why zn acetylides?
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Catalytic, Enantioselective Carbonyl AdditionReactions of Metal Acetylides
An Evans Group Afternoon SeminarJake Janey
May 31st, 2002
I. Introduction II. Stoichiometric Zn, catalytic ligandIII. Catalytic Zn and ligand (Carreira)IV. Other metal acetylides
R HO
R'+
Catalytic
Metal/Ligand
OH
R'
R
Keywords: Acetylene, Metal Acetylide, Enantioselective, Carbonyl, Catalytic, Zinc, Copper, Iridium, Lithium, Ephedrine, Asymmetric, Addition, Imine, Nitrone, Aldehyde, Alkyne
01 Introduction 6/5/02 9:31 AM
A Versatile Synthetic Intermediate
OH
R'
RR''
• Propargylic alcohols are an important synthetic building block
• Subunit in Merck's HIV-1 reverse transcriptase inhibitor Efavirenz
OH
R'
RR''
OH
R'R''
R
OH
R'R''
R
orH2
XNH2OH
R'R''
R
NHX
[3+2] or[4+2]
ZY
XR'R''
OH
R ZY
XW
R'R''
R
OH
or
OH
R'R''
X
XY
R = H
R
BaseE+
OH
R'
ER''
Yhydrohalogenationhydrozirconationhydroborationcarboaluminationcarbocupration
Cu2Cl2OH
R'R''
R
Pd(0)
CuI
OH
R'R''
R
The Chemistry of Triple Bonded Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1983Preparative Acetylene Chemistry; Brandsma, L., Ed.; 2nd ed.; Elsevier: Amsterdam, 1988Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, 1995
02 Synthetic Importance 6/5/02 9:32 AM
Common Methodology
R MO
R'+
OH
R'
RR'' R''
• Resolution or diastereoselective
M = Li, MgBr, Cs, K, Na, SnX3
O
R'
R
" H- "
Chiral Catalyst
OH
R'
R
O
R'
R
(R'')2Zn
Chiral Ligand
OH
R'
RR''
O
H
R
OM
R'+
Chiral CatalystOH
R
R'
O
O
R'R
HO
MeMe
Al(OR)3 or
Zr(Ot-Bu)4+
OH
R'
R
Maruoka, K. et. al. Tetrahedron, 2001, 867-873 (and ref. cited therein)
03 Alkynlation 5/31/02 11:24 AM
Alkyne Acidity
HR
pKaR=H 24 (H2O)R=Ph 23 (H2O) 28.8 (DMSO)
High kinetic acidity
HR
pKaR=H 50 (H2O)R=Ph 43 (H2O) 44 (DMSO)
HR
R
pKaR=H 48 (H2O) 56 (DMSO)R=Me 51 (H2O)
Typical Bases: n-BuLi or EtMgBr
t-BuO Me
O
pKa24.5 (H2O) 30.3 (DMSO)
A few known examples of catalytic base...
HRR' R''
O
R'
OH
RR''
+cat. base
THF or DMSO
KOH or NaOH: Shachat, N.; Bagnell, J. J. J. Org. Chem. 1962, 27, 1498-1504KOt-Bu: Babler, J. H.; Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61, 416-417CsOH: Tzalis, D.; Knochel, P. Angew. Chem. Int. Ed. 1999, 38, 1463-1465
04 Acidity 5/30/02 11:23 AM
Catalytic, Enantioselective Alkynylation
R H
X
R'XML*
R'
R
R''
R''
cat. ML*R ML*
chiral nucleophile
XH
R'
RR''
ML*
• Need either catalytic base to transfer proton, or a metal capable of oxidative addition
A Simple Analogy...
R MXChiral Ligand
(L*)R MXL*
X
R'XML*
R'
R
R''
R''chiral nucleophile
XM
R'
RR''
L*
• Stoichiometric formation of a metal acetylide with a catalytic amount of chiral ligand
Reviews of organozinc additions:Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69Pu, L.; Yu, H. -B. Chem. Rev. 2001, 101, 757-824Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856
05 Catalytic schemes 6/5/02 9:32 AM
Why Zn Acetylides?
Me2Zn + HRTHF/tol.
ZnR2
insoluble white ppt.
conditions: • 30% conversion in 17h at 0 °C without ligand• NMR shows no dialyknyl zinc formation when Me2Zn and alkyne mixed without ligand• Addition of chiral ligand gives 100% conversion in 3h at 0 °C
R'CHOR'
R
OH
Ligand Acceleration !
Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999, 1453-1458
R Zn R
Why?
sp hybridized
nonpolar
unreactive
RZn
Xδ+δ−
X = alkyl, N, O, Halogen, etc...
spn hybridizedpolar
reactive
OZn
R'2N
ZnO
NR'2
R
R
OZn
R'2N
R2
reactive
Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69
unreactive
06 Why Zn Acetylides 5/30/02 11:33 AM
R
Organozinc Catalytic Cycle
OZn
R'2N
ZnO
NR'2
R
ROZn
R'2N
Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69
OH
NR'2
+R2Zn-RH
1/2
+R2Zn
-R2ZnZn
R
RR
+ArCHO-ArCHO
OZn
R'2N O
R
Ar
OZn
R'2N+R2Zn
-R2ZnZn
R
RR
+ArCHO-ArCHO
OAr
Slow
OZn
R'2N
ZnO
R
Ar
R
ArCHO
1/4 A
R2Zn
Zn
O
O
O
ZnZn
Zn
O
R
R
Ar
R
ArR
ArR
R
A
1/4insoluble aggregate
drives reaction forward=> ligand turnover
R
07 Zn Catalytic Cycle 6/5/02 9:32 AM
Model for Asymmetric InductionGeneral for β-Amino Alcohols
Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69
OZn
R'2N
Ph
Me
OZnR2
R
α
β
(S)
(R)
OZn
R'2N
Ph
Me
RZnR2
O
α
βAr
(S)
(R)N-alkyl-ephedrine
N
OZn
ZnO
R
R'
R'Me
(S)α
β
α gears ZnR2
Disfavoredinteraction between Ar and ZnR2
Favored
or
General Features:• α stereocenter dictates observed product selectivity without exception• trans α,β chelate offset and show lower selectivity, α still dominates -->Cis best• Gearing effect --> direct sterics between aldehyde and ligand unimportant
H
ArR
R
N
OZn
ZnO
R
R'
R'Me
(R)α
β
Ar
HR
R
Evans, D. A. Science 1988, 240, 420-426.
Ar
08 Model for induction 6/5/02 9:32 AM
Origins of Non-Linear Effect
Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69
Large positive non-linear effect: 15% ee catalyst delivers 95% ee product for diethylzinc addition to benzaldehyde in presence of 3-exo-(dimethylamino)isoborneol [DAIB]
OZn
Me2N
ZnO
NMe2
R
R1/2
(2S, 2'S)
OZn
Me2N
ZnO
NMe2
R
R1/2
(2R, 2'R)
OZn
Me2N
R
OZn
Me2N
ZnO
NMe2
R
R
(2S, 2'R)
ZnO
NMe2
R+
(2S) (2R)
Heterochiral dimer very stableno activity
Homoochiral dimer not stableno activity
Chiral monomeractive
• Slight excess of one enantiomer is enhanced as all of the minor enantiomer is tied up as heterochiral dimer
09 Nonlinear 6/5/02 9:33 AM
Kinetic Chicanery...(Don't be fooled by rates)
Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028-4036
Et2Zn + PhCHODAIB
tol. 0 °C Et Ph
OH
• Example: using 34 mM DAIB, 0.42M Et2Zn, and 0.42M PhCHO indicates that (-)-DAIB is merely 14-times faster than (±)-DAIB• 15% ee catalyst gives 95% ee product indicates that chiral is 171-times faster than racemic
The independant and competitive figures are not the same !
• Answer: The rate of (-)-DAIB catalysis is not as affected by [Et2Zn] or [PhCHO], whereas rate for (±)-DAIB is very dependent upon substrate concentration.
10 Kinetics 6/5/02 9:33 AM
Chelate Controlled Additions
R CHO
OBnMR1 + -78 °C
R
OR1
OH
R1
R
OR1
OH
R1
+
syn anti
Entry
1
2
3
4
5
6
7
8
9
10
11
12
R'
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Hex
n-Hex
Aldehyde (R)
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
BnOCH2
Me
i-Pr
M
Li
MgBr
ZnCl
ZnBr
ZnBr
MgBr
ZnCl
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
Solvent
THF
THF
THF
THF
THF, 0 °C
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
syn : anti
45:55
62:38
66:34
81:19
76:24
74:26
88:12
95:5
99:1
86:14
84:16
98:2
Yield (%)
-
-
-
75
70
82
65
95
92
76
79
78
• Zn acetylide formed by transmetalation of Li acetylide with ZnX2• 2 equiv. of Zn acetylide used, as 1 equiv. gave same selectivity, but lower yields.• Zn chelate is proposed to explain syn selection
Mead, K. T. Tetrahedron Lett. 1987, 28, 1019-1022
For chelate controlled Sn-acetylide additions, see: Evans, D. A.; Halstead, D. P.; Allison, B. D.Tetrahedron Lett. 1999, 40, 4461-4462
11 Chelate addition 6/5/02 9:33 AM
Early Example of Zn Acetylide Addition
R1CHO + ZnR2
2
5 mol%
Hex/THF, r.t.2 equiv.
OHn-Bu2N
Me PhH H
R1
OH
R2(R)
(R)(S)
Entry
1
2
3
4
5
6
7
8
R1
Ph
n-Octyl
PhCH=CH
Ph
Ph
Ph
n-Octyl
Ph
R2
Ph
Ph
Ph
n-Hex
Bu
Me3Si
Me3Si
c-Hex
Time (h)
14
5
14
44
52
168
48
48
Yield (%)
99
78
97
81
93
36
80
88
ee (%)
34
9
10
22
20
21
24
7
• Zn-acetylides formed by heating Et2Zn and the acetylene• Stereochemistry in accord with Noyori's model• Mixed alkylalkynyl zinc reagents (e.g. MeZn-≡C-Ph) gave only alkynylation with 40% ee
Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937-943
12 Soai Zn-ephedrine 6/5/02 9:33 AM
Improved Zn Acetylide Addition
RCHO + ZnBrPh1 equiv.
toluene2 equiv.
