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A Perspective on Professor Scott Eric Denmark:The Man, The Myth, The Chemist
Russell C. SmithStoltz/Reisman Group Meeting
January 24, 2011
O
SiR3
Si
O–M+
MeMe
ONO
H
MeH
MeO2C
MeN
NMe
PNMe
O(CH2
)5
2
Ph OMe
OMeOH
n-C5H9
PhO2SO
From Humble Beginnings…• Born in Lynbrook, New York on 17 June 1953• Obtained an S. B. degree from M.I.T. in 1975
– Conducted research with both Richard H. Holm (ferredoxin analogs) andDaniel S. Kemp (functionalized cyclophanes).
• Received D. Sc. Tech degree in 1980– Prof. Dr. Albert Eschenmoser (“On the Stereochemistry of the S N’
Reaction”).• 1980– Independent career as assistant professor at the University of
Illinois at Urbana-Champaign.• 1986 – Associate Professor• 1987 – Full Professor• 1991–Reynold C. Fuson Professor of Chemistry.
O
OO
steps HO H
O OSO2
N N
OH
OSO
O O
H
H
B
B
J. Org. Chem. 1981, 46, 3144
To A Thriving Career In Organic Chemistry: Outline• Silicon-Directed Nazarov Cyclization
• Inter/Intramolecular [4+2]/[3+2] Cycloaddition of Nitro Olefins
• Lewis-Base Activation of Lewis Acids – Enantioselective Carbon-Carbon Bond Formation
OOBn
SiMe3
thexylMe2SiO
BF3•OEt2
C6H5Et, 125 °C
thexylMe2SiOHH
O
Me
NO2 CN
+Me
Me
Me
Me 1. SnCl4 CH2Cl2, -78 °C
2. toluene, 80 °C
ONO
Me
HNC
H
Me
Me
Me
Me
EtO
OTBS+
BnMe2SiCHO
SiCl4
N
P
N O
NMe
CH2
Me
Me
2
BnMe2SiCO2Et
OH
To A Thriving Career In Organic Chemistry: Outline• Silicon-Directed Nazarov Cyclization
• Inter/Intramolecular [4+2]/[3+2] Cycloaddition of Nitro Olefins
• Lewis-Base Activation of Lewis Acids – Enantioselective Carbon-Carbon Bond Formation
OOBn
SiMe3
thexylMe2SiO
BF3•OEt2
C6H5Et, 125 °C
thexylMe2SiOHH
O
Me
NO2 CN
+Me
Me
Me
Me 1. SnCl4 CH2Cl2, -78 °C
2. toluene, 80 °C
ONO
Me
HNC
H
Me
Me
Me
Me
EtO
OTBS+
BnMe2SiCHO
SiCl4
N
P
N O
NMe
CH2
Me
Me
2
BnMe2SiCO2Et
OH
Nazarov Cyclization – Background
• Named after the Russian chemist I. N. Nazarov (1900-1957)
• Proved later that the cyclization proceeds through a divinylketone
• Incorporation of nucleophile gave further insight into mechanism
MeOH, H2O
HgSO4, H2SO4
O
Me
Me
Me
O
O
Me
O
Me
H3PO4, HCO2H
90 °C
O
PhPh
H2SO4
Ac2O, 25-30 °C
NaOH
Ph Ph
O
OH
Org. React. 1994, 45, 1-158
Nazarov Cyclization – Mechanism
• Promoted by thermal or photochemical initiation
O
R
R
H+OH
R
R
*
**
R
R
OH
* *
O
RR AcOH, H3PO4
50 °C
254 nm, C6H6
O
O
H
H
R R
R R
Org. React. 1994, 45, 1-158
Nazarov Cyclization – Mechanism
• Remote substituents can cause changes in the torquoselectivityof the cyclization
