An Expedient Asymmetric Synthesis of N-Protected (S,S)-2-Aminomethyl-1-cyclopropanecarboxylic Acid

Abstract

An enantioselective synthesis of a N-Boc-protected trans-cyclopropane γ-amino acid is reported. The key chiral aldehyde intermediate is prepared in enantiomerically pure form using a three-step aldol-cyclopropanation-retro-aldol protocol.

aldol reaction - amino acids - asymmetric synthesis - carbocycle - chiral auxiliary - enantioselectivity

References and Notes

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9 Both enantiomers of the parent trans-cyclopropane γ-amino acid 1, as well as the cis congeners, have been obtained by resolution procedures: Duke RK. Allan RD. Chebib M. Greenwood JR. Johnston GAR. Tetrahedron: Asymmetry  1998,  9:  2533 

10 Mohapatra DK. Synth. Commun.  1999,  29:  4261 

11 Morikawa T. Sasaki H. Hanai R. Shibuya A. Taguchi T. J. Org. Chem.  1994,  59:  97 

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13 Danishefsky S. Berman EM. Ciufolini M. Etheredge SJ. Segmuller BE. J. Am. Chem. Soc.  1985,  107:  3891 

14 Anderson JC. McDermott BP. Griffin EJ. Tetrahedron  2000,  56:  8747 

15

( S )-4-Benzyl-3-[(2 S ,3 R , E )-6-(benzyloxy)-3-hydroxy-2-methylhex-4-enoyl]-5,5-dimethyloxazolidin-2-one (7)
Colorless oil. [α]_D ^²5 -4.7 (c 0.87, CHCl₃). IR (film): ν = 3461 (OH), 1774 (C=O) cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.45-7.21 (10 H, m, Ph), 5.93 (1 H, dtd, J = 15.5, 5.5, 1.0 Hz, C=CHCH₂), 5.78 (1 H, ddt, J = 15.5, 5.0, 1.0 Hz, C=CHCHOH), 4.62-4.41 (4 H, m, CHN, CH ₂Ph, CHOH), 4.08 (2 H, br d, J = 5.5 Hz, CH ₂OBn), 3.94 (1 H, qd, J = 7.0, 4.0 Hz, CHCH₃), 3.10 (1 H, dd, J = 14.5, 4.5 Hz, CH ^AH^BPh), 2.94 (1 H, dd, J = 14.5, 9.0 Hz, CH^A H ^BPh), 1.43 [3 H, s, (CH ^A ₃)C(CH^B ₃)], 1.40 [3 H, s, (CH^A ₃)C(CH ^B ₃)], 1.20 (3 H, d, J = 7.0 Hz, CH ₃CH₂). ^¹³C NMR (90 MHz, CDCl₃): δ = 176.6, 152.4, 138.3, 136.6, 131.8, 129.1, 128.9, 128.7, 128.4, 127.7, 127.6, 126.9, 82.4, 72.2, 70.0, 63.4, 42.7, 35.5, 28.4, 22.2, 11.5. ESI-HRMS: m/z calcd for C₂₆H₃₁NNaO₅: 460.2094 [M + Na]⁺; found: 460.2086.

16a Furukawa J. Kawabata N. Nishimura J. Tetrahedron Lett.  1966,  7:  3353 

16b Furukawa J. Kawabata N. Nishimura J. Tetrahedron  1968,  24:  53 

17

( S )-4-Benzyl-3-{(2 S ,3 R )-3-[(1 S ,2 S )-2-(benzyloxymethyl)-cyclopropyl]-3-hydroxy-2-methyl propanoyl}-5,5-dimethyloxazolidin-2-one (8)
Colorless oil. IR (film): ν = 3454 (OH), 1774 (C=O) cm^-¹; [α]_D ^²5 +5.6 (c 0.75, CHCl₃). ^¹H NMR (300 MHz, CDCl₃):
δ = 7.49-7.18 (10 H, m, Ph and CH₂ Ph), 4.61-4.46 (3 H, m, CH ₂Ph, CHN), 4.02 (1 H, qd, J = 7.0, 3.5 Hz, CHCH₃), 3.49-3.30 (3 H, m, CH ₂OBn, CHOH), 3.11 (1 H, dd, J = 14.5, 4.0 Hz, CHCH ^AH^BPh), 2.91 (1 H, dd, J = 14.5, 9.0 Hz, CHCH^A H ^BPh), 2.65 (1 H, br s, OH), 1.40 [3 H, s, (CH ^A ₃)C(CH^B ₃)], 1.36 [3 H, s, (CH^A ₃)C(CH ^B ₃)], 1.29 (3 H, d, J = 7.0 Hz, CHCH ₃), 1.20-1.09 (1 H, m, CH-cyclopropyl), 1.01-0.90 (1 H, m, CH-cyclopropyl), 0.71 (1 H, dt, J = 5.0, 8.5 Hz, CH ^AH^B-cyclopropyl), 0.56 (1 H, dt, J = 5.0, 8.5 Hz, CH^A H ^B-cyclopropyl). ^¹³C NMR (90 MHz, CDCl₃): δ = 176.8, 152.6, 138.6, 136.7, 129.1, 128.7, 128.3, 127.7, 127.6, 127.5, 126.9, 82.2, 74.7, 73.2, 72.5, 63.5, 43.1, 35.4, 28.4, 22.2, 20.3, 15.9, 11.5, 8.9. ESI-HRMS): m/z calcd for C₂₇H₃₃NNaO₅: 474.2251 [M + Na]⁺; found: 474.2241.

