Synthesis of the Tricyclic Core of the Marine Alkaloid Lepadiformine

Abstract

A stereoselective synthesis of the tricyclic core in ra­cemic form of the marine alkaloid Lepadiformine is described from 4-methoxy-3-pyrrolin-2-one (methyl tetramate). Key steps involve 5,5-dialkylation of the tetramate, metathesis closure to an A/C 1-azaspirocycle and stereoselective hydrogenation for the trans A/B 1-azadecalin system.

marine alkaloid - metathesis - silyloxypyrrole alkyl­ation - tetramate reduction - 1-azaspiro[4.5]decane

References

1 Biard JF. Guyot S. Roussakis C. Verbist JF. Vercauteren J. Weber JF. Boukef K. Tetrahedron Lett.  1994,  35:  2691 

2 Juge M. Grimaud N. Biard JF. Sauviat MP. Nabil M. Verbist JF. Petit JY. Toxicon  2001,  39:  1231 

3a Pearson WH. Ren Y. J. Org. Chem.  1999,  64:  688 

3b Werner KM. De los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  4865 

3c Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2000,  122:  4583 

3d Maeng JH. Funk RL. Org. Lett.  2001,  3:  3511 

4 Sun P. Sun C. Weinreb SM. J. Org. Chem.  2002,  67:  4337 

5a Golden JE. Aubé J. Chemtracts  1999,  12:  1026 

5b Snider BB. Lin H. J. Am. Chem. Soc.  1999,  121:  7778 

5c Scheffler G. Seike H. Sorensen EJ. Angew. Chem. Int. Ed.  2000,  39:  4593 

5d Ousmer M. Braun NA. Ciufolini MA. Org. Lett.  2001,  3:  765 

5e Funk RL. Maeng JH. Org. Lett.  2001,  3:  1125 

5f Wardrop DJ. Zhang W. Org. Lett.  2001,  3:  2353 

6a Snider BB. Lin H. Org. Lett.  2000,  2:  643 

6b Wardrop DJ. Basak A. Org. Lett.  2001,  3:  1053 

6c Mizutani H. Takayama J. Soeda Y. Honda T. Tetrahedron Lett.  2002,  43:  2411 

6d Nagumo S. Nishida A. Yamazaki C. Matoba A. Murashige K. Kawahara N. Tetrahedron  2002,  58:  4917 

7a Kuehne ME. Horne DA. J. Org. Chem.  1975,  40:  1287 

7b Fujimoto RA. Boxer J. Jackson RH. Simke JP. Neale RF. Snowhill EW. Barbaz BJ. Williams M. Sills MA. J. Med. Chem.  1989,  32:  1259 

7c Kawase M. Kitamura T. Kikugawa Y. J. Org. Chem.  1989,  54:  3394 

7d Sawamura M. Nakayama Y. Tang W.-M. Ito Y. J. Org. Chem.  1996,  61:  9090 

7e Bagley MC. Oppolzer W. Tetrahedron: Asymmetry  2000,  11:  2625 

8a Jones RCF. Patience JM. J. Chem. Soc., Perkin Trans. 1  1990,  2350 

8b Gill GB. James GD. Oates KV. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1993,  2567 

9 Reuschling D. Pietsch H. Linkies A. Tetrahedron Lett.  1978,  615 

10a Casiraghi G. Rassu G. Synthesis  1995,  607 

10b Rassu G. Carta P. Pinna L. Battistini L. Zanardi F. Acquotti D. Casiraghi G. Eur. J. Org. Chem.  1999,  6:  1395 

10c Rassu G. Zanardi F. Battistini L. Casiraghi G. Chem. Soc. Rev.  2000,  29:  109 

