InCl₃-Mediated Cascade Reactions for the Construction of Highly Functionalized 1-Oxadecalins

Abstract

A one-pot, two-component InCl₃-mediated cascade reaction has been developed. Starting from readily available β-keto ester and alkynal substrates, this cascade reaction provided highly functionalized 1-oxadecalins in good yields and excellent diastereoselectivities.

1-oxadecalin - indium - cascade cyclizations - Prins - Conia­-ene reactions

References and Notes

Phomactin A:

<A NAME="RW19107ST-1A">1a</A> Sugano M. Sato A. Iijima Y. Oshima T. Furuya K. Kuwano H. Hata T. Hanzawa H. J. Am. Chem. Soc.  1991,  113:  5463 

<A NAME="RW19107ST-1B">1b</A> Forskolin: Bhat SV. Bajwa BS. Dornauer H. de Souza NJ. Fehlhaber H.-W. Tetrahedron Lett.  1977,  33:  1669 

<A NAME="RW19107ST-1C">1c</A> Scutorientalin D: Malakov PY. Papanov GY. Spassov SL. Phytochemistry  1997,  44:  121 

<A NAME="RW19107ST-2">2</A> Tang Y. Oppenheimer J. Song Z. You L. Zhang X. Hsung RP. Tetrahedron  2006,  62:  10785 

Examples of Diels-Alder cycloadditions:

<A NAME="RW19107ST-3A">3a</A> Hsung RP. J. Org. Chem.  1997,  62:  7904 

<A NAME="RW19107ST-3B">3b</A> Seth PP. Chen D. Wang J. Gao X. Totah NI. Tetrahedron  2000,  56:  10185 

<A NAME="RW19107ST-3C">3c</A> Chemler SR. Iserloh U. Danishefsky SJ. Org. Lett.  2001,  3:  2949 

<A NAME="RW19107ST-3D">3d</A> Wender PA. Gamber GG. Scanio MJC. Angew. Chem. Int. Ed.  2001,  40:  3895 

Examples of hetero-Diels-Alder cycloadditions:

<A NAME="RW19107ST-3E">3e</A> Tietze LF. Evers H. Töpken E. Angew. Chem. Int. Ed.  2001,  40:  903 

<A NAME="RW19107ST-3F">3f</A> Génisson Y. Tyler PC. Ball RG. Young RN. J. Am. Chem. Soc.  2001,  123:  11381 

<A NAME="RW19107ST-3G">3g</A> Rodriguez R. Adlington RM. Moses JE. Cowley A. Baldwin JE. Org. Lett.  2004,  6:  3617 

<A NAME="RW19107ST-3H">3h</A> Cole KP. Hsung RP. Chem. Commun.  2005,  5784 

<A NAME="RW19107ST-4A">4a</A> Nakamura S. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  8131 

<A NAME="RW19107ST-4B">4b</A> Linares-Palomino PJ. Salido S. Altarejos J. Sánchez A. Tetrahedron Lett.  2003,  44:  6651 

<A NAME="RW19107ST-4C">4c</A> Ishibashi H. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2004,  126:  11122 

<A NAME="RW19107ST-4D">4d</A> Kumazawa K. Ishihara K. Yamamoto H. Org. Lett.  2004,  6:  2551 

<A NAME="RW19107ST-4E">4e</A> Koh JH. Gagné MR. Angew. Chem. Int. Ed.  2004,  43:  3459 

<A NAME="RW19107ST-4F">4f</A> Kurdyumov AV. Hsung RP. J. Am. Chem. Soc.  2006,  128:  6272 

<A NAME="RW19107ST-5A">5a</A> Dumez E. Faure R. Dulcère J.-P. Eur. J. Org. Chem.  2001,  2577 

<A NAME="RW19107ST-5B">5b</A> Lesch B. Bräse S. Angew. Chem. Int. Ed.  2004,  43:  115 

<A NAME="RW19107ST-6A">6a</A> Mi B. Maleczka RB. Org. Lett.  2001,  3:  1491 

<A NAME="RW19107ST-6B">6b</A> Boeckman RK. del Rosario Rico Ferreira M. Mitchell LH. Shao P. J. Am. Chem. Soc.  2002,  124:  190 

<A NAME="RW19107ST-6C">6c</A> Anikin A. Maslov M. Sieler J. Blaurock S. Baldamus J. Hennig L. Findeisen M. Reinhardt G. Oehme R. Welzel P. Tetrahedron  2003,  59:  5295 

<A NAME="RW19107ST-7A">7a</A> Yang XF. Mague JT. Li C.-J. J. Org. Chem.  2001,  66:  739 

<A NAME="RW19107ST-7B">7b</A> Kjellgren J. Szabó KJ. Tetrahedron Lett.  2002,  43:  1123 

<A NAME="RW19107ST-7C">7c</A> Cossey KN. Funk RL. J. Am. Chem. Soc.  2004,  126:  12216 

<A NAME="RW19107ST-8A">8a</A> Durand A.-C. Rodriguez J. Dulcère J.-P. Synlett  2000,  731 

