chapter 5 cadmium-proline catalyzed aldol...
TRANSCRIPT
-
165
CHAPTER 5
CADMIUM-PROLINE CATALYZED ALDOL
REACTIONS
5.1 Introduction The aldol reaction1,2 is one of the most venerable reactions in organic
chemistry, firstly discovered by Wurtz in 1872,1b although Kane previously described
the prevently known Aldol condensation.1a This useful transformation allows the
formation of a C–C bond by reaction of an enolizable carbonyl compound acting as a
source of nucleophile with itself or another carbonyl compound acting as an
electrophile to give a β-hydroxy carbonyl compound known as aldol. Without any
doubt, catalytic enantioselective methods are the most attractive alternative for
providing chiral compounds with high selectivity and atom efficiency.3 Biochemical
methods based on the use of aldolase enzymes4and antibodies5 have shown their
usefulness to perform this task, with the scope of substrates being very narrow. In
search of a wider substrate scope, different enantioselective chemical methods have
been extensively developed in recent years, especially after the introduction of the
Mukaiyama-aldol version of this reaction.6 In this case, the generation of a silyl enol
ether (or chemical equivalent) is compulsory, requiring the use of stoichiometric
amounts of bases and silylating reagents and therefore having low atom efficiencies.
In order to enhance the global efficiency of the process, an effort has been made to
develop enantioselective direct aldol reactions,7 where the use of performed enolates
(or their equivalents) is avoided. In general, the asymmetric aldol reactions can be
categorized into the following five types, (i) chiral auxiliary assisted aldol reaction
based on the use of stoichiometric quantities of the chiral appendages; (ii) chiral Lewis
acid and Lewis base catalysed (iii) heterobimetallic bifunctional Lewis acid/Bronsted
-
166 base catalysed aldol reeactions (iv) Enzyme or antibody catalysed reaction and (v)
organocatalysis with L-proline or its structural analogs. Out of these methods the
above three methods (i-iii) have successfully been used with the unmodified carbonyl
compounds while the two methods (iv-v) require some sort of pre-activation of the
carbonyl group of the ketones used for successful operations.
A remarkable success has been achieved on the substrate scope and reaction
selectivities by the use of so-called enantioselective organocatalytic direct aldol
processes. The adjective organocatalytic is applied to processes in which reagents and
catalysts are all small organic molecules containing only C, H, O, N, S, P, and halogen
atoms.8Therefore, processes in which a metal (including boron and silicon atom) is
involved should be excluded in strict sense. Furthermore, those processes involving
high molecular weight organic compounds such as enzymes, antibodies, even
polymers, and dendrimers, should be excluded.Although according to the above strict
definition, reactions involving silicon atoms, polymers, and inorganic materials should
be excluded. We considered that processes where the silyl group has only a steric role
(or increase the solubility) should be included as well as cases in which the catalyst is
immobilized in a polymer, dendrimer, or inorganic material, since in these cases the
matrix does not play any relevant role in the reaction, and is only important in the
recovery of catalysts.
The enantioselective aldol reaction is a powerful method for constructing one
or two successive chiral carbon centers.9 Progress in catalytic, enantioselective aldol
reaction has been made by chiral Lewis acid-catalyzed reactions of trimethylsilyl enol
ethers, which act
as aldol donors and are prepared from parent carbonyl compounds.In the last decades,
catalytic enantioselective direct aldol reactions, which do not require masked enol
ethers to be prepared beforehand from ketones or esters (aldol donors), have attracted
much attention due to their simple manipulation and high atom economy.10 Two types
of direct aldol reactions have been reported: the reactions catalyzed by chiral metal
alkoxide complexes, which were initially reported by Shibasaki,11,12 and the reactions
involving enamine process, which were pioneered by List and Barbas.13,14 Both
strategies have been extensively investigated, and are commonplace in the
development of asymmetric reactions.15 Shunsuke et al.16 reported a novel type of
enantioselective direct aldol reaction of cyclohexanone derivatives (1) and
benzaldehyde derivatives (2) in high stereoselectivities with tetrachlorosilane and
-
167 diisopropylethylamine in dichloromethane at rt using BINAPO (BINAP dioxide) as an
organocatalyst (Scheme 1). Benzaldehyde was slowly added to the mixture containing
all the other components at rt, 17 which afforded the aldol adduct (3, 4) with good anti-
selectivity, but in low chemical and optical yields (rt, 4 h, 30% yield, syn/anti = 1/5,
16% ee (anti)).
O
PhCHO
P
O
P
O
PhPh
BINAPO(10 mol%)
SiCl4iPr2NEt
syn- anti-
+
PhPh
Ph Ph
OH OHO O
+
1 2 3 4
Scheme 1
The direct asymmetric aldol reaction is one of the most important C–C bond-
forming reactions in nature, and it is catalyzed by aldolase enzymes with excellent
stereocontrol.18 The enzyme’s ability to control the enantioselectivity of the direct
aldol reaction has inspired chemists and raised this transformation to prominence in
the asymmetric assembly of complex natural products.19,20 In particular, the
development of catalytic stereoselective methods for the asymmetric directed aldol
reaction has recently been the subject of intense research.21 For example, the
utilization of organometallic complexes and Lewis bases as catalysts has been highly
successful for the asymmetric Mukaiyama-type aldol reaction between activated silyl
enol ethers and aldehydes.22a-g Furthermore, the enantioselective aldol reaction
between unmodified ketones and aldehydes is catalyzed by chiral organometallic
complexes.22h-k Another approach to the catalysis of the direct asymmetric aldol
reaction is the use of aldolase enzymes.18,23 Recently, organocatalysis has experienced
a renaissance in asymmetric synthesis.24 In this context, proline and its derivatives
have proved to be the best catalysts for the direct intermolecular asymmetric aldol
reaction.25,26 Armando et al.27 described the linear amino acid-catalyzed direct
asymmetric intermolecular aldol reaction; simple amino acids such as alanine, valine,
isoleucine, aspartate, alanine tetrazole 3 and serine catalyzed the direct catalytic
asymmetric intermolecular aldol reactions between unmodified ketones and aldehydes
with excellent stereocontrol and furnished the corresponding aldol products in up to
-
168 98% yield and with up to 99% ee. They reported the L-alanine catalyzed asymmetric
aldol reaction between different ketones (5) and acceptor aldehydes (6) affording aldol
product (7) (Scheme 2).
L-alanine(30 mol%)
H2O(10 equiv)
DMSO,rt3-4 days
O
+ H R R
O OH
R2 R2R1
O
R1 5 6 7
Scheme2
Maruoka and coworkers28 reported a novel amino acid derived from optically
pure binaphthol. Various amines, most of which are synthesized from optically pure
proline, have also been employed in the direct aldol reactions.29a,29b,30 Recently,
Cheng31 developed a simple primary-tertiary diamine-Brønsted acid catalyst that has
been successfully applied to direct aldol reactions, and this catalytic system was highly
efficient for both linear and cyclic aliphatic ketones.Prolinamides have also received
great success for their easy preparation and high efficiency.29c,29d-29f,32 Zhao et al.33
reported enantioselective direct aldol reactions catalyzed by prolinamide derived from
cinchonine and optically pure proline (i-iii). Both cyclic and acyclic ketones (5,8) were
reacted with various aldehydes (6) furnishing the desired aldol products (9) in up to
90% yield with excellent enantioselectivities (up to 95%) and moderate
diastereoselectivities (up to 3.6/1) in the case of cyclic ketones (Scheme 3).
N
N
HH2N
N
N
HHN
ONH
N
N
HHN
ONH
CHO10 mol%cat.10 mol% TFA
- 18oC
Cat.= i. ii. iii.
+R
OOOH
6 5,89
(i-iii)
Scheme 3
-
169
After the discovery of a proline-catalyzed enantioselective intramolecular aldol
reaction in the 1970s, the corresponding intermolecular enantioselective direct aldol
reactions between ketones and aldehydes were reported by Barbas et al. in 2000.34a,34b
Although proline is a rather good catalyst, it is not without some potential drawbacks,
such as (1) a low solubility that limits its reactivity in typical organic solvents, (2)
potential side reactions and established parasitic equilibria with substrates,35 and (3)
low selectivities with planar aromatic aldehydes in direct aldol reactions. Therefore,
considerable effort has been directed at the development of proline analogs in order to
improve their reactivity, selectivity and scope. Considering the practical synthetic
issues, the carboxylic acid moiety of proline has been targeted as a site for
modification. Its reactivity and selectivity is enhanced in custom-made catalysts, even
though the identification of a good catalyst in turn requires the synthesis of various
analogs of a proposed design in order to identify the optimum one. Moreover, the
improved catalyst is usually obtained through the modification of proline with chiral
molecules that have additional functionality, and are much more precious than the
proline itself.36
‘‘To make a good asymmetric catalyst perfect’’, the role of suitable additives,
or co-catalysts, can be crucial in enhancing the reactivity and stereoselectivity of the
catalytic system. For example, it has been shown that the addition of a small amount
of water often accelerates the reaction rate and increases the enantioselectivity of
proline-catalyzed aldol reactions.37b-37i Recently, Shan has shown that using chiral
diols as additives can improve the enantioselectivity of proline catalyzed aldol
reactions, probably through their involvement
in the transition state, via the formation of a hydrogen bonding network.37a Miller et
al. showed the cooperative effect of a co-catalyst in a proline-catalyzed Baylis–
Hillmann reaction, where the proline and co-catalyst were proposed to interact in a
transition state assembly, in turn forming a catalytic system that was ‘‘greater than the
sum of its parts’’.38
Prolinecatalyzed direct aldol reactions have been shown experimentally and
computationally to proceed through enamine intermediates, in which the transition
state is highly stabilized by hydrogen bond donation from the carboxylic acid moiety
to the electrophile, with concurrent development of partial iminium and carboxylate
ions on the proline .39 Moreover, proline is known to exist as a zwitterion, forming a
-
170 highly insoluble network of hydrogen-bonded units. Omer Reis et.al40 reported a
proline–thiourea host–guest complex catalyze direct asymmetric aldol reactions of
various aromatic aldehydes (6) and cyclohexanone (10) in non-polar solvents giving
product (11) with high diastereo- and enantioselectivities (up to 94 : 6 dr and 499% ee)
(Scheme 4). O
proline:thiourea10:10
Hexane,rt+
O
Ar
OH
Ar H
O
6 10 11
Scheme 4
The development of enantioselective reactions in water was long thought to be
mainly confined to the realm of enzymes. The aldol condensation is a key carbon–
carbon bond forming reaction, which creates the β-hydroxy carbonyl structural unit
found in many natural products and drugs.42 In nature, type I and II aldolases catalyze
this reaction in water with perfect enantiocontrol through an enamine mechanism and
by using a zinc cofactor, respectively.43 A Zn-proline catalyzed aldol reaction occurs
in aqueous media with moderate enantiomeric excess.44 However, proline can catalyze
direct aldol reactions in polar organic solvents with high enantioselectivity,41,45 but it
affords the racemate in water.46 Although several chiral organocatalysts have been
developed for the aldol reaction,41,47 and some of them provide aldols
enantioselectively in aqueous organic solvents,48 they still require the use of an
organic solvent.49 It was found that only enzymes and antibodies of very high
molecularweight have been able to catalyze the direct aldol reaction in water with high
enantioselectivity.42,43 Yujiro et.al50 reported that 4-tert-butyldimethylsiloxyproline,
which is easily prepared from commercially available trans-4-hydroxyproline, is a
highly active proline surrogate and used as a catalyst to the asymmetric aldol reaction
of cyclohexanone (10) and benzaldehyde (2) in the presence of water and the anti-
aldol product (12) was obtained with excellent diastereoselectivity in a nearly optically
pure form (Scheme 5). The effectiveness of the siloxyproline catalysts compared to
proline and hydroxyproline can be attributed to the solubility of the catalysts.
Although proline and hydroxyproline dissolve in water, siloxyproline is only partially
soluble in water and forms an organic phase with the aldehyde andketone in which the
aldol reaction proceeds efficiently.
-
171
ONH
10 mol%
water,RT 18 h
synisomer
anti isomer
+H
OO OH
CHO2H
THBDPSO
+
10 2 12
Scheme 5
Evans,51 Heathcock,52 Masamune53 and Mukaiyama54 have established aldol
reaction as the principal chemical method for the stereoselective construction of
complex polyol architecture. Recently, studies by Barbas,55 Evans,56 List,57 Shair,58
Shibasaki,59 and Trost60 have outlined the first examples of enantioselective direct
aldol reactions, an important class of metal or proline catalyzed transformation that
does not require the pregeneration of enolates or enolate equivalents.With these
remarkable advances in place, a fundamental goal for asymmetric aldol technology has
become the development of catalytic methods that would allow the direct coupling of
aldehyde substrates.61 R. Ian Storer et.al 62 reported an asymmetric proline catalyzed
aldol reaction with a-thioacetal aldehydes (13). Thioacetal bearing aldehydes readily
participate as electrophilic cross-aldol partners with a broad range of aldehyde and
ketone (6, 5) donors. High levels of reaction efficiency as well as diastereo- and
enantiocontrol are observed in the production of anti-aldol adduct (14) (Scheme 6).
L-proline, DMF
slow addition of donorH
X
O
H
SR
SR
O
H
X SR
SR
O OH
+
6, 5 13 14
Scheme 6
Chemically, aldol reaction is dominated by approaches that utilize preformed enolate
equivalents in combination with a chiral catalyst.63Typically, a metal is involved in the
reaction mechanism.63d Most enzymes, however, use a fundamentally different
strategy and catalyze the direct aldolization of two unmodified carbonyl compounds.
Class I aldolases utilize an enamine based mechanism,64 while Class II aldolases
-
172 mediate this process by using a zinc cofactor.65 The development of aldolase
antibodies that use an enamine mechanism and accept hydrophobic organic substrates
has demonstrated the potential inherent in amine-catalyzed asymmetric aldol
reactions.66 Recently, the first small-molecule asymmetric class II aldolase mimics
have been described in the form of zinc, lanthanum, and barium complexes.67,68
Benjamin et al. 69 reported that the amino acid proline is an effective asymmetric
catalyst for the direct aldol reaction between unmodified acetone (15) and a variety of
aldehydes (6) affording aldol adduct (16) with 68% yield and 76% ee (Scheme 7).
20 vol%
DMSO
30 mol%
68 % (76% ee)
+
NH
COOH
O
NO2
O OH
NO2
O
15 6 16
Scheme 7
The Mukaiyama aldol reaction of silyl enol ethers with aldehydes catalyzed by
Lewis acid transition metals and main group elements chiral complexes is regarded as
the first efficient approach in the field of asymmetric aldol reaction.70 This strategy
involves a preliminary transformation of the ketone into a more active silyl enol ether,
whereas biocatalytic pathways based on aldol reactions between a ketone and an
aldehyde do not require this chemical activation. Considering a possible interaction
between Lewis acids, L-proline and the aldehyde generating a more activated catalytic
system has recently been described by Darbre and co-workers with a Zn (prolinate)2
complex prepared under basic conditions71a And by Mlynarski and co-workers with
bis(prolinamides)/zinc(II) complexes.71b Aldol reactions catalyzed by Zn(prolinate)2
were found to be moderately stereoselective (ee up to 56% and de up to 54%). Bis
(prolinamides)/zinc (II) complexes proved to be one of the more stereoselective
catalytic systems for direct aldol reactions. In both cases, the use of water as a
cosolvent is required in order to obtain a complete solubilization of the complex. The
enamine pathway in L-proline catalysis is analogous to the one observed in class I
aldolases and Lewis acid activation is similar to class II aldolases mechanism
involving a zinc (II) cofactor.
-
173
Lewis acid catalysis in the presence of water is not trivial, since most of them
are decomposed under aqueous conditions. Nevertheless, a few examples of water-
tolerant Lewis acids have previously been reported by Kobayashi et al.72 Furthermore,
Lewis acids in aqueous media are known to coordinate to a molecule of water to
generate metallo-hydroxonium species leading to a nearly neutral pKa value.73 In the
presence of ligands, those metallohydroxonium species are able to dissociate and
equilibrate with different ligand–metal complexes. Such dynamic behaviours are
observed in metallo-enzymes. Moreover, L-proline could activate the ketone via an
enamine intermediate and at the same time interact with various metal salts to activate
the aldehyde partner.Furthermore; the nature of the metal could have important effects
on both stereo- and chemical selectivities. Mael et.al 74 described chloride salts from
group 75 elements (ZnCl2, CdCl2, HgCl2) based on combinations of various water
compatible Lewis acids and L-proline co-catalysts has been evaluated for the direct
asymmetric aldol reaction of cyclohexanone (10) with various aromatic aldehydes (6)
with optimized catalytic conditions (catalytic system: L-proline: 20%/ZnCl2: 10%;
solvent mixture: DMSO/H2O, 8:2) gave anti aldol products (17) with improved
enantioselectivity (>99% ee) along with syn aldol products (18) compared to a
moderately stereoselective procedure based on proline activation only (Scheme 8).
O
NH
COOH
(20 %)
Lewis acid,DMSO/H2O
(8:2)R.T., 24 h
anti(1'R,2S) and (1'S,2R)
syn(1'R,2R) and (1'S,2S)
+O
NO2
OH
H
O
O2N
O
NO2
OH
+10
6
17
18 Scheme 8
The enantioselective aldol reaction with small organic molecules in an
aqueous medium had limited success until recently when Barbas76 and Hayashi77
independently reported efficient proline-derived chiral catalysts which catalyzed the
aldol reaction with high enantiocontrol in the presence of a large excess of water.78
-
174 Most of the studies have been done with 10 mol % catalyst loading except in one
example where Hayashi has shown that the catalyst loading can be reduced to 1 mol
%, but at the cost of a longer reaction time (2 days). Therefore, there is a great need
for efficient chiral organocatalysts, which can work at a lower loading without
affecting the enantioselectivity and the reaction time. The catalysts should also have a
wide substrate scope, with respect to both ketones and aldehydes. Vishnu et.al 79
reported that L-proline-derived organocatalysts iv and v (Scheme 9) are very effective
organocatalysts which catalyzed the direct aldol reaction of both acyclic and cyclic
ketones (5, 8) with different aldehydes (6) in an excess of water/brine affording aldol
product (19) with excellent enantioselectivities up to >99% and diastereoselectivities
up to 99% with very good yields were obtained by using much lower catalyst loadings
(0.5 mol %).
1 or 2 (0.5 mol%),brine,-5oC
iv: R= i-Buv: R= Ph
>99% ee
+
NH
NH
Ph
OHPh
O R
O
R2
O OH
R2 H
O
5, 8 6 19
Scheme 9
Direct catalytic and enantioselective aldol reactions of unmodified ketones or
aldehydes were reported by the research groups of Shibasaki,80 Trost,81 Jorgensen,82
MacMillan,83 List,84 Barbas III85 and Cordova86 using organometallic or purely
organic catalysts.Recent work has been attempted by using a recyclable ionic liquid as
the solvent,87 buffered aqueous media,88 Zn-proline complexes in aqueous media or
aqueous micelles.89 It is always economical if the catalytic reaction is performed in an
ecofriendly solvent, which allows both solvent and catalyst to recycle. S.
Chandrasekhar et.al90 described an efficient synthesis of chiral β-hydroxy ketones
from various aldehydes (6) and acetone (15) in poly (ethylene glycol)-400 catalysed
by L-proline giving aldol adduct (20) (Scheme 10). They studied the asymmetric aldol
reaction by using 4-nitrobezaldehyde, acetone and L-proline (10 mol %) in PEG-400.
The reaction was completed in 30 min and yielded 94% of product with 67% ee.
Enantiomeric excess was determined using chiralcel OB-H column. After workup
-
175 (extraction with ether) mother liquor (PEG+proline) was kept aside for further runs.
The transformation in conventional solvent (DMSO) took 4 h for completion of the
reaction. Several groups studied the mechanism of L-proline catalysed direct
asymmetric aldol reaction and proposed an enamine mechanism based on the Hajos–
Parrish–Eder–Sauer–Wiechert reaction mechanism.91
L-proline(10 mol%)acetone (4 eq.)
PEG,r.t.30 minO2N
H
O2N
OO OH
15
6 20 Scheme 10
Catalytic asymmetric aldol reactions of aldehydes with silyl enol ethers (the
Mukaiyama aldol reaction92) mediated by chiral Lewis acids have been elaborated into
the most powerful and efficient asymmetric aldol methodology. Tomoaki et al.93
reported catalytic asymmetric aldol reactions in aqueous media using Pr (OTf)3 and
chiral bis-pyridino-18-crown-6vi. The binding ability of the crown ether with the RE
cation and the catalytic activity of the complex are important for attaining high
selectivity in the asymmetric aldol reaction. Various aromatic and α, β-unsaturated
aldehydes (6) and silyl enol ethers (21) derived from ketones and a thioester can be
employed in the catalytic asymmetric aldol reactions using Pr (OTf)3 and vi, to
provide the aldol adducts (22) in good to high yields and stereoselectivities. In the
case using the silyl enol ether derived from the thioester, 2, 6-di-tert-butylpyridine
significantly improved the yields of the aldol adducts (Scheme 11).
-
176
vi.(24 mol%)Pr(OTf)320 mol%
H2O/EtOH=1/90oC,18 h
90% yieldsyn/anti=90/10
79% ee
+
NO
O
O
ON
PhPh
OOH
HPh
O OSiMe3
Ph
Scheme 11
Cordova et al., Amedjkouh andTeo et al. achieved excellent stereoselectivities
with other aminoacids too when the enantioselective aldol reactions were performed in
ionic liquids or DMSO in the presence of small amounts of water or in
water,respectively.97-101 In intramolecular aldol reaction phenyl- alanine was even
more efficient than proline.102, 103 Protonated arginine and lysine also performed well
in aldol reactions in IL.104 On the other hand,manyderivatives of proline were
developed and succcessfully applied in aldol reactions.94-96,105 Sadaf et al 106 reported
on IL-tagging of (S)-proline by 1, 2, 3- triazolium salts and the successful application
of these IL-tagged organo catalysts in direct aldol reactions of aromatic aldehydes (6)
with cyclic as well as open chain ketones (5, 8) giving aldol adduct (23) with high
diastereo- and enantioselectivities. The 1, 2, 3-triazolium tag substituents were limited
to unbranched alkyl groups (Scheme 12, viia, viib (R=alkyl)).
-
177
(20 mol% catalyst) viia, viib, viic
argon,rt
viia (R =H)viib (R =Me)
viic.
vii=viia,viib,viic
+
O
R1R3
R2
OH
R3
OO
R1 R2
NN
N
O
NH
OH
O
RO
O
BF4
NN
N
O
NH
OH
O
BF4N2H
O OH
Scheme 12
Direct asymmetric catalytic aldol reactions have been successfully performed
using aldehydes and unmodified ketones together with chiral cyclic secondary amines
as catalysts.107 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were
found to be the most powerful amino acid catalysts for the reaction of both acyclic and
cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the
corresponding aldol products with high regio-, diastereo-, and enantioselectivities.
Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the
major product with ee values up to >99%. The observed stereochemistry of the
products was explained by a metal-free Zimmerman-Traxler-type transition state and
involves an enamine intermediate.The reactions tolerate a small amount of water (
-
178 metabolite capable of being used as a catalyst (Scheme 13).109 Various aldehydes and
ketones including carbohydrate derivatives can be chosen as the substrates. It is
predicted that the synthetic method will get further attention as a prebiotic route to
sugar.110 Proline catalyzed Aldol reaction of nitrobenzaldehydes with various ketones
was investigated in aqueous anionic micelles. Satisfactory reaction yields were
obtained with SDS (sodium dodecylsulfonate), SDBS (sodium
dodecylbenzenesulfonate), and SLS (sodium laurylsulfate), all anionic surfactants.
Other surfactants such as Triton-100, CTAB (cetyltrimethylammonium bromide), and
OTAC (octadecyltrimethylammonium chloride), which are either neutral or cationic
surfactants, did not promote the reaction in aqueous media even with proline as
catalyst.11
(30 mol%)
phosphate buffer+
NO2
OHO
NO2
O
O
NH
5 6 24
Scheme 13
Tang et al.112 reported L-Prolinamides (viiia-viiid), prepared from L-proline
and simple aliphatic and aromatic amines which is a class of organic catalysts, (S)-
pyrrolidine-2-carboxamides (L-prolinamides) have been found to be active catalysts
for the direct aldol reaction of 4-nitrobenzaldehyde (6) with neat acetone (15) at room
temperature. They give aldol adduct (25) with moderate enantioselectivities of up to
46% enantiomeric excess (ee). The enantioselectivity increases as the amide NOH
becomes a better hydrogen bond donor (Scheme 14).
-
179
20 mol% viiia,viib, viic, viid
25oC
NH
O
NH2
NH
O
NHCH3
CH3CH3
NH
O
NH CH2
NH
O
NCH2CH3
CH2CH3
viii= a
b
c
d
+
OOH
OH
O
H2N6
15 25
Scheme 14
Wolfgang et al.113 reported enamine-based direct aldol reaction of α, α-
disubstituted aldehydes (26) with aryldehydes (6) by using diamine and trifluroacetic
acid as additives giving aldol products (27) in excellent yield and very high
enantiomeric excess (Scheme 15).
(5 mol%)
TFA(5 mol%)DMSO,rt
R= Me,Et,Pr X=NO2,CN,Br
OHO
RX
NH
N
OHC
X
H
O
R
+
26 6 27
Scheme 15
The direct aldol reaction avoids the pre- formation of silyl enol ethers.
Recently proline and chiral zinc-proline complexes have been described as an
enantioselective catalyst in organic synthesis especially in direct aldol addition of
acetone and a variety of aldehydes, 114 with formation of an iminium ion which is
converted to the corresponding enamine nucleophile,mimicking the class I
aldolases.The methods utilizing Lewis acids rely on the catalysis of metal complexes
bearing chiral ligands ,such as the heterobimetallic LaLi3tris(binaphthoxide) and the
-
180 Zn-BINOL homobimetallic catalysts developed by Shibasaki 115 as well as Trost’s Zn
III-semi crown ether.116 The reaction described above have been carried out under
anhydrous conditions in organic solvents and the metal complexes were reported to be
water sensitive. Tamis et al.117 tried to develop water soluble Lewis acids having
unprotected amino acids as chiral lihands and to investigate their activities as catalysts
for the direct aldol reaction. They reported the aldol reaction of acetone (15) and p-
nitrobenzaldehyde (6) catalyzed by a Zn-proline complex in the presence of water
giving aldol product (28) quantitative yields and enantiomeric excesses up to 56%
with 5 mol% of the catalyst at room temperature. The catalytic ability of Zn-proline
complexes bearing other amino acids such as lysine and arginine is also reported
(Scheme 16).
[(L)-Proline]2Zn5 mol%
H2O66 vol%
100% yield,56% ee33 vol%
+
NO2
OHO
NO2
H
O
O
15 6 28
Scheme 16
In this last chapter the aldol reactions of unmodified ketones with
aldehydes catalyzed by Cd-proline complex in the presence of water are reported
at room temperature.
5.2 RESULTS AND DISSCUSSION The aldol reactions of unmodified ketones (5) with aldehydes (6) catalyzed by
Cd-proline complex in the presence of water are reported (Scheme 17). At first,
several substituted benzaldehyde derivatives (6) with acetone (5b) were investigated
and aldol reaction products (29) have been isolated after simple extraction of the
reaction mixture.
-
181
+
R2
R
OHO
R
OCd(Pro)2
H2O R1
R1
CHOR2
5 6 29
a: R = CH3, R1 = CH3 a: R2 = NO2 a: R = CH3, R1 = H, R2 = NO2 b: R = CH3, R1 = H b: R2 = Cl b: R = CH3, R1 = H, R2 = Cl
c: R = R1 = (CH2)4 c: R2 = OCH3 c: R = CH3, R1 =CH3, R2 = NO2 d: R = CH3, R1 = CH3CO d: R2 = Br d: R = CH3, R1 = CH3, R2 = Cl e: R = CH3, R1 = PhCO e: R2 = H e: R = R1 = (CH2)4, R2 = NO2
f: R = CH3, R1 = CH3CO, R2 = NO2
g: R = CH3, R1 = CH3CO, R2 = Cl
h: R = CH3, R1 = PhCO, R2 = NO2
i: R = CH3, R1 = R2 = H
j: R = CH3, R1 = H, R2 = OCH3
k: R = CH3, R1 = H, R2 = Br
l: R = CH3, R1 =H, R2= 2-Cl (ortho Cl)
Scheme 17
Preliminary studies revealed that this aldol reaction was indeed possible to
provide the aldol adduct in 99% ee. Gratifyingly, the aldol union can be
comprehensively occurred involving both the enamine and enolate mechanism via the
slow addition of 4-Nitrobenzaldehyde (6a) to an excess of the acetone, (5b) ketone.
The results for some of the screening investigations for the enantioselective direct
aldol condensation of the unmodified ketones 5 and various aldehydes 6 catalyzed by
Cd-proline complex in the presence of water are presented in Table 1. The Cd-proline
complex was prepared by adding triethylamine to a mixture of proline (5 mmol) in
methanol (10 mL); cadmium acetate (2.5 mmol) was then added to the reaction
mixture after 10 min. After stirring for half an hour, a white precipitate was collected
by filtration. Thus various aldol products can be synthesized by using Cd-proline as
catalyst in water medium.
-
182 Table1. Aldol reaction of unmodified ketones and various aldehydes catalyzed by
Cd-proline complex
1 100
entry Product Reaction timea (h) Yieldb eec
24
NO2
OHO
2Cl
OHO
24 98
NO2
OHO
Me3 26 100
4
Cl
OHO
Me120 97
5
O
NO2
OH
240 75
6
Cl
OH
COMe
O
NO2
OH
COMe
O
NO2
OH
COPh
O
Br
OHOOMe
OHO
OHO
19285
7 168 82
8 120 92
9
10
11
> 99
83
88 65
8324
32
96 7263
65
> 99
56
58
72
48
12OHO Cl
24 95 85
> 99
-
183 The aldol addition product, 4-Hydroxy-4-nitrophenyl)-butan-2-one, (29a) was
prepared by stirring acetone (5 ml) with 4-nitrobenzaldehyde (1 m mol,0.1512 g) in
the presence of cadmium-proline complex (50 µ mol,0.016 g) in water (10 ml) at room
temperature for 24 hours with quantitative yield and 78% ee.The structure of (29a)
was assigned assigned by the presence of hydroxyl group band at 3292.60 cm-1, the
presence of aromatic C-H stretching band at 3100-3000 cm-1, the presence of carbony
stretching band at 1716 cm-1 , the presence of aromatic asymmetric and symmetric N-
O stretching band in the range of 1524-1360 cm-1 in its IR spectrum. It was further
confirmed by the presence of broad singlet at δ 3.70 due to O-H protons in its 1 H
NMR spectrum, presence of singlet at δ 2.22 due to the presence of 3H protons due to
methyl protons and also the presence of mutiplet signals at δ 2.90-2.81 due methylene
protons in its 1H NMR spectrum. It was further confirmed by its 13C NMR spectrum
due to the presence of carbon atoms at δ 208.55, 150.04, 147.28, 126.43, 123.76,
68.89, 51.51, 30.72. The enantiomeric excess was determined by using chiral HPLC
using chiral column-ChiraDex and found to be 80 % ee.
Fig.1. HPLC chromatogram of compound (29a)
-
184
When 4-Chlorobenzaldehyde (0.5 m mol, 0.07g) (6b) was made to stir with
acetone (5b) (5 ml) in the presence of Cadmium-proline catalyst (50 µmol,0.016 g) in
water medium (10 ml) for 24 hours at room temperature giving the aldol addition
product , 4-Hydroxy-4-(4- Chlorophenyl)-butan-2-one, (29b). The structure of
compound 29b was determined by the presence of hydroxyl band at 3338cm-1,
aromatic C-H band at 3011, 2901cm-1, also the band at 1716 due to the presence of
carbonyl and also at 1417-835 cm-1 due to aromatic asymmetric and symmetric N-O
stretching in its IR spectrum. Its structure was further assigned by its 1H NMR
spectrum due to the presence of multiplet signals due to methine protons at δ 5.15-5.12
and also by the presence of broad single signal at δ 3.40 due to –OH protons. The
compound, (29b) was further confirmed by its 13C NMR and Mass spectral data. Its
purity was also confirmed by HPLC using chiral column –Lichro Cart 250-4, Chira
Dex and optical rotation by measuring on an Autopol II, serial number 30415.
Fig.2. 1H NMR spectrum of compound (29b)
-
185
Fig.3. 13C NMR spectrum of compound (29b)
When 4-Nitrobenzaldehyde (0.0756g, 0.5 mmol) (6a) was made to stir with 2-
butanone (10 ml) (5a) in the presence of cadmium-proline complex (0.016g, 50µmol)
in water medium for 26 hours giving 4-Hydroxy-3-methyl-(4’Nitrophenyl)-butan-2-
one, (29c). Its structure was assigned by the presence of hydroxyl band at 3398cm-1,
the presence of aromatic C-H stretching band at 3112, 2923 cm-1, band at 1701cm-1
due to carbonyl stretching and also the band in the range of 1419-869 cm-1 due to the
presence of aromatic asymmetric and symmetric stretching due to N-H band in its IR
spectrum. The compound was further confirmed by its 1H NMR spectral data by
showing signals at δ 8.21, 7.51, 3.41, 2.22, 0.99 due to aromatic protons, -OH protons
and two methy protons. Its structure was further assingned by its 13C NMR, Mass
spectral data, optical rotation and also the purity of the compound was confirmed by
HPLC using chiral column –Lichro Cart 250-4, Chira Dex.
-
186
Fig.4. IR spectrum of compound (29c)
Fig.5. 1H NMR spectrum of compound (29c)
-
187
Fig.6. 13 C NMR spectrum of compound (29c)
The aldol addition product,4-Hydroxy-3-methyl-(4-Chlorophenyl)-butan-2-one
,(29d) was prepared by stirring 2-Butanone (5a) ( 5 ml) with 4-Chlorobenzaldehyde
(6b) (0.5 mmol, 0.07 g) in 10 ml of water medium for 120 hours .Its structure was
confirmed by its IR spectral data by showing bands at 3497 cm-1 due to –OH
stretching , 2974 cm-1 due to aromatic C-H stretching , the presence of carbonyl group
is shown by showing band at 1711 cm-1. The structure of compoung (29d) was further
confirmed by the presence of broad singlet at δ 3.24 due to –OH protons and two
singlets at δ 2.17 and δ1.07 due to the presence of two methyl protons in its 1H NMR
spectrum.Its structure was further confirmed by its 13C NMR and mass spectral data
and also the purity of the compound (29d) by HPLC by using chiral column –Lichro
Cart 250-4, Chira Dex.
-
188
Fig.7. IR spectrum of compound (29d)
Fig.8. 1H NMR spectrum of compound (29d)
-
189
Fig.9.NMR spectrum of compound (29d)
Similary , the aldol addition product , (29e), 2-((R-Hydroxy(4-
Nitrophenyl)methyl) cyclohexanone (5c) was prepared by reacting 4-
Nitrobenzaldehyde (6a) (0.5 mmol, 0.076g) with cyclohexanone (3 ml) in the presence
of cadmium-proline complex (50 µmol, 0.016g) in 6 ml of water for 240 hours at room
temperature . The compound (29e) was obtained as white crystalline solid and its
structure was assigned by the presence of hydroxyl group at 3506 cm-1, the presence of
aromatic C-H stretching at 2949 cm-1 and also the presence of carbonyl stretching at
1693 cm-1, the presence of aromatic asymmetric and symmetric C-N stretching band in
the range of 1344-800 cm-1 in its IR spectrum. Its structure was further confirmed by
its 1H NMR, 13C NMR and mass spectral data. The compound (29e) was further
purified by calculating the diastereomeric anti/syn ratio from its 1H NMR analysis of
the crude sample: δ 5.48(d, J=1.8 Hz, 1H, syn, minor), 4.89 (d, J=8.8Hz, 1H, anti,
major). Enantiomeric excess was determined by HPLC with a Chiralcel column (n-
hexane/i-PrOH 90/10, 1.0 mL/min, λ = 254 nm, 25oC); tR= 26.3 min (minor) and 34.9
min (major).
When 4-Nitrobenzaldehyde (6a) (0.5 mmol, 0.0756g) was reacted with
acethylacetone (5d) (5mL) in the presence of Cadmium-proline complex ( 50µmol,
0.016g) in 10 mL of water afforded the aldol addition product, 4-Hydroxy-3-Acetyl-
-
190 (4’Nitrophenyl)-butan-2-one, (29f). The compound (29f) was assigned by the presence
of hydroxyl group at 3500 cm-1, the presence of aromatic C-H stretching band at 2974,
2910 cm-1, the presence of carbonyl stretching band at 1695 cm-1 and also the presence
of aromatic asymmetric and symmetric N-O stretching band in the range of 1348 -798
cm-1 in its IR spectrum. Its structure was further assigned by the presence of a singlet
at δ 3.31 due to the presence of O-H protons and also presence of two singlets at δ1.76
and δ 1.22 due to the presence of two methyl protons in its 1H NMR spectrum. Its
structure was further assigned by its 13C NMR and mass spectral data. Its purity was
also confirmed by HPLC using chiral column –Lichro Cart 250-4, Chira Dex and
optical rotation by measuring on an Autopol II, serial number 30415.
Similarly, all other aldol addition compounds from (29f-29l) were prepared
and their structures were confirmed by their IR, 1H NMR, 13C NMR, Mass spectral
data and HPLC by using chiral column.The 4-chlorobenzaldehyde (entries 2, 4 and 7)
aldol reaction products with different ketones were found to obtain in 82-98% yields
but lower enantioselectivities (50-72% ee) compared to that of 4-nitrobenzaldehyde
(except entry 8). The benzaldehyde (entry 9) aldol reaction product with acetone was
obtained in 83% yield and 78% ee which was found to be of better reaction as
compared with the literature.118 We are also able to improve the yield and
enantioselectivity by using the Cd-proline complex for the asymmetric aldol reaction
of p-anisaldehyde with acetone (entry 9) compared to results obtained by using ionic
liquid.119 However, we could not improve the enantioselectivity of the aldol products
(entries 7 and 8), although the yields are relatively high. Thus a variety of substituted
benzaldehydes (6) and unmodified ketones (5) were employed and aldol products (29)
were in good yields (72-100%) and reasonable enantioselectivities (48-83% ee).
-
191
Fig.10. IR spectrum of compound (29l)
Fig11. 1H NMR spectra of compound (29l)
-
192
Fig.12. 13C NMR spectrum of compound (29l)
The mechanistic paths for the Cd-proline catalysis may be assumed to occur
through both enamine and enolate type mechanisms ((Scheme 18).120
N
OO
Cd
H
2+
OO
NH
N
OO
Cd
H
2+
OO
NH
ON
OO
Cd 2+
OO
NH
O
O
Cd 2+
OO
NH
N
O
OH
O
Cd 2+
OO
NH
N
O
OH2
RCHO
si- Facial attack
O
Cd 2+
OO
NH
N
O
OH
R
OH
N
OO
Cd
H
2+
OO
NHR
OHO
+
O
Cd 2+
OO
NH
OHN
O
HO
RH
Scheme 18
-
193
5.3 Experimental 5.3.1 General
Organic solutions were concentrated under reduced pressure on a Buchi rotary
evaporator. Chromatographic purification of products was accomplished using column
chromatography using silica gel 60-120 mesh size. Thin-layer chromatography (TLC)
was performed on glass Plates using silica gel –G. Visualization of the developed
chromatograms was performed by ultraviolet irradiation (254 nm) or stained using
iodine vapours, alkaline potassium permanganate solution or 2, 4-
dinitrophenylhydrazine solution. The IR spectra were recorded as KBr pellets on FT–
IR Shimazdu IR-408 spectrometer. Absorption maxima were recorded in wave
numbers (cm-1). 1H NMR spectra were recorded on Bruker AC-400 spectrometers.
Residual non-deuterated solvent was used as an internal reference and all chemical
shifts (δ H and δ C) are quoted in parts per million (ppm) downfield from
tetramethylsilane (TMS). Mass spectra were recorded on a Kratas concept-IS mass
spectrometer couples to a Mach 3 data system, or on a Jeol-D 300 mass
spectrometer.Chemical shifts (δ) are given in parts per million (ppm), and coupling
constants (J) are given in Hertz (Hz). The proton spectra are reported as follows:
chemical shift (d/ppm) multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
p=pentet, sept=septet, m=multiplet), coupling constant (J/Hz), number of protons,
assignment).13C NMR spectra were recorded in CDCl3 at ambient temperature on
Bruker AC-100MHz spectrometer at 75 MHz, with the central peak of CHCl3 as 13
the internal reference (dC=77.3 ppm). Data for 13C NMR are reported in terms of
chemical shift. Where a compound has been characterized as an inseparable mixture of
diastereoisomers, the NMR data for the major isomer has been reported. Optical
rotations were measured on an Autopol II, serial number 30415, manufactured by
Rudolph Research Analytical, Automatic Polarimeter equipped with a Sodium lamp
(589 nm) and a 10 cm microcell. The purity of compounds were performed by reverse
phase HPLC (Merck Hitachi) using C-18 column and a UV Detector L-2400, pump L-
2130 (Merck). Compounds prepared and used subsequently without further
purification were judged to be of suitable purity by NMR analysis. The mobile phase
used for HPLC was a mixture of Methanol: Water in the ratio of 40:60 at oven
temperature 20oC.The working flow rate was 0.8 ml/min.High performance liquid
chromatography (HPLC) was also performed on Hewlett-Packard 1100 Series
chromatographs using a Chiralcel AD column (25 cm) and AD guard (5 cm), a
-
194 Chiralcel OJ column (25 cm) and OJ guard (5 cm), a Chiralcel AS column (25 cm)
and AS guard (5 cm), or a Chiralcel ODH column (25 cm) and ODH guard (5 cm) as
noted. Syringe pump additions were made using a 10 syringe parallel pump (in all
cases the syringe needle tip was submerged below the surface of the liquid in the
receiver vessel to ensure continuous mixing).
All the commercial chemicals were distilled before used.
5.3.2 Synthesis of Cd-proline complex The Cd-proline complex was prepared by adding triethylamine (0.7 mL) to a
mixture of L-proline (0.58g, 5 mmol) in methanol (10mL), followed after 10 min by
cadmium acetate (0.67g,2.5 mmol).After stirring for 45 minutes a white precipitate
was collected by filtration.The complex was thus obtained as a white amorphous
compound. The presence of –OH stretching band is shown at 3265.59 cm-1 and also
bands at 3198.08 cm-1,2960.83 cm-1 due to C-H stretching and the presence of
carboxylate ion is shown by the presebce of strong bant at 1566.25 cm-1 and weak
band at 1431.23 cm-1 in its IR specrtrum. The presence of N-H proton is shown by the
presence of singlet at δ 2.758 and also the preence of CH2 protons at δ 3.72-3.69, δ
3.04-3.02, 2.14-2.09, 1.71-1.59, 1.64-4.46 in its 1H NMR spectrum. It was further
confirmed by the presence of peaks at δ 25.69, 30.12, 47.82, 60.66 due to carbon
atoms in its 13C NMR spectrum.
5.3.3 Synthesis of 4-Hydroxy-4- nitrophenyl)-butan-2-one, 29a Yellow liquid.Yield = 100%. IR (KBr, cm-1): 3580, 3292, 3100-3000, 1716,
1523-858. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=7.0 Hz, 2H, Ar-H), 7.52 (d,
J=7.0 Hz, 2H, Ar-H), 5.28-5.22 (m, 1H, -CH-OH), 3.70 (br, s, 1H, -OH), 2.90-2.81
(m, 2H, -CH2CO), 2.22 (s, 3H,-COCH3): 13 C NMR: (75MHz, CDCl3): δ 208.55,
150.04, 147.28, 126.43, 123.75, 68.89, 51.51, 30.72; Mass (EI): m/z 209 (M+), 43 ;
Optical rotation = -0.010 which was measured on an Autopol II,serial number
30415,manufactured by Rudolph Research Analytical , Hackettstown , NJ , USA.
Enantiomeric excess : > 99% , which was determined by HPLC analysis using Lichro
Cart 250-4 Chira dex column ( methanol/water 40/60) UV-VIS 254 nm , flow rate 0.8
mL/min: major isomer, tR 9.46 min and minor isomer ,tR 11.25 min.
5.3.4 Synthesis of 4-Hydroxy-4-(4- Chlorophenyl)-butan-2-one, 29b Colourless liquid.Yield = 98%. IR (KBr, cm-1): 3338, 3011, 2901, 1716, 1417-
835; 1H NMR ( 300 MHz, CDCl3) : δ 7.333 (dd, 1H, Ar-H), 7.278 (dd, 1H, Ar-H),
5.14-5.12 ( m, 1H, -CHOH ), 3.403 (br, s, 1H, -OH), 2.83-2.78 ( m, 2H,-CH2CO ),
-
195 2.20 (s, 3H,-COCH3) ; 13 C NMR (75 MHz, CDCl3) : δ 209.18, 141.33,133.53, 128.87
, 127.21 , 69.35 , 51.97 , 30.95; Mass (EI) : m/z 198 (M+), 43: Optical rotation
measured at 589 nm = -0.010 which was which was measured on an Autopol II , serial
number 30415 , manufactured by Rudolph Research.
5.3.5 Synthesis of 4-Hydroxy-3-methyl-(4-Nitrophenyl)-butan-2-one,
29c White crystalline solid compound.Yield = 100 % ; IR (KBr, cm-1): 3398,
3113, 2924, 1701and 1342-869; 1H NMR ( 300 MHz , CDCl3 ) : δ 8.21 ( d, J=8.3 Hz,
2H) , 7.51 ( d, J= 8.3 Hz , 2H ), 4.87-4.84 ( m, anti-0.72 H), 3.41 (d, J=4.8 Hz, 1H),
2.93-2.86 ( m, 1H), 2.05 (s, 3H), 0.98 (d, J=7.4 Hz, 3H): 13C NMR ( 75 MHz, CDCl3) :
δ 213.09, 127.65, 123.82, 149.47, 147.67, 53.43, 30.28, 14.22; ee = 83%. (anti), the ee
value of compound 29c was determined by HPLC analysis using a DIACEL
CHIRALPAK AS Column ( hexane / i-PrOH , 90:10 , λmax 280 nm , flow rate=2.0
mL/ min), tR=16.2 min (minor) and 22.4 min (major). Due to the small amount of the
syn , the enantiomeric excess could not be determined.
5.3.6 Synthesis of 4-Hydroxy-3-methyl-(4-Chlorophenyl)-butan-2-one,
29d Colourless liquid.Yield = 97%. IR (KBr, cm-1): 3496, 2974, 2933, 1710, 1355-
825. 1H NMR ( 300 MHz, CDCl3) : δ 7.83- 7.21 ( m , 5 H , Ar-H ) , 5.14- 5.09 ( m ,1H
,-CH-OH ), 3.24 ( br , s, -OH ) , 2.82-2.75 ( m, 1H , -CH-CO ) , 2.12 ( s , 3H , CH3CO
) , 1.07 ( m , 3H , CH3CH ) ; 13C NMR ( 75 MHz , CDCl3) :δ 213.60 , 190.95 , 141.35
, 1330.01-127.03 , 72.17 , 69.30 , 52.89 , 36.85 , 29.35 , 9.89 ; ee = > 99 % . The
enantiomeric excess was determined by HPLC using chiral column –Lichro Cart 250-
4, Chira Dex. ( Methanol / Water , 40 : 60 , λmax 254 nm , flow rate = 0.8 ml/min ) , tR
= 3.99 min ( major ) and minor very small peak negligible.
5.3.7 Synthesis of 2-(R-Hydroxy (4-Nitrophenyl) methyl)
cyclohexanone, 29e White amorphous solid compound.Yield = 75 %. ; mp = 129-130 oC; IR (KBr,
cm -1): 3506, 2948, 1693, 1344-856. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=8.6 Hz,
2H), 7.50(d, J=8.7 Hz, 2H), 4.89 (dd, J=8.4 Hz, 1H), 4.04 (s, 1H), 2.63-2.33 (m, 2H),
2.12-1.36 (m, 6H). 13C NMR ( 75 MHz, CDCl3): δ 214.8, 148.4, 147.6, 127.9, 123.5,
74.0, 57.2, 42.7, 30.8, 27.7, 24.7 ppm The diastereomeric anti/syn ratio was
determined by 1H NMR analysis of the crude product : δ 5.48 ( d, J=1.8 Hz, 1H, syn,
-
196 minor), 4.89 ( d, J=8.8 Hz, 1H, anti, major ). Enantiomeric excess was determined by
HPLC with a Chiracel AD column (n-hexane/ i-PrOH 90/10, 1.0 mL/min, λ = 254 nm,
25oC): tR =26.3 min (minor) and 34.9 min (major). Optical rotation= - 0.012 which
was measured at λ= 589 nm on an Autopol II, serial number 30415, manufactured by
Rudolph Research Analytical, Hackettstown.
5.3.8 Synthesis of 4-Hydroxy-3-Acetyl-(4-Nitrophenyl)-butan-2-one,
29f White amorphous solid compound.Yield = 85 %. IR (KBr, cm-1):3500, 2974,
2910, 1695.31, 1348– 798; 1H NMR (300 MHz, CDCl3):δ 8.20 ( d , J= 7.0 Hz, 2H, Ar-
H), 7.48(d, J= 7.0 Hz, 2H, Ar-H ), 4.302 -4.135 ( m , 1H , CH-Ph), 3.340- 3.256 ( m,
1H, -OH), 2.85-2.77( d, 1H, -CH-CO), 1.75( s, 3H, CH3), 1.254(s, 3H, CH3); 13C
NMR(75 MHz , CDCl3): δ 214.43, 209.38, 151.99, 128.99-124.42, 108.93, 69.24,
63.23, 44.31, 34.95, 27.05; ee = 58% which was determined by chiral HPLC using
Chira dex column.
5.3.9 Synthesis of 4-Hydroxy-3-Acetyl-(4-Chlorophenyl)-butan-2-one,
29g White amorphous solid compound.Yield = 82 %. IR ( KBr, cm-1 ): 3412, 2972,
1718, 1695; 1H NMR(300 MHz, CDCl3): δ 7.32 - 7.24( m, 3H, Ar-H); 7.18(dd, 1H,
Ar-H); δ 7.09(dd, 1 H, Ar-H), 4.09-3.86 (m, 1H, -CH-Ph ), 3.45(s, 1H, -OH), 2.8 -
2.43(m, 1H, -CHCO), 1.67(m,3H,CH3), 1.39 (m, 3H, CH3): 13C NMR(75 MHz,
CDCl3): δ 215.53, 203.56, 179.27, 142.59, 136.91 -128.99, 73.88, 69.20, 63.35, 53.61,
44.14, 34.58, 30.65, 27.84. ee=72 %; The enantiomeric excess was determined by
HPLC using chiral column –Lichro Cart 250-4, Chira Dex. (Methanol/Water, 40:60,
λmax 254 nm, flow rate = 0.8 ml/min), tR = 2.23 min (major) and tR= 4.01 min (minor).
5.3.10 Synthesis of 4-Hydroxy-3-Benzoyl-(4-Nitrophenyl)-butan-2-
one, 29h White amorphous solid compoundYield = 92 %. IR (KBr, cm-1): 3439, 3049,
1678, 1659, 1234-914; 1H NMR (300 MHz, CDCl3): δ 8.10(d, J= 6.7 Hz, 2H, Ar-H),
7.90(dd, J=7.0 Hz, 2H, Ar-H), δ 7.59 -7.45 (m, 5H, Ar-H), δ 2.41(s, 3H, CH3), δ
1.61(s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 196.98, 195.08, 148.21, 142.67,
139.20, 137.71, 135.44, 134.77, 130.65, 129.24, 129.24, 129.17, 123.95, 27.65; ee
=>99 %. The enantiomeric excess was determined by HPLC using chiral column –
-
197 Lichro Cart 250-4, Chira Dex. (Methanol/Water, 40:60, λ = 254 nm, flow rate=0.8
ml/min), tR= 3.98 min (major) associated with a very small negligible peak for minor.
5.3.11 Synthesis of (4R)-Hydroxy-4-phenyl-butan-2-one, 29i Colourless oil.Yield = 83%. 1H NMR (300 MHz, CDCl3): d 7.33–7.17(m, 5H,
Ar-H), 5.15–5.04 (m, 1H, –CHOH), 3.17 (br s, 1 H,–OH), 2.80–2.75 (m, 2H, –
CH2CO), 2.17 (s, 3H, –COCH3); Mass(EI): m/z 164(MC), 43; IR(neat): 3413, 2932,
1718, 1450, 890cm K1; [a]D25 C60.0 (c 1, CHCl3) for 83% ee [lit.value].
5.3.12 Synthesis of (4R)-Hydroxy-4-(4-methoxyphenyl)-butan-2-one,
29j Colourless oil.Yield = 88%; 1H NMR (300 MHz, CDCl3): d 7.27 (d, J=8.8 Hz,
2H, Ar-H), 6.88 (d, J=8.8 Hz, 2H, Ar-H), 5.10 (dd, J=9.0, 3.3 Hz, 1H, –CHOH), 3.80
(s, 3H,–OCH3), 3.22 (br s, 1H, –OH), 2.86–2.78 (m, 2H,–CH2CO), 2.19 (s, 3H, –
COCH3); Mass (EI): m/z 194 (MC), 43; IR (neat): 3424, 2917, 1730, 1450, 1100, 1070
cmK1; ee = 65%. The enantiomeric excess was determined by HPLC using chiral
column –Lichro Cart 250-4, Chira Dex. (Methanol / Water, 50:50, λ = 254 nm, flow
rate = 0.8 ml/min).
5.3.13 Synthesis of (4R)-Hydroxy-4-(4-bromophenyl)-butan-2-one,
29k Colourless oil.Yield = 72 %. 1H NMR (300 MHz, CDCl3): d 7.47(d, J=8.4 Hz,
2H, Ar-H), 7.22 (d, J=8.4 Hz, 2H, Ar-H),5.08 (dd, J=5.6, 7.8 Hz, 1H, –CHOH), 3.38
(br s, 1H,–OH), 2.80–2.70 (m, 2H, –CH2CO), 2.20 (s, 3H, –COCH3); Mass (EI): m/z
243 (MC), 43; IR (neat): 3418, 2934, 1713,1489, 1369, 1077, 538 cmK1; [α] 25D C53.3
(c 1, CHCl3) for 90% ee [lit. value]. Enantiomeric excess: 63%. The enantiomeric
excess was determined by HPLC using chiral column –Lichro Cart 250-4, Chira Dex.
(Methanol / Water, 50:50, λ = 254 nm, flow rate = 0.8 ml/min), (compared with the
literature value).
5.3.14 Synthesis of (4R)-Hydroxy-4-(2-Chlorophenyl)-butan-2-one,
29l Colourless oil.Yield = 95%. IR (KBr, cm-1): 3492, 3064, 2916, and 1708,
1429-948. 1H NMR ( 300 MHz, CDCl3): δ 7.61 (d, J=8.6 Hz, 1H, Ar-H), 7.32–7.19
(m, 3H, Ar-H), 5.49 (d, J=10.4 Hz, 1H, -CH-OH ), 3.64 (s,1H, -OH ), 2.71-2.65 (m,
1H, -CH2OH ), 2.21 (s, 3H, -COCH3); 13C NMR (75 MHz, CDCl3): δ 209.31, 140.08,
131.08,129.38-127.05, 66.56, 50.01, 50.61.[α] 25D = + 97.0 (c 1,CHCl3) for 85% ee [lit
-
198 value].ee., which was determined by optical rotation ( compared with the literature
value ).
5.4 Conclusion In summary, we have concluded an enantioselective direct aldol reaction which
enables flexible design of asymmetric chiral organometallic catalyst- Cadmium-
proline complex based on proline architectures, prepared by reacting L-proline ( 0.58
g, 5 mmol ) with cadmium-acetate ( 0.67g, 2.5 mmol) in the presence of triethylamine
( 0.7 mL ) in methanol ( 10 mL ) for 45 minutes at room temperature. This catalyst
was found to promote the aldol reactions of unmodified ketones with various
aldehydes in water medium, giving aldol products in excellent yield and ee. Since this
kind of reaction is easily carried out in water, it is notable that the reaction is
developed on the basis of Green Chemistry protocol. Green Chemistry that possesses
the spirit of sustainable development was booming in the 1990s, 1and has attracted
more and more interest in the 21st century. Large amounts of organic solvents are used
in chemical processes, many of which are volatile, flammable, and toxic. The use of
non-hazardous and renewable materials is one of the most important goals of Green
Chemistry. With the increasing concerns about the environmental protection;
development of direct aldol reaction in aqueous media through a Green Chemistry
procedure is desirable.
The Cadmium-proline-catalyzed asymmetric aldol reaction was proposed to
proceed in the enamine mechanism, where imine functionality converts the aldol
donor to enamine, whereas the carboxylic acid group provides a hydrogen bond to the
acceptor.121 The enamine attacks the carbonyl group of aldehyde to generate the
transition state, whose stereochemistry is stabilized by the chiral carboxyl and leads to
an enantioselectivity. In the reaction of acetone with 4-nitrobenzaldehyde in aqueous
media, the reactions with Cadmium-proline typically lead to S-aldol, whereas the
reaction with L-proline provides R-aldol product. Hence, direct aldolization process
using water soluble chiral asymmetric catalyst, Cadmium-proline complex were found
to be atom economic, and thus they serve as attractive approaches for the synthesis of
versatile β-hydroxy carbonyl compounds.
5.5 References:
-
199 1. Kane, R. Ann. Phys. Chem., Ser. 2 1838, 44, 475; (b) Wurtz, A. Bull. Soc. Chim.
Fr. 1872, 17, 436–442.
2. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004;
Vols. 1–2.
3. Trost, B. M. Science 1991, 254, 1471–1477; (b) Sheldon,R. A. Pure Appl.
Chem. 2000, 72, 1233–1246; (c) Trost, B.M. Acc. Chem. Res. 2002, 35, 695–
705; (d) Guillena, G.;Ramo n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46,
2358–2364.
4. For recent reviews, see: (a) Silvestri, M. G.; Desantis, G.; Mitchell, M.; Wong,
C.-H. Top. Stereochem. 2003, 23, 267–342; (b) Sukumaran, J.; Hanefeld, U.
Chem. Soc. Rev. 2005,34, 530–542; (c) Samland, A. K.; Sprenger, G. A.
Appl.Microbiol. Biotechnol. 2006, 71, 253–264.
5. Reymond, J.-L. J. Mol. Catal. B: Enzym.1998, 5, 331–337; (b) Hertweck, C. J.
Prakt. Chem. 2000, 342, 832–835;(c) Zhu, X.; Tanaka, F.; Hu, Y.; Heine, A.;
Fuller, R.;Zhong, G.; Olson, A. J.; Lerner, R. A.; Barbas, C. F., III;Wilson, I. A.
J. Mol. Biol. 2004, 343, 1269–1280.
6. See for example: Carreira, E. M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3,
pp 997–1065.
7. Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595–1601; (b) Alcaide,
B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858–860.
8. For reviews covering different aspects of enantioselective organocatalytic
reactions, see: (a) Dalko, P. I.; Moisan, L.Angew. Chem., Int. Ed. 2001, 40,
3726–3748; (b) Jarvo, E.R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495; (c)
Berkessel, A. Curr. Opin. Chem. Biol. 2003, 7, 409–419; (d) Gro ger, H.;
Wilken, J.; Berkessel, A. In Organic Synthesis Highlights V; Wiley-VCH:
Weinheim, 2003; pp 178–186; (e)Schreiner, P. R. Chem. Soc. Rev. 2003, 32,
289–296; (f)Oestreich, M. Nachr. Chem. 2004, 52, 35–38; (g) Pihko, P.M.
Angew. Chem., Int. Ed. 2004, 43, 2062–2064; (h) Miller,S. J. Acc. Chem. Res.
2004, 37, 601–610; (i) Bolm, C.;Rantanen, T.; Schiffers, I.; Zani, L. Angew.
Chem., Int. Ed.2005, 44, 1758–1763; (j) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis—From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005; (k) Palomo, C.; Mielgo, A. Angew.
Chem., Int.Ed. 2006, 45, 7876–7880; (l) Taylor, M. S.; Jacobsen, E. N.Angew.
-
200
Chem., Int. Ed. 2006, 45, 1520–1543; (m) Lelais, G.; MacMillan, D. W. C.
Aldrichim. Acta 2006, 39, 79–87; (n)Marcelli, T.; van Maarseveen, J. H.;
Hiemstra, H. Angew.Chem., Int. Ed. 2006, 45, 7496–7504; (o) Marigo,
M.;Jorgensen, K. A. Chem. Commun. 2006, 2001–2011; (p)Guillena, G.;
Ramon, D. J. Tetrahedron: Asymmetry 2006,17, 1465–1492; (q) Gaunt, M. J.;
Johansson, C. C. C.;McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8–
27; (r) Rueping, M. Nachr. Chem. 2007, 55, 35–37; (s) Enders, D.; Grondal, C.;
Hu ttl, R. M. Angew. Chem., Int.Ed. 2007, 46, 1570–1581; (t) Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; (u)
Guillena,G.; Ramo´ n, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693–
700; (v) Pellissier, H. Tetrahedron 2007, 63,9267–9331.
9. For recent reviews on enantioselective aldol reaction, see: (a) Nelson, S.
G.Tetrahedron: Asymmetry 1998, 9, 357–389; (b) Groger, H.; Vogl, E. M.;
Shibasaki,M. Chem. Eur. J. 1998, 4, 1137–1141; (c) Mahrwald, R. Chem. Rev.
1999, 99,1095–1120; (d) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int.
Ed. 2000, 39, 1352–1374; (e) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem.
Soc. Rev. 2004, 33,65–75.
10. For reviews on direct aldol reaction, see: (a) Alcaide, B.; Almendros, P. Eur.
J.Org. Chem. 2002, 1595–1601; (b) Saito, S.; Yamamoto, H. Acc. Chem. Res.
2004,37, 570–579; (c) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron:
Asymmetry 2007, 18, 2249–2293.
11. Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem.,
Int.Ed. 1997, 36, 1871–1873; (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev.
2002, 102, 2187–2210; (c) Shibasaki, M.; Matsunaga, S. Chem. Soc. Rev. 2006,
35, 269–279.
12. For related catalyses, see: (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000,
122,12003–12004; (b) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto,
S.;Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetrahedron Lett. 2001, 42, 4669–
4671.
13. List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396;
(b)Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580–591;
(c)Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471–5569.
-
201 14. For related catalyses, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983–1986; (b) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808–1809;
(c) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem., Int. Ed. 2005,
44, 3055–3057.
15. Although the substrates are limited to glycine Schiff bases, the aldol reactions
promoted by phase transfer catalysts have been reported, see: Ooi, T.;
Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41,
4542–4544.
16. Shunsuke Kotani, Yasushi Shimoda, Masaharu Sugiura, Makoto Nakajima,
Tetrahedron Lett. 50,2009,4602-4605.
17. Although adding tetrachlorosilane to the mixture of the other components gave
the same results, adding a ketone to the mixture decreased the stereoselectivities.
18. W.-D. Fessner, in Stereoselective Biocatalysis; R. N. Patel, Ed.;Marcel Dekker,
New York, 2000, p. 239; (b) T. D. Machajewski and C.-H. Wong, Angew.
Chem., Int. Ed., 2000, 39, 1352.
19. Comprehensive Organic Synthesis, Vol. 2, B. M. Trost, I. Fleming, C.-
H.Heathcock, Eds.; Pergamon, Oxford, 1991.
20. For examples of application in total synthesis see: (a) T.Mukaiyama, Angew.
Chem., Int. Ed., 2004, 43, 5590; (b) K. C. Nicolaou,D. Vourloumis, N.
Winssinger and P. S. Baran, Angew. Chem., Int.Ed., 2000, 39, 44.
21. Modern Aldol Reactions, Vol. 1 & 2, R. Mahrwald, Ed.; Wiley-VCH,Weinheim,
2004; E. M. Carreira, in Comprehensive Asymmetric Catalysis; E. N. Jacobsen,
A. Pfaltz, H. Yamamoto, Eds.; Springer,Heidelberg, 1999; J. S. Johnson and D.
A. Evans, Acc. Chem. Res.,2000, 33, 325.
22. K. Mikami and S. Matsukawa, J. Am. Chem. Soc., 1994, 116, 4077; (b) G. E.
Keck, X.-Y. Li and D. Krishnamurthy, J. Org. Chem., 1995,60, 5998; (c) D. A.
Evans, D. M. Fitch, T. E. Smith and V. J. Cee,J. Am. Chem. Soc., 2000, 122,
10033; (d) K. Juhl, N. Gathergood and K. A. Jørgensen, Chem. Commun., 2000,
2211; (e) E. M. Carreira,R. A. Singer and W. S. Lee, J. Am. Chem. Soc., 1994,
116, 8837; (f)H. Ishita, Y. Yamashita, H. Shimizu and S. Kobayashi, J. Am.
Chem.Soc., 2000, 122, 5403; (g) S. E. Denmark and R. A. Stavanger, J.
Am.Chem. Soc., 2000, 122, 8837; (h) N. Kumagai, S. Matsunaga,T. Kinoshita, S.
Harada, S. Okada, S. Sakamoto, K. Yamaguchi and M. Shibasaki, J. Am. Chem.
-
202
Soc., 2003, 125, 2169; (i) B.M. Trost, H. Ito and E. R. Silcoff, J. Am. Chem.
Soc., 2001, 123, 3367; (j) Y. M. A.Yamada, N. Yoshikawa, H. Sasai and M.
Shibasaki, Angew. Chem.,Int. Ed., 1997, 36, 1871; (k) D. A. Evans, C. W.
Downey and J. L. Hubbs, J. Am. Chem. Soc., 2003, 125, 8706.
23. R. Schoevaart, F. Van Rantwijk and R. A. Sheldon, J. Org. Chem.,2000, 65,
6940; H. J. M. Gijsen, L. Qiao, W. Fitz and C.-H Wong,Chem. Rev., 1996, 96,
443.
24. Reviews see: P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138;
B. List, Tetrahedron, 2002, 58, 5573.
25. For the proline-catalyzed intermolecular aldol reaction see: (a) Z. G. Hajos and
D. R. Parrish, J. Org. Chem., 1974, 39, 1615; (b) U. Eder, R. Sauer and R.
Wiechert, Angew. Chem., Int. Ed., 1971, 10,496; (c)C. Pidathala, L. Hoang, N.
Vignola and B. List, Angew. Chem., Int. Ed., 2003, 42, 2785. For the
stoichiometric use of phenylalanine and tyrosine to mediate asymmetric
intermolecular aldol condensations see:(d) S. Danishefsky and P. Cain, J. Am.
Chem. Soc., 1975, 97, 5282; (e) I. Shimizu, Y. Naito and J. Tsuji, Tetrahedron
Lett., 1980, 21, 4975; (f)H. Hagiwara and H. Uda, J. Org. Chem., 1988, 53,
2308; (g) E. J. Corey and S. C. Virgil, J. Am. Chem. Soc., 1990, 112, 6429.
26. B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc., 2000,122, 2395;
(b)W. Notz and B. List, J. Am. Chem. Soc., 2000, 122, 7386;(c) K. S.
Sakthivel,W. Notz, T. Bui and C. F. Barbas, III, J. Am. Chem.Soc., 2001, 123,
5260; (d) B. List, P. Porjarliev and C. Castello, Org.Lett., 2001, 3, 573; (e) A.
Cordova, W. Notz and C. F. Barbas, III,Chem. Commun., 2002, 3024; (f) A.
Cordova, W.Notz and C. F. Barbas,III, J. Org. Chem., 2002,67, 301; (g) A. B.
Northrup and D. W. C.MacMillan, J. Am. Chem. Soc., 2002, 124, 6798; (h) A.
Bøgevig,N. Kumaragurubaran and K. A. Jørgensen, Chem. Commun., 2002,620;
S. Saito, M. Nakadai and H. Yamamoto, Tetrahedron, 2002, 58,8167; (i) Z.
Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang and Y.-D.
Wu, J. Am. Chem. Soc., 2003, 125, 5262; (j)H. Torii, M. Nakadai, K. Ishihara, S.
Saito and H. Yamamoto, Angew.Chem., Int. Ed., 2004, 43, 1983; (k) A. Hartikaa
and P. I. Arvidsson,Tetrahedron: Asymmetry, 2004, 15, 1831; (l) A. Berkessel,
B. Koch and J. Lex, Adv. Synth. Catal., 2004, 346, 1141; (m) A. J. A.
Cobb,D.M. Shaw, D. A.Longbottom, J.B.Gold and S. V.Ley, Org.
Biomol.Chem., 2005, 3, 84.
-
203 27. Armando Cordova, Weibiao Zou, Ismail Ibrahem, Efraim Reyes, Magnus
Engqvist and Wei-Wei Liao, Chem. Commun.,2005,3586-3588.
28. Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew.Chem., Int. Ed. 2005, 44,
3055.Kano, T.; Tokuda, O.; Maruoka, K. Tetrahedron Lett.2006, 47, 7423.
29. Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2006, 128,734.(b) Hayashi, Y.; Sumiya, T.; Takahashi, J.;
Gotoh, H.;Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, (c) Chimni,
S. S.; Mahajan, D.; Babu, V. V. S. TetrahedronLett. 2005, 46, 5617 (d) Chen, J.-
R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.;Xiao, W.-J. Org. Lett. 2005, 7,
4543. (e) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett.2005, 7, 5321.
(f) Gryko, D.; Lipinski, R. Adv. Synth.Catal. 2005, 347, 1948.
30. (a)Hayashi, Y.; Sekizawa, H.; Yamagushi, J.; Gotoh, H. J.Org. Chem., 2007, 72,
6493.Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thoson, J.E. Chem. Commun.
2005, 3802.Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z.Org. Lett.
2006, 8, 1263.
31. Luo, S.-Z.; Xu, H.; Li, J.-Y.; Zhang, L.; Cheng, J.-P. J.Am. Chem. Soc. 2007,
129, 3074.(b) Luo, S.; Li, Y.; Xu, H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273.
32. Tang, Z.; Jiang, F.; Yu, L.-T.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem.
Soc. 2003, 125, 5262.(b) Tang, Z.; Jiang, H.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang,Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U. S. A. 2004,101, 5755.(c) Guo,
H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang,Y.-Z. Chem. Commun. 2005,
1450.(d) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi,A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. J. Am. Chem. Soc. 2005,127, 9285.He, L.; Tang, Z.; Cun, L.-F.; Mi,
A.-Q.; Jiang, Y.-Z.;Gong, L.-Z. Tetrahedron 2006, 62, 346.(f) Jiang, M.; Zhu,
S.-F.; Yang, Y.; Gong, L.-Z.; Zhou, X.-G.;Zhou, Q.-L. Tetrahedron: Asymmetry
2006, 17, 384.(g) Tang, Z.; Marx, A. Angew. Chem., Int. Ed. 2007, 46, 7297.
33. Zhao, Jing, Chen, Aijun, Liu and Quanzhong, Chinese Journal of Chemistry,
2009, 27, 930-936.
34. B. List, A. R. Lerner and C. F. Barbas, J. Am. Chem. Soc., 2000,122, 2395; (b)
K. Sakthivel, W. Notz, T. Bui and C. F. Barbas,J. Am. Chem. Soc., 2001, 123,
5260
35. C. Isart, J. Bures and J. Vilarrasa, Tetrahedron Lett., 2008, 49,5414; (b) B. List,
L. Hoang and H. J. Martin, Proc. Natl. Acad. Sci.U. S. A., 2004, 101, 5839; (c)
-
204
F. Orsini, F. Pelizzoni, M. Forte,R. Destro and P. Gariboldi, Tetrahedron, 1988,
44, 519.
36. Z. Tang, F. Jiang, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang and Y. Dong, Proc.
Natl. Acad. Sci. U. S. A., 2004, 101, 5755;(b) A. Hartikka and P. I. Arvidsson,
Eur. J. Org. Chem., 2005, 11,4287; (c) A. Berkessel, B. Koch and J. Lex, Adv.
Synth. Catal., 2004,346, 1141; (d) M. R. Vishnumaya, S. K. Ginotra and V. K.
Singh,Org. Lett., 2006, 8, 4097; (e) F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-
Q. Mi, Y.-Z. Jiang and Y.-D. Wu, J. Am. Chem. Soc., 2005, 127,9285; (f) D. E.
Ward, V. Jheengut and O. T. Akinnusi, Org. Lett.,2005, 7, 1181; (g) H. Zhang,
S. Mitsumori, N. Utsumi, M. Imai,N. Garcia-Delgado, M. Mifsud, M.
Albertshofer, P. H.-Y. Cheong,K. N. Houk, F. Tanaka and C. F. Barbas, J. Am.
Chem. Soc., 2008,130, 875; (h) S. Luo, H. Xu, L. Zhang, J. Li and J.-P. Cheng,
Org.Lett., 2008, 10, 653; (i) M. Pouliquen, J. Blanchet, M.-C. Lasne and J.
Rouden, Org. Lett., 2008, 10, 1029; (j) J. Wang, H. X. Xie, H. Li,L. S. Zu and
W. Wang, Angew. Chem., Int. Ed., 2008, 47, 4177. For excellent reviews of
proline-catalyzed reactions, see: (k) B. List, Tetrahedron, 2002, 58, 5573; (l) S.
Mukherjee, J.-W. Yang,S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471.
37. Y. Zhou and Z. Shan, J. Org. Chem., 2006, 71, 9510;(b) A. I. Nyberg, A. Usano
and P. M. Pihko, Synlett, 2004, 1891;(c) H. Torii, M. Nakadai, K. Ishihara, S.
Saito and H. Yamamoto,Angew. Chem., Int. Ed., 2004, 43, 1983; (d) M.
Amedjkouh, Tetrahedron: Asymmetry, 2005, 16, 1411; (e) Z. Tang, Z.-H.
Yang,L.-F. Cun, L.-Z. Gong, A.-Q. Mi and Y.-Z. Jiang, Org. Lett., 2004,6, 2285;
(f) D. E.Ward and V. Jheengut, Tetrahedron Lett., 2004, 45,8347; (g) P. M.
Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg and J. A. Kaavi, Tetrahedron,
2006, 62, 317; (h) P. Dziedzic,W. Zou, J. Ha fren and A. Co rdova, Org. Biomol.
Chem., 2006, 4,38. For a review on additive-improved asymmetric catalysis, see:
E.M. Vogl, H. Gro ger and M. Shibasaki, Angew. Chem., Int. Ed., 1999, 38,
1570.
38. M. M. Vasbinder, J. E. Imbriglio and S. J. Miller, Tetrahedron,2006, 62, 11450;
(b) J. E. Imbriglio, M. M. Vasbinder and S. J. Miller, Org. Lett., 2003, 5, 3741.
39. L. Hoang, S. Bahmanyar, K. N. Houk and B. List, J. Am. Chem.Soc., 2003, 125,
16; (b) S. Bahmanyar, K. N. Houk, H. J. Martin and B. List, J. Am. Chem. Soc.,
2003, 125, 2475; (c) F. R. Clemente and K. N. Houk, Angew. Chem., Int. Ed.,
-
205
2004, 37, 5766; (d) C. Allemann, R. Gordillo, F. R. Clemente, P. H.-Y. Cheong
and K. N. Houk, Acc. Chem. Res., 2004, 37, 558.
40. Omer Reis, Serkan Eymur, Barbaros Reis and Ayhan S. Demir, Chem. Commun.
2009, 1088-1090.
41. A. Berkssel, H. Groger, Asymmetric Organocatalysis, Wiley-VCH, Weinheim,
2005; b) P. I. Dalko, L. Moisan, Angew.Chem.2004, 116, 5248; Angew.Chem.
Int. Ed. 2004, 43, 5138; c) Y.Hayashi, J. Syn. Org. Chem. Jpn. 2005, 63, 464.
42. Modern Aldol Reactions, Vols. 1, 2 (Ed.: R. Mahrwald), Wiley-VCH,
Weinheim, 2004.[6] T. D. Machajewski, C.-H. Wong, Angew. Chem. 2000, 112,
1406; Angew. Chem. Int. Ed. 2000, 39, 1352.
43. T. Hamada, K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro, S.Kobayashi, J.
Am. Chem. Soc. 2003, 125, 2989.
44. T. Darbre, M. Machuqueiro, Chem. Commun. 2003, 1090.
45. For representative reports, see; a) Z. G. Hajos, D. R. Parrish, J.Org. Chem. 1974,
39, 1615; b) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492;
Angew. Chem. Int. Ed. Engl. 1971,10, 496; c) B. List, R. A. Lerner, C. F. Barbas
III, J. Am. Chem.Soc. 2000, 122, 2395; d) A. B. Northup, D. W. C. MacMillan,
J.Am. Chem. Soc. 2002, 124, 6798.
46. A.Cordova, W. Notz,C. F. Barbas III, Chem. Commun. 2002, 3024.
47. Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z.Jiang, L.-Z. Gong,
J. Am. Chem. Soc. 2005, 127, 9285, and references therein.
48. H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto, Angew. Chem. 2004,
116, 2017; Angew. Chem. Int. Ed. 2004, 43,1983; b) A. I. Nyberg, A. Usano, P.
M. Pihko, Synlett 2004, 1891;c) Z. Tang, Z.-H. Yang, L.-F. Cun, L.-Z. Gong,
A.-Q. Mi, Y.-Z.Jiang, Org. Lett. 2004, 6, 2285; d) J. Casas, H. Sunden,
A.Cordova, Tetrahedron Lett. 2004, 45, 6117; e) D. E. Ward, V.Jheengut,
Tetrahedron Lett. 2004, 45, 8347; f) I. Ibrahem, A.Cordova, Tetrahedron Lett.
2005, 46, 3363; g) M. Amedjkouh, Tetrahedron: Asymmetry 2005, 16, 1411; h)
A. Cordova, W. Zou,I. Ibrahem, E. Reyes,M. Engqvist,W.-W. Liao, Chem.
Commun.2005, 3586.
49. Nornicotine was reported to promote the aldol reaction in water,but low
asymmetric induction (ca. 20%ee) was observed: a) T. J.Dickerson, K. D. Janda,
J. Am. Chem. Soc. 2002, 124, 3220;b) C. J. Rogers, T. J. Dickerson, A. P.
Brogan, K. D. Janda, J. Org.Chem. 2005, 70, 3705.
-
206 50. Yujiro Hayashi, Tatsunobu Sumiya, Junichi Takahashi, Hiroaki Gotoh, Tatsuya
Urushima, and Mitsuru Shoji, Angew. Chem. Int.Ed.2006, 45, 958-961.
51. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.1981, 103, 2127. (b)
Evans, D. A.; Nelson, J. V.; Vogel, E.;Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099. (c) Evans,D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc.
1979,101,6120.
52. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem.1990, 55, 173. (b)
Heathcock, C. H. Science 1981, 214, 395.(c) Heathcock, C. H. Asymmetric
Synthesis; Morrion, J. D.,Ed.; Academic: New York, 1984; Vol. 3, p 111. (d)
Heathcock, C. H.; White, C. T. J. Am. Chem. Soc. 1979, 101. (e) Kleschick,W.
A.; Buse, C. T.; Heathcock, C. H. J. Am. Chem. Soc. 1977,99.
53. Kim, B. M.; Williams, S. F.; Masamune, S. Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol.
2, p 239, Chapter 1.7. (b) Masamune, S.; Ali, S.; Snitman, D. L.; Garvey, D.
S.Angew. Chem. 1980, 92, 573. (c) Masamune, S.; Choy, W.; Kerdesky, F. A. J.;
Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566. (d) Masamune, S.; Sato, T.;
Kim, B. M.; Wollmann,T. A. J. Am. Chem. Soc. 1986, 108, 8279–8281.
54. Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T.Tetrahedron 1993, 49,
1761. (b) Mukaiyama, T. The Directed Aldol Reaction. Organic Reactions;
Wiley: New York, 1982; Vol. 28, p 203. (c) Mukaiyama, T.; Banno, K.;
Narasaka, K.R. Ian Storer, D. W. C. MacMillan / Tetrahedron ,60 ,(2004) 7705–
7714 7713 J. Am. Chem. Soc. 1974, 96, 7503. (d) Mukaiyama, T.; Narasaka, K.;
Banno, K. Chem. Lett. 1973, 9, 1011.
55. (a) Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas,C. F. Tetrahedron
Lett. 2002, 43, 9591. (b) Cordova, A.; Notz, W.; Barbas, C. F. Chem. Commun.
2002, 3024. (c) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000,
122, 2395. (d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. J. Am.Chem. Soc.
2001, 123, 5260.
56. Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.Chem. Soc.
2002, 124, 392.
57. (a)List, B. Tetrahedron 2002, 58, 5573. (b) List, B.; Pojarliev, P.; Castello, C.
Org. Lett. 2001, 3, 573. (c) Notz, W.; List, B.J. Am. Chem. Soc. 2000, 122, 7386.
(d) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003,
42, 2785.
-
207 58. Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003,125, 2852.
59. (a) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M.
Org. Lett. 2001, 3, 1539. (b) Yamada, Y. M. A.;Yoshikawa, N.; Sasai, H.;
Shibasaki, M. Angew.Chem., Int.Ed.Engl.1997,36,1871.(c) Yoshikawa, N.;
Kumagai, N.;Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki,M. J.
Am. Chem. Soc. 2001, 123, 2466. (d) Yoshikawa, N.; Shibasaki, M. Tetrahedron
2001, 57, 2569. (e) Yoshikawa, N.;Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am.Chem. Soc. 1999, 121, 4168.
60. (a)Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc.2004, 126, 2660.
(b) Trost, B. M.; Ito, H. J. Am. Chem. Soc.2003, 122, 1. (c) Trost, B. M.; Ito, H.;
Silcoff, E. R. J. Am.Chem. Soc. 2001, 123, 3367. (d) Trost, B. M.; Silcoff, E. R.;
Ito, H. Org. Lett. 2001, 3, 2497.
61. Denmark, S. E.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40, 4759.
62. R. Ian Storer and David W. C. MacMillan, Tetrahedron, 2004 60, 7705-7714.
63. (1) Reviews: (a) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389. (b)
Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137.(c) Bach,
T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417. (d) A notable exception is
Denmark’s chiral Lewis base-catalyzed Mukayama-type aldol reaction:
Denmark, S. E.; Stavenger, R. A.; Wong, K.-T. J. Org. Chem. 1998, 63, 918-
919.
64. March, J. J.; Lebherz, H. G. TIBS 1992, 17, 110. (b) Rutter, W. J.Fed. Proc. Am.
Soc. Exp. Biol. 1964, 23, 1248. (c) Lai, C. Y.; Nakai, N.; Chang, D. Science
1974, 183, 1204. (d) Morris, A. J.; Tolan, D. R.; Biochemistry 1994, 33, 12291.
65. Fessner, W.-D.; Schneider, A.; Held, H.; Sinerius, G.; Walter, C.; Hixon,M.;
Schloss, J. D. Angew. Chem., Int. Ed. Engl. 1996, 35, 2219-
2221.Phosphoenolpyruvate aldolases use a preformed enolate,
phosphoenolpyruvate, to accomplish aldol addition reactions. For studies of this
and other aldolase enzymes in organic synthesis see: Gijsen, H. J. M.; Qiao, L.;
Fitz, W.; Wong, C.-H. Chem. ReV. 1996, 96, 443-473.
66. (a) Wagner, J.; Lerner, R. A.; Barbas, C. F., III Science 1995, 270, 1797. (b)
Barbas, C. F., III; Heine, A.; Zhong, G.; Hoffmann, T.; Gramatikova,S.;
Bjo¨rnestedt, R.; List, B.; Anderson, J.; Stura, E. A.; Wilson, E. A.; Lerner,R. A.
Science 1997, 278, 2085-2092. (c) Hoffmann, T.; Zhong, G.; List, B.;Shabat, D.;
Anderson, J.; Gramatikova, S.; Lerner, R. A.; Barbas, C. F., III J.Am. Chem.
-
208
Soc. 1998, 120, 2768-2779. (d) List, B.; Shabat, D.; Barbas, C.F., III; Lerner, R.
A. Chem. Eur. J. 1998, 881-885. (e) Zhong, G.; Shabat,D.; List, B.; Anderson,
J.; Sinha, S. C.; Lerner. R. A.; Barbas, C. F., III Angew. Chem., Int. Ed. 1998,
37, 2481-2484. (f) Zhong, G.; Lerner. R. A.; Barbas, C. F., III Angew. Chem.,
Int. Ed. 1999, 38, 3738-3741. (g) Sinha, S. C.;Sun, J.; Miller, G.; Barbas, C. F.,
III; Lerner, R. A. Org. Lett. 1999, 1, 1623-1626. (h) Turner, J. M.; Bui, T.;
Lerner, R. A.; Barbas, C. F., III; List, B.Manuscript submitted for publication.
67. (a) Nakagawa, M.; Nakao, H.; Watanabe, K.-I. Chem. Lett. 1985, 391-394. (b)
Yamada, Y.; Watanabe, K.-I.; Yasuda, H. Utsunomiya Daigaku Kyoikugakubu
Kiyo, Dai-2-bu 1989, 39, 25-31.
68. Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.Chem., Int.
Ed. Engl. 1997, 36, 1871. (b) Yamada, Y. M. A.; Shibasaki, M.Tetrahedron Lett.
1998, 39, 5561. (c) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178.
69. Benjamin List, Richard A. Lerner, and Carlos F. Barbas III,
J.Am.Chem.Soc.2000, 122, 2395-2396.
70. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503–
7506; (b) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem. Lett. 1990, 1455–
1458.
71. Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090–1091; (b) Kofoed, J.;
Reymond, J.-L.; Darbre, T. Org.Biomol. Chem. 2005, 3, 1850–1855.
72. Kobayashi, S.; Manabe, K. Pure App. Chem. 2000, 1373–1380; (b) Kobayashi,S.
Eur. J. Org. Chem. 1999, 15227–15232; (c) Kobayashi, S.; Nagayama,
S.;Busujima, T. J. Am. Chem. Soc. 1998, 120, 8287–8288; (d) Otto, S.;
Bertoncin, F.;Engberts, J. B. F. N. J. Am. Chem. Soc. 1996, 118, 7702–7707; (e)
Engberts, J. B. F.N.; Feringa, B. L.; Keller, E.; Otto, S. Rec. Trav. Chim. Pays-
Bas 1996, 115, 457–464; (f) Kobayashi, S.; Ogawa, C. Chem. Eur. J. 2006, 12,
5954–5960.
73. For a review on the roles of zinc in zinc enzymes: Kimura, E.; Kikuta, E. J.
Biol.Inorg. Chem. 2000, 5, 139–155.
74. Mael Penhoat, Didier Barbry and Christian Rolando, Tetrahedron Lett. 52, 2011,
159-162.
75. Lutz, M.; Bakker, R. Acta Crystallogr., Sect. C 2003, 59, 18–20.
-
209 76. Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;Barbas, C. F.,
III. J. Am. Chem. Soc. 2006, 128, 734.
77. (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958. (b) Hayashi, Y.; Aratake,S.; Okano, T.;
Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.2006, 45, 5527.
78. Vishnu Maya, Monika Raj, and Vinod K. Singh, Organic Lett. 2007, Vol. 9, No.
13, 2593-2595.
79. For some recent selected references on aldol reaction in water via asymmetric
organocatalysis, see: (a) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G.
Org. Lett. 2007, 9, 1247. (b) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S.
Org. Lett. 2006, 8, 4417. (c) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem.
Commun. 2006, 2801. (d) Dziedzic, P.; Zou, W.; Hafren,J.; Cardova, A. Org.
Biomol. Chem. 2006, 4, 38. (e) Chimni, S. S.; Mahajan, D. Tetrahedron:
Asymmetry 2006, 17, 2108. (f) Guillena, G.; Hita, M. D.C.; Najera, C.
Tetrahedron: Asymmetry 2006, 17, 1493. (g) Fu, Y.-Q.; Li,Z.-C.; Ding, L.-N.;
Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron: Asymmetry 2006, 17, 3351.
(h) Pihko, P. M.; Laurikainen, K. M.; Usano,A.; Nyberg, A. I.; Kaavi, J. A.
Tetrahedron 2006, 62, 317.
80. (a) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki,
T.; Shibasaki, M. J. Am. Chem. Soc.2001, 123, 2466. (b) Yamada, M. A. Y.;
Shibasaki, M.Tetrahedron Lett. 1998, 39, 5561.
81. Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
82. Bogevig, A.; Kumaragurubaran, N.; Jorgensen, K. A. Chem.Commun. 2002,
620.
83. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,124, 6798.
84. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.2000, 122, 2395.
85. Cordova, A.; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67, 301.
86. Cordova, A. Tetrahedron Lett. 2004, 45, 3949.
87. Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E.Chem. Commun.
2002, 2510.
88. (a) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun.2002, 3024. (b)
Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891. (c) Hartikka, A.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831. (d) Peng, Y.-Y.; Ding,
Q. P.; Li, Z.;Wang, P. G.; Cheng, J.-P.Tetrahedron Lett. 2003, 44, 3871.(e)