Page 1
Chemistry of the Double BondChemistry of the Double Bond1. Reactions of the Carbonyl Group1.1 At Carbonyl1.1.1 Reduction (hydride addition)1.1.2 Alkylation1.1.3 Allylation/Propargylation1.2 At αααα-Center (Enolate Chemistry)1.2.1 Alkylation1.2.2 Aldol Reaction1.3 At ββββ-Carbon of Enone1.3.1 Michael (1,4-) Addition2. Reactions of Olefins2.1 Oxidation2.1.1 Epoxidation2.1.2 Dihydroxylation2.1.3 Aminohydroxylation2.2 Reduction
Creation ofCreation of StereocentersStereocenters
Y
X R1R2
Y
XR1
R2
sp2 sp3
prochiral sp 2 center
mirrorXR1
R2
Enantiofacial differentiation
Ph Me
O
Me Ph
O
si re
Hanson J. Am. Chem. Soc. 1966, 88, 2731.Tetrahedron 1974, 30, 3649.
Page 2
Carbonyl Group Addition ReactionsCarbonyl Group Addition Reactions
O
A B
OH
A BH
OH
A BR
Reduction
H-
R-
C-C bond formation
Difference between A and B determines A.I.If steric, useful only if difference large:
Electronic effects may play a significant role- these are not yet fully understood!
R
RR
R
R
RCH3 H> > > > >
Addition to Carbonyl GroupAddition to Carbonyl Group
OSM
L
OL S
ML
OM
S
Cram Karabatsos Felkin-Anh
All give the same result!Karabatsos and Felkin-Anh consistent with ground state or TS arguments.
R CHO
MeR
MeNu
OH
Nu-
Page 3
Chemistry of the carbonyl group:Chemistry of the carbonyl group:BürgiBürgi--Dunitz angleDunitz angle
Nu
C OMe
Me C OMe
Me
ππππ∗∗∗∗ C=OππππC=O
107°
Nu
Electrostaticrepulsion
between thenucleophile
and the carbonyl filled ππππ orbital....
...causes the nucleophile to
attack at obtuseangle — theBürgi-Dunitz
angle!
Chemistry of the carbonyl group:Chemistry of the carbonyl group:reactivity boosted by Lewis acidsreactivity boosted by Lewis acids
Nu Nu
C OMe
Me C OMe
Me
BF
F FππππC=O
Electrostatic repulsion between the nucleophile and the carbonyl filled ππππ
orbital....
... is eased if the oxygen can donate electrons to a
powerful electrophile — i.e., a strong Lewis acid
sp2 oxygentwo lone pairs
ππππC=O
Lewis acidBF3
Page 4
Hydride Reducing AgentsHydride Reducing Agents1 2 3 4 5 6 7 8 9 10
AldehydeKetoneAcid chlorideLactone Complete reduction in 1 hEpoxideEster Reduction takes place in inert solventAcidAcid salt Only partial reduction in 1 htert-AmideNitrile Insignificant reduciton in 1 hNitroOlefin
1 NaBH4 in EtOH2 Li(t-BuO)3AlH3 LiBH44 Al(BH4)35 B2H66 Sia2BH in THF7 9-BBN in THF8 AlH3 in THF9 Li(MeO)3AlH in THF
10 LiAlH4 in THF
Brown, H.C. Chem. Engng. News March 5, 1979, 24.
EnantioselectiveEnantioselective Reduction Reduction -- ReviewsReviewsAsymmetric Synthesis, vol. 2 (Morrison, J.D., Ed.)
Chapter 2Reductions with Chiral Boron Reducing Agents
M.M. Midland
Chapter 3Reductions with Chiral Modifications of Lithium Aluminium Hydride
E.R. Grandbois, S.I. Howard and J.D. Morrison
Chapter 4Reductions with Chiral Dihydropyridine Reagents
Y. Inouye, J. Oda and N. Baba
A Critical Examination of the Relative Effectiveness of Various Reducing Agents for the Asymmetric Reduction of Different Classes of Ketones
H.C. Brown et al. J. Org. Chem. 1987, 52, 5406.
Asymmetric Reductions with Organoborane ReagentsM.M. Midland Chem. Rev. 1989, 89, 1553.
Page 5
EnantioselectiveEnantioselective Reductions Reductions -- DarvonDarvon
O
O
O
H
H
HOOLiAlH4, Darvon
> 95 % yield> 98 %ee Asteriscanolide
P.A. Wender J. Am. Chem. Soc. 1988, 110, 5904.
NMe2OH
Ph
PhDarvon
Cohen JOC 1980, 45, 582.
EnantioselectiveEnantioselective Reductions Reductions -- DarvonDarvon
NMe2OH
Ph
PhDarvon
Cohen JOC 1980, 45, 582.