<A NAME="RW19107ST-8B">8b</A> Joshi SN. Phalgune UD. Bhawal BM. Deshmukh ARAS. Tetrahedron Lett.  2003,  44:  1827 

<A NAME="RW19107ST-8C">8c</A> Nicolaou KC. Roecker AJ. Monenschein H. Guntupalli P. Follmann M. Angew. Chem. Int. Ed.  2003,  42:  3637 

<A NAME="RW19107ST-9A">9a</A> Bunce RA. Tetrahedron  1995,  51:  13103 

<A NAME="RW19107ST-9B">9b</A> Tietze LF. Chem. Rev.  1996,  96:  115 

<A NAME="RW19107ST-9C">9c</A> Pellissier H. Tetrahedron  2006,  62:  1619 

<A NAME="RW19107ST-9D">9d</A> Pellissier H. Tetrahedron  2006,  62:  2143 

<A NAME="RW19107ST-9E">9e</A> Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 

<A NAME="RW19107ST-10A">10a</A> Clarke PA. Martin WHC. Org. Lett.  2002,  4:  4527 

<A NAME="RW19107ST-10B">10b</A> Clarke PA. Martin WHC. Hargreaves JM. Wilson C. Blake AJ. Chem. Commun.  2005,  1061 

<A NAME="RW19107ST-10C">10c</A> Clarke PA. Martin WHC. Hargreaves JM. Wilson C. Blake AJ. Org. Biomol. Chem.  2005,  3:  3551 

<A NAME="RW19107ST-11">11</A> Xu C. Yuan C. Tetrahedron  2005,  61:  2169 

<A NAME="RW19107ST-12">12</A> Adams TC. Combs DW. Daves GD. Hauser FM. J. Org. Chem.  1981,  46:  4582 

<A NAME="RW19107ST-13">13</A> Kitagawa O. Suzuki T. Inoue T. Watanabe Y. Taguchi T. J. Org. Chem.  1998,  63:  9470 

<A NAME="RW19107ST-14">14</A>

General ProceduresTo a stirred solution of a β-keto ester (1.5 equiv) and an alkynal (1 equiv) in the appropriate solvent (alkynal concentration = 0.1 mol/L) at 0 °C or r.t. was added a Lewis acid (1 equiv or the amount indicated). The resulting mixture was stirred at the indicated reaction temperature and the reaction was monitored by TLC analysis. After the substrates and intermediates were consumed, the mixture was cooled to r.t., treated with sat. aq NaHCO₃, and extracted with EtOAc (3×). The combined extracts were washed with brine and H₂O, dried over anhyd MgSO₄, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane-EtOAc = 100:1 to 70:1).

<A NAME="RW19107ST-15">15</A>

Tetrahydropyran 3: colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 12.21 (s, 0.1 H), 7.30-7.42 (m, 5 H), 4.74 (dd, J = 3, 12 Hz, 0.9 H), 4.63-4.68 (m, 0.1 H), 4.57 (dd, J = 4, 10 Hz, 0.1 H), 4.22-4.34 (m, 2 H), 4.07-4.15 (m, 2 H), 3.38 (d, J = 11 Hz, 1 H), 2.75 (dd, J = 3, 14 Hz, 1 H), 2.57 (dd, J = 12, 14 Hz, 1 H), 2.22-2.26 (m, 2 H), 1.95 (t, J = 3 Hz, 1 H), 1.68-1.90 (m, 4 H), 1.32 (t, J = 7 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 201.7, 168.0, 140.2, 128.7, 128.2, 125.5, 83.9, 78.4, 78.3, 68.7, 62.9, 61.3, 48.8, 33.9, 24.3, 18.2, 14.2. HRMS (+ESI): m/z calcd for C₁₉H₂₂O₄Na⁺ [M + Na⁺]: 337.1416; found: 337.1433. The NOE (%)of 3 are consistent with the boat conformation of a similar compound (E = CO₂Me, R = i-Pr) that reported in the literature (Figure [3] ).^10a

Figure 3

<A NAME="RW19107ST-16">16</A> Gao Q. Zheng B.-F. Li J.-H. Yang D. Org. Lett.  2005,  7:  2185 

<A NAME="RW19107ST-17">17</A> Kennedy-Smith JJ. Staben ST. Toste FD. J. Am. Chem. Soc.  2004,  126:  4526 

<A NAME="RW19107ST-18">18</A> Jackson WP. Ley SV. J. Chem. Soc., Perkin Trans. 1  1981,  1516 

<A NAME="RW19107ST-19A">19a</A> Endo K. Hatakeyama T. Nakamura M. Nakamura E. J. Am. Chem. Soc.  2007,  129:  5264 

<A NAME="RW19107ST-19B">19b</A> Tsuji H. Yamagata K. Itoh Y. Endo K. Nakamura M. Nakamura E. Angew. Chem. Int. Ed.  2007,  46:  8060 

