Applications of Mn(III) in Organic Chemistry Florina Voica
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Applications of Mn(III) in Organic Chemistry Florina Voica Baran lab GM 2/6/2010 Contents: Oxidative radical cyclization of β-keto acids Discussion of the reaction mechanism Oxidative radical cyclization of β-keto esters Oxidative radical cyclization of 1,3-diketones Oxidative cyclization of ketones Oxidative fragmentation-cyclization Asymmetric radical cyclization Miscellaneous applications of Mn(III) salts Some common commercially available Mn(III) species: Mn(OAc) 3 •2H 2 O (Aldrich, $6/g) Mn(acac) 3 (Aldrich, $3.1/g) MnF 3 (Aldrich, $3.2/g) Mn 2 O 3 (Aldrich, $10/g) Excluding the applications in olefin epoxidation (or alkane oxidation), Mn(III) is most commonly used for oxidative radical cyclizations. This chemistry, largely developed by Barry Snider (Chem. Rev. 1996, 96, 339) has found broad applications in the total synthesis of natural products. Mn(OAc) 3 Thornton, J. Chem. Soc. Chem. Comm., 1978, 62. - crystallizes as Mn 3 O(OAc) 7 - anhydrous form does not exist - sold as Mn(OAc) 2 • 2H 2 O - insoluble in most organic solvents; soluble in hot AcOH - can be prepared in situ from Mn(OAc) 2 and KMnO 4 in AcOH F i r s t r e p o r t s . . . Bush J. Am. Chem. Soc. 1968, 90, 5903 Heiba J. Am. Chem. Soc. 1968, 90, 5905 Ph + 2 Mn III AcOH reflux xs O Ph O 60% a) b) O OR O Ph Mn(OAc) 3 •2H 2 O AcOH, 45 °C Ph O O OR Heiba J. Org. Chem. 1974, 39, 3456 This summary will not address the chemistry of Mn(III)salen complexes and Mn(III)porphyrins. For a review on the Jacobsen-Katsuki epoxidation see: Jacobsen, Catal. Asymmetric Synth. (ed. Ojima, I.), 159-202, (VCH, New York, 1993) and ref therein For a representative example in the field of Mn(III) porphyrins see Groves, J. Am. Chem. Soc., 1988, 110, 8628. Br R 3 Sn• R 3 SnH H Reductive processes Oxidative processes cyclization O Mn III Mn III Mn III O AcO - slow O Mn III Mn III Mn III O O fast O Mn III Mn III Mn II O O Ph O Mn III Mn III Mn II O O Ph O OMn III Ph O O Ph -Mn II
Transcript of Applications of Mn(III) in Organic Chemistry Florina Voica
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
Contents: Oxidative radical cyclization of β-keto acids Discussion of the reaction mechanism Oxidative radical cyclization of β-keto esters Oxidative radical cyclization of 1,3-diketones Oxidative cyclization of ketones Oxidative fragmentation-cyclization Asymmetric radical cyclization Miscellaneous applications of Mn(III) salts
Some common commercially available Mn(III) species:Mn(OAc)3•2H2O (Aldrich, $6/g)Mn(acac)3 (Aldrich, $3.1/g)MnF3 (Aldrich, $3.2/g)Mn2O3 (Aldrich, $10/g)
Excluding the applications in olefin epoxidation (or alkane oxidation), Mn(III) is most commonly used for oxidative radical cyclizations. This chemistry, largely developed by Barry Snider (Chem. Rev. 1996, 96, 339) has found broad applications in the total synthesis of natural products.
Mn(OAc)3
Thornton, J. Chem. Soc. Chem. Comm., 1978, 62.
- crystallizes as Mn3O(OAc)7- anhydrous form does not exist- sold as Mn(OAc)2• 2H2O- insoluble in most organic solvents; soluble in hot AcOH- can be prepared in situ from Mn(OAc)2 and KMnO4 in AcOH
First reports...
