epoxidation & opening.pdf
DESCRIPTION
different reagents used for epoxidation and opening of epoxide ringTRANSCRIPT
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1
Epoxidations of Alkenes: The Reagents
vElectrophilic reagent - electron rich double bonds react faster.
vNucleophilic reagent conjugate carbonyl derivatives
A. m-Chloroperoxybenzoic acid (MCPBA)
R1
R2
R3
R4
R1
R2
R3
R4O
[O]
O
O
Cl
O
H
Electrophilic reagent
O O
Cl
O H
O O
Cl
O HO H
In the case of an allylic alcohol, an additional hydrogen bond is present (directing effect):
Mechanism:
Nucleophilic substrate
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2
Epoxidations of Alkenes: The Reagents
B. Dioxirane
Adam Acc. Chem. Res. 1989, 22, 205-211.
Murray Chem. Rev. 1989, 89, 1187-1201.
Adam Eur. J. Org. Chem. 1998, 349-354.
Adam J. Org. Chem. 1996, 61, 3506-3510.
vCan be isolated as a solution in the corresponding ketone or produced in-situ
vCould be directed by hydrogen bonding with allylic alcohols, but more sensitive to steric hindrance than other reagents.
Potentially explosive!
Always be careful when exposing acetone to strong oxidant
H3C CX3
OO
Dimethyldioxirane (DMDO) or trifluoromethylmethyldioxirane (TFDO)
H3C CX3
O Oxone
R1
R2
R3
R4 R1
R2
R3
R4O
H3C CX3
OX = H or F
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3
Epoxidations of Alkenes: The Reagents
C. Metal-Catalyzed Epoxidations: Peroxide-Based Catalysts
t-BuOOH
VO(acac)2orTi(i-PrO)4
+
O
O
M
R
O
O
M
R
M-ORO
O
O
M
R
MOO
R
R = H, alkyl, etc.
+
+
Capable of being directed by hydroxy groups.
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4
Epoxidations of Alkenes: The Reagents
C. Metal-Catalyzed Epoxidations: Oxo- Based Catalysts
Efficient for the epoxidation of unfunctionalized olefins
Model on Cytochrome P-450.
NN
N N
R
R
RR M O
M
N N
O
R R
M = Fe, Mn, Ru, Cr
Y
M
Y
M[O]
O
O
[O] = NaOCl, Oxone, H2O2, ROOH, RC(O)OOH....
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5
Epoxidations of Alkenes: The Reagents
D. Nucleophilic Epoxidations
Chemoselectivity is inverse to the one of electrophilic reagents.
O
HOO
ROO
or O
OHO
OO
Me
O
AcO
Me H
Me
H H
H2O2
NaOH
Me
O
AcO
Me H
Me
H H
O
-
HO
m-CPBA
HO
O
O
H
H
O
DCM
75%
m-CPBA
DCM
O
H
H
O
O
71%
6
Epoxidations of Alkenes: Chemoselectivity
m-CPBA favoured reactions with the most electron donating double bond.
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7
Epoxidations of Alkenes: Chemoselectivity
No H-bond directing effect with DMDO.
OH
OAc
OH
VO(acac)2t-BuOOH
1.00 1.00
0.55 (92:8) >200 (98:2)
0.046 (37:63) ---
0.42 (60:40) 10.0 (98:2)
m-CPBA
O
HO
H
m-CPBA
DCM
O
HO
H
73%
O
OH
VO(acac)2TBHP, 80 C
OHO
DMDOAcetone, MeOH
OHO
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8
Epoxidations of Alkenes: Diastereoselectivity
OH OH
O
OAc
MCPBA MCPBA
OAc
O
10 : 1
but...
4 : 1
R
R
R
OH
R
R
R
O
HO
OH
O
Ar
R
R
R
OHO
HO HO
O
n n
n VO(acac)2
0 99.2
% syn
84
1 99.7 95
2 99.6 61
3 97 0.2
4 91 0.2
MCPBA
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9
Epoxidations of Alkenes: Diastereoselectivity
OH
Me
OH
Me
O
>20 : 1
Me
HO
OH
Me
HO
OHO
1 isomer
Me
OH
Me
OHO
1 isomer
MCPBA
HN
HO
HO
Me
O
HN
HO
HO
Me
O
O
1 isomer
MCPBA
MCPBAMCPBA
Carboxamides are better H-bonding directing groups
PGO
PGO
PGO
PGO
O
PGO
PGO
O
Bz
Me
TBS
MCPBA
O'Brien Tetrahedron Lett. 1999, 40, 391-392.
+
A mixture of oxone/trifluoroacetone is sometimes better
PG Oxone/CF3COCH3
56:44 98:2
TES 39:61 98:2
75:25 94:6
80:20 81:19trans cis
trans:cis
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10
Epoxidations of Alkenes: Diastereoselectivity with Acycli Olefins
OH OH
O
OH
O
+
anti syn
Me
OHMe
Me5 1 : 5 1 : 19
Me
OH
Me
OH
Me
MCPBAEntry Substrate Vo(acac)2
1 4 : 1 1 : 1.5
2 19 : 1 1 : 1
Me
OH
Me
Me
OHMe
3 4 : 1 1 : 1.5
4 1 : 2.4 1 : 19Rtrans(H) R
Rgem
H OH
A(1,2) strainRtrans(H) R
Rgem
H OHO
Rtrans(H) R
H
Rcis OH
A(1,3) strainRtrans(H) R
H
Rcis OHO
VO(acac)2, t-BuOOH
OHH
R1
R2
R3
R4
~50
MCPBA
OH
R1H
R2
R3
R4
~120
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11
Epoxidations of Alkenes: Diastereoselectivity with Acyclic Olefins
Cl
MeO NH
OMeMe OMe
OMe
OTBS
Me
Me
OHMe Cl
MeO NH
OMeMe OMe
OMe
OTBS
Me
Me
OHMeO
Ti(Oi-Pr)4, TBHP
Diastereoselection: >20:1
Synthesis of maysine
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12
Epoxidation of Homoallylic Alcohols TBHP, VO(acac)2
Me
OH
Me
OHO
2 : 1
Me
OH
Me
OHO
4.6 : 1Me Me
Me
OH
Me
Me
Me
Me
OH
Me
Me
MeO
8 : 1
Me
OH
Me
Me
OH
MeO
8 : 1
Me Me
VL2OOt-BuOH
Me
H
H
Me
H
Me
Me
H
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13
Catalytic Asymmetric Sharpless Epoxidation
R1 OH
R2
R3
R1 OH
R2
R3O
Ti(OiPr)4 (0.05 eq)(+)-DET or DIPT (0.06 eq)
1.0 eq
t-BuOOH (2 eq)4A mol sieves-20 C, CH2Cl2 ee usually 80-94%
yield: 63 - 99%Z-substituent: lower ee's
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Synthesis. Ojima Ed. p. 103.
