Litterature Meeting
Enantioselective Total Synthesis of
Avrainvillamide
and
Stephacidins A and B
Aspergillus ochraceus
Aspergillus: A source of complexe prenylated indole alkaloids
O
O
Stephacidin B
O
N
O
N
20
N
H
N
H
H
N
21
N
O
O
55 N O
O
O
HN
O
39 N
O
- Isolation from Aspergillus ochraceus WC76466: 2002 – Bristol Myers Squibb
HO 62
-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)
O
N
Me
N
51
Stephacidin A
N
CH3
O
O
O
Paraherquamide F
O
O
21
N
O
H
N
N
N
H
H
N
ON
O
N
N
H3CO
O
Avrainvillamide (CJ-17665)
N
O
8
20
O
O
N
H
9
O
HN
Spirotryprostatins A and B
- 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
Brevianamide A
OH
O
O
O
O
N
N
O
O
N
N
H
N
N
H
O
Aspergamide A
Aspergamide B
Biosynthesis of Stephacidin B: a lesson for the chemist
O
* Birch and coworkers,
J. Chem. Soc. Perkin I, 1974, 50.
N
Prenylation
HN
Reverse
Prenylation
HN
O
Sammes and coworkers
Chem. Comm., 1970, 1103.
.
O
N
Brevianamide F
HN
HN
O
N
O
HN
Tryprostatin B
Deoxybrevianamide E
HN
O
O
N
[O]
2 [O]
N
2 [O]
OH
O
Diels-Alder *
O
N
HN
N
N
N
H
N
O
Demethoxyfumitremorgin C
O
Deoxyaustamide
2 [O]
[O]
bicyclo[2.2.2]diazaoctane
O
O
O
O
O
H
N
N
HN
N
N
N
H
N
N
H
N
O
O
Spirotryprostatin B
O
Austamide
O
Brevianamide A
Presumed biosynthesis of Stephacidins A and B
O
O
O
N
ON
H
N
20
55
NO
N
N
O
21
O
O
O
[O]
O
Avrainvillamide
N
51
39
O
N
N
H
[O]
HO 62
O
Stephacidin B
O
O
N
N
H
N
H
Stephacidin A
Intramolecular
Diels-Alder
Tryptophane
O
OH
NH2
HN
O
O
O
Prenylation
O
N
HN
HN
HO
N
HN
[O]
HN
N
O
O
Proline
OH
Brevianamide F
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Williams’ approaches
H
N
H
O
PMB
O
N
NaH
SN2’
N
PMB
O
N
N
H
O
N
Cl
H
N
H
N
N
H
O
OMe
Diels-Alder
N
H
O
N
N
2:1 mixture
J. Am. Chem. Soc. 1990, 112, 808.
Acc. Chem. Res. 2003, 36, 127.
Tetrahedron Lett. 2004, 45, 4489.
OMe
PMB
O
N
Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach
N
H
N
O
OHC
O
1. TFA, pentane, 92
%
O
O
CH2NHLi
OH
NH
N
2. LDA, THF, hexane, -78 °C
O
N
H
THF, -78 °C
NH
OMe
then
L-Proline
quant.
Br
1. BrCH2COBr
DCM/ K2CO3
, THF,
-78 °C to -30 °C, 87
Seebach and coworkers,
J. Am. Chem. Soc. 1983, 105, 5390.
%
2. 50 % aq. NaOH,
DCM
Me
Me
TBDMSO
1.
Ph3P
O
N
CHO
3. TBDMSCl, Et3N,
DMAP, DCM
1. nBuLi, THF
O
71 %
85 %
O
O
2. NaBH4, EtOH
NPMB
2. ClCO2Me
MeO
O
O3 / MeOH,
Me2S
NPMB
N
99 %
O
NPMB
N
O
85 %
TBDMSO
NMe2
Me
Me
TBDMSO
O
O
NPMB
N
CO2Me
O
4:1 mixture
N
H
Bu3P, MeCN, 
62 %
NPMB
CO2Me
N
Somei and coworkers,
Heterocycles 1981, 16, 941.
O
N
H
PMB
O
N
Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2)
1. LiCl, HMPA, H2O,
100°C
TBDMSO
HO
Me
2. Boc2O, tBuOK, THF
then
Bu4NF, THF, rt
NPMB
CO2Me
N
N
Me
O
O
MsCl, LiCl, DMF,
collidine
NPMB
O
NPMB
H
N
85 %
quant.
H
N
O
O
N
H
N
Boc
N
Boc
H
H
H
H
H
Base / Solvant
H
Me
Me
+
BocN
BocN
pMB O
N
pMB O
N
N
N
O
O
ANTI
Brevianamide B
O
Cl
Me
O
N
H
SYN
Solvent
Temperature
(°C)
Base
Ratio
anti:syn
Yield (%)
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
PMB
O
N
Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2)
Cl
O
O
N
(Me)3CO
N
(Me)3CO
Me
NaH, DMF
O
O
O
N
O
Na
O
N
H
OMe
N
O
NaH, benzene, 80 °C
18-crown-6
O
H
OMe
N
O
O
O
"OPEN" transition state
ANTI
H
H
O
O
Cl
Tight
ion pair
N
N
(Me)3CO
OC(Me)3
Na
NaH, benzene, 80 °C
Me
O
O
N
H
OMe
N
Me
OMe
N
O
O
"CLOSED transition state
SYN
O
N
H
N
Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder approach
H
H
N
N
H
O
OMe
N
N
H
N
N
H
O
OMe
N
OMe
N
O
O
1. 6M aq. HCl, NaNO2, 0°C
1.