Bush J. Am. Chem. Soc. 1968, 90, 5903Heiba J. Am. Chem. Soc. 1968, 90, 5905
Ph + 2 MnIII AcOHrefluxxs
OPh
O
60%
a)
b) O
OR
OPh
Mn(OAc)3•2H2O AcOH, 45 °C
Ph
O O
OR
Heiba J. Org. Chem. 1974, 39, 3456
This summary will not address the chemistry of Mn(III)salen complexesand Mn(III)porphyrins.For a review on the Jacobsen-Katsuki epoxidation see:Jacobsen, Catal. Asymmetric Synth. (ed. Ojima, I.), 159-202,(VCH, New York, 1993) and ref thereinFor a representative example in the field of Mn(III) porphyrins seeGroves, J. Am. Chem. Soc., 1988, 110, 8628.
Br
R3Sn• R 3S
nH
H
Reductive processes
Oxidative processes
cyclization
O
MnIII
MnIII MnIII
O
AcO-
slowO
MnIII
MnIII
MnIII
O
O
fastO
MnIII
MnIII
MnII
O
O
Ph
OMnIII
MnIII
MnII
O
O
PhO
OMnIII
Ph
O
O
Ph
-MnII
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
The experts: Barry Snider E. J. Corey M. P. Bertrand Janine Cossy Phillip Zoretic and others
O
OH
O
1.3 eq Mn3O(OAc)7 AcOH, 20 min, rt
O
O
H
H
HH
63%
OO
O
H
H
HO
H
O
Corey, J. Am. Chem. Soc. 1984, 106, 5384
Early paper by Corey hinted at the potential of this new methodology to efficiently assemble complex polycyclic structures.
OH
OX
O
X OMn(OAc)3AcOH, 70 °C
H
X = CN (50%), only cisX = CO2Me (64%) cis:trans 4:1
Fristad, Tetrahedron Lett. 1985, 26, 3761
CHO
OMOM
CO2MeMeO2C
the major isomerafter a Luche reduction
1. KOH, MeOH2. Mn3O(OAc)7 (2 eq) AcOH, 70 °C
(one pot) OO
H OMOM
OMe
O
68% yield
OO
CHO
(±) - 14-epiupial
Upial could not be obtainedby the same strategy sincethe other isomer did notreact in the radical cyclization!
Paquette, Tetrahedron Lett. 1987, 43, 5567
For syntheses of upial see:Taschner, J. Am. Chem. Soc. 1985, 107, 5570 (key step: intramolecular aldol); Honda, Angew. Chem. Int. Ed. 2008, 47, 131 (key step: carbonyl ene reaction)
O
OCO2Me
O
OO
O Mn(OAc)3AcOH, 80 °C
58%
O
OCO2Me
H
HOMeO2C O
H
Mn(OAc)3AcOH, 65 °C
31%
Mechanism?Wallace, J. Chem. Soc. Perkin Trans. 1, 2001, 206.
Oxidative cyclization of β-keto acids
Reaction mechanism
O
CO2Me
Et
R
R = HR = Me
Mn(OAc)3 AcOH
Mn(OAc)3
Cu(OAc)2 AcOH
OR
CO2Me
HO
RCO2Me
R = H 71%R = Me 56%
Key concepts: - single electron oxidant - oxidative radical cyclization - radical oxidation - tandem radical cyclization - hydrogen abstraction
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
Factors that determine the reaction mechanism/product distribution:
The oxidant
Mn(OAc)3 - most common oxidant/initiator for these reactions. Other oxidants/initiators used: Fe(ClO4)3; CAN; Co(OAc)2 - in the termination step, its oxidative ability is limited: ∼ γ-carboxy radicals (2° and 3°) will be oxidized to carbocations ∼ tertiary radicals will be oxidized to carbocations to give alkene or to form a tertiary acetate ∼ allylic radicals will be oxidized to allylic acetates ∼ isolated 1° and 2° radicals wont be oxidized. If no oxidant is present they will be quenched by H-abstraction from the solvent or
Cu(OAc)2 - oxidizes 2° radicals 350X faster than Mn(OAc)3 - reacts rapidly with radicals (∼ 106 M/sec) to form alkyl-CuIII species - 1° and 2° radicals are taken to alkenes via direct oxidative elimination from the alkyl-Cu intermediate (E-olefins and the less substituted alkene) - allylic, 3° radicals are oxidized to carbocations
Kochi, Acc. Chem. Res. 1974, 7, 351
The solvent
AcOH is the most common solvent with Mn(OAc)3.
