Conservation of Helical Asymmetry
N. Z. Burns
chirality = helicity
Term "chirality" coined in 1893, derived from Greek "cheir" (hand):
I call any geometrical figure, or group of points, chiral,
and say it has chirality if its image in a plane mirror,
ideally realized, can not be brought to coincide with itself.
-Lord Kelvin
Molecular chirality often seen as solely a geometrical property, and thus
enantioselection and asymmetric reaction design are rationalized using
mostly steric-based arguments.
Left-handed helix
(LHH)
For example:
Ph
Ph
Me
O
Ph
N
Me
B
H2B
vs.
O
Ph
B
N
H2B
H
O
H
Favored
Determining a point chiral molecule's helicity- Yin method:
Me
O
Right-handed helix
(RHH)
d
Me
a
C
b
Take a simple 5-atom chiral molecule whose groups
have the following polarizability: a > b > c > d
c
Disfavored
Because of this, any 2 bonds will be distorted dissimilarly, with larger distortions
arising from more highly polarized groups.
Are there alternatives?
Each of the six distortions creates a micro-helix.
Helical theory of chirality:
(Wand, D. Z. Tetrahedron, 2005, 61, 7125; 7134)
a
C
b
David Zhigang Wang, graduate student of professor Thomas J. Katz at Columbia,
puts forth a novel electronic theory of chiral interactions (can also think of as a
chiral version of standard HSAB theory), that views all chiral molecules as helices.
a>b
a
C
b
a
C
c
How can a chiral center have helicity?
a
C
d
a>d
a>c
b>d
c>d
a
C
d
b
C
d
b>c
C
c
C
d
C
d
a
b>d
a>c
b
c>d
c
Since all bonds at a chiral center are dissimilar, unbalanced electronic
interactions arise.
The magnitude of these interactions comes from the polarizability of the
groups attached to the center.
b
C
c
b>c
a>d
b
C
c
c
C
d
a>b
The end result is to deform the bonds into helices.
The sum of these helices gives a chiral molecule a net helicity that is either
right- or left-handed.
The sum of these micro-helices creates an overall helix or net helicity.
Here there are 4 RHH and 2 LHH resulting in a net RHH.
1
Conservation of Helical Asymmetry
N. Z. Burns
Quick and Dirty Helicity Determination:
For axially chiral biaryls with polarizability X > Y:
(works for simple cases)
• Place least polarizable substituent coming out of plane
• Travel from most to least polarizable substituent
d
a
C
c
c
Y
X
Y
X
Y
X
Y
X
b
a
b
a
b
c
RHH
a
C
b
b
d
c
a
a
c
(trace helix made by X–C–C–C–C–X)
c
LHH
b
Examples:
(point thumb at least, move fingers from most to least)
OH
OH
NH2
Polarizability rankings:
• I > Br > SR > Cl > CN > Ar > C
CN
Me
X (X = N, O) > C > NR2 > OR > H > D > F
• transition metals (Rh, Ru, Pd, Ti, Os) > C, N
LHH
RHH
• higher order bonded > lower order bonded
C
C
>
C
C
> C
Me
LHH
OH
C
H
>
Me
Ph
O
• strained alkyls > unstrained alkyls
CH2
Ph
OH
N
CH2
>
MeO
H2
C
NO2
OH
Me
RHH
LHH
• for simple* alkyls, CH3 > CH2 > CH > C
(* non-heteroatom containing alkyls)
• for aromatics, electon rich > electron poor
RHH
SH
PPh2
PhOMe > PhR > Ph > PhNO2
PPh2
Ph > Pyridine > thiazole > oxazole
SH
• epoxide O > C
RHH
• R3P > C
2
LHH
B
Conservation of Helical Asymmetry
N. Z. Burns
Principle of homohelicity- homohelical interactions are always lower
in energy than heterohelical interactions.
