A comprehensive investigation and optimisation on the proteinogenic amino acid catalysed homo aldol condensation

Article abstract of DOI:10.1016/j.tet.2015.11.069

A systematic investigation regarding the application of catalytic amounts of all 20 proteinogenic amino acids in the homo aldol condensation of aldehydes is described obtaining excellent yields of the desired α,β-unsaturated aldehyde. These investigations

Full text of DOI:10.1016/j.tet.2015.11.069

Accepted Manuscript
A Comprehensive Investigation and Optimisation on the Proteinogenic Amino Acid
catalysed Homo Aldol Condensation
Karoline A. Ostrowski, Dominik Lichte, Moritz Stuck, Andreas J. Vorholt
PII:
S0040-4020(15)30251-9
10.1016/j.tet.2015.11.069
TET 27326
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 August 2015
Revised Date: 25 November 2015
Accepted Date: 30 November 2015
Please cite this article as: Ostrowski KA, Lichte D, Stuck M, Vorholt AJ, A Comprehensive Investigation
and Optimisation on the Proteinogenic Amino Acid catalysed Homo Aldol Condensation, Tetrahedron
(2016), doi: 10.1016/j.tet.2015.11.069.
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ACCEPTED MANUSCRIPT
Graphical Abstract
20 proteinogenic amino acids were applied as organocatalysts in the homo aldol condensation of
aldehydes. Basic amino acids were highly active at low catalyst concentrations and aromatic amino
acids generated very good yields in short reaction times. The side chain groups have no catalytic
activity, but they have a big impact on the catalytic activity. A general method was developed, being
transferable to other substrates.

ACCEPTED MANUSCRIPT
A Comprehensive Investigation and Optimisation on the Proteinogenic
Amino Acid catalysed Homo Aldol Condensation
Karoline A. Ostrowski, Dominik Lichte, Moritz Stuck, Andreas J. Vorholt*
Department of Bio- and Chemical Engineering, TU Dortmund, Emil-Figgestr. 66, 44227 Dortmund, Germany;
Fax: (+49)-231-755-2311; phone: (+49)-231-755-2313; e-mail: andreas.vorholt@bci.tu-dortmund.de
Abstract
A systematic investigation regarding the application of catalytic amounts of all 20 proteinogenic amino acids in the
homo aldol condensation of aldehydes is described obtaining excellent yields of the desired α,β-unsaturated aldehyde.
These investigations proved the basic amino acids, lysine and arginine, are effective as organocatalysts, if comparably
low concentrations are applied. Through the stepwise and systematic condition alteration, the reaction could be
optimised and successfully transferred to other substrates with longer, branched or functionalised alkyl chains. The
highest yields are observed with tryptophan as organocatalyst in only one hour reaction time with TONs of up to 27.
Keywords
Aldol Condensation; Aldehyde; Organocatalysis; Amino Acid
1. Introduction
The aldol reaction is a C-C bond forming reaction between aldehydes and/or ketones and was already described in the
19th century.1 The aldol condensation of aldehydes is a very effective tool, gaining α,β-unsaturated aldehydes, which
can be used in further organic reactions, especially in the dienamine catalysis2 or in tandem catalyses3.
In industry, the homo aldol condensation (HAC) is an essential reaction step to form the precursor 2-ethylhex-2-enal
from butanal, which is used in the synthesis of different plasticisers, e.g. DEHP = bis(2-ethylhexyl)phthalate. The latter
has the highest market share of 54% regarding the global plasticiser consumption.4 Therein, butanal undergoes a base
catalysed homo aldol condensation to 2-ethylhex-2-enal in a sodium hydroxide solution.
Besides the base catalysed homo aldol condensation of aldehydes in industry,5 further investigations and catalyst
developments were made with organic metal salts (2,4,6-trimethylphenoxymagnesium bromide)6, transition metal
complexes7, electrolysis8, acids9, amines10, amine/acid mixtures11 and immobilised amines on silica12.