18

( S , S )-2-(Benzyloxymethyl)cyclopropane Carboxaldehyde (9) Colorless oil. IR (film): ν = 2859, 2731 (CHO), 1708 (C=O) cm^-¹. [α]_D ^²5 +80 (c 0.45, CHCl₃). ^¹H NMR (360 MHz, CDCl₃): δ = 9.17 (1 H, d, J = 5.0 Hz, CHO), 7.40-7.21 (5 H, m, Ph), 4.53 (2 H, s, CH ₂Ph), 3.50 (1 H, dd, J = 10.5, 5.5 Hz, CH ^AH^BOBn), 3.42 (1 H, dd, J = 10.5, 5.0 Hz, CH^A H ^BOBn), 1.89-1.77 (2 H, m, CH-cyclopropyl), 1.33 (1 H, dt, J = 8.5, 5.0 Hz, CH ^AH^B-cyclopropyl), 1.12-1.04 (1 H, m, CH^A H ^B-cyclopropyl). ^¹³C NMR (90 MHz, CDCl₃): δ = 200.2, 138.0, 128.4, 127.7, 127.6, 72.8, 70.9, 28.1, 12.4. ESI-HRMS: m/z calcd for C₁₂H₁₄NaO₂: 213.0886 [M + Na]⁺; found: 213.0886.

19 Our synthesis of aldehyde (S,S)-9 provided material whose specific rotation of +80 (c 0.45, CHCl₃) did not match that described in the literature for the R,R-enantiomer [+43.37 (c 0.52, CHCl₃)]: Kazuta Y. Abe H. Yamamoto T. Matsuda A. Shuto S. J. Org. Chem.  2003,  68:  3511 ; we are grateful to Prof. Shuto and his group for cooperative discussions, and for disclosing a revision of their [α]_D value for (R,R)-9: -78.8 (c 0.51, CHCl₃)

20 Abdel-Magid AF. Carson KG. Harris BD. Maryanoff CA. Shah RD. J. Org. Chem.  1996,  61:  3849 

21

[(1 S ,2 S )-2-(Dibenzylaminomethyl)cyclopropyl]-methanol (10)
Yellow oil which solidified to give an amorphous solid on standing. [α]_D ^¹5 +18 (c 2.1, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 0.30 (1 H, ddd, J = 5.0, 5.0, 10.5 Hz, CH^A H ^B-cyclopropyl), 0.39 (1 H, ddd, J = 5.0, 5.0, 10.5 Hz, CH ^AH^B-cyclopropyl), 0.80-0.86 (2 H, m, CH-cyclopropyl), 2.27 (1 H, dd, 7.0, 13.0 Hz, CH ^AH^BOBn), 2.41 (1 H, dd, J = 6.0, 13.0 Hz, CH^A H ^BOBn), 3.26-3.32 (2 H, m, CH₂NBn₂), 3.59 (2 H, d, J = 13.5 Hz, CH₂NBn), 3.65 (2 H, d, J = 13.5 Hz, CH₂NBn), 4.47 (2 H, s, CH ₂Ph), 7.16-7.40 (15 H, m, ArH). ^¹³C NMR (100 MHz, CDCl₃): δ = 140.0 (2 × Cq), 138.6 (Cq), 128.7 (4 × ArCH), 128.3 (2 × ArCH), 128.1 (4 × ArCH), 127.5 (2 × ArCH), 127.4 (ArCH), 126.7 (2 × ArCH), 73.9 (CH₂), 72.4 (CH₂), 58.1 (2 × CH₂), 57.2 (CH₂), 17.9 (CH), 14.8 (CH), 9.5 (CH₂). ESI-HRMS: m/z calcd for C₂₆H₃₀NO: 372.2322 [M + H]⁺; found: 372.2349.

