Post on 17-Mar-2018
Royal ChemistryHans Renata Group Meeting10/16/2010
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
Things you already know (Or you should know)
NMe
O
Tropinone, Robinson, 1917
OHO
Ac
OH
OOHMe AcMe
Usnic acid, Barton, 1956
PhSe O
O
SePh
O
(See tetracycline GM)
CeCl3-NaBH4
Luche, 1978O
MeHO
OO
OAc
aldosterone acetate, Barton, 1960
Also:- Baldwin rules- Barton named reactions (deoxygenation, decarboxylation etc)
Recent Highlights
O
O OHMe
OHAcO
O
MeO2C
OMe
Me
MeO2C
OO
Me
O
HO
azadirachtin, Ley, 2007
O
Me
Me
Me
HO
frondosin, MacMillan, 2010
Natural products isolation
O N NMe
O
Me
Me
Me
H
OHOAcO
O CH2OH
Sn
Sirodesmins, JCS Perkins 1, 1977, 180
O
O
OO
HOMe O
OHO
O
Me
physalin B, JCS (C), 1970, 664
N
OO
OH MeHO
HO
O
AcO
MeOH
leucogenenol (incorrect), JCS (C), 1971, 2599
NN
OMe MeHH
NO2 O
MeMe
OMe
cyclopiamine A, JCS Perkins 1, 1979, 1751
OO
O N
O
O
OMeOMe
O
OAcOAcMe
OR
OR'O
OMe
O O
N
Me
Me
HO
cathedulin E3,JCS Perkins 1, 1976, 2982
Other noteworthy isolation papers:baccatin III, andibenin, andilesin, verticillin,laurenene, phorbol
Me
H
Royal ChemistryHans Renata Group Meeting10/16/2010
Synthesis of lanosterol
HO
Me
MeMe
MeMe
cholesterolO
Me
MeMe
MeMe
MeMeAcO
Me
MeMe
MeMe
MeMe
AcO
Me
MeMe
MeMe
MeMeBzO
Me
MeMe
MeMe
MeMe
OBzO
Me
MeMe
MeMe
MeMe
Me
Synthesis of the withanolides skeleton
O
R
Me
Me
OAc
O
R
Me
Me
OAc
OR
Me
MeO
R
Me
MeO
O
R
Me
MeO
O
R
Me
MeO
OH
R
Me
MeO
OHO
R=C8H17
Me
MeO
OHO
OMe
Me OH
OH
withaferin A
1. [O]2. KOtBu, MeI
1. LiAlH42. Ac2O, C6H5N
3. NBS, CCl4 then collidine
HCl, CHCl3-40 oC
then NH3, MeOH-60 oC
CO2H
CO3H
thenHCl/EtOH
and benzoylation
1. KOtBu, MeI2. Wollf-Kishner
BzO
Me
Me R
MeMe
Me
HCl
CHCl3
lanostenyl benzoate
JCS, 1957, 1131
1. N2H42. Jones
1. KOH2. POCl3 mCPBA
NaOH1. MsCl2. OsO4
45% 90%2:1 α:β
quant. 85%
JCS Perkins 1,1975, 2295
Royal ChemistryHans Renata Group Meeting10/16/2010
2 step synthesis of deoxybruceol
Precedence:
HO
O
OH
O O
Me
Me
Me
pyridine
O
MeO
OO
MeMe
JCS, 1960, 3734Model substrate
OH
HO OH
O
Me
Me
Me
pyridineO
O
MeMe
Me
OH
Actual substrate
O
HO OH
O
O
Me
Me
Me
pyridine OO
MeMe
Me
O
O
deoxybruceol
JCS (C), 1971, 788
A model study towards the morellinscf. Nicolaou's synthesis of 1-O-methylforbesione (2001), Theodorakis' synthesis of forbesione anddesoxymorellin (2003)
O
OO
OO
OHMe
MeO
OO
OHMe
Me
O O
decalinreflux
via:
O
OO
OHMe
Me
O O
O
OO
OO
OHMe
Me
MeMe
MeMe Me Me
desoxymorellin
O
HOO
OO
OH MeMe
MeMe Me Me
MeMe
hanburin
JCS Chem Comm, 1971, 966
40%
10%
Royal ChemistryHans Renata Group Meeting10/16/2010
Oxidative rearrangement of chalcone
Inspiration from biosynthetic pathway
O
OH
enzyme
O
O
Labelling studies: Chem Comm, 1968, 395
O
OMe
OOMe
OTl(OAc)3
MeOHreflux
via:
O
OMe
OMeTl
AcO
OAcJCS (C), 1970, 119JCS (C), 1970, 125
MeO OH MeO
OHMeO
Further applications:
O
O
HO
MeO
OMe
OH
H
H
philenopteran, JCS Perkins 1, 1974, 305
OO
MeMe
Me
OH
OMeheminitidulan, JCS Perkins 1, 1980, 2463
Synthesis of isorotenone from isoflavone
O O
O
OMeMeO
OH
iPr
SOMe
CH2Me
O O
O
OMeMeO
OH
iPrS
MeMe
O
O O
O
OMeMeO
OH
iPrS
MeMe
O
O
O
O
iPr
OH
MeOOMe
O O
O
OMeMeO
O
iPr
pyridine100 oC
O
O
HO
OH
OMeMeO
iPr
In the presence of excess reagent, the following product is observed:
JCS Chem Comm, 1970, 563
(isolated)
80%
Royal ChemistryHans Renata Group Meeting10/16/2010
OH
OHO
OOH
HO
OH
OH
HO
OBn
OBn
Me
MeO
COCl
OBn
2. hν
Me
MeOOBn OR
O OH OBn
OBn
1. Me4NOH2. KOH
O
OMe
MeO
OH
BnO OBn
K2Cr2O7
O
OMe
MeO
O
BnO OBn
O
O
OMe
MeO
O
silicagel
O
OBn
OBn O
OMe
MeO
OH
OH
O
OHO
norbikaverin
MnO2
JCS Chem Comm, 1977, 645
Note: A similar rearrangement also occurred in Pettus' model study towards rubromycin
Synthesis of norbikaverin and bikaverin via quinone rearrangement Synthesis of silybin by oxidative phenol coupling
OH
OMe
OH
O
OO
OOH
HO
OH
OH
OMe
OH
+ regioisomer
JCS Perkins 1, 1980, 775
57%
Note the absence of protecting groups!
