Helical Asymmetry: Electronic Effects in Enantioselective Reactions

OH PPh2

Me PPh2 Helical Asymmetry Electronic Effects in Enantioselective Reactions

homohelical interaction k S slow P CatalystR R CatalystR CatalystR-----SR R P S CatalystR----S*R R + + k + S fast P L CatalystR-----SL L prochiral homohelical induction heterohelical interaction

David Ebner Literature Presentation March 29, 2004 8 pm, 147 Noyes

Outline

I. Intro to Helicity

A. Polarizability B. Assignment of Helicity C. Optical Rotation

II. Helicity in Reactions ? A. Asymmetric Catalysis B. Kinetic Resolution C. Tandem Processes David Z. Wang

III. Helicity Matching

References: D. Z. Wang, CPS: orgchem/0403001. URL: http://preprint.chemweb.com/orgchem/0403001. D. Z. Wang, CPS: orgchem/0403002. URL: http://preprint.chemweb.com/orgchem/0403002.

These references, as well as supplementary information and a personal communication from D. Z. Wang answering some issues can be found on the group server. (Group Items –> Things from Brian –> David Wang Helical Asymmetry)

1 What is Helicity?

Helicity is the property of having a screw-type or spiral pattern.

In molecules, there are two types of helices:

A geometric helix exists when atoms in a molecule are arranged into a spiral pattern, such as in a DNA molecule. These helices may be smaller than a full helix turn, as in BINAP. A physical helix exists when electrons (bonds) in a molecule twist in a particular direction. This twisting leads to electrons moving in a helical path.

Helicity is a common concept in physics and biochemistry. In organic chemistry, however, its use has been limited to theories of optical rotation, in attempts to relate the stereochemistry of molecules to the clockwise or counter-clockwise rotation of light. Enantiomers will have opposite helicity.

Theories of optical rotation have tried to identify helical structures in chiral molecules by recognizing that net rotation is due to the chiral molecules having different refractive indices for left- and right- polarized light. Since refractive indices are directly related to polarizability, physical helices are determined using polarizability differences.

Some Geometric Helices:

PPh2

PPh2 DNA (R)-BINAP

Polarizability Polarizability characterizes the sensitivity of a group's electron density to distort in an electric field.

Though unknown for many functionalities, polarizability usually follows general trends, increasing with: –Larger numbers of electron shells within a group (I > Br > Cl > F) –Lower nuclear charge within a period (C > N > O > F) –Lower HOMO-LUMO gap (more conjugation) –Less substituted alkyl carbons (CH3 > CH2R > CHR2 > CR3) –More strained bonds (cyclopropyl CH2 > linear CH2) –Higher electron density (B- > C)

Some polarizabilities have been quantified based on Brewster's refractive indices list: I > Br > SH > Cl > CN > Ph > C=O > CH3 > NH2 > OH > H > D > F

Further relationships can be gathered, for example: –Transition metals > any organic group –Alkyne > Alkene > Alkane –P in R3P > C –Ph > C=O, C=N, Cyclopropyl –CH2NR2, CH(OR)2 > CH3 –Ketone > Ester

Note that the most important contributor to the polarizability of a group is the atom that is directly attached to the rest of the molecule. Thus, the polarizability of would be best Ph Brewster, J. Am. Chem. Soc. 1959, 81, 7475 Miller, J. Am. Chem. Soc. 1990, 112, 8533 represented as a CH2. 2 Assigning Helicity in Molecules

Helicity is either right- or left-handed (clockwise or counterclockwise, respectively). Determining helicity depends on the type of chirality within the molecule.

Point Chiral Molecules: D For point chiral molecule A B , let the polarizabilities of the substituents be A > B > C > D. C

Net electronic D B C A D B repulsion: A B A C A D B D B C C D

C D B C A A

C > D B > D B > C A > C A > D A > B

A A B C Micro-helix: B C D D C D A B

right left right left right right

More right-handed than left-handed micro-helices results in a net right-handed molecule

While this procedure is general, there is an easier way...

Helicity in Point-Chiral Molecules

The physical helicity in point-chiral molecules can be assigned using polarizability. This method is similar to that for determining R or S configuration.

1. Assign polarizability ranking to all four groups attached to chiral center. For example: 2 Br 1 4 I F (Polarizability: I > Br > Cl > F) Cl 3 2. Rotate molecule so that atom with lowest polarizability is facing away.

