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Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
Born on October 3, 1937 in New York City-Brief Biography: http://www.arkat-usa.org/get-file/18783/
Education:-Columbia University, B.A. 1959-Columbia University, Ph.D. 1962-University of Wisconsin, Postdoc 1962-1963
Academic Appointments:-Assistant Professor of Chemistry - Ohio State University 1963-1966-Associate Professor of Chemistry - SUNY at Buffalo, 1966-1969-Professor of Chemistry - State University of New York at Buffalo, 1969-1979-William P. Timmie Professor of Chemistry, Emory University, Atlanta, Ga., 1979-present
-Recipient of Many Awards (http://euch6f.chem.emory.edu/padwa.html)
-Mentored around 200 Graduate Students and Postdocs
-Aproximately 820 publications including 130 reviews and book chapters
-Editorial Boards of JACS, JOC, Org. Lett. among others
-Avid Mountain Climber and RunnerAlbert Padwa Ph.D.
Research Interests Broadly Summarized:-Tandem Cascade Chemistry-1,3-Dipolar Cycloaddition Chemistry-Pummerer Induced Processes-Amino Furan Cycloadditions-Synthetic Organic Photochemistry-Heterocycle Synthesis-Alkaloid Synthesis
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
O
PhPh
Mechanistic Photochemistry:Tet. Lett. 1964, 15, 813-817.JACS 1964, 86, 4212-4213.
KOH, H2O2
MeOH
O
PhPh
O
h!
O
PhPh
O
PhPh
O
O
PhPh
O
OO
Ph
Ph
O
h!
O
Ph
Ph
O
O
Ph
Ph
O
O
Ph
Ph
Ph
Ph
O
OO
[-2CO2]
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
h!
+
Ph
Ph
Ph
Ph
[4+2]
Ph
Ph
Ph
Ph
initial product (formed rapidly)
continuted irradiation
ether
isolated products
Reactions of Aziridines with DMAD:Tet. Lett. 1965 48, 4363-4367.
NH
PhPh
MeO2C CO2MePhH
reflux85%
MeO2C CO2Me
NPh
Ph
NH
Ph
MeO2C CO2Mexylenes
reflux80%
O
Ph
NH
Ph
CO2MeMeO2C
O
Ph!
Oxidation of Substituted Aziridines with Peracids:JOC 1966, 88, 1995-1996.
however:
N
PhPh
Ph
RCO3HN
PhPh
Ph ON Ph
Ph
PhPh
PhCHO
PhNO2
Ph
Ph O
Ph
Ph
PhNO
desired rearrangement
N OPh
Ph Ph
x
Novel Rearrangements of cis-Dibenzoylstilbene Oxide with Hydrazines:Tet. Lett. 1968, 3, 281-284.
N
NO
R
R
first reported 1924,however structure was misassigned
first reported 1921,however structure was misassigned
Ph
O
Ph
O
OTsNHNH2
x
MeOHreflux N N
O
PhPh
Ph PhPh Ph
continuted on next page...
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
Novel Rearrangements of cis-Dibenzoylstilbene Oxide with Hydrazines:Tet. Lett. 1968, 3, 281-284.
Ph
O
Ph
O
OTsNHNH2
MeOHreflux
O
PhPh
Ph PhPh Ph
OMeO OMeNH
N
PhPh
Ph NN
Ph
Ph
Ph
Ph
O
PhPh
Ph Ph
OHO NHNTs
PhCO2H
Ph Ph
Ph
NH2NH2O
NH
N
PhPh
Ph
Ph
O
Ph
O
OPh Ph
NH2NH2
rt then refluxCHCl3
-H2O
-PhCO2H
Ph
O
Ph
O
OTsNHNH2
MeOHreflux
Ph Ph
NN
Ph
Ph
Ph
Ph
N N
Ts
PhPh
PhO
Ph
HO
N N
PhPh
PhOH
Ph
TsO
HN NH
N N
PhPh
PhOH
Ph
TsO
H H
HN NHTsNHNH2
JACS 1961, 83, 3729
!