DMSO, MeOH, dioxane, CH3CN can also be used but they requirehigher temp and the yields are sometimes lower.
EtOH is a better H-donor than AcOH so it is preferred when vinyl radicalsare involved in the termination step (vinyl radicals cannot be oxidized sothey need to be quenched).
CuX2 (X = Cl, Br, I, SCN) - oxidize radicals to carbocations or they undergo ligand transfer
O
Et
OMe
O O
fast
O O
OMe
Et
slow
Cu(OAc) 2
O O
OMe
solventO O
OMe
O
Et
OMe
O
Me
Mn(OAc)3
- MnII
Mn(OAc)3
slow
MnIIIO
Et
CO2Me fast
- MnII
O
Et
CO2Me
Et
OMe
CO2Me
O
Me
CO2Me
Cu(OAc)2
O
OMe
OMe
H
OMe
OMnIII
Et
56%
or
OMe
CO2Me
HEtO
Me
CO2Me
Et
O
OMe
OMe
14%O
OMe
OMe
H3%
CuII
Et
Snider, J. Org. Chem. 1988, 53, 2137
boat TS
OH O
OMe
no discrete keto-ester radical detected!
cis
trans
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
Radical cyclizations of β-keto esters
OMe
OMe CO2Me
Mn(OAc)3 AcOH
50%O
MeO2C Me
Me
OMe
H MeO2C Me
Me
OMe
H
Zn, HCl
60%
O-methylpodocarpateSnider, J. Org. Chem. 1985, 50, 3659
OMe CO2Me
MeO
OMeMn(OAc)3 AcOH
70%O
MeO2C Me
Me
H
MeO
OMe
(±)-Triptoquinone B and C
Takaishi, J. Chem. Soc., Chem. Commun. 1993, 793
Proposed reaction mechanism:
OMe CO2Me
R'Mn(OAc)3
O
CO2Me
Me
Me
RO
MeO2C
Me
Me
R
Mn(OAc)3
O
MeO2C
Me
Me
R
O
OMe
MeOR'
Me
H
HH
MeMeO2C
MeHO
R'
OCO2Me
O
O
Mn(OAc)2•2H2O AcOH
O
O
OMeO2C
Me
H 40%
O
O
HOMeO2C
Me
H 7%+O
OHO
OMe
HO
O
triptolide
Yang, J. Org. Chem. 1998, 63, 6446
Trick to improve selectivity... (we shall see more of this later)
OCO2Et
OMe
Cl
Mn(OAc)2•2H2O AcOH OMe
OEtO2C
Me
HCl
90%
triptolide
OO
MeOOMe
Mn(OAc)3 (3 eq)Cu(OAc)2 (2 eq) AcOH, 80 °C
O
MeOO
OMe
76% vannusal A
Nicolaou, Chem Commun. 2002, 2480
O Mn(OAc)3 (1eq)Cu(OAc)2 (1 eq) AcOH, rt
61%
O
CO2Me
H
HMeO2C
H
HO
dehydropallescensin DWhite, Tetrahedron Lett. 1990, 31, 59
a. Monocylization
b. Bicycle formation with termination onto an arene
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
Oxidative cyclization of ketones
Me
Me
Me
TMS
O
Mn(OAc)3 (15eq)9:1 EtOH/AcOH 90 °C, 22h
TMS
Me
Me
O
Me
25%
Me
Me
O
Me
TMS37%
+
Me
Me
O
MeNaBH4, MeOH88%
Me
Me
HO
Me
H
gymnomitrol
AcOH100 °C
80%
Snider, J. Org. Chem. 1997, 62, 1970
O
Cl
+
OMe
Mn(OAc)3 (4eq)benzene, 100 °C
25%
O
Me
OMe
Cl
1. KOtBu (92%)2. LiPPh2 (84%)O
Me
OH
conocarpan
Mechanism?
