enolates: z(o,r)- and e(o,r)-enolates - uef · 2003-03-13 · effect of base on enolisation! base...
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EnolatesEnolates::ZZ(O,R)(O,R)-- and and EE(O,R)(O,R)--enolatesenolates
R'R
O-
HH
RO-
R'
(E)-enolate (Z)-enolate
Regardless of other groups the encircled R' and O-
determine whether one is Z(O,R)- or E(O,R)- enolate.
EnolatesEnolates: : deprotonationdeprotonation
Corey, E.J.; Sneen, R.A. J. Am. Chem. Soc. 1956, 78, 6269.
Most stable conformation
ROH
R'H
R
O
R' H
R
O
HR'
ROH
HR'R
HR'
H O
H H
R
HR'
O-R
R'H
O-
σC-H σC-H
π*C=O π*C=O
30°
90°
(E)-enolate (Z)-enolate
O
Heq
Hax
OH
H 104 °
-12 °
Effect of base on Effect of base on enolisationenolisation
! Base must be large and hard.! Thus functions only as a base and not as a nucleophile.
NLi
NLi
SiN
Si
M
PhSi
NSiPh
MO-K+
LDA LiTMP MHMDS ((Me2Ph)2Si)NLi t-BuOK
pKa 36 37 26 25 18-20M = Li, Na, K
Selective formation of E/ZSelective formation of E/Z--enolatesenolates
Masamune, S. Aldrichimica Acta 1982, 15, 47.
R
O
Z(O,R) E(O,R)
base TMSCl
R
OTMS
R
OTMS
R base Z E
Et LDA 30 70(Me3Si)2NLi 70 30(Et3Si)2NLi 99 1(Me2PhSi)2NLi >100 <1
cC6H11 LDA(Me3Si)2NLi(Et3Si)2NLi(Me2PhSi)2NLi
61 3985 1594 699 1
EnolisationEnolisation::IrelandIreland--mechanismmechanism
! According to the Ireland-mechanism an (E)-enolate is formed via a chair form transition state (R = large alkyl group)
! If also R’ is large, a (Z)-enolate is formed!! Note the actual proton abstractor and the role of the metal!
H
NH
O
Li
R'
R
"R
R
Ireland, R.E. J. Am. Chem. Soc. 1976, 98, 2868.Collum, D.B. J. Am. Chem. Soc. 1991, 113, 9571.Collum, D.B. J. Am. Chem. Soc. 1997, 119, 4765.
O
R
O-
R
O-
R+
NLi
, LiBr
- 78 °C
R = EtR = i-PrR = t-Bu
50211
:::
11>20
Dimeric LiDimeric Li--enolate enolate -- LDA complexLDA complex
! First X-ray structure for a dimeric complex.
Willard, P.G. J. Am. Chem. Soc. 1987, 109, 5539.
SiOO Li
N LiO
O
LiLiN
O
O SiR3
R3Si200 mol-% LDA
STEREO STRUCTURE:CCSD-code FOGRIC
Application: Application: TaxolTaxol
Stork, G. 1995.
O
OO
O
OO
O
OO
K D
t-BuOK D2O
Ketoni Enolaatti
Approach of the electrophileApproach of the electrophile
R RO RR
E
-O H
E
NB! This angle is similar to the Flippin-Lodge angle!
Houk: 106o (compare:
Burgi-Dunitz angle)
side view end view
O- O
E
E
O
Re
Siaxial
attackequatorial
attack
Agami, C. Tetrahedron Lett. 1977, 2801-2804.Tetrahedron Lett. 1979, 1855-1858.
Tetrahedron 1979, 35, 961-967.Houk, K.N. J. Am. Chem. Soc. 1986,108, 2659-2662.
Asymmetric Induction in Enolate and Asymmetric Induction in Enolate and Azaenolate AlkylationsAzaenolate Alkylations
Evans, D.A. Asymmetric Synthesis 1984, 3, 1-110.
