Catalytic asymmetric reactions with chiral titanium amide-alkoxide complexes

Adam R. JohnsonDepartment of Chemistry

Harvey Mudd College, Claremont, CA 91711

Modular ligand synthesis

NH

OH

R*

R

R* = L-Valine

L-Phenylalanine

D-Phenylglycine

R =

R' R'

R' = CH3, n-Bu, Ph

NH

OR

O

H2NO

O

KetoneNaBH(OAc)3

LiAlH4 orR'MgBr65-95%

80-90%

1st generation, R’ = H2nd generation, R’ = alkyl

Ligand nomenclature

1st generation 2nd generation

2nd generation 2nd generation

2nd generation

2nd generation

Can’t be made …

NH OH NH OH

NH OHNH OH

PhPh

D-H2PhgAdO

L-H2ValPrOMe2

L-H2PheAdOPh2

L-H2ValCyOBu2

NH OH

NH OH

Ph Ph

L-H2PheCyOMe2

L-H2ValPrOPh2

Initial hydroamination results

1st generation ligands

ee’s by chiral GC of benzamide derivative

“blue” ee’s are opposite enantiomer (lower Rf found with D-ligands)

Ligand 2b Z-3b ee E-3b ee 3c eeL-H2ValPrO 20 41 1 39 4 4L-H2ValCyO 19 41 0 41 5 4L-H2ValAdO 24 40 0 36 5 5L-H2PhePrO 33 34 6 33 4 2L-H2PheCyO 32 33 8 35 5 6L-H2PheAdO 22 42 7 36 16 15D-H2PheAdO 23 42 10 35 13 3D-H2PhgPrO 20 50 2 30 4 3D-H2PhgCyO 20 48 0 32 4 4D-H2PhgAdO 14 53 5 33 8 10L-H2PhgAdO 18 51 11 31 15 12none 22 47 0 31 0 0

Yield (%, by NMR)

Organometallics, 2004, 4614

10 mol % cat., 110˚ C10 mol % cat., 135˚ C

NH

3c

NH2

·

N NH

NH

2b Z-3b E-3b1b, R = H1c, R = CH3

Hydroamination with 2nd generation ligands

2nd generation ligands

ee’s by chiral shift NMR using R-O-acetylmandelic acid

“red” isomers (more downfield shift) correspond to same enantiomer as before (longer Rf by GC)

5 mol % cat., 135˚ COvernight reaction, >95% completion, single product

NH2

·

NH

Ligand ee Ligand eeL-H2ValPrOMe2 2 L-H2PhePrOMe2 4L-H2ValPrOBu2 5 L-H2PhePrOBu2 3L-H2ValPrOPh2 --- L-H2PhePrOPh2 16

L-H2ValCyOMe2 1 L-H2PheCyOMe2 1L-H2ValCyOBu2 1 L-H2PheCyOBu2 5L-H2ValCyOPh2 5 L-H2PheCyOPh2 16L-H2ValAdOMe2 2 L-H2PheAdOMe2 15L-H2ValAdOBu2 10 L-H2PheAdOBu2 1L-H2ValAdOPh2 0 L-H2PheAdOPh2 7

Benzaldehyde alkylation

-78° to room temperature overnight

Same reaction conditions for titanium complexes: •1.1 eq Et2Zn•5 mol% ligand•5 mol% Ti(OiPr)4

H

O

(S) Et

OH

1 eq

+ Et2Zn

1.1 eq 5 mol %

NH OH

Alkylation data highlights

85-98% conversion; some reductionR product favored with L-amino alcoholsIncrease in %ee using Ti, but same enantiomer (in almost all cases)

(R) Et

OH

NH OHAd

58 %ee with H2L73 %ee with Ti

(R) Et

OH

NH OHAd

18 %ee with H2L41 %ee with Ti

(R) Et

OH

NH OHAd

61 %ee with H2L63 %ee with Ti

Ph Ph

PhPhPh

(R) Et

OH

NH OHPr

26 %ee with H2L36 %ee with Ti

Ph BuBu

Datacatalyses using conditions (I) catalyses using conditions (II)

yield conversion selectivity yield conversion selectivity(%) (%) (%) %ee Confgn (%) (%) (%) %ee Confgn

Pr H2 63 89 65 1 R 57 95 93 6 RMe2 94 93 91 3 S 78 83 76 12 SBu2 53 98 98 31 R 100 96 93 29 RPh2