Photocycloadditon of Arylazirenes with Electron-Deficient Olefins:JACS 1971, 93, 548-550.
N
Ph
h"R NPh
RR= CO2Me, CN
N
Ph
h"CO2Me NPh
CO2Me
Ph
Ph
however:
N
OPh
Ph
OCO2Me !
NPh
CO2Me
Ph
intermediate must be:
NPhPh
Novel Thermal Epoxidation of Bicyclo[3.1.0]hex-2-ene by O2:Tet. Lett. 1973, 1045-1048.
Ph!
HPh
Ph
O2, !
xylenes
Ph!
HPh
Ph
O
Ph!
HPh
Ph
O2, !
xylenes
Ph!
HPh
Ph
O
Ph!
HPh
PhPh!
HPh
Ph
mechanism:
mechanism:
mechanism:
Ph!
Ph
Ph
!
Ph!
Ph
Ph
O2
Ph!
Ph
Ph
OOH
Ph!
HPh
Ph
O
O
76% along with polymers
48 hrs
RH
(no reaction in tetrachloroethylene)
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
Utilization of the 1,4-Conjugated Wittig Reaction for the Synthesis of Substituted 1,3-cyclohexadienes:JOC 1973, 39, 1318-1320.
O
Ph Ph
Ph
Ph
PPh3Br
LiOEt, EtOH
rt
Ph
Ph
Ph
Ph
mechanism:
O
Ph Ph
Ph
Ph
PPh3
O
Ph Ph
Ph
PPh3
Ph
O
Ph Ph Ph
PPh3
Ph
-PPh3O
Rearrangement of Aziridinyl Ketones to Pyrroles:JACS 1973, 95, 7168-7169.JACS 1975, 97, 2822-2829.
N
Me
O
Ph
N
Me
O
Ph
t-Bu t-Bu120°C80°C
N
H
t-BuMeOH MeOH
N
H Me
t-BuN
Me
t-Bu
H
H HMe
H
OPh
OPh
O
Ph
thermal conrotatory opening forces the substitutents on the cis-azaridine tosterically interact with the N-t-Bu group
N
Me
t-Bu
H H
OHPh
N
t-Bu
Ph
Intramolecular 1,3-Dipolar Cycloaddition Reactions of Alkenyl-Sustituted Nitrile Imines:JOC 1978, 43, 1664-1671.
N
NN
N
Ph
h! NN
PhN N
Ph
N
NN
N
Ph
h!N N
Ph
-N2
DMAD
N N
PhCO2Me
CO2Me
N
NN
N
Me
O
h!
-N2
-N2
N N
Me
O
NNH
Ph
O
Cl
TEAN N
Ph
O
HN
N
O
TEA
Cl
CO2Et
N
N
O
CO2Et
some epimerizationobserved
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
Syntheis of Pyrrolidines Using an !-Cyanoaminosilane as an Azomethine Ylide Equivalent:Tet. Lett. 1983, 24, 3447-3450.
Ph NH2
1) TMS-CH2Cl
2) H2CO, KCNN
Bn
TMSNC AgF
MeCN, rt
N
Bn
Dipolarophile:
HN O
O
O2N O
O
MeO2CCO2Me
MeO2C
CO2Me
NH
O
O
BnN
Products:
NBn
BnN
NBn
MeO2C
MeO2C!CO2Me
CO2Me
NO2
O
O
NPhO2S
Br
AIBN
Bu3SnHNPhO2S
87%
NPhO2S
Br
AIBN
Bu3SnHNPhO2S
85%
NPhO2S
Br
AIBN
Bu3SnHNPhO2S
84%
N
SO2Ph
AIBN
SH
ON
PhO2S
S
O
100% (cis:trans 2:1)
N
SO2Ph
AIBN
SH
O
N
SO2Ph
S
O
64%
Synthesis of the Pyrrolidine Ring System by Radical Cyclization:JOC 1985, 50, 5620-5627.
