Synthesis of 2-epi-Pumiliotoxin C via a Challenging Intramolecular Hydroamination Key Step

Abstract

The synthesis of 2-epi-pumiliotoxin C was achieved in ten steps from cyclohexadiene oxide, using a challenging Cope-type hydroamination key step. This cyclization was performed on a mixture of two epimeric hydroxylamines, and a boat transition state is proposed to explain the kinetic preference observed for the cyclization of the epimer leading to N-hydroxy-epipumiliotoxin C.

Key words

total synthesis - alkaloids - amination - cyclization - ­heterocycles

References and Notes

• 1 Müller TE. Beller M. Chem. Rev.  1998,  98:  675 
• 2a Hultzsch KC. Org. Biomol. Chem.  2005,  3:  1819 
• 2b Hultzsch KC. Adv. Synth. Catal.  2005,  347:  367 
• 2c Roesky PW. Müller TE. Angew. Chem. Int. Ed.  2003,  42:  2708 
• For selected examples highlighting the potential of hydroamination in heterocyclic synthesis, see:
• 3a Trost BM. Tang W. J. Am. Chem. Soc.  2003,  125:  8744 
• 3b Hong S. Kawaoka AM. Marks TJ. J. Am. Chem. Soc.  2003,  125:  15878 
• 3c Trost BM. Tang W. J. Am. Chem. Soc.  2002,  124:  14542 
• 3d Molander GA. Dowdy ED. Pack SK. J. Org. Chem.  2001,  66:  4344 
• For selected recent examples of 2-methylpiperidine formation via intramolecular hydroamination of a terminal alkene, see:
• 4a Liu Z. Hartwig JF. J. Am. Chem. Soc.  2008,  130:  1570 
• 4b Müller C. Saak W. Doye S. Eur. J. Org. Chem.  2008,  2731 
• 4c Bauer EB. Andavan GTS. Hollis TK. Rubio RJ. Cho J. Kuchenbeiser GR. Helgert TR. Letko CS. Tham FS. Org. Lett.  2008,  10:  1175 
• 4d Quinet C. Jourdain P. Hermans C. Ates A. Lucas I. Markó IE. Tetrahedron  2008,  64:  1077 
• 4e Stubbert BD. Marks TJ. J. Am. Chem. Soc.  2007,  129:  4253 
• 4f Yu X. Marks TJ. Organometallics  2007,  26:  365 
• 4g Komeyama K. Morimoto T. Takaki K. Angew. Chem. Int. Ed.  2006,  45:  2938 
• 4h Han X. Widenhoefer RA. Angew. Chem. Int. Ed.  2006,  45:  1747 
• 4i Müller C. Loos C. Schulenberg N. Doye S. Eur. J. Org. Chem.  2006,  2499 
• 4j Michael FE. Cochran BM. J. Am. Chem. Soc.  2006,  128:  4246 
• 4k Gribkov DV. Hultzsch KC. Hampel F. J. Am. Chem. Soc.  2006,  128:  3748 
• 4l Riegert D. Collin J. Meddour A. Schulz E. Trifonov A. J. Org. Chem.  2006,  71:  2514 
• 4m Bender CF. Widenhoefer RA. Org. Lett.  2006,  8:  5303 
• 4n Thomson RK. Bexrud JA. Schafer LL. Organometallics  2006,  25:  4069 
• 4o Crimmin MR. Casely IJ. Hill MS. J. Am. Chem. Soc.  2005,  127:  2042 
• 4p Bender CF. Widenhoefer RA. J. Am. Chem. Soc.  2005,  127:  1070 
• 4q Bextrud JA. Beard JD. Leitch DC. Schafer LL. Org. Lett.  2005,  7:  1959 
• 4r Kim JY. Livinghouse T. Org. Lett.  2005,  7:  1737 
• 4s Hong S. Marks TJ. Acc. Chem. Res.  2004,  37:  673 
• 4t Gribkov DV. Hultzsch KC. Angew. Chem. Int. Ed.  2004,  43:  5542 
• 4u Ryu J.-S. Marks TJ. McDonald FE. J. Org. Chem.  2004,  69:  1038 
