1
Highly Enantio- and Diastereoselective One-Pot Synthesis ofAcyclic Epoxy Alcohols and Allylic Epoxy Alcohols
Ann Rowley Kelly, Alice E. Lurain, and Patrick J. Walsh*University of Pennsylvania, Philadelphia, PA
Adam Hoye, Oct. 15, 2005
R4
R2
OH
R1
R3
OR4
R2
OH R3
OR1
R6
R5
J. Am. Chem. Soc., ASAP (ja051291k)
Adam Hoye @ Wipf Group 1 10/15/2005
2Sharpless Asymmetric Epoxidation
Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S.; Walker, F. J.; Woodard, S.S.Pure Appl. Chem. 1983, 55, 589
Kinetic Resolution:
R2 R1
R3
D-(-)-tartrate (unnatural)
L-(+)-tartrate (natural)
"O"
"O"
t-BuOOH, Ti(Oi-Pr)4
CH2Cl2, -20oC
R2 R1
R3OH
O*
*70-87% yields,! 90% ee
OH
R2 R1
R3
D-(-)-tartrate (unnatural)
L-(+)-tartrate (natural)
"O"
"O"
t-BuOOH, Ti(Oi-Pr)4
CH2Cl2, -20oC
R2 R1
R3OH
O*
*
fast reactingstereoisomer
R4 R5
R2 R1
R3OH
R5 R4
Slow reactingstereoisomer
high ee
OHR4
R5
Adam Hoye @ Wipf Group 2 10/15/2005
3Epoxy Alcohols in Natural Product Synthesis
Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149Wender, P. A;, Hedge, S. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 4956Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A. J. Am. Chem. Soc., 2002, 124, 13654
Gabarda, A. E.; Du, W.; Isarno, T.; Tangirala, R. S.; Curran, D. P. Tetrahedron 2002, 58, 6329
NTMS OMe
OMOM
CH2OH
O
NTMS OMe
OMOM
CH2OH
(+)-DET, TBHP
Ti(O-iPr)4
HNTMS O
O
OHO
N
NO
O
OOH
Et
Homocamptothecin
1. LAH2. DMP
3. NaClO2
NTMS OMe
OMOM
CO2HHO
3 steps
OH
O
O O
O
H
H
H
OH
(+)-DIPT, Ti(Oi-Pr)4,
TBHP, CH2Cl2, -27 0COH
O
O O
O
H
H
H
OHO
fastslow
Laulimalide
Adam Hoye @ Wipf Group 3 10/15/2005
4Potential Limitations of Sharpless Methodology
• If epoxy alcohol is the desired product, kineticresolution must be quenched at low conversion to ensurehigh ee (i.e. quenching early to inhibit ‘mismatched’enantiomer from reacting)• Alternatively, the resolved allylic alcohol is oftenisolated and epoxidized in an additional step• Inherent to the KR of a racemic substrate, the maximumyield is 50%
Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237
OH
OH
racemicmixture
(L)-(+)-DIPT
Ti(Oi-Pr)4, t-BuOOH
+
FAST
SLOW
H OHH
H
O
OHH
(S)
(R)
+
45% yield, 99% ee
<50% yield, 97:3 d.r.
Adam Hoye @ Wipf Group 4 10/15/2005
5Previous Work in the Walsh Group
PhCHO
Et2Zn, -23 0C, hexane
HO
R
R
SO2HNNHO2S
OH
R
R
+ Ti(Oi-Pr)4
Ph Et
HO H
98-99% yield, 63-99% ee
Guo, C.; Qui, J. Zhang, X.; Verdugo, D.; Larter, M. L.; Christie, R.; Kenney, P.; Walsh, P. J. Tetrahedron 1997, 53, 4145
Adam Hoye @ Wipf Group 5 10/15/2005
6Walsh Cyclopropanation Strategy
Kim, H. Y.; Lurain, A. E.; García-García, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138
Via Method A:
Via Method B:
R3 R4
R2
O
Hi. Zn(R1)2
(-)-MIB
R4
R3
R2
OZnR1
R1
ii. 2 CF3CH2ZnCH2I
iii. H2OR4
R3
R2
OH
R1
H
R4
i. HBEt2
ii. ZnEt2, (-)-MIB
OH
N
O
R4ZnEt
iii. R1CHO
iv. 5 EtZnCH2Iv. H2O
R4
H
H
OH
R1
75-91% yield, 89-99% ee(>20:1 dr)
71-84% yield, 87-99% ee(>20:1 dr)
(A)
(B)
Adam Hoye @ Wipf Group 6 10/15/2005
7Walsh Epoxidation Strategy
R2 R3
R1
O
H (-)-MIBOH
N
O
(A)+ ZnR2
4 mol%R2 R3
R1
OZnEt
R
i.
ii. O2 (1 atm)
iii. Ti(Oi-Pr)4(20 mol%) R3R2
R1
OH
RO
3 equiv.
R2 R3
R1
O
H(B) + ZnMe2 Ti(Ot-Bu)4
3 equiv.
+ NHSO2CF3
NHSO2CF3i.
ii. O2 (1 atm)
(4 mol%)
R3R2
R1
OH
MeO
(C)
Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 13608
Adam Hoye @ Wipf Group 7 10/15/2005
8Current Paper
Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP
ZnEt2 O2+Et
OOZnEt
ZnEt2 +t-Bu
OOZnEt
t-BuOOH
Adam Hoye @ Wipf Group 8 10/15/2005
9Epoxidation Results
Adam Hoye @ Wipf Group 9 10/15/2005
10Diastereoselectivity of Epoxidation
R4
R2
OH
R1
R3
Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP
Adam Hoye @ Wipf Group 10 10/15/2005
11Determination of Predominant Steric Interaction in Epoxidation
Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP
Adam Hoye @ Wipf Group 11 10/15/2005
12Allylic Epoxy Alcohol Synthesis - in Situ Vinylzinc Reagents
Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAPOppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 10677
Adam Hoye @ Wipf Group 12 10/15/2005
13Allylic Epoxy Alcohol Synthesis - Isolated Divinylzinc Reagents
Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP
Adam Hoye @ Wipf Group 13 10/15/2005
14Conclusion
• Convenient one-pot method for the synthesis of epoxyalcohols and allylic epoxy alcohols, involving an initialasymmetric C-C bond formation followed bydiastereoselective epoxidation in high yields andstereoselectivities.
• Circumvents the need to prepare and isolate allylic orbis(allylic) alcohol intermediates, and offers a choice ofboth stoichiometric oxidant and ligand environment tobe used.
Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP
Adam Hoye @ Wipf Group 14 10/15/2005