use of cp2ticl in synthesis reagent control of radical
TRANSCRIPT
Reactions of Cp2TiCl
ChemoselectivityActivated aldehydes (aromatic, a,b-unsaturated) more reactive than aliphatic aldehydes.Esters, nitriles, ketones unaffected.Br, Cl, tosylate stable.Mild radical initiator.
O
HR R
HO
R
OH
1. Pinacol Coupling
2. Epoxide Opening
O
OH
E
R
R
OH
R R
HO
OO
O
Preparation of Cp2TiClIII
TiCl3
Cp
CpTi
Cl
S
IIIIII
IV
Cp
CpTi
Cl
Cl
Cp
CpTi
Cl
ClTi
Cp
Cp
IIIM=Znether
IIITi
ClCp
ClCpM
Cl
ClTi
Cp
Cp
III Solvent (S)2
Zn or MnTHF15 min
Zn, neat TlCp2
Ti(III): [Ar] 3d1
Cp2TiCl generated by in situ reduction with Mn or Zn.Both dimer and trimer work equally well in most cases.In situ regeneration of Ti(III) possible allowing it to function catalytically.
R. Jungst; D. Sekutiwski; J. Davis; M. Luly; G. Stucky, Inorg. Chem. 1977, 16, 1645.
M-Ti-M : 132o
Substrate Controlled Stereoselective Radical Reaction
D. Curran, D. Rakiewicz, Tetrahedron, 1985, 41, 3943.
Substrate directs the stereoselectivity of the reaction.
I
TMS
Bu3SnH
AIBN
TMS
H
H
1. Substrate has stereogenic center
70% yield, 86-97% ee.
2. Chiral Auxiliary
N
O
O
Nt-BuIBu3SnHAIBN
N
O
O
N
t-Bu
N. Porter, D. Scott, I. Rosenstein, B. Giese, A. Viet, H. Zeitz, J. Am. Chem. Soc. 1991, 113, 1791.
72% yield
Reagent Controlled Stereoselective Radical Reaction
M. Sibi, N. Porter, Acc. Chem. Res. 1999, 32, 163.
Control Features:
Chelation locks substrate into rigid conformation.
Chiral ligand allows only 1 face of radical to be accessible.
N
O
O
O
SnBu3t-Bu N
O
O
O
Zn(OTf)2, Ligand5 mol%
t-BuI, Et3B, O2
N
O
N
O
Ph Ph
92% yield, 90% ee
Ligand
1. Complexation
Reagent Controlled Stereoselective Radical Reaction
M. Haque, B. Roberts, Tetrahedron. Lett. 1996, 37, 9123.
2. Chiral Hydrogen Source
O O O OPh3Si
O
OAc
AcOAcO
OAcSH
O OPh3Si
H
+ Ph3SiH5 mol %
72% yield, 50% ee
Ph COMeBr Ph COMe
H
"Sn"Et3B
SnHMe
30% yield, 41% ee
D. Nanni, D. Curran, Tetrahedron Asymm. 1996, 37, 2417.
3. Formation of radical: Cp2TiCl
Pinacol Coupling
Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717.
D. Gibson, Y. Ding, M. Mashuta, J. Richardson, Acta Crys. 1996, 52, 559.
R
OTiCp2ClO
HR
Cp
CpTi
ClS
+
R
OTiCp2Cl
R
ClCp2TiO
R
OTiCp2Cl
R
HO
R
OH
H3O+
General Mechanism
IV
Cp
CpTi
Cl
OCH3
Ti-O 1.839 Cl-Ti-O 93.8 Ti-Cl 2.412 O-Ti_M(1) 109.6 Ti-M 2.088 O-Ti-M(2) 105 Ti-M 2.093 Cl-Ti-M(1) 105 O-C 1.367 Cl-Ti-M(2) 106.3
M(1)-Ti-M(2) 130.8 Ti-O-C 141.4
Bond Lengths and anglesDistorted Tetrahedral
Pinacol Coupling
Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717.
Proposed intermediate leadingto high diastereoselectivity.
Cl Cl
Development of Catalytic Pinacol Coupling
T. Hirao, B. Hatano, M. Asahara, Y. Muguruma, A. Ogawa, Tetrahedron Lett. 1998, 39, 5247.
R
ClCp2TiO
R
OTiCp2Cl
2 TMSCl
R
TMSO
R
OTMS2 TiCp2Cl2+
Product resting statebefore hydrolysis
Development of Catalytic Pinacol Coupling
A. Gansäuer, Synlett. 1998, 801.
TMSCl and Zn can effect the pinacol coupling and proceeds with low diastereoselctivity.
Initial catalytic reactions gave worse diastereoselectivities than stoichiometric (86:14 to 50:50).
Silylation of Ti alkoxide determined to be the slow step in the reaction.
Low diastereoselectivies solved by slow addition of TMSCl, MgBr2 and aldehyde to Ti(III) and Zn.
cis:trans
Modification of Catalytic Pinacol Coupling
Reference
Radicals are stable under protic conditions.