Cy H2 81 97 94 2 R 78 89 81 13 RMe2 59 77 71 25 S 86 100 99 25 RBu2 86 65 55 29 R 90 98 97 7 RPh2 65 100 100 2 R 74 100 100 29 R

Ad H2 80 99 97.3 18 R 90 98 95 41 RMe2 71 84 80 14 S 51 82 79 57 RBu2 78 95 89 49 R 90 98 97 3 SPh2 66 99 99 61 R 98 97 95 63 R

Pr H2 81 100 74 5 R 65 93 67 11 RMe2 77 92 92 12 R 48 93 93 24 RBu2 75 96 93 26 R 80 100 97 36 RPh2 75 97 95 9 R 77 98 97 19 R

Cy H2 76 95 93 3 R 68 96 94 5 RMe2 66 96 96 6 R 58 98 98 10 RBu2 82 100 100 38 R 66 93 97 36 RPh2 90 96 96 59 R 63 90 89 59 R

Ad H2 89 97 92 29 R 79 100 99 3 RMe2 66 95 88 10 R 60 93 92 14 RBu2 100 92 86 9 R 100 100 98 15 SPh2 70 99 98 58 R 96 98 97 73 R

unable to prepare this ligand

New directions

Sulfonamides

Tridentate ligands H2N OH

S +NH OHS

O

O

O

OCl

HN OH

OH

NOO

O

H2NO

O

OH

+

Electron withdrawing

More rigidity

Sulfonamide ligands

Electron withdrawing ligands

Faster rate would allow for lower T and increase %ee

Sulfonamide % conversion % ee % conversion % ee % conversion % ee

A 100 10 30 3 0.5 N/A

B 100 9 27 3 6 5

C 100 6 no reaction no reaction

D 100 4 no reaction 10 N/A

E 100 2 no reaction not performed

F 71 2 16 3 2 7

At 135 ˚C At 110 ˚C At 95 ˚C

NH OHSO

ONH OHSF3C

O

ONH OHS

O

O

F3C

F3C

NH OHSO

ONH OHSF3C

O

ONH OHS

O

O

F3C

F3C

Sulfonamide A Sulfonamide B Sulfonamide C

Sulfonamide D Sulfonamide E Sulfonamide F

TiCl2(NMe2)2 starting material

Precipitates quantitatively (for 5a 92% isolated) and analytically pure from reaction mixture

insoluble Et2O, C6H6, C7H8; soluble in thf, CH2Cl2

Complex 5b is more soluble, only 35% yield Thermolysis gives new product/decomposition 1H NMR spectrum incompatible with monomer

OHNH

R

+ TiCl2(NMe2)2

O TiCl

Cl

NHMe2

N

- HNMe2

R

5a, R = CH2Ph5b, R = CHMe2

Inorg. Chim. Acta, 2005, 358, 687

Low T Limit: 11 °C

No change in spectrum down to -56 °C

NH

CH(CH3)2

NCH3

CH(CH3)2

O Ti NCl

N

Cl

PhH2C

OTi

Cl

NCl

N

CH2Ph

H

H

HH

O Ti NHCl

N

Cl

PhH2C

OTi

Cl

NCl

NH

CH2Ph

-8

-6

-4

-2

0

2

4

2.80E-03 3.00E-03 3.20E-03 3.40E-03 3.60E-03 3.80E-03

1/T (1/K)

ln(k/T)

PhePrOd6-PhePOr

Dynamic NMR Behavior

Deuterated derivatives to simplify spectra

VT NMR used to determine first order rate constants

∆H‡ = 16-20 kcal/mol∆S‡ = 2-16 e.u.

Proposed dynamic model

Acknowledgements

ACS-PRF, NSF-RUI, NSF-REU

Undergraduate co-workers: Benzaldehyde alkylation: Casey M. Jones (Reed, ‘05), Hanhan Li (HMC, ‘05), Joanne E. Redford (HMC ‘09), Sam J. Sobelman (HMC ‘08), J. Andrew Kouzelos (HMC ‘07),

Ryan J. Pakula (HMC ‘09)Hydroamination: Amanda J. Hickman (HMC ‘07), Lauren D.

Hughs (HMC ‘09)New directions: Dianna C. McAnnally-Linz (Agnes Scott, ‘08), Katie E. Near (‘10), Minh T. Nguyen (U. La Verne, ‘08), Andrew H. Stewart (HMC, ‘08), Camille M. Sultana

(HMC, ‘10)