<A NAME="RW19107ST-20">20</A>

Oxadecalin 4a: colorless oil (73%). ¹H NMR (500 MHz, CDCl₃): δ = 7.29-7.38 (m, 5 H, Ph), 5.22 (d, J = 2 Hz, 1 H, H_f), 4.82 (dd, J = 3, 12 Hz, 1 H, H_a), 4.57 (d, J = 2 Hz, 1 H, H_e), 4.55 (t, J = 3 Hz, 1 H, H_d), 4.25-4.32 (m, 2 H, ethyl ester), 2.92 (dd, J = 12, 15 Hz, 1 H, H_c), 2.62 (dd, J = 3, 15 Hz, 1 H, H_b), 2.48 (d, J = 15 Hz, 1 H, H_g), 2.21-2.28 (m, 1 H, H_h), 2.17-2.14 (m, 1 H), 1.95-2.05 (m, 1 H), 1.57-1.66 (m, 2 H), 1.31 (t, J = 7 Hz, 3 H, ethyl ester). ¹³C NMR (125 MHz, CDCl₃): δ = 204.8, 169.3, 143.0, 140.8, 128.7, 128.2, 125.6, 115.8, 79.1, 78.0, 69.0, 61.7, 47.1, 33.5, 28.6, 20.2, 14.1. HRMS (+ESI): m/z calcd for C₁₉H₂₂O₄Na⁺ [M + Na⁺]: 337.1416: found_ 337.1406.

<A NAME="RW19107ST-21">21</A>

Characterizations of Selected Products in Table 2Oxadecalin 4e: colorless oil (52%). ¹H NMR (500 MHz, CDCl₃): δ = 5.16 (d, J = 2 Hz, 1 H), 4.62 (t, J = 3 Hz, 1 H), 4.53 (d, J = 2 Hz, 1 H), 4.21-4.28 (m, 2 H), 2.79 (d, J = 14 Hz, 1 H), 2.39-2.42 (m, 1 H), 2.24 (d, J = 14 Hz, 1 H), 2.13-2.19 (m, 1 H), 1.93-1.98 (m, 1 H), 1.83-1.92 (m, 1 H), 1.48-1.59 (m, 2 H), 1.33 (s, 3 H), 1.28 (t, J = 7 Hz, 3 H), 1.26 (s, 3 H). ¹³C NMR(125 MHz, CDCl₃): δ = 206.0, 169.4, 142.9, 115.7, 75.1, 71.3, 68.2, 61.5, 50.3, 33.6, 30.9, 28.8, 24.3, 19.9, 14.0. HRMS (+ESI): m/z calcd for C₁₅H₂₂O₄Na⁺ [M + Na⁺]: 289.1416; found: 289.1411.Oxadecalin 4f (major): colorless oil (53%). ¹H NMR (500 MHz, CDCl₃): δ = 7.31-7.37 (m, 5 H), 5.27 (d, J = 2 Hz, 1 H), 4.59 (d, J = 2 Hz, 1 H), 4.55 (t, J = 3 Hz, 1 H), 4.33 (d, J = 11 Hz, 1 H), 3.81 (3 H, s). 2.99-3.06 (m, 1 H), 2.50 (d, J = 15 Hz, 1 H), 2.18-2.24 (m, 1 H), 2.08-2.11 (m, 1 H), 1.95-2.04 (m, 1 H), 1.52-1.63 (m, 2 H) 0.84 (d, J = 7 Hz, 3 H). ¹³C NMR(125 MHz, CDCl₃): δ = 206.4, 169.9, 143.8, 140.0, 128.6, 128.5, 127.0, 115.8, 86.2, 78.2, 69.4, 52.6, 48.8, 33.6, 28.7, 20.2, 9.5. HRMS (+ESI): m/z calcd for C₁₉H₂₂O₄Na⁺ [M + Na⁺]: 337.1416; found: 337.1433.Compound 4g: colorless oil (70%). ¹H NMR (300 MHz, CDCl₃): δ = 7.28-7.41 (m, 5 H), 5.34 (t, J = 2 Hz, 1 H), 5.06 (t, J = 2 Hz, 1 H), 4.79-4.84 (m, 2 H), 4.25 (q, J = 7 Hz, 2 H), 2.74-2.88 (m, 1 H), 2.72 (dd, J = 12, 16 Hz, 1 H), 2.62-2.68 (m, 1 H), 2.56 (dd, J = 3, 16 Hz, 1 H), 2.16 (q, J = 7 Hz, 1 H), 1.71-1.85 (m, 1 H), 1.30 (t, J = 7 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 202.7, 168.9, 146.7, 140.2, 128.7, 128.3, 125.7, 113.6, 85.6, 77.7, 72.7, 62.0, 45.0, 31.1, 29.6, 14.1. HRMS (+ESI): m/z calcd for C₁₈H₂₀O₄Na⁺ [M + Na⁺]: 323.1259; found: 323.1255.

<A NAME="RW19107ST-22">22</A> Adams TC. Dupont AC. Carter JP. Kachur JF. Guzewska ME. Rzeszotarski WJ. Farmer SG. Noronha-Blob L. Kaiser C. J. Med. Chem.  1991,  34:  1585