2 4 Br 2 F 1 1 4 Br I I F 3 Cl 3 Rotate Cl 3. Trace a path around the molecule from highest to lowest polarizability. If the path traced is clockwise, the molecule has right-handed helicity. If the path traced is counter-clockwise, the molecule has left-handed helicity.

4 2 F Br I 1 Counter-clockwise = left-handed molecule 3 Cl

3 Axial Helicity

For axial helicity, there are four main micro-helices to investigate. Two will be right-handed, and two will be left-handed. Thus, look for the dominant micro-helix (the two most polarizable groups).

In allenes, look at the Newman projection:

A A Newman B • Right-Handed: A-C or B-D interaction dominates D Projection D C Left-Handed: A-D or B-C interaction dominates C B

The helicity even predicts the sign of optical rotation! Thus,

H Et Cl H Ph

Ph • Bu3Sn • H • Me • H • Ph H Me Me Me

H Me CMe3 SO2Ph CO2H

(+), right (–), left (–), left (–), left (+), right

Previously, Lowe's Rule was used to determine rotation. This rule states that if an allene is viewed in its Newman projection as above with the most polarizable substituent on top, then if the more polarizable substituent along the horizontal axis is to the right, the allene is dextrorotary (right- handed). We will see more about helicity and optical rotation soon...

Biaryl Helicity

Atropisomeric biaryls can also be assigned.

A D If A-B or C-D is the dominant interaction, the molecule is right-handed. B C If A-C or B-D is the dominant interaction, the molecule is left-handed.

Note that for atropisomeric biaryl systems, the micro-helices (and thus the overall helicity) are both geometric and physical. Thus, an easier method may be to view the geometric helix turns: Left-Handed Right-Handed

PPh2 Ph2P

Dramatic variations in the net helicity are possible due to the atropisomeric dihedral angle, so definite assignments for optical rotation can be difficult. A C atropisomeric angle D B 4 Optical Rotation and Helicity

We saw before that for allenes, helicities predict the same sign of optical rotation as Lowe's Rule. For simple molecules with point-chirality, the helicity also correctly predicts stereochemistry (Polarizability sequence for each molecule is red > green > blue > black):

HO H Me3C H Me H HO H HO H

C Me Cl CN H2

(S)-(–)-left (R)-(–)-left (R)-(+)-right (R)-(+)-right (S)-(–)-left

O O S S H OH H H H H H2C H2C H2C H2C Ph Me Ph Me Me t-Bu (S)-(–)-left (S)-(–)-left (S)-(+)-right (S)-(–)-left (S)-(+)-right

Me CHO H Br Me H Me H H2N H Ot-Bu CH CO2H Cl C N CH CN H C O 2 (S)-(–)-left (S)-(–)-left (R)-(+)-right (R)-(–)-left (R)-(+)-right

Important Note: This method is based on the physical helices' contribution to optical rotation. It works well when the geometrical contribution is minimal, as in small and conformationally flexible molecules with no geometrical helices. Also, inter- and intramolecular associations must be small.

Helicity in Chiral Interactions Any two chiral molecules will either have the same helicity (homohelical interaction) or different helicity (heterohelical interaction).

SR CR CR-----SR CR-----SL OR CL SL CL-----SL CL-----SR

For many types of interactions, including asymmetric reactions and kinetic resolutions, steric arguments (geometric helices) have commonly been used to explain the specific interactions that occur. Electronics (physical helices) are important too, though!

In fact, example after example demonstrates that electronic homohelical interactions are favored and correctly predict the interactions that occur! This preference is presumably due to an energetic stabilization from homohelical interactions, both in induction and recognition interactions.

Homohelical induction: One molecule with a particular helicity causes a prochiral molecule to have the same helicity. C-----S* homohelical interaction: favored S prochiral C C-----S* heterohelical interaction: disfavored

Homohelical recognition: One molecule with a particular helicity interacts more favorably with another molecule of the same helicity than one with opposite helicity.

SR C-----S* homohelical interaction: more stable (less reactive) + C SL C-----S* heterohelical interaction: less stable (more reactive)

5 Helices in Reactions: Simplifications

While the overall helicity is useful for assigning a sign of optical rotation to a molecule, in reactions, this picture can be simplified.

