-trimethylenemethane cyclization - university of illinois · -trimethylenemethane cyclization oo ph...
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M.C. White, Chem 153 ππππ-allyl chemistry -375- Week of December 9, 2002
π-Trimethylenemethane cyclization
O O
Ph
SiMe3AcO
(Ph3P)4Pd
O O
Ph
H
H
Provide a mechanism for the following transformation.
mixture of stereoisomers
+toluene, ∆∆∆∆
LnPd(0)Ph
AcO
SiMe3 Ph SiMe3OAc Ph
LnPd(II)
LnPd(II)
O O
Ph
Pd(II)Ln
O O
Ph
Pd(II)Ln
O O
Ph
H
H
Pd(0)Ln
O O
Ph
H
H
Pd(0)
H
Trost JACS 1980 (102) 6359, JACS 1983 (105) 2326.
M.C. White, Chem 153 Metal alkylidenes -376- Week of December 9, 2002
Metal Carbenes
singletcarbene
M CX
sp2
pz
R'
R
O C LnM=CR2
δ+δ-
Fischer Carbenes (formally derived from a singlet carbene)
(CO)5Cr0OMe
Ph OR
(CO)5CrII
PhOMe
OR
(CO)5CrII
Ph OMe
OR
COPh
OMeRO
Cr0(CO)6
Fischer Chem. Ber. 1972 (105) 3966.
· Low oxidation state, late metals· π-acceptor ligands on the metal· π-donar substituents on the carbene C
δ+δ-
+
· electrophilic carbenes· σ-donation is stronger than π-backbonding resulting in a partial positive charge on thecarbene carbon
note: that the formal charge for the carbene unit is zero, the #of electrons donated is 2.
π-donation from the carbene substituents competes w/π-donation from the metal
The presence of strongπ-acceptor ligands on themetal renders π-backbonding into the empty carbene porbital weak.
R'
X = heteroatoms
likened to a carbonyl:O
OMe
Me
δ+δ-
18 e-
triplet carbene
Schrock Carbenes (formally derived from a triplet carbene)
M CR
sp2
pz
R
· The metal-carbon bonds are morecovalent in nature and highly polarizedtowards C resulting in a partial negative charge on the carbene C.
alkyl (or H)
XR'
R'
LnM=CR2
δ-δ+
· High oxidation state, early metals· Non-π acceptor ligands on the metal (often π-donor ligands such as Cp or Cl)· alkyl (or H) substituents on the carbene.
· nucleophilic carbenes
The first characterized Schrock carbene:
TaV
t-Bu
t-Bu
t-Bu
t-Bu
δ-δ+
+
likened to a phosphorus ylide:Ph3P
t-Bu
δ-δ+
O
pentane/N2
O2 and moisture sensitive
-2 charge/4 electron donor
10 e-
(t-BuCH2)3TaV
t-Bu
O
(t-BuCH2)3TaV
O
t-Bu
highly oxophilic,early metal
(t-BuCH2)3TaV O
t-Bu
+
85%
Schrock JACS 1974 (96) 6796, 1976 (98) 5399.
M CR
sp2
pz
R
alkyl (or H)
XR'
R'
extreme π-backbonding: where the 2e- in theM(dπ) orbital aretransfered to the C(pz)orbital.
M.C. White, Chem 153 Metal alkylidenes -377- Week of December 9, 2002
The first isolated and characterizedSchrock carbenes
The first isolated Schrock carbene:
TaV
Me
MeMe
18 e-
C(Ph)3 BF4
MeC(Ph)3
TaV
Me
CH2
16 e-
BF4H
base TaV
Me
CH2
18 e-
Schrock JACS 1975 (97) 6577, 6579.
2.026 Å
2.246Å
~ 10 % shorter Ta-C bondis suggestive of a significant amount of db character
The first characterized Schrock carbene:
(t-BuCH2)2(Cl)TaV t-BuCl
H
10 e- complex
α-agostic interactionprovides the metalw/extra electron density
2 eq t-BuCH2Li (t-BuCH2)2(Cl)TaV t-Bu
H
t-Bu
steric conjestion induces direct α-proton abstraction by one of the neopentane ligands resulting in the metal alkylidene.
(t-BuCH2)2TaV
t-Bu
ClCMe4
(t-BuCH2)3TaV
t-Bu
LiCl LiCl
Schrock JACS 1974 (96) 6796, Acc. Chem. Res. 1979 (12) 98.
M.C. White, Chem 153 Metal alkylidenes -378- Week of December 9, 2002
Carbonyl methylenation: Tebbe’s reagent
TiIV
Cl
Cl
16 e-
+ 2 AlMe3
toluene
rt
TiIV
Cl
16 e-
AlMe2
CH4, AlMe2Cl
Tebbe's reagent: Tebbe JACS 1978 (100) 3611.
Tebbe's reagent 0.5M soln 100 mL/$363
(Aldrich 2001) TiIV
ClAlMe2 TiIV
O
TiIV
OR
R
CH2
16 e-
TiIV
ClAlMe2
stoichiometric
toluene, -15 oC
65%
Synthetic applications:
EtO2C
O
OTBS
OTBS
OBn
OBn
OTBS
OTBSCp2TiCH2ClAlMe2
tol-THF-Py,
-78oC to -15oC
82%
EtO2C
OTBS
OTBS
OBn
OBn
OTBS
OTBS
key intermediate in the total synthesisof Hikizimycin
Schreiber JACS 1990 (112) 9657.
