MIT OpenCourseWare
http://ocw.mit.edu
5.37 Introduction to Organic Synthesis Laboratory
Spring 2009
For information about citing these materials or our Terms of Use, visit: http://ocw.mit.edu/terms.
Massachusetts Institute of Technology
Chemistry 5.37
Professor Rick L. Danheiser
Lecture 5
The Invention of
Cycloaddition and Annulation Strategies
May 12, 2008
The Diels-Alder Reaction
Historical Background
“ . . . . I consider the teaching and study of
the historical development of science as
indispensable . . . . Our textbooks fail in this
respect . . . . “
Richard Willstätter
“ . . . . Science is not an abstract thing, but rather,
as a product of human labor, is tightly bound in its
development to the particularity and fate of the
individuals who dedicate themselves to it.“
Emil Fischer
Discovery and Invention
Alternate Paths for the Development of
New Synthetic Methods
Discovery:
to find something not
previously known
Invention:
deriving from a deliberate attempt
to solve a problem
The Diels-Alder Reaction
RE
RZ
RE
EWG
RZ
R1
R'Z
R2
R'E R'Z
EWG
+
R2
R1
R'E
The single most powerful ring-forming
reaction in the arsenal of organic
chemistry!
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
RE
RZ
RE
EWG
R1
R2
R1
R'E
R'E R'Z
RE
RE
R'Z
+
R'Z
R2
RZ
EWG
RZ
+
Y
Y
R'E
R'E
[4 + 1]
Annulation
Strategy
RZ
R'Z
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
RE
RZ
RE
EWG
R1
R'Z
R2
+
R2
R1
R'E
R'E R'Z
EWG
R2
EWG
RZ
R1
EWG
R1
R2
[3 + 2]
Annulation
Strategy
Annulation Strategies for the Synthesis of
Carbocyclic and Heterocyclic Compounds
Annulation strategies previously developed in our laboratory
RE
RZ
RE
LiTMP, Et2O
ClCH2OCH2CH2Cl
RZ
n-BuLi
THF-Hexane-HMPT
0 - 25°
RE
RZ
OH
R'Z
R'Z
R'E
ClCH2CH2O
R'E
R
W
RE
RZ
R2
+
SiMe3
C
R3
C
R'E
R
Lewis
acid
R1
W
C
SiMe3
RZ
R1
RE
R'Z
R3
R2
[4+1] Annulation Strategy
Stereocontrolled synthesis of fivemembered carbocycles based on
anion-accelerated
vinylcyclopropane
rearrangements
[3+2] Annulation Strategy
Stereocontrolled synthesis of fivemembered carbocycles and
heterocyclic compounds based
on allenylsilanes and allylsilanes
Reaction of Carbenes with 1,3-Dienes
Potential Basis for a [4 + 1] Annulation Strategy
H
+
Z
Z
Reaction of Carbenes with 1,3-Dienes
Potential Basis for a [4 + 1] Annulation Strategy
H
not
observed
+
Z
Z
H
+
Z
Z
The Vinylcyclopropane Rearrangement
Potential Basis for a [4 + 1] Annulation Strategy
H
+
Z
1,3-sigmatropic
rearrangement
Z
Z
H
O
68%
O
+
580 °C
0.1 mmHg
vapor phase
pyrolysis
H
O
10%
+
O
22%
Stereocontrolled [4 + 1] Annulation Strategy
Anion-accelerated Vinylcyclopropane Rearrangement
RE
RE
LiTMP, Et2O
ClCH2OCH2CH2Cl
RZ
RZ
R'Z
R'Z
R'E
ClCH2CH2O
R
RE
5 equiv n-BuLi
THF-Hexane-HMPT
0 - 50 °C
RZ
OH
45-82%
R'E
R'E
R'Z
> 50 : 1
R
OH
OH
> 50 : 1
H
OH
> 50 : 1
R
R
OH
> 50 : 1
R= CH2CH2Ph
OH
> 50 : 1
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
RE
RZ
RE
EWG
RZ
R1
R'Z
R2
+
R2
R1
R'E
R'E R'Z
EWG
+
R2
EWG
R1
EWG
R1
R2
[3 + 2]
Annulation
Strategy
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
+
O
O
Allyl Cations
Allyl Anions
Oxyallyl Anions
Homoenolate Anions
Vinylcarbenes
EWG
Met
EWG
Allylmetal Compounds
Electrophilic Cyclopropanes
Trimethylenemethane
Diradicals
Trimethylenemethane
Zwitterions
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
+
Met
[3 + 2] Annulation Strategy Based on
Allylmetal Compounds
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
+
Met
Met
Electrophilic addition of alkene to
nucleophilic allylmetal compound
Carbocation stabilized
by the ! effect
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
+
Met
Met
Met
Reversible 1,2-shift
of metal group
Invention of New Annulation Strategies for
the Synthesis of Five-Membered Rings
+
Met
Met
Met
Met
Ring closure furnishes
five-membered ring
Stereocontrolled [3 + 2] Annulation Strategy
SiMe3
1 equiv
O
H2C
C
C
O
CH3
1.2 equiv TiCl4, CH2Cl2
-78 to 0 °C
Me
SiMe3
89%
Si(Oi-Pr)Me2
H2C
O
C
C
CH3
O
TiCl4, CH2Cl2
O
then 30% H2O2, KHCO3
MeOH-THF
74%
11.5 : 1 stereoisomers
Stereocontrolled [3 + 2] Annulation Strategy
Application to the Synthesis of Five-Membered
Heterocycles
R1
X
H
+
R2
Y
C
C
C
SiMe3
X
R1
Y
C
X
C
H
C
Y
SiMe3
H
R2
R2
R1
R1
X
X
X = O, S, NR
Y = N, CR
R1
SiMe3
SiMe3
Y
SiMe3
Y
H
R2
R2
Stereocontrolled [3 + 2] Annulation Strategy
Application to the Synthesis of Five-Membered
Heterocycles
H
Sit-BuMe2
C C C
CH3
Hept
C C C
Et
Ph
Br
O
N
72%
H
O
CH3
1 eq NOBF4, CH3CN, -30 °C;
then add Br2, CCl4
Hept
Sit-BuMe2
CH3
CH3
AlCl3, CH2Cl2, -20 °C 1 h
Cl
O
Ph
80%
Sit-BuMe2
Et