total synthesis of illicium sesquiterpeneskanai/seminar/pdf/lit_a_iwai_b4.pdf · introduction...
TRANSCRIPT
-
TotalSynthesisofIllicium Sesquiterpenes
LiteratureSeminar2020/01/23
B4AtsushiIwai
1
-
Contents
1. Introduction
2. Pseudoanisatin
3. Majucin
4. Summary
2
-
Contents
1. Introduction
2. Pseudoanisatin
3. Majucin
4. Summary
3
-
Introduction
Sesquiterpene
isoprene
× 3
Sesquiterpene
caryphyllan
bisabolan germacran
seco-prezizaane4
-
Introduction
Sesquiterpene
isoprene × 3
Sesquiterpene
caryphyllan
bisabolan germacran
seco-prezizaane
Illicium(シキミ)
5
-
Me
HOO
OHMe
OH
O
OO
MeO
Introduction
Illiciumsesquiterpene familymembersubtypes
6
O
O
OO
O
O
seco-prezizaane
pseudoanisatinoids
majucinoids
anisatinoids
H
Me
OH OHMe
O
HO
H
O
O
H
Me
OH
OO
OHMe
HOH
O
HO
H
O
H
Me
HO
O
OH
HOH
HO
H
O
Me
O
O
pseudoanisatin
majucin
anisatin
jiadifenin
H
Me
OH OHMe
O
O
O
O
3-oxo-pseudoanisatin
H
Me
HO
O
OH
HOH
HO
H
O
COOCH3
O
O
veranisatinsC
-
7
Introduction
Previoustotal-synthesisexample
Danishefsky,S.J.etal.J.Am.Chem.Soc.2004,126,14358.
l OxidizedFGwasinstalledatearlystage.l C-Cbond formation reactionmakescoreskeletonofilliciumsesquiterpene.
-
8
Introduction
Maimone’ssynthesisstrategybyoxidation
H
Me
OH OHMe
O
HO
H
O
O
pseudoanisatin
H
Me
OH
OO
OHMe
HOH
O
HO
H
O
majucin
seco-prezizaane
seco-prezizaane
DirectC-HorC-Cfunctionalization ofseco-prezizaaneskeletonwouldmakeshortanddiversesynthesisofilliciumsesquiterpene.
-
OPP
Me
Me Me
Me
Me
Me Me
Me
Me
Me Me
MeH
Me
Me Me
Me
Me
Me
MeMe
Me
MeMe
Me
Introduction
Proposedbiosyntheticpathway
9
cyclase
alkylshift
C-Cscission
-OPP
seco-prezizaaneskeleton
H
H
Me
Me
Me
Me
OHH
(+)-cedrol
$52USD/kgFukuyama,Y.;Huang, J.-M.BioactiveNaturalProducts (PartL);StudiesinNaturalProductsChemistry;Atta-ur-Rahman,Ed.;2005,Vol.32,p395.
-
Introduction
Synthesisstrategy
10
H
H
Me
Me
Me
Me
OHH
(+)-cedrol
$52USD/kg
l Introduceposition-selectivehydroxylgroupsbasedonnearbyhydroxylgroupsorcarboxylicacids.(Redox-relay)
l Skeletalrearrangement byringexpansion andC−Ccleavage.
H
Me
OH OHMe
O
HO
H
O
O
(+)-pseudoanisatin
-
Introduction
Synthesisstrategy
11
H
Me
OH OHMe
O
HO
H
O
O
H
Me
OH
OO
OHMe
HOH
O
HO
H
O
(+)-pseudoanisatin (-)-majucin
Synthesizedifferentlyaccordingtooxidationorderandlocation.
radical-mediatedC-14methyloxidation
Fe-catalyzedC-4methineactivation
C-10andC-12oxidation
radical-mediatedC-4methineactivation
H
H
Me
Me
Me
Me
OHH
HH
144
10
12
-
Contents
1. Introduction
2. Pseudoanisatin
3. Majucin
4. Summary
12
-
Pseudoanisatin
Keyreaction
13
H
H
Me
Me
Me
Me
OHH
HH
3 4 14
7
11
(1) C-14oxidationbySuarez’s radical-basedmethod.
(2) Introductionofhydroxylgroup toC-7through acyloxylationwithCuBr2.
(3) α-Ketolrearrangement.
(4) Regioselectiveoxidationreactionusing intramolecularcarboxylicacidasdirectinggroupatC-4position.
Carbontobeoxidized
H
Me
OH OHMe
O
HO
H
O
O
K.Hung,M.L.Condakes,T.Morikawa,T.J.Maimone,J.Am.Chem.Soc.,2016,138,16616
-
Pseudoanisatin
Synthesisscheme
14
FeL L
NNN
N
MeMe
MeMe
MeMe
L = MeCNX = SbF6
2X
[Fe]=
H
H
Me
Me
Me
Me
OHH
a. PhI(OAc)2, I2, hν73 %
HMe
MeH
OMe
Me
H
HMe
MeH
OMe
Me
H
HOOC O
b. Me3OBF4,proton sponge
97 %
c. NaIO4RuCl3・xH2O
72 %
H
O
Me
MeH
OMe
O
Me
O
d. CuBr2t-BuOH diglyme,∆
H
OK
Me
MeH
OMe
Me
O
OK
OH
MeOMe
Me
OHOOH
Me
H
Oe. KOHKOt-Bu
45 %(2 steps)
4:1 dr
H
MeOMe
Me
OTBSOOH
Me
H
O
MeOR1
Me
OR2O
Me
H
O
O
f. NaH, TBSClthen
aq. HCl88 %
g. [Fe]TBHP
37 % combinedC-H [O]
20 % R1 = Me, R2 = TBS11 % R1 = H, R2 = TBS 6 % R1 = H, R2 = H
-
H
H
Me
Me
Me
Me
OH R
H
H
H
Me
Me
Me
OH
H
H
HMe
Me
Me
OH
H
I I
HMe
Me
Me
OH
H
IH
Me
Me
Me
HO
HMe
Me
Me
HO
HMe
Me
Me
HOO
MeMe
MeMe
HMe
MeH
Base
H
OMe
Me
H
H
Pseudoanisatin
Reactionmechanism
15
1,5-hydrogentransfer
H
H
Me
Me
Me
Me
OHH
a. PhI(OAc)2, I2, hν73 %
HMe
MeH
OMe
Me
H
b. Me3OBF4,proton sponge
97 %
R.Baker,M.A.Brimble,J.A.Robinson,TetrahedronLett.,1985,26,2115.
