Total Synthesis of (+)-Complanadine A Using an Iridium ...ccc.chem.pitt.edu/wipf/Current...
Transcript of Total Synthesis of (+)-Complanadine A Using an Iridium ...ccc.chem.pitt.edu/wipf/Current...
Filip Petronijevic Current Literature Presentation April, 24th 2010.
Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C-H Functionalization
Daniel F. Fischer and Richmond Sarpong J. Amer. Chem. Soc., ASAP
Synthesis of (+)-Complanadine A, an Inducer of Nerutrophic Factor Excretion
Changxia Yuan, Chih-Tsung Chang, Abram Axelrod, and Dionicio Siegel J. Amer. Chem. Soc., ASAP
NH
Me
N
HN
Me
N
HHComplanadine A
2'3
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Lycopodium Alcaloids and Complanadine A
For review see: Hudlicky, T.; and Reed, J.W. In The Way of Synthesis, 1st ed.; Wiley-VCH, 2007; pp 573-602.. Conroy, H. J. Tetrahedron Lett. 1960, 10, 34. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.
NH
Me
O NH
Me
OOH N
H
Me
N
NH
NH
H
Me
H
HN
NH
H
MeH
H
NH
Me
NHN
Me
N
HH
Lycopodine Fawcettimine Lycodine
Phlegmarine
A
BC
D
1
5
7
8
9
1012
14
15
16
NH
Me
N
HN
Me
N
HHComplanadine A
2'3
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How Does Nature Make Complanadine A: Biosynthesis of Lycopodium Alcaloids
H2N H2N CO2HH
H2N NH2
-CO2 diamine oxidase
H2N O N
-CO2X
O O O
Xmalonyl CoA
NH
X
O
O
HN
O-CO2
cadaverineLys (K)
pelletierine
oxidative
dimerizationHN
NHNH
Me
NH
oxidation
NH
Me
N
lycodine
dimerization NH
Me
N
HN
Me
N
HHcomplanadine A
Hudlicky, T.; Reed, J.W. In The Way of Synthesis, 1st ed.; Wiley-VCH, 2007; pp 573-602 and references therein. Conroy, H. J. Tetrahedron Lett. 1960, 10, 34. Stork, G. Pure Appl. Chem. 1968, 17, 383.
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Retrosynthetic Approaches in the Sarpnog and Siegel Groups
NBoc
Me
N
BO
OBocN
Me
N
HH
TfO
+NBoc
Me
N OTf
N Boc
Me
NH O
N
MeHNMe O
+
Sarpong's group
NR'
Me
N
R'N
Me
N
HH
R3Si1 2
6
34
5
+
R'N
Me
HH
NN
R'
Me
N1 2
6 5
R3Si 34
SiR3
Siegel's group
NH
Me
N
HN
Me
N
HHcomplanadine A
3
45
12
6
Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.
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The Key Step in Siegel’s Synthesis: [2+2+2] Cycloaddition
CpCoL2 (L = CO, PR3, olefin)
L
CpCoL
L
CpCo
CoCp
CoCp
CoCp CoCp
"CpCo"
2
1
2
3
4
56
CoCp
CoCp
CoCpN
CR
NCR
CoCp
NR
N
CpCo
R
"CpCo"
NR
2 CN R
or
3
7 89
10
For an excelent review on pyridine synthesis by metal Mediated cyclotrimerization, see: Varela, J.A.; Saá, C. Chem. Rev. 2003, 103, 3787. Funk. R.L.; Volhardt, K.P.C. J. Amer. Chem. Soc. 1980, 102, 5253.
Benzene and Pyridine Synthesis by Cyclotrimerization
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The Key Step in Sarpong’s Synthesis: Suzuki Reaction
LnPd
LnPdX
R2
LnPdOR
R2
LnPdR1
R2
R2-XL
R1-R2
M+OR-
M+X-
BR2
ORR1
BR2
ORRO
+ LBR2R1 M+OR-+
oxidative addition
transmetallation
reductive elimination
Kurti, L.; Czako, B.In Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA, 2005; pp 448-449.
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Näslund, G.; Senning, A.; Lawesson, S.-O. Act. Chem. Scand. 1962, 16, 1324. Koylovich, M.N.; Kukushkin, V.Y.; Haukka, M.; Fransto da Silu, J.J.R.; Pombeiro, A.J.L. Inorg. Chem. 2002, 41, 4798. Liu, K.-M.; Sha, C.-K. Chem. Commun. 2008, 1, 91. Schyster, E.; Jas, G.; Schumann, D. Org. Prep. Proc. Int.. 1992, 24, 670. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.
Sarpong: Precursors Syntheses
O
O OCN
NaOEtEtOH
0 °C to rt
O
O O
CN
p-TsOH 150 °C
53%
OCN
Zn(NO3)2acetone oxime
H2O, 90 °C
O O
NH2
120 °C
vacuum53%
HNMe O
O
Me
O
Me
O
30% H2O2
LiOH, MeOH30 °C94%
(trans/cis 66:34)
PhSH, tAmONaMTBE, reflux
73%(trans/cis 40:60) O
Me
SPh
1. NaBO3, AcOH 40 °C quantitative
2. CaCO3, 80 °C 52% O
Me
1. I2, pyr. DCM, 95%2. AIBN, TBTH acrylonitrile PhH, 70%
O
Me1. (CH2OH)2, H+
2. LiAlH4, Et2O 0 °C, 90%
Me
O
O
H2N
N
Me
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Sarpong: Tricyclic Intermediate Synthesis
HNMe O
70% HClO4dioxane
105 °C, 20 h
O NH2
O
O NH2
O
N
Me
H
H+
NH
MeNH2
OO
NH
MeNH2
OOH
N H
Me
H2NOO
N
Me
NH O
Boc
then Boc2O, Et3N
THF, 60 °C65%
Schyster, E.; Jas, G.; Schumann, D. Org. Prep. Proc. Int.. 1992, 24, 670. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.