OR
O
O
O Cp2TiCH2ClAlMe2
THF, rt, 1h85%
ORO
O
Nicolaou ACIEE 1994 (33), 2184, 2187, 2190
key intermediate in the total synthesisof Zaragozic acid
In situ prep: Grubbs JOC 1985 (50) 2386.
M.C. White, Chem 153 Metal alkylidenes -379- Week of December 9, 2002
Tebbe’s reagent
TiIV
ClAlMe2 TiIV
16 e-
+
AlClMe2
TiIV
TiIV
Tebbe's reagent reacts with olefins to give metallocyclobutanes:
Titanium metallocyclobutane 1 reacts with acid chlorides to form Ti enolates.
1
Grubbs OM 1982 (1) 1658.
O
ClPh
tol, -20oC to 0oC
OTiClCp2
PhPhCHO
O
Ph
OH
Ph69%
TiIVTiIV O
ClPh
OCl
Ph
Grubbs JACS 1983 (105) 1665.
M.C. White, Chem 153 Metal alkylidenes -380- Week of December 9, 2002
Olefin metathesis: Tebbe’s reagent
TiIV
ClAlMe2 TiIV
16 e-
+
t-Bu
AlClMe2
TiIV
t-Bu
Tebbe's reagent reacts with olefins to give titanacyclobutanes:
1
D
D D
t-Bu t-Bu
TiIV
t-Bu
D
t-Bu t-BuD
D
TiIV
D
D D
t-But-Bu
TiIV
D
DD
t-Bu
TiIV
t-Bu
D
DD
TiIV
t-Bu
DD
TiIV
t-Bu
DD
t-Bu
t-Bu
D
t-Bu
t-Bu
t-BuD
D
+1, cat
+
Titanacyclobutanes are effective catalysts for α-olefin metathesis .
Grubbs JACS 1982 (104) 7491.
O
t-BuO
O
t-BuO
TiCp2
O
t-BuO
TiCp2
t-BuO
HO OH
O
O
H H
H
Cp2TiCH2ClAlMe2
DMAP, benzene
25oC
90oC
p-TsOH
81% overallyield
Cp2Ti(O)
(±)-Capnellene
First application of olefin metathesis to synthesis:
Grubbs JACS 1986 (108) 855.
M.C. White, Chem 153 Metal alkylidenes -381- Week of December 9, 2002
Carbonyl methylenation: Petasis reagent
OO
H
H3C
Me
O O
H3C O
OH3C OH3C
OTiCp2CD3
H3C CD3
H
H3C
Me
O
D3C
OH3C
H3C
OH3C
D
D
O
OCH3
O
OCH3
O
8 8 62 %
83 %
aldehydes ketones
esters chemoselectivity for ketones in the presence of esters
80 % 60 %
Cp2TiMe 2
3 eq.
toluene
60-65 oC
Cp2TiMe 2
3 eq.
toluene
60-65 oC
Cp2TiMe 2
3 eq.
toluene
60-65 oC
Cp2TiMe 2
1 eq.
toluene
60-65 oC
Based on deuterium labelling studies, Petasis originally proposed a mechanism involving initial carbonyl complexation to Cp2TiMe2 followed by methyl transfer and subsequent loss of methane and titanocene oxide.
Petasis JACS 1990 112 6392.
Difficulties with the Tebbe and Grubbs' Ti-mediated olefinations include the high cost of Ti reagent, long preparation times, short shelf life, and the need for specialtechniques due to sensitivity to air and water. Many of these difficulties are overcome with Petasis' procedure which uses dimethyltitanocene. Petasis JACS 1990 112 6392.
11
Cp2Ti(CD3)2
11 ?11
11
~50%
"significant amount of deuterium detected at C-3."
H313C O
OH3CO
TiCp2
H313C
EtO
H313C
OH3C
<1% incorporation of 13C
label into methylene position
Hughes finds that in the reaction with C-13 labelled ethyl acetate shown below, scrambling of the label only occurs if trifluoroacetic acid is present and proposes that this scrambling is due to an acid-catalyzed, degenerate [1,3]-hydrogen shift. He proposes that the scrambling observed by Petasis was likely due to adventitious acid present on all acid-washed glassware. To support this argument, Hughes repeated the deuterium labelling experiments reported by Petasis using glassware that was not acid washed and, contrary to Petasis, observed no scrambling of the label.
O Me
TiCp2
Me
O
Cp2Ti
CH2
H
CH3
CH2
O TiCp2
Petasis JACS 1990 112 6392.
Me
TiCp2
MeO
TiCp2
O
TiCp2
CH2
O TiCp2
Hughes uses these experiments in conjunction with detailed kinetic studies to provide strong support for a mechanism involving a titanium carbene.
Hughes OM 1996 15 663.
12
3
12
3
M.C. White, Chem 153 Metal alkylidenes -382- Week of December 9, 2002
Olefin metathesisThe first reports of olefin cross metathesis (heterogeneous cat) by Banks:
2 Mo(CO)6 supported on Al
150oC, 30 atm.+
Banks Ind. and Eng. Chem. (Product Res. and Development) 1964 (3) 170.Haines Chem. Soc. Rev. 1975 (4) 155.
The first report of ROMP (ring opening metathesis polymerzation):
MXn + Al(Et)3
nMXn = TiCl4,ZrCl4, MoCl5, WCl6
Natta Makromol. Chem. 1963 (69) 163.Natta ACIEE 1964 (3) 723.
