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Scalable Total Syntheses of N-Linked Tryptamine Dimers byDirect Indole-Aniline Coupling:
Psychotrimine and Kapakahines B and F
Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S.J. Am. Chem. Soc., 2010,132, 7119–7137
John MaciejewskiWipf Group - Current Literature
22 May 2010
N N O
N H
O Ph
NH
O
HNO
HN
OHH2N
kapakahine F
N N O
N H
O Ph
NH
O
HNO
HN
OHHN
kapakahine B
O
NH2
Ph
NH
N
N
N H
NH
NH
psychotrimine
NH
NH
I
X
tryptamine
NH2
electrophilic nitrogen source
methodology development
innovative application
John Maciejewski @ Wipf Group Page 1 of 18 7/10/2010
Isolation of Targets
Takayama, H. Org. Lett. 2004, 6, 2945Scheuer, P. J. J. Am. Chem. Soc., 1995, 117, 8271Scheuer, P. J. Org. Lett. 2003, 5 1387Synthesis of kapakahine B and F, see Baran, P. J. Am. Chem. Soc., 2009, 131, 6360Synthesis of psychotrimine, see Baran, P. J. Am. Chem. Soc., 2009, 130, 10886
N N O
N H
O Ph
NH
O
HNO
HN
OHH2N
kapakahine F
N N O
N H
O Ph
NH
O
HNO
HN
OHHN
kapakahine B
O
NH2
Ph
NH
N
N
N H
NH
NH
psychotrimine
PsychotrimineIsolated from leaves of Psychotria rostrata in 2004 (Takayama)Shown to possess activity against colon and lung cancers
KapakahinesKapakahine B: 0.3 mg isolated from sponge Cribrochalina olemda in 1995 (Scheuer)Kapakahine F: 0.8 mg isolated from C. olemda in 2003 (Scheuer)Exhibit promising anti-leukemia activity
John Maciejewski @ Wipf Group Page 2 of 18 7/10/2010
Bond Connectivity in Indole-based Natural Products
N N O
N H
O Ph
NH
O
HNO
HN
OHH2N
kapakahine F
N N O
N H
O Ph
NH
O
HNO
HN
OHHN
kapakahine B
O
NH2
Ph
NH
N
N
N H
NH
NH
psychotrimine
NH
N
OH
MeO2C
H
N
MeO
N
OAcHO
H CO2Me
vinblastine
NH
NH
HN
N
H
chimonanthine
NH
N
NH
H
NH
NH
HN
O
O
OO
Ph
Ph
asperazine
C-C linkages N-C linkages
John Maciejewski @ Wipf Group Page 3 of 18 7/10/2010
Proposed Biosynthetic Routes to the N1-C3 Bond
For [1,5] rearrangement, see: J. Am. Chem. Soc., 2006, 128, 14028
N
NH
NHR
NH
NH
N H
NHR
"
NHR
"
radical or cationic-based oxidative dimerization
NH N
H
NH
N Hoxidative
dimerization
NH
N
[1,5]
N
N
NHR
HO2C
NH2HO2C
NH2
CO2H
NH2HO2C
NH2
CO2H
HO2C
CO2H
NH2
tautomerization
oxidative dimerization of tryptophan
As applied by Baran and Shenvi in the total synthesis of chartelline C
John Maciejewski @ Wipf Group Page 4 of 18 7/10/2010
Direct Oxidative Dimerization
Extensive screening of oxidants did not affordthe desired N1-C3 linkage
Koser’s reagent afforded trace amounts ofthe desired dimer
Attempts at oxidative coupling of 35 to arrive at36 were not fruitful
John Maciejewski @ Wipf Group Page 5 of 18 7/10/2010
Screening for the Indole Cation Equivalent
NH
NH
HN
H
I
CO2H
NH
NHBoc
CO2Me
NH2
I
conditions
MeCN:MeOH (20:1), NIS (1.5 equiv.), -45 oC 79%, >20:1 dr
Instead of employing tryptamine dimerization, o-iodoaniline was screened as the nitrogen donorNIS was the optimal reagent for conversion, isolated yield, diastereoselectivity, and scalabilityLow temperature and the absence of any amine base were critical
John Maciejewski @ Wipf Group Page 6 of 18 7/10/2010
Mechanistic Considerations
Figure 7
John Maciejewski @ Wipf Group Page 7 of 18 7/10/2010
Rationalization of Diastereoselectivity
Order of addition, as well as the oxidant used effect the diastereoselectivity of the reactionSuggests the halogen may be involved in the stereochemistry-determining step or effect the reaction rate