Katsuki, T.; Martin, V. S. Organic Reactions 1996, 48, 1-299
Ti
OO
TiO
O
RO
O
OR
O
RO
RO2C
CO2RCO2R
O
t-Bu
O
R1
R3
R2
Proposed transition state model:
OH
R1R2
R3
(-)-(S,S)-D-tartrate
OH
R1R2
R3
(+)-(R,R)-L-tartrate
Mnemonic model:
OH
R1R2
R3R
H
H
R
(-)-(S,S)-D-tartrate
(+)-(R,R)-L-tartrate
(-)-(S,S)-D-tartrate
(+)-(R,R)-L-tartrate
MATCHED PAIR
MISMATCHED PAIR
MISMATCHED PAIR
MATCHED PAIR
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14
Catalytic Asymmetric Sharpless Epoxidation: Substrate Scope
Pr OHO
C7H15 OHO
C8H17 OHO
Ar OHO
R
OHO
OHO
R
OHO
Me
Ph OH
O
OH
O
94% ee 96% ee 94% ee >98% ee
R = C7H15 86% ee
R = C8H17 >80% ee
R = PhCH2OCH2 85% ee
R = C3H7 95% ee
R = C14H29 96% ee
>98% ee 93% ee95% ee
OHO
OHO
Me
OHO
Ph
Me
Ph
OHO
90% ee
91% ee
94% ee
95% ee
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15
Catalytic Asymmetric Sharpless Epoxidation: Kinetic Resolution
Me
OH
Me
OH
Me
OH
O
Me
OH
O
Me
OH
O
Me
OH
O
(+)-DIPT
+
(+)-DIPT
+
98 2
62 38
fast
slow
Me
OH
Bu
OH
Me
OH
n-C6H13
OH
>98% ee
54% conversion>98% ee
53% conversion
>98% ee
63% conversion>98% ee
66% conversion
>98% ee, 53% conversionO
Men-C5H11
OH
Ti(Oi-Pr)4, (+)-DIPT
TBHP (0.6 equiv), -21 C OMe
n-C5H11
OH O
O
HOMe
n-C5H11H
+
OMe
n-C5H11
OH
O
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16
Synthesis of (+)-Trehazolin
ClO
O
NHO
HO
HO
NH
OH
O
OHHO
OHHO
H
O CCl3
NH
OH
NH2HO
HO
HO
OH
H2NO
OHHO
OHHO
H
OH
OOH
O
OHOH
N
O
HO
CCl3
Ledford, B. E.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 11811-11812.
+
1. NaH, CpLi, THF, 60%2. NaH, Cl3CCN, THF, 95% I(sym-collidine)2ClO4
NaHCO3, aq. CH3CN
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17
Synthesis of (+)-Trehazolin
1. TIPSOTf2,6-lutidine2. Li2NiBr4, THF80%
NH
TIPSO
CCl3
Br
O
OO
NH
TIPSO
CCl3
Br
O
O
1. BF3OEt22. Bu3SnH,Et3B, NaBH4
TIPSO
HO
ON
CH2Cl
1. PPTS, CH3CN aq.2. Ac2O, DMAP, 77%
TIPSO
AcO
OAcNH
CH2ClO
1. Chx2BH2. H2O2
TIPSO
AcO
OAcNH
CH2ClO
3. Swern4. PhMgBrLiBr, THF5. Swern
1. h
2. OsO4, NMO
TIPSO
AcO
OAcNH
CH2ClO
OHOH
Ph
O
N
O
HO
CCl3
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18
Synthesis of (+)-Trehazolin
SCN
O
OBnBnO
OHBnO
OOH
O
OHOH
1. BnCl
2. Bu4NNCS, BF3OEt2
TIPSO
AcO
OAcNH
CCl3O
OHOH
1. 4N HCl
SCNO
OBnBnO
OHBnO
2.
OH
HO
HO
HO
OHHN
S
NH
O
OBn
OBn
OH
OBn
1. HgO, Et2O/Me2CO2. PdOH/C, H2 (1 atm), MeOH, 40%
DMAP, MeOH
OH
HO
HO
HO
OHHN
O
NH
O
OH
OH
OH
OH
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19
Epoxy Alcohols: Synthetic Applications
OH
O
NUC
O
NUC
HO OHOH
OHNUCa,b
c
d
OH
NUCHO
a
bd
c
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20
Epoxy Alcohols: Synthetic Applications
Reactions of Type a:
OH
O
Mitsunobu
ROH
OR
O
MsCl or TsCl or Tf2O
OMs (OTs, OTf)
O
RLi or R2CuLi R
OO
HO
H
O
TBDPSO
Me
OH
Me
O
O
Ot-Bu
OLi
OHO
TBDPSO
Me
Me
O
O
CO2t-Bu
Disparlure100% ee
(55% yield after recrystallization of dinitrobenzoate)
1. TsCl2. (n-C9H19)2CuLi, ether
1. TsCl, pyr2. NaI3.
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21
Epoxy Alcohols: Synthetic Applications
Me OH
Me MeO
1. MsCl, Et3N2. NaBr3. (i-PrO)2Si(Me)CH2MgCl4. H2O2
Me
Me MeO
OH
R OTsO
RMe
OH
DIBAL-H
CH2Cl2, 0 C
98%
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22
Epoxy Alcohols: Synthetic Applications
I
MeO Zn, AcOH
Me
OH
Chem. Comm. 1990, 843.