R
OM
R
OM
OM R2
R1
R2
R1
OMO O
MR OO
MR
OM*
OMLn
*
Intraligand asymmetric induction
Interligand asymmetric induction
intraannular extraannular chelate-mediated intraannular
* *
**
*
*
1,3- 1,4- 1,2- 1,2-1,3- 1,3-
Controlling Face SelectivityControlling Face Selectivity
Tomioka, K.; Koga, K. J. Am. Chem. Soc. 1984, 106, 2718.Tomioka, K.; Koga, K. Tetrahedron Lett. 1984, 5677.
NCO2Me
CO2tBu
H
CO2MeO
CO2MeO
1) LDA 2) MeI
N OLi
OMe
OtBuO
L
OLi
NO
L
OtBu
tBuO
MeI L = HMPA
L = THFMeI
hydrolysis
SAMPSAMP--Hydrazones in Ketone Hydrazones in Ketone AlkylationAlkylation
NNLi
OMe
NN
OMe
NNLi
Me
OMe
NN
OMe
O
OMe
LDASAMP
Me-XH3O+
NOMe
NH2
or O3
X = IX = OSO2Me
67 %ee99 %ee
SAMPEnders, 1976
Enders, D. Asymmetric Synthesis, vol. 3.
CChiralhiral BBicyclicicyclic LLactamactam EEnolatesnolatesO
OH
N
OH
OH
NH2
OH
N
O
O
R1
H
R1O
OHO
N
O
O
Me
H
p-TsOH, toluene
NH2OH.HCl
acetone
KMnO4
LiAlH4
Oxidation of pinene:Carlson, R.G.; Pierce, J.K. J. Org. Chem. 1971, 36, 2319-2324.
Reduction of oxime:Masui, M.; Shioiri, T. Tetrahedron 1995, 51, 8363-8370.
Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711.
CChiralhiral BBicyclicicyclic LLactamactam EEnolatesnolates
N
O
O
R1
HN
O
OLi
R1
HN
O
O
R1
HR3
R2s-BuLi
exo:endo selectivities typically > 98:2(except: H, Me, H 2:1
R2X
repeat:s-BuLi; R3X
R1 = H, Me, PhR2 = Me, Bn, allylR3 = H, Me, Bn
Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711.
AldolAldol ReactionReaction
O
H R
O+
O
R
OH O
R
OH+
syn anti
Chirality can reside in:
•nuclephile•electrophile•catalyst
One of the most extensively studied reactions
Review: Heathcock, C.H. Science 1981, 214, 395.
AldolAldol ReactionReaction
Heathcock, C.H. J. Org. Chem. 1980, 45, 1066.
R
O
H Ph
O+
O
R Ph
OH O
R Ph
OH+
syn anti
R
H Z
Enolate syn anti
50 50
E 65 35
iPr Z 90 10
E 45 55
tBu Z 98 2
E 8 92
Bulky R - high selectivity
Z-enolate -> synE-enolate -> anti
Generation of E/ZGeneration of E/Z--enolatesenolates
R
O
Z(O,R) E(O,R)
base TMSCl
R
OTMS
R
OTMS
R base Z E
Et LDA 30 70(Me3Si)2NLi 70 30(Et3Si)2NLi 99 1(Me2PhSi)2NLi >100 <1
cC6H11 LDA(Me3Si)2NLi(Et3Si)2NLi(Me2PhSi)2NLi
61 3985 1594 699 1
Masamune, S. Aldrichimica Acta 1982, 15, 47.
AldolAldol ReactionReaction
R1
O-
R2 R3 H
OR1
R2
R3
O OH
* *+
Open TSCyclic (chelated) TS
OMO
L
LH
R3
R1
RE
RZRZ
RE
R3
H
OMLn
R1
O
Reviews: Heathcock, C.H. Science 1981, 214, 395.Heathcock, C.H. Aldrichimica Acta 1990, 23, 99.
