Direct Catalytic Aldol Reactions
Shibasakiʼs and Trostʼs contributions toward the development of catalytic enolate reactions.
ʻThe time has come,ʼ the Walrus said,ʻTo talk of many things:
Of shoes–and ships–and sealing wax–Of cabbages–and kings–
And why the sea is boiling hot–And whether pigs have wings.ʼ
ON N
O O PhPh
PhPh Zn
Zn
Me
Me
OOO O
OO
LnLi Li
Li
The Definition of a Direct Catalytic Enolate Addition
A large number of enantioselective aldol reactions exist:
Ar
R R
OEt
OTBSOSnBu3
RBINAP•AgOTfO O
OSiMe3
Me Me
CuF2•Tol-Binap
Carriera, 1998 Yamamoto, 1997 Chen, 1997
Preconversion to the ketone is a prerequisite for the reactions.
These are not direct aldol reactions.
Me R1
O
R H
O+
catalystR1
O
R
OH∗
A route to this reaction without stoichiometric amounts of base and/or adjunct reagents was desirable
Aldolases as Inspiration
fructose-1,6-bisphosphate and dihydroxyacetone phosphate (DHAP) aldolases are found in E. coli.
Fessner, W.-D.; Schneider, A.; Held, H.; Sinerius, G.; Walter, C.; Hixon, M.; Schloss, J. V. ACIE 1996, 35, 2219-2221
HOO
OPO32–H
OMe
OH
+enzyme O OPO3
2–
OH
OHHO
Me
L-fuculose
Key Points
• facilitates both electrophilic activation and proton abstraction
• Lewis acid and Brønsted base
• Multifunctional
ZnHis
His HIs
GluCO2
2+
deprotonation
HOO
OPO32–
OOPO3
2–
ZnHOGlu
CO2H
GluCO2H
H
OMe
OHO
OPO32–
ZnHO
HO
Tyr
H
OMe
OH
C-C bondformation
Me
OH
OH
OO
OPO32–
Zn
O OPO32–
OH
OHHO
Me
Professor Masakatsu Shibasaki
• Ph. D, University of Tokyo, 1974 (Yamada)• Post-doc, Harvard, 1974-77, (Corey)• Associate Prof, Teikyo, 1977-83 (Ikegama)• Professor, Hokkaido, 1986-1991• Professor, University of Tokyo, 1991-present
• To date, 465 publications
The 1970ʼs Corey GroupShibasakiNicolauBogerTius
FuchsSeebachNoyori
H. YamamotoB. SniderTakedaLipshutzMulzer
DanheiserKeck
Enders
Professor Masakatsu Shibasaki
The catalyst:
OOO O
OO
LnLi Li
Li
Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. JACS 1992, 114, 4418-4420Sasai, H.; Suzuki, T.; ItoH, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 851-854
Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. JACS 1993, 115, 10372-10373
MeNO2 H
O OHNO2catalyst
+ 91% yield90% ee
• The lithium is important, Na gave much lower selectivities and yields• small amounts of H2O are needed• Uncertain of success in aldol reaction due to low basicity of alkoxide
S-U-C-C-E-S-S thatʼs the way you spell Success
H
O
Me
OMe
MeMe
catalyst
THF+ Ph
OH OMe
MeMe
81% yield91% ee
• A variety of ketones are compatible• A variety of aldehydes are compatible• selectivity is generally high
• Long reaction times (up to 253 h)• Large excess of ketone (up to 50 equiv)• High catalyst loading (20 mol %)
Positives Negatives
In this case, the rxn worked better without the addition of water.
Mechanistic Insight:
Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. ACIE 1997, 36, 1871-1873
• Employment of the Pr related catalyst resulted upfield shift of the aldehyde proton
• Using dilithium salt of (R)-binapthol resulted in no chemical shift, afforded racemate
Improvement to the Reaction
catalyst
THF+Ph H
O
Me Me Me Ph
O
Ph
OH
Me Me
O
Ph
O
BnO OBn
OO catalystLiHMDS, H2O
+
O
BnO2C
CO2Bn
12 h99% yield
97% ee
Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem.–Eur. J. 1996, 2, 1368-1372
trace amount
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. JACS 1999, 121, 4168-4178
catalyst
THF+Ph H
O
Me Me Me Ph
O
Ph
OH
Me Me
O
Ph
O
BnO OBn
OO catalystLiHMDS, H2O
+
O
BnO2C
CO2Bn
Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem.–Eur. J. 1996, 2, 1368-1372
Improvement to the Reaction
with KHMDS and H2O as an additivewith only 8 mol % catalyst
5 h74% yield
84% ee
12 h99% yield
97% ee
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. JACS 1999, 121, 4168-4178
catalyst
THF+Ph H
O
Me Me Me Ph
O
Ph
OH
Me Me
O
Ph
Improvement to the Reaction
5 h74% yield
84% eewith KHMDS and H2O as an additive
with only 8 mol % catalyst
OHMe
MeMe
O
Ph
75%, 88% ee
OHMe
Me
ONO2
68%, 70% ee
OH O
PhMe Me
BnO
70%, 93% ee
OH O
Me MePh
Me
72%, 88% ee
OHMe
OTBS
ONO2
48 h73% yield
99% ee
no racemization of pre-existing stereocenter
Self-condensation of the aldehyde was not observed.Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. JACS 1999, 121, 4168-4178
New Player in the Game
•This catalyst uses Zn, which mimics aldolases.