Well-defined WVI and MoVI olefin cross metathesis and ROMP catalysts:
WVI
N
t-BuO
O
F3C
H3C
F3C
F3CF3C
CH3
i-Pr i-Pr
MoVI
N
t-BuO
O
F3CH3C
F3C
F3CF3C
CH3
i-Pr i-Pr
· Wittig-type chemistry with aldehydes>ketones>> and esters(slow rates).
· Wittig-type chemistrywith aldehydes>>ketones (slow rates).
Schrock JACS 1986 (108) 2771.Schrock JACS 1990 (112) 3875, 8378;1991 (113) 6899.
Olefin cross metathesis:
Mn
t-Bu
12 e- 12 e-
Mn
t-Bu
Mn
Mn
Mn
Mn
ROMP (Ring opening metathesis polymerization)
Mn
R M
R
MnR
MnR
MnR
m
propagation
PhCHO
PhR
m
termination
+ Mn=O
initiation
Often called a "living polymerization" because termination only occurs uponaddition of a capping unit (oftenaldehyde).
Grubbs Science 1989 (243) 907.
M.C. White, Chem 153 Metal alkylidenes -383- Week of December 9, 2002
Mo-mediated ring closing metathesis (RCM) of acyclic diene ethers
O PhO Ph
Me
benzene, rt15 min
92 % yield
O Ph
Me
O
Me
Ph
92 % yield
benzene, rt
15 min
O
O
Me
O
BnO OBn
Me
O
O
O
BnO
OBn
O
O
O
HO
OH
Me
O
Me
Ph
Me
O Ph
MeMebenzene, rt
3 h
93 % yieldMe
OPh
Et
Me
O Ph
benzene, rt4 h
75 % yield
1, 5 mol% 1, 5 mol%
1, 5 mol% 1, 5 mol%
MoV I
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
Me
F3C CF3
1
Grubbs JACS 1992 (114) 5426.
1, 12 mol%
85 % 95 %
Sophora compound IGrubbs JOC 1994 (59) 4029.
H2, Pd-C
Grubbs recognized the potential for applying olefin metathesis towards a productive synthetic pathway: RCM (Ring Closing Metathesis)
General mechanism:
X
LnMoVIR
LnMoVI
X
VIMoLn
X
RR
X
LnMoVI
X
LnMoVI
X
5-membered ring formation: dihydrofurans Tri-and tetrasubstituted olefins:
6-membered ring formation: dihydropyrans 7-membered heterocycles
R
Evaporative loss of the low molecularweight acyclic olefin generated and theentropic gain of generating 2 molecules from 1 are thought to be two factorsfavoring the RCM pathway.
An early synthetic application of RCM:
M.C. White, Chem 153 Metal alkylidenes -384- Week of December 9, 2002
Mo-mediated RCM of acyclic diene amines and amides
N
Me
Bn
N
Me
Bn
N
O
R
N
Me
Bn
N
O
R Mo
N
Bn
Me
MoVI
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
Me
F3C CF3
N
O
R
N
OF3C
N
Bn
O
N
OF3C
N
Bn
O
benzene, rt3 h
93 % yield
86 % yield
benzene, rt
1 h
benzene, rt15 min
83 % yield
benzene, rt1.5 h
90 % yield
1, 4 mol% 1, 4 mol%
1, 4 mol% 1, 4 mol%1
Grubbs JACS 1992 114 5426.
Formation of 5- and 6-membered lactams via RCM of acyclic diene-amides is hindered by formation of stable chelate intermediates. This may be due to the Lewis acidic properties of the formally 12 e- Mo alkylidene.
1 N
O
R1
N
O
R
Mo
N
O
R
N
O
Bn
Me
N
O
Bn
Mo
Me
N
O
Bn
stablechelate
stablechelate
N
O
BnN
O
Bn
MoEt
N
O
Bn1, 10 mol%benzene
50 oC
1.5 h
74 % yieldEt 80 % yield
1, 10 mol%benzene
50 oC
1.5 h
This problem can be averted by directing the catalytic cycle with appropriate olefin substitution patterns. Because metathesis of monosubstituted olefins by 1 is faster thanthat of disubstituted olefins, the initial Mo alkylidene preferentially forms at the less substituted olefin where intramolecular chelate formation with the amide carbonyl is not favored.
Grubbs JACS 1992 (114) 7324, see also Schrock OM 1989 (8) 2260.
5-membered rings
6-membered rings 7-membered ring - lactam formation
12e-
M.C. White, Chem 153 Metal alkylidenes -385- Week of December 9, 2002
Application of RCM-mediated macrolactam formation in TOS
MoVI
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
Me
F3C CF3
HN
Me
O
MeMe O
O
HO Me
OHH2N
Fluvirucin B1(Sch 38516)
HN
Me
OTBS
MeMe O
HN
OTBS
MeMe O
Me
25 mol %
THF (0.01M)
60 oC;
silica column
Hoveyda JACS 1995 117 2943-2944.
60 % yield>98% Z
N
O
Bn
CO2Me
H
N O
MoVI
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
Me
F3C CF3
5 mol %
benzene, 50 oC 4 h
63 % yield
N
O
Bn
CO2Me
H
NO
N
H
N
NNH
OH
Manzamine A
Martin TL 1994 35:5 691-694.
The high levels of stereoselectivity in these examples is an exception.Attaining reliable E/Z selectivity isstill an unsolved problem with thischemistry.
