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中国科学技术大学有机合成讲义-2
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Oxidation
1. Oxidation of Alcohols
1.1. Metal Based Reagents
Chromium Reagents
- Cr(VI) based, exact structure depends on solvent, concentration and pH.
- The mechanism of chromic acid-mediated oxidation has been extensively studied and
is commonly used as a model for other chromium-mediated oxidations.
H
CrOR2C=OR2CHOH
R2
H2Cr(III)H2CrO3
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Holloway, F.; Cohen, M.; Westheimer, F. H. J. Am. Chem. Soc.
1951, 73, 65.
Collins Reagent: CrO3?2Py
- CrO3?2Py is a hygroscopic red solid, useful for the oxidation of acid-sensitive
compounds.
Typically, 6 eq. of oxidant in a chlorinated solvent leads to rapid and clean oxidation
of alcohols.
- Caution: Collins reagent should be prepared by the portionwise
addition of solid CrO3 to
pyridine. Addition of pyridine to solid CrO3 can lead to a violent reaction. In situ
preparation
of
the
cirhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlcumvents
and danger of preparing the pure complex.
OH(70-84%)CH2Cl2
Collins, J. C. et al. Org. Synth. 1972,
52, 5.
Jones Oxidation
reagent
the
difficulty
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- Jones reagent is a standard solution of chromic acid in aqueous sulfuric acid, which
generates a mixture of H2Cr2O7 and H2CrO4. Acetone is often beneficial as a solvent
and serves to protect substrate from over oxidation. Isolated olefins usually do not
react, but some olefin isomerization may occur with unsaturated carbonyl compounds.
1,2-diols and α-hydroxy ketones are
susceptible to cleavage under the reaction conditions. It is not a good method for
acid-sensitive groups and compounds.
Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75,
422.
OH
Me3Si
JACS 1982, 104, 5558
1) Jonesreagento2) CH2N2, ether, 0 C
Me3Si
75% (two steps)://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlar
OCH3
2Me
Jones reagent
o2Me
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Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed.
1999,38, 3175.
Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825.
Pyridinium Chlorochromate (PCC)
Preparation: CrO3 (1 eq.)
6 M HCl (1 eq.)
pyridine (1 eq.)
ClCrO3
Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 26, 2647.
- PCC is an air-stable yellow solid which is not very hygroscopic. Typically, alcohols
are oxidized rapidly and cleanly by 1.5 equivalents of PCC as a solution in DMF or
a suspension in chlorinated
solvents. The slightly acidic character of the reagent can be moderated by buffering
the reaction mixture with powdered sodium acetate. Addition of molecular sieves can
accelerate the rate of reaction (Antonakis, K.; Egron, M. J.; Herscovici, J.
J.http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Chem. Soc., Perkin Trans. I
1982, 1967).
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Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871.
SPh
OH
Me3Si
Me3Si
JACS 1982, 104, 5558
- The slight acidity of PCC may cause side reactions, but can also be taken advantage
of in PCC oxidation reactions.
Corey, E. J. Tetrahedron Lett. 1978, 2461.
- In the oxidation of 3°, allylic alcohols, [3,3]-sigmatropic rearrangement may
occur.
OH
Srikrishna, A.; Gharpure, S. J.; Kumar, P. P. Tetrahedron Lett. 2000, 41, 3177.
Pyridinium Dichromate (PDC)
ClCrO3
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PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume
of water, adding pyridine and collecting the precipitatedproduct (Corey, E. J.;
Schmidt, G. Tetrahedron Lett. 1979, 20
, 399).
-
PDC
is
not
as
acidic
as
PCC,
can
selectively
alcohohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlls
to
oxidize
aldehyde
1°
or
carboxylic acid depending on the solvent
Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron 1988, 44, 2149.
CH2OH
S
CHO
CrO3-H5IO6
- It is catalytic in CrO3 (1-2%, industrial scale chromium-based oxidations), can
oxidize 1° alcohols to carboxylic acids with no racemization, and oxidize 2°
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alcohols to ketones.
Terpstra, J. W.; van Leusen, A. M. J. Org. Chem. 1986, 51, 230.
Zhao, Reider Tetrahedron Lett. 1998,
39, 5323.
Manganese Reagents
Manganese Dioxide (MnO2
)
- A heterogenous suspension of active manganese dioxide in a neutral medium can
selectively oxidize allylic, benzylic and other activated alcohols to the
corresponding aldehyde or ketone. The structure and reactivity of active manganese
dioxide
depends
on
the
method
of
preparation.
mahttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlnganese
nonstoichiometric materials (in general MnOx, 1.93
MnO, CHCl62%
J. Chem. Soc. 1953, 2189; JACS 1955, 77, 4145.
Bu3
oxides
Active
are
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Ruthenium Reagents
Ruthenium Tetroxide: RuO4
- RuO4 is used to oxidize alcohols to the corresponding carboxylic acids. It is a
powerful oxidant that also attacks aromatic rings, olefins, diols, ethers, and many
other functional groups. Catalytic
Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659.
procedures employ 1-5% of ruthenium metal and a stoichiometric oxidant, such as sodium
periodate (NaIO4) (Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838).
Sharpless has introduced the use of acetonitrile as solvent to improve catalyst
turnover. It is proposed to avoid the formation of insoluble Ru-carboxylate complexes
and
return
the
metal
to
the
catalytic
cycle
(Carlsen,
http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlP. H. J.; Katsuki, T.; Martin,
V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936).
RuO2(H2O)2, NaIO4
BocClinch, K.; Vasella, A.; Schauer, R. TetrahedronLett.1987,28,6425.
