New Applications of PhI(OAc)₂ in Synthesis: Total Synthesis and SAR Development of Potent Antitumor Natural Product Psymberin/Irciniastatin A

Abstract

A novel PhI(OAc)₂-mediated oxidative cyclization reaction is discovered for the synthesis of α-oxy N-acyl aminals and hemiaminals in good yields from readily synthesized N-acyl enamines. This methodology represents a cascade process to construct the core structure of the pederin family of natural products. The total synthesis of psymberin, a member of the pederin family, is accomplished using this ring-closure reaction as the key step. This new method is further showcased in the preparation of advanced psymberin analogues. The biological data of these analogues are presented.

1 Introduction

2 Methodology Development

3 Total Synthesis of Psymberin

4 Synthesis of Psymberin Analogues: The Discovery of C11-Deoxypsymberin

5 Conclusion

(diacetoxyiodo)benzene - psymberin - oxidative cycli­zation - total synthesis - antitumor

References

<A NAME="RC02009SS-1">1</A> Simmons TL. Andrianasolo E. McPhail K. Flatt P. Gerwick WH. Mol. Cancer Ther.  2005,  4:  333 

<A NAME="RC02009SS-2">2</A> Narquizian R. Kocienski PJ. The Pederin Family of Antitumor Agents: Structures, Synthesis and Biological Activity, In The Role of Natural Products in Drug Discovery   Mulzer J. Bohlmann R. Springer; New York: 2000.  p.25-56  ; Ernst Schering Research Foundation Workshop 32

<A NAME="RC02009SS-3">3</A> Ding F. Jennings MP. J. Org. Chem.  2008,  73:  5965 

<A NAME="RC02009SS-4">4</A> Coleman RS. Walczak MC. Campbell EL. J. Am. Chem. Soc.  2005,  127:  16038 

<A NAME="RC02009SS-5A">5a</A> Smith AB. Safonov IG. Corbett RM. J. Am. Chem. Soc.  2002,  124:  11102 

<A NAME="RC02009SS-5B">5b</A> Kagawa N. Ihara M. Toyota M. Org. Lett.  2006,  8:  875 

<A NAME="RC02009SS-5C">5c</A> Petri AF. Bayer A. Maier ME. Angew. Chem. Int. Ed.  2004,  43:  5821 ; Angew. Chem. 2004, 116, 5945

<A NAME="RC02009SS-5D">5d</A> Troast DM. Porco JA. Org. Lett.  2002,  4:  991  and references therein

<A NAME="RC02009SS-5E">5e</A> Wan S. Green ME. Park J.-H. Floreancig PE. Org. Lett.  2007,  9:  5385  and references therein

<A NAME="RC02009SS-5F">5f</A> Kiren S. Ning S. Williams LJ. Tetrahedron Lett.  2007,  48:  7456 

<A NAME="RC02009SS-6">6</A> Jiang L. Job GE. Klapars A. Buchwald SL. Org. Lett.  2003,  5:  3667 

<A NAME="RC02009SS-7">7</A> Shen R. Lin C.-T. Porco JA. J. Am. Chem. Soc.  2002,  124:  5650 

<A NAME="RC02009SS-8A">8a</A> Stang PJ. Zhdankin VV. Chem. Rev.  1996,  96:  1123  and references therein

<A NAME="RC02009SS-8B">8b</A> Moriarty RM. Chany CJ. Kosmeder JW. Du Bois J. e-EROS Encyclopedia of Reagents for Organic Synthesis [Online]   Paquette LA. Crich D. Fuchs PL. Molander G. John Wiley & Sons Ltd.; Hoboken: 2006. and references therein

<A NAME="RC02009SS-9A">9a</A> Moriarty RM. Kosmeder JW. e-EROS Encyclopedia of Reagents for Organic Synthesis [Online]   Paquette LA. Crich D. Fuchs PL. Molander G. John Wiley & Sons Ltd.; Hoboken: 2001. 

<A NAME="RC02009SS-9B">9b</A> Correa A. Tellitu I. Dominguez E. SanMartin R. J. Org. Chem.  2006,  71:  8316 

<A NAME="RC02009SS-10">10</A> Baran PS. Richter JM. Lin DW. Angew. Chem. Int. Ed.  2005,  44:  609  and references therein; Angew. Chem. 2005, 117, 615

<A NAME="RC02009SS-11A">11a</A> Cichewicz RH. Valeriote FA. Crews P. Org. Lett.  2004,  6:  1951 ; and references cited therein

<A NAME="RC02009SS-11B">11b</A> Pettit GR. Xu JP. Chapuis JC. Pettit RK. Tackett LP. Doubek DL. Hooper JNA. Schmidt JM. J. Med. Chem.  2004,  47:  1149 

<A NAME="RC02009SS-12">12</A> Jiang X. Garcia-Fortanet J. De Brabander JK. J. Am. Chem. Soc.  2005,  127:  11254 ; and references cited therein

<A NAME="RC02009SS-13">13</A> Ning S. Kiren S. Williams LJ. Org. Lett.  2007,  9:  1093 

<A NAME="RC02009SS-14">14</A> Smith AB. Jurica JA. Walsh SP. Org. Lett.  2008,  10:  5625 

<A NAME="RC02009SS-15">15</A> Huang X. Shao N. Palani A. Aslanian R. Buevich A. Org. Lett.  2007,  9:  2597 

<A NAME="RC02009SS-16">16</A> Huang X. Shao N. Palani A. Aslanian R. Buevich A. Seidel-Dugan C. Huryk R. Tetrahedron Lett.  2008,  49:  3592 

<A NAME="RC02009SS-17">17</A> Parmee ER. Tempkin O. Masamune S. J. Am. Chem. Soc.  1991,  113:  9365 

<A NAME="RC02009SS-18">18</A> Mulzer J. Mantoulidis A. Ohler E. J. Org. Chem.  2000,  65:  7456 

<A NAME="RC02009SS-19">19</A> Evans DA. Hoveyda AH. J. Org. Chem.  1990,  55:  5190 

<A NAME="RC02009SS-20">20</A> Takai K. Nitta K. Utimoto K. J. Am. Chem. Soc.  1986,  108:  7408 

<A NAME="RC02009SS-21">21</A> Grieco PA. Takigawa T. Schillinger WJ. J. Org. Chem.  1980,  45:  2247 

<A NAME="RC02009SS-22">22</A> Maffioli SI. Marzorati E. Marazzi A. Org. Lett.  2005,  7:  5237 

<A NAME="RC02009SS-23">23</A> Huang X. Shao N. Huryk R. Palani A. Aslanian R. Seidel-Dugan C. Org. Lett.  2009,  11:  867