O
O
OH
O
OPMB
Cp2TiClO
OOPMB
OH
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23
Epoxy Alcohols: Synthetic Applications
BnOOH
OH
1. t-BuCOCl, Et3N2. TBDPSCl, imidazole
3. DIBAL4. (-)-DET, TBHP
BnOOH
OTBDPSO
1. Swern2. Ph3P=CHCO2Me
BnO
OTBDPSO
COOMe
1. DIBAL2. t-BuCOCl, pyr
3. TBDMSCl, imidazole4. DIBAL
BnO
TBDPSO
OH
OTBDMS
1. Sharpless
2. Red-Al
3. F-
BnO
OH
OH
OH OH
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24
Epoxy Alcohols: Synthetic Applications
R OMe
OH O
R OMe
OO
R OMe
OH O
SmI2
R OH
OHDIBAL-H
Pd(0)HCO2H
R OMe
OO
Pd(0), CO2OMe
OR
O
O
O
Pd(0), PhNCOOMe
OR
O
NPh
O
R OH
MeO LiCuMe2
R OH
Me
OHMe
68% (+13% of diastereomer)
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25
Epoxy Alcohols: Synthetic Applications
R OH
MeO LiCuMe2
R OH
Me
OHMe
68% (+13% of diastereomer)
R R'O
Oor
NaBH4-(PhSe)2
R R'
OOH
SmI2
R OHO
O
1. i-BuOCOCl
2. CH2N23. h, EtOH
R CO2Et
OH
OH
O
Me
BnO
LiCuMe2
OH
OH
MeMe
BnO
Kishi, Tetrahedron 1981, 3873.
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26
Epoxy Alcohols: Synthetic Applications
O
O
Me
H
O OH
OH
O
O
Me
H
O OH
OH
OH
OH
O O
OH
OH
O O
endo-brevicomin
exo-brevicomin
Synthesis 1988, 854.
TsO
OPG
OPG
OTsO
TsO
OPG
OPG
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27
Epoxy Alcohols: Payne and Pummerer Rearrangement
R OH
O
R
OPG
OPG
SPh
R
OH
O
R
OPG
OPG
H
O
R
OH
OH
Nuc
Nuc
1. PhS
2. Me2C(OMe)2, H+
1. MCPBA2. Ac2O
3. DIBAL
With K2CO3, MeOH: epimerization
Nucleophiles:
OH-, BH4-, TsNH-, CN-, N3
-, R2NH
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28
Chemoselective Ring-Opening
R OPG
O
R OPG
Nuc
OH
R OPG
OH
Nuc
Nuc
+
R OH
O
R
O
O
O
R OH
O
R O
O
OR2HN
R
Nuc
OH
O
O
R OH
NEt2
OH
NaH
R
HN
O
OH
O
R OH
OH
NEt2
Nuc Nuc = H, N3, PhS, Me
Nuc
+
Et2NH, reflux: 3.7 : 1
Et2NH, Ti(OiPr)4, reflux: < 1 : 10
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29
Chemoselective Ring-Opening
R OH
OH
R OH
OR OH
OH
Red-Al
THF
90%
DIBAL-H
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30
Chemoselective Ring-Opening
X
HO O
X
OHHO
H
X
OHHO
5,6-endo-tetare disfavored
X
O
X
OH
HX
OH
Vinyl-directing group:
OHO
O
BnOOH
Ph
O
OO
O
BnO
OH
OH
Ph
Applications: Brevetoxin's synthesis
Nicolaou J. Am. Chem. Soc. 1995, 117, 10227.
O
OHBnO
BnO
H Me
CO2Et
MeO
PPTS, CH2Cl2
97%
O
OBnO
BnO
H Me
CO2Et
Me
H H
OH
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31
Oxidation of Sulfides, Selenides and Amines
MeS
C6H4MeMe
SC6H4Me
O
93% ee (90%)
PhN
OH
Ti(OiPr)4, DET
Ti(OiPr)4, (+)-DIPT
PhN
OH
PhN
OH
O
+
CHP
CHP
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32
Catalytic Epoxidation of Alkenes: Mn-Salen
References:
Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Vol. 12, Chapter 11.1.Jacobsen, E. N. In Catalytic Asymmetric Synthesis, Ojima Ed. 1993, Chap. 4.2Recent mechanistic paper: J. Am. Chem. Soc. 1998, 120, 948.
N N
O O
Mn
Cl
H H
t-Bu
t-Bu t-Bu
t-Bu
Catalyst:
H
R2R1
H
NaOCl
H
R2R1
HO H
HR1
R2O
Reaction:
+
Catalyst (0.5-10 mol%)
+
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33
Epoxidation of Unfunctionalized Olefins: The Jacobsen Catalyst - Ligand Design
Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L.!J. Am. Chem. Soc. 1991, 113, 7063-7064.
84% ee
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34
Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes
Proposed transition structures for the epoxidation of cis--mehtylstyrene.(A) epoxidation with catalyst 13 and (B-D) epoxidation with catalyst 14. [Structures created with the program Chem 3D based on the coordinates frm the X-ray crystal structure of 13 (PF6 salt).-
A B (favored)
C (disfavored) D (disfavored)
Jacobsen, E. N.; Wei, Z.; Loebach, J. L.; Wilson, S. R. J. Am. Chem. Soc. 1990, 112, 2801-2803.
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35
Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Substrate Scope
Higher ee if:!-R is bulky!-Allylic oxygen
NaOCl
+
NR O
N N
O O
Mn
Cl
H H
t-Bu
t-Bu t-Bu
t-Bu
(4 mol%)
R
NaOCl(S,S)-catalyst
NaOCl(R,R)-catalyst
R
O
R
O
Ar RO
X
Ph
Ph CO2i-Pr
O
OR2
R1
90-98% ee>95% ee
93% ee
n
87-94% ee
96% ee
94% ee90-98% ee(trans epoxide)
86% ee
R
R
Ph88-95% ee
Ar80-86% ee
RAr
-
36
Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Substrate Scope
N N
O O
Mn
Cl
H H
t-Bu
t-Bu t-Bu
t-Bu
(4 mol%)
R1 R2+ NaOCl
N
Ph
N
OMe
OH
Cl
25 mol%
/ PhCl
R1R2
O
PhPh
OAr
CO2i-Pr
Ot-Bu
Et
O
27 : 1, trans:cis90% ee
8 : 1, trans:cis86% ee
2 : 1, trans:cis84% ee
Chang, S. B.; Galvin, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 6937-6938.
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37
Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Synthetic Applications
Jacobsen, E. N.; wLarrow, J. F.; Jacobsen, E. N. Org. Synth., 1998, 75, 1-11.!Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; Mcdaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I. W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Nat.l Acad. Sci. USA 1994, 91, 4096-4100.
Bell, D.; Davies, M. R.; Finney, F. J. L.; Geen, G. R.; Kincey, P. M.; Mann, I. S. Tetrahedron Letters 1996, 37, 3895-3898. !!Buckle, D. R.; Eggleston, D. S.; Pinto, I. L.; Smith, D. G.; Tedder, J. M. Bioorg. Med. Chem. Lett. 1992, 2, 1161-1164.
