Hans Renata
Scope:
- RSC journals (J. Chem. Soc., Chem. Comm. and Perkins Trans. 1 & 2)
- Pre-1980 chemistry; non-systematical library reading limited to 1970-1980; online reading limited
to 1950-1980
- Steroids, morphinans, prostaglandins, tetracyclines, β-lactams antibiotics are (mostly) excluded
- 'Land war type' syntheses will be minimized
- Well-known and esoteric materials will be covered, the former only in brief
Natural products isolation
Me O OAcOH
O
O MeO C
Me
2
O
OH
O
O
Me
HO
O
Me
Me
O
AcO
MeO2C
OH
HO
HO
OH
O
Ac
N
Me
physalin B, JCS (C), 1970, 664
OMe
NO2
O
N
OH
HO
Me
O
PhSe
Ac
O
N
O
leucogenenol (incorrect),
JCS (C), 1971, 2599
H Me Me
O
Me
Me
OMe O
(See tetracycline GM)
OMe
O
O
O
HO
cyclopiamine A, JCS Perkins 1, 1979, 1751
SePh
Usnic acid, Barton, 1956
O
OAc
O
OR
Me
CeCl3-NaBH4
O
O
O
Me
OH O
Tropinone, Robinson, 1917
Me
O
H
OH
Me
O
H
O
O
AcO
frondosin, MacMillan, 2010
HO
O
Me HO
Me
Things you already know (Or you should know)
Me
O
N
O
azadirachtin, Ley, 2007
O
H
CH2OH
Sirodesmins, JCS Perkins 1, 1977, 180
O
Me
N Sn NMe
H
O
Me
O
O
O
Me
Me
Recent Highlights
Me
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R'O
Luche, 1978
Me
O
O
N
O
OAc
OAc
Me
O HO O
O Me
Other noteworthy isolation papers:
baccatin III, andibenin, andilesin, verticillin,
laurenene, phorbol
O
aldosterone acetate, Barton, 1960
Also:
- Baldwin rules
- Barton named reactions (deoxygenation, decarboxylation etc)
N
Me
cathedulin E3,
JCS Perkins 1, 1976, 2982
Hans Renata
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Synthesis of lanosterol
Me
Me
Me
Me
1. [O]
2. KOtBu, MeI
Me
Me
Me
Me
O
Me
cholesterol
Me
Me
CO3H
Me
Me
AcO
Me
Me
CO2H
Me
Me
Me
3. NBS, CCl4
then collidine
Me
then
HCl/EtOH
and benzoylation
AcO
Me
then NH3, MeOH
-60 oC
Me
Me
Me
1. KOtBu, MeI
2. Wollf-Kishner
Me R
HCl
Me
BzO
Me
Me
Me
Me
Me
Me
Me
O Me
BzO
Me
Me
Me
HCl, CHCl3
-40 oC
Me
Me
Me
HO
Me
Me
1. LiAlH4
2. Ac2O, C6H5N
CHCl3
Me
Me
BzO
Me
Me
Me
lanostenyl benzoate
JCS, 1957, 1131
Synthesis of the withanolides skeleton
Me R
O
Me R
1. N2H4
2. Jones
Me
O
O
Me
Me R
Me R
1. KOH
2. POCl3
O
O
mCPBA
Me
90%
45%
OAc
Me
O
OAc
R=C8H17
Me R
Me R
O
Me
NaOH
O
Me
quant.
