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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Authored by one of the world?s leading synthetic chemists in the field, this reference presents modern enolate chemistry with an emphasis on metal O-enolates in asymmetric synthesis.
While great care is taken to cover novel, successful concepts, such classical methods as the famous Evans enolates are equally highlighted. Throughout the book representative reaction procedures are presented, thus helping readers to find the best solution for their own synthetic problem.
Of high interest to synthetic chemists in academia, as well as the pharmaceuticals, agrochemicals and fine chemicals industries.
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Veröffentlichungsjahr: 2015
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Table of Contents
Related Titles
Title Page
Copyright
Preface
Chapter 1: Introductory Remarks
References
Chapter 2: General Methods for the Preparation of Enolates
2.1 Enolate Formation by Deprotonation
2.2 Enolate Formation by Conjugate Addition to α,β-Unsaturated Carbonyl Compounds
2.3 Alkali Metal Enolates by Cleavage of Enol Acetates or Silyl Enol Ethers
2.4 Enolates from Ketenes and Organolithium Compounds
2.5 Enolates from α-Halogen-Substituted Carbonyl Compounds by Halogen–Metal Exchange
2.6 Formation of Enolates by Transmetallation
2.7 Enolates by Miscellaneous Methods
References
Chapter 3: Structures of Enolates
3.1 Enolates of Alkali and Alkaline Earth Metals
3.2 Enolates of Other Main Group Metals
3.3 Transition Metal Enolates
References
Chapter 4: Enolates with Chiral Auxiliaries in Asymmetric Syntheses
4.1 Auxiliary-Based Alkylation of Enolates
4.2 Auxiliary-Based Arylation of Enolates
4.3 Auxiliary-Based Aldol, Vinylogous Aldol, and Reformatsky Reactions
4.4 Auxiliary-Based Mannich Reactions and Ester Enolate-Imine Condensations
4.5 Auxiliary-Based Conjugate Additions
4.6 Auxiliary-Based Oxidation of Enolates
References
Chapter 5: Enolates in Asymmetric Catalysis
5.1 Enantioselective Catalysis in Alkylations and Allylations of Enolates
5.2 Enantioselective Catalysis for Enolate Arylation
5.3 Catalytic, Enantioselective Aldol, Vinylogous Aldol, and Reformatsky Reactions
5.4 Catalytic Enantioselective Mannich Reactions, Ester Enolate–Imine Condensations, and Imine Reformatsky Reactions
5.5 Catalytic Enantioselective Conjugate Additions
5.6 Enantioselective Protonation of Enolates
5.7 Enantioselective Oxidation of Enolates
References
List of Procedures
Index
End User License Agreement
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Guide
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 1: Introductory Remarks
Figure 1.1 Formation of the enolate anion by removal of an α-hydrogen by base is the first step in the aldol addition [2].
Scheme 1.1 General enolate structures.
Scheme 1.2 Examples of nonequivalency of α-substituents in lithium enolates
4
and
5
, rhodium enolate
6
, and palladium enolate
7
.
Scheme 1.3 General structures of diastereomeric
cis
- and
trans
-O-bound enolates.
Scheme 1.4 Opposite assignment of configurations (
Z
and
E
) in an ester enolate depending on the O-bound metal.
Scheme 1.5 Examples of contradictory assignment of configurations in enolates.
Scheme 1.6 Rhodium and palladium enolates. Equilibrating O- and C-bound tautomers
14
and
15
; rhodium complex
16
, characterized by its crystal structure, as an example of an
η
3
-oxallyl enolate; cationic palladium complex
17
, proven as intermediate in Shibasaki's enantioselective aldol addition.
Scheme 1.7 Diastereoselective methylation of 3-hydroxybutanoate
18
–an example of a diastereoselective conversion of a lithium enolate with a chiral skeleton.
Chapter 2: General Methods for the Preparation of Enolates
Figure 2.1 (a) Top: Structure of LiHMDS (crystallized from pentane). Copied from Ref. [61a]. (b) Bottom: Structure of LDA (crystallized from THF).
Scheme 2.1 Standard bases for the formation of alkali metal enolates.
Scheme 2.2 Preparation of Rathke's enolate
11
.
Scheme 2.3 Preparation of Ivanov's reagent
12
and dilithiated carboxylic acids
13
.
Scheme 2.4 Regioselective preparation of less substituted enolates derived from 2-methylcyclohexanone.
Scheme 2.5 Kinetically controlled, regioselective deprotonation of selected ketones.
Scheme 2.6 Contrathermodynamic formation of lithium enolates
18a
and
18b
derived from 2-arylcyclohexanones.
Scheme 2.7 Example for formation of the higher-substituted enolate by deprotonation under thermodynamic control; R = CH
2
CH
2
OSi
t
BuMe
2
.
Scheme 2.8 Regioselective deprotonation reactions of α,β unsaturated ketones. Compound
25e
: cholest-4-en-3-one.
Scheme 2.9 Formation of
cis
-enolates from alkyl–aryl ketones
31
and
34
and
N
-acyl-pyrroles
37
.
Scheme 2.10 Enolates derived from α- and β-hetero-substituted carbonyl compounds.
Scheme 2.11 Stereochemistry in the formation of ester enolates: Ireland's cyclic model (top) and Heathcock's acyclic model. The latter was originally formulated with HMPA that has been replaced here by DMPU which is known to a similar effect.
Scheme 2.12 Stereochemistry in the formation of amide and ketone enolates according to Ireland's model.
Scheme 2.13 Dimeric solution structures of LDA with lithium coordinating to donor ligands.
Scheme 2.14 Transition-state models for the deprotonation of cyclohexanoic ester
54
with LDA in different solvents and cosolvents.
Scheme 2.15 Participation of triethylamine in the deprotonation of ketones with LiHMDS.
Scheme 2.16 Rationale for the deprotonation of 4-fluoroacetophenone by LDA, based on rapid-injection
19
F-NMR studies. Solvation of lithium not shown; Ar = 4-FC
6
H
4
.
Scheme 2.17 Mixed aggregates of lithium amide bases and lithium halides.
Scheme 2.18 Mechanism of enolate formation starting from a mixed LiBr–LiNH
2
aggregate according to a computational study.
Scheme 2.19 Proposed transition-state models for enolate formation starting from heterotrimers of carbonyl compound, lithium amide base, and lithium halide.
Scheme 2.20 Enantioselective enolate formation by treatment of 4-
t
-butylcyclohexanone with
C
2
-symmetric lithium amide bases (
R
,
R
)-
72a
or (
S
,
S
)-
72a
.
Scheme 2.21 Selected chiral lithium amide bases used for enantioselective enolate formation.
Scheme 2.22 Enantioselective formation of axially chiral lithium enolate
80
.
Scheme 2.23 Dimeric structures of chiral lithium amide bases and their mixed aggregates with lithium halides.
Scheme 2.24 Regioselective formation of boron enolates according to Mukaiyama's protocols; transition-state model
91
for kinetically controlled enolate generation.
Scheme 2.25 Selected
cis
-configured boron enolates.
Scheme 2.26 Controlled generation of
cis
- and
trans
-boron enolates from ketones.
Scheme 2.27 Controlled generation of
cis
- and
trans
-boron enolates from thioesters.
Scheme 2.28 Formation of boron enolates derived from carboxylic esters and thioesters.
Scheme 2.29 Generation of tin enolates by deprotonation; selected examples of tin enolates
105
used in asymmetric aldol reactions.
Scheme 2.30 Generation of titanium enolates by deprotonation; equilibrium of titanate
106
and titanium enolate
107
.
Scheme 2.31 Formation of zinc enolate
109
, embedded in Trost's Bis-Pro-Phenol ligand.
Scheme 2.32 General scheme of a conjugate addition as a route to enolates.
Scheme 2.33 Enolate formation and quenching in a Birch reduction.
Scheme 2.34 Regioselective generation of enolate
112
by reduction and subsequent alkylation.
