Baran Meeting
Wolfgang Oppolzer (1937 - 1996)
11 / 8 / 2006
Moritz Bosse Biskup
Biography:
1937
born in Vienna, Austria;
undergraduate studies at the University of Vienna
1960 - 1964 Ph.D. at the ETH Zürich, CH
with Prof. V. Prelog
structure elucidations of rifamycines
1964 - 1965 PostDoc at Harvard University, USA
with Prof. E.J. Corey
alkylidene transfer from sulfonium ylides
1965 - 1967 PostDoc at the Woodward Res. Inst., CH
with Prof. R.B. Woodward
synthesis of cephalosporin
1967 - 1974 research chemist at Sandoz Ltd., CH
synthesis of N-heterocycles
1974 - 1996 faculty at the University of Geneva, CH
full professor (1975)
Research Interests:
- pericyclic, esp. intramolecular pericyclic reactions
- DA-rx,
- ene-rx,
- 1,3-dipolar-additions,
- electrocyclic ringclosures;
- chiral auxiliaries
Publications:
author / coauthor on over 210 publications
~ 180 original research papers
~ 80 Helvetica Chim. Acta
~ 70 Tetrahedron Letters
~ 15 J. Am. Chem. Soc.
- 14 Tetrahedron
- 6 Angewandte Chemie
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
Baran Meeting
Ph.D. - Rifamycin B and derivatives:
Me
Moritz Bosse Biskup
Me
Me
HO
In 1959 a complex mixture (containing rifamycins A - F) with
antibiotic properties was isolated from A. mediterranei in 1959;
rifamycin B is the main active component;
Me
O
Me
O
Me
OH
CH3
29
OH
O
15
1
8
Me
O
Me
O
12
O
O
rifamycin S
O
Pt / C, H2
Pd / C, H2
Ox
hexa-Hydro rif SV
hexa-Hydro rif S
Ox
tetra-Hydro rif SV
H
O
CH
H
tetra-Hydro rif S
HNO3 / H2O
rifamycin S
Red
OH
O
Me
rifamycin B
C37H45NO12
HO
OH
HO
O
HO
O
O
O
O
HO
OH
O HO2C
i. O3
ii. HCO3H
HO
HO
OH
HOOC
OH
Me
O
HO
OH
Me
Me
OH
O
O
CO2H O
Me
HO
Me
O
OH
O
OH
NH
Me
rifamycin S
O
O
O
Me
O
NH
3
10
rifamycin S
NH
H+
rifamycin O
O
O
Me
O
NH
Ox
OH
O
OH
O
HNO3 /HOAc
Me
23
MeO
OH
abs. config.
Me
rifamycin SV
COOH
COOH
OH
Me
COOH
O
COOH
HO
Me
O
CH3
OMe O
rifamycin S
MeO 29
MeI / Ag2O Me
O
OH
MeO
O
O
H+ / MeOH
O
1
Me
Me
R2
NH2
R3
C25H42O8 / C24H38O7
9:1
O
HO 12
O
syn.
a
O
O
acidic extract
neutral extract
MeO
C2-N-C15 !
C12-O-C27/29 ?
MeO-C23/27 ?
R1 MeCOO
UV
NMR
MS
O
N
connectivity:
Me degrad.
R3
R2
a
Me
OMe
15
R1
NH
OH
O
O
MeO
Me
O
Me
Me
OH
b
c
d
Me
HO
Me
MeCOO
Me
HO
OH
MeCOO MeCOO
X-ray
full connectivity
relative stereoconfig.