Selection of correct base important as to notoxidize the metal reductant or complex withthe Titanium catalyst.
Addition of Amine HCl salt leads to increaseddiastereoselectivity, faster turnover comparedto TMSCl catalyzed system.
ArAr
OH
OH1
ArAr
OH
OH2
A. Gansäuer, D. Bauer, J. Org. Chem. 1998, 63, 2070.
2,4,6-Collidine
Enantioselective Pinacol Coupling
M. Dunlap, K. Nicholas, Syn. Comm. 1999, 29, 1097.
A. Bensari, J. Renaud, O. Riant, Org. Lett. 2001, 3, 3863.
Mechanism of Epoxide Opening
T. RajanBabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986.
A. Gansäuer, H. Bluhm, Chem. Rev. 2000, 100, 2771.
Product ratios show higher substituted radical formed.Titanium attached to radical it created--reagent control.
OTiCp2Cl
R
OTiCp2Cl
R
OTiCp2Cl TiCp2Cl
R
D3O+
OTiCp2Cl
R
D
O
O
D7
D8
OD
R
DCp2TiCl
+
Reductive termination pathway depends on reactivity ofintermediate radical.
Epoxide Opening and Trapping
T. RajanBabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986.
O
C8H17
CN
OH
CNOH
CN
H17C8 H17C8
88% 12%
1) Cp2TiCl+
2) H3O+
Radical formation at the higher substituted carbon.
Electrophilic workup
Complementary to nucleophilic epoxide opening
Diastereoselectivity in 5-member ring formation
A. Gansäuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500
O
Y
Y= CH2, NTs, O
YH
HO CH3
10 mol% Cp2TiCl2Mn, Coll*HClTHF
Diastereoselectivity in 5-member ring formation
A. Gansäuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500.
Deoxygenation of Epoxides
T. RajanBabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986
Deoxygenation discouraged in thepresence of trapping agents withinverse addition of Cp2TiCl tominimize the concentration of Ti(III).
Effective for sensitive functionalgroups, especially acid sensitive.
Effects of Solvent and Water
A. Barrero, J. Oltra, J. Cuerva, A. Rosales, J. Org. Chem. 2002, 67, 2566.
(+)-3a-hydroxyreynosin
Conditions
Effects of Solvent and Water
A. Barrero, J. Oltra, J. Cuerva, A. Rosales, J. Org. Chem. 2002, 67, 2566.
Proposed concerted transition stateleads only to 6-endo cyclization withno 5-exo product.
Tertiary radical hindered--it is nottrapped by Ti(III) or reduced by 1,4-cyclohexadiene.
Deuterium incorporation is observedat C4 when D2O is used.
Formation of a-glycosides
J. Parrish, R. Little, Org. Lett. 2002, 4, 1439
Reaction Scheme
Complementary to NucleophileReaction Scope
Formation of a-glycosides
J. Parrish, R. Little, Org. Lett. 2002, 4, 1439
Reduction
Lewis acidic epoxide opening yieldsthe undesired product.
Trapping agent must be of the correctelectronic nature.
Catalytic Epoxide Opening
A. Gansäuer, H. Bluhm, Chem. Rev. 2000, 100, 2771
A. Gansäuer, M. Pierobon, H. Bluhm, Angew. Chem, Int. Ed. 1998, 37, 101
A. Gansäuer, H. Bluhm, Chem. Rev. 2000, 100, 2771.A. Gansäuer, H. Bluhm, M. Pierobon, M. Keller, Organometallics, 2001, 20, 914.
6
7
Catalytic Asymmetric EpoxideOpening
ReferenceA. Gansäuer, H. Bluhm, T. Lauterbach, Adv. Synth. Catal. 2001, 343, 785
7
7
6666
Catalytic Asymmetric Epoxide Opening
7
7
Conclusion
Cp2TiCl is a mild reducing agent for pinacol and epoxide opening reactions.
Opposite chemoselectivity to nucleophilic epoxide opening.
Reagent controlled enantioselective modifications to the Ti(III) reagent now emerging.
A wide range of functional groups are tolerated.
The oxidation/reduction of reagents and substrates can have significant effect on successof reaction.
Li--Li+ + e
Na--Na+ + e
Mg --> Mg2+ + 2e
Al --> Al3+ + 3e
Mn --> Mn2+ + 2e
Zn --> Zn2+ + 2e
Fe --> Fe2++ 2e
Ni --> Ni3+ + 3e
3.05
2.71
2.37
1.66
1.18
0.76
0.44
0.25
Eo reduction potential
Ti(IV) --> Ti(II)
Ti(IV) --> Ti(III)
Ti(III) + MClx--> Ti(IV) + M
D. Sekutowski, Low Valent Organometallic Titanium Compounds, Dissertation, UIUC, 1975
R. Flowers, Tetrahedron Lett. 1997, 1137
T. Skrydstrup, Chemistry, 2001, 435