Snider, J. Org. Chem. 1997, 6978
Oxidative fragmentation-cyclization
H
Me
Me
HO
Mn(pic)3 DMF
58%
Me
H
MeO
Me
H
Mesilphiperfol-6-ene
Snider, J. Org. Chem. 1994, 59, 5419
O
OO
Ph2t-BuOO
OO
O
H
OO
O
H
tricycloillicinone
Mn(OAc)3Cu(OAc)2
AcOH, 50 °C75%
Danishefsky, J. Am. Chem. Soc. 1998, 120, 12684
N
O
Mn(OAc)3AcOH, reflux
60%
OO
N
O
O
O
N
N
Omersicarpine Kerr, Org. Lett. 2008, 10, 1437
HO
OTHP
Mn(pic)3Bu3SnH
DMF, 0 °C
H Me
HTHPO
O
H Me
HSCNMe
10-isothiocyanatoguaia-6-ene
Narasaka, Chem. Lett. 1994, 1697
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
OCO2Me
Mn(OAc)3Cu(OAc)2, AcOH
44%CO2Me
O H OAcMechanism?
CO2MeO
Mn(OAc)3Cu(OAc)2, AcOH
37% CO2MeO
H
OAc
H
CO2MeO
Mn(OAc)3Cu(OAc)2, AcOH
8%MeO2CO
H
HH
CO2MeO
Mn(OAc)3Cu(OAc)2, AcOH
40%CO2MeO
H
Pattenden, Synlett. 1997, 398
OEtO2C
Mn(OAc)3Cu(OAc)2 MeOH
rt, 3h
Me
H
Me
HMeEtO2C
O
35% yieldOther observed products:
Me
O
MeEtO2C H 1.5%
Me
O
MeEtO2C H 3%
Mechanism?
Me
O
H
Me
HMeEtO2C
isosteviol
Me
H
Me
HMe
HO
OHBeyer-15-ene-3,19-diolSnider, J. Org. Chem. 1998, 63, 7945
CO2MeO
Mn(OAc)3Cu(OAc)2, AcOH
35%
Me
H
Me
HMe CO2MeO
OAc
OAc
Me
H
Me
HMe CO2MeO
OAc
+
A
B
A : B / 1 : 2
Me
H
Me
HMeO
HOO
HO isospongiadiolZoretic, J. Org. Chem. 1996, 61, 1806
Me
H
Me
HMeEtO2C
O
OCO2Et
CN
2 eq Mn(OAc)31 eq Cu(OAc)2 AcOH
38-45%
OEtO2C Me
Me
H
H
CN
Me
H
O
Me
Me
H
H
H
Me
H
O
Zoretic, Tetrahedron Lett. 1996, 7909
5 13
confirmed by X-rays
5
13
5
4
8
HH
OCO2Me
H
H
HH
HOCO2Me
Mn(OAc)3
transanular cyclization
d. Tandem polycyclizations
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
OCl CO2Me
CN 2 eq Mn(OAc)31 eq Cu(OAc)2 AcOH
OMeO2C Cl
Me
H
H
CN
Me
H
OAc
5% yield
OMeO2C Cl
Me
H
H
CN
Me
H
61% (mixture of three isomers)
CF2CO2H
OMeO2C Cl
Me
H
H
CN
Me
H 70%
HO
Me
H
H
H
Me
H
HO
Me
H
H
H
Me
H
O
Zoretic, J. Org. Chem. 1998, 63, 7213
+
Oxidative Radical Cyclization of 1,3-diesters
H
HMe
THPO
O
O
Cl
CO2Me
Mn(OAc)2•2H2OCu(OAc)2•H2O
EtOH, reflux
H
HMe
THPO
O
O
Cl
CO2Me65%
H
H
MeHOO O
CO2MeZn, HCl 87%H
H
Me
O OO
(-)-Estafiatin
Lee, J. Am. Chem. Soc. 1997, 119, 8391
MeMe
HH
OO
O Mn(OAc)3 EtOH, rt
65% O
MeMe
HOO
H
O
MeMe
HOHO
H
SmI2
1. TBAF2. AcCl
70%O
MeMe
HOAc
O H
9-Acetoxyfukinanolide
92%
Greene, J. Am. Chem. Soc. 1996, 118, 9992
α-Chloro substitution prevents overoxidation of the product!
