Académique Documents
Professionnel Documents
Culture Documents
Simplified Computational Approach (Fig. 2) provides the necessary insight for the preferential
conjugate addition. In general we note that soft nucleophiles
An easy graphical display technique based on the Fukui
will add in the Michael sense, whereas hard nucleophiles will
functions can also be achieved. Instead of calculating the
add 1,2. A soft nucleophile can be considered one that is more
molecular orbitals for the neutral species, cation, and anion,
diffused in its electrons. In the chemistry of the SN2 reaction
one can just add or subtract electrons from the molecular
we readily appreciated that these nucleophiles include sulfide
orbitals of the neutral species. This procedure isnt as good
and iodide ion. We can expand this to include many enolate-
as the one described above, but it does give a quick graphical
type nucleophiles such as cyanide ion and Gilman reagents.
display of the susceptibility of the molecule to different kinds
Literature examples will show that hard nucleophiles such as
of attack. So rather than being a definitive calculation of a
alkyl lithium reagents and Grignard reagents tend to undergo
molecular property, freezing the molecular orbitals to those for
chemistry at the carbonyl carbon, as do LiAlH4 and NaBH4.
the neutral molecule gives a useful graphical technique that
can be rapidly applied. To use the frozen orbitals approach
for nucleophilic attack: The Michael Reaction in Organic Synthesis
1. Build and minimize your molecule. Only the neutral The Michael reaction has been used widely in organic
molecule is needed for this approach. synthesis for its CC bond-forming ability. It is employed
2. Enter the Expert mode of the Volumes setup. Define in the traditional sense where an enolate reacts with an ,-
the following volume in the Volume setup dialog box: unsaturated carbonyl as seen in the work of Rubio et al. (7)
volume=density[EADD=LUMO].-.density for the synthesis of ()--kainic acid (Scheme II).
3. Use resolution=med and submit your job with a single
TBDMSO CO2Et
point MO calculation.
You can then set up slices or isosurfaces to display the results. CO2Et
These results provide a very clear understanding for the
course of the reaction. If we had simply looked at the elec- CO2Et
N
tronic structure associated with the LUMO of methyl vinyl
O O
ketone (MVK), we would predict that the carbonyl carbon is Boc
most receptive to attack (Fig. 1). However, a Fukui analysis EtO C CH2 C OEt
NaH/THF
65%
TBDMSO
CO2Et
CO2Et
CO2Et N
N
Boc
Boc
Kainic Acid
Scheme II. Synthesis of ()--kainic acid.
NaOH
dioxane
O O
Me O
Et
Me
O OH
Me Me
O
Figure 2. Volume plots of the Fukui functions for MVK using the O
(left) standard and (right) simplified computational approaches. Cortisone
(Shown in color on page 140.) Scheme III. Synthesis of cortisone.
OMOM OMOM O O
O
O 2
LDA, THF,
CO2Et 3 O
-78 C 1
4 OEt
O 5
O O
6
OMOM
O O 5 O
O 4 3
O
H 6 2
MOMO
CO2Et
1
Claenone (82%, racemic)
O
H3C O
O 7 O
H3C 6
5 95%
1 Et3N Ph
O 2 O S
7 10-20% 1
2
4
6 3 3 4
H3C 5 Ph S
CH3
Scheme VI. Michael reaction employing non-enolic
Scheme V. Example of an intramolecular Michael addition. carbon nucleophile.
Ac
TBSO Ac Ac
N
O N N
O O
MOMO
MOMO HO
Me O 1) TASF
O OTf Me O OTf
2) PhNTf2,
O TEA
(95%) O O
TBSO
H HO
OTBS H
()-Batrachotoxinin A
CO2t-Bu
CO2t-Bu
S 2
CO2t-Bu S 3 S
CO2t-Bu 1
2 3 S N O O
O H N
H 1 N 2 N H S
Me HO SN
O N 1 O
H Me O Me
O OH
CH2OH
H
Gliotoxin