Stereocontrolled Synthesis of Functionalized Spirocyclic Compounds Based on Claisen Rearrangement and its Application to the Synthesis of Spirocyclic Sesquiterpenes and Pyrrolidinoindoline Alkaloids

Abstract

Spirocyclic scaffolds are embedded in many biologically active natural compounds, including candidates for medicines, perfumes and agricultural chemicals. Therefore, the development of efficient synthetic methods directed at those structures is strongly in demand. To this end, we have recently developed synthetic methodologies for two different spirocyclic frameworks, spiro[4.5]decanes and spirocyclic oxindoles, based on the Claisen rearrangement.

We have developed the Claisen rearrangement protocol by which bicyclic 2-(alkenyl)dihydropyrans with functionality at the 4-position can be transformed into spiro[4.5]decanes in good-to-excellent yields with excellent stereoselectivities. We applied this method to a concise total synthesis of several biologically active spirocyclic sesquiterpenes.

Related Claisen rearrangement in alkenyl pyranoindole systems can also be achieved. Thus, a one-pot intramolecular Ullmann coupling (IUC)/Claisen rearrangement sequence from 2-iodoindoles was found to provide spirocyclic oxindoles in good yields with excellent stereoselectivities. We applied this sequence to the synthesis of pyrrolidinoindoline alkaloids.

1 Introduction

2 Reported Claisen Rearrangement of 2-(Alkenyl)dihydro­pyran Systems

3 Claisen Rearrangement of Multi-Functionalized 2-(Alkenyl)dihydropyran Systems

3.1 Synthetic Strategy for Spiro[4.5]decanes

3.2 Synthesis of Claisen Substrates and their Rearrangement

3.3 Claisen Rearrangement in 2-(Z-Alkenyl)dihydropyran Systems

4 Application to the Synthesis of Spirocyclic Sesquiterpenes

4.1 Synthesis of Racemic Vetivane Sesquiterpenes

4.2 Synthesis of Racemic Gleenol and Axenol

4.3 Asymmetric Synthesis of (+)-α-Vetispirene and (–)-Agarospirol

4.4 Stereocontrolled Synthesis of (–)-Gleenol

4.5 Solvent Effects in the Claisen Rearrangement of 2-(Alkenyl)dihydropyrans

4.6 Stereocontrolled Synthesis of the Antimalarial Sesquiterpene, (+)-Axisonitrile-3

5 Claisen Rearrangement in Pyranoindoles Providing Spirocyclic Oxindoles

5.1 Synthetic Strategy for Spirocyclic Oxindoles

5.2 One-Pot Intramolecular Ullmann Coupling (IUC)/Claisen Rearrangement

6 Application to the Synthesis of Pyrrolidinoindoline Alkaloids; Synthesis of (–)-Flustramine B

7 Conclusion

Key words

spirocyclic compounds - Claisen rearrangement - total synthesis - one-pot reaction - Ullmann coupling

• References

• 1a Krapcho AP. Synthesis 1974; 383
• 1b Sannigrahi M. Tetrahedron 1999; 55: 9007
• 2 For a review, see: Castro AM. M. Chem. Rev. 2004; 104: 2939
• 3 Danishefsky SJ, Funk RL, Kerwin JF. J. Am. Chem. Soc. 1980; 102: 6889
• 4 Büchi G, Powell JE. Jr. J. Am. Chem. Soc. 1970; 92: 3126
• 5 Ireland RE, Dow WC, Godfrey JD, Thaisrivongs S. J. Org. Chem. 1984; 49: 1001
• 6 Desimoni G, Faita G, Gamba A, Righetti PP, Tacconi G, Toma L. Tetrahedron 1990; 46: 2165
• 7 Nakazaki A, Miyamoto H, Henmi K, Kobayashi S. Synlett 2005; 1417
• 8 Nakazaki A, Era T, Numada Y, Kobayashi S. Tetrahedron 2006; 62: 6264
• 9a Borowitz IJ, Gonis G. Tetrahedron Lett. 1964; 5: 1151
• 9b Borowitz IJ, Gonis G, Kelsey R, Rapp R, Williams GJ. J. Org. Chem. 1966; 31: 3032
• 10 Nakazaki A, Kobayashi S. J. Synth. Org. Chem., Jpn. 2008; 66: 124
• 11 Miyamoto H, Okawa Y, Nakazaki A, Kobayashi S. Angew. Chem. Int. Ed. 2006; 45: 2274

