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Conservation of Helical Asymmetry
Bryon SimmonsMacMillan Group Meeting
November 20, 2007
Wang, D. Z., Tetrahedron, 2005, 61, 7125Wang, D. Z., Tetrahedron, 2005, 61, 7134
Wang, D. Z., Mendeleev Comm., 2004,14, 244Wang, D. Z., Chirality, 2005,17, 2005
Ph
Ph
Traditional Rationale for Enantioselective Catalysis■ Enantioselection is usually thought to have a geometric origin, and therefore favorably develop through a transition state that has less steric hindrance. It is often analyzed by steric size-based considerations.
For example:
■ Our models are usually generated after an empirical investigation of substrate scope.
ON B
Me
H2BHO Me
Ph
PhO
N BMe
H2BHO
MeFavored Disfavoredvs.
O
RL RS
"H-"
O
RL RS RL RS
HO H(S)-cat.
Me
O
Me
MeMe
Me
O
97% ee
OMe
O
MeMe
O
97% ee 93% ee 93% ee
Corey, ACIE, 1998, 37, 1986
When the Steric Rationale Fails?■ However, experimental observations contradicting the prevalent steric theories abound in the literature. For example, these intriguing CBS reduction results don't seem to fit well within the steric model.
O
RL RS
"H-"
O
RL RS RL RS
HO H(S)-cat.
97% ee
95% ee
Corey, ACIE, 1998, 37, 1986
NO2MeO
Me
OH
OH
NC
OH
OMeOMe
OH
Me
Me
91% ee
OH
98% ee
H
82% ee
■ In these cases RL is essentially isosteric with RS. Why is the selectivity so high?
■ Why would these examples give the opposite enantiomer than the model predicts?
Molecular Chirality: Something Beyond Geometry?
■ Term "chirality" first coined in 1893, 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, cannot be brought to coincide with itself."
-Lord Kelvin
■ Chirality was descriptor used by physicists to descibe objects in the macro world even before the electron was discovered. Since then molecular chirality has been understood as a purely geometrical property.
■ While it is true that chiralities in everyday objects and those in the molecular world share a geometrical link, it is intriguing to ask whether in the former there are also electronic implications. What is the common electronic structural character of these diverse molecular chiralities that makes them optically active?
H
H
a d
b c
C
b c
a d
a bd
c
Molecular Chirality: Something Beyond Geometry?
- J. H. Brewster [Top. Stereochemistry1967, 2, 1]:
"...a helix system in which electrons are constrained to move on helical paths generally enters, explicity or implicity, into all of the major theoretical models of optical activity... A generally sucessful model of optical activity must require a connection between polarizability and bond structure."
■ Helical electronic topology exists in all chiral molecules. However despite the helix model's success, there seems to be a gap between theory and reality because helices in many simple molecules are hard to identify.
PPh2
HO2CHN
HPPh2
LHH(C-C-C-C-C-C-C)
LHH(C-C-C-C-C)
LHH(P-C-C-C-C-P)
LHH
left-hand helix
LHHright-hand helix
RHH
■ It was first suggested by Fresnel in 1827 that a chiral microstructure, helical in nature is required for a substance to have different refractive indices for right and left-circular polarized light and thus exibit optical activity.
■ Tinoco and Woody elegantly showed in 1964 that an electron constrained to move on a helix (the simplest chiral potential) does indeed lead to optical rotation and the sign is positive at long wavelengths.
Assigning Helicity to Point-Chiral Molecules
■ For a simple point-chiral molecules suppose that the polarizabilities of the substituents follow the trend a > b > c > d. The anisotropic fields of c and d should distort a-C-b from coplanarity into a microhelical structure.
■ If as in electronic theories of optical activity, the distortion increases with group polarizability, it is reasonable to expect the strength of repulsion represented by the double arrow to twist the a-C-b bond up. The bonds will thus be twisted into a right hand microhelix (RHH).