NR
PhS
AIBN
Bu3SnH
NR
if R=Bn
if R=SO2Ph
NR
NR
89%
36%
N
SO2Ph
AIBN
SH
O
S
NPhO2S
55%
N
SO2Ph
BrBr
AIBN
Bu3SnH
N
SO2Ph
52%N
SO2Ph
expected (not observed)
84%
70%
23%
51%
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
JOC 1986, 51, 1157-1158.
O
O
O
1) 1-butene-4-ol
2) SO2Cl23) CH2N2
O
O
O
N2 Rh2OAc4O
O
O
O
O
O
O
O
O
87%
10%O
O
O
via:
BnN
O
O
N2 Rh2OAc4O
O
BnN
DMAD
RO
O
O
CO2Me
CO2Me
O
O
O
H+h!
O
CO2Me
OHC
MeOH MeOH
O
CHO
O
O
O
CO
O
CHO
MeOH
OHO
O
H
O
OHC OH
-H2Omechansim:
ON2
O
O
Rh2OAc4 complex mixture
Rh2OAc4 complex mixtureDMAD
Z
O
N2 Rh2OAc4
Z
O
Z
O
Z=O 1.2:1Z=S 9:1
O
O
O
N2
Rh2OAc4
O
O
O
OH
COCHN2
COPh
Rh2OAc4
O
COPh
O
O
N2
Rh2OAc4O
O
ON2
O
Ph
Rh2OAc4
DMAD
O
O
Ph
OO
Ph CO2Me
CO2Me
JOC 1989, 54, 817-824.
Rhodium Carbenoid Induced Tandem Cyclization-Cycloaddition Reactions of "-Diazoketones
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
Rhodium(II)-Catalyzed Cyclization Reactions of Alkynyl-Substituted !-Diazo Ketones:JOC 1991, 56, 2523-2530.
O
N2
O
Rh
O
O
Rh
O
rhodiummandelate
O
N2 rhodiummandelate
O
Me
Mechanism?
O
N2
O
rhodiummandelate
N
Ph
O O
O O
N
PhO
O
O NO
O
Ph
O
Mechanism?
1:1mixture
Tandem Pummerer Diels-Alder Sequence for the Preparation of !-Thio Substituted Naphthalene Derivatives:Tet. Lett. 1995, 36, 3495-3498.
O
Ph
SO Et
Ac2O
Ph
O
SEt
PhNO
O
NPh
O
O
73%
TsOH
THF/H2O
Ph
SEt
NPh
O
Ort
120°C
O
Ph
SO Et
Ac2O120°C S
Et
OPh
CO2Me
CO2Me
DMAD
38%
Mechanism?
Utilization of the Intramolecular Cycloaddition-Cation "-Cyclization of an Isomüchnone Derivative for the Synthesis of Lycopodine:JOC 1997, 62, 78-87.
EtO
N2
NBn
O O O CH2ArMe
synthesized in 7 steps
Ar=m-MeOC6H3
Rh2(pfb)4
N Me
CH2ArH
Bn
O
O
EtO2C
N Me
CH2ArH
Bn
O
O
EtO2C
3:2
97%
BF3•2AcOH
NBn
O
EtO2COH
Me
OMe
4:1 mixture71%
NH
Me
OMe
4 steps
Stork's Intermediate
N O
Me
Lycopodine
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
Application of Furanyl Carbamate Cycloadditions Toward the Synthesis of Hexahydroindoline Alkaloids:JOC 2001, 66, 3119-3128.
MeO
OMe
1) AlCl3, Br Cl
O
2) Tebbe reagent
MeO
OMe
Br
ONH
CO2Et
K2CO3
MeO
OMe
N
CO2Et
O
PhMe, 155°C
20 hrs.