Baran Meeting
2nd Postdoc - Cephalosporin C
J. Am. Chem. Soc. 1966, 88, 852 - 853. / Nobel Lecture 1965
antimicrobial activity
12
n-octane
CO2H
H2N
RO2C
HO2C
Me2CO
t-BuOH, Cl2CO
HN
S
R=H
O
N
pyr, CH2Cl2
SH
2
BocN
S
ii. NaN3, H2O
N NH
BocN
O H
TrocHN
O
NH
Al(Oi-Pr)3, Tol
BocN
O H
S
TrocHN
O
OH
9
i. Cl3CCH2OH
p-TsOH, Tol
ii. NaIO4, MeOH
H2O
OHC
O
O
CCl3
OCH2CCl3
CHO
OCH2CCl3
H
CHO
N
O H
H
S
N
H
S
15
i. B2H6, THF
ii. Ac2O, pyr
O
O
OCH2CCl3
N
OAc
H
N
OAc
H
S
N
H
S
S
OCH2CCl3
O
O H
N
H
O
O
CO2H
CHO
O
H
H
8
HO2C
O
O
19
O
7
OH
CCl3
CCl3
S
N
H
O
4
N
pyr, Tol
O
i. B2H6, THF
ii. Ac2O, pyr
NH2
S
NH
S
OCH2CCl3
O
Al / Hg
MeOH
BocN
O
O
Cl
OH
HO
ii. Cl3CCH2OH
DCC, pyr
COOMe
S
5
MeO2C
S
14
i. DCC, THF
O
i. Pb(OAc)4, C6H6
ii. NaOAc, MeOH
CHO
H
O
CO2Me
MeO2C
6
13
COOMe
S
H2N
N
CH2N2
CO2Me
OH
BocN
H2O
S
3a /3b
MeO2C
i. MsCl, DIPEA
DMF
H
O
N
N3
O
H
H
BocN
O
TFA
H
OCH2CCl3
R = Me
N
MeO2C
N
S
t-BuO
1
O
O
O
80 °C
Moritz Bosse Biskup
OCH2CCl3
O
8
H
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
16
CCl3
20
CHOH
Na+
O
CHO
O
H
O
O H
11
10
RHN
!
O
O
H
OR
OCH2CCl3
H
H
O
OR
O
O
O
12
N
H
21
22
OR
O
N
H
OAc
O H
S
N
H
S
R = CH2CCl3
R=H
N
17
18
OAc
S
R = CH2CCl3
R=H
Zn, HOAc
cephalosporin c
H
Zn, HOAc
cephalothin
Baran Meeting
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
Chemical Reactions
Chemical reactions can be categorized into three classes:
Moritz Bosse Biskup
iv. cheletropic reactions are reactions in which two "-bonds
terminating at the sam atom are formed or broken.
- ionic, e.g. reactions of fragments with paired electrons,
where charges are formed or combined,
- radical, e.g. reactions in which species with unpaired
electrons propagate the reaction,
R
i.
R
R
R
R R
- pericyclic, e.g. reactions which are characterized by
concerted shifts of electrons in 'cyclic' transition states.
Pericyclic Reactions are characterized by their high
stereoselectivity with regard to products formed.
h$
ii.
h$
These high selectivities are rationalized on a MO-level by the
"Conservation of Orbital Symmetry", leading to the highly
ordered TS mentioned.
Major Types of Pericyclic Reactions:
i. electrocyclic reactions are reactions in which a single bond
bond is formed between the termini of a linear system
containing k !-e- and the reversal of these reactions.
%
iii.
D/H
H/D
D/H
H/D
D/H
H/D
iv.
O
O
H/D
ii. cycloadditions & cycloreversions are reactions in which a
contiguous, cyclic moiety is formed from linear precursors or
such a cycle fragments into linear parts.
iii. [i,j]-sigmatropic reactions are reactions in which a "-bond
migrates along flanking systems of #-bonds to the positons [i1] and [j-1].
R
R
D
[1,3]
D
[1,5]
H/D
D/H
H/D
D/H
D/H
O
CO
Angew. Chem. Int. Ed. 1969, 8, 781 - 853.
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
Baran Meeting
Moritz Bosse Biskup
O
i.
Intramolecular Diels-Alder Reactions
Angew. Chem. Int. Ed. 1977, 16, 10 - 23;
ibid. 1984, 23, 876 - 889.
Type I DA
Me
N
H2N
H
H
Me
H
O
130 °C
H
Me
N
H H2 H
H
N
H H2 H
ClH
CO2Me
CO2Me
CO2Me
H
H
H
130 °C
Cl-
Helv. Chim. Acta 1977, 60, 204.
