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."