R.A. Rodriguez
Born in Worcester, Mass., July 15, 1934
1390 publications (111 reviews)
42 patents
17 books
38 book chapters
Research interests
Heterocyclic chemistry
Hydrocarbon chemistry
Natural product synthesis
Synthetic methodology
Catalytic asymmetric methods
Organoetallic chemistry
Organosulfur reagents
Leo Armand Paquette
B.S., Holy Cross College, 1956
Ph.D., MIT, 1959 synthesis of azasteroids
and regioselectivity in Baeyer-Villiger
(Adv. Norman A. Nelson)
Upjohn, medicinal chemist, 1959-63
Prof. Ohio State University, 1969-present
Honors and Awards
1965 Alfred P. Sloan Fellow
1971 Morley Medalist Cleveland Section
1976 Guggenheim Fellow
1979 Columbus Section Award
1980 Senior Research Award, OSU
1981 Kimberly Professorship in Chemsitry
1987 Arthur C. Cope Scholar
1984 National Award for Creative Work
in Synthetic Organic Chemistry
1989 Senior Humboldt Fellow
1990 Sullivant Medal, OSU highest honor
1992 Awardee of the Japanese Society for
the Promotion of Science
1992 Ernest Guenther Award
2002 S.T. Li Prize Science and Technology
Syntheses Discussed
[4]peristylane
Elassovalene
OH
Dodecahedron
[22](1,5)Cycloctatetraenophane
Me
Me
H
O H H Me
Me
Me
Me
Me
Me
Pentalene
Me
OAc
Me
Me
Me Salsolene oxide
4aβ, 10β-doladiol acetate
Me
HO
Me
Me
O
O
Me
O
Me
Me
O
MeO
Me
O
O
OMe
Me
H
HO 3
C(3) OH α; C(3) OH β
(-)-Austalide B
Timeline: Career in review
Natural Product Synthesis 1979-present
Gymnomitrol and Isocomene 1979
55 total syntheses to date
Hydrocarbons 1974-1990
Dodecahedrane 1982
Heterocyclic chemsitry
1962-1975
Azepine 1962
Oxy-Cope RR 1978-2000
Ag(I) cat. RR di-π−methane RR
1975-1984
1970-75
Postdoctoral Researchers
from the Paquette group:
Steven Ley (1972-1974)
Louis Barriault (1997-1999)
(-)-polycarvernoside A
Baran GM
2011-08-20
1962
1968
1975
Organosulfur 1964-74
α-Halosulfones 1964
1981
Squarate esters Indium reagents
1993-97 1995-2000
1987
1993
2000
Silicon chemistry
Polyspiro tetrahydrofurans
1977-1984
1981-2004
2006
2011
Leo Armand Paquette
R.A. Rodriguez
Heterocyclic and Carbocycle Chemistry 1962-1975
Upjohn and OSU
Syntheses and derivatives:
N
H
Azepine
Baran GM
2011-08-20
MeO
N
N
Syntheses and derivatives:
JACS 1962, 84, 4987
JACS 1963, 85, 4053
JACS 1964, 86, 4092
JACS 1964, 86, 4096
JACS 1965, 87, 1718
JACS 1965, 87, 3417
JACS 1968, 90, 6148
JACS 1972, 94, 6751
O
Oxepin
MeO
Azabullvalene
1967
Azasemibullvalene
1969
Bullvalene
Semibullvalene
e.g. phenol and chloramine
A Synthetic Entry into the Azasemibullvalene System
Photochemistry of Carbocycles
O
O
Me
H
hv
hv
H
1/4 products
acyclic
α,β-cyclopropane
ester
Me
Me
Me
O
Me
Me
ClO2SN
Me
C O
Me
Me
Me O
O
JACS 1969, 91, 7108
ClO2SN
Me
Me
The Protonation of Hexamethyl Dewar Benzene and Hexamethylprismane
in FSO3H−SbF5−SO2 "magic acid"
Me
Me
Me
HN
Me NaOH Me
Me
Me
1.
