Enantioselective NHC-Catalysed Formal [4+2] Cycloaddition of Alkylaryl­ketenes with β,γ-Unsaturated α-Ketophosphonates

Abstract

NHC-mediated enantioselective formal [4+2] cycloadditions of alkylarylketenes with γ-substituted-β,γ-unsaturated α-ketophosphonates is described. A substrate-dependent switch in diastereoselectivity was observed, with γ-aryl α-ketophosphonates providing preferentially the syn-dihydropyranone-phosphonates and γ-methyl α-ketophosphonates favouring the anti-dihydropyranone-phosphonate. In addition, ketene generation in situ retained high levels of stereoselectivity and led to improved product yields when compared with the corresponding two-step procedure.

Key words

N-heterocyclic carbenes - cycloaddition - asymmetric catalysis - asymmetric synthesis - lactones

• References and Notes

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For recent examples of β,γ-unsaturated α-ketophosphonates in asymmetric catalysis, see:
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• 19 Consistent with our previous series, see ref. 16.
• 20 Asymmetric formal [4+2] cycloaddition; Typical procedure: To a flame-dried Schlenk flask under an atmosphere of argon was added triazolium salt 1 (14.0 mg, 0.0245 mmol), Cs₂CO₃ (7.2 mg, 0.0221 mmol) and toluene (1.5 mL), and the resultant suspension was stirred at r.t. for 30 min, then (E)-dimethyl cinnamoylphosphonate (3a; 58.8 mg, 0.245 mmol) was added as a solution in toluene (1.5 mL). As soon as the addition was complete, a solution of ethylphenylketene 2a (86.0 mg, 0.588 mmol) in toluene (4 mL) was added over 1 h by using a syringe pump. When the addition was complete, the solution was stirred at r.t. overnight before concentration in vacuo to give the crude product (63:37 dr syn/anti). Purification by column chromatography on silica gel (petroleum ether–EtOAc, 70:30) gave a fully inseparable mixture of lactones 4a and 4b (80 mg, 84%) as a colourless solid. The syn/anti ratio was determined by both ¹H and ³¹P NMR spectroscopy of the unpurified reaction mixture and the ee was determined by chiral HPLC analysis of the purified product. Analytical Data for the Mixture of 4a and 4b: Mp 58–59 °C; IR (KBr): 2955 (C–H), 1769 (C=O), 1267 (P=O), 1032 (P–OMe) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ (4a) = 1.05 (t, J = 7.3 Hz, 3 H, CH₂CH ₃), 2.26–2.44 (m, 2 H, CH ₂), 3.87–3.92 [m, 1 H, C(4)H], 3.90 (d, J = 2.8 Hz, 3 H, OMe), 3.94 (d, J = 2.8 Hz, 3 H, OMe), 6.50 [dd, J = 10.0, 4.8 Hz, 1 H, C(5)H], 6.66–6.69 (m, 2 H, PhH), 6.82–6.88 (m, 2 H, PhH), 7.07–7.16 (m, 6 H, PhH); δ (4b) = 0.58 (t, J = 7.4 Hz, 3 H, CH₂CH ₃), 1.48 [dq, J = 14.4, 7.4 Hz, 1 H, C(3)CH _AH_B], 1.91 (dq, J = 14.4, 7.4 Hz, 1 H, CH_A H _B), 3.12 (d, J = 11.3 Hz, 1 H, OMe), 3.76 (d, J = 11.3 Hz, 1 H, OMe), 4.26 [d, J = 6.8 Hz, 1 H, C(4)H], 6.60 [dd, J = 9.7, 6.8 Hz, 1 H, C(5)H], 7.19–7.24 (m, 2 H, PhH), 7.29–7.40 (m, 8 H, PhH); ¹³C (75 MHz, CDCl₃): δ (4a) = 9.5 (CH₃), 29.0 (CH₂), 50.2 [d, J = 12.7 Hz, C(4)], 53.7 (d, J = 5.7 Hz, 2 × OMe), 55.1 [C(3)], 124.0 [d, J = 19.6 Hz, C(5)], 127.0 (PhH), 127.7 (2 × Ph), 128.1 (Ph), 128.2 (Ph), 129.1 (Ph), 136.0 [C(3)Ph(1)], 136.4 [d, J = 1.0 Hz, C(4)Ph(1)], 142.2 [d, J = 234.4 Hz, C(6)], 168.4 [d, J = 8.0, C(2)]; δ (4b) = 8.2 (CH₂ CH₃), 28.3 (CH₂), 45.7 [d, J = 12.5 Hz, C(4)], 52.7 (d, J = 4.6 Hz, OMe), 53.5 (d, J = 5.7 Hz, OMe), 54.3 [C(3)], 125.0 [d, J = 19.4 Hz, C(5)], 127.2 (Ph), 128.0 (Ph), 128.4 (Ph), 128.6 (Ph), 128.8 (Ph), 129.8 (Ph), 135.9 [d, J = 2.4 Hz, C(4)Ph(1)], 137.7 [C(3)Ph(1)], 141.8 [d, J = 238.8 Hz, C(6)], 170.4 [d, J = 8.1 Hz, C(2)]; HRMS (NSI⁺): m/z [M+H]⁺ calcd for C₂₁H₂₄O₅P⁺: 387.1356; found: 387.1364 (+2.4 ppm). Chiral HPLC (Chiralpak OD-H; 5% IPA–hexane; flowrate: 1 mL min^–1; 220 nm): t_R = 25.9 (4b minor), 29.5 (3R,4R), 35.3 (3S,4S), 43.2 (4b major) min; 93% ee syn, 29% ee anti. For a full list of unreactive ketenes screened in this process see the Supporting Information.
• 21 When para-halogen substituted alkylarylketenes were employed, the anti-diastereoisomer was not isolated after purification. In all of the examples presented in Table 2, resonances consistent with the presence of both syn- and anti-diastereoisomers are clearly visible by both ¹H and ³¹P NMR spectroscopic analysis of the unpurified reaction mixture. However, following purification, the anti-diastereoisomer was no longer visible in any of the isolated fractions and the yield given is for the recovered syn-diastereoisomer only. The reasons for this remain unclear.
• 22 Dihydropyranone phosphonate 13a was characterised by single-crystal X-ray diffraction. Crystallographic data is available free of charge from the Cambridge Crystallographic Data Centre, www.ccdc.ac.uk/data-request/cif, as CCDC 930998.
• 23 The formation of product 17 has recently been described through a Lewis acid mediated transformation, and presumably arises from a bimolecular reaction of the α,β-ketophosphonate starting material, see: Sun Y.-W, Zhu P.-L, Xu Q, Shi M. Tetrahedron 2012; 68: 9924
• 24 See Supporting Information for details.
• 25 For a recent example of ketene formation in situ in catalysis, see: Rasik C, Brown M. J. Am. Chem. Soc. 2013; 135: 1673
• 26 Me₂EtN was preferred over Et₃N because it did not require distillation over CaH₂ prior to use.
• 27 Asymmetric formal [4+2] cycloaddition with ketene generation in situ; Typical procedure: To a flame-dried Schlenk flask under an atmosphere of argon and at 0 °C, was added sequentially 2-phenylbutanoyl chloride (112 mg, 0.613 mmol) as a solution in toluene (1.5 mL), (E)-dimethyl cinnamoylphosphonate (3a; 58.8 mg, 0.245 mmol) as a solution in toluene (1.5 mL) and triazolium salt 1 (14.0 mg, 0.0245 mmol) as a solid. Finally, dimethylethylamine (93 μL, 0.858 mmol) was added in one portion and the reaction mixture warmed to r.t. overnight before concentration in vacuo to give the crude product (63:37 dr syn/anti). Purification by column chromatography on silica gel (petroleum ether–EtOAc, 70:30) gave a fully inseparable mixture of lactones 4a and 4b (23 mg, 24%) as a colourless solid with spectroscopic data as described in ref. 20. The syn/anti ratio was determined by both ¹H and ³¹P NMR spectroscopy of the unpurified reaction mixture and the ee was determined by chiral HPLC analysis of the purified product. Chiral HPLC (Chiralpak OD-H; 5% IPA–hexane; flowrate 1 mL min^–1; 220 nm): t_R = 26.0 (4b minor), 30.7 (3R,4R), 36.2 (3S,4S), 42.8 (4b major) min; 98% ee syn, 37% ee anti.
• 28 A control experiment in which isolated and purified ketene was used in the NHC-mediated formal [4+2] cycloaddition with phosphonates 3a and Me₂EtN gave similar results to those with Cs₂CO₃ reported in Table 2, entry 6. See the Supporting Information for full details.
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