22

N - tert -Butoxycarbonyl [(1 S ,2 S )-2-(Aminomethyl)-cyclopropyl]methanol (12)
Colorless oil. IR (film): ν = 3344 (OH), 1691 (C=O) cm^-¹. [α]_D ^²0 +7.1 (c 0.50, CHCl₃). ^¹H NMR (250 MHz, CDCl₃):
δ = 0.42 (2 H, dd, J = 5.0, 5.0 Hz, CH ^A H ^B-cyclopropyl), 0.83-0.91 (1 H, m, CH-cyclopropyl), 0.93-1.10 (1 H, m, CH-cyclopropyl), 1.42 [9 H, s, (CH ₃)₃C], 2.90 (1 H, dd, J = 5.0, 9.5 Hz), 3.09 (1 H, dd, J = 4.5, 9.5 Hz), 3.28 (1 H, dd, J = 5.0, 8.0 Hz), 3.57 (1 H, dd, J = 4.5, 8.0 Hz). ^¹³C NMR (60 MHz, CDCl₃): δ = 156.1 (C=O), 79.2 [(CH₃)C], 66.0 (CH₂), 44.5 (CH₂), 28.3 [(CH₃)C], 19.9 (CH), 17.1 (CH), 8.2 (CH₂). ESI-HRMS: m/z calcd for C₁₀H₁₉NNaO₃: 224.1257 [M + Na]⁺; found: 224.1254.

23

N -Benzyl N - tert -Butoxycarbonyl [(1 S ,2 S )-2-(Aminomethyl)cyclopropyl]methanol (11)
Colorless oil. IR (film): ν = 3354 (OH), 1698 (C=O), 1172 cm^-¹. [α]_D ^²7 +16 (c 1.77, CHCl₃). ^¹H NMR (250 MHz, CDCl₃): δ = 0.42-0.50 (2 H, m, CH ^A H ^B-cyclopropyl), 0.86-0.93 (1 H, m), 0.95-1.04 (1 H, m), 1.45 [9 H, s, C(CH₃)₃], 2.95-3.10 (2 H, m), 3.29 (1 H, dd, J = 6.5, 10.0 Hz), 3.37 (1 H, dd, J = 6.5, 10.0 Hz), 4.53 (2 H, s, CH₂Bn), 7.27-7.39 (5 H, m, ArCH). ^¹³C NMR (86 MHz, CDCl₃): δ = 156.0 (C=O), 138.6 (ArC), 128.5 (2 × ArCH), 127.7 (2 × ArCH), 127.6 (ArCH), 100.1 (CH₂Bn), 73.5 (CH₂), 72.6 (CH₂), 71.0 (Cq), 28.5 [C(CH₃)₃], 17.4 (CH), 17.2 (CH), 8.8 (CH₂). ESI-HRMS: m/z calcd for C₁₃H₁₇NNaO₃: 314.1732 [M + Na]⁺; found: 314.1716.

24 Evans DA. Adams DJ. J. Am. Chem. Soc.  2007,  129:  1048 

25

(1 S ,2 S )-2-( tert -Butoxycarbonyl)aminomethyl Cyclopropanecarboxylic Acid (3)
Colorless oil. [α]_D ^²7 +51 (c 0.30, CHCl₃) {lit. for (S,S)-3: [α]_D +52.4 (c 2, CHCl₃);^¹0 lit. for (R,R)-3: [α]_D ^²5 -53.3 (c 1.87, CHCl₃)^¹¹}. ^¹H NMR (360 MHz, CDCl₃): δ = 0.93 (1 H, dd, J = 7.0, 11.0 Hz), 1.23 (1 H, ddd, J = 13.0, 4.5, 4.5 Hz), 1.48 (9 H, s), 1.57 (1 H, ddd, J = 13.0, 4.5, 4.5 Hz), 1.60-1.74 (1 H, m), 2.95-3.15 (1 H, m), 3.16-3.30 (1 H, m), 4.72 (1 H, br s), 5.62 (1 H, br s). ESI-HRMS: m/z calcd for C₁₀H₁₇NNaO₄: 238.1050 [M + Na]⁺; found: 238.1049.