O
R
R
H+OH
R
R
*
**
R
R
OH
* *
counterclockwise
clockwise
O
R2
R1
O
R1 R2
O
R1 R2
+
H
H
O
R1 R2
O
R1 R2
+
H
H
Org. React. 1994, 45, 1-158
Silicon-Directed Nazarov Cyclization
Use of Si functionality directs collapse of cation
J. Am. Chem. Soc. 1982, 104, 6242.
CHO
+
MgBr
Me3Si
1. THF, -20 °C
2. NH4Cl
OH
SiMe3
O
SiMe3
NiO2
Et2O, 0 °C
O
SiMe3
FeCl3 (1.05 equiv)
CH2Cl2
OH
H
OH
H
55%, 100% cis
OH
H
84%, 100% cis
OH
H
74%, 85/15 cis/trans
O
Me
Me
95%, 59/41 cis/trans
SDNC – Effect of Allylic Position• Larger substituents promote increased levels of torquoselectivity
(presence of vinyl silane)O
R
SiMe3
FeCl3
CH2Cl2
R
H
H
O
R
H
H
O
+
(C,T) (C,C)
761090OCH2Ph
63694t-Bu
76694Ph
663070CH2=CH2
992278Me
yield, %(C,C)(C,T)R
Tetrahedron 1986, 48, 2821
SDNC – Effect of Silicon Functionality
701090I-Pr3Si
151387Ph3Si
831486MePh2Si
631684Me2PhSi
992278Me
yield, %(C,C)(C,T)R
Tetrahedron 1986, 48, 2821
O
Me
SiR3
FeCl3
CH2Cl2
Me
H
H
O
Me
H
H
O
+
(C,T) (C,C)
O
Me
H
H
For SiMe3 = 54/46
for Si(i-Pr)3 = 79/21
Formation of Enantioenriched Carbocycles ViaSDNC
OSiMe3 OSiMe3MXn
anti
syn
OSiMe3MXn
H H
OSiMe3MXn
H H
O
H H
O
H H
H
H
OSiMe3
FeCl3
CH2Cl2, -50 °C
OH
H H
58%, 88% ee
O
H H
Br2
CCl4
BrBr Br
70% yield
J. Org. Chem. 1990, 55, 5544
Total Synthesis of Silphinene: Application ofSDNC
Me
Me
Me
Me
Tetrahedron 1997, 53, 2103
Presence of silicon functionality directs formation of cyclopentenone
OH
Me
Me
RO
OBn
R = SiMe2thexyl
MnO2
CH2Cl2, 20 °C
OHC
Me
Me
RO
OBn
98% yieldH H
Me3SiMgBr
THF, -30 °C
80% yield
Me
Me
RO
OBn
SiMe3
HO
H
MnO2
CH2Cl2, -40 °CMe
Me
RO
OBn
SiMe3
O
H
BF3•OEt2
C6H5Et, 125 °C
Me
Me
RO
O
H
silphinene
To A Thriving Career In Organic Chemistry: Outline• Silicon-Directed Nazarov Cyclization
• Inter/Intramolecular [4+2]/[3+2] Cycloaddition of Nitro Olefins
• Lewis-Base Activation of Lewis Acids – Enantioselective Carbon-Carbon Bond Formation
Me
NO2 CN
+Me
Me
Me
Me 1. SnCl4 CH2Cl2, -78 °C
2. toluene, 80 °C
ONO
Me
HNC
H
Me
Me
Me
Me
OOBn
SiMe3
thexylMe2SiO
BF3•OEt2
C6H5Et, 125 °C
thexylMe2SiOHH
O
EtO
OTBS+
BnMe2SiCHO
SiCl4
N
P
N O
NMe
CH2
Me
Me
2
BnMe2SiCO2Et
OH
Intramolecular Cycloaddition of Nitrosoalkenes
• Reactivity of Nitrosoalkenes
– Intermediate nitrosoalkene can act as 2π or 4π cycloadditioncomponent
R
NOH
R'
Cl
base–
- HXR
NO
R'
Nuc–
R
NOH
R'
Nuc
J. Org. Chem. 1984, 49, 4714
Me
OMeN
Me2t-BuSiO
Cl CsF (3.0 equiv)
CH3CN, 20 °C
ON
OMe
H
R
H
70% yield + 13% isomer75/25 E/Z
50/50 E/Z 32% yield (3.4/1 ratio of isomers
Nitroolefins as 4π Components in Cycloadditions
• Nitro groups serve as useful functionality for further elaboration
Me
N+-O O Me
SnCl4
