Baran Lab
•
Ekkehard Winterfeldt
born 1932 in Danzig (former Germany, now
Poland)
In 1958 he got his PhD for his work on „The
Synthesis of Hydroxysparteines“
Finished his habilitation in 1962
In 1970 he accepted an offer for a full
professorship from the University of Hannover,
where he worked and taught till 2000
Over the years more than 200 diploma and grad
students worked in his group
For his work on Natural Product synthesis he got
numerous awards (for example the Emil Fischer
Medal), he joined the University of California
(Irvine) in 1990 for a guest professorship
•
•
•
•
•
M. Maue
Indol Chemistry
Synthesis of the Aglycons of Staurosporine1
1) CDI
2) Hünnig base
O
O
O
O
NH2
OH
OH
N
H
N
N
H
O
O
O
1) base, SEM-Cl
2) KOtBu, tBuOH, ∆T
3) TBAF
O
H
N
O
H
N
O
H
N
hν, acetone/O2
37%
N
N
N
Me
N
H
O
N
O
OMe
NHMe
O
Staurosporine
Complete total synthesis of Staurosporine was
published by Wood & Stoltz in 1997
J. Brüning, T. Hache, E. Winterfeldt, Synthesis 1994, 25-27.
O
N
O
H
1
NH
N
H
O
N
H
Ekkehard Winterfeldt
Baran Lab
M. Maue
Indol Chemistry
Enantioselective Synthesis of (+)-Tetrahydroalstonine,
(+)-Acricine and (+)-Reserpine2
On their way to a Stereoselective Synthesis of
Geissoschizine3
O
O
O
base
H
MeO2C
H
CO2Me
H
O
O
MeO2C
MeO2C
H
MeO2C
OAc
1) KOtBu, MeI
2) 6N HCl, ∆T
3) mCPBA
H
O
H
H
CO2Me
H
Me
41%
H
O
1) NaH, HCO2Me
then HCl, DT
2) CH2N2
3) KOtBu, AcCl
O
O
OAc
CO2tBu
MeO2C
H N
R2
N
H
H
H Me
O
AcO
CO2tBu
MeO2C
H
Me
mechanism?
1) tryptamine
2) NaBH4
3) POCl3
4) NaBH4
N
H
MeO2C
CO2Me
H
HN
tryptamine
MeO2C
NaBH 4/glacial acid
O
O
R1
OH
Geissoschizine
CO2Me
enzyme
O
N
N
H
CO2Me
OAc
O
O
H
1) OsO4
40% 2) H5IO6
3) CH2N2
MeO2C
H
H
N
H
O
MeO2C
1) POCl3
2) NaBH 4
N
CO2tBu
R1 = R2 = H
(+)-tetrahydroalstonine
R1 = OCH3 R2 = H (+)-acricine
R1 = H R2 = OCH3 (+)-reserpinine
acid/Ac 2O mechanism?
H
N
N
H
CO2tBu
MeO2C
MeO2C
Me
O
O N
O
N
H
MeO2C
2
P. Hölscher, H.-J. Knölker, E. Winterfeldt, Tetrahedron Lett. 1990, 31, 19, 2705-2706.
3
W. Benson, E. Winterfeldt, Angew. Chem. 1979, 18, 11, 862-863.
Ekkehard Winterfeldt
Baran Lab
M. Maue
Indol Chemistry
Stereoselective Synthesis of Eburnamonine4
NH2
OHC
CO2Me
Et
CO2Me
N
H
H N
mechanism?