O
OC2F5
94% ee, 75% y.O
OHC2F5
N O
BRL 55834
O
OH
NH2
CH3CNH2SO4 / SO3
Hexanes
~85% ee>99% ee after
recrystallisation
OHHN
O
OHPh
N
N
N
NHt-BuO
Indinavir
-
38
Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Synthetic Applications
Ph
NO
OMe
O
89% ee, 58% y.
Ph
N
OMe
O
CDP840
NBoc
OBn
O
93% ee70% y.
HN
N
MeO2C
O
O NH
OMe
OMe
OMe
Duocarmycin SA
Boger, D. L.; McKie, J. A.; Boyce, C. W. Synlett 1997, 515.
Lynch, J. E.; Choi, W. B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G.!J. Org. Chem. 1997, 62, 9223-9228.
-
39
Catalytic Asymmetric Epoxide Ring-Opening Chemistry
Desymmetrization
Kinetic Resolution
Nielsen, L. P. C.; Jacobsen, E. N. in Aziridines and Epoxides in Organic Synthesis, Yudin Ed, 2006, Chap. 7, p. 229.
R
R
ONuH
Chiral catalystR
R
OH
Nu
R
O
R
O+
NuH
Chiral catalyst R
O
R
OH
+ Nu
-
40
Desymmetrization of meso-Epoxides: Nitrogen-Centered Nucleophiles
Seminal work: Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768-2769.!Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897-5898.!Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924-10925.!Thiol as nucleophile: Wu, M. H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 5252-5254.
X O
N N
O O
Cr
H H
t-Bu
t-Bu t-Bu
t-BuCl
2 mol%
1. TMSN3 (1.05 equiv) / ether, rt 18-36h2. CSA / MeOH
X
OH
N3
N3
OH
N3
OH
80% y., 88% ee 85% y., 92% ee(-10 C)
FmocN
OH
N380% y., 95% ee
O
OH
N380% y., 98% ee
OH
N380% y., 94% ee
O
OH
N380% y., 94% ee
-
41
Desymmetrization of meso-Epoxides: Oxygen-Centered Nucleophiles
Wu, M. H.; Hansen, K. B.; Jacobsen, E. N.!Angew. Chem. Int. Ed. 1999, 38, 2012-2014.
N N
O O
Co
H H
t-Bu
t-Bu t-Bu
t-BuOAc
1-2 mol%
O
OH HOO
96% y. 98% ee
O
HOO
86% y. 95% eeOH
OH
HO
O 45% y. 99% ee
OH
OH O
HO
OH
O
HO OHHO
OH
O81% 96% ee
OMe
Me
TsOH60% (2 steps)
O
O
O
-
42
Desymmetrization of meso-Epoxides: Oxygen-Centered Nucleophiles
N N
O O
Co
H H
t-Bu
t-Bu t-Bu
t-BuOAc
1-2 mol%
Meng, Z. Y.; Danishefsky, S. J.!Angew. Chem., Int. Edit. 2005, 44, 1511-1513.!Yun, H. D.; Meng, Z. Y.; Danishefsky, S. J.!Heterocycles 2005, 66, 711-725.
O
O
OO
O
HO
Merrilactone A
CO2Me
CH2OH
CH2OH
DMDO / CH2Cl2
CO2Me
CH2OHCH2OH
O(R,R)-(salen)CoOAc
THF, -78 C, then -25 C
CO2Me
CH2OH
HO
O
86% y., 86% ee
O
CO2H
CO2Me
H
MeO2C
MeO
OTBS
MeO2C
O
O
OTBS
O
O
OO
Br
Merrilactone A
-
43
Hydrolytic Kinetic Reaction of Terminal Epoxides
N N
O O
Co
H H
t-Bu
t-Bu t-Bu
t-BuOAc
1-2 mol%
R
O
R
O+
Chiral catalyst(0.2-2.0 mol%)
R
O
R
OH
+ OHH2O
Aliphatic Epoxides
Repox
% yieldepox% ee
diol% yield
diol% ee
CH3(CH2)3CH3(CH2)11CH3(CH2)2CH=CH2CH2Ph
c-C6H11t-C4H9
46
43
42
43
46
44
41
>99
>99
>99
>99
>99
>99
>99
45
44
40
44
40
41
40
99
99
99
99
95
99
95
Halogenated Epoxides
Repox
% yieldepox% ee
diol% yield
diol% ee
CH2Cl
CH2Br (dynamic)
CH2F
CF3
43
41
42
42
>99
43
>99
>99
40
90
38
42
95
96
97
>99
Epoxides bearing ether and carbonyl functionality
Repox
% yieldepox% ee
diol% yield
diol% ee
CH2OBn
CH2OTBS
CH2OPh
CH2O(1-naphtyl)
CH2CH2OBn
oxiranyl
CH2OCOn-Pr
CH2CO2Et
CH2NHBoc
CO2CH3COCH3COCH2CH3
48
47
47
38
42
36
46
44
36
43
40
41
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
40
42
41
42
42
36
45
41
36
37
40
33
95
98
95
97
95
96
43
95
78
97
97
96
-
44
Hydrolytic Kinetic Reaction of Terminal Epoxides
N N
O O
Co
H H
t-Bu
t-Bu t-Bu
t-BuOAc
1-2 mol%
R
O
R
O+
Chiral catalyst(0.2-2.0 mol%)
R
O
R
OH
+ OHH2O
Jacobsen, E. N.; Tokunaga, M.; Larrow, J. F.; Kakiuchi, F. Science 1997, 277, 936-938.!!Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431.!!Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315.
Aryl, vinyl and alkynyl epoxides
Repox
% yieldepox% ee
diol% yield
diol% ee
Ph
4-ClC6H43-ClC6H43-MeOC6H43-NO2C6H42-ClC6H4CH=CH2CCTBS
44
38
40
41
38
38
36
41
>99
>99
>99
>99
>99
>99
>99
>99
42
37
44
41
44
42
38
41
98
94
91
95
99
94
97
99
-
45
Enantioselective Epoxidation with Dioxiranes
R
R
R
R
O
O
R1
R2
R1
R2O
O
HSO5-
HSO4-
[Oxone]1 equivCatalytic
Shi, Y., Acc. Chem. Res. 2004, 37, 488-496.
Wong, O. A.; Shi, Y., Chem. Rev. 2008, 108, 3958-3987.