-
Pseudoanisatin
Suarez’sradical-basedmethod
16J.I.Concepcion,C.G.Francisco,R.Hernandez,J.A.Salazar,E.Suarez,TetrahedronLett.,1984,25,1953.
Entry Alcohol(1eq)
PhI(OAc)2/I2(eq)
Time(min.)
Temperature(℃)
Product(Yield %)
1 1 1.1/1.0 50 40 2(90)2 1 1.1/0.0 120 40 Noreaction3 3 1.1/1.0 30 25 4(53)4 6 1.1/0.5 40 40 7(90)
C8H17
AcOOH
H
C8H17
AcOO
H AcO
H OH
AcO
I OH
AcOH
O
HO
AcOH
O
O
C8H17
AcOOH
H
C8H17
AcOO
H
PhI(OAc)2, I2, hν
cyclohexane
AcO
O
1. 2. 3. 4.
5. 6. 7.
-
Pseudoanisatin
Reactionmechanism
17[O]wasinstalledtotwodifferentposition by3stepsusingC-6-OH
HMe
MeH
OMe
Me
H
HMe
MeH
OMe
Me
H
HOOC Oc. NaIO4
RuCl3・xH2O72 %
HMe
MeH
OMe
Me
H
RuOO
O O
HMe
MeH
OMe
H
OMe
O RuO
O
HMe
MeH
OMe
Me
H
O
H
O
RuOO
O O
HMe
MeH
OMe
Me
H
OH
O ORuO
O O
HMe
MeH
OMe
Me
H
HOOC O
-
HMe
MeH
OMe
Me
H
HOOC O
Br
HMe
MeH
OMe
MeHOOC O
HMe
MeH
OMe
MeO
OHO
H
O
Me
MeH
OMe
O
Me
O
OH
H
OK
Me
MeH
OMe
Me
O
OK
O H
MeOMe
Me
OHOOH
Me
H
O
Pseudoanisatin
Reactionmechanism
18
electrontransfer
CuBr2
HMe
MeH
OMe
Me
H
HOOC O
d. CuBr2t-BuOH
diglyme,∆H
O
Me
MeH
OMe
O
Me
O
e. KOHKOt-Bu
45 %(2 steps)
H
MeOMe
Me
OHOOH
Me
H
O
cf)substratescopeofoxidativelactonization(Maimone,T.J.etal.JACS,2019,141,3083.)
Stereoselectiveoxidation
-
HMe
MeH
OMe
Me
H
HOOC O
Br
HMe
MeH
OMe
MeHOOC O
HMe
MeH
OMe
MeO
OHO
H
O
Me
MeH
OMe
O
Me
O
OH
H
OK
Me
MeH
OMe
Me
O
OK
O H
MeOMe
Me
OHOOH
Me
H
O
Pseudoanisatin
Reactionmechanism
19
electrontransfer
CuBr2
HMe
MeH
OMe
Me
H
HOOC O
d. CuBr2t-BuOH
diglyme,∆H
O
Me
MeH
OMe
O
Me
O
e. KOHKOt-Bu
45 %(2 steps)
H
MeOMe
Me
OHOOH
Me
H
O
Stereoselectiveoxidation
Miyake,H.;Nishimura,A.;Yago,M.;Sasaki,M.Chem.Lett.2007,36,332.
-
H
MeOMe
Me
OTBSOOH
Me
H
OH
MeOMe
Me
OTBSOOFeLn
Me
H
OO
MeOMe
Me
OTBSOOFeLn
Me
H
OOH
OH
MeOMe
Me
OTBSOOH
Me
H
O
MeOMe
Me
OTBSO
Me
H
O
O
Pseudoanisatin
Reactionmechanism
20
H
MeOMe
Me
OTBSOOH
Me
H
O
MeOR1
Me
OR2O
Me
H
O
O
g. [Fe]TBHP
37 % combinedC-H [O]
20 % R1 = Me, R2 = TBS11 % R1 = H, R2 = TBS 6 % R1 = H, R2 = H
Site-selectiveoxidation
M.A.Bigi,S.A.Reed,M.C.White,J.Am.Chem.Soc.,2012,134,9721.
-
Pseudoanisatin
C-Hoxidationbyironcomplexes
21M.A.Bigi,S.A.Reed,M.C.White,J.Am.Chem.Soc.,2012,134,9721.
L.Gómez, I.Garcia-Bosch,A.Company,J.Benet-Buchholz,A.Polo,X.Sala,X.Ribas,M.Costas,Angew.Chem.Int.Ed.,2009,48,5720.
cat3=[Fe(CF3SO3)2((S,S,R)-mcpp)]
-
Pseudoanisatin
C-Hoxidationbyironcomplexes
22
M.A.Bigi,S.A.Reed,M.C.White,J.Am.Chem.Soc.,2012,134,9721.