2. SnCl2, 10M aq. HCl, 0 °C
NH2
toluene, 
3. 10M aq. NaOH
NHNH2
NMe2
H2CO, MeNH,
AcOH, rt
N
H
2. ZnCl2, diglyme, 170 °C
N
H
83 %
45 %
1. SOCl2, benzene, 
HO2C
Cbz
N
2. (MeO2C)2-CHNH2,
Et2O, 0 °C
then
Na2CO3, H2O, 15 °C
1. H2, Pd/C, MeOH, 70 °C
H
O
NH
MeO2C
O
H
MeO2C
MeO2C
Cbz
N
2.
, 70 °C
N
OH
HN
NaH, DMF,
60 °C
N
O
H
H
69 %
93 %
N-Z-L-Proline
77 %
O
N
HN
HN
H
O
2.5:1
NaOH, MeOH, rt
then
dioxane, 65 °C
MeO2C
O
N
HN
HN
H
82 %
O
2.5:1
H
N
Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach
O
O
N
O
N
HN
N
H
OMe
N
HN
HN
HN
H
H
O
Williams et al. Bioorg. Med. Chem., 1998, 6, 1233.
O
epi-deoxybrevianamide E
deoxybrevianamide E
2.5
:
1
O
Me3OBF4, DCM, 0 °C
O
N
HN
DDQ, toluene, -78 °C
N
HN
N
79 %
H
OMe
N
31 %
OMe
KOH, MeOH, H2O
90 %
H
N
H
N
+
H
S
O
N
R
OMe
N
OMe
HN
N
N
N
N
O
O
2
:
1
OMe
H
N
Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach
OMe
H
H3C
N
H3C
N
HN
HN
H
N
O
"EXO"
"ENDO"
OMe
OMe
CH3
R
N
N
O
H
O
OMe
CH3
H3C
N
H
OMe
O
H3C
N
N
S
N
HN
N
H
HN
N
N
HN
OMe
O
O
KOH, MeOH, H2O
90 %
H
N
H
N
H
O
+
N
S
R
OMe
OMe
N
HN
N
N
N
N
O
O
2
:
1
OMe
William’s synthesis of bicyclo[2.2.2]diazaoctane nucleus
H
N
H
O
PMB
O
N
PMB
O
N
NaH
N
H
SN2’
N
O
N
Cl
 16 steps in 12 % yield overall
 High stereoselectivity of alkylation based on the presence or absence of metal chelation
H
N
H
N
N
H
O
OMe
Diels-Alder
N
H
O
N
N
2:1 mixture
MeO2C
NMe2
 4 steps in 17 % yield overall from
H
O
and
N
H
HN
N
O
H
Medium stereoselectivity of cycloaddition based on steric effects
OMe
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Liebscher’ approach
H
N
MOM
H
N
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)
AcCl
O
H
Diels-Alder
O
N
H
N
H
N
O
O
N
Liebscher and coll. J. Org. Chem. 2001, 66, 3984.
O
R1
N
R3
O
HN
R2
O
N
AcCl or HCO2H or DCM, BF3.OEt2
A
N
P = atm, 10 kbar
T = rt, reflux
H
O
R3
1
N
N
OCOR
B
R1 = iPr, Ph
R2 = H, Ph
R3 = Ph, (CH2)4
R = Me, CH2Br, Ph
major
R2
O
R1
N
N
+
H
O
R
R1
O
+
H
R2
R3
R1
N
N
O
X
H
X=
OCOR
Cl
OH
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
O
Liebscher’ approach (2)
H
H
N
CHO
O
HN
+
MeO
N
MOM
O
N
H
N
MeO
N
P
O
O
1. 6M aq. HCl, NaNO2, 0°C
O
1.
2. SnCl2, 10M aq. HCl, 0 °C
3. 10M aq. NaOH
NHNH2
toluene, 
NH2
ClHC=NMe2Cl,
DCM,
then aq. NaOH,
EtOAc
2. ZnCl2, diglyme, 170 °C
Cl
9-BBN
N
H
Williams and coll. Tetrahedron Lett. 2005, 46, 9013.
N
H
O
ZHN
OH
MeO
P
O
N
H
N
H
Et3N
NCS, DMF, rt
MeO
CHO
+
H
N
O
DCC,
O
O
DCM, rt
O
Z-Admpa
Lieberknecht and coll. Tetrahedron Lett. 1987, 28, 4275.
H2, Pd/C, AcOH, MeOH
HN
O
92 %
ZHN
MeO
MeO
N
P
O
O
95 %
MeO
MeO
N
P
O
O
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Liebscher’ approach (3)
H
CHO
tBuOK
O
N
MOM
78 %
HN
MeO
MeO
N
MOM
O
H
N
N
N
H
N
AcCl
N
H
Diels-Alder
O
N
rt, 20 days
P
O
O
R
H
one stereoisomer !