Me
Me
Me
Me
Me
Me
JACS 1968, 90, 7147
Me
Me 2. K2CO3
Protonation of cis-Bicyclo[6.1.0]nona-2,4,6-trienes in superacidic media
H
−95 °C
H
JACS 1973, 95, 3386
Me
Me
Me
Me
Me
Me
N
MeO
Novel aromatics 1976
The First 8C-6π Huckeloid System:
1,3,5,7- Tetramethylcyclooctatetraene Dication
Me
FSO3H−SO2ClF
Me
Me
Me
Me3O+BF4-
JACS 1969, 91, 6107; JACS 1967, 89, 5480;
JACS 1975, 97, 6124; JACS 1970, 92, 4338
Me
Me
Me
O
Identification of cationic species 1968 (collaboration with Olah)
Me
Me
trans-Bicyclo[6.1.0]nonan-2-ones
2,3 Homotropone
JACS 1967, 89, 5633
Me
Me
Me
NSO2Cl
Me
Me
Me
ClO2SN
+
initial trans cation
JACS 1976, 98, 1267
Me
2+
Me
Me
Me
+
+
Me
Me
Me
Me
JACS 1976, 98, 4327 Bis(tetramethylhomocyclopropenyl) Dication
Leo Armand Paquette
R.A. Rodriguez
Synthetic Methods:
1. Ramberg-Backlund 1964-74
Baran GM
2011-08-20
3. di-π-methane RR 1975-80
Upjohn: Conversion of Mercaptans to Homologous Terminal Olefins
1989 [3]peristylane
HO
O
[O]
SH
SCH2Cl
90%
SO2CH2Cl
97%
4. Silanes 1977-84
- cyclopentanone synthesis
Cl
S
O
S
O
O
O
Me
O
HO
X
SO2CH2Cl
base
Cl
R
S
-HCl
O
JACS 1967, 89, 4487
O
TMS
+
base
-SO2
-HCl
Me
Me
Me
Me
Me
Me
Me
Me
Me
α−Vetispirene
Tet.Lett 1982, 23, 3227
Ag
Ag
Ag
H
(AgBF4)
vs >150 °C w/o Ag (I)
Br
Br
H
Me
TMS
2. Ag I cat. RR 1970-75
Ag+
O
Me
SnCl4
TMS
TMS
Me
O
Me
R
AlCl3
Cl
Me
Me
JOC 1980, 45, 3017
Chem. Rev. 1986, 86, 733
(silyl cylopropanes)
RR of α,α-Dichloromethyl Sulfones
CH2SO2CHCl2
O
Me
2. nBuLi
3. TMSCl
O
JACS 1964, 86, 4383
R
1. PhSO2NHNH2
O
oxydi-π-methane
Tetrahedron 1989, 45, 3099
OH-
OH
hv
Diels-Alder equivalents
Phenyl Vinyl Sulfoxide as
Acetylene Equivalent
trans-1-(Phenylsulfonyl)-2-(TMS)ethylene as
Ethylene Equivalent
H
O
SO2Ph
H
H
H
H
PhS
MeLi
80%
JACS 1971, 93, 1288; JACS 1980, 102, 637
Ag+
(AgBF4)
40 °C
H
via ene-type
quant. clean
non-conjugated triene
JACS 1978, 100, 1597
• Indium 1995
• Zr 2002
TMS
* cis found to be less reactive
JACS 1980, 102, 4976
Leo Armand Paquette
R.A. Rodriguez
Baran GM
2011-08-20
Men of learning in ancient Greece took especial concern for "the putting together of cosmic figures.' their regular polyhedra whose mathematical elegance inspired
considerable wonder. The heritage of that wonder inevitably passed into the realm of synthetic organic chemistry and attracted the practitioners of this science to
apply their skills to the construction from carbon and hydrogen of such strained molecules...
A journey to dodecahedron: selected syntheses of hydrocarbons
[4] peristylane
octahedrane
[8 faces]
decahedrane
[10 faces]
top view
[5] peristylane
Eaton and Muller
dodecahedrane
[12 faces]
X
Tetrahedron, 1989, 45, 3099
[3] peristylane
"triaxane"
JACS, 1983, 105, 4113
[4] peristylane
top view
R
R
1. SeO2 H
2. Al2O3,
quinoline
H
1. BF3,
Et3SiH
I
[3+2]
N
wurtz
O
CO2H
Cl
O
80%
2.
CO2H
Br
S
I
O
Ts
O O
O
OH
TsOH
63% 2 steps
O MsCl/TEA 0 °C;
rt NO GOOD!!
85%
H
H
Cl
10%aq
MeOH
95%
O
O
quant [5 gram] 1. hv
76% 2. H+,Δ
O
I 1. sulfene
N NHTs
N
SOCl2
Cl
O
O
O
HO
OH
H
HIO4,
Me
HO2C
1.
N
NaK-alloy
54% wurtz-type
Δ
O
Ts
77%
O
O
TS
hv
quant
acetone
3.H3O+
69% 3 steps
NaOEt,
EtONO
OH
2. I2, PPh3
N NHTs
1.eth.gly., H+
2. Li, EtNH2
Hypostrophene
1. hv
Δ
O
N OH
Several years later, Garratt and White noted that the top row (vide supra)
hydrocarbons constitutes a series of compounds characterized by the
interconnection of a smaller n-memberd ring to one twice the original size at
alternate carbons of the latter and the community decided to generalize the
Eaton nomenclature.
O
O
98%
2 steps
Ts
2. TsCl, py
3. LAH, Δ
64% 3 steps
After successful preparation of one of these hydrocarbons, Eaton named it
"peristylane" after a Greek word hat alludes to the similarity to "a group of
columns arranged about an open space in a manner designed to support a roof".
I
mCPBA
PhH, Δ
Ts
It was initially named "triaxane" in an effort to capture the C3v symmetry of its
tetracyclic framework and to depict that the cyclopropane ring rests on three
axial pillars fixed to a cyclohexane chair.
OH
O
H
When first synthesized, trixane was viewed predominantly as a chemical curiosity.
[3] peristylane
"triaxane"
• molecular modeling shows
serious nonbonded steric strain
H
I
Tet. Lett., 1974, 17, 1615
2. NaI
90%
OH LAH
O
84%
HO
O
O
Leo Armand Paquette
R.A. Rodriguez
Baran GM
2011-08-20
B
JACS, 1990, 112, 1258; Tetrahedron, 1981, 37, 4521
Br
A
B
Br
A
45 °
E
[22](1,5)Cyclooctatetraenophane
The Weiss-Cook reaction:
E
E
R
+
O
2 equiv
O
O
E
aq. buffer
O
R
E
E
2 equiv
O
1.LAH
2.NaH,
CS2, MeI;
Δ
O
70%
1.
