Enantioselective Total Synthesis of 3-epi-Ottelione A

Abstract

An enantioselective total synthesis of (+)-3-epi-ottelione A (2), the earlier proposed stereostructure of the antitumor natural product ottelione A (4), was achieved for the first time starting from the known tetracyclic compound 9. The synthesis involves the following three crucial steps: (i) a coupling reaction of aldehyde 8 and aryllithium 7 to introduce the aromatic portion, (ii) base-induced lactol-opening/epimerization at the C1 position of 6 to deliver the requisite hydrindane 15, and (iii) Corey-Winter’s reductive olefination of the cyclic thiocarbonate 19 to install the C5-C6 double bond.

3-epi-ottelione A - total synthesis - otteliones A and B - natural products - antitumor agents

References

1 Ayyad S.-EN. Judd AS. Shier WT. Hoye TR. J. Org. Chem.  1998,  63:  8102 

2 Combeau C. Provost J. Lancelin F. Tournoux Y. Prod’homme F. Herman F. Lavelle F. Leboul J. Vuilhorgne M. Mol. Pharm.  2000,  57:  553 

3a Clive DLJ. Fletcher SP. Chem. Commun.  2002,  1940 

3b Mehta G. Islam K. Org. Lett.  2002,  4:  2881 

3c Mehta G. Islam K. Synlett  2000,  1473 

3d Trembleau L. Patiny L. Ghosez L. Tetrahedron Lett.  2000,  41:  6377 

3e Mehta G. Reddy DS. Chem. Commun.  1999,  2193 

4 Mehta G. Islam K. Angew. Chem. Int. Ed.  2002,  41:  2396 

5 Mehta G. Islam K. Tetrahedron Lett.  2003,  44:  6733 

6 Araki H. Inoue M. Katoh T. Org. Lett.  2003,  5:  3903 

7

In 2002 Mehta and Islam reported the total synthesis of racemic (±)-3-epi-ottelione A derivative (3-epi-O-isopropylottelione A) (see, ref. [3b] ), while, to the best of our knowledge, 3-epi-ottelione A (2) itself has not yet been synthesized.

8

In May 2002, we achieved the total synthesis of 2 in an enantiomerically pure form; however, to our disappointment, spectral data of the synthetic 2 did not match those of the natural product ottelione A.

9a Izuhara T. Katoh T. Tetrahedron Lett.  2000,  41:  7651 

9b Izuhara T. Katoh T. Org. Lett.  2001,  3:  1653 

10

4-Bromo-1-methoxy-2-(methoxymethoxy)benzene has previously been reported in our laboratory, see ref. [6]

11

Data for 6: Colorless needles, mp 113-114 °C, [α]_D ²⁰ -36.6 (c 0.77, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.10 (3 H, s), 0.13 (3 H, s), 0.91 (9 H, s), 1.36 (3 H, s), 1.47 (3 H, s), 1.43-1.49 (1 H, m), 1.62 (1 H, ddd, J = 13.5, 6.3, 3.0 Hz), 1.90-1.95 (1 H, m), 1.96-2.03 (1 H, m), 2.07 (1 H, dd, J = 13.1, 10.4 Hz), 2.15 (1 H, d, J = 2.1 Hz), 2.64-2.70 (1 H, m), 2.93-2.99 (1 H, m), 3.34 (1 H, dd, J = 13.1, 3.7 Hz), 3.52 (3 H, s), 3.85 (3 H, s), 3.93 (1 H, dd, J = 7.7, 4.1 Hz), 4.23-4.27 (1 H, m), 4.46-4.49 (2 H, m), 5.07 (1 H, d, J = 2.1 Hz), 5.20 (2 H, s), 6.97 (1 H, dd, J = 8.2, 1.9 Hz), 6.80 (1 H, d, J = 8.2 Hz), 6.91 (1 H, d, J = 1.9 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = -4.50, -4.42, 18.22, 25.25, 25.96, 27.88, 36.87, 41.18, 42.46, 43.84, 49.05, 49.57, 55.97, 56.21, 72.85, 76.37, 76.91, 77.83, 95.71, 103.49, 107.32, 111.75, 117.43, 122.50, 134.69, 146.18, 148.01. IR (KBr): 3449, 2955, 1516, 1257, 1132, 1082, 1006, 837, 779 cm^-1. MS (EI): m/z = 550 (M⁺). Anal. Calcd for C₂₉H₄₆O₈Si: C, 63.24; H, 8.42. Found: C, 63.3; H, 8.55.

