The Kulkinovich Reac0on Modern Routes to Cyclopropyl Deriva0ves Using Titanium-‐ “Lord of the Small Rings”
Njamkou N. Nouc0 University of North Carolina at Chapel Hill
Literature Presenta0on 21 June 2011
1
Cyclopropanes
• Common drug and agrochemical targets
• Important intermediates in complex molecular synthesis
• Present in more than 4,000 natural products
2
X
X = OH, NR2, NH2
Cyclopropanes in Nature
3
O
N
S
O OOH
HO
Epothilone D
NH2
CO2H
Hypoglycine A
H2N
NH
NH
H2N
N
O
N
NH
O
NH
NH2
O
TAN-1047
(ß-aminoacid analogue)
HN
HO OH
HO
Iminosugars
Kulinkovich Reac0on
4
X
R2
R1
X = OH, NR2, NH2
R1 OMe
O
Kulinkovich
R1 N
O
R4
R3
De Meijere
R1
N
Szymoniak
Mechanism
5
2 eq. EtMgBr
Ti
RO
RO
Et
Et
Ti(OR)4
Ethane
Ti
RO
RO
O
Ti(OR)2
MeO
R'
O
R' OMe
R' OTi(OMe)(OR)2
2 eq. EtMgBr
R' OMgBr
+ MeOMgBr
H2O
R' OH
Kulinkovich, O. et. al., Synthesis, 1990, 234.
Mechanism
6
1 eq. EtMgBr
Ti
RO
RO
Me
Et
MeTi(OR)3
Ti
RO
RO
H CH3
O
Ti(OR)2
MeO
R'
O
R' OMe
R' OTi(OMe)(OR)2
R' OH
H2O
De Meijere, A. et al., J. Organometallic Chem., 2004, 689, 2033-‐2055.
Subs0tuted Cyclopropanols
7 De Meijere, A.; Kulinkovich, O. Chem Rev., 2000, 100, 2789-‐834
R1 OR
O
1) Ti(OiPr)4
EtMgBr
2) H3O+
Et2O
OHR1
R1 R Yield
Me OMe 76
n-C9H19 OMe 98
iPr OMe 88
c-Hex OMe 85
OMe 11HC CH2
Ph OEt 93
CH2CH2Br OMe 86
CH2SiMe3 OMe 67
CH2CH2P(O)(OiPr)2 OMe 67
1,2-‐Disubs0tuted Cyclopropanols
8 Corey, E. J.; Rao, S. A.; Noe, M. S. J. Am. Chem. Soc. 1994, 116, 9345-‐9346 De Meijere, A.; Kulinkovich, O. Chem Rev., 2000, 100, 2789-‐83
R1 R2 Yield
n-C3H7 C2H5 79
n-C6H13 C2H5 81
n-C6H13 n-C6H13
72H n-C6H13
71
77CH2CH2OTIPS
88
R1 OMe
O Ti(OiPr)4R2CH2CH2MgBr
HO R1
R2
HO R1
R2
+
CH2CH2P(O)(OiPr)2 Et
Asymmetric Variant
9 Corey, E. J.; Rao, S. A.; Noe, M. S. J. Am. Chem. Soc. 1994, 116, 9345-‐9346
OEt
O Ti cat.
PhCH2CH2MgBr
HO Me
Ph
up to 78% ee
CF3
CF3
Ar =
O
O
Et
Et O
O
Ar
Ar Ar
Ar
H
H
Ti
2
Ti cat. =
Hydroxycyclopropana0on of Alkenes
10
Ti
RO
RO
Ti
RO
RO
Titanacyclopropane Alkenetitanium Complex
2 eq. EtMgBr
Ethane
Ti
RO
RO
Ti
RO
RO
Et
Et
Ti(OR)4
Ti
RO
RO
Ph
Ph
O
Ti(OR)2
MeO
R'
O
R' OMe
R' OTi(OMe)(OR)2
2 eq. EtMgBr
R' OMgBr
+ MeOMgBr
H2O
R' OH
Ph
Ph
PhPh
Kulinkovich, O. et al. Mendeleeve Commun., 1993, 230-‐231.
Hypoglycine A
11
OEt
OEt
OEt
OiPrMgBr (2 eq.)
Ti(OiPr)4 (1 eq.)
OH
OEt
OEt
1)TsCl, Py
2) tBuOK
46% over 3 stepsOEt
OEt
NH2
CO2H
62% over 4 steps
Hypoglycine A
Kulinkovich, O. G. et al. Russ. J. Org. Chem. (Engl. Transl.) 1999, 35, 225-‐228.