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Takagi, J.; Sato, K.; Hartwig, J.F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. Ishiyama, T.; Miyaura, N. Pure Appl. Chem. 2006, 78, 1369. Cho, J.-Y.; Tse, M.K.; Holmes, D.; Maleczka, R.E.; Smith III, M.R. Science 2002, 295, 305. Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N.R.; Hartwig, J.F. J. Amer. Chem. Soc. 2002, 124, 390. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.
Sarpong’s Synthesis: Complanadine A Formation
NN
tBu
tBu
dtBu-dipy
B BO
O O
O
[B(pin)]2
IrN
N
tBu
tBu BpinBpin
COE
Bpin
N
Me
NH O
Boc
Pb(OAc)4CHCl3, rt
84% NBoc
MeHN O
Tf2O, pyridine -78 °C to rt
72%
NBoc
Me
N
cat. [Ir(COD)(OMe)]2 dtBu-dipy[B(pin)]2
THF, 80 °C 75%
NBoc
Me
N
BO
O
NBoc
Me
N OTf
cat. Pd(OAc)2 dppf, HCO2NH4
Et3N, 60 °C
90%
BocN
Me
N
HH
TfO
NBoc
Me
N
BO
O
BocN
Me
N
HH
TfO
+1. PdCl2(dppf), K3PO42. 6N HCl, 70 °C
42% (over 2 steps)
NH
Me
N
HN
Me
N
HHComplanadine A
2'3
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Siegel’s Synthesis: Starting Material Preparation
OSPh
1. NaH, I(CH2)3OAc DMF, 23 °C, 63%
2. m-CPBA, CH2Cl2 -78 to 23 °C, 77%
O OAc 1. a) TMSCH2CN, n-BuLi b) ethyl salicilate, Et2O -78 °C
2. CsF, CH3CN, 23 °C 45% (over 2 steps)
O OAc
CN
1. HCCMgCl, THF 23 °C, 97%
2. Ac2O, Mg(ClO4)2 23 °C, 97%3. PhCH2NH2, CuCl THF, 66 °C, 92%
OAc
CN
HNPh 1. K2CO3, MeOH
23 °C, 99%
2. PPh3, imidazole CCl4, 77 °C, 75%
HNClCN
HBnMe
NCN
Me
H
Bn NBn
CN
MeH
Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP
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Siegel’s Synthesis: Cyclotrimerization and Regioselectivity Problem
NBn
CN
MeH TMS
TMS
+CpCo(CO)2
THF, 140 °C82%
NBn
Me
N
H
TMS TMS
NBn
Me
N
H
H
TMS
+
25:1
NBn
Me
N
H
TMS TMS
1. TBAF, THF 66 °C, 85%
2. LiHMDS, TMSCl THF, 23 °C, 90%
CpCo(CO)2
THF, 140 °C82%
NBn
Me
N
H
TMS
NBn
Me
N
H
BnN
Me
N
HH
TMS
Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP
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Siegel’s Synthesis: End Game
NBn
Me
N
H
TMS
NCHO
CN
MeH
CpCo(CO)2dioxane, 140 °C
NBn
Me
N
H
CHON
Me
N
HH
TMS
NBn
Me
N
H
TMS
OHCN
Me
NH
H
A
B
A : B = 3.3 : 1 (47% yield)with 8 equiv. PPh3 A : B = 1 : 3 (56% yield)
NBn
Me
N
H
TMS
OHCN
Me
NH
H
1. TBAF, dioxane 101 °C, 99%
2. Pd/C, H2, 23 °C MeOH, 78%3. HCl, MeOH 50 °C, 90%
NH
Me
N
H
HN
Me
NH
H
Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP
Changing the regioselectivity:
“The use of formyl in place of the benzyl group was required as “coupling partners” failed to react” “The ability of PPh3 to change the regioselectivity warrants furhter study”
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CoCp
N
TMS
TMS TMS
TMS
+
N
N
TMS
TMS+
CoCp
TMS
N
TMS
TMS
TMS
~ 0.5 hartree
~ 0.4 hartree
LUMO
CoCp
TMS
N
TMS
biggest lobeof diyne's LUMO
ß to the metal
route 1
route 2
prefered
CoCp
H3Si
H3Si
N
CoCp
H3Si
N
H3Si
Ab initio energies: -789.740069812 -789.746989353prefered
Siegel’s Synthesis: Cyclotrimerization Regioselectivity Explanation
Varela, J.A.; Castedo, L.; Saá, C. J. Amer. Chem. Soc. 1998, 120, 12147. Stockis, A.; Hoffmann, R. j. Amer. Chem. Soc. 1980, 102, 2952.
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Conclusions
• Both syntheses are based on the “symmetry” of Complanadine A: Nature mimicking approaches
• Sarpong’s key step: Hartwig-Miyaura Ir(I)-catalyzed borylation and Suzuki -Miyaura coupling
• Siegel’s key step: Co(I)-catalyzed [2+2+2] cycloaddition – cyclotrimerization
NBoc
Me
N
BO
OBocN
Me
N
HH
TfO
+
R'N
Me
HH
NNR'
Me
N
R3Si
SiR3
• Biological studies in progress: The influence of the compound on primary cultures of rat glial cells and examining the effects on the biosynthesis of neurotrophin mRNA
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