• For examples, see:

• 12a Ko H, Kim E, Park JE, Kim D, Kim S. J. Org. Chem. 2004; 69: 112
• 12b Ilardi EA, Isaacman MJ, Qin Y.-c, Shelly SA, Zakarian A. Tetrahedron 2009; 65: 3261
• 13 Nakazaki A, Kobayashi S. Synlett 2009; 1605

• For the structure of 41, see:

• 14a Andersen NH, Falcone MS, Syrdal DD. Tetrahedron Lett. 1970; 11: 1759

For the total synthesis of (±)-41, see:
• 14b Yamada K, Aoki K, Nagase H, Hayakawa Y, Hirata Y. Tetrahedron Lett. 1973; 14: 4967
• 14c Caine D, Boucugnani AA, Chao ST, Dawson JB, Ingwalson PF. J. Org. Chem. 1976; 41: 1539
• 14d Ibuka T, Hayashi K, Minakata H, Ito Y, Inubushi Y. Can. J. Chem. 1979; 57: 1579
• 14e Yan T.-H, Paquette LA. Tetrahedron Lett. 1982; 23: 3227
• 14f Balme G. Tetrahedron Lett. 1985; 26: 2309

• For the structure and first total synthesis of (±)-42, see:

• 15a Marshall JA, Brady SF. J. Org. Chem. 1970; 35: 4068

For the total synthesis of this substance, see:
• 15b Nyström J.-E, Helquist P. J. Org. Chem. 1989; 54: 4695

For first total synthesis of (–)-42, see:
• 15c Du Y, Lu X. J. Org. Chem. 2003; 68: 6463

• For the structure and first total synthesis of 43, see:

• 16a Marshall JA, Johnson PC. Chem. Commun. 1968; 391
• 16b Marshall JA, Johnson PC. J. Org. Chem. 1970; 35: 192

For the total synthesis of this substance, see:
• 16c Yamada K, Nagase H, Hayakawa Y, Aoki K, Hirata Y. Tetrahedron Lett. 1973; 4963

For the total synthesis of (–)-43, see:
• 16d Posner GH, Hamill TG. J. Org. Chem. 1988; 53: 6031

• Some biologically active spirocyclic terpenes have been isolated. For gleenol, see:

• 17a Kurvyakov PI, Gatilov YV, Yu V, Khan VA, Dubovenko ZhV, Pentegova VA. Khim. Prir. Soedin. 1979; 164

For axisonitrile-3, see:
• 17b Di Blasio B, Fattorusso E, Magno S, Mayol L, Pedone C, Santacroce C, Sica D. Tetrahedron 1976; 32: 473

For axenol, see:
• 17c Barrow CJ, Blunt JW, Munro MH. G. Aust. J. Chem. 1988; 41: 1755

For axamide-3, see:
• 17d Hirota H, Tomono Y, Fusetani N. Tetrahedron 1996; 52: 2359
• 18 Nakazaki A, Era T, Kobayashi S. Chem. Pharm. Bull. 2007; 55: 1606
• 19 Nakazaki A, Kobayashi S. Chem. Lett. 2007; 36: 42
• 20 Nakazaki A, Era T, Kobayashi S. Chem. Lett. 2008; 37: 770
• 21 Tamura K, Nakazaki A, Kobayashi S. Synlett 2009; 2449
• 22 Reisman SE, Ready JM, Hasuoka A, Smith CJ, Wood JL. J. Am. Chem. Soc. 2006; 128: 1448
• 23a Klein JE. M. N, Taylor RJ. K. Eur. J. Org. Chem. 2011; 6821
• 23b Zhou F, Liu Y.-L, Zhou J. Adv. Synth. Catal. 2010; 352: 1381
• 23c Marti C, Carreira EM. Eur. J. Org. Chem. 2003; 2209
• 23d Toyota M, Ihara M. Nat. Prod. Rep. 1998; 327
• 23e Dounay AB, Hatanaka K, Kodanko JJ, Oestreich M, Overman LE, Pfeifer LA, Weiss MM. J. Am. Chem. Soc. 2003; 125: 6261 ; and references therein

• For examples, see:

• 24a Huang A, Kodanko JJ, Overman LE. J. Am. Chem. Soc. 2004; 126: 14043
• 24b Bagul TD, Lakshmaiah G, Kawabata T, Fuji K. Org. Lett. 2002; 4: 249
• 24c Ohmatsu K, Kiyokawa M, Ooi T. J. Am. Chem. Soc. 2011; 133: 1307
• 25 For a review on intramolecular Heck reactions, see: Dounay AB, Overman LE. Chem. Rev. 2003; 103: 2945