-
Pseudoanisatin
C-Hoxidationbyironcomplexes
23
M.A.Bigi,S.A.Reed,M.C.White,J.Am.Chem.Soc.,2012,134,9721.
-
MeOMe
Me
OTBSO
Me
H
O
O
H
OTBS
Me
OMe
OEt
O
Me
OMe
H
OH
Me
OMe
Me
O
O
OH
Me
OMe
Me
O
O
HO OH
HH
OH
Me
OMe
Me
O
O
H OH
HHO
h. Et3OPF6,proton spongethen, TFA/H2O
66 %(85 % BRSM)
i. TMSClNaI
j. TBAFAcOH64 %
(2 steps)
k. OsO4・TMEDA
l. MsCl, pyr.;NaOH( aq.)
80 %(2 steps)
Pseudoanisatin
Synthesisscheme
24
(+)-pseudoanisatin
-
4
11
14Redox-relayC6 →C11,C14
Redox-relayC11 →C7
11
7
α-ketolrearrangement
Redox-relayC11 →C4
Pseudoanisatin
SummaryofPseudoanisatin synthesis
Redox-relayC4 →C3
11
4
3
l (+)-Pseudoanisatinwassynthesizedbyfullyoxidative strategy.l Isthisstrategyapplicableforotherilliciumsesquiterpenes?
H
Me
OH OHMe
O
HO
H
O
O
25
6
(+)-pseudoanisatin
-
Contents
1. Introduction
2. Pseudoanisatin
3. Majucin
4. Summary
26
-
Majucin
Keyreaction
27
H
H
Me
Me
Me
Me
OHH
HH
3 4 14
7
11
(1) C-4selectiveoxidationbySuarez’sradical-basedmethod.
(2) C-7&C-12oxidationbySeO2 withoutH2O.
(3) α-ketolrearrangement.
(4) C-10oxidation.
Carbontobeoxidized
10
12
H
Me
OH
OO
OHMe
HOH
O
HO
H
O
M.L.Condakes,K.Hung,S.J.Harwood,T.J.Maimone,J.Am.Chem.Soc.,2017,139,17783
-
28
C6 →C11,C14 C11 →C4
Majucin
Firsttrial:C6 →C11,C14 →C4
a. PhI(OAc)2, I2, hν73 %
b. Me3OBF4,proton sponge
97 %
43 %
34 %
-
29
C6 →C11,C14 C11 →C4
Majucin
Firsttrial:C6 →C11,C14 →C4
a. PhI(OAc)2, I2, hν73 %
b. Me3OBF4,proton sponge
97 %
43 %
34 %
-
Majucin
Synthesisscheme
30
H
H
Me
Me
Me
Me
OHH
a. PhI(OAc)2, I2, hνthen add
HMe
MeH
OAc
Me
H
Ac2O,H3PO467 %
b. BH3・THF;
CrO3・2pyr
HMe
MeH
OAc
H
OH
c. NaBH4 72 %(2 steps)
d. PhI(OAc)2, I2, hν
e. RuCl3・xH2OKBrO3
72 %
f. SeO2, 4 Å MS;
g. L-selectride;
KOH/MeOH
H
H
Me
Me
H
MeH
OAc
O
MeH
93 %
HMe
Me
OAc
HMeH
H
O
H
H
Me
Me
OAc
O
O
MeO
K2CO3,Me2SO4
HMe
Me
OAc
O
O
O OMe
O
HMe
Me
O
O
O
OOH
50 %(2 steps)
-
Majucin
Reactionmechanism
e. RuCl3・xH2OKBrO3
72 %H
Me
Me
OAc
HMeH
H
O
H
H
Me
Me
OAc
O
O
MeO
H
H
Me
Me
H
MeO
OAc
H
Ru
O
OO
O
H
H
Me
Me MeO
OAc
HRu
OH
OO
O
H
H
Me
Me MeO
OAc
RuOH
OO
HO
H
H
Me
Me MeO
OAc
RuO
OO
O
H
H
Me
Me
OAc
O
O
MeO
31
KBrO3
A.Tenaglia,E.Terranova,B.Waegel,J.Org.Chem., 1992,57,5523.
-
Majucin
C-HoxidationbyRuO4
32
A.Tenaglia,E.Terranova,B.Waegel,J.Org.Chem., 1992,57,5523.E.McNeillandJ.DuBois,J.Am.Chem.Soc., 2010,132,10202.
-
Majucin
Reactionmechanism
33
H
H
Me
Me
OAc
O
O
MeO
HMe
Me
OAc
O
O
O OMe
O
f. SeO2, 4 Å MS;K2CO3,Me2SO4
H
H
Me
Me
OAc
O
O
MeOSeO
O
HMe
Me
OAc
O
O
OSe
OH
O
HMe
Me
OAc
O
O
MeO
OSe OH
H
HMe
Me
OAc
O
O
OH Se
O
O
HMe
Me
OAc
O
O
OSe
HO O
HMe
Me
OAc
O
O
OO
SeOH
H
HMe
Me
OAc
O
O
OO
H
HMe
Me
OAc
O
O
OO
OH
Base
SOMe
O O
OMe
HMe
Me
OAc
O
O
OO
OMe
-
Majucin
Reactionmechanism
HMe
Me
OAc
O
O
O OMe
OB
H
LiH
Me
Me
O
O
O
O OMe
OLiO
OHH
Me
Me
O
O
O
O OMe
OK
HMe
Me
O
O
O
OOH
H
H
HMe
Me
O
O
O
OOH
g. L-selectride;
KOH/MeOH
HMe
Me
OAc
O
O
O OMe
O
HMe
Me
O
O
O
OOH
50 %(2 steps)
34K.Hung,M.L.Condakes,L.F.T.Novaes,S.J.Harwood,T.Morikawa,Z.Yang,T.J.Maimone,J.Am.Chem.Soc.,2019,141,3083.
