lab a: vincent lindsay, cyril nicolas, pascal cérat and sébastien goudreau synthesis meeting...
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Lab A: Vincent Lindsay, Cyril Nicolas, Pascal Cérat and Sébastien Goudreau
Synthesis Meeting
Proposed Total Synthesis of Proposed Total Synthesis of Haliclonin AHaliclonin A
November 7th, 2009
N
N
O
HO
O
H
O
2
RetrosynthesisRetrosynthesis
N
N
O
HO
O
H
O
Haliclonin A
N
N
O
O
Boc
OTBS
O O OO
MOM
Corey-WinterN
N
O
O
O
Boc
X
S
OTBS
O OO
O
Barton
HN
O
N
O
Boc
OTBS
CN
O
EtO2C
N
Boc
6
O O O OOBn
Li+
TBSOOBn
CN
O
N
Boc
O
NO
O
Bn
+
OEt
CN
N
Boc
O
NO
O
Bn
3
EtO
O
CN
H H
O
Chem. Eur. J. 2006, 12, 8228.
base, Pdnano
EtO
O
CN
0.10$/g
Cp2TiMe2
THF, Δ
Petasis 2 steps
OEt
CN
Boc NH2
+
Br
base
Boc NH
H
O
JACS 1999, 121, 866.JACS 2002, 124, 8584.
N
Boc
O
H
3 steps
EtOP
OEtO
N
O
O
O
Bn
LiCl, i-Pr2EtNCH3CN, r.t.
N
Boc
O
NO
O
Bn
Phosphonate: Tet. Lett. 1991, 32, 5907
Synthesis of Diels-Alder PrecursorsSynthesis of Diels-Alder Precursors
HN
O
N
O
Boc
OTBS
HWE: Paintner, F.F.; Bauschke, G.; Polborn, K. Tet. Lett. 2003, 44, 2549
4
Me N
O
O
O
Bn
+Me Et2AlCl
CH2Cl2, -30°C
Me
O
N O
O
BnMe
84%, 20.7:1 d.r.
Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238.
OEt
CN
Diels-AlderCN
O
N
Boc
O
NO
OCN
O
N
Boc
EtO2C
Ti(OEt)4+
N
Boc
O
NO
O
Et2AlCl
CH2Cl2, -30°C
BnBn
Diels-AlderDiels-Alder
HN
O
N
O
Boc
OTBS
5
Br6
K2CO3
Axial Attack CN
O
EtO2C
N
Boc
6
EtO2C
NR
BocOKNC
CN
O
N
Boc
EtO2C
DMF
1. LDA; Ph H
ONTs
2. TBSCl, ImidCN
O
EtO2C
N
Boc
6
OTBS
Quaternary CenterQuaternary Center
HN
O
N
O
Boc
OTBS
6
1. DBU, Δ
O
MeO2C
OTBS
NHBn
NBoc1. Grubbs II
2. H2, Raney-Ni3. BnCl, TEA
CNO
EtO2C
NBoc
6
OTBS
ONC
MeO2C
N
OTBS
Boc
ONHBn
MeO2C
N
OTBS
Boc
NO
N
O
Boc
OTBSBn
MacrocyclisationMacrocyclisation
HN
O
N
O
Boc
OTBS
7
HO OH1) NaH (1 eq.), BnCl
2) Ph3P, I2I OBn
H
H EtMgBr, THF
Organic Synth. 1963, 4, 792
MgBrOTs
Synthesis 1979, 4, 292
CuBr (cat.), THF
i) BuLi (1 eq.), THF
ii)I OBn
i) BuLi, THF
ii) O
iii) TBSCl, Imid
1. H2, Pd(quinoline)
TBSO 2. OsO4, NMO3. Acetone, TsOH
OBnTBSO
O O O O
BnO BnO
2nd Macrocycle Chain2nd Macrocycle Chain
O O O OOBn
Li
8
OBnTBSO
O O O O
1) TBAF
2) PCCOBn
O
O O O O
O O O OOBn
Li
t-BuLi, Et2OOBn
O O O O
1. CBr4, PPh3, DCM2. Bu3SnH, Pd(PPh3)4, benzene, r.t.
Br
2nd Macrocycle Chain2nd Macrocycle Chain
O O O OOBn
Li
vinyl bromide: Tet. Lett. 2004, 45, 2563
9
N
O
N
O
Boc
OTBS
Li
O O O OO
exo attack
Bn
Bn
N
N
O
HOBn
Boc
OTBS
O OO
OBnO
OOH OHMe
Me
Pietra, F.; Guerriero, A. J. Chem. Soc., Perkin Trans. 1. 1982, 979
MeMgI (slight excess)
Et2O, 20 °C, 90%
+
19 1
Addition of the 2nd Macrocycle ChainAddition of the 2nd Macrocycle Chain
10
2. PPh3, I23. KH (diluted)
N
N
O
HOBn
Boc
OTBS
O OO
OBnO
N
N
O
O
HO
Boc
OTBS
O OO
O
1. H2, Pd/C N
N
O
HO
Boc
OTBS
O OO
O
mCPBA
Macrocyclisation & EpoxydationMacrocyclisation & Epoxydation
11
AIBN (0.6 eq.), Et3SiH, 90 °C
1.5 h, evaporation, TBAF, THF
20°C, 1h, 70%
Ogasawara, K.; et al. Tetrahedron Lett. 2000, 41, 3631-3636
O
OC9H19
OHC9H19
SMe
S
1. i) Et3SiH, AIBN, Toluene, Δ ii) 2% HF, pyr
Barton-McCombie
N
N
O
O
Boc
OTBS
O O OO
MOM
X = Imid
N
N
O
OO
Boc
X
S
OTBS
O OO
O
Cl N
S
N
N
N
O
OHO
Boc
OTBS
O OO
O
2. MOMCl, TEA
Double Bond: Radical Deoxygenation-Epoxyde Opening Double Bond: Radical Deoxygenation-Epoxyde Opening
12
N
N
O
O
Boc
OTBS
O OO
O
N
N
O
O
Boc
OTBS
O OO
O
N
N
O
Boc
O O O
O
O
N
N
O
Boc
O O O
O
O
Epoxyde OpeningEpoxyde Opening
favored not favored
13
N
N
O
O
Boc
OTBS
O O OO
MOM
1. H+ / H2O2. TCDI
3. P(OEt)3
Corey-Winter
N
N
O
O
Boc
OTBS
MOM
N
N
O
O
Boc
MOM
O1. TBAF
2. PCC
Haliclonin A
N
N
O
HO
O
H
O
1. AlCl3, NaIDCM, 0°C
H
O
O Bu
EtOAc, rt
2.
Final stepsFinal steps
27 steps
14
RetrosynthesisRetrosynthesis
N
N
O
HO
O
H
O
Haliclonin A
N
N
O
O
Boc
OTBS
O O OO
MOM
Corey-WinterN
N
O
O
O
Boc
X
S
OTBS
O OO
O
Barton
HN
O
N
O
Boc
OTBS
CN
O
EtO2C
N
Boc
6
O O O OOBn
Li+
TBSOOBn
CN
O
N
Boc
O
NO
O
Bn
+
OEt
CN
N
Boc
O
NO
O
Bn
15
16
N
N
O
O
Boc
N
N
O O
Boc
OH
N
N
O
HO
Boc
OTBS
N
N
OOH
Boc
OH
Epoxyde OpeningEpoxyde Opening
favored not favored