ACIEE: 1996 Year in Review
Ruben Martinez
A New Multifunctional Heterobimetallic Asymmetric Catalyst
for Michael Additions and Tandem Michael−Aldol Reactions
Shibasaki et al; ACIEE 1996, 35, 104−106.
O
O
O
O
+ R1O
R2
n
H
n
THF, RT
O
R2
O
O
OR1
O H
O
Me
cat. (10 mol %)
H
Me
RT, 36 h
O
H
CO2Et
AlLi-(R)-BINOL
LaLi-(R)-BINOL
La-(R)-BINOL
LaNa(R)-BINOL
7
46
73
57
ee [%]
90
3
86
83
1
I [Li Cu(CN)Me ]
2
2
Me
Cu(CN)Li2
Ph
CH(OH)Ph
PhCHO
− 78 °C
THF, − 40 °C, 2.5 h
OH
RT
CO2Et
89 %
Functionalized organocopper reagents are typically prepared by
transmetalation of functionalized oraganozincs or direct oxidative
addition of activated copper to organic halides.
Modern Organocopper Chemistry; Norbert Krause, Ed.; Wiley-VCH: GmbH, 2002.
2
O
2
CO2Et
1
Yield [%]
Cuprates as Selective Metalating Reagents for Aromatic Halides
Sakamoto et al; ACIEE, 1996, 35, 736−738.
CO2Et
+
H
Catalyst
CO2Et
"This is the first example of a catalytic asymmetric tandem Michael−aldol reaction."
H
Et + Ph
Ph
H
quant. yield
89% ee
O
+ Et
82%
Use of LaLi−BINOL, LaNa−BINOL or Li free La−
BINOL gave poor results in the three-component
coupling reaction.
O
CO2Et
catalyst prepared from LiAlH4 and (R)−BINOL
O
CO2Et
CO2Et
Mechanism?
OR1
M
O
O
Al
O
O
O
Ph
RT, 72 h
Me
PCC
O
H
OH
O
AlLi-(R)-BINOL
(10 mol %)
O
OEt + Ph
+ EtO
cat. (10 mol %)
OR1
O
O
Baran Group Meeting
10/20/12
Yield [%]
64
30
trace
trace
O
ee [%]
91
−
−
−
Me
Cu(CN)Li2
Et2O
61%
O
HO
(excess)
THF
53%
ACIEE: 1996 Year in Review
Ruben Martinez
Determining the structure of the aryl−copper intermediate
(2 equiv)
-78 °C
MeO2C
Acyclic Stereocontrol in Radical Reactions:
ρ-Selectivity with OxazolidinoneAuxiliaries
Me
Cu(CN)Li2
I [Li Cu(CN)Me ]
2
2
Baran Group Meeting
10/20/12
Sibi et al; ACIEE, 1996, 35, 190−192.
ρ is defined as the prochiral radical center
Rotomers
MeO2C
O
R1
N
O
aq. NH4Cl
−20 °C
O2
−78 °C
O
O
O
H
R
H
N
O
R1
R
Me
MeO2C
MeO2C
76%
O
85%
O
OH
R'O
OH
R'O
N
R
O
N
R
N
R
H
R1
N
O
O
O
R1
H
N
O
R
R
For a discusion on acyclic stereocontrol in free−radical reactions see:
Acc. Chem. Res.1991, 24, 296-304.
CC-1065 and duocomycin A pharmacophore
O
O
I
∗
MeO
OH
O
reagent
N
SO2Ph
Reagent
∗
∗
+
R'O
3
Temperature
4
4
3
Yield [%] (ee [%])
n-BuLi
−90 °C
43 (93)
0
[Li3ZnMe3(SCN)2]
−78 °C
72 (90)
15(91)
[Li3Cu(CN)Me3]
−78 °C
0
73(92)
Reversed regioselectivity with use of Cu
Br
Ph
O
SnBu3
CH3
N
OH
N
SO2Ph
R'O
N
SO2Ph
O
Lewis acid
Et3B/O2
O
O
CH3
N
Ph
Ph
Ph
Lewis Acid
Conditions
Yield [%]
Ratio (RS:RR)
none
MgBr2
Yb(OTf)3
−78 °C, CH2Cl2, 3 h
93
1:1.8
−78 °C, CH2Cl2, 2 h
−78 °C, Et2O, 2 h
94
91
≥100:1
Sc(OTf)3
−78 °C, Et2O, 2 h
94
≥100:1
16:1
"These experiments present the first examples of the use of scandium triflate in radical
reactions."
ACIEE: 1996 Year in Review
Ruben Martinez
A Mild General Procedure for the One-Pot Conversion of Amides to Aldehydes
Buchwald et al; ACIEE 1996, 35, 1678−1680.
Diastereoselective C−C Bond Formation with
Nonracemic Planar-Chiral η2- Manganese Complexes
Schnizer et al; ACIEE 1996, 35, 1678−1680.
O
Br
HO
HO
NaBH4
CeCl33
Novozym 435
Br
MeOH
AcO
Br
isopropenyl acetate
pet. ether
4:1
HO
Br
+
45%, 94% ee
O
R'
NR2
HO
HO
O
OC Mn
90%
CO
Most modern oxidation systems
gave MnO2 as the only product.