-
Majucin
Synthesisscheme
h. DMDO,i. PhCF3, Δ
j, Me4NBH(OAc)3
64 %(3 steps)
k. TsOH・H2On-BuOH, Δ
71 %
l. LiHMDSMoOPH
m. [Ru2(PEt3)6(OTf)3][OTf]i-PrOH
75 %
HMe
Me
O
O
O
OOH
H
Me O
O
Me
OO
OH
OH
H
Me
Me
OO
OH
O
O
65 %
H
Me
Me
OO
OH
O
OHOH
H
Me
Me
OO
OH
O
OH
HOn. OsO4・TMEDA
61 %
H
Me
Me
OO
OH
O
OH
HO
OHHO
35
-
Majucin
Reactionmechanism
OHMe
Me
O
O
O
OOH
OO
HMe
Me
O
O
O
OOH
HMe
MeO
O
OO
OH
O
H
Me O
O
Me
OO
OH
OBOAcH
OAcAcO
H
Me O
O
Me
OO
OH
OH
O B(OAc)2
H
O
h. DMDO,i. PhCF3, Δ
j, Me4NBH(OAc)3
64 %(3 steps)
HMe
Me
O
O
O
OOH
H
Me O
O
Me
OO
OH
OH
36
-
Majucin
Reactionmechanism
H
Me O
O
Me
OO
OH
OH
HH2O
H
Me HO
Me
OO
OH
OH
O
OH
H
Me HO
Me
OO
OH
O
OH
H
Me H2O
Me
OO
OH
O
O
HH
Me
Me
OO
OH
O
O
k. TsOH・H2On-BuOH, Δ
71 %
H
Me O
O
Me
OO
OH
OH
H
Me
Me
OO
OH
O
O
37
-
Majucin
Reactionmechanism
H
Me
Me
OO
OH
O
O
H
NSi
Si
Li
H
Me
Me
OO
OH
O
OLi
O
OMo
O
O
O
APMH Py
H
Me
Me
OO
OH
O
OHOH
H
Me
Me
OO
OH
O
O
H
Me
Me
OO
OH
O
OHOHl. LiHMDS
MoOPH
65 %
38
-
Majucin
Reactionmechanism
RuLn
RuLnO H
RuLnH
RuLnHO
OH
OH
O O
39
H
Me
Me
OO
OH
O
OHOH
H
Me
Me
OO
OH
O
OH
HO
m. [Ru2(PEt3)6(OTf)3][OTf]i-PrOH 75 %
OH
or
O
orO
or
OHor
Almeida,M.L.S.,Beller,M.,Wang,G.,Backvall,J.,Chem.Eur.J.,1996,1533.
-
Majucin
TransferhydrogenationbyRutheniumcomplex
40Hill,C.K.;Hartwig,J.F.Nat.Chem.2017,9,1213.
Oxidation Reduction
Ru-2=[Ru2(PEt3)6(OTf)3][OTf]
Results and discussionDevelopment of catalysts and conditions for the selectiveoxidation of hindered secondary alcohols. Several sequentialphases of catalyst development described in the SupplementaryInformation led to a new ruthenium complex (Fig. 1a andSupplementary Section 2). The precursor Ru(DMSO)4(OTf)2(DMSO, dimethylsulfoxide; OTf, SO2CF3) was generated inacetone solvent and treated with various phosphine ligands to givepotential catalysts. The complexes that result from the addition ofunhindered alkylphosphines PEt3, PMePh2 and PEt2(p-Me2N–Ph)all gave active catalysts for the dehydrogenation of the hinderedmodel alcohol diisopropylcarbinol. Thereafter, a synthesis of aseries of catalyst precursors lacking DMSO ligands was developed(Ru-1, Ru-2 and Ru-3), and the activity of these complexes wasfound to be an order of magnitude greater than that of the systemgenerated in situ. The initial results of the oxidation of a modelhindered alcohol are shown in Fig. 1b. In contrast to priortransition-metal catalysts that do not oxidize such hinderedsecondary alcohols, this ruthenium complex converteddicyclohexylcarbinol into the corresponding ketone at roomtemperature in only three hours. The same oxidation alsooccurred when 1,4-cyclohexanedione or trifluoroacetophenone
was used as a stoichiometric oxidant and the reaction was run intrifluoroethanol solvent.
The reactions of a series of primary and secondary alcohols andmixtures of primary and secondary alcohols with acetone as thehydrogen acceptor and Ru-2 as the catalyst are shown in Fig. 1c.These results show that the oxidation of secondary alcoholsoccurs over the oxidation of primary alcohols. The individual reac-tions of primary alcohols occur to a low conversion over a time thatleads to the full conversion of secondary alcohols, and reactions witha mixture of primary and secondary alcohols preferentially convertthe secondary alcohol into the ketone.