N
CO2Et
O78%
TESH, TFA
MeOOMe
NaBH3CN, AcOH
trans-product
or
H2 (80 atm), Pd/CEtOH, 50°C, 7days
N
Ar
CO2Et
EtO
H
1) LAH2) NaBH3CN, AcOH
N
Ar
Me
HO
H5:1desired
2) HSCH2CH2SH3) Ra-Ni
1) PCC
N
Ar
MeH
(±)-mesembrane
OO
N
CO2Et
O
PhMe, 180°C
15 hrs.75%
N
Ar
CO2Et
O
TFA
t-Bu2MeSiHN
Ar
CO2Et
O
H10:1desired
F3C O
1) K2CO32)PhOCSCl, DMAP, TEA3) AIBN, n-Bu3SnH4) KOH
NHH
OO
NI
O
O NH
(±)-crinane
40°C
O
CO2H
N3PO(OPh)2
!, tBuOH
O
NHt-BuO2C
MeBr
(5 steps)
50% NaOHTBAB, DCM
O
Nt-BuO2C
Me
165°C, PhMe 15 hrs.74%
71%
83%
N
O
Me
H
H
H1) NaBH4
2) NaH, BnBr
3) B2H6 H2O2, NaOHN
OBn
Me
H
H
H
HHO
t-BuO2Ct-BuO2C72% overall
1) DMP2) H2, Pd/C3) MsCl, NEt3
N
Me
H
HHO
t-BuO2C
1) TFA
2) MeI, K2CO3
N
Me
H
HHO
Me
62% overall
65% overall
Kende's Intermediate
1) (CH2=CH2)2CuLi2) RuO4, CH2N23) NaOMe, MeOH4) NaBH4
N
Me
H
HH
O
Me
O
(±)-dendrobine
Paul KrawczukBaran Group Meeting The Chemistry of Albert Padwa
Total Synthesis of (±)-Jamtine Using a Thionium/N-Acyliminium Ion Cascade:Org. Lett. 2002, 4, 715-717.
N
MeO
MeOCO2Me
OS
Et
O
Br
CSA, PhMereflux, 98%
N
MeO
MeO O
MeO2C SEt
BrNaH, THFreflux
N
MeO
MeO O
MeO2C SEt
1) NaIO4 MeOH/H2O
2) !3) Lawesson's4) Meerween's Salt NaBH4, MeOH
N
MeO
MeO
MeO2C
H
HH
(±)-jamtine
Dichloroketene-Induced Cyclizations of Vinyl Sulfiminies: Applications of the Method in the Synthesis of (±)-Desoxyeseroline:JOC 2005, 70, 8538-8549.
SNTs
Me
RRC O
Cl
Cl
NTs
O
Cl Cl Cl Cl
O
NHTs
SMe
13%-19%
NBoc
SEt
NTs
C OCl
Cl
NBoc
NTsSMe
MeO
Cl ClMe
78%
O
AcO
SBu
NTs
C OCl
Cl
40% O
NTs
ClCl O
SBu
AcO
THFmechanism?
NBoc
NTsSMe
MeO
Cl Cl1) Zn, AcOH
NNTs
H
MeO
TMEDA, EtOHreflux
O H2) HCO2H
72%1) Na Napthalide
NN
H
MeO
O H
2) NaH, MeI
Me
BH3•THF
NN
H
Me
MeMe
(±)-desoxyeseroline
Application of the Rh(II) Cyclization/Cycloaddition Cascade for the Total Synthesis of (±)-Aspidophytine:Org. Lett. 2006, 8, 3275-3278.
NMe
HN
OMeMeO
CO2H
5 steps36% overall
O
CO2tBu
O
CO2MeN2
4 steps47% overall
(COCl)2
4Å mol sieves92%
NMe
OMeMeO
N
O
CO2tBu
O
CO2MeN2
O
Rh2(OAc)4 97%
NMe
OMeMeO
N
O
CO2tBu
CO2Me
O
O
H
BF3•OEt2
NMe
OMeMeO
N
OHCO2Me
O
O
H
O
O
70%
continued on next page...
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
NMe
OMe
MeO
N
OHCO2Me
O
O
H
O
O
1) MgI2, wet MeCN, !, 75%
2) AcCl, TEA3) SmI2, 90%
NMe
OMe
MeO
N
O
O
H
O
O
1) KHMDS, PhNTf22) Pd(PPh3)4, n-Bu3SnH
NMe
OMe
MeO
NO
H
O
O
1) P2S5, 95% 2)Et3OBF4
3) LiAlH(OtBu)34) AIBN, n-Bu3SnH 61%, 3 steps
NMe
OMe
MeO
N
H
O
O
(±)-aspidophytine
Sequential Aminodiene Diels-Alder Approach to the Ergoline Skeleton:JOC 2005, 70, 6833-6841.
