The Road to Maoecrystal V Curtis Seizert | 8 April 2013 Isolation - PowerPoint PPT Presentation

O O O O O The Road to Maoecrystal V Curtis Seizert | 8 April 2013

Isolation and Characterization Originally isolated in 1994 from isodon eriocalyx, a perennial shrub in southwestern China. Over 50 ent-kauranoids isolated from this species H H ent -kaurene The structure was not unambiguously determined by NMR at this time. Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.-D.; Li, M.- L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004 , 6 , 4327–4330.

Isolation and Characterization 1) Petroleum ether MeOH wash EtOAc crude extract extract extraction 2) EtOAc extraction 395 g 978 g SiO 2 column, CHCl 3 -acetone gradient O O 1) decolorization fraction 2/7 O 2) SiO 2 column chromatography O O Maoecrystal V 5 mg 0.000 04% yield leaves of Isodon eriocalyx 11.9 kg Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.-D.; Li, M.- L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004 , 6 , 4327–4330.

Biological Activity Cytotoxicity IC 50 (  g/mL) K562 A 549 BGC-823 HeLa 6.43 x 10 4 2.63 x 10 5 1.47 x 10 4 Maeocrystal V 0.02 cis -Platin 0.38 1.161 0.25 0.99 Potent and selective cytotoxicity against human gynocological cancer lines Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004 , 6 , 4327–4330.

Biosynthesis of kauranoids ent -copalyl OPP ent -kaurene OPP diphosphate H H synthase synthase H H geranylgeranyl ent -copalyl ent -kaurene pyrophosphate diphosphate [O] O O O H O oxidative H O H O cleavage OH O O O H O O O OH CHO maoecrystal V epi -eriocalyxin A eriocalyxin B Krawczuk, P. J. S tudies Toward the Total Synthesis of Maoecrystal V. Ph.D Dissertation, The Scripps Research Institute, La Jolla, CA, 2011 .

Proposed biosynthetic conversion of eriocalyxin A to maoecrystal V O O O O H [1,2] [O] O O O O O O CHO CHO O O CHO epi -eriocalyxin A H 2 O O O O O O O [O] H HO HO O O O O O O O CHO maoecrystal V This sequence would be extremely hard to replicate in vitro because of the instability of the intermediate carbocations Krawczuk, P. J. S tudies Toward the Total Synthesis of Maoecrystal V. Ph.D Dissertation, The Scripps Research Institute, La Jolla, CA, 2011 .

What synthetic chemists are up against 2 quaternary 2 quaternary 1,4-diketone 1,4-diketone stereocenters stereocenters left hand ring in arene oxidation state O O O O O O O O O O O O [2.2.2] [2.2.2] [2.2.2] O O O O O O O O bicyclooctane bicyclooctane bicyclooctane trans-THF ring 4 stereocenters 4 stereocenters 4 stereocenters 4 stereocenters diff icult substitution for C-O ether closure

Two Conceptually Different Strategies O O D/E A B O C O O R R' R' Standard IMDA Strategy R A D D/E ● A ring in place before Diels-Alder O O O A ● One or both heterocycles closed as tethers B or C O ring closed variation in tether The “Non-Standard” Strategy ● Rely on means other than the standard intramolecular Diels-Alder ● Has not produced a total synthesis of Maoecrystal V

O O The “Non-Standard” Routes D/E A B O C O O O 2 N OH OH OH NO 2 Thomson 2010 Carbocyclic Core O O OH OH Li OTBS OTBS OH OTBS Trauner 2010 O O TMS EtO 2 C Tetracyclic “right-hand” then NaH O O portion O O OH OEt OEt O O H OEt H OEt Zakarian 2011  [2.2.2]bicycle & THF ring O O O O O O O O AcOH Thomson 2013 OH Tricyclic “left-hand” portion H O O O O O (a) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010 , 12 , 3010–3013. (b) Baitinger, I.; Mayer, P.; Trauner, D. Org. Lett. 2010 , 12 , 5656–5659. (c) Gu, Z.; Zakarian, A. Org. Lett. 2011 , 13 , 1080–1082. (d) Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

The Thomson 2010 Route – Synthesis of O O D/E A the carbocyclic core B O C O O OTBS OTBS 1) LDA, TMSCl; O 1) NaH, A O m CPBA 2) B O 2) TBSCl, imid. 73% yield (2 steps) single sterioisomer 70% yield O O (2 steps) O P FeCl 3 N Li O 72% yield O single diastereomer B A O 2 N OR OR OR NO 2 DIBAL R = TBS OH O OH 44% yield (2 steps) single regioisomer and diastereomer net installation of 1,4-diketone O 2 N O OR OR OR Nef NO 2 reaction OH OH OH (a) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010 , 12 , 3010–3013. (b) Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

