) in THF (10 mL) was refluxed for 2 h. After cooling to r.t. H₂O (5 mL) was added. Then, THF was evaporated and the residue was extracted with CH₂Cl₂ (3 × 15 mL). The combined extracts were dried (MgSO₄) and the solvent was removed. The crude 5 were purified by column chromatography.
Analytical Data. Ethyl 2-(tert-Butoxycarbonylaminomethyl)acrylate (5a): oil (CHCl₃-EtOAc = 95:5 as eluent). IR (film): 1716, 1684 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.31 (t, ^³ J _HH = 7.25 Hz, 3 H, CH ₃ CH₂O), 1.44 [s, 9 H, (CH ₃ )₃C], 3.95 (br d, ^³ J _HH = 6.25 Hz, 2 H, CH ₂ NH), 4.23 (q, ^³ J _HH = 7.25 Hz, 2 H, CH₃CH ₂O), 4.95 (br s, 1 H, CHNH), 5.77 (s, 1 H, CHHCH₂NH), 6.25 (s, 1 H, CHHCH₂NH). ¹³C NMR (62.9 MHz, CDCl₃): δ = 14.02 (s), 28.23 (s), 41.48 (s), 60.69 (s), 79.28 (s), 125.74 (s), 137.38 (s), 155.57 (s), 166.05 (s). Anal. Calcd for C₁₁H₁₉NO₄: C, 57.63; H, 8.35; N, 6.11. Found: C, 57.78; H, 8.24; N, 6.03.
Ethyl 2-(tert-Butoxycarbonylamino-isopropyl-methyl)acrylate (5b): oil (CHCl₃-hexane = 7:3 as eluent). IR (film): 3384, 1712, 1684, 1628 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 0.84 (d, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH), 0.93 (d, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH), 1.31 (t, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH₂O), 1.43 [s, 9 H, (CH ₃ )₃C], 1.89-2.01 [m, 1 H, (CH₃)₂CH], 4.08 (t, ^³ J _HH = 9.00 Hz, ^³ J _HH = 9.00 Hz, 1 H, CHNH), 4.22 (q, ^³ J _HH = 7.00 Hz, 2 H, CH₃CH ₂O), 5.27 (br d, ^³ J _HH = 9.00 Hz, 1 H, CHNH), 5.67 (s, 1 H, CHHC), 6.21 (s, 1 H, CHHC). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.95 (s), 18.62 (s), 20.00 (s), 28.21 (s), 31.01 (s), 59.63 (s), 60.49 (s), 78.88 (s), 126.47 (s), 139.65 (s), 155.31 (s), 165.98 (s). Anal. Calcd for C₁₄H₂₅NO₄: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.16; H, 9.39; N, 5.19.
Ethyl 2-[tert-Butoxycarbonylamino(1′-methyl-butane)methyl]acrylate (5c): oil (CHCl₃-hexane = 7:3 as eluent); a 60:40 mixture of diastereomers was obtained. IR (film): 3392, 1716, 1628 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ (major isomer) = 0.79-1.30 (m, 10 H, CH ₃ CHCH ₂CH ₂CH ₃), 1.31 (t, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH₂O), 1.43 [s, 9 H, (CH ₃ )₃C], 1.70-1.92 (m, 1 H, CH₃CHCH₂CH₂CH₃), 4.22 (q, ^³ J _HH = 7.00 Hz, 2 H, CH₃CH ₂O), 4.44 (dd, ^³ J _HH = 9.50 Hz, ^³ J _HH = 9.50 Hz, 1 H, CHNH), 5.10 (br d, ^³ J _HH = 9.50 Hz, 1 H, CHNH), 5.64 (s, 1 H, CHHC), 6.22 (s, 1 H, CHHC); δ (minor isomer) = 0.79-1.30 (m, 10 H, CH ₃ CHCH ₂CH ₂CH ₃), 1.26 (t, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH₂O), 1.43 [s, 9 H, (CH ₃ )₃C], 1.70-1.92 (m, 1 H, CH₃CHCH₂CH₂CH₃), 4.08-4.13 (m, 1 H, CHNH), 4.12 (q, ^³ J _HH = 7.00 Hz, 2 H, CH₃CH ₂O), 5.25 (br d, ^³ J _HH = 9.50 Hz, 1 H, CHNH), 5.66 (s, 1 H, CHHC), 6.20 (s, 1 H, CHHC). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.99 (s), 14.14 (s), 14.80 (s), 16.86 (s), 19.74 (s), 19.93 (s), 28.25 (s), 34.57 (s), 35.00 (s), 35.55 (s), 36.09 (s), 57.20 (s), 58.79 (s), 60.52 (s), 79.00 (s), 125.85 (s), 126.54 (s), 139.60 (s), 140.09 (s), 155.32 (s), 166.04 (s). Anal. Calcd for C₁₆H₂₉NO₄: C, 64.18; H, 9.76; N, 4.68. Found: C, 64.01; H, 9.80; N, 4.55.
Ethyl 2-(tert-Butoxycarbonylaminophenyl-methyl)acrylate (5d): white prisms (from Et₂O), mp 81-83 °C (CHCl₃ as eluent). IR (film): 3392, 1716, 1684, 1630 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.18 (t, ^³ J _HH = 7.25 Hz, 3 H, CH ₃ CH₂O), 1.45 [s, 9 H, (CH ₃ )₃C], 4.11 (q, ^³ J _HH = 7.25 Hz, 2 H, CH₃CH ₂O), 5.47 (d, ^³ J _HH = 8.00 Hz, 1 H, CHNH), 5.68 (d, ^³ J _HH = 8.00 Hz, 1 H, CHNH), 5.89 (s, 1 H, CHHC), 6.37 (s, 1 H, CHHC), 7.21-7.31 (m, 5 H, C₆ H ₅ ). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.83 (s), 28.24 (s), 55.99 (s), 60.66 (s), 79.61 (s), 125.95 (s), 126.49 (s), 127.30 (s), 128.38 (s), 139.94 (s), 140.28 (s), 154.81 (s), 165.51 (s). Anal. Calcd for C₁₇H₂₃NO₄: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.69; H, 7.52; N, 4.68.
Ethyl 2-(tert-Butoxycarbonylamino-1-naphthyl-methyl)acrylate (5e): oil (CHCl₃ as eluent). IR (film): 3360, 1724, 1684, 1632 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.04 (t, ^³ J _HH = 7.00 Hz, 3 H, CH ₃ CH₂O), 1.45 [s, 9 H, (CH ₃ )₃C], 4.06 (q, ^³ J _HH = 7.00 Hz, 2 H, CH₃CH ₂O), 4.98 (d, ^³ J _HH = 8.00 Hz, 1 H, CHNH), 5.89 (s, 1 H, CHHC), 6.50 (s, 1 H, CHHC), 6.56 (br d, ^³ J _HH = 8.00 Hz, 1 H, CHNH), 7.31-8.20 (m, 7 H, C₁₀ H ₇). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.76 (s), 28.22 (s), 51.14 (s), 60.64 (s), 79.75 (s), 123.41 (s), 123.96 (s), 124.99 (s), 125.24 (s), 125.79 (s), 126.49 (s), 128.56 (s), 131.00 (s), 133.93 (s), 135.86 (s), 141.11 (s), 154.59 (s), 165.73 (s). Anal. Calcd for C₂₁H₂₅NO₄: C, 70.96; H, 7.09; N, 3.94. Found: C, 70.76; H, 7.14; N, 3.84.

