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)