O
O
R
2. HCl, Δ
85%
- 4CO2
O
HCl, Δ
92%
E
O
HO
O
Br
3.Ph3PBr2
66% 3 steps
ether, rt
two-fold
Br cation-olefin
cyclization
CO2Me
1. OsO4
2.HO
OH
TsOH
OH 1.LAH
2.NaH, CS2
MeI; Δ
SiO2
(10X weight)
1.LAH
2. DHP/H+
83%
83%
Me
Me
O
O
H
H
Br
AgClO4
H
Br
H
PhH/pentane
Br
Br
Bu3SnH
3.TsOH
56%
69%
O
A
B
O
minor
Br
+
(~ 1:2)
major
B
Ni(CO)4
DMF
34%
Br 2 steps
all mixtures
O
all mixtures
NBS 4 eq
AIBN/CCl4
CO2Me
E
(COCl)2,
DMSO
2 eq E
E
O
E
all mixtures
Br
O
cis-bicyclo[3.3.0]
octanedione
O
85%
O
- 4CO2
E
pH = 5.6
+
E
Br
R
E
O
R
O
E
O
E
R
[3,3]
H2, Pt
EtOAc
500 °C
40%
brsm
bicyclo
[3.2.1]octane
A
JACS, 1979, 101, 4773
bicyclo
[2.2.2]octane
Leo Armand Paquette
R.A. Rodriguez
Elassovalene
Used in studies towards the evaluation of homoaromaticity-special
case of aromaticity in which conjugation is interrupted by a single
sp3 hybridized carbon atom. Although this sp3 center disrupts the
continuos overlap of p-orbitals, considerable thermodynamic
stability and many other properties or aromatics are still observed.
Baran GM
2011-08-20
[4.4.4]Propella-2,4,7,9,12-pentaene & [4.4.4]Propellahexaene
luche/
burgess
O
Br
Br
Br
Br
Ph
Ph
O
N
O
O
O
O
N
N
Ag I
N
O
N
O
CO2Me
N
RR
Cl
S
O
Me
O
O
OH
CN
O
CO2Me
CO2Me
O
O
O
120 °C, 12h
sealed vessel
O
O O
O
O
O
S
JACS, 1977, 99, 6935
Org. Reactions, 1977, 25
O
N
O
O
N N
O
H2
N
N
O
O
O
Br
O
O
Br
4,5-Diazatwist-4-ene
N
Br
JACS, 1979, 101, 2131
Br
Ramberg
Backlund
Isotriquinacene
JOC, 1984, 49, 1445
study of bridgehead olefins
NHSO2Ph
N
NHSO2Ph
N
triple shapiro
N N
N N
Pd-C
(-)
O
R*
R*
R*
N N
O
COT / Br2
bromination/
elimination
JACS, 1986, 108, 3731
JACS, 1987, 109, 3174
NHSO2Ph
Ph
CO2Me
CO2Me
Ph
Tricyclo[5.3.0.02,8]deca-3,5,9-triene
JACS, 1987, 109, 2857
O
Tricyclo[5.5.0.02,8]dodecatetraene
JACS, 1986, 108, 1986
Me
Leo Armand Paquette
R.A. Rodriguez
Syntheses of dodecahedrane
Norrish II
radical
stitching
σ−bond
metathesis
Wurtz/Acyloin
desymmetrization
Baran GM
2011-08-20
Trost
annulation/
Ring expansion O
E
Corey
lactonization/
Oxidation
E
E
O
Dodecahedrane
1982
Polyhedron
Tetrahedron
1974 Domino DA
1976 Annulation/expansion
1978 Hexaquinacene route
abandoned
1979 Desymmetrization
Hexahedron
Octahedron
4
6
8
Dodecahedron
Icosahedron
12
20
Faces
Edges Vertices
6
4
12
8
12
6
30
30
20
Oh
Oh
Ih
12
I
I
KOH, MeOH;
I2, NaHCO3
CO2Me
1. NaOH,
MeOH
I
Ph
S
OMe
Cl
O
O
O
PhOCH2Cl
chemoselective
alkylation
blocking
group
prevents
over [O]...
O
CHO
MeO2C
Cl
O
OPh
MeO2C
hv
Norrish II
OMe
Cl
PhO
MeO2C
O
JACS, 1982, 104, 4504; JACS, 1981, 103, 228
OH
wurtz-type?
O
MeO
Norrish II:
HCl,
MeOH H
O
O
H
MeO
O
O
HO OPh
OPh
H2, Pd/C
EtOAc
O
MeO2C O
H
MeOH
81%
O
[gram-scale]?
OH
1. HN NH
hv
2.DIBAL
-78 °C
36%
3. PCC
O
CO2Me
O
1. Li,
NH3
2. H3O+
quant.