O
O R
RO
O R
R
Spiro Transition StateFavored
Planar Transition StateUnfavored
180
O
O
L(S)
S(L)
180
O
O
L(S)
S(L)
180
-
46
Shis Enantioselective Catalytic Epoxidation: Catalytic Cycle
R1R3
R2
O
O
O
OO
O
O
R1R3
R2
O
O
O
O
OO
O
O
O
O
OO
OH
OO SO3
-
HSO5-
O
O
O
OO
O-
OO SO3
OH-
SO42-
O
O
O
OO
O
O
O
O
OO
O
O
O
+
B.V.
Competing pathwayEpoxidationCycle
O
OO
O
O
OO
R3
R1R2
Spiro (A)Favored
-
47
Shis Enantioselective Catalytic Epoxidation: Scope
Wang, Z. X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 1999, 64, 6443-6458.
O
O O
OCH2OAc
O
O
O
O
OO
O
PhR
C6H13C6H13
--
O
O O
OCMe2OH
O
85% (98%ee)
94% (96%ee)
49% (96%ee)
89% (95%ee)
--
-- 91% (96%ee)
-- 94% (80%ee)
-- 95% (84%ee)
51% (42%ee) --
-- 35% (89%ee)
--
--
--
PhPh
Ph
Ph
C8H17
O
O
--
--
--
90% (24%ee)
92% (17%ee)
43% (61%ee)
Ph R
O--
--
--
54% (97% ee)
R = Ph
R = Me
R = i-Pr
80% (94%ee) 85% (96%ee)
-- 75% (82%ee)
-- 70% (89%ee)
-- 95% (92%ee)
-- 79% (69%ee)
-- 85% (15%ee)
-- 93% (21%ee)
--
--
--
--
--
--
R = Ph
R = Me
R = CH2Cl
R = OEt
-
48
Shis Enantioselective Catalytic Epoxidation: Scope
Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675-7677.
O
O
O
OO
O
R2
SiMe3
R1
Oxone
H2O-Solvent
R2
SiMe3
R1
O
84-94% ee
TBAF
R2
R1
O
-
49
Shis Enantioselective Catalytic Epoxidation: Scope
Shi, Y.; and Coworkers, J. Org. Chem. 1998, 63, 2948.
O
O
O
OO
OR1
R2R1
R2
O
R1
R2
OOxone
H2O-Solvent+
PhPh
PhPh
O
CO2Et CO2EtO
OTBS OTBSO
OMe OMe
O
CO2Et CO2EtO
PhSiMe3
PhSiMe3
O
SiMe3
Ph
SiMe3
Ph
O
CO2EtO
PhPh
O O
OTBSO
PhSiMe3
O
Entry Dienes Epoxides
1 94 22:1 77 97
2 69 7:1 41 96
3 100 4.6:1 68 96
100 65 894
5 88 82 95
6
100 81 957
92 14:1 77 94
Conv(%)
Ratio Yield(%)
ee(%)
-
50
Shis Enantioselective Catalytic Epoxidation: Scope
Wang, Z. X.; Cao, G. A.; Shi, Y. J. Org. Chem. 1999, 64, 7646-7650.
O
O
O
OO
OR1R1
OOxone
H2O-Solvent
R2R2
Yield(%)
ee(%)
Entry Enynes
R
R = H
R = CH3R = SiMe3
R = CO2Et
78
88
86
71
93
90
94
93
SiMe3
84 95
Ph
SiMe3
64 94
1
2
3
4
6
5
Ph
SiMe359 96
Yield(%)
ee(%)
Entry Enynes
SiMe371 897
8
R
9
10
R = H
R = SiMe3
60 93
83 97
-
51
Chiral Alkynyloxiranes as Useful Synthons
R1
OR3
R2R1
OH
R2
R4
R3
SN2'
Ag+
O R3
R4R1
R2
Nu
R1
OH R3
R2 Nu
PdCl2SnCl2PR3, CO
(R3=H)
O
O
R1 R2Nu
Mo(CO)6R3=H
O
R1 R2Nu
Marshall, JOC 1993, 7180
McDonald JACS 1996, 6648Norton JACS 1981, 7520
R4Cu
-
52
Shis Epoxidation of Allylic Alcohols and Trisubstituted Olefins
Shi, Y.; and Coworkers J. Org. Chem. 1998, 63, 3099.
O
O
O
OO
OR1 OH
R2
R1 OH
R2
O
Oxone
H2O-Solvent
Ph OH
OH
PhOH
Ph OH
Ph
OH
OH
OH
OH
PhOH
Ph OH
PhOH
Yield(%)
ee(%)
Entry Olefins
1
2
3
4
5
685
43
68
87
93
8594
92
91
94
94
92
Yield(%)
ee(%)
Entry Olefins
7
8
9
10
11
75
82
90
83
87
74
90
91
91
91
-
Yield(%)
ee(%)
Yield(%)
ee(%)
Ph
OTBS
Ph
O
OH
OTBS O
OH
OR ORO
OBz
OBz
Ph
OAc
OOBz
OBzO
Ph
OAcO
Entry Substrate Product
1 80 90
2 70 83
Entry Substrate Product
92 88
66 91
n = 5 79 80
n = 7 87 91n = 8 82 95
3 R = Ac 59 74
4 R = Bz 82 93
nn
8
9
5
67
53
Epoxidation of Enol Ethers and Esters
Shi, Y.; and Cowokers Tetrahedron Lett., 1998, 39, 7819.
R1
OR
R2
R1
OR
R2
O
R1
O
R2
OSiR'3R1
O
R2
OH
Oxone
H2O-Solvent
orR = SiR'3
R = R'CO
O
O
O
OO
O
-
54
Epoxidation of Enol Ethers and Esters
Shi, Y.; and Coworkers J. Am. Chem. Soc. 1999, 121, 4080.
R1
OBz
R2
O
R1
O
R2
OBz
R1
O
R2
OBz
R
S
Yield(%)
Entry Epoxide Acid Epoxide ee (%)
OOBz
p-TsOH 93929291
89837385
1silica gel
2p-TsOH 97
9797
68
8779
AcO
CH3
PhO
OBzO
3
4
p-TsOH 94
94
72
71
p-TsOH 99999999
79458781
silica gel
(S)
(R)
(R)
(R)
Product ee (%)
90 (R)91 (S)88 (S)87 (S)
97 (R)
94 (R)
90 (R)
99 (R)38 (R)57 (R)93 (R)
YbCl3AlMe3
OBzO
silica gel 97 (S)96 (S)69 (S)
YbCl3AlMe3 97
AlMe3
YbCl3AlMe3
90
-
55
Epoxidation of Enol Ethers and Esters
Shi, Y.; and Coworkers J. Am. Chem. Soc. 1999, 121, 4080.