toluene, -29 °C
80% yield
NO Me
HH
Me
-O
> 98/2 trans/cis
H
N+-O O Me
SnCl4
CH2Cl2, -70 °C
NO Me
HH
H
-O
KOt-amyl
-70 °C
OMe
H
H
HON
OMe
H
H
HON
HCl
CH2O
J. Am. Chem. Soc. 1986, 108, 1306
Me
N+-O O Me
SnCl4
CH2Cl2, -70 °C
NO Me
HH
Me
-O
CO2Me NO Me
HH
O
Me
MeO2C
Helv. Chim. Acta. 1986, 69, 1971
Intramolecular [3+2] CycloadditionN+
O-O
MeZ'Z
+
MeMe
MeMe
1. SnCl4 toluene, -78 °C
2. toluene, 70 °C
NOO
Me
Me
Me
Me
Z'
ZMe
HH
72>100:107CO2EtH
7820:138HCO2Et
yield, %dstime, h[3+2]
time, h[4+2]
Z’Z
N+O-O
Me +
MeMe
MeMe
1. SnCl4 CH2Cl2, -78 °C
2. toluene, 80 °C
NOO
Me
Me
Me
Me
Z'
ZMe
Z'
Z
HH
93>100:1725CO2EtH
902.6:11410HCO2Et
yield, %dstime, h[3+2]
time, min[4+2]
Z’Z
J. Am. Chem. Soc. 1990, 112, 311
Tandem Double Intramolecular [4+2]/[3+2]Cycloaddition
• Fused/bridged C(6)
• Fused/bridged C(5)
N+
O
O-
Me 1. SnCl4 toluene, -78 °C
2. NaHCO3 toluene, 80 °C
CO2Me
82% yield
N
OO
MeO2CH
HMe
H
OHH
NH
HOMe
HH
O
Ra-NiH2 (160 psi)
MeOH, rt
71% yield
AcN
N+O-O
Me
1. SnCl4 CH2Cl2, -78 °C
2. NaHCO3 toluene, 100 °C
79% yield
1. Ra-NiH2 (160 psi)MeOH, rt
2. Ac2O, py
82% yield
MeO
N OO
H
MeO
MeAcO
Me
Org. Lett. 2001, 3, 2907
Cycloaddition can be rendered diastereoselective by presence of chiralauxiliary
Total Synthesis of (+)-Crotanecine N
HHO OH
OH
N
OH
HO
HHO
rosmarinecine (intra)
N
OHHHO
hastanecine (inter)
N
HHO
macronecine (inter)
HO
CO2i-Pr
O
NO2
+
O
Ph SiMe2Ph
OMeAl
2
toluene, -14 °C
73% yield
NOO
OO
SiMe2Ph
OG*H
H
i-PrO2C
H
L-selectride
CH2Cl, -78 °C
91% yield
NOO
OHO
SiMe2Ph
OG*H
H
i-PrO2C
H
Ra-Ni
200 psi H2EtOH
58% yield
N
O
HO SiMe2Ph
OH
HH
HO 94.9% ee
N
O
MeO3S OH
OH
HH
HO
1. CH(OMe)3 TsOH2. Me2SO2Cl, Et3N
3. HOOAc, KBr HOAC, NaOAc4. 90% TFA
BH3, THF NMeO3S OH
OHH
HH
HO
BH3Et3N, MeOH
120-130 °C
N
HHO OH
OH
J. Am. Chem. Soc.1997, 119, 125
1-Azafenestranes: Planarization of sp3 Carbon Center
N+
H H
H
BH3–
BF3•OEt2 N+
H H
H
BF3–
X-ray quality
1
2
5
8
N-C(1)-C(5)C(8)-C(1)-C(2)
121.8°121.9°119.2°121.2°119.8°120.7°
NO2 Cu(CN)ZnI
then PhSeBr
NO2
SePh
H2O2 NO2
Ot-Bu
AlMe3CH2Cl2, -78°C
NO
O
H H
Ot-Bu
H
ON+
-O Ot-Bu
H
+
2.6 1
HN
H H
H
OH
Ra-Ni, H2
10% H2O in EtOAc
N+
H H
H
BH3–
PPh3, DIAD
then BH3•THF-78 °C to rt
To A Thriving Career In Organic Chemistry: Outline• Silicon-Directed Nazarov Cyclization
• Inter/Intramolecular [4+2]/[3+2] Cycloaddition of Nitro Olefins
• Lewis-Base Activation of Lewis Acids – Enantioselective Carbon-Carbon Bond Formation
EtO
OTBS+
BnMe2SiCHO
SiCl4
N
P
N O
NMe
CH2
Me
Me
2
BnMe2SiCO2Et
OH
OOBn
SiMe3
thexylMe2SiO
BF3•OEt2
C6H5Et, 125 °C
thexylMe2SiOHH
O
Me
NO2 CN
+Me
Me
Me
Me 1. SnCl4 CH2Cl2, -78 °C
2. toluene, 80 °C
ONO
Me
HNC
H
Me
Me
Me
