Total Synthesis of the Chartellines
O
Y
N
X
Br
Cl
N
Br
N
N
H
chartelline A, X = Y = Br
chartelline B, X = H, Y = Br
chartelline C, X = Y = H
Mariam Shamszad
November 1, 2006
Background




Chartellines A, B, and C were isolated in the 1980s by
Christophersen and co-workers
Isolated from the marine bryozoan Chartella papyracea collected in
the North Sea
Chartelline A lacks completely lacks any significant biological activity
but remains a target of interest due to its novel and complex
structure
In 2006, the Weinreb group reported their progress toward the total
synthesis of chartelline A and the Baran group reported the first
total synthesis of chartelline C
The Chartellines as Synthetic Targets




Structure and stereochemistry of chartelline A confirmed by Xray crystallography
10-membered ring adopts a rigid tube-like conformation,
indicating little conjugation present between the ring systems
Indolenine system almost perpendicular to the spiro-β-lactam
ring and is close to parallel to the imidazole ring
Dense array of sensitive functionalities: spiro-β-lactam,
indolenine, chloroenamide, and 2-bromoimidazole units
Weinreb’s Retrosynthesis of Chartelline A
O
Br
N
Br
Br
O
Cl
Br
N
Br
N
H
N
chartelline A
O
Br
Br
Br
N
Boc O
Br
P'
N
N
N
Boc O
O
Br
N
Br
Br
Br
Br
CHO
NH
Br
P'
N
MeO
NP
N
Boc
+
OMe
Li
P'
N
O
N
Br
Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71, 3159.
N
O
Model Studies
Br
O
O
N
H
1 ) p- an is id in e
E tO H, H OAc
2) C l CH 2 C OC l
N E t 3, C H 2C l 2
72%
N PM P
O
N
H
O
N
(TM S) 3S iH
A IBN
P hM e
10 0 oC
91%
N P MP
O
N
H
1 ) Cb zC l
N aH , TH F
2) C A N, M eC N
8 3%
Ph
Ph
N
C HO
O
Cb z
Br
N
H
O
NH
N
N
O
Cl
O
N
Br
Br
Cl
O
p- TsOH
Ph Me
1 00 o C
67 %
N
Cbz
NH 2
OMe
p-anisidine
O
Br
More Model Studies
O
O
N P MP
O
N
H
1) (Bo c)2 O
D M AP, N Et 3
C H 2 C l2 , 9 1 %
2 ) TH F
-78 o C , 9 6 %
Li
t -Bu
NO H
Bo c
Bo c H O
TFA , 0 C
C H 2 C l2 , 9 1 %
or
n-B u 4N R e O 4
p -TsOH
C H 2C l 2, rt
1 0 0%
O
N PM P
N
N
O
N P MP
N H PM P
N
O
O
u n d es ire d
N P MP
N
X
X= H
X = Bo c
O
N
Br
o
O
TFA
C H2 C l2
8 5%
N
Br
Br
Cl
L iB H4 , TH F
0 o C , 56 %
N
H
Synthesis of Tribrominated β-lactam Moiety
O
O
Cl
O
O 2N
O
N
H
1 ) p- an is id in e
P h H, !
2 ) C lC H 2 C OC l
NE t 3, P hH
74%
Cl
N PM P
O 2N
O
N
H
(B oc )2 O
D M AP
N Et 3
C H 2 Cl 2
64%
O
1 ) Zn , HOA c
TH F
2 ) (TM S)3 Si H
AIBN , Ph Me
88%
H 2N
N PM P
N
Bo c
B nM e3 N Br 3
Ca C O 3
Me OH
CH 2 C l2
91 %
Br
Br
B oc
B oc
CA N , H 2 O
Me C N , 9 0 %
N PM P
H 2N
O
Br
N
Bo c
O
O
N
N
Br
O
N P MP
O
O
O
Br
N P MP
O 2N
Br
NH
Br
O
Br
N
Bo c
t -Bu ON O
C u Br 2
Me C N
88 %
Preparation of Imidazole Fragment
Tr
H
N
T rC l, Et 3 N
C H 2C l 2, rt
9 6%
N
C O 2E t
N
tB u OK, Me I
1 8 -C -6, TH F
N
-7 8 o C
9 5%
C O 2 Et

Tr
N
N
C O 2E t
More Efficient Route:
H
N
N
CO2Et
BOMCl
NEt3
THF, 0 o C
55%
Tr
1 ) L iA lH 4
THF , 9 9 %
2 ) A c2 O, p yr
D MA P
C H 2 C l2 , 9 7 %
1) tBuOK, MeI
18-C-6, THF
N BOM
-78 oC, 84%
2) BOMCl (cat)
N
THF, !