R1
R2
OOR
O
R1
R2
OLAOR
O[TsOH] R1
R2
O
OLA
R
O
R1
R2
O
O
R
O
AL
R1
R2
O
OCOR
R1
R2
O
OCOR
+LA+
+
pathway a
pathway b
-LA+
-LA+
retention
inversion
+
or when R1 = Ar
-
56
Epoxidation of Enol Ethers and Esters
Feng, X. M.; Shu, L. H.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 11002-11003.
O
OOBz
Racemic
OH
OH10 mol%
5 mol%
O
OOBz
O
OBz
O
99% ee 99%ee
51% conversion
+
10% TsOHCH2Cl2, 0 C
5 - 20 min
O
OBz
O
97%ee
77%
O
OOBz
[(R)-BINOL]2-Ti(OiPr)4
Not efficient for styrene oxidesand acyclic epoxides
Ti(OiPr)4
-
57
Synthesis of Polyepoxides
Vilotijevic, I.; Jamison, T.F. Science 2007, 317, 1189-1192
-
58
Synthesis of Polyepoxides
Vilotijevic, I.; Jamison, T.F. Science 2007, 317, 1189-1192
-
59
Synthesis of Polyepoxides
Vilotijevic, I.; Jamison, T.F. Science 2007, 317, 1189-1192
-
60
Synthesis of Polyepoxides
Vilotijevic, I.; Jamison, T.F. Science 2007, 317, 1189-1192
-
61
Dihydroxylation of Olefins: Introduction
H
R2H
R1 OsO4HO OH
HR1 R2
HCo-oxidantsyn addition of two OH groups
Co-oxidant: NMO or K3Fe(CN)6/K2CO3
L*
R
R
O
Os OR
R
O
O L
O
Os
O
OH
OH
HO
HO
2 K2CO34 H2O
HO
RR
OH
O
Os
O
OH
OH
O
O
2 K2CO32 H2O
OsO4
General mechanism:
OsO4L
Ligand (L)
ORGANIC LAYER
AQUEOUS LAYER2- 2-
3 K3Fe(CN)62 K2CO3
2 K4Fe(CN)62 KHCO3
-
62
Dihydroxylation of Olefins: Introduction
R
R
Os
O
O
O
O
Stepwise [2+2]
Mechanism
Os
O
OO
O
L
R
R
Os
O
L
O
O O
R
R
R
LigandR
Conc
erted
[3+2
]
Mech
anism
O
O
Os
L
O
O
-
63
Diastereoselective Dihydroxylation of Olefins
Generally, the reaction is under steric control
OH
OH
OH
OH
OsO4
NMO
OsO4
NMO
OH
OH
OH
OH
HO
HO
HO
HO
only product
>50 : 1
Me
OsO4
NMO
Me
OH
OH
>20 : 1
Exceptions:
Me
MeMe
OH
SNMe
PhO
OsO4
NMO Me
MeMe
OH
SNMe
PhO
OHOH
Me
OH
OH
OH
OH
OH
OH
Me
OH
Me
+
cat. OsO4, NMO : 91%, dr = 1 : 4
OsO4, TMEDA: 88%, dr = >25 : 1
-
64
Diastereoselective Dihydroxylation of Olefins
Me
OO
OsO4
OO
Me OsO4
Me
OO
OH
OH
Me
OO
OH
OH
Kishi Tetrahedron Lett. 1983, 24, 3943, 3947.
3.7 : 1
7.6 : 1
Me
OBn OsO4
OBn Me OsO4
Me
OBn
OH
OH
Me
OBn
OH
OH
7 : 1
9 : 1
BnO
BnO
BnO
BnO
CO2Et
OH
OsO4
OH CO2Et
OsO4
CO2Et
OH
OH
OH
Me
Me
MeNMO
NMO
Me
Me
Me
CO2Et
OH
OH
OH
Me
Me
OOEt
Me OHHO
OOEt
Me OHHO
only isomer
only isomer
-
65
Diastereoselective Dihydroxylation of Olefins
Evans, D. A. J. Org. Chem. 1990, 55, 1698-1700.
OBn
Me
O
Me
OSi
t-Bu t-Bu
OBn
Me
O
Me
OSi
t-Bu t-Bu
HO
HO
diastereoselection60:1
OBn
Me
O
Me
OC
H C6H4OMe
HO
HO
OBn
Me
O
Me
OSi
t-Bu t-Bu
OBn
Me
OH
Me
OH
OBn
Me
OAc
Me
OAc
Me
Me
OBn
Me
60 : 1 35 : 1
Me
Me
OBn
16 : 1
17 : 1 5.1 : 1
61 : 1
Level of diastereoselection varies with slight modifications:
-
66
Diastereoselective Dihydroxylation of Olefins
OX
H
C CR2 R2
HH
C CR2 R2
HC CR2 R2
H
R1 OX
R1
R1
H
XO
Vedejs Model Houk Model Kishi Model
Based on ground-state conformational effects and an implied stereoelectronic p-facial bias imposed by the allylic oxygen.
"inside alkoxy effect"Based on the steric hindranceof the osmium reagent
References:
Houk, K. N. Science 1986, 231, 1108.J. Am. Chem. Soc. 1986, 108, 2754.
Vedejs, E. J. Am. Chem. Soc. 1986, 108, 1094.J. Am. Chem. Soc. 1989, 111, 6861.
Kishi, Y. Tetrahedron Lett. 1983, 24, 3943.Tetrahedron 1984, 40, 2247.
-
67
Dihydroxylation with Chiral Catalysts/Ligands
O
Os
O
OH
OH
HO
HO
R
R
O
OsO
R
R
O
O L
O
Os
O
OH
OH
O
O
HO
RR
OH
2 K2CO34 H2O
2 K2CO32 H2O
OsO4
OsO4L
Ligand (L)
ORGANIC LAYER
AQUEOUS LAYER2- 2-
3 K3Fe(CN)62 K2CO3
2 K4Fe(CN)62 KHCO3
-
68
Ligand-accelerated Dihydroxylation: Basic Principle
O
Os OO
O L
Monodentate Ligands:
OsO4 L
Bidentate Ligands:
L
16 e- 18 e-
18 e-
OsO4
hydrolysis / reoxidation
LL Os
O
O
O
OL
L+ L*
16 e- 18 e- 16 e-
hydrolysis / reoxidation
L
OsO4
OK
OsO4
X
Three important points:
- Level of enantioselection (Ligand design).