O
48 %
minimal steric repulsion
OAc
H
OAc
H
R
H3C
N
"EXO"
N
H3 C
HN
N
HN
N
O
O
defavoring steric repulsion
OAc
CH3
"ENDO"
H3C
H3C
HN
OAc
CH3
N
S
N
H
N
O
HN
H
N
O
O
Liebscher’s synthesis of bicyclo[2.2.2]diazaoctane nucleus
H
N
MOM
H
N
AcCl
O
H
Diels-Alder
O
N
H
N
H
N
O
O
CHO
 2 steps in 37 % yield overall from
HN
and
N
MOM
MeO
MeO
N
P
O
O
 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 !!
N
O
Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus
Myers’ approach
O
PhS
H
H
N
O
H
TBDPSO
H
O
t-amyl
O
Ph
O
O
H
TBDPSO
tBuPh
RN
H
N
O
N
Acyl radical approach
R=
J. Am. Chem. Soc. 2005, 127, 5342.
O
H3C
H3 C
Abrams and coll. Tetrahedron 1991, 47, 3259.
PhS
O
H
H
N
O
O
H
TBDPSO
O
RN
iPr
S
OH2C
NBoc
O
NBoc
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
O
H3C
Ph
Ph
H
H3C
S
N
O
O
OTBS
(0.1 equiv)
B
O
O
OH
(S)-CBS
(92 % ee)
HO
CH3
R1
R2
LiHMDS, TMS-Cl,
R1 > R2
Pd(OAc)2, CH3CN, rt
R1
BH3.THF (0.6 equiv), THF
O
H
O
R2
Corey and coworkers,
Tetrahedron Lett. 1991, 32, 5025.
84-97.6 % ee
98 %
or
Ph
H
Ph
IBX, MPO, DMSO,
O
60°C
N
70 %
O
H3C
Ph
Ph
H
BH3.DMS
O
N
B
H2BO H
R
B
R
H3 C
H3B
H3C
H3C
O
O
O
Ph
O
N
B
H2B
BH3.DMS,
HCl, MeOH
H
(S)-CBS catalyst,
THF, 0 °C
BH3
HO
H
O
B
H
H
H 3C
O
CH3
O
R
O
R
O
R
O
Ph
O
O
O
Ph
OH
H3 C
H
O
R
H3C
H3C
H3C
H3C
Ph
H
O
94 %, >95 % ee
O
H3C
Ph
N
O
B
H2B
O
H
H3C
O
Ph
N
O
B
O
O
H2B
H
H 3C
CH3
CH3
O
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
O
OH
H3C
H3C
1. TBDPSOTf, 2,6-lutidine,
H3C
O
iPr
OTBDPS
H3 C
H3 C
O
O
NBoc
70 %
O
Me2CO/H2O/THF,
0 °C
S
2. -35 °C,
2. 1N H2SO4,
O
1. KHMDS, -78 °C
CH2O
BocN
H3C
DCM, rt
R
OTBDPS
rt
91 %
TMS-CN,
HFIPA, 0 °C
4:1 dr, 81 %
H
O
H
H3C
OTBDPS
H3C
O P
P
Pt
P
OH
H3 C
EtOH, H2O, 70 °C
85 %
O
NBoc
H3 C
H3C
NC
OTBDPS
H3 C
R
O
H2N
OTBDPS
O
NBoc
KHMDS, PivOH, -78 °C
88 %
H3 C
OTBDPS
H3 C
S
NC
O
NBoc
(65 %)
NC
O
NBoc
(16 %)
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
H
O
O
O
H3C
OH
Pt
H
Ghaffar T., Parkins A. W.
J. Mol. Cat. A 2000, 160, 249.
Me2
P
Me2
P
OTBDPS
H
O P
H 3C
Pt
H3 C
P
P
H3C
OH
H
P
Me2
OTBDPS
O
EtOH, H2O, 70 °C
H2O
NC
H2N
O
NBoc
O
NBoc
85 %
H2
Me2
P
Me2
P
O
OH
Pt
H
O
OH
P
Me2
S = H2O
O
R
NH2
Me2
P
Me2
P
O
O
O
X
H
O
Pt
H
S
P
Me2
Me2
P
Me2
P
O
OH
Pt
H
R-CN
P
Me2
O
OTBDPS
NC
O
Me2
P
Me2
P
Pt
H
O
O
O
N
H
C
H
O
O
R
P
Me2
NBoc
7-membered ring !
OH
Pt
H
H
P
Me2
Me2
P
Me2
P
N
C
R
O
O
P
Me2
O
P
Me2
O
O
Pt
H
H2O
Me2
P
Me2
P
O
Pt
H
O
Me2
P
Me2
P
OTBDPS
NC
N
C
R
NBoc
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
H 3C
OTBDPS
H3C
OTBDPS
SPh
H3C
H 3C
O
H 2N
98 %
OH
NH
O
NBoc
95 %
NH
Cl
2.
