Synthesis of novel cinchona-amino acid hybrid organocatalysts for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2014.05.003

Three novel subclasses of cinchonidine derivatives coupled to diverse amino acids were prepared in very good overall yield and tested in a benchmark organocatalytic aldol reaction, between acetone and aromatic aldehydes. These subclasses are a family of a

Full text of DOI:10.1016/j.tetasy.2014.05.003

Tetrahedron: Asymmetry 25 (2014) 923–935
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of novel cinchona-amino acid hybrid organocatalysts
for asymmetric catalysis
Pedro Barrulas a, Maurizio Benaglia b, , Anthony J. Burke a,
⇑
a Universidade de Évora e Centro de Química de Évora, Rua Romão Ramalho 59, 7000 Évora, Portugal
b Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 February 2014
Revised 5 May 2014
Accepted 9 May 2014
Available online 18 June 2014
Three novel subclasses of cinchonidine derivatives coupled to diverse amino acids were prepared in very
good overall yield and tested in a benchmark organocatalytic aldol reaction, between acetone and
aromatic aldehydes. These subclasses are
a family of amino acid-cinchonidine (subclass A),
N-formamides-cinchonidine (subclass B) and dipeptide-cinchonidine (subclass C) hybrids. Our main goal,
besides obtaining very good yields and enantioselectivities, was to understand the influence of the amino
acid side chain residues on the enantioselectivity of the asymmetric aldol reactions. Different amino acid
tethered cinchonidine hybrids were compared and their catalytic behaviour was evaluated, allowing
good enantioselectivities to be achieved, 92% ee in one case. Other reactions such as Biginelli, Michael
addition and ketimine hydrosilylation reactions were screened with these ligands, but the outcome
was less successful.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric catalysis,12–14 and also as NMR discriminating
agents.15 Cinchona alkaloids have a bifunctional nature, which is
One of the most powerful means for obtaining enantiomerically
enriched compounds is via asymmetric catalysis.1,2 The most
common way of achieving this is with metal based catalysts or
enzymes. Over the last 15 years, organocatalysts have become
important alternatives to these traditional catalysts.2,3
apparent in the case of both quinine QN and cinchonidine CD
(Fig. 1).
10
3
11
2
R
6'
4
In the early 70s, Eder et al.4a and Hajos and Parrish4b reported
ground-breaking work on the proline catalysed Robinson annulation,
thus giving rise to the field of organocatalysis. However, only in 2000
did this field experience a remarkable renaissance, with key reports
7
5
N
5'
9'
7'
8'
8
6
Lewis base
Lewis acid
9
OH
10'
4'
3'
N
by List5a (aldol condensation with -proline) and MacMillan5b
L
2'
(H-bond donor;
R = OMe - quinine QN
R = H - cinchonidine CD
(Diels–Alder reaction with imidazolidinone). From this time this
field has witnessed significant and exponential growth.
Due to their considerable success, cinchona alkaloid based
organocatalysts are considered to be ‘privileged chiral catalysts’.6,7
Cinchona alkaloids are recognized as having many medicinal appli-
cations, particularly with regard to malaria,8 and also functioning
as antiarrythmics,9 sodium-channel blockers10 as well as potential
cytostatic agents.11
easy derivatization)
Figure 1. Structural attributes of quinine QN and cinchonidine CD alkaloids.
One of the beneficial characteristics of these molecules is the
presence of a chiral cavity, and the potential to functionalize the
9-OH group; for instance, the functionalization of the OH group
into more acidic groups or ones which are more effective as
hydrogen bond donors. With regard to their organocatalytic activ-
ity, several key reactions can be successfully carried out, such as:
Michael additions, Mannich, aldol, Baylis–Hillman, cycloadditions
and Henry reactions.12–14
On the other hand, due to their structural complexity and ready
availability, they can be used as chiral resolving agents, ligands for
⇑
Corresponding author. Tel.: +351 266745310; fax: +351 266744971.
E-mail addresses: maurizio.benaglia@unimi.it (M. Benaglia), ajb@uevora.pt
(A.J. Burke).
Amino acids are another class of natural compounds that play a
very important role in asymmetric synthesis.16,17 They have many
Tel.: +39 025031 4171; fax: +39 025031 4159.
http://dx.doi.org/10.1016/j.tetasy.2014.05.003
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

924
P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
diverse applications, and have been successfully applied in
asymmetric organocatalytic reactions such as: Michael additions,18
ketimine reductions with trichlorosilane,19,20 multicomponent
Biginelli reactions21 and aldol reactions.22–26
Our main goal herein was the synthesis of three novel subclass-
es of cinchonidine-amino acid hybrids for asymmetric organocatal-
ysis, using a benchmark aldol condensation as the test reaction.