John Maciejewski @ Wipf Group Page 8 of 18 7/10/2010
Rationalization of exo Diastereoselectivity
Danishefsky, S. J. J. Am. Chem. Soc., 1999, 121, 11953Crich, J J. Org. Chem. 1999, 64, 7218
John Maciejewski @ Wipf Group Page 9 of 18 7/10/2010
Probing the Nature of the Electrophilic Aniline
Figure A: aniline addition may occur through addition at C2 followed by migrationFigure B: phenylnitrenium and iodide pair react reversibly with tryptamine; explains high diastereoselectivity as well as the dependence on the NXS oxidant (X=Cl, Br, or I)
John Maciejewski @ Wipf Group Page 10 of 18 7/10/2010
Comparing the Influence of Substituted Anilines
NH
R2
NHR3R1
NH2
R4
NIS
MeCN/MeOH
20:1NH
N
NHH
R4
R2
H
R3
R1
NH
N
NH H
CO2Me
Br
68%
NH
N
NHH
CO2Me
O2N
74%
NH
N
NH H
CO2Me
I
N
MeO2CN
24%
NH
N
NH H
CO2Me
F
43%
Cl
I
NH
N
NH H
CO2Me
OMe
0%
NH
N
NH H
CO2Me
I
Br
67%
NH
N
NH H
CO2Me
I
63%
NH
N
NH H
Boc
I
Br
79%
NH
N
NH H
Boc
I
Br
78%
CO2Me
H
NH
CO2Me
BnO
Electron-deficient aniline substrates perform better in reaction than electron-richSupports the presence of an electrophilic phenylnitrenium ion
John Maciejewski @ Wipf Group Page 11 of 18 7/10/2010
Initial Route to Psychotrimine
Buchwald-Goldberg-Ullmann couplingfollowed by indole-aniline oxidativecoupling afforded 98 in lower thanexpected yield
Larock indolization was employed toafford 107
John Maciejewski @ Wipf Group Page 12 of 18 7/10/2010
Gram-scale Preparation of Psychotrimine
Indole-aniline oxidative coupling was performed first to afford 101Larock indole synthesis was used to efficiently prepare 109Buchwald-Goldberg-Ullmann coupling installed the final tryptamine moiety
John Maciejewski @ Wipf Group Page 13 of 18 7/10/2010
Kapakahines B and FOxidative coupling at C3 followedby [1,5] shift to afford 119
Decreased nucleophilicity ofamide relative to carbamate
Pyrroloindoline core accessible
Possibility to equilibrateconstitutional isomers
Indole-aniline oxidative couplingaffords pyrroloindoline core ingood yields
John Maciejewski @ Wipf Group Page 14 of 18 7/10/2010
Kapakahines B and F
Larock indole synthesis affords 123Peptide coupling affords iodide 127Unable to isomerize 124 into the desired carboline scaffold
John Maciejewski @ Wipf Group Page 15 of 18 7/10/2010
Kapakahines B and F
Removal of both the Cbz and benzyl groups allow equilibrium between 136 and 138
John Maciejewski @ Wipf Group Page 16 of 18 7/10/2010
Kapakahines B and F
John Maciejewski @ Wipf Group Page 17 of 18 7/10/2010
Conclusions
Biological data on synthetic natural products:Kapakahines B and F did not possess significant cytotoxicity in the NCI 60-cell lineKapakahine B had an IC50 value of 11.7 µM for breast cancer cells (tested by BMS)Psychotrimine showed broad biological activity between 1.3 and 40 µM in the NCI 60-cell line
This methodology not only broadens our understanding of chemical reactivity, but allowsaccess to complex molecules in quantities that would otherwise be unavailable from traditionalisolation practices
N N O
N H
O Ph
NH
O
HNO
HN
OHH2N
kapakahine F
N N O
N H
O Ph
NH
O
HNO
HN
OHHN
kapakahine B
O
NH2
Ph
NH
N
N
N H
NH
NH
psychotrimine
NH
NH
I
X
tryptamine
NH2
electrophilic nitrogen source
methodology development
innovative application
John Maciejewski @ Wipf Group Page 18 of 18 7/10/2010
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