CO2Et
86%
N
N
B OM
B OMC l
Me C N , !
86%
N
N
O Ac
O Ac
BOM
N
N
CO2Et
H
N
N
+
N
N
BOM
CO2Et
CO2Et
Cl
Completion of Imidazole Fragment
B OM
BOM
Bn Me 3 N Br3
C a C O3
M eO H
C H 2 Cl 2
63%
N
N
C O 2 Et
Br
N
C sF, Pd 2 (d b a)3 , t-B u3 P
di ox a ne , 10 0 oC
80 %
N
C O 2 Et
N
O
N
BO M
NB S, TH F
9 5%
N
O
O
CO 2E t
P(OM e )2
N2
9 6%
Br
N
C O 2 Et
BO M
K2 C O 3, M eO H
0 o C to rt
O
O
N
O
O
Br
N
N
N
1 ) OsO 4 , N MO
H2 O, Me 2 C O
2 ) Me 2 C O, H 2 SO 4
7 3%
C O 2 Et
B OM
O
B OM
S nB u3
DIB AL H
C H 2C l 2
-7 8 oC
9 8%
B OM
N
O
Br
O
O
N
H
Coupling of Fragments
B OM
Br
NH
Br
2 eq . Li H MD S
TH F, - 78 o C
9 1%
N
O
+
Br
O
O
Br
O
O
O
N
Br
Br
N
B OM
Br
N
Br
N
B oc
O
NH
OH
N
B oc
2 eq u iv
O
O
Br
1) TFA. TH F
H 2 O, rt, 99 %
2 ) Pb (OA c)4
Ph H , r t
NH
OH
Br
N
B oc
Br
CHO
B OM
N
Br
N
p -TsO H
Ph M e
rt
CH O
Br
NH
Br
N
B oc O
Br
B OM
N
Br
N
O
Br
Br
Br
NH
N
B oc O
u n d es ire d
BOM
N
Br
N
O
BOM
Br
N
Br
Br
N
Br
N
N
B oc O
d e si re d
O
Br
New Methodology
Br
Br
NH
O
Br
N
BOM
1 0 m o l% C uI
C s2 C O 3 , TH F
70 o C
Cl
N
+
I
N
CO 2M e
BO M
N
Br
M eH N
Cl
Br
N
N
N B OM
O
NHM e
N
BOM
Br
C O 2M e
4 5 % ( 67 % br sm )
Sun, C.; Camp, J. E.; Weinreb, S.M. Org. Lett. 2006, 8, 1779.
N
H
N
O
Br
N
Br
Br
O
Cl
Baran’s Approach to Chartelline Carboskeleton
O
O
N
N
H
H
N
Br
Br
Cl
R
N
N
H
Me
Me
N
O
C O 2 Me
HN
R
N
N
H
N
HN
N
H
ch a rte lli n e C
“…there are no examples for such a ring contraction of a pyrroloindoline unit and ample precedent that
suggests its failure…”
X
R'
NR
N R"
H
R'
not observed
X = OH, Br, Cl, Se, etc.
NR
R"
N
Baran, P.S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed. 2005, 44, 3714.