Hoffmann, R.W. Angew. Chem. Int. Ed., Engl. 1987, 26, 488.Mukaiyama, T. Org. React. 1982, 28, 203.
Possible Transition States:
Classification of aldolsClassification of aldols
! Type I– follow Zimmermann-Traxler TS
! Type II– open TS; syn-selective– enol silanes, stannanes, borates, zirconates
! Type III– open TS; anti-selective– ketene acetals and thioacetals
AldolAldol -- ZimmermannZimmermann--TraxlerTraxler TSTS
OMO L
H
L
R2
H
R1R3
OMO L
R3
L
R2
H
R1H
R1
OH
MLn
R2
R1R2
R3
O OH
R1R2
R3
O OHE(O,R)-enolate
anti
syn
Aldol Aldol -- ZimmermannZimmermann--TraxlerTraxler TSTS
OMO L
H
L
H
R2
R1R3
OMO L
R3
L
H
R2
R1H
R1
OR2
MLn
H
R1R2
R3
O OH
R1R2
R3
O OHZ(O,R)-enolate
syn
anti
Diastereoselectivity maximized when R1 and R3 largeDiastereoselectivity: B > Li > Na > K
Li-OMg-OZn-OAl-OB-OTi-OZr-O
1.92-2.00 Å2.01-2.03 Å1.92-2.16 Å1.92 Å1.36-1.47 Å1.62-1.73 Å2.15 Å
AldolAldol -- Open TSOpen TS
Z(O,R)-enolate
Z(O,R)-enolate
E(O,R)-enolate
E(O,R)-enolate
syn
anti
R1
R2
R3
O OH
R1
R2
R3
O OH
R1
H R2
OM
O
H R3
HR3
O
R1
H R2
OMR1
R2 H
OM
O
H R3
HR3
O
R1
R2 H
OM
Boron EnolatesBoron Enolates
OX
OR1X
OR1X
BR2OTf OBR2R1X
HRe
HSi R1
BR2
OX
HSi
R1 HReBR2
OBR2R1X
OBR2
XR1
Z(O,R)-enolate
E(O,R)-enolate
typical outcome
can be favored:R = cC6H11X = tBuS
Evans, D.A. J. Am. Chem. Soc. 1981, 103, 3099-3111.
Boron Enolate Mediated Boron Enolate Mediated AldolAldol
Masamune, S. J. Am. Chem. Soc. 1986, 108, 8279.
For a similar example, see also:Reetz, M.T. Tetrahedron Lett. 1986, 27, 4721.
anti:syn 33:198-99.9 %ee
- 78 C
RCHO
DIPEASCEt3
OBOTf
SCEt3
BOSCEt3R
OOH
Evans Evans AldolAldol: Non: Non--Coordinating MetalCoordinating Metal
ββββ-attack
αααα-attack
ON
O
R
O OH
NO R
OO OH
ON
OB
O R
L2
O
NO
O OB
O R
L2
NO
O OB
LL
NO
O O
BuBO OR
H
Me
H
Bu
N
OO
Evans, D.A. J. Am. Chem. Soc. 1981, 103, 2127.
Explanation: opposing dipoles!
Evans Evans AldolAldol -- Coordinating MetalCoordinating Metal
Non-chelated Z(O,R)-enolate
Chelated Z(O,R)-enolate
E+
Re attack
Si attack
E+NO
O O
E
NO
O O
E
ON
OM
O
NO
O OM
NO
O OM
Evans, D.A. J. Am. Chem. Soc. 1982, 104, 1737.
Evans Evans AldolAldol
NO
O O
NO
O OM
NO
O O
E
NO
O O
Ph
NO
O O
PhE
LDA
NaHMDS
E+, 0 oC
E+, -78 oC
E = MeI, EtI, BnBr, allylBr
kinetic ratio > 94 : 6
Evans, D.A. J. Am. Chem. Soc. 1982, 104, 1737.