Selective oxidation of polyol natural products to ketonederivatives. Figure 2 summarizes the transfer dehydrogenation of13 polyol natural products and three methyl esters of naturalproducts. This figure shows the products from the oxidationreactions and the configuration of the alcohol unit that underwentoxidation. These reactions occur with several classes of naturalproducts, including steroids, diterpenoids, sesquiterpenoids,iridoids, carbohydrates, alkaloids and macrolides, which shows thebroad applicability of the catalyst system. The ruthenium catalystswe developed display a remarkable selectivity for the oxidation of
OH
OH
Selectivity
OH
OH
11.5 (7.8)
OH
OH OH
OH OH
OH
*10 min reaction*4% loading
*8% loading *8% loading,65 °C
64% (64%)
15% (16%)
*69% (70%)
*6% (9%)
*82% (82%)*88% (91%)
*(2%)
*10 min reaction
*51% (54%)
*24% (58%)
*75% (77%)
*(13%)*13% (27%)
4.3 (4.0)6.3 (3.0)
(45.5) 2.1 (0.9) (5.9)
OH OH
OHOH OH
98% (98%)84% (85%)7% (16%) 5% (12%) (2%)
0.5% Ru-2, 1% NMM
r.t., Me2CO (0.2 M, 65 equiv.), 45 minR R'
OHR" OHand/or
R R'
OR" Oand/or
0.1% Ru-2r.t., 1:1 Me2CO:TFE, 3 h
Cy Cy
O
Cy Cy
OH
99%
cis-Ru(DMSO)4Cl2 + PR3CH3OH
r.t. to 65 °C[Ru2(PR3)6Cl3]Cl
PR3 Catalyst
PMePh2 Ru-1PEt3 Ru-2PEt2(p-Me2N-Ph) Ru-3
[Ru2(PR3)6(OTf)3][OTf] AgOTf, TFE
r.t.
Reaction yields for oxidation of individual alcohols
Reaction yields for competitive oxidation of pairs of alcohols
a
b
c
d
or
0.1% Ru-2, 0.2% NMMr.t., 1.1 equiv. acceptor, TFE, 4 h
Stoichiometric ketone acceptors
CF3
O
OO
tBu Me
O 0.2% Ru-2, 0.4% NMM
1:1 iPrOH:TFE, 45 °C, 3 h tBu Me
OH
99%
Ru-2
NMM
O N
Figure 1 | Model alcohol oxidation and catalyst synthesis. a, Synthesis of the ruthenium catalyst for alcohol-transfer dehydrogenation. b, Mild oxidation of ahindered secondary alcohol is enabled by the catalyst Ru-2. c, Reactions of primary and secondary alcohols show the selectivity for the oxidation ofsecondary alcohols over primary alcohols. Conversions are shown in parentheses. d, The mild reduction of a hindered ketone is enabled by Ru-2 with iPrOHas the reductant. r.t., room temperature. NMM; N-methylmorpholine.
ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2835
NATURE CHEMISTRY | VOL 9 | DECEMBER 2017 | www.nature.com/naturechemistry1214
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Results and discussionDevelopment of catalysts and conditions for the selectiveoxidation of hindered secondary alcohols. Several sequentialphases of catalyst development described in the SupplementaryInformation led to a new ruthenium complex (Fig. 1a andSupplementary Section 2). The precursor Ru(DMSO)4(OTf)2(DMSO, dimethylsulfoxide; OTf, SO2CF3) was generated inacetone solvent and treated with various phosphine ligands to givepotential catalysts. The complexes that result from the addition ofunhindered alkylphosphines PEt3, PMePh2 and PEt2(p-Me2N–Ph)all gave active catalysts for the dehydrogenation of the hinderedmodel alcohol diisopropylcarbinol. Thereafter, a synthesis of aseries of catalyst precursors lacking DMSO ligands was developed(Ru-1, Ru-2 and Ru-3), and the activity of these complexes wasfound to be an order of magnitude greater than that of the systemgenerated in situ. The initial results of the oxidation of a modelhindered alcohol are shown in Fig. 1b. In contrast to priortransition-metal catalysts that do not oxidize such hinderedsecondary alcohols, this ruthenium complex converteddicyclohexylcarbinol into the corresponding ketone at roomtemperature in only three hours. The same oxidation alsooccurred when 1,4-cyclohexanedione or trifluoroacetophenone
was used as a stoichiometric oxidant and the reaction was run intrifluoroethanol solvent.
The reactions of a series of primary and secondary alcohols andmixtures of primary and secondary alcohols with acetone as thehydrogen acceptor and Ru-2 as the catalyst are shown in Fig. 1c.These results show that the oxidation of secondary alcoholsoccurs over the oxidation of primary alcohols. The individual reac-tions of primary alcohols occur to a low conversion over a time thatleads to the full conversion of secondary alcohols, and reactions witha mixture of primary and secondary alcohols preferentially convertthe secondary alcohol into the ketone.
