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
Originally isolated in 1994 from isodon eriocalyx, a perennial shrub in southwestern China. Over 50 ent-kauranoids isolated from this species 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.
H H ent-kaurene
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.
SiO2 column, CHCl3-acetone gradient fraction 2/7 O O O O O Maoecrystal V 5 mg 0.000 04% yield 1) decolorization 2) SiO2 column chromatography MeOH extraction crude extract 978 g leaves of Isodon eriocalyx 11.9 kg 1) Petroleum ether wash 2) EtOAc extraction EtOAc extract 395 g
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.
Cytotoxicity IC50 (g/mL) K562 6.43 x 104 0.38 A 549 2.63 x 105 1.161 BGC-823 1.47 x 104 0.25 HeLa 0.02 0.99 Maeocrystal V cis-Platin
OPP H H OPP H H ent-copalyl diphosphate synthase ent-kaurene synthase geranylgeranyl pyrophosphate ent-copalyl diphosphate ent-kaurene H H O OH OH O O O H O O O CHO eriocalyxin B epi-eriocalyxin A O O O O O H maoecrystal V
cleavage [O]
Krawczuk, P. J. Studies Toward the Total Synthesis of Maoecrystal V. Ph.D Dissertation, The Scripps Research Institute, La Jolla, CA, 2011.
This sequence would be extremely hard to replicate in vitro because
Krawczuk, P. J. Studies Toward the Total Synthesis of Maoecrystal V. Ph.D Dissertation, The Scripps Research Institute, La Jolla, CA, 2011.
O O O O O O O O O H [O] H2O maoecrystal V HO O O O CHO O HO O O O O CHO O O O CHO O O H O O O CHO [O] [1,2] epi-eriocalyxin A
O O O O O O O O O O [2.2.2] bicyclooctane 4 stereocenters O O O O O [2.2.2] bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters O O O O O [2.2.2] bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters left hand ring in arene oxidation state
diff icult substitution for C-O ether closure
O O O O O A B C D/E
O O O O variation in tether R R' R' R A A D D/E B or C ring closed
Standard IMDA Strategy
The “Non-Standard” Strategy
OH OH OH OH O2N O O OH NO2 O O OH O O O O H O AcOH H O OEt OEt O O O H O OEt OEt O O O
O OH O OTBS O OH O OTBS O OTBS EtO2C O Li TMS then NaH
Thomson 2010 Carbocyclic Core Trauner 2010 Tetracyclic “right-hand” portion Zakarian 2011 [2.2.2]bicycle & THF ring Thomson 2013 Tricyclic “left-hand” portion
(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.
Thomson, R. J. Tetrahedron Lett. 2013, 54, 635–637.
O O O O O A B C D/E
(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,
O O O O O A B C D/E O O OTBS OTBS O 1) LDA, TMSCl; mCPBA 2) TBSCl, imid. 70% yield (2 steps) 1) NaH, A 2) B
O P O O N O O
Li A B 73% yield (2 steps) single sterioisomer OR OH NO2 OH OR O2N OH OR O net installation
Nef reaction OR OH OH OR O2N NO2 OR O FeCl3 72% yield single diastereomer R = TBS 44% yield (2 steps) single regioisomer and diastereomer DIBAL
(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,
O O O O O A B C D/E OH OR O2N O OR O2N H O OR O2N HO 1) KOH 2) Pd/C, H2 3) CrO3, H2SO4 86% yield (3 steps) TMSI, HMDS; mCPBA 88% yield O OR N+ O O OR O
O
PhI(OAc)2 I2, h 95% yield O OR O2N O OR HO H 1) AIBN, Bu3SnH 2) HMDS, TMSI; mCPBA 40% yield (2 steps) OR O O "various conditions"
O O O O O A B C D/E
OH OR O2N O OR O2N O OR O2N HO 1) KOH 2) CrO3, H2SO4 86% yield (2 steps) TMSI, HMDS; mCPBA 88% yield
(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,
O O OH O OR HO Pd/C, H2 71% yield 1) H5IO6, MeOH 2) NaBH4 75% yield (2 steps) OH OR O2N OH OR O2N H Pd/C, H2 H no cyclopropane formation O OR O OR O2N HO HO Pd/C, H2 Pd(OAc)2, H2 etc. cyclopropane formation
O O O O O A B C D/E
O OR O2N HO O OR O2N O I O OR O2N O H H H O OR O2N HO O OR O2N HO I O OR O2N O PhI(OAc)2 I2, h
1,5-H shift I I
The key 1,5-H shift is apparently not as facile as one would assume based on proximity arguments
O O OH O O O O O A B C D/E A C D/E F? Unable to form B ring by C-H etherification vs.
