F I C S SF I C S SF I C S SF I C S SF I C S S F I C S SF I ...
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J ... · 3/5/2010 · I. B. Seiple, S. Su, I. S....
Transcript of I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J ... · 3/5/2010 · I. B. Seiple, S. Su, I. S....
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.
Hong Ren @ The Wulff Group 03-05-10
Synthesized naturally by Stylotella agminata
Cytotoxic and immunosuppressive
In 1993, first isolated by P. J. Scheur and co-workers
In 2007, structure revision proposed by M. Kock
26 Ph. D theses and 31 publications
In 2009, first total synthesis accomplished by P. Baran
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
OHNHN
NH2
ClH2N N
N
O
NNH
NH2
H
H
palau'amine
Synthesized naturally by Stylotella agminata
Cytotoxic and immunosuppressive
In 1993, first isolated by P. J. Scheur and co-workers
In 2007, structure revision proposed by M. Kock
26 Ph. D theses and 31 publications
In 2009, first total synthesis accomplished by P. Baran
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
OHNHN
NH2
ClH2N N
N
O
NNH
NH2
H
H
palau'amine
OHNHHN
NH2
ClH2N N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
Nine nitrogens
OHNHHN
NH2
ClH2N
N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
Nine nitrogens
Eight contiguous stereogenic centers
OHNHHN
NH2
ClH2N N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
Nine nitrogens
Eight contiguous stereogenic centers
Reactive (hemi)aminal moieties
OHNHHN
NH2
ClH2N N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
Nine nitrogens
Eight contiguous stereogenic centers
Reactive (hemi)aminal moieties
Highly polar bis-guanidines
OHNHHN
NH2
ClH2N
N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
Nine nitrogens
Eight contiguous stereogenic centers
Reactive (hemi)aminal moieties
Highly polar bis-guanidines
Oxidation-prone pyrroles
OHNHHN
NH2
ClH2N N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
Nine nitrogens
Eight contiguous stereogenic centers
Reactive (hemi)aminal moieties
Highly polar bis-guanidines
Oxidation-prone pyrroles
Strained trans – fused 5,5’- azabicyclic ring
Nine nitrogens
Eight contiguous stereogenic centers
Reactive (hemi)aminal moieties
Highly polar bis-guanidines
Oxidation-prone pyrroles
Strained trans – fused 5,5’- azabicyclic ring
Unprecedented hexacyclic core
OHNHHN
NH2
ClH2N
N
N
O
HNNH
NH2
H
H
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
OHNHHN
NH2
ClH2N N
N
O
HNNH
NH2
H
H
palau'amine
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.
1
2
2’
NH
HN
N
NH2
OH
ClH2N
1
6
14
11
20
17
NH
N
HN
O
NH2
H
10
transannularclosure
NH
HN
N
NH
OH
ClH2N
1
6
14
11
20
17
NH
N
HN
O
NH210
H
amidine tautomer
macro-palau'amine
tautomerization
3 4
amide
formation
NH
HN
N
NH
OH
ClN3
1
6
11
20
17
NH
N
HO
O
NH2
10H
N3
NH
HN
NH
OH
ClN3
6
11
20
17
NH
NNH2
10H
N3
SNAr
Br
N
NH
HN
NH
HN
NO
NH2
H
NH2
OH
ClH2N
HH
1
6
1014
11
20
17
Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580. Gosselin, P.; Bourdy, C.; Mille, S.; Perrotin, A. J. Org .Chem. 1999, 64, 9557-9565.
Me
Me
OTIPS
CO2MeMeO2C
Me
Me
CO2Me
CO2Me
OTIPS
1. LAH
2. MsCl
3. NaN3
4. TBAF
Me
Me
OH
N3
N3
64%
5 6 7
EtO OEt+ O
BF3•OEt20 °C then RT
OEt OEt
OEt
HCOOH/
HCOONa
H2O, 100 °C
CHO TIPSOTf
NEt3, 0 °C
Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.
