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Angewandte Chemie International Edition. 2012, 51(28), 6870-6873DOI: 10.1002/anie.201200959
Bioinspired Total Synthesis of Agelastatin A
Jeremy Chris P. Reyes and Daniel Romo
Benjamin R. EyerWipf Group-Current Literature
August 25, 2012Benjamin Eyer @ Wipf Group Page 1 of 13 8/31/2012
Agelastatins: Isolation and Bioactivity • Tetracyclic pyrrole-2-aminoimidazole
alkaloids (PAIs) isolated from axinellid sponges
• 1993: Agelastatin A and B isolated from Agelas dendromorpha
• 1998: Agelastatin C and D isolated from Cymbastela sp.
• 2010: Agelastatin E and F isolated from Agelas dendromorpha
• Agelastatin A– Most bioactive of PAIs– Highly cytotoxic to human-cancer cell lines
(IC50 ’s 97-103 nm)– Potent inhibitor of osteopontin-mediated
neoplastic transformation and metastasis– Potentially antiangiogenic, antidiabetic, and
insecticidal
The molecular structures of all the agelastatin alkaloids and biogenetically related naturally occurring simpler pyrrole imidazole alkaloids
Nat. Prod. Rep. 2011, 28, 1229–1260.J. Chem. Soc. Chem. Commun. 1993, 1305–1306.J. Nat. Prod. 2010, 73, 720–723.Oncol. Res. 2005, 15, 11–20.Mol. Cancer Ther. 2008, 7, 548–558. Chem. Biol. 2000, 7, 51–63.
Benjamin Eyer @ Wipf Group Page 2 of 13 8/31/2012
Previous synthetic work on Agelastatin A• 12 total syntheses to date• C-ring has all 4 stereogenic centers
in Agelastatin A– Synthetic challenge– Previous syntheses focused on the
cyclopentane then late stage B and D ring construction
N
NH
BrNR
N
O
H
HO O
A B
CD
All syntheses
Trost
MovassaghiMaruoka
FeldmanTrostWardropTanaka
DuBoisHale
WeinrebFeldmanHaleDavisIchikawaWardropChida
Maruoka
Weinreb- JOC 1998, 63,7594 and JACS 1999, 121, 9574. (1st synthesis)Feldman- JACS 2002, 124, 9060 and JOC 2002, 67, 7096. (1st asymmetric synthesis)Hale- OL 2003, 5, 2927 and OL 2004, 6, 2615.Davis- OL 2005, 7, 621 and Syn. Comm. 2009, 39, 1914. (Wipf Group Current Lit. Feb. 2005)Trost- JACS 2006, 128, 6054 and Chem. Eur. J. 2009, 15, 6910.Ichikawa- OL 2007, 9, 2989.Wardrop- OL 2009, 11, 1341.Chida- OL 2009, 11, 2687.Tanaka- OL 2008, 10, 5457 and OL 2009, 11, 3402.DuBois- ACIE 2009, 48, 3802. (Wipf Group Current Lit. May 2009)Movassaghi- Chem. Sci. 2010, 1, 561. (Wipf Group Current Lit. Aug. 2010)Maruoka- JACS 2012, 134, 7516.
Benjamin Eyer @ Wipf Group Page 3 of 13 8/31/2012
Proposed biogenetic synthesis of Oroidin-based pyrrole-imidazole alkaloids
ACIE. 2012, 51(28), 6870-6873.Eur. J. Org. Chem. 2001, 237–243.