The subclasses that we targeted were amino acid hybrids based
on cinchonidine (subclass A), N-formamides of some compounds
from subclass A (subclass B) and dipeptide hybrids based on
cinchonidine (subclass C) (Fig. 2).
1) mesylation
2) azidation
N
N
(S)
(R)
(S)
OH
(S) NH2
3) Staudinger
reaction
N
N
cinchonidine
global yield = 87%
Scheme 1. General synthesis of amine (8S,9S)-9-amino(9-deoxy)-epi-cinchonidine.
Subclass A, has already been reported on,27 however, our goal
was to develop further specific examples of this class, with diverse
amino side-chains. Subclass B is currently unknown in the litera-
ture, although N-formylated amine organocatalysts have already
been extensively studied for organocatalyzed imine hydrosilyla-
tion reactions. Some molecules belonging to subclass C, are already
known,28 but to the best of our knowledge have not been exploited
in catalysis to date. Our main motive was to carefully study and
compare these three structural subgroups in a bench-mark aldol
reaction (and other reactions) with a view to obtaining: (a) new
efficient modular catalytic systems whose reactivity and asymme-
try inducing capabilities could be easily tuned, and (b) to gain an
insight into the most basic structural requirements within the
molecule’s chemical structure for controlling the reaction enanti-
oselectivity. These molecules contain a number of structural and
functional group diversity points, such as: the amino acid side-
chain (aliphatic, aromatic or hydrogen), the amino acid nitrogen
(primary, secondary cyclic or acyclic), as well as the incorporation
of a carbonyl group or a new amino acid residue, which all have a
potential influence on the stereochemical outcome of the reaction.
The first organocatalytic application of this type of compound
was published by Chen et al.27b in 2008 when they synthesized
Cinchona-(cinchonidine, cinchonine, quinidine and quinine)pro-
according to the literature from commercially available cinchoni-
dine30–32 (Scheme 1).
With amine 4 in hand, we proceeded with the synthesis of our
first library of cinchonidine derivatives: subclass A, and for this
purpose we used the mixed anhydride method of Girgis and
Prashad (Scheme 2).33
With this method we were able to successfully obtain a library
of eight compounds with good results for subsequent screening in
asymmetric aldol reactions (Fig. 3).
After concluding the synthesis of subclass A, we advanced with
the synthesis of the respective N-formamide derivatives, subclass
B, which were prepared (with the exception of compounds 1g
and 1h) by N-formylation, including 2g the formamide of amine
ˇ
´
4. Malkov and Kocovsky have shown the importance of the pres-
ence of an N-formyl group in a variety of organocatalysts used in
this reaction.34 We wished to determine if the presence of this
group might enhance the catalytic activity for other reaction types,
such as: asymmetric aldol reactions,35,36 Biginelli,21 Michael18 and
ketone hydrosilylation reactions.34,37,38,41,42
Accordingly, based on the method used by Malkov and
34a
ˇ
´
Kocovsky
for the N-formylation of L-valine derivatives, we
created a library of amino acid cinchonidine N-formamide hybrids
in good to excellent yields 62–99%, with overall yields of between
43% and 77% (Fig. 4).
Finally, subclass C was easily obtained in good yields using 1a as
the substrate by the mixed anhydride method (Fig. 5).
At this point, we started to evaluate the organocatalytic poten-
tial of these catalysts. Based on the pioneering work of Xiao27 and
Liu27c on the synthesis and application of prolinamides derived
from Cinchona alkaloids in the asymmetric aldol reaction, we
began studying the influence of various amino acid units on the
outcome of a bench-mark aldol reaction. This was followed by their
evaluation in various other asymmetric catalytic reactions such as
Michael, Biginelli and hydrosilylation reactions.
line (D and L) hybrids, and applied them to enantioselective aldol
reactions, affording very good results (97% yield and 98% ee).
Zhao et al.27c suggested a transition state model for the same
prolinamides synthesized by Chen et al. that involves hydrogen
bonding interactions between the protonated organocatalyst and
the electrophile.