■ Similar effects will twist the a-C-d, b-C-c, and c-C-d bond pairs into RHH's and the a-C-c and b-C-d bonds into LHH's. Since there are more RHH's than LHH's, the molecule has a net right handed helicity. If any two groups were indentical the molecule's helicity and optiocal activity would dissappear.
Ca b
d
c
C
d
cb
a
net repulsiona +c > a +d
Ca
b
d
c
RHH
orbital deformation
Ca
b
RHH
Ca
d
RHH
Cb
c
RHH
Cc
d
RHH
Ca
c
LHH
Cb
d
LHH
Assigning Helicity to Point-Chiral Molecules
■ There is an easier way determine helicity for simple molecules. Place least polarizable substituent coming out of plane. Travel from most to least polarizable substituent.
■ Polarizability characterizes the sensitivity of a group's electron density to distort in an electronic field. It increases with higher electron density, lower nuclear attraction, larger electron shells, larger volume and smaller HOMO-LUMO gap.
Ca b
d
c
c
a b
c
a b
RHH
I > Br > SR > Cl > CN > Ar > C=X (X=N, O) > C > NR2 > OR > H > D > F
M (Rh, Ru, Pd, Ti, Os) > C, N
higher bond order > lower bond order: C C C C C C> >
strained alkyls > unstrained: Me>
for simple alkyls CH3 > CH2 > CH > C
for aromatics e- rich > e-poor: PhOMe > PhR > Ph > PhNO2
epoxide O > C R3P > CBrewster, JACS, 1959, 81, 7475
Miller, JACS, 1990, 112, 8533
Assigning Helicity to Chiral Molecules
■ Examples of helicity on point-chiral molecules:
Me
OH
CN
OH
Me
NH2
H Br
FCl
OH
MeO NO2
N BO
Me
H PhPh
NH
HO
Me
NHN
NH2
H
NH
N
O
HN
(+)-1 RHH (+)-2 RHH (-)-3 LHH
(-)-4 LHH
(+)-5 RHH
(-)-6 LHH (+)-7 RHH
■ For simple molecules with point chirality, the helicity also correctly predicts sign of optical rotation and stereochemistry base on polarizability sequence.
Brewster, JACS, 1959, 81, 7475
Br > Cl > H > F Ar > Me > OH > H CN > Ar > OH > H PhOMe > PhNO2 > OH > H
C=C > Me > NH > H PhOH > Het > Me > H CH2 > CR3 > N > H
Are There Alternatives to Steric Rationale?
■ David Z. Wang, of Columbia University, puts forth an electronic theory of chiral interactions or chiral version of standard HSAB theory that views all chiral molecules as helices.
Wang, D. Z., Tetrahedron, 2005, 61, 7125Wang, D. Z., Tetrahedron, 2005, 61, 7134
Wang, D. Z., Mendeleev Comm., 2004,14, 244Wang, D. Z., Chirality, 2005,17, 2005
homohelical interaction
catalyst substrate
RHH + RHH
versus
heterohelical interaction
catalyst substrate
RHH + LHH
■ Any two chiral molecules (eg. catalyst and substrate) will interact in such a way that their chirality/electronic helicity match resulting in a homohelical interaction or oppose each other giving rise to a heterohelical interaction.
■ The homohelical interaction is calculated to be as high as 9.5 (kcal/mol) lower in energy than the complimentary heterohelical interaction. This has its physical roots in the fact that the homohelical interaction expands the helicity of the system while the heterohelical interaction compresses the helix. .
■ The conservation of electronic helicity therefore has implication anytime two chiral molecules interact--for example asymmetric catalysis, kinetic resolution, chiral chomatography and even liquid crystals. .