Selective oxidation of polyol natural products to ketonederivatives. Figure 2 summarizes the transfer dehydrogenation of13 polyol natural products and three methyl esters of naturalproducts. This figure shows the products from the oxidationreactions and the configuration of the alcohol unit that underwentoxidation. These reactions occur with several classes of naturalproducts, including steroids, diterpenoids, sesquiterpenoids,iridoids, carbohydrates, alkaloids and macrolides, which shows thebroad applicability of the catalyst system. The ruthenium catalystswe developed display a remarkable selectivity for the oxidation of
OH
OH
Selectivity
OH
OH
11.5 (7.8)
OH
OH OH
OH OH
OH
*10 min reaction*4% loading
*8% loading *8% loading,65 °C
64% (64%)
15% (16%)
*69% (70%)
*6% (9%)
*82% (82%)*88% (91%)
*(2%)
*10 min reaction
*51% (54%)
*24% (58%)
*75% (77%)
*(13%)*13% (27%)
4.3 (4.0)6.3 (3.0)
(45.5) 2.1 (0.9) (5.9)
OH OH
OHOH OH
98% (98%)84% (85%)7% (16%) 5% (12%) (2%)
0.5% Ru-2, 1% NMM
r.t., Me2CO (0.2 M, 65 equiv.), 45 minR R'
OHR" OHand/or
R R'
OR" Oand/or
0.1% Ru-2r.t., 1:1 Me2CO:TFE, 3 h
Cy Cy
O
Cy Cy
OH
99%
cis-Ru(DMSO)4Cl2 + PR3CH3OH
r.t. to 65 °C[Ru2(PR3)6Cl3]Cl
PR3 Catalyst
PMePh2 Ru-1PEt3 Ru-2PEt2(p-Me2N-Ph) Ru-3
[Ru2(PR3)6(OTf)3][OTf] AgOTf, TFE
r.t.
Reaction yields for oxidation of individual alcohols
Reaction yields for competitive oxidation of pairs of alcohols
a
b
c
d
or
0.1% Ru-2, 0.2% NMMr.t., 1.1 equiv. acceptor, TFE, 4 h
Stoichiometric ketone acceptors
CF3
O
OO
tBu Me
O 0.2% Ru-2, 0.4% NMM
1:1 iPrOH:TFE, 45 °C, 3 h tBu Me
OH
99%
Ru-2
NMM
O N
Figure 1 | Model alcohol oxidation and catalyst synthesis. a, Synthesis of the ruthenium catalyst for alcohol-transfer dehydrogenation. b, Mild oxidation of ahindered secondary alcohol is enabled by the catalyst Ru-2. c, Reactions of primary and secondary alcohols show the selectivity for the oxidation ofsecondary alcohols over primary alcohols. Conversions are shown in parentheses. d, The mild reduction of a hindered ketone is enabled by Ru-2 with iPrOHas the reductant. r.t., room temperature. NMM; N-methylmorpholine.
ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2835
NATURE CHEMISTRY | VOL 9 | DECEMBER 2017 | www.nature.com/naturechemistry1214
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
3
3
11
-
the catalyst to generate acetal 2o in an 84% yield. Treatment of theacetal product with Ir-1 and ammonium formate salts (NH3RO2CHfor R = H, Ph) led to N-substituted lactam derivatives 2p and 2q in78 and 77% yields, respectively.
Epimerization of alcohol units in polyol natural products. Oursystem not only catalyses the transfer of hydrogen from hinderedalcohols to acetone with isopropanol as the by-product, but italso catalyses the reverse transfer of hydrogens from isopropanolto hindered ketones, such as pinacolone (Fig. 1d). This resultsuggested the potential to epimerize a single hydroxy group incomplex polyols with a single catalyst. For example, the ketonegenerated from the dehydrogenation of fusidic acid methyl esterwas reduced by catalytic Ru-2 and isopropanol to give 3-epi-fusidic acid methyl ester (4a) in an 80% yield, with theremaining material identified as the parent fusidic acid methylester (Fig. 5a). Similarly, ouabain, which was oxidized selectivelywith acetone, was reduced with isopropanol catalysed by Ru-2 toform 1-epi-ouabain (4b) in 90% yield. With other polyols, such
as D-glucal and andrographolide, reduction of the ketoneregenerated the starting natural product.
A one-step epimerization also occurred in some cases. Forexample, the site-selective epimerization of fusidic acid methylester at the C3 position catalysed by Ru-2 occurred in an 84%yield, whereas that of ouabain occurred at the C1 position in a60% yield (Fig. 5b and Supplementary Section 4). AlthoughShvo’s catalyst, which is widely used for dynamic kinetic resol-utions15, also catalysed the epimerization of fusidic acid methylester at 70 °C to give 84% of the C3 epimer, it did not react withouabain up to the decomposition temperature of 100 °C. The com-bination of (Ph5Cp)Ru(CO)Cl and KO
tBu, which also has been usedto epimerize simple alcohols16,17, did not react with either of thesemolecules (Supplementary Section 4).
Comparison with alternative methods for alcohol oxidationapplied to polyol natural products. Although the catalyticoxidation of alcohols has been the subject of much research, fewstudies targeted the oxidation of complex polyols. Instead, moststudies focused on the reactions of unhindered benzylic andallylic alcohols, linear alkanols or cyclohexanols18–22. In the mostrecent and arguably most impressive example, a series ofpolyglycosides were oxidized by Waymouth’s catalyst in 30–60%yields at the terminal sugar23. Prior to this study, the polyketideantibiotic mupirocin methyl ester was oxidized by thecombination of TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl),NaOCl and KBr to give only a 31% yield of a monooxidationproduct24, and the labdane diterpene forskolin was oxidized bystoichiometric CrO3/pyridine in an 80% yield25, whereas anotherlabdane diterpene, andrographolide, was oxidized to the 3-ketonein only a 5% yield under the optimized conditions26. Thesestudies illustrate that the conditions developed for the reaction ofone structure do not translate into the oxidation of anotherstructure of the same or different class, and some molecules haveresisted selective oxidation under all known conditions27–29.
