First Enantioselective Total Synthesis of the Angucyclinone-Type Antibiotic YM-181741

Abstract

A simple and efficient strategy for angucyclinone anti­biotics is described with the disclosure of first total synthesis of YM-181741.

Grubbs’ catalyst - enyne metathesis - Diels-Alder reaction - quinones - angucyclinone antibiotic

References and Notes

1a Peterson WL. N. Engl. J. Med.  1991,  324:  1043 

1b Van der Hults RWM. Rauws EAJ. Koycu B. Keller JJ. Bruno MJ. Tussen JGP. Tytgat GNJ. Gastroenterology  1997,  113:  1082 

2a Domizio P. Farthing MJG. Aliment. Pharmacol. Ther.  1995,  9:  205 

2b Megraud F. Brit. Med. Bull.  1998,  54:  207 

3 Taniguchi M. Nagai K. Watanabe M. Niimura N. Suzuki K.-I. Tanaka A. J. Antibiot.  2002,  55:  30 

4 Bowie JH. Johnson W. Tetrahedron Lett.  1967,  34:  1449 

5a Rohr J. Thiericke R. Nat. Prod. Rep.  1992,  9:  103 

5b Carreño MC. Urbano A. Synlett  2005,  1 

For sequential enyne metathesis and Diels-Alder reaction with quinones as well as other dienophiles, see:

6a Kaliappan KP. Ravikumar V. Org. Biomol. Chem.  2005,  848 

6b Dolhem F. Lievre C. Demailly G. Eur. J. Org. Chem.  2003,  2336 

6c Yang Y.-K. Tae J. Synlett  2003,  2017 

6d Guo H. Madhushaw RJ. Shen F.-M. Liu R.-S. Tetrahedron  2002,  58:  5627 

6e Moreno-Mañas M. Pleixats R. Santamaria A. Synlett  2001,  1784 

6f Kotha S. Sreenivasachary N. Brahmachary E. Eur. J. Org. Chem.  2001,  787 

6g Bentz D. Laschat S. Synthesis  2000,  1766 

For selected examples of utility of Diels-Alder reaction in the synthesis of angucyclinone, see:

7a Krohn K. Sohrab MH. Flörke U. Tetrahedron: Asymmetry  2004,  15:  713 

7b Landells JS. Larsen DS. Simpson J. Tetrahedron Lett.  2003,  44:  5193 

7c Krohn K. Michael J. Zukowski M. Tetrahedron  2000,  56:  4753 

7d Matsuo G. Miki Y. Nakata M. Matsumura S. Toshima K. J. Org. Chem.  1999,  64:  7101 

7e Carreño MC. Urbano A. Fischer J. Angew. Chem., Int. Ed. Engl.  1997,  36:  1621 

7f Matsuo G. Miki Y. Nakata M. Matsumura S. Toshima K. Chem. Commun.  1996,  225 

7g Kim K. Sulikowski GA. Angew. Chem., Int. Ed. Engl.  1995,  34:  2396 

7h Datta SC. Franck RW. Triphaty R. Quigley GJ. Huang L. Chen S. Sihaed A. J. Am. Chem. Soc.  1990,  112:  8472 

7i Carreño MC. Somoza A. Ribagorda M. Urbano A. Chem. Eur. J.  2007,  23:  879 

8 Ghosh AK. Gong G. J. Org. Chem.  2006,  71:  1085 

9 Hu X. Nguyen KT. Verlinde CLMJ. Hol WGJ. Pei D. J. Med. Chem.  2003,  46:  3771 

10 Pettigrew JD. Wilson PD. Org. Lett.  2006,  8:  1427 

11

HPLC conditions: YMC Pack Pro-C18, 4.6 × 250 mm, eluents H₂O-MeCN (10:90), flow 1.0 mL/min, UV detector at 254 nm; t _R = 2.928 min.

12 Mori M. Sakakibara N. Kinoshita A. J. Org. Chem.  1998,  63:  6082 

For reviews on enyne metathesis, see:

13a Mori M. Top. Organomet. Chem.  1998,  1:  133 

13b Poulsen CS. Madsen R. Synthesis  2003,  1 

13c Diver ST. Giessert J. Chem. Rev.  2004,  104:  1317 

14 Heinzman SW. Grunwell JR. Tetrahedron Lett.  1980,  21:  4305 

15a Krohn K. Ballwanz F. Baltus W. Liebigs Ann. Chem.  1993,  911 

15b Motoyoshiya J. Masue Y. Iwayama G. Yoshioka S. Nishii Y. Aoyama H. Synthesis  2004,  2099 

