total synthesis of the polycyclic fungg(al metabolite ...ccc.chem.pitt.edu/wipf/current...
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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 FCommunesin Fg (g ( ))
Li P S J H W i b S MLi P S J H W i b S M A Ch I EdA Ch I Ed 20102010 4949 20002000 20032003Liu, P.; Seo, J. H.; Weinreb, S. M. Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. EdAngew. Chem. Int. Ed. . 20102010, , 4949, 2000, 2000––2003.2003.
H
OMe
MeMe
NN
HH
NNH
Me
Current Literature PresentationCurrent Literature PresentationMarch 6March 6thth, 2010, 2010Mi h l YMi h l YMichael YangMichael Yang
Mike Yang @ Wipf Group Page 1 of 19 4/26/2010
Isolation of Communesin FIsolation of Communesin Fff
Isolated from Penicillium mold on marine algaeIsolated from Penicillium mold on marine algae
Enteromorpha interstinalisPenicillium expansum Enteromorpha interstinalisenicillium expansum
Kerzaon, I.; Pouchus, Y. F.; Monteau, F.; Le Bizec, B.; Nourrisson, M. R. Rapid Commun. Mass Spectrom. 2009, 23, 3928.
Mike Yang @ Wipf Group Page 2 of 19 4/26/2010
Communesin BackgroundCommunesin BackgroundCommunesin BackgroundCommunesin 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 aminalsTwo 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 TryptamineOxidative 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 AurantioclavineDimerization of Tryptamine and Aurantioclavine
O id ti di i ti b t t t i d ti l iOxidative dimerization between tryptamine and aurantioclavine
Aurantioclavine – Penicillium fungal metabolite
May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.
Mike Yang @ Wipf Group Page 5 of 19 4/26/2010
Biosynthetic Proposal 3:Biosynthetic Proposal 3:DielsDiels--Alder ReactionAlder 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.
Mike Yang @ Wipf Group Page 6 of 19 4/26/2010
Model Study:Model Study:yyCommunesin via DielsCommunesin via Diels--AlderAlder
NHHMeMe
NHHMeMeCl
TsHNCs2CO3 CH2Cl2
NBoc
NNTs
MeHN
NTs
MeH
+
Mg
89% (2:1 d.r.)
Cs2CO3, CH2Cl2-78 °C
NMe
Mg,NH4Cl,MeOH,80%
NHHMeMe
NHHMeMe
+
NNH
MeHN
NH
MeH
May, J. A.; Zeidan, R. K.; Stoltz, B. Tetrahedron Lett. 2003, 44, 1203–1205.May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.
Mike Yang @ Wipf Group Page 7 of 19 4/26/2010
Retrosynthetic Analysis Retrosynthetic Analysis -- Qin Qin
N NHO
Me
HMeMe
NHHN
MeMeHO
R O
NNH
MeN
N
MeR
BrO
OBr O
Br
NN
MeR
NH
O
N2 N3
Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.
Mike Yang @ Wipf Group Page 8 of 19 4/26/2010
Diastereomers? Diastereomers? Br
NH
OH
OBr O
N2
1) SOCl22) Et3N, CH2Cl2, 95% (2 steps)3) TsNHNH2, TsOH, 85%4) DBU, CH2Cl2, 85%
+
N3
OHO
O
NH
N2 N3+
CuOTf,CH Cl
OBrO
HO O
H O OAr
CH2Cl2,88%
NMe
N3N
Me
ArN
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.
Mike Yang @ Wipf Group Page 9 of 19 4/26/2010
Cyclopropane RingCyclopropane Ring--openingopening
OBrO
NH
OBrO
N3 THF
PBu3
NMe
NNH
Me
N3
PBu3, aq THF
aq. THF83% single diastereomer
protontransfer
OBrO
OBrO
OBrO
aq. THF transfer
NMe
NH2NMe
NH2N
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 RationaleQin’s Mechanistic RationaleQ M RQ M R
Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187–2190.
Mike Yang @ Wipf Group Page 11 of 19 4/26/2010
Formation of the CFormation of the C--8 Quaternary Center:8 Quaternary Center:Formation of the CFormation of the C 8 Quaternary Center:8 Quaternary Center:Claisen RearrangementClaisen Rearrangement
Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.
