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D. A. Evans
Chem 206
Chemistry 206
Advanced Organic Chemistry
Lecture Number 16
Cycloaddition Reactions-1
! Cycloadditions: Introduction
! Ketene Cycloadditions
! The Diels-Alder Reaction
O
PhCH2
CHO
Pavel Nagorny
+
R
5% catalyst
MeOH-H2O
Me
N
H Me
Wednesday,
October 25, 2006
Me
N
catalyst
CHO
R
D.A. Evans
Chem 206
The carbonyl ene reaction is a very powerful transformation that I want to introduce to you. Accordingly, I have prepared a
series of problems taken from the Problems Database to familiarize you with this reaction. Problem 210 is provided as an
introduction to the FMO analysis for the process. Subsequent problems have the ene reaction imbedded in reaction
cascades.
Problem 210. Question and Answer. The carbonyl ene reaction is illustrated below. Using FMO analysis, evaluate the
transition state of this reaction. Your answer should include: a transition state drawing; clear orbital depictions and HOMOLUMO assignments; an indication of the number of electrons from each segment; and indication of whether the reaction is
thermally allowed.
H
O
Ra
CH2
Rb
Ra
Rb
Ra
Rb
Answer
Rb
Rb allyl HOMO
bonding
Ra
bonding
Ra
O
Ra
H
Rb
bonding
CH2
Rb
Ra
O
H
C
carbonyl LUMO
6!e- "cycloaddition"
suprafacial
thermally allowed
Cycloaddition Reactions-1
D. A. Evans
Why does maleic anhydride react easily with 1,3-butadiene, but not with
ethylene? So what are the "rules"?
O
!*
[4+2]
LUMO
new
HOMO
!*
[2+2]
bonding
bonding
C !
light
concerted
C
C
+ energy
! Nomenclature
C
suprafacial
!2s
antarafacial
!2a
h!
+ !2s cycloaddition
Me
+ !2s]
bonding
C
antibonding
!2s
+ !2s] "forbidden"
Me
Me
h!
Me
Me
Me
["2s + "2s]
Me
Me
Prismane-Der.
[!2s + !2a]
bonding
[ !2s
!2a
C
C
Me
Dewar benzene-Derivative
C
C
bonding
Me
Me
Me
["2s + "2s]
[ !2s
HOMO
C
+
The frontier orbitals of the reacting species must have the proper symmetries
!2s
!2s
+ !2s]
light
[ !2s
Chem 206
+ !2a] "allowed"
Cycloaddition Reactions-2
D. A. Evans
R'
B:
R
R'
ZnCl2
Cl
Electrocyclic
Ring Opening
R'
R'
O
C O
R
Cl
R'
Cl
Zn
Cl
O
O
R'
Chem 30
h!
or "
R
R
R'
H
R
R'
R
Y
R'
Ketene Preparation
BH
B:
R3N
Antarafacial
R
Cl
E2 Elimination
O
O
OR
Suprafacial
C O
Cl
R
LiNR2
Cl
[!2s!2a]
R = -CH=CH2
C O
or !
N2
R'
h"
Imine
Alkene
Carbonyl
OR
R
E1cb Elimination
bonding
C O
HOMO
bonding
R
LUMO
R
O
Cycloaddition Reactions-3
D. A. Evans
H
C
R'
MeO
R'
Chem 30
O
CMe3
R'
CMe3
2. NBu3, toluene, !
least hindered
bond rotation
Stepwise
1. (COCl)2, PhH, !
CO2H
NEt3
CH2COCl
Concerted
Cl
Cl
Cl
Zn
Cl
Cl
Cl
Cl
Cl
Ketene-Alkene [2+2]
O
Me
C
Me
Me
Me
Me
Me
Me
Me
Me
Fast
Me
Me
Me
Me
Me
ab initio Calulations
Me
Me
O
+
Me
1:2
Me
Me
Me
+
32 kcal/mol
Me
+ Me
Me
Me
H
Me
Me
C O
Me
Me
H
Me
Me
O
Me
H
H
H
38 kcal/mol
path A
path B
O
Pons, J. -M.; et. al.
JACS 1997, 119, 3333.