NaBH4
62%
1,4 diester
CO2Me
O
Li
PhO
MeO2C
TsOH
Cl
48%
O
+
OMe
Cl
O
O OMe
Cl
83% 2 steps
O
then
PhOCH2Cl
MeO
P4O10, MsOH
O
O
OMe
Cl
E
CO2Me O
CO2Me
NH3, Li
O
unstable
OPh
E
O
CO2Me
Cl
β−keto ester
O
H2O2
MeOH
O
OMe
Cl - Cl-
- MeOO
O
O
CO2Me
fragmentation
OH
Domino
Diels-Alder 90 °
CO2Me
O
77%
- cannot attack ester (sterics)
OMe
Cl
CO2Me
O
O
O
E
Oxidative
dimerization
Ph
O
2. Jones [O]
3. Zn/Cu, MeOH
O
78%
E
E
O
O
E
E
C2-symmetric
*Shenvi Platonic Hydrocarbons GM
E
94%
E
Symmetry Group
Td
O
1. KOH, EtOH
retro-aldol
CHO 37% 4 steps
2. hv
3. TsOH
4. HN NH
65% 3 steps
Pd/C
50% 250 °C
Leo Armand Paquette
R.A. Rodriguez
5. Squartate esters
MeO
O
BF3•OEt2
RO
gloiosiphone A
RO
X = Pb(OAc)3
N
Bu3Sn
OMe
O
R1 OAc
O
O
RO
R1
RO
X = I, Br, Cl
O
R1
O
R
RO
RO
O
RO
R1
R1
H
O
Me
H
Me
H
Me
Me
O
OH
RO
Me
2. Me
Me H
Me
Ceratopicanol
i-PrO
O
O
O
[2+2]
R
H
RO
RO
OR
Oi-Pr
i-PrO
O
i-PrO
O
Me
O
O
Me
steps
OH
RO
HO
H
Me
mechanism
R3
OH
i-PrO
Li
R1
Me
OH
i-PrO
O
RO
O
R2
Achieving high complexity in a single step: selected examples
H
HO Me
Me
Me
O
1. Li
R3
OR
Coriolin
Me
O
H
O
Hypnophilin
RO
OH
R1
R
OH R
O
OH
R2
OH
R1
RO
X = I, Br, Cl
Tetrahedron 1997, 53, 8913
O
X
O
OH
O
R1
RO
O
O
O
O
R2
RO
X
RO
O
R2
RO
RO
O
R2
OH
X
O
R1
R2
O
RO
RO
R1
O
O
R1
R
O
R
Z
OAc
R
Li
RO
N
Z
O
RO
R
RO
N
RO
RO
R
OAc
OH
O
RO
N
OMe
O
O
O
O
R
R
RO
MeO
RO
RO
HO
MeO
O
OMe
O
Baran GM
2011-08-20
Me
Me
Pentalene
JACS 2002, 124, 9199; Org. Lett. 2002, 4, 4547
38%
O
N
35%
O
H
i-PrO
i-PrO
OH
38%
O
Leo Armand Paquette
R.A. Rodriguez
6. Oxy-Cope RR 1978-2000 then Claisen RR
Baran GM
2011-08-20
Enolate trapping: kinetic, thermodynamic and electrophiles
320 °C
gas phase
OH
H
O
H
HO
Me
H
KH, 18-cr-6
THF, 0 °C;
H2O
O
Me
KH,
Me 18-cr-6
Me
Me
Me
Me
Me
H
OH
via
retro ene
Me
HO
High basicity of "naked" potassium alkoxide vs less basic sodium salt
Me
OH
18-cr-6
O2, THF
OH
THF, -25 °C;
H2O
NaH
OMe
MeO
H
prostaglanins,
(algal sperm attractant) multifidene
O
Me
OH
H
OMe
OMe
H
O
88%
O
H
+
O
Me
H
O
Δ, 1h,
THF
retro [4+2] Me
-
OMe
HO
OMe
MeO
18-cr-6,
KH, THF
Me SePh
Me
-O
O
preparation of 1,5-Diene-3-ols
-addition of vinyl organometallics to β,γ−unsat aldehydes or ketones
-condensation of allyl anions with conjugated carbonyl compounds
O
Me
O Me
Me
THF, Δ;
H2O
H
OH
Me
Me
KH,
18-cr-6
O
O-
MeO
H
Aromatic participants
H
Me
PhSeCl
Me Me
KN(TMS)2
Me
H
H
Me
OMe
Me
THF, Δ;
H2O
O
OMe
MeO
O
NaH
CCl4, Δ
Me
H
Me
O
80 °C
Rate accelerations up to 1015 !!!
Me
H
α H = kinetic protonation
β H = thermodynamic epimerization
1975 Evans
O
H
O
1964 "oxy-Cope"
Me
Jung, M. E. et. al. JACS, 1980, 102, 2463-2464
Alkyne, Allene and Diene participation
HO
Me
O
Me
KOH
MeOH
H2O O
Me
Me
MeO
O
H
H
OH
MeO
O
O
[3,3]
OMe
H
Et
Et
H
O
O
O
MeO
OMe
OMe
[3,3]
OH
Me
O
Me
Leo Armand Paquette
R.A. Rodriguez
Besides trapping with electrophiles: Ultimate TANDEM Oxy-Copes
Oxy-Cope in total synthesis
A. Cope-ene (as well as Cope-aldol-not shown)
o-DCB
Δ
Me
O
Me
Me
OH
OH
O
mechanism
Me
Salsolene oxide
(R)-(−)-carvone
Me
OEt
OH
H
H
O
[3,3]
H
ene
Me
TMS
TMS
TBAF
THF, rt
rt
OH
O
SPh
HO
O
C. Cope-SN2'
OH
Δ
[3,3]
H
OH
Cl
Me
O
- HCl
H
K. Foo JACS YIR
Me
H
Me
O
Me
KH,
18-cr-6
diglyme
100 °C
Me
O
Me
H+
CHO
H
Me
Pallescensin A. JOC 1992, 57, 7118
Me
O
Me
Me
Me
Me
Me
Me
O
Δ
Me
SPh
Me
[2+2] Me
57%
Me
SPh
H
Li
THF, -78 °C
NOE
Me
H
H
LAH
H
SPh
H
OMe
CO2Et
H
Me
Me
H
MeI
O
H
Me
SPh
kinetic
87%
H
O-Li+
Me
H
H
1. mCPBA,
NaHCO3
H
2. LAH
AcO H
Me
H
NOE
H
O
SPh
Me
1. Li, EtNH2
78% 2 steps
2. Ac2O, py
NOE
H
Br
O
H
2. (COCl)2,
TEA
OH
SN2'
H
2. PhSH, TiCl4
88% 2 steps
Me
H
D. Cope-retro oxy-michael
HO
Me
1. 14M KOH;
H3O+
OMe
Me
[2+2] ketene-olefin factoids:
• trans olefin = retention of stereochem
• cis olefins = nonstereospecific
• nucleophilic alkenes best
• unsat. ketenes prefer criss-cross behavior
when matched with nucleophilic alkenes
LDA, HMPA -78 °C
H
KH, I2
Me
1. NaI, acetone
2.
