Total Synthesis of Peloruside A Through Kinetic Lactonization and Relay Ring-Closing Metathesis Cyclization Reactions
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1 Total Synthesis of Peloruside A Through Kinetic Lactonization and Relay Ring-Closing Metathesis Cyclization Reactions Thomas R. oye, Junha Jeon, Lucas C. Kopel, Troy D. Ryba, Manomi A. Tennakoon, and Yini Wang. Angew. Chem. Int. Ed. 2010, Me Me Me Peloruside A Eric E. Buck Current Literature August 28, 2010 Eric Wipf Group Page 1 of 16 9/26/2010
2 Isolation and Background" Peloruside A was Isolated from the marine sponge Mycale hentscheli (pictured left) by Northcote in The marine sponge Mycale hentscheli, located in Pelorus Sound (pictured below), is also responsible for the production of mycalamide A and pateamine. Peloruside A demonstrated LD50 vaulues in the 6-18 nm range towards several cancer cell lines. Peloruside A is a microtubule stabilizer that binds to a different site than paclitaxel. West, L. M.; Northcote, P. T. J. rg. Chem. 2000, 65, ood, K. A.; West, L. M.; Rouwé, B.; Northcote, P. T.; Berridfe, M.V.; Wakefield, St. J.; Miller, J.. Cancer Res. 2002, 64, Teesdale-Spittle, p.; Andreu, J. M.; Miller, J.. Cancer Res. 2004, 64, Eric Wipf Group Page 2 of 16 9/26/2010
3 First Synthesis and the Confirmation of Absolute Configuration" Mukaiyama aldol Me Me Mitsunobu macrolactonization C 2 Me C PG Me PG PG PG Me Me PG (-)-peloruside A TES R 1) PTSA 2) Luche Reduction R mcpba, NaC 3 DCM/Me Me R Liao, X.; Wu, Y. De Brabander, J. K. Angew. Chem. Int. Ed. 2003, 42, Eric Wipf Group Page 3 of 16 9/26/2010
4 Taylorʼs and Ghoshʼs Synthesis of Peloruside A" aldol addition Me Me peloruside A Yamaguchi macrolactonization Me Me TIPS TBS MM MM Me Me X c 1) LDA 2) [] 3) PTSA Me TIPS TBS MM TESMe X c MM Jin, M.; Taylor, R. rg. Lett. 2005, 7, aldol addition Me Acid mediated annulation and selective methylation Me Yamaguchi macrolactonization Me Me MM TBS Me Me TES MM TBS PMB Me peloruside A Gosh, A. K.; Xu, X.; Kim, J.; Xu, C. rg. Lett. 2008, 10, Eric Wipf Group Page 4 of 16 9/26/2010
5 Evanʼs and Jacobsenʼs Synthesis of Peloruside A" Yamaguchi macrolactonization aldol addition Me Me aldol addition X c Me MM TBS TES PMB Me peloruside A Evans, D. A.; Welch, D. S.; Speed, A. W..; Moniz, G. A.; Reichelt, A.; o, S. J. Am. Chem. Soc. 2009, 131, aldol addition Me Me Yamaguchi macrolactonization Me Me PMB TBS Me MM TBS TBS Me TBS Me MM Ac Me peloruside A McGrown, M. A.; Stevenson, P. C.; Schiffler, M. A.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49, Eric Wipf Group Page 5 of 16 9/26/2010
6 Title Paper: Retro Synthesis" RRCM aldol addition Me Me peloruside A Yamaguchi macrolactonization Me TBS PMB Me() C 2 Me MM Me (Me) PMB BPS Y X X = -C 2 Ph 2 Si- Y = X = C(), Y = Me MM Me 2 C C 2 Me Me MM Me MM Me Thomas R. oye, Junha Jeon, Lucas C. Kopel, Troy D. Ryba, Manomi A. Tennakoon, and Yini Wang. Angew. Chem. Int. Ed. 2010, Eric Wipf Group Page 6 of 16 9/26/2010
