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
NH2
NH2
N NH
OH
H
H2N
N
NH
N
N
Cl
H
palau'amine
O
 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.
NH2
NH2
N NH
OH
H
H2N
N
NH
N
N
Cl
H
palau'amine
O
 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.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
N
Cl
H
O
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
 Eight contiguous stereogenic centers
N
Cl
H
O
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
N
Cl
H
 Eight contiguous stereogenic centers
 Reactive (hemi)aminal moieties
O
palau'amine
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
N
Cl
H
palau'amine
 Eight contiguous stereogenic centers
 Reactive (hemi)aminal moieties
O
 Highly polar bis-guanidines
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
N
Cl
H
palau'amine
 Eight contiguous stereogenic centers
 Reactive (hemi)aminal moieties
O
 Highly polar bis-guanidines
 Oxidation-prone pyrroles
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
N
Cl
H
palau'amine
 Eight contiguous stereogenic centers
 Reactive (hemi)aminal moieties
O
 Highly polar bis-guanidines
 Oxidation-prone pyrroles
 Strained trans – fused 5,5’- azabicyclic ring
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H
H2N
 Nine nitrogens
N
N
Cl
H
palau'amine
 Eight contiguous stereogenic centers
 Reactive (hemi)aminal moieties
O
 Highly polar bis-guanidines
 Oxidation-prone pyrroles
 Strained trans – fused 5,5’- azabicyclic ring
 Unprecedented hexacyclic core
Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
NH2
NH2
HN NH
NH
OH HN
H2N
11
H
14 N
N
H
NH
H OHNH
N
2
HN
20
11
20
N
Cl
17
transannular
closure
HN
17
H
H
NH2
Cl
H2N
NH2
Cl
H2N
10
O
O
10
NH
6
N H
N
1
O
1
amidine tautomer
1
17
11
20
N3
10
6
Br
4
NH
OH
N
NH2
H
NH
SNAr
N3
10
6
HO
N
1
O
3
H2N
HN
20
HN
11
NH
Cl
NH
17
2’
tautomerization
N3
N3
NH2
NH
H
6
HN 14
palau'amine
Cl
NH
OH
N
NH
OH
N
NH2
H
NH
NH
Cl
17
HN
20
amide
formation
11
10
HN 14
6
NH
OH
N
NH2
H
NH
N
1
O
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.
2
EtO
OEt
O
+
MeO2C
Me
Me
BF3•OEt2
0 °C then RT
OEt
OEt
CO2Me Me
Me
OTIPS
5
OEt
CHO TIPSOTf
NEt3, 0 °C
H2O, 100 °C
CO2Me
1. LAH
2. MsCl
Me
CO2Me
3. NaN3
4. TBAF
Me
OTIPS
6
HCOOH/
HCOONa
64%
N3
N3
OH
7
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
N3
1. PMBCl
2. O3
N3
85%
Me
O
N3
O
OH
8
78%
10
HO
Br
9
1. SO2Cl2
2,6-lutidine
O
Cl
HO
Br
N3
N3
HO
PMBO
N3
N3
1. LiCl
2. TFA
O
N3
Me 2. SiO2
57%
PMBO
7
N3
1. TMSOTf
iPr NEt
2
then NBS
Br
O
N3
38-43%
Cl
Cl
Br
11
Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.
N3
N3
N3
O
N3
NaBH4
Cl
Cl
NH2
OH
N3
CeCl3
BocHN
Cl
Cl
NBoc
DBU
55%
N
BocHN
12
11
IBX
70%, dr = 1.3:1
N3
O
N3
Cl
BocN
O
BocHN
O
OH
14
NHBoc
13
N3
O
Cl
Cl
Br
Br
I
OH
N3
NaN(CHO)2
Cl
N
72%
O
N3
N(CHO)2
Cl
BocN
N
BocHN
15
IBX
Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.
N3
11
O
N
N3
H3N
15
16
N3
then aq 10% TFA
NH2
Cl
HN
17
20
11
O
Ag
O
N
O
NH
20
N(CHO)2
BocHN
N
HN
17
50% aq. TFA
Cl
BocN
NH2
Cl
N3
O
N3
O
N3
H3N
17
NH
OH
O
H2NCN
brine
N3
NH2
Cl
HN
17
20
11
65%
N3
10
6
NH
OH
N
NH2
H
NH
18
64%
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.
OMe
N3
NH2
Cl
N3
HN
17
20
11
N3
10
NH
OH
N
NH2
H
TFAA/TFA
20
N3
18
10
4
N3
17
20
10
NH
OH
N
NH2
H
NH
6
OMe
HN
tBuO2C
NH
OH
N
NH2
H
OMe
NH
N3
HN
11
N3
Br
NH2
Cl
OMe
HN
11
then Br2
54%
NH
6
17
H2N
NH2
Cl
NH2
Cl
17
HN
20
11
then TFA
N3
10
NH
OH
N
NH2
H
NH
OMe
HN
OMe
tBuO2C
19
OMe
tBuO2C
OMe
20
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.
N3
NH2
Cl
17
HN
20
11
N3
N3
10
NH
OH
N
NH2
H
NH
20
11
N3
OMe
10
44%
H2, Pd(OAc)2
N
HO2C
1
3
20
NH2
Cl
17
HN
20
11
H2N
10
6
HO2C
21
NH
OH
N
NH2
H
NH
6
-
OMe
H2N
HN
17
-2MeOH
HN
tBuO2C
NH2
Cl
N
1
H2N
17
NH
EDC, HOBt
OH
N
NH2
H
NH
NH2
Cl
HN
20
11
10
HN 14
6
NH
OH
N
NH2
H
NH
N
1
O
macro-palau'amine
2
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.
H2N
NH2
Cl
17
HN
20
11
10
6
HN 14
NH
OH
N
NH2
H
NH2
Cl
H2N
17
HN
20
11
then TFA
10
NH
70 °C
HN 14
N
6
NH
OH
N
NH2
NH
N
1
1
O
macro-palau'amine
O
macro-palau'amine
2’
2
NH2
NH2
HN NH
NH
OH HN
H
17%
H2N
N
N
Cl
H
O
palau'amine
1
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.
 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
N3
NH2
Cl
N3
HN
17
20
11
then aq 10% TFA
NH
HN
17
20
11
O
N3
NH2
Cl
N
H3N
O
Ag
O
O
64%
O
N3
H3N
NH
OH
O
 The ambiphilic reactivity of 2-aminoimidazole
NH2
NH2
H
N
N
N
E
N
Nuc
H2N
N3
NH2
Cl
17
HN
20
11
N3
10
6
NH
OH
N
NH2
H
N3
TFAA/TFA
then Br2
54%
NH
NH2
Cl
17
10
Br
9
HN
20
11
20
 Across ring stitching
17
HN
11
N3
NH2
Cl
6
NH
OH
N
NH2
H
NH
10
HN 14
6
NH
OH
N
NH
N
1
O
macro-palau'amine
NH2