Post on 21-Jan-2016
description
Litterature Meeting
Enantioselective Total Enantioselective Total Synthesis of Synthesis of
Avrainvillamide Avrainvillamide
andand
Stephacidins A and BStephacidins A and B
Aspergillus ochraceus
N
N
ON
O
O
Stephacidin B
N
N
O
HN
OO
O
HO
51
20 21
39
62
55
N
N
ON
O
O
Stephacidin B
N
N
O
HN
OO
O
HO
51
20 21
39
62
55
N
N
ON
O
O
Stephacidin B
N
N
O
HN
OO
O
HO
51
20 21
39
62
55
N
N
O
NH
OO
O
Avrainvillamide (CJ-17665)
N
N
O
NH
OO
O
Avrainvillamide (CJ-17665)
NH
N
O
NH
OO
Stephacidin A
N
N
O
NH
OO
O
Avrainvillamide (CJ-17665)
Aspergillus: A source of complexe prenylated indole alkaloids
N
N
Spirotryprostatins A and B
OHN
O
O
H3CO
N
N
O
NH
OO
O
Aspergamide A
OH
NH
N
O
NH
OO
Stephacidin A
N
N
O
NH
OO
Aspergamide B
NNMe
O
CH3
HN
O
OParaherquamide F
N
O
NH
O
Brevianamide A
HN
O
- Isolation from a fungal species found in an Indian clay sample (Sirsaganj, Uttar Pradesh, India) - Sources: 1/ Marine fungal strain Aspergillus: 2000 - Fenical and coworkers 2/ Fermentation broth of Aspergillus ochraceus: 2001 – Sugie and coworkers
- Isolation from Aspergillus ochraceus WC76466: 2002 – Bristol Myers Squibb-In vitro citotoxic activity (human tumor cell lines) ⇒ SPC B: 5-30 fold more active than SPC A (testosterone-dependent prostate LNCaP cell line: IC50=0.06 µM)
98
2021
N
O
NH
O
Brevianamide A
HN
O
N
N
O
O
HN
Deoxyaustamide
Biosynthesis of Stephacidin B: a lesson for the chemist
HN HN
N
O
O
Brevianamide FHN HN
N
O
O
Tryprostatin B
N
N
O
O
Demethoxyfumitremorgin C
NH
[O]
Prenylation Reverse Prenylation
2 [O]
N
N
Spirotryprostatin B
OHN
O
O
HN HN
N
O
ODeoxybrevianamide E
N
N
O
OAustamide
NH
O
[O]
N
O
NH
O
Brevianamide A
HN
O
N
N
O
OH
2 [O]2 [O]
Diels-Alder *
bicyclo[2.2.2]diazaoctane
* Birch and coworkers, J. Chem. Soc. Perkin I, 1974, 50.
Sammes and coworkers Chem. Comm., 1970, 1103.
.
NH
N
O
NH
O
HN N
N
O
OH
O
HN HN
N
O
O
Brevianamide F
O
HN HN
N
O
O
HN N
N
O
OH
Presumed biosynthesis of Stephacidins A and B
N
N
O
NH
OO
O
Avrainvillamide
NH
N
O
NH
OO
Stephacidin A
N
N
ON
O
O
Stephacidin B
N
N
O
HN
OO
O
HO
51
2021
39
62
55
[O]
Prenylation
IntramolecularDiels-Alder
[O]
[O]
HN NH2
O
OH
Tryptophane
HN
O
HO
Proline
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Williams’ approaches
PMBN
N
O
ONH
H
Cl
NaH
SN2’
PMBN
N
O
ONH
N
N
OMe
ONH
HN
N
OMe
ONH
H
2:1 mixture
Diels-Alder
J. Am. Chem. Soc. 1990, 112, 808.Acc. Chem. Res. 2003, 36, 127.Tetrahedron Lett. 2004, 45, 4489.
Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approachPMBN
N
O
ONH
NH
O
OH
L-Proline
OHC
1.
2. LDA, THF, hexane, -78 °C
then
, THF,
-78 °C to -30 °C, 87 %Br
N O
OTFA, pentane, 92 % MeO CH2NHLi
THF, -78 °C
quant.
NH
NH
O
OMe
1. BrCH2COBr
DCM/ K2CO3
2. 50 % aq. NaOH,
DCM
85 %
N
NPMB
O
O
N
NPMB
O
O
O
O3 / MeOH,Me2S
99 %N
NPMB
O
O
1. 2. NaBH4, EtOH
3. TBDMSCl, Et3N, DMAP, DCM
85 %
MePh3P
Me
CHOTBDMSO
N
NPMB
O
O
Me
TBDMSO
1. nBuLi, THF
2. ClCO2Me71 %
4:1 mixture
CO2Me
N
NPMB
O
O
Me
CO2Me
TBDMSO
Bu3P, MeCN,
62 %
NH
NMe2
NH
Seebach and coworkers, J. Am. Chem. Soc. 1983, 105, 5390.
Somei and coworkers, Heterocycles 1981, 16, 941.