OLin-Bu2N
H HMe Ph
R
OH
Ph
(R) (S)
(S)
Entry
1
2
3
4
R
Ph
t-Bu
n-Pent
T (°C)
-30
-30
-30
0-5
Time (h)
19
24
20
20
Yield (%)
70
50
90
80
ee (%)
80
67
19
88O
F
Cl
Cl
O
MeMe
Ph
O
F
H
OInsecticide
ZnEtPh
delivers product in42% ee
Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett. 1990, 547-548
• Catalytic reaction with 10 mol% isolated Zn acetylide amino alcoholcomplex gives product in only 35% ee
13 Amino alkoxide cat 5/30/02 1:03 PM
Tridentate Chiral Ligand
R1CHO + ZnEtR2 10 mol%
THF R1
OH
R2(R)
Entry
1
2
3
4
5
6
7
8
9
R1
Ph
n-Octyl
c-Hex
t-Bu
Ph
n-Octyl
c-Hex
t-Bu
c-Hex
R2
Ph
Ph
Ph
Ph
n-Hex
n-Hex
n-Hex
n-Hex
Ph3Si
Time (h)
15
4
10
10
2
1
3
3
5
Yield (%)*
64
65
88
61
41(52)
62(22)
79(18)
67
55
ee (%)
90
83
91
95
78
73
82
87
91
Temp. (°C)
0
0
0
0
r.t.
r.t.
r.t.
r.t.
r.t.
* Values in parenthesis are yields of ethylated product
N
O
HO
ArAr(S)
Ar = α-naphthyl
• Opposite facial selectivity as Noyori's bidentate ligand model• Zn acetylide formed by diethylzinc and acetylene heated at reflux
Ishizaki, M.; Hoshino, O. Tetrahedron: Asymm. 1994, 5, 1901-1904
14 Tridentate ligand 6/5/02 9:34 AM
Merck's Ephedrine Derivative
OHN
H HMe Ph(R) (S)
1. ZnMe2
2. ROH Ph
Me
N
ZnO
ORM
Ph
Me
N
ZnORO
M+
+
ClCF3
O
NH2
ClOH
NH2
F3CClO
NH
F3C
O
Efavirenz: HIV reversetranscriptase inhibitor
1 equiv.
M
Li
MgCl
MgBr
MgI
ee (%)
83.0
87.0
53.6
50.6
ROH
MeOH
EtOH
(CH3)3CCH2OH
CH2=CHCH2OH
BnOH
CF3CH2OH
CF3CO2H
(CH3)3CCO2H
p-NO2PhOH
ee (%)
87.0
55.0
95.6
90.0
89.0
95.7
89.4
71.6
89.0
M = MgCl
ClOH
NH2
F3CCl
OH
NH2
F3C
OH
F3C
Cl
O CF3
95.2% ee 97.0% ee
97.0% ee
NH2
Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Che,. Int. Ed. 1999, 38, 711-713
15 Merck Zn 6/5/02 9:34 AM
Merck's Catalytic Process
Ar
O+ Ph H
ZnMe2, toluene/THF
10mol% ligand, -30 °C Ar
OH
Ph
OHN
H HPh Ph(R) (S)
OHN
Ph PhH H(S) (R)
A B
Entry
1
2
3
4
5
6
7
8
9
Ar
Ph
o-F-Ph
m,o-di-F-Ph
o-Cl-Ph
o-Br-Ph
o-NO2-Ph
o-MeO-Ph
o-Me-Ph
2-naphthyl
Ligand
A
B
B
A
A
A
A
A
B
Yield (%)
70
90
94
77
77
81
74
65
87
ee (%)
68(-)(S)
82(-)
81(+)
80(+)
80(+)
76(+)
82(+)
62(+)
75(-)
• Use of toluene/THF eliminate methyl addition• Small non-linear effect observed• Stereochemistry in accord with Noyori's model• Zn-acetylide only forms upon addition of ligand (by NMR)
Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999, 1453-1458
16 Merck's catalytic Zn 6/5/02 9:34 AM
BINAP Derived Amino Alcohol
Ar
O+ Ph H
ZnMe2 (2 equiv.), tol.
10mol% ligand, 0 °C Ar
OH
Ph
OHN
H HPh Ph
(R)(S)
Entry
1
2
3
4
5
6
7
Ar
o-F-Ph
o-Br-Ph
o-NO2-Ph
o-MeO-Ph
o-Me-Ph
2-naphthyl
Ph
Conv. (%)
>95
>95
>95
>95
>95
>95
>95
ee (%)
87(+)
90(+)
87(+)
71(+)
71(+)
61(+)
70(-)(S)
• Other diasteromers of ligand give low ee• Stereochemistry in accord with Noyori model• OH bearing stereocenter on ligand determines facial selectivity
Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C. Tetrahedron: Asymm. 2001, 12, 2147-2152
(R)
(1R, 2S, 3R)
2 equiv.
Time (h)
12
12
24
6
24
24
24
(S)
17 BINAP derived ligand 6/5/02 9:35 AM
Titanium H8-BINOL Catalyzed
R
O+ Ph H
ZnMe2, Ti(Oi-Pr)4 (1.5 equiv.)