N
Boc
SPh
H3C
DCM, -78 °C 0 °C
PhSH, Et3N, THF, 70 °C
OTBDPS
H3C
1. TMSOTf, 2,6-lutidine,DCM,
N
, DIPEA, DCM, rt
O
O
O
O
92 %
O
O
R
X
O
R
Me
N
+
t-amyl
O
Ph
Ph
In
N
O
tBuPh, 120 °C
Ph
O
R
N
+
62 %
MePh
Ph
Jackson L. V., Walton J. C. Chem. Commun. 2000, 2327.
OTBDPS
H3C
H3 C
O
TBDPSO
N
O
O
N
NH
N H
O
Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach
Ph
Ph
O
N
N
Ph
O
In
N
- MePh
O
X
O
R
N
Ph
R=
H
Ph
N
O
+
N
O
Ph
N
Ph
N
O
major product
Ph
O
minor product
6-endo-trig
5-exo-trig
O
6-exo-trig favored
N
O
TBDPSO
SPh
H
N
O
OTBDPS
N
O
O
H

SPh
H
N
O
OTBDPS
H
N
NH
O
H
NH
62 %
SPh
H
O
TBDPSO
NH
TBDPSO
Me
N
7-membered ring closure
PhS
BUT
O
vs
Me
minor conformation
N
O
H
Myers’ synthesis of bicyclo[2.2.2]diazaoctane nucleus
O
H3C
OTBDPS
H3C
H3C
H3C
O
O
O
TBDPSO
N
O
N H
O
Enantioselective synthesis of the desired nucleus
O
H3C
O
H3C
12 steps in 19 % yield overall from
and
O
iPr
S
OH2C
O
O
Product used as precursor for synthesis of Stephacidin B
NBoc
N
O
NH
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
H
N
H
H
N
O
N
O
2/ Application of the strategy to a functionalized system for eventual
elaboration into Stephacidin A
H
H
N
O
N
H
O
O
N
3/ Formation of Stephacidin A
H
H
N
O
N
H
O
O
N
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 Br
Intramolecular
vinyl radical
cyclisation
H
N
H
H
N
O
O
N
H
O
N
O
H
N
Intramolecular
Diels-Alder
N
H
N
H
N
O
Intramolecular
oxidative enolate
heterocoupling
O
N
PG
N
N
Boc O
MeO O
N
O
- 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
H
N
O
Dehydrogenation
H
N
O
H
Peptide coupling
CO2H
NHBoc
N
H
O
N
H
N
O
+
N
N
H
N
H
N-Boc-L-Trp
CO2Me
Br
p-TsOH, toluene,
reflux
H
N
Boc
CO2Me
LHMDS, THF, -78 °C
N
Boc
N
H
CO2Me
83 %
CO2Me
Boc-L-Trp-OH, BOP-Cl,
DIEA, DCM, rt
84 %
48 %
O
H
N
Dehydrogenation
O
CO2Me
NHBoc
190 °C, neat
N
H
O
N
N
H
54 %
NH
- 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 (2)
Y
X
Dehydrogenation:
Y
H
X
H
N
O
PhNO, ZrCl4, DCM
0 °C
rt
H
N
92 %
N
H
N
H
N
O
O
O
⇒ Study of direct dehydrogenation of simplified Trp derivatives
N
O
O
MLn
N
+
R1
O
R1
Ph

O
Ph
N
H
R2
R2
Yamamoto and coll. J. Am. Chem. Soc. 2004, 126, 5962.
NO
Path A
H
CO2Me
CO2Me
H
O
NHCO2Me
N
NHCO2Me
O H
N
CO2Me
NHCO2Me
ZrCl4
N
H
N
H
N
H
NHOH
Path B
H
NO
CO2Me
N H
O
NHCO2Me
CO2Me
H
NHCO2Me
CO2Me
CO2Me
NHCO2Me
NHCO2Me
ZrCl4
N
H
N
H
N
N
H
- 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 (3)
H
N
O
X
N
H
O
N
H
Diels-Alder
N
H
O
conditions
H
N
O
N
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
OAc
X
N
H
OAc
N
H
Diels-Alder
Liebscher method
N
H
O
H
N
N
O
- 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
H
N
H
H
N
O
H
O
N
H
N
H
N
O
Br
O
H
N
N
H
N
O
N
O
1. LHMDS, THF, -78 °C,
2.
H
N
Boc
CO2Me
Br
Br
Br
O
N
H
3.p-TsOH, toluene,
reflux
CO2Me
N
Br
H
Boc-L-Trp-OH, BOP-Cl,
DIEA, DCM, rt
CO2Me
NHBoc
54 %
NH
71 %
O
H
N
H
H
N
O
Br
AIBN, nBu3SnH
X
O
N
N
H
O
H
N
N
O
PhNO, ZrCl4,
DCM, rt
N
Br
H
O
79 %
NH
p-TsOH, toluene,
reflux
46 %
- 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
PG
H
N
H
H
N
H
O
N
O
N X
H
MeO O
X=O
PG
O
N
Intramolecular
Oxidative Coupling
N
X = CH2
N
Z
CO2Me
OTBS
2. H2, Pd/C, MeOH, rt
Br
N
Z
3. 9-BBN, H2O2, NaOH
H
N
H
CO2Me
NHZ
96 %
74 %
PMB
N
O
N
Boc
H
N
N
Boc
TBSO O
O
1. H2, Pd/C, MeOH,
AcOEt, rt
CO2Me
2. toluene, reflux
N
74 %
N
1. TBAF, THF
PMB
2. DMP, DCM, rt
N
3. NaClO2, NaH2PO4.H2O, THF, H2O, rt
N
Boc
TBSO O
N
HATU, DIEA,
DMF, rt
ZHN
N
Boc
TBSO O
4. CH2N2, MeOH, 0 °C
72 %
N O
Boc
MeO O
N
CO2H
CO2Me
78 %
NaH, PMB-Cl, DMF,
0 °C
N
1. TBSCl, ImH, DCM, rt
1. LHMDS, THF, -78 °C,
2.