- Catalytic turnovers (OsO4 is very expensive).
- OsO4 Ligand must be regenerated.
-
69
Sharplesss Dihydroxylation: Chiral Ligands
Reviews: Sharpless, K. B. et al. Chem. Rev. 1994, 94, 2483-2547.Sharpless, K. B. In Catalytic asymmetric synthesis, Ojima Ed. p. 227.
Dihydroquinidine derivatives
N
O
N
OMe
H
Et
O
ClN
O
N
OMe
H
Et
DHQD-PHNDHQD-CLB
N
O
N
OMe
H
Et
NN
O
N
N
MeO
H
Et
(DHQD)2-PHALLigand used in AD-mix-
N
O
N
OMe
H
Et
N
O
N
O
N
OMe
H
Et
O
N
N
MeO
H
Et
(DHQD)2-PYR
N N
Ph
Ph
DHQD-IND
-
70
Sharplesss Dihydroxylation: Chiral Ligands
Dihydroquinidine derivatives
N
O
N
OMe
H
Et
NN
O
N
N
MeO
H
Et
(DHQD)2-PHALLigand used in AD-mix-
N
O
N
OMe
H
Et
N
O
DHQD-IND
N
O
N
MeO
HN
O
N
O
N
OMe
H
NN
O
N
N
MeO
H
Et Et
DHQ-IND
Dihydroquinine derivatives
(DHQ)2-PHALLigand used in AD-mix-
Et
-
71
Sharplesss Dihydroxylation: Scope & Model
BuMe
Me PhBu
Bu
n-C5H11COOEt
Ph
Me
n-C8H17
(DHQD)2-PHAL98% ee
(DHQ)2-PHAL95% ee
(DHQD)2-PHAL99% ee
(DHQ)2-PHAL97% ee
(DHQD)2-PHAL97% ee
(DHQ)2-PHAL93% ee
(DHQD)2-PHAL99% ee
(DHQ)2-PHAL96% ee
Ph CO2i-PrMe Bu
n-C5H11
OMe
(DHQD)2-PHAL94% ee
(DHQ)2-PHAL93% ee
(DHQD)2-PHAL84% ee
(DHQ)2-PHAL80% ee
(DHQD)2-PHAL95% ee
(DHQ)2-PHAL96% ee
DHQD-IND80% ee
DHQ-IND72% ee
DHQD-IND56% ee
DHQ-IND44% ee
RM
H
RS
RL
DHQ ligands () - attack
DHQD ligands () - attack
-
72
Sharplesss Dihydroxylation: Scope
n-C5H11COOEt
PhCOOEt
PhPh
n-C5H11
Me
Ph
Me
Ph
n-C8H17COOBn
Ph MeBu
n-C5H11
OMe
DHQD-IND72% ee
(DHQD)2-PHAL99% ee
(DHQD)2-PHAL97% ee
(DHQD)2-PHAL>99.5% ee
(DHQD)2-PHAL78% ee
(DHQD)2-PHAL94% ee
(DHQD)2-PHAL97% ee
(DHQD)2-PHAL84% ee
(DHQD)2-PYR89% ee
(DHQD)2-PHAL77% ee
(DHQD)2-PHAL95% ee
Ph CO2i-PrMe
t-Bu
DHQD-IND80% ee
DHQD-IND56% ee
(DHQD)2-PHAL88% ee
(DHQD)2-PYR96% ee
(DHQD)2-PHAL64% ee
(DHQD)2-PYR92% ee
-
73
Sharplesss Dihydroxylation: Scope
PhPh
PhPh
OH
OH
OEt
O(DHQD)2-PHAL
OEt
O
(DHQD)2-PHAL
OH
OH
84% (>99% ee)
93% (95% ee)
Ph
DHQD-PHN
OH
OH
PhOH
OH
OH
OH
(DHQD)2-PHAL
+
13 : 156% (94% ee)
73% ee(DHQD)2-PHAL
53% ee
-
74
Sharplesss Dihydroxylation: Catalyst
Structure of the Bis OsO4 complex of (DHQD)2PHAL based on molecular mechanics calculations and NOE experiments.
-
75
Sharplesss Dihydroxylation: Catalyst
N
N
OR
OMe
9
Its presence has a smalleffect on the rates; however,it increases the binding
The nature of R has a very large effect on the rates, but only a small influence on the binding
Oxygenation is essential toallow binding to OsO4 - acarbon substituent is too bulky
The configuration is important: onlyerythro allows high rates and binding
Increases binding toOsO4 as well as rates
The presence of a flat, aromaticring system increases binding andrates; the nitrogen has no influence
attractivearea
-face
-face
SW
"HO OH"
SE
NENW
DihydroquinineDerivatives
DihydroquinineDerivatives
"HO OH"
Relationship between ligand structure and Keq and ceiling rate constants.The alkaloid core is ideally set up to ensure high rates, binding, and solubility.The rates are influenced considerably by the nature of the O9 substituent, while the binding to OsO4 is almost independent of that substituent.
Mechanistic Discussion:
Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038-11053.
Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319-329.
Corey, E. J.; Guzmanperez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805-10816.
Delmonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A.
J. Am. Chem. Soc. 1997, 119, 9907-9908.
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76
Sharplesss Dihydroxylation: Synthetic Applications
O
O
OH
OH
R1R2
OH
OH
R1 OR2
OH
OH
O
R1
COOR2
O
O
O
O
Reading: Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547.
Differentiation of the hydroxyl groups of a Diol: tosylation
Unselective tosylation leads to racemization!