SolventTemperature
(°C)Base
Ratio
anti:synYield (%)
Benzene 80 NaH 3:97 82
DMF 85 NaH 2:1 63
Benzene 25 NaH/18-crown-6 6:1 14
Benzene 80 NaH/18-crown-6 3.9:1 56
Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2)PMBN
N
O
ONH
N
NPMB
O
O
Me
CO2Me
TBDMSO
NH
1. LiCl, HMPA, H2O,100°C
2. Boc2O, tBuOK, THFthen
Bu4NF, THF, rt
85 % N
NPMB
O
O
Me
H
HO
NBoc
N
NPMB
O
O
Me
H
Cl
MsCl, LiCl, DMF,
collidine
quant.
NBoc
Base / Solvant
N
N
OBocN
Me
HH
H
pMB
N
N
OBocN
Me
HH
H
pMB
OO
SYNANTI
+
Brevianamide B
N
N
O
OMe
O
N
O
(Me)3CO
Me
Cl
"OPEN" transition state
N
N
O
OMe
O
N
O
OC(Me)3
Me
Cl
HH
"CLOSED transition state
Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2)PMBN
N
O
ONH
O
O
O
O O
O
Na NaH, benzene, 80 °C
NO
OMe
O
N
O
(Me)3CO
Me
H
SYN
NO
OMe
O
N
O
(Me)3CO
H
ANTI
Tightion pair
NaH, DMF
NaH, benzene, 80 °C18-crown-6Na
N
HN
O
OH
HN
NaOH, MeOH, rtthen
dioxane, 65 °C
82 %
Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder approach N
N
OMe
ONH
H
N
HNO
O
MeO2C
H
H
1. SOCl2, benzene,
2. (MeO2C)2-CHNH2, Et2O, 0 °C
thenNa2CO3, H2O, 15 °C
69 %
CbzN
HO
NHMeO2C
MeO2C1. H2, Pd/C, MeOH, 70 °C
2. , 70 °C 93 %
N OH
NH
NHNH2 NH
NMe2
1. 6M aq. HCl, NaNO2, 0°C
2. SnCl2, 10M aq. HCl, 0 °C
3. 10M aq. NaOH 45 %
1.
toluene,
2. ZnCl2, diglyme, 170 °C
O
H2CO, MeNH, AcOH, rt
83 %
NaH, DMF, 60 °C
77 %
N
HN
O
OH
HN
MeO2C
N
N
OMe
ONH
HN
N
OMe
ONH
H
2.5:1
CbzN
HO2C
H
N-Z-L-Proline
NH2
2.5:1
Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach N
N
OMe
ONH
H
N
HN
O
OH
HN
epi-deoxybrevianamide E
N
HN
O
OH
HN
deoxybrevianamide E
2.5 : 1
Me3OBF4, DCM, 0 °C
79 %
N
N
O
OMeH
HN
DDQ, toluene, -78 °C
31 %
N
N
O
OMe
HN
N
N
O
OMe
HN
KOH, MeOH, H2O
NN
HN
O
OMe
NN
HN
O
H
OMe
+
2 : 1
90 %
Williams et al. Bioorg. Med. Chem., 1998, 6, 1233.
S R
Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach N
N
OMe
ONH
H
N
N
O
OMe
HN
KOH, MeOH, H2O
N
N
O
OMe
HN
N
N
OMe
O
H
H3C
H3C
HN
NN
HN
O
OMe
NN
HN
O
H
OMe
+
2 : 1
N
N
OMe
O
H
HN
R
R
"EXO" "ENDO"
N
N
OMe
O
H
H3C
CH3
HN
N
N
OMe
O
H
H3C
CH3
HN
S
S
90 %
William’s synthesis of bicyclo[2.2.2]diazaoctane nucleus
PMBN
N
O
ONH
H
Cl
NaH
SN2’
PMBN
N
O
ONH
N
N
OMe
ONH
HN
N
OMe
ONH
H
2:1 mixture
Diels-Alder
16 steps in 12 % yield overall
High stereoselectivity of alkylation based on the presence or absence of metal chelation
4 steps in 17 % yield overall from and
Medium stereoselectivity of cycloaddition based on steric effects
NH
NMe2
N
HNO
O
MeO2C
H
H
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Liebscher’ approach
HN
N
O
ON
H
MOMDiels-Alder
AcCl HN
N
O
ONH
H
Based on intermolecular Diels-Alder model reactions
⇒ acidic conditions such as HCl and BF3.OEt2 not as effective as AcCl or HCO2H
⇒ high pression and temperature
⇒ slow rates (6-20 days)
HN
N
O
R1
O
A
N
N
O
R1
OCOR
B
N
N
O
R1
O
H
R3R2
H
N
N
O
R1
O
H
R3R2
H
R1 = iPr, PhR2 = H, PhR3 = Ph, (CH2)4
N
N
O
R1
X
+ +
major
R = Me, CH2Br, Ph
X = OCOR Cl OH
R3
R2
P = atm, 10 kbarT = rt, reflux
AcCl or HCO2H or DCM, BF3.OEt2
Liebscher and coll. J. Org. Chem. 2001, 66, 3984.
