Effect of addition of Lewis/Br?nsted acids in the asymmetric aldol condensation catalyzed by trifluoroacetate salts of proline-based dipeptides

Article abstract of DOI:10.1016/j.tet.2012.07.006

Proline-based dipeptides catalyze aldol condensations with good yield and stereoselectivity after addition of zinc or sodium acetate to the trifluoroacetate peptide. The chirality of the N-terminal proline in the catalyst determines the absolute configura

Full text of DOI:10.1016/j.tet.2012.07.006

Tetrahedron 68 (2012) 7966e7972
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
€
Effect of addition of Lewis/Bronsted acids in the asymmetric aldol condensation
catalyzed by trifluoroacetate salts of proline-based dipeptides
,
b
a
Cecilia Andreu a , Marcel$lí del Olmo , Gregorio Asensio
*
a
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
ꢀ
Departament de Química Organica, Universitat de Valencia, Facultat de Farmacia, Vicent Andres Estelles s/n, 46100 Burjassot, Valencia, Spain
Departament de Bioquímica i Biologia Molecular, Universitat de Valencia, Facultat de Ciencies Biologiques, Dr Moliner 50, 46100 Valencia, Spain
b
ꢀ
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2012
Received in revised form 28 June 2012
Accepted 3 July 2012
Available online 7 July 2012
Proline-based dipeptides catalyze aldol condensations with good yield and stereoselectivity after addi-
tion of zinc or sodium acetate to the trifluoroacetate peptide. The chirality of the N-terminal proline in
the catalyst determines the absolute configuration of the aldol product, but stereoselectivity depends on
the configuration of both amino acids, and is higher for the enantiomeric pair ReS, SeR. Regarding the
nature of the second component, optimal results in both yield and stereoselectivity are obtained when
neutral unbranched primary amino acids are used.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The use of organocatalysts based on proline and other amines
basically has two main problems. Firstly the general base catalysis
In the last few years, organocatalysis has developed as a growing
field in organic synthesis, basically due to the use of environment-
friendly conditions.1 The importance of the aldol reaction in the
formation of CeC bonds and in the generation of new stereogenic
centres is the main reason because this reaction has been one of the
most explored in organocatalysis.2 Many organocatalytic systems,
including proline, have been described since the first works de-
scribed the catalytic activity of this amino acid in direct in-
termolecular aldol reactions.3
The use of peptides as organocatalysts is very attractive for
various reasons:4 they mimic the action of natural enzymes; their
building blocks with inherent chirality and functional diversity are
easily available; their synthesis is easy, especially when the solid
phase methodology is employed; finally, they offer high stability.
Some of these derivatives, used as catalysts in aldol reactions, are
dipeptides, which have terminal end primary amino acids5 or the
secondary one proline.6 In addition, tripeptides were used by
Wennemers et al. who, by employing the combinatorial method of
catalystesubstrate coimmobilization to screen a library of tripep-
tides, found optimal catalytic sequences to perform aldol reactions
with excellent stereoselectivity. In them all, proline was the N-
terminal amino acid of the sequence.7
can be competitive with the enamine via lowering the enantiose-
lectivity.9 Secondly, the formation of oxazolidinone or imidazoli-
dinone species, which have usually been described as parasitic
species in aldol condensations catalyzed by proline and prolina-
mide derivatives, respectively.8c,10 Both problems have been solved
€
by protonation of the amine with Bronsted acids with the optimal
pKa.9,10
Some years ago, Darbre’s group described the use of the
Zn(Pro)2 complex as a catalyst of the various asymmetric aldol-type
reactions.11 Since then, other authors have used zinc salts as addi-
tives to improve the yield and stereoselectivity of these kind of
reactions.1h,12
Recently, we studied the role of zinc acetate salt in the aldol
condensation catalyzed by single L
-prolinamide (Pde).13 We found
that Zn2þ acts like Bronsted acids by enhancing the yield and
stereoselectivity of the reaction because its coordination as a Lewis
acid to the amine nitrogen diminishes its basicity, thus preventing
the non-specific base catalyzed reaction. Zn2þ could also act by
maintaining the conformation of the acceptor fixed during the
addition of the nucleophile (Fig. 1).13a
€
On the other hand, zinc ion also acts by preventing the forma-
tion of the imidazolidinone intermediate13b (Scheme 1), resulting
in faster reactions, which are also more stereoselective than those
catalyzed by the free amine.
Despite this, the stereoselectivity achieved with the single
prolinamide model was moderate.13 In this work, we applied the
findings with this model to the more complex catalysts dipeptides.
In our study, we used dipeptides based on proline as the N-terminal
amino acid. We discovered the optimal reaction conditions to
Mechanistic studies have shown that these kind of catalysts
operate via an enamine mechanism, although different in-
termediates can be formed.8
* Corresponding author. Tel.: þ34 96 3543048; fax: þ34 96 3544328; e-mail
address: cecilia.andreu@uv.es (C. Andreu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.006

C. Andreu et al. / Tetrahedron 68 (2012) 7966e7972
7967
4-nitrobenzaldehyde and acetone was considered as test
(Scheme 2). The water content in the reaction medium was 5%,
OH
Cat
Fig. 1. Coordination of Zn2þ to (S)-Pde-enamine and to the acceptor aldehyde. The Re
attack was favoured to minimize the steric interaction between the aromatic ring
(aldehyde) and the CH3 group (enamine). Only one molecule of Pde is shown in the
complex for clarity purposes.