(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 O O O A B C D/E
O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
Thomson 2010 problems with C-H etherification Polarity disfavors joining A and D/E rings as such Thomson 2010
OH OH OH OH O2N O O OH NO2 O O OH O O O O H O AcOH H O OEt OEt O O O H O OEt OEt O O O
O OH O OTBS O OH O OTBS O OTBS EtO2C O Li TMS then NaH
Thomson 2010 Carbocyclic Core Trauner 2010 Tetracyclic “right-hand” portion Zakarian 2011 [2.2.2]bicycle & THF ring Thomson 2013 Tricyclic “left-hand” portion
(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.
Thomson, R. J. Tetrahedron Lett. 2013, 54, 635–637.
O O O O O A B C D/E
O O O O O O TMSI, NaH DMSO 86% yield
CO2Me
Cp2TiCl 33-54% yield O O O O 1) LHMDS, MoOPH 2) TBSOTf, 2,6-lutidine O O O O OTBS 51% yield (2 steps)
Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013, 54, 635–637.
O O O O O A B C D/E
TsOH 99% yield O O OTBS O 1) LDA, TMSCl 2) Pd(OAc)2 75% yield (2 steps) 1:1 dr O O OTBS O 1) LHMDS TMSCl 2) DDQ O O OTBS O OH O O O TFA H2O 70% yield 78% yield (2 steps) TBAF, AcOH THF O O O H O 64% yield brsm incorrect stereochemistry
“...our results indicate some caution is likely warranted if [this] strategy is to be
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.”
Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013, 54, 635–637.
O O O O O A B C D/E O O O H O incorrect stereochemistry A B C vs. O O O O O A B C D/E
O O O O O O D/E C A MeO2C A O O Ti(III) anti-Bredt O O O O O O O A CO2Me A C Ti(III)
O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
Thomson 2010 Thomson 2013 certain disconnections lead to anti-Bredt intermediates Thomson 2013
O O O O O A B C D/E
problems with C-H etherif ication disfavored sterochemistry? Polarity disfavors joining A and D/E rings as such Thomson 2010 Thomson 2013
O O O O O A B C D/E
O O O O variation in tether R R' R' R A A D D/E B or C ring closed
Standard IMDA Strategy
The “Non-Standard” Strategy
O O O OAcO O O O O H OAc O O SO2Ph OTBS O O O TBSO O O O O OAc O O OAcO TBSO O H (ent) OTBS OMe O MeO2C MeO O O O OMe
Yang 2010, 21 Steps Lactone and THF closed as tether Danishefsky 2012, 32 Steps Lactone closed as tether Baran 2009, Not Completed Lactone closed as tether Ether not formed Nicolaou 2010 & Chen 2011, Not Completed THF closed as tether
(a) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org Lett 2009, 11, 4774–4776. (b) Gong, J.; Lin, G.; Li, C.; Yang, Z. Org. Lett. 2009, 11, 4770–4773. (c) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J Am Chem Soc 2010, 132, 16745–6. (d) Nicolaou, K. C.; Dong, L.; Deng, L.; Talbot, A. C.; Chen, D. Y.-K. Chem Commun 2010, 46, 70–72. (e) Dong, L.; Deng, L.; Lim, Y. H.; Leung, G. Y. C.; Chen, D. Y.-K. Chem.--Eur. J. 2011, 17, 5778–5781. (f) Peng, F.; Danishefsky, S. J. J Am Chem Soc 2012, 134, 18860–7.
O O O O O A B C D/E
O O O O O O O O O OH O H O O OAcO RO O H H trans-THF ring by hemiacetal reduction [2.2.2]bicycle by IMDA 1,4-diketone by late stage allylic oxidation RO O O O O OAc O TBSO OHC OR O OH TBSO OR Cl2Bi
2
1 quaternary stereocenter by enolate arylation
(a) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org Lett 2009, 11, 4774–4776. (b) Krawczuk, P. J. Studies Toward the Total Synthesis
A A A D C D
Ultimately, the Baran synthetic effort was thwarted by their inability to form the THF ring
O O O O O A B C D/E
3
O O O O O A B C D/E
O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
Thomson 2010 Thomson 2013 certain disconnections lead to anti-Bredt intermediates Thomson 2013 Baran 2009 disfavored sterochemistry? problems with C-H etherif ication Polarity disfavors joining A and D/E rings as such Thomson 2010 Thomson 2013
O O O OAcO O O O O H OAc O O SO2Ph OTBS O O O TBSO O O O O OAc O O OAcO TBSO O H (ent) OTBS OMe O MeO2C MeO O O O OMe
Yang 2010, 21 Steps Lactone and THF closed as tether Danishefsky 2012, 32 Steps Lactone closed as tether Baran 2009, Not Completed Lactone closed as tether Ether not formed Nicolaou 2010 & Chen 2011, Not Completed THF closed as tether
O O O O O A B C D/E
(a) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org Lett 2009, 11, 4774–4776. (b) Gong, J.; Lin, G.; Li, C.; Yang, Z. Org. Lett. 2009, 11, 4770–4773. (c) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J Am Chem Soc 2010, 132, 16745–6. (d) Nicolaou, K. C.; Dong, L.; Deng, L.; Talbot, A. C.; Chen, D. Y.-K. Chem Commun 2010, 46, 70–72. (e) Dong, L.; Deng, L.; Lim, Y. H.; Leung, G. Y. C.; Chen, D. Y.-K. Chem.--Eur. J. 2011, 17, 5778–5781. (f) Peng, F.; Danishefsky, S. J. J Am Chem Soc 2012, 134, 18860–7.