THF, 20mol% H8-BINOL, 0 °C Ar
OH
Ph(S)
OHOH
(R)-H8-BINOL
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
R
Ph
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
p-Me-Ph
p-F-Ph
p-Br-Ph
p-NO2-Ph
m-NO2-Ph
2-naphthyl
p-CF3-Ph
i-Pr
c-Hex
n-Pr
Yield (%)
85
90
87
91
84
82
89
89
88
75
89
84
86
87
ee (%)
92 (S)
76
95
94
86
87
94
95
96
80
93
82
74
77
• BINOL gave slightly reduced yieldsand selectivity
Lu, G.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172-173
18 TiBINOL catalyzed 6/5/02 9:35 AM
Titanium BINOL Catalyzed
R
O+Ph ZnEt
50 mol%Ti(Oi-Pr)4
20 mol% (S)-BINOL, r.t. Ar
OH
Ph(R)
Entry
1
2
3
4
5
6
7
8
9
10
11
R
Ph
m-Cl-Ph
p-Cl-Ph
o-Me-Ph
m-Me-Ph
o-MeO-Ph
m-MeO-Ph
p-F-Ph
p-NO2-Ph
2-naphthyl
1-naphthyl
Yield (%)
77
79
81
81
77
73
78
74
79
77
71
ee (%)
96
92
92
96
94
93
93
96
97
98
92
Ph HEt2Zn
tol. reflux2 equiv. CH2Cl2/toluene
i-Pr3Si H + PhCHOgives 75% yield and 92% ee
Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855-1857
19 TiBINOL catalyzed II 5/28/02 7:05 PM
"Soft" Metal Acetylide Formation
R HCuX or
AgXR H
M(I)X
:NR3
HNR3X
R M
Advanced Inorganic Chemistry; Cotton, F. A., Wilkinson, G.; 5th ed.; Wiley: New York, 1988, p.765, 945
R
M
R
M
n
sp-C-H activation:R H
MLn
R MLn
H
R H
+
Ox. Add.
Insertion
MLn
HR
R or
MLn
H
R
R
Red. Elim.
RR R
Ror
Metals: Ru(II), Ir(I), Ti(IV), Pd(0), Rh(I), others?
Ru(II): Naota, T.; Takaya, H.; Murahashi, S.-I. Chem Rev. 1998, 98, 2599-2660
Unreactive to electrophiles
20 Metal Acetylide 6/5/02 9:35 AM
Early Examples of Catalytic Metal
Ph H + CH2O HNR2+
5-8h, 100 °Cdioxane
or cat. Cu(X) or ZnX2
-30 °C to r.t.
R2N
Ph
Thermal: Mannich, C.; Chang, F. T. Ber. 1933, 418-420Catalytic ZnX2 or CuX: for an example, see: Stutz, A.; Granitzer, W.; Roth, S. Tetrahedron 1985, 41, 5685-5696.
H + CH2O HNR2+ R2N
HO
Cu(SO4)2
H2O (pH 9)+ Cu(0)
• A copper acetylide is proposed• Extensive screening found basic medium is best, as acidic conditions cannot form Cu-acetylide
Salvador, R. L.; Simon, D. Can. J. Chem. 1966, 44, 2570-2575
Ph H +cat.
0.5-3h, 135 °CHC(OEt)3 Ph
OEt
OEt
H H +cat.
0.5-3h, 135 °CHC(OEt)3 H
OEt
OEt+
OEt
OEt
EtO
EtO
EtO
OEt
OEt
OEt+
indicates ionic mechanism
cat. = ZnCl2, ZnI2, Zn(NO3)2, CdI2
Howk, B. W.; Sauer, J. C. J. Am. Chem. Soc. 1958, 80, 4607-4609
OH
21 Precedent 6/5/02 9:35 AM
Sn Acetylide Formation
R H R'CHO+
Sn(OTf)2 or SnCl4(1-3 equiv.)
R3N (1-3 equiv.)R
R'
OH
• Propose formation of Sn-acetylide• Also reacts with acetals and adds 1,4 to enones
Yamaguchi, M.; Hayashi, A.; Minami, T. J. Org. Chem. 1991, 56, 4091-4092Yamaguchi, M.; Hayashi, A.; Hirama, M. Chem. Lett. 1992, 2479-2482
"...copper or palladium acetylides have been generated with amine bases, although these species are not reactive enough to add to aldehydes. It seemed to us that the proper slection of a metal salt in combination with an amine base might allow generation of metal acetylides that are reactive enough to add to C=O bonds."
22 More early examples 6/5/02 9:35 AM
Zn(OTf)2 Catalyzed Additions to Nitrones
R1 H + NO
R2
Bn10 mol% Zn(OTf)225 mol% i-Pr2NEt
"In this context, we have been interested in developing methods that lead to the generation of metal alkynilides directly from terminal acetylenes under conditions that parallel those involving Ag(I) or Cu(I) in simplicity and mildness but that can be utilized in catalytic nucleophilic C=O and C=N addition reactions."