The closer a stereocenter is to the site of reaction, the greater influence its helicity will have on the outcome of the reaction.

This left-handed induced stereocenter may play some role in the reaction

Ph These right-handed N stereocenters only Ru indirectly affect the reaction N Ph H H2

This left-handed stereocenter at Ru is closest to the reactive site. Thus, it will have the greatest influence.

More Simplifications for Reactions Furthermore, chiral chelating ligands will create rings. The actual helicity of the ligand by itself is not as important as the helicity of the ring helix in the reactive complex. The ring atoms are closer to the action than the pendant groups.

Technically, this center is left-handed, but within the ring (shown in red) it acts as a right-handed ring helix. O R H N Me N H O

NO2 O H N O R O C=O > N and R > H This interaction is the most important in 2 4 O R H deforming the bonding orbitals, and H creates the dominant micro-helix, 3 1 N leading to a right-handed ring helix twist. Me N H O

C=O > R > N > H AcHN CONHR' Therefore, the arrow goes counter-clockwise. Thus, left-handed. H

6 Asymmetric Catalysis and Kinetic Resolution Asymmetric Catalysis Initial coordination of pro-chiral substrate (S) to catalyst (C) induces helicity in substrate (S*). Greater stability of homohelical interaction does not prevent transformation from occuring. Preference for one enantiomer of product (P) is observed. homohelical favored interaction, !!G‡ favored product Reaction C-----S* P S C prochiral Reaction S*-C C-----S* P S*-C S + C heterohelical disfavored interaction, product P/P + C disfavored Kinetic Resolution Both enantiomers of substrate (SR and SL) bind to catalyst (CR). The stabilizing interaction leads to a decreased rate for the homohelical substrate-catalyst complex compared to the heterohelical complex. homohelical interaction, disfavored more stable, product less reactive Reaction S P R CR-----S* !!G SL-C C R Reaction SR-C SL C-----S* P heterohelical SL SR interaction, favored less stable, product more reactive PL PR

Puzzling Results Explained

Asymmetric Allylations: OR

N O RO OR Catalyst Ts OR THF R' R' R' R' R = CONHTs RO O ! ! O ! ! NH HN HN NH O N Ts O O

P Pd P P Pd P Ph2 Ph2 Ph2 Ph2

right-handed left-handed (–) 88% ee (+) 88% ee R' = trans-9,10-dihydro-9,10-ethanoanthracene Trost, Angew. Chem. Int. Ed. 1995, 34, 2386

Hydrogenation: MeO H H2 ! CO2Me catalyst RS RL Me CMe3 CO2Me Ph Ph P H C P P MeOH NHAc 2 H2C NHAc Rh Rh Rh H C H C 2 P P 2 P

RL RS Me3C Me right-handed OMe (–) 99.9% ee left-handed (+) 96% ee Imamoto, J. Am. Chem. Soc. 1998, 120, 1635 Knowles, J. Am. Chem. Soc. 1977, 99, 5946 7 Ketone Reductions: Ru Functionalized Ketone Hydrogenation Left-handed Ru catalyst:

O Catalyst OH Ph Func H2 Func 2 P R R OAc Ru P OAc Ph2 P Func left-handed ligand ring helix ! Ru P OH+ H R OH O OH O P(OR')2 R XR' R R'' R'' R'' R'' homohelical left-handed substrate helix OH OH OH OH

NMe2 OH R R' R R

In other cases, OH Y OH Br OH OH polarizability of OH ONa R > OH+. Since + XR' O OH > D, other D Me O R S R enantiomer O is observed! O O

R, R', R'' = alkyl, aryl X = NH, NR', O, S Y = OMe, Br

Noyori, Angew. Chem. Int. Ed. 2001, 40, 40

Ketone Reductions: More Ru Transfer Hydrogenation of Unfunctionalized Ketones

O Catalyst OH Base P P P P L S iPrOH L S B Left-handed Ru catalysts: left-handed ligand helix Ts Ts Ph N ! Ph N Ru H A Ru L Ph N ! Ru H2 Ph N H H2 HN H P H L C P O S Both backbone stereocenters H H H are right-handed (A), but they N N Ru enforce a left-handed nitrogen homohelical left-handed center (B), which causes the Ru substrate helix P H P to arrange in a left-handed Ph2 Ph2 octahedral structure (C)!