Benjamin Eyer @ Wipf Group Page 4 of 13 8/31/2012
Movassaghi’s biosynthetic approach: B-ring then C-ring
N
O
OMeO
OMe
Br N
O
OMeO
OMe
Br
H2NO
N
Br
NH
O
OMeO
O
N
Br
NH
O
OMeOMe
O
N
Br
NH
OMe
O
NHN
O
NNH
Br NH
N
O
H
MeO O
3 steps
NNH
Br NH
N
O
H
HO O
2 : 1
ClSO2NCO,MeCN;Na(Hg), NaH2PO4
82%
NaBH4, MeOH;TsOH, H2O
90%, 99% ee
>10 g scale
MeSO3H, H2O,100oC; MeOH
71%
MeSO3H, H2O,100oC; MeOH
66%
>1 g scale
Chem. Sci. 2010, 1, 561–566.Benjamin Eyer @ Wipf Group Page 5 of 13 8/31/2012
Title Paper’s bioinspired approach: C-ring then B-ring
N
O
NHBr
NNR
O
H N
O
NHBr
NNR
O
H
or
NH
O
NHBr NR
N
H
O
NNH
Br NR
N
O
H
HO O
A B
C D
C-ringthen
B-ringformation
hydration NH
O
NHBr
NNR
O
OEt
Proposed bioinspiredcascade cyclizations
HN
O
HN OMeBrN NR
O
EtO
OEtAgelastatin A
NH
O
NH
NN
NH2
NHNH
Br N
HN
O
H
O NH2
Br
RR= HN
NH2N
NH
O
HN Br
Br
Br
nagelamide J keramadine
Tetrahedron Lett. 2000, 41, 9917–9922. Org. Lett. 2007, 9, 2369–2371. ACIE. 2012, 51(28), 6870-6873
Benjamin Eyer @ Wipf Group Page 6 of 13 8/31/2012
Synthesis of the Coupling Partners
OHHO2C
OHHO2C
OMeHN
NH2
N NH
O
HO2C
H2SO480oC54%
N NTse
O
OHC
1. K2CO3, MeI, then K2CO3TseOMs, DMF, 60oC
2. DIBAL-H, DCM, -78oC3. MnO2, DCM, 23oC
85%, 3 steps
NaOMe, MeOH/CH2Cl2
-40oC to 23oC56%
PO
N2
OMeO
MeO
ZnI2, CH(OEt)3110oC84%
N NTse
O
N NTse
O
EtO
OEt
HN
O
CCl3HN
O
HN OMe HN
O
HN OMeBrNH2OMe HClNEt3, 80oC
98%
NBSTHF/MeOH
95%
ACIE. 2012, 51(28), 6870-6873Benjamin Eyer @ Wipf Group Page 7 of 13 8/31/2012
Coupling of imidazolone alkynyl acetal and pyrrole amide
ACIE. 2012, 51(28), 6870-6873Benjamin Eyer @ Wipf Group Page 8 of 13 8/31/2012
Biomimetic C-Ring Closure
Addition of a variety of Lewis and Brønstedacids resulted in deer-red colored solution
Single diastereomer
ACIE. 2012, 51(28), 6870-6873Benjamin Eyer @ Wipf Group Page 9 of 13 8/31/2012
Probing the Reaction Mechanism
Experimental vsTD-DFT predicted absorption bands
ACIE. 2012, 51(28), 6870-6873Benjamin Eyer @ Wipf Group Page 10 of 13 8/31/2012
Completion of Synthesis: Closing the B-Ring
• Tse group removed to allow greater confirmational mobility• 4,5-bis-epi-agelastatin formed by retro-Nazarov reaction (retro-5-exo-trig)
then recyclization• Absence of the Tse group, the C5 unprotected alcohol and the C13 bromine
in the pyrrole ring essential to cyclization
ACIE. 2012, 51(28), 6870-6873Benjamin Eyer @ Wipf Group Page 11 of 13 8/31/2012
Enantioselective Nazarov-type Cyclization
• Preliminary Studies with (R)-TRIP hydrogen phosphate show promise for an enantioselective route and further studies are currently underway
ACIE. 2012, 51(28), 6870-6873Benjamin Eyer @ Wipf Group Page 12 of 13 8/31/2012
Summary• Concise total synthesis of agelastatin A that complements Movassaghi’s
approach to the agelastatins (B-ring then C-ring)
• Completion of the total synthesis by two sequential, potentially biomimetic cyclizations (C-ring then B-ring)– C-ring: sets three contiguous centers diastereoselectively– B-ring: unique solvent-free conditions on silica gel with mild heating
• Proposal for the biosynthesis of the agelastatins through a reaction sequence leading from an oxidized keramadine analogue via a nagelamide J like intermediate to agelastatin A– The assembly of C followed by B rings provides evidence for the
proposed reactivity of a linear alkenyl imidazolone pyrrole
NNH
Br NR
N
O
H
HO O
A B
C D
agelastatin A
NH
O
NH
NN
NH2
NHNH
Br N
HN
O
H
O NH2
Br
R
R= HNN
H2NNH
O
HN Br
Br
Br
nagelamide J keramadine
NNH
Br NH
N
O
NH2
cyclooroidin
Br
Benjamin Eyer @ Wipf Group Page 13 of 13 8/31/2012