Recently, Huang et al.29 reported on the synthesis of a small
library of cinchona alkaloids (cinchonine and quinine) with a
diverse range of amino acid residues in their structure (Ala, Val,
Leu). They were screened in a series of asymmetric aldol reactions,
giving very good yields (up to 96%) and enantioselectivities (up to
92% ee).
In the case of the aldol reactions, we examined the bench-mark
aldol reaction between acetone and p-nitrobenzaldehyde (Table 1)
using the three subclasses of catalysts (see Table 1). It was possible
to verify the reliability of our results; in the case of the cinchoni-
dine-amino acid hybrids (subclass A) the results compared well
to those of Xiao27b for the same reaction with prolinamide 1f.
Using the same conditions, Xiao obtained the desired product 6a
2. Results and discussion
The synthesis of all subclasses A, B and C was achieved using a
common precursor; the amine (8S,9S)-9-amino(9-deoxy)-
epi-cinchonidine, which was easily obtained in three reaction steps
Subclass A
Subclass B
Subclass C
N
N
(S)
(S)
(S)
N
(S)
(S)
(S)
NH
NH
NH
NH2
H
N
N
H
H
N
N
NH2
O
N
O
(S)
O
R1
(S)
(S)
(S)
R
O
R
R
3
O
1
2
Figure 2. Novel subclasses of cinchonidine derivatives synthesized in this work.

P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
925
1st step - coupling reaction
O
O
O
O
amine 4
NH-Fmoc
NEt3 (1.1 eq.)
THF
NH-Fmoc
HO
iBu-O
O
(S)
Cl
O-iBu
(S)
THF
R
R
2nd step - deprotection
piperidine
(S)
(S)
N
(S)
(S)
N
(20% in DMF)
NH
NH
CO2 iBuOH
N
NH2
N
NH-Fmoc
O
O
R
R
1
Scheme 2. Synthesis of compounds of subclass A.
N
N
N
NH
NH
NH
N
N
N
NH2
NH2
NH2
O
O
O
Bn
iPr
1a
1b
1c
93% yield
88% yield
70% yield
77% global yield
61% global yield
81% global yield
N
N
N
NH
O
NH
O
NH
O
H
N
N
NH2
N
N
NH2
iBu
1d
1e
1f
51% yield
84% yield
80% yield
45% global yield
74% global yield
70% global yield
N
N
NH
NH
H
N
N
N
NH2
O
O
Bn
1g
1h
OH
97% yield
85% global yield
93% yield
81% global yield
Figure 3. Organocatalyst candidates of subclass A synthesized herein.
in 79% yield with an enantiomeric excess of 44% for the (R)-
enantiomer, (see entry 6, Table 1).
The results were very encouraging; subclass A gave the best
results with yields of between 28% and 96% and with a highest
enantioselectivity of 77% ee with catalyst 1e (Table 1, entry 5).
Subclass C was the next best type of catalyst, giving yields of
13–89%, and enantioselectivities of up to 45% ee (with catalyst
3c, entry 18).

926
P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
N
N
(S)
(S)
(S)
(S)
Ac2O, HCO2H
0ºC, 24h
NH
NH
H
N
N
NH2
N
H
O
O
(S)
(S)
R
R
O
1
2
N
N
N
(S)
(S)
(S)
(S)
(S)
(S)
NH
NH
NH
H
N
H
N
H
N
N
N
N
O
O
O
CHO
CHO
CHO
(S)
(S)
Bn
iPr
2a
2b
2c
98% yield
97% yield
94% yield
76% global yield
59% global yield
77% global yield
N
N
N
(S)
(S)
(S)
(S)
(S)
(S)
NH
NH
NH
CHO
H
N
H
N
N
N
(S)
N
N
O
O
O
CHO
CHO
(S)
(S)
(R)
iBu
2e
2f
2d
96% yield
99% yield
62% yield
44% global yield
43% global yield
73% global yield
N
(S)
(S)
NH
N
O
H
2g
99% yield
87% global yield
Figure 4. Generic synthesis of compounds of subclass B including the respective yields.
After careful analysis of the results, we found that the nature of
amino acid side chain play a vital role in the asymmetric induction
process, but so does the nature of the amino nitrogen.
the amino acid side chain, incorporated into the 9-amino-(9-
deoxy)-epi-cinchonidine, was of great importance with regard to
the enantioselectivity. Catalyst 1h was the only example that gave
the aldol product 6a in racemic form (entry 8, Table 1) and this was
presumed to be due to the nature of its side-chain: that is, it was
the only one that contained a functional group, i.e. a phenol group
(Fig. 3). Opposing internal competition between H-bonding (due to
We observed that 1g, which contains an N-methylated
L-phenylalanine residue (entry 7, Table 1), affords a lower enanti-
oselectivity when compared with its unmethylated counterpart
1a (entry 1, Table 1) affording enantioselectivities of 28% and
36% ee, respectively.