OH R3 OH OH OH OH OH OEt R2 R4 R2 Ph Ar R Het R 1 1 R R MeO CN O

Noyori, Acc. Chem. Res. 1997, 30, 97 Noyori, J. Org. Chem. 2001, 66, 7931 8 Ketone Reductions: CBS

O right-handed OH (S)-CBS cat.

PL PS PL PS R2BH

OH OH O OEt P R O R t-BuO R Ot-Bu B N PS OEt O Induced right-handed H substrate helix P OH H2B H L OH Ar Ar Right-handed O Ligand helicees

O OH OH Br O OH TBSO N OH OTBS

Me MeO NO2 OMe OH OH OH OMe OH R D OMe Het R Ar R N OTf OH MeO NC Corey, Angew. Chem. Int. Ed. 1998, 37, 1986

Kinetic Resolution: Hydrogenation Dynamic kinetic resolution of ß-ketoesters

Both ketoesters, which are in equilibrium in the reaction, bind to the catalyst. Binding of the left- handed ketoester leads to a homohelical interaction - too stable for hydrogenation. Right-handed ketoester binding leads to a heterohelical interaction, which promotes hydrogenation through destabilization of the intermediate. Note that the reduction leads to a left-handed helix at the alcohol center. Also, reduction of the ketone reverses the helicity at carbon 1, leading to a left-handed helix there too! heterohelical interaction: fast active state hydrogenation OR3 O OR3 OR3 OR3 P X R2 P X O O O major 1 O ! Ru R2 ! Ru O R2 1 R2 R1 P H O P H HO R1 R1 R1 left-handed (R)-BINAP-Ru syn (major)

H2 3 3 3 3 OR OR OR OR P X P X O O O O minor ! 1 ! Ru R2 Ru O R2 1 R2 R2 P H O P H HO O R1 R1 R1 R1 homohelical slow anti (minor) recognition: hydrogenation resting state Noyori, Bull. Chem. Soc. Jpn. 1995, 68, 36 9 Kinetic Resolution: RCM Asymmetric Ring Closing Metathesis Based Kinetic Resolution heterohelical interaction: reactive Me R R i-Pr i-Pr R N productive Ph R X X right-handed O Mo Me O Mo RCM X Mo catalyst n n ! O O high ee n R

Me R R R = OR, alkyls nonproductive Me X = O, CH2 X X n = 1, 2, 3 O Mo plus several n metathesis n ! O similar catalysts homohelical interaction: unreactive (recovered)

But, Me Ph Ar Ph Me Ph Me Ph N right-handed Mo catalyst O Mo NAr NAr NAr n + ! O n n n Induced helicity of amine closer to Mo than carbon stereocenter. Also, lone pair is highly polarizable, creating greater ring twist than original stereocenter. Hoveyda, Schrock, Chem. Eur. J. 2001, 7, 945 Hoveyda, Schrock, J. Am. Chem. Soc. 2002, 124, 6991

Oxidative Kinetic Resolution of Alcohols

2 6 2 6 3 4 3 4 ! N ! N ! N ! N 1 1 Pd 5 Pd 5 Cl Cl Cl Cl

ring A: left-handed ring B: left-handed C1 > C2 and Pd >> C3 C5 > C6 and Pd >> C4 Thus, the left nitrogen Thus, the right nitrogen is left-handed. is left-handed. The right nitrogen does The left nitrogen does not contribute to helicity not contribute to helicity in this ring since C4 ! C5. in this ring since C1 ! C3.

homohelical interaction Un OH N O Protonation left-handed ! Pd OH Pd complex N H R Un R + Un R O 2 R Oxidation O N O ! Pd N H Un Un R

heterohelical interaction

Polarizabilities Un > R, O > H

10 Tandem Processes: Asymmetric Catalysis and Kinetic Resolution

Enantioselective Sulfide Oxidation for Synthesis of Sulfoxides

Initial: Final: homohelical 44% yield homohelical 24% yield induction 50% ee recognition > 99% ee t-Bu t-Bu O O O O O O ! Ti major O ! Ti slow O left-handed O Ar S O Ar S (R)-BINOL-Ti S Ar R O S [O] Ar R S R R Ar R tBuOOH + + + achiral Ar Ar S R minor O S R fast O O S [O] Ar S R O Ar R O ! Ti O ! Ti O O O O O O t-Bu t-Bu heterohelical heterohelical interaction interaction

Asymmetric Kinetic Catalysis Resolution

Uemura, J. Org. Chem. 1993, 58, 4529

Another Tandem Process

Hydrogenation of Enamides - Tandem Asymmetric Catalysis and Dynamic Kinetic Resolution!

