R.A. Rodriguez Leo Armand Paquette Baran GM 2011-08 · PDF fileβ−keto ester--Cl -...
Transcript of R.A. Rodriguez Leo Armand Paquette Baran GM 2011-08 · PDF fileβ−keto ester--Cl -...
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Born in Worcester, Mass., July 15, 1934
1390 publications (111 reviews)42 patents17 books38 book chapters
Research interestsHeterocyclic chemistryHydrocarbon chemistryNatural product synthesisSynthetic methodologyCatalytic asymmetric methodsOrganoetallic chemistryOrganosulfur reagents
Syntheses Discussed
Timeline: Career in review Natural Product Synthesis 1979-presentGymnomitrol and Isocomene 197955 total syntheses to date
Heterocyclic chemsitry1962-1975
Azepine 1962
Organosulfur 1964-74α-Halosulfones 1964
Hydrocarbons 1974-1990Dodecahedrane 1982
Ag(I) cat. RR1970-75
Oxy-Cope RR 1978-2000
di-π−methane RR1975-1984
Silicon chemistry1977-1984
Squarate esters1993-97
Polyspiro tetrahydrofurans1981-2004
1962 201119871975 20001968 1981 1993 2006
Dodecahedron
OH
MeOAc
Me
Me
Me
4aβ, 10β-doladiol acetate
MeMe
OH MeHH
Salsolene oxide
MeO
Me
Me
H
HO
Me
3
C(3) OH α; C(3) OH β
O
O
O
O
Me
OMe
MeHO
MeMe
O
MeO
Me
(-)-Austalide B
[22](1,5)Cyclo-ctatetraenophane
Elassovalene[4]peristylane
Indium reagents1995-2000
Me
MeMe
Me
Pentalene
Honors and Awards1965 Alfred P. Sloan Fellow1971 Morley Medalist Cleveland Section1976 Guggenheim Fellow1979 Columbus Section Award1980 Senior Research Award, OSU1981 Kimberly Professorship in Chemsitry1987 Arthur C. Cope Scholar1984 National Award for Creative Work in Synthetic Organic Chemistry1989 Senior Humboldt Fellow1990 Sullivant Medal, OSU highest honor1992 Awardee of the Japanese Society for the Promotion of Science1992 Ernest Guenther Award2002 S.T. Li Prize Science and Technology
B.S., Holy Cross College, 1956Ph.D., MIT, 1959 synthesis of azasteroidsand regioselectivity in Baeyer-Villiger(Adv. Norman A. Nelson)Upjohn, medicinal chemist, 1959-63Prof. Ohio State University, 1969-present
Postdoctoral Researchersfrom the Paquette group:
Steven Ley (1972-1974)Louis Barriault (1997-1999)(-)-polycarvernoside A
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Heterocyclic and Carbocycle Chemistry 1962-1975Upjohn and OSU
Azepine Oxepin
Bullvalene SemibullvaleneAzabullvalene1967
Azasemibullvalene1969
Novel aromatics 1976
Identification of cationic species 1968 (collaboration with Olah)
NH O
NMeO
N
MeO
O
2,3 Homotropone
OH
H
trans-Bicyclo[6.1.0]nonan-2-ones
Photochemistry of Carbocycles
The First 8C-6π Huckeloid System:1,3,5,7- Tetramethylcyclooctatetraene Dication
2 +
Bis(tetramethylhomocyclopropenyl) Dication
Me
Me
Me
Me
Me
MeMe
Me+ +
The Protonation of Hexamethyl Dewar Benzene and Hexamethylprismanein FSO3H−SbF5−SO2 "magic acid"
Protonation of cis-Bicyclo[6.1.0]nona-2,4,6-trienes in superacidic media
JACS 1973, 95, 3386
H
H
FSO3H−SO2ClF
−95 °C+
initial trans cation
MeMe
Me
Me
Me
Me
MeMe
Me
Me Me
Me
MeMe
Me
Me
Me
Me
ClO2SN C OMe
Me
Me
Me
Me
Me O
MeMe
Me
Me
Me Me
O
ClO2SN
MeMe
Me
Me
Me Me
O
ClO2SN
NMeMe
Me
Me
Me Me
O
HNNaOH
MeOMe
MeMe
MeMe
Me
A Synthetic Entry into the Azasemibullvalene System
1. Me3O+BF4-
2. K2CO3
JACS 1969, 91, 6107; JACS 1967, 89, 5480;JACS 1975, 97, 6124; JACS 1970, 92, 4338