Oxidative Radical Cyclization of 1,3-diketones
OMe
OMe
O
OH
NMeO
MeO
N
O
O
MeO
MeO
OMe
OMe
Mn(OAc)3Cu(OAc)2
AcOH, rt72%
Fredericamycin A
Rao, J. Chem. Soc. Perkin Trans. 1, 1993, 3171
8
5-α pregnane
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
Oxidative cyclization of ketones
Me
Me
Me
TMS
O
Mn(OAc)3 (15eq)9:1 EtOH/AcOH 90 °C, 22h
TMS
Me
Me
O
Me
25%
Me
Me
O
Me
TMS37%
+
Me
Me
O
MeNaBH4, MeOH88%
Me
Me
HO
Me
H
gymnomitrol
AcOH100 °C
80%
Snider, J. Org. Chem. 1997, 62, 1970
O
Cl
+
OMe
Mn(OAc)3 (4eq)benzene, 100 °C
25%
O
Me
OMe
Cl
1. KOtBu (92%)2. LiPPh2 (84%)O
Me
OH
conocarpan
Mechanism?
Snider, J. Org. Chem. 1997, 6978
Oxidative fragmentation-cyclization
H
Me
Me
HO
Mn(pic)3 DMF
58%
Me
H
MeO
Me
H
Mesilphiperfol-6-ene
Snider, J. Org. Chem. 1994, 59, 5419
O
OO
Ph2t-BuOO
OO
O
H
OO
O
H
tricycloillicinone
Mn(OAc)3Cu(OAc)2
AcOH, 50 °C75%
Danishefsky, J. Am. Chem. Soc. 1998, 120, 12684
N
O
Mn(OAc)3AcOH, reflux
60%
OO
N
O
O
O
N
N
Omersicarpine Kerr, Org. Lett. 2008, 10, 1437
HO
OTHP
Mn(pic)3Bu3SnH
DMF, 0 °C
H Me
HTHPO
O
H Me
HSCNMe
10-isothiocyanatoguaia-6-ene
Narasaka, Chem. Lett. 1994, 1697
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
PhO
O O Mn(OAc)3Cu(OAc)2
90%86% de
O
O
O
Me
Ph
N
O O Mn(OAc)3Cu(OAc)2 28%92% de O
O
Me
N
Snider, J. Org. Chem. 1993, 58, 7640
O
CO2Me
+N
O
O
O
PhPh
O
CO2MeO
N O
Ph
Ph
MeO
MeO
MeO
MeOO
MeO OMe
O
OMeO
MeO
O
O
OO
(-)-virgatusin
Mn(OAc)3AcOH70%
40% yield80% deBrun, Eur. J. Org. Chem. 2009, 2306
Miscellaneous applications of Mn(III) salts
NBn
O
HO
O
EtO
tetramic acid
+
2eq
Ph
Ph1 eq
air
Mn(OAc)3 (1eq) AcOH, rt
OO
NBn
OPh
Ph
OH
OEtO
93%Mechanism?