12

Data for 5: Colorless viscous oil, [α]_D ²⁰ +9.8 (c 0.77, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.03 (1 H, s), 0.04 (3 H, s), 0.83 (9 H, s), 1.09-1.19 (1 H, m), 1.35 (3 H, s), 1.49 (3 H, s), 1.78-1.84 (1 H, m), 2.17-2.25 (1 H, m), 2.26-2.32 (1 H, m), 2.45 (1 H, dd, J = 13.4, 8.9 Hz), 2.46-2.54 (1 H, m), 2.61-2.68 (1 H, m), 2.78 (1 H, dd, J = 13.4, 5.5 Hz), 3.50 (3 H, s), 3.63-3.67 (1 H, m), 3.85 (3 H, s), 4.18 (1 H, dd, J = 7.4, 3.0 Hz), 4.61 (1 H, d, J = 7.4 Hz), 4.94 (1 H, dd, J = 10.3, 1.0 Hz), 5.00-5.08 (3 H, m), 5.18-5.23 (2 H, m), 5.81 (1 H, ddd, J = 17.4, 10.3, 7.3 Hz), 6.77 (1 H, dd, J = 8.2, 1.9 Hz), 6.80 (1 H, d, J = 8.2 Hz), 6.97 (1 H, d, J = 1.9 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = -4.73, -4.37, 17.92, 24.01, 25.68, 26.37, 40.52, 41.01, 41.08, 42.87, 45.07, 48.39, 55.95, 56.13, 70.20, 78.39, 79.17, 95.60, 108.73, 111.60, 112.25, 113.62, 117.23, 122.53, 134.19, 143.01, 145.61, 146.30, 147.86. IR (neat): 2928, 2856, 1512, 1462, 1379, 1261, 1209, 1155, 1080, 1030, 902, 837, 810, 775 cm^-1. HRMS (EI) m/z calcd for C₃₁H₄₈O₆Si (M⁺): 544.3220. Found: 544.3224.

13a Corey EJ. Winter RAE. J. Am. Chem. Soc.  1963,  85:  2677 

13b Corey EJ. Carey FA. Winter RAE. J. Am. Chem. Soc.  1965,  87:  934 

14

Data for 3- epi -ottelione A ( 2): White cloudy viscous oil, [α]_D ²⁰ +15.6 (c 0.32, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.20 (1 H, ddd, J = 17.7, 10.3, 7.4 Hz), 1.98 (1 H, dt, J = 13.1, 7.8 Hz), 2.19-2.28 (1 H, m), 2.54-2.60 (2 H, m), 2.73 (1 H, dd, J = 10.6, 8.4 Hz), 2.79 (1 H, dd, J = 13.7, 7.1 Hz), 2.90-2.98 (1 H, m), 3.85 (3 H, s), 4.84-4.89 (1 H, m), 4.97-5.02 (1 H, m), 5.36 (1 H, s), 5.53 (1 H, s), 5.64 (1 H, ddd, J = 17.0, 10.2, 8.1 Hz), 5.88-5.92 (1 H, m), 6.73 (1 H, dd, J = 8.1, 1.9 Hz), 6.77 (1 H, d, J = 8.1 Hz), 6.81 (1 H, d, J = 1.9 Hz), 6.94 (1 H, d, J = 9.9 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 37.52, 41.34, 41.91, 48.69, 50.16, 53.73, 55.97, 110.61, 115.35, 115.85, 120.34, 121.51, 126.51, 133.88, 140.49, 140.65, 144.89, 145.33, 145.58, 199.83. IR(neat): 3423, 2920, 1655, 1589, 1510, 1440, 1273, 1234, 1130, 1028, 912, 804, 760 cm^-1. HRMS (EI) m/z calcd for C₂₀H₂₂O₃ (M⁺): 310.1569. Found: 310.1565.