M.C. White, Chem 153 Metal alkylidenes -386- Week of December 9, 2002
Synthesis of cycloalkenes via olefin metathesis/carbonyl olefination
OO Ph
3
MoVI
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
MeF3C CF3
O Ph
3
1 eq.
benzene, 20 oC
30 min[M]
OO Ph
3[M]
[M] OO Ph
3
[M] O
O Ph
3
[M] O
86 % yield
olefin metathesis carbonyl olefination
Effecting this process requires an alkylidene whichmetathesizes olefins more rapidly than it olefinatesketones. It had been demonstrated previously that thisMo-alkylidene efficiently metathesizes acyclic mono- and disubstituted alkenes at rt, but requires elevatedtemperatures to olefinate ketones.
six-membered rings seven-membered rings
O
O
Ph
MeO
Ph
Me
as above
84 % yield
O
OBn
OBn
86 % yield
as above
Grubbs JACS 1993 (115) 3800.
Schrock JACS 1990 (112) 3875.
M.C. White, Chem 153 Metal alkylidenes -387- Week of December 9, 2002
Ru alkylidenesO OMe
OMe[RuII(H2O)6 ]2+(Tos)2
H2O
O OMe
OMeH2OnRuII RuIV
2+(Tos)2
R" "
proposed catalytically active species
O
m
MeO OMenote: RuCl3·H2O is also effective. Since identical olefin resonances are
observed by NMR during the reaction as those for RuII/olefin complex A (RuIII
does not form stable olefin complexes), Grubbs speculates that RuIII becomes
reduced in situ to RuII.
A
Grubbs JACS 1988 (110) 960, 7542.
RuII coordination complexes may form RuIV alkylidenes with strained cyclic olefins:
ClRuII
Cl PPh3
PPh3
PPh3
PPh3
+
Ph Ph
CH2Cl2/C6H6
53oC, 11h ClRuIV
Cl
PPh3
PPh3
Ph
Ph
·Stable to H2O (but insoluble pure H2O), alcohols, and acids·Unstable to O2
m
Grubbs JACS 1992 (114) 3974.
Efficient Ru catalyst for acyclic olefin metathesis.
Cl
RuIVCl
PCy3
PCy3
Ph
Ph
stronger σ-donor ligands
·Stable to O2
· High activity for low-strain cyclic olefins and for acyclic olefins.
ClRuIV
Cl
PCy3
PCy3
ClRuIV
Cl
PCy3
PCy3
propagating species: Ruethylidene and Ru propylidene observed by NMR
+
Grubbs JACS 1993 (115) 9858.
·No Wittig-like activity observed even with aldehydes· Poor activity for low-strain cyclic olefins and no activity for acyclic olefins.
Cl
RuIVCl
PCy3
PCy3
Ph
Generation 2 catalyst:
Cl
RuIICl PPh3
PPh3
PPh3
PPh3
1. N2CHR2. PCy3
Advantages of 2 vs. 1: More facile synthesis due to greater availability of diazoalkanes relative tocyclopropenes. Ru catalyst 2 is significantly morereactive than 1 because of more facile initiation.
1
2 Grubbs ACIEE 1995 (34) 2039.
M.C. White, Chem 153 Metal alkylidenes -388- Week of December 9, 2002
Ru vs. Mo alkylidene catalysis of RCM
ClRuIV
Cl
PCy3
PCy3
Ph
Ph
1 (16e-, d4)
vs. MoVI
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
Me
F3C CF3
3 (12e-, d0)
Cl
RuIVCl
PCy3
PCy3
Ph
2 (16e-, d4)
Ru alkylidene complexes 1/2 are effective RCM catalyst in the presence of atmospheric O2, water and trace solvent impurities. Reagent grade solvents may be used directly for thereactions. Alternatively, Mo alkylidene complex 3 is highly sensitive to atmospheric O2,moisture and solvent impurities.
BocN
1 (2 mol%)solvent, air
BocN
88-93%
solvents: reagent-grade (undistilled): benzene, CH2Cl2, THF, t-BuOH
Ru alkylidenes 1/2 are highly functional group tolerant. Unlike Mo complex 3 which isknown to react with acids, alcohols, aldehydes (and ketones intramolecularly), complexes 1/2 are stable to these functionalities.
X
1 (2 mol%)C6H6, rt, 1h
XX = CO2H, 87% CH2OH, 88% CHO, 82%
RCM of acyclic diene-amides in 5- and 6-membered lactam formation is not complicated by the formation of stable chelated species as observed with 3. This may be due in part to theless oxophilic character of Ru vs. Mo. Moreover, the 16 e-, d4 Ru complex is lesselectrophilic than the 12e- d0 Mo complex.
N
O
Rn 1 (3 mol%)
C6H6, rt, 1hN
O
Rn
n= 0, 78% 1, 93%
Grubbs JACS 1993 (115) 9856.
Free amines are not tolerated by Ru catalysts and must be masked as the corresponding HCl salts:
NPh H
Cl 1. 1 (4 mol%)CH2Cl2, rt
36 h2. NaOH
NPh
(note: RCM of this amine with 3 took 40 min and proceeded in 89% yield; JACS 1992 (114) 5426)
79%
RCM of substituted olefins is problematic with 1 and 2. Dienesw/sterically demanding and/or electron withdrawing substituents can be cyclized more effectively w/ Mo catalyst 3.