Stereoselective Synthesis of Vincamine4
O
N
H
CO2Me
H
Et
CN-
O
base MeO
N
HO
O
N
OH
acid
H
N
N
O
N
H
H N
N
H
CO2Me
Et
O
H
Br
H
O
H N
CO2Me
N
H Et
OEt
OMe
N
O
Et
O
N
O
H
N
(-)-eburnamonine
Et
N
1) NBS
2) KOAc
H
N
Et
N
HO
O
N
OH
OEt3BF4
then NaBH4
Et
N
H
O
O
H
OAc
N
Et
1) hydrolysis
2) oxidation
Et
H
CH2Br2, Zn
then TiCl4
O
N
N
N
Et
(-)-eburnamonine
(-)-eburnamonine
O
1) 1,2-ethanediol
2) Raney-Ni
N
N
H
H
Et
N
H
MeO2C
1) NaH
2) LiI/DMF
H
N
H Et
1) NaOMe
2) TFA
H NH
O
Et
O
O
O
O
N
N
O
H NH
O
Et
CO2Me
F-
H
N
vincamine
O
CN
1) OEt3PF6
then MeOH
OEt
2)
4
Et
CN
Et
N
O
H N
degradation
N
N
German Patent
H
N
O
Et
vincamine
N
O
Et
(+)-eburnamonine
K. Hakam, M. Thielmann, T. Thielmann E. Winterfeldt, Tetrahedron 1987, 43, 9, 2035-2044.
OH
Et
N
Ekkehard Winterfeldt
Baran Lab
M. Maue
Diels-Alder Chemistry
Discrimination of enantiotopic groups in a DA-reaction5
Synthesis of Didemnone C6
OMe
O
O
O
LDA, acrolein
O
O
O
OH
O
O
H
O
O
OAr
OAr
ee >98%
O
O
Ar
CO2Et
O
O
H
O
O
O
6.5 kbar, 21d
Li
O
O
O
1) MsCl
2) DBU
retro-DA
O
O
O
O
H
O
O
H
H
O
OH
41%
1) NaBH4
2) cat. HCl, acetone/H2O
only small differentiation!
OMe
O
O
CO2Et
CO2Et
O
O
O
O
I2
O
ee >98%
O
OTBS
48%
1) CAN
2) TBS-Cl
3) DIBALH
O
O
O
O
O
O
O
O
O
CO2Et
OH
ee >98%
ee >98%
OH
OH
didemnone C
5
P. G. Jones, H. Weinmann, E. Winterfeldt, Angew. Chem. Int. Ed. 1995, 34, 4, 448-450.
6
M. Göres, E. Winterfeldt, J. Chem. Soc. Perkin Trans. I 1994, 3525-3531.
O
OAr
O
O
OAr
O
Ekkehard Winterfeldt
Baran Lab
M. Maue
Diels-Alder Chemistry
Enantioselective Synthesis of (+)-Clavularin A7
Synthesis of enantiopure cyclopentenones8
OMe
O
OMe
O
OMe
OMe
OMe
O
O
O
OH
HO
O
pivaloyl chloride
1) Me2CuLi, TMS-Cl
2) TBAF
OMe
OMe
OMe
OMe
1) LDA
2) I
O
SiMe3
O
O
MeLi
Me
90%
SiMe
Me
O
Me
O
O
H
H
90% Ph2CuCNLi2
1) mCPBA
2) acid
OMe
O
O
O
OMe
O
∆T
Me
Ph
Me
H
(+)-clavularin A
regioselectivity 95:5
O
7
H. Weinmann ,E. Winterfeldt, Synthesis 1995, 1097-1101.
8
P. Riviere, A. Mauvais, E. Winterfeldt, Tetrahedron Asymmetry 1994, 5, 9, 1831-1846.
∆T
Ph
Me
O
Ekkehard Winterfeldt
Baran Lab
M. Maue
Diels-Alder Chemistry
Application for the Synthesis of complex cyclohexenones10
Synthesis of enantiopure cyclohexenones9
OMe
O
O
Br
O
Br
OMe
Br
14d
O
HO O
92%
OH
H
N
N
O
O
OH
O
O
O
prochiral
Br
Br
O
H
N
O OH
N
O
Br
agelorin A
H2O2
90%
OH
O
OMe
OMe
O
OH
O
O
O
O
N
88% over two steps
O
N
N
Me
Me
O
O
O
PIFA
O
∆T, 81%
O
OMe
Me
1) KOH, H2O2
80% 2) ∆T
enantiopure cyclohexenones from simple benzoquinone
OMe
O
OMe
1) H2
more sterically
2) selectride
hindered
O
O
O
HO
H
O
∆T
O
O
OH
N
O
Br2, NEt3
48%
O
Me
O
H
R
and many more....
