synthesis of ( )-actinophyllic acid and analogsstarting with readily available, known compounds. the...
TRANSCRIPT
Synthesis of (±)-Actinophyllic Acid and Analogs: Applications of Cascade Reactions and Diverted Total Synthesis
Reporter: Bo SongCChecker: Wen-Xue HuangDate: 2013/11/26
Martin, S. F. et al.J. Am. Chem. Soc. 2013, 135, 12984. University of Texas at Austin
C t tContents
Introduction of (±)-Actinophyllic Acid
Martin’s Method for Synthesis of (±)-Actinophyllic Acid
Overman’s Method for Synthesis of (±)-Actinophyllic Acid
Summary of the Two Methods
Introduction
Characters:Six rings, indole alkaloid; Five contiguous stereocenters;Five contiguous stereocenters;1-azabicyclo[4.4.2]dodecane and 1-azabicyclo[4.2.1]nonane.
Martin’s Method
Proposed Retrosynthesis
NOH
N
OSemiketalization
N
O
RO2C 2
19ClH
O
NH
O
CO2HNH
(±)-Actinophyllic Acid (1) 2
NH
3
Alkylation
OBnOBn
OBnOBn
NRO2C OSiR3
NH
O
Cascade reaction
Carbocation/ -nucleophile
NH
OAc
N
16+
OBnOBn
OBn
Martin S F et al J Am Chem Soc 2013 135 12984
3 4CO2R5
OBn
Martin, S. F. et al. J. Am. Chem. Soc. 2013, 135, 12984.
Synthesis of β-Heteroaryl Propionates
OH R3R2
+OMe
OTMS
N
R1
TMSOTf
THF, -40 oC N
R1
CO2Me
R2
R3
CO2MeCO2MeCO2Me
R1
93%
N
Me
N
Me95%92%
N
Me
CO2MeCO2Me
Martin S F et al Tetrahedron Lett 2009 50 3253
NH
78%
NH
76%
Martin, S. F. et al. Tetrahedron Lett. 2009, 50, 3253.
Synthesis of β-Heteroaryl Propionates
Martin, S. F. et al. Tetrahedron Lett. 2009, 50, 3253.
Synthesis of β-Heteroaryl Propionates
OMe
TMSO TMSO CO2MeO
O
H
O+
N
O
N
OMeO2C
THF, -78 oC
TMSOTf
OH
N
Me
MeN
Me
Martin, S. F. et al. Org. Lett. 2012, 14, 3834.
TBDPSOO
O O
OTMS
CH Cl 78 oC
BrOO
OO
O
H
MeO2C+TMSOTf
N
BrCH2Cl2, -78 oC
N
Me
OH
OTBDPSN
Me
O
N
MeMartin, S. F. et al. Tetrahedron 2013, 69, 5588.
Synthesis of Key Intermediate 12
Martin, S. F. et al. J. Am. Chem. Soc. 2013, 135, 12984.
Synthesis of Key Intermediate 12
AllocOTIPS
TMSOTf, 2,6-(t-Bu)2Pyr
then TBAF92% N
N
O
Alloc
NH N
OTIPS
+OAc
Lewis acid
NH
12
NBnO OBn
Alloc8 11
OBnOBn
Lewis acid
NAllocOTIPS
Cascade reaction
Carbocation/ -nucleophile+
NH
N
OTIPSNH
BnO OBn N
All OBnHAllocOBn
OBn
Martin, S. F. et al. J. Am. Chem. Soc. 2013, 135, 12984.
Completion of the Synthesis
NAlloc HNN
Alloc
NH
O Boc2O, DMAP Pd2(dba)3, dppb
N
O
BOBn OBn
83%N
O
OBn
NDMBA92%
12 14
BocOBn OBnBoc OBn13
ClCH2CHO,N N
O O
NCl
NHNCl
NaBH(OAc)3O
NDMBA
N
O
BOBn
t-BuONa, t-BuOH
N
O
Boc OBnOBn
aq. HCl, MeOH
then H2, Pd/C86%
NH
O
OH
OH
83% (2 steps)
Boc OBnBoc OBn17
OH
1516
Martin, S. F. et al. J. Am. Chem. Soc. 2013, 135, 12984.