To assess in more detail the suitability of known procedures withclassical stoichiometric reagents and modern catalysts for the selec-tive oxidation of a broader range of polyols, we conducted reactionson several representative densely functionalized structures shown inFig. 3: andrographolide, ouabain, mupirocin methyl ester andkirenol (Supplementary Section 5). Each of these four natural pro-ducts gave mixtures of products with classical reagents, and no con-ditions gave a significant yield of the ketone product obtained fromthe reaction with Ru-1 or Ru-2 as the catalyst and acetone as thehydrogen acceptor. The reactions we conducted with simple pub-lished substrates occurred as described with both classical reagents.However, the reactions under these conditions with the four selectednatural products gave complex mixtures. Andrographolide reactedwith Dess Martin periodinane (DMP) to oxidize the primaryalcohol over the secondary alcohols to generate a mixture of 49%aldehyde, 35% keto-aldehyde and only 3% of the ketone. N-bromo-succinimide in acetone, tested because of the selective oxidation ofsimple bile acids28, gave a complex mixture. Swern oxidationconverted 65% of andrographolide into an unknown structurethat lacks a ketone or aldehyde, and Oppenhauer conditions withtrifluoroacetone catalysed by AlEt2OEt gave little to no conversion.The oxidation of mupirocin, ouabain methyl ester and kirenolalso gave mixtures of products with these oxidation systems. Thereaction of mupirocin with DMP gave an unselective oxidation toa complex mixture of products (at least five), the 1H NMR spectrumof which contained multiple new olefin resonances that signalledelimination processes. The reaction of the same substrate withAlEt2OEt/trifluoroacetone or the Swern reagent formed a mixtureof many products with a low selectivity. The oxidation of ouabainwith DMP formed one or more aldehyde products in 45% yieldfrom the oxidation of the primary alcohol, along with multiple
Me
Me
MeHO
HOH
H
H OAcOMe
O
Me
Me
Me80% (84%)
(14%)
+
3-epi-fusidic acid methyl ester
fusidic acid methyl ester
90% (95%)1-epi-ouabain
2% Ru-2, 4% NMM
O
HO OHOH
Me
OO
H
OH
HOH
OOH
HOOH
H
3:1 TFE:iPrOH, 65 °C, 1 h
Me
Me
MeHO
HOH
H
H OAcOMe
O
Me
Me
Me80% (84%)
3-epi-fusidic acid methyl ester
Fusidic acidmethyl ester
1-epi-ouabain
Ouabain
4% Ru-2, 8% NMM
O
HO OHOH
Me
OO
HMe
OH
HOH
OOH
HO OH
H
TFE, 70 °C, 11 h
+ S.M.
(60%)
(35%)
a
b
3a
3b
2% Ru-2, 4% NMM
3:1 TFE:iPrOH, 65 °C, 1 h
6% Ru-2, 12% NMM
TFE, 70 °C, 11 h
1f
1e
1
1
3
3
Figure 5 | The reduction of complex ketones and one-step epimerization ofcomplex alcohols. a, Reduction of complex ketones with isopropanol enablessite-selective epimerization within polyol natural products. b, Site-selectiveepimerization of complex polyols is achieved in one step with Ru-2 as thecatalyst in the absence of an acceptor. S.M., starting material. NMM;N-methylmorpholine.
NATURE CHEMISTRY DOI: 10.1038/NCHEM.2835 ARTICLES
NATURE CHEMISTRY | VOL 9 | DECEMBER 2017 | www.nature.com/naturechemistry 1219
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Majucin
TransferhydrogenationbyRutheniumcomplex
41Hill,C.K.;Hartwig,J.F.Nat.Chem.2017,9,1213.
HO
OH
3
1
Ru-2=[Ru2(PEt3)6(OTf)3][OTf]
-
Majucin
Reactionmechanism
O OsO
ON
O
N
O OOs
O
O
NN
OH
HH
Me
Me
OO
O
O
OH
HO
H
Me
Me
OO
OH
O
OH
HO
H H
Me
Me
OO
OH
O
OH
HO
OHHO
H
Me
Me
OO
OH
O
OH
HOn. OsO4・TMEDA
61 %H
Me
Me
OO
OH
O
OH
HO
OHHO
42Donohoe, T.J.;Moore,P.R.;Waring,M.J.;Newcombe,N.J.TetrahedronLett.1997,38,5027.
-
H
H
Me
Me
Me
MeOH
[O]
[O]
H
H
Me
Me
HMe
OAc
OH
H
H
Me
Me
OAc
O
O
MeO
[O][O]
[O]
H
Me O
O
Me
OO
OH
OH[O]
H
Me
Me
OO
OH
O
O
H
Me
Me
OO
OH
O
OH
HO
OHHO
[O]
43
Majucin
SummaryofMajucinsynthesis
Redox-relayC6 →C11,C14
Redox-relayC11 →C4
Redox-relayC11 →C10
Redox-relayC4 →C3
Redox-relayC6 →C7,C12α-ketol
rearrangement
l (-)-Majucinwassynthesizedbyfullyoxidative strategy.l Thestrategyofpseudoanisatin isapplicableformajucin.
(-)-majucin
6
11
14
11
4
6
7
12
4
3
1110
-
Contents
1. Introduction
2. Pseudoanisatin
3. Majucin
4. Summary
44
-
Summary
45
H
Me
OH OHMe
O
HO
H
O
O
H
Me
OH
OO
OHMe
HOH
O
HO
H
O
(+)-pseudoanisatin
(-)-majucin
H
H
Me
Me
Me
Me
OHH
14steps
12steps
l Introduceposition-selectivehydroxylgroupsbyRedox-relay.l Skeletalrearrangementbyα-ketolrearrangement.(onlyonestep)l Twocompounds couldbesynthesizedusing thesamestrategy.