N O
H
MeO O
Baran and coll. Angew. Chem. Int. Ed. 2005, 44, 609.
OH
H
O
N
O
79 %
- Baran’s Synthesis of Stephacidin A –
- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus Burgess reagent
Third strategy: Ring closure by intramolecular oxidative enolate coupling
O
O
O
S
N
PMB
O
N
N O
Boc
MeO O
6
N O
Boc
MeO O
4
65 %
N
N
Boc
4
41 %
N
N
Me O
MO
PMB
PMB
N O
Boc
MeO O
O
N
2. Burgess reagent, benzene,
50 °C
Diastereoselectivity
N
PMB
H
O
7 N
LDA, -78 °C, then Fe(acac)3,
THF, -78 °C
rt
1. MeMgBr, toluene, 0 °C
PMB
H
6R
NEt3
N
O
OMe
PMB
O
N
O
LDA
N
Boc O
N
O
LnFe
N
Boc
N
MO
OMe
N
"non-chelated"
"chelated"
Mechanism ?
PMB
N
N
Boc O
O
LnFe
N
OMe
A (ionic/ concerted)
O
N
N
Boc O
O
N
OMe
B (diradical)
PMB
PMB
PMB
O
N
N
Boc O
O
LnFe
O
N
OMe
C (initial amide oxidation)
N
N
Boc O
O
LnFe
O
N
OMe
D (initial ester oxidation)
- Baran’s Synthesis of Stephacidin A –
- Second step: Application to the elaboration of a suitable functionalized system CO2H
H
H
N
O
N
H
O
H
O
O
N
H O
N
O
OMe
H
N
O
Amide bond
formation
NHZ
N
N
H
Benzopyran
Tryptophan
CO2Me
NHZ
I
Pd(OAc)2, DABCO, TBAI, DMF, 105 °C
+
HO
NH2
N
Z
CO2Me
TsO
75 %
N
H
.HI
N
N
-hydride
elimination
N
N
X = PdI
X
Pd
CO2Me
NHZ
TsO
CO2Me
Ln
X=I
N
H
CO2Me
Ha
N
H
PdLn
migratory
insertion
Reider and coll. J. Org. Chem. 1997, 62, 2676.
NHZ
NHZ
TsO
TsO
CO2Me
Proline-derived
Ester
Benzopyran Tryptophan Synthesis:
TsO
OMe
+
N
H
O
Stephacidin A
O
N
Hb
- Baran’s Synthesis of Stephacidin A –
- Third step: Final formation of Stephacidin A Benzopyran Tryptophan Synthesis (2):
CO2Me
CO2Me
NHZ
NHZ
N
H
2. Mg(0), MeOH, 0 °C
OCO2Me
O
rt
NHZ
o-dichlorobenzene,
190 °C
1. Boc2O, DMAP, DCM/MeCN, rt, 95 %
TsO
CO2Me
N
Boc
N
H
O
95 %
3. A, CuCl2 (O.1 mol%), DBU,
DCM/MeCN, 0°C
75 %
CO2H
A
1. Boc2O, DMAP,
DCM/MeCN, rt,
NHZ
77 %
N
Boc
O
2. LiOH, THF/H2O, 0°C
100 %
Proline Synthesis:
9-BBN, THF, rt
then
3M aq. NaOH/ 35 % aq. H2O2
N
Z
CO2Me
OTBS
TBSCl, ImH, DCM, rt
92 %
96 %
N
Z
100 %
CO2Me
OTBS
H2, Pd/C, toluene, rt
N
H
O
1. PhI(OAc)2, TEMPO,
MeCN/H2O, rt
O
OMe
H2, Pd/C, toluene, rt
OMe
97 %
2. CH2N2, AcOEt, rt
86 %
CO2Me
N
Z
CO2Me
N
H
CO2Me
- Baran’s Synthesis of Stephacidin A –
- Third step: Final formation of Stephacidin A Union of Tryptophan and Proline Fragments
CO2H
NHZ
N
Boc
O
2a or 2b, HATU, DIEA,
DMF,rt
R1
ZHN MeO
O
O
R1
N
O
Boc
N
H
CO2Me
3a: R= CH2OTBS
3b: R= CO2Me
2a: R= CH2OTBS
2b: R= CO2Me
1
N
62 %
81 %
Ohfune and coll.
