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5.37 Introduction to Organic Synthesis Laboratory
Spring 2009
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Massachusetts Institute of Technology
Organic Chemistry 5.37
April 25, 2008
Prof. Rick L. Danheiser
Lecture 4
Introduction to Organic Synthesis
The Diels-Alder Reaction, Part IV
RE
RZ
RE
EWG
RZ
R1
R'Z
R2
R'E R'Z
R'E
EWG
+
R2
R1
Stereochemical Course of the Diels-Alder Reaction
Intrinsic Stereoselectivity
 Suprafacial with respect to the diene
 Suprafacial with respect to the dienophile
 Alder endo rule
Asymmetric Induction
 Substrate control by chiral dienophiles
 Substrate control by chiral dienes
 Stereocontrol via chiral auxiliaries
Catalytic Asymmetric Cycloadditions
Case Study
Total Synthesis of Prostaglandins
Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675
OH
9
8
CO2H
CO2H
11
HO
12
HO
OMe
HO
Key Subtarget
Prostaglandin F2α
Controlling the Relative Stereochemistry
In the previous lecture, we saw how Corey's synthesis of prostaglandin F2α exploits
two of the stereochemical features of the Diels-Alder reaction:
 the intrinsic stereoselectivity (suprafacial addition with respect to the diene)
 asymmetric induction (substrate control by the diene)
Controlling the Absolute Stereochemistry
 Approach I: Resolution
Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinshenker, N. M.
J. Am. Chem. Soc. 1970, 92, 397
Controlling the Absolute Stereochemistry
 Approach II: Chiral Auxiliaries
Corey, E. J.; Ensley, H. E.
J. Am. Chem. Soc. 1975, 97, 6908
2.5 equiv
BnO
OCH2Ph
H
H
BnO
Ph
H
O
H
O
2
0.7 equiv AlCl3
CH2Cl2, -55 °C
+
CO2R*
CO2R*
97:3 ratio
major cycloadduct isolated in 89% yield
also obtained 7% exo cycloadducts
prepared in 4 steps
from (-)-pulegone
OH
O
1) LDA, O2;
then P(OEt)3
2) LiAlH4
3) NaIO4
BnO
H
(-)-Pulegone
(-)-Menthol
Peppermint
"The Worlds's Oldest Medicine"
O
 Approach III: Catalytic Asymmetric Diels-Alder Reactions
Example 1: Corey's "Stein" ("Stilbene Diamine") Catalyst
Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493
Corey, E. J.; Imai, N.; Pikul, S. Tetrahedron Lett. 1991, 32, 7517
Corey, E. J.; Sarshar, S.; Bordner, J. J. Am. Chem. Soc. 1992, 114, 7938
? equiv
O
H
BnO
OCH2Ph
H
BnO
H
N
O
O
2
H
Ph
Ph
+
O
0.1 equiv
F3CO2S
N
N
Al
O
SO2CF3
N
O
O
N
O
Me (prepared in 7 steps)
98:2 ratio (96% ee)
major cycloadduct isolated in 93% yield
CH2Cl2, -78 °C, 18 h
BnO
1) LiOH, aq H2O2
2) MsOH, EtOH
HC(OEt)3
H
H
CO2Et
O
 Approach III: Catalytic Asymmetric Diels-Alder Reactions
Example 2: Yamamoto's "CAB" ("Chiral Acyloxy Borane") Catalyst
Ishihara, K.; Gao, Q.; Yamamoto, H. J. Org. Chem. 1993, 58, 6917
Furuta, K.; Gao, Q.-Z.; Yamamoto, H. Org. Synth. 1995, 72, 86
Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. J. Org. Chem. 1989, 54, 1481
Furuta, K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 6254
O
O
BH
O
HO2C
O
O
R
4 equiv
Br
CHO
CHO
0.1 equiv CAB
CHO
CH2Cl2, -78 °C, 10 h
+
Br
Br
97.5:2.5 ratio (95% ee)
100% yield
94:6 exo/endo cycloadducts
Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966
BnO
H
1) NH2OH-HCl, aq THF, pH 4
2) TsCl, pyr
3) NaOH, H2O
BnO
H
CHO
Br
O