As expected, the catalysts containing aliphatic and bulky side
chains gave 6a with the highest enantioselectivities. For example,
1e (entry 5, Table 1) gave the desired aldol product in moderate
yield but with high enantioselectivity (77% ee), even exceeding
the results achieved when using the prolinamide derivative as
reported by Xiao’s group.27b
the phenolic hydroxyl group) and
p–p interactions between the
aryl groups might generate two distinct diastereomeric transition
states leading to no overall enantioselectivity in the reaction.
The presence of a side chain in the amino acid structure plays an
important role with regard to the enantioselectivity of the reaction.
This deduction was related to the low ee observed for 1b (entry 2,
Table 1), since it was the only candidate containing an achiral
amino acid residue (i.e., glycine). However, not only does the
For the remaining subclasses, the results were conclusive. The
incorporation of a carbonyl group or a second amino acid unit is
disadvantageous, as the enantioselectivities revealed an abrupt

P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
927
Table 1
Results for the aldol reaction using aldehyde 4a and acetone 5. Entries 1–8: subclass
A; entries 9–15: subclass B; entries 16–20: subclass C
N
N
(S)
(S)
(S)
(S)
catalyst
O
OH
O
O
(10 mol%)
NH
HN
NH
NH2
∗
H
H
N
H
N
N
N
(S)
O
(S)
O
Bn
(S)
(S)
O2N
O2N
5
6a
4a
Bn
3b
O
Bn
3a
O
Entrya
Catalyst
Yieldb (%)
eec (%)
90% yield
83% yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
89
28
42
49
42
96
74
59
6
28
20
6
44
13
9
36 (R)
11 (S)
42 (R)
74 (R)
77 (R)
44 (R)
28 (R)
Rac.
12 (S)
12 (S)
12 (S)
10 (S)
13 (S)
33 (R)
11 (S)
34 (R)
37 (R)
45 (R)
10 (S)
Rac.
70% global yield
64% global yield
N
N
(S)
(S)
(S)
(S)
NH
NH2
NH
NH2
H
N
H
N
N
N
(S)
O
iPr
O
(S)
(R)
Bn
3c
O
Bn
O
3d
86% yield
88% yield
68% global yield
35
89
13
14
16
66% global yield
a
Reaction proceeded at room temperature in the presence of 0.53 mmol of
aldehyde, 10 mol % of catalyst and 1 mL of acetone over 24 h.
N
b
(S)
(S)
Isolated yield.
Enantiomeric excess was determined by chiral HPLC.
c
NH
NH2
H
N
N
(S)
O
S
(S)
Contrary to the model proposed by Zhao et al.27c we suggest a
double interaction via two hydrogen bonds involving the nitro
Bn
3e
O
group of the aldehyde simultaneously with
p–p interactions
95% yield
73% global yield
between the aromatic ring of the substrate and the quinoline ring
of the alkaloid, resulting in the exposure of the Si-face of the alde-
hyde to the enamine and thus the formation of the (R)-enantiomer
of the product.
Figure 5. Organocatalyst candidates of subclass C synthesized herein.
Computational studies will be required to gain a better insight
into the nature of this mechanism.
decrease (Table 1). All of the results obtained for these two
subclasses were lower than those observed with the simpler
hybrid structures (subclass A).
In light of these results, substrate screening was performed
using 1e and the results are given in Table 2.
We found that the presence of a substituent on the aromatic
ring was a key factor in obtaining the products with the highest
enantioselectivities, for example benzaldehyde gave racemic
aldol-product (entry 2, Table 2). It seems that the presence of
strong electron-withdrawing groups in the para-position gave the
best results (Table 2, entries 1 and 6). The presence of a nitro-group
at the para-position seems to be crucial for the formation of critical
H-bonds, thus enabling high enantiofacial selectivity (our model,
Fig. 6). However, electron-donating substituents at the ortho posi-
tions gave racemic products (Table 2, entries 4 and 8). This might
be due to critical steric hindrance issues that remove the transition
state from that which gives the best enantiofacial selectivity.