1) LiAlH4, Darvon
quant yield> 98 %ee
O
OSiR3
BMPO
OSiR3 O
O
O
O H2) NaH, PMBBr
(+)-Sterepolide
B.M. Trost Angew. Chem., Int. Ed. Engl. 1989, 28, 1502.
Page 6
Hydride Reduction Hydride Reduction -- Chiral AuxiliariesChiral Auxiliaries
B B B
Alpine boraneM.M. Midland
JOC 1984, 49, 1316.
Eapine boraneH.C. Brown
JOC 1990, 55, 6328.
Prapine boraneH.C.Brown
JOC 1990, 55,6328.
BH
Eapine hydrideH.C. Brown
THAS 1990, 1, 433.
BH
OBn
Li NB-EnantrideM.M. Midland
JOC 1991, 56, 1068.
Li Li
BCl
2
H.C. BrownJOC 1985, 50, 5446.JOC 1986, 51, 3394.
BH
S. MasamuneJACS 1986, 108, 7402, 7404.
H2NPh
OH
Ph
S. ItsunoJOC 1984, 49, 555.
OAl
O
OEt
H
R. NoyoriJACS 1984, 106, 6709.
Ph NH
O2S
NH
Ph
K.B. SharplessJOC 1984, 49, 3861.
NH OH
PhPh
E.J. CoreyJACS 1987, 109, 7925.
NH
H
HHO Ph
E.J. CoreyTHL 1989, 30, 5547.
NH HN
T. MukaiyamaChem. Lett. 1984, 2071.
Catalytic CBS ReductionCatalytic CBS Reduction
O
OCO2Et
OH
OCO2Et
N BO
Me
PhPhH
94 % yield93 %ee
OOH
OHOAc
O
OH
H
25 mol-%65 mol-% BH3
.THF
Forskolin
Corey, E.J.; da Silva Jardine, P. Tetrahedron Lett. 1989, 30, 7297.
Page 7
Catalytic CBS ReductionCatalytic CBS Reduction
Corey, E.J.; da Silva Jardine, P. Tetrahedron Lett. 1989, 30, 7297.
N BO
Me
PhPhH
99 % yield94 %ee
10 mol-%60 mol-% BH3
.THF
Cl
O
Cl
OH
NH
O
CF3
Me
.HCl
Fluoxetine hydrochlorideProzac (Eli Lilly)
Catalytic CBS ReductionCatalytic CBS Reduction
O
RL RS
OH
RL RS
BH3.THF 60 mol-%
10 mol-% cat (R=H,Me)
O
R H R H
OHD2H-catecholborane
150 mol-%
30 mol-% cat (R=Bu)
-126 ºC, 3.5 h12 examples
82.2-97.8 %ee 6 examples82-95 %ee
N BO
H NpNp
R
Np = β-naphthyl
Catalyst
Corey, E.J.; Link, J.O. Tetrahedron Lett. 1989, 30, 6275.
Page 8
Oxazaborolidine Oxazaborolidine Reduction: Reduction: RationalizationRationalization
N BO
PhPhH
H
N BO
PhPhH
HBH3
N BO
PhPhH
OH2B
RL
RSH
N BO
PhPhH
OH2B
RL
RSH
H
HOBLn
RL
RSHH2O
BH3.THF
BH3.THF
OH
RL
RSH
Asymmetric Reduction: BINALAsymmetric Reduction: BINAL--HH
O
OAl
OEt
H O
OAl
OEt
HLi Li
(S)- BINAL-H (R)- BINAL-H
X
O
X
OHBrI(n-Bu)3Sn
>95>95>90
969798
% yield % eeX300 mol-% (S)-BINAL-H
THF
X R
O
X R
OH
(S)-BINAL-H
THF
c-C6H11c-C6H11CH2n-BuC(Me)2CH2
969495
% eeR
50-76 % yield
Page 9
Asymmetric Reduction: BINALAsymmetric Reduction: BINAL--HH
O
OAl
OEt
H O
OAl
OEt
HLi Li
(S)- BINAL-H (R)- BINAL-H
O OH
300 mol-% (S)-BINAL-H
THF
100 mol-% (S)-BINAL-H
THF
65 % yield94 %ee
87 % yield, 84 % ee(with methoxy-BINAL-H)
O
O
O
HO
BINALBINAL--H: Transition State H: Transition State ModelModel
O
OAl
OEt
H O
OAl
OEt
HLi Li
(S)- BINAL-H (R)- BINAL-H
Al
OLi
O
H
H
AlO
Li
O
O
O
R'
RR
O
O
R' R
RS
S
favored unfavored because ofbinaphthyl/R' repulsion
H
Page 10
BINALBINAL--H: H: Enantioface Enantioface DifferentiationDifferentiation
O
OAl
OEt
H O
OAl
OEt
HLi Li
(S)- BINAL-H (R)- BINAL-H
favored unfavored
Al
OLi
OH
R
Un
R'
O
O
Al
OLi
OH
Un
R
R'
O
Oπ
S R
Effect of Methyl Group on the Effect of Methyl Group on the Enantioselectivity in BINALEnantioselectivity in BINAL--H ReductionH Reduction
R
O
O
R
O
R
O
R
R
OH
OH
R
OH
R
OH
RR
S
S
S
(S)-BINAL-H
(S)-BINAL-H
(S)-BINAL-H
(S)-BINAL-H
Me n-alkyl
95 %ee 98-100 %ee
79 91
84 90
R in 24 %ee!!!