CO2Me
65%
2 steps
OH
Me
Me
OEt
OEt
O
O
Me
• Silane anion promoter: two step process
Cl
SPh
SPh
KH
O 0 °C
Me
1. DIBAL, -78 °C
B. Cope-ene: a more programmed approach
• Acidity of allylic hydrogen
O
46% 2 steps
Br
Br
O
2. NaBH4,
aq NaOH;
H3O+
Me
ene
[3,3]
1. i. H2, Pt
ii. O3
Me
O H H Me
H
H
Me
Baran GM
2011-08-20
Martin
Sulfurane
H
H
H
O H H Me
H
HO
Me
Me
Me
78% Me
Me
3 steps
Salsolene oxide
Leo Armand Paquette
R.A. Rodriguez
Baran GM
2011-08-20
Recognizing the cope transform within cyclic systems: Its all about the vinyl grignard
+
H
H
H
O
OH
O
H
H
cis
MX
H
[3,3]
OH
H
O
H
H
OH
H
H
H
H
Ikarugamycin
H
Me
H
O
Me
O
O
Me
O
O
Cyathins studies towards
OH
O
O HO
H
H
cis required for norbornane
system trans is too strained
O
O
Me
O
XM
OH
OH
OH
O
H
H
H
H
O
+
O
OH
HO
XM
∗
H
H
H
O
NH
H
H
bridgehead olefin
H
H
N
Me
Me
H
OH
H
H
H
possible pre-cope
O
H
H
H
H
H
H
(E)
H
O
H
H
OH
Cerorubenic Acid 3
MX O
OH
H
H
H
(E)
OH
O
O
H
H
H
O
H
Alternatives....
H
H
XM
H
JACS 1989, 111, 8037
JACS 1990, 112, 9292
JACS 1989, 112, 9284
H
acidic, conjugation
O
H
H
H
H
XM
OH
OH
1995_vulgarolide
+
Ikarugamycin &
Spinosyn A Relay
H
OH
H
H
O
1.
SPh
Δ (or)
S
OH
O
O
O
O
O
[Li]
SPh
S
2. Dibal-H,
MeCN,
HMPA/THF
SePh
+
O
S
S chlor-
amine-T
MX
OH
Leo Armand Paquette
R.A. Rodriguez
Baran GM
2011-08-20
Recognizing the claisen RR within cyclic systems: Find the γ - vinyl ketone
Me
Me
Me
H
Me
Me
I2, PhI(OAc)2 Me
CycHex
Me
Me
H
Me
H
H
Me
O
H
HO
H
Me
H
Me
Me
O
Me
Me
Me
Me
Me
JACS 1993, 115, 1676
H
OH
H
H
H
Me O
Me
Cl
O
Me O
O
Me O
Me O
H R
O
91%
Me O
via epoxy lactone
(zwitterionic or biradical)
H
PO
O
O
H
H
MeO
HO
O
PO
(S)
PO
Me
O
MeO
H
SePh
H
OMe
(S)
MeO
H
Me
PO
H
O
O
Me
OMe
SePh
H
Me
Me
N O
P
N
Me [Li]
H
Me
H
O
O
O
Me
Me
O
O
Me
H
O
mCPBA, NaHCO3,
CH2Cl2, reflux
O
4
3
Me
H
Me
O
O
Me
O
OAc
Me
PO
O
Me O
Me
O
Cl
O
Me
H
O
Acetoxycrenulide
O
O
O
1 H
MX
12 steps from
(R)-carvone
H
7
1
O
O
O
CuLi
O
7
H
DMS
3. CH2N2, rt
H
O
O
2
Me O
H
H
4
O
Ceroplastol I
Me
H
AcO
C6H15 3
O
Me
Me
+
1. LDA, TMSCl
2. O3, MeOH;
H
Me
H
Me
Me
O
H
Me
Me
H
H
OMe
Me
H
O
Me
Me
Me
H
MeO2C
Me
7,8-Epoxy-2-basmen-6-one
O
O
Me
O
O
H
Me
A) Keep in mind where O-alkylation will take place
B) Move unsaturation into one another
C) Break bond were unsaturation meets
D) Rotate bond to connect oxygen to carbon
Me
Me
Me
Me
H
O6
H
O D Me
A
Me
H
Me
B
C
B
OAc
Epoxydictymene
O
O
H
Me
Me
OAc
Me
Me
H
H
Me
hv, 50 C
95%
O
H
A
Me
Me
Me
asymm.