JACS 1968, 90, 7147
JACS 1962, 84, 4987JACS 1963, 85, 4053JACS 1964, 86, 4092JACS 1964, 86, 4096
Syntheses and derivatives: Syntheses and derivatives:
e.g. phenol and chloramine
JACS 1965, 87, 1718JACS 1965, 87, 3417JACS 1968, 90, 6148JACS 1972, 94, 6751
JACS 1976, 98, 1267
JACS 1976, 98, 4327
JACS 1967, 89, 5633
hv
1/4 products
acyclicα,β-cyclopropane
ester
hv
JACS 1969, 91, 7108
NSO2Cl
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Synthetic Methods:1. Ramberg-Backlund 1964-74
3. di-π-methane RR 1975-80
• Indium 1995• Zr 2002
TMS
Me Me α−Vetispirene
4. Silanes 1977-84
1989 [3]peristylane
Diels-Alder equivalents
2. Ag I cat. RR 1970-75
Upjohn: Conversion of Mercaptans to Homologous Terminal Olefins
SH SCH2Cl90%
SO2CH2Cl97%
OH-
SCl
O OS
O O
SO2CH2ClHO OXJACS 1964, 86, 4383
R CH2SO2CHCl2base-HCl S
O O
ClR
Rbase-HCl
-SO2
RR of α,α-Dichloromethyl Sulfones
JACS 1967, 89, 4487
[O]
Br BrH MeLi Ag+
(AgBF4)
Ag+
(AgBF4)
JACS 1971, 93, 1288; JACS 1980, 102, 637
quant. cleannon-conjugated triene
40 °C
vs >150 °C w/o Ag (I)
Ag Ag Ag
H
O
PhS
H
H
Phenyl Vinyl Sulfoxide asAcetylene Equivalent
via ene-type
JACS 1978, 100, 1597
trans-1-(Phenylsulfonyl)-2-(TMS)ethylene asEthylene Equivalent
SO2Ph
TMS
JACS 1980, 102, 4976
HH
H H
* cis found to be less reactive
JOC 1980, 45, 3017Chem. Rev. 1986, 86, 733(silyl cylopropanes)
- cyclopentanone synthesis
OMe Me
TMS1. PhSO2NHNH2
2. nBuLi3. TMSCl Me Me
Cl
O
+AlCl3
Me
Me Me
OMe
MeMe
O
SnCl4
Tetrahedron 1989, 45, 3099
OHO OH
O
hv
80%
oxydi-π-methane
Me Me
TMS
Me MeMe
TMS
Tet.Lett 1982, 23, 3227
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Hypostrophene
A journey to dodecahedron: selected syntheses of hydrocarbons
N
N OH
OH O
OO
O
O
O
O O
I
I
H
H
IH O
NaOEt,EtONO
77%
Men of learning in ancient Greece took especial concern for "the putting together of cosmic figures.' their regular polyhedra whose mathematical elegance inspiredconsiderable 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...
[3] peristylane [4] peristylane [5] peristylane"triaxane"
When first synthesized, trixane was viewed predominantly as a chemical curiosity.
dodecahedrane[12 faces]
[4] peristylane
decahedrane[10 faces]
octahedrane[8 faces]
Eaton and Muller
X • molecular modeling shows serious nonbonded steric strain
RR
H
Ts Ts
O
TS
Ts
O
Ts
OO
OO 1.eth.gly., H+
2. Li, EtNH2
3.H3O+
N NHTs
Δ
N NHTsN N
CO2HCl
ClCl
O
SOCl2
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.
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".
It was initially named "triaxane" in an effort to capture the C3v symmetry of itstetracyclic framework and to depict that the cyclopropane ring rests on three
axial pillars fixed to a cyclohexane chair.
OH OI OH
O
1. hv2. I2, PPh3
top view
top view
80% BrO CO2H
PhH, Δ
HH mCPBA
98%2 steps
hvacetone
quant
HIO4,10%aqMeOH95%
69% 3 steps
1. BF3, Et3SiH2. TsCl, py3. LAH, Δ
64% 3 steps
JACS, 1983, 105, 4113
Tetrahedron, 1989, 45, 3099
Tet. Lett., 1974, 17, 1615
1.
63% 2 steps
Me
O
HO2C
OHHO2.
TsOH
1. hv2. H+,Δ
quant [5 gram]76%
O
I
H
HO
OH LAH
84%
SOO
1. sulfene85%
2. NaI90%
NaK-alloywurtz-type54%
1. SeO22. Al2O3,quinoline
[3] peristylane"triaxane"
[3+2]Δ
wurtz
MsCl/TEA 0 °C;rt NO GOOD!!