H
H
favored
Me
Cycloaddition Reactions-4
D. A. Evans
Transformations of !-Lactones
R2
R2
" or BF3
-CO2
R1
R1
Most soft Nu
attack Csp3
+S
Me2S
R2N
H H
N
O
conrotatory
closure
R'
R'Li (2eq)
CuCN
O
R2N
H H
C
O
Chem 30
R
R
CO2H
H
C
O
conrotatory
closure
S
N
O
S
H H
N
R
R
S
H H
S
N
There are two contortaory modes. If you control the conrotatory mode, you control
the absolute stereochemistry of the reaction:
H
R
Et3N
O
Cl
H H
S
N
(Z)
S
(1)
H
N
Bn
C
O
O
O
Ph
R
R
(E)
H H
(2)
N
Ar
O
Et3N
Cl
O
H H
O
Ar
+
Ph
N
O
Bn
Ph
H H
N
Ar
Bn
Cycloaddition Reactions-5
D. A. Evans
Chem 206
Me
O
+
Me
Br
i-Pr2NEt
R3N
Me3Si
Al
R
SO2CF3
Aldehyde 2 (R)
catalyst
[time (h), temp (C)]
% yield
% ee 3
(configuration)
5b (8, -40)
91
92 (R)
5a (16, -50)
93
92 (S)
PhCH2CH2
5a (72, -78)
89
95 (S)
CH2CH(CH2)8
5b (16, -50)
91
91 (S)
Me2CHCH2
5a (24, -50)
80
93 (S)
BnOCH2CH2
5b (16, -40)
90
91 (S)
TBDPSOCH2
5b (16, -40)
74
89 (R)
BnOCH2
5a (16, -50)
86
93 (R)
Me3C
5a (16, -50)
91
85 (R)
5b (24, -40)
56
54 (R)
C6H11
EtO2C
EtO2C
3: >99% yield, 92% ee
BnOCH2
PhCH2CH2
KF, CH3CN
cat. = 5a: R = Me
5b: R = Cl
2+
Me
entry
EtO2C
77% yield, 93% ee
i-Pr
O
O
-78 C, 24 h
PhMe2Si
Bn
F3CO2S
CH2
R3NHBr
i-Pr
N
OTf
Cu
Me3C H2O OH2 CMe3
OTf
PhMe2Si
OEt
1 mol%, THF, 3 MS
C +
[RCHO cat.]
O
N
Me
H
N
N Cu O R
RO
OR2
Me
Me3Si
observed product
Me3Si
2+
O
N
N
Cu
Me3C
H2O
OH2
R2O
R1
O
H C C
Me Me
R1
CMe3
+ 2 CF3SO3
Nelson, S. G.; Peelen, T. J.; Wan, Z. JACS, 1999, 121, 9742-9743
D. A. Evans
Chem 206
HO
H
NMe2
H
Et
H
H
Lepicidin
Compactin: R = H
Mevinolin: R = Me
Et
Me
(Synthesis)
JACS, 1993, 115, 4497
H
Me
Me
Me
Me
! The Reaction:
Me
These natural products could well have incorporated the DA rxn into the
biosynthesis
Ph
H
H
Endiandric Acid C
Me
Et
Me
ent-FR182877 (WS9885B)
J. Antibiotics 2000, 53, 204
TBSO
TBSO
CO2Et
Me
Me
DA
Het DA
Me
Br
H
OTBS
CO2H
Endiandric Acid B
(Syntheses)
Nicolaou, JACS 1982, 104, 5555-5562
OTBS
CO2Et
H
H
Ph
H
Me
HO
Et
TBSO
H
OH
X-14547A
HO2C
O
COOH
Me
TBSO
Br
Me
Me
O
Me
D. A. Evans
The Alder Endo Rule
H
+
H
disfavored
favored
"Exo product"
"Endo product"
Observation: The endo Diels-Alder adduct is formed faster even though the exo
product is more stable. There is thus some special stabilization in the transition state
leading to the endo product which is lacking the exo transition state.
Exo TS
Chem 206
Energy
Endo TS
HOMO-!2
C
C
LUMO-!3
C
C
LUMO-!3
HOMO-!2
H
H
C HOMO-!2
! Note that the termini only match at one end for the
HOMO-LUMO pairing. Hence we say that the symmetry
C
requirements for the reaction in question are not met.
This does not mean that the reaction will not occur,
only that the reaction will not be concerted. Such reactions
are called "symmetry-forbidden".