R
Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717.
Page 11
Kinetic Discrimination in BINALKinetic Discrimination in BINAL--H H Reduction of a Prostaglandin Reduction of a Prostaglandin
Intermediate Intermediate
CO2Me
O
TBSO TBSO
CO2Me
HO
TBSO TBSO
BINAL-H
rel rate 9α:9β
(R)-BINAL-H >130 99:1(S)-BINAL-H 1 95:5
9
Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 4718.
INTERNAL AIINTERNAL AI
O
CO2Me
OHPh
O
CO2MePh
OB
H
OAcAcO
CO2Me
OHPh
OH
Turnbull, M.D. et al. Tetrahedron Lett. 1984, 25, 5449.
Chelation controls selectivity
(Saksena, A.K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24, 273.)
Page 12
StereocontrolledStereocontrolled ReductionReduction
PMBOOH
OAc
OPMBPMBO O
PMBOOH
OAc
OPMBPMBO OH
NaBH(OAc)3
HOAc, MeCN, rt
Saksena Tetrahedron Lett. 1983, 24, 273.Turnbull Tetrahedron Lett. 1984, 25, 5449.
Evans, D.A. J. Am. Chem. Soc. 1988, 110, 3560.Prestwich J. Am. Chem. Soc. 1991, 113, 9885.
PMBOPMBO
OOAc
OB
HOAcAcO
OBMP
INTERNAL AIINTERNAL AI
Evans, D.A. et al J. Org. Chem. 1991, 56, 761.
H B OMeOOC R
OAc
AcO
O
O B OMeOOC R
Et
Et
H-
axial attack
via
diastereoselection 12:1
diastereoselection 9:1
82 %
Et2BOMe, NaBH4
82 %
Me4NHB(OAc)3
O OHMe
MeOOTIPS
OH
O OHMe
MeOOTIPS
OH
O O OHMe
MeOOTIPS
Page 13
StereoselectiveStereoselective ReductionReduction
Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.
O
O O
H
Ph
O
OMe
HO
O O
H
Ph
OH
OMe
HO
O O
H
Ph
OH
OMe
H
NaBH4 0 1
LiAlH4
L-selectride
BH3.THF
ZhBH4)2
NaBH3CN
NaBH3CN/CeCl3
NaBH(OAc)3/CeCl3
0
0
0
1
1
1
1
1
1NaBH4/CeCl3
1
3
3
5
2
1
12
OO
O OMe
PhO
BINAPBINAP--RuRu Ketone ReductionKetone Reduction
R C
OY
R C
OHY
R C
OHY
(R)-BINAP-Ru
H2, X=Cl, Br, I
(S)-BINAP-Ru
H2, X=Cl, Br, I
R C
OC
R C
OHC
R C
OHC
(R)-BINAP-Ru
H2, X=Cl, Br, I
(S)-BINAP-Ru
H2, X=Cl, Br, I
Y Y
Y = heteroatom, C = sp2 or achiral sp3 carbon
Y
NMe2
O O
SEt
O O
R R
O O
O OH
OHO
RNMe2
O
O Br
O CO2H
96 %ee
93 %ee
94-100 %ee
98 %ee
92 %ee
93-96 %ee
92 %ee
92 %ee
Representative ketones
Noyori R, Chem. Soc. Rev. 1989, 18, 187.
Page 14
Catalytic Asymmetric Catalytic Asymmetric ReductionReduction
O OH
98.2 %
O OH
30 g19.7 mg catalyst1.2 mg en4 mg KOH4 atm H2200 mL iPrOH
29.4 g
NH2
NH2Asymmetric version:
BINAP and 70 - 98 %eeRuCl2.(PPh3)3 catalyst to substrate ratio:1: 5000
Catalytic Asymmetric Catalytic Asymmetric ReductionReduction
2.2 mg cat
H2 (45 atm)iPrOH, 30 oC, 48h100% conversion
80 %ee
cat=
O OH
PP
RuNH2
H2NCl
Cl
Ph
Ph
Tol2
Tol2
Noyori, R. Angew. Chem,., Int. Ed. Engl. 1988, 37, 1703.