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
bicyclo[3.2.1]octane
bicyclo[2.2.2]octane
CO2MeBr
Br
Br
Br
Br
HH
HH
A B
A
B
[22](1,5)Cyclooctatetraenophane
JACS, 1990, 112, 1258; Tetrahedron, 1981, 37, 4521
E
EO O
R
R
E E
EE
O O
R
Rcis-bicyclo[3.3.0]
octanedione
O
E
E
O R
RO
- 4CO2
2 equiv
+aq. buffer
The Weiss-Cook reaction:
O
E
E
O
E
E
- 4CO2
+pH = 5.6 O
O
O
OOHCl, Δ
O
O
OO
MeMe
OHHOOO
O
O
2 equiv
all mixtures
BrBr
BrBr
all mixtures
all mixtures
Ni(CO)4
DMF[3,3] 500 °C
Br
Br
1. OsO42. OH
HO
TsOH
E
E
1.LAH2.NaH, CS2 MeI; Δ
(COCl)2,DMSO
O
E
E2 eq
2. HCl, Δ
1.1.LAH2.NaH,CS2, MeI; Δ
NBS 4 eqAIBN/CCl4
83%
56%3.TsOH69%
85%70%
34%2 steps
40%brsm
85% 92%
1.LAH2. DHP/H+
3.Ph3PBr2
CO2MeBr66% 3 steps
ether, rt
SiO2(10X weight)
83%
Bu3SnH
majorminor (~ 1:2)
H2, PtEtOAc
+
two-fold cation-olefincyclization
AgClO4
PhH/pentane
JACS, 1979, 101, 4773
A B
A
B
45 °
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
IsotriquinaceneJOC, 1984, 49, 1445 Tricyclo[5.3.0.02,8]deca-3,5,9-triene
JACS, 1987, 109, 2857Tricyclo[5.5.0.02,8]dodecatetraene
JACS, 1986, 108, 1986
Elassovalene
NN
NO
OPh
NN
NO
OPh
Ag I
SO O
O OO
4,5-Diazatwist-4-ene
NN
(-)
Br
Br
Br Br
NN
NOO
N N
NO ONO O
[4.4.4]Propella-2,4,7,9,12-pentaene & [4.4.4]Propellahexaene
O
O
O120 °C, 12h
sealed vessel
Cl
Org. Reactions, 1977, 25
O OO
R*R*
NN
R*
H2
Pd-C
JACS, 1977, 99, 6935
JACS, 1979, 101, 2131
O
N
N
NHSO2Ph
NHSO2Ph
NNHSO2Ph
triple shapiro
Oburgessluche/
Br
Br
Br
Br
O
O
O
Me
CO2Me
CO2Me
JACS, 1986, 108, 3731JACS, 1987, 109, 3174
S
OHO
O OO
OO
CN
CO2Me
O
Me
Used in studies towards the evaluation of homoaromaticity-specialcase of aromaticity in which conjugation is interrupted by a singlesp3 hybridized carbon atom. Although this sp3 center disrupts the continuos overlap of p-orbitals, considerable thermodynamicstability and many other properties or aromatics are still observed.
COT / Br2
RambergBacklund bromination/
elimination CO2MeCO2Me
Ph
Ph
study of bridgehead olefins
RR
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
[gram-scale]?
ClO OMe
O
β−keto ester
- Cl-- MeO-
- cannot attack ester (sterics)
ClO OMe
OMeO
Li
ClO OMe
O
wurtz-type?
ClO OMe
O
ClO OMe
OH
Cl
O
MeO2C
chemoselectivealkylation
O
MeO2C
fragmentation
MeO2CMeO2C
OH
OPh OPh PhO PhO OPhO HO OPh OCHO
PhOCH2Cl
Pd/C250 °C
2. hv3. TsOH4. HN NH
1. Li, NH32. H3O+
3. PCC
hv1.HN NH
2.DIBAL -78 °C
TsOHhv
Norrish II
Dodecahedrane1982
Polyhedron Tetrahedron Hexahedron Octahedron
Dodecahedron Icosahedron
Symmetry Group Td Oh Oh Ih I
Vertices 4 8 6 20 12
Edges 6 12 12 30 30
Faces 4 6 8 12 20
Norrish IIradical
stitchingWurtz/Acyloin
desymmetrization
C2-symmetric
E
E
E
E
O
O
Trostannulation/
Ring expansionE
E
Coreylactonization/
Oxidation
EE
90 °Domino
Diels-Alder
E
EOxidativedimerization
*Shenvi Platonic Hydrocarbons GM
Syntheses of dodecahedrane
E
E
O
O
O
I
I
O
CO2Me
CO2Me
O
O
CO2Me
CO2Me
OCO2Me
CO2Me
OO
O
CO2Me
CO2Me
MeO2C
CO2Me
O
OO
O
O
O
1974 Domino DA1976 Annulation/expansion1978 Hexaquinacene route abandoned1979 Desymmetrization
O
O
O
O
Cl
Cl
H
H
O OMe
OMeO1,4 diester
NH3, Li
thenPhOCH2Cl
HCl,MeOH
62%48%
NaBH4
MeOH81%
H2, Pd/CEtOAc
quant.
P4O10, MsOH
83% 2 stepsH2O2
MeOH77%
1. NaOH, MeOH
2. Jones [O]3. Zn/Cu, MeOH
78%
KOH, MeOH;I2, NaHCO3
94%
36%
OH
OH
65% 3 steps
1. KOH, EtOH retro-aldol37% 4 steps
50%
SPhPh
JACS, 1982, 104, 4504; JACS, 1981, 103, 228
σ−bondmetathesis
Cl
Cl
O OMe
OMeO
O
Norrish II:
CHO
unstable
blockinggrouppreventsover [O]...