LiO
O
LDA, THF
− 78 °C
OC Mn
CO
O
CO
Δ, MeCN
air
75%, 88% ee
8
N
HO
90
H
8
NEt2
O
NEt2
8
N
NEt2
71
H
9
O
O
C
74
O
O
O
10
O
R1
OC Mn
R = Me, allyl, Bn
52-65%
HO
R
air
44-66%, 85% ee
CO
41-59%
O
Δ, MeCN
RX
OC Mn
R1CHO
R
Yield [%]
O
O
9
50
H
O
C
10
H
Acid sensitive compounds worked up with THF and wet silica gel
R1
R1 = iPr, Ph
O
R'
H
8
NEt2
8
OC Mn
CO
25%
Me
O
TPAP, NMO
[Mn(MeCp)(CO)2].THF
Product
O
NMe2
8
NR2
H3O+
ca. 20°C
Enamine selectively formed
No overreduction to amine observed
O
Me
69%
Δ
ca. 20°C
R'
Amide
− 78 °C, Et2O
HO
1 equiv Ti(OiPr)4
1.1 equiv Ph2SiH2
46%, 94% ee
tBuLi (3 equiv)
Br
Baran Group Meeting
10/20/12
80
H
ACIEE: 1996 Year in Review
Ruben Martinez
Palladium−Catalyzed Carbonylative Cyclization Cascades with Iododienes and -trienes
Negishi et al; ACIEE 1996, 35, 2125−2126.
O
I
O
PdLn, CO
CO2Me
k, l = 0,1
kR
l
kR
l
Stereoselective Synthesis of Steroids with the Heck Reaction
Tietze et al; ACIEE 1996, 35, 2259−2261.
OtBu
H
O
m = 0,1
X
+
MeO
H
less traditional disconnection
O
MeO2C
Pd(PPh3)2Cl2 (5 mol%)
CO (40 atm)
MeOH (4 equiv)
NEt3 (4 equiv)
acetonitrile/benzene 1:1
95 °C, 8 h
For a review of steroid synthesis approaches see:
Nat. Prod. Rep., 1994,11, 607−612.
O
O
H
Br
O
Me
OtBu
Br
+
MeO
H
H
CO2Me
70%, 2:2:1 d.r.
O
H
58%, 5:1 d.r.
+
MeO2C
H
H
OtBu
H2 (3 bar)
Pd/C 10 mol%
H
MeOH/EtOAc 1:1
18h, RT
MeO
Herrmann and Beller palladacycle catalyst for Heck reaction:
ACIEE, 1995, 45, 1844−1848.
H
H
H
63% β-9H
13% α-9H
estrone derivative
OtBu
Domino Heck
Br
H
H
H
H
O
For a review on cascades in total synthesis see:
ACIEE, 2006, 45, 7134−7186.
Br
OtBu
99%
CO2Me
O
OtBu
Pd0
n-Bu4NOAc
50%
DMF/CH3CN/H2O, 1:1:0.2
4.5 h, 115 °C
MeO
H
Pd(PPh3)2Cl2 (5 mol%)
CO (40 atm)
MeOH (4 equiv)
NEt3 (4 equiv)
acetonitrile/benzene 1:1
95 °C, 10 h
O
DMF/CH3CN/H2O, 1:1:0.2
4.5 h, 115 °C
MeO
Pd0
n-Bu4NOAc
O
I
OtBu
m
m
Me
H
MeO
PdLn, CO
I
X
H
O
I
Baran Group Meeting
10/20/12
12%,
O
seven carbon−carbon bonds formed
MeO
OtBu
Br
+
H
Pd0
n-Bu4NOAc
H
DMF/CH3CN/H2O, 1:1:0.2
MeO
168 h, 60 °C
H
H
35%
30% recovered starting material
ACIEE: 1996 Year in Review
Ruben Martinez
Heterogenous Palladium−Catalyzed Regioselective Hydrostannation of Alkenes
Lautens et al; ACIEE 1996, 35, 1329−1330.
[Pd(OH)2]/C (10 mol%)
Bu3SnH (1.5 equiv)
OH
THF
ca. 20 °C, 1 h
Alkene
Bu3Sn
Yield [%]
OH
Ph
Ph
SnBu3
HO
HO
SnBu3
Ph
CHO
94
OH
Me
CHO
TIPSO
Me
Me
CHO
Ph
Use of Pearlman's catalyst as a Pd source gave superior yields
compared to homogeneous Pd catalyst systems.
CHO
O
Ph
O
Ph
H
t [h]
Yield [%]
ee [%]
4
90
94
20
93
84
20
92
93
20
81 [a]
74
4
85
80
OCH3
OH
[a] Based on 25% recovered aldehyde
OCH3
-Asymmetric, catalytic
TsN-ClNa.3 H2O
-Ligand suppresses formation of diol
-Ligand influences regioselectivity
-Example of ligand accelerated catalysis
R
O
Ts NH
64%, 99% ee
K2OsO2(OH)4
(DHQ)2-PHAL
OH
Me
Catalytic Asymmetric Aminohydroxylation (AA) of Olefins
Sharpless et al; ACIEE 1996, 35, 451−454.
