Highly Diastereoselective Synthesis of Manoyl Oxide Derivatives by TiCl₄-Catalyzed Nucleophilic Cleavage of Ambracetal Derivatives

Abstract

The treatment of acetal 11 with KCN and AlCNEt₂ in the presence of TiCl₄ produces in high diastereoselectivity 2-cyanooxane 14, which can be easily converted into manoyl oxide derivatives. Using this strategy, 19-hydroxymanoyl oxide 20, diterpene from P. viscosum, was prepared from communic acids 7a-c after an 8-steps sequence in a 17% overall yield.

natural products - acetal cleavage - manoyl oxides - Lewis acids - labdane diterpenes

References

<A NAME="RD18603ST-1A">1a</A> Leclaire M. Levet R. Ferreira F. Ducrate P.-H. Ricard J.-YLL. Chem. Commun.  2000,  18:  1737 

<A NAME="RD18603ST-1B">1b</A> Hanna I. Wlodyka P. J. Org. Chem.  1997,  62:  6985 

<A NAME="RD18603ST-1C">1c</A> Nicolau KC. Kubota S. Li WS. Chem. Commun.  1989,  512 

<A NAME="RD18603ST-1D">1d</A> Corey EJ. Da Silva Jardine P. Rohloff JC. J. Am. Chem. Soc.  1988,  110:  3672 

<A NAME="RD18603ST-2A">2a</A> Arew SVB. Prog. Chem. Org. Nat. Prod.  1993,  1 

<A NAME="RD18603ST-2B">2b</A> Kopras E. Greeley T. Babcock GF. Gastroenterology  2002,  122:  W1096 

<A NAME="RD18603ST-2C">2c</A> Yool AJ. Stamer WD. Regan JW. Science  1996,  273:  1216 

<A NAME="RD18603ST-2D">2d</A> Robbins JD. Boring DL. Tang WJ. Shank R. Seamon KB. J. Med. Chem.  1996,  39:  2745 

<A NAME="RD18603ST-2E">2e</A> Tang WJ. Gilman AG. Science  1995,  268:  1769 

<A NAME="RD18603ST-3">3</A> Kalpoutzakis E. Aligiannis N. Mitaku S. Chinou L. Charvala C. Skaltsounis AL. Chem. Pharm. Bull.  2001,  49:  814 

<A NAME="RD18603ST-4A">4a</A> Skaltsa HD. Lazari DM. Chinou IB. Loukis AE. Planta Med.  1999,  65:  255 

<A NAME="RD18603ST-4B">4b</A> Roussis V. Tsoukatou M. Chinou IB. Ortiz A. Planta Med.  1998,  64:  675 

<A NAME="RD18603ST-4C">4c</A> Kalpoutzakis E. Chinou L. Mitaku S. Skaltsounis AL. Charvala C. Nat. Prod. Lett.  1998,  11:  173 

<A NAME="RD18603ST-5">5</A> García-Granados A. Liñán E. Martínez A. Onorato ME. Parra A. Arias JM. Phytochemistry  1995,  38:  287 

<A NAME="RD18603ST-6">6</A> Konishi T. Takasaki M. Tokuda H. Kiyosawa S. Konoshima T. Biol. Pharm. Bull.  2001,  24:  1440 

<A NAME="RD18603ST-7A">7a</A> Dimas K. Demetzos C. Mitaku S. Vaos B. Marselos M. Tzavaras T. Kokkinopoulos D. Anticancer Res.  1999,  19:  4065 

<A NAME="RD18603ST-7B">7b</A> Angelopoulou D. Demetzos C. Dimas C. Perdetzoglou D. Loukis A. Planta Med.  2001,  67:  168 

<A NAME="RD18603ST-7C">7c</A> Demetzos C. Mitaku S. Couladis M. Harvala C. Kokkinopoulos D. Planta Med.  1994,  60:  590 

<A NAME="RD18603ST-8">8</A> Garcia Granados A. Liñan E. Martinez A. Rivas F. Mesa Valle CM. Castilla Calvente JJ. Osuna A. J. Nat. Prod.  1997,  60:  13 