J. Org. Chem. 1990, 55, 870.
MOM
N
O
LDA, THF, -78 °C
then
Fe(acac)3, -78 °C
N
Boc
Conditions
R1
O
N
5a: R= CH2OTBS; Base = NaH
5b: R= CO2Me ; Base = NaHMDS
H
O
MOM
N
BocN
O
MeO O
6
N
O
Conditions
H
N
O
O
Base, MOMCl, THF,
-78 °C rt
65 %
63 %
61 %
O
Pd2dba3.CHCl3, Et3SiH,
Et3N, DCM, rt
then
MeOH, reflux
then
toluene,reflux
1. TBAF, THF, rt
2. DMP, DCM, rt
3. NaClO2, NaH2PO4.H2O, THF, rt
4. CH2N2, MeOH, rt
69 %
R1
N
O
Boc
4a: R= CH2OTBS
4b: R= CO2Me
N
53 %
85 %
- Baran’s Synthesis of Stephacidin A –
- Third step: Final formation of Stephacidin A Union of Tryptophan and Proline Fragments (2)
O
1. BCB, DCM, 0 °C
MOM
N
O
O
H
N
63 %
BocN
N
O
MeO O
BocN
2. MeMgBr, toluene, rt
then
Burgess reagent, benzene, 50 °C
6
Me O
O
N
200 °C,
sulfolane
7
88 %
28 - 45 %
O
H
N
Yield: 4.5 % from 1 in 8 steps
Comparison with natural Stephacidin A (spectra and optical data)
HN
O
N
O
8
O
H
N
BocN
Me O
7
O
N
O
H
N
HN
Me O
O
N
O
H
N
O
H
N
O
N
- Baran’s Synthesis of Stephacidin A –
- Third step: Final formation of Stephacidin A ?
Determination of absolute configuration
H
H
N
O
 1H and 13C NMR: identical in all respects to natural Stephacidin A
N
H
 Optical properties
O
N
O
CO2Me
H
N
H
N
H
CO2H
CO2Me
ZHN MeO
H
H
O
O
O
R N
O
L-Proline
R1
N
O
Boc
R
N
H
N
N
O
+
CO2H
NHZ
N
Boc
O
1
+
ZHN MeO
O
H
O
S N
O
D-Proline
CO2Me
R1
N
O
Boc
N
N
H
O
N S
H
N
H
CO2H
N
H
CO2Me
Stephacidin A
O
Synthesis of Stephacidin B
O
O
N
H
N
20
DIMERIZATION
O
NO
ON
N
O
21
55
O
N
H
N
Stephacidin A
O
O
O
N
51
N
39
Avrainvillamide
O
HO 62
Double Michael addition pathway
Stephacidin B
61
Cationic pathway
61
O
H
9N
61
8
H
N
O
9N
ON
20
O
8
O
nitrone
9N
8
21
O
20
50
d
21
H
N
H
N
51
O
O
50
O
O
38
39 N
62 O
a
39 N
nitrone
38
c
H
61
61
O
9N
61
8
20
50
b
H
N
62 HO
N-hydroxyindole
8
20
d
20
50
21
51
52
50
O
51
N
O
55
55
39 N
H
O
9N
nitrone
9N
21
51
O
39 N
62 HO
O
38
62 O
62 O
H
H
N
52
56 N
52
21
51
50
51
52
39 N
20
c
39 N
38
62 O
N-hydroxyindole
H
nitrone
21
N
O
Synthesis of Stephacidin B
Myers’ approach:
Three steps:
1/ Preparation and reactivity study of a model of Avrainvillamide
O
J. Am. Chem. Soc. 2003, 125, 12041.
O
ON
N
H
N
N
O
O
Avrainvillamide
Model of Avrainvillamide
2/ Enantioselective synthesis of Avrainvillamide from bicyclodiazaoctane nucleus
3/ Formation of Stephacidin B
O
N
H
N
20
O
55
NO
O
N
O
21
O
O
O
Oxidation
ON
2X
N
N
51
39
N
N
H
O
O
Avrainvillamide
HO 62
Stephacidin B
J. Am. Chem. Soc. 2005, 127, 5342.
-Myer’s Synthesis of Stephacidin B –
- First step: Preparation and reactivity study of a model of avrainvillamide -
O
H 3C
I2, DMAP,
CCl4-pyridine,50°C
H 3C
H3C
A, Pd2(dba)3, Ba(OH)2.8H2O,
2-(di-t-butylphosphino)biphenyl,
H2O, THF, 38 °C
O
I
H3C
O 2N
O
H3C
H 3C
73 %
or
H3C
CH3
H3 C
CH3
B, Pd2(dba)3, Cu (powder), DMSO,
70 °C
H3C
CH3
NO2
70 %
X
O2N
O
A: X= B(OH)2
B: X= I
O
I
PdL4
Shimizu and coworkers, Tetrahedron Lett. 1993, 34, 3421.