michael
OH
(R)-citronellol
Leo Armand Paquette
R.A. Rodriguez
controlled by facial
approach of vinyl,
which is fixed
Selected examples using cope RR
OAc
H
O H
O
O
Me
Me
H
H
Me
TMS
H
Me
OPMB
H
PMBO
O-methylshikoccin
JACS 1997, 119, 9662
OH
H
H
Me
OMe
Me
H
Me
O
OPMB
H
OR
Me
O
Me O
Me
Me
H
Me Me
Baran GM
2011-08-20
Me O
O
O
Me
O
Me
Me
Me
H Me
Me
HO
Jatrophatrione
Me
Cl
H Me
Me Me
BnO
Me
H Me
O
Me
Cl
3. H2PtCl6,
HMDS
H Me
Me
Me
OMe
ii. MeI
Me
Me
Me
BnO
Me
OMe
Me
O
Ozaonlysis/
Jones[O]
Me
I
O
Me
OH
Me
Me
BnO
98%
H
Me
OH
18-c-6, 0 °C
JACS 2002, 124, 6542; JOC 1999, 64, 3244
O
Me
Me
BnO
Cope-ene
Me i. tBuOK, THF
Me
BnO
1. LAH
2. Me Me
Me
HO
H
Me
Si
O
Wieland
Miescher
ketone
Me
Me
OH
Et
PMBO
TMS
Me
Me
Me
TMS
O
HSi
Me
Me
O
Cl
O
H2O2, KF Me
BnO
OH
H
O
Me
OH
H Me
Me
H
OH
Me
Me
Me
O
H
O
SePh
restricted reactivity to
boat conformation
OH
O
O
O
O
HO
Me
Me
O
O
HO
O
Vulgarolide
JACS 1996, 118, 5620; Tet. Lett. 1995, 36, 673
HO
O
HMPA
Me
O
SEMO
O
KN(TMS)2
CO2Et
CO2Et
SEMO
O
THF, Δ
Me
O
Me
OH
OSEM
Me
(see Cerorubenic acid synthesis)
Leo Armand Paquette
R.A. Rodriguez
Baran GM
2011-08-20
Selected examples using Cope RR
JACS 1998, 120, 5953
OTBS
Me
H
H
H
Me
H
H
Me
H
CO2H
Me
H
H
Me
O
OH
1. CH2(CO2Et)2
Na, EtOH
Me
OAc
Me
Me
Me
Me
AcO
Me
OAc AcO
H
H
Me
OAc
Me
O H
H
OAc
Taxusin
Me
Me
Me
Me
Me
OH
O
Me
Me
Me
H
H
H
Me
Me
chair CycHex = syn
H2SO4
Me
Me
O
Me
* product
crystallize
out of soln
mechanism
SO3H
O
Me
[3,3]
Me
H
Me
Me
flagpole
Me
Me
Me
Me
CH2N2,
TEA
Me
H
O
O2S
O
O
H
RO
Me
OH
grignard
Δ
Z, trans
exo-chair
Me
Me
H
H
Z, syn RO
Me
O
Me
O-
H
Me
Me
Me
H
H
exo-boat
OR
Me
O
Me
H
OH
Et2O, 0 °C
SO2Cl
OH
RO
O-
RO
Me
Me
RO
Me
H
endo-boat
Me
Ac2O
Me
H
E, trans H
RO
endo-chair
O
H
endo vinyl = E
Me
Me
Me
H
O
H
H
O
2. FeCl3
DMF, -78 C
Me
(inverse addition)
O
H
O
O-
O
• dihydroxylation
Me • pinacol shift
1. LDA (2 eq)
THF, -78 C
O
HOAc,
100 °C
via acylium Me
Me
OAc
Me
PPA
O
OH
Me
O
O
OH ,
Me
Me
H
O
2. BH3-THF
3. Jones [O]
Me
OH
Me
Me
TsOH
O
Me
AcO
1.
vinyl
1. cuprate
2. ozonolysis
2. KOH; HCl
H
Me
HO
THF, Δ
O
H
CO2Me
O
O
KN(TMS)2
O
Cerorubenic Acid 3 (studies towards)
O
H
Me
RO
JACS 1998, 120, 5203; Org.Syn. v.45, p12 (1965); coll.v. 5, p194 (1973), Org.Syn. v.48, p106 (1968); coll.v. 5, p877 (1973)
OH
Leo Armand Paquette
R.A. Rodriguez
O
Selected syntheses
OH
Me
OAc
1.i. NaH, PhMe,
110°
O
Me
Me
Cl
1. NaH,
hydrolysis/
Robinson
Me
Me
Me
Me
SBu
Me
Me
O
Me
O
1. 1O2,
MeOH/DCM
OH
O Me
66%
2 steps
Me
Me
OAc
1. DIBAL
2. Ac2O, py 4aβ, 10βdoladiol
Me 92%
acetate
O
O
O
Me
1. LDA,
NCCO2Me
2. KN(TMS3)2,
PhTf2
O
Me
JACS 1996, 88, 3408; JOC 1986, 51, 4807; Org.Biomol.Chem 2007, 5, 1522
Me O
1. OsO4
2. SEMCl
Me
Me
80%
OH
Me
Me
O
O
Me
OTf
Me
O
1. Me3Sn
O
Me
Pd2(dba)3
CO2Me
O
KN(TMS3)2
O
O
O
H
89%
Me
Me
O
71%
Me
O
O
O
Me
OMe
O
Me
O
CO2Me
O
O
MeO
Me
HO
1.TBAF
2. TPAP [O]
3. NaBH4
65% 3 steps
H
O
Me
Me
Me
O
Me
SEMO
O
KN(TMS3)2, HMPA,
46%
Me2SO4, 80 °C
SEMO
MeO
Me
H
O
H
O
Me
MeO
O
Me