The Thomson 2010 Route – Attempted O O D/E A C-H etherification B O C O O O 2 N O 2 N O 2 N 1) KOH OR OR OR TMSI, HMDS; 2) Pd/C, H 2 H m CPBA 3) CrO 3 , H 2 SO 4 HO 88% yield OH O O 86% yield (3 steps) PhI(OAc) 2 I 2 , h  95% yield O N + - O OR -NO 2 OR O O O O O 2 N OR OR "various OR 1) AIBN, Bu 3 SnH conditions" H HO O 2) HMDS, TMSI; m CPBA O O O 40% yield (2 steps) (a) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010 , 12 , 3010–3013. (b) Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

The Thomson 2010 Route – O O D/E A Cyclopentanone ring expansion B O C O O O 2 N O 2 N O 2 N OR OR OR 1) KOH TMSI, HMDS; 2) CrO 3 , H 2 SO 4 m CPBA HO 88% yield OH O O 86% yield (2 steps) Pd/C, H 2 71% yield OR OH 1) H 5 IO 6 , MeOH HO 2) NaBH 4 O O O 75% yield (2 steps) O 2 N O 2 N O 2 N OR OR OR OR Pd/C, H 2 Pd/C, H 2 H HO Pd(OAc) 2 , H 2 H HO etc. O O OH OH cyclopropane formation no cyclopropane formation (a) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010 , 12 , 3010–3013. (b) Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

O O Why the Thomson 2010 route failed D/E A B O C O O O 2 N O 2 N O 2 N O 2 N OR OR OR 1,5-H shift OR PhI(OAc) 2 - I H H H I 2 , h  O HO O HO I O O O O I I O 2 N O 2 N The key 1,5-H shift is apparently I OR OR -HI not as facile as one would assume O based on proximity arguments HO O O F? O A O D/E D/E A OH vs. B O C C O O O O Unable to form B ring by C-H etherification (a) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Mylari, B. L.; Wenkert, E. J. Org. Chem. 1986 , 51 , 1505–1509. (b) Concepción, J. I.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E. Tetrahedron Lett. 1984 , 25 , 1953–1956.

O O What synthetic chemists are up against D/E A B O C Polarity disfavors O O joining A and D/E rings as such Thomson 2010 1,4-diketone 2 quaternary stereocenters O O A ring in arene oxidation state [2.2.2]bicyclooctane O 4 stereocenters O O problems with C-H trans-THF ring etherification 4 stereocenters Thomson 2010

O O The “Non-Standard” Routes D/E A B O C O O O 2 N OH OH OH NO 2 Thomson 2010 Carbocyclic Core O O OH OH Li OTBS OTBS OH OTBS Trauner 2010 O O TMS EtO 2 C Tetracyclic “right-hand” then NaH O O portion O O OH OEt OEt O O H OEt H OEt Zakarian 2011  [2.2.2]bicycle & THF ring O O O O O O O O AcOH Thomson 2013 OH Tricyclic “left-hand” portion H O O O O O (a) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010 , 12 , 3010–3013. (b) Baitinger, I.; Mayer, P.; Trauner, D. Org. Lett. 2010 , 12 , 5656–5659. (c) Gu, Z.; Zakarian, A. Org. Lett. 2011 , 13 , 1080–1082. (d) Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

O O The Thomson 2013 Route D/E A B O C O O O O O O 1) LHMDS, MoOPH CO 2 Me TMSI, NaH O O OTBS Cp 2 TiCl 2) TBSOTf, 2,6-lutidine DMSO 51% yield O O O O 33-54% yield 86% yield O O O O (2 steps) TsOH OH 99% yield O O O 1) LHMDS 1) LDA, TMSCl TFA TMSCl OTBS OTBS OTBS 2) Pd(OAc) 2 H 2 O 2) DDQ O O O O O O O 70% yield 75% yield (2 steps) O O 78% yield (2 steps) 1:1 dr TBAF, AcOH THF O incorrect stereochemistry H O O O 64% yield brsm Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

O O Why the Thomson 2013 route failed D/E A B O C O O O O O A incorrect A D/E stereochemistry vs. B O B H C O C O O O O “...our results indicate some caution is likely warranted if [this] strategy is to be undertaken. In fact, the recently reported total synthesis of maoecrystal V completed by Peng and Danishefsky utilized a related 'east-to-west' etherification that also provided the incorrect stereochemistry, thereby necessitating significant steps to correct the issue.” O A O Ti(III) A O CO 2 Me C O O O O A O O O Ti(III) O D/E A C MeO 2 C O O O O anti-Bredt Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013 , 54 , 635–637.

O O What synthetic chemists are up against D/E A B O C Polarity disfavors O O joining A and D/E rings as such Thomson 2010 1,4-diketone 2 quaternary stereocenters O O A ring in arene oxidation state [2.2.2]bicyclooctane O 4 stereocenters Thomson 2013 O certain disconnections lead O to anti-Bredt intermediates problems with C-H trans-THF ring etherif ication 4 stereocenters Thomson 2013 Thomson 2010 disfavored Thomson 2013 sterochemistry?