O+
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Me
MeMe
Me
Pentalene
Me
MeOH
H
HO
O
Me
Hypnophilin
Me
MeOH
H
HO
O
MeO
OH
Coriolin
Me
Me
H
HMe
MeHO
Ceratopicanol
O
O
RO
RO
1.
2.
Li
Me
Me Li
Me
Me
O
i-PrO
i-PrO
JACS 2002, 124, 9199; Org. Lett. 2002, 4, 4547mechanism
OH
Oi-Pri-PrO
HOO
H38%
OO
i-PrO
i-PrO OH O
H
38%
NO
i-PrO
i-PrO O
O
Achieving high complexity in a single step: selected examples
O
O
RO
RO
5. Squartate esters
O
RO
Tetrahedron 1997, 53, 8913RO R
R
OH
O
O
R1OAcRO
RO
O
OX
R1RO
RO
O
O
R2
RO
OR
R
O
NRO
R
OO
O
RO
RO
O
O
R1
RO
O
OH
R2R1
RO
OH
OH
R1
RO
R2
R3
RRO
R1O
OH
R2
RO
R1O
OH
R3
O
O
RO
RO
R1
RO
RO
O
R1
O X
O
O
RO
RO
R1R2
O
NR
RO
O
ZR
R
R
OAcOAc
N
N
ZR
R
Li
Bu3Sn
RO
R1O
O
R2
X
X = Pb(OAc)3
X = I, Br, Cl
X = I, Br, Cl
H
RO
R1O
OR
O
RO
ROOH
OMe
OMe
MeO
MeO
OMe
BF3•OEt2O
OHO
MeO
gloiosiphone A
[2+2]
35%
steps
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
6. Oxy-Cope RR 1978-2000 then Claisen RR
OH
320 °Cgas phase
KH, 18-cr-6THF, 0 °C;
H2O
OH
H
Rate accelerations up to 1015 !!!
1964 "oxy-Cope"
1975 Evans
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
Me
OH Me
O
Me
OH
KH,18-cr-6
THF, -25 °C;H2O
NaH
THF, Δ;H2O
High basicity of "naked" potassium alkoxide vs less basic sodium salt
prostaglanins,multifidene
Alkyne, Allene and Diene participation
Aromatic participants
Enolate trapping: kinetic, thermodynamic and electrophiles
α H = kinetic protonationβ H = thermodynamic epimerization
Me
Me
Me
O
NaH
THF, Δ;H2O
CCl4, Δ OMeMeMeMe
OHviaretro ene
O
MeHO
KOHMeOHH2O
Me
O
O
Et
OH
Me
Et
Me
HH
OMeMeO
OHO
MeO HMeO
HOMe
HOMe
Me
MeO
Me MeO-
Me
H
OKH,18-cr-6
Me MeO-
Me
H
OH
Me MeO
Me
H
OH
SePh
PhSeCl
80 °C
OMe
Me
MeO OMe
O
O
H
HO
H
OMeOMeO
88%
Δ, 1h,THF
Jung, M. E. et. al. JACS, 1980, 102, 2463-2464
-
-
Me
O
retro [4+2]
18-cr-6,KH, THF
HO
H
HH
O
O
Me OMe
OO
OMe
MeO
MeMe
HO
OMe
KN(TMS)2
18-cr-6O2, THF
OMeMeO
Me
HH
H
Me
OH
O
[3,3][3,3]
+(algal sperm attractant)
MeO
Me
HOH
OMe
MeO
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Oxy-Cope in total synthesis
MeMe
OH MeHH
Salsolene oxideBr
Me Me
CO2Et
Me
OMe
(R)-(−)-carvone
O
Me Me
O
1. i. H2, Pt ii. O3
2. NaBH4, aq NaOH; H3O+
Br
Me Me
SPh
Br
Me Me
SPh
1. DIBAL, -78 °C
2. PhSH, TiCl4
Me Me
SPh
OMe
O
1. NaI, acetone2. CO2Me
LDA, HMPA -78 °C
1. 14M KOH; H3O+
2. (COCl)2, TEA
MeMe
H
SPhH
O
MeMe
H O
SPh
MeMe
H
SPhH
O-Li+MeI
kineticMe
Me
HMeH
O
SPhHMe
Me
HMeH
SPhHH
OH
MeMe
OH MeHH
Salsolene oxide
MeMe
OH H
HOMe
H
MeMe
H H
AcOMe
H
HH
H
H
LiTHF, -78 °C
LAH
Δ
1. Li, EtNH22. Ac2O, py
NOE
NOE
NOE
1. mCPBA, NaHCO3
2. LAH
MartinSulfurane
[2+2]
Besides trapping with electrophiles: Ultimate TANDEM Oxy-Copes
A. Cope-ene (as well as Cope-aldol-not shown)
Me
OHO
Me
OH
H
Me
B. Cope-ene: a more programmed approach
• Acidity of allylic hydrogen
• Silane anion promoter: two step process
O
OEtOH
Me
O
OEtO
H
H
H
OH
Me O
OEt[3,3]
[3,3]ene
eneKH0 °C
o-DCBΔ
TMS
OH
TMS
O
H
HO
KH, I2
THF, rt
TBAFrt
C. Cope-SN2'
D. Cope-retro oxy-michael
Pallescensin A. JOC 1992, 57, 7118
HOMe
Me
Me
O
Me MeO-
MeOKH,
18-cr-6
diglyme100 °C
H+
Me MeO
MeCHO
OH OH
H
OH
H
Cl
[3,3]
ΔCl
H SN2'
- HCl
K. Foo JACS YIR
46% 2 steps
88% 2 steps
65%2 steps
[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
57%
87%
78% 2 steps
78%3 steps
mechanism
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
Ikarugamycin
HO
H
HH
OH O
OH
H H
HO
H
HH
HO
H
HH
Recognizing the cope transform within cyclic systems: Its all about the vinyl grignard
HOH
H
HH
HOH
H
HH
OHH
HH
HH
HOH
H
∗
H
OH
HH
OMX+
cis
Alternatives....