Scheme 2.35 Correlation between enone conformation and enolate configuration.
Scheme 2.36 Enolates
122
in consecutive conjugate additions of lithiated thioacetals to butenolide
120
and subsequent and hydroxyalkylation/alkylation.
Scheme 2.37 Copper catalyzed generation of magnesium enolate
123
by conjugate addition.
Scheme 2.38 Consecutive conjugate addition of vinylcopper reagent
126
and vinylogous addition of enolate
128
in stereoselective prostaglandin synthesis R = Si
t
BuMe
2
.
Scheme 2.39 Simplified mechanism [135] of enolate formation by conjugate addition of lithium cuprates to α,β-unsaturated carbonyl compounds.
Scheme 2.40 Enantioselective conjugate addition catalyzed by bimetallic complex
135
and consecutive aldol addition of aluminum enolate
136
.
Scheme 2.41 Enantioselective rhodium-catalyzed conjugate addition of a borane and subsequent diastereoselective aldol addition of boron enolate
140
.
Scheme 2.42 Conjugate addition of chiral lithium amide
142
and under formation of
cis
-lithium enolates
43b
and quenching as silyl ketene acetal (
Z
)-
144
.
Scheme 2.43 Stereochemical stability of lithium enolates
cis
-
146
and
trans
-
148
generated by cleavage of enol acetates.
Scheme 2.44 Formation of lithium enolates by cleavage of silyl enol ethers.
Scheme 2.45 Diastereoselective formation of lithium enolates by addition of alkyllithium reagents to ketenes.
In situ
preparation of ketenes from BHT esters.
Scheme 2.46 Formation of lithium, magnesium, and zinc enolates by halogen–metal exchange.
Scheme 2.47 Preparation of molybdenum and tungsten enolates
163
through halogen–metal exchange in various α-chloro carbonyl compounds.
Scheme 2.48 General scheme for transmetallation of enolates.
Scheme 2.49 Controlled preparation of the different metalla tautomers of rhodium enolates:
η
3
-oxallyl tautomer
168
,
η
1
-oxygen-bound enolate
169
, and
η
1
-carbon-bound enolate
170
.
Scheme 2.50 C-bound nickel and palladium enolates prepared by transmetallation.
Scheme 2.51 Formation of titanium enolates
174
by cleavage of silyl enol ethers.
Scheme 2.52 O-bound palladium enolate
177
generated
in situ
from silyl enol ether
176
by transmetallation.
Scheme 2.53
In situ
formation of palladium enolates
180
and/or
181
in catalytic enolate arylation reactions.
Scheme 2.54 Preparation of O-bound palladium ester enolate
184
by transmetallation.
Scheme 2.55 Generation of enolates by miscellaneous methods.
Scheme 2.56 Ion pair
194
and palladium complex
195
as alternatives of enolates formed in the course of decarboxylative allylic alkylation.
Scheme 2.57 Generation of enolates
198
through oxy-Cope rearrangement of alkoxides
197
.
Chapter 3: Structures of Enolates
Figure 3.1 Crystal structures (illustrative examples) of lithium enolates.
Figure 3.2 (a) Structure of dimeric THF-solvated lithium enolate of
p
-fluorophenyl benzyl ketone. Copied from Ref. [7]. (b) Structure of a
cis
-configured magnesium enolate of
t
-butyl ethyl ketone.
Figure 3.3 (a) Structure of a mixed aggregate formed from sodium pinacolate and pinacolone and (b) structure of lithium pinacolate–pinacolone aldolate.
Figure 3.4 Structure of the monomeric lithium enolate of dibenzyl ketone with the metal complexed by the tridentate PMDTA ligand.
Figure 3.5
1
H-DOSY spectrum of mixed enolate aggregate
4
.
Figure 3.6 Job plot showing relative integrations of R
n
S
6−
n
hexamers derived from enolates (
R
)- and (
S
)-
9
as a function of the mole fraction of the (
R
) enantiomer. The curves correspond to a parametric fit to a hexameric enolate.
Figure 3.7 Computed transition structures (HF 6-31+g
*
) for the reaction monomeric (top) and dimeric (bottom) lithium enolate of acetaldehyde with methyl chloride.
Figure 3.8 The aldol reaction of tetrameric lithium enolate of 4-fluoroacetophenone (
10
) with 4-fluorobenzaldehyde in 3:2 THF/Et
2
O at −125 °C monitored by
19
F rapid injection NMR. The lines correspond to simulations based on the kinetic scheme shown above with the rate constants indicated on the graph.
Figure 3.9 B3LYP/6-31 + G(d) optimized geometries of tetra-solvated tetrameric lithium enolates. Hydrogens are omitted for clarity. From (a–d): acetaldehyde enolate, acetone enolate, cyclohexanone enolate, and pinacolone enolate.
Figure 3.10 (a) Calculated
η
3
global minimum of unsolvated lithium enolate of acetaldehyde and (b) calculated O-bound global minimum of lithium enolate of acetone, tri-solvated by dimethyl ether.
Figure 3.11 Molecular structure of bis(diisopropylamino)boron enolate of pinacolone (
14
). Hydrogen atoms are omitted for clarity.
Figure 3.12 Palladium(II) enolates: examples of C-bound tautomers
44
and O-bound tautomers
45
. Molecular structures of
44
(R
1
= R
2
= H, R
3
= 4-MeC
6
H
4
, Ar = 2-MeC
6
H
4
) and
45
(R
1
= Me, R
2
= H, Ar = Ph).
Figure 3.13 Molecular structure of the unligated enolate of ethyl phenylacetate with bis(phenanthroline) complexed Cu(I) cation.
Figure 3.14 Molecular structure of the Reformatsky reagent [BrZnCH
2
CO
2
CMe
3
·THF]
2
.
Scheme 3.1 Preparation and structure of the lithium enolate – LDA aggregate
2
. In the drawings within this chapter, no distinction is made between covalent and coordinative bonds.
Scheme 3.2 Preparation and structure of a mixed aggregate
4
composed of
cis
-configured lithium enolate of 3-pentanone and lithiated chiral amino alcohol
3
.
Scheme 3.3 Preparation methods and structure of lithium enolate–lithium halide aggregates
5
.
Scheme 3.4 Enolates
6–8
, studied by multinuclear NMR titration. Structures of tridentate ligands PMDTA and TMTAN.
Scheme 3.5 Dimeric O-bound aluminum enolates
15
and
16
, derived from N,N-dimethylglycine ester and aryl methyl ketone, respectively.
Scheme 3.6 Calculated relative energies of equilibrating O- and C-bound tautomers of tin enolates derived from acetophenone and methyl acetate.
Scheme 3.7 O-metal bound dimeric yttrium enolate
17
and monomeric scandium enolate
18
, both derived from acetaldehyde.
Scheme 3.8 Selected structures of O-bound titanium and zirconium enolates, confirmed by crystal structure analyses.
Scheme 3.9 O-metal-bound enolate
24
and aldolate
25
with hexa-coordinated titanium, both characterized by crystal structure analyses.
Scheme 3.10 Typical examples of manganese, molybdenum, and tungsten: C-bound enolates
26
and
27
and
η
3
-oxallyl enolates
28
and
29
.
Scheme 3.11 O-bound rhenium(I) enolate
30
and iron(II) enolates
31
and
32
.
Scheme 3.12 Representative examples of different tautomers of rhodium(I) enolates: C-bound enolate
33
, O-bound enolates
34
, and
η
3
-oxallyl-type enolates
35
and
36
.
Scheme 3.13 C-bound nickel and palladium enolates
37
, O-bound palladium enolate
38a
, and equilibrium between O-bound tautomer
38b
and C-bound tautomer
39
.
Scheme 3.14 Representative examples of palladium(II) enolates: O-bound palladium enolates
40
and
42
; dimeric C,O-bridged palladium enolates
41
and
43
.
Scheme 3.15 Chelated zinc enolate
47
and tetramer
48
.