Ag2O
18:5 C6H6/Me2CO
1.
14%2 steps
59%
52%
quant.
28%
+
Synthesis of actinioerythrol
X
Me Me
Me Me
X
X=
O
Me Me
MeHO Me
MeMe
O
HO
1. MnO22. NaBH4
astacene actinioerythrol
JCS Chem Comm, 1969, 128
Royal ChemistryHans Renata Group Meeting10/16/2010
C-H Activation in Total Synthesis
Total synthesis of ishwaraneTotal synthesis of panamine
O
MeMe
O
MeMe
Me
MeMe
MeMeHO
MeMe
MeMe
Me
MeMe
Me
Me
MeMe
ishwarane
JCS Chem Comm, 1977, 587
NH
NHN
H
HH
N NHN
H
HH
H H
H
NCS
CH2Cl2
70%
NH
N
N
HH
HO
O
O
CNN
N
H
O
O
N
N
H
O
O
N
N
H
O
O
AcO
Br
N
N
H
O
O
O
JCS Chem Comm, 1970, 1116
Me2CuLi
77%
MeMgI
50% H2SO4
74%2 steps
1. CBr4, MeLi -75 oC
2. warmed to -30 oC, then MeLi
26%
"Three of these steps each results solely in the addition of one carbon atom to the frameworkof the preceding intermediate; only one step involves functional group modification, and pro-tection of sensitive functional groups is not necessary." (Sounds familiar?)
1. hν
OAc
2. PHPB
47%
Na2CO3
76%
NH3
EtOH
65%
Royal ChemistryHans Renata Group Meeting10/16/2010
RhCl
RhCl
O O
CO CO
RhPPh3
PPh3
O
Cl[RhCl(CO)2]2
40-50 oC
PPh3
Organometallics
C-C Activation
JCS (A), 1968, 845
[RhCl(CO)2]2
RhOCCl O
n
PPh3
RhO OCl PPh3Ph3P
JCS Chem Comm, 1970, 1082
Palladium-catalyzed cyclization
MeMe
Me
Na2PdCl4
MeMe
Me Na2PdCl4
Me
Me
limonenecis-ocimene trans-ocimene
JCS (C), 1970, 2196
Divergent Cyclization of 3,7-Dimethylocta-1,6-diene
Me
Me Me
Me
Me
Me Me
OMe
Me
HOMe
Me
Me
OHMeMe
MeCO2H
MeMe
HCO2H-H2SO4PdCl2
Me2CO(aq)
PdCl2-CuCl2
DMF
Hg(OAc)2
H2O-THF-NaBH4
JCS Perkins 1, 1974, 809
Metal-catalyzed cyclodimerization
NiPEt3
PEt3
Cl
Me
MeOH
Catalyst is "stable in alcohols or even in air" but "was no longer stable after the reaction anddecomposed to a green solid on exposure to air."