CH3COCH3
O2N
CHCH2COCH3
+
CHO
O2N
Scheme 2. The reaction tested in this work.
which was found to be optimal in a previous work.13a Table 1 shows
that the addition of zinc acetate as a cocatalyst led to a significant
increase in the conversion of the reaction. The use of Tris buffer
Table 1
Optimization of the reaction conditions employing 5% of PFNH2 as a catalyst
Entry Conditionsa
Time (h) Conversionb/eec (%)
1
2
3
4
5
6
7
8
9
5% Water, rt
2.5% Zn(CH3COO)2, 5% water, rt
5% Buffer, rt
24
24
24
24
42
15/49
62/50
34/55
95/53
23/60
85/60
10/63
76/64
70/64
2.5% Zn(CH3COO)2, 5% buffer, rt
5% Buffer, 0 ꢁC
2.5% Zn(CH3COO)2, 5% buffer, 0 ꢁ
5% Buffer,ꢀ20 ꢁC
C
42
120
120
120
2.5% Zn(CH3COO)2, 5% buffer,ꢀ20 ꢁ
C
5% NaCH3COO, 5% buffer,ꢀ20 ꢁ
C
Scheme 1. Inhibition by Zn2þ of imidazolidinone intermediate formation (in the
complex, only the coordination between the ion and Pde is shown. The counterion is
also bound to the Zn2þ ion.13c).
a
b
c
Reactions in acetone with 5% of water or buffer (Tris 0.04 M, pH 7.6).
Determined by NMR.
HPLC (IC, Hex/i-PrOH 94:6, 1 ml/min). When PFNH2was the catalyst the main
aldol enantiomer was that with an R configuration.
obtain the best stereochemical result, which, as expected, was
higher than with the prolinamide model.
instead of distilled water also determined a certain increase in it.
None of these additives modified stereoselectivity, which, in turn,
was affected by the drop in the temperature. The best results in this
sense were obtained at ꢀ20 ꢁC, although they were still moderate
and the reaction rate was markedly slower.
2. Results and discussion
2.1. Reaction conditions
In our experiments the non-specific base catalyzed reaction9
and also the imidazolidinone intermediate formation were pre-
vented by the use of the catalysts as trifluoroacetate salts. The
stereoselectivity was in consequence the same than when zinc salts
were used as additives.10 However, reactions were very slow when
trifluoroacetate salts were used because, under these conditions,
pyrrolidine nitrogen was not nucleophilic enough, which made the
formation of activated enamine difficult. According to the results
shown in Table 1, zinc acetate can be considered a convenient ad-
ditive in the reactions catalyzed by proline-based dipeptides.
The proline-based dipeptides used as catalysts in this study are
shown in Fig. 2. Amino acids with different characteristics were
employed as second members of the sequence, and derivatives
with different configurations in each component were obtained.
They were all easily prepared by standard solid phase synthesis
procedures using the Fmoc strategy, cleaved from the resin with
TFA and used as trifluoroacetate salts without additional
purification.
Optimization of the reaction conditions was carried out using
PFNH2 as
a catalyst, and the aldol condensation between
O
O
O
O
O
N
H
CO2H
N
H
CONH2
N
H
CONH2
N
H
CONH2
N
H
CONH2
N
H
N
H
N
H
N
H
N
H
pF-OH
Pf-NH2
pf-NH2
PF-NH2
pF-NH2
NH
CO2H
CONH2
NH2
OH
CONH2
O
O
N
O
O
O
O
N
N
H
CONH2
N
H
N
H
CON
H2
N
H
CONH2
N
H
N
N
N
N
H
N
H
H
CONH2
H
H
H
pV-NH2
pD-NH2
pW-NH2
pS-NH2
pDap-NH2
PP-NH2
Fig. 2. Proline-based dipeptides used as catalysts (protonation of the pyrrolidine ring with TFA is not shown): P¼L-proline, p¼D-proline, F¼L-phenylalanine, f¼D-phenylalanine, V¼L-
valine, W¼L-tryptophan, S¼L-serine, D¼L-aspartic acid, Dap¼L-2,3-diaminopropionic acid.

7968
C. Andreu et al. / Tetrahedron 68 (2012) 7966e7972
Nevertheless, after addition of zinc acetate, acetic acid was also
protonate the pyrrolidine nitrogen in DMSO (the broad signal at
3 ppm must contain the amine NeH and also water from the salts).
However, the zinc ion coordinates with the proline moiety, as
suggested by the deshielded broad signal corresponding to the
amide group, and also by the signals marked with numbers in Fig. 3.
The same experiments were carried out in deuterated methanol,
and similar results were obtained when we studied the region
between 1 and 5 ppm (Supplementary data). The spectra recorded
in a deuterated mixture of acetone/water (85:15) showed the
presence of different intermediate species. In this case, the in-
terpretation was also difficult because the sample was poorly sol-
uble (Supplementary data).
generated, and this (instead of Zn2þ ion) could act as a Bronsted
€
acid, which is responsible for improved yield and stereoselectivity.
In both cases, pyrrolidine nitrogen must be more nucleophilic than
when protonated with trifluoroacetic acid.1h,12
In order to know the role of both acids in the observed results,
1 equiv of sodium acetate was used as an additive under the opti-
mized conditions to reach, in this case, a similar conversion and
stereoselectivity to when the zinc salt was used (compare entries 8
and 9).
This result is not indicative of which acid, zinc, proton (or both)
coordinates with the proline moiety when zinc acetate is in use. In
order to clarify this point, we decided to run some NMR experi-
ments. Although the reactions were carried out in acetone/water
(95:5), first, and in order to visualize changes in the signals corre-
sponding to the coordinating groups (the pyrrolidine amine and the
amide group), the NMR spectra were recorded using deuterated
DMSO. Fig. 3 compares the spectrum of the PFNH2 trifluoroacetate
salt with those corresponding to this peptide after the addition of
zinc acetate and sodium acetate. Different chemical shifts of the
signals corresponding to the proline moiety were observed in all
cases. Those corresponding to trifluoroacetate salt were always the
most deshielded, while the least deshielded ones were the signals
of the species obtained after the addition of sodium acetate. The
changes observed in the ammonium/amide region (between 8 and
9 ppm) were particularly significant. When the dipeptide was as
trifluoroacetate salt, these three hydrogens appeared together.
