the kulinkovich reaction: generation of 1,2-dicarbanionic titanium species and their use in organic...
TRANSCRIPT
The Kulinkovich Reaction:
Generation of 1,2-dicarbanionic Titanium Species and Their Use in Organic Synthesis
Literature meeting
Olga Lifchits
September 18, 2007
The next blockbusterThe next blockbuster
“Low-valence titanium – Lord of the small rings”
(M. Oestreich, Nachrichten aus der Chemie, 2004, 52, 805.)
TitaniumTitanium
22Ti [Ar] 3d2 4s2
• Oxophilic early transition metal
• Pure metal is non-toxic even in large quantities
• Toxicity associated with Ti complexes comes from ligands (e.g. cyclopentadienyl)
• Salts are typically harmless except the chlorides
Reactivity of Ti-C sigma bondReactivity of Ti-C sigma bond
• Ti-C bond is strong (typically > 60 kcal/mol) but very reactive (thermally unstable)
TiCH3
CH3Cp
CpCp2Ti=CH2
- CH4
AlMe2ClTi AlMe2
ClCp
Cp
Tebbe's reagent
Ti-C-H angle distortionsuggests an agostic interaction
• Low-energy empty d-orbitals favour agostic interactions with neighbouring σ bonds
• Agostic interaction with Cα-H promotes decomposition into alkylidenetitanium species by α-hydrogen abstraction in the absence of β-hydrogens
organyl TiX3
X = Cl, OR, NR2
Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789; Telnoi, V.I. et al. Dokl. Akad. Nauk SSSR 1967, 174, 1374; Brookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395.
Reactivity of the Ti-C sigma bondReactivity of the Ti-C sigma bond
• When β-hydride is present, analogous agostic interaction with Cβ-H assists in β-hydride elimination
86o
LnTi-L
R
R
LnTi R
R
H+ L
RLnTi
RLnTi
RA B
_
• Resulting complex exists as two resonance forms favouring titanacyclopropane B (general trend for oxidized early metals)
• Reactivity patterns of both resonance forms are observed
“1,2- dicarbanion”
Brookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395; Steigerwald, M; Goddart, W.A. JACS, 1985, 107, 5027
Oleg G. KulinkovichOleg G. Kulinkovich
• Born in Estonia in 1948
• Honors B.Sc., Belorussian State University (BSU), Minsk (1971)
• PhD, BSU with Prof. I.G. Tishschenko (1975)
• D.Sc., BSU (1987)
• Professor and Head of the Department of Organic and Polymer Chemistry at BSU (since 1991)
The Kulinkovich ReactionThe Kulinkovich Reaction
R1 OR2
OMgBr (2 eqv)
Ti(OiPr)4 (5-10 mol%)
Et2O, 18-20oC
1.
2. H3O+ 10-99%
R1
HO
• Original reaction (1989) used a mixture of stoichiometric amount of Ti(OiPr)4 (1 equiv), EtMgBr (3 equiv) and ester at -78oC to -40oC
• Catalytic version (1991) uses slow addition of EtMgBr (2 equiv) to a mixture of ester and Ti(OiPr)4 (5-10 mol%) at 18-20oC
Kulinkovich, O.G. et al. Zh. Org. Khim. 1989, 25, 2245; Kulinkovich, O.G. et al. Synthesis 1991, 234.
Proposed reaction mechanismProposed reaction mechanism
(OR')2TiEt
EtTi(Oi-Pr)4
2 EtMgBr 2 iPrOMgBr
R' = iPr or R2
CH3-CH3
(OR')2TiR1 OR2
O
(R'O)2TiO R1
OR2
1st C-C bond formation
R1
O(R'O)2Ti
OR2
2nd C-C bond formation
Likely initiated by the attack of Grignard on Ti center
(OR')2Ti
O
OR2
R1
2 EtMgBr
R1 OMgBr
+R2OMgBr
H3O+R1 OH
R'OH
R' = iPr or R2
(R'O)2TiO R1
OR2
Et
MgBr
(R'O)2TiO
R1
Et
Kulinkovich, O.G. Russ. Chem. Bull. Int. Ed. 2004, 53, 1065.