O O O O O A B C D/E
Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J Am Chem Soc 2010, 132, 16745–6.
O O O O O O O O OAcO O O O O H OAc
* *
1,4-diketone by late stage allylic oxidation [2.2.2]bicycle by IMDA THF ring closed by C-C bond formation 1,4 OH OR O O N2 P(O)(OEt)2 O MeO2C OR O CO2Me (AcO)3Pb OR O O P(O)(OEt)2 O OMOM H
*
Ether of THF formed by O-H insertion 1 quaternary stereocenter by enolate arylation final C-H bond of THF ring precursor removed by HWE 1,4
O O O O O A B C D/E
Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J Am Chem Soc 2010, 132, 16745–6.
O CO2Me
OMOM Pb(OAc)3
O MeO2C OMOM pyridine, CHCl3 reflux, 88% yield OH OMOM HO 1) Bu4NBH4 65% yield (89% brsm) 2) LAH 88% yield O O P(O)(OEt)2 O OMOM H O O O OH H
P(O)(OEt)2 HO2C
Rh2(OAc)4, PhH, reflux 60% yield OH OMOM O O N2 P(O)(OEt)2 1) t-BuOK, (HCHO)2 2) TFA, DCM 1) EDCI, DMAP, A 2) TsN3, DBU, O °C A 66% yield (2 steps) 86% yield (2 steps)
O O O O O A B C D/E OH OMOM O O N2 P(O)(OEt)2 O O P(O)(OEt)2 O OMOM H Rh2(OAc)4, PhH, reflux 60% yield Yang: OH OMOM O O P(O)(OEt)2 TsN3, DBU 81% yield O OH HO O O P(O)(OEt)2 N2 O O O OH (EtO)2(O)P O Rh2(OAc)4 or Rh(esp) 94% yield Krawczuk & Baran: O OH HO O O P(O)(OEt)2 pABSA DBU 41% yield H+, MeOH O OH
+H2O
O R O O+ OH O R O O O O O O O R O MeO OMe acetalization R 1,3
(a) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745–6. (b) Krawczuk, P. J. Studies Toward the Total Synthesis of Maoecrystal V. Ph.D Dissertation, The Scripps Research Institute, La Jolla, CA, 2011.
O O O O O A B C D/E
(a) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745–6. (b) Krawczuk, P. J. Studies Toward the Total Synthesis of Maoecrystal V. Ph.D Dissertation, The Scripps Research Institute, La Jolla, CA, 2011.
O OAc O OAc O O O O O O O O O OAcO O O O OAc O O O O O H OAc Pb(OAc)4 AcOH, 0 °C O O O OH H PhMe 145 °C 36% yield, desired (only -OAc epimer) 40 % yield total, undesired (28% yield -OAc 12% yield -OAc) PhMe 145 °C Yang: O OR HO O O O O O O OAc OR O HO O OAcO O O O O OAcO OH HO O O OAcO O Pb(OAc)4 [4 + 2] R = H Krawczuk & Baran: [4 + 2] R = Ac O AcO O OAcO O tentatively assigned
Maeocrystal V
Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J Am Chem Soc 2010, 132, 16745–6.