Addition of zinc acetate (0.5 equiv) transformed this signal into
a broad one, but with less intensity. After the addition of sodium
acetate (1 equiv), a less intense and more shielded doublet
appeared (NH amide). These changes seem to indicate that the
acetic acid formed by the addition of both acetate salts does not
The positive electrospray ionization mass spectrum (ESIþ/MS) of
PFNH2etrifluoroacetate salt with 0.5 equiv of zinc acetate was also
recorded (Fig. 4). According to the results obtained in the NMR
experiments, the most intense signals (showing the characteristic
zinc isotopic pattern) corresponded to peptideezinc complexes (m/
z 324, [PFNH2$Zn]þ; m/z 585, [(PFNH2)2$Zn]þ). A less intense peak
corresponding to the protonated dipeptide was also detected (m/z
262, (PFNH2$H)þ).
All these results suggest that the addition of zinc acetate to the
trifluoroacetate peptide led to the almost quantitative deprotona-
tion of pyrrolidine nitrogen, and probably to the peptide co-
ordination mainly with the zinc ion, although some protonation
with acetic acid should not be ruled out (Scheme 3).
€
The data provided in Table 1 indicate that Bronsted and Lewis
acids are useful additives in aldol reactions catalyzed by prolina-
mide derivatives. Nonetheless, as other authors have described
9,10
€
before using Bronsted acids,
and as we found using Lewis
acids,13c acid strength must be taken into account. In this sense, it is
worth using that for which an equilibrium with the free chiral
amine allows both the reaction with the ketone and the formation
(c)
3’,4,4’
O
2,2’
N
H
CONH2
+ NaCH3COO
CF3COO-
NH amide
N
1
3
H
H
2,2’
3’,4,4’
(b)
1
O
3
N
H
CONH2
+ Zn(CH3COO)2
CF3COO-
N
H
H
NH amide
2,2’
3’,4,4’
3,3’O
1
4,4’
2,2’
3
NH ammonium
+ NH amide
N
CONH2
(a)
1
H
N
H
H
CF3COO-
Fig. 3. 1H NMR spectra in DMSO of (a) PFNH2 trifluoroacetate salt, (b) PFNH2 trifluoroacetate salt with 0.5 equiv of zinc acetate 2-hydrate, (c) PFNH2 trifluoroacetate salt with
1 equiv of sodium acetate 3-hydrate.

C. Andreu et al. / Tetrahedron 68 (2012) 7966e7972
7969
Fig. 4. ESIþ/MS in methanol of PFNH2 after addition of 0.5 equiv of Zn(CH3COO)2.
O
O
Zn2+
2
CH3COOH
2
+
N
H
CONH2
N
H
CONH2
CF COO-
+ Zn(CH3COO)2
2
+
3
.
N
N
H
CF3COO
H
H
2
Scheme 3. Species present in the equilibrium after the addition of zinc acetate to trifluoroacetate peptides.
of the activated enamine. In our case, acetic acid (generated from
trifluoroacetate salt after the addition of sodium acetate) and zinc
acetate were more convenient than trifluoroacetic acid.
Table 2
Influence of the absolute configuration of the amino acid components and the na-
ture of the dipeptide terminal end in the stereochemistry of the aldol reaction
2.2. Catalyst optimization
Entry
Catalysta
Conversionb(%)
eec(%)
1
2
3
4
5
6
7
8
9
PFNH2/Zn(CH3COO)2
PFNH2/NaCH3COO
PfNH2/Zn(CH3COO)2
PfNH2/NaCH3COO
pFNH2/Zn(CH3COO)2
pFNH2/NaCH3COO
pfNH2/Zn(CH3COO)2
pfNH2/NaCH3COO
pFOH/Zn(CH3COO)2
pFOH/NaCH3COO
76
70
89
93
80
75
88
80
87
78
64
64
86
86
86
86
64
64
86
86
Having determined the best reaction conditions, we proceeded
with catalyst optimization. It is known that the absolute configu-
ration of the aldol product depends on the configuration of the
proline in the N-terminal end.6e,6f,9 In order to verify the influence
of the second component configuration in the stereochemical
course of the reaction, we carried out aldol condensation by
employing the four prolineephenylalanine diastereomeric di-
peptides (Table 2). We found that the best stereoselectivity results
were obtained with the enantiomeric pair with configurations S,R
and R,S (entries 3e6). Differences in the dipeptide C-terminal end
did not determine a relevant influence on the stereochemical
course (entries 5, 6e9 and 10). In all cases, conversion was between
2 and 10% when the catalytic peptide was used as trifluoroacetate
salt without any additive (not shown in the table).
10
a
The reactions atꢀ20 ꢁC in acetone with 5% of buffer (Tris 0.04 M, pH 7.6).
Dipeptide of 5% and 2.5% of zinc salt or 5% of sodium acetate in relation to the
starting material were used. The mixture was analyzed after 120 h.
b
Determined by NMR.
HPLC:the aldol main enantiomer configuration was R when the dipeptides
c
starting with
-Pro (p) were being used.
L-Pro (P) were the catalysts, and S when the dipeptides starting with
D

7970
C. Andreu et al. / Tetrahedron 68 (2012) 7966e7972
Table 3 shows the results when the reaction was carried out
general the aldol reaction of ortho-disubstituted aldehydes showed
the best stereoselectivities. With non-activated aldehydes (benz-
aldehyde or 4-methoxybenzaldehyde) aldol reaction was much
slower (data not shown in the table).
using proline-based dipeptides, in which the nature of the second
component changed, using apolar (V, W, P), polar (S), acid (D) and
basic (Dap) amino acids. The synthesized catalysts configuration
With both diastereomeric catalysts, configuration of the main
enantiomer was R, but, as in the case of 4-nitrobenzaldehyde, the
enantioselectivity was higher when PfNH2 was used.