Nishino, Tetrahedron Lett. 1998, 39, 7931
O
Ph
OO Ph
Ph+
1.5 eq 1 eq
Mn(OAc)3 (3eq) AcOH, reflux
77%O O
O
PhPh
Ph
Nishino, Tetrahedron Lett. 2006, 47, 7259O
Ph
OO Ph
Ph+
1.5 eq 1 eq
Mn(OAc)3 (0.1eq) AcOH, rt
O O
O
PhPh
PhO
85%
Nishino, Eur. J. Org. Chem. 2008, 2404
B(OH)2
benzene reflux
Mn(OAc)3 (3eq)
95%
B(OH)2
thiophene reflux
Mn(OAc)3 (3eq)
73%
B(OH)2
furan reflux
Mn(OAc)3 (3eq)
S
O
62%
Demir, J. Org. Chem. 2003, 68, 578
Asymmetric radical cyclizationO
S
O
PhMn(OAc)3Cu(OAc)2 Me
O
SPh O 44%
100% de
Me
O
H1. oxone2. Na/Hg
Snider, J. Org. Chem. 1991, 56, 328
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
Mn(OAc)3 (5eq)benzene, reflux
O
O Ph
O
O Ph
OAc64% O
OAc Ph
OAc
1. NaBH4/CeCl32. Ac2O/Et3N
89%
Danishefsky, Tetrahedron Lett. 1985, 26, 3411
N
NMe
N
O
OH
MeO
Me
OMe
CNOH
H H
H
H
Mn(OAc)3 (xs)0.3% H2SO4-ACN rt, 2h
55%
N
NMe
N
O
O
MeO
Me
O
CNOH
H H
H
H
(±)-Cyanocycline AFukuyama, J. Am. Chem. Soc. 1987, 109, 1587
O
OTBS
TBSOO
H
OMeH
H
H
O
O
OTBS
TBSOO
H
OMeH
H
H
Mn(OAc)3 (0.1eq) TBHP (5eq)
72%
Shing, Org. Lett. 2006, 8, 3149
O
N
O
OH
O
O
OMn(OAc)3 (1eq)benzene, reflux
88%
N OH
Mn(OAc)3 (1eq)benzene, reflux
91%O
Demir, Tetrahedron Lett. 1997, 38, 7267
NC
NH2
+
CHO
OMe
OMeAcOH
CO2Et
CO2EtNH
MeO
MeO
O1. MeOH, rt2. Mn(OAc)3 (4.5eq) AcOH
EtO2C CO2Et4 eq
59%
MeO
MeO
N
O
t-BuHN
O CO2Et
CO2Et
MeO
MeO
N
O
t-BuHN
O
CO2EtEtO2C
MeO
MeO
N
O
t-BuHN
O
CO2EtEtO2C
MeO
MeO
N
O
t-BuHN
O
CO2EtEtO2C
1,4 aryl transfer
O
O OEt
Br
OMe
H
OBzO
O OEt
Br
OMe
H
OBzAcO
Mn(OAc)3benzenereflux, 24h
67%
Watt, Synth. Commun. 1989, 19, 1127
For a review on methods of α'-oxidation of enones see: Demir, Synthesis 1991, 235
Proposed reaction mechanism:
Applications of Mn(III) in Organic Chemistry Florina VoicaBaran lab GM 2/6/2010
MeO
MeO
N
O
t-BuHN
O
CO2EtEtO2C
Mn(III)AcOH
Nt-BuHN
O
CO2EtCO2Et
O
OAc
OMeMeO
H2O
OMeMeO CO2Et
CO2EtNH
O
Mn(III)
5-exo-trig
CO2Et
CO2EtNH
MeO
MeO
O
indane Vieu, Org. Lett. 2007, 9, 4171
N3
MeO
O O
+
1.5 eq
Mn(OAc)3•2H2O (0.1eq)AcOH (2 eq), MeOH, 40 °C
HN
Me
Ph
CO2Me90%
Mechanism?
Narasaka, Org. Lett. 2008, 10, 5019
Ph
N3
HO Ph(1.5 eq)
Mn(acac)3 (1.7eq)MeOH, rt, 5 min thenAcOH (2eq), rt, 1h
N PhPh
84%
OH
1.2 eq(slow addition)
Mn(acac)3 (0.1eq) MeOH, rt, 1h
N
OH
Ph
Mechanism?
Chiba, J. Am. Chem. Soc. 2009, 131, 12570
O
OH
TMS
CO2Me
CO2Me
+
MnF3 (1.2eq) DCM
61%O
CO2Me
CO2Me
via O
Mikami, Synlett. 2002, 1868
Underdevelopped aspects of this chemistry: - efficient asymmetric radical cyclization - catalytic oxidative radical cyclization - model studies to understand the tandem cyclizations better - more creative examples for the termination step
Conclusions: - oxidative tandem cyclization provides access to complex carbon skeletons - stereo- and regiospecific method for rapid assembly of polycyclicstructures from simple linear precursors - numerous applications in natural product synthesis - Mn(OAc)3 selective, mild oxidant - very little chemistry of Mn(III) salts other than Mn(OAc)3