RuO4, NaIO4CCl
, HO, MeCN, rt
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75%
96% ee
RuO4, NaIO4
CCl
, HO, MeCN, rt
92%
94% ee
Carlsen, P. H. J.; Katsuki, T.; Martin,V.S.;Sharpless,K.B.J.Org.Chem. 1981, 46,
3936.
Tetra-n-propylammonium Perruthenate (TPAP, n-Pr4N
RuO4-)
- Review: Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639-666. - Ruthenium tetroxide (RuO4, Ru(VIII)) and, to a lesser extent, the
perruthenate ion (RuO4-, Ru(VII)) are powerful and rather nonselective oxidants.
However, perruthenate salts with large organic counterions prove to be mild and
selective oxidants in a variety of organic solvents. In conjunction with a
stoichiometric http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmloxidant such
as N-methylmorpholine-N-oxide (NMO), TPAP oxidations are catalytic in ruthenium, and
operate at room temperature. The reagents are relatively non-toxic and non-hazardous.
To achieve high catalytic turnovers, the addition of powdered molecular sieves (to
remove both the water of crystallization of NMO and the water formed during the
reaction) is essential.
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TPAP, NMO, CHCl22o
Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew.
Chem.,
Int. Ed. 2000, 39, 2290.
Silver Reagent
Fétizon's Reagent
- Silver carbonate absorbed on Celite has been found to selectively oxidize primary
diols to
lactones [a) Fétizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969,
1102. b) Fétizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 13, 4445.
c) Kakis, F. J.; Fétizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T.
Jhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html. Org. Chem. 1974, 39, 523.]
Lange, G. L.; Lee, M. J. Org. Chem. 1987, 52
, 325.
Ag2CO3 on Celite, o
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Coutts, S. J.; Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305.
Ag2CO3 on
Celite, tolueneo
Clive, D. L. J.; et al. J. Am. Chem. Soc. 1990, 112, 3018.
O2/Pt
- Molecular oxygen in the presence of a platinum catalyst is a classic method for
the oxidation of primary alcohols to the corresponding carboxylic acids.
Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron Lett. 1992, 33, 4313.
1. O2/Pt
Pf = 9-phenylfluorenyl
Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394.
Pt/O2
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Kretchmer, R. A.; Thompson, W. J. J. Am. Chem. Soc. 1976, 98, 3379.
Oppenauer Oxidation
-
Review:
de
Graauw,
C.
F.;
Peters,
J.
A.;
van
Bekkum,
H.;http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Huskens, J. Synthesis 1994,
1007-1017.
- A classic oxidation method achieved by heating the alcohol to be oxidized with a
metal alkoxide in the presence of a carbonyl compound as a hydride acceptor (the
reverse of the Meerwein-Pondorff-Verley Reduction). The reaction is an equilibrium
process and is believed to proceed through a cyclic transition state. The use of easily
reduced carbonyl compounds, such as quinone, helps drive the reaction in the desired
direction.
6F5
(2 mol%)
99%
Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62
, 5664.
Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M.
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Synthesis 1996, 1341.
1.2. Non-Metal Based Reagents
Dimethylsulfoxide-Mediated Oxidations
- Review: Tidwell, T. T. Organic Reactions 1990, 39, 297-557.
-
Dimethylsulfoxide
(DMSO)
can
be
activated
http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlby reaction with a variety of
electrophilic reagents, including oxalyl chloride, dicyclohexylcarbodiimide, sulfur
trioxide, acetic anhydride, and N-chlorosuccinimide.
O
NuE-O
E =(CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F3CSO2H,PO5,
H3PO4, Br2
Nu =R-OH, Ph-OH, R-NH2, RC=NOH, enols
Swern Oxidation
- Typically, 2 equivalents of DMSO are activated with oxalyl chloride in
dichloromethane at or below –60 °C. Subsequent addition of the alcohol substrate
and triethylamine leads to carbonyl formation. The mild reaction conditions have been
exploited to prepare many sensitive
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aldehydes. Careful optimization of the reaction temperature is often necessary (Huang,
S. L.; Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480).
SMe2
B:
CO2
1. TBSCl, Im, DMAP, CH2Cl2
23-78 to -50 oC;http://doc.xuehai.net/bc956988fd90b0ed78020c467.html 66%
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens,
M. Angew.Chem., Int. Ed
. 1998, 37, 2354.
(COCl)2, DMSO,o
Smith, A. B., III; Wan, Z. J. Org. Chem.2000,65,3738.
Moffatt Oxidation
- The first reported DMSO-based oxidation procedure (Pfitzner, K. E.; Moffatt, J.
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G. J. Am. Chem. Soc. 1965, 87, 5661). Dicyclohexylcarbodiimide (DCC) functions as
the electrophilic activating agent in conjunction with a Br?nsted acid promoter.
Typically, oxidations are carried out with an excess of DCC at or near 23 °C.
Separation of the by-product dicyclohexylurea and MTM ether formation can limit
usefulness. Alternative carbodiimides that yield water-soluble by-products (e.g.,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)) can simplify
workup procedures.
O-
RR'
Cl
OH
OBu-t
DMSOhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html, DCCCl
O
OBu-t
Corey, E. J.; Kim, C. U.; Misco, P. F. Org. Synth. Coll. Vol. VI 1988, 220.
HO
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OBzOMe
OBzOMe
DMSO, EDC,Hanessian, S.; Lavallee, P. Can. J. Chem. 1981, 59, 870.
Parikh-Doering Oxidation
- Sulfur trioxide-pyridine is used to activate DMSO. Ease of work-up and at-or-near
ambient reaction temperatures make the method attractive for large-scale reactions
(Parihk, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505).
3
JOC, 1998, 63, 6597.
