Concise Synthesis of the Tricyclic Skeleton of Cylindricines Using a Radical Cascade Involving 6-Endo Selective Cyclization

Abstract

On treatment with Bu₃SnH and azobis(cyclohexanecarbonitrile) (ACN), enamide 19 underwent a 6-endo-trig/5-endo-trig radical cascade to afford perhydropyrrolo[2,1-j]quinoline derivative 21, a cylindricine skeleton.

cyclizations - cylindricine - regioselectivity - radical ­cascade - acyl radical

References

1a Blackman AJ. Li C. Hockless DCR. Skelton BW. White AH. Tetrahedron  1993,  49:  8645 

1b Li C. Blackman AJ. Aust. J. Chem.  1994,  47:  1355 

1c Li C. Blackman AJ. Aust. J. Chem.  1995,  48:  955 

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

Total synthesis of cylindricines:

3a Snider BB. Liu T. J. Org. Chem.  1997,  62:  5630 

3b Liu JF. Heathcock CH. J. Org. Chem.  1999,  64:  8263 

3c Molander GA. Ronn M. J. Org. Chem.  1999,  64:  5183 

3d Trost BM. Rudd MT. Org. Lett.  2003,  5:  4599 

3e Canesi S. Bouchu D. Ciufolini MA. Angew. Chem. Int. Ed.  2004,  43:  4336 

3f Arai T. Abe H. Aoyagi S. Kibayashi C. Tetrahedron Lett.  2004,  45:  5921 

3g Liu J. Hsung RP. Peters SC. Org. Lett.  2004,  6:  3989 

Total synthesis of lepadiformine:

4a Greshock TJ. Funk RL. Org. Lett.  2001,  3:  3511 

4b Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2000,  122:  4583 

4c Abe H. Aoyagi S. Kibayashi C. Angew. Chem. Int. Ed.  2002,  41:  3017 

4d Sun P. Sun C. Weinreb SM. J. Org. Chem.  2002,  67:  4337 ; see also ref. 3g

We previously reported that radical-induced 7-endo-trig/5-endo-trig radical cascade gave a cephalotaxine skeleton. See:

5a Taniguchi T. Ishita A. Uchiyama M. Tamura O. Muraoka O. Tanabe G. Ishibashi H. J. Org. Chem.  2005,  in press 

See also:

5b Ishibashi H. Sato T. Ikeda M. Synthesis  2002,  695 

5c Ishibashi H. Ishita A. Tamura O. Tetrahedron Lett.  2002,  43:  473 

Reviews on radical cascade:

6a McCarroll AJ. Walton JC. Angew. Chem. Int. Ed.  2001,  40:  2224 

6b McCarroll AJ. Walton JC. J. Chem. Soc., Perkin Trans. 1  2001,  3215 

7 Grillot A.-L. Hart DJ. Tetrahedron  1995,  51:  11377 

8 Booth H. Griffiths V. J. Chem. Soc., Perkin Trans. 2  1975,  111 

9

The structure of compound 9 was determined by its ¹³C NMR spectrum, which showed the presence of a quaternary carbon atom (δ = 66.3 ppm).

Reviews on the synthesis of five- and six-membered heterocyclic compounds using radical cyclization:

10a Majumdar KC. Mukhopadhyay PP. Basu PK. Heterocycles  2004,  63:  1903 

10b Li JJ. Alkaloids: Chemical Perspectives   Vol. 5:  Pelletire SW. Wiley; New York: 2001.  Chap. 4.

11

Enamide 10 was synthesized by treatment of the imine, prepared from ethylamine and cyclohexanone, with 3-bromopropionyl chloride in the presence of NaHCO₃.

12

¹³C NMR spectrum of compound 11 showed the presence of a quaternary carbon atom (δ = 64.0 ppm) and the IR spectrum of 11 exhibited absorption at 1665 cm^-1 due to the five-membered lactam.

13 Radical reactions of some sterically fixed 3-bromo-N-(cyclohex-1-enyl)propionamides, which are closely related to compound 8, leading to the formation of 6-endo cyclization product or a mixture of 6-endo and 5-exo cyclization products have been reported. See: Schultz AG. Guzzo PR. Nowak DM. J. Org. Chem.  1995,  60:  8044 

14 An analogous example on the aryl radical cyclization: Ishibashi H. Kato I. Takeda Y. Kogure M. Tamura O. J. Chem. Soc., Chem Commun.  2000,  1527 

15a Aubé J. Milligan GL. J. Am. Chem. Soc.  1991,  113:  8965 

15b Hunter R. Richards P. Synlett  2003,  271 

16

Crystallographic data of 13 and 21 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 262989 (13) and 262990 (21), respectively. Copies of these data may be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].

A review on acyl radical:

17a Chatgilialoglu C. Crich D. Komatsu M. Ryu I. Chem. Rev.  1999,  99:  1991 

Leading references on acyl radical cyclizations:

17b Wong LS.-M. Sherburn MS. Org. Lett.  2003,  5:  3603 

17c Yoshikai K. Hayama T. Nishimura K. Yamada K. Tomioka K. J. Org. Chem.  2005,  70:  681 

18 Masamune S. Hayase Y. Schilling W. Chan WK. Bates GS. J. Am. Chem. Soc.  1977,  99:  6756 

19

The structure of compound 20 was confirmed by transforming it to compound 8 by removal of the carbonyl group of the ketone.

20

(7a S *,11a S *)-Octahydro-3 H -pyrrolo[2,1- j ]quinoline-3,7 (7a H )-dione ( 21). To a boiling solution of 19 (530 mg, 1.46 mmol) in toluene (70 mL) was added dropwise a solution of Bu₃SnH (649 mg, 2.20 mmol) and ACN (71.5 mg, 0.292 mmol) in toluene (70 mL) over 3 h using a syringe pump. The reaction mixture was cooled to r.t. and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane-EtOAc, 1:1) to give 21 (113 mg, 37%) as colorless crystals; mp 106-107 °C (hexane). IR (CHCl₃): ν = 1715, 1680 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 1.19-1.79 (m, 9 H), 2.00 (td, J = 8.3, 13.5 Hz, 1 H), 2.16 (ddd, J = 6.6, 8.3, 13.5 Hz, 1 H), 2.25-2.31 (m, 1 H), 2.33-2.53 (m, 3 H), 3.04 (ddd, J = 6.3, 10.2, 13.5 Hz, 1 H), 4.38 (ddd, J = 2.3, 6.3, 13.5 Hz, 1 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 20.5, 21.7, 22.3, 29.0, 29.4, 32.4, 35.0, 39.7, 55.2, 64.6, 173.1, 207.3. Anal. Calcd for C₁₂H₁₇NO₂: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.31; H, 8.42; N, 6.61.