TON > 1,000,000similar catalyst, 99 %ee, TON > 100,000
Page 15
Carbonyl Reduction ReactionsCarbonyl Reduction Reactions
nC5H11
O
nC5H11
OH
nC5H11
OHO
nC5H11
O
Alpine borane
NH2 NH-K+
KAPA
1) n-BuLi
2) CO23) H2 - Lindlar
Midland, M.M. Tetrahedron Lett. 1984, 40, 1371.
Carbonyl Reduction ReactionsCarbonyl Reduction Reactions
OH
HO2C
OMeN
OMeO
Me OMe
O
OMe
OH
OMeMO
PhOMeM
OPh
via
1) MeO(Me)NH.HCl Et3N, pyBOP 81%2) MeI, Ag2O 88 %
MeC=CLi
89%
K-selectride -100 ºC 72 %
D'Aniello, F.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 4870-1.Takahashi, T. et al. Tetrahedron Lett. 1985, 26, 4463, 5139.
Page 16
Carbonyl addition reactionsCarbonyl addition reactions
O O
O
R*O
O
OHMeHO
O
OHMeMeMgI
Et2O/PhH
86 %
KOH
Atrolactic acid69 % ee
OPh
O
OR
OPh
OR
HO R'
R'MgBr
90-98 % ee
Dauben, W.G.; Prelog, V. Helv. Chim. Acta 1953, 36, 325.
Whitesell, J.K. Chem. Commun. 1982, 888.Chem. Commun. 1983, 802.
Carbonyl Addition ReactionsCarbonyl Addition Reactions
H
O
Li SiMe3
NMe
N
HOOH
SiMe3-123 oC
92 %ee
Mukaiyama, T. J. Am. Chem. Soc. 1979, 101, 1455.
Page 17
Asymmetric CarbonylAsymmetric CarbonylAlkylationAlkylation
RCHO + Et2ZnR Me
OH
RCHO cat yield (%) config (% ee)
123233223
-9790
1004790857882
R (86)R (98)S (92)R (92)S (82)S (94)R (99)R (99)S (75)
Ph
Ph(CH2CH2)
4-MeOC6H4PHCH=CHC5H11C6H13
NB
OMe
H
NH
TfTf
HN
OHHN
NMe
H
Brown, H.C.Tetrahedron Lett. 1989, 30, 5551.
Ohno, M.Tetrahedron Lett. 1989, 30, 7095.
Tanaka, K.Chem. Commun. 1989, 1700.
AlkylationAlkylation ((PhCHO PhCHO + Et+ Et22Zn)Zn)
NB
OMe
H
NH
TfTf
HN
OHHN
NMe
H
Brown, H.C.Tetrahedron Lett. 1989, 30, 5551.
95 % ee (R)
Ohno, M.Tetrahedron Lett. 1989, 30, 7095.
98 % ee (S)
Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.
92 % ee (R)
OHHN
Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.
97 % ee (R)
Noyori, R.J. Am. Chem. Soc. 1989, 111, 4028.
99 % ee (S)
Ph
Ph
OHNMe2
NMeH
Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.
88 % ee (S)
OHHN
Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.
93 % ee (R)
NMe
Corey, E.J.Tetrahedron Lett. 1987, 28, 5233.
95 % ee (S)
MeN Me
HO Ph
NMe OH
PhPh
Soai, K.J. Am. Chem. Soc. 1987, 109, 7111.
99 % ee (S)
OH
HN
Page 18
Allylation (PhCHO)Allylation (PhCHO)
Ph
NBr
N
Ph Ph
SO2TolTolO2SO
OB O
NB
SO2Me
OB
OPriO2C
PriO2CB
B
TMS
B2
CoreyJACS 1989, 111, 5459.
94 %ee (R)
Hoffmann, R.W.Ber 1981, 114, 375.
Reetz, M.Chem. & Ind. 1988, 663.
Roush, W.R.JACS 1985, 107, 8786.
87 %ee (S)
Masamune, S.JOC 1987, 52, 4831.
88 %ee (S)
Masamune, S.JACS 1989, 111, 1892.
96 %ee
Brown, H.C.JACS 1983, 105, 2092.
94 %ee
Reagent Control in Double Reagent Control in Double StereodifferentiationStereodifferentiation
S,S-reagent
R,R-reagent
Allyl-MgCl
99.5 %0.5 %
1.9 %98.1 %
44.9 %55.1 %
Reagent
R,R-reagent
+
TiO
O
OO
PhPh
PhPh
ON
BOC
OH
ON
BOC
OH
ON
BOC
H
O
Duthaler, R.O. et al. J. Am. Chem. Soc. 1992, 114, 2321.