Table 3
Influence of the nature of the second amino acid component in stereochemistry and
the aldol reaction rate
3. Conclusion
Entry
Catalysta
Conversionc(%)
eed(%)
1
2
3
pVNH2/Zn(CH3COO)2
pWNH2/Zn(CH3COO)2
PPNH2/Zn(CH3COO)2
pSNH2/Zn(CH3COO)2
pDNH2/Zn(CH3COO)2
pDapNH2/Zn(CH3COO)2
50
87
6
90
6
62
80
0
80
87
85
Proline-based dipeptides catalyze aldol condensations with
good stereoselectivity, which is enhanced at low temperatures.
Conversion is low when dipeptides are used as trifluoroacetate
salts, but can increase by using zinc acetate or sodium acetate
(acetic acid) as a cocatalyst. In this work, we provide a more
in-depth insight into the knowledge of how these additives can
affect the activity and stereoselectivity of the catalyst. As we reveal,
and as other authors have shown before, addition of Zn salts11e13 or
4
5b
6
20
a
The reactions atꢀ20 ꢁC in acetone with 5% of buffer (Tris 0.04 M, pH 7.6).
Dipeptide of 5% and 2.5% of zinc salt in relation to the starting material were used.
The mixture was analyzed after 120 h.
b
The complex of pD with zinc acetate was not totally soluble in the reaction
Bronsted acids9,10 to reactions catalyzed by a proline-based catalyst,
€
mixture. The reaction was also carried out at rt for 24 h (20% conversion, 83% ee).
c
Determined by NMR.
HPLC (IC, Hex/i-PrOH 94:6, 1 ml/min). The aldol main enantiomer configuration
usually yields better stereoselectivity results. However, as we
d
recently showed using several zinc salts,13c or as other authors have
was S when using dipeptides starting with D-Pro (p).
10
€
reported when they employed different Bronsted acids, the
strength of these additives as acids must be taken into account
because a strong coordination with the pyrrolidine nitrogen can be
negative and can diminish the catalyst’s reactivity. This fact also
comes over quiet clearly in this study when trifluoroacetate salts
are employed.
We also demonstrate that the absolute aldol product configu-
ration depends only on the chirality of the N-terminal proline in the
catalyst but, on the other hand, stereoselectivity is markedly
affected by the configuration of both amino acids, and is higher for
the enantiomeric pair ReS, SeR. The nature of the second amino
acid also has some effect on product stereoselectivity and on the
reaction rate, especially when using proline.
was R,S in almost all the cases. Stereoselectivity was between
moderate and high, except when PPNH2 was used. The reaction
with this peptide was also very slow, indicating the importance of
the presence of acidic hydrogens in the peptidic bond.14 When the
branched amino acid valine was used as a second component, the
reaction was slower and less stereoselective than when other
neutral amino acids were in use. The best stereoselectivity results
were achieved for charged dipeptides pDapNH2 and pDNH2, al-
though conversion was low, perhaps due to the lower solubility of
the catalysts.
Finally, and in order to explore the general scope of this meth-
odology, the aldol reaction of acetone and a variety of aromatic
aldehydes was performed using as catalyst the diastereomeric
peptides PFNH2 and PfNH2. Table 4 shows that the nature and
position of the substituents in the aromatic ring affected both the
stereoselectivity and the reactivity of the reaction. Aldehydes with
the most electron withdrawing substituents showed high re-
activity, and the reactions were performed atꢀ20 ꢁC(entries 1e6).
With less activated aldehydes reactions were carried out at rt, and
higher amounts of catalyst had to be employed (entries 7e14). In
These results have been observed in a variety of activated
aldehydes under the optimized conditions, obtaining in some cases
excellent stereoselectivities in the aldol product.
4. Experimental
4.1. General
All the commercially available reagents were purchased from
SigmaeAldrich. The NMR spectra were recorded with Bruker DRX
300 spectrometers in different deuterated solvents. Chemical shifts
are reported in parts per million in relation to the residual solvent
peaks. High resolution mass spectra were measured in an ABSciex
TripleTOFTM-Analyzer (source gas 1 was 35 psi, gas 2, 35 psi; cur-
tain gas, 30 psi; source temperature, 400 ꢁC and IonSpray Voltage
Floating, 5500 V). Optical rotations were measured in a Perkin
Table 4
Scope of the aldehydes for the reaction with acetone under the optimized conditions
Entry
ReCHO
Catalyst
eec (%)
1
2
3
4
5
6
7
8
2-NO2C6H4CHOa
2-NO2C6H4CHOa
3-NO2C6H4CHOa
3-NO2C6H4CHOa
2,6-(CF3)2C6H3CHOa
2,6-(CF3)2C6H3CHOa
2-BrC6H4CHOb
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
PFNH2/Zn(CH3COO)2
PfNH2/Zn(CH3COO)2
75
92
75
90
88
93
50
73
47
72
90
96
60
73
Elmer 241 Polarimeter at
chromatography (HPLC) was carried out with a Merck Hitachi
Lachrom system. Determination of enantiomeric excess was
l
¼589 nm. High performance liquid
performed with a Chiralpak IC column (5
i-PrOH 94:6, 1 ml/min, wavelength for detection fixed at 254 nm).
m
m, 250ꢂ4.6 mm ID, Hex/
2-BrC6H4CHOb
9
2-ClC6H4CHOb
The analysis of the peptides used as catalysts was carried out with
10
11
12
13
14
2-ClC6H4CHOb
a LiChrospher 100 RP-18 column (10
different acetonitrile/water mixtures, detection at 214 nm).
m
m, 250ꢂ10 mm ID, 1 ml/min,
2,6-Cl2C6H3CHOb
2,6-Cl2C6H3CHOb
4-ClC6H4CHOb
4-ClC6H4CHOb
4.2. Synthesis of catalysts
a
Reactions in acetone with 5% of buffer (Tris 0.04 M, pH 7.6) and 5% of dipeptide/
2.5% of zinc salt atꢀ20 ꢁC. The mixtures were analyzed after 120 h, and the con-
version was almost quantitative.