““Classical” Kulinkovich reaction scope Classical” Kulinkovich reaction scope
.
Ester scope:
Grignard scope (cis geometry in the absence of chelating groups):
R1 OR
O
R
MgX
OHn OH OH
O
OH
X
X = Cl, Br
OH
OH
TMS
OH
OR
R = alkyl, aryl
OH
N
OR
HO
OH
HOOH
(PrOi)2P
O
OH OH OH OH OH
Br
Et TIPSO
OMe
MeO
4
Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
Initial Limitation and ImprovementsInitial Limitation and Improvements
Problem: the reaction requires one “sacrificial” equivalent of the Grignard reagent, which might be expensive and/or difficult to make
Solution: methyltitanium triisopropoxide provides a “sacrificial” methyl group (no β-hydrogens on methyl)
MeTi(OiPr)3R
MgBr(PrOi)2Ti
Me
R- CH4
(PrOi)2Ti
R
De Meijere, A. et al. Synlett, 1997, 111.
Generating titanacycles through ligand exchangeGenerating titanacycles through ligand exchange
Problem: some olefins failed to exchange (eg. 1-heptene, ethyl vinyl ether) likely due to unfavourable equilibrium
Solution: a strained precursor from cyclopentyl or cyclohexyl Grignard
Ti(OiPr)4MgBr
(PrOi)2Ti (PrOi)2Ti
H R1
(PrOi)2Ti
R1R2 OR3
O
R1HO
R2
Monosubstituted olefins only,with a signle exception of norbornene
Ti(OiPr)3XMgBr
(PrOi)2Ti
H R1
(PrOi)2Ti
R1
X = OiPr, Cl 0-1 0-1
Kulinkovich, O.G. et al. Mendeleev Commun., 1993, 230; Cha, K.J. et al. JACS, 1996, 118, 4198.
Extended scope through ligand exchangeExtended scope through ligand exchange
(RO)2B
OHR1
(RO)2B
OH OH OH
OH
HO
Me3Si
(from
(PrOi)3TiO )
OH
HO
(from
HO)
OTBDMS
Bu3Sn
OH
(H2C)7
n-C18H37
87%, 98:2 dr 56% 37% 71%
64% 82%, 7:93 dr
O
51%
Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
Intramolecular Nucleophilic Acyl Substitution (INAS)Intramolecular Nucleophilic Acyl Substitution (INAS)
O
OMe
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2
O
OMe
Ti(OiPr)2 O
(OiPr)2Ti
OEtOH
Can generate a wide variety of bicyclic cyclopropanols:
X OH
R1
R2
X = C, N
R3
n
n = 0, 1, 2
OH
HTIPSO N
HO
OH
75% 94% 98% 88%
OH
Cha, J.K. JACS, 1996, 118, 291; Sato, F. et al. 1997, 119, 6984; Sato, F. Tet. Lett. 1996, 37, 1849.
Intramolecular Nucleophilic Acyl Substitution (INAS)Intramolecular Nucleophilic Acyl Substitution (INAS)
Proximity of the vinyl group to the ester matters:
.. but unsaturated oxacarboxylic acid esters work well for large rings:
HO
H
HO
H
HOH
HO
H
55% 62% 11% does not form
O O
HOH
HO
H
49%62%
O
OMen
Cha, J.K. JACS, 1996, 118, 291; Ollivier, J. Org. Biomol. Chem. 2003, 1, 3600.
Intramolecular Nucleophilic Acyl Substitution (INAS)Intramolecular Nucleophilic Acyl Substitution (INAS)
INAS is otherwise not so easy to achieve!
• Reactive nucleophile must be generated in presence of carbonyl
• The nucleophile must react only intra- and not intermolecularly
• Zn, B are not reactive enough; Mg, Li are too reactive
X X
OR
Nu
Marek, I.,ed. Titanium and Zirconium in Organic Synthesis; Wiley: Weinheim, 2002.
