The Utility of the Classical and Oxidative Heck Reactions in Natural Product Synthesis: Studies Directed toward the Total Synthesis of Dragmacidin F

Abstract

The syntheses of complex pyrrole-fused [3.3.1] and [3.3.2] bicycles using classical and oxidative Heck cyclizations are described. While both [3.3.1] and [3.2.2] bicyclic products are formed in the classical Heck reaction, the oxidative Heck cyclization reaction furnishes solely the [3.3.1] bicycle. The [3.3.1] bicyclic product has been used as an intermediate to synthesize the complex marine alkaloid dragmacidin F.

Key words

Heck reaction - palladium - oxidative cyclization - bicyclic compounds - total synthesis

References and Notes

• 1a Metal-Catalyzed Cross-Coupling Reactions   Diederich F. Stang PJ. Wiley-VCH; Weinheim: 1998. 
• 1b Geissler H. In Transition Metals for Organic Synthesis   Beller M. Bolm C. Wiley-VCH; Weinheim: 1998.  Chap. 2.10. p.158 
• 1c Tsuji J. In Transition Metal Reagents and Catalysts   Wiley; Chichester, UK: 2000.  Chap. 3. p.27 
• For seminal reports, see:
• 2a Heck RF. Nolley JP. J. Org. Chem.  1972,  37:  2320 
• 2b Dieck HA. Heck RF. J. Org. Chem.  1975,  40:  1083 
• 2c Tao W. Silverberg LJ. Rheingold AL. Heck RF. Organometallics  1989,  8:  2550 
• For recent reviews of the Heck reaction, see:
• 3a Dounay AB. Overman LE. Chem. Rev.  2003,  103:  2945 
• 3b Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 
• 3c Amatore C. Jutand A. J. Organomet. Chem.  1999,  576:  254 
• 3d Braese S. de Meijere A. In Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 1:  Negishi E.-I. Wiley; Hoboken, New Jersey: 2002.  p.1223-1254  
• 3e Link JT. Org. React.  2002,  60:  157 
• 4 The Ni-catalyzed Negishi couplings of secondary halides have also been used to create stereogenic centers. For a pertinent review, see: Netherton MR. Fu GC. Adv. Synth. Catal.  2004,  346:  1525 
• 5a Garg NK. Caspi DD. Stoltz BM. J. Am. Chem. Soc.  2004,  126:  9552 
• 5b Garg NK. Caspi DD. Stoltz BM. J. Am. Chem. Soc.  2005,  127:  5970 
• 7a Stoltz BM. Chem. Lett.  2004,  33:  362 
• 7b Ferreira EM. Stoltz BM. J. Am. Chem. Soc.  2003,  125:  9578 
• 7c Zhang H. Ferreira EM. Stoltz BM. Angew. Chem. Int. Ed.  2004,  43:  6144 
• For catalytic intermolecular oxidative Heck arylations that employ main group organometallic arenes with a range of olefinic coupling partners and Pd(II) catalysis, see:
• 8a Andappan MMS. Nilsson P. von Schenck H. Larhed M. J. Org. Chem.  2004,  69:  5212 
• 8b Farrington EJ. Brown JM. Barnard CFJ. Rowsell E. Angew. Chem. Int. Ed.  2002,  41:  169 ; and references cited therein
• For related examples of Pd-mediated carbocyclizations in natural product synthesis, see:
• 9a Baran PS. Corey EJ. J. Am. Chem. Soc.  2002,  124:  7904 
• 9b Williams RM. Cao J. Tsujishima H. Cox RJ. J. Am. Chem. Soc.  2003,  125:  12172 
• For reviews and examples regarding the use of (-)-quinic acid in natural product synthesis, see:
• 10a Barco A. Benetti S. De Risi C. Marchetti P. Pollini GP. Zanirato V. Tetrahedron: Asymmetry  1997,  8:  3515 
• 10b Huang P.-Q. Youji Huaxue  1999,  19:  364 
• 10c Hanessian S. Pan J. Carnell A. Bouchard H. Lesage L. J. Org. Chem.  1997,  62:  465 
• 10d Hanessian S. In Total Synthesis of Natural Products: The ‘Chiron’ Approach   Baldwin EJ. Pergamon Press; Oxford: 1983.  p.206-208  