This assay allowed us to conclude that the deactivating substit-
uents on the ring of the aromatic aldehydes provide better enanti-
oselectivities (e.g., NO2 and Br), while substitution at the ortho and
meta positions has a negative effect on the enantioselectivity.
Following the strategy of Chen27b and Liu27c we were curious to
know the precise effect of an acid in the reaction medium and
whether protonation of the quinuclidine nitrogen could improve
the reaction enantioselectivity, by establishing crucial hydrogen
bonds. Thus we decided to test different organic and inorganic
Brønsted acids with counter-anions of different sizes and basicities
(Table 3).
Zhao et al.27c proposed a transition state for the asymmetric
aldol reaction involving 1f that only comprises of one hydrogen
bonding interaction between the aldehyde and the organocatalyst.
However in our opinion, this mechanistic proposal appears to be
incomplete. The hydrogen bond needed for the relevant stereocon-
trol seems to be insufficient to warrant a specific orientation of the
aldehyde. This single hydrogen bond does not limit free rotation
around its own axis, and in our opinion is insufficient to induce
the high enantioselectivities reported (Fig. 6).
Another limitation of the proposed model is based on the lack of
information on the hypothetical effect that the protonated amine
could have on activation of the aldehyde unit for enantioselective
nucleophilic attack. We also note that inadvertently Zhao et al.27c
have mentioned that the attack of the enamine nucleophile to
the aldehyde was Re-face and not Si-face (although this was cor-
rectly indicated in the figure) which gives the desired product with
an (R)-absolute configuration.
We thus propose a slightly different transition state model with
hydrogen-bonding and other stabilizing interactions (Fig. 6).
According to this hypothetical model, the organocatalyst should
form a chiral cavity defined by the perpendicular relationship
between the quinoline and prolinamide units.

928
P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
Zhao et al.'s model
proposed model
H-bond
A
O
HN
enamine
N
A
N
H
N
H
Si-face
O
N
attack
NH
H
O
O
N
enamine
N
N
O
O
H
O2N
H-bond
π-π
interactions
Si-face
attack
O2N
O2N
(R)
(R)
HO
H
O
HO
H
O
Figure 6. Comparison of Zhao et al.’s27c and our transition state models.
Table 2
Table 3
The aldol reaction using aldehydes 4 and acetone 5 in the presence of catalyst 1e
The acid effect on the aldol reaction between aldehyde 4a and acetone 5 in the
presence of catalyst 1e
Cat. 1e
O
O
OH
O
(10 mol%)
1e
Cat.
O
OH
O
O
(10 mol%)
∗
Ar
H
Ar
(R)
HX
H
4
5
6
(10 mol%)
6a
4a
5
O2N
O2N
Entrya
Aldehyde
Aryl
Product
Yieldb (%)
eec (%)
Entrya
Acid (HX)
pKa
Yieldb (%)
eec (%)
39
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
p-NO2–C6H4
Ph
p-MeO–C6H4
o-MeO–C6H4
2,4-(MeO)2–C6H3
p-Br–C6H4
m-Me–C6H4
o-Me–C6H4
o-Cl–C6H4
6a
6b
6c
6d
6e
6f
6g
6h
6i
42
25
2
71
5
19
11
2
14
11
77 (R)
rac
1
2
3
HCl
AcOH
TFA
p-TsOH
H3PO4
HClO4
<1
36
46
15
40
0
Rac.
37
20
5
-
5
44 (R)
rac
4.75
<1
<1
2.12
<1
49d
4
56 (R)
35 (R)
rac
5d
6
42
a
22 (R)
Reaction proceeded at room temperature in the presence of 0.53 mmol of
aldehyde, 10 mol % of catalyst, 10 mol % of acid and 1 mL of acetone over 24 h.
10
4j
p-BnO–C6H4
6j
27d
b
Isolated yield.
a
Reaction proceeded at room temperature in the presence of 0.53 mmol of
aldehyde, 10 mol % of catalyst and 1 mL of acetone over 24 h.
c
Enantiomeric excess was determined by chiral HPLC.
d
No reaction.
b
Isolated yield.
Enantiomeric excess was determined by chiral HPLC.
No available data in the literature for the attribution of the absolute
c
d
configuration.
Table 4
The solvent effect on the aldol reaction between aldehyde 4a and acetone 5 in the
presence of catalyst 1e
In a similar test, Chen et al.27b observed an approximate 25%
increase in the enantioselectivity of the product when using
10 mol % of an acid additive (i.e., acetic acid). Contrary to this,
our results using various acid additives revealed a decrease in
the enantioselectivities and in fact no reaction occurred in the
presence of phosphoric acid (entry 5, Table 3).