JCS Chem Comm, 1970, 131050% (distillation)
80 psi CO,Ph3P,
Pd(acac)2
EtOH
OEt
O
71.5%JCS Chem Comm, 1971, 1067
Me2CO
Royal ChemistryHans Renata Group Meeting10/16/2010
Organometallics
Synthesis of lactones via iron carbonyl complexes
Me
Me
O hν,Fe(CO)5
Me
Me
O
Fe(CO)3O
CAN
EtOH-H2O
OMe
Me O
O samecondition
OO
O O
samecondition
OO
not observed
JCS Chem Comm, 1977, 581
Extension to lactam synthesis
Me
Me
O
Fe(CO)3O
ZnCl2,PhCH2NH2
Me
Me
N
Fe(CO)3O
CH2Ph
CANN
O
MeMe
Ph
N
Me
Me
O
Ph
Other substrates led exclusively to β-lactams
JCS Chem Comm, 1980, 297
Synthesis of casbene- putative biogenetic precursor of tigliane and ingenane terpenoids
O
MeO2CMe
Me
Br
MeMe
Me
Me
Me
Br
MeMe
Me
Me
MeJCS Perkins 1, 1980, 1711
Palladation and platination
Ph
NOH
Me
MePh
N
Me
NaOAc,Na2PdCl4
HO
2
JCS Chem Comm, 1978, 1061
NNO
Me Na2PdCl4 NMe
Pd
PdCl
NO
Cl
2
JCS Dalton, 1980, 2282
Me
Me Me Me Me
N2
Side note:CuI, THF
0 oC
Ni(CO)4
10%
75%
34%
56%
38%
65-70%
79%
O
Royal ChemistryHans Renata Group Meeting10/16/2010
Heterocyclic Chemistry
Nitrenes in heterocyclic chemistry
ClNO2
Cl
FeC2O4
NN
Cl
Cl
Cl
Cl
N
NCl
ClCl
Cl
230-250 oC
HN
NO2
PhCl N
N
Ph
ClFeC2O4
270-290 oC
JCS (C), 1968, 119
Using ferrous oxalate
Using triethyl phosphite
NO2
R P(OEt)3
reflux NH
R
36-83% yield
+ 2 (EtO)3PO
Also applicable to the preparation of
NN Ar
NN
NAr
JCS, 1965, 4831
Extension of this methodology to other heterocycles
NMe Cl
PhO2N
NH
N
Cl
Me
JCS (C), 1968, 1006
O
N
O2N O
O
OPh
N O
NO
OPh
JCS (C), 1969, 385
O2NO
OMe
ON
OO
OMe
JCS (C), 1974, 861S
NO2X N
H
S X
JCS (C), 1970, 2437
Ph
O
H
R OH
O RPhca. 20%
OH
H
R OH
Ph
ORHO
JCS Perkins 1, 1979, 1703Applicable to the synthesis of substituted N-alkyl pyrroles as well
hν
via
A photochemical synthesis of furans
+
P(OEt)3
reflux
P(OEt)3
reflux
P(OEt)3
reflux
P(OEt)3
reflux50-85% yield
45%
17%
57%
Royal ChemistryHans Renata Group Meeting10/16/2010
Heterocyclic ChemistryPyridynes and quinolynes
N
NNN
H2N
Pb(OAc)4
N
PhPh
Ph
Ph
N
NNN
H2NPb(OAc)4
N
PhPh
Ph
Ph
63%
70%
Note: 2,3-pyridyne and 2,3-quinolyne gave poor yields
CH2Cl2
CH2Cl2
JCS (C), 1969, 1758
Quinolone synthesis
NHMe
PhSCH2CH2CO2EttBuOCl
then NaOMe NMe
OX X
JCS Chem Comm, 1977, 694
Indole synthesis
NH2
MeOH
R
Br
KNH2
NH3 NH
MeO
RR
NH
JCS Perkins 1, 1979, 827
Modification:
NH2
R2 OH
R1
Br
R1NR'
R2R'NH2
MeOHheat
17-82%
JCS Perkins 1, 1979, 829
An interesting reaction of nitroarenes with Grignard reagents
X
Y
NO2X
Y
NO
OMgR
R HX
Y
NOR
JCS Perkins 1, 1980, 692
PhPh
O
Ph Ph
PhPh
O
Ph Ph
2 RMgX
R = nBu or Ph(CH2)2
BF3
Me
Royal ChemistryHans Renata Group Meeting10/16/2010
Biosynthesis of quinine from loganin - A labelling study
O
HO Me
OGlu
MeO2C
H
HNH
NH
O
MeO2C
OGlu
H
H
N
NH
HO
MeO
Barton's proposal for the biosynthesis of acutumine
JCS Chem Comm, 1970, 194
O OMe
OMeO OMe
NMe
O OMe
OMeO OMe
NMeO
O
OMeO OMe
NMe
O
HO2C OMeOH
OMeO OMe
NMe
OH
O
MeO
OMeO OMe
NMe
OH
O
MeO
OMeO OMe
NMe
OH
O
MeO
HCl
acutumineJCS (C), 1968, 929
Also, see Wipf's discussion on this pathway:Org Biomol Chem, 2007, 5, 58
Organoborane chemistryAnnelation via hydroboration-carbonylation
Alkaloid Biosynthesis
RBH2RB
H
H 1. 70 atm CO2. H2O2, NaOAc
H
H O
60% isolated
Product scope
O O O OH HH H
H H H H67% 40% 66% 62%
JCS Chem Comm, 1968, 594
Reaction of cyclic organoboranes with MVK
1. BH3, THF, 0 oC2. MVK iPrOH/THF reflux
3. alkaline H2O2 HO Me
O
85%, prep GLC yield
JCS Chem Comm, 1969, 1009
Formation of brominated boracyclanes and their reaction
B
HBr2
B
H
Br
alkalineH2O2
H
OH 60%
JCS Chem Comm, 1973, 801
**
*