HN
N
O
O
PMeO
MeOO
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Liebscher’ approach (2)
NH
CHO
ClHC=NMe2Cl, DCM,
then aq. NaOH, EtOAc
NH
NH2
1. 6M aq. HCl, NaNO2, 0°C
2. SnCl2, 10M aq. HCl, 0 °C
3. 10M aq. NaOH NHNH2
1.
toluene,
2. ZnCl2, diglyme, 170 °C
O
Et3N9-BBN
NH
Cl
NCS, DMF, rt
NH
HN
N
O
ON
H
MOMNH
CHO
HN
N
O
O
PMeO
MeOO
+
ZHN
N
O
PMeO
MeOO
O
O H2, Pd/C, AcOH, MeOH
95 %
ZHN
OH
O
PMeO
MeOO
DCC,
DCM, rt
92 %
HN
O
O+
Lieberknecht and coll. Tetrahedron Lett. 1987, 28, 4275.
Williams and coll. Tetrahedron Lett. 2005, 46, 9013.
Z-Admpa
N
N
OAc
O
H
H3C
H3C
HN
N
N
OAc
O
H
H3C
CH3
HN
N
N
OAc
O
H
HN
N
N
OAc
O
H
H3C
CH3
HN
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
HN
N
O
O
PMeO
MeOO
NMOM
CHO
tBuOK
78 %
HN
N
O
ON
H
MOM Diels-Alder
AcClHN
N
O
ONH
H
48 %
rt, 20 daysone stereoisomer !
"EXO"
"ENDO"
Liebscher’ approach (3)R
minimal steric repulsion
defavoring steric repulsion
R
S
Liebscher’s synthesis of bicyclo[2.2.2]diazaoctane nucleus
HN
N
O
ON
H
MOMDiels-Alder
AcCl HN
N
O
ONH
H
2 steps in 37 % yield overall from and
Stereospecificity of cycloaddition based on steric effects due to presence of acetoxy group
BUT
Cycloaddition step achieved in 20 days and in only 48 % yield !!
NMOM
CHOHN
N
O
O
PMeO
MeOO
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Myers’ approach
HN
RN
OHPhS
TBDPSOH
HN
N
OH
TBDPSOH
O
t-amylO
O Ph
O
tBuPh
R =
O Acyl radical approach
HN
RN
OHPhS
TBDPSOH
H3C
H3C
O O
O
NBoc
OH2CS
O
O
iPr
NBoc
Abrams and coll. Tetrahedron 1991, 47, 3259.
J. Am. Chem. Soc. 2005, 127, 5342.
H3C
H3C
O O
H2BO H
H3C
H3C
O O
HO H
HCl, MeOH
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
H3C
H3C
O O
O
LiHMDS, TMS-Cl,
Pd(OAc)2, CH3CN, rt
98 %
or
IBX, MPO, DMSO,
60°C
70 %
H3C
H3C
O O
O
H3C
H3C
O O
OH
R
BH3.DMS,
(S)-CBS catalyst,
THF, 0 °C
94 %, >95 % ee
R1 R2
O
N B
O
H PhPh
CH3
S(0.1 equiv)
BH3.THF (0.6 equiv), THFR1
HO
R2
H
(S)-CBS
84-97.6 % eeR1 > R2
N B
O
H PhPh
R
N B
O
H PhPh
R
BH3.DMS
H3B
H3C
H3C
O O
O
BO
N
R
CH3H3C
O
O
O
H2B H
Ph
PhB
O
N
R
CH3H3C
O
O
OH2B
Ph
Ph
H
BH3
N B
O
H PhPh
RH2B
CH3H3C
O
O
O
HHB
HH
O O
OH
OTBS
(92 % ee)
Corey and coworkers, Tetrahedron Lett. 1991, 32, 5025.
Corey E. J., Bakshi R. K., Shibata S. J. Am. Chem. Soc. 1987, 109, 5551.
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
H3C
H3C
O O
OH
R
1. TBDPSOTf, 2,6-lutidine,
DCM, rt
2. 1N H2SO4,
Me2CO/H2O/THF,
0 °C rt
91 %
H3C
H3COTBDPS
O
1. KHMDS, -78 °C
2. -35 °C,
70 %
BocN
CH2O S
O
O
iPr
H3C
H3COTBDPS
ONBoc
H3C
H3COTBDPS
ONBoc
NC
H3C
H3COTBDPS
ONBoc
NC
(65 %) (16 %)
TMS-CN,
HFIPA, 0 °C
4:1 dr, 81 %
KHMDS, PivOH, -78 °C
88 %
H3C
H3COTBDPS
ONBoc
NC
H3C
H3COTBDPS
ONBoc
EtOH, H2O, 70 °C
85 %
O
H O
P
PtP
H
P OH
O
H2N
SR
Pt
PMe2
Me2P
Me2PO
O
OH
OTBDPS
O
NBoc
NC
H
H3C
H3COTBDPS
ONBoc
EtOH, H2O, 70 °C
85 %
O
H O
P
PtP
H
P OH
O
H2N
Ghaffar T., Parkins A. W. J. Mol. Cat. A 2000, 160, 249.
