total synthesis of (+)-perophoramidine
TRANSCRIPT
Bionano Chemistry Lab
Muhammad Ehsan(Student ID 2013652616)
Date: 2013-11-26
dx.doi.org/10.1021/ja408336v | J. Am. Chem. Soc. 2013, 135, 14098−14101
(+)-
Philippine ascidian Perophora namei by
Ireland and co-workers resulted in the isolation of the
metabolite perophoramidine ,2002.
(−)-Communesins and (+)-perophoramidine are two architecturally intriguing natural
products.
Contain a complex multiring system with two crucial vicinal all-carbon quaternary
stereocenters.
The asymmetric assembly, especially in a catalytic fashion, of chiral all-carbon quaternary
stereogenic centers is one of the most challenging and dynamic research areas in modern
organic synthesis.
They present an enantioselective synthesis of indolenines 4 containing two vicinal all carbon
quaternary stereocenters.
Optimization of the Reaction
3-substituted indole 1a
bromooxindole 2a
NH
N3
NH
Br N
OO
O
Ni
NRRNR2
R1
Substrate Scopes
Conversion to Ns-imide derivative
N
NPhth
Br
NH
OCl
NH
N Br
O
HN
Ns
1. NsCl, NaH, THF rt, 1 h
2. N2H4.H20
THF : MeOH = 1:1
Reflux, 2h
84%7
Cl
N3 N3
4p
N
NPhth
Br
N
OCl
N3
N
NPhth
Br
N-
OCl
N3
N
NPhth
Br
N
OCl
N3Ns
SCl
O
O
NO2H
H-
SCl
O
O
NO2
NsCl: 4-nitrobenzenesulfonyl chloride
Mechanism:
Cascade Transamidation and Aminal formation
N
NH
Br
N
OCl
N3Ns
N2H4.2H2O
N
NH2
Br
N
OCl
N3Ns
N
BrHN
Cl
N3Ns
NH
O
N
BrHN
Cl
N3Ns
NH
O
NH
N Br
O
HN
Ns
Cl
O
O
N3
PhthalamideDeprotection
Transamidation
Aminal Formation
Chlorination and Denosylation
NH
N Br
ClO
HN
Ns
1. NCS, AcOHrt, 2 h, 86%
2. K2CO3, PhSHDMF, rt, 12 h88%
N3
NH
NH
Br
ClO
HN
N3
Cl
O
O
N Cl
N N Br
ClO
HN
NH
N Br
ClO
HN
Ns
N3
ClH
O
O
N
Ns
NH
N Br
ClO
HN
N3
Cl NsNH
NH
Br
ClO
HN
N3
Cl
Deprotection
NCS: N-chlorosucinimide
N3
97
Mechanism:
Denosylation Mechanism :
N S
O
O
NO2
SH S-K+
NHS S
O
O
NO2+
Generation of pentacyclic compound
9
NH
NH
Br
Cl
Cl
HN
ON Ns
CH3
12
1. NaHMDS, NsClTHF 1h, 78%
2. PMe3, THF,
rt, 3h, 78%
3. CS2CO3, MeI, rt
CH3CN, 3h, 90%
NH
NH
Br
ClO
HN
N3
Cl
Mechanism:
Sodium bis(trimethylsilyl)amide
NaHMDS
O2N S
O
O
Cl
Staudinger Reaction
NH
NH
Br
Cl
Cl
HN
OHN Ns
H3C I
NH
NH
Br
Cl
Cl
HN
ON Ns
CH3
NH
NH
Br
ClO
N
N3
Cl
H
NH
NH
Br
ClO
N
N3
Cl
Ns
NH
NH
Br
ClO
N
H2N
Cl
Ns
12
Nosylation
Transamidation
N-methylation
N
Si
Si
Staudinger Reaction:
Oxidation of amine to imine
NH
NH
Br
Cl
Cl
HN
ON
Ns
CH3
12
NH
N Br
Cl
Cl
HN
ON Ns
14
PCC, CH2Cl2
rt, 1h, 71%
NH
NH
Cr
O
O
ClONH
N
NHCr
H
O
ClO
OH
H
N
NHH
Cr
O
OH
Cl
ON
NH
Mechanism:
NH
N Br
Cl
Cl
HN
ON Ns
14
N N Br
Cl
Cl
NO
N Ns
Boc
Boc
15
Boc2O, DMAPEt3N, CH2Cl2
90%
O O
O
O
O
NO
O
N N
N
Mechanism:
HN
O
O
N-DMAP-H+
Boc- Protection
Boc: Di-t-butyl dicarbonate
DMAP: 4-dimethylaminopyridine
N N Br
Cl
Cl
NO
N Ns
Boc
Boc
N NH
Br
Cl
Cl
HN
ON Ns
Boc
16
LiAlH4, THF,
- 20 OC, 20 min
61%
15
N N Br
Cl
Cl
NO
N Ns
Boc
Boc
H-
N NH
Br
Cl
Cl
HN
ON Ns
Boc
Reduction of amidine group
Mechanism:
Conversion of amide into imidate group
NH
N Br
Cl
Cl
HN
ON Ns
16
NH
N Br
Cl
Cl
NOMe
N Ns
BocBoc
17
Me3OBF4, NaHCO3
rt, CH2Cl2, 2h, 87%
NH
N Br
Cl
Cl
HN
ON Ns
O
Me
Me
Me
BF4
NH
N Br
Cl
Cl
NOMe
N Ns
BocBoc
Mechanism:
NH
N Br
Cl
Cl
NOMe
N Ns
Boc
17
NH
N Br
Cl
Cl
NMeN
(+) - PEROPHORAMIDINE
1. K2CO3, CS2CO3PhSH, DMF, 83%
2.HCl, PCCDioxane, 84%
Synthesis of target compound
Ns-deprotection/ denosylation
Boc-deprotection
One-pot oxidation
NH
N Br
Cl
Cl
NOMe
NH
Boc
NH
N Br
Cl
Cl
N
Boc
MeN
NH
NH
Br
Cl
Cl
NMeN
NH
N Br
Cl
Cl
NMeN
(+) - PEROPHORAMIDINE
NH
N Br
Cl
Cl
NOMe
N Ns
Boc
Ns Deprotection
Boc Deprotection
OxidationPCC
O
O
NH+
Cl-
Highly congested vicinal all-carbon quaternary stereocenters are generated
via catalytic asymmetric alkylation.
Total synthesis of (+)- perophoramidine using bromooxindole and 3-
substituted indole.
Key Chemistry Ni catalyzed alkylation
Conclusion: