Thesis-PerLindecrantz-2009

University of Gothenburg
Department of Chemistry
Göteborg, Sweden, May 2009
Direct aldol reactions
mediated by dimethylzinc
Synthesis and autocatalytic properties of
aromatic aldol products
PER LINDECRANTZ
Master of Science Thesis

2
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_____
Direct aldol reactions mediated by dimethylzinc
Synthesis and autocatalytic properties of aromatic aldol products
PER LINDECRANTZ
© PER LINDECRANTZ, May 2009.
Examiner: GÖRAN HILMERSSON
University of Gothenburg
SE 412 96 Göteborg, Sweden
+ 46 31 772 10 00 , +46 31 772 28 53 (fax)
Cover:
The cover illustration shows two molecules of 3-hydroxy-2-methoxy-1,3-diphenylpropan-1-one bound to zinc.
Göteborg, Sweden March 2009

3
Abstract
This paper describes autocatalytic aldol reactions between acetophenone and a few different
aldehydes. Three biphenylic β-hydroxyketones were synthesized and their (1
H and 13
C) NMR
data is reported. In addition, successful asymmetric catalysis and autocatalysis were done. The
use of magnesium bromide to effect the aldol reaction between aromatic ketones and aldehydes
were successfully implemented and proved an efficient and easy process.
O
+ R2
CHO
O OH
R2
THF, MS 4Å, rt
P
5-10% P
10-20% Me2Zn
R1
R1
In conclusion, this paper shows that some products of aldol reactions are capable of facilitating
catalysis of both their own formation and reaction between other substrates. The process
requires and deserves further studies and attention.

4
Abbreviations
DCM dichloromethane
DIPEA diisopropylethylamine
ee enantiomeric excess
er enantiomeric ratio
HPLC high performance liquid chromatography
LDA lithium diisopropylamide
LLB lanthanum lithium binaphtoxide
MS molecular sieves
NMR nuclear magnetic resonance
rt room temperature
THF tetrahydrofuran

5
Table of Contents
i Abstract 3
ii Abbreviations 4
iii Table of contents 5
1. Introduction 6
1.1 The aldol reaction 6
1.2 Catalysis and Autocatalysis 7
2. Results and discussion 10
2.1 Racemic aldol products 11
2.2 Chiral aldol products 12
2.3 Examination of autocatalysis 12
3. Conclusion 14
4. Experimental 14
5. Acknowledgement 17
6. References 18
7. Appendix 19

6
1. Introduction
1.1 The aldol reaction
The aldol reaction is the addition of the enolate of a carbonyl compound to an aldehyde or
ketone. A β-hydroxycarbonyl compound is the the product of this first step, but it may undergo
loss of water to yield an α,β-unsaturated carbonyl compound which is said to be the product of
aldol condensation. The name aldol is derived from the product of acid catalyzed reaction
between two molecules of acetaldehyde, 3-hydroxybutanal – also called aldol1
.
R1
O
R4
O
R3
R1
R4
OHO
+R2
R2
R3
acid or base
work-up R1
R4
O
R2
dehydration
-H2O
R3
Scheme 1. Classical aldol reaction
The aldol reaction is generally regarded as one of the most powerful and efficient carbon-
carbon bond forming reactions in modern catalytic synthesis. The products, namely β-
hydroxycarbonyl compounds, are key players in the production of pharmaceuticals.
The occurrence of two new stereogenic centra in the aldol adduct demonstrates the importance
of the aldol reaction in the organic chemists arsenal. An asymmetric aldol reaction was used in
the synthesis of fostriecin – a topoisomerase inhibitor.2
The aldol reaction was also utilized in a
key step in the synthesis of atorvastatin3
– the active compound in Pfizer’s block buster drug
Lipitor, that has been the best selling drug in the world for several years.
Almost all of the efforts devoted to develop catalytic asymmetric aldol reactions, require
preconversion of the ketone or ester moiety into a more reactive species such as an enol silyl
ether or a ketene silyl acetal by using no less than stoichiometric amounts of bases and reagents
like(CH3)3SiCl.4
Since its discovery, the Mukaiyama aldol reaction witnessed steady
improvements of chiral lewis acids activating the aldehyde acceptor towards reaction with the
enol silane.5
Later, Denmark introduced the concept of enol silanes activation with
phosphoramides as Lewis base catalysts, and demonstrated that that the use of a catalytic
amount of Lewis acid (transition metal) was no longer a prerequisite in the Mukaiyama-type
aldol reaction.
For the development of practical, economic, and environmentally benign processes, it is
ideal to perform the aldol reaction with unmodified ketones and aldehydes using only catalytic
amounts of reagents.

7
1.2 Catalysis and Autocatalysis in direct aldol reaction
In 1999 the first direct, catalytic asymmetric aldol reaction was reported by Shibasaki
et.al.6
In the introduction of their paper they theorize that reaction between unmodified
ketones and aldehydes may be realized by designing a catalyst incorporating both a Brönsted
base and Lewis acid functionality. This type of synergistic cooperation allowed the
development of asymmetric catalysts based on the concept of a dual center catalysis, following a
catalytic cycle illustrated in Scheme 2.
R2
O
O
O LA
M
H
O
R2
O
O LA
M
H
O
R2
O
H
O
O LA
M
H
O
R1
R2
O
O
O LA
M
R1
H
O
LA : Lewis Acid
M : Metal of Brönsted base
: Chiral ligand
O
O
R2
O
R1
OH
Product
ketone aldehyde
Scheme 2. Catalytic cycle as proposed by Shibasaki and coworkers.
The idea stems from the mechanisms of aldolases which can carry out the reaction
efficiently under mild in vivo conditions, illustrated in Figure 1. Let us consider the case of
aldolase class II to illustrate similarities in the mechanism of action. As we can see, Zn2+
acts as a
Lewis acid activator for the enolate in the aldolase, but in the reaction under investigation the
theory is that the zinc will coordinate and activate the reactants at the same time as it acts as an
anchor for newly formed product which is cyclically replaced.
Figure 1. General concept of two-center catalysis.

8
Based on a similar approach, Trost et.al also presented an enantioselective direct aldol
reaction catalyzed by a chiral semi-crown Zn complex (Scheme 3), which provides an
asymmetric environment with both Brönsted base and Lewis acid activity incorporated.7,8
The
authors also noticed the influence of weak coordinating agents to zinc on the turnover
frequency. While trimethyl phosphate and triphenylphosphine sulfide both increased turnover,
triphenylphosphine sulfide was the best in terms of both turnover and enantiomeric excess.
The ability of weak ligands to increase turnover indicates that the system is prone to product
inhibition.
OHN N
Ph
Ph
Ph
Ph
OH HO
ON N
Ph
Ph
Ph
Ph
O
OZn Zn
R
2 eq. R2Zn
Scheme 3. The catalyst developed by Trost et.al.
When the product of a reaction also acts as a catalyst for it’s own formation, autocatalysis is
said to be in effect. Self-replicating assemblies of molecules have been constructed, and some are
even capable of asymmetric amplification9
(Figure 2). These sustainable systems are of special
interest in the generation and propagation of optical activity on earth and closely related to the
origin of life.
Figure 2. Scematic mechanism proposal trying to explain homochirality. In each cycle of
replication product molecule (T) binds substrate molecules A and B. The complex ABT forms,
and T helps A and B to join stereo specific to form a new T bound to the first T. The TT
complex dissociate into two T molecules.

9
This kind of catalysis can be very attractive from both a synthetic, industrial and
environmental viewpoint. The lack of additional auxiliaries may make work up much easier,
and the additives used in non-autocatalytic processes may be both expensive and hazardous to
health and environment.
Soai et al. reported the first asymmetric autocatalytic reaction in 1989, and in 1996 the
same research group of Kenso Soai published their discovery of an enantioselective
autocatalytic process involving the addition diisopropylzinc to pyrimidine-5-carbaldehyde
(Scheme 4), which proceeded with amplification of chirality.10
The study consisted in a
repetitive process where a very small excess of one enantiomer was used in the first run, and
enantiomeric excess was greater than 99.5% after three consecutive asymmetric autocatalyses.
In the paper Soai discusses what importance autocatalytic reactions may have had in the origin
of life and the evolution of chirality in for example amino acids and sugars. Since a small
amount of chirality may be induced by polarized light, the sequential amplification of a tiny
enantiomeric excess to almost enantiomeric purity demonstrated a possible path that
biochirality may have evolved through.
N
N
H
O
N
N
(S)
OH
N
N
(S)
OH
+ (iPr)2Zn
Scheme 4. Soai’s autocatalytical reaction
A recent paper by Fujisawa et.al. described a product-catalyzed aldol reaction between TMS
ketene acetals and aldehydes to afford the corresponding aldols in DMF, indicating that the
initially-formed aldolate anion effectively worked to catalyze the reaction.11
In this case, a
hypervalent silicate complex is the supposed key player in the catalytic cycle. (Figure 5) When
complexed, the enolate is activated and increases its reactivity and attacks the aldehyde. The
lithium aldolate thus generated similarly activates the TMS enolate to form the silylated aldol
and lithium aldolate, and consequently a catalytic cycle is established.
MeO
O O
Si
R
O
MeO
DMF
Figure 3. Activation of enolate
In a more recent report, Tsogoeva et al. described a spontaneous random generation of
chirality in an Aldol reaction under achiral conditions. Thus, in the best run, the reaction of
acetone and p-Nitrobenzaldehyde, enantiomeric excess values of up to 50.8% with 10% yield
were achieved when stopping the homogenous reaction after 10 days in acetone. However, the
authors also had a cautionary note that “contamination” with trace impurities, e.g. in dust or

10
residues, containing enantiomerically enriched product cannot be precluded. Another non-
negligible limiting factor for the achievable enantiomeric excess is the extent of the
(unavoidable) uncatalyzed “background reaction” that gives racemic product because the chiral
product is not involved in it. These findings have also potential significance for the
understanding of homochirality.
Asymmetric autocatalysis is the process of automultiplication of a chiral compound in
which the chiral product acts as a catalyst for its own formation. Such reactions offer many
advantages: 1) the catalyst does not need to be separated from the reaction mixture since it is
the product. 2) Decreasing amount of catalyst (i.e. product) does not change the catalytic
activity since the amount of product increases during the reaction. 3) the efficiency is high since
the process is an automultiplication.
With the success of rational catalyst design for direct aldol type reactions, as evidenced by
research groups of Shibasaki and Trost in their respective work, it seemed quite possible that β-
hydroxycarbonyl compounds – products of the aldol reaction - might actually be able to act as
part of a catalyst themselves, effectively creating an autocatalytic cycle. By reacting a dialkylzinc
compound with the sought aldol product, one might create a catalytic complex that has both
the necessary functions – Brönsted base and Lewis acid - required for catalytic activity. If an
enantiomerically enriched compound is used when forming the complex, one might also be
creating the necessary asymmetric environment required for enantioselective autocatalysis.
2. Results & Discussion
Considering 1) the effectiveness of class II aldolase, in which the Zn moiety has a crucial
role in promoting the direct aldol reaction of hydroxyketone derivative, 2) the effectiveness of
the previously reported Zn/linked-BINOL (Shibasaki et al.) and Zn/semi-crown (Trost et al.)
complexes in asymmetric catalysis, and 3) the reminiscence of the Zn-O function in the Zn-
aldolate formed as intermediate in the catalytic cycle, the potential use of aldol compounds as
catalysts seemed very attractive.
In developing a rational strategy we also considered that the binding affinities of the Zn-
aldolate would offer organization while still allowing catalysis. Trost’s catalyst has been shown
to consist of a dimer while the Shibasaki’s catalyst was found to occur as a trinuclear
Zn3(linked-binol)2 with three Zn atoms aligned in almost a straight line.
Since activation is necessary for both acceptor and donor in the direct aldol reaction, we
considered a bimetallic complex would be a minimum structure requirement for a model
autocatalyst.
Ar
R
Several aldol products was synthesised in order to pursue the possibility of autocatalysis.
The objective was to examine if aromatic aldol products could act autocatalytically and evaluate
possible effects the nature of the acceptor aldehyde had on the reaction yield. Racemates were
synthesised by two different methods, either dialkylzink/dialcohol or magnesium
bromide/DIPEA. (S,S)-(+)-2,6-Bis[2-(hydroxydiphenylmethyl)-1-pyrrolidinyl-methyl]-4-
methylphenol, the Trost catalyst was used for achiral synthesis. Progress of reactions were
monitored by 1
H-NMR and enantiomeric excess was determined by HPLC in all experiments.
O
Zn
O
Zn
OH

11
2.1 Racemic aldol products
R
O
R'
O
H R R'
OHO
+
R''2Zn, dialcohol
THF, 24 h
Scheme 5. Dialkylzinc mediated aldol reaction
Synthesis of racemic aldol products were carried out by two different methods. Me2Zn and
1,2-ethanediol was used in early experiments, because of similarities with the catalytic reaction
that was to be examined. The glycol was thought to react with the dialkylzinc to form a
complex that could act as a catalyst for the aldol reaction. However, the results were not as good
as hoped for so another method to produce racemic aldols was searched for. The solution came
in the shape of magnesium halides – used to effect the racemic aldol reaction in a very short
amount of time with very good yields in general. Later we discovered that dimethylzinc in the
presence of the reactants sufficed to facilitate the conversion (see below). It is likely that the
ketone is first deprotonated and thus enolized in in a non catalytic manner. The product of
that reaction may then take part in a catalytic process.
Table 1. The aldol reaction between a few ketones and aldehydes facilitated by magnesium
bromide
CH2Cl2, rt, 30 min
MgBr2*Et2O
Et(iPr)2N
O
+ R2
CHO
R1
O OH
R2
R1
1a R1
= H R2
= Ph
1b R1
= H R2
= p-NO2-C6H4
1c R1
= H R2
= cyclohexyl
1d R1
= -O-Me R2
= Ph
Entry R Isolated yield (%)
1 1a 72
2 1b 45
3 1c 38
4 1d 31
The second synthetic strategy involves a magnesiumhalide and amine base to effect the
transformation of an aromatic ketone and aromatic aldehyde into a β-hydroxy ketone (Table
1).12
Thus, the aldol reaction between benzaldehyde and magnesium enolate generated from
acetophenone in the presence of Hünig’s base and MgBr2 proceeded very quickly and cleanly at
room temperature to afford the corresponding aldol in 72 % yield (Table1, entry 1). Under the
same reaction conditions, other aldol adducts were obtained in lower isolated yields, which in
part can be explained by the substrates used and in part by losses in isolation (Table 1, entries 2-
4). Magnesium iodide, as used in the original reference, would likely have given even better
yields, but only the bromide was available to us. Because nearly equimolar amounts of the

12
reactants were used, and the reaction generally gave good yields, clean up was fairly easy. On the
other hand, the aldol reaction involving cyclohexanecarbaldehyde as acceptor aldehyde and
MgBr-enolate, generated from acetophenone, (entry 3) the desired aldol product was obtained
along with a minor amount of a new aldehyde. Since cyclohexanecarbaldehyde is enolizable due
to it’s α-hydrogen, the latter new compound likely arose from a self aldol addition of
cyclohexanecarbaldehyde,. However, our attempts to perform the aldol reaction of
acetophenone and benzaldehyde under catalytic conditions of MgBr2 and Hünig’s base were
unsuccessful, and the desired product was detected only in an amount stoichiometrically
equivalent to the amount amine and magnesium bromide employed.
2.2 Chiral aldol products
O O Trost 5 mol%
dimethyl zinc 10 mol%
MS 4Å, THF, rt, 24 h
O OH
5 eq.
+
Scheme 6. Asymmetric direct aldol reaction with the Trost catalyst
Following the reaction conditions developed by Trost et al., (S,S)-(+)-2,6-Bis[2-
(hydroxydiphenylmethyl)-1-pyrrolidinyl-methyl]-4-methylphenol was used to produce 3-
cyclohexyl-3-hydroxy-1-phenylpropan-1-one with >99% ee and a yield of 39%. (Scheme 5)
Several attempts were made with aromatic aldehydes, but there was significant formation of
dehydration product.
2.3 Examination of autocatalysis
In a series of preliminary experiments racemic autocatalysis was examined with three
different aldol products. In the rational development of the present autocatalytic process, the
choice of acetophenones is motivated by considering the following background: 1) there is only
one enolizable position within aryl ketones while, functioning as place holder, the aryl group
would lead to steric interactions, 2) methoxysubstituted acetophenone is potentially
advantageous as MeO- would also facilitate the formation of the Zn-enolate through
coordination to the Zn center, increasing the preference of a chelate complex. The later
coordination has also to account for in the Zn-aldolate catalyst.
The complex prepared by treating 10 mol % aldol product 1 in THF with a solution of up
to 20 mol % dimethylzinc in hexane was used to promote the corresponding aldol reaction as
summarized in table 2.
Zn-Aldolate complexes formed from 1b and 1c gave the best conversion rates. In the case
of aldol 1b it is likely due to the high reactivity of para-nitrobenzaldehyde compared to
unsubstituted benzaldehyde. In the case of 1c which involves 2-methoxyacetophenone, the very
high conversion percentage confirms the activating property of the methoxy group – which
makes the ketone more readily enolizable than unsubstituted acetophenone. It is also likely that
the methoxy group adds extra coordinating activity, which seems very beneficial. Comparing
entry 11 and 12 shows that very little has happened from 18 hours to 36 hours, and it is likely
that the reaction rate has already slowed down considerably even before 18 hours.
With neither initial product or dimethyl zinc present in the mixture (table 2, entry 9), no
formation of product could be detected. With dimethyl zinc but no initial product present

13
(table 2, entry 10), formation of product was above the amount that dimethyl zinc could
theoretically induce by base action – indicating a catalytic process is present.
Table 2. The autocatalytic aldol reaction
O
+ R2
CHO
O OH
R2
THF, MS 4Å, rt
P
0-10% P
0-20% Me2Zn
R1
R1
1a R1
= H R2
= Ph
1b R1
= H R2
= p-NO2-C6H4
1c R1
= -O-Me R2
= Ph
Entry R Time (h) Initial P (%) Me2Zn (%) Conversion (%)a
1 1a 4 4 8 7
2 1a 96 4 8 12
3b
1a 50 10 20 7
4 1a 40 10 20 30
5 1b 20 10 20 43
6c
1b 0.5 10 20 36
7c
1b 2 x 0.5 10 20 47
8 1b 46 5 10 77
9 1b 48 0 0 0
10 1b 48 0 10 35
11 1c 18 10 20 71
12 1c 36 10 20 75
a
measured by 1
H-NMR. b
in CH2Cl2.c
Carried out in microwave reactor at 60˚C.
A few different solvents were tried for the autocatalytic reaction between p-nitrobenzaldehyde
and acetophenone. Diethylether proved superior to THF, perhaps because of a less pronounced
coordinating power.
Table 3. A few solvents show differences in conversion in an autocatalytic aldol reaction
OH O
Solvent Conversion (%)
Diethylether 39
Toluene 20
DCM 20
THF 24
H
O O
O2N
+
O2N
THF, MS 4Å
rt, 20h
5% P
10% Me2Zn
P