Amino acids occupy a special position in organocatalysis having an amine and an acid function in their molecular
structure. An advantage of applying amino acids is given by their ubiquitous existence being precursors of proteins.13
They are easily accessible and have no GHS hazard statements. Therefore, they can be described as green reagents, if
applied in chemical reactions.14
The first amino acid catalysed HAC was carried out with alanine as catalyst and acetaldehyde as substrate.15 Later,
only scattered examples were dealing with the amino acid catalysed HAC of aldehydes.16 The multiple homo aldol
condensation of acetaldehyde with proline led to 2,4-hexadienal, which was not investigated intensively and was
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formed in 5% yield after two aldol condensation steps with 3 equivalents of acetaldehyde.16a A kinetic study with
arginine, glycine, serine, alanine and proline16b,c revealed a complex kinetic behaviour, if arginine was used as catalyst
in the HAC of acetaldehyde, which can form higher aldol condensation products. Therein, large rate constants were
observed with a maximum at small catalyst concentrations, due to the transition from a first order reaction into a
second order reaction. Therefore, the second order reaction is limiting the aldol condensation.
An environmentally friendly, green (water as solvent or no solvent) and transferable method to other substrates was
established, wherein 10 mol% of lysine catalyses the HAC of aldehydes with unfunctionalised alkyl chains up to
C9-aldehydes in moderate to good yields of 46% - 75%. The application of arginine as catalyst was not pursued any
further in this case, since only a yield of 24% was obtained. Therein, a turnover number (TON) up to 7.5 and a
turnover frequency (TOF) up to 3.75 h-1 was achieved for unfunctionalised aldehydes.16d (Scheme 1)
Scheme 1. Established homo aldol condensation (HAC)16d
Amino acids can be used in the cross aldol condensation, which is described by an intermolecular aldol condensation
between different substrates. With proline-triethylamine as catalyst, a ketone C-glycoside undergoes the aldol
condensation with different ketones and aromatic aldehydes.17
Furthermore, an aldol condensation allows the generation of a stereo centre depending on the initial substrates. The
application of enantiopure organocatalysts in an intramolecular aldol condensation enables asymmetric
organocatalyses leading to products with high enantiomeric excesses. The first examples were given with stereoid
cyclodione backbones as substrates and amino acids as catalysts. Therein, L-proline, L-alanine and L-phenylalanine
were applied as organocatalysts and HClO4 as additive simulating the dehydration.18 Later, this reaction was extended
to other product derivatives and up to 14 proteinogenic amino acids were compared with each other regarding their
catalytic activities, reaction times, yields and enantiomeric excesses in the intramolecular aldol condensation. The
“organocatalyst” was used equimolar to the substrate with HClO4 as additive.19
In the beginning of this millennium, first investigations towards the asymmetric cross aldol addition with amino acids
have been made. The cross aldol addition of acetone with aldehydes is catalysed with 30 mol%
achieving very high yields and enantiomeric excess. This protocol was extended to α-unsubstituted substrates as
aldehydes.21 The cross aldol addition between aldehydes in DMF with 10 mol%
-proline at low temperatures led to
L
-proline20 in DMSO
L
comparable results.22 Therefore, proline has an exceptional position in organacatalysis, since a lot of organocatalysts
are based on the five membered ring structure of proline.23
The cross aldol addition between ketones and aldehydes was extended to primary amino acids24 using 20 mol%
catalyst, e.g. isoleucine, with long reaction times of 7 d25 or 30 mol% catalyst, e.g. valine, with very high yields and
also long reaction times of 3 d.26
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In this publication we fill the gap by giving a comprehensive overview on the reactivity of all 20 proteinogenic amino
acids at same reaction conditions in the homo aldol condensation (HAC) of aldehydes. This systematic investigation
enables a direct comparison between each amino acid, which was not possible yet, due to a scattered data set.16 The
model substrate butanal was chosen as linear alkyl aldehyde with an industrial background being an important
precursor for plasticisers. From this data, we established a general method for the homo aldol condensation with
different substrates using simple, green, mild and environmentally friendly conditions. Short reaction times (down to
1 h), amino acids as green catalysts with low catalyst loading (down to 3.33 mol%) and ethanol as a green solvent,
which can be removed easily, were employed. Excellent yields, with high TONs and TOFs, were obtained if compared
to other amino acid cataysed aldol reactions, which needed long reaction times in questionable solvents, e.g. DMF.27
2. Results & Discussion
We set our focus on the homo aldol condensation of unmodified aldehydes as starting material (Scheme 2). In all
experiments the trans aldol condensate of butanal was the major product with a trans/cis ratio of > 20.