CH2Cl2, r.t.R2
NHO Bn
R1
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
R1
TMS
TMS
TMS
TMSCH2
TMSCH2
TMS
n-Bu
Ph(CH2)2
TBSOCH2
Ph
t-Bu
BrCH2
R2
c-Hex
Ph
n-Pent
n-Pent
t-Bu
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Time (h)
12
24
12
12
12
12
3
3
6
1
1
3
3
Yield (%)
95
43
62
90
67
99
95
96
85
94
93
68
85
• Zn-acetylide detected by 13C NMR• Also adds to ketones, aldehydes, N-Ts imines• ZnCl2 and ZnO also catalyze reaction (unpub.)
Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121, 11245-11246
23 Nitrone add. 6/5/02 9:35 AM
ZnI2 Catalyzed 5-endo Dig Cyclization
R2
NHO Bn
R1
10 mol% ZnI210 mol% DMAP
CH2Cl2, r.t. 1-28h
N OR1
R2
Bn
R2
NHO Bn
R1Zn(II)
-H+N O
R1
R2
Bn
Zn(II)
+H+
• DMAP is vital, as Et3N gives no product• Other Zn(II) salts work, but ZnI2 is fastest• Other Lewis acids and protic acids gave no product• Crossover experiments preclude retro-addition followed by [3+2]
Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331-2333
24 5-endo dig 6/5/02 9:36 AM
Enantioselective Addition (Stoichiometric)
R1 H +O
R2
Zn(OTf)2 (1 equiv.)
i-Pr2NEt (1 equiv.)toluene, r.t.
R2
OH
R1
OHMe2N
Me PhH H (R)(S)
(R)
Entry
1
2
3
4
5
6
7
8
9
1 equiv.
R1
Ph
Ph(CH2)2
Ph(CH2)2
Ph
Ph(CH2)2
Ph(CH2)2
Ph
Ph(CH2)2
Ph
R2
c-Hex
c-Hex
i-Pr
i-Pr
PhCH=CH
t-Bu
t-Bu
Ph
Ph
Yield (%)
99
98
90
95
39
84
99
52
53
ee (%)
96
99
99
90
80
99
95
96
94
Entry
10
11
12
13
14
15
16
17
R1
TMS
Ph(CH2)2
Ph
TMSCH2
TBDMSOCH2
(EtO)2CH
R2
c-Hex
Me3CCH2
Me3CCH2
c-Hex
c-Hex
c-Hex
c-Hex
i-Pr
Yield (%)
93
72
90
84
83
90
94
97
ee (%)
98
99
97
98
98
98
98
98
HO
• Alipahtic aldehydes more reactive than aromatic• Unbranched alipahtic aldehydes give good ee, but poor yield from self-aldol condensation• Facial selectivity of (2R ) ephedrine in accord with Noyori model• Slight non-linear (20% ee ephedrine gives 39% ee product)• Insensitive to moisture and oxygen
Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806-1807Epothilone Synthesis: Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611-3612
25 Enantioselective Addition 6/5/02 9:36 AM
Acetylene as a Nucleophile
H H +O
R
Zn(OTf)2 (1 equiv.)
i-Pr2NEt (1 equiv.)toluene, r.t.
R
OH
OHMe2N
Me PhH H (R)(S)
1 equiv.
(R)excess
sat. tol. at -40 °C
Entry
1
2
3
4
5
6
7
R
n-Pent
i-Pr
c-Hex
t-Bu
Ph
PhCH=CH
Ph
Me
Yield (%)
30
76
70
92
35
34
28
ee (%)
97
98
98
98
97
92
91
• Reactions were sluggish, 7-14 days• Mass balance was recovered s.m.
Sasaki, H.; Boyall, D.; Carreira, E. M. Helv. Chim. Acta 2001, 84, 964-971
26 Acetylene 6/5/02 9:36 AM
An Acetylene Equivalent
H +O
R
Zn(OTf)2 (1 equiv.)
NEt3 (1 equiv.)toluene, r.t.
R
OH
OHMe2N
H HMe Ph(R) (S)
1 equiv.
OH
OH(S)1. BzCl
2. cat. 18-C-6, K2CO3toluene, reflux
R
OBz
(S)H
$3/kg70-91% yield
Entry
1
2
3
4
5
6
7
8
R
i-Pr
c-Hexyl
t-Bu
n-Pentyl
n-Propyl
Ph
PhCH=CH
TIPSO(CH2)2
Yield (%)
97
89
82
81
77
96
99
82
ee (%)
98
99
98
98
99
98
88
97
• Protection of alcohol needed for good yields in fragmentation reaction• Protection performed in same pot as Zn reaction• Many aldehydes required 2-3 equivalents of Zn(OTf)2 and ephedrine
Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233-4236
27 Terminal alkyne equiv. 6/5/02 9:36 AM
Propargyl Alcohol Functionalization
H +O
R
Zn(OTf)2 (1 equiv.)
NEt3 (1 equiv.)toluene, r.t.
R
OH
OHMe2N
Me PhH H (R)(S)
1 equiv.