Scheme 3.16 O-bound zinc enolates with complexation of the metal by diamines.
Chapter 4: Enolates with Chiral Auxiliaries in Asymmetric Syntheses
Scheme 4.1 Diastereoselective alkylation of propionate
1
via lithium enolates
trans
-
2
and
cis
-
3
.
Scheme 4.2 An early auxiliary-based enolate alkylation: preparation of pheromone (
S
)-
10
from
N
-propionyl (1
S
,2
R
)-ephedrine
8
.
Scheme 4.3 Alkylation of
N
-propionyl prolinol
11
through lithium and lithium/potassium enolates and cleavage of the auxiliary.
Scheme 4.4 Alkylation of
C
2
-symmetric amides
18
.
Scheme 4.5 Diastereoselective alkylation reactions of pseudoephedrine-based auxiliaries
21
. Cleavage of the auxiliary and model
29
for the stereochemical outcome.
Scheme 4.6 Alkylation of glycine through the amide auxiliary
30
.
Scheme 4.7 Glycine alkylation through camphor-derived auxiliary
35
.
Scheme 4.8 Diastereoselective alkylations of aminoindanol-derived amides
38
and
40
. Applications in syntheses of indinavir and endothelin receptor antagonist
44
.
Scheme 4.9 Evans auxiliaries
45–47
and examples for alkylation reactions of enolates
49
and
52
.
Scheme 4.10 Selected examples for the cleavage of Evans auxiliaries from alkylation products
54
.
Scheme 4.11 “Post-Evans” heterocyclic auxiliaries used after N-acylation for enolate alkylations.
Scheme 4.12 Alkylation of oxazolidinone-derived enolates with α-oxy substituents.
Scheme 4.13 Application of Evans' auxiliary for a synthesis of alcohol
72
, a building block for ionomycin.
Scheme 4.14 Alkylation reactions of oxazolidinones
73
and
78
through titanium enolates.
Scheme 4.15 Methoxyalkylation of thiazolidinethiones
80
and
80b
through titanium enolates. Transition state model
84
.
Scheme 4.16 Alkylation of thiazolidinethiones (
R
)- and (
S
)-
80
with glycals via titanium enolates.
Scheme 4.17 Application of Evans enolates in large-scale synthesis of PNP405.
Scheme 4.18 Application of Oppolzer sultams
91
and
ent
-
91
in enolate alkylations.
Scheme 4.19 Iterative alkylations of Meyers' bicyclic lactams
99
; model
104
for the approach of alkyl halide to the enolate.
Scheme 4.20 Alkylation of the fused δ-lactam
105
and cleavage of the chiral auxiliary.
Scheme 4.21 Enolate alkylation in Seebach's self-regeneration of chirality.
Scheme 4.22 Alkylation of dioxolanone
115
via the lithium enolate and application in a synthesis of (+)-frontalin.
Scheme 4.23 Alkylation reactions of imidazolidinone (
S
)-
118
and application for a synthesis of NMDA-receptor antagonist
123
.
Scheme 4.24 Alkylation reactions of Davies–Liebeskind enolates
125
and
128
.
Scheme 4.25 Application of Davies–Liebeskind enolates in a synthesis of (−)-captopril.
Scheme 4.26 Arylation of chiral silicon enolates
132
and
134
.
Scheme 4.27 Palladium-catalyzed arylation and vinylation of dioxolanone
137
.
Scheme 4.28 General mechanism of aldol reactions with preformed enolates
143
.
Scheme 4.29 General overview on the stereochemistry of the aldol addition with preformed enolates
143
.
Scheme 4.30 Stereochemical correlation between enolate and aldol configuration according to Zimmerman–Traxler transition state models
149
and
151
.
Scheme 4.31 Mulzer's transition state model
153
of the aldol addition.
Scheme 4.32 Noyori's open transition state models
156
and
157
of the aldol addition. Independence of
syn
-aldol configuration from enolate configuration.
Scheme 4.33 Open and cyclic transition state models of the Mukaiyama aldol addition.
Scheme 4.34 Selection of chiral ketones used as enolates in aldol reactions.
Scheme 4.35 Solladié–Mioskowski acetate aldol reaction with chiral sulfoxides
168
.
Scheme 4.36 Braun–Devant acetate aldol addition of doubly deprotonated triphenylglycol ester (
R
)-
173
.
Scheme 4.37 Selection of natural products and drugs synthesized through Braun–Devant aldol addition of (
R
)- and (
S
)-triphenylglycol acetates
173
.
Scheme 4.38 Application of the acetate aldol addition of triphenylglycol ester (
S
)-
173
for syntheses of HMG-CoA reductase inhibitors atorvastatin, lovastatin, and fluvastatin.
Scheme 4.39 Aldol addition of triphenyl glycol ester
173
to bicyclic ketone
180
as the key step in a synthesis of the selective α7 nicotinic receptor agonist AR-R17779.
Scheme 4.40 Acetate aldol reaction of Yamamoto's ester
183
.
Scheme 4.41 Aldol reactions with Helmchen's and Oppolzers's auxiliaries
1
and
188
. Transition state models
192
and
193
for rationalizing the stereochemical outcome.
Scheme 4.42 Mukaiyama aldol addition with ephedrine-derived silicon enolate
195
.
Scheme 4.43 Masamune's aldol addition of ephedrine-derived boron enolate
198
.
Scheme 4.44 Aldol addition of aminoindanol-derived propionate
200
via the titanium enolate; transition state model
203
.
Scheme 4.45 Propionate aldol addition via triphenylglycol ester (
R
)-
204
.
Scheme 4.46 “Evans-
syn
” selective aldol addition of valine-derived
N
-propionyl oxazolidinone
48
via boron enolate
208
. Dipole-minimized transition state model
210
.
Scheme 4.47 Evans aldol addition with phenylalanine-derived imide
73
and cleavage of the auxiliary by hydrolysis.
Scheme 4.48 Evans aldol reaction of ephedrine-derived
N
-propionyloxazolidinone
51
and conversion of the adduct
213
into Weinreb amide
214
under cleavage of the auxiliary.
Scheme 4.49 Access to “non-Evans-
syn
” aldol adducts
216
via titanium tetrachloride-mediated aldol addition; proposed transition state model
217
with boron chelation and titanium coordination.
Scheme 4.50 Crimmins' stereodivergent aldol additions of oxazolidinethione
218
and thiazolidinethiones
220
. Transition state models
222
and
223
as rationale for the formation of “Evans-
syn
” and “non-Evans-
syn
” aldol adducts.
Scheme 4.51
Anti
-selective aldol reactions through magnesium enolates. Transition state models
224
and
227
for the stereodivergent access to diastereomeric
anti
-aldols
225
and
228
, respectively.
Scheme 4.52 Aldol additions of
N
-acyl-oxazolidinones
229
carrying α-hetero substituents.
Scheme 4.53 Unselective Evans'
N
-acetyl oxazolidinone
231
and selected auxiliaries
232
,
234
, and
237
for acetate aldol additions.
Scheme 4.54 Evans' remote asymmetric induction in aldol additions of keto imides
238
via titanium and tin enolates. Transition state models
239
and
241
for rationalizing the stereochemical outcome.
Scheme 4.55 Selection of natural products synthesized by using aldol reactions with Evans' chiral auxiliaries. Stereogenic centers generated by these methods are marked by an asterisk.
Scheme 4.56 Multiple use of Evans auxiliary-based protocols in a total synthesis of calyculin A.
Scheme 4.57 Application of Evans' auxiliary
73
and Seebach's oxazolidinone
247
in the Novartis large-scale synthesis of (+)-discodermolide.
Scheme 4.58 Evans aldol protocol as the key step in Novartis' synthesis of ritalin.
Scheme 4.59 Kobayashi's vinylogous Mukaiyama aldol reactions of silicon dienolates
252
and
255
. Open transition state models
257
and
258
for rationalizing the stereochemical outcome.