RRO2C CO2R
R
RO2C CO2R
R= Et, 2 93%; 3 >99% t-Bu, 2 NR; 3 96% Ph, 2 25%, 3 97% CO2Me, 2 5%, 3 89%
RO2C CO2R RO2C CO2R
2 NR, 3 93%Grubbs JOC 1997 (62) 7310.
M.C. White, Chem 153 Metal alkylidenes -389- Week of December 9, 2002
Grubbs’ third generation Ru alkylidene catalyst
Cl
RuIVCl
PCy3
PCy3
Ph
1 (16e-, d4)
Cl
RuIVCl
PCy3
Ph
NN MesMes
2 (16e-, d4)
MoV I
NO
O
i-Pr
i-Pr
MeMe
Ph
CF3F3C
Me
Me
F3C CF3
3 (12e-, d0)
t-BuRO2C CO2R
t-Bu
RO2C CO2R
RO2C CO2R
CO2R
CO2R
RO2C CO2R
RO2C CO2R
Improved E/Z ratios for macrocyclization
O
OO
O
LnRuIV
LnRuIV LnRuIV
Grubbs OL 2000 (2) 2145.
OHOH
Increased reactivity of 2 makes it comparable to 3 in many cases:
2 (5 mol%)
45oC, 60 min
recall: 1 gave NP
2 (5 mol%)
45oC, 90 min
>99%
90%
tetrasubstituted olefins
1 gave NP
not entirely general:
2 (5 mol%)
45oC, 24h
31%1 gave NP3 , 93%
Despite increased reactivity 2 has retained it's functional group tolerance (as well as air and H2O stability).
2 (5 mol%)
45oC, 10 min>99%
1, NP; 3, NP
Grubbs OL 1999 (1) 953.
Cross metathesis of terminal olefins with α-carbonyl functionalized olefins:
TBSO
7 CO2CH3
Cl
RuIVCl
PCy3
NN MesMes
4 (16e-, d4)
3 eq.slow addition
0.5 eq.
4 (5 mol%)
40oC, CH2Cl2
62%
TBSO
7
E/Z (>20:1)
CO2CH3
8 22 (1 mol%)
40oC, CH2Cl2, 40 min
>99%
1, E/Z (4.5:1)2, E/Z (11.5:1)
E/Z ratio increases over time with catalyst 2:Most likely due to a secondary "metathetical" isomerization via ring opening metathesis/ ring closing metathesis:
LnRuIV
CO2CH3
The ester-carbene complex isunstable and is not thought to be effective in olefin metathesis.
Grubbs JACS 2000 (122) 3783.
M.C. White, Chem 153 Metal alkylidenes -390- Week of December 9, 2002
Mechanism of Grubbs’ third generation Ru alkylidene catalyst
ClRuIV
Cl
PCy3
PCy3
Ph
1 (16e-, d4)
ClRuIV
Cl
PCy3
Ph
NN MesMes
2 (16e-, d4)
CNR
NR
stable diaminocarbene
Arduengo JACS 1995 (117) 11027.
M
Fisher-type carbene, strong σ-donor
Proposed mechanism:
ClRuIV
Cl
L
PCy3
Ph
L = PCy3
NN MesMes
or Phosphine dissociation
-PCy3
+PCy3 ClRuIV
Cl
LPhk1
k-1
14 e-
Cl
RuIVCl
L
Ph
R
R
k2k-2
R
ClRuIV
Cl
LPh
R
(or R after 1st cycle)
Cl
RuIVCl
LR
Ph
Ph
· The reaction is thought to proceed via adissociative mechanism to form the active 14e- catalytic species. Excess phosphineinhibits the rxn.
· Catalyst 2, whose propagation rates significantly exceed those of 1,exchanges phosphine 2 orders ofmagnitude slower than 1.
· The ratio of k-1/k2 determines if the 14e- intermediatebinds olefin to initiate metathesis or binds phosphine toreturn to its resting state. This ratio is 4 orders ofmagnitude greater for 1 than for 2 (1 = 15 300, 2 = 1.25).While 1 is faster to initiate by loosing phosphine, therebinding of phosphine is competitive with olefin binding. Alternatively, 2 dissociates phosphine more slowly butbinds the olefin with such high affinity that it may cyclethrough many times before binding phosphine andreturning to its resting state.
The strongly σ-donating N-heterocycliccarbene ligand of 2 is thought tosignificantly improve the bindingselectivity of 14 e- intermediate A forrelatively π-acidic olefins vs. σ-donating phosphines.
A
Grubbs JACS 2001 (123) 749.
M.C. White, Chem 153 Metal alkylidenes -391- Week of December 9, 2002
OSiEt3
ClRuIV
Cl
PCy3
PCy3
Ph
PhOSiEt3
OSiEt3
OSiEt3
RuLn
OSiEt3
RuLn
OSiEt3
OSiEt3
RuLn
OSiEt3
RuLn
ClRuIV
Cl
PCy3
PCy3
ROSiEt3
OSiEt3
RuLn
LnRu
OSiEt3
RuLn
OSiEt3
RuLn
OSiEt3
OSiEt3
3 mol%+
1:1unsymmetrical dienyne
Cycle A Cycle B
OSiEt3
Et
RuLn
OSiEt3
EtLnRu
OSiEt3
OSiEt3
LnRu
Me
RuLn
OSiEt3
Me
OSiEt3
83%
Sterically differentiating the two olefins biases the intial site of metallocyclobutane formation and results in selectivity for one cycle vs. the other.
78%
Grubbs JACS 1994 (116) 10801.