7 Tennakoon and Yini: Initial Work on Peloruside A" Y X (R) citronellene Se 2 tbu 1) LiC 2 2) SP-435 Ac 95:5 er N Cl Me N Me LiMDS, MPA 2 Zn N dr = 70 : 30 LiB 4 Low diastereoselectivity and seperation of diastereomers proved difficult i) Ph 2 SiCl 2, pyr ii) Si Ph Ph Si Ph Ph Si Ph Ph 40 % dr = 95 : 5 21% 18% Tennakoon, M. A., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2001 Eric Wipf Group Page 7 of 16 9/26/2010
8 Tennakoon and Yini: Initial Work on Peloruside A" Si Ph Ph Ru G2 Ru Si Ph Ph Ru Si Ph Ph SiPh 2 3) CSA 1) TBAF 2) TBSCl N PMB CCl 3 TBS PMB 92% C 2 Me Me MM Me 2 C MM Me 1) Zn, 2) Na, PMBCl Br PMB 1) i) 3 ii) NaB 4 2) TBSCl 3) S 3 pyr TBS PMB Bu 2 BTf, 3 N N TBS PMB N Ac 2 -or- MMCl TBS PMB R N R = Ac or MM Tennakoon, M. A., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2001 oye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao,. J. Am. Chem. Soc. 2004, 126, Eric Wipf Group Page 8 of 16 9/26/2010
9 Troy : The Issue of Scalability" TBS PMB N C 3 N Cl nbuli Me Me N nbuli Br N 1) RhCl 3 3 2, / 2, 98% 2) Li, 2 2, TF/ 2, 99% E:Z 15:1 (CCl) 2, 3 N Ru G2 C 2 2 Ru G2 Ryba, T. D., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2005 Roulland, E.; Ermolenko, M. S. rg. Lett. 2005, 7, Eric Wipf Group Page 9 of 16 9/26/2010
10 Junha : Completion of a Scalable Route to the Northern Fragment " DCC, DMAP, 82% Ru G2, 70% 1) NaB 4, Ac 2) TBSCl 3) CSA N TBS PMB A poor substrate for lipase resolution although Troy s diastereoselective RRCM was a great reaction, I thought it was not scalable. PMB CCl 3 3 steps 77% 1) Zn 0, Cp 2 TiCl 2, allyl 2-bromoacetate 2) p 3 buffer, ipr/ 2 /TF (4:1:2) TBS PMB Allyl Pd(Ph 3 ) 4, C 2, 3 N 3 steps 61% TBS PMB Me Nitrile to ketone or to complementary aldehyde was not easy. The nitrile was extremely base sensitive. Eric Wipf Group Page 10 of 16 9/26/2010
11 Troy : The Issue of Scalability" TBS ()-(Icr-4) 2 B MM MM Me 2 C C 2 Me 1) NaB 4 2) TBSCl 3) DIBAL- TBS MM MM TBS MM MM TBS MM dr = 1:2:1 er = 5:1 MM TBS MM 2) 3, Na, Me 1) Na, MeI 3) F, Me Me 2 C Me MM Me C 2 Me MM MM 20 mol% cat. C 6 D 6 Me Me C 2 Me Me from a total synthesis perspective it was a total nightmare. From a training exercise it was a blessing. Catalyst time Lactone Ratio DBU TMG DBN :1 13:1 10:1 Me 2 C Me Me MM Me Ryba, T. D., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2005 Eric Wipf Group Page 11 of 16 9/26/2010
12 Troy : The Issue of Scalability" Me 2 C C 2 Me DIBAL-; Na () 2 P C 6 13 nexc 2 C 2 nex SAD, 88% nexc 2 C 2 nex 80% 1) I, 83% 2) Me 3 BF 4, 84% nexc 2 Me C 2 nex Me 1) BF 3 2 S S 2) MMCl nexc 2 Me S MM S Me C 2 nex MM The formation of the spirocycle was the big breakthrough. 2 steps 90% 1) I 2, NaC 3, 91% Me Me 20 mol% cat. nexc 2 C 2 nex 2) Raney-Ni 2 C 6 D 6 MM MM MM Me Me C 2 nex Me Catalyst % Conv. Time (h) Lactone Ratio DBU TMG DBN 100 < :1 13:1 10:1 nexc 2 Me Me MM Me Ryba, T. D., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2005 Eric Wipf Group Page 12 of 16 9/26/2010