Scheme 2. Homo aldol condensation of butanal
For a better overview and a separate assessment we divide the investigated 20 proteinogenic amino acids in five
groups, which are displayed in Figure 1. We used them as drawn, since their L-form is easily commercially available.
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O
O
O
O
O
O
OH
OH
OH
OH
OH
OH
NH2
NH2
NH2
NH2
NH2
NH
Proline
Isoleucine
Glycine
Alanine
Valine
Leucine
Group I
O
O
O
OH
OH
OH
NH2
Tyrosine
NH2
NH2
HN
HO
O
Tryptophan
Phenylalanine
Group II
O
O
OH
O
S
OH
HS
OH
OH
HO
OH
NH2
NH2
Cysteine
NH2
NH2
Serine
Threonine
Methionine
Group III
O
O
O
O
O
O
H2N
HO
OH
H2N
OH
OH
HO
OH
O
NH2
NH2
O
NH2
NH2
Asparagine
Glutamine
Aspartatic Acid
Glutamatic Acid
Group IV
NH
O
O
O
H2N
N
H2N
N
H
OH
OH
OH
NH2
NH2
NH2
HN
Lysine
Arginine
Histidine
Group V
Figure 1. Amino acids divided in different groups
2.1 Systematic investigation of all 20 amino acids
We wanted to use simple conditions with only a few reagents, which can be easily removed and are non-toxic. The
established reaction system should be transferable to other substrates, wherefore we used ethanol to ensure a
homogenous solution of polar and non-polar reagents. Furthermore, we are already thinking about future developments
using this homo aldol condensation as a tool for more complex conversions in e.g. tandem catalyses,28 wherefore a
simple reaction system is desirable for having more changing options.
In the first part of our investigation, different catalytic amounts between 1.67 mol% and 20 mol% of each amino acid
were employed in the homo aldol condensation of butanal for a better comparability regarding their catalytic activity
as organocatalysts by not using them in stoichiometric amounts.
Aromatic amino acids are characterised by aromatic groups in their side chain. The results of applying aromatic amino
acids, Group II (Figure 1) is given in Figure 2 displaying observed yields over catalyst concentration. Tryptophan
(indol side chain) and phenylalanine (phenyl side chain) already led to excellent yields, if only 3.33 mol% were used.
This is a great catalyst amount, since other publications regarding the amino acid catalysed aldol reaction are dealing
with higher catalyst concentrations of 20-30mol%. A quantitative yield was observed, if 20 mol% tryptophan were
used. Nevertheless, it is quite astonishing why no conversion could be observed, if tyrosine was applied. The only
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difference to phenylalanine is given by the phenol group. Presumably, tyrosine is active at higher concentrations (from
approx. 30 mol%) needing higher reaction times. This is strengthened due to the investigation regarding the cross aldol
addition of ketones with aldehydes. While 20 mol% tyrosine gave only traces of the product after 7 d,25 a moderate
yield of the cross aldol product was obtained after 53 h by applying 30 mol% of tyrosine.26b
Aromatic Amino Acids - Goup II
100
90
80
70
60
50
Tryptophan
40
Phenylalanine
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
Amino Acid [mol%]
Figure 2. Yield over catalyst concentration plot of Group II; Conditions: 3 mmol butanal, amino acid, 1 mL
EtOH, r.t., 16 h; tyrosine is not displayed due its inactivity at given catalyst concentrations.
An interesting trend is given in the aldol catalysed reaction with basic amino acids from Group V (Figure 1) displayed
in Figure 3. These amino acids have further basic functionalities in their side chain. Experiments with histidine
(imidazole side chain) as catalyst showed a general trend: the more catalyst is applied, the more yield can be observed
with 29% yield at a concentration of 20 mol% catalyst. On the other hand, lysine (primary amino side chain) and
arginine (guanidin side chain) as catalysts led to a maximum regarding the obtained yield, which resulted in high
yields at low catalyst amounts. Lysine has its maximum at 3.33 mol% giving 82% yield and arginine at 6.67 mol%
giving 85% yield. The results of arginine in the homo aldol condensation of butanal are in good agreement with the
kinetic studies of Córdova and coworkers regarding the homo aldol condensation of acetaldehyde.16b,c Therein, the rate
constants are varying with the concentration of the amino acid arginine. At low concentrations the rate constant is
described by the first order, which is increasing linearly with the catalyst concentration and limited by the enamine
formation. At higher concentrations, the reaction is described by the second order, which is limiting the overall
reaction speed leading to lower yields controlled by the C-C bond formation. With arginine as catalyst, the transition
from the first to the second order was reached at quite low catalyst amounts. In this publication, we could proof the
same tendency with lysine as organocatalyst and with the application of longer chain aldehydes.