Dess-Martin Periodinane (DMP)
- DMP has found wide utility in the preparation of sensitive, highly functionalized
molecules. DMP oxidations are characterized by short reaction times, use of a single
equivalent of oxidant, and can be moderated with regard to acidity by the
incorporation of additives such as pyridine. DMP and its precurser o-iodoxybenzoic
acid (IBX) arehttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html potentially
heat and shock sensitive and should be handled with appropriate care. See: a) Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155. b) Boeckman, R. K.; Shao, P.;
Mulins, J. J. Org. Synth. 1999, 77, 141.
IBX
DMP
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Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
Danishefsky, S. J.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. K. J. Am. Chem. Soc.
1988,110, 6890.
DMP, PhCO2H,
Ph3P=CHCO2Me,
MeO2C
CO2Me
Barrett, A. G. M.; Hamprecht, D.; Ohkubo,M.J.Org.Chem.1997,62,9376.
o-Iodoxybenzoic Acid (IBX)
- A simpler preparation of IBX has recently been reported.
IBX
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
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H
IBX (2.0 eq.)H
OTIPS
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122,
http://doc.xuehai.net/bc956988fd90b0ed78020c467.html7596.
N-Oxoammonium-Mediated Oxidation
- Review: de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153-1174.
- N-Oxoammonium salts are mild and selective oxidants for the conversion of primary
and
secondary alcohols to the corresponding carbonyl compounds. These oxidants are
unstable and are invariably generated in situ in a catalytic cycle using a stable,
stoichiometric oxidant.
XRR'RR'N-oxoammonium salt
- N-Oxoammonium salts may be formed in situ by the acid-promoted disproportionation
of nitroxyl radicals. Alternatively, oxidation of a nitroxyl radical or hydroxyl
amine can generate the
corresponding N-oxoammonium salt (Golubev, V. A.; Sen', V. D.; Kulyk, I. V.;
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Aleksandrov, A. L. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1975, 2119).
nitroxyl radical
.
.
TEMPO
OH
2,2,6,6-Tetramhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlethyl-1-piperi
dinyloxyl (TEMPO) catalyzes the oxidation of alcohols to aldehydes and ketones in
the
presence
of
a
m-chloroperoxy-benzoic
variety
acid
[bis(acetoxy)iodo]benzene
of
stoichiometric
(m-CPBA),
(BAIB),
sodium
sodium
bromite
oxidants,
including
hypochlorite
(NaOCl),
(NaBrO2),
and
Oxone
(2KHSO5?KHSO4?K2SO4).
TEMPO, NaOCl, NaBr
EtOAc:toluene:HO (1:1:0.15)
BocCHO
Jurczak, J.; Gryko, D.; Kobrzycka, E.;Gryza,H.;Prokopoxicz,P.Tetrahedron 1998, 54
, 6051.
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TEMPO, BAIB,CH2Cl2,De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
- TEMPO catalyzes the selective oxidation of primary alcohols to aldehydes in a
biphasic mixture of dichloromethane and aqueous buffer (PH = 8.6) in the presence
of N-chlorosuccinimide (NCS) as a stoichiometric oxidant and tetrabutylammonium
chloride (Bu4N Cl–).
TEMPO, NCS, Bu4N Cl-8
http://doc.xuehai.net/bc956988fd90b0ed78020c467.html.
882%
8
OH
Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452.
HO
OH
TEMPO,
NaBrO2,
Inokuchi,
Nishiyama,T.;Torii,S.J.Org.Chem.1990,55,462.
Sodium Hypochlorite: NaOCl
T.;
Matsumoto,
S.;
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- Sodium hypochlorite in acetic acid solution selectively oxidizes secondary alcohols
to ketones in the presence of primary alcohols. A modified procedure employs calcium
hypochlorite, a stable and easily handled solid hypochlorite oxidant.
1. NaOCl,AcOHKende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999,
121, 7431.n-C9
Winter, E.; Hoppe, D.
Tetrahedron 1998, 54, 10329.
N-Bromosuccinimide (NBS) or Bromine
- NBS in aqueous dimethoxyethane selectively oxidizes secondary alcohols in the
presence of primary alcohols.
Corey,
E.
J.;
Ishiguro,
M.
Tetrahedrohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlnLett.1979,20,2745
.
2. Oxidation of Aldehydes
Sodium Chlorite: NaClO2
- Sodium chlorite is a mild, inexpensive, and selective reagent for the oxidation
of aldehydes to the corresponding carboxylic acids under ambient reaction conditions.
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2-methyl-2-butene is often incorporated as an additive and has been proposed to
function as a scavenger of any electrophilic chlorine species generated in the
reaction.
O
CHO
TBSO
NaClO2, NaH2PO4,2TBSO
O
COOH
Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825.
Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A. J. Org.
Chem. 1999, 64, 2616.
1. TPAP, NMO, CH2Cl2n-Bu3n-Bu32. NaClO2, NaH2PO4
2-methyl-2-butene,
Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. J.
Chem. Soc.,Chem. Commun. 1999, 809.
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Potassihttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlum Permanganate: KMnO4
- Review: Fatiadi, A. J. Synthesis 1987, 85-127.
- Potassium permanganate is a mild reagent for the oxidation of aldehydes to the
corresponding
carboxylic acids over a relatively large pH range. Alcohols, alkenes, and other
functional groups are also oxidized by potassium permanganate. Oxidation occurs
through a coordinated permanganate intermediate by hydrogen atom-abstraction or
hydride transfer. Potassium
permanganate in the presence of t-butyl alcohol and aqueous NaH2PO4 was shown to
effectively oxidize the aldehyde in the following polyoxygenated substrate to the
corresponding carboxylic acid whereas Jones reagent, RuCl3(H2O)n-NaIO4, and silver
oxide failed.