O
O
Me
Me
Me
O
85%
OH
Me
Me R
1. MsCl
2. OsO4
2:1 α:β
H O
OH
O
Me
O
OH
O
OH
withaferin A
JCS Perkins 1,
1975, 2295
Hans Renata
2 step synthesis of deoxybruceol
A model study towards the morellins
cf. Nicolaou's synthesis of 1-O-methylforbesione (2001), Theodorakis' synthesis of forbesione and
desoxymorellin (2003)
Precedence:
Me
O
O
HO
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Me
Me
O
O
O
OH
Me
Me O
O
O
OH
pyridine
Me
O
OH
Me
Me O
Me
O
Me
O
decalin
reflux
O
JCS, 1960, 3734
O
O
O
O
Model substrate
OH
Me
OH
O
O
O
O
pyridine
OH
via:
Me
O
HO
OH
Me
Me
Me O
Me
Me
O
O
Me
40%
JCS Chem Comm, 1971, 966
Actual substrate
O
Me
O
OH
O
Me
O
O
Me
Me
Me
O
OH
HO
pyridine
HO
OH
10%
Me
O
O
O
Me
Me
O
Me
deoxybruceol
JCS (C), 1971, 788
hanburin
Me
Me Me
Me
O
O
O
Me
Me
Me
Me O
Me
O
O
Me
Me
Me
desoxymorellin
Me
Hans Renata
Group Meeting
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Oxidative rearrangement of chalcone
Synthesis of isorotenone from isoflavone
Inspiration from biosynthetic pathway
O
OH
OMe
OMe
Me
MeO
O
Me
enzyme
O
O
S
O
MeO
CH2
OH
OH
O
Labelling studies: Chem Comm, 1968, 395
OH
MeO
OMe
Me
OMe
O
MeO
OH
Tl
O
O
OH
O
Me
iPr
OMe
JCS (C), 1970, 119
JCS (C), 1970, 125
pyridine
100 oC
Further applications:
Me
MeO
Me
O
O
iPr
O
OMe
O
iPr
HO
O
OH
OMe
O
O
O
OH
O
philenopteran, JCS Perkins 1, 1974, 305
O
MeO
O
H
HO
S
Me
O
In the presence of excess reagent, the
following product is observed:
OMe
OH
O
80%
Me
H
O
OMe
OAc
MeO
iPr
OMe
(isolated)
AcO
O
MeO
O
OH
via:
Me
O
OMe
MeO
MeOH
reflux
S
O
Tl(OAc)3
O
O
O
iPr
MeO
O
OMe
heminitidulan, JCS Perkins 1, 1980, 2463
iPr
JCS Chem Comm, 1970, 563
Hans Renata
Group Meeting
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Royal Chemistry
Synthesis of norbikaverin and bikaverin via quinone rearrangement
1.
Synthesis of silybin by oxidative phenol coupling
Me
OH
COCl
OH OBn
MeO
O
OH
O
HO
OBn
OH
OH
OH
2. hν
HO
Me
OBn
MeO
OBn
Ag2O
+
14%
2 steps
OH
1. Me4NOH
2. KOH
O
OH O
OBn
OBn OR
HO
O
18:5 C6H6/
Me2CO
59%
OH
O
O
Me
O
MeO
silica
gel
OMe
57%
+ regioisomer
OH
52%
MeO
Note the absence of protecting groups!
O
OBn
BnO
JCS Perkins 1, 1980, 775
OBn
Synthesis of actinioerythrol
quant.
Me
Me
O
O
OBn
Me
O
OH
Me
X
X
O
Me
MnO2
MeO
OH
K2Cr2O7
O
BnO
O
OMe
OH O
OH
Me
O
O
OBn
O
28%
MeO
O
OH
OH
X=
Me
Me
O
1. MnO2
2. NaBH4
Me
Me
Me
HO
norbikaverin
HO
Me
O
JCS Chem Comm, 1977, 645
Note: A similar rearrangement also occurred in Pettus' model study towards rubromycin
astacene
Me
O
actinioerythrol
JCS Chem Comm, 1969, 128
Hans Renata
Group Meeting
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C-H Activation in Total Synthesis
Total synthesis of panamine
O
Total synthesis of ishwarane
1. hν
Br
H
O
O
H
N
N
2. PHPB
O
Me2CuLi
N
AcO
N
O
H
Na2CO3
OAc
76%
Me
O
N
O
N
O
Me
Me
O
47%
77%
Me
Me
MeMgI
Me
H
O
CN
N
EtOH
O
Me
65%
Me
Me
H
H
H
H
N
H
N
70%
N
H
N
CH2Cl2
H
Me
Me
Me
Me
Me
1. CBr4, MeLi
-75 oC
2. warmed to
-30 oC, then
MeLi
Me
Me
ishwarane
26%
H
NCS
N
H H
N
Me
N
N
O
HO
74%
2 steps
Me
Me
H
NH3
N
H
N
50% H2SO4
O
H
H
O
Me
H
"Three of these steps each results solely in the addition of one carbon atom to the framework
of the preceding intermediate; only one step involves functional group modification, and protection of sensitive functional groups is not necessary." (Sounds familiar?)