AcOOAc(R)
1. TBDPSCl, Im., DMF
R
OTBDPS
25-72% overall Yield
2. 2 mol% Pd2(dba)3•CHCl3 23 mol% Ph3P, HOAc toluene, reflux3. Et3N, MeOH
54-95% Yield88-97% ee
Me
O
OTBS
H +AcO
MeMe
HO NMe2
OH
OAc
Me
OTBS
OH
OAc
Me
OTBS
OHMe2N
Me PhH H (R)(S)
OHMe2N
H HMe Ph(R) (S)
syn
anti
d.r. (syn:anti)
96:4
80:20
9:91
CHO
Catalyst Control...
El-Sayed, E.; Anand, N. K.; Carreira, E.M. Org. Lett. 2001, 3, 3017-3020
28 Propargyl alcohol Pd 6/5/02 9:37 AM
Enantioselective Nitrone Addition
Ph H + NO
cat. Zn(OTf)2cat. i-Pr2NEt
NHO
Ph
Me
Me
Ph
BuMe
Me
Bu
Ph
10:1 diastereoselection
H + NO Bn
cat. Zn(OTf)2cat. i-Pr2NEt
NHO Bn
Me
Me
Me
Me88% ee
85% Yield
Ph
PhO
N N
OMeMe
Ph Phcat.
Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Rec. 2000, 33, 373-381
29 Enantio. nitrone addition 6/5/02 9:37 AM
Catalytic, Enantioselective Acetylene Addition
R1 H +O
R2
20 mol% Zn(OTf)250 mol% NEt3toluene, 60 °C
R2
OH
R1
OHMe2N
Me PhH H (R)(S)
(R)
22 mol%
Entry
1
2
3
4
5
6
7
8
R1
Bn2NCH2
Ph(CH2)2
Ph
Ph(CH2)2
Ph(CH2)2
TBSOCH2
(EtO)2CH
TMSO
R2
c-Hex
c-Hex
c-Hex
i-Pr
n-Heptyl
t-Bu
t-Bu
c-Hex
Yield (%)
91
89
94
77
45
77
81
88
ee (%)
97
94
86
98
92
93
93
94
Entry
9
10
11
12
13
14
15
16
R1
n-Bu
TES
Bn2NCH2
TBSOCH2
Bn2NCH2
Ph(CH2)2
Bn2NCH2
TMSO
R2
c-Hex
c-Hex
c-Hex
c-Hex
n-Heptyl
Yield (%)
81
80
85
80
88
81
80
55
ee (%)
93
99
96
95
90
94
93
91
TIPSO
NBn
• Racemic reaction proceeds in CH3CN w/o ephedrine• ArCHO yields are low due to Canizzaro reaction• Reactions proceed neat• Some self-aldol condensation observed
Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688
O
Ar CF3
also works75% ee (unpub.)
30 Catalytic in Zn and ligand 6/5/02 9:37 AM
Catalytic Nitrone Addition
R1 H + NO
R2
R320 mol% ZnEt2
toluene, r.t. R2
NHO R3
R1
Entry
1
2
3
4
5
6
7
8
9
10
R1
n-Bu
n-Decyl
p-Pent-Ph
Cl(CH2)3
TMS
NC(CH2)3
MeCO2CH2
(EtO)2CH
t-BuOCH2
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R3
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Yield (%)
92
82
88
92
96
90
78
62
90
82
Entry
11
12
13
14
15
16
17
18
19
R1
t-BuO2C
n-Bu
p-Pent-Ph
Cl(CH2)3
MeCO2CH2
n-Bu
TMS
MeCO2CH2
R2
Ph
p-MeO-Ph
p-MeO-Ph
p-MeO-Ph
Ph
Ph(Me)CH
Ph(Me)CH
Ph(Me)CH
Ph(Me)CH
R3
Bn
Ph
Ph
Ph
t-Bu
Me
Me
Me
Me
Yield (%)
<42
72
56
61
>99*
94
97
87
91
d.r.
-
-
-
-
-
78:22
74:26
76:24
77:23
ON
AcO
Ph
t-Bu
* isolated only
Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463-1466
31 Another nitrone add. 6/5/02 9:37 AM
Enantioselective Li-Acetylide AdditionsEarly Examples
R1 H + R2CHO
n-BuLi (6.7 equiv.)Ligand (4 equiv.)
DME, -123 °C2.7 equiv.
R2
R1
OH
NN
Me
Ligand
Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979, 447-448Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255-256
Entry
1
2
3
4
5
6
R1
H
TMS
TES
TBS
Ph2MeSi
TPS
R2
Ph
Ph
Ph
Ph
Ph
Ph
Yield (%)
76
87
93
67
88
83
ee (%)
54
92
80
72
80
76
Entry
7
8
9
10
11
12
13
R1
TMS
TMS
TMS
TMS
TMS
TMS
TMS
R2
Et
n-Pent
n-Octyl
n-C11H23
n-C13H27
(CH3)2CHCH2
CH3(CH2)2CH=CH
Yield (%)
77
87
83
82
76
54
74
ee (%)
68
76
80
70
73
65
40
• Aromatic aldehydes gave (S) alcohol, whereas aliphatic gave (R)
HO
32 Early Li-acetylide 6/5/02 9:38 AM
Enantioselective Li-Acetylide AdditionsEarly Merck Examples
R2 Li
quinine-Li (1.5 equiv.)