Dipeptides were manually synthesized as either amides using
a Rink amide (aminomethyl)polystyrene resin (1.1 mmol/g) or acids
on a Wang resin (0.6e1 mmol/g). Coupling processes were followed
with 3 equiv of Fmoc amino acids, 3 equivof HOBt and 3 equivof DIC
in DMF for at least 90 min (completion was checked by the Kaiser’s
b
Reactions in acetone with 5% of buffer (Tris 0.04 M, pH 7.6) and 10% of
dipeptide/5% of zinc salt at rt. The mixtures were analyzed after 120 h, and the
conversion was almost quantitative except in the case of 4-ClC6H4CHO (50%).
c
HPLC (ExperimentalandSupplementary data).

C. Andreu et al. / Tetrahedron 68 (2012) 7966e7972
7971
test). The Fmoc group in each cycle was removed by washing twice
with 25% piperidine in DMF. After the synthesis, the resin was
washed with methylene chloride and ethyl ether, and was dried
under vacuum. For resin cleavage, the dried resin was suspended in
a fresh mixture of trifluoroacetic acid, water, phenol and triisopro-
pylsilane (88:5:5:2, 10 ml/g of resin) for 5e6 h. Then, the cleavage
cocktail containing the peptide was filtered down into chilled
diethyl ether (10 volumes in relation to the cleavage cocktail) and
stored at ꢀ80 ꢁC overnight. When dipeptide precipitated, it was
separated by centrifugation (3500 rpmꢂ15 min) and was washed
twice with cold ether. When it did not precipitate, the solvent was
removed under vacuum and then the peptide was precipitated after
the addition of chilled ethyl ether, and was centrifuged and washed
in the same way as before. The crude material was analyzed by 1H
NMR, HRMS (ESI) and HPLC after lyophilization.
(m, 1H), 2.39e2.25 (m, 1H), 3.34e3.46 (m, 2H), 4.28 (d, 6.5 Hz, 1H),
4.30e4,40 (m, 1H); tR¼7.3 min (10% acetonitrile in water); HRMS
(ESI): calcd for NaC10H19N3O2 [MþNa]þ: 236.1398, found:
236.1364; calcd for KC10H19N3O2 [MþK]þ: 252.1109, found:
252.1102; [
a
]
22 þ25 (c 0.45, MeOH).
D
4.2.8. pWNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.35e1.46
(m, 1H), 1.50e1.64 (m, 1H), 1.71e1.84 (m, 1H), 2.0e2.16 (m, 1H),
3.04e3.18 (m, 3H), 3.37 (dd,14.6, 5.1 Hz,1H), 4.05e4.14(m,1H), 4.82
(dd, 9.7, 5.1 Hz, 1H), 6.98e7.13 (m, 3H), 7.32 (d, 8H, 1H), 7.63 (d,
7.7 Hz, 1H); tR¼10.1 min (20% acetonitrile in water); HRMS (ESI):
calcd for C16H21N4O2 [MþH]þ: 301.1659, found: 301.1651; calcd for
22
NaC16H20N4O2 [MþNa]þ: 323.1478, found: 323.1470; [
(c 0.45, MeOH).
a
]
þ20.5
D
4.2.9. PPNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.92e2.14 (m,
6H), 2.22e2.59 (m, 2H), 3.32e3.75 (m, 4H), 4.34 (dd, 7, 8.5 Hz, 1H),
4.44e4.63 (m, 1H); tR¼6.8 min (2% acetonitrile in water); HRMS
(ESI): calcd for C10H18N3O2 [MþH]þ: 212.1394, found: 212.1389;
4.2.1. PFNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.92e2.09 (m,
3H), 2.31e2.44 (m, 1H), 2.94 (dd, 13.9, 9.3 Hz, 1H), 3.17 (dd, 13.9,
5.7 Hz, 1H), 3.22e3.37 (m, 2H), 4.15 (m, 1H), 4.66 (dd, 9.3, 5.7 Hz,
1H), 7.18e7.33 (m, 5H); 1H NMR (DMSO): 1.70e1.90 (m, 3H),
2.12e2.31 (m, 1H), 2.80 (dd, 14, 10 Hz, 1H), 3.08 (dd, 14, 5 Hz, 1H),
3.09e3.18 (m, 1H), 4.06 (m, 1H), 4.45e4.53 (m, 1H), 7.15 (s, 1H),
7.18e7.28 (m, 5H), 7.61 (s, 1H), 8.60, 8.71 (m, 3H); tR¼5.9 min (20%
acetonitrile in water); HRMS (ESI): calcd for C14H20N3O2 [MþH]þ:
262.1550, found: 262.1541; calcd for NaC14H19N3O2 [MþNa]þ:
284.1369, found: 284.1360.
[a
]
22 ꢀ56 (c 0.375, MeOH).
D
4.2.10. pSNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.99e2.16
(m, 3H), 2.35e2.52 (m, 1H), 3.33e3.48 (m, 2H), 3.82 (2, 5.3 Hz, 2H),
4.31e4.41 (m, 1H), 4.44 (t, 5.3 Hz, 1H); tR¼4.3 min (2% acetonitrile
in water); HRMS (ESI): calcd for C8H16N3O3 [MþH]þ: 202.1186,
found: 202.1178; calcd for NaC8H15N3O3 [MþNa]þ: 224.1006,
found: 224.1000; [
a
]
22 þ31 (c 0.38, MeOH).
D
4.2.2. Zn$(PFNH2)2. 1H NMR (DMSO): 1.64e1.70 (m, 3H), 2.15e2.27
(m, 1H), 2.84 (dd, 14, 10 Hz, 1H), 2.88e2.94 (m, 1H), 3.03 (dd, 14,
5 Hz, 1H), 3.81e3.86 (m, 1H), 4.45e4.53 (m, 1H), 7.17 (s, 1H),
7.18e7.28 (m, 5H), 7.62 (s, 1H), 8.60, 8.91 (s, 1H); ESIþ/MS (MeOH):
m/z 324, [PFNH2$Zn]þ; m/z 585, [(PFNH2)2$Zn]þ.