12
X
R2
R1
X = OH, NR2, NH2
R1 N
O
R4
R3
De Meijere
R1 OMe
O
Kulinkovich
De Meijere Modifica0on
13
R1 N(R2)2
O Ti(OiPr)4R3CH2CHR
4MgBr
(R2)2N R1
R4R3
Ti
RO OR
R4R3
(iPrO)2Ti
OR1
NH(R2)2
R4R3
(iPrO)2Ti
O R1
NH(R2)2
R4R3
De Meijere, A. Kulinkovich, O., Chem. Rev., 2000, 100, 2789-‐2834.
De Meijere Scope
14 De Meijere, A. et al. J. Organometallic Chem., 2004, 689, 2033-‐2055.
R1 R2 Yield
H Bn 73
H t-Bu 20
Et Bn
35n-Pr Bn
63
R1 N(R2)2
O
Ti(OiPr)4R3CH2CHR
4MgBr
(R2)2N R1
R4R3
R3
H
H
H
n-Bu
R4
H
H
H
H
De Meijere Scope
15 De Meijere, A. et al. J. Organometallic Chem., 2004, 689, 2033-‐2055.
R1 R2 Yield
H Bn 73
H t-Bu 20
Et Bn
35n-Pr Bn
95H
Bn
49CH2CH2Cl Bn
63CH(OMe)CH3Bn
80 (1:3.5)CH2CH2P(O)Ph2 CH3
63
R1 N(R2)2
O
Ti(OiPr)4 / MeTi(OiPr)3
R3CH2CHR4MgBr
(R2)2N R1
R4R3
R3
H
H
H
n-Bu
H
H
H
CH3
R4
H
H
H
H
H
H
H
H
Yield
-
-
-
-
-
-
-
-
TAN-‐1047 Analogues
16
1) B2H6. THF
2) NaOH, H2O2
3) PPh3, HN3, DIAD
BenzeneNBn2
BnO
N3
58%
BnO NBn2
O MgBr
MeTi(OiPr)3
THF NBn2
BnO56%
1) PPh3, H2O
2) Boc2O, MeOH
NBn2
BnO
NHBoc
93%
1) H2, Pd/C
2) Boc2O, MeOH
3) H2, Pd/C
NHBoc
HO
NHBoc
53%
1) KMnO4
NaOH
tBuOH
2) HCl
NH2
NH
HN
NH2
N
O
N
HN
O
HN
H2N
O
TAN-1047
(ß-aminoacid analogue)NHBocHO2C
NHBoc
34%
De Meijere, A. et al. J. Organometallic Chem., 2004, 689, 2033-‐2055.
17
X
R2
R1
X = OH, NR2, NH2
R1
N
Szymoniak
R1 OMe
O
Kulinkovich
R1 N
O
R4
R3
De Meijere
Szymoniak Modifica0on
18
R1
1) Ti(OiPr)4
3) H3O+
NH2
R2
2) F3B . OEt
MgBr
R2
R1
N
(iPrO)2Ti
NR1
R2
(iPrO)2Ti
NR1
R2
BF3
Ti
RO OR
R2
Bertus, P.; Szymoniak, J. J. Org. Chem., 2003, 68, 7133-‐7136
Szymoniak Scope
19 Bertus, P.; Szymoniak, J. Chem. Commun., 2001, 1792-‐1793 Bertus, P.; Szymoniak, J. J. Org. Chem. Note, 2003, 7133-‐7136
Bn H 70
n-C9H19H 70
C6H11H
57 (64:36)Bn n-Bu
54 (55:45)Bn s-Bu
52
R1 R2 Yield
R1
1) Ti(OiPr)4
3) H3O+
NH2
R2
2) F3B . OEt
MgBr
R2
R1
N
R
R = OMe43
R = Me
R = F
73
64
H
H
H
Imino Sugars
20
O
BnO OBn
OH
BnO
1) NH2OH (91%)
2) MsCl (76%)
OBn
OBn
CN
BnO
OMs
Protected sugars
EtMgBr (2.2 eq.)
Ti(OiPr)4 (1.1 eq.)
-78 C to 20 C
then BF3. OEt2 (2 eq.)
HN
BnO OBn
BnO
46%
HN
HO OH
HO
44%
Iminosugars
OBn
OBn
BnO
OMsTi(OiPr)2N
F3B
Szymoniak, J; Behr, J.-‐B. SynleH. 2006, 223
Conclusion
• Kulinkovich: Esters to cyclopropanols – De Meijere: Amides to cyclopropylamines – Szymoniak: Nitriles to cyclopropylamines
• Enan0oselec0ve variants using TADDOL based ligands
21
X
R2
R1
X = OH, NR2, NH2
Esters
Amides
Nitriles