13oxidations
7oxidations
(+)-cedrol
-
46
-
Appendix
47
-
Pseudoanisatin
Reactionmechanism
48
H
MeOMe
Me
OHOOH
Me
H
O
HH
H
MeOMe
Me
OOO
Me
H
O TBS Cl
H
MeOMe
Me
OOO
Me
H
O TBS Cl H
MeOMe
Me
OTBSOOH
Me
H
O
H
MeOMe
Me
OHOOH
Me
H
O f. NaH, TBSClthen
aq. HCl
88 %
H
MeOMe
Me
OTBSOOH
Me
H
O
-
Pseudoanisatin
Reactionmechanism
49H
MeOMe
Me
OTBSO
Me
H
O
OBase
OEtEt
Et
OTBS
Me
OMe
OEt
O
Me
OMe
H
MeOMe
Me
OTBSO
Me
H
O
EtO H
MeOMe
Me
OTBS
O
Me
H
O
EtO
H
H
H
OTBS
Me
OMe
OEt
O
Me
OMe
H
H
MeOMe
Me
OTBSO
Me
H
O
O
H
OTBS
Me
OMe
OEt
O
Me
OMe
h. Et3OPF6,proton spongethen, TFA/H2O
66 %(85 % BRSM)
-
Pseudoanisatin
Reactionmechanism
50
H
OTBS
Me
OMe
OEt
O
Me
OMe
H
OTBS
Me
OMe
OEt
O
Me
OTMS
H
O
Me
OMe
Me
O
O
H
OTBS
Me
OMe
Me
O
O
TMS I
IMe
I
H
OTBS
Me
OMe
OEt
O
Me
O
FTBS F
H2O
TMS
H
OH
Me
OMe
Me
O
O
H
OTBS
Me
OMe
OEt
O
Me
OMe
H
OH
Me
OMe
Me
O
O
i. TMSClNaI
j. TBAFAcOH64 %
(2 steps)
-
Pseudoanisatin
Reactionmechanism
51
H
OH
Me
OMe
Me
O
O
k. OsO4・TMEDA
OH
Me
OMe
Me
O
O
HO OH
HH
H
O
Me
OMe
Me
O
O
O OsO
ON
O
N
OH
Me
OMe
Me
O
O
O OOs
O
O
NN
HOH
Me
OMe
Me
O
O
HO OH
HHO
H
H
Donohoe, T.J.;Moore,P.R.;Waring,M.J.;Newcombe,N.J.TetrahedronLett.1997,38,5027.
-
Pseudoanisatin
Reactionmechanism
52OH
Me
OMe
Me
O
O
H OH
HHO
SO
Cl CH2
O H N
OH
Me
OMe
Me
O
O
HO OH
HH
SO
CH2
OOH
Me
OMe
Me
O
O
MsO OH
HH
OH
OH
Me
OMe
Me
O
O
HO OH
HH
l. MsCl, pyr.;NaOH( aq.)
80 %(2 steps)
OH
Me
OMe
Me
O
O
H OH
HHO
-
Pseudoanisatin
AcyloxylationwithCuBr2
53K.Hung,M.L.Condakes,L.F.T.Novaes,S.J.Harwood,T.Morikawa,Z.Yang,T.J.Maimone,J.Am.Chem.Soc.,2019,141,3083.
-
Pseudoanisatin
C-Hoxidationbyironcomplexes
54
K.Hung,M.L.Condakes,L.F.T.Novaes,S.J.Harwood,T.Morikawa,Z.Yang,T.J.Maimone,J.Am.Chem.Soc.,2019,141,3083.
-
H
H
Me
Me
Me
Me
OH R
H
H
H
Me
Me
Me
OH
H
H
HMe
Me
Me
OH
H
I I
HMe
Me
Me
OH
H
IH
Me
Me
Me
HO
HMe
Me
Me
HO
HMe
MeH
HMe
MeH
OAc
Me
H
H
HOH
O
O OMe
Majucin
Reactionmechanism
1,5-hydrogentransfer
H
H
Me
Me
Me
Me
OHH
a. PhI(OAc)2, I2, hνthen add
HMe
MeH
OAc
Me
H
Ac2O,H3PO467 %
55
R.Baker,M.A.Brimble,J.A.Robinson,TetrahedronLett.,1985,26,2115.
-
Majucin
Reactionmechanism
HMe
MeH
OAc
Me
H b. BH3・THF;
Cro3・2pyrH
H
Me
Me
H
MeH
OAc
O
c. NaBH4
72 %(2 steps)
HMe
MeH
OAc
H
OH
MeH
HMe
MeH
OAc
Me
H
H2B H
HMe
MeH
OAc
Me
H
BH2H CrO
OO
pyr
pyr
HMe
MeH
OAc
Me
H
BH
OHOO
HMe
MeH
OAc
Me
H
OH
B
OH
OHCrO
OO
pyr
pyr
HMe
MeH
OAc
Me
H
OH
B
OH
OHCr
O
O
pyr
pyrHO
H
H2O
HMe
MeH
OAc
Me
H
HO
BH3H
HMe
MeH
OAc
Me
H
OHH
56
-
Majucin
OxidationbySe2OundernoH2Ocondition
57K.V.Chuang,C.Xu,S.E.Reisman,Science,2016,353,912.
K.Hung,M.L.Condakes,L.F.T.Novaes,S.J.Harwood,T.Morikawa,Z.Yang,T.J.Maimone,J.Am.Chem.Soc.,2019,141,3083.
-
Majucin
Stereochemicalconsiderationsfortheα-Ketolrearrangement
58
M.L.Condakes,K.Hung,S.J.Harwood,T.J.Maimone,J.Am.Chem.Soc.,2017,139,17783.