4.2.11. pDNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.93e2.09
(m, 3H), 2.32e2.45 (m, 1H), 2.70 (dd, 16.7, 9.2 Hz, 1H), 2.90 (dd, 16.7,
4.7 Hz, 1H), 3.34e3.46 (m, 2H), 4.30e4.35 (m, 1H), 4.77 (dd, 9.2,
4.7 Hz,1H); tR¼4.0 min (2% acetonitrile in water); HRMS (ESI): calcd
for C9H16N3O4 [MþH]þ: 230.1135, found: 230.1128; calcd for
4.2.3. PfNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.41e1.53
(m, 1H), 1.65e1.74 (m, 1H), 1.82e1.94 (m, 1H), 2.08e2.22 (m, 1H),
3.00 (dd, 13.9, 10.6 Hz, 1H), 3.16e3.36 (m, 3H), 4.15e4.24 (m, 1H),
4.76 (dd, 10.6, 4.9 Hz, 1H), 7.18e7.33 (m, 5H); tR¼8.0 min (20%
acetonitrile in water); HRMS (ESI): calcd for C14H20N3O2 [MþH]þ:
NaC9H15N3O4 [MþNa]þ: 252.0955, found: 252.0951; [
a]
22 þ16.5 (c
D
0.52, MeOH).
4.2.12. pDapNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.98e2.19
(m, 3H), 2.36e2.48 (m, 1H), 3.21 (dd, 13.1, 7.3 Hz,1H), 3.34e3.46 (m,
3H), 4.38 (dd, 8.3, 6.8 Hz, 1H), 4.72 (dd, 7.2, 6.3 Hz, 1H); tR¼4.1 min
(2% acetonitrile in water); HRMS (ESI): calcd for C8H17N4O2
262.1550, found: 262.1545; calcd for NaC14H19N3O2 [MþNa]þ:
22
284.1369, found: 284.1364; [
a
]
ꢀ38 (c 0.61, MeOH).
D
[MþH]þ: 202.1186, found: 202.1178; calcd for NaC8H16N4O2
22
4.2.4. pFNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.42e1.53
(m, 1H), 1.64e1.74 (m, 1H), 1.82e1.94 (m, 1H), 2.08e2.22 (m, 1H),
3.00 (dd, 13.9, 10.6 Hz, 1H), 3.16e3.36 (m, 3H), 4.17e4.24 (m, 1H),
4.76 (dd, 10.6, 4.8 Hz, 1H), 7.18e7.33 (m, 5H); tR¼8.3 min (20%
acetonitrile in water); HRMS (ESI): calcd for C14H20N3O2 [MþH]þ:
262.1550, found: 262.1543; calcd for NaC14H19N3O2 [MþNa]þ:
284.1369, found: 284.1362.
[MþNa]þ: 223.1165, found: 223.1158; [
a
]
þ10 (c 0.49, MeOH).
D
4.3. The typical aldol condensation procedure
Aldol reactions were monitored by thin-layer chromatography
(TLC) on Merck silica plates 60 F254. Flash chromatography was
performed on Merck silica gel (60-particle size: 0.040e0.063 mm).
The absolute configurations of the products were determined by
comparing them with the optical rotations reported in the litera-
ture. The enantiomeric excess was determined by high perfor-
mance liquid chromatography HPLC (Chiralpak IC).
4.2.5. pfNH2 (trifluoroacetate salt). 1H NMR (MeOD): 1.98e2.06
(m, 3H), 2.33e2.44 (m, 1H), 2.94 (dd, 13.9, 9.3 Hz, 1H), 3.17 (dd, 13.9,
5.6 Hz, 1H), 3.19e3.42 (m, 2H), 4.09e4.21 (m, 1H), 4.66 (dd, 9.3,
5.6 Hz, 1H), 7.18e7.33 (m, 5H); tR¼5.9 min (20% acetonitrile in
water); HRMS (ESI): calcd for C14H20N3O2 [MþH]þ: 262.1550,
found: 262.1543; calcd for NaC14H19N3O2 [MþNa]þ: 284.1369,
The 4-nitrobenzaldeyde (0.1 mmol, 15 mg) solution was pre-
pared in acetone (2.375 ml) in a capped vial. The dipeptide catalyst
found: 284.1364; [
a
]
22 þ18 (c 0.46, MeOH).
(5%), dissolved in Tris buffer (0.08 M, PH 7.6, 62.5
ml), and the zinc
D
acetate dehydrate (2.5%), dissolved in deionized water (62.5
ml),
4.2.6. pFOH (trifluoroacetate salt). 1H NMR (MeOD): 1.40e1.51
(m, 1H), 1.60e1.74 (m, 1H), 1.81e1.94 (m, 1H), 2.08e2.22 (m, 1H),
2.83 (dd, 13.9, 10.8 Hz, 1H), 3.21e3.27 (m, 3H), 4.21 (dd, 8.20, 6.4 Hz,
1H), 4.76 (dd, 10.8, 4.8 Hz, 1H), 7.18e7.31 (m, 5H); tR¼7.6 min (20%
acetonitrile in water); HRMS (ESI): calcd for C14H19N2O3 [MþH]þ:
were mixed and added to the substrate. The reaction mixture was
kept at the indicated temperature, monitored by TLC and quenched
by the addition of a saturated ammonium chloride solution. After
acetone evaporation, water was extracted with methylene chloride
and the organic phase was dried over sodium sulfate. The crude
material was employed to determine the conversion by NMR and
the ee by HPLC using a chiral stationary phase.
263.1390, found: 263.1388; [
a
]
22 þ37 (c 0.47, MeOH).