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Basic Amino Acids - Group V
100
90
80
70
60
50
40
30
20
10
0
Arginine
Lysine
Histidine
0
2
4
6
8
10
12
14
16
18
20
Amino Acid [mol%]
Figure 3. Yield over catalyst concentration plot of Group V; Conditions: 3 mmol butanal, amino acid, 1 mL
EtOH, r.t., 16 h.
Results of group I, III and IV showed lower yields and can be found in the supporting information.
In summary, the systematic investigations revealed each activity of the 20 proteinogenic amino acids applied in
catalytic amounts in the homo aldol condensation of the unfunctionalised aldehyde butanal in ethanol. Tryptophan,
phenylalanine, arginine and lysine led to very good to excellent yields. In contrast to other publications in the field of
amino acid catalysed aldol reactions, which often used about 30 mol% of amino acid, in here, low catalyst
concentrations (3.33 mol% - 6.67 mol%) are sufficient furnishing 82% to 94% yield for the desired product.
2.2 Elaborating the catalytically active centre
There is no doubt that the α-amine in the amino acid is a catalytic active in the mechanism of the homo aldol
condensation, since the amino acids in Group I are leading to the desired product if applied as organocatalysts.
However, some amino acids are having further potential catalytically active centres by bearing other amine groups in
their side chains. In order to shed some light into the catalytic activity of the side chain groups of the amino acid, we
applied amines as surrogates of the side chains of lysine (n-butyl amine), arginine (guanidine) and tryptophan (indole).
Additionally, these experiments were carried out with and without acetic acid simulating an amino acid muixture under
same conditions as the experiments before.
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Table 1: Applying model catalysts in the homo aldol condensation
No.
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
amine
acetic acid
Y
<1
<1
<1
6
-
+
-
indole
n-butyl amine
+
-
<1
3
guanidine carbonate
+
-
<1
<1
---
guanidine hydrochloride
---
+
+
Conditions: 3 mmol butanal, 6.67 mol% amine, 6.67 mol% acetic acid, 1 mL EtOH, r.t., 16 h. Results in %.
No significant catalytic activity was observed, if indole, n-butyl amine and guanidine were applied as organocatalysts
in the homo aldol condensation (entries 1.1, 1.3 and 1.5). Guanidine was used as carbonate and hydrochloride salt, due
to their easily availability. The addition of acetic acid is slightly increasing the yield to 6% (entry 1.4) and 3% (entry
1.6), if applied together with n-butyl amine or guanidine carbonate. Similar results with n-butyl amine and acetic acid
(entry 1.4) are achieved if compared to the glycine catalysed homo aldol condensation (please see the Supporting
Information), which is quiet well explainable, since both catalytic systems are having no substituents. Acetic acid has
no catalytic activity (entry 1.9). These experiments proved, that the catalytically active centre is the α-amino group.
The corresponding side groups are increasing or decreasing the catalytic activity of the α-amino group. Interactions
with aromatic side groups within the mechanism are conceivable in the case of phenylalanine and tryptophan. These
interactions are increasing the activity obtaining excellent yields. Lysine and arginine are the most basic applied amino
acids with an unusual trend as seen in Figure 3. Therefore, the basicity should be responsible and determining the
catalytically activity at low catalyst amounts, since at high catalyst amounts the reaction order is changing.
2.3 Reaction progress
For getting a better insight into the reaction, we investigated the reaction progress over time, simultaneously
optimising the reaction to shorter reaction times. Tryptophan, phenylalanine, lysine and arginine were chosen for the
detailed investigation, due to their high reactivity obtaining high yields.
First, the reaction progress of tryptophan and phenylalanine was investigated and the results are displayed in Figure 4.