11 Jones RCF. Bates AD. Tetrahedron Lett.  1986,  27:  5285 

12

The following experimental procedure for conversion of 3b to 4 applies: The substrate 3b (0.73g, 3mmol) was dissolved in anhyd THF (30 mL) under N₂ and cooled to -78 °C. A solution of n-BuLi in hexane (2.25 mL of a 1.6 M solution, 3.6 mmol, 1.2 equiv) was added dropwise. After stirring for 30 min at -78 °C TMSCl (0.57 mL, 4.5 mmol, 1.5 equiv) was added dropwise and the solution was stirred for a further 30 min at -78 °C. Trimethyl orthoformate (1.00 mL, 9.0 mmol, 3 equiv) was then added, followed by BF₃·OEt₂ (0.57 mL, 4.5 mmol, 1.5 equiv). The reaction was allowed to slowly warm to -20 °C over 2 h. Sat. NaHCO₃ solution was then added and the THF was removed by evaporation. The remaining aqueous layer was extracted with 3 portions of EtOAc. The organic layers were combined, dried and concentrated to give an oily residue. The product was isolated by column chromatography to give the acetal as an oil that slowly crystallised as a colourless, waxy solid 4 (0.699 g, 2.20 mmol) in 88% yield based on recovered starting material (0.125 g, 0.51 mmol). Data for 4: IR: ν_max (CH₂Cl₂) = 3019, 1669, 1640, 1346 cm^-1. Found: M⁺ (+ H), 318.17144. C₁₈H₂₄NO₄ requires M⁺: 318.17053. ¹H NMR (400 MHz, CDCl₃): δ = 2.37 (1 H, ddt, J = 1.1, 7.7, 14.7 Hz, CH ₂), 2.54 (1 H, dd, J = 6.6, 14.7 Hz, CH ₂), 3.27 (3 H, s, OCH ₃), 3.32 (3 H, s, OCH ₃), 3.75 (3 H, s, OCH ₃), 4.21 (1 H, s, OCHO), 4.61 (2 H, s, PhCH ₂), 4.84 (2 H, m, CH=CH ₂), 5.12 (1 H, s, H-3), 5.18 (1 H, m, CH=CH₂), 7.15-7.38 (5 H, m, aromatic). ¹³C NMR (100 MHz, CDCl₃): δ = 33.8 (CH₂), 43.6 (PhCH₂), 57.8, 57.9 and 58.0 (3 × OCH₃), 71.8 (C-5), 95.2 (C-3), 107.6 (OCHO), 118.6 (CH=CH₂), 126.6, 128.0 and 128.5 (aromatic), 130.9 (CH=CH₂), 139.6 (aromatic), 172.2 (C-4), 174.5 (C=O).

13 Sanford MS. Ulman M. Grubbs RH. J. Am. Chem. Soc.  2001,  123:  749 

14 Fischer R, Graff A, Bretschneider T, Erdelen C, Drewes MW, and Feucht D. inventors; WO Patent  2001023354. 

15 Laffan DP. Baenziger M. Duc L. Evans AR. McGarrity JF. Meul T. Helv. Chim. Acta  1992,  75:  892 

16

Prepared from the phosphonium bromide in ref. [17b] by treatment with KOH.

Prepared from the bromide:

17a Kozikowski AP. Stein PD. J. Org. Chem.  1984,  49:  2301 

17b Ziegler FE. Klein SI. Pati UK. Wang T.-F. J. Am. Chem. Soc.  1985,  107:  2730 

18 Hoffman RV. Bishop RD. Fitch PM. Hardenstein R. J. Org. Chem.  1980,  45:  917 

19 Yoda H. Kitayama H. Katagiri T. Takabe K. Tetrahedron: Asymmetry  1993,  4:  1455 

20a Aubé J. Milligan GL. J. Am. Chem. Soc.  1991,  113:  8965 

20b

Data for the trans diastereomer 11a, (7aS ^*,11aS ^*)-Decahydro-3H-pyrrolo[2,1-j]quinolin-3-one: IR: ν_max (CH₂Cl₂) = 2935, 2864,1674, 1418 cm^-1. Found: M⁺, 193.14725. C₁₂H₁₉NO requires M⁺: 193.14666. ¹H NMR (400 MHz, CDCl₃): δ = 1.11-1.39 (4 H, m, CH ₂), 1.41-1.87 (10 H, m, CH ₂), 1.93 (1 H, dd, J = 7.7, 12.3 Hz, CH₂), 2.20 (1 H, dd, J = 8.8, 16.5 Hz, H-2), 2.49 (1 H, dddd, J = 0.9, 7.9, 12.6, 16.5 Hz, H-2), 2.77 (1 H, dddd, J = 1.1, 7.0, 11.2, 13.7 Hz, H-5), 3.88 (1 H, dd, J = 8.4, 13.7 Hz, H-5). ¹³C NMR (75 MHz, CDCl₃): δ = 21.4 (CH₂), 22.5 (CH₂), 23.5 (CH₂), 24.9 (CH₂), 26.0 (CH₂), 27.4 (CH₂), 30.6 (CH₂), 33.3 (C-5), 33.8 (C-2), 42.1 (C-7a), 64.1 (C-11a), 175.9 (C=O).

Several papers have appeared on asymmetric synthesis of 5,5-disubstituted pyrrolidin-2-ones:

21a Uno H. Baldwin JE. Russell AT. J. Am. Chem. Soc.  1994,  116:  2139 

21b Nagasaka T. Imai T. Heterocycles  1995,  41:  1927 

21c Nagasaka T. Imai T. Chem. Pharm. Bull.  1997,  45:  36 

21d Langlois N. Choudhury PK. Tetrahedron Lett.  1999,  40:  2525 

21e Schuch CM. Pilli RA. Tetrahedron: Asymmetry  2000,  11:  753 

21f Choudhury PK. Le Nguyen B. Langlois N. Tetrahedron Lett.  2002,  43:  463