KMnO4
, NaH2PO4
t-BuOH, HO; 85%
Abiko, A.; Roberts, J. C.; Takemasa,T.;Masamune,S.TetrahedronLett.1986, 27, 4537.
1. KMnO4, NaH2PO4,t-BuOH, H2O, 0 oC
A number of ohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlther oxidants
(including Jones reagent, NaOCl, and RuO2) failed.
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Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237.
Silver Oxide: Ag2O
- A classic method used to oxidize aldehydes to carboxylic acids. Cis/trans
isomerization can be a problem with unsaturated systems under the strongly basic
reaction conditions employed.
CHO
HO
Pearl, I. A. Org. Synth. Coll. IV 1963, 972.
o
Sonawane, H. R.; Sudrik, S. G.; Jakkam, M. M.; Ramani, A.; Chanda, B. Synlett. 1996
, 175.
Pyridinium Dichromate
- Non-conjugated aldehydes are readily oxidized to the corresponding carboxylic acids
in good yields in DMF as solvent.
1. PDC, DMF
2Me
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Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem.
1985,50, 2095.
MeO
OTBDPS
CHO
OTBDPS
COOH://doc.xuehai.net/bc956988fd90b0ed78020c467.html
Mazur, P.; Nakanishi, K. J. Org. Chem. 1992, 57, 1047.
Corey-Gilman-Ganem Oxidation
- A convenient method to convert unsaturated aldehydes directly to the corresponding
methyl esters. Cis/trans isomerization, a problem when other reagents such as basic
silver oxide are employed, is avoided. The aldehyde substrate is initially
transformed into a cyanohydrin
intermediate. Subsequent oxidation of the cyanohydrin furnishes an acyl cyanide which
is then trapped with methanol to give the desired methyl ester. Conjugate addition
of cyanide ion can be problematic.
MnO2, NaCN
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Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121
, 5176.
- In the following example, stepwise addition of reagents proved to be essential to
achieve high yields.
1. NaCN, AcOH,
2
2Me
97%
(2Z, 4E)-xanthoxin
Yamamotohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html,
H.;
Oritani,
T.
Tetrahedron Lett. 1995, 36, 5797.
Bromine
- Review: Palou, J. Chem. Soc. Rev. 1994, 357-361.
- Bromine in alcoholic solvents is a convenient and inexpensive method for the direct
conversion of aldehydes into ester derivatives. Under the reaction conditions
employed, secondary alcohols are not oxidized to the corresponding ketones. Oxidation
of a hemiacetal intermediate is proposed. Olefins, benzylidine acetals and thioketals
are incompatiable with the reaction conditions. A variety of esters can be prepared.
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Br2, H2O, MeOH2Me
Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W.
Tetrahedron Lett. 1988, 29, 5087.2Br2, H2
O, MeOH2
Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenl?nder, F. Tetrahedron 1996, 52, 6409.
3. Oxidations of Ketones
Bayer-Villiger Oxidation
- Reviews: Krow, G. R.http://doc.xuehai.net/bc956988fd90b0ed78020c467.html In
Organic Reactions, Paquette, L. A., Ed., John Wiley and Sons: New York, 1993, Vol.
43, p. 251-296.
- A classic method for the oxidative conversion of ketones into the corresponding
esters or
lactones by oxygen insertion into an acyl C-C bond. The migratory preference of alkyl
groups has been suggested to reflect their electron-releasing ability and steric bulk.
Typically, the order of migratory preference is tertiary > secondary > allyl > primary
> methyl. The reactivity order of Bayer-Villiger oxidants parallels the acidity of
the corresponding carboxylic acid (or alcohol): CF3CO3H > p-nitroperbenzoic acid >
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m-CPBA = HCO3H > CH3CO3H > HOOH > t-BuOOH.
OR
R'
R"COH
ROOR'
Primary and secondary stereoelectroniceffectsintheBayer-Villiger
reactionhave been demonstrated.
effect
secondary
effect
-Primary
effecthttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html:
antiperiplanar alignment of RL and σO-O
-Secondary effect: antiperiplanar alignment of Olp and σ?C-RL
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Proposed TS
Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2852.
- The Bayer-Villiger reaction occurs with retention of stereochemistry at the
migrating center.
m-CPBA, NaHCO3MeOMeOCorey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J. Am. Chem. Soc. 1969, 91, 5675.
n-C16HMiller, M.; Hegedus, L. S. J. Org. Chem. 1993, 58, 6779.
m-CPBA, Li2CO3n-C16H
Meinwald J. Am. Chem. Soc. 1960, 82, 5235.
exo face.
Sauers J. Am. Chem. Soc.1961, 83, 2759.
4. Oxidative Cleavage of Carbon-Carbon Multiple Bonds
Potassium Permanganate
RRR R'R'
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R'
2H
Midland, M. M.; Lee, P. E. J. Org. Chem. 1981, 46, 3933.
://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlrRuthenium Reagents
2Bn
.Bn
42HOOC
2BnBnTakano, S.; Kamikubo, T.; Moriya, M.;Ogasawara,K.Synthesis1994,601.
Ozonolysis
- Ozone is best viewed as a resonance species with four contributors.
Mechanism, Review: Criegee Angew. Chem., Int. Ed. 1975
, 14, 745.
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1,3-dipolar1,3-dipolar
carbonyl oxide
(Criegee zwitterion)
ozonide
in situ
Note: Ozonide explosive when isolated or concentrated.
- Ozone (O3) exhibits very light blue color, and ozonolysis completes when color
persists. The reaction rate for this electrophilic reagent is: electron-rich >
neutral > electron-deficient olefin.
1) O3Smith, III, A. B.; Wan, Z. J. Org. Chem. 2000, 65, 3738.