H3C
H3COTBDPS
ONBoc
NC
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
Pt
PMe2
OH
Me2P
Me2PO
O
OHH
Pt
PMe2
S
Me2P
Me2PO
O
OHH
H2O
H2
Pt
PMe2
Me2P
Me2PO
O
OH
N C
R
Pt
PMe2
Me2P
Me2PO
O
OH
N C
RHH
H2O
O
H
R
O
NH2
Pt
PMe2
Me2P
Me2PO
O
OHH
R-CN
NC
R
Pt
PMe2
Me2P
Me2PO
O
O
H
OTBDPS
O
NBoc
NC
X
7-membered ring !
Pt
PMe2
H
Me2P
Me2PO
O
OHH
S = H2O
H3C
H3COTBDPS
ONBoc
O
H2N
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
PhSH, Et3N, THF, 70 °C
95 %
H3C
H3COTBDPS
NHOH
N
SPh
OBoc
1. TMSOTf, 2,6-lutidine,DCM,
DCM, -78 °C 0 °C
98 %
2. , DIPEA, DCM, rt
92 %
H3C
H3COTBDPS
NH
N
SPh
O
Cl
O
O
Jackson L. V., Walton J. C. Chem. Commun. 2000, 2327.
H3C
H3COTBDPS
N
t-amylO
O Ph
O
tBuPh, 120 °C
62 %
O
NO
H
N
NH
O
TBDPSO
O
N
OR
Ph
In
Me +
O
NR
Ph
O
NR
Ph
+ MePh
X
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
N
OR
Ph
N O
Ph
R =
InN O
Ph
- MePhN O
Ph
NH
O
Ph+NO
PhNO
Ph minor product
X
major product
5-exo-trig
N Ph
O
6-endo-trig
N
NH
O
TBDPSO
O
PhS
N
NH
O
TBDPSO
O6-exo-trig favored
vs
7-membered ring closure
N NH
O
TBDPSO
SPh
O
H
H
MeN
HN
OOTBDPS
SPh
OH
HMe
minor conformation
N
HN
OOTBDPS
SPh
O
H
BUT
62 %
Myers’ synthesis of bicyclo[2.2.2]diazaoctane nucleus
H3C
H3C
O O
O
H3C
H3COTBDPS
N O
N
O
H
N
NH
O
TBDPSO
O
Enantioselective synthesis of the desired nucleus
12 steps in 19 % yield overall from and
Product used as precursor for synthesis of Stephacidin B
H3C
H3C
O O
O
NBoc
OH2CS
O
O
iPr
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Baran’ s approach
Three steps:
1/ Synthesis of a model of the bicyclo[2.2.2]diazaoctane nucleus
2/ Application of the strategy to a functionalized system for eventual elaboration into Stephacidin A
3/ Formation of Stephacidin A
HN
N
O
ONH
H
HN
N
O
ONH
HO
HN
N
O
ONH
HO
J. Am. Chem. Soc. 2006, 128, 8678.
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
HN
N
O
ONH
H HN
N
O
O
NH
HN
N
O
O
NH
Br
N
N
O
O
NBoc
MeO
O
PG
IntramolecularDiels-Alder
Intramolecular vinyl radical cyclisation
Intramolecular oxidative enolate heterocoupling
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
First strategy: Ring closure by intramolecular Diels-Alder reaction
HN
N
O
O
NH
HN
N
O
O
NH
NH
NHBoc
CO2HH
NH CO2Me
+
Dehydrogenation Peptide coupling
NBoc
CO2Me
HLHMDS, THF, -78 °C
83 %
Br
NBoc
CO2Me
p-TsOH, toluene,reflux
84 %
NH
CO2Me
Boc-L-Trp-OH, BOP-Cl,DIEA, DCM, rt
48 %
N
CO2Me
O
NH
NHBoc
HHN
N
O
O
NH
190 °C, neat
54 %
N-Boc-L-Trp
Dehydrogenation
HN
N
O
O
NH
X
YH
HN
N
O
O
NH
HN
N
O
O
NH
First strategy: Ring closure by intramolecular Diels-Alder reaction (2)
NH
NHCO2Me
CO2MeH
NO
ZrCl4NH
NHCO2Me
CO2MeH
N
O
N
NHCO2Me
CO2Me
H
N
O H
NHOH
N
NHCO2Me
CO2MeH
NH
NHCO2Me
CO2Me
Path A
NH
NHCO2Me
CO2MeH
NO
ZrCl4N
NHCO2Me
CO2Me
Path B
H
O
N H
Dehydrogenation:
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
R1
O
R2
PhN
O
+ R1
O
R2
ONH
PhMLn
Yamamoto and coll. J. Am. Chem. Soc. 2004, 126, 5962.
92 %
PhNO, ZrCl4, DCM
0 °C rt
⇒ Study of direct dehydrogenation of simplified Trp derivatives
Y
X
First strategy: Ring closure by intramolecular Diels-Alder reaction (3)
HN
N
O
O
NH
Diels-Alder
conditions
HN
N
O
O
NH
H
X
Conditions: - Reflux in toluene, xylenes...
- Use of Lewis Acids: AlCl3, TiCl4, ZrCl4 - Use of Rh(I) catalyzer
- Heating of the substate neat at high temperature (300 °C)
N
N
OAc
OAc
NH
Diels-Alder
Liebscher method
HN
N
O
O
NH
H
X
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
Second strategy: Ring closure by intramolecular vinyl radical cyclization
NBoc
CO2Me
H
1. LHMDS, THF, -78 °C,
2.