O
H
HH
XM
HH
OH
possible pre-cope
(E)
(E)
cis required for norbornanesystem trans is too strained
1995_vulgarolideOH
H
O
HOH
H
O OH
H
H H O OH
Cerorubenic Acid 3
H
H H OH
H
H H O OHbridgehead olefin
OXM
OXM
H
H
MX O
O
HXM
acidic, conjugation
+
+
OH
OH
O
MX+
OH
OMe
MeMe
Me
HO
Cyathins studies towardsO
HN
O
NH
HO
O
H
H
HMe
H
H
Me
Ikarugamycin &Spinosyn A Relay
[3,3]
O
H
SePh
O
O
O
O
O
O
O
O
O SPh
O
SPh1.
2. Dibal-H, MeCN, HMPA/THF
O
SS chlor-
amine-T
S
S [Li]
(or)Δ
JACS 1989, 111, 8037JACS 1990, 112, 9292JACS 1989, 112, 9284
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
HO
MeH Me
HMe
Me
Epoxydictymene
HO
MeH Me
HMe
Me
OAcH
MeH Me
H
OAcHO
Me
Me
I2, PhI(OAc)2CycHex
hv, 50 C95%
Me
Me
HOO
Me Me
Me
7,8-Epoxy-2-basmen-6-one
HMe
HMe
Me
O
O
Me
H
H
Me
HMe
H MeMe
Me 6
B
BC
A
A D
B) Move unsaturation into one anotherC) Break bond were unsaturation meets
D) Rotate bond to connect oxygen to carbon
A) Keep in mind where O-alkylation will take place
O
Recognizing the claisen RR within cyclic systems: Find the γ - vinyl ketone
Me
Me
O
Me
Me O
Me
Me
Me
Me
MeH
Me
Me
Me
Me
HOH
Ceroplastol I
OH
MeOO
O
MeOO
Cl
O
MeOO
CuLiCl
2
MeOO
O
MeOO
O
MeOO
O
O
O
MeOO
O
mCPBA, NaHCO3,CH2Cl2, reflux
O
O H HMe
H
OAcMeMe
Me
Acetoxycrenulide
H
C6H15
H HAcO
H
H
O O
4
31
7
43
1 7
O
OMe
H
MePO O
O
O
MePO
O
Me
SePhH
H
H
O
O MeR
HH O
H
O
O
MePO
O
SePhH
H
OMe
Me Me
(S)HO
MePO
H
H
OMe
MeO(S)
MePO
H Me
OH
Me
Me
(R)-citronellolH
O
OMeO
MeO NP
N OMe
Me [Li]
asymm.michael
O
Me
H
H
MeO
OMeH
Me
Me
MX
+
12 steps from(R)-carvone
H
H
Me
O
Me
1. LDA, TMSCl2. O3, MeOH;
DMS3. CH2N2, rtH
H
O
Me
MeO2C
JACS 1993, 115, 1676
91%via epoxy lactone
(zwitterionic or biradical)