N
N
R1
O
Cl+
N
NH
R1
O
Cl
R2
NH
NH
O
Cl
N
HIV reverse transcriptaseinhibitor
N
N
HOLi
HOMe
1.5 equiv.THF, -25 C
Entry
1
2
3
4
5
6
7
R1
PMB
Bn
p-Cl-Bn
Me
2,4,6-Me3Bn
2,6-Cl2Bn
9-anthrylmethyl
R2
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
best ee (%)
64
56
37
70
74
80
97
Entry
8
9
10
11
12
13
14
15
R1
9-anthrylmethyl
9-anthrylmethyl
9-anthrylmethyl
9-anthrylmethyl
9-anthrylmethyl
9-anthrylmethyl
9-anthrylmethyl
9-anthrylmethyl
R2
2-pyridyl
3-pyridyl
4-pyridyl
p-MeOPh
Ph
p-Cl-Ph
Bu
TMS
ee (%)
94
22
6
86
65
58
77
82
Huffman, M. A.; Yasuda, N.; DeCamp, A.E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590-1594
33 Li-acetylide/Merck 6/5/02 9:38 AM
THF
Enantioselective Li-Acetylide AdditionsEphedrine Mediated
Li
NH
CF3
PMB
Cl
+
2 equiv.
O OLiN
H HMe Ph(R) (S)
2 equiv.
THF, -50 °CNH
OH
PMB
ClF3C
• 2 equiv. of ligand and acetylide required for complete conversion• Low ee if ephedrine and Li-acetylide not warmed above -40 °C prior to addition at -50 °C
Li
O
O
C
LiLi
Li
CN
N
Me
Ph
Me
Ph
O
CF3Ar
reactive 2:2 tetramer
THF
Li
O
O
C
LiLi
Li
ON
N
Me
Ph
Me
Ph
THF
CF3Ar
unreactive
Based on calculations, extensive NMR (1H, 13C, 6Li), and X-ray of various aggregates
Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937-8940Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028-2038Pierce, M. E.; Chen, C.; Tillyer, R. D. et. al. J. Org.Chem. 1998, 63, 8536-8543 (Efavirenz Synthesis)Xu, F.; Reamer, R. A.; Collum, D. B.; Huffman, J. C.; et. al. J. Am. Chem. Soc. 2000, 122, 11212-11218 (X-Ray)
C2-Symmetric
>97% Yield98% ee
34 Merck's Li/Ephedrine 6/5/02 9:38 AM
R2
Enantioselective B-Acetylide Additions
R1 SnBu3 R2
R12. R2CHO
OHMe2BBr
-78 °Ctoluene
1.NH
BR
O
Ph
Ph
R1 BMe2
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
R1
Ph
n-Pent
Ph
n-Pent
Ph
n-Pent
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2
c-Hex
c-Hex
Ph
Ph
n-Pent
n-Pent
c-Hex
t-Bu
n-Pent
Ph
c-Hex
p-MeO2C-Ph
p-NO2-Ph
R (equiv.)
Bu (1)
Bu (1)
Bu (1)
Bu (1)
Bu (1)
Bu (1)
Me (1)
Bu (1)
Ph (0.25)
Ph (0.25)
Ph (0.25)
Me (1)
Ph (1)
Yield (%)
96
82
78
28
90
80
95
71
77
72
80
80
86
ee (%)
90
95
96
94
96
96
90
97
93
97
85
96
96
O
NHB
BMe
R
O R1
H
MeCorey's model(also similar to his modelfor R2Zn additions with
amino alcohols)
• Comments that R = Ph on B is catalyticbecause bulk of Ph promotes dissociationfrom the formed alkoxide
Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151-3152
35 Corey's Boron 6/5/02 9:38 AM
Cu/Ru Catalyzed Addition to Imines
Ph HR
NHAr
Ph
+ ArNH2 RCHO+
3 mol% RuCl320 mol% CuBr
H2O or neat40 °C, 20 hpreheated
60 °C, 2h
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
R
Ph
p-Cl-Ph
m-Cl-Ph
p-Br-Ph
m-Br-Ph
p-Me-Ph
p-tBu-Ph
p-CF3-Ph
t-Bu
p-Ph-Ph
1-naphthyl
Ph
Ph
Ph
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Cl-Ph
p-Br-Ph
p-Me-Ph
Yield (%)
91
90
89
95
93
87
86
87
64
85*
96*
82*
88*
77*
* Conducted neat
Ph HRu(III)
1.2 equiv.