• For examples, see:

• 26a Yong SR, Williams MC, Pyne SG, Ung AT, Skelton BW, White AH, Turner P. Tetrahedron 2005; 61: 8120
• 26b Beccalli EM, Clerici F, Gelmi ML. Tetrahedron 2003; 59: 4615

• For examples, see:

• 27a Somei M, Yamada F, Izumi T, Nakajou M. Heterocycles 1997; 45: 2327
• 27b Booker-Milburn KI, Fedouloff M, Paknoham SJ, Strachan JB, Melville JL, Voyle M. Tetrahedron Lett. 2000; 41: 4657
• 27c Mao Z, Baldwin SW. Org. Lett. 2004; 6: 2425
• 27d Kawasaki T, Ogawa A, Terashima R, Saheki T, Ban N, Sekiguchi H, Sakaguchi K, Sakamoto M. J. Org. Chem. 2005; 70: 2957
• 27e Duguet N, Slawin AM. Z, Smith AD. Org. Lett. 2009; 17: 3858
• 28 Hino T, Miura H, Murata R, Nakagawa M. Chem. Pharm. Bull. 1978; 26: 3695

• For reviews on copper-catalyzed C–O bond formation, see:

• 29a Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400
• 29b Beletskaya IP, Cheprakov AV. Coord. Chem. Rev. 2004; 248: 2337
• 29c Kunz K, Scholz U, Ganzer D. Synlett 2003; 2428
• 29d Dehli JR, Legros J, Bolm C. Chem. Commun. 2005; 973
• 29e Chemler SR, Fuller PH. Chem. Soc. Rev. 2007; 36: 1153
• 30a Larock RC, Yum EK. J. Am. Chem. Soc. 1991; 113: 6689
• 30b Larock RC, Yum EK, Refvik MD. J. Org. Chem. 1998; 63: 7652
• 31 Fagan PJ, Hauptman E, Shapiro R, Casalnuovo A. J. Am. Chem. Soc. 2000; 122: 5043
• 32 Nordmann G, Buchwald SL. J. Am. Chem. Soc. 2003; 125: 4978
• 33 Fukuyama T, Liu G. J. Am. Chem. Soc. 1996; 118: 7426
• 34 Hirano H, Iwakiri K, Miyamoto H, Nakazaki A, Kobayashi S. Heterocycles 2009; 79: 805
• 35 For a review, see: Anthoni U, Christophersen C, Nielsen PH. In Alkaloids: Chemical and Biological Perspectives . Vol. 13. Pelletier SW. Wiley; New York: 1999: 163
• 36a Wright JL. C. J. Nat. Prod. 1984; 47: 893
• 36b Laycock MV, Wright JL. C, Findlay JA, Patil AD. Can. J. Chem. 1986; 64: 1312
• 36c Holst PB, Anthoni U, Christophersen C, Nielsen PH. J. Nat. Prod. 1994; 57: 997
• 36d Peters L, König GM, Terlau H, Wright AD. J. Nat. Prod. 2002; 65: 1633
• 37a Carlé JS, Christophersen C. J. Am. Chem. Soc. 1979; 101: 4012
• 37b Carlé JS, Christophersen C. J. Org. Chem. 1980; 45: 1586
• 38 Sjöblom T, Bohlin L, Christophersen C. Acta Pharm. Suec. 1983; 20: 415
• 39 Smith BP, Tyler MJ, Kaneko T, Garraffo HM, Spande TF, Daly JW. J. Nat. Prod. 2002; 65: 439
• 40a Hodgson JW, Mitchell MO, Thomas ML, Waters KF. Bioorg. Med. Chem. Lett. 1995; 5: 2527
• 40b Dix AV, Meseck CM, Lowe AJ, Mitchell MO. Bioorg. Med. Chem. Lett. 2006; 16: 2522
• 41a Kawasaki T, Shinada M, Kamimura D, Ohzono M, Ogawa A. Chem. Commun. 2006; 420
• 41b Kawasaki T. J. Synth. Org. Chem., Jpn. 2009; 67: 1012
• 42 For the synthesis of racemic pyrrolidinoindolines, see: Miyamoto H, Okawa Y, Nakazaki A, Kobayashi S. Tetrahedron Lett. 2007; 48: 1805