Mike Yang @ Wipf Group Page 12 of 19 4/26/2010
Synthesis of Communesin F Synthesis of Communesin F -- QinQinMe1) DMP
Br
N
HNO
HO
N
OBrO CHO
NHHNO
Me MeBocHO
1) DMP2) NH2OH·HCl, Na2CO33) H2, Raney-Ni4) Boc2O, Na2CO350% - 4 steps
5) Pd(OA ) P( T l)
1) NH2OH·HCl, Na2CO32) H2, Raney-Ni, (87%, 2 steps, brsm)3) MeONa, MeOH, 70 °C, 98%
NN
MeCO2MeN
N
MeCO2Me
PPTS,
NN
MeCO2Me
5) Pd(OAc)2, P(o-Tol)3, 68%Me Me
HO
HO
Me
NH NHOEt1) silica gel, MeOH/CH2Cl2,
81% - 2 steps2) KOH M OH/H O 65% HOBoc
,CHCl366%
MeMeMeMe Me
MeN
NNH
NHH NH
NN
NH
M
2) KOH, MeOH/H2O, 65%3) NaBH4, AcOH/Ac2O, 73%
CO2Me
1) BF4OEt3, iPrNEt2, 95%2) 5% TFA, CH2Cl2 N
NN
HNO
CO Me
BocMe
MeMe N
MeCO2Me
Communesin F
Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.
Mike Yang @ Wipf Group Page 13 of 19 4/26/2010
Retrosynthetic Analysis Retrosynthetic Analysis -- WeinrebWeinreb
N NHO
Me
HMeMe
NHHN
MeMeHO
R ONBOMO
OBoc
NNH
MeN
N
MeR N
NBoc
Me
BOMO N N NO2
CO2EtCO2EtBOMO
N
I
O
BOMO N
NMe
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 -- WeinrebWeinreb
BnN
Bn
EtO[Pd(PPh ) ] DME
NO2
B(OH)2
I
BOMO
1) LiOH, H2O, MeOH, 86%2) SOCl2; iPr2NEt, 87%
BOMO NBn
NBn
EtO
O OTf
O NO2
[Pd(PPh3)4], DME,H2O, Na2CO3
98%
NH2
NH
I
O
NO2
1) ClCO2Et, CH2Cl2, 96%2) NaH, THF, MeI, 92%
CO Et
N
I
O
BOMO N
NO
N NO2
CO2EtCO2Et
NO2Pd(OAc)2, PPh3, DMA, K2CO3, nBu4NBr, 150 °C, 90%
BOMO
N ONMe Me
Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.
Mike Yang @ Wipf Group Page 15 of 19 4/26/2010
1,3 Dipolar Cycloaddition 1,3 Dipolar Cycloaddition -- WeinrebWeinreb
a) 5% Pt/C, H2 (40 atm), PhMeb) Boc2O, K2CO3, THF, H2O, 87% (2 steps)
N NO2
CO2Et
BOMO N NHBocCO2Et
BOMO NEtO2C
BOMOAlH3·Me2NEt, THF74%
NMe
ONMe
ON
NBoc
Me
1M KOH, EtOH
HNBOMO
94 °C
NH NCN
HNO ON
NC
NNBoc
Me
HNBOMO
N
Me
NBoc
HN
NN
NCN3, MeCN93% (2 steps)
NNBoc
Me
HNBOMOOBOM
Me
Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.
Mike Yang @ Wipf Group Page 16 of 19 4/26/2010
Formation of CFormation of C--8 Quaternary Center8 Quaternary Center
HNBOMON
NC
1) 1M KOH, EtOH, 94 °C, 60%2) Boc O LiHMDS THF 95%
NBOMOOBoc
HN O
OBOM
KOtBu,allyl iodideTHF 78 °C
Boc
NNBoc
Me
2) Boc2O, LiHMDS, THF, 95%
NNBoc
Me3:1 mixture of epimers
N
Me
NBoc
THF, −78 C
87%
OBocOOMsO
OMs 1) 1M KOH, EtOH, 80 °C, 94%2) OsO4, NMO, THF, H2O;
NaIOa) Pearlman's catalyst
NNBoc
NBOMOOBoc
NNBoc
HNBOMOO
NNBoc
Me
HNO NaIO43) NaBH4, EtOH4) MsCl, NEt3, CH2Cl2, 0 °C, 83% (3 steps)
H2, THFb) DMP, CH2Cl2 75% (2 steps)
MeMeMe
Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.
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Qin’s IntermediateQin’s IntermediateOMs N3
1) Me2CO, 10% NaOH/H2O,60 °C 93% N3O Me
NNBoc
HNOO
OMs
NNBoc
HNOO
N3NaN3, DMF,90 °C, 61%
60 °C, 93%2) Boc2O, LiHMDS, THF, 81%
NNBoc
NO
N3BocO
NMe
NMe
NMe
PMe3, THF, H2O,70 °C, 88%,
NHHNOBoc
O Me
NHHNO
Me MeBocHO MeLi, THF,
-78 °C, 73%NH
HNO
Me MeBocHO
NNBoc
MeN
NBoc
MeN
N
MeCO2Me
Qin's IntermediateQin s Intermediate
Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.
Mike Yang @ Wipf Group Page 18 of 19 4/26/2010
SummarySummarySummarySummary
Qin Weinreb
C-7 Quaternary Center Cyclopropanation Heck
C 8 Q t C t Cl i t E l t lk l tiC-8 Quaternary Center Claisen rearrangement Enolate alkylation
Overall yield 3% 1%
Steps 23 30
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