Dienyne metathesis
M.C. White, M.S. Taylor Chem 153 Metal alkylidenes -392- Week of December 9, 2002
O O
Me
Me
H
H
Me OO
OH
(–) - Longithorone A
Me
MeO OTBS
TBSOH
OTBS
OTBS
TBSO OMe
Me
Me
Macrocyclization via ene-yne metathesis
Me
TBSO
OMe
Me OTBS
Ru
PCy3
PCy3Ph
HCl
Cl
OTBS
TBSO OMe
Me
Me
[Ru]
Me
OMe
Me
[Ru]
OTBS
TBSO
Ru
PCy3
PCy3Ph
HCl
Cl
OTBS
TBSO OMe
Me
Me
[Ru]
OTBS
TBSO OMe
Me
Me
(0.5 equiv.)
Ethylene (1 atm)CH2Cl2
>20:1 favoring atropisomer shown
Shair JACS 2002 (124) 773.
the protected benzylic hydroxyl was used to gear the atropisomerism of the aromatic rings during ene-yne metathesis
Me
TBSO
OMe
OTBS
TBSO
Ru
PCy3
PCy3Ph
HCl
Cl
Me
[Ru]
MeO OTBS
TBSOH
OTBS
Me
TBSO
OMe
OTBS[Ru]
TBSO
Me
[Ru]
MeO OTBS
TBSOH
OTBS
Me
MeO OTBS
TBSOH
OTBS
(0.5 equiv.)
Ethylene (1 atm)CH2Cl2
M.C. White, Chem 153 Metal alkylidynes -393- Week of December 9, 2002
Schrock Carbynes (formally derived from a triplet carbene)
M C R
M CR trianionic ligand (-3), 6 electron donor
Early example of catalytic alkyne metathesis by WVI-alkylidyne
Ph Et
WVI
ClCl Cl
OPEt3
Tol, rt
5 mol%
Ph Ph
+
Et Et
WLn
R
WLn
RPh
Et
WLn
RPh
Et
Ph Et Ph R
Schrock JACS 1981 (103) 3932.
Ring-closing diyne metathesis: Furstner ACIEE 1998 (37) 1734.
O
OO
O
WVI
(Me)3CO(Me)3CO
OC(Me)3
O
OO
O
4-6 mol%
C6H5Cl, Ar, 80oC73%
Functional group tolerance demonstrated for esters, amides, and sulfones.
note: catalyst isincompatible with terminal alkynes.
Lindlar hydrogenationstereoselectively generates Z-alkenes (still anunsolved problem forRCM of alkenes).
Novel Mo alkyne metathesis catalyst:
MoIV
Cl
N NN
N
O
O
O
O
O
OO
O
N
It is unclear how the halide Mo catalyts initiates the catalytic cycle. Thiscatalyst demonstrates increasedfunctional group tolerance (relative tothe W catalyst) for basic amines,thioethers, and ketones.
Furstner JACS 1999 (121) 9453.
Diyne metathesis
M.C. White/Q. Chen Chem 153 Metal alkylidynes -394- Week of December 9, 2002
OO
ROOR
O
OR
ORO
RO O
OR
CH3
CH3
O
H3C
OO
ROOR
O
OR
ORO
RO O
OR
CH3
O
N MoN
N
DDQ
R = PMB (note that this Mo-based catalystrequires protection of the hydroxyl groups.
Sophorolipid lactone
CH2Cl2/toluene, 80 °C
OO
ROOR
O
OR
ORO
RO O
OR
CH3
O
78% yield
H2 (1 atm)Lindlar catalyst
quinoline
CH2Cl2, rt
Corresponding RCM of a related substrate with terminal olefins gave 3:1 olefin ratio favoring the
undesired trans isomer.
OO
HOOH
O
OH
OHO
HO O
OH
CH3
OCH2Cl2/MeOH (18:1)
global deprotection
quantitative conversion
rt, 8 h
93 % yield
10 mol%
known to generate a mixture of LnMo-Cland LnMo CH , both known to initiate
diyne metathesis.
Ring-closing alkyne metathesis in TOS
Fürstner JOC 2000 (65) 8758.
M.C. White, Chem 153 Metal alkylidenes -395- Week of December 9, 2002
Asymmetric ring-closing metathesis with chiral molybdenum alkylidene complexes
R
MeMe
O
[Mo]
[Mo]
R
R
MoVI
N
OO
Me Me
Me
PhMe
R
R
O
Me
HMe
AcO
MoVI
NO
O
i-Pr
i-Pr
Me MePhCF3F3C
F3CCF3
O
O
AcO
O
AcO
O
benzene, 25 oC, 20 min
90 % conversion
+
Kinetic resolution in ring-closing metathesis
10 % recovered from reaction mix84% ee, krel = 2.02
k2(a)
k2(b)
k1
k-1
Grubbs and coworkers reasoned that the second (ring-closing) step would be suitable for asymmetric induction, because this step involves diastereomeric cyclic transition states which differ in energy. Diene substrates were chosen which contained a trisubstituted olefin to slow the cyclization step (and thus presumably increase the selectivity) and to control the site of the first metathesis.
Enantioselective synthesis of dihydrofurans by Mo-catalyzed desymmetrization.
Grubbs JACS 1996 (118) 2499.
Hoveyda/Schrock JACS 1999 (121) 8251.
5 mol %
benzene, rt, 6 h
86% yield, 93% ee
Mo*
toluene
-25 oC, 18h
Mo*
toluene
-25 oC, 18h
84% yield, 73% ee
91% yield, 82% ee
= Mo*
Enantioselective synthesis of quaternary carbon centers
M.C. White, Chem 153 Olefin Oxidation -396- Week of December 9, 2002
Directed epoxidations
VV
OO
OR
O
O
t-Bu
VO
OOR
O
t-Bu
O
Sharpless Aldrichimica Acta 1979 (12), 63.