5. Epoxidation of Olefins
- The value of epoxides in synthesis is due largely to their opening by nucleophilic
reagents, which alhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlmost always
takes place with high stereoselectivity, and often with high regioselectivity. The
range of effective nucleophiles is wide, and it is rare for epoxide opening to be
complicated by elimination.
Peroxide Induced Epoxidations
- Peroxides used for epoxidation: hydrogen peroxide (H2O2), alkyl hydroperoxide and
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peroxyacids.
- The oxidizing power of the epoxide is inversely related to the pKa of the conjugate
acid generated by loss of the leaving group (ROH): ROOH
ROH
5.1. Peracid Epoxidation
-Antiperiplanar arrangement of O-O bond and reacting alkene, n-π* stabilization by
reacting lone pair in plane. The synchronicity of epoxide C-O bond formation and an
overall transitionstate structure postulated using ab initio calculations and
experimental kinetic isotope effects(Singleton, Houk J. Am. Chem. Soc. 1997, 119,
3385).
R://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlpar
Reaction rates are governed by olefinnucleophilicity.Theratesofepoxidation of the
indicatedolefin relative to cyclohexene are provided below:
OHOAcOH
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krel
1.000.550.0460.42
The isolated double bond is more reactive toward electrophiles than the double bond
having ahydroxy group at the allylic carbon because the interaction between the
π-orbital of the doublebond and the σ*-orbital of the C-O bond lowers the level
of HOMO of the allylic alcohol.
White, J. D.; Somers, T. C. J. Am. Chem. Soc. 1994, 116, 9912.
R =HR =Me
99%
1?%
Less hindered face of olefin is epoxidized.
Brown J. Am. Chem. Soc. 1970, 92, 6914.
- Review: Hoveyda, Evans, Fu Chem. Rev. 1993, 93, 1307
Ganem TL 1985, 26, 4895
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Transition State Hydrogen Bonding
HR
ethersOK
7http://doc.xuehai.net/bc956988fd90b0ed78020c467.html5%
ds 95:5
JOC 1987, 52, 5127.
5.2. Alkyl hydroperoxide
- Reviews: Org. React. 1996, 48, 1-299.
- Catalysts: VO(acac)2, Mo(CO)6, Ti(OiPr)4; Oxidants: t-BuOOH, PhC(CH3)2OOH;
Regioselective epoxidation of allylic and homo-allylic alcohols; Will not epoxidize
isolated double bonds; Epoxidation occurs stereoselectively with respect to the
alcohol.
Bu
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Relative
Rates
and
DiastereoselectivitiesfortheEpoxidationofCyclohexene
Derivatives
SubstratemCPBAMo(CO)6VO(acac)21.00
1.00
1.00
The relative rate data OH
apply only to a given 0.55 (92:8)
4.5 (98:2)>200 (98:2)
column.
Values in parenthesis OAc
refer to the ratio of 0.046 (37:63)
0.07 (40:60)--
syn:anti epoxide.JACS 1973, 95, 6136
OH
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0.42 (60:40)
11.0 (98:2)10.0 (98:2)
://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlar
JACS 1973, 95, 6136
threo
erythro
Reagentthreo:erythro
MCPBA
95:5TBHP/VO(acac)271:29
X
TBHP/Mo(CO)684:16
YHMeHH
HX =H, V, Mo ...HY =RCO, tBu
HMe
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XMajor TS
MinorTS
RCO3H Transition States and BiteAngles
1,3-allylic strain!
o
Major TS
H
Minor TS
~120V Transition States and Bite Angleso
Major TS
threo
erythro
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ReagentmCPBATBHP/VO(acac)2TBHP/Mo(CO)6TBHP/Al(OtBu)3threo:erythro95:5
86:14
95:5
100:0
threo
erythro
ReagentmCPBATBHP/VO(acac)2TBHP/Mo(CO)6TBHP/Al(OtBu)3threo:erythro
64:36
29:71
62:38
64:36
TL 1980, 21, 1657, 4843; TL 1979, 20,4733
http://doc.xuehai.net/bc956988fd90b0ed78020c467.html
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1978, 19, 2869.
Homoallylic Alcohols (Mihelich, JACS
1981,103,7690)
n-C5HTBHP
n-C
5H n-C5H
104:1 dr
OHMe
n-C5H11
Me
TBHP
n-C5H11
OHMe Me
n-C5H1:70 dr
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Bishomoallylic Alcohols (JACS, 1978,100,2933.)
1) VO(acac)22) HOAc
5.3 Sharpless Asymmetric Epoxidation (AE)
- K. Barry Sharpless received the 2001 Nobel Prize in chemistry for his contribution
to catalytic asymmetric epoxidation and dihydroxylation of olefins.
- Reviews: a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis,
Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158. b) Katsuki, T. Comprehensive
Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. II,
chap. 18, p 621-648.
D-(-) dialkyl tartrate[Ohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html]
RO22RR =Me, D-(-)-dimethyl tartrate (DMT)R =Et, D-(-)-diethyl tartrate (DET)
R =iPr, D-(-)-diisopropyltartrate(DIPT)
RO2C
CO2RR =Me, L-( )-DMTR =Et, L-( )-DETR=iPr,L-( )-DIPT
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- Typical "catalytic conditions" use 5-10 mol% of chiral tartrate and Ti(OiPr)4 (ratio
1.1:1 to 1.2:1). The addition of molecular sieves is to "soak" up any water. The sense
of enantioface selection is determined by the chirality of the dialkyl tartrate used.
High enantioselectivity has been obtained for a wide substrate scope. The empirical
model provided by Sharpless enables one to predict the stereochemical outcome of the
epoxide formed in the reaction.
