Leo Armand Paquette R.A. Rodriguez Baran GM 2011-08-20 B o r n i n W o r c e s t e r , M a s s . , J u l y 1 5 , 1 9 3 4 1390 publications (111 reviews) 42 patents 17 books 38 book chapters R e s e a r c h i n t e r e s t s Heterocyclic chemistry Hydrocarbon chemistry Natural product synthesis Synthetic methodology Catalytic asymmetric methods Organoetallic chemistry Organosulfur reagents Syntheses Discussed Timeline: Career in review Natural Product Synthesis 1979-present Gymnomitrol and Isocomene 1979 55 total syntheses to date Heterocyclic chemsitry 1962-1975 Azepine 1962 Organosulfur 1964-74 α-Halosulfones 1964 Hydrocarbons 1974-1990 Dodecahedrane 1982 Ag(I) cat. RR 1970-75 Oxy-Cope RR 1978-2000 di-π−methane RR 1975-1984 Silicon chemistry 1977-1984 Squarate esters 1993-97 Polyspiro tetrahydrofurans 1981-2004 1962 2011 1987 1975 2000 1968 1981 1993 2006 Dodecahedron OH Me OAc Me Me Me 4aβ, 10β-doladiol acetate Me Me O H Me H H Salsolene oxide Me O Me Me H HO Me 3 C(3) OH α; C(3) OH β O O O O Me OMe Me HO Me Me O MeO Me (-)-Austalide B [2 2 ](1,5)Cyclo- ctatetraenophane Elassovalene [4]peristylane Indium reagents 1995-2000 Me Me Me Me Pentalene H o n o r s a n d A w a r d s 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 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 Postdoctoral Researchers from the Paquette group: Steven Ley (1972-1974) Louis Barriault (1997-1999) (-)-polycarvernoside A
Transcript
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
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
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...
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
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
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