After 6 h comparable yields of 91% to 94% were obtained by either using tryptophan or phenylalanine. The superior
advantage of the catalyst tryptophan is its high activity, wherefore an excellent yield of 95% was reached after only 1 h
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with a TON of 14, if 6.67 mol% tryptophan was used. The addition of 3.33 mol% tryptophan is still leading to a very
good yield of 90% after 1 h, with a higher TON of 27.
Aromatic Amino Acids - Reaction Progress
100
90
80
70
3.33 mol%
Tryptophan
60
50
6.67 mol%
Tryptophan
40
30
20
10
0
6.67 mol%
Phenylalanine
0
2
4
6
8
10
12
14
16
time [h]
Figure 4. Yield over time plot; conditions: 3 mmol butanal, amino acid, 1 mL EtOH, r.t.
The same investigation of the reaction progress was made with lysine and arginine. (Figure 5) The reaction rate of
arginine was lower resulting in a longer reaction time of 16 h yielding 85%. Lysine was applied in two different
concentrations for a better insight regarding the kinetics. After only 45 min a maximum yield of 75% was obtained, if
5 mol% lysine was added. The reaction was slower with a lower amount of 3.33 mol% lysine. However, a higher
maximum yield of 82% was achieved. These results validate the previous kinetic studies,16c wherein higher catalyst
concentrations increase the reaction rate, but limit the overall reaction. This results in lower yields, as can be seen in
these investigations.
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Basic Amino Acids - Reaction progress
100
90
80
70
60
50
40
30
20
10
0
5 mol%
Lysine
3.33 mol%
Lysine
6.67 mol%
Arginine
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16
time [%]
Figure 5. Yield over time plot; Conditions: 3 mmol butanal, amino acid, 1 mL EtOH, r.t.
A short summary of the achieved results with catalytic amounts of proteinogenic amino acids as organocatalysts in the
homo aldol condensation of butanal is given in Figure 6.
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Figure 6. Summary of the results after the systematic investigation applying 20 proteinogenic amino acids;
Conditions: 3 mmol butanal, amino acid, 1 mL EtOH, r.t.
2.4 Substrate scope
In the next step, the transferability of the optimised reaction conditions will be explored using other substrates with
longer, branched and functionalised alkyl chains (Table ). Tryptophan was chosen for the substrate scope due to its
high activity obtaining excellent yields in a short time. The reaction was carried out in ethanol on the one hand and in
water on the other hand, since the use of amino acids is usually associated to aqueous reaction media.
Consistently, very high yields have been observed for every applied substrate after only 3 h reaction time and
6.67 mol% organocatalyst tryptophan in ethanol. Very good yields of 77% - 87% were observed for the aldol
condensation products from the entries in 2.2, 2.3 and 2.7. Excellent yields of 90% - 95% have been observed for the
products displayed in 2.1, 2.4, 2.5 and 2.6. Methyl-12-oxododecanoate was converted almost quantitatively to its aldol
condensation product (entry 1.8). These results are showing a successful established homo aldol condensation which is
catalysed by an amino acid and transferable to other substrates as well. Performing the reactions in aqueous medium
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led to phase transfer limitations, since all reaction mixtures showed a two phase system, which resulted in lower yields
for the longer chain aldehydes (entry 2.3 – 2.9). A very poor yield of 9% was obtained by using citronellal.
Products from entries 2.2 – 2.5 are of high interest, since butanal is already being used as a plasticiser precursor (entry
2.1). The product from citronellal could represent a potential lubricant precursor, due its high branched structure29
(entry 2.6). The product of the renewable methyl-12-oxododecanoate is a potential polymer precursor having an
α,ω-bifuncionality (entry 2.8).
Table 2. Substrate screening with optimised conditions
No.
Substrate
Product
Y
Ya
2.1
95 96
77 78
84 77
2.2
2.3
2.4
2.5
90 77
94 71
2.6
2.7
2.8
94
9
87 99
99 --b
Conditions: 3 mmol substrate, 6.67 mol% tryptophan, 1 mL EtOH, rt, 3 h. Results in %; a reactions were
performed in 1 mL H2O instead of EtOH; b n.d. = not determined.