SEMO
MeO
* low tendancy to aromatize due to conformational bias of neighboring rings
Me
Me 2. P(OEt)3
Me
Me
Me
66%
67% tBuOK, MeI
1. mCPBA 80%
SEMO
Me
n-BuSH, HOAc
78%
Me
O
O
MeO
MeO
O 2 steps
Me
Me O
Me
2. Me3O+BF4- Me
51% 2 steps
O
O
O
33% + 52% rsm
84%
Li-NH3/MeI, then
alk./Robinson
SEMO
Me
1. hν
2. Ac2O, py
Me
98% ee
1. mCPBA
Me
Me
Me
i-PrMgBr,
CuCN
Me
O
eliminates
with NH4Cl
O
O
Me O
SEMO
H2O2,
NaOH
Me
OMe
(-)-Austalide B
MeO
Me
Me
Me O
H
30%
4 steps
O
O
SEMO
O
Me
Me
O
Me
Me O
O
Me
O
CO2Me
3. NaHMDS,
MeI
82% 3 steps
1. Hg(OAc)2,
HOAc
2. BF3•Et2O
3. K2CO3, Δ
37% 3 steps
OH
H
53%, 4 steps
Me
Me
O
protection/deprotection
Me
Me
MeLi 93%
H
2. Ba(OH)2, Δ
O
Me
Me
HO
O
Me
Cl
Cl
Me
HO
64%
Hagemann's 2. decarboxylate
Ester
Me
4aβ, 10β-doladiol acetate
Me
Me
Me
CO2Et
Me
C3 selective
Me 2 ii. Br
1
Me
Me
O
3
4
Baran GM
2011-08-20
Me
Me
O
Me
O
Me
O
MeO
JACS 1994, 116, 11323; JACS 1994, 116, 2665
O
OMe
(-)-Austalide B
* nice redox economy
O
Leo Armand Paquette
R.A. Rodriguez
Baran GM
2011-08-20
Me
Me
O
Me
Me
Me
Ozonolysis/
Robinson
Me
HO 3
Me
C(3) OH α; C(3) OH β
Hydroxykempenones
HO
Me
Me
O
O
Me
KOH, Δ
MeOH/H2O
Me
Me
Me
TMS
42%
4 steps
Me
O
MeO2C
HO
DDQ
Me
H
H
Not responsive to [3+2]
JACS. 1992, 114, 7375
TMS
Me
O-Li+
O
OH
Me
Me
Me
O
O
Me
Me
Me
OAc
Pd(OAc)2, P(OEt)3,
THF, Δ
MeO2C
1. LAH
Me
H
O
98%
H
Me
O
Me
Me
Me
O
Me
Li, NH3;
Me
H
Me
2. TsCl, py
DMAP
60% 2 steps
TsO
Me
H
HO
H
1. LiBHEt3 88%
2. TBSOTf 2 steps
O
Me
77%
MeO2C
O
Me
Me
TMS
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-BuO
TMS
Me
Me
Me
O
H
NaH, DME Δ
(MeO)2CO
Me
Me
Li, NH3;
tBuOH;
NH4Cl
Stork-Danheiser
O
80%
81%
O
Robinson
H
Me
Me
Me
[3+2]
H
Me
Me
HO
H
H
Me
HF
MeCN
Me
O
Me
Me
TBSO
Me
TBSO
(5:1)
O
Me
Me +
H
H
Me
H
H
Me
KOH,
MeOH
60 % Me
H
Me
O
TBSO
Me
H
H
Me
Me
O3;
Me2S
63%
Me
Me
TBSO
H
H
Me
O
Me
OH
OR
HH
O
Me
OMe
Me
Me
Me Me OH
O
Sclerophytin A; R = OH
Sclerophytin B; R = OAc
Org. Lett. 2000, 2, 1875
Org. Lett. 2000, 2, 1879
JACS 2001, 123, 9021
Org. Lett. 2001, 3, 135 (w/ Overman)
Maimone Cladiellin GM
7,8-Epoxy-2-basmen-6-one
O
11, O (3)-Dihydropseudopterolide
JACS 1990, 112, 4078
Newhouse Cembranoid GM
JACS 1990, 112, 3252
JACS 1991, 113, 2610
Newhouse Cembranoid GM
O
O
Me
O
JACS 1981, 103, 722
Rodriguez JACS 1981 GM
JACS 1992, 114, 3926
Newhouse Cembranoid GM
Me
O
OH
H
O
HO
OH
Me
O
Me
O
Punctatin A
JACS 1986, 108, 3841
Gutekunst JACS 1986
Me
Acerosolide
JOC 1993, 58, 165
Newhouse Cembranoid GM
Me H
Me
Me
OH
Pentalenolactone P
Methyl Ester
JACS 1991, 113, 9384
JACS 1992, 114, 7387
DeMartino Pentalenolactone GM
JACS 2002, 124, 9199
Gallagher Coriolin GM
H
O
H
HO Me
Me
Me
Coriolin
Tetrahedron Lett. 1987, 28, 5017
JACS 1988, 110, 5818
McKerrall JACS 1988
O
Me
HO
Me
H
O
OH
CO2Me
H
O
Me
Sterpuric Acid
Gymnomitrol
Me
OH
O
Me
O
O
O
Me
HO2C
OMe
Me
Me
JACS 1983, 104, 7358
Cherney JACS 1981 GM
OH Me
Me
Tetrahedron Lett. 1993, 34, 3523
JACS 1994, 116, 3367
Newhouse Cembranoid GM
O