Synthesis of Synthesis of MeBMTMeBMT, Amino Acid in , Amino Acid in CyclosporineCyclosporine
Evans, D.A. J. Am. Chem. Soc. 1986, 108, 6757.
NO
O O
Bn
H
O
NO
O
Bn
O
NCS
OSnL
X*NNCS
OOH
HONHMe
O O
X*N OHN
S
Sn(OTf)2
1) NaHMDS2) MeI
3) LAH4) Swern
1) Me3O+ BF4-
2) H2O
3) KOH4) H3O+
NonNon--Evans synEvans syn--Aldol: Ti Aldol: Ti EnolatesEnolates
H
L3
TiOO
O NR
O
L4
TiOO
O NH
O
RNO
O O
NO R
O OHO
Thornton, E.R. J. Org. Chem. 1991, 56, 2489.X-ray: Hinterman, T.; Deebach, D. Helv. Chim. Acta 1998, 81, 2093.
GOMLUP
Open Transition State: Effect of Lewis AcidOpen Transition State: Effect of Lewis Acid
large Lewis acids
small Lewis acids
anti
syn
O NMe
R
O OHO
O NMe
R
O OHO
NOH
Me
O OB
L L
R
OLA
H
R OLA
H
NOH
Me
O OB
L L
Heathcock, C.H. J. Org. Chem. 1990, 55, 173.Heathcock, C.H. J. Org. Chem. 1991, 56, 5747.
Shioiri, T. Tetrahedron Lett. 1991, 32, 7287.
All Four Aldols from a Single Precursor: Heathcock
TBSO
t-BuO
TBSO
t-BuO OH
TBSO
t-BuO OH
TBSO
t-BuO OH
TBSO
t-BuO OH
Li
B
Mg
Ti
Heathcock, C.H. J. Org. Chem. 1991, 56, 2499.Heathcock, C.H. Aldrichimica Acta 1990, 23, 99.
Summary of Best AldolsSummary of Best Aldols
NO
O O
Ph
B-enolateTi enolateB-enolate + LA
syn (S1)syn (S2)anti
EvansThorntonHeatcock
S
N O
O
O
B-enolateSi-enol ether
synanti
OppolzerOppolzer
Chiral Catalysis inChiral Catalysis in AldolAldol: Corey: Corey
R2*BBr
NB
NSO2 SO2CF3 CF3
CF3 CF3Ph Ph
Br
R2*BBr
R2*BBr
R-CHO
Et3N
O
O
OH
RMe
OBR2*H
OtBuMe
O+O
tBu
MeBr
R2*B
O
O
Ester enolates: anti products; thioesters: syn products
Corey, E.J. J. Am. Chem. Soc. 1990, 112, 4976.
HO B
O
N
N
H
Me R
SPh Ph
Ph
SO2
SO2Ar
Ar
Chiral Chiral AcyloxyborolidinesAcyloxyborolidines
OSiMe3
R'R
RR'
R"
O OH
+ R"CHO
O
OOH
CO2HCO2H
O O
CAB
+ BH3
CAB
Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 1041.X-ray HASVOM: Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 10412.
O
BO O
O
R
O
H
Me
H
R'
ROCO
CO2H
R R'
OHO
"Anomeric"
anti-coordination
synsyn--Selective Boron Selective Boron AldolAldol
Bu
OB
H N
OO
R
H
Bu
Bu
OB
H N
OO
R
H
BuOH O
H N
OO
R
HR
iPr
NO
OH O O
OBBu2
N
OOH
R O
approach from least hindered enolate
diastereoface dipoles?
Acetate aldolAcetate aldol
Carreira, E. J. Am. Chem. Soc. 1994, 116, 8837.
R H
O
OMe
OSiMe3
R
OH
OMe
O+
2.5 mol-% cat., -10 oC
then TBAF
Aldehyde %ee:
97
95
97
94
96
95
Me CHO
Me CHO
Ph CHO
Ph CHO
C6H11CHO
Ph CHO
NO
TiOO
OO
But
tBu
tBu
tBu
Acetate aldolAcetate aldol
Smith, A.B. Org. Lett. 1999, 1, 909-912.