R1R2R3
Me
CH2OBn
CH2CH=CHC5H11HHHHMeMeHnBuHHBnHHHMe
Tartrate( )-DIPT(-)-DET( )-DMT( )-DIPT( )-DET( )-DIPT( )-DET(-)-DET( )-DET(-)-DE
T( )-DET( )-DET(-)-DIPT( )-DIPT(-)-DET( )-DET( )-DET( )-DIPT
://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlaree?92949294>91959595>958994909
4>95>959394
HHHHHHHMe
iPrH
CH=CH2H
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(CH2)3CH=CH2H
CH2CH2OTBSH
CH2CH=CHMe2H
HMe
HMe
MeMe
CH2OBnMe
PhMe
HCH2OBn
cyclohexylH
R1, R2 =(CH2)2R1, R2 =(CH2)10
Complied from a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis,
Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158. b) Katsuki, T. Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New
York, 1999; Vol. II, chap. 18, p 621-648.
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-Sharpless AE is sensitive to the geometry of olefins and the position of
substituents.
t
75%, 25% eet52%, 95% ee
42%, 85% ee
t
- Proposed transition state of Sharpless AE
Burns,
C.
J.;
Martin,
C.
A.;
Sharpless,
K.
B.
J.
54,http://doc.xuehai.net/bc956988fd90b0ed78020c467.html 2826.
- Reagent control overrides substrate control:
TBHP, Ti(Oi
Pr), (single isomer)
BnO
Org.
Chem.
1989,
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OH
222CH2ClBnO
OH(single isomer)
TL, 1995, 36, 8247
(-)-DET; 91%
2CH2Cl
- Alkenyldimethylsilanols, which are structurally similar to allylic alcohols, are
amenable to epoxidation.
n-C8H90% eeChan, T. H., Chen, L. M., Wang, D.,
Li,L.H.Can.J.Chem.1993,60,60.
- The reactivity of the substrate bearing an electronwithdrawing group is low and
the epoxidation of this class of substrates requires a long reaction time or an
elevated reaction temperature.
91% ee
TL,1991,32,2045.
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- Nucleophilic functional groups such as hydroxy, carbonyl, and carbamate groups
often react in
situ
with
the
produced
epoxides
intramolecularly
to
products.://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlar
, 49
, 2582.TBHP, Ti(OiPr)4,
Me
OHO
PMBO2TL, 1987, 28, 3605. JOC, 1982, 47, 5384.
PMBO2TBHP, Ti(OiPr)4,
- Derivatize or open the epoxy alcohol in situ
water soluble
TBHP, Ti(OiPr)(-)-DIPT
OH
4,
give
the
cyclized
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88-92% ee
m-NO
2C6H4SO2Cl
JOC, 1986, 51, 3710; JOC, 1986, 51, 5413
Kinetic Resolution of Racemic Allylic Alcohols
- Sharpless AE of an allylic alcohol which carry a substituent at C-1 is also a most
useful
procedure. The above Sharpless empirical model for the predication of stereochemical
outcome can also be applied.
(-)-tartrate
R2R
1
RRR3
OHRR( )-tartrate
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(-)-tartrate
( )-tartrate
RRRR
- The enantiomeric excess of both product epoxide and unreacted allylic alcohol will
dehttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlpend on the relative rate of
epoxidation and on the extent of reaction, which will depend on the structure of the
substrate.
krel =104
krel =700T, 1988, 44, 4073
krel =20
JACS, 1981, 103, 6237
JACS, 1988, 110,2978
, 52, 2187
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OH
The enantiomeric excess of the major anti-epoxy alcohol was observed to increase (84,
93,
>97% ee) as the reaction time was extended (3, 24, 140 h) (Schreiber, JACS, 1987,
109, 1525).
-Nucleophilic opening of terminalepoxidesisoftenhighlyregioselective.
LiAlH4
(CH
3)2CuLi
Behrens, C. H.; Sharpless, K. B.;AldrichimicaActa,1983,16,67.
MeS I-, BuLi, THF, -10~25 oC99%
BnOBnO
OH
Crimmins, M. JACS, 2004, 126, 10264.
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Ti(OPr-i)4 can catalyze the additionofnucleophilestoC-3of2,3-epoxyalcohols:
://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlparO
OH
C-3
C-2
NuEt2NHEt2NHi-PrOHi-PrOH(allyl)2NHallyl alcoholNH4OBzNH4OAcKCN
Ti(OiPr)4 (eq.)
01.501.51.51.51.51.51.7
C-3:C-23.7 : 120 : 1--100 : 1100 : 1100 : 1100 : 165 : 12.4 : 1
yield (%)4900889690747376
RiPr)3
Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
- The heat stability, reactivity, and easy preparation of dimethylsulfoxonium
methylide allows convenient access to 2,3-disubstituted THF rings in a highly
diastereoselective and
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enantioselective fashion. The stereochemistry that is set by the asymmetric
epoxidation is translated fully to the final product.
O
HO
97% eeOBn
MeS OI-, NaH, DMSO, 85 oC
78%
97% ee
- Catalytic and regio- and stereoselective rearrangement of epoxides to aldehydes
via
alkyl
migration
can
http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlusing
be
realized
a
high-valent
metalloporphyrin complex, Cr(TPP)OTf
(chromium(III) tetraphenylporphyrin triflate), in low catalyst loading (1-20 mol %).
The yield and regio- and stereoselectivity of the catalytic process are generally
good to high.
Cr(TPP)OTf:
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chromium(III) tetraphenylporphyrin triflate
99%, 96% ee
Suda, K. JACS, 2004, 126, 9554.
- Internal nucleophiles may be used to open 2,3-epoxy alcohols.