Asymmetric homohelical Kinetic Catalysis interaction Resolution O Me P k ! Rh slow CO2Me P NH Ph

MeO2C NHAc right-handed Ph R (S)-BINAP-Rh Ph

NHAc H2 O Me R = CO2Me, CO2H, CN k CO Me P Ph fast 2 C(O)NH2, Ph, C(O)Ph ! Rh Ph P(O)(OR) , etc. NH 2 P NHAc MeO2C right-handed This R group is critical for high ee. (R), high ee It was previously believed to be due heterohelical to some electron-withdrawing property. interaction Helicity makes it very clear: polarizability!

The initial coordination appears to be highly selective for homohelical induction. However, this is the much slower reacting complex to reach the product. Eventually, all of the enamide is channeled through the heterohelical complex to reach the product with high ee.

Halpern, Pure Appl. Chem. 1983, 55, 99 Koenig, in Asymmetric Synthesis, 1985, Vol. 5, Ch. 3. 11 Helical Character Matching

Recall: Asymmetric Kinetic Catalysis Resolution

!!G‡ !!G SL-C

S*-C SR-C S*-C SL SR S + C

P/P + C PL PR

For the most selective reaction, !!G must be maximized. This occurs when the helicities of S* (SR) and C are equal. Similar to hard-soft acid-base theory (which is also based on polarizabilities), optimal interaction will occur when S* and C have the same helicity character, as well as the same handedness. Thus, by modifying the catalyst helicity (or substrate helicity), a rational method for optimizing selectivity in asymmetric reactions is realized.

Return to Enamide Hydrogenations

Extensive study of bisphosphine ligands in the Rh-catalyzed hydrogenation of enamides provides opportunity to see helicity matching in action!

R Rh cat. ! R Ph Ph NHAc H2 NHAc C Me C Bisphoshinoethane ligands: Me P P Rh Ph t-Bu Ph Me Ferr Me Me t-Bu Me Ad Me Ad Rh P P P P P P P P Me C Me Rh > Rh > Rh >> Rh ~ Rh ~ Rh ~ C ~ ~ P P P P P P t-Bu Ph Me Ph Me Ferr t-Bu Me Ad Me t-Bu Me 6.3% ee 22% ee 35% ee 99.9% ee 99.9% ee 99.2% ee >99% ee 93.5% ee

ee decreases optimal catalysts ee decreases

Me HC Me C(Et) Me t-Bu Me Ad Me t-Bu Me t-Bu Me Ad Me Cy 3 P P P P P P P P Rh ~ > ~ ~ ~ ~ ~ ~ Rh Rh Rh Rh Rh Rh Rh P P P P P P P P CH Me (Et)3C Me Cy Me Cy Me t-Bu Me i-Pr Me i-Pr Me Cy Me 95% ee 68.7% ee 77.7% ee 75.5% ee 75.5% ee 77.0% ee 43.0% ee 47.1% ee

ee decreases 12 Return to Enamide Hydrogenations 2

Helix Ring Size Affects Helicity!

Me t-Bu Me t-Bu Me t-Bu Me t-Bu P P P P Rh > Rh > Rh ~ Me2Si Rh P P P P t-Bu Me t-Bu Me t-Bu Me t-Bu Me 97% ee 99.9% ee 14% ee 0% ee

ee decreases optimal catalyst ee decreases

i-Pr Me Et i-Pr P i-Pr P Me P Et P i-Pr Rh Rh Rh Rh P Me P Et P i-Pr P i-Pr Me Et i-Pr i-Pr

74% ee 98% ee 99% ee 87% ee

ee decreases optimal catalyst ee decreases

Similar effects can be seen for a variety of other ligand variations, as well as substrate variations:

1 Ar CO2Me H R R CO2Me R CO2Me

H NHAc Ar NHAc Ar NHAc R2 NHAc