Helical argument:
Some instances where simple steric arguments fail-
R
R
R
R
O
HN
Trost desymmetrization of meso-allylic alcohols:
P
Pd
Ph2
Ph2P
Ph2P
PPh2
NH
NH
O
Ligands A and B should be isosteric:
O
HN
O
P
Pd
Ph2
P
Ph2
ligand A = LHH
P
Ph2
ligand B = RHH
PPh2
O
HN
Due to polarizability rankings, A and B are not isohelical!
O
NH
NH
O
HN
Furthermore, helicity accounts for absolute sense of stereoinduction:
O
O
A
OR
B
O
However,
TsN
O
Pd
OR
O
2.5% Pd2(dba)3
OR
TsN
A
lig. A (LHH) interacts
with LHH OR
RHH
5-10% lig. A
L2Pd
LHH
99%, 88% e.e.
OR
OR
B
Pd
OR
2.5% Pd2(dba)3
5-10% lig. B
TsN
OR
TsN
O
lig. B (RHH) interacts
with RHH OR
OR
O
94%, 88% e.e.
R = CONHTs
3
O
O
Conservation of Helical Asymmetry
N. Z. Burns
PL = group of larger polarizability
PS = group of smaller polarizability
RL = larger group
RS = smaller group
Asymmetric Rh hydrogenations:
RS
P
P
Rh
OMe
Previous rationale based on sterics:
Ph
O
RS
R2BH
RL
RS
(S)-cat.
RHH
P
RS
RL
Me
Rh
OH
(S)-cat.
B
P
P
RL
Ph
N
t-Bu
Rh
P
MeO
H
O
Me
RL
CBS reductions:
Me
t-Bu
How can steric arguments account for the following results with the (S)-cat.?
RHH
Me
LHH
OH
MeO
OH
Two catalysts should have same relative sterics, however they give opposite
absolute stereoinductions:
O
N
MeO
MeO2C
LHH cat., H2
(+)-96% e.e.
MeOH
NHCOMe
BF3
93% e.e.
RHH cat., H2
OH
OH
Me
Helicity argument: polarizability rankings- Me > t-Bu, PhOMe > Ph, thus two
catalysts have opposite helicities:
P
Rh
MeO
PL
PL
P
O
Me
OMe
51% e.e.
PL
LHH
All products are RHH, matching (S)-CBS helicity.
Rh
P
PS
t-Bu
P
Rh
Rh
P
P
Me
PS
P
OMe
(i-PrO)2P
91% e.e.
PS
O
OTBS
(–)-99.9% e.e.
MeOH
Ph
97% e.e.
PS
Possible new model for CBS reductions:
P
PL
t-Bu
Ph
Me
O
RHH
PL
Thus, Wang theory predicts opposite enantiomers for the two catalysts.
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(S)-cat.
PS
RHH
Ph
N
OH
Me
O
PS
B
O
H2B
H
PL
PL
PS
RHH
Conservation of Helical Asymmetry
N. Z. Burns
Asymmetric radical reductions:
Homohelical point-to-axial chirality transfer:
Chemists at Chirogen have discovered the following highly enantioselective free
radical reaction (C&EN, July 14, 2003, 34-35):
Me
Me
Br
OEt
OEt
R*2SnHPh
Me
O
MgBr2, -78˚
Me
HO
Ph
HO
Ph
Me
O
Me
96 % e.e.
Based on these results and the polarizability rankings, predict the product of the
following reaction:
O
HN
R*2SnHPh
OBn
Me
HN
MgBr2, -78˚
OMe
CHCl3
Ph
O
O
Ph
9:1 d.r.
achiral
CF3
Me
Br
Me
4-Å M.S.
O
CF3
Me
OMe
OBn
PPh2
Me
O
Me
O
PPh2
H2
Ph2 Cl N
P
Ru
P
Ph2 Cl N
H
Ph
H2N
RuCl2
H2N
Ph
2
Ph
Ph
Trost DYKAT of allenes (JACS ASAP):
For allenes with X > X' and Y > Y':
X
Y'
X
X'
O
NH
Y
X'
2:1 d.r.
achiral
O
Y
HN
Wang's proposed model for Sharpless AD:
Y'
RHH
PPh2
LHH
Ph2P
RHH
DHQD-cat.