Further possibilities with ligand exchangeFurther possibilities with ligand exchange
Exchange withalkynes:
Exchange with a diene:
OCO2Et
iPrMgClTi(OiPr)4 Ti
(OiPr)2O
O OEt
O
O
Ti(OiPr)2
EtO
O
O(PrOi)2Ti
EtO
Allyltitanium
RCHO
O
O
R
HO
R1 O
OR2
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2
R1 O
OR2
(OiPr)2Ti O
R1
(PrOi)2TiOR2
E+O
R1
E
E+ = H+, I2, PhCHO
Sato, F. et al. JACS, 1996, 118, 2208; Sato, F. et al. J. Chem. Soc. Chem. Comm. 1996, 197.
Asymmetric strategies – Titanium bisTADDOLateAsymmetric strategies – Titanium bisTADDOLate
OEt
O
Ph
MgBr(2 eqv)
Et2O, 20oC
O
OO
O
Et
Et
H
H
Ar Ar
Ar Ar
Ar =
CF3
CF3
Ti
2
(0.3-1 eqv)
65-72%, 70-78% ee
PhMeHO
(1S, 2R)-ent
Ti(TADDOL)2
Ti(TADDOL)2 =
Corey, E.J., et al. JACS 1994, 116, 9345.
Proposed origin of stereoselectivityProposed origin of stereoselectivity
OTi
O
ArAr
ArAr
H H
O
O
Et
Et
H
R1
stablest titanacycle, controlledby axial Ar groups sets absolute stereochemistry of R1 at this step
R2 OMe
O
OTi
O
ArAr
ArAr
H H
O
O
Et
Et
H
R1
O OEt
R2
Insertion is bond-specific; R1 and R2grops prefer to sit trans to each other
OTi
O
ArAr
ArAr
H H
O
O
Et
Et
H
R1
OR2O
Et
R1
H
"face-specific pi-donor coordination of C=O to Ti(IV)"
OTi
O
ArAr
Ar
Ar
H H
O
O
Et
EtO
OMe
R2
H R1HO
R2
H R1
Corey, E.J., et al. JACS 1994, 116, 9345.
But why the cis geometry?But why the cis geometry?
Quantum-chemical calculations of a model reaction suggest..
MeOMe
O(MeO)2Ti
OTi(OMe)2
MeO
Insertion into least hindered Ti-C bond (kinetically favoured)
OMe
Me
H
Ti(OMe)3Agostic interaction with the Hatom of alpha carbon bringstwo methyls cis to each other
Me
Me
(MeO)3TiO
When applied to the Ti-TADDOLate reaction, this mechanism gives the same absolute configuration
Wu, Y-D., Yu, Z.-X. JACS, 2001, 123, 5777.
Question for the audienceQuestion for the audience
Draw the mechanism of this intramolecular Kulinkovich reaction and
explain the observed high diastereoselectivity for the trans product:
O
O
Ph
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2OH
Ph
85%, dr >97:3
HO
Note: diastereoselectivity is
under thermodynamic control
OH
Ph
HO
EtTemperature Trans:cis
-45oC to 0oC 41:59
-45oC to 20oC 95:5
Trans-selective cyclopropanation: answerTrans-selective cyclopropanation: answer
Sato, F., Kastakin, A. Tet. Lett. 1995, 34, 6079.