HO
H
9
I. Gerstenberger, M. Hansen, A. Mauvais, R. Wartchow, E. Winterfeldt, Eur. J. Org. Chem. 1998, 643-650.
10
W. Beil, P. G. Jones, F. Nerenz, E. Winterfeldt, Tetrahedron 1998, 54, 7273-7292.
O
O
N
N
Me
HO
H
Br
PPh3Br2
O
O
O
Br
HO H
O
HO
O
Br
Me
Baran Lab
Ekkehard Winterfeldt
Diels-Alder Chemistry
Enantiopure polycycles by sequential cycloadditions11
11
M. Wolter, C. Borm, E- Merten, R. Wartchow, E. Winterfeldt, Eur. J. Org. Chem. 2001, 4051-4060.
M. Maue
Ekkehard Winterfeldt
Baran Lab
Enantioselective Synthesis of (-)-Myltaylenol12
M. Maue
Investigations of the Brefeldin A cyclization13
OH
O
∗ ∗
O
HO
∗ ∗
OH
OH
O
O
brefeldin A
O
X
X
1) HCl
OTHP
KOtBu,
then PhSCH2I
83%, 96% de
O
OTHP 2) N2H4, ∆T
S
3) Ts-Cl
4) KOtBu
60%
O
O
S
1) cuprate addition
2) reduction
O
S
CO2Mem
MemO
OMem
OH
1) reduction
2) Wittig
SPh
SPh
S
1) NaIO4
90% 2) Ac O
2
1) Cl-SO2CH=CH2
2) toluene, ∆T
3) Pd/C/H2
S
1) KOH
2) NaBH4
S
S
O
O
MemO
Mukaiyama
S
CO2H OH
MemO
80%
O
OH
SO2
AcO
1:1 mixture
SPh
name reaction?
S
sBuLi, O2
S
O
OH
MemO
1) TsNHNH2
2) BuLi
O
O
Me2O(O)P
S
S
OH
O
O
MemO
O
1) TIPSOTf
2) BH3-THF
90%
OH
P(O)OMe2
DCC
OH
name reaction?
Wittig
90%
TIPSO
OH
P(O)OMe2
1) Swern
80% 2) Ph3PCH3Br
3) TBAF
S
S
O
MemO
O
O
O
MemO
S
O
O
Me
recovered starting material (10:1)
HO
S
after ester hydrolysis
succesful synthesis of
Brefeldin A via lactonisation
12
S. Doye, T. Hotopp, R. Wartchow, E. Winterfeldt, Chem. Eur. J. 1998, 1480-1488.
13
P. Raddatz, E. Winterfeldt, Angew. Chem. Int. Ed. 1981, 286-287.
10:1 wrong epimer
Ekkehard Winterfeldt
Baran Lab
Synthesis of Cephalostatin Analogues14
• isolated by Pettit out of the marine worm
Cepalodiscus gilchristi
•strong cytostatic activity (400x stronger than Taxol)
•Limited bioavailability (139 mg out of 166 kg worm)
Cephalostatin 1
14
M. Drögemüller, T. Flessner, R. Jautelat, U. Scholz, E. Winterfeldt, Eur. J. Org. Chem. 1998, 2811-2831.
M. Maue
Baran Lab
Ekkehard Winterfeldt
Synthesis of Cephalostatin Analogues15,16
Controlled oxidation of C17
15
R. Jautelat, A. Müller-Fahrnow, E. Winterfeldt, Chem. Eur. J. 1999, 1226-1233.
16
S. Bäsler, A. Brunck, R. Jautelat, E. Winterfeldt, Helv. Chim. Acta 2000, 1854-1880.
M. Maue