Primary vs secondary: unsually not a problem
1. p-TsCl, pyr
2. NaOMe
85%
48-91%
1. TsCl, pyr2. K2CO3MeOH
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77
Sharplesss Dihydroxylation: Synthetic Applications
Differentiation of the hydroxyl groups of a Diol: Cyclic Sulfates
R1R2
OH
OH
1. SOCl2 R1 2. NaIO4, RuCl3
R2
O S
O
O
R1
R2
O SO2
O
When R1 = R2: C2 symmetric compound
OSO2
O
OOOO 1. LiN32. H2SO4, H2O
N3 OH
OOOO
R1
R2
O S
O
OAc
OO
5-endo tet
OR1
OH
R2
Me
O S
O
O
CO2Me
Me
OH
CO2Me
Me
SN2' (anti)
NaOEtEtOH
MeCuCNLi2BF3OEt2
R1 R2
OSO2
O
MeO2C CO2MeR1 R2
MeO2C CO2Me
Double displacement of cyclic sulfates:
NaH, DME
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78
Sharplesss Dihydroxylation: Synthetic Applications
Double displacement from 1,2-diols: halohydrin and epoxides formation
R1R2
OH
OHR1
R2
OH
BrR1
R2O
R1R2
Br
OH
R1R2
O
R1R2
OH
OH1. MeC(OMe)3, PPTS (cat.)2. CH3COBr or TMSX3. K2CO3, MeOH R1
R2O
Taxol side-chain: (JOC 94, 5014)
Ph OMe
O
OH
OH1. MeC(OMe)3, PPTS (cat.)2. CH3COBr or TMSX
3.NaN34. H2, Pd
Ph OMe
O
OH
NHAc
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79
Sharplesss Asymmetric Aminohydroxylation
R
R K2OsO2(OH)4 cat., XNCl-M+
(DHQD)2-PHAL or (DHQ)2-PHAL
R
HO
R
NHX
(DHQ)2-PHAL66% y. 81% ee
Chloramine TTsNClNa (3.5 equiv.)
Chloramine MMsNClNa (3 equiv.)
PhCO2Me
NHTs
OH
(DHQ)2-PHAL65% y. 95% ee
PhCO2Me
NHMs
OH
(DHQ)2-PHAL52% y. 74% ee
MeCO2Et
NHTs
OH
(DHQ)2-PHAL63% y. 80% ee
MeCO2t-Bu
NHMs
OH
(DHQ)2-PHAL52% y. 62% ee
PhPh
NHTs
OH
(DHQ)2-PHAL71% y. 75% ee
PhPh
NHMs
OH
Higher yields and enantioselectivities with sterically less demanding nitrogen nucleophiles
Drawback: Removing the sulfonyl group.
Products are solid, ee can be increased by recrystallisation
-
80
Sharplesss Asymmetric Aminohydroxylation
R
R K2OsO2(OH)4 cat., XNCl-M+
(DHQD)2-PHAL or (DHQ)2-PHAL
R
HO
R
NHX
(DHQ)2-PHAL65% y. 94% ee
CbzNClNa(3 equiv)
TeoCNClNa(3 equiv.)
PhCO2Me
NHCBz
OH
(DHQ)2-PHAL70% y. 99% ee
PhCO2i-Pr
NHTeoC
OH(DHQ)2-PHAL52% y. 74% ee
MeCO2t-Bu
NHCBz
OH
(DHQ)2-PHAL89% y. 84% ee(DHQD)2-PHAL89% y. 87% ee
BzCHNCO2Me
OH
BOCNClNa(3 equiv.)
(DHQ)2-PHAL60% y. 97% ee
3:1 regioselectivity
OH
NHBOC
TMSO
O
NClNa
MeO
MeO
(DHQ)2-PHAL65% y. 99% ee
3:1 regioselectivity
OH
NHBOC
MeO
BnO
(DHQD)2-PHAL68% y. 94% ee
3:1 regioselectivity
OH
NHCBz
MeO
MeO
(DHQ)2-PHAL70% y. 99% ee
3.5:1 regioselectivity
OH
NHBOC
MeO
BnO
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81
Sharplesss Asymmetric Aminohydroxylation
R
R K2OsO2(OH)4 cat., RCONBrLi (1 equiv)
(DHQD)2-PHAL or (DHQ)2-PHAL
R
HO
R
NHAc
(DHQ)2-PHAL81% y. 99% ee
PhCO2i-Pr
NHAc
OH(DHQ)2-PHAL75% y. 95% ee
PhCO2i-Pr
NHC(O)CH2Cl
OH
(DHQ)2-PHAL50% y. 94% ee
PhPh
NHAc
OH
(DHQD)2-PHAL46 y. 90 ee
AcHNCO2Me
OH
(DHQ)2-PHAL77% y. 97% ee
1.3:1 regioselectivity
PhOH
NHC(O)CH2Cl
(DHQ)2-PHAL40% y. 50% ee
2.5:1 regioselectivity
OH
NHC(O)CH2Cl
Ph
AcNBrLi ClNHBr
O
NHBr
O
(DHQ)2-PHAL94% y. 95% ee
PhCO2i-Pr
NHC(O)n-Pr
OH
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82
Sharplesss Dihydroxylation: Synthetic Targets
O
Me O
OH
OH
OH
OHOH
OH
OH
HOOH
OH
Me
OH
OH
OH
EtOOC
OHOH
OH
OH
EtOOCHO
(+)-Aspicilin (JOC 1994, 59, 949)
OHOH
OH
OH
HOOH
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83
Sharplesss Dihydroxylation: Synthetic Targets
1. AD-mix- (2 equiv)
2. (CH3O)2CMe2, H+
O
O
O
O
1. AD-mix-2. TBDMSCl (1 equiv)3. MEMCl (1 equiv)4. TBAF5. DMS/NCS6. Horner-Emmons
O
O
O
O
EtO2C
OMEM
1. AcOH, H2O (cleave 1 acetonide)2. (EtO)3CMe, TMSBr (bromoester)3. AIBN, Bu3SnH (reduction C-Br)4. LiOH (saponification)
5. Yamaguchi6. HSCH2CH2SH, BF3
O
Me O
OH
OH
OH
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84
Sharplesss Dihydroxylation: Camptothecin Synthesis
NMeO
N
N
O
O
HO
O
HN O
OHO
O
N Br
Br
NMeO
OHC
I
HO Me
HN O
O
Me
NMeO
Comins J. Am. Chem. Soc. 1992, 114, 10971. / Fang J. Org. Chem. 1994, 59, 6142.
1. t-BuLi2. MeN(CHO)CH2CH2NMe2
3. BuLi4. I2
Et3SiH, TFA
NMeO
I
O
N O
OMe
Me
N O
OMe
Me
+
1. I2, CaCO3
1. KOt-Bu+bromide2. Pd(OAc)2
Pd(OAc)2K2CO3 Bu4NCl, DMF
(Ph3P)3RhCl
Heck
Alkylation
Dihydroxylation
Heck
N O
OMe
Me
OHOH
SADHN O
O
Me
OOH
94% ee
2. HCl