Scheme 4.60 Vinylogous Mukaiyama aldol addition of silyldienolates
259
and
ent
-
255
as a key step in total syntheses of palmerolide A.
Scheme 4.61 Aldol reaction of tethered silicon enolate
263
. Pseudorotation of enolate–aldehyde complexes
265
and
266
.
Scheme 4.62 Stereodivergence in aldol additions of Oppolzer's sultam
92
via boron, tin, and silicon enolates. Proposed transition state models
273–275
.
Scheme 4.63 Mukaiyama acetate aldol reaction with silyl enol ether
276
derived from Oppolzer's sultam. Proposed open transition state
277
.
Scheme 4.64 Acetate aldol addition with iron acetyl complex
124b
via Davies–Liebeskind enolates.
Scheme 4.65 Masamune's aldol reaction mediated by the
C
2
-symmetric borolane as a chiral controller in enolates
283
. Transition state model for the propionate and acetate aldol additions
286
and
287
, respectively.
Scheme 4.66 Aldol additions of methyl ketones, mediated by chiral borane ligands
282b
and
289
. Applications in syntheses of
ent
-gingerol and statin.
Scheme 4.67 Diisopinocampheylboranes
292
as controllers in Paterson's aldol procedure. Application in a total synthesis of swinholide A.
Scheme 4.68 Corey's
syn
- and
anti
-selective aldol protocols based on the
C
2
-symmetric diazaborolidines. Transition state models
308
and
309
for rationalizing the correlation between enolate and aldol configurations.
Scheme 4.69 Application of oxazaborolidine
300
for mediating
anti
-selective aldol additions of bromoacetate
310
.
Scheme 4.70 Acetate aldol additions mediated via titanium enolates with chiral ligands derived from diacetone glucose and TADDOL
312
and
313
, respectively.
Scheme 4.71 Aldol additions of N-protected glycinates
318
mediated via chiral titanium enolates
319
and
321
.
Scheme 4.72 α-Bromo
N
-acyloxazolidinones
323
and
326–328
as auxiliaries for asymmetric Reformatsky reactions.
Scheme 4.73 Influence of imine protecting group on the stereodivergent titanium tetrachloride-mediated Mannich reactions of thiazolidinethione
80a
.
Scheme 4.74 Application of the Mannich reaction of
N
-acyl oxazolidinone
335
in a synthesis of the β-lactam ezetimibe.
Scheme 4.75 Mukaiyama–Mannich reactions with galactosamine-derived imines
338
.
Scheme 4.76 Domino Mannich–Micheal sequence in Kunz' synthesis of (
S
)-coniine.
Scheme 4.77 Mannich reactions of glycinates and sulfinylimine (
S
)-
348
. Transition state models
355
and
357
for the reactions of
trans
-enolate
354
and
cis
-
356
, respectively.
Scheme 4.78 Ojima's condensation of imines with esters
358
and
364
derived from menthol and phenylcyclohexanol. Application in a synthesis of the phenylisoserine side chain of Taxol.
Scheme 4.79
Trans
- and
cis
-β-lactams
367
and
368
, respectively, by condensation of triphenylglycol-derived esters
204
and
205
with imine
359a
.
Scheme 4.80 Synthesis of the cholesterol absorption inhibitor SCH48461 by ester enolate-imine condensation.
Scheme 4.81 Mannich reactions mediated by Corey's diazaborolidine. Transition state model
374
and conversion of β-amino thioesters
375
into β-lactams
376
.
Scheme 4.82 Rhodium catalyzed difluoro imine Reformatsky reaction of menthyl ester
378
for the synthesis of difluoro β-lactams
379
.
Scheme 4.83 Large-scale application of a Reformatsky–Mannich reaction in a synthesis of the α
v
β
3
-integrin antagonist
386
.
Scheme 4.84 Selection of chiral auxiliaries used in acceptors for conjugate additions.
Scheme 4.85 Conjugate additions to enoyl sultams
391
. Models
392
and
394
for rationalizing the dichotomy of the reactions in the absence and presence of cuprous chloride.
Scheme 4.86 Application of the conjugate addition of aryllithium compound
398
to the chiral acceptor
397
in a synthesis of endothelin A receptor antagonist
400
.
Scheme 4.87 Regioselective and diastereoselective formation of enolate
403
by conjugate addition to dienoyl sultam
401
and subsequent aldol addition of the enolate.
Scheme 4.88 Formation of lithium enolate
407
by conjugate addition of lithiated hydrazine
406
and subsequent diastereoselective alkylation.
Scheme 4.89 Conjugate additions of the chiral lithium amide
409
to α,β-unsaturated esters and amides and subsequent alkylation.
Scheme 4.90 Conjugate addition of the chiral lithium amide
409
as a key step in Merck's synthesis of the α
v
β
3
integrin antagonist
420
.
Scheme 4.91 General stereochemical scheme of the Michael addition.
Scheme 4.92 Corey's procedure for Michael additions of phenylmenthyl ester
424
. Influence of the configuration of the Michael acceptor on the stereochemical outcome and its rationalization by transition state model
428
.
Scheme 4.93 Transition state model for Michael additions of lithium enolates
430
and
431
with opposite configurations.
Scheme 4.94 Selected chiral enolates as donors for Michael additions.
Scheme 4.95 Conjugate additions of Evans' oxazolidinones to acrylonitrile and nitroalkene
442
via titanium enolates.
Scheme 4.96 Stereodivergent course in Davis' hydroxylation of amide
445
, depending on the enolate metal. Models
446
and
449
as a rationale for the stereochemical dichotomy.
Scheme 4.97 Evans' hydroxylation of
N
-acyl oxazolidinones
452
,
454
,
456
, and
458
via the sodium enolates.
Scheme 4.98 Oxidation of
N
-acyl oxazolidinones
459
with TEMPO via the titanium enolates.
Scheme 4.99 Brigaud's enolate oxidation with molecular oxygen. Hydroxylation of
N
-acyl oxazilidines
464
, cleavage of the auxiliary, and transition state model
467
.
Scheme 4.100 Evans' azidation of
N
-acyl oxazolidinones
468
and
474
via the potassium enolates. Cleavage of the auxiliary and application of enolate amination for a synthesis of tripeptide OF-4949-III (
476
).
Scheme 4.101 Amination of
N
-acyl oxazolidinones
468
by reaction of the lithium enolates with azodicarboxylate.
Scheme 4.102 Stereodivergent reactions of potassium versus lithium enolates of
N
-acyl pyrazolidinones
481
and reductive cleavage of the auxiliary.
Scheme 4.103 Amination of Oppolzer sultams
92
by reaction of the potassium enolates with nitroso compound
486
. Cleavage of the auxiliary and model
491
as a rationale of the stereochemical outcome.
Scheme 4.104 Bromination of Evans' boron enolates
493
with NBS and replacement of the halogen by azide. Halogenation of silyl ketene acetals
497
with NCS and NBS.
Scheme 4.105 Electrophilic fluorination of
N
-acyl oxazolidines
464
via the sodium enolate by reaction with
N
-fluorobenzenesulfonimide. Cleavage of the auxiliary and transition state model
501
.
Scheme 4.106 Homodimerization of
N
-acyl oxazolidinones
468
by reaction of the lithium enolate with titanium tetrachloride.
Scheme 4.107 Baran's hetero dimerization of imide and ketone enolates
507
and
504
. Proposed mechanism and transition state models
514
and
515
.
Scheme 4.108 Application of Barans's enolate heterodimerization in a synthesis of (−)-bursehernin.
Chapter 5: Enolates in Asymmetric Catalysis
Figure 5.1 Calculated transition state for the allylic alkylation of the lithium enolate of (
R
)-γ-valerolactone
49a
mediated by (
S
)-BINAP. Visualization of the outer-sphere mechanism.
Figure 5.2 Transition state model of Mukaiyama's aldol addition, mediated by the tin(II) complex of ligand
176a
.