13 Lucas: ptimization of the Kinetic Lactonization" nexc 2 Me S MM S Me C 2 nex MM 1) I 2, NaC 3, 91% 2) tera's Catalyst, Me, 77% Me Me 2 C MM Me C 2 Me MM 3) Raney-Ni, 2, 91% TMG, C 6 6 ; TFA, 98% (d.r. 12:1) MM Me 2 C Me Me MM Me MM Me Me MeC 2 Me MM MM Me Me C 2 Me Me I observed that as the ratio of DBN increased, so too did the peaks that I initially assigned as being associated with byproducts. the additional peaks are in fact coming from an amine-product complex and unpon treatment with TFA, this adduct collapses to regenerate the desired lactone product. it was decided to use TMG as the catalyst in C 6 D 6 because of its high selectivity for forming the desired product. TMG was also reported not to have the problems associated with decomposition of product. Kopel, L. C., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2009 Eric Wipf Group Page 13 of 16 9/26/2010
14 Lucas: Finishing the Southern Fragment" MM Me Me C 2 Me Me 1) L-Selectride, 87% 2) indium powder Me Me MM MM Me 1) AlCl 3, NaI, 92% 2) (p-me)-phc(me) 2, CSA, 87% 3) MMCl, 99% Br Me 80% PMP Me MM Me 1) LA, 96% 2) TBDPSCl, 92% 3) DIBAL-, 95% PMB BPS Me ME BPS MM 1) DMP 2) Zn(B 4 ) 2, 62% 3) TBSTf, 89% PMB BPS Me TBS Me BPS MM 1) F pyr, 91% 2) DMP 3) NaCl 2, Na 2 P 4 PMB BPS Me TBS Me C 2 Me MM 3, 75% PMB BPS Me TBS Me C 2 Me MM 4) C 2 N 2 3 steps 87% The C8 stereocenter was previously inverted by a lengthy intramolecular inversion strategy: mesylation, ozonolysis, oxidation to the acid, cyclization to invert, DIBAL- reduction, and wittig to reveal the inverted C8 hydroxyl. Kopel, L. C., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2009 Eric Wipf Group Page 14 of 16 9/26/2010
15 Junha and Lucas: End Game" PMB BPS Me TBS Me C 2 Me MM TBS TBS PMB BPS 1) cex PMB 2 BCl, 64% PMB Me 2) NMe 4 B(Ac) 3, 95% TBS Me Me C 2 Me MM 1) Me 3 BF 4, 82% 2) MMCl, 98% 3) DDQ, 94% TBS MM Me BPS Me TBS Me C 2 Me MM 1) Li, 2 2, 100% 2) Yamaguchi macrolactonization, 54% TBS Me MM MM BPS TBS Me Me 1) DMP, 83% 2) F pyr 3) Cl Me Me Me Me Me Me After a final removal of 5 protecting groups, on TLC I saw two spots, which correspond to peloruside A and isopeloruside. I don t understand why others didn t see the this because virtually all the synthesis used almost identical deprotection conditions. peloruside A isopeloruside A 2 steps 49% 2 steps 5% Eric Wipf Group Page 15 of 16 9/26/2010
16 Summary" RRCM aldol addition Me Yamaguchi macrolactonization Me A detailed look into the synthesis of peloruside A from an author perspective. ighlights from the synthesis include a RRCM strategy to set the z-olefin and desymmetrizing kinetic lactonization to assemble the southern fragment. Me The final synthesis yielded 6.9 mg followed by another 5 mg. There remains enough addition material to produce ca 100 mg. peloruside A A Special thanks to Lucas, Junha, and Troy. Eric Wipf Group Page 16 of 16 9/26/2010
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