<A NAME="RD18603ST-9">9</A> Dimas K. Demetzos C. Vaos V. Ioannidis P. Trangas T. Leukemia Res.  2001,  25:  449 

<A NAME="RD18603ST-10">10</A> Duan H. Takaishi Y. Momota H. Ohmoto Y. Taki T. Jia Y. Li D. J. Nat. Prod.  1999,  62:  1522 

<A NAME="RD18603ST-11A">11a</A> De las Heras B. Hoult JR. Planta Med.  1994,  60:  501 

<A NAME="RD18603ST-11B">11b</A> De las Heras B. Villar A. Vivas JM. Hoult JR. Agents Actions  1994,  41:  114 

<A NAME="RD18603ST-11C">11c</A> Alcaraz MJ. Jiménez MJ. Valverde S. Sanz J. Rabanal RM. Villar A. J. Nat. Prod.  1989,  52:  1088 

<A NAME="RD18603ST-12A">12a</A> Fraga BM. Hernández MG. González P. López M. Suárez S. Tetrahedron  2001,  57:  761 

<A NAME="RD18603ST-12B">12b</A> Fraga BM. González P. Hernández MG. López M. Suárez S. Tetrahedron  1999,  55:  1781 

<A NAME="RD18603ST-12C">12c</A> Fraga BM. González P. Guillermo R. Hernández MG. J. Nat. Prod.  1998,  61:  1237 

<A NAME="RD18603ST-12D">12d</A> Fraga BM. González P. Guillermo R. Hernández MG. Tetrahedron  1998,  54:  6159 

<A NAME="RD18603ST-12E">12e</A> García-Granados A. Liñán E. Martínez A. Onorato ME. Arias JM. J. Nat. Prod.  1995,  58:  1695 

<A NAME="RD18603ST-12F">12f</A> Amate Y. García-Granados A. López FA. Sáenz Buruaga A. Synthesis  1991,  371 

<A NAME="RD18603ST-13">13</A> Barrero AF. Alvarez-Manzaneda EJ. Alvarez-Manzaneda R. Chahboun R. Meneses R. Aparicio M. Synlett  1999,  713 

<A NAME="RD18603ST-14">14</A> Rychnovsky SD. Dahanukar VH. Tetrahedron Lett.  1996,  37:  339 

<A NAME="RD18603ST-15A">15a</A> Kotsuki H. Ushio Y. Kadota I. Ochi M. Chem. Lett.  1988,  927 

<A NAME="RD18603ST-15B">15b</A> Kotsuki H. Ushio Y. Kadota I. Ochi M. J. Org. Chem.  1989,  54:  5153 

<A NAME="RD18603ST-15C">15c</A> Kotsuki H. Synlett  1992,  97 

<A NAME="RD18603ST-15D">15d</A> Ishihara K. Mori A. Yamamoto H. Tetrahedron Lett.  1987,  28:  6613 

<A NAME="RD18603ST-15E">15e</A> Ishihara K. Mori A. Yamamoto H. Tetrahedron  1990,  46:  4595 

<A NAME="RD18603ST-15F">15f</A> Kim Y. Mundy BP. J. Org. Chem.  1982,  47:  3556 

<A NAME="RD18603ST-15G">15g</A> Masaki Y. Serizawa Y. Nagata K. Kaji K. Chem. Lett.  1983,  1601 

<A NAME="RD18603ST-15H">15h</A> Lewis MD. Cha JK. Kishi Y. J. Am. Chem. Soc.  1982,  104:  4976 

<A NAME="RD18603ST-15I">15i</A> Fotsch CH. Chamberlin AR. J. Org. Chem.  1991,  56:  4141 

<A NAME="RD18603ST-16">16</A> Barrero AF. Altarejos J. Alvarez-Manzaneda EJ. Ramos JM. Salido S. Tetrahedron  1993,  49:  9525 

<A NAME="RD18603ST-17">17</A> Fotsch CH. Chamberlin AR. J. Org. Chem.  1991,  56:  4141 

<A NAME="RD18603ST-18">18</A> Stierle DB. Stierle AA. Larsen RD. Phytochemistry  1988,  27:  517 