Scheme 5.1 Examples of Koga's tetradentate ligands
1
and formation of aggregates
2
by deprotonation of a carbonyl compound.
Scheme 5.2 Examples of enantioselective alkylation after formation of enolates by means of chiral lithium amide
1a
.
Scheme 5.3 Catalytic use of chiral lithium amide
2b
in enantioselective benzylation of α-tetralone.
Scheme 5.4 Enantioselective alkylation of tin enolates, catalyzed by chromium salen complex
5
.
Scheme 5.5 Enantioselective alkylation of
ci
s/
trans
-mixtures of tin enolates
6
, catalyzed by chromium salen complex
7
.
Scheme 5.6 Simplified catalytic cycle of the palladium-catalyzed allylation of preformed enolates. MX and MX′ may be not identical in cases where the anion undergoes conversion, for example, decarboxylation in the case of a leaving group ROCO
2
−
.
Scheme 5.7 Trost's asymmetric allylic allylation of 2-methyl-1-tetralone through the tin enolate
13a
.
Scheme 5.8 Enantioselective allylic alkylation as a key step in a synthesis of hamigeran B.
Scheme 5.9 Diastereoselective and/or enantioselective palladium-catalyzed allylic alkylation of cyclohexanone through the magnesium or lithium enolate.
Scheme 5.10 Regioselective, diastereoselective, and enantioselective palladium-catalyzed allylic alkylation of acyclic ketones
25
through their lithium enolates.
Scheme 5.11 Regioselective, diastereoselective, and enantioselective palladium-catalyzed allylic alkylation of acylsilanes through their lithium enolates.
Scheme 5.12 Enantioselective palladium-catalyzed allylic alkylation of tertiary amides
32
through their lithium enolates.
Scheme 5.13 Rhodium-catalyzed enantioselective allylation of lithium enolates derived from α-oxy-substituted ketones
36
.
Scheme 5.14 Diastereoselective and enantioselective allylic alkylation of glycinate-derived chelated zinc enolate
41
.
Scheme 5.15 Diastereoselective and/or enantioselective palladium-catalyzed allylation of δ-valerolactone through the lithium enolate
46
.
Scheme 5.16 Cooperative and antagonistic effects of reagent and substrate stereocontrol in allylic alkylations of (
R
)-lactones
49
.
Scheme 5.17 Reagent control in the highly diastereoselective allylic alkylation of δ-caprolactone (
R
)-
49b
through the lithium enolate.
Scheme 5.18 Palladium-catalyzed allylic alkylations of doubly deprotonated carboxylic acids.
Scheme 5.19 Diastereoselective and enantioselective allylation of doubly deprotonated phenylacetic acid.
Scheme 5.20 Stereochemical course of the palladium-catalyzed allylic substitution. Inner- and outer-sphere mechanisms.
Scheme 5.21 Stereochemical course of the palladium-catalyzed allylic substitution at the substrate (
Z
)-
60
as a diastereomerically and enantiomerically pure probe.
Scheme 5.22 Complementary stereochemical course of the palladium-catalyzed allylic substitution at the substrate (
E
)-
65
as diastereomerically and enantiomerically pure probe.
Scheme 5.23 Stereochemical course in the palladium-catalyzed reaction of lithium enolate with the probe
rac
-
68
, mediated by the chiral ligand (
R
,
R
)-
69
.
Scheme 5.24 Enantioselective palladium-catalyzed allylic alkylation of silyl enol ethers
74
and
76
in the presence of
t
-butyl-PHOX ligand
42b
and the activator Bu
4
NPh
3
SiF
2
.
Scheme 5.25 Catalytic cycle of the palladium-catalyzed allylic alkylation of silyl enol ethers under activation by fluoride and/or alkoxide.
Scheme 5.26 Enantioselective palladium-catalyzed allylic alkylation of fluoro-substituted silyl enol ethers
80
.
Scheme 5.27 Regioselective and enantioselective iridium-catalyzed allylic alkylation of silyl enol ethers
82
.
Scheme 5.28 Kinetic resolution in the reaction of racemic allylic acetate
86
with 2-trimethylsiloxyfuran, mediated by palladium with the chiral ligand (
R
,
R
)-
14
.
Scheme 5.29 Enantioselective palladium-catalyzed allylic alkylation of silyl ketene acetals
88
without external activation.
Scheme 5.30 Mechanistic pathways in the palladium-catalyzed decarboxylative allylic alkylation, starting from allyl β-keto esters
91
or allyl enol carbonates
92
.
Scheme 5.31 Enantioselective decarboxylative allylic alkylation of β-keto esters
99
, reported by Tunge.
Scheme 5.32 Enantioselective decarboxylative allylic alkylations, starting from allyl enol carbonates
101
(reported by Stoltz) and allyl enol carbonates
103
(reported by Trost).
Scheme 5.33 Influence of the configuration at the enol double bond on the stereochemical outcome of the decarboxylative allylic alkylation, mediated by ligand (
R
,
R
)-
69
.
Scheme 5.34 Diastereoselective and enantioselective formation of diketone (
R
,
R
)-
108
by decarboxylative allylic alkylation of a stereoisomeric mixture of
107
.
Scheme 5.35 Enantioselective decarboxylative allylic alkylation of enediol-derived carbonates
110
and
111
. Controlled formation of allylated α-oxy-substituted aldehydes
112
and ketones
114
.
Scheme 5.36 Rationale for the regiochemical outcome in the decarboxylative allylic alkylation of enediol-derived carbonates
110
and
111
.
Scheme 5.37 Enantioselective formation of lactams
117
and cyclic imides
119
by decarboxylative allylic alkylation of esters
116
and
118
, respectively.
Scheme 5.38 Crossover experiment of palladium-catalyzed decarboxylative allylic alkylation reported by Stoltz
et al.
The authors measured the exact molecular masses by HRMS. The whole numbers are indicated here for reasons of simplification.
Scheme 5.39 Opposite topicity in the palladium-catalyzed allylic alkylation of lithium enolate
13b
and decarboxylative allylic alkylation of carbonate
103a
. The same enantiomer (
R
)-
15
forms with quasienantiomeric ligands (
S
,S)-
14
and (
R
,
R
)-
69
.
Scheme 5.40 Inner-sphere mechanism in the decarboxylative allylic alkylation, proposed by Stoltz.
Scheme 5.41 Evidence for outer-sphere mechanism in the decarboxylative allylic alkylation, reported by Trost.
Scheme 5.42 Visualization of Trost's rationale for the stereochemical outcome in the allylation of an LDA–lithium enolate aggregate (left) and a “naked” enolate (right).
Scheme 5.43 Enantioselective palladium-catalyzed decarboxylative allylic alkylation under ring opening of bicyclic racemic ketone
130
.
Scheme 5.44 Enantioselective formation of butenolides
133
by palladium-catalyzed decarboxylative allylic alkylation of furan-derived enol carbonate
132
.
Scheme 5.45 Cascade of palladium-catalyzed decarboxylative allylic alkylation and trapping of the palladium enolate, assumed as O-bound tautomer
135
, by Michael acceptors.
Scheme 5.46 General, simplified catalytic cycle of enolate arylation, mediated by [L
n
Pd
0
]. The intermediate palladium enolates are assumed to exist as equilibrium of C- and O-bound tautomers
140
and
141
, respectively.
Scheme 5.47 Enantioselective palladium-catalyzed enolate arylation of racemic aminomethylene ketones
143
mediated by chiral ligands
144
.
Scheme 5.48 Enantioselective nickel-catalyzed arylation of enolates derived from racemic butyrolactones
147
, mediated by (
S
)-BINAP (
23
).
Scheme 5.49 Palladium- and nickel-catalyzed enantioselective reaction of aryl triflates with enolates derived from racemic ketones
149
, catalyzed by palladium or nickel complexes with ligand
150
.