O
O
Ph
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2
O
O
Ph(PrOi)2Ti
Ti(OiPr)2
OPh
O
O Ti(OiPr)2
Ph
O
O Ti(OiPr)2O
Ph
H+OH
OH
Ph
85%, dr >97:3
Ti(OiPr)2
O
O
Ph
Asymmetric strategies: Oppolzer’s auxiliary Asymmetric strategies: Oppolzer’s auxiliary
SO2
N
O
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2HO
90%, 32% ee
SO2
N
O
R1
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2HO
R1
SO2
N
O
dr >99:156-87%92:8 - 99:1 dr(>98% ee)
Base
R1X
1 2
3
Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
Proposed origin of stereoselectivity Proposed origin of stereoselectivity
• Cooperative effect of the auxiliary and the chiral α-alkyl group
• “Mismatched” sultam 3 gave a lower dr (92:8)
• Absence of auxiliary (ester 4) gave a lower dr (66:34)
• Evans auxiliary (N-acyloxazolidinone 5) gave a lower dr (74:26)
N
O
Bn3
SO2
EtO
O
Bn4
N
O
Bn
O
O
MePh5
SO2
N
O
Bn
Ti(OiPr)4 + i-PrMgCl
Ti(OiPr)2HO
Bn
dr >99:1
86%> 99:1 dr> 98% ee
1 2
Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
Bicyclic cyclopropanol scopeBicyclic cyclopropanol scope
HO
58%, >95:5 dr>98% ee
HO
80%, >95:5 dr>98% ee
HO
87%, >95:5 dr>98% ee
HO
74%, >95:5 dr>98% ee
HOTBDMSO
84%, >95:5 dr>98% ee
HOtBuO2C
56%, 92:8 dr>98% ee
Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
Kulinkovich-de Meijere ReactionKulinkovich-de Meijere Reaction
R1 NR2
OR3 R4
MgBr
Ti(OiPr)4
R1
NR2
R3
R4
R1 NR2
OR3 R4
MgBr
Ti(OiPr)4
(PrOi)2Ti O R1
NHR2
R4
R3
(PrOi)2TiO
R1
NR2
R4
R3Ti(OiPr)2
O
n
R1
NR2
R3
R4
H2O
TiO2
De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.
Kulinkovich-de Meijere ReactionKulinkovich-de Meijere Reaction
• Requires stoichiometric Ti(OiPr)4 for useful yields
• Diastereoselectivity is generally lower than with esters
• Can use ligand exchange to generate active titanacycles
• Disubstituted alkenes and cycloalkenes react!
• Can easily access primary amines by catalytic debenzylation:
R1 NBn2
OR3 R4
MgBr
Ti(OiPr)4
R1
NBn2
R3
R4
H2, Pd/C R1
NH2
R3
R4
De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.
Kulinkovich-de Meijere Reaction scopeKulinkovich-de Meijere Reaction scope
NBn2
EtOMe
61%
NBn2
OO
92%
NBn2
89%
NBn2
63%
H
NBn2
28%
NBn2
43%
Bu3Sn O
NEt2
68%
Me Et
NBn2
26%
Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
Surprising behaviour with dienesSurprising behaviour with dienes
NBn2
Bn2N
Given a choice, a more substituted double bond is cyclopropanated..
… but in the absence of a less substituted bond, there’s no conversion:
no conversion
no conversion
De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
Surprising behaviour with dienes - rationalizationSurprising behaviour with dienes - rationalization
R
Ti(OiPr)2
Ti(OiPr)2R Ti(OiPr)2R
RNBn2
H NBn2
O
Ti(OiPr)2
O
R
Bn2N
Ti(OiPr)2
O
R
Bn2N
Intramolecular allyl addition
De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
Application in natural product synthesisApplication in natural product synthesis
NH
NH2
87% over 2 steps> 2:98 dr
N N
F
O
HO
O
F
F
HH
N
NH2
H
H
Antibiotic Trovafloxacin (Trovan)
NBn
H NBn2
O MeTi(OiPr)3 (1.2 eqv)
MgCl
(2.5 eqv) NBn
NBn2
H2, Pd/C
MeOH/AcOH
De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
Intramolecular Kulinkovich – de Meijere reactionIntramolecular Kulinkovich – de Meijere reaction
O
NEt2
N
Ph
O
MgCl
ClTi(OiPr)3
64%
H
NEt2
NPh
H
Me
MgCl
ClTi(OiPr)3
93%
Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
Beyond cyclopropanes – J.K. ChaBeyond cyclopropanes – J.K. Cha
HTBSO
ROHOOxy-Cope O
OMe
Kulinkovich
Making the Oxy-Cope precursor HOO
OMeTiX(OiPr)3
X = OiPr or Cl
MgBr
R1
R
R1
RMgBr
RO
R = TIPS, 77%R = THP, 46%
TiCl(OiPr)3
HO
OR
1. TBAF (75%) PPTS (60%)
2. Swern3. TBSOTf, Et3N
TBSO
TBSO
exclusively (Z)
single diastereomer
Lee, J., Kim, H., Cha, J.K. JACS, 1995, 117, 9919.