CO2Me
Alternate Route
racemic
H.O. House, J. Org. Chem. 1965, 30, 1061.
OH
Pumiliotoxin C
from the venom of Dendrobates pumilio and D. auratus
H
i. Hg(OAc)2,
O
MgBr
O
H
ii. !
O
OH
62%
LiAlH4 / NaOMe
i. base, TBDMSCl
ii. Zn / KCN
iii. TBAF
75%
N
H H H
TsO
KOH
MeOH
i. LiAlH4
ii. TsCl / Py
H
N
i. H2 / Pd
ii. DIBAL
iii. HCl
(S)-norvaline
H2N
H
Type II DA
H2N
COOH
230 °C
H
O
ii. NaH (2 eq.)
DME, -30°C
iii. i-PrCOCl
COOH
Me
H
H
Ts
(R)-norvaline
CH2
N
HN
H
87%
Ts
OH
H
H3C C C CH2 MgBr
32%
OH
i. TMSCl, base
51 % ii. 245 °C
iii MeOH / KF
Me
H
i. TMSCl, base
ii. 245 °C
iii MeOH / KF
Me
i. H2 / Pt
ii. CrO3
41%
1/3
H
1/5
H
Na / NH3
H2N
H
HN
Ts
OH
Me
C
H
HN
Ts
H
H
O
Me
4/5
H
2/3
H
H
O
i. H2 / Pt
ii. CrO3
H
OH
O
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
Baran Meeting
Moritz Bosse Biskup
Intramolecular Diels-Alder Reactions
Pumiliotoxin C
continued
Me
CO2Me
NO2
Me
H
p-TsCl, NaOH
H2O, dioxane
H
R = NOH
H
Me3O+
N
H H
R
R=O
Me
NaOMe
MeOH
H
BF4+
HN
O
H
N
H2NOH
EtOH
CO2Me
TiCl3 / NH4OAc
N+ OO-
MeOH /H2O
O
HN
OMe
HN
64%
n-PrMgBr
C6H6, !
Me
H
H2 / Pd
H2N-OMe
MeOH / H2O
CO2Me
N
H
44%
exo-product
N
H H H
H
Me
CO2Me
CO2Me
CO2Me
!, dilute
N OMe
N OMe
N OMe
Helv. Chim. Acta 1977, 60, 48.
HN
HN
Lysergic Acid
racemic synthesis
Me
OHC
Bu
R
CO2Et
P(Bu)3, C6H6
4 steps
Bu
P
CO2Me
Bu
Br -
N
R = Br
CO2Me
H
N
Ts
R = OH
67%
NaH, DMSO
62 %
80°C, 100%
NO2
HN
Ts
N OMe
H
PPh3, CBr4
DMF, 97%
HN
i. HCHO, Me2NH
CO2Me
HOAc
CO2Me
CO2Me
H
MeOSO2F
DCM
HN
N+ OMe
H Me
i. Al / Hg
THF / H2O
ii. KOH
EtOH, H2O
CO2Me
NO2
ii. MeNO2, DMAD
HN
48%
N
N
R
R = Ts
R=H
H
NaOH, MeOH
95%
HN
d/l - mixture
Me
Baran Meeting
Intramolecular Ene- & metallo-Ene-Reactions
Angew. Chem. Int. Ed. 1978, 17, 476 - 486;
ibid. 1989, 28, 38 - 52.