VIV
O
OO
OO
VO
OOR
Ot-Bu
O
OH
t-BuOOH (TBHP)
OHO
t-BuOH
O
OM
R
planar orientation: the planedefined by the lone pair of theoxygen of the η2-peroxo isperpendicular to the planedefined by the olefin π-orbital. This orientation avoidsunfavorable lone pair-πinteractions
O
OM
R
spiro orientation favored: theplane defined by the lone pair ofthe oxygen of the η2-peroxo isparallel to the plane defined by the olefin π-orbital. This orientationaligns the lone pair-π* orbitalsthereby facillitating C-O bondformation.
HOMO
O
O LUMO
LUMO
O
O
M
R
M
R
Formation of covalent, intramolecular allyloxide intermediates leads to large rate accelerations in the V catalyzed epoxidation of allylic alcohols. Methyl ethersundergo epoxidation 1000 times slower than the corresponding alcohols.
VO
OOR
O
t-Bu
O
vs. VO
OOR
O
t-Bu
OR
OMe1000 x faster
Sharpless Chem. Br. 1986 (22) 38.
Stereoelectronic factors lead to a highly ordered TS. Perfect for asymmetric induction....
Ph
PhOH
V
O
RO OROR 1 mol%
N
F3C O
O
N OH
PhH
3 mol%
TBHP (2 eq)
2 open coordination sites required foreffective catalysis. Appending a chiral ligand occupies these sites and resultsin ligand-decelerated catalysis.
Ph
PhOH
O
optimal substrate90%, 80% ee
tol, -20oC, 4 days
Bystander oxo ligands arepresent in many early d0 metals capable of oxidation. Theyoccupy potentially usefulbinding sites for appendingchiral ligands.
M.C. White, Chem 153 Olefin oxidation -397- Week of December 9, 2002
OHMn+(OR)n cat.
TBHPOH
O
For all metals capable of effecting catalytic epoxidation of allylic alcohols with TBHP, only Ti displayed ligand accelerated catalysis. All other systems were strongly inhibited or entirely deactivated with addedtartrate ligand.
Sharpless ACIEE 2002 (41) 2024.
The Sharpless epoxidation
"For years, right up until January of 1980, when the asymmetric epoxidation was discovered, every expert in asymmetric synthesis and catalysis advised me that what we sought- a catalyst that was both selective and versatile- was simply impossible." K.B. Sharpless Chem. Br. 1986 (22) 38.
R OH
Oi-Pr
Oi-PrTiIV
i-PrOi-PrO
(+)-DET or (+)-DIPT
TBHP, 3 Å MS,
CH2Cl2, -20oC
R OHO
Uniformly >90% ee, 60-70% yields
HO
HO
O
OR'
O
OR'R' = Et : (+)-DET i-Pr: (+)-DIPT
C2-symmetric ligand
note: no bystander oxo ligand
H15C7
OHAll olefin substitution patterns result in high ee's and good yields, with theexception of cis-disubstituted olefinsthat generally react slowly and givemoderate ee's (80's)
C7H15
OH
95% ee88% yield
Unsymmetrical disubstituted Trisubstituted
Ph
Me
OH
>98% ee79% yield
Tetrasubstituted
94% ee90% yield
86% ee74% yield
cis-disubstituted
OH
Sharpless JACS 1987 (109) 5765.Sharpless In Asymmetric Synthesis, Morrison, Ed.; Academic Press: New York, 1986 (5) 247.
M.C. White, Chem 153 Olefin Oxidation -398- Week of December 9, 2002
Mechanism
R OH
Oi-Pr
Oi-PrTiIV
i-PrOi-PrO
(+)-DET or (+)-DIPT
TBHP, 3 Å MS,
CH2Cl2, -20oC
R OHO
Uniformly >90% ee, 60-70% yields
HO
HO
O
OR'
O
OR'R' = Et : (+)-DET i-Pr: (+)-DIPT
C2-symmetric ligand
note: no bystander oxo ligand
OTiIV
RO
RO
OTiIV
O O
O
R'(O)C
R'OR
OR'
OR
C(O)R'
The catalyst self-assembles under the reaction conditions to give predominantly a dimeric species that epoxidizesallylic alcohols with high levels of ee. The dimericspecies is significantly more active than Ti tetraalkoxidealone or Ti-tartrates of other than 1:1 stoichiometrywhich lead to zero or low ee products (respectively).
Oi-Pr
Oi-PrTiIV
i-PrOi-PrO
OTiIV
RO
RO
OTiIV(OR)3
O
OR' C(O)R'
Major species in solution and kinetically most active. Leads to high ee products.
R OHO
high ee's
rel. rate: 1.0
R OHO
low ee's
rel. rate: 0.28rel. rate: 0.38
R OHO
0 ee
OTiIV
RO
OR
OTiIV
O O
R'(O)C
CO2R
O
OR'
O
O
t-Bu
R
C(O)R'
proposed intermediate
Sharpless JACS 1991 (113) 106, 113.