14
Concerning asymmetric catalysis, it was tried with (S)-3-cyclohexyl-3-hydroxy-1-
phenylpropan-1-one; both as an autocatalytic reaction and in the reaction between
acetophenone and benzaldehyde. The results from the achiral autocatalytical experiment, made
very early in the project, cannot confidently be presented here due to insufficiency in analytical
data. Luckily, succesful asymmetric catalysis in the reaction between acetophenone and
benzaldehyde was observed. 40% ee was achieved, but information on yield is missing. These
preliminary results are very promising, and indicates that a closer investigation of the
asymmetric reaction should be carried out.
When it was evident that these direct autocatalytical aldol reactions exists, we sketched an
autocatalytical cycle influenced by crystallographic data published by Visintin et.al. in 2005. 13
It was soon realised that proposing any kind of detailed autocatalytic cycle would be a pure
guessing game at this stage, so it seemed prudent to not engage in such speculations in this
paper.
3. Conclusion
The project aimed to screen for possible autocatalytic properties of aromatic aldol products
and give an indication on whether further research is worthwhile or not. From the results
presented in this paper, one can conclude that autocatalytic aldol reactions are certainly a
reality – a reality that deserves further studies to discover the real potential. The data presented
indicates that the success of the reaction follows the reactivity and complexation possibilities of
the substrates – reactions involving para-nitrobenzaldehyde or 2-methoxyacetophenone
performed much better than their non-substituted counterpart. None or very little
dehydration product was observed in all autocatalytic reactions, which is very advantageous.
Together these results points in the direction that this kind of autocatalytic process might
become a real asset in the synthesis of aromatic β-hydroxyketones and can likely be upscaled
and adapted to industrial scale synthesis with further development. Further investigations of
the reaction should focus on: 1) Stoichiometry and isolation of the catalytic complex. 2)
Kinetic analysis. 3) Chiral catalysis.
For the general aldol reaction between unsubstituted aromatic aldehydes and ketones,
magnesium bromide proved to be a valuable, easy and efficient way to complete the
transformation without significant side products.
4. Experimental
4.1 General
(S,S)-(+)-2,6-Bis[2-(hydroxydiphenylmethyl)-1-pyrrolidinyl-methyl]-4-methylphenol
(95%) was purchased from Aldrich. Acetophenone was distilled. All other chemicals were used
as received from the place of purchase. Glassware was dried over night in an oven.
HPLC
Reactions were followed and products examined with HPLC and 1
H-NMR. HPLC
analyses were carried out on a Varian system consisting of a 9010 solvent delivery module and a
9050 UV detector. Enantiomers were identified on a Varian system with a 9010 Solvent
Delivery System and a 9065 Polychrom UV-DAD detector coupled with a PDR-Chiral Inc.
Advanced Laser Polarimeter. All separations were achieved using a Chiracel OD column with a

15
mobile phase consisting of hexane and isopropyl alcohol in a 90:10 ratio (v/v) and flow rate of
1.0 ml/min.
Figure 4. Laser polarimeter chromatogram from identification of enantiomers. The two latter
peaks represents the enantiomers of 3-cyclohexyl-3-hydroxy-1-phenylpropan-1-one.
NMR
1
H- and 13
C-NMR was recorded on a Varian Unity 400 MHz with CDCl3 as the solvent.
General procedure for the direct DIPEA/MgBr2*Et2O aldol reaction
A 25 ml dry, round-bottomed flask was loaded with MgBr2*Et2O (1.2 mmol, 0.301 g),
DCM (5 ml), acetophenone (1.2 mmol, 0.144 g) and aldehyde (1 mmol). DIPEA (0.23 ml, 1.3
mmol) was added dropwise via syringe, and the resulting mixture was stirred at room
temperature for 30 minutes. The reaction was quenched with aqueous HCl (5 ml, 1 M) and
extracted with ethyl acetate (2 x 8 ml). The combined organic phases were dried with
magnesium sulphate and evaporated under vacuum. The crude product was purified on silica or
by recrystallisation.
General procedure for the direct, catalytic asymmetric reaction with Trost’s catalyst
Generation of catalyst: Under a nitrogen atmosphere, a solution of dimethylzinc (2 M in
toluene, 2 eq.) was added to a solution of ligand Trost (32 mg, 0.05 mmol) in THF (0.4 ml) at
room temperature. MS 4Å was used. Methane gas evolved and the mixture was stirred for 30
minutes.
Aldol reaction: A mixture of aldehyde and ketone was added to the catalyst solution. The
mixture was stirred for 24 hours. Thereafter it was mixed with HCl (aq., 1M, 1 ml) and
extracted with diethylether (3 x 1 ml). The combined organic phases were washed with brine (3
x 1 ml), dried with magnesium sulphate and evaporated under vacuum. The resulting raw
product was purified on silica.