Electron-on-a-Helix Model
■ In 1964 Tinoco and Woody showed that the states and eigenvalues of an electron constrained to move on a helix can be solved exactly. The model is simplest for a chiral molecule and has proven analytically effective when applied to a variety of real systems. The energy of an electron of mass m constrained on a k-turn helix of a radius a and pitch 2πb is:
homohelical interaction
catalyst substrate
RHH + RHH
heterohelical interaction
catalyst substrate
RHH + LHH
h2n2
8mk2(a2 + b2)En =
where n = 1,2,3 ...
h2n2
8m(k + k')2([a + a']2 + [b + b']2)Ehomo=
h2n2
8m(k - k')2([a - a']2 + [b - b']2)Ehetero=
■ A homohelical interaction extends the helix, it can be viewed as adding an additional turn k' radius a' and pitch 2πb to the original helix. Contrast a diastereomeric heterohelical interaction compresses the helix and subtracts the same.
■ It follows that Ehomo is always less than Ehetero.
PP
a
2πb
■ ΔΔG = Ehomo -Ehetero. For BINAP + a perfectly helically matched substrate this could be as high as 9.5 kcal/mol.
a = 1.5A
b = 0.24 A
k = 1
n = 2
ΔΔG = Ehomo = 2EBINAP
= 2NAh2 x10-3/ 8nmek2(a2 +b2) x4.2 x10-20
= 43.7/ nk2(a2 +b2)
= 9.5 (kcal/mol)
Asymmetric Catalysis and Kinetic Resolution
■ Initial coordination of pro-chiral substrate (S) to catalyst (C) induces helicity in substrate (S*). Turnover then occurs and preference for one enantiomer of product (P) is observed.
catalyst substrate
catalyst substrate
■ Both enantiomers of substrate (SL and SR) bind to catalyst (CR). The higher-energy heterohelical interaction leads to an increased rate for the heterohelical substrate-catalyst complex to form product (PL) compared to the homohelical complex.
ΔΔG
ΔΔGRHH LHH
C --- S*
C --- S*
C + S RHH RHH
C + P
heterohelical interactionhigher in energy
homohelical interactionlower in energy
SRSL
CR --- SLCR --- SR PRPL
ΔGhomoΔGhetero
Asymmetric Catalysis
Kinetic Resolution or Desymmetrization
homohelical interactionlower in energy
heterohelical interactionhigher in energy
Key:
Key:
Jacobsen Epoxidation■ The right-handed helical twisting in the Salen ring is homohelically transferred to the (R)-epoxide shown.
■ The shown homohelical induction transition state is constructed on the basis of the mechanistic model proposed by Jacobsen.
ΔΔG
1 --- S*
1 --- S*
1
1
N N
O OMn
Cl t-Bu
t-But-Bu
t-Bu
R
RHH
R
O
1
(high ee's)
Mn
OR
H
mCPBA
polarizability:strained O > strained CH2
> alkyl > H
polarizability:N=C > CHN=C
>CH2 > H
Jacobsen, Acc. Chem. Res., 2000, 33, 421
Jacobsen Kinetic Resolution■ Changing the metal from Mn to Cr and the axial ligand to OAc doesn't change the catalyst's helical handedness, but transforms the epoxidation catalyst into an efficient ring-opening catalyst.
■ The stereochemical interactions between the catalyst 2 and the epoxide should resemble the epoxidation transition state. It is indeed observed that the heterohelical (S)-epoxides undergo facile ring opening to afford enantioenriched 1,2 diols.
N N
O OCr
OAcl t-Bu
t-But-Bu
t-Bu
RHH
R
O
2
(R)-epoxide (high ee's)
Cr
O
R
H
Jacobsen, Acc. Chem. Res., 2000, 33, 421
ΔΔG 2 --- SL
2 --- SR
R
O
R
OHOH
racH2O
faster reaction slower reaction
heterohelicalinteraction
(S)-diol (high ee's)
O
Ph
Ph
Homohelical Rationale for CBS Reduction■ Previous rationale based on sterics.
■ How can steric arguments account for the following results? In each case the more polarizable group is highlighted in blue.
ON B
Me
H2BHO
PL
O
RL RS
"H-"
O
RL RS RL RS
HO H(S)-cat.