Acetate aldolAcetate aldol
Evans, D.A. J. Am. Chem. Soc. 1997, 119, 7893.
R1O
OStBu
OSiMe3 OH
StBu
O+
10 mol-% cat., -10 oC
then 1 M HCl
R2MeMeMeEtiBuiBu
%ee:999999949436
R2
OR1O
O
R2
N CuNOO
But tBu
2 OTf-
R1MeBntBuMeMeEt
Cyclic enolates: Cyclic enolates: antianti--Selective AldolsSelective Aldols
S
O
S
OMLn
S
O OHH O OH
MLn yield anti:syn
57
85
86
84
19:1
10:1
24:1
99:1
OB
O
SnPh3
SnMe3
Ti(OiPr)3
O
LnM O
H
Hayashi, T. Tetrahedron Lett. 1991, 32, 5369.
AmphotericinAmphotericin
S
O
S
O
O
O
S
O
O
O
R
OH
S
O
O
R
OHOH
R
OPOP
O
MeO NH
OH
OHMe2N
O R
N
O
O
O
OMeOHOH
CNOH
(HO)2PO2
HO Me
Me O
O
OH
MeO O
HONH2
Me
OH
COOH
OH
OHOH
OH
OHOHO
Calyculin C
Amphotericin B
Alkylation Alkylation –– Towards Amphotericin BTowards Amphotericin B
Karisalmi, K. Tetrahedron 2003, 59, 1421-1427
S
O
O
O
S
OSiMe3
O
O
LDA, TMSCl
-78 oC, THF64 %
S
O
O
O OH
TiCl4, PhCHO
CH2Cl2, -78 oC H
Major product
Final stepsFinal steps
S
HO
O
O
6OH
Raney Nickel (W-2)EtOH, 20-70 oC
OH
O
O
7OH50 %
H
Karisalmi, K. Tetrahedron 2003, 59, 1421-1427
SynSyn--aldol from Zaldol from Z--enolateenolate
O O OBBu2
OMe
O OTBDMS
OBn
OMe
OH OTBDMS
OBn
O O O+
CH2Cl2, -78 to -26 oC, 16 h
69 %, 82 %ds
OOH
OMe
O
OMe
OH
OHO
HO
Bafilomycin A
weakly 17S-directing
weakly 17S-directing
Paterson, I. Tetrahedron Lett. 1995, 36, 175.
Anti-aldols from E-enolates
Walkup, R.D.; Kim, Y.S. Tetrahedron Lett. 1995, 36, 3091.
OOO
Me
Me
Me
O
O
O
O
MeMe
Me
NMe Me
Me
Pamamycin
+
OMe
tBu
But
O
LiO OMe
tBu
But
O
OO OHaldol
55 %; 19:1 ds
1. Hg(OCOCF3)22. PdCl2, CO, MeOH, CuCl2
100 %
OCO2MeAcO
C1-C8 sequence of pamamycins
AntiAnti--aldol from Ealdol from E--enolateenolate
Pilli, R.A.; Murta, M.M. J. Org. Chem. 1993, 58, 338.
H
+
tBu
But
O
LiO OMe
tBu
But
O
OOHaldol
64 %; 2:1 ds
O
OMe
tBu
But
O
OOH
H
Me O
HFelkin-AnhMe O Li
OH
Me
ArO
H
Heathcock TH 1981, 37, 4087.
AntiAnti--aldol for macrolide synthesisaldol for macrolide synthesis
Tamm, C. Synthesis 1991, 435.
H
+O
LiO OMe
O
OOHaldol
50 %
O
H
MeO
H Felkin-Anh
Me O Li
OH
Me
ArO
HO
O
Me
Me
OO
H
OOOO