1) NBS, (PhCO2)2 2) TEMPO, Bu3SnH O O O OAcO OH O O O OAcO O O O OAcO O N 68% yield (2 steps) Zn, AcOH 70 °C, 2 h 85% yield
O O O O O A B C D/E SmI2, THF MeOH, rt, 10 min 88% yield. O O O O OH 1) Lindlar's cat., H2 2) Dess-Martin periodinane O O O O O O O O O O DBU, toluene 100 °C, 1 h 48% yield (90% brsm) 81% yield (2 steps) H
O O O O O A B C D/E O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
O O O OAcO O O O O H OAc
C-O bonds of THF ring formed early 3ether installed by C-C bond f ormation vicinal quaternary stereocenter by IMDA IMDA to complete bicycle avoids anti-Bredt disconnections O CO2Me
OMOM Pb(OAc)3
O MeO2C OMOM H H H H 1,4-diketone installed by enolate arylation and late stage oxidation A ring arene aromatization blocked by installing quaternary centers before oxidation
O O O O O A B C D/E
O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
Thomson 2010 Thomson 2013 certain disconnections lead to anti-Bredt intermediates Thomson 2013 Baran 2009 Methyl epimers are similar in energy Yang 2010 disfavored sterochemistry? problems with C-H etherif ication Polarity disfavors joining A and D/E rings as such Thomson 2010 Thomson 2013
-hydroxy ketone intermediates
are capable of retroaldol Krawczuk & Baran unpublished Rotameric IMDA transition states Yang 2010
O O O OAcO O O O O H OAc O O SO2Ph OTBS O O O TBSO O O O O OAc O O OAcO TBSO O H (ent) OTBS OMe O MeO2C MeO O O O OMe
Yang 2010, 21 Steps THF ring closed by IMDA Danishefsky 2012, 32 Steps Ether after IMDA Baran 2009, Not Completed Lactone as tether Ether not formed Nicolaou 2010 & Chen 2011, Not Completed THF ring closed by IMDA
O O O O O A B C D/E
(a) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org Lett 2009, 11, 4774–4776. (b) Gong, J.; Lin, G.; Li, C.; Yang, Z. Org. Lett. 2009, 11, 4770–4773. (c) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J Am Chem Soc 2010, 132, 16745–6. (d) Nicolaou, K. C.; Dong, L.; Deng, L.; Talbot, A. C.; Chen, D. Y.-K. Chem Commun 2010, 46, 70–72. (e) Dong, L.; Deng, L.; Lim, Y. H.; Leung, G. Y. C.; Chen, D. Y.-K. Chem.--Eur. J. 2011, 17, 5778–5781. (f) Peng, F.; Danishefsky, S. J. J Am Chem Soc 2012, 134, 18860–7.
O O OR O H O O OR O HO O O O O O OTBS O 1,4-diketone by 1,2- carbonyl transposition late stage A ring elaboration [2.2.2]bicycle by IMDA A B B ring by hemiketal reduction C A D/E RO OTBS O O O RO O HO OR OMe O Li 1 quaternary stereocenter set by [2,3] Wittig Stork-Danheiser A D OMe O OMe OMe O OH X Central bond by enolate arylation A D
O O O O O A B C D/E
O OMe OPiv MOMO OMe OPiv MOMO OMe O SnBu3 1) HCl, MeOH 2) PivCl, pyridine 72% yield (2 steps) 1) NaBH4, CeCl3 2) MOMCl , i-Pr2NEt 88% yield (2 steps) 1) DIBAL 2) KH, 18-crown-6 ICH2SnBu3 86% yield (2 steps)
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E O O O OMe OMe O OMe OMOM 1) Pd(OAc)2, L K3PO4, THF, 80 °C 2) TMSCHN2, iPr2NEt 91% yield (2 steps)
PtBu2
B, BuLi, THF then HCl, H2O 75% yield L
OMOM Bu3Sn
B Br OMe
MOMO O HO MOMO O O O CO2Me MOMO OTBS O O CO2Me 1M HCl THF-MeOH 78% yield (2 steps) A, pyridine DCM 72% yield TBSOTf, Et3N DCM, 0 °C 81% yield
Cl CO2Me O
A
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E
MOMO OMe HO MOMO OMe HO BuLi, THF
88% yield MOMO OMe O SnBu3 Li, NH3, t-BuOH
unintended reduction
O O O O O Maoecrystal V
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E RO O HO A D 1,5 O O OTBS O O OTBS O O OTBS CO2Me O O CO2Me OTBS OMOM OMOM OR OR H E H E MOMO OTBS O O CO2Me favored disfavored
not observed 180 C
O O O O O A B C D/E
O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
Thomson 2010 Thomson 2013 certain disconnections lead to anti-Bredt intermediates Thomson 2013 Baran 2009 Methyl epimers are similar in energy Yang 2010 Danishefsky 2009 Polarity disfavors joining A and D/E rings as such disfavored sterochemistry? problems with C-H etherif ication Thomson 2010 Thomson 2013 Rotameric IMDA transition states Yang 2010 Danishefsky 2009