PS
N BO
H
Me
PhPh
(S)-cat RHH
97% ee
NO2MeO
OH OH
98% ee
H
OH
Me
Me
91% ee
■ Wang proposes a new model based upon group polarizabilities.
PL
HO H
PSPL PS
(S)-cat.
RHHRHH
catalyst substrate
RHH + RHH
Asymmetric Desymmetrization of meso-Allylic Alcohols
■ Ligands A and B should be isosteric:
■ However they afford products of the opposite enantiomeric series:
HNNH
OO
Ph2PPPh2
HNNH
Ph2PPPh2
OO
A B
OCONHTs
OCONHTs
2.5 mol% Pd2(dba)3
5 mol% A
OTsN
O
OCONHTs
OCONHTs
2.5 mol% Pd2(dba)3
5 mol% B
99% IY
88% ee
TsNO
O
99% IY
88% ee
Trost, ACIE, 1995, 34, 2386
O O
Asymmetric Desymmetrization of meso-Allylic Alcohols
■ The polarizability of the catalyst flips from C=0 > C to N < C. The helical nature of the catalyst then determines which enantiomer of product is formed.
P P
HN NH
Pd
R R
O O
Ph2 Ph2
LHH
P P
NH HN
Pd
R R
Ph2 Ph2
RHH
polarizabilityC=O> C*> R >H
polarizabilityR > C* > N > H
OCONHTs
OCONHTs
2.5 mol% Pd2(dba)3
5 mol% A
OTsN
O
OCONHTs
OCONHTs
2.5 mol% Pd2(dba)3
5 mol% B
99% IY
88% ee
TsNO
O
99% IY
88% ee
Trost, ACIE, 1995, 34, 2386
■ While the two catalysts have the same sense of chirality, inverting the amide function reverses the sense of the catalysts helical character.
Asymmetric Rh Catalyzed Hydrogenations
■ According to the quadrant rule, two chiral diphosphine catalysts with the same relative sterics should afford the same enantiomer of hydrogenation product.
RHHLHH
Rh +
Ph
MeO
Ph
OMe
Rh +
Rs
RLRs
RLso...
Rh +
Ph
MeO
Ph
OMe
■ However even though the two catalysts belong to the same quadrant class they give opposite absolute stereoinductions.
Ph
MeO2C NHAc
Rh +
Me
Me
Me
MeMe
Me
MeMe
■ Interestingly, TECH predicts the exact stereochemical outcomes for the two catalysts.
Rh +
Me
Me
Me
MeMe
Me
MeMe
BisP*DiPAMP
DiPAMP BisP*
H2H2 Ph
MeO2C NHAc
Ph
MeO2C NHAc
99.9% ee96% ee
Imamoto, JACS, 1998, 120, 1635Knowles, JACS, 1977, 99, 5946
RHHLHH
Asymmetric Rh Catalyzed Hydrogenations
■ In fact all these catalysts give rise to the same enantiomer of recuced product.
■ If all these catalysts/"keys" can open the same "lock," what is it that they really have in common?
PPh2
PPh2
Rh+
O
O
Ph
MeO2C NHAc catalyst
H2 Ph
MeO2C NHAcRHH
Fe
Ph
Ph
Rh+
PPh2
Me
PRh+Ph2
PNMe2
Rh+
2
Me tBu
But Me
Rh+
PPh2
PPh2
Rh+
Ph2P
PPh2
Rh+Rh+
Et
EtEt
Et
Fe
Josi-Phos99% ee
Mono-Phos98.7% ee
Phane-Phos98% ee
Du-Phos99% ee
Ferro-Phos98.7% ee
BisP*99.9% ee
Spiro-Phos99% ee
BINAP100% ee
O
Stoltz Oxidative Kinetic Resolution■ Recent mechanistic work shows that intramolecular deprotonation in th e Pd-bound alcohol generates a readily accessible site for the β-hydrogen. it is therefore expected that the Pd-O and Pd-H coordinations should couple the catalyst and substrate ring helices together.