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3. Conclusion
The homo aldol condensation of unfunctionalised aliphatic aldehydes was investigated in respect to the used amino
acid, catalyst loading, side chain and reaction time. Therein, we applied every single proteinogenic amino acid in
catalytic amounts and established a general method for the homo aldol condensation for different substrates with very
good to excellent yields up to 99% in only 3 h. Tryptophan was the most effective amino acid catalyst regarding
reaction time and yield with a TON and TOF of 27 or 27 h-1. The catalytic activity depends on the respective side
chain, which has an activating or deactivating effect. Therefore, the side chain groups have no catalytic activity, but
they have a big impact on the catalytic activity. Furthermore, the investigations displayed, that arginine and lysine
have their maximum rate constant at low catalyst concentrations of 6.67 mol% or 3.33 mol%, due to their unique
behaviour. Obtained products are already used as plasticiser precursors in the industry or they represent potential
lubricants or polymer precursors, if the renewables, citronellal or methyl-12-oxododecanoate, are applied as substrates.
Based on these results, a combination of the homo aldol condensation with a further organocatalysed establishing a
tandem catalysis would be an interesting development for future investigations.
4. Experimental
4.1 General techniques and materials
The solvent ethanol was purchased from VWR with a purity of 99.8%, all amino acids were purchased from Sigma
Aldrich and all substrate were purchased from ABCR, Acros, Alfa Aesar and Sigma Aldrich. All reagents were used
without further purification. For column chromatography technical quality solvents were used. Thin-layer
chromatography (SiO2, TLC) was performed on Merck TLC silica gel 60 F254. Column chromatography was
performed on Merck silica gel 60 (0.040 – 0.063 nm). NMR spectra were recorded on Bruker DRX400 (400 MHz)
spectrometers with TMS as internal standard. CDCl3 was used as solvent and purchased from DEUTERO. Chemical
shifts are reported in parts per million as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, bs = broad singlet, dt = doublet of triplet), coupling constant, and integration. Gas
chromatography was performed on a HP 6890 (Hewlett‐Packard, Waldbronn, Germany) using a FID at 325°C and a
HP‐5 column (30 m, diameter 0.32mm, film thickness 25mm) in connectionwith an auto sampler. The carrier gas was
nitrogen (v = 1.2mL/min, 30 cm/s). The injection volume was 1µL and the split ratio 1:30.
4.2 General procedure for the aldol condensation
0.2 mmol tryptophan, 1mL ethanol and 3 mmol butanal were added into a screwed test tube. The reaction mixture
was stirred at room temperature for one hour. The catalyst was removed by a short silica colomn. Afterwards, the
sample for the gas chromatography was prepared with 0.0250 g dibutyl ether, 0.4750 g reaction mixture and 0.5000 g
isopropanol. A yield of 95% for 2-ethylhex-2-enal was obtained.
4.3 Isolation of the aldol condensation product
1.1. Dimethyl 11-formyltricos-11-enedioate (Product from entry 2.8)
0.2 mmol tryptophan, 1mL ethanol and 3 mmol methyl-12-oxododecanoate were added into a screwed test tube.
The reaction mixture was stirred at room temperature for three hours. Afterwards, the solvent was evaporated and the
product was purified by column chromatography (cyclohexane/ethyl acetate 50:1 ꢀ 5:1) yielding 99% of
dimethyl 11-formyltricos-11-enedioate. 1H NMR (400 MHz, CDCl3) δ: 9.37 (s, 1H), 6.45 (t, J = 7.5 Hz, 1H), 3.68 (m,
6H), 2.31 (m, 6H), 2.23 (m, 2H), 1.62 (m, 4H), 1.50 (m, 2H), 1.30 (m, 24H); 13C NMR (100 MHz, CDCl3) δ: 195.5,
174.7 x 2, 155.8, 144.2, 51.9, 34.5, 30.1, 29.9, 29.8 x 5, 29.7, 29.6, 29.5 x 2, 29.4, 29.2, 29.1, 25.3 x 2, 24.4.
The characterisation data of the other aldol condensation products from table 2 were already determined and are
matching with the analytical data from the literature30
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Acknowledgments
We thank T. Seidensticker for synthesising methyl-12-oxododecanoate, which was applied in our substrate scope.
Supplementary data
Supplementary data with detailed experimental procedures and 1H & 13C NMR spectra of the compounds
associated with this article are available in the Supporting Information.
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