1. PMBCl
2. O3
85%
O Me
Me
O
PMBO
N3
N3
1. TMSOTf
iPr2NEt
then NBS
2. SiO2
57%
O
Br
HOBr
PMBO
N3
N3
8 9
10 11
1. LiCl
2. TFA
78%
O
Cl
HO Br
HO
N3
N3
1. SO2Cl22,6-lutidine
38-43%
O
ClCl
N3
N3
Br
Me
Me
OH
N3
N3
7
Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.
NaBH4
CeCl3
OH
ClCl
N3
N3
Br
NH2
BocHN NBoc
DBU
OH
ClCl
N3
N3
N
NHBocBocHN
55%
O
ClCl
N3
N3
Br
11 12 13
IBX
70%, dr = 1.3:1
O
ClCl
N3
N3
BocNN
BocHN
72%
O
N(CHO)2Cl
N3
N3
BocNN
BocHN
NaN(CHO)2
14 15 I
O
O
O OH
IBX
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.
15 16
NH
HN
NH2ClN3
11
20
17
N3
H3N
O
O
N(CHO)2Cl
N3
N3
BocNN
BocHN
50% aq. TFA
then aq 10% TFA
N
OO
Ag
O
N
O
NH
HN
NH2
OH
ClN3
11
20
17
N3
H3N
O
64%
H2NCNbrine
65%
NH
HN
NH2
OH
ClN3
6
11
20
17
NH
NNH2
10H
N3
17 18
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.
18 4
NH
HN
NH2
OH
ClN3
6
11
20
17
NH
NNH2
10H
N3
TFAA/TFA
then Br2
NH
HN
NH2
OH
ClN3
11
20
17
NH
NNH2
10H
N3
Br
54%
OMe
H2N
tBuO2C
OMe
OMe
6
19 20
OMe
HN
tBuO2C
OMe
OMe
NH
HN
NH2
OH
ClN3
11
20
17
NH
NNH2
10H
N3
then TFA
OMe
HN
tBuO2C
OMe
NH
HN
NH2
OH
ClN3
11
20
17
NH
NNH2
10H
N3
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.
20 3 OMe
HN
tBuO2C
OMe
NH
HN
NH2
OH
ClN3
11
20
17
NH
NNH2
10H
N3
NH
HN
N
NH2
OH
ClN3
1
6
11
20
17
NH
N
HO2C
NH210
HN3
H2, Pd(OAc)2
-2MeOH
-
44%
21 2
NH
HN
N
NH2
OH
ClH2N
1
6
11
20
17
NH
N
HO2C
NH210
HH2N
EDC, HOBtNH
HN
N
NH2
OH
ClH2N
1
6
14
11
20
17
NH
N
HN
O
NH210
H
macro-palau'amine
I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.
OHNHHN
NH2
ClH2N
N
N
O
HNNH
NH2
H
H
palau'amine
17%
2 2’
1
NH
HN
N
NH2
OH
ClH2N
1
6
14
11
20
17
NH
N
HN
O
NH210
H
macro-palau'amine
then TFA
70 °C
NH
HN
N
NH2
OH
ClH2N
1
6
14
11
20
17
NH
N
HN
O
NH210
macro-palau'amine
25 steps, 0.015% overall yield
Multiple cascade reactions
Minimal use of protection groups: PMBCl
Late-stage, chemoselective, silver-mediated oxidation to the hemiaminal unit
NH
HN
NH2ClN3
11
20
17
N3
H3N
O
then aq 10% TFA
N
OO
Ag
O O
NH
HN
NH2
OH
ClN3
11
20
17
N3
H3N
O
64%
The ambiphilic reactivity of 2-aminoimidazole
Across ring stitching
N N
NH2
N N
NH2
H
E Nuc
NH
HN
NH2
OH
ClN3
6
11
20
17
NH
NNH2
10H
N3
TFAA/TFA
then Br2
NH
HN
NH2
OH
ClN3
11
20
17
NH
NNH2
10H
N3
Br
54%
6
NH
HN
N
NH2
OH
ClH2N
1
6
14
11
20
17
NH
N
HN
O
NH210
macro-palau'amine
9