ON
Boc
MeO2C
Me2N
OTBS
Rawal's Diene
1) MeCN (anhydrous) reflux
2) HF, 0°C (same pot)3) NaHCO3 (workup)4) PhMe, reflux (crude) N
Boc
CO2Me
O
60% overall
1) TFA, DCM, rt2) KOTMS, rt3) Pb(OAc)4, DMF 0°C
NH
O
58%
ON
Boc
MeO2C
ON
Boc
MeO2C
reactionsequence
reactionsequence
NH
O
NH
O
NH
TfOTf2O
base
General Access to the Vinca and Tacaman Alkaloids Using a Rh(II)-Catalyzed Cyclization/Cycloaddition Cascade:JOC 2008, 73, 2792-2802.
Acid Promoted Cyclization Reactons of Tetrahydroindolinones. Model Studies for Possible Application in a Synthesis of Selaginoidine:JOC 2007, 72, 538-549.
O
NH2 OCO2Bn
CO2Et62%
!
ON
CO2BnO
TFA 95%
O N
CO2Bn
OO
MeO2C
N
MeOselaginoidine works with thiophenes, indoles, pyrroles
under similar conditons
N
N
O N2
MeO2C
O
O
Et
Rh2(OAc)4
PhH, reflux95% N
N
O
O
EtO
CO2Me
N
N
O
Et
HO CO2Me
1) Lawesson's 2) Raney Ni3) Zn, AcOH
HN
N
HO
H
EtMeO2C
steps
(±)-3H-epivincamine
71%
Paul KrawczukBaran Group MeetingThe Chemistry of Albert Padwa
A General Synthetic Entry to the Pentacyclic Strychnos Alkaloid Family, Using a [4+2]-Cycloaddition/Rearrangement Cascade Sequence:JOC 2008, 73, 3539-3550.
2nd generation strategy:
NAc
N
O
O
150°Cmicrowave
NAc
NO
H O
1) NaBH42) NaOMe3) LiAlH44) NaBH(OAc)3
NH
N
H OH
1) H2, Pd(OH)2
Me
I
Br2)
NH
N
H OH
I
Me
1) ArCHO, NaBH(OAc)3, AcOH2) TPAP, NMO
N
N
H O
I
Me
DMB
Pd(PPh3)4
PhOK
N
N
H O
Me
R
H
R=DMBR=Ac
1) HCl2) Ac2O
40%
79%
56%
95%
65%
strychnopivotine(R=Ac)
A Steroselective Approach to the Azaspiro[5.5]undecane Ring System Using a Conjugate Addition/Dipolar Cycloaddition Cascade:JOC 2008, 73, 9601-9609.
O
O
1) LDA, THF2) n-BuLi
3) MOMCl4) HONH2-HCl
NOH
OMOM
nBu
72%
PhO2S
SO2Ph
!
OMOM
nBu
NO
SO2Ph
SO2Ph
OMOM
nBu
N O
SO2Ph
SO2Ph
82%
(both diasteromers)
OMOM
nBu
HNSO2Ph
O
5% Na/Hg
THF/EtOH
OMOM
nBu
HN
O
AIBN
n-Bu3SnH
69%
82%
BzCl, Et3N
OMOM
nBu
BzN
O
1) LiTMP TMSCl
2) Pd(OAc)2
84%
OMOM
nBu
BzN
OC5H11MgBr
CuBr•SMe2BF3•OEt2
OMOM
nBu
BzN
O
C5H12
95%
1) KHMDS PhNTf2
2) H2, Pd/C
OMOM
nBu
BzN
C5H12
LiAlH4, THF
T
84%
78%
OMOM
nBu
N
C5H12
Ph1) TMSBr
2) H2, Pd/C
OH
nBu
HN
C5H12
2,7,8-epi-PHTx
73%