3.p-TsOH, toluene, reflux
71 %
NH
CO2Me
BrBrBr
Boc-L-Trp-OH, BOP-Cl,DIEA, DCM, rt
54 %
N
CO2Me
O
NH
NHBoc
HBr
p-TsOH, toluene, reflux
46 %
NO
NH
HBr
O
PhNO, ZrCl4, DCM, rt
79 %
HN
N
O
O
NH
Br
AIBN, nBu3SnHHN
N
O
ONH
H
X
HN
N
O
O
NH
BrHN
N
O
ONH
H HN
N
O
ONH
H
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
Third strategy: Ring closure by intramolecular oxidative enolate coupling
N
N
O
O
NH
MeO
X
HN
N
O
ONH
HPG
HN
N
O
O
NH
MeO
O
PG
X = O
X = CH2
Intramolecular Oxidative Coupling
1. LHMDS, THF, -78 °C,
2.
3. 9-BBN, H2O2, NaOH
78 %
NZ
CO2Me
OH
Br
NZ
CO2Me
H
1. TBSCl, ImH, DCM, rt
2. H2, Pd/C, MeOH, rt
96 %
NH
CO2Me
OTBS
NBoc
CO2H
NHZ
H
HATU, DIEA, DMF, rt
79 %
N
CO2Me
O
NBoc
TBSO
ZHNHN
N
O
O
NBoc
TBSO
1. H2, Pd/C, MeOH, AcOEt, rt
2. toluene, reflux
74 %
N
N
O
O
NBoc
TBSO
PMB
NaH, PMB-Cl, DMF,0 °C
74 %
N
N
O
O
NBoc
MeO
O
PMB1. TBAF, THF
2. DMP, DCM, rt
3. NaClO2, NaH2PO4.H2O, THF, H2O, rt
4. CH2N2, MeOH, 0 °C
72 %
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
Baran and coll. Angew. Chem. Int. Ed. 2005, 44, 609.
Third strategy: Ring closure by intramolecular oxidative enolate coupling
N
N
O
O
NBoc
MeO
O
PMB
N
N
O
O
NBoc
MeO
O
PMBH
N
N
O
O
NBoc
MeO
O
PMB
LDAN
N
O
O
NBoc
OMe
O
PMB
LnFe
"chelated"
N
N
O
MO
NBoc
PMB
MO
OMe
"non-chelated"
Diastereoselectivity
N
N
O
O
NBoc
OMe
O
PMB
LnFe
A (ionic/ concerted)
N
N
O
O
NBoc
OMe
O
PMB
LnFe
C (initial amide oxidation)
Mechanism ?
N
N
O
O
NBoc
OMe
O
PMB
B (diradical)
N
N
O
O
NBoc
OMe
O
PMB
LnFe
D (initial ester oxidation)
1. MeMgBr, toluene, 0 °C
2. Burgess reagent, benzene, 50 °C
41 %
N
N
O
O
NBoc
Me
PMBH
- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -
NS
NEt3
O O O
Burgess reagent
4 4
6
6R
LDA, -78 °C, then Fe(acac)3, THF, -78 °C rt
65 %
7
- Baran’s Synthesis of Stephacidin A –- Second step: Application to the elaboration of a suitable functionalized system -
HN
N
O
ONH
HO
Stephacidin A
HN
N
O
ONH
H
OMe
O
O
O NH
NHZ
CO2H
OMe
O
NH
CO2Me
+
Benzopyran
Tryptophan
Proline-derived
Ester
I
TsO NH2
+NZ
CO2MeHOPd(OAc)2, DABCO, TBAI, DMF, 105 °C
75 %NH
NHZ
CO2Me
TsO
X
TsO NH
NHZ
CO2Me Pd
TsO NH
NHZ
CO2Me
Ln
N
NHZ
CO2Me
TsO
PdLn
Ha
migratory
insertion Hb
N
N
N
N.HI
-hydride
elimination
Benzopyran Tryptophan Synthesis:
Amide bondformation
X = I
X = PdI
Reider and coll. J. Org. Chem. 1997, 62, 2676.
- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -
NH
NHZ
CO2Me
TsO
1. Boc2O, DMAP, DCM/MeCN, rt, 95 %
2. Mg(0), MeOH, 0 °C rt
3. A, CuCl2 (O.1 mol%), DBU, DCM/MeCN, 0°C
75 %
NBoc
NHZ
CO2Me
O
OCO2Me
A
o-dichlorobenzene,190 °C
95 %NH
NHZ
CO2Me
O
NBoc
NHZ
CO2H
O
1. Boc2O, DMAP, DCM/MeCN, rt,
77 %
2. LiOH, THF/H2O, 0°C
100 %
Benzopyran Tryptophan Synthesis (2):
Proline Synthesis:
NZ
CO2Me
OMe
O
NZ
CO2Me
NZ
CO2Me
OTBS
1. PhI(OAc)2, TEMPO, MeCN/H2O, rt
2. CH2N2, AcOEt, rt
86 %
9-BBN, THF, rtthen
3M aq. NaOH/ 35 % aq. H2O2
92 %
TBSCl, ImH, DCM, rt
96 %NH
CO2Me
OTBSH2, Pd/C, toluene, rt
100 %
NH
CO2Me
OMeH2, Pd/C, toluene, rt
97 %
O
- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -
Union of Tryptophan and Proline Fragments
NBoc
NHZ
CO2H
O
R1
NH
CO2Me
1 2a: R= CH2OTBS2b: R= CO2Me
2a or 2b, HATU, DIEA, DMF,rt MeO
N
O
ONBoc
R1
O
ZHN
3a: R= CH2OTBS 62 %3b: R= CO2Me 81 %
Pd2dba3.CHCl3, Et3SiH, Et3N, DCM, rt
thenMeOH, reflux
thentoluene,reflux
N
O
ONBoc
R1
O
4a: R= CH2OTBS 53 %4b: R= CO2Me 85 %
HNH
N
O
ONBoc
R1
O
5a: R= CH2OTBS; Base = NaH 65 % 5b: R= CO2Me ; Base = NaHMDS 63 %
MOMN
Base, MOMCl, THF,-78 °C rt
Conditions
1. TBAF, THF, rt2. DMP, DCM, rt3. NaClO2, NaH2PO4.H2O, THF, rt4. CH2N2, MeOH, rt
69 %
Conditions
N
O
O
BocN
O MOMN
LDA, THF, -78 °Cthen
Fe(acac)3, -78 °C
61 %
MeOO
6
Ohfune and coll. J. Org. Chem. 1990, 55, 870.
- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -
Union of Tryptophan and Proline Fragments (2)
N
O
O
BocN
O MOMN
MeOO
6
1. BCB, DCM, 0 °C
63 %
2. MeMgBr, toluene, rtthen
Burgess reagent, benzene, 50 °C
88 %
N
O
O
BocN
O HN
Me
7
200 °C, sulfolane
28 - 45 %
N
O
O
HN
O HN
8
N
O
O
BocN
O HN
Me
7
N
O
O
HN
O HN
MeN
O
O
N
O HNH
Yield: 4.5 % from 1 in 8 steps
Comparison with natural Stephacidin A (spectra and optical data)
- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -
Determination of absolute configuration
CO2Me
NH
CO2MeNH
CO2H
H
L-Proline
MeO
N
O
ONBoc
R1
O
ZHN
CO2Me
NH
CO2MeNH
CO2H
H
D-Proline
MeO
N
O
ONBoc
R1
O
ZHN
HN
N
O
ONH
HO
HN
N
O
ONH
O
+
+
NBoc
NHZ
CO2H
O
1
Stephacidin A
R
S
1H and 13C NMR: identical in all respects to natural Stephacidin A Optical properties
HN
N
O
ONH
HO
?
R
S
N
O61
9 8
2021
N
HO
55
5150
39
62
HN O
Synthesis of Stephacidin B
N
N
ON
O
O
Stephacidin B
N
N
O
HN
OO
O
HO
51
2021
39
62
55N
N
O
NH
OO
O
Avrainvillamide
DIMERIZATION
N
N
OHN
O
O
O
N
N
O
HN
OO
O61
9 8
2021
5652
5150
3839
62
H
Stephacidin A
N
O61
9 8
2021
N
O
52
5150
3839
62
H
HN O
a
N
O61
9 8
20 21
N
HO
55
5150
39
62
N O
nitrone
N-hydroxyindole
b
N
O61
9 8
2021
N
O
52
5150
3839
62
H
HN O
nitrone
nitrone
Double Michael addition pathway
c
N
O61
9
2021
N
O
52
5150
3839
62
N O
N-hydroxyindole
nitrone
H
H
d
cd
Cationic pathway
Synthesis of Stephacidin B
Myers’ approach:
Three steps:
1/ Preparation and reactivity study of a model of Avrainvillamide
2/ Enantioselective synthesis of Avrainvillamide from bicyclodiazaoctane nucleus
3/ Formation of Stephacidin B
N
N
ON
O
O
Stephacidin B
N
N
O
HN
OO
O
HO
51
2021
39
62
55
N
N
O
NH
OO
O
Avrainvillamide
2 XOxidation
N
N
O
NH
OO
O
Avrainvillamide
N
O
Model of Avrainvillamide
J. Am. Chem. Soc. 2005, 127, 5342.
J. Am. Chem. Soc. 2003, 125, 12041.
-Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide -
H3C
H3C
H3C CH3
OI2, DMAP,
CCl4-pyridine,50°C H3C
H3C
H3C CH3
O
I
A, Pd2(dba)3, Ba(OH)2.8H2O, 2-(di-t-butylphosphino)biphenyl,
H2O, THF, 38 °C
73 %
or
B, Pd2(dba)3, Cu (powder), DMSO,70 °C
70 %
H3C
H3C
H3C CH3
OO2N
I
O
Pd
O
I
L
L
I
NO2
Cu
NO2
Cu
Pd
O L
L
O2N
PdL4
OO2N
X
NO2
A: X= B(OH)2
B: X= I
Oxidative addition
Formation of
aryl copper derivative
1,1-reductive elimination
Shimizu and coworkers, Tetrahedron Lett. 1993, 34, 3421.