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
OO
Me
H MeMe Me
OMe
Jatrophatrione
O
H
OOAc
Me
Me
Me OMe
HH
O-methylshikoccin
Me
H
Me
MeH
OPMB
O
H
Me
OHOH
TMS
O
OMe
H
Me
MeH
OPMB
O
OTMS
TMSSePh
Me
PMBOMe Me
O
O
O
ClCl
Me
H
H
Me
H
H
OH
Et
O
Me
HBnO
Me
HO
Me
Me
OMe
MeOH
Me
Me
MeBnO
MeO
OMe
H MeMe Me
Me
BnO
OMe
H MeMe Me
Me
BnO
SiMe Me
OHMe
H MeMe Me
Me
BnO
OH
H2O2, KF
1. LAH2.
HSi
Me Me
Cl
3. H2PtCl6, HMDS
OMe
H MeMe Me
Me
HO
O
O
OH
Vulgarolide
O O
O
OHO
Me
Me
OHO O
Me
HO OO
Me
SEMO O CO2Et
Me
SEMO O MeOSEM
OH
Selected examples using cope RR
(see Cerorubenic acid synthesis)
O
Me
KN(TMS)2
THF, ΔI CO2Et
HMPA
MeOH
Me
Me
MeBnO
MeOMe
JACS 1996, 118, 5620; Tet. Lett. 1995, 36, 673
JACS 2002, 124, 6542; JOC 1999, 64, 3244
98%
i. tBuOK, THF 18-c-6, 0 °C
ii. MeI
Cope-ene
JACS 1997, 119, 9662MeMe
PMBO
Me
H
O
OH
OR
H
controlled by facialapproach of vinyl,
which is fixed
restricted reactivity toboat conformation
WielandMiescherketone
Ozaonlysis/Jones[O]
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
H
Me
H
Me CO2H
MeH
Cerorubenic Acid 3 (studies towards)
H
Me
HO
OH
O
O
O
Me
MeMe
OOH
O
Me
OAc
MeMe
Me
AcOH
OAcAcOMe
H
Taxusin
MeMe
OH
MeMe
O
MeMe
OO2SSO2Cl
MeMe
O
CH2N2,TEA
Et2O, 0 °CMe
MeMe
O SO3H
MeMe
O
H2SO4
Ac2O
OH
MeMe
RORO
Me Me
Me
AcOH
OAc
OAc
Me MeOAc
Me
H H
OMe
RO
Me
O 1. , TsOH2. BH3-THF3. Jones [O]
HOOH
PPAHOAc,100 °C
H
Me
H
Me CO2Me
MeH
KN(TMS)2
THF, Δ
O
O
Me
1. LDA (2 eq) THF, -78 C
2. FeCl3 DMF, -78 C
(inverse addition)
O
Me
OOH
1. CH2(CO2Et)2 Na, EtOH2. KOH; HCl
1. cuprate2. ozonolysis
mechanism
Selected examples using Cope RR
OH
OH
OMe
H
MeMe
OR
MeMe
O-
MeMe
O-
H
MeMe
O-
H
H
MeMe
O-
HHH
H
H
H
flagpole
endo-chair endo-boat exo-boat exo-chair
H
RO
Me Me
Me
H
OH
endo vinyl = E
chair CycHex = syn RO
Me Me
MeO
H
HRO
Me Me
MeH
O
HRO
Me Me
MeO
HHE, trans
Z, syn Z, trans
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)
JACS 1998, 120, 5953
H
Me
H
OTBS
O
H
OH
Me Me
Me
H
O
O
• dihydroxylation• pinacol shift [3,3]
vinylO
via acylium
* productcrystallizeout of soln
Δ grignard
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
OH
MeOAc
Me
Me
Me
4aβ, 10β-doladiol acetate (-)-Austalide B
O
O
O
O
Me
OMe
MeHO
MeMe
O
MeO
Me
Selected syntheses
Me
MeO
Me
O
Me
O
CO2EtHagemann's
Ester
JACS 1996, 88, 3408; JOC 1986, 51, 4807; Org.Biomol.Chem 2007, 5, 1522
Me
MeO CO2Me
Cl
Cl
Me
Me
Cl
Me
1. NaH,
2. Ba(OH)2, Δ
3. NaHMDS, MeI
Me
Me
Me
O
Me
Me
Me
OO
Me
H2O2,NaOH
MeO
OAc
Me
1. hν2. Ac2O, py
Me
MeSBu
O
Me
Me
Me O
Me
Me
Me MeO
Me
Me
Me
OH4aβ, 10β-doladiolacetate
1. Hg(OAc)2, HOAc2. BF3•Et2O3. K2CO3, Δ
n-BuSH, HOAci-PrMgBr,CuCN
1. 1O2,MeOH/DCM2. P(OEt)3
1. DIBAL2. Ac2O, py
OMe
O
30%4 steps
O
Me O
Me
O
Me O
MeMeMe
O
Me O
MeMeMe
SEMO
OH
Me O
Me
SEMO
O
Me
MeO
MeO
Me
Me
SEMO
O
MeMe
O
MeO
O OMe
Me
SEMO
O
Me
MeO
MeO
O OTf
CO2Me
Me
Me
SEMO
O
MeMe
O
MeO
O
CO2Me
O
H
O
Me
Me
SEMO
O
MeMe
O
MeO
O
O
O O
H
H
Me
Me
SEMO
O
MeMe
O
MeO
O
O
Me
OMe O
Me
Me
HO
O
MeMe
O
MeO
O
O
Me
OMe O
(-)-Austalide BJACS 1994, 116, 11323; JACS 1994, 116, 2665
tBuOK, MeI
H
1. OsO42. SEMCl1. mCPBA
2. Me3O+BF4-
1. mCPBA
1. LDA, NCCO2Me
2. KN(TMS3)2, PhTf2
Pd2(dba)3
O
H
O
Me3Sn1.