Me
Lewis-Base Activation of Lewis Acids
• Preparative Examples
PMe3 + BH3P
B
MeMeMe
H H
Hstable Adductmp = 100 °Cstable in H2O
CHO ZnEt2
Ti(Oi-Pr)4 (1.2 equiv)-20 °C, 1.5 h
NHTf
NHTf OH
Et
98% ee
ZnEt2
Ti(Oi-Pr)4 (1.2 equiv)23 °C, 12 h
OH
Et
REVIEW: Angew. Chem Int. Ed. 2008,47, 1560
Me
Me
OLi
Ph
MeIdioxolane
4 eq. HMPA
t1/2 = < 1 min
Ph
O
Me
MeMe
MeIdioxolane
Ph
O
Me
MeMe
t1/2 = 80 min
Lewis-Base Activation of Lewis Acids – Principles• Gutmann Analysis
REVIEW: Angew. Chem Int. Ed. 2008,47, 1560
D
L
LL
+
A
X
X X
Lewis Base
Lewis Acid
e.g. BR3
D A
LL
L X X
X
!+
!–
!+
!–
increasednegative charge
increasedpositivecharge
D A
LL
L X
X
+
X–
D
L
LL
+
A
Lewis Base
Lewis Acid
e.g. SiCl4
D A
LL
L X X
X
!+
!–
!+
!–
increasednegative charge
increasedpositivecharge
D A
LL
L X
X
+
X–
X
XX
X
XX
cationic Lewis Acid
cationic Lewis Acid
Lewis-Base Activation of Lewis Acids – Principles• Hybridization of Silicon
REVIEW: Angew. ChemInt. Ed. 2008,47, 1560
Aldol Reaction of Silicon-Substituted Enolates
• UncatalyzedOSiCl3
OMe
+
R
O
H
1. CH2Cl2, 0 °C
2. sat. aq NaHCO3
O
R
OH
H
99t-Bu89(E)-cinnamyl
96Cy98Phyield, %R
OSiCl3
+R H
O
P
N
N
O
N
Me
Me
Ph
Ph
R = Ph (E)-cinammyl
1. 0.1 equiv
CH2Cl2, -78 °C
2. sat. aq. NaHCO3
O
R
OH
Ph, anti/syn 65/1, 93% ee(E)-cinnamyl, anti/syn >99/1, 88% ee
J. Am. Chem. Soc. 1996, 118, 7404
Addition to Ketones – Silyl Ketene Acetals
Ph Et
O
O
O O
Me
Ph
Me
OO
Me
O
F3C
Me
O
MeO
Me
O
95%, 83% ee 91%, 76% ee 94%, 68% ee 97%, 49% ee
86%, 8% ee 91%, 32% ee 90%, 80% ee 94%, 35% ee
OSiCl3
OMe
+
R
O
R'
1. CH2Cl2, 0 °C
2. sat. aq NaHCO3
O
R
OH
R'
N N
O O
OBu
t-Bu
BuO
t-Bu
J. Am. Chem. Soc. 2002, 124, 4234
Vinylogous Aldol
R1 H
O+
OR2
OTBS
R5
R4
R3
SiCl4, CH2Cl2, -78 °C
N
P
N O
NMe
CH2
Me
Me
2R1
OH
OR2
O
R5
R4
R3
Ph
OH
OEt
O
89%, >99:1 !/", 98% ee
Ph
OH
OMe
O
Me
93%, >99:1 !/", 99% ee
OH
OEt
OMe
73%, >99:1 !/", 95% ee
Ph
Ph
OH
Ot-Bu
O
Me
92%, >99:1 !/", 89% ee, 98% de
OH
Ot-Bu
O
Me
71%, >99:1 !/", 82% ee, 98% de
Ph
Ph H
O+
OTBS
OO
SiCl4, CH2Cl2, -78 °C Ph
OH
O
OO
MeMe MeMe
92% yield, >99:1 !/", 74% ee
chiral phosphoramide
J. Am. Chem. Soc. 2003, 125, 2800
Formation of Quaternary Centers – Silyl Ketene IminesCHO
+CR1
R2
NTBS CN
R1 R2
OH5 mol% chiral phosphormaide
SiCl4 CH2Cl2, -78 °C
CN
Ph Me
OH
87%, 95/5 dr, 97% ee
PhCN
Et
OH
F3C73%, 97/3 dr, 99% ee
PhCN
Et
OH
74%, 87/13 dr, 89% ee
Me
CHO
+CPh
Me
NTBS CN
Ph Me
OH5 mol% chiral phosphormaide
SiCl4 CH2Cl2, -78 °C
RR
929099:12-furyl7697>99:11-naphthyl8499>99:12-Me8899>99:14-CF3
yield, %ee, %drR
J. Am. Chem. Soc. 2007, 129, 14864
N-Silyl Oxyketene Imines – Aldol Surrogates
C
R1
NR3Si
OPg
+
H
O
R2
catOH