<A NAME="RD18603ST-19">19</A>

Typical Procedure for the Nucleophilic Cleavage of 11; Synthesis of Oxanes 14 and 15: To a stirred solution of 11 (0.25 g, 0.78 mmol), 18-crown-6-ether (0.57 g, 2.14 mmol) and KCN (0.2 g, 3.10 mmol) in CH₂Cl₂ (15 mL), was added AlCNEt₂ (1.0 M in CH₂Cl₂, 6.2 mL) and TiCl₄ (1.0 M in CH₂Cl₂,1.9 mL) at -78 ºC, under Ar atmosphere. The reaction mixture was then stirred at the indicated temperature during the time showed in Table [2] . Then an aq 1 M NaHCO₃ solution (8 mL) was added and the resulting mixture was stirred for 3 h, and extracted with t-BuOMe (2 × 30 mL). The organic phase was successively washed with 5% aq NaHCO₃ (2 × 30 mL), water (2 × 30 mL), brine (2 × 30 mL), dried over anhyd Na₂SO₄ and evaporated to give a crude product which was chromatographed (hexane- t-BuOMe, 3:2) to yield 14 and 15.

<A NAME="RD18603ST-20">20</A>

All new compounds were fully characterized spectroscopically and had satisfactory HRMS data.
Selected data:
Compound 14: ¹H NMR (400 MHz, CDCl₃): δ = 0.58 (s, 3 H, Me-10a), 1.04 (dc, J = 13.7, 4.2 Hz, 2 H), 1.16 (s, 3 H, Me-7), 1.20-1.54 (m, 2 H), 1.57 (s, 3 H, Me-3), 1.65-2.30 (m, 11 H), 3.40 (dd, J = 11.1, 1.5 Hz, 1 H, 4a-CH₂OH-A), 3.60 (s, 3 H, 7-COOMe), 3.61 (d, J = 11.6 Hz, 1 H, 4a-CH₂OH-B).
¹³C NMR (100 MHz, CDCl₃): δ = 177.4 (7-COOCH₃), 122.4 (3-CN), 79.3 (C-4a), 66.8 (C-3), 63.7 (4a-CH₂OH), 56.3* (C-10b), 51.3 (7-COOMe), 48.3* (C-6a), 43.7 (C-7), 38.8 (C-10), 37.9 (C-10a), 37.7 (C-8), 36.6 (C-6), 31.9 (C-2), 29.2 (Me-3), 28.5 (Me-7), 21.2 (C-5), 18.9 (C-9), 14.4 (C-1), 12.7 (Me-10a).
Compound 18: ¹H NMR (400 MHz, CDCl₃): δ = 0.57 (s, 3 H, Me-20), 0.88 (dt, J = 13.3, 4.1 Hz, 1 H), 0.98 (dt, J = 12.9, 3.9 Hz, 1 H), 1.00-1.25 (m, 1 H), 1.17 (s, 3 H, Me-18), 1.28 (s, 3 H, Me-16), 1.65-1.95 (m, 7 H), 2.16 (d, J = 13.1 Hz, 1 H), 2.23 (dt, J = 12.7, 3.4 Hz, 1 H), 3.56 (dd, J = 10.5, 1.7 Hz, 1 H, 17-CH₂OH-A), 3.62 (d, J = 10.5 Hz, 1 H, 17-CH₂OH-B), 3.62 (s, 3 H, 19-COOMe), 4.99 (dd, J = 10.8, 1.1 Hz, 1 H, =CH₂), 5.20 (dd, J = 17.4, 1.1 Hz, 1 H, =CH₂), 5.93 (dd, J = 17.4, 10.8 Hz, 1 H, -CH=).
¹³C NMR (100 MHz, CDCl₃): δ = 177.7 (19-COOCH₃), 146.7 (C-14), 111.4 (C-15), 77.1 (C-8), 74.4 (C-13), 63.2 (C-17), 56.9* (C-9), 51.4* (C-5), 51.3 (19-COOMe), 43.8 (C-4), 40.0 (C-1), 38.1 (C-3), 37.8 (C-10), 37.7 (C-6), 33.0 (C-12), 30.0 (C-14), 28.6 (C-18), 21.5 (C-7), 19.1 (C-2), 15.1 (C-11), 13.0 (C-20).