Zn (dust), 1M NH4Cl, EtOH, 48°C
64 %
HN
CH3
H3CH3C
H3C
HEtO
NCH3
H3CH3C
H3C
OH
O
NCH3
H3CH3C
H3C
O
(48 %) (9 %) (7 %)
5-exo-trig 5-endo-trig
-Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide (2) -
H3C
H3C
H3C CH3
OO2N
Identification of the Mickael acceptor group
NCH3
H3CH3C
H3C
O
NCH3
H3CH3C
H3C
OH
NuH
Nu
Base or acid
A B
T = 23 °C A:B = 2:1T = -20 °C A:B = 10:1
h
HN
O
H3CH3C
, EtOH 67 %
Nu: OCD3, SPh, SC6H4OCH3
N
O
N
ON
O
N
O
OH
O
H
NO
NO
H
-Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide (2) -
NCH3
H3CH3C
H3C
O
NCH3
H3CH3C
H3C
OH
NuH
Nu
BaseX
Nu: nPrNH2, , ,NH
O
N
HO
OH2NHN O
Si,
!!!
N
N
OHN
O
O
O
N
N
O
HN
OO
O61
9 8
2021
5652
5150
3839
62
H
N
ONH
O
N
O
OH3C CH3
N
O
O
H
NO
NO
H
H3C CH3
N
H3C
H3CO
H3CCH3
-Myer’s Synthesis of Stephacidin B –- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus -
H3C
H3COTBDPS
N O
N
O
H
N
NH
O
TBDPSO
O
1. HF, CH3CN, 35 °C93 %
2. DMP, DCM, 23 °C85 %
3. I2, DMAP, Pyr-CCl4,, 60 °C91 %
N
NH
O
O
O
I
N
NH
O
O
O
A, Pd2(dba)3, Ba(OH)2.8H2O, 2-(di-t-butylphosphino)biphenyl,
H2O, THF, 38 °C
56 %
or
B, Pd2(dba)3, Cu (powder), DMSO,70 °C
72 %
O
O2N
NO2
I
OH
NO2
I
OCH3
CH3
TBAI, K2CO3,Me2CO, 65 °C
91 %Cl
CH3
H3C
NO2
X
OCH3
CH3
, m-xylène,
140 °C.
CH3
tBu tBu
OH
(BHT)
78 %
NO2
X
OCH3
CH3
A: X =
B: X =
O
B
O
I
B: X =
A: X =O
B
O
I
PhMgCl, -40 °C
O
B
O
iPrO
44 %
Knochel and coll. Angew. Chem. Int. Ed. 2002, 41, 1610.
-Myer’s Synthesis of Stephacidin B –- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus -
N
NH
O
O
O
O
O2N
Zn, NH4Cl, EtOH, 40 °C
49 %
NO
O
N O
NO
H
Avrainvillamide
OHN
OH
NHO
HO
N
O
O
NHOH
OH
N
OH
O
N
OH
Nicolaou and coll. Angew. Chem. Int. Ed. 2005, 44, 3736.
-Myer’s Synthesis of Stephacidin B -- Third Step: Final Formation of Stephacidin B -
NO
O
N O
NO
H
Avrainvillamide Optical property:
Synthetic D25 = -35,1 (c 1,0; CHCl3)
Natural D25 = + 10,6 (c 1,0; CHCl3)
Comparison 1H and 13C NMR spectra:
1H NMR: lack of correspondence in the region 2.45-2.6013C NMR: identical spectra
NO
O
N O
NO
H
N
O
N
ON
O
N
O
HO
O
H
NO
NO
H
Et3N, CH3CN, rt
> 95 %
Optical property:
Synthetic D25 = +91,0 (c 1,0; CHCl3)
Natural D25 : unknown
Comparison 1H and 13C NMR spectra:
⇒ Exact correspondence
Stephacidin B
Interconversion in various solvent-acetonitrile systems:
T = 38 °C AVR : SPC B = 2 : 1T = 23 °C AVR : SPC B = 1 : 2 after 48h
-Synthesis of Stephacidin B -
Baran’s approach:
HN
N
O
ONH
HO
Stephacidin A
HN
N
O
ON
HO
HN
N
O
ON
HO
Aspergamide B Aspergamide A
O
HO
HN
N
O
ON
HO
Avrainvillamide
O
HN
N
O
ON
O
O
NH
N
O
O
N
O
O
H
Stephacidin B
Increasing Oxidation State
J. Am. Chem. Soc. 2006, 128, 8678.
-Synthesis of Stephacidin B -
Baran’s approach: HN
N
O
ON
HO
Aspergamide A
O
HO HN
N
O
ON
HO
Avrainvillamide
O
-H2O (occured gradually
during storage/shipping)
100 %
KMnO4
X
HN
N
O
ONH
HO
Stephacidin A
HN
N
O
ON
HO
Aspergamide B
DDQ,
IBX,
or
Pd/C/O2
HN
N
O
ON
HO
OH
1. O2 (g), MeOH, hv,
2. Me2S
80 %
X
p-TsOH
or
Burgess reagent
X
HN
N
O
ON
HO
OH
-Synthesis of Stephacidin B -
Baran’s approach:
1/ Initial oxidation studies performed on simplified Stephacidin A models
2/ Total synthesis of Stephacidin B starting from Stephacidin A via Avrainvillamide
3/ Biological evaluation of Avrainvillamide and simplified mimics
HN
N
O
ON
H
O
HN
N
O
ONH
HO
Stephacidin A
HN
N
O
ON
HO
Avrainvillamide
ON
N
O
ON
O
OH
NH
N
O
ON
O
O
Stephacidin B
J. Am. Chem. Soc. 2006, 128, 8678.Angew. Chem. Int. Ed. 2005, 44, 3892.
-Synthesis of Stephacidin B -- First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models -
NBoc
NHZ
CO2H
CO2Me
NH
CO2Me
HATU, DIEA, DMF,rt
74 %
MeO
N
O
O
NBoc
R
ZHN
R= CO2Me
H
H
N
O
ONBoc
R
MOMN
1. H2, 10% Pd/C, toluene, rtthen
toluene, reflux
87 %
2. NaHMDS, MOMCl, THF,-78 °C rt
86 - 92 % R= CO2Me
H
LDA, THF, -78 °Cthen
Fe(acac)3, -78 °C
53 %
N
O
ONBoc
R
MOMN
R= CO2Me
(single diastereomer)
BCB, DCM, 0 °C
68 %N
O
ONBoc
R
HN
R= CO2Me
MeMgBr, toluene, rtthen
Burgess reagent, benzene, 50 °C
59 %
N
O
O
BocN
HN
Me
R= CO2Me
p-TsOH, toluene, reflux
68 % N
O
O
HN
HN
Stephacidin A model
Synthesis of a Stephacidin A model :
-Synthesis of Stephacidin B -- First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models -
Oxidation of Stephacidin A models:
NaBH3CN, AcOH, rt
N
O
O
HN
RN
1a: R = PMB1b: R = H
N
O
O
HN
RN
2a: R = PMB2b: R = H
H
HNa2WO4.2H2O, aq. 35% H2O2,
MeOH,H2O, rt
N
O
O
N
RN
N
O
O
N
PMBN
3a: R = PMB (non isolable) 3b: R = H (isolable) 54 % over 2 steps
HOO
N
O
O
N
PMBN
O
spontaneous
16 % over 2 steps
N
O
O
N
HN
O
p-chloranil, THF, reflux
88 %
- Synthesis of Stephacidin B -- Second Step: Formation of Stephacidin B starting from Stephacidin A via Avrainvillamide -
NaBH3CN, AcOH, rt
95 %
HN
N
O
ONH
HO
1: Stephacidin A
HN
N
O
ONH
HO
2
HN
N
O
ON
HO
3: Avrainvillamide
O
4: Stephacidin B
N
N
O
ON
O
OH
NH
N
O
ON
O
O
Conditions
Preparative TLC (SiO2, AcOEt) 15 - 20 % (70 - 80 % recovered 3) Et3N, MeCN, rt, 45 min. 95 %
DMSO, drying in vacuo, 30 min - 1h 2 : 1 (4 : 3)
Conditions
Synthetic Compound Natural Compound
3 []D = +11 (c 0.1, CHCl3) []D = + 10.7 (c 0.1, CHCl3)
4 []D = -33 (c 0.1, MeCN) []D = -21.1 (c 0.19, CDCl3)
Identical in all respects to the natural Stephacidin B:
LCMS TLC in several solvent mixtures 1H NMR Optical rotation
SeO2, 35% aq. H2O2,
1,4 - dioxane, rt
27 %(50 % recovered 2)
Na2WO4.2H2O, aq. 35% H2O2, MeOH,H2O, rt
X
HN
N
O
ONH
H
- Synthesis of Stephacidin B -- Third Step: Biological Evaluation of Avrainvillamide and Simplified Mimics
Biological assays of simplified analogues using the human colon HCT-116 cell line
HN
N
O
ONH
HO
(+)-Stephacidin A
HN
N
O
ON
H
OH
N
N
O
ON
OH
NH
N
O
O
N
O
(±)-Stephacidin B Model
N
N
O
ON
OH
NH
N
O
O
N
O
(-)-Stephacidin B
Stephacidin AModel
HN
N
O
ON
H
O
(±)-Avrainvillamide Model
(+)-Avrainvillamide
HN
N
O
ON
HO
O
Activity (µg/mL)
9.36
5.47
2.0
no significant activity
10.4
Activity (µg/mL)
3.95
0.41
Essential for anti-cancer activity
Low activity
Activity restored
Best candidate for in vivo studies
HN
N
O
ON
HO
O
HN
N
O
ON
HO
O
- Conclusions -
Avrainvillamide (2) Stephacidin B (3)
Myers - 17 steps 4.2 % overall 1 step from 2 95 %
Baran 8 steps 4.5 % overall 3 steps from 1 26 % overall 1 step from 2 15 – 95 %
NO
O
N O
NO
HN
O
N
ON
O
N
O
HO
O
H
NO
NO
H
HN
ON O
NO
H
Stephacidin A (1)
The End