Ru(II)
Ph Ru(IV)H
ArN
R
CuX
R
ArHN
Ph
CuX
Ru(II)
Ru(II) + CuX
+
R
NHAr
Ph
Ph H+
N
R
Ar
• CuX salts mediate reaction alone (30% yield with CuBr)• RuCl3 allowed for complete conversion• RuCl3 alone gives no product• Enolizable aldehydes give self-aldol Li, C. -J.; Wei, C. Chem. Commun. 2002, 268-269
36 Cu/Ru catalyzed 6/5/02 9:39 AM
Cu Catalyzed Asymmetric Addition to Imines
Ph HR
NHAr
Ph
+
10 mol% CuOTf10 mol% PhPyBox
toluene, r.t., 2-4 d
NAr
R
Entry
1
2
3
4
5
6
7
8
9
10
11
R
Ph
p-Me-Ph
p-Et-Ph
p-Cl-Ph
p-Br-Ph
p-Ph-Ph
2-naphthyl
p-CF3-Ph
Ph
Ph
Ph
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Br-Ph
p-Cl-Ph
p-Me-Ph
Yield (%)
78
85
70
85
87
81
63
71
93
92
93
ee (%)
96
92
96
94
94
94
88
93
91
91
94
O
N
N
N
O
Ph Ph
• CuBr gave low ee and CuSbF6 (in H2O)gave good ee, but low yield• Other Box and PyBox gave low ee • All reactions conducted in H2O gaveslightly lower ee and yield
Wei, C.; Li, A. -J. J. Am. Chem. Soc. 2002, 124, 5638-5639
37 Cu Enantio. addition 6/5/02 9:39 AM
Catalytic Cu Acetylide Additions to Nitrones
R1 H + NO
R2
R310 mol% CuI, ligand
K2CO3/DMFN
O
R1R2
R3
+N
R2
R3
R1
• most ligands (PPh3, dppe, dppp, dppb, bpy, phen, pyr, etc...) give a mixture of products• Box ligands give β-lactam with low d.r. and 40% ee
R1 CuL3
NO
R2
R3
R1
NR3
OL3Cu
R2
Cu(OH)L3
NO
R2
R3
[3+2]O
NR3
R1
L3Cu
R2
HOHNR3
O
R2R1
L3Cu
OH
imine
Cu(OH)L3
β-lactam
Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999-5004
Original Reaction: Kinugasa, M.; Hashimoto, S. J. Chem Commun. 1972, 466-467
H
CNHR3
R1R2
O
38 Cu-acetylide and nitrones 6/5/02 9:39 AM
Fe
Catalytic, Asymmetric Cu Acetylide Additions to Nitrones
R1 H + NO
R2
R31-2.5 mol% CuCl•ligand
Cy2NMe, MeCN, 0 °CN
O
R1R2
R3
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
R1
Ph
p-CF3-Ph
p-MeO-Ph
Bn
Ph
1-cyclohexenyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2
c-Hex
c-Hex
c-Hex
c-Hex
PhCO
PhCO
Ph
p-CF3-Ph
p-MeO-Ph
c-Hex
PhCO
Ph
Ph
Ph
Ph
R3
PMP
PMP
PMP
PMP
Ph
Ph
PMP
PMP
PMP
PMP
PMP
Ph
PMP
p-Br-Ph
p-EtO2C-Ph
cis:trans
>95:5
>95:5
92:8
71:29
90:10
90:10
95:5
93:7
93:7
93:7
91:9
95:5
95:5
94:6
94:6
ee (%)
92
93
91
73
90
91
85
90
83
89
72
77
85
72
67
Yield (%)
65
57
60
43
56
45
53
50
46
57
42
69
53
74
79
N
Me
Me
Me
MeMeMe
NMe
FeMeMe
MeMe
Me
Ligand
Lo, M. M. -C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572-4573
39 Fu Cu Kinugasa reaction 6/5/02 9:39 AM
Ir(I) Catalyzed Acetylene Addition
O
n-Prn-Pr NH2
+ TMS+cat. [{Ir(cod)Cl}2]
60 °Cn-Pr N n-Pr
TMS
n-Pr NH
n-Pr
TMS
+
Desired(C-H activation
next to N)
Observed(spC-H activation)
Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew. Chem. Int. Ed. 2001, 40, 2534-2536
• All other acetylenes give desired product
TMSH
Ir(I)Ln
TMSHIr(I)Ln
TMSLn(III)Ir
H
TMSLn(III)Ir
H
NR'R
NR'R
TMSNR'Ln(III)Ir
R
H
TMSR'HN
R
40 Ir(I) 6/5/02 9:40 AM
Ir(I) Catalyzed Acetylene Addition
NAr
RTMS+
5 mol% [IrCl(cod)]2
THF, r.t., 1 d R
TMS
NAr
Entry
1
2
3
4
5
6
R
Ph
t-Bu
n-Pr
i-Pr
p-Br-Ph
Ph
Ar
Bn
Bn
Bn
Bn
Bn
p-MeO-Ph
Yield (%)
76
84
69
65
54
85
• Reactions conducted neat gave better yields• Only effective for silyl acetylenes• Only (t-Bu)3P leads to rate acceleration• Employing 2 mol% MgI2 allows Ir(I) loading to drop to 0.5 mol% (unpub.)
Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319-4321
41 Ir(I) Carreira 6/5/02 9:40 AM
Conclusions
• Metal acetylide additions to carbonyls giveversatile and useful synthetic building blocks.
• There are a few examples of stoichiometric,enantioselective additions, the most useful beingZn acetylide additions with a chiral amino alcoholcatalyst.
• Carreira's system is catalytic in both metal andchiral ligand and works well for aliphatic aldehydes.
• Cu(I) and Ir(I) offer a more efficient means (C-Hactivation) of generating transient metal acetylides and show some promising results.
42 Conclusion 6/5/02 9:40 AM
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