Total Synthesis of Gracilamine

Total Synthesis of Gracilamine
Reporter:
p
Ji Zhou
Checker: Bo Wu
Date: 2014/11/04
Gao, S.
G
S ett al.
l
Angew. Chem. Int. Ed. 2014, 53, 9539.
1
Shuanhu Gao
East China Normal University
Contents
Introduction
Total Synthesis by Gao’s Group
Total Synthesis by Ma’s Group
Summary
2
Introduction
Gracilamine (1)
Galanthus gracilis
z Isolated
I l t d from
f
the
th Galanthus
G l th gracilis
ili in
i 2005 b
by Unver
U
and
d Kaya
K
z These alkaloids have shown significant biological effects, ranging from
antitumor,, antiviral,, and antiinflammatoryy activities to immunostimulatory and acetylcholinesterase inhibitory activities
3
Total Synthesis by Gao’s Group
¾ Mild photo-Nazarov reaction to form the B ring
¾ 1, 4-Addition to form the D ring
¾ Intramolecular Mannich reaction to form the E ring
Gao S
Gao,
S. et al.
al Angew.
Angew Chem.
Chem Int.
Int Ed.
Ed 2014,
2014 53,
53 9539.
9539
4
Total Synthesis by Gao’s Group
5
Total Synthesis by Gao’s Group
6
Total Synthesis by Gao’s Group
A. B. Smith III. et al. J. Am. Chem. Soc. 1973, 95, 1961.
J. Leitich, I. et al . J. Photochem. Photobiol. A . 1991, 57, 127.
7
Total Synthesis by Gao’s Group
8
Total Synthesis by Gao’s Group
9
Total Synthesis by Ma’s Group
Ma, D. et al. Angew. Chem. Int. Ed. 2012, 51, 10141.
10
Total Synthesis by Ma’s Group
11
Total Synthesis by Ma’s Group
12
Total Synthesis by Ma’s Group
EtO
O
O
CHO
N
OTBDPS
Leucine ethyl easter
hydrochloride salt
O
H
OTBDPS
O
O
NM
NMe
O
EtO
Troc
H
NH2
HCl
NMe
Troc
11
10
EtO
H
H
N
O
H
N
OEt
O
toluene
O
reflux
Intramolecular
[3+2] Cycloaddition
H
O
H
H
NMe
Troc
12, 55%
OTBDPS
+
H
O
H
O
OTBDPS
NMe
Troc
13, 11%
13
Total Synthesis by Ma’s Group
EtO
EtO
H
N
H
O
O
H
O
OTBDPS
H
O
O
(1) Zn,
Zn AcOH
H
H
N
H
(2) TBAF
80%
O
OH
H
NMe
NHMe
Troc
12
14
EtO
H
H
N
O
O
NaOEt, EtOH
TFAA, DMSO, Et3N
H
O
75%
Swern Oxidation
64%
O
H
NCOCF3
Me
15
EtO
H
H
N
O
O
H
H
O
Me
16
H
NaBH4
85%
N
O
O
H
O
EtO
H
N
O
H
OH
N
Me
e
gracilamine
14
Summary
Ma's Method
Me
O
O
Me
HN
H
CHO
+
OH
NH2
O
O
COOEt
H
OH
H
First total synthesis
17 linear steps,
steps 4.5%
4 5% overall yield
Intramolecular [3+2] Cycloaddition
N
Me
gracilamine
il i
Gao's Method
Me
O
Me
HN
H
O
O
H
O
O
COOEt
H
OH
Photo-Nazarov Reaction, Michael
Addition, Intramolecular Mannich
Reaction
18 linear steps, 1.4% overall yield
N
Me
gracilamine
15
Amaryllidaceae plants have proven to be an important source of natural
products with appealing structures and promising biological activities.
Gracilamine (1),
(1) a member of the Amaryllidaceae alkaloid family,
family was isolated
from Galanthus gracilis collected from a mountain in Turkey by Unver and Kaya
in 2005. The structure and relative stereochemistry of 1, except for the
configuration of the hydroxy group on C6, were determined by NMR
spectroscopy.
p
py However,, the biological
g
activities of this p
potentially
y valuable
natural product are unknown because of its scarcity in nature. In 2012, Ma and
co-workers reported the first total synthesis of 1 using a biomimetic
intramolecular [3+2] cycloaddition. This synthetic breakthrough not only
suggested how the compound is produced in nature, but it also provided
evidence of the relative stereochemistry of C6.
16
Since our research group is devoted to the synthesis of bioactive natural
products,
d t we sett outt to
t develop
d
l
a new strategy
t t
t solve
to
l the
th efficiency
ffi i
off the
th
chemical synthesis of 1 and facilitate the preparation of its analogues and
derivatives for medicinal studies.
studies We report herein the total synthesis of 1 using
a photo-Nazarov reaction, Michael addition, and an intramolecular Mannich
reaction as key steps.
steps Our synthesis provides additional evidence to support
the C6 stereochemistry of natural product reported by Ma and co-workers.
17
In summary, we have accomplished the total synthesis of gracilamine, a
pentacyclic
t
li Amaryllidaceae
A
llid
alkaloid.
lk l id Our
O synthetic
th ti approach
h relies
li on three
th
k
key
ring-forming steps: 1) a mild photo-Nazarov reaction to form the B ring, 2) 1,4addition to form the D ring,
ring and 3) intramolecular Mannich reaction to form the
E ring. Our research findings further confirm the C6 configuration of natural
gracilamine The synthetic strategies developed here should facilitate
gracilamine.
production of a variety of gracilamine derivatives and structurally related natural
products thus leading to biological studies.
products,
studies
18
Total Synthesis by Gao’s Group
Intramolecular Mannich Reaction
Me
NH2
H
9
Me
O
Me
Me
EtO
O
Me
20 O
N
Me
O
N
COOEt
COOEt
H
O
O
20, TFA
43%
N
H
O
O
O
O
O
Me
O
O
N
N
Me
19
Me
21
22
Me
M
Me
Me
H
protonation
H
N
COOEt
enolization
O
H
OH
H
Me
HN
H
O
H
O
O
O
N
N
Me
Me
23
COOEt
24
19
Total Synthesis by Gao’s Group
Saegusas-Ito oxidation
OTMS
OTMS
PdII O
II
Pd(OAc)
(
)2
Pd
H
TMSOAc
O
O
+ Pd0 + HOAc
HPdII
20

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