Scheme 5.50 Enantioselective palladium-catalyzed arylation of enolates derived from racemic oxindoles
152
, mediated by the axially chiral and P-stereogenic ligand
153
.
Scheme 5.51 Enantioselective synthesis of carboxylic esters
156
with a tertiary stereogenic α-carbonyl center by arylation of silyl ketene acetals
155
.
Scheme 5.52 Enantioselective intramolecular arylation in anilides
rac
-
157
under formation of oxindoles
160
.
Scheme 5.53 Enantioselective intramolecular enolate arylation of racemic
ortho
-bromoanilides
161
,
163
, and
165
.
Scheme 5.54 Enantioselective intramolecular arylation of aldehydes
167
to 1-formylindanes
168
.
Scheme 5.55 Enantioselective and diastereoselective aldol addition mediated by the chiral lithium amide
170
.
Scheme 5.56 Enantioselective enolate formation of tropinone
173
and preparation of β-hydroxy ketone
174
in a diastereoselective aldol addition.
Scheme 5.57 Mukaiyama's enantioselective aldol addition of silicon enolates
175a
and
178
; proposed catalytic cycle.
Scheme 5.58 Selection of chiral boron catalysts used for the asymmetric Mukaiyama aldol reaction.
Scheme 5.59 Stereoconvergent aldol reaction of silyl enol ethers
186
and
187
mediated by acyloxyborane
182a
.
Scheme 5.60 Enantioselective aldol addition of silyl ketene O- and S-acetals
191
and
193
mediated by oxazaborolidinone
183
. Proposed catalytic cycle.
Scheme 5.61 Titanium and zirconium catalysts used for the asymmetric Mukaiyama aldol reaction.
Scheme 5.62 Enantioselective Mukaiyama aldol additions mediated by titanium–BINOL complexes
196
according to Mikami and Keck. Proposed Zimmerman–Traxler-type transition state model.
Scheme 5.63 Vinylogous aldol addition of silyl dienolate
203a
mediated by titanium–BINOL complex; enantioselective synthesis of phorbaside A building block
205
.
Scheme 5.64 Stereoconvergent aldol addition of silicon enolates mediated by Kobayashi's zirconium complex. Application in the synthesis of khafrefungin building block
210
.
Scheme 5.65 Carreira's enantioselective aldol reaction of silicon enolates
211
and dienolate
214
. Application for the synthesis of macrolactin A building blocks
215
and
ent
-
215
.
Scheme 5.66 Selection of frequently applied Evans' BOX and PYBOX ligands
216–218
.
Scheme 5.67 Evans' Mukaiyama aldol and vinylogous aldol reactions mediated by the copper PYBOX catalyst 217; enantioselective synthesis of callipeltoside A building block
225
.
Scheme 5.68 Proposed catalytic cycle of Evans' enantioselective catalytic aldol addition and model
229
for rationalizing the stereochemical outcome.
Scheme 5.69 Stereodivergent Evans' aldol addition mediated by copper complex
216a
and tin complex
218
. Model
233
for rationalizing the topicity in the copper–BOX-catalyzed aldol reaction.
Scheme 5.70 Stereodivergent course in Denmark's aldol addition of silicon enolate
236
, mediated by chiral phosphoramides
234a
and
234b
.
Scheme 5.71 Diastereoselective and enantioselective aldol addition of aldehyde-derived trichlorosilyl enolates
241
and
243
, mediated by bisphosphoramide
235
.
Scheme 5.72 Denmark's asymmetric aldol additions of silyl ketene acetals
246
and
248
mediated by silicon tetrachloride and catalyzed by bisphosphoramide
235
; proposed catalytic cycle.
Scheme 5.73 Application of Denmark's silicon tetrachloride-mediated aldol protocol in a total synthesis of the polyene macrolide RK-379.
Scheme 5.74 Diastereoselective and enantioselective Mukaiyama aldol addition catalyzed by doubly lithiated BINOL
262
; proposed transition state model
264
.
Scheme 5.75 Catalytic cycle of the aldol addition of silicon enolates
220
under transmetallation into transition metal enolate
265
.
Scheme 5.76 Shibasaki–Sodeoka aldol reaction catalyzed by palladium complex
268
.
Scheme 5.77 Carreira's copper-catalyzed vinylogous aldol addition of silyl dienolate
214
; postulated catalytic cycle.
Scheme 5.78 Shibasaki's copper-catalyzed aldol addition of silyl ketene acetals to prochiral ketones.
Scheme 5.79 Rawal's stereoselective Mukaiyama aldol addition under hydrogen-bonding catalysis.
Scheme 5.80 Hayashi's gold-catalyzed direct aldol reaction of isocyano ester
281
.
Scheme 5.81 Shibasaki's direct aldol reaction mediated by the lanthanum–lithium complex
285
; assumed structures of loaded intermediate catalysts
288
and
289
.
Scheme 5.82 Trost's direct aldol reaction catalyzed by the dizinc complex of ligand
290
.
Scheme 5.83 Catalytic cycle proposed for the aldol reaction mediated by dizinc complexes of ligand
290
.
Scheme 5.84 Evans' direct aldol reaction of thiazolidinethione
299
, catalyzed by nickel complex
300
; proposed catalytic cycle.
Scheme 5.85 Nishiama's direct aldol reaction of enones
307
, catalyzed by rhodium complex
308
; models
310
and
311
for rationalizing the stereochemical outcome.
Scheme 5.86 Cozzi's enantioselective Reformatsky reaction, mediated by manganese salen complex
313
.
Scheme 5.87 Feringa's enantioselective Reformatsky reaction mediated by BINOL-type ligand
315
.
Scheme 5.88 Enantioselective Reformatsky reaction mediated by amino alcohol
323
.
Scheme 5.89 Enantioselective difluoro Reformatsky reaction.
Scheme 5.90 Kobayashi's Mukaiyama–Mannich reaction of imines
328
, mediated by BINOL–zirconium complex
329
.
Scheme 5.91 Proposed catalytic cycle of Mukaiyama–Mannich reaction mediated by BINOL–zirconium complex
329
; stereochemical model
339
.
Scheme 5.92 Mukaiyama–Mannich reaction of imino esters
340
, mediated by copper complex
341
; proposed catalytic cycle.
Scheme 5.93 Mukaiyama–Mannich reaction of phosphinoyl imines
346
and
350
, mediated with copper complexes of ligands
348
and
351
, respectively.
Scheme 5.94 Mannich and vinylogous Mannich reactions mediated by silver complexes of ligands
354
.
Scheme 5.95 Mukaiyama–Mannich reaction under proton catalysis of the chiral urea derivative
363
.
Scheme 5.96 Mukaiyama–Mannich reaction catalyzed by Akiyama's chiral phosphoric acid
367
.
Scheme 5.97 Sibasaki's Mannich procedure based on zinc complexes of “linked BINOL”
371
.
Scheme 5.98 Enantioselective and diastereoselective direct Mannich reactions catalyzed by ligands
290
.
Scheme 5.99 Enantioselective ester enolate–imine condensation mediated by the stoichiometric additive
379
.
Scheme 5.100 Enantioselective ester enolate–imine condensation mediated by the ligand
383
.
Scheme 5.101 Cozzi's multicomponent imino Reformatsky reaction.
Scheme 5.102 Enantioselective preparation of β-lactams
392
through imino difluoro Reformatsky reaction
Scheme 5.103 Evans' Mukaiyama–Michael procedure based on catalyst
216b
; proposed catalytic cycle.
Scheme 5.104 Correlation of configuration in enolates
401
and
403
with products
402
and
404
in Evans' procedure for conjugate additions.
Scheme 5.105 Conjugate addition of silyl enol ethers
405
to crotonylphosphonates
406
, mediated by aluminum complex
407
.
Scheme 5.106 Enantioselective formation of metal enolate
409
in conjugate addition and quenching by protonation. Selection of ligands
410–416
frequently used in enantioselective conjugate addition.