-hydroxy ketone intermediates
are capable of retroaldol Krawczuk & Baran unpublished
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E O O O HO O O O O O O O O O O O O O O H THF ring by cationic ether closure 1,4-diketone by 1,2- carbonyl transposition late stage A ring elaboration A B A 1,4 O O O O O SO2Ph OTBS CO2Me O CO2Me Cl O 1 quaternary center set by formal enolate alkenylation [2.2.2]bicycle by IMDA C D/E A A A D D D A 1,5
CO2Me Cl O LDA, THF
C 40% yield 1) DIBAL 2) MnO2 68% yield (2 steps)
Cl SO2Ph O
Pyridine, DCM 86% yield HO O CO2Me O O O SO2Ph O
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E
O O SO2Ph O O O SO2Ph OTBS TBSOTf, Et3N 91% yield
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E
O O OTBS O O OTBS SO2Ph O O SO2Ph OTBS O O OTBS 166 °C 166 °C TBAF TBAF O O O (+/-) 62% yield enantiomers
NaOH, H2O2 MeOH 95% yield 1) MgI2, DCM 2) Bu3SnH, AIBN toluene, reflux 50% yield (2 steps) m-CPBA 72% yield TsOH 90% yield incorrect sterochemistry O O O O O O O HO O O O HO O H O O O O HO H H O O O
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E
1) Ac2O, pyridine 2) NaBH4, EtOH DCM 1) MOMCl, DIPEA 2) K2CO3, MeOH 85% yield (2 steps) 90% yield (2 steps) O O O O HO H H O O OH O AcO H H O O OMOM O HO H H O O O O O A B C D/E
m-CPBA 95% yield 1) Dess-Martin periodinane, NaHCO3 2) Ac2O, pyridine 77% yield (2 steps) PhSH, Et3N then NaBH4 78% yield O O OMOM O HO H H O H O O OMOM O H OAc O O O OMOM O PhS AcO OH BF3OEt2 82% yield 1) Raney-Ni 2) MsCl, DMAP 3) K2CO3, MeOH 51% yield (3 steps) O O OMOM O OH O O OMOM O HO O H O O OMOM O H O OH DMDO
PCC 76% yield CH2Br2 TiCl4, Zn DCM, rt 85% yield H2, PtO2 AcOH 40% yield O O O O H O O O O O H O O O O H O
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
O O O O O A B C D/E
CH2Br2 TiCl4, Zn DCM, rt 85% yield CH2I2, Zn(Ag) Et2O, reflux 88% yield O O OMOM O H O OH O O O O H OH O O O O H OH OMe CH3 OMe
Maeocrystal V
(a) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587. (b) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–2106 (c) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860–18867.
TsOH, PhH 85% yield 1) LDA, TMSCl 2) Pd(tfa)2 72% yield (2 steps) O O O H O O O O O O O O H O TFDO -78 to 0 °C 90% yield, 1:1 dr BF3OEt2 DCM, rt 85% yield O O O O O O O O O O O O O O O desired undesired O O O O O A B C D/E
O O O O O A B C D/E O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
-hydroxy group provides handle
for stereochemical inversion O O O HO O H O O O O HO H H O O OMOM O H O OH H+ O O SO2Ph OTBS O O O non-stereogenic spirocycle leads to one possible IMDA diastereomer
H 1,4-diketone installation is delayed until all C-C bonds are formed
O O O O O A B C D/E
O O O O O [2.2.2]bicyclooctane 4 stereocenters 1,4-diketone 2 quaternary stereocenters trans-THF ring 4 stereocenters A ring in arene
Thomson 2010 Thomson 2013 certain disconnections lead to anti-Bredt intermediates Thomson 2013 Baran 2009 Methyl epimers are similar in energy Yang 2010 Danishefsky 2009 Polarity disfavors joining A and D/E rings as such disfavored sterochemistry? problems with C-H etherif ication Thomson 2010 Thomson 2013 Danishefsky 2012 Rotameric IMDA transition states Yang 2010 Danishefsky 2009 Danishefsky 2012
-hydroxy ketone intermediates
are capable of retroaldol Krawczuk & Baran unpublished
O O O O O A B C D/E
O O O O OAc O OAc O O O heterocycle(s) closed by C-C bond formation avoids anti-Bredt intermediates
The difficulty in synthesizing Maoecrystal V arises not from individual bottlenecks, but from the interaction of having several bottlenecks in close proximity to each other. Skeletal C-C bond formation should not necessarily be prioritized over other skeletal bond formation A continuing challenge in organic synthesis is the construction of all-carbon quaternary (stereo)centers, a challenge which is lessened by rendering the bond forming steps intramolecular