Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic - - PowerPoint PPT Presentation

Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic Fungal Metabolite ( Fungal Metabolite (±) )-Communesin F Communesin F g ( g ( ) )

Li P S J H W i b S M Li P S J H W i b S M A Ch I Ed A Ch I Ed 2010 2010 49 49 2000 2000 2003 2003 Liu, P.; Seo, J. H.; Weinreb, S. M. Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed

• Angew. Chem. Int. Ed.

. 2010 2010, , 49 49, 2000 , 2000–2003. 2003.

H O Me Me Me N N H H N NH Me

Current Literature Presentation Current Literature Presentation March 6 March 6th

th, 2010

, 2010 Mi h l Y Mi h l Y Michael Yang Michael Yang

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Isolation of Communesin F Isolation of Communesin F f

Isolated from Penicillium mold on marine algae Isolated from Penicillium mold on marine algae Enteromorpha interstinalis Penicillium expansum Enteromorpha interstinalis enicillium expansum

Kerzaon, I.; Pouchus, Y. F.; Monteau, F.; Le Bizec, B.; Nourrisson, M. R. Rapid Commun. Mass Spectrom. 2009, 23, 3928.

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Communesin Background Communesin Background Communesin Background Communesin Background

Biological Activities: Biological Activities:

• Communesins A−D are active against

various leukemia cell lines

• Communesins D−F are insecticidal

Key Structural Features

• Two contiguous quaternary centers

(C-7 and C-8)

• Two aminals

Two aminals

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, early view.

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Biosynthetic Proposal 1: Biosynthetic Proposal 1: Oxidative Dimerization of Tryptamine Oxidative Dimerization of Tryptamine

Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561–569.

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Biosynthetic Proposal 2: Biosynthetic Proposal 2: Dimerization of Tryptamine and Aurantioclavine Dimerization of Tryptamine and Aurantioclavine

O id ti di i ti b t t t i d ti l i Oxidative dimerization between tryptamine and aurantioclavine

• Aurantioclavine – Penicillium fungal metabolite

May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.

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Biosynthetic Proposal 3: Biosynthetic Proposal 3: Diels Diels-

• Alder Reaction

Alder Reaction

May, J. A.; Zeidan, R. K.; Stoltz, B. Tetrahedron Lett. 2003, 44, 1203–1205. May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.

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Model Study: Model Study: y Communesin via Diels Communesin via Diels-

• Alder

Alder

NH H Me Me NH H Me Me Cl TsHN Cs2CO3 CH2Cl2 N Boc N NTs Me H N NTs Me H + Mg 89% (2:1 d.r.) Cs2CO3, CH2Cl2

• 78 °C

N Me Mg, NH4Cl, MeOH, 80% NH H Me Me NH H Me Me + N NH Me H N NH Me H

May, J. A.; Zeidan, R. K.; Stoltz, B. Tetrahedron Lett. 2003, 44, 1203–1205. May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.

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Retrosynthetic Analysis Retrosynthetic Analysis - Qin Qin

N N H O Me H Me Me NH H N Me Me HO R O N NH Me N N Me R Br O O Br O Br N N Me R N H O N2 N3

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

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Diastereomers? Diastereomers?

Br N H OH O Br O N2 1) SOCl2 2) Et3N, CH2Cl2, 95% (2 steps) 3) TsNHNH2, TsOH, 85% 4) DBU, CH2Cl2, 85% + N3 O HO O N H N2 N3 + CuOTf, CH Cl O Br O H O O H O O Ar CH2Cl2, 88% N Me N3 N Me Ar N Me 1 6 : 1 + Br Br 1.6:1 d.r. 1.6 : 1

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

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Cyclopropane Ring Cyclopropane Ring-

• opening
• pening

O Br O NH O Br O N3 THF PBu3 N Me N NH Me N3 PBu3, aq THF

• aq. THF

83% single diastereomer proton transfer O Br O O Br O O Br O

• aq. THF

transfer N Me NH2 N Me NH2 N NH2 Me

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

Mike Yang @ Wipf Group Page 10 of 19 4/26/2010

Qin’s Mechanistic Rationale Qin’s Mechanistic Rationale Q M R Q M R

Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187–2190.