Completion of the Synthesis
ClHNCl
N
HN
O
OH
NH
HN
O
OH
CO2H
1) IBX, DMSO
2) N-hydroxysuccinimide3) aq. NaOH
31%NH OH
H CO2H
117
Martin, S. F. et al. J. Am. Chem. Soc. 2013, 135, 12984.
Overman’s method
Retrosynthesis Analysis
Overman, L. E. et al. J. Am. Chem. Soc. 2008, 130, 7568.
Synthesis of Tetracyclic Ketone 11
OH
CO2t-Bu
CO2t-Bu
Mg(OMe)2, 6O
NO2
CO2t-Bu
CO2t-Bu5 7
Pd(OH)2/C, H2
69% NH
CO2t-Bu
CO2t-Bu
8
78%
5 7 8
85%
COCl
NO2 NBoc
O
Br
O
6Boc
9
LDA (3 2 i )BocO
N
NBocO
CO2t-Bu
CO2t-Bu
LDA (3.2 equiv.)[Fe(DMF)3Cl2][FeCl4] (3.5 equiv.)
60% - 63%(up to 10 g scale)
NH
N
Boc
CO2t-BuCO2t-Bu
Intramolecular HCO2t Bu
10
H CO2t-Bu
11
IntramolecularOxidative Coupling
Overman, L. E. et al. J. Am. Chem. Soc. 2008, 130, 7568.
Completion of the Synthesis
Overman, L. E. et al. J. Am. Chem. Soc. 2008, 130, 7568.
Aza-Cope-Mannich Reaction
N
BocHO
TFA N
HOHN
HO
(CH2O)n, CSA
1
2 3
12
3
NH CO2t-Bu
CO2t-Bu
12
NH CO2t-Bu
CO2t-BuNH CO2t-Bu
CO2t-Bu
O
HHO
NH
N
CO2t-BuCO2t-Bu
NHO
Mannich
NH
N
CO2t-BuCO2t-Bu
213
Overman, L. E. et al. J. Am. Chem. Soc. 2008, 130, 7568.
SummaryMartin’s Method:
NRO2C
cascade reaction
carbocation/ -nucleophile
NH
OAc
NH
N
O
OBOBn
OB
Nine steps, 12% overall yieldCascade reaction of N-stablilized carbocations with π- nucleophile
HOBnOBn
OBn
Overman’s Method:Cascade reaction of N stablilized carbocations with π nucleophile
HO N
aza-Cope-Mannich
NH
HN
NH
N
O
RO CCO2R
RO CCO2R
Seven steps, 8% overall yield, the first total synthesisIntramolecular oxidative coupling of ketone and malonate enolates
H H RO2CRO2C
p gAza-Cope-Mannich rearrangement
Actinophyllic acid (1) is an indole alkaloid that was isolated in 2005 by
Carroll and co-workers from the leaves of Alstonia actinophylla. Initially
isolated on the basis of its biological activity as a potent inhibitor of
carboxypeptidase U(CPU), 1 has possible therapeutic indications for the
treatment of thrombotic diseases. We were first attracted to actinophyllic
acid by its unique skeleton, which afforded an opportunity to develop
novel chemistry. When we initiated our work toward 1, we were aware of
no other synthetic efforts in the area. However, since that time Overman
and co-workers have published an elegant approach that culminated in
syntheses of racemic and enantiomerically pure actinophyllic acid.
F h h f W d T i hi d M ld d hFurthermore the groups of Wood, Taniguchi, and Maldonado have
revealed alternate entries to this novel alkaloid.
A concise synthesis of (±)-actinophyllic acid (1) was achieved by a route thaty ( ) p y ( ) y
required only 10 chemical operations and the isolation of nine intermediates
starting with readily available, known compounds. The synthesis features a
novel cascade of reactions of N-stabilized carbocations with π-nucleophiles to
create the tetracyclic core of actinophyllic acid in a single operation. Notably,
some synthetic intermediates were diverted by refunctionalization and
derivatization to furnish novel compounds that induce death in several cancer
cell lines, whereas actinophyllic acid itself is inactive. Further optimization of
the potency of these small molecules and mode-of-action studies are a focus of
current efforts. The discovery of actinophyllic acid analogs that exhibit
potentially promising anticancer activity validates the importance of developing
alternative entries to complex natural products as a critical strategy for
identifying compounds that would not otherwise be accessible for biological
screening and evaluation.