M.C. White, Chem 153 Olefin Oxidation -399- Week of December 9, 2002
Non-directed epoxidations: transferable metal oxo
N N
N N
CO2HHO2C
FeII
S-Cys
P-450 catalyzed epoxidations
O O
N N
N N
CO2HHO2C
FeIII
S-Cys
OO
N N
N N
CO2HHO2C
FeIII
S-Cys
OO
N N
N N
CO2HHO2C
FeIII
S-Cys
OON N
N N
CO2HHO2C
FeV
S-Cys
O
N N
N N
CO2HHO2C
FeIII
S-Cys
H2O
R
N N
N N
CO2HHO2C
FeIV
S-Cys
O
FeV
O LUMO
RHOMO
Stereoelectronically favored side-on approach:
R
R
N N
N NFeIII
Cl
1 e-
2H+
1 e-
O O
OO
O
O
O O
O
O
O
catalyst
PhIO
85% yield84% ee
Collman JACS 1993 (115) 3834.
Chiral P-450 mimics
M.C. White, Chem 153 Olefin Oxidation -400- Week of December 9, 2002
Jacobsen epoxidation
The Jacobsen epoxidation
Ph Me
N N
O O
MnIII
0.1-4 mol%t-Bu t-Bu
t-But-Bu
NaOCl, CH2Cl2, pyridine N-Oxide (20 mol%)
Cl
cis-disubstituted substratesgive optimal yields and ee's
Ph Me
O
84% yieldcis: trans (11.5:1)
92% ee
O
Jacobsen JACS 1990 (112) 2801.Jacobsen JACS 1991 (113) 6703.Jacobsen JOC 1991 (56) 2296.Jacobsen TL 1996 (37) 3271.
PhO
O
BrO
88% ee90% yield
93% ee69% yield
TrisubstitutedCis-disubstituted
96% ee84% yield
Jacobsen TL 1995 (36) 5123.
Tetrasubstituted Cis-enynes give trans-epoxides :TMS
Cy
TMS
Cy
O
Jacobsen JACS 1991 (113) 7063.
N N
O O
MnIII
PF6
4 mol%OMe MeO
The first report of epoxidation activity:
PhIO (1 eq), CH3CN
2 eq limiting reagent
O
56% based on iodosylbenzene (PhIO)
Kochi JACS 1986 (108) 2309.
Bleach as a terminal oxidant:
N N
O O
NiII
cat
NaOCl (pH 13)/CH2Cl2
Bu3NBz+Br-
O
Radical intermediate envoke toaccount for exclusive formation of the E-epoxide from the Z.
84%
N N
O O
NiIV
ON N
O O
NiIII
O
Ph
NaCl
Burrows JACS 1988 (110) 4087.
N N
O O
MnV
PF6
OMe MeO
O
PhI
M.C. White, Chem 153 Olefin Oxidation -401- Week of December 9, 2002
MechanismProposed mechanism:
Ph Me
N N
O O
MnIII
0.1-4 mol%t-Bu t-Bu
t-But-Bu
NaOCl, CH2Cl2, pyridine N-Oxide (20 mol%)
Cl
cis-disubstituted substratesgive optimal yields and ee's
Ph Me
O
84% yieldcis: trans (11.5:1)
92% ee
N N
O O
MnV
t-Bu t-Bu
RR
t-But-BuL
ON N
O O
MnIV
t-Bu t-Bu
R
t-But-BuL
O
Ph
R
Me
N N
O O
MnIV
t-Bu t-Bu
R
t-But-BuL
O
R
Me
Ph
Me
OPh+
Rationale for enantioselection:
All trajectories to Mn oxoare sterically blocked except the one over the chiraldiimine backbone.
NN
O
OMnV
OH
H
Me
Ph
Jacobsen JOC 1991 (56) 6497.
M.C. White, Chem 153 Olefin Oxidation -402- Week of December 9, 2002
Sharpless dihydroxylation
OH
OH
OsVI
O
O
HO OHHO OH
2- +K2
0.2 mol%
(DHQD)2-PHAL (1 mol%)K3Fe(CN)6 (3 eq)
K2CO3 (3 eq)t-BuOH: H2O (1:1)
98% ee>90% yield
Commercially available as a mix:AD-mix-α uses the ligand (DHQ)2-PHALAD-mix-β uses the ligand (DHQD)2-PHAL
N
H
N
MeO
O
NN
O
N
H
N
OMe
(DHQD)2-PHAL
N
MeO
N
Et
HO
NN
O
N
Et
N
OMe
H
(DHQ)2-PHAL
pseudo-enantiomericWorks well for all olefin substitution
patterns with the exception ofcis-disubstituted and tetrasubstituted.
OsVI
O
O
HO OHHO OH
+K22-
General mechanism: Sharpless Chem. Rev. 1994 (94) 2483.
OsVIII
O
O
O OHO OH
+K22-
Sharpless JOC 1992 (57) 2768.
2 K3Fe(CN)62 OH-
2 K4Fe(CN)62 H2O
OsVIII
O
O
O
OOsVI
O
O
R
R
L
O
O
OsVIII
L
O
OO
O
2 OH-2 H2O
R
R
HO OH
R R
Evidence favors the [3+2] mechanism vs. [2+2]:Corey TL 1996 (28) 4899.Houk, Sharpless, Singleton JACS 1997 (119) 9907.
The enzyme-like binding cleft is especially well suited for π-stacking with aromatic substrates. Large rate accelarations are observed for aromatic substrates with the phalazine class of ligands.
ligand accelarated catalysis:although OsO4 is capable ofdihydroxylating olefins, the ligand bound complex does so at a muchgreater rate. Corey JACS 1993 (115) 2861, 12579.
Sharpless JACS 1994 (116) 1278.
Os
O
OO
L
O RR
[3+2]