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Formation of the C Formation of the C-8 Quaternary Center: 8 Quaternary Center: Formation of the C Formation of the C 8 Quaternary Center: 8 Quaternary Center: Claisen Rearrangement Claisen Rearrangement

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

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Synthesis of Communesin F Synthesis of Communesin F - Qin Qin

Me 1) DMP Br N H N O HO N O Br O CHO NH H N O Me Me Boc HO 1) DMP 2) NH2OH·HCl, Na2CO3 3) H2, Raney-Ni 4) Boc2O, Na2CO3 50% - 4 steps 5) Pd(OA ) P( T l) 1) NH2OH·HCl, Na2CO3 2) H2, Raney-Ni, (87%, 2 steps, brsm) 3) MeONa, MeOH, 70 °C, 98% N N Me CO2Me N N Me CO2Me PPTS, N N Me CO2Me 5) Pd(OAc)2, P(o-Tol)3, 68% Me Me HO H O Me NH N H OEt 1) silica gel, MeOH/CH2Cl2, 81% - 2 steps 2) KOH M OH/H O 65% H O Boc , CHCl3 66% Me Me Me Me Me Me N N NH N H H NH N N N H M 2) KOH, MeOH/H2O, 65% 3) NaBH4, AcOH/Ac2O, 73% CO2Me 1) BF4OEt3, iPrNEt2, 95% 2) 5% TFA, CH2Cl2 N N N H N O CO Me Boc Me Me Me N Me CO2Me Communesin F

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

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Retrosynthetic Analysis Retrosynthetic Analysis - Weinreb Weinreb

N N H O Me H Me Me NH H N Me Me HO R O N BOMO O Boc N NH Me N N Me R N NBoc Me BOMO N N NO2 CO2Et CO2Et BOMO N I O BOMO N N Me O NO2 Me BOMO

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

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Intramolecular Heck Intramolecular Heck - Weinreb Weinreb

Bn N Bn EtO [Pd(PPh ) ] DME NO2 B(OH)2 I BOMO 1) LiOH, H2O, MeOH, 86% 2) SOCl2; iPr2NEt, 87% BOMO N Bn N Bn EtO O OTf O NO2 [Pd(PPh3)4], DME, H2O, Na2CO3 98% NH2 N H I O NO2 1) ClCO2Et, CH2Cl2, 96% 2) NaH, THF, MeI, 92% CO Et N I O BOMO N N O N NO2 CO2Et CO2Et NO2 Pd(OAc)2, PPh3, DMA, K2CO3, nBu4NBr, 150 °C, 90% BOMO N O N Me Me

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

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1,3 Dipolar Cycloaddition 1,3 Dipolar Cycloaddition - Weinreb Weinreb

a) 5% Pt/C, H2 (40 atm), PhMe b) Boc2O, K2CO3, THF, H2O, 87% (2 steps) N NO2 CO2Et BOMO N NHBoc CO2Et BOMO N EtO2C BOMO AlH3·Me2NEt, THF 74% N Me O N Me O N NBoc Me 1M KOH, EtOH HN BOMO 94 °C NH N CN HN O O N NC N NBoc Me HN BOMO N Me N Boc H N N N NCN3, MeCN 93% (2 steps) N NBoc Me HN BOMO OBOM Me

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

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Formation of C Formation of C-

• 8 Quaternary Center

8 Quaternary Center

HN BOMO N NC 1) 1M KOH, EtOH, 94 °C, 60% 2) Boc O LiHMDS THF 95% N BOMO O Boc H N O OBOM KOtBu, allyl iodide THF 78 °C Boc N NBoc Me 2) Boc2O, LiHMDS, THF, 95% N NBoc Me 3:1 mixture of epimers N Me N Boc THF, −78 C 87% O Boc O OMs O OMs 1) 1M KOH, EtOH, 80 °C, 94% 2) OsO4, NMO, THF, H2O; NaIO a) Pearlman's catalyst N NBoc N BOMO O Boc N NBoc HN BOMO O N NBoc Me HN O NaIO4 3) NaBH4, EtOH 4) MsCl, NEt3, CH2Cl2, 0 °C, 83% (3 steps) H2, THF b) DMP, CH2Cl2 75% (2 steps) Me Me Me

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

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Qin’s Intermediate Qin’s Intermediate

OMs N3 1) Me2CO, 10% NaOH/H2O, 60 °C 93% N3 O Me N NBoc HN O O OMs N NBoc HN O O N3 NaN3, DMF, 90 °C, 61% 60 °C, 93% 2) Boc2O, LiHMDS, THF, 81% N NBoc N O N3 Boc O N Me N Me N Me PMe3, THF, H2O, 70 °C, 88% , NH H N O Boc O Me NH H N O Me Me Boc HO MeLi, THF,

• 78 °C, 73%

NH H N O Me Me Boc HO N NBoc Me N NBoc Me N N Me CO2Me Qin's Intermediate Qin s Intermediate

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

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Summary Summary Summary Summary

Qin Weinreb C-7 Quaternary Center Cyclopropanation Heck C 8 Q t C t Cl i t E l t lk l ti C-8 Quaternary Center Claisen rearrangement Enolate alkylation Overall yield 3% 1% Steps 23 30

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