KN(TMS3)2
KN(TMS3)2, HMPA, Me2SO4, 80 °C
1.TBAF2. TPAP [O]
3. NaBH4
Li-NH3/MeI, thenalk./Robinson
protection/deprotection
64%
1.i. NaH, PhMe, 110°
ii. Br
OH
Me
Me
MeO H
O
MeLi
eliminateswith NH4Cl
93%
HO
O
H Me
53%, 4 steps
82% 3 steps
37% 3 steps
84%33% + 52% rsm2 steps
66%78%
66%2 steps
92%
98% ee67%
80%51% 2 steps
80%
71%
89%
46%
65% 3 steps
2. decarboxylate
1 2
34 C3 selective
* nice redox economy
* low tendancy to aromatize due to conformational bias of neighboring rings
hydrolysis/Robinson
Leo Armand Paquette R.A. Rodriguez Baran GM2011-08-20
MeO
Me
Me
H
HO
Me
Hydroxykempenones
3
C(3) OH α; C(3) OH β
Me
i-BuO
O
Me
O
Me
Me
O
Me
Me
MeTMS
Me
O-Li+Me
O
TMS
Li, NH3;Me
Me
Me
O
TMS
MeOH
Me
Me
Me
O
Me
Me
Me
O
Me
Me
Me
HO
MeO2C Me
Me
Me
O
MeO2C Me
Me
Me
O
MeO2C
Me
Me
Me
HO
TsO
Me
Me
Me
TBSO
Me
Me
MeO
Me
TBSO
O
Me
MeMe
TBSO
O
Me
Me
H
H H
HH
H
HHH H
H HH
MeMe
TBSO
O
Me
Me
H
H
MeMe
HO
O
Me
Me
H
H
+
KOH,MeOH/H2O
ΔLi, NH3;tBuOH;NH4Cl
NaH, DME(MeO)2CO
Δ
DDQTMS OAc
Pd(OAc)2, P(OEt)3,THF, Δ
1. LAH
2. TsCl, py DMAP
1. LiBHEt32. TBSOTf
O3;Me2S
KOH, MeOH
JACS. 1992, 114, 7375
Me
Me
Me
O
Me
HNot responsive to [3+2]
98%
(5:1)
42%4 steps
80%
81%
77%
60% 2 steps
88% 2 steps
63%
H
60 %
HFMeCN
Stork-Danheiser
Me
Me
Me
H
HO
Me
Me
Me
Me
O
Me
O
MeMe
MeOzonolysis/Robinson [3+2] Robinson
O
MeOH
OR
Me OHH
HH
H
MeMe
Sclerophytin A; R = OH Sclerophytin B; R = OAc
Org. Lett. 2000, 2, 1875Org. Lett. 2000, 2, 1879JACS 2001, 123, 9021Org. Lett. 2001, 3, 135 (w/ Overman)Maimone Cladiellin GM
OMe
OHO
Me
O
O
OMeMe
Me
HOO
Me Me
Me
7,8-Epoxy-2-basmen-6-one
JACS 1990, 112, 3252JACS 1991, 113, 2610Newhouse Cembranoid GM
11, O (3)-Dihydropseudopterolide
JACS 1990, 112, 4078Newhouse Cembranoid GM
Cleomeolide
Tetrahedron Lett. 1993, 34, 3523JACS 1994, 116, 3367Newhouse Cembranoid GM
O
O
MeOHMe
Me
Gorgiacerone
JACS 1992, 114, 3926Newhouse Cembranoid GM
Acerosolide
JOC 1993, 58, 165Newhouse Cembranoid GM
O
Me
OO
O
O
OMe
Me
OMe
OO
Me
O
O
OMe
Me
MeOH
H
HO
O
Me
Hypnophilin
JACS 2002, 124, 9199Org. Lett. 2002, 4, 71Gallagher Coriolin GM
Me
MeOH
H
HO
O
MeO
OH
Me
Me
H
HMe
MeHO
Coriolin
JACS 2002, 124, 9199Gallagher Coriolin GM
Ceratopicanol
JACS 2002, 124, 9199Gallagher Coriolin GM
MeMe
Me R1R2
MeMe
MeOH
Modhephene (R1 = H, R2 = Me)Epimodhephene (R1 = Me, R2 = H)
JACS 1981, 103, 722Rodriguez JACS 1981 GM
Gymnomitrol
JACS 1981, 103, 1831Rodriguez JACS 1981 GM
Silphinene
JACS 1983, 104, 7352Cherney JACS 1981 GM
Pentalenene
JACS 1983, 104, 7358Cherney JACS 1981 GM
MeMe
Me Me H
H
Me
Me
Me
Me
Me
Me
OH
HO
MeHO
Punctatin A
JACS 1986, 108, 3841Gutekunst JACS 1986