26

Typical Experimental Procedure for Ethyl 2-( tert -Butoxycarbonylaminomethyl)-4-methyl-2-pentenoate ( 6a).
To a suspension of NaH (0.024 g, 1.0 2 mmol) in THF (5 mL) a solution of alkanoate 4a (0.300 g, 0.85 mmol) in THF (3 mL) at 0 °C was added and the reaction mixture was stirred under an argon atmosphere for 0.5 h. Next, a solution of isobutyric aldehyde (0.093 mL, 1.02 mmol) in THF (1 mL) was added. The mixture was warmed to r.t. and refluxed for 4.5 h. After cooling to r.t. the reaction mixture was quenched with H₂O (5 mL) and THF was evaporated. Extraction with CH₂Cl₂ (3 × 15 mL), drying (MgSO₄) and evaporation of the solvent yielded crude 6a, which was purified by column chromatography (eluent, CHCl₃-hexane 6:4). A mixture of diastereomers (E:Z = 83:17) was obtained; oil; yield 0.095 g (41%). IR (film): 3384, 1720,1700, 1655 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ (E isomer) = 1.01 [d, ^³ J _HH = 6.64 Hz, 6 H, (CH ₃ )CH], 1.31 (t, ^³ J _HH = 7.25 Hz, 3 H, CH ₃ CH₂O), 1.44 [s, 9 H, (CH ₃ )₃C], 3.21-3.35 [m, 1 H, (CH₃)CH], 3.86 (d, ^³ J _HH = 6.00 Hz, 2 H, CH ₂ NH), 4.21 (q, ^³ J _HH = 7.25 Hz, 2 H, CH₃CH ₂O), 4.89 (br s, 1 H, CHNH), 5.96 (d, ^³ J _HH = 10.25 Hz, 1 H, (CH₃)CHCH); δ (Z isomer) = 1.04 [d, ^³ J _HH = 6.64 Hz, 6 H, (CH ₃ )CH], 1.32 (t, ^³ J _HH = 7.25 Hz, 3 H, CH ₃ CH₂O), 1.43 [s, 9 H, (CH ₃ )₃C], 2.75-3.10 [m, 1 H, (CH₃)CH], 3.97 (d, ^³ J _HH = 6.25 Hz, 2 H, CH ₂ NH), 4.21 (q, ^³ J _HH = 7.25 Hz, 2 H, CH₃CH ₂O), 5.05 (br s, 1 H, CHNH), 6.66 [d, ^³ J _HH = 10.5 Hz, 1 H, (CH₃)CHCH]. ¹³C NMR (62.9 MHz, CDCl₃): δ = 14.13 (s), 22.25 (s), 22.37 (s), 28.14 (s), 28.30 (s), 36.46 (s), 44.19 (s), 60.28 (s), 60.61 (s), 79.16 (s), 126.36 (s), 127.03 (s), 152.02 (s), 152.32 (s), 155.52 (s), 166.86 (s). Anal. Calcd for C₁₄H₂₅NO₄: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.05; H, 9.33; N, 5.29.

27 Macomber RSA. Complete Introduction to Modern NMR Spectroscopy   John Wiley and Sons; New York: 1998.  p.416