RHH ligand
O
Et
O
N
EtO
1.1 eq
n-C4H9
PS
OEt
n-C4H9
Me
AcO
2.5% Pd2(dba)3
7.5% ligand
5% THACl
O
H
1.1 eq LHMDS
H
R
PL
H
H
C9 helix induces
chirality
MeO
CO2Et
Me
R = PL or PS
CO2Et
86 %
85 % e.e.
(6 other examples follow prediction as well)
5
LHH
DHQ-cat.
Het.
2
N
(DHQD)2-PHAL
Conservation of Helical Asymmetry
N. Z. Burns
O
H
Me
Leighton allylation (Leighton, ACIEE, 2003, 42, 946):
P
cat. L2Ru
OH
H2
Ph
dissociation
Ru
P
H
O
Ph
H
O
OH
Me
O
Me
Ph
Br
homohelical
interaction
Homohelical adduct is lower in energy, hence
less reactive leading to unreacted material.
O
OH
N
Ph
H
Si
Ph
Cl
N
DCM, -10˚
98 % e.e. LHH
OH
O
H
LHH strained
silacycle
OH
Me
cat. L2Ru
P
H2
P
Ph
Ph
H
O
[H]
Ru
H
O
Ph
Me
homohelical
induction
heterohelical
interaction
Br
OH
Me
Heterohelical adduct is higher in energy, hence
more reactive leading to reduction.
Free enegy diagram:
Helicity in kinetic resolution:
O
O
Ph
OH
(R)-BINAP-Ru
Me
OH
Me
OH
H2
∆Ghom
∆Ghet
OH
Me
Ph
49.5 %
92 % e.e.
Ph
50.5 %
92 % e.e.
H
P
Ph
H
O
Ru
P
H
O
Me
H
hetero
One enantiomer reacts at a faster rate with chiral catalyst resulting in product and
starting material being recovered in high enantiomeric excess.
P
H
O
Ph
Ru
O
P
O
H
OH
Me
OH
Me
Ph
O
Me
homo
Ph
OH
OH
OH
OH
Me
Me
Ph
6
Free energy rationale: ∆Ghom > ∆Ghet
Ph
Conservation of Helical Asymmetry
N. Z. Burns
Helicity fine-tuning:
With this knowledge, rationalize the following result:
(G. Bringmann, JOC, 2000, 65, 2517)
Me
O
Me
O
O
OH
O
O
(S)-CBS
Me
n
OH
O
PPh2
PPh2
O
0.5% Ru
1.2 % lig
O
Me
OH
H2
OMe
O
Me
OMe
BH3
Me
Me
H
Ph
Me
Ph
96 % e.e.
O
N
(S)-CBS
B
+ unreacted atropisomer
n
1
2
3
4
5
6
q
60˚
74˚
77˚
88˚
94˚
106˚
% e.e.
90.9
90.8
97.7
99.1
97.1
96.5
Me
Reaction design based on helicity?
Recall that homohelical interactions are always favored.
MeO
PPh2
PPh2
MeO
PPh2
PPh2
87˚, 97.9 % e.e
For a reaction to be highly enantioselective, the overall helicity as well as
the helical characters of the interacting species (i.e. catalyst and substrate)
must be matched.
87˚, 98.4 % e.e.
What is next for this theory?
In practical term this comes down to polarizability matching.
"Simple steric-based stereochemical rationals formulated AFTER one
knows the experimental results are not appealing to me anymore
(they abound in literature really; They are typically more arts
than sciences!). I firmly believe, as expressed in that thesis
chapter, there MUST be a more general scenario that is beyond
steric effects."
–David Zhigang Wang (personal communication)
Wang proposes the following: "to design a good catalyst . . ., rather than
focusing on the rigidity, bulkiness or C2–symmetry of the catalyst, one
should focus more on the polarizability properties, thus the helical
character, of the substrate . . . with which the catalyst will interact."
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