C HOMO-!2
C
C
C
C LUMO-!3
C
D. A. Evans
Chem 206
LUMO2
LUMO1
leading references:
energy
! The lengths of the forming CC bonds are Ca. 1.5 times the normal bond
distance. This factor comes out of the ab initio work of Jorgensen & Houk
E(LUMO1) - E(HOMO2)
or
E(LUMO2) - E(HOMO1)
HOMO1
HOMO2
Dienophile
Diene
! The closer the two orbitals are in energy, the better they interact
! As !E decreases for the relevant ground state FMOs, rxn rates increase
O
+
LUMO2
LUMO1
LUMO3
E
HOMO1
HOMO2
Me
HOMO3
Me
log k = 2.12
log k = 1.83
Rate Acceleration
D. A. Evans
Chem 206
CO2H
CO2H
CO2H
COX RO
COX
CO2H
RO
RO
favored
CO2H
favored
disfavored
4.5 : 01 @ 100 C
PhS
MgBr2
COX Me
Me
COX
COMe
AcO
disfavored
toluene, 120 C
59 : 41
C6H6, SnCl4, 25 C
96 : 04
Ni(Raney)
PhS
COMe PhS
AcO
AcO
Me
favored
disfavored
COX
disfavored
favored
COMe
RO
NO2
CO2Me
RO
CO2Me
Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity
CO2Me
RO
base
CO2Me
NO2
RO
CO2Me
RO
CO2Me
CO2Me
H
CO2Me
favored
NO2
disfavored
CH2Cl2, 0 C
80 : 20
C6H6, SnCl4, 25 C
95 : 05
NO2
or by reduction
Ono, Tet. 1985, 4013
RO
R3SnH
CO2Me
O
83%
R3SnH
86%
NO2
Me
O2N
Me
Me
mixture of ring-fusion
isomers
Chem 206
D. A. Evans
O
Me
Me
Me
Me
MeOCH2
Cu(BF4)2
CH2OMe
Me
Cl
Cl
0 C
CN
CH2OMe
Cl
CN
CN
MeO
MeO
O
Me
Me
Me
SnCl4 (-20 )
<5 : 95
Me
80 : 20
O
X
Me
Me
NPh
!+ Me
O
PhN
Me
X=
Me
O
X
selection >95 :5
Sn O
Cl4
PhN
O
MeO
25-50 C
selection 80 : 20
MeO
Ratio: 90 : 10
Ratio
50 : 50
!+
thermal (100 )
BF3OEt2 (-20 )
Me
Conditions
MeO
Me
Me
OR
Me
O
NPh
Ratio
OH
36 : 64
Me
83 : 17
OMe
>97 : 3
Me
OR
OR
O
25-50 C
NPh
NPh
OMe
BF3OEt2
OMe
RO
selection >95 :5
0.4 equiv
OH
Me
O
Me
selection >95 :5
OH
OMe
Me
Me
H
0.5 equiv
Me
R = Me: Ratio; 83 : 17
R = Me3Si: Ratio; 88 : 12
RO
Me
O
O
MgI2
OMe
Me
Me
RO
OH
Me
Me
PhN
O
RO
H
OR
better than
Me
PhN
O
D. A. Evans
Problem 76, Bodwell has disclosed an interesting thermally initiated reaction cascade that
was designed to cuminate in a formal synthesis of strychnine(Angew. Chem. Int. Ed 2002,
41, 3261). One of his reported transformations is illustrated below.
NCO2Me
N
NCO2Me
heat, 48 h
Problem 157. A short reaction sequence that results in the rapid assemblage of the taxane
skeleton has been reported by Winkler (Tetrahedron Lett.1995, 36, 687). This
transformation is illustrated below wherein intermediate A is subsequently induced to react
with divinyl ketone.
Provide a concise mechanism for this reaction. For full credit, the relative stereochemical
relationships at the indicated stereocenters must be provided.
Problem 86. In 1983 Masamune introduced a new family of chiral controllers for the DielsAlder reaction (J. Org. Chem. 1983, 48, 4441).
Me
ZnCl2
45 C
OEt
C7H15
(1)
Please provide a mechanism for the reaction shown in equation 1. Be sure to include
clear transition state drawings in your answer, and predict the stereochemistry of the
major product diastereomer.
C7H15
OH
H
O
OEt
OH
HO
C7H15
Problem 778. Boger and co-workers recently reported the synthesis of the indole alkaloid
minovine (1). This pivotal transformations leads to the construction of the minovine skeleton.
Provide plausible mechanisms for this transformation.
heat
Me
MeAlCl2
Me
Me
CH2Cl2
Me
160 oC
Problem 112. In a recent article, Roush reported the highly endo-selective, Lewis acid
catalyzed Diels-alder reaction illustrated below (Org. Lett 2001, 3, 957). Using your
knowledge of Diels-Alder transition states, draw the transition state of this reaction, and
from this drawing, predict the relative stereochemical relationships that are to be anticipated
in the product.
MgBr2Et3N
CMe3
exo:endo = 94:6
endo diastereoselection >99:1
Me
EtO
OH
+ A
O S
Me
Me
Me
Lewis acid
Problem 739. The rapid assembly of the bicyclo[5.3.1]undecane core of penostatin F was
recently reported by Barriault and coworkers (Org. Lett. 2004, 6, 1317). In this remarkable
transformation dihydropyran 1 is converted to the highly complex tricycle 3 in only two
operations. Please provide a detailed mechanism for this reaction sequence. Be sure to
indicate all pericyclic reactions.
heat
Provide a detailed mechanism for this reaction cascade. Your answer should include threedimensional structures that accurately depict ground and transition state representations.
CMe3
Me
Me
N2
OH
Chem 206
diastereoselection >99:1
Problem 794. Doering and Rosenthal reported the interesting conversion of Nenitzescu's
hydrocarbon (1) to dihydro-naphthalene (2). Provide a mechanistic rationalization for this
transformation. (Reference: Doering, W.v.E.; Rosenthal, J.W., JACS 1966, 88, 2078)
Me
R
300 C