1) PhNCO, TEA511Corey, E. J.; Hopkins, P. B.; Munroe, J. E.; Marfat, A.; Hashimoto,
S.-I. J. Am. Chem. Soc.1980, 102, 7986.
(HCHO)n, Cs2CO3o
Ph
OH
McCombie, S. W.; Metz, W. A. TetrahedronLett.1987,28,383.
- In the sharpless AE, the substrate must possess a group capable of coordinating
to the catalyst, almost always a hydroxyl group, and without such a group asymmetric
epoxidation
does
not
take
http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlHowever,
place.
highly
enantioselctive asymmetric epoxidation of “isolated” alkenes lacking this type of
coordination site can be realized by other catalytic systems, the most useful of which
are the Jacobsen asymmetric epoxidation and the Shi asymmetric epoxidation. In
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addition, the catalysts for both Jacobsen AE and Shi AE are also readily available.
(S,S)-1 (4 mol %)CH2Cl2, 4 C
t
R77%, 92% ee
2Et
Ph
2Et15%, 78% ee
(S,S)-
1
52%, 97% ee
t-Bu
Bu-t
96%, 97% ee63%, 94% ee79%, 84% eett(R,R)-1
Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc.
1991, 113, 7063.
-Selectivity is determined through nonbonded interactions.
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-In general, R is aryl, alkenyl or alkynyl and R' is a bulky group.
-cis-Disubstituted
conjugated
olefins
are
epoxidizedwith
high
levels
of
enantioselectivityhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html.
-trans-Disubstituted olefins react more slowly and with diminished selectivity.
-Terminal olefins are poor substrates.
-Addition of substoichiometric amounts of 4-phenylpyridine N-oxide improves both
catalyst selectivity and turnover numbers.
Related: Jacobsen Catalytic Asymmetric Epoxide-Opening Reactions
Hydrolytic Kinetic Resolution (HKR):
(S,S)-1
RMe
CH2Cl(CH2)3MePhCH=CH2
krel>400502902030
Bu-t
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tM =Co(OAc)(OH2)
(S,S)-1
t-BuMBu-t
R
H2O
(0.50-0.70 eq.)
Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936-938.
Kinetic Resolution of Terminal EpoxideswithTrimethylsilylAzide:
(R,R)-1R
CH2ClCH2CNCH(OEt)2CH2Ph
3
t-Bu
Bu-t
R
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TMSN3(0.50 eq.)
krelhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html100454471
O3tt(R,R)-1
Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420.
5.5. Shi Asymmetric Epoxidation
- Review: "Organocatalytic Asymmetric Epoxidation of Olefins by Chiral Ketones", Shi,
Y.Acc. Chem. Res. 2004, 37, 488-496.
R
1
R2R3
ketone 1, oxone, 23R2
- Ketone 1 can be readily prepared from D-fructose by ketalization (acetone, HClO4,
0 °C, 53%) and oxidation (PCC, 23 °C, 93%). L-Fructose can be prepared in 3 steps
from readily available L-sorbose. Ketone 1 can be used catalytically (20–30 mol %).
Oxone (a commercial mixture of 2:1:1 KHSO5:KHSO4:K2SO4) is used as the stoichiometric
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oxidant but H2O2/CH3CN can also be used (peroxyimidic acid is the proposed oxidant).
Generally, the optimum pH for dioxirane epoxidation is 7–8. At higher pH, Oxone tends
to decompose. However, at pH 7–8 the Shi
http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlcatalyst decomposes due to the
competing Baeyer-Villiger reaction. By increasing the pH to 10.5
(by addition of K2CO3), the amount of ketone used can be reduced to a catalytic amount
(30 mol %) and the amount of Oxone can be reduced to a stoichiometric amount (1.5
equiv), suggesting that at this pH the ketone is sufficiently reactive to compete
with Oxone decomposition.
Dimethoxymethane (DMM) and CH3CN (2:1 v/v) solvent mixtures generally provide higher
ee's. Reaction temperatures range from –10 to 20 °C.
Catalytic Cycle:
2
R
R2
R1
SO4
2-
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Competing spiro and planar transition states for the epoxidation with ketone 1
23
spiroplanar
It is proposed that the Shi epoxidation proceeds through a dioxirane intermediate
and a spirotransition state and that a so-called planar transition state is a main
comphttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmleting pathway. The spiro
transition state is believed to be electronically favored as a result of a stabilizing
interaction between an oxygen lone pair of the dioxirane with the π* orbital of the
olefin.
Epoxidation Examples of Trans andTrisubstitutedOlefinswithKetone1
95% ee
94% ee
98% ee
6H13-n
94% ee95% ee
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93%
92% ee
92% ee
94% ee94% ee
n98% ee97% ee91% ee
94% ee
94% ee
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,
11224.Warren, J.D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.Wang, Z.-X.; Shi, Y. J. Org.
Chem. 1998, 63, 3099.
Epoxidation Examples of ConjugatedDienesandEnyneswithKetone1
96% ee
89% ee
95% ee
93% ee
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Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63,
2948.Wang,http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Z.-X.; Cao, G.-A.;
Shi, Y. J. Org. Chem. 1999, 64, 7646.
Epoxidation of α,β-Unsaturated EsterswithKetone2
The original Shi catalyst decomposes (via the Baeyer-Villiger pathway)faster than
it reacts with electron-deficient α,β-unsaturated esters. A second-generation
catalyst,
incorporating
electronwithdrawing
acetate
groups,
Baeyer-Villiger decomposition.
2EtCO2Et
Ph
CO2
Et
96% ee96% ee93% ee
94% ee
82% ee
Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792.
Epoxidation of Cis and Terminal OlefinswithKetone3
slows
the
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91% ee
97% ee
85% ee
Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551.Tian,
H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929.