16
General procedure for autocatalytic aldol reaction
Generation of catalyst: A vial was loaded with aldol product (0.05 mmol), MS 4Å and THF
(0.4 ml). Under a nitrogen atmosphere, a solution of dimethylzinc (0.1 mmol, 50 μL, 2 M in
toluene) was added and the solution was stirred at room temperature for 30 minutes.
Aldol reaction: A mixture of aldehyde (0.5 mmol) and ketone (2.5 mmol) was added to the
catalyst solution. The mixture was stirred for 24 hours. The contents of the vial was mixed with
aqueous HCl (aq., 1 M, 1 ml) and extracted with diethylether (3 x 1 ml). The combined
organic phases were washed with brine (3 x 1 ml), dried with magnesium sulphate and
evaporated under vacuum. The resulting raw product was purified on silica.
3-cyclohexyl-3-hydroxy-1-phenylpropan-1-one
OH O
NMR (1
H, 400 MHz) 7.97 (2H, d) 7.58 (1H, t) 7.48 (2H, t) 4.01 (1H, t) 3.23-3.03 (2H, m)
1.96-1.08 (10H, m)
(S)-3-cyclohexyl-3-hydroxy-1-phenylpropan-1-one
OH O
NMR (1
H, 400 MHz) 7.97 (2H, d) 7.58 (1H, t) 7.48 (2H, t) 4.03 (1H, t) 3.26-3.06 (2H, dd-
dd) 1.96-1.08 (10H, m) NMR (13
C, 400 MHz) 198.4, 137.3, 133.3, 128.7, 72.1, 43.3, 42.4,
29.3, 28.6, 26.9, 26.5 HPLC Tr (major isomer) 12.3 min (minor isomer) 8.9 min
3-hydroxy-1,3-diphenylpropan-1-one
OH O
NMR (1
H, 400 MHz) 7.91-7.24 (10H, m) 5.28 (1H, t) 3.31 (2H, d) NMR (13
C, 400 MHz)
200.3, 143.3, 136.8, 133.9, 128.9, 128.3, 127.9, 126.0, 70.3, 47.7

17
3-hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-one
OOH
O2N
NMR (1
H, 400 MHz) 8.25 (2H, d) 7.95 (2H, d) 7.63 (3H, d) 7.50 (2H, t) 5.46 (1H, d) 3.85
(0.75H, s) 3.41 (2H, m) NMR (13
C, 400 MHz) 199.8, 150.4, 136.4, 134.3, 129.1, 128.4,
126.8, 124.1, 69.5, 47.2
3-hydroxy-2-methoxy-1,3-diphenylpropan-1-one
OOH
O
NMR (1
H, 400 MHz) 7.85-7.13 (10H, m) 5.09-4.57 (2H, dd-dd) 3.36-3.24 (3H, 2s) NMR
(13
C, 400 MHz) 199.1, 139.1, 136.3, 133.7, 128.9, 128.7, 128.6, 127.0, 88.3, 75.1, 58.7
5. Acknowledgement
First and foremost I would like to thank my supervisor, Mohamed Amedjkouh, for all his
support and patience. Also Johan Eriksson, Anders Lennartson and David Bliman has helped
me through valuable discussions and advice. All other co-workers and staff at the chemistry
institution are also thanked for discussions, advice and company. Last, but not least, I would
like to thank my recently married wife Kajsa.

18
6. References
1
Kürti, L.; Czakó, B. Strategic applications of named reactions in organic synthesis 2005, 8
2
Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733-736
3
Patent WO-2006-089401, An improved process for the preparation of atorvastatin and
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19
Appendix
3-hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-one
1
H
13
C

20
3-cyclohexyl-3-hydroxy-1-phenylpropan-1-one
13
C
3-hydroxy-2-methoxy-1,3-diphenylpropan-1-one
13
C
3-hydroxy-1,3-diphenylpropan-1-one
13
C

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