16

Spectral Data for Selected Compounds
Diene 15: R _f = 0.9 (EtOAc-PE, 3:7); [α]_D ²⁰ +99.1 (c 1.35, CHCl₃). IR (neat): 3454, 2930, 1655, 1465, 1257, 1104 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.37 (2 H, dd, J = 17.6, 10.8 Hz), 5.75 (1 H, br s), 5.07 (1 H, d, J = 17.7 Hz), 4.9 (1 H, d, J = 10.8 Hz), 3.59-3.49 (2 H, m), 2.30-2.18 (2 H, m), 2.30-2.18 (1 H, m), 1.80-1.76 (2 H, m), 1.29-1.20 (1 H, m), 0.89 (9 H, s), 0.06 (6 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 140.0, 135.3, 129.6, 109.8, 67.9, 36.3, 26.9, 26.0, 25.3, 18.4, -5.4, -5.3. Compound 18: R _f = 0.4 (EtOAc-PE, 1:19); mp 86-88 °C; [α]_D ²⁰ +130.0 (c 0.9, CHCl₃). IR (KBr): 3444, 2896, 2930, 1667, 1634, 1454, 1284, 1256, 1107 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 12.55 (1 H, s), 8.14 (1 H, d, J = 8.4 Hz), 7.72 (1 H, dd, J = 7.6, 1.2 Hz), 7.64 (1 H, t, J = 7.8 Hz), 7.50 (1 H, d, J = 7.6 Hz), 7.24 (1 H, dd, J = 8.4, 1.2 Hz), 3.68-3.29 (2 H, m), 3.28-3.20 (1 H, m), 3.00 (1 H, dd, J = 17.2, 2.8 Hz), 2.67 (1 H, dd, J = 17.2, 10.8 Hz), 2.09-2.0 (2 H, m), 1.47-1.25 (1 H, m), 3.05-2.81 (2 H, m), 0.92 (9 H, s), 0.07 (6 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 188.8, 161.9, 146.2, 141.7, 136.6, 136.5, 135.1, 135.0, 132.8, 131.2, 124.8, 123.1, 119.4, 115.7, 67.5, 35.7, 34.5, 28.9, 26.1, 18.5, -5.1, -5.2; HRMS (EI): m/z calcd for C₂₅H₃₁O₄Si: 423.1992; found: 423.1981.
Ketone 19: R _f = 0.33 (EtOAc-PE, 1:9); mp 91-93 °C; [α]_D ²⁰ +56.5 (c 0.52, CHCl₃). IR (KBr): 3425, 2927, 1706, 1672, 1592, 1457, 1363, 1284, 1099 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 12.30 (1 H, s), 8.30 (1 H, d, J = 7.8 Hz), 7.69 (1 H, dd, J = 5.4, 1.8 Hz), 7.65 (1 H, d, J = 7.8 Hz), 7.58 (1 H, d, J = 8.1 Hz), 7.28 (1 H, dd, J = 8.1, 2.1 Hz), 3.71 (1 H, dd, J = 9.9, 5.1 Hz), 3.62 (1 H, dd, J = 10.2, 6.3 Hz), 3.05-2.81 (2 H, m), 2.73 (2 H, dd, J = 16.2, 10.8 Hz), 2.56-2.49 (1 H, m), 0.91 (9 H, s), 0.07 (6 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 199.3, 187.6, 183.0, 162.2, 150.4, 137.2, 136.9, 135.8, 135.1, 133.5, 133.4, 129.1, 123.8, 119.8, 115.5, 66.2, 42.3, 38.0, 33.0, 26.0, 18.4, -5.3. HRMS (EI): m/z calcd for C₂₅H₂₉O₅Si: 437.1784; found: 437.1779.
Natural product YM 181741 (1): 68% yield (0.05 g); R _f = 0.3 (EtOAc-PE, 6:4); mp 192 °C; [α]_D ²⁵ +27.2 (c 0.367, CHCl₃). IR (KBr): 3433, 2927, 1702, 1671, 1588, 1453, 1362, 1276, 1588, 1453, 1362, 1276, 1215 cm^-1. UV (MeOH): λ_max (ε) = 276, 402 nm. ¹H NMR (400 MHz, CDCl₃): δ = 12.30 (1 H, s), 8.30 (1 H, d, J = 7.6 Hz), 7.68 (1 H, dd, J = 7.6, 2.4 Hz), 7.65 (1 H, d, J = 7.2 Hz), 7.58 (1 H, d, J = 8 Hz), 7.28 (1 H, dd, J = 8.0, 2.4 Hz), 3.77 (1 H, dd, J = 10.4, 4.8 Hz), 3.70 (1 H, dd, J = 7.2, 10.4 Hz), 3.10 (1 H, dd, J = 16.8, 4.8 Hz), 3.03 (1 H, dd, J = 16, 6.4 Hz), 2.85 (1 H, dd, J = 16.4, 10.4 Hz), 2.69 (1 H, dd, J = 16.0, 10.4 Hz), 2.61-2.54 (1 H, m), 1.86 (1 H, br s). ¹³C NMR (100 MHz, CDCl₃): δ = 198.8, 187.4, 182.9, 162.0, 149.8, 137.0, 136.7, 135.6, 134.9, 133.5, 133.2, 129.1, 123.8, 119.6, 115.4, 65.8, 42.0, 37.6, 32.7. HRMS (EI): m/z calcd for C₁₉H₁₅O₅: 323.0919; found: 323.0910.