D
4.2.7. pVNH2 (trifluoroacetate salt). 1H NMR (MeOD): 0.96
(d, 6.5 Hz, 3H), 0.98 (d, 6.5 Hz, 3H), 1.96e2.09 (m, 3H), 2.09e2.20
The reaction product was purified previously by column chro-
matography (hexane/ethyl acetate 4:1) and was characterized by

7972
C. Andreu et al. / Tetrahedron 68 (2012) 7966e7972
ꢃ NMR SPECTRA in DMSO-d6, S2
NMR and chiral HPLC. Data were consistent with those described in
the literature.15
ꢃ NMR SPECTRA in MeOD, S4
ꢃ NMR SPECTRA in deuterated acetone/water, S6
ꢃ ESI-MS (PFNH2 trifluoroacetate salt)$Zn(AcO)2, S7
ꢃ Products: NMR spectra/HPLC analysis, S8
4.3.1. 4-Hydroxy-4-(4-nitrophenyl)-butan-2-one. 1H NMR (CDCl3):
2.21 (s, 3H), 2.84 (m, 2H), 3.60 (s, 1H), 5.26 (m, 1H), 7.53 (d, 8.8 Hz,
2H), 8.20 (d, 8.8 Hz, 2H). Enantiomeric excess: HPLC, Chiralpak IC
column, Hex/i-PrOH 94:6, 1 ml/min (tR¼31.5 min S; tR¼33.6 min R).
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.006.
4.3.2. 4-Hydroxy-4-(2-nitrophenyl)-butan-2-one.15 1H NMR (CDCl3):
2.16 (s, 3H), 2.63 (dd, 17.8 Hz, 9.4 Hz, 1H), 3.09 (dd, 17.8 Hz, 2.0 Hz),
3.90(s, 1H), 5.60 (m,1H), 7.46 (m,1H), 7.67 (m,1H), 7.88 (m, 1H), 7.96
(m, 1H). Enantiomeric excess: HPLC, Chiralpak IC column, Hex/i-
PrOH 90:10, 1 ml/min (tR¼20.8 min S; tR¼34.6 min R).
References and notes
1. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Guillena, G.; Najera, C.;
ꢁ
Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (d) Dondoni, A.; Massi, A.
Angew. Chem., Int. Ed. 2008, 47, 4638; (e) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (f) Bertelsen, S.; Jorgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178; (g) Buckley, B. P.; Fatah, M. M. Annu. Rep. Prog.
Chem., Sect. B 2011, 107, 102; (h) Paradowska, J.; Stodulski, M.; Mlynarski, J.
Angew. Chem., Int. Ed. 2009, 48, 4288.
2. (a) Modern Aldol Reactions; Marhwald, R., Ed.; Wiley-VCH: Weinheim, 2004; (b)
Zlotin, S. G.; Kucherenko, A. S.; Beletskaya, I. P. Russ. Chem. Rev. 2009, 78, 737.
3. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395; (b)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260;
(c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
4.3.3. 4-Hydroxy-4-(3-nitrophenyl)-butan-2-one.15 1H NMR (CDCl3):
2.23 (s, 3H), 2.90 (m, 2H), 3.59 (s,1H), 5.30 (m,1H), 7.53 (m,1H), 7.70
(m, 1H), 8.09 (m, 1H), 8.24 (m, 1H). Enantiomeric excess: HPLC,
Chiralpak IC column, Hex/i-PrOH 86:14, 1 ml/min (tR¼17.4 min R;
tR¼18.9 min S).
4.3.4. 4-Hydroxy-4-(2-bromophenyl)-butan-2-one.11d 1H
NMR
4. (a) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759;
(b) Wennemers, H. Chem. Commun. 2011, 12036.
5. (a) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sunden, H.; Cordova, A. Chem. Commun.
(CDCl3): 2.26 (s, 3H), 2.65 (dd, 18, 10 Hz, 1H), 3.00 (dd, 18, 2 Hz, 1H),
3.5 (s, 1H), 5.44 (dd, 10, 2 Hz, 1H), 7.13 (dd, 7.8, 2 Hz, 1H), 7.34 (dd,
7.8, 2 Hz, 2H), 7.5 (dd, 7.8, 2 Hz), 7.6 (dd, 7.8, 2 Hz). Enantiomeric
excess: HPLC, Chiralpak IA column, Hex/i-PrOH 97:3, 1 ml/min
(tR¼15.6 min R; tR¼17.7 min S).
ꢁ
ꢁ
ꢁ
ꢁ
2005, 4946; (b) Dziedzic, P.; Zou, W. M.; Hafren, J.; Cordova, A. Org. Biomol.
Chem. 2006, 4, 38.
6. (a) Martin, H. J.; List, B. Synlett 2003, 1901; (b) Kofoed, J.; Nielsen, J.; Reymond,
J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445; (c) Shi, L. X.; Sun, Q.; Ge, Z. M.; Zhu,
Y. Q.; Cheng, T. M.; Li, R. T. Synlett 2004, 2215; (d) Tang, Z.; Yang, Z. H.; Cun, L. F.;
Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett. 2004, 6, 2285; (e) Luppi, G.; Cozzi, P.
G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005,
70, 7418; (f) Chen, F.; Huang, S.; Zhang, H.; Liu, F.; Peng, Y. Tetrahedron 2008, 64,
9585; (g) Tian, H.; Gao, I.-J.; Xu, H.; Zheng, L.-Y.; Huang, W.-B.; Liu, Q. W.;
Zhamg, S. Q. Tetrahedron: Asymmetry 2011, 22, 1074.
4.3.5. 4-Hydroxy-4-(2-chlorophenyl)-butan-2-one.11d 1H NMR (CDCl3):
2.21 (s, 3H), 2.68 (dd,18, 9 Hz,1H), 2.98 (dd,18, 2.2 Hz,1H), 3.65 (s,1H),
5.50 (dd, 9, 2.1 Hz, 1H), 7.20 (m, 1H), 7.34 (m, 2H), 7.62 (m, 1H). En-
antiomeric excess: HPLC, Chiralpak IA column, Hex/i-PrOH 97:3, 1 ml/
min (tR¼14.7 min R; tR¼16.7 min S).