ene-reactions can formally be viewed as a type of
sigmatropic rearrangements, where the !-system, that is
traversed during the reaction, is not fully connected:
R2
R1
X
Moritz Bosse Biskup
Type I Ene-Reaction as the Key Step in the Synthesis of
(+/-)-Isocomene
Me
Me
Me
Me
O
O
H
Me
R2/H
R2
R3
R1
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
R1
R3
R2/H
X
R3/H
X
H/R3
i. t-AmOK
C6H6
ii. MeI
Me
i. NaOMe, MeOH
Me
X = H --> ene-reaction
X = M --> metallo-ene-reaction
O
O
ii. t-BuOK, t-BuOH
O
Me
H
55%
Me
O
H2C
49%
intramolecular ene-reactions
Type I
R
CR
Z
H
Z
C
X
Y
280 °C
24h
17%
Type II
Z
H
Z H
X
Me
H
Y
X Y
CO2Me
Type III
Me
Me
Z
Z
H
X
X
Me
h#
X Y
Y
MeOH
80%
Me
H3C
N2
i. H2 / Pd/C
ii. t-BuOK / AmONO
O
iii. NaOCl / NH3
67%
Me
"
"
H3C
"
"
Me
O
i. LiAlH4
ii. ArSeCN,
PBu3, pyr
71%
Y
O2N
Me
H
Me
Se
CH2
Me
i. NaIO4
ii. 80 °C
Me
58%
CH2
Me
Me
Me
TsOH
DCM, 25 °C
75%
Me
Me
Me
(+/-)-isocomene
Helv. Chim. Acta 1979, 62, 1492.
Baran Meeting
Intramolecular Tandem Pd-Ene / Keck-Insertion Reaction
E E
11 / 8 / 2006
Wolfgang Oppolzer (1937 - 1996)
EE
E E
Pd0(dba)2 / PR3
HOAc
H E
E
E H
H E
Total Synthesis of (dl)-Chelidonine
H H
H
Electrocyclic Ring-Opening of Cyclobutanes
ortho-Quinodimethanes as Building blocks
Synthesis 1978, 793 - 802.
E
H
Pd H H
L2
H
OAc
CN
O
E = COOMe
Moritz Bosse Biskup
3
:
CO2H
O
KOH, H2O
O
OBn
O
i. Curtiusrearrang.
NH
O
ii. BnOH
O
O
4
E
E H
H E
E
O
H H
Me
H
Br
OEt
CHO
O
H2N
H , Pd/C H2
OEt
O
i. Hofmann
degrad.
+
NaH, DMF
NaI
77%
O
ii. Braun
degrad.
H2 PtO2, EtOH
O
i. Br2, DCM
ii. t-BuOK, DBU
HMPA
O
E
E
E
E
Pd0(dba)2 / PR3
HOAc
E
E
H
H
Pd H H
L2
H
H
E
E
NBoc
O
H H
Pd
L2
OAc
O
O
O
30%
O
!
H
H
BocN
O
O
O
O
BocN
BocN
73%
O
O
O
O
O
O i. B H
2 6
O
ii. H2O2
BocN
H
68% 1:1 O
H
O
H
E
E
H
H
E
i. LC
ii. CrO3, 0°C
32%
E
H H
H
H
O
O
Me
H
O
N
O
H
O
J. Org. Chem. 1991, 56, 6256.
OH
J. Am. Chem. Soc. 1971, 93, 3836.
OH
i. NaBH4, MeOH
dioxane
ii. H2 / Pd, EtOH
O
iii. MeI, K2CO3
~80% over 3 steps
O
O
BocN
H
H
O
Wolfgang Oppolzer (1937 - 1996)
Baran Meeting
Camphor Derivatives a Chiral Auxiliaries
Tetrahedron 1987, 43, 1969 - 2004.
Pure & Appl. Chem. 1990, 62, 1241 - 1250.
e.g. sultams
i. sulfonation
ii. SOCl2
iii. NH3
iv. NaOEt
v. LiAlH4
O
O
i. NaH
NH ii. RCOCl
N
S
O
R
S
O
O
O
(+)-camphor
O
O
N
S
O
H
R
LiAlH4
N
R
R
S
O
O
O
OH
e.g. esters
i. NaBH4
ii. TsCl, pyr
HO3S
O
O
i. LDA
ii H+, H2O
OH
S N(i-Pr)2
O O
S
O
O
RCOCl
R
1,4-addition
O
S N(i-Pr)2
O O
DA-rx
And quite some more applications!
O
reductions
11 / 8 / 2006
Moritz Bosse Biskup