Scheme 5.107 Formation of zinc enolate
418
by enantioselective conjugate addition, transmetallation into silicon enolate
419
, and oxidation to ketone
420
.
Scheme 5.108 Simplified tentative catalytic cycle of the copper-catalyzed conjugate addition of dialkylzinc to cyclohexenone.
Scheme 5.109 Copper-catalyzed enantioselective conjugate addition of dimethyl zinc and enolate trapping by palladium-catalyzed allylic alkylation to ketone
427
. Application to a synthesis of pumiliotoxin C.
Scheme 5.110 Copper-catalyzed enantioselective conjugate addition of zinc reagent
429
and aldol addition to cyclopentanone
431
. Application to a synthesis of PGE
1
methyl ester.
Scheme 5.111 Rhodium-catalyzed enantioselective conjugate addition of phenylboronic acid to cyclohexenone according to Hayashi and Miyaura; proposed catalytic cycles.
Scheme 5.112 Rhodium-catalyzed enantioselective conjugate addition and subsequent diastereoselective aldol addition/allylation of boron enolate
438
. Model for rationalizing the stereochemical outcome.
Scheme 5.113 Rhodium-catalyzed enantioselective conjugate addition and subsequent diastereoselective intramolecular aldol addition to bicyclic ketone
445
; transition state model
444
.
Scheme 5.114 Rhodium-catalyzed enantioselective conjugate addition of vinyl zirconium compounds
446
and subsequent diastereoselective aldol addition.
Scheme 5.115 Enantioselective conjugate addition of malonates
448
to cyclopentenone, mediated by Shibasaki's catalyst
449
and subsequent aldol addition. Conversion of adduct
452
into 11-deoxy-PGF
1α
.
Scheme 5.116 Proposed catalytic cycle of conjugate addition/aldol reaction mediated by the complex
449
.
Scheme 5.117 Rhodium-catalyzed acrylate reduction followed by an aldol addition.
Scheme 5.118 Selected procedures for enantioselective enolate protonation with stoichiometric or overstoichiometric proton sources.
Scheme 5.119 Enantioselective enolate with stoichiometric and catalytic amounts of proton source
472.
Conversion of thioester
473
into α-damascone. Proposed catalytic cycle.
Scheme 5.120 Stoichiometric and catalytic use of imide
476
as a chiral proton source. Proposed catalytic cycle.
Scheme 5.121 Enantioselective protonation of silicon enolates
482
and
484
using BINOL monomethyl ether
481
in catalytic amounts; proposed catalytic cycle.
Scheme 5.122 Enantioselective protonation of chiral palladium enolates generated by decarboxylation of β-keto esters
487
and
489
; simplified proposed catalytic cycle.
Scheme 5.123 Mechanism of the enolate oxidation with sulfonyloxaziridines.
Scheme 5.124 Selected examples of enantioselective enolate oxidations mediated with chiral sulfonyloxaziridines
501
.
Scheme 5.125 Conversion of silyl enol ethers
506
and
509
into α-hydroxy ketones
508
and
510
, respectively, by Sharpless asymmetric dihydroxylation.
Scheme 5.126 Enantioselective oxidation of silicon enolates
512
mediated by salen complex
511b
.
Scheme 5.127 Ambidoselectivity in the reaction of silicon and tin enolates
514
with nitrosobenzene.
Scheme 5.128 Enantioselective silver-catalyzed reaction of tin enolates
518
with nitrosobenzene
515
to α-aminooxy ketones
519
as intermediates for the formation of α-hydroxy ketones.
Scheme 5.129 Enantioselective silver-catalyzed reaction of silicon enolates
521
with nitrosobenzene
515
to α-aminooxy ketones
519
, mediated by ligand
522
. Reagent control in the reaction of enantiomeric silicon enolates
523
.
Scheme 5.130 Enantioselective copper-catalyzed amination of silicon enolates
526
,
529
, and
531
with azoimide
527
; proposed catalytic cycle.
Scheme 5.131 Enantioselective silver-catalyzed enolate amination with azodicarboxylate
535
.
Scheme 5.132 Regioselective N-attack reaction of tin enolates
537
to nitrosobenzene
515
, mediated by BINAP–silver complex
538
.
Scheme 5.133 Stoichiometric reagents
540
and
541
for enantioselective enolate fluorination.
Scheme 5.134 Lectka's enantioselective fluorination of acid chlorides
543
catalyzed by benzoylquinidine
545
. “Trifunctional” reaction mechanism.
Scheme 5.135 Homocoupling of titanium enolates of oxazolidinone
552
, mediated by TADDOL
553
.
Scheme 5.136 Heterocoupling of octanal with silicon enolates
556
, mediated by imidazolidinone
557
; model
559
for rationalizing the stereochemical outcome.
List of Tables
Chapter 2: General Methods for the Preparation of Enolates
Table 2.1 Selected examples of diastereoselective formation of lithium enolates [37–47]
Table 2.2 Selected, illustrative examples of enantioselective formation of lithium enolates
Chapter 5: Enolates in Asymmetric Catalysis
Table 5.1 Combinations of imines
359
and catalysts
360
used in Mukaiyama–Mannich protocols
Related Titles
Mahrwald, R. (ed.)
Modern Methods in Stereoselective Aldol Reactions
2013
Print ISBN: 978-3-527-33205-2; also available in electronic formats ISBN: 978-3-527-65671-4
Gruttadauria, M., Giacalone, F. (eds.)
Catalytic Methods in Asymmetric Synthesis
Advanced Materials, Techniques, and Applications
2011
Print ISBN: 978-1-118-08797-8; also available in electronic formats
Manfred Braun
Modern Enolate Chemistry
From Preparation to Applications in Asymmetric Synthesis
Author
Manfred Braun
Inst. für Organische Chemie und Makromolekulare Chemie
Heinrich-Heine-Universität Düsseldorf
Universitätsstr. 1
40225 Düsseldorf
Germany
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Preface
Undoubtedly, natural product synthesis over the past 50 years has been the flagship of organic chemistry. Has it, in the early days, required a lonely genius such as R. B. Woodward to master structural complexity, there is now a whole bunch of researchers well in a position to handle even much more complicated targets. This remarkable advance in scope and capability is due to several factors, in part to the advent of powerful instrumentation such as crystal diffraction, NMR spectroscopy, high-pressure liquid chromatography, and so on, but equally to the development of new chemical methodology mainly based on mechanistic insights. This has resulted in numerous spectacular innovations, in particular in the control of stereo- and regiochemistry and catalytic transformations, thus avoiding waste and enhancing efficiency.
There can be no doubt that enolate chemistry has been a cornerstone in these developments from early on up to the present day. I remember very well how macrolides such as erythromycins have been elusive targets in the early 1970s, and it was these very target molecules that stimulated the interest in aldol chemistry as the obvious biomimetic access. In this way enolates, which had, so far, been generated as transitory intermediates in protic media, were pinned down structurally and exploited with respect to their full synthetic potential.
Many people have noted that these developments have now come to a head and so, a broad and comprehensive overview of the subject has been overdue, although multifaceted aspects of enolate chemistry have been highlighted in numerous reviews. Fortunately, one of the main players in this field has now stepped in, presenting an ambitious textbook, which in a highly systematic way gives an answer to almost any question that may arise when applying enolate chemistry. Enol ethers are included as well, which is inevitable in view of Mukaiyama aldol chemistry and catalytic alkylation.
The text starts with a brief historic overview and then describes in great detail the various ways of enolate generation and the structural properties of metallated enolates (Chapters 1–3). This sets the stage for asymmetric enolate reactions. In Chapter 4, diastereoselective auxiliary-controlled enolate alkylations and aldol additions are presented with main focus on Evans' type auxiliaries, without, however, neglecting alternative auxiliaries. The largest chapter (Chapter 5) is devoted to enantioselective catalysis in enolate alkylations (i.e., mostly Trost–Tsuji allylation), aldol additions, Reformatsky reactions, and others.