7. (a) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005,
7, 1101; (b) Revell, J. D.; Wennemers, H. Curr. Opin. Chem. Biol. 2007, 11, 269; (c)
Revell, J. D.; Wennemers, H. Adv. Synth. Catal. 2008, 350, 1046.
4.3.6. 4-Hydroxy-4-(2,6-dichlorophenyl)-butan-2-one.15 1H
NMR
8. (a) Hoang, L.; Bahmanyar, S.; Houk, K. M.; List, B. J. Am. Chem. Soc. 2003, 125, 16;
(b) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273; (c) List, B.;
Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5839; (d) Isart, C.;
(CDCl3): 2.21 (s, 3H), 2.68 (dd, 17.3, 3.1 Hz, 1H), 3.24 (m, 1H), 3.41
(dd, 17,2, 7 Hz, 1H), 5.26 (m, 1H), 7.01 (dd, 7.2, 7.2 Hz, 1H), 7.23 (m,
2H). Enantiomeric excess: HPLC, Chiralcel ODH column, Hex/i-PrOH
98:2, 1 ml/min (tR¼21.2 min S; tR¼22.7 min R).
ꢁ
Bures, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 5414; (e) Sharma, A. K.; Sunoj, R. B.
Angew. Chem., Int. Ed. 2010, 49, 6373; (f) Schmid, M. B.; Zeitler, K.; Gschwind, R.
M. Angew. Chem., Int. Ed. 2010, 49, 4997; (g) Zhu, H.; Clemente, F. R.; Houk, K. N.;
Meyer, P. M. J. Am. Chem. Soc. 2009, 131, 1632.
9. (a) Chimni, S. S.; Majan, D. Tetrahedron: Asymmetry 2006, 17, 2108; (b) Chimni,
S. S.; Singh, S.; Majan, D. Tetrahedron: Asymmetry 2008, 19, 2276; (c) Chimni, S.
S.; Singh, S.; Kumar, A. Tetrahedron: Asymmetry 2009, 20, 1722.
4.3.7. 4-Hydroxy-4-(2,6-ditrifluoromethylphenyl)-butan-2-one. 1H
NMR (CDCl3): 2.21 (s, 3H), 2.80 (m, 2H), 3.70 (s, 1H), 5.60 (m, 1H),
7.64 (d, 8.4 Hz), 7.7 (d, 8.4 Hz, 1H), 8.13 (m, 1H). Enantiomeric ex-
cess: HPLC, Chiralpak IA column, Hex/i-PrOH 97:3, 1 ml/min
(tR¼7.8 min R; tR¼9.3 min S).
10. (a) Gryko, D.; Lipinski, R. Eur. J. Org. Chem. 2006, 3864; (b) Gryko, D.; Zimnicka,
ꢁ
M.; Lipinski, R. J. Org. Chem. 2007, 72, 964; (c) Fuentes de Arriba, A. L.; Simon, L.;
ꢁ
ꢁ
Raposo, C.; Alcazar, V.; Moran, J. R. Tetrahedron 2009, 65, 4841; (d) Fuentes de
ꢁ
ꢁ
~
ꢁ
Arriba, A. L.; Simon, L.; Raposo, C.; Alcazar, V.; Sanz, F.; Muniz, F. M.; Moran, J. R.
Org. Biomol. Chem. 2010, 8, 2979.
11. (a) Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090; (b) Kofoed, J.;
Reymond, J. L.; Darbre, T. Org. Biomol. Chem. 2005, 3, 1850; (c) Kofoed, J.;
Machuqueiro, M.; Reymond, J.-L.; Darbre, T. Chem. Commun. 2004, 1540; (d)
4.3.8. 4-Hydroxy-4-(4-chlorophenyl)-butan-2-one.11d 1H
NMR
(CDCl3): 2.19 (s, 3H), 2.80 (m, 2H), 3.38 (s, 1H), 5.11 (dd, 8, 4 Hz, 1H),
7.30 (m, 4H). Enantiomeric excess: HPLC, Chiralpak IA column, Hex/
i-PrOH 97:3, 1 ml/min (tR¼23.4 min R; tR¼24.8 min S).
ꢁ
ꢁ
Fernandez-Lopez, R.; Kofoed, J.; Machuqueiro, M.; Darbre, T. Eur. J. Org. Chem.
2005, 5268; (e) Kofoed, J.; Darbre, T.; Reymond, J.-L. Chem. Commun. 2006,
1482.
12. (a) Paradowska, J.; Stodulski, M.; Mlynarski, J. Adv. Synth. Catal. 2007, 349, 1041;
(b) Penhoat, M.; Barbry, D.; Rolando, C. Tetrahedron Lett. 2011, 52, 159; (c) Itoh,
S.; Kitamura, M.; Yamada, Y.; Aoki, S. Chem.dEur. J. 2009, 15, 10570; (d)
Paradowska, J.; Pasternak, M.; Gut, B.; Gryzlo, B.; Mlynarski, J. J. Org. Chem.
2012, 77, 173.
Acknowledgements
ꢁ
This work has been supported by Spanish Direccion General de
ꢁ
ꢁ
1
3. (a) Andreu, C.; Asensio, G. Tetrahedron 2011, 67, 7050; (b) Andreu, C.; Varea, T.;
Investigacion Científica y Tecnica (CTQ 2010-19999). We gratefully
Asensio, G. Tetrahedron 2011, 67, 8705; (c) Andreu, C.; Sanz, F.; Asensio, G., in
press. http://dx.doi.org/10.1002/ejoc.201200430.
ꢀ
acknowledge SCSIE (Universitat de Valencia) for access to its in-
strumental facilities.
Supplementary data
Description:
14. (a) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad.
ꢁ
ꢁ
Sci. U.S.A. 2004, 101, 5755; (b) Gryko, D.; Chrominski, M.; Pielancinska, D. J.
Symmetry 2011, 3, 265.
15. (a) Russo, A.; Botta, G.; Lattanzi, A. Tetrahedron 2007, 63, 11886; (b) Tang, Z.;
Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am.
Chem. Soc. 2003, 125, 5262.