R2NC
OPg R1
cross-benzoin
glycolate-Aldol
R1R2
O
OH
R3
O
R2
OH
OPg R1
N-Silyl Oxyketene Imines – Aldol SurrogatesRNC
Ot-Bu
KHMDS (1.2 equiv)i-Pr3SiCl (1.1 equiv)
THF, -78 °C
C
Ot-Bu
N(i-Pr)3Si
R
where R = Me, Er, i-Bu, Bn, allyl
RC
Ot-Bu
N(i-Pr)3Si
+H
O
R
N
P
N O
NMe
CH2
Me
Me
2
SiCl4, i-Pr2EtNCH2Cl2, -78 °C
Aryl
OH
R
t-BuO CN
OH
Me
t-BuO CN
84%, 96:4 dr, 99% ee
OH
t-BuO CN
93%, 99:1 dr, 99% ee
Ph
OH
t-BuO CN
90%, 99:1 dr, 99% ee
OH
t-BuO CN
91%, 98:2 dr, 97% ee
Ph
OH
t-BuO CN
93%, 99:1 dr, 97% ee
Ph
OH
t-BuO CN
91%, 99:1 dr, 99% ee
Ph
CO2Me
Me
O
Nat. Chem. 2010, 2, 937
O
O
OH OH OH OH OH OH
OH
OH
Me
Me
Me
Total Synthesis of RK-397• Synthesis of Polyol Fragment
OH
BnMe2Si 1. Red-Al
2. DMSO (COCl)2 Et3N
BnMe2SiCHO
N
P
N O
NMe
CH2
Me
Me
2
SiCl4
OEt
OTBS+
BnMe2SiCO2Et
OH
75%, 96% ee
BnMe2SiCO2Et
OPhCHO
KHMDS
O
Ph
74%, 19/1 dr
BnMe2SiC(O)Me
O O
Ph
1. MeNHOMe-HCl i-PrMgCl
2. MeMgBr
1. TMSOTf, DIPEA
2. SiCl4, Hg(OAc)23.
CHO
OPMB
Me
P
N
N
Ph
PhN
O
Me
Me
BnMe2Si
O O
Ph
OHO
Me
OPMB
Me
Me
BnMe2Si
O O
Ph
OO
Me
OPMB
Me
Me
1. NaBH42. PhC(OMe)2 CSA
Ph
O
O
OH OH OH OH OH OH
OH
OH
Me
Me
Me
Total Synthesis of RK-397
• Synthesis of Polyene Fragment
8 of 10 stereocenters were generated by substrate control
SiMe2OHBnMe2Si
+ OTHPI
1. NaH
2. Pd2(dba)3•CHCl3 BnMe2Si OTHP
77%, 3/1 dr
ICO2Et
Pd(dba)2
OTHP
79%, 5/1 drOEt
O
93%OEt
O
1. TsOH, I22. PBr3, py
3. P(OEt)3
P(OEt)3
O
Awards/Recognition• Eli Lilly Research Grantee, 1983• Beckman Endowment Research
Award, 1983• University of Illinois Center for
Advanced Study, Beckman Fellow,Spring 1985
• A. P. Sloan Foundation Fellow,1985-1987
• NSF Presidential YoungInvestigator Award, 1985-1990
• Procter and Gamble UniversityExploratory Research ProgramAward, 1986-89
• University Scholar, University ofIllinois, 1986-1989
• School of Chemical SciencesTeaching Award, University ofIllinois, 1986
• Stuart Pharmaceuticals Award inChemistry, ICI Americas, 1987
• A. C. Cope Scholar Award,American Chemical Society, 1989
• Fellow, American Association forthe Advancement of Science, 1990
• Reynold C. Fuson Professor ofChemistry, 1991
• Pedler Medal (Royal Society ofChemistry), 2002-2003
• ACS Award for Creative Work inSynthetic Organic Chemistry, 2003
• Yamada-Koga Prize (JapanResearch Foundation for OpticallyActive Compounds), 2006
• Fellow, Royal Society of Chemistry(FRSC), 2006
• Prelog Medal (ETH-Zürich,Switzerland), 2007
• Robert Robinson Medal andLectureship (Royal Society ofChemistry), 2009-2010
• H. C. Brown Award for CreativeResearch in Synthetic Methods(ACS), 2009
• Fellow, American Chemical Society,2009 (inaugural year)