Tian, H.; She, X.; Yu, H.; Shu, L.; Shi,Y.J.Org.Chem.2002,67,2435.
http://doc.xuehai.net/bc956988fd90b0ed78020c467.html2O, Morimoto, Y.; Nishikawa,
Y.; Takaishi, M. J. Am. Chem. Soc. 2005, 127, 5806.
6. Dihydroxylation of Olefins
6.1 Dihydroxylation with Osmium Tetroxide
- Criegee found that osmium tetroxide (OsO4) is reduced by alkenes to give the cis-diol
(Justus Liebigs Ann. Chem. 1936, 522, 75).
O
OOs (VIII)
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- Osmium Tetroxide is an electrophilic reagent, and it behaves as a large reagent.
Ligands such as pyridine accelerate the osmylation of olefins (Criegee, R.; Marchand,
B.; Wannowius, H. Liebigs Ann. Chem. 1942, 550, 99). Strained, unhindered olefins
react faster than unstrained, sterically hindered olefins. Electron-rich olefins
react faster than electron-deficient olefins. The dihydroxylation with osmium
tetroxide is diastereospecific, with attack on the C=C from the least hindered face.
But OsO4 is expensive, volatile, and toxic. Various improvements include: 1) only
catalythttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlic amount of OsO4 used;
2) use of an equivalent osmium salt [K2OsO2(OH)4].
Turnover
is
achieved
by
re-oxidation
with
stoichiometric
oxidants:
N-methylmorpholine N-oxide (NMO)
O
VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.K3Fe(CN)6Minato,
M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.
6.2 Sharpless Asymmetric Dihydroxylation (AD)
- Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483-2547.
Os (VI)
- In the original Sharpless procedure, using NMO as the cooxidant, reoxidation was
believed to compete with hydrolysis, leading to a competing 2nd-cycle oxidation that
was less
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enantioselective (Ogino, Y.; Chen, H.; Kwong, H.-L.; Sharpless, K. B. Tetrahedron
Lett. 1991, 32, 3965). Using the potassium ferricyanide cooxidant system, the
non-enantioselective
secondary
cycle
appears
to
suppressed,http://doc.xuehai.net/bc956988fd90b0ed78020c467.html
higher enantiomeric excesses are obtained.
Catalytic Cycle of the AD ReactionUsingNMOastheCooxidant
low ee
R
OH
Catalytic Cycle of the AD ReactionUsingK3Fe(CN)6astheCooxidant
2OH-
2Fe(CN)63-2H2O
2Fe(CN)64-
C2-symmetric, pseudo-enantiomeric ligands:
(DHQ)2AQN(DHQ)2PYR
AD-mix reagents are commercially available:
have
been
consequently
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1) 1.4 g AD-mix-α will oxidize 1 mmol olefin, contains: 0.98 g K3Fe(CN)6 (3 mmol),
0.41 g K2CO3 (3 mmol), 0.0078 g (DHQ)2PHAL (0.01 mmol), 0.00074 g K2OsO2(OH)4 (0.002
mmol)
2) AD-mix-β contains (DHQD)2PHAL as the ligand.
Conditions: t-BuOH, H2O (1:1), 0 °C, 6-24 h. For non-terminal olefins, the addition
of
CH3SO2NH2 leads to faster reaction (Sharpless, K. B., et al. J. Org. Chem. 1992, 57,
2768).
Mnemonic Device of Sharpless ADReaction
DHQD-R://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlr
Sharpless Asymmetric Dihydroxylation Reaction (Sharpless, K. B., et al. J. Org. Chem.
1992, 57, 2768.)
ligandee(%)configurationolefin
n-BuPhn-C5H11
Phn-Bu
Bu-nPhCO2EtCO2Et
(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2
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PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(D
HQ)2PHAL
9793>99>99999697959895999797978480
R,RS,SR,RS,S2S,3R2R,3S2S,3R2R,3SRSR,RS,SRSRS
PhPhn-C8H17
(DHQD)2PHAL
ClBnO
Ph
44% ee63% ee77% ee,
(DHQD)2AQN90% ee88% ee78% ee
(DHQD)2AQN is often a superior ligand.
Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 448.
Asymmetric Dihydroxylation of Dienes
- The asymmetric dihydroxylation of dienes tends to be highly regio- and
chemoselective.
Indeed,
in
most
cases
and
withohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlut special control of the
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reaction conditions, selective monohydroxylation of the diene takes place, affording
enediols which are useful precursors to a range of optically active intermediates.
It appears that the presence of the diol moiety significantly lowers the
reactivity of the remaining olefin towards further dihydroxylation. Moreover, we have
already seen earlier that the addition of the diol unit typically occurs on the most
electron-rich alkene. Furthermore, it was also shown that unsubstituted olefins
reacted more sluggishly than disubstituted or conjugated olefins.
Regioselectivity of AD with Diene Substrates(Using(DHQD)2PHALasthe Ligand)
olefin
product78
73
70
Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570.
On the Origin of the Enantioselectivity in the AD Process
-
The
explanation
of
the
high
enantioselectivity
ihttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmln the AD reaction has been
divided into two proposals, one by Sharpless and one by Corey.
The Sharpless Model
- The key point of the Sharpless model is the two-step mechanism for the addition
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of osmium tetroxide to an alkene.
9898
Et
93
95
78
9293
yield (%)
ee (%)
Schematic representation of the concerted (3 2) and the stepwise (2 2) addition of
osmium tetroxide to an alkene. Balance of evidence appears to favor 3
(vs. 2
2 Mechanism
2 pathway). See: Corey, E.J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett.
1996, 37, 4899. 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.
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