Cat. 1e
O
OH
O
O
(10 mol%)
(R)
H
Solvent
5
6a
O2N
4a
O2N
We then carried out some solvent screening studies to deter-
mine if the solvent might affect the enantiocontrol of the reaction
(Table 4). We observed no particular correlation between the sol-
vent polarity and enantioselectivity, as both polar (DMF, entry 7
Table 4) and apolar (toluene, entry 6), gave good enantioselectivi-
ties. In fact, with the exception of methanol, DMF and water, all
other solvents allowed us to obtain the desired product with enan-
tiomeric excesses of 70–79% ee. THF (entry 3, Table 4) provided the
best enantioselectivity (79% ee), but with a modest yield. It is note-
worthy that the catalyst was also active in water (entry 9, Table 4),
giving an enantioselectivity of 49% ee and 45% yield.
Entrya
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
THF
20
20
36
30
57
30
42
27
45
42
73
70
79
73
59
73
Rac.
70
49
77
Et2O
MeOH
Toluene
DMF
DMSO
H2O
10
Neat
a
Reaction proceeded at room temperature in the presence of 0.53 mmol of
aldehyde, 10 mol % of catalyst, 0.5 mL of acetone and 0.5 mL of solvent over 24 h.
The reaction could also be conducted under solvent free condi-
tions (entry 10, Table 4), giving an enantioselectivity of 77% ee and
42% yield.
b
Isolated yield.
Enantiomeric excess determined by chiral HPLC.
c

P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
929
Table 5
UV light (254 e 366 nm), developed with phosphomolybdic acid
in ethanol or with a Drangendorff reagent followed by heating.
Melting points were determined on a Barnstead/Electrothermal
9100 apparatus. The 1H NMR and 13C NMR spectra were recorded
on a Bruker Avance III instrument (1H: 400 MHz; 13C: 100 MHz)
at FCT-UNL (Faculdade de Ciências e Tecnologia da Universidade
Nova de Lisboa), using CDCl3, DMSO-d6 or D2O as solvents and
TMS as internal standard. All chemical shifts (d) were expressed
in ppm and the coupling constants, expressed in Hz. Mass spectra
were recorded on a Waters–Micromass spectrometer. The specific
rotation determinations were performed in LNEG (Laboratório
Nacional de Energia e Geologia, Lisbon) on a Perkin–Elmer 241 at
the temperatures indicated. High performance liquid chromatogra-
phy (HPLC) was performed on a Agilent 1110 Series instrument
using Chiralcel OD-H (0.46 cm ꢁ 25 cm) or an AD-H
The temperature effect on the aldol reaction between aldehyde 4a and acetone 5 in
the presence of catalyst 1e
Cat. 1e
O
OH
O
O
(10 mol%)
(R)
HX
H
(10 mol%)
5
O2N
6a
O2N
4a
Entrya
Solvent
T (°C)
Yieldb (%)
eec (%)
1
2
3
4
Neat
THF
Neat
THF
0
0
50
47
24
29
78
68
92
87
ꢀ40
ꢀ40
a
Reaction proceeded in the presence of 0.53 mmol of aldehyde, 10 mol % of
catalyst, 0.5 mL of acetone and 0.5 mL of solvent over 24–72 h.
b
Isolated yield.
Enantiomeric excess determined by chiral HPLC.
(0.46 cm ꢁ 25 cm) as chiral columns both equipped with
a
c
pre-column.
With these optimized conditions already in hand, we investi-
gated the effect of temperature on the reaction (Table 5).
4.2. General procedure for the synthesis of (8S,9R)-9-O-mesyl-
cinchonidine
At low temperatures (ꢀ40 °C) the highest enantioselectivities
were obtained, either under solvent free conditions or with THF
(Table 5, entries 3 and 4, giving 92% and 87% ee, respectively).
These catalysts were also screened in other asymmetric
catalytic reactions, notably in Biginelli, Michael and in ketimine
hydrosilylation reactions.40 Unfortunately the results were not
encouraging. For the Biginelli reaction40 with methyl acetoacetate,
benzaldehyde and urea, the best results were achieved with 3d,
giving an enantioselectivity of 23% ee and the best yield (44%) with
1b. This catalyst only provided a highest enantioselectivity of 32%
ee for the Michael addition40 between b-nitrosyrene and