In summary, as far as I can judge, all important aspects of the field have been covered. Mechanistic aspects have been widely discussed, and the practical relevance of the individual methodology has been illustrated by many synthetic applications taken from both academia and industry. I am sure that this book will find its way into the library of all those actively involved in any area of asymmetric synthesis.
August 2015
Johann MulzerUniversität Wien
Chapter 1Introductory Remarks
The “central role in synthetic organic chemistry played by the carbonyl group” [1] is well recognized, and enolate chemistry is definitely a major part of carbonyl chemistry; the number of conversions involving enolates became legion. In textbooks of organic chemistry dating back to the 1950s or earlier, the question of the structure of enolates–the reactive species in widely applied carbon–carbon bond forming reactions like the aldol addition, the Claisen condensation, and the Mannich and Michael reactions–was simply answered by the concept of the enolate anion, described as a resonance hybrid of the carbanionic and the oxyanionic resonance formulas. The metal cation was usually ignored completely or little attention was paid to it. The mechanism given in the 1965 edition of Roberts and Caserio for the aldol addition (Figure 1.1) may serve for a representation of the enolate concept in teaching.
Figure 1.1 Formation of the enolate anion by removal of an α-hydrogen by base is the first step in the aldol addition [2].
This point of view was acceptable as long the corresponding reactions were run in highly polar protic, frequently aqueous solvents that allowed for a at least partial dissociation into an enolate anion and a metal cation. At the times however when, initiated by Wittig's seminal contributions, the concept of the “directed aldol reaction” [3] came up, the protic milieu had to be given up, and the generation and conversion of preformed enolate were moved into moderately polar solvents like cyclic and acyclic ethers, chlorinated hydrocarbons, or even alkanes and arenes, frequently with tertiary amines as cosolvents, the idea of charge separation or even dissociation into a “free” enolate anion and a metal cation became doubtful. As a consequence, the question arose whether the metal is linked to the carbonyl oxygen (O-bound enolates 1) or to the α-carbon atom (C-bound enolates 2). Is it the oxygen or the carbon atom that balances on the ball? In addition, a third structure is possible, wherein the metal forms an η3 bond to the enolate (oxallyl enolate 3) (Scheme 1.1).
Scheme 1.1 General enolate structures.
After almost half century of intensive, fundamental, and fruitful investigations of enolate structures, there is now clear evidence indicating that enolates of groups 1, 2, and 13 metals–lithium and boron being the most relevant ones–exist as the O-bound tautomers 1; the same holds in general for silicon, tin, titanium, and zirconium enolates [4]. Numerous crystal structure analyses and spectroscopic data confirmed type metalla tautomer 1 to be the rule for enolates of the alkali metals, magnesium, boron, and silicon [5].
The metal–oxygen interaction may be considered a highly polar covalent bond or a tight ion pair in the case of alkali and earth alkali metals. The O–metal bond and the resulting carbon–carbon double-bond character were early recognized in enolate chemistry by means of NMR spectroscopy that revealed a rotation barrier of at least 27 kcal mol−1 for the enolate 4, as determined in triglyme [6]. Not only the methyl groups in 4 are nonequivalent but also the α-protons (3.14 and 3.44 ppm in benzene) in “Rathke's enolate” 5 derived from t-butyl acetate [7]–to give just two illustrative examples of lithium enolates. The double-bond character holds of course also all O-bound enolates, including those of transition metals – rhodium enolate 6 [8] and palladium enolate 7 [9] may serve as illustrative examples: in their 1H NMR spectra, the nonisochronous olefinic protons displaying two singlets at 4.40 ppm/4.62 ppm and 4.90 ppm/4.99 ppm, respectively (Scheme 1.2).
Scheme 1.2 Examples of nonequivalency of α-substituents in lithium enolates 4 and 5, rhodium enolate 6, and palladium enolate 7.
The structural feature of the O–metal bond has a substantial consequence that holds for carbonyl compounds with nonidentical substituents in the α-position: the configurational isomerism with respect to the carbon–carbon double bond giving rise to cis- or trans-enolates 8 (Scheme 1.3). This diastereomerism was recognized in the early stage of enolate research by NMR spectroscopy [10, 11] and later impressively confirmed by crystal structure analyses [12]. Chemists learned to generate cis- or trans-enolates selectively and to handle them under conditions that prohibited them from cis–trans isomerization. In an early, fundamental work in enolate chemistry, House and Trost disclosed that cis- and trans-8 (X = Me, M = Li, R = nBu) do not interconvert even at elevated temperature [13]. Seminal contributions in the groups of Dubois and Fellmann [14] and Ireland et al. [15] revealed the distinct influence of enolate configurations to the stereochemical outcome of the aldol reaction and the Claisen–Ireland rearrangement, so that, in turn, these reactions served as a probe for deducing the configuration of enolates.
Scheme 1.3 General structures of diastereomeric cis- and trans-O-bound enolates.
At a glance, the descriptors Z and E might seem to be appropriate for O–metal-bound enolates like 6. Indeed, E/Z nomenclature causes no problems when the configuration of preformed enolates derived from aldehydes, ketones, and amides has to be assigned, because the O–metal residue at the enolate double bond has the higher priority. However, application of the E/Z descriptors to ester enolates leads to the dilemma that enolates with different metals but otherwise identical structures will be classified by opposite descriptors, as illustrated by lithium and magnesium enolates 9 and 10, respectively: the former would have to be termed Z, and the latter E (Scheme 1.4).
Scheme 1.4 Opposite assignment of configurations (Z and E) in an ester enolate depending on the O-bound metal.
In order to circumvent this complication, a pragmatic solution has been proposed by Evans: irrespective of the formal Cahn–Ingold–Prelog criteria, the oxygen atom bearing the metal (the OM residue) is given a higher priority, and the ipso-substituent X (in enolates 8) the lower one [4]b. Although this convention has been accepted by other authors, there are both practical and principal objectives against it. The following examples (Scheme 1.5) may illustrate the confusing situation that occurs: the identical diastereomer of enolate 11 has been termed E by Heathcock [4]d, and Z by Seebach [12]b, the latter using the correct Cahn–Ingold–Prelog assignment. Another nightmare in this respect is thioester enolates, as again opposite descriptors are spread out in the literature by using either Evans' convention [4]b, [16] or CIP-based nomenclature [17], as demonstrated by the related boron enolates 12 and 13.
Scheme 1.5 Examples of contradictory assignment of configurations in enolates.
Aside this confusion, there is a principal argument, not to use Evans' convention, because the hard descriptors E and Z must not be redefined. The soft descriptors cis and trans, however, can be used without violation of the strict definitions of the unequivocal E and Z. Therefore, in this book, the recommendation of Eliel et al. [18] is followed using the soft descriptors cis and trans, if a series or a class of enolates are addressed [19]. Thereby, “cis” means that the OM substituent is on the same side as the higher-priority group at the α-carbon atom, and “trans” means that the OM substituent is on the opposite side. Only in those cases, where an individual enolate is concerned, E/Z nomenclature is used according to its strict definition.
The C-bound metalla tautomers 2 are typical for the less electropositive metals [4]e. They have been postulated occasionally for zinc [20] and copper [21] but are a rule for mercury [10]a. Carbon-bound enolates of molybdenum, tungsten, manganese, rhenium, iron, rhodium, nickel, iridium, and palladium have been detected and characterized [22], but one has to be aware of the phenomenon that they exist in equilibrium with the O-bound metalla tautomers. The interconversion of the palladium enolates 14 and 15 (Scheme 1.6), whose activation barrier has been determined to amount to approximately 10 kcal mol−1, may serve as a typical example [8]. The dynamic of O- and C-bound tautomers 1 and 2 (Scheme 1.1) with transition metals is obviously a delicate balance depending on the individual enolate, the metal, and the ligands [9, 23].
Scheme 1.6 Rhodium and palladium enolates. Equilibrating O- and C-bound tautomers 14 and