• 11a Edwards MP. Ley SV. Lister SG. Palmer BD. J. Chem. Soc., Chem. Commun.  1983,  630 
• 11b Muchowski JM. Solas DR. J. Org. Chem.  1984,  49:  203 
• 11c Edwards MP. Ley SV. Lister SG. Palmer BD. Williams DJ. J. Org. Chem.  1984,  49:  3503 
• 11d Edwards MP. Doherty AM. Ley SV. Organ HM. Tetrahedron  1986,  42:  3723 
• 12 Bailey DM. Johnson RE. J. Med. Chem.  1973,  16:  1300 
• 13a Tada H. Tozyo T. Chem. Lett.  1988,  5:  803 
• 13b For a discussion regarding the instability of bromopyrroles, see: Audebert P. Bidan G. Synth. Met.  1986,  15:  9 
• 14 Jeffery T. David M. Tetrahedron Lett.  1998,  39:  5751 ; see also references cited therein
• 15a Herrmann WA. Brossmer C. Öfele K. Reisinger C.-P. Priermeier T. Beller M. Fischer H. Angew. Chem., Int. Ed. Engl.  1995,  34:  1844 
• 15b Herrmann WA. Brossmer C. Reisinger C.-P. Reirmeier TH. Öfele K. Beller M. Chem. Eur. J.  1997,  3:  1357 
• 15c Herrmann WA. Brossmer C. Öfele K. Beller M. Fischer H. J. Mol. Catal. A: Chem.  1995,  103:  133 
• 16a Littke AF. Fu GC. J. Am. Chem. Soc.  2001,  123:  6989 
• 16b Littke AF. Fu GC. J. Org. Chem.  1999,  64:  10 
• 17a Corey EJ. Guzman-Perez A. Angew. Chem. Int. Ed.  1998,  37:  388 
• 17b Fuji K. Chem. Rev.  1993,  93:  2037 
• 17c Martin SF. Tetrahedron  1980,  36:  419 
• 17d Douglas CJ. Overman LE. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5363 
• DMSO has commonly been employed in oxidative Pd(II) chemistry. See:
• 18a Larock RC. Hightower TR. J. Org. Chem.  1993,  58:  5298 
• 18b Van Benthem RATM. Hiemstra H. Michels JJ. Speckamp WN. J. Chem. Soc., Chem. Commun.  1994,  357 
• 18c Rönn M. Bäckvall J.-E. Andersson PG. Tetrahedron Lett.  1995,  36:  7749 
• 18d Chen MS. White MC. J. Am. Chem. Soc.  2004,  126:  1346 
• 18e Stahl SS. Angew. Chem. Int. Ed.  2004,  43:  3400 , see also references cited therein
• Recently, related oxidative cyclizations of pyrrole substrates have been reported. See:
• 19a Beccalli EM. Broggini G. Martinelli M. Paladino G. Tetrahedron  2005,  61:  1077 
• 19b Beck EM. Grimster NP. Hatley R. Gaunt MJ. J. Am. Chem. Soc.  2006,  128:  2528 
• 20 Gilow HM. Hong YH. Millirons PL. Snyder RC. Casteel WJ. J. Heterocycl. Chem.  1986,  23:  1475 
• The instability of pyrroles to oxidants is well known. See:
• 22a Ciamician G. Silber P. Ber. Dtsch. Chem. Ges.  1912,  45:  1842 
• 22b Bernheim F. Morgan JE. Nature (London)  1939,  144:  290 
• 22c Chierici L. Gardini GP. Tetrahedron  1966,  22:  53 

6

In the case of the oxidative Heck route, an alternative Wacker-type mechanism involving nucleophilic attack of a Pd-activated olefin by the pyrrole species cannot be ruled out. It should be noted that in two extensively studied systems for oxidative Heck cyclization, both were shown to involve initial palladation of the aromatic system followed by olefin insertion and β-hydrogen elimination, see ref. 7.

21

Reactions conducted in the presence of CH₃COOD led to deuterium incorporation in the pyrrole ring of both the starting material (3) and the product (5), mostly at C(4).

23

The instability of the starting material and product to oxidation was confirmed by a series of control experiments where aliquots of reactions were carefully monitored by ¹H NMR analysis with an internal standard. In the presence of oxidants, substantial non-specific decomposition readily took place.