PL PS PL PS
LHH
N NPd
Cl Cl
N NPd
Cl Cl
N NPd
Cl Cl
N
NPd
OH
rac-1
Pd[(-)-sparteine]Cl2
N
NPdLX
H
O
R
Un
N
NPd
O
H
R
UnUn R
OH
Un R
O
Un R
OHhigh ee%
Un = unsaturated
Pd[(-)-sparteine]Cl2LHH
LHH
PL PS
OH
Stoltz, Chem. Lett., 2004, 33, 362
■ Homohelical recogition control easily predicts the reaction outcome.
polarizabilities
Un > R > O > H
Proline Organocatalysis & Desymmetrization■ Some meso-ketones are catalytically desymmetrized by L-pro (right handed) in extremely high ee's. The stereochemical courses in them can again be deduced from the homohelical catalyst/substrate associations.
Hajos, JOC, 1974, 39, 1615
■ Meso-anhydrides are desymmetrized using L-pro methyl ester.
polarizabilities
C=O > C=O' > Me > CH2
NH
CO2H
O
OMeMe
ON
O
Me
O
O
H O
DMF or DMSO
LHH
RHH
Me
OOH
O
O
O
O
H
H
NH
CO2Me
O
O
O
H
HN
HCO2Me
polarizabilitiesC=O > C* > CH2 > H
O
O
H
H
OH
N
CO2Me
Albers, Synthesis, 1996, 393
moderate to high deheterohelical interaction
heterohelical
Kinetic Resolution: RCM
■ Right handed catalyst interacts with both enantiomers of 1. The heterohelical complex is higher in energy lowering the activation barrier to form cyclized product.
O
OMo
Hoveyda, Schrock Chem. E. J., 2001, 7, 945
polarizabilities
Un > CH2 > OR > H
O
OMo
NPri
MeMePh
iPr
tBu
tBuO
OMo
NPri
MeMePh
iPr
tBu
tBu
MeOR
Me
O
OMo
ORRHH
rac-1
Me
O
OMo
OR Me
OR
n
n = 1,2,3high ee's
MeOR
nrecovered
O
OMo
heterohelical
homohelical
n
Desymmetrization: RCM
polarizabilities
Un > R > O > H
O
OMo
NPri
MeMePh
iPr
tBu
tBuO
OMo
NPri
MeMePh
iPr
tBu
tBu N N
RuPhPCy3
Cl
Cl
Pri
iPr
Ph Ph
OR'
R''
R'
R''
R'O
MR''
R'
R''
O
R'
R'R''
1, 2, or 3
RHH
high ee's
1 2
3
LHH
Hoveyda, Schrock JACS, 2003, 125, 12502Grubbs OL, 2001, 3, 3225
■ Right handed catalyst interacts with the prochiral substrate. The heterohelical complex is higher in energy lowering the activation barrier to form cyclized product.
heterohelical
Predictive Power of Helical Arguments■ Zhao et. al. reported this transformation recently (ACIE, 2007, 46, ASAP), using helical arguments which is the major enantiomer formed?
O
OP
OHO
HN NHAc
Br
NHAc
BrNH
Me
or
NHAc
BrNH
Me
A
B
RHH
RHH
■ Brinkman et. al. reported this transformation (JOC, 2000, 65, 2517), using helical arguments which is the major product formed?
N BO
H
Me
PhPh
(S)-cat
RHHMe
Me
O
O
Me
Me
OH
OH
Me
Me
OH
OH
LHH
Conclusions■ Chirality = Helicity. Relative orientation of polarizable groups in space gives rise to optical activity.
■ Homohelical interactions are electronically favored and lower in energy.
■ For a reaction to be highly enantioselective, the overall helicity as well as the helical characters of the catalyst and substrate must be matched (i.e. matched polarizabilities).
■ 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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