1
Epoxide Bond Formation and Cleavage
Presented By
Gurudutt DubeyM. Tech. (Pharm.) I Semester
Department of Pharmaceutical Technology (Process Chemistry)National Institute of Pharmaceutical Education and Research, Mohali, Punjab (India)
2
Epoxide Bond Formation
3KATSUKI-SHARPLESS ASYMMETRIC EPOXIDATION
R'
R"R"'
OH
R"
R"'R'
OH
O
R"
R"'R'
OH
O
O
O
Ti(OPri)4
TBHP
(S,S)-(-)-Diethyl tartrate
(R.R)-(+)-Diethyl tartrate
J. Am. Chem. Soc. 1980, 102, 5914
4 OH
TBHP
M(OR)n 2ROH
O
(RO)n-2MO
OBut
O
(RO)n-2MO
OBut
O
(RO)n-2MO
OBut
O
(RO)n-2M
OOBut
O
(RO)n-2M
OBut
O
OH
TBHP
O
OH
tBuOH
1
2 3
45
a
bb
a
Mechanism:
M= Ti R= i-Pr
5
Clayden, J. Warren, S. Greeves, N. Wothers, P. Organic Chemistry, 2001, 1242
Formation of Active Complex
6
Clayden, J. Warren, S. Greeves, N. Wothers, P. Organic Chemistry, 2001, 1242
Stereoselectivity:
7
J. Am. Chem. Soc. 1962, 84, 867−868
COREY-CHAYKOVSKY REACTION
Mechanism :
8 Preparation of Corey-Chaykovsky Reagent
Dimethyloxosulfonium methylide - known as the Corey Chaykovsky Reagent
s I
B
- BH
HHH
s
H H
s
9
RR'
aq. NaOClMn-salen catalyst
CH2Cl2R
R'
OHH
R = Ar, alkenyl, alkyl< alkynylR' = Bulky Alkyl group
JACOBSEN-KATSUKI EPOXIDATION
O
N
O
NM
HH
X
Salen complex:
(1R, 2R)(t-Bu)2SalenMX
J. Am. Chem. Soc. 1991, 113, 7063-7064
10 PRILEZHAEV REACTIONR
R'R
R'
OHH
R"CO3H
Org. Lett. 2003, 5, 3787-3790
Mechanism :
11
Epoxide Bond cleavage
12
Clayden, J. Warren, S. Greeves, N. Wothers, P. Organic Chemistry, 2001, 434
Epoxide ring opening by azide
13
O
RNaN3
[bmim]PF6/H2O(2:1)
65 oC RN3 R
OHOH N3
ONaN3
[bmim]PF6/H2O(2:1)
65 oCn n
OH
N3
n= 1, 2, 4 n= 1, 2, 4
N N PF6n
n= 1= [bmim]PF6 n = 3 = [hmim]PF6 n= 5 = [octim]PF6
Ionic liquids/H2O systems for the reaction of epoxides with NaN3 :a new protocol for the synthesis of 2-azidoalcohols
Tetrahedron Lett. 2005, 46, 6559-6562
14Regioselective Ring Opening of Epoxides Using NaN3
MeO
COOEt
MeO
COOEt
OH
OHMeO
COOEt
OH
OTs
(DHQD)2PHAL, OsO4
t-BuOH/H2O(1:1)0oC, 16h
94%
TsCl, Et3N
CH2Cl2, 5oC, 72h
95%
95% MeO
COOEt
MeO
COOEt
N3
OH
NaN3, 4 oA molecular sieves
CH3CN, rt, 1.6h
95%
(i) PhCOCl, pyridine, CH2Cl2
(ii) PPh3, THF/H2O, 50oC(iii) NaBH4, MeOH, 0oC
67%
O
K2CO3
MeOH, rt, 12h
MeO
HN
O
O
OH
CytoxazoneTetrahedron Lett. 2004, 45, 7355–7358
15Polyepoxide-Opening Cascades Promoted by
Water
Science. 2007, 317, 1189
O
O
O
OHOH
MeHH
HOH
O
O
H
H H H
H2O
70 oC, 24 h
3:1 dr
57%O
H
H
MeO
O
OO
OO
O
O
O
O
O O
O
Me
CHO
H Me H H Me Me HH
H
Me
MeH H H
H H H H
H
H
H
HO
Brevetoxin B
16
O
O
O
O
OMe
H H
HH
HH
O
Me H H
H
OHH O
H
H2O
HO
H
O
H H
O
O
O
O
OMe
H H
HH
HH
O
Me H H
H
OHH O
H
H2O
HO
H
O
H H
OMe
O
H
HOH
OMe
HO
H
OH
OHOH
OH
H
H
Me
H
H2O
H2O
H2O
H2O
-H2O
-H2O
-H2O
-H2O
THF
THF
THF
THF
THF
THF
Minor Major
Mechanism:
17
O
R1
R2
OHR1
R2 NHAr(R)
H2NAr(R)Zn(ClO4)2.6H2O (2 mol%)
neat, rt or 80 oC10 min to 1h
88-100%
Epoxide Ring Opening Catalyzed by Zinc(II) Perchlorate Hexahydrate
O
R2
R1
R4
R3
O
R2
R1
R4
R3
O
R2R1
R4
R3
HO
R2
R1 R4
R3
M(ClO4)x
M(ClO4)x
NH2Ar(R)
NHAr(R)
M(ClO4)x
NH2Ar(R)
O
R2
R1 R4
R3
M(ClO4)xH
NHAr(R)
I
IIIII
Mechanism:
J. Org. Chem. 2007, 72, 10, 3719
18Synthesis of (RS)/(R)-Propranolols and (RS)/(R)/(S)-
Naftopidils
OH O
O
O
O
N
N
NH
OH
H
OH
OCH3
Zn(ClO4)2.6H2O (2 mol%)
Zn(ClO4)2.6H2O (2 mol%)neat, 80 oC, 10 min, 85%
iPrNH2, neat, rt, 1h, 72%MeCN, ref lux, 16 h80%
O
Cl
1-(2-methoxyphenyl)piperazine (RS)-Propranolol
(RS)-Naftopidil
HK2CO3
HN
N
OCH3
1-(2-methoxyphenyl)piperazine
J. Org. Chem. 2007, 72, 10, 3719
19Asymmetric Catalysis with CO2: Direct Synthesis of
Optically ActivePropylene Carbonate from Racemic Epoxides
J. Am. Chem. Soc. 2004, 126, 3733
OMe
H
CO2
O
N
O
NCo
HH
OCOCH3
n-Bu4NBr
OO
O
HOMe
H
HMe
OO
O
HMe
OMe
H
OMe
H
(major)
(minor)
O
N
O
NM
HH
X
Salen complex:
(1R, 2R)(t-Bu)2SalenMX
20Mechanism:
21
Thank You