C O 2 Me
Synthesis of Chartelline Carboskeleton
OTBS
NH2
1 ) KN C S, N H 4C l
to lu e n e, 1 10 o C
OTB S
2 ) H Cl
N H2
3 ) i. H 2O 2, TH F
ii . N a OH /sa t. N a HC O 3
O
4 ) TBS C l, Et 3 N
Me Me
C H2 C l2
M gB r
TH F, -7 8 oC
9 3%
C O 2 Me
OTBS
N
Me Me
84 %
N
H
1 ) N aIO 4 , OsO 4
TH F/H 2 O
2 ) K2 C O 3 , M e OH
Me OC
P( O)(OE T)2
N2
63 %
M eO 2C
OTB S
N
Me Me
N
H
Br
Me O 2 C
TBSO
N
N
B oc
Pd (PP h 3) 4
C u I, 7 1 %
N
Bo c
Me
1 ) Pd /C , H 2
EtOH
NH
2 ) TB AF, TH F
M e 3 ) Mn O 2 , C H2 C l2
98%
CO 2 M e
N
Bo c
N
N
H
CHO
Me
Me
Continued…
O
N
H
1) LiOH, THF/H2 O
2) BOPCl, DIPEA
0 oC
N
Boc
P(O)(OEt)2
H2 N
P(O)(OEt)2
CO2 Me
86%
CO2 Me
CHO
N
N
H
O
HN
DIPEA, LiCl
CH 3CN, 70 o C
75%
N
Boc
Me
Me
O
1) 180 o C
2) NBS, KHCO 3
THF/H 2O
Br
N
N
[1,2]
N
HN
N
H
N
N
H
O
CO2 Me
88%
Me
Me
N
CO2 Me
N
N
H
CO2 Me
Me
Me
19% overall yield
10 steps
Me
Me
Dead End Routes to the Chartelline Skeleton
O
HN
O
CO2 Me
OH NH 2
O
N
N
R N
Me
N
H Me
Ring-closing metathesis
Boc
N
Me
N
H Me
Macrolactamization
O
HN
N
CO2 Me
H N
Me
N
H Me
Heck-type ring closure
Baran’s Total Synthesis of Chartelline C
M eO 2 C
OTB S
N
I
Br
+
N
Bo c
M e Me
N
Bo c
N
N
H
N
H
Pd (PP h3 )4
C uI
DM E:E t 3N
85%
TBS O
CHO
Br
N
B oc
Me
Me
H 2N
C O 2M e
8 9%
N
Bo c
1 ) R an e y N i, Me OH
2 ) TB AF, TH F
3 ) Mn O 2 , CH 2 C l2
4 8 % o ve r 3 ste ps
P( O)(OE t)2
N
H
Br
Me
Me
1) L i OH , TH F/H 2 O
2 ) BOP C l, DIP EA
0 oC
P( O)(OE t)2
N
NH
O
C O 2M e
Br
M eO 2C
N
N
H
C O 2R
CHO
Me
Me
R = TM SE
Baran, P.S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, ASAP.
D IP EA , L i Cl
C H 3C N , 70 o C
56 %
Continued…
O
O
C O 2R
HN
Br
N
B oc
N
N
H
Me
B r2 , N BA
Ph H
36 % , 60 % b as ed o n
re co ve re d di b ro mi de
i nte rm ed i ate
HN
N
Br
Bo c
Me
O
Br
N
N
Br
Br
N
Me
Me
O
H CO R
2
N
K2 C O 3 , 1 8 -C -6
Br
N
Br
N
N
H
1 85 o C, C H 3C N
N BS
Br
N
H
Br
C O 2R
Me
Me
Br
O
N
TFA/D C E (1 :1) ;
o -D C B, 2 00 o C
6 4%
N
Br
Br
C O 2R
Br
93%
N
N
H
N
br in e w /u p
N
Br
Me
C O 2R
Cl
N
Me
N
H
Br
Me
Me
O
O
H
H
O
Cl
N
N
H
O
N
H
[- CO 2]
64%
N
Br
Me
Me
Br
Cl
N
N
H
ch a rte ll in e C
Me
Me
10 steps
from indole from
Heck coupling