Oxidative addition
O
L
Pd
1,1-reductive
elimination
I
L
O2N
O
L
Pd
L
Cu
I
NO2
NO2
Cu
Formation
of
aryl copper derivative
-Myer’s Synthesis of Stephacidin B –
- First step: Preparation and reactivity study of a model of avrainvillamide (2) -
H3C
O 2N
O
H3C
CH3
O
H3C
N
CH3
OH
H3C
N
CH3
H
N
Zn (dust), 1M NH4Cl,
EtOH, 48°C
H 3C
H3C
H3C
H3C
64 %
CH3
H3C
H3C
(48 %)
H3C
H3C EtO
O
(9 %)
5-exo-trig
(7 %)
5-endo-trig
Identification of the Mickael acceptor group
H3C
CH3
O
H3C
N
CH3
Base or acid
H3C
H3C
Nu: OCD3, SPh, SC6H4OCH3
H
Nu
B
A
O
h , EtOH
T = 23 °C A:B = 2:1
T = -20 °C A:B = 10:1
N
Nu
H3C
H3C
OH
67 %
H3C
H3C
H
N
H
-Myer’s Synthesis of Stephacidin B –
- First step: Preparation and reactivity study of a model of avrainvillamide (2) CH3
H3 C
!!!
O
H3C
N
OH
CH3
N
Nu
Nu: nPrNH2, O
X
Base
H3C
H3C
H3 C
H3C
, HO
,
N
H
H2N
,
O
N
H
N
O
Si
H
Nu
H 3C
CH3 O
H3 C
N
H 3C
O
H3C
N
61
O
9N
N
8
20
O
CH3O
H
N
O
O
O
N
H
ON
N
OH
21
N
O
O
O
H
N
O
50
O
56 N
N
N
O
O
39 N
38
O
H
H
H
62 O
O
O
N
N
H3C
O
N
CH3
O
O
H
H
O
51
52
N
N
-Myer’s Synthesis of Stephacidin B –
- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus 1. HF, CH3CN, 35 °C
OTBDPS
H3C
93 %
H3C
N
O
O
TBDPSO
N
N H
N
O
O
O
2. DMP, DCM, 23 °C
85 %
NH
O
NH
3. I2, DMAP, Pyr-CCl4,, 60 °C
O
I
91 %
A, Pd2(dba)3, Ba(OH)2.8H2O,
2-(di-t-butylphosphino)biphenyl,
H2O, THF, 38 °C
56 %
or
NO2
I
NO2
TBAI, K2CO3,
Me2CO, 65 °C
OH
91 %
Cl
H3C
B, Pd2(dba)3, Cu (powder), DMSO,
70 °C
I
O
CH3
72 %
CH3
(BHT)
CH3
, m-xylène,
tBu 140 °C.
tBu
CH3
NO2
X
OH
O
iPrO
B: X =
O
78 %
I
CH3
CH3
O
N
O
B
NO2
O
PhMgCl, -40 °C
44 %
O
A: X =
O
O
B
O
Knochel and coll. Angew. Chem. Int. Ed. 2002, 41, 1610.
NH
X
O
CH3
A: X =
O2N
B
O
CH3
B: X =
I
O
-Myer’s Synthesis of Stephacidin B –
- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus -
O
N
O
O
O
NH
N
O
Zn, NH4Cl, EtOH, 40 °C
N
O2N
O
O
N
H
49 %
Avrainvillamide
O
OH
O
HO
HN
N
N
O
HO
O
OH
NH
OH
Nicolaou and coll. Angew. Chem. Int. Ed. 2005, 44, 3736.
O
N
N
OH
OH
-Myer’s Synthesis of Stephacidin B - Third Step: Final Formation of Stephacidin B Optical property:
Avrainvillamide
O
N
Synthetic
Natural
O
N
N
O
aD25 = -35,1 (c 1,0; CHCl3)
aD25 = + 10,6 (c 1,0; CHCl3)
O
Comparison 1H and 13C NMR spectra:
H
1H
NMR: lack of correspondence in the region d 2.45-2.60
NMR: identical spectra
13C
O
Stephacidin B
N
HO
N
O
N
O
Et3N, CH3CN, rt
O
O
N
O
N
H
O
H
N
> 95 %
Synthetic
Natural
N
O
aD25 = +91,0 (c 1,0; CHCl3)
aD25 : unknown
Interconversion in various solvent-acetonitrile systems:
Comparison 1H and 13C NMR spectra:
AVR : SPC B = 2 : 1
AVR : SPC B = 1 : 2 after 48h
H
O
Optical property:
T = 38 °C
T = 23 °C
O
N
⇒ Exact correspondence
N
O
-Synthesis of Stephacidin B Baran’s approach:
O
H
H
N
N
O
O
N
H
Stephacidin A
O
H
H
N
H
N
O
O
O
N
N
N
HO
H
N
O
O
O
Aspergamide A
Aspergamide B
H
N
O
H
O
Increasing Oxidation State
N
N
O
O
Avrainvillamide
O
O
N
N
N
H
O
O
O
H
H
N
O
N
J. Am. Chem. Soc. 2006, 128, 8678.
N
O
O
Stephacidin B
-Synthesis of Stephacidin B Baran’s approach:
O
H
N
H
-H2O (occured gradually
HO
O
N
N
O
H
N
O
during storage/shipping)
N
X
N
O
N
H
O
O
KMnO4
H
H
N
O
Avrainvillamide
Aspergamide A
O
O
N
100 %
O
H
H OH
H
N
O
1. O2 (g), MeOH, hv,
2. Me2S
O
N
N
O
80 %
Stephacidin A
DDQ,
X
IBX,
X
or
p-TsOH
or
Burgess reagent
Pd/C/O2
O
H
H
N
O
O
H
N
H
O
N
N
O
Aspergamide B
N
N
O
OH
-Synthesis of Stephacidin B Baran’s approach:
1/ Initial oxidation studies performed on simplified Stephacidin A models
H
N
O
O
H
N
O
N
2/ Total synthesis of Stephacidin B starting from Stephacidin A via Avrainvillamide
N
O
H
H
N
N
O
O
O
H
N
H
N
O
N
O
O
N
N
H
O
O
O
O
N
H
O
N
O
N
N
Stephacidin A
O
OH
Avrainvillamide
Stephacidin B
3/ Biological evaluation of Avrainvillamide and simplified mimics
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 Synthesis of a Stephacidin A model :
CO2Me
1. H2, 10% Pd/C, toluene, rt
then
toluene, reflux
CO2H
H
N
H
NHZ
CO2Me
ZHN MeO
H
HATU, DIEA, DMF,rt
N
Boc
R
N
Boc
74 %
O
H
O
87 %
2. NaHMDS, MOMCl, THF,
-78 °C rt
N
H
N
MOM
N
O
O
N
Boc
N
p-TsOH, toluene, reflux
HN
68 %
N
(single diastereomer)
H
N
BocN
O
R= CO2Me
R= CO2Me
O
R
68 %
R= CO2Me
Me
N
53 %
R
59 %
O
O
O
BCB, DCM, 0 °C
N
Boc
N
R
LDA, THF, -78 °C
then
Fe(acac)3, -78 °C
MeMgBr, toluene, rt
then
Burgess reagent,
benzene, 50 °C
H
N
O
R= CO2Me
86 - 92 %
R= CO2Me
N
Boc
MOM
N
O
N
O
Stephacidin A model
-Synthesis of Stephacidin B - First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models Oxidation of Stephacidin A models:
R
N
R
N
H
O
H
NaBH3CN, AcOH, rt
O
Na2WO4.2H2O, aq. 35% H2O2,
MeOH,H2O, rt
HN
HN
O
N
N
O
2a: R = PMB
2b: R = H
1a: R = PMB
1b: R = H
PMB
N
R
N
O
N
O
N
O
N
O
HO
3a: R = PMB
3b: R = H
N
O
(non isolable)
(isolable)
54 % over 2 steps
p-chloranil, THF, reflux
spontaneous
PMB
N
88 %
H
N
O
N
O
N
O
N
16 % over 2 steps
O
O
N
O
- Synthesis of Stephacidin B - Second Step: Formation of Stephacidin B starting from Stephacidin A via Avrainvillamide -
O
H
H
N
N
O
O
N
H
NaBH3CN, AcOH, rt
O
N
95 %
SeO
Na2WO
35%
2, 35%
2O2,H2O2,
4.2H
2O, aq. H
MeOH,H
1,4
- dioxane,
rt
2O, rt
H
H
N
O
X
N
H
O
1: Stephacidin A
27 %
(50 % recovered 2)
2
Synthetic Compound
Natural Compound
3
[a]D = +11 (c 0.1, CHCl3)
[a]D = + 10.7 (c 0.1, CHCl3)
4
[a]D = -33 (c 0.1, MeCN)
[a]D = -21.1 (c 0.19, CDCl3)
O
H
H
N
O
N
N
N
O
3: Avrainvillamide
O
O
O
N
O
Identical in all respects to the natural Stephacidin B:
O
N
H
O
 LCMS
 TLC in several solvent mixtures
 1H NMR
 Optical rotation
Conditions
O
N
N
N
O
OH
4: Stephacidin B
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)
- 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
Activity (µg/mL)
Best candidate
for in vivo studies
O
Activity (µg/mL)
H
H
N
O
O
N
9.36
N
N
O
N
OH
O
(±)-Avrainvillamide
Model
H
H
N
O
O
O
3.95
N
N
O
O
OH
(±)-Stephacidin B Model
H
H
N
N
5.47
N
N
N
H
O
Activity restored
O
2.0
(+)-Avrainvillamide
N
N
O
O
O
O
N
N
O
Stephacidin A
Model
H
H
N
N
N
H
O
no significant activity
N
H
O
O
0.41
N
N
O
H
H
N
O
(+)-Stephacidin A
N
O
N
H
N
O
OH
Low activity
10.4
(-)-Stephacidin B
Essential for anti-cancer activity
- Conclusions -
Stephacidin A (1)
Myers
Baran
Avrainvillamide (2)
8 steps
4.5 % overall
Stephacidin B (3)
17 steps
4.2 % overall
1 step from 2
95 %
3 steps from 1
26 % overall
1 step from 2
15 – 95 %
O
O
H
N
O
N
O
N
O
O
N
O
N
N
O
H
N
HO
N
H
O
N
O
O
H
N
H
N
O
O
N
O
H
H
N
O
N
N
O
O
O
The End