Enantioselective Synthesis
of α-Aminophosphonates via Organocatalytic Sulfenylation
and [2,3]-Sigmatropic Sulfimide Rearrangement

Alan Armstrong; Neil Deacon; Craig Donald

doi:10.1055/s-0030-1260309

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Synlett 2011(16): 2347-2350
DOI: 10.1055/s-0030-1260309

LETTER

Enantioselective Synthesis of α-Aminophosphonates via Organocatalytic Sulfenylation and [2,3]-Sigmatropic Sulfimide Rearrangement

Alan Armstrong*^a, Neil Deacon^a, Craig Donald^b
Department of Chemistry, Imperial College London, South Kensington, SW7 2AZ, UK
e-Mail: A.Armstrong@imperial.ac.uk;
AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK

Further Information

Publication History

Received 25 July 2011
Publication Date:
13 September 2011 (online)

Abstract
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Abstract

β,γ-Unsaturated-α-aminophosphonates are prepared in enantiomerically enriched form via organocatalytic aldehyde α-sulfenylation/olefination followed by oxaziridine-mediated sulfimidation and sulfimide [2,3]-sigmatropic rearrangement. Subsequent N-deprotection and amino acid coupling are also accomplished.

Key words

asymmetric catalysis - amination - rearrangement - organocatalysis - oxaziridine

References and Notes

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20

Typical Procedure for One-Pot Sulfenylation-Olefination Hexane sulfanyl triazole 3 ^¹7 (480 mg, 2.6 mmol) was added to a solution of aldehyde (2.0 mmol) and catalyst 2 (238 mg, 0.4 mmol) in toluene (1.34 mL). The reaction was allowed to stir for 3 h before addition of THF (7 mL). The mixture was then added dropwise to a prepared solution of tetraethyl methylenediphosphonate (1 mL, 4 mmol) and n-BuLi (1.8 mL, 2.22 M, 4 mmol) in THF (7 mL) at -78 ˚C. After 30 min the reaction was allowed to warm to 0 ˚C. The reaction was stirred until completion (approx. 1 h). The reaction was taken up in EtOAc (70 mL) and washed with NaHCO₃ (sat.), H₂O, and NaCl (sat.) The organics were dried with MgSO₄ and concentrated in vacuo. The crude was purified on silica eluting with EtOAc-PE (1:1).
Typical Data for Compound 8a
Colourless oil (0.566 g, 88%). IR (film): ν_max = 2962 (s), 2924 (s), 2839 (m), 1624 (m), 1460 (m), 1390 (m), 1248 (s), 1166 (m), 1100 (m), 1054 (s), 1028 (s), 962 (s), 856 (m), 823 (m), 791 (m), 750 (m) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.51 (1 H, ddd, J = 20.7, 16.9, 9.2 Hz, SCHCHCHP), 5.60 (1 H, dd, J = 20.0, 17.2 Hz, SCHCHCHP), 4.14-4.05 (4 H, m, POCH ₂CH₃), 3.17 (1 H, td, J = 7.7, 9.2 Hz, SCH), 2.43-2.37 (2 H, m, SCHCH ₂), 1.73-1.59 (2 H, m, SCH₂), 1.60-1.47 (2 H, m, SCH₂CH ₂), 1.34 (6 H, t, J = 7.1 Hz, POCH₂CH ₃), 1.35-1.22 [4 H, m, S(CH₂)₂CH ₂CH ₂], 1.00
(3 H, t, J = 7.4 Hz, SCHCH₂CH ₃), 0.89 [3 H, t, J = 7.0 Hz, S(CH₂)₅CH ₃] ppm. ^³¹P NMR (162 MHz, CDCl₃): δ = 17.801 (s)ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 152.3 (d, J = 4.5 Hz) 116.2 (d, J = 186.5 Hz), 61.7 (d, J = 5.5 Hz), 50.0 (d, J = 23.5 Hz), 31.4, 30.6, 29.3, 28.6, 26.7, 22.5, 16.4, 14.0. 11.8. MS (CI): m/z = 323 [MH⁺], 340 [MNH₄ ⁺]. HRMS:
m/z calcd for C₁₅H₃₂O₃SP: 323.1810, Δ = 1.2 ppm; found: 323.1806 [MH⁺]. The enantiomers were separated by HPLC over an AD-H column eluting with 2% 2-PrOH in hexane [t _R = 15 min(major) and 18 min(minor)]; a sample of 87% ee gave [α]^²4 _D -40 (c 1, CHCl₃).

21

Typical Procedure for Amination-Rearrangement-Desulfurisation
The starting phosphonate (0.62 mmol) in CH₂Cl₂ (0.6 mL) was added to oxaziridine 9 (216 mg, 0.74 mmol) in CH₂Cl₂ (0.6 mL) dropwise at -78 ˚C. The reaction was stirred for 24 h. To this was added Ph₃P (210 mg, 0.81 mmol) and MeOH (0.1 mL); the reaction was stirred for a further 30 min before being allowed to warm to r.t. The reaction was then concen-trated in vacuo. The crude was purified on silica eluting with EtOAc-PE (1:1).
Typical Data for Compound 11a
Clear and colourless oil (127 mg, 64%). IR (film): ν_max = 3436 (w), 3156 (w), 2982 (w), 2933 (w), 2361 (w), 2253 (w), 1712 (w), 1496 (w), 1373 (w), 1247 (w), 1166 (w), 1031 (w), 969 (w), 909 (s), 735 (s), 650 (m), 546 (w) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.81 (1 H, m, PCHCHCH), 5.51 (1 H, m, PCHCH), 4.94 (1 H, br, NH), 4.62 (1 H, br, PCH), 4.19-4.10 [4 H, m, P(OCH ₂CH₃)₂], 2.15-2.05 (2 H, m, PCHCHCHCH ₂), 1.47 [9 H, s, C(CH ₃)₃], 1.33 [6 H, dt, J = 1.7, 7.1 Hz, P(OCH₂CH₃)₂], 1.01 (3 H, t, J = 7.4 Hz, PCHCHCHCH₂CH ₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 135.8 (d, J = 11.6 Hz, CH), 121.5 (CH), 80.2 (CCH₃), 62.9 (d, J = 6.7 Hz, CH₂), 62.7 (d, J = 6.6 Hz, CH₂), 50.2 (CH), 48.6 (CH), 28.3 (CH₃), 25.4 (CH₂), 16.4 (t, J = 7.0 Hz, CH₃), 13.2 (CH₃). MS (CI): m/z = 322 [MH⁺] 339 [MNH₄ ⁺]. HRMS: m/z calcd for C₁₄H₂₉NO₅P: 322.1783, Δ = 2.2 ppm; found: 322.1790 [MH⁺]; a sample of 85% ee gave [α]^²4 _D -9 (c 1, CHCl₃).