Gorgiacerone
Me
H
Tetrahedron Lett. 1982, 23, 3227
JOC 1984, 49, 3610
Burns Vetivane GM
Pentalenene
Cleomeolide
O
Modhephene (R1 = H, R2 = Me)
Epimodhephene (R1 = Me, R2 = H)
JACS 1981, 103, 1831
Rodriguez JACS 1981 GM
Me
α Vetispirene
Me
O
Me
O
Me
R1
JACS 1983, 104, 7352
Cherney JACS 1981 GM
Me
Me
Me
Me
Me
Me
OMe
R2
Me H
Me
Silphinene
OH
Me
Me
Me
H
Me
Me
HH
Me
O
O
O
Me
Me
Me
H
O
Me
O
O
Me
Me
Me
OH
Ceratopicanol
Hypnophilin
JACS 2002, 124, 9199
Gallagher Coriolin GM
JACS 2002, 124, 9199
Org. Lett. 2002, 4, 71
Gallagher Coriolin GM
CO2Me
Me
H
Pentalenolactone E
Methyl Ester
JACS 1981, 103, 6526
DeMartino Pentalenolactone GM
Me
Me
Me
Me
Me
H
Isocomene
Laurenene
O
H
N
Me
Me
Me
H
Me
N
H
Me
CHO
O
O
O
Me
H
Me
Trixikingolide
Me
H
H
Ikarugamycin
Me
OH
O
Me
Me
H
O
O
Me
O
Spinosyn A Relay
Me
H
H
* good step count
Asteriscanolide
H
Me
Me
Me
Me
RuO4
Dactylol
Retigeranic acid A
[Zr] contraction
strategy
Me
Me
O
H
H
Me
H
O
HO
Me
O
HO
Me
O
OMe
O
O
H
Me
Me
MeO
OH
O
Me
O
OH
Me
Me
H
Me
Me
Senoxydene
(synthesis of
H
proposed structure)
Me
Me
HO2C
O
O
Pestalotiopsin
(studies towards)
H
H
Me
H
Me
H
O
OH
Me
Me
OMe
OMe
Me
Ring expansion
strategy
Me
O Me
ent-Grindelic Acid
MeO
O
O
18-Oxo-3-virgene
Me
H
Me
Me
Africanol
CO2H
Me Me
Zaragozic Acid
Me
H
Me
OH Me
Me
Me
H
H
Me
Me
H
prins pinacol
strategy
AcO
R2
O
CO2H
OH
O
O HO
Fomannosin
HO2C
HO2C
HO
NH
Me
Me
Me
H
OH
R1O
N
O
O
H
Me
H
7β,-Amino-7α-methoxy-3-methyl1-oxacephalosporin
H
N
O
Me
O
O
O
Me
Me
O
N
H
RCM
Upial
O
sugar [Zr] contraction
strategy
H
MeO
CO2H
O
Me
Subergoric acid
Me2N
Ph
O
O
H
O
Me
Me
H
O
Dactyloxene B and Dactyloxene C
O
Me
CO2H
Multifidene
Zingiberene
Magellanine and Magellaninone
Me
Me
Co chemoselective [H]
OH
Me
O
Me
Tandem michael/aldol
O
Me
Me
Me
Me
Me
H
Capnellene
Me
H
Me
Me
Me
H
Me
Me
H
Me
Me
O
O
O
OMe
OMe
Me
Polycavernoside A (w/ Barriault)
OH
Me
Me
O
O
Me
O
Pleuromutillin
(studies towards)
OH
RCM
O
H
O
H
O
O
AcO
OHC
Me
AcO
Me
Me
Me
O
O
Me
Me
O
OH
Me
Me
Me
Me
OH
O
H
O
Cochleamycin A
O
O
Me
H
H
O
HO
O
Me H
OH
Lancifodilactone G
Me
O
O
O
O
H
O
Me
OH
OH
O
H
N
O
N
Me
H
N
HN
O
Me
O
OH
O
Evans aldol
O
O
Enyne RCM
Radical
cyclization
Me
O
Me
HO
OTBS
E Boron
enolate
OTBS
B-alkyl suzuki
Me
H
H
Me H
O
TBDPSO
Me
Negishi coupling
Me
O
H
O
O
I
Me
OH
Me
HWE
Me
OH
BnO
Me
OH
Me
Me
Macrolactonization O
H
O
H
H
Me
Oxy-michael/
lactonization
OMe
O
H
Stille
NH
O
O
OH
HO
AcO
OH
O
Cross
metathesis
Me
O
Spongistatin 1 (Altohyrtin A)
Me
O
OH
H
Me
Me
Me
O
H
H
Me
H
O
Me
H
Mangicol A
Me
OAc
OH
Me
OH
HO
O
Me
Me
(-)-Sanglifehrin A
OH
Me
HO
O
Pectenotoxin-2 (PTX2)
Me
H
HO
O
O
OH
Me
O
OH
Me
O
HO
HO
OH
Cl
O O
Me
Kalmanol (studies towards)
H
O
OH
cis-Lauthisan and trans-Lauthisan
Me
Me
Me
O
H
OH
Me
O
O
Me
Me
[4+2] with tropone
oxy cope strategy
Cyathins (studies towards)
O
claisen strategy
Me
Me
Me
HO
Me
H
H
HO
Me
O
Me
O
Teubrevin G and Teubrevin H
Me
OH
OHC
Me
O
O
O
OH
O
O
O
OH
HO
O
HO Me
H
OTBS
Me
OMe
H
O
Pinacol
O