Sterpuric Acid
Tetrahedron Lett. 1987, 28, 5017JACS 1988, 110, 5818McKerrall JACS 1988
HO2C
Me
H Me
OHMe
O
Me
MeH
CO2Me
O
O
O
Me
CO2Me
O
Pentalenolactone PMethyl Ester
JACS 1991, 113, 9384JACS 1992, 114, 7387DeMartino Pentalenolactone GM
Pentalenolactone EMethyl Ester
JACS 1981, 103, 6526DeMartino Pentalenolactone GM
Me
Me Me
α Vetispirene
Tetrahedron Lett. 1982, 23, 3227JOC 1984, 49, 3610Burns Vetivane GM
Me
MeMe
Me
Isocomene
Me
Multifidene
H
H
Me
H
Capnellene
Me
Me Me
Me
Zingiberene
MeOH
MeMe Me
Dactylol
MeH
MeMeMe OH
Africanol
Me
Me
H
Me
Me
Laurenene
Me
Me
O
Me
Me
H HMe
Me
18-Oxo-3-virgene7β,-Amino-7α-methoxy-3-methyl-1-oxacephalosporin
NO
NH
MeO H
CO2H
Me
O
Ph
O
Me
Me
Me Me
Me
Me
Me O
Me
Dactyloxene B and Dactyloxene C
OH
H HO
Me
O
MeOO
OOMe2NMe
MeO MeOMe
OMe
Spinosyn A Relay
Ring expansionstrategy
O
CO2H
Me
MeMe
Subergoric acid O
Me
Me
Me
H H
H
H
O
O
Asteriscanolide
HO2C
Me H
Me
MeH
Me
Me
Retigeranic acid A
OCHO
MeMe
OUpial
OHN
O
NH
HO
O
H
H
HMe
H
H
Me
Ikarugamycin
N
Me
OH
HMe
OHN
Me
OH
HMe
O
Magellanine and Magellaninone
RuO4
RCM
Tandem michael/aldol
Co chemoselective [H]
* good step count
O
O
H H
Me
O
OOOHO
MeMe
MeMe Me
H
OO
OMeO OMe
OOH
Me
Me
MeO
Polycavernoside A (w/ Barriault)
O
O
O
H
MeMe
OH
Fomannosin
Me
MeMe
O
Me
Me
CO2H
ent-Grindelic Acid
prins pinacolstrategy
sugar [Zr] contractionstrategy
MeAcO
OMe
OHHH
Me
MeO
HO
Pestalotiopsin(studies towards)
OO
CO2HOH
HO2CHO2C
R1O OH
R2
Zaragozic Acid
O
OH
Me
O
HO
Trixikingolide
Me
Me O
MeOHMe
O O
OHPleuromutillin(studies towards)
HH
H
Me
Me
Me
Me
Senoxydene(synthesis of
proposed structure)
[Zr] contractionstrategy
O
O
OO
MeAcO O
O H
O
O
OO
MeAcO O
O H
Teubrevin G and Teubrevin H
RCM
O
Me
cis-Lauthisan and trans-Lauthisan
H
OH
OMe
MeMe
Me
OHOHC
OMe
MeMe
Me
OHOHC
OMe
MeMe
Me
HO
Cyathins (studies towards)
claisen strategy
[4+2] with troponeoxy cope strategy
O
OOOH
O
MeMe
Me
O
O
O
MeHO
H
H
H
O
Lancifodilactone G
O
O
MeBnO
H
H
O
OH
Enyne RCMCrossmetathesis
Oxy-michael/lactonization
O
O
Me
OMe
Me
H
B-alkyl suzuki
Pinacol
OTBS
Me
H
Me
HO
OTBSMeTBDPSO
Radicalcyclization
Negishi coupling
H
MeMe
HMe
OHHO
OH
MeOH
OHMe
Mangicol A O
OO
OH
Me
OAc
H
H
H
Cochleamycin A
O
OH
MeOH
OMe Me
OMe
O
O
Me
O
OOH
O
Me
O
O O
Me
Pectenotoxin-2 (PTX2)
O
O O
OO
O
OO
Me
OH
OMe
H
HO
H
Me
OH
HOHO
H
H
Me
OH
H
AcO
Me OH
H H Me
OH
HO
Cl
Spongistatin 1 (Altohyrtin A)
HO
Me HOHO
Me
MeHOH
Me
H
H
OH
OH
Kalmanol (studies towards)
O
NH
Me
Me
Me
Me
O
Me
OH
Me Me
O
OH
Me
OH
OHN
Me
O
Me
MeO
HN
OH
N
OHN
O
(-)-Sanglifehrin A
O
Me
O
OHO
Me
Evans aldol
E Boronenolate
Stille
Macrolactonization
Me
I
OTBS
HWE