• It is easily prepared from 2,6-(bromomethyl)-p-cresol.
•Similarly, phenoxide should assist in both deprotonation and then protonation of alkoxide in product.
•One Zn is used for formation of enolate, the other for aldehyde coordination
ON N
O O PhPh
PhPh Zn
Zn
Me
Me
Professor Barry M. Trost
Ph.D- MIT, 1965 (House)Assistant Prof.- University of Wisconsin, 1965-68Associate Prof.- University of Wisconsin, 1968-69
Professor- University of Wisconsin, 1969-87Professor- Stanford, 1987-present
Over 720 publications
Best known for p-allyl palladium chemistry.
CurranFerreiraFrontier
MolanderToste
Krische
StambuliTaber
LautensMcIntoshParquette
Former Students/Post-docs:
Substrate Scope
R
O
H Me
O
Ar
5 mol % ligand10 mol % ZnEt2
15 mol % Ph3PS4Å MS
R
O
Ar
OH+ ON N
O O PhPh
PhPh Zn
Zn
Me
MeNotice two equiv of ZnEt2 and use of triphenylphosphine sulfide
O
Ph
OHMe
Me
49%, 68% ee
O
Ph
OH
60%, 98% ee
O
Ph
OH
Ph
Ph
79%, 99% ee
O
Ph
OH
Me
Ph
67%, 2:1 dr, 94% ee
O
Ph
OH
Me MeTBSO
61%, 93% ee
OOH
Me
Me O
66%, 97% ee
OOH
Me
MeOMe
48%, 97% ee
Trost, B. M.; Ito, H. JACS 2000, 122, 12003-12004
Trostʼs Explanation of Pathway
• 3 active Hʼs suggest that 2 Zn atoms may be involved• 2 equiv of ZnEt2 per 1 equiv of ligand liberates 3 equiv of ethane• Addition of H2O, liberates 4 equiv of ethane
ON N
O O PhPh
PhPh Zn Zn
O
Me
Ar
O
RH
ON N ��
O O PhPh
PhPh Zn Zn
O
Me
Ar
O
R
H
ON N
O O PhPh
PhPh Zn Zn
Me
O
R O
ArO
Ar
R
O
Ar
OH
Application to Other Manifolds
Henry Reaction:
R
O
H
catalyst+
OHNO2
MeNO2 Me
Me
90% yield92% ee
Trost, B. M.; Yeh, V. S. C. ACIE 2002, 41, 861-863
Mannich Reaction:
catalystHO
O
Ph
N
EtO2C H
MeO
+O
PhOH
NH
EtO2C
Ar70% yield
15:1 dr99% ee
Trost, B. M.; Terrell, L. R. JACS 2003, 125, 338-339
Diol Desymmetrization:
catalyst
OH
OH
MeOO
O
Ph+
OCOPh
OH
MeO
H93% yield
99% ee
Trost, B. M.; Mino, T. JACS 2003, 125, 2410-2411
Incorporation of Methyl Vinyl Ketone
Trost, B. M.; Shin, S.; Sclafani. JACS 2005, 127, 8602-86-3
R
O
H Me
O catalyst+
R
OH O
OH O OH O
Me
MeMe
OH O
Me MeBnO
OH OMe
MeMe
53%, 92% ee 74%, 86% ee 64%, 83% ee 49%, 98% ee
• MVK is extremely unstable in both acidic and basic conditions
• Main problems associated with elimination of b-hydroxy ketone product
• There is a profound negative nonlinear effect
Recent Advances
Me Me
OH
O
NO2
Me
O OH
NO2
(S)-proline+ 68% yield
76% ee
List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122, 2395
Secondary Amine Catalysis:
Palladium Catalysis:
Me
O O
Me
ArO
Me
PdOH2
OH2
PP
2+2 OTf
Me
O OAr
+ MeO
Me
84% yield90% ee
Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240
Nickel Catalysis:
N
OMe
S
S
(MeO)3CHNi(II)•tol-BINAP
BF3•OEt2+ N
O
S
S
OMe
OMe
Me
73% yield97% ee
Evans, D. A.; Thomson, R. J. J. Am. Chem. Soc. 2005, 127, 10506