• 4v Lauterwasser F. Hayes PG. Bräse S. Piers WE. Schafer LL. Organometallics  2004,  23:  2234 
• 4w Ryu J.-S. Li GY. Marks TJ. J. Am. Chem. Soc.  2003,  125:  12584 
• 4x Molander GA. Pack SK. J. Org. Chem.  2003,  68:  9214 
• 4y Kim YK. Livinghouse T. Angew. Chem. Int. Ed.  2002,  41:  3645 
• 4z Schlummer B. Hartwig JF. Org. Lett.  2002,  4:  147 ; see ref. 3d
• Pumiliotoxin C has been synthesized numerous times using a variety of creative routes. However, to the best of our knowledge hydroamination routes have not been reported. For recent syntheses, see:
• 6a Amat M. Griera R. Fabregat R. Molins E. Bosch J. Angew. Chem. Int. Ed.  2008,  47:  3348 
• 6b Lauzon S. Tremblay F. Gagnon D. Godbout C. Chabot C. Mercier-Shanks C. Perrault S. DeSève H. Spino C. J. Org. Chem.  2008,  73:  6239 
• 6c Girard N. Hurvois J.-P. Moinet C. Toupet L. Eur. J. Org. Chem.  2005,  2269 
• 6d Dijk EW. Panella L. Pinho P. Naasz R. Meetsma A. Minnaard AJ. Feringa BL. Tetrahedron  2004,  60:  9687 
• 6e Oppolzer W. Flaskamp E. Bieber LW. Helv. Chim. Acta  2001,  84:  141 
• 6f Akashi M. Sato Y. Mori M. J. Org. Chem.  2001,  66:  7873 
• 6g Shieh Y. Yeh MP. Rao UN. J. Chin. Chem. Soc.  2000,  47:  283 
• 6h Padwa A. Heidelbaugh TM. Kuethe JT. J. Org. Chem.  2000,  65:  2368 
• 6i Riechers T. Krebs HC. Wartchow R. Habermehl G. Eur. J. Org. Chem.  1998,  2641 
• 6j Back TG. Nakajima K. J. Org. Chem.  1998,  63:  6566 
• 6k Weymann M. Schultz-Kukula M. Kunz H. Tetrahedron Lett.  1998,  39:  7835 ; for a detailed list of references, see ref. 6d
• 6l For a review of the literature until 1976, see: Inubushi Y. Ibuka T. Heterocycles  1977,  8:  633 
• 7a Beauchemin A. Moran J. Lebrun M. Séguin C. Dimitrijevic E. Zhang L. Gorelsky SI. Angew. Chem. Int. Ed.  2008,  47:  1410 
• 7b Cebrowski PH. Roveda J.-G. Moran J. Gorelsky SI. Beauchemin AM. Chem. Commun.  2008,  492 
• 7c Moran J. Gorelsky SI. Dimitrijevic E. Lebrun M.-E. Bédard A.-C. Séguin C. Beauchemin AM. J. Am. Chem. Soc.  2008,  130:  17893 
• 7d Bourgeois J. Dion I. Cebrowski PH. Loiseau F. Bédard A.-C. Beauchemin AM. J. Am. Chem. Soc.  2009,  131:  874 
• Such reactions are also referred to as ‘reverse Cope cyclizations’ or reverse Cope eliminations in the literature. For an excellent review, see:
• 8a Cooper NJ. Knight DW. Tetrahedron  2004,  60:  243 
• For examples of such cyclizations leading to the formation of 2-methylpiperidines, see:
• 8b House HO. Lee LF. J. Org. Chem.  1976,  41:  863 
• 8c Ciganek E. J. Org. Chem.  1990,  55:  3007 
• 8d Ciganek E. Read JM. J. Org. Chem.  1995,  60:  5795 
• 8e Tronchet JMJ. Zsely M. Yazji RN. Barbalat-Rey F. Geoffroy M. Carbohydr. Lett.  1995,  1:  343 
• 8f Coogan MP. Knight DW. Tetrahedron Lett.  1996,  37:  6417 
• 8g Takano I. Yasuda I. Nishijima M. Hitotsuyanagi Y. Takeya K. Itokawa H. J. Org. Chem.  1997,  62:  8251 