K2OsO2(OH)4
(DHQD)2-PHAL
TsN-ClNa.3 H2O
SiMe3
1. (S)-(−)-BINOL (20 mol %)
TiF4 (10 mol %)
CH2Cl2, MeCN
0 °C
2. Bu4NF/THF
Aldehyde
Me
SnBu3
OH
+
H
96
94
Ph
O
R
Product
OH
Catalytic, Enantioselective Additons of Allylsilanes to Aldehydes:
Generation of a Novel, Reactive TiIV Complex from TiF4
Carreira et al; ACIEE 1996, 35, 2365−2363.
OH
82%
Baran Group Meeting
10/20/12
Ts NH O
Ph
OCH3
OH
64%, 81% ee
ACIEE: 1996 Year in Review
Ruben Martinez
Propargylation of Carbonyl Compounds by Umpolung
of Propargylpalladium Complexes with Diethylzinc
Tamaru et al; ACIEE 1996, 35, 878−880.
Baran Group Meeting
10/20/12
Synthesis of Novel Difluoroprostacyclin Derivatives:
Unprecedented Stabilizing Effect of Fluorine Substituents
Matsumura et al; ACIEE 1996, 35, 1019−1021.
R1
CO2H
CO2H
Ph
R1
OBz +
R2
[Pd(PPh3)4] (0.05 equiv)
PhCHO
OH
+
Et2Zn (2.4-3.6 equiv)
R2
O
R2
Ph
Mechanism?
R
OH
R1
HO
OH
HO
OH
The electron withdrawing effect of the fluorine atoms
prevents the hydrolysis of the acid labile vinyl ether.
prostacyclin
half life of 76 seconds
New Cobalt− and Iron−Catalyzed Reactions of Oganozinc Compunds
Knochel et al; ACIEE 1996, 35, 1700−1701.
CO2Me
O
O
R2
'Zn
+
R
Cl
O
CoBr2 (cat.)
O
Ph
R'
THF/NMP
−10 °C, 0.5 h
Hept
R
84% (80%)
CO2H
O
HO F
CF3
78% (74%)
82%
R
O
(ironII cat. yields)
or
X
CoBr2 (cat.)
R
R'
THF
−10 °C, 1 h
R'ZnI
Me
F
F
HO
R
HO
+
CO2H
OH
O
O
R'O
Ph
Me
Me
90%; > 98% E
Me
Me
89%; > 98% Z
AcO
Me
Me
89%; > 98% Z
F
F
O
88%; 100% E
CO2H
F
F
+
OR''
OR''
Pent
Pent
OR1
Cyclization of prostaglandin F2α not possible
because of the low reactivity of the electron
deficient olefin bearing two fluorines
R
Me Pent
Me
F
OAc
OPiv
R'2Zn
F
F
O
R'O
PPh3+Br -
ACIEE: 1996 Year in Review
Ruben Martinez
Baran Group Meeting
10/20/12
Syntheses not covered today
O
O
O
OTBS
KN(SiMe3)2
ZnCl2
(PhSO2)2NF
F
O
LiN(SiMe3)2
(PhSO2)2NF
OTBS
THF
THPO
N
F
F
O
OTBS
THF/PhMe
THPO
THPO
61%
protected Corey lactone
S
O
THPO
NaN(SiMe3)2, THF
O
2. MeI, EtNiPr2, DMSO
63%
F
F
Me
CO2Na
Me
Me
H
O
OO
HO
O
H
1. NaBH4, CeCl4, MeOH
2. TsOH, MeOH
3. NaOH, MeOH
F
F
N
Me
F
F
OH
No decomposition observed
after 30 days in aqueous solution
O
H
NMe
H
Semisynthesis of Taxol
Gennari ACIEE 1996, 35, 1723−1725.
HO
(−)-morphine
Mulzer; ACIEE 1996, 35, 2030−2032.
N
Me
O
THPO
30%
N
HO
The complete structure of maitotoxin elucidated
Tachibana; ACIEE 1996, 35, 1672−1675.
HO
H
(−)-stenine
Morimoto; ACIEE 1996, 35, 904−906.
90%
O
H
H
O
hapalosin
Ghosh; ACIEE 1996, 35, 74−76.
CO2H
O
O
H
OTBS
THPO
(OMe)2P
O
HH
O
Me
epothilone A
Danishefsky; ACIEE 1996, 35, 2801−2803.
CO2H
57%
1. Bu4NF, THF 94%
2. DMSO, DCC, CF3CO2H, Py
3. NaH
Me
Me
Me
PPh3+Br OTBS
THF/PhMe
O
OH
O
OH
1.
F
F
O
O
H
O
O
O
70%
CO2H
KN(SiMe3)2
MnBr2
(PhSO2)2NF
H
H
O
O
HO
O
(+)-camptothecin
Ciufolini; ACIEE 1996, 35, 1692−1694.