Asymmetric Synthesis of (1S,2R)-1-Amino-2-methylcyclopropanephosphonic Acid: A Phosphonic Analogue of (–)-Norcoronamic Acid – Influence of Stereochemistry on Regioselectivity in Sulfoxide–Metal Exchange

Abstract

Asymmetric synthesis of (–)-(1S,2R)-1-amino-2-methylcyclopropanephosphonic acid, a phosphonic analogue of (–)-norcoronamic acid was developed. The presence of the nitrile group as a precursor of the amino moiety, by changing stereoselectivity in the alkylation step, in consequence allowed to avoid 1,2-migration of a phosphoryl group on the cyclopropane ring and to obtain the required cyclopropylphosphonate of the retained structure and configuration.

Key words

cyclopropanes - ylides - amino acids - cyclopropyl sulfoxide - asymmetric synthesis

• References and Notes


For a recent review, see:
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• 11 Compound cis-7: ³¹P NMR (81 MHz, CDCl₃): δ = 14.0. ¹H NMR (500 MHz, CDCl₃): δ = 1.46 [t, J _HH = 7.0 Hz, 3 H, (CH ₃CH₂O)P], 1.48 [t, J _HH = 7.0 Hz, 3 H, (CH ₃CH₂O)P], 1.49 (s, 3 H, CH₃), 1.66 (dd, J _HH = 6.1 Hz, J _PH= 7.7 Hz, 1 H, CH _cis ), 2.25 (dd, J _HH = 6.1 Hz, J _PH = 16.1 Hz, 1 H), 2.43 (s, 3 H, C₆H₄CH ₃), 4.29–4.40 (m, 2 H, POCH ₂CH₃), 4.41–4.44 (m, 2 H, POCH ₂CH₃), 7.32 and 7.51 (A₂B₂, 4 H, C₆ H ₄CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 11.9 (CH₃), 16.3 [m, (CH₃CH₂O)P], 20.0 [d, J _CP = 190.4 Hz, CP(O)], 21.4 (C₆H₄ CH₃), 24.1, 50.0 (CHSO), 64.2 [d, J _CP = 6.2 Hz, (CH₃ CH₂O)P], 64.9 [d, J _CP = 6.5 Hz, (CH₃ CH₂O)P], 116.5 (CN), 124.5, 129.9, 138.0, 142.2. HRMS (CI): m/z calcd for C₁₆H₂₄NPO₄ [M + H]⁺: 356.10833; found: 356.108465.Compound trans-7: ³¹P NMR (81 MHz, CDCl₃): δ = 13.8. ¹H NMR (600 MHz, CDCl₃): δ = 1.17 [t, J _HH = 7.1 Hz, 3 H, (CH ₃CH₂O)P], 1.24 (s, 3 H, CH₃), 1.27 [t, J _HH = 7.1 Hz, 3 H, (CH ₃CH₂O)P], 2.06 (dd, J _HH = 5.8 Hz, J _PH = 14.0 Hz, 1 H, CH _cis ), 2.40 [dd, J _HH = 5.8 Hz, J _PH = 8.9 Hz, 1 H, CHS(O)], 2.43 (s, 3 H, C₆H₄CH ₃), 3.96–3.99 (m, 1 H, POCHHCH₃), 4.01–4.05 (m, 1 H, POCHHCH₃), 4.23–4.27 (m, 2 H, POCH ₂CH₃), 7.36 and 7.73 (A₂B₂, 4 H, C₆ H ₄CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 9.1, 16.1 [m, (CH₃CH₂O)P], 21.5 (C₆H₄ CH₃), 25.6, 47.8 (CHSO), 63.7 (d, J _CP = 6.5 Hz, [CH₃ CH₂O)P], 64.4 [d, J _CP = 6.2 Hz, (CH₃ CH₂O)P], 116.6 (CN), 124.9, 129.8, 136.9, 142.4. HRMS (CI): m/z calcd for C₁₆H₂₄NPO₄ [M + H]⁺: 356.10833; found: 356.108545.
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• 13 Compound 8: ³¹P NMR (81 MHz, CDCl₃): δ = 18.0. ¹H NMR (600 MHz, CDCl₃): δ = 1.40 [t, J _HH = 7.0 Hz, 3 H, (CH ₃CH₂O)P], 1.42 [t, J _HH = 7.0 Hz, 3 H, (CH ₃CH₂O)P], 1.44 (d, J _HH = 6.7 Hz, 3 H, CH₃), 1.55 (ddd, J _HH = 4.8 Hz, J _HH = 7.1 Hz, J _PH = 14.2 Hz, 1 H, CH _cis ), 1.70 (ddd, J _HH = 4.8 Hz, J _HH = 8.9 Hz, J _PH = 7.3 Hz, 1 H, CH _trans ), 1.90 (m, 1 H, CHCH₃), 4.24 (m, 1 H, POCH ₂CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 8.6 (d, J _CP = 198.8 Hz, C1), 13.0 (d, J _CP = 3.4 Hz, CH₃) 16.3 [d, J _CP = 6.0 Hz, (CH₃CH₂O)P], 16.4 [(CH₃CH₂O)P], 21.9, 24.4, 63.3 [d, J _CP = 6.5 Hz, (CH₃ CH₂O)P], 63.6 [d, J _CP = 6.0 Hz, (CH₃ CH₂O)P], 119.9 (CN). HRMS (CI): m/z calcd for C₉H₁₇NPO₃ [M + H]⁺: 218.09497; found: 218.094607.
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• 16 Compound 9: ³¹P NMR (81 MHz, CDCl₃): δ = 26.1. ¹H NMR (500 MHz, CDCl₃): δ = 1.11 (ddd, J _HH = 5.0 Hz, J _HH = 5.5 Hz, J _PH = 13.5 Hz, 1 H, CHH), 1.39 [t, J _HH = 7.0 Hz, 3 H, (CH₃ CH₂O)P], 1.40 [t, J _HH = 7.0 Hz, 3 H, (CH₃ CH₂O)P], 1.47 (d, J _PH = 13.0 Hz, 3 H, CH₃CP), 1.62 (ddd, J _HH = 5.0 Hz, J _HH = 9.0 Hz, J _PH = 14.0 Hz, 1 H, CHH), 2.04 (ddd, J _HH = 5.5 Hz, J _HH = 9.0 Hz, J _PH = 14.3 Hz, 1 H, CHCN), 4.13 (m, 4 H, POCH₂). ¹³C NMR (125 MHz, CDCl₃): δ = 15.9 (CH₂C), 16.4 [d, J _CP = 5.7 Hz, (CH₃ CH₂O)P], 17.1 (d, J _CP = 194.0 Hz, CP), 18.2, 29.7 (d, J _CP = 2.9 Hz, CCN), 62.8 (d, J _CP = 6.2 Hz, POCH₂), 127.1 (CN). HRMS–FAB: m/z calcd for C₉H₁₆NPO₃[M]⁺: 9217.0872; found: 217.086782.
• 17 Other factors which have an influence on the behavior of carbanion formed after sulfinyl exchange are under our current investigations.
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