• 8h O’Neil IA. Southern JM. Tetrahedron Lett.  1998,  39:  9089 
• 8i O’Neil IA. Cleator E. Southern JM. Hone N. Tapolczay DJ. Synlett  2000,  695 
• 8j O’Neil IA. Woolley JC. Southern JM. Hobbs H. Tetrahedron Lett.  2001,  42:  8243 
• For examples leading to the formation of other heterocyclic six-membered ring systems, see:
• 8k O’Neil IA. Cleator E. Ramos VE. Chorlton AP. Tapolczay DJ. Tetrahedron Lett.  2004,  45:  3655 
• 8l Henry N. O’Neil IA. Tetrahedron Lett.  2007,  48:  1691 
• 8m Ellis GL. O’Neil IA. Ramos VE. Cleator E. Kalindjian SB. Chorlton AP. Tapolczay DJ. Tetrahedron Lett.  2007,  48:  1683 
• 11 Toyota M. Asoh T. Matsuura M. Fukumoto K. J. Org. Chem.  1996,  61:  8687 
• 12 Marino JP. Jaén JC. J. Am. Chem. Soc.  1982,  104:  3165 
• 13a Côté A. Lindsay VNG. Charette AB. Org. Lett.  2007,  9:  85 
• 13b Gomez L. Denmark SE. Org. Lett.  2001,  3:  2907 
• 14 Ghosh AK. Gong G. Org. Lett.  2007,  9:  1437 
• For the use of similar conditions in a challenging five-membered system, see:
• 15a Oppolzer W. Spivey AC. Bochet CG. J. Am. Chem. Soc.  1994,  116:  3139 
• 15b Hydroxylamines can be sensitive to oxygen and prone to decomposition via bimolecular pathways: Horiyama S. Suwa K. Yamaki M. Kataoka H. Katagi T. Takayama M. Takeuchi T. Chem. Pharm. Bull.  2002,  50:  996 
• 17 Walts AE. Roush WR. Tetrahedron  1985,  41:  3463 
• 18 For 2-epi-pumilotoxin C, comparison of the free base was in good agreement with literature data. See: Meyers AI. Milot G. J. Am. Chem. Soc.  1993,  115:  6652 
• For pumilotoxin C, data obtained for the free base (ref. 6d, 19a) and the HCl salt (ref. 19b) was in good agreement with literature data:
• 19a Brandi A. Cordero FM. Goti A. Guarna A. Tetrahedron Lett.  1992,  33:  6697 
• 19b Schultz AG. McCloskey PJ. Court JJ. J. Am. Chem. Soc.  1987,  109:  6493 

5

To the best of our knowledge, there are only few reported examples of a formation of six-membered piperidine ring via hydroamination onto an internal alkene: see ref. 4e,g,z for examples.

9

O’Neil has reported cyclizations of unsaturated N-methyl-hydroxylamines leading to various six-membered ring systems: see ref. 8h-m. The cyclization to form morpholine N-oxides is compatible with distal alkene substitution: see ref. 8k,l.

10

A first generation synthesis designed to provide access to various hydroamination precursors is shown in Scheme  [8] .

16

None of the hydroxylamine 1a could be recovered from the reaction mixture. ^¹³C NMR analysis indicated that recovered hydroxylamine 1b was diastereomerically pure (within detection limits).

20

This rationale is consistent with results from DFT calculations in simpler systems: Dr. Serge I. Gorelsky, private communication.

21

Complete experimental procedures and characterization data for all new compounds can be obtained from the authors.