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Synlett 2013; 24(10): 1243-1249
DOI: 10.1055/s-0033-1338851
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© Georg Thieme Verlag Stuttgart · New York

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

Stuart M. Leckie
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Fax: +44(1334)463808   Email: ads10@st-andrews.ac.uk
,
Charlene Fallan
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Fax: +44(1334)463808   Email: ads10@st-andrews.ac.uk
,
James E. Taylor
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Fax: +44(1334)463808   Email: ads10@st-andrews.ac.uk
,
T. Bruce Brown
b   Pfizer Global Research and Development, 388 Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
,
David Pryde
c   Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, UK
,
Tomáš Lébl
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Fax: +44(1334)463808   Email: ads10@st-andrews.ac.uk
,
Alexandra M. Z. Slawin
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Fax: +44(1334)463808   Email: ads10@st-andrews.ac.uk
,
Andrew D. Smith*
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Fax: +44(1334)463808   Email: ads10@st-andrews.ac.uk
› Author Affiliations
Further Information

Publication History

Received: 01 April 2013

Accepted after revision: 03 May 2013

Publication Date:
28 May 2013 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

  • 2 Breslow R. J. Am. Chem. Soc. 1958; 80: 3719
    Search in Google Scholar
  • 3 Stetter H. Angew. Chem. Int. Ed. Engl. 1976; 15: 639
    CrossrefSearch in Google Scholar
  • 5 Phillips E, Chan A, Scheidt K. Aldrichimica Acta 2009; 42: 55
    Search in Google Scholar
    • 7a Duguet N, Donaldson A, Leckie SM, Douglas J, Shapland P, Brown TB, Churchill G, Slawin AM. Z, Smith AD. Tetrahedron: Asymmetry 2010; 21: 582
      CrossrefSearch in Google Scholar
    • 7b Duguet N, Donaldson A, Leckie SM, Kallström EA, Campbell CD, Shapland P, Brown TB, Slawin AM. Z, Smith AD. Tetrahedron: Asymmetry 2010; 21: 601
      CrossrefSearch in Google Scholar
    • 7c Irgolic KJ In Houben-Weyl . Klamann D. Thieme; Stuttgart: 1990. 4th ed., Vol. E12b, 150
      Search in Google Scholar
  • 9 Concellón C, Duguet N, Smith AD. Adv. Synth. Catal. 2009; 351: 3001
    CrossrefSearch in Google Scholar
  • 10 Douglas J, Ling KB, Concellón C, Churchill G, Slawin AM. Z, Smith AD. Eur. J. Org. Chem. 2010; 5863
  • 12 Lv H, Zhang Y.-R, Huang X.-L, Ye S. Adv. Synth. Catal. 2008; 350: 2715
    CrossrefSearch in Google Scholar
  • 13 Shao PL, Chen XY, Ye S. Angew. Chem. Int. Ed. 2010; 49: 8412
    Search in Google Scholar
  • 15 Wang XN, Lv H, Huang XL, Ye S. Org. Biomol. Chem. 2009; 7: 346
    Search in Google Scholar
  • 16 Leckie SM, Brown TB, Pryde D, Lébl T, Slawin AM. Z, Smith AD. Org. Biomol. Chem. 2013; 11: 3230
    CrossrefPubMedSearch in Google Scholar
  • 18 Shie J.-J, Fang J.-M, Lai P.-T, Wen W.-H, Wang S.-Y, Cheng Y.-SE, Tsai K.-C, Yang A.-S, Wong C.-H. J. Am. Chem. Soc. 2011; 133: 17959
    CrossrefSearch in Google Scholar
  • 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 AHB], 1.91 (dq, J = 14.4, 7.4 Hz, 1 H, CHA 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): tR = 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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): tR = 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.