Beyond cyclopropanes – J.K. ChaBeyond cyclopropanes – J.K. Cha
H H
TBSO
OTBS H H
TBSO
OTBSH H
TBSO
TBSO
PhH, reflux
76-81% over 3 steps
TBSO
HTBSO
Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
Beyond cyclopropanes – J.K. ChaBeyond cyclopropanes – J.K. Cha
TBSO
HTBSO
Et2ZnCH2I2
PhH, reflux75%
TBSO
HTBSO
1. H2, PdC95%
2. HF, MeCNH2O, 73%
O
HHO
H3C
Cl3CCO2EtNaOMe99%
OTBS
HTBSO
Cl Cl1. H2, Pd/C100%
2. AgNO3acetone-H2O70%
H
Cl OTBS
O
Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
Beyond cyclopropanes – G. MicalizioBeyond cyclopropanes – G. Micalizio
Typical convergent approaches must form a central ketone first
Take that, aldol!
• No protecting group manipulations (free -OH)
• Stereodefined trisubstituted double bond with no intermediate ketone
• Double bond can be further functionalized
Me
OH
Me Me
OH
Me
R2
Me
OH
Me Me
Ti(OiPr)2H
O
R2
Me
R1
Me
OH
Me
Me
Me
OC
Me
H Me
SiMe3
OR OR
OR
Bahadoor, A.B., Flyer, A., Micalizio, G.G. JACS, 2005, 127, 3694.
Beyond cyclopropanes – G. MicalizioBeyond cyclopropanes – G. Micalizio
• Various diastereomers of the homopropargylic alcohol and aldehyde were coupled – Felkin selectivity in all cases (generally ≥ 2:1)
• Regioselectivity was found to be a function of the stereochemistry of both coupling partners!
• The role of a neighbouring alkoxide implicated in regioselectivity
Me
OLi
Me Me
Ti(OiPr)2
H
O
Me
OR
Me
OH
Me
MeOR
1. n-BuLi, PhMe, -78oC2. ClTi(OiPr)3, cPentMgCl-78oC to -40oC
3. BF3-OEt2, -78oCthen
Pr
OTBSMe
OH
Me Me
OH
Me
OR
Pr
OTBS
66%19:1 regioselectivity
1.5:1 dr
Felkin product
Bahadoor, A.B., Flyer, A., Micalizio, G.C. JACS, 2005, 127, 3694; Bahadoor, A.B., Micalizio, G.C. J. Org. Lett. 2006, 8, 1181.
SummarySummary
TiOiPr
OiPr
R1
R2
R3 OR
O
OH
R3
R1
X
O
OMenR3
R4
R5
X OH
R5
R4
X = C, N,O
R3
n
n = 0-3
R3 O
OR2nO
R3
E
n
R3 NR4 2
O
R1
NR4 2
R3
R4
HO
R4
SO2
N
O
R4
Micalizio’s polypropionate synthesisMicalizio’s polypropionate synthesis
Substrate-controlled diastereoselective cyclopropanationSubstrate-controlled diastereoselective cyclopropanation
Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.
R
OH Ti(OiPr)4
toluene, RT R
OTi(OiPr)3 c-HexMgCl
THF, RT
Ti O
R
OiPr
R1 OR2
O
OHR1
RHO
trans onlydr = 3.5:1 to 12.2: 1
R
O
O
c-HexMgCl
TiCl(OiPr)3
OHR1
RHO
trans onlyno 1,3 diastereoselectivity
Substrate-controlled diastereoselective cyclopropanationSubstrate-controlled diastereoselective cyclopropanation
Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.