H
JCS Chem Comm, 1977, 587
JCS Chem Comm, 1970, 1116
Hans Renata
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Organometallics
Metal-catalyzed cyclodimerization
Me
C-C Activation
Cl
CO CO
Cl
Rh
Rh
Cl
[RhCl(CO)2]2
40-50 oC
O
PPh3
Rh
Ni Cl
PEt3
PPh3
PPh3
MeOH
O
O
50% (distillation)
JCS (A), 1968, 845
[RhCl(CO)2]2
JCS Chem Comm, 1970, 1310
Catalyst is "stable in alcohols or even in air" but "was no longer stable after the reaction and
decomposed to a green solid on exposure to air."
80 psi CO,
Ph3P,
Pd(acac)2
PPh3
OC Rh
Cl
PEt3
O
O
EtOH
Rh
O
O
Ph3P Cl PPh3
n
OEt
71.5%
JCS Chem Comm, 1971, 1067
Divergent Cyclization of 3,7-Dimethylocta-1,6-diene
JCS Chem Comm, 1970, 1082
Me
Me
O
Palladium-catalyzed cyclization
Me
Me
Me
Na2PdCl4
Me
Na2PdCl4
Me
Me
Me
cis-ocimene
Me
Me
trans-ocimene
DMF
Me
Me
PdCl2
Me2CO(aq)
Me
H2O-THFNaBH4
Me
Me2CO
Hg(OAc)2
PdCl2-CuCl2
Me
Me
Me
Me
HO
Me
HCO2H-H2SO4
Me
CO2H
limonene
JCS (C), 1970, 2196
Me
Me
OH
Me
Me
JCS Perkins 1, 1974, 809
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Group Meeting
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Organometallics
Synthesis of casbene- putative biogenetic precursor of tigliane and ingenane terpenoids
Synthesis of lactones via iron carbonyl complexes
Me
Me
hν,
Fe(CO)5
O
Me
O
Fe(CO)3
Me
Me
Me
CAN
O
EtOH-H2O
Me
O
Me
MeO2C
O
Me
Me
Br
Ni(CO)4
O
38%
Me
Me
Br
Me
same
condition
O
O
O
O
Me
O
Me
Me
Me
65-70%
not observed
same
condition
O
O
Side note:
JCS Perkins 1, 1980, 1711
10%
O
79%
Me
CuI, THF
0 oC
Me
Me
Me
Me
JCS Chem Comm, 1977, 581
Me
Extension to lactam synthesis
Me
Me
O
O
Fe(CO)3
ZnCl2,
PhCH2NH2
75%
N2
Palladation and platination
Me
Me
Fe(CO)3
O
N
CH2Ph
O
Ph
CAN
N
Me
N
OH
NaOAc,
Na2PdCl4
HO
Cl
N
Ph
2
Ph
Me
Me
Pd
Me
Me
34%
Me
Me
JCS Chem Comm, 1978, 1061
O
N
O
Ph
Me
56%
N
N
Me
Na2PdCl4
O
N
N
Pd
Cl
2
Other substrates led exclusively to β-lactams
JCS Chem Comm, 1980, 297
JCS Dalton, 1980, 2282
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Group Meeting
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Royal Chemistry
Extension of this methodology to other heterocycles
Heterocyclic Chemistry
N
reflux
R
P(OEt)3
Me
N
Cl
N
H
17%
+ 2 (EtO)3PO
reflux
NO2
P(OEt)3
O2N
Using triethyl phosphite
R
Cl
Ph
Nitrenes in heterocyclic chemistry
N
H
36-83% yield
JCS (C), 1968, 1006
N
O
Also applicable to the preparation of
Ph
O
O
O2N
P(OEt)3
O
reflux
O
O
N Ar
JCS (C), 1969, 385
OMe
OMe
N
P(OEt)3
JCS, 1965, 4831
O
O2N
Using ferrous oxalate
Cl
S
Cl
N
X
NO2
Cl
Cl
N
hν
N
R
Ph
Cl
Ph
H
Cl
via
N
Ph
OH
H
JCS (C), 1968, 119
OH
ca. 20%
R
Ph
50-85% yield
N
H
A photochemical synthesis of furans
O
o
Cl 270-290 C
reflux
JCS (C), 1970, 2437
N
FeC2O4
X
+
Cl
H
N
O
P(OEt)3
N
230-250 oC
O
45%
S
Cl
FeC2O4
N
reflux
O
JCS (C), 1974, 861
Cl
Cl
NO2
Ph
O
N
N Ar
N
Cl
N
57%
N
NO2
Me
HO
O
OH
R
O
R
Ph
Applicable to the synthesis of substituted N-alkyl pyrroles as well
JCS Perkins 1, 1979, 1703
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Group Meeting
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Royal Chemistry
Heterocyclic Chemistry
Indole synthesis
Pyridynes and quinolynes
O
Me
Ph
H2N
Ph
R
Ph
N N
N
Ph
Ph
Ph
Ph
OH
NH2
Me
KNH2
Me
O
R
R
NH3
N
H
NH
Br
Pb(OAc)4
JCS Perkins 1, 1979, 827
Ph
CH2Cl2
N
Modification:
N
63%
O
Ph
H2N
N N
N
R2
Ph
Ph
Ph
Ph
Ph
Pb(OAc)4
Ph
R1
NH2
Br
CH2Cl2
OH
R2
R'NH2
R1
MeOH
heat
N
R'
Ph
N
N
17-82%
70%
JCS Perkins 1, 1979, 829
Note: 2,3-pyridyne and 2,3-quinolyne gave poor yields
JCS (C), 1969, 1758
Quinolone synthesis
X
PhSCH2CH2CO2Et
tBuOCl
X
NHMe
An interesting reaction of nitroarenes with Grignard reagents
then NaOMe
Y
X
N
Me
O
R
NO2 2 RMgX
X
Y
H O
N
BF3
OMgR
R
X
NO
Y
R = nBu or Ph(CH2)2
JCS Perkins 1, 1980, 692
JCS Chem Comm, 1977, 694
Hans Renata
Alkaloid Biosynthesis
Barton's proposal for the biosynthesis of acutumine
OMe
O
Organoborane chemistry
Annelation via hydroboration-carbonylation
OMe
O
O
MeO
OMe
O
OMe
OMe
O
OH
H
MeO
OMe
O
H
H
67%
40%
O
H
H
H
66%
62%
O
NMe
MeO
OMe
O
Reaction of cyclic organoboranes with MVK
O
1. BH3, THF, 0 oC
2. MVK
iPrOH/THF reflux
JCS (C), 1968, 929
acutumine
H
JCS Chem Comm, 1968, 594
O
NMe
H
H
OH
OMe
O
H
MeO
OH
Cl
O
O
Product scope
O
MeO
NMe
H
60% isolated
MeO
O
O
1. 70 atm CO
2. H2O2, NaOAc
H
NMe
NMe
MeO
H R
B
RBH2
O
NMe
OMe
OMe
OH
HO2C
O
MeO
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Royal Chemistry
Also, see Wipf's discussion on this pathway:
Org Biomol Chem, 2007, 5, 58
O
HO
3. alkaline H2O2
Me
85%, prep GLC yield
Biosynthesis of quinine from loganin - A labelling study
JCS Chem Comm, 1969, 1009
HO
*
Me
NH
H
OGlu
H
MeO2C
O
*
N
H
H
MeO2C
Formation of brominated boracyclanes and their reaction
H OGlu
O
*
HO
H
MeO
N
H
H
alkaline
H2O2
Br2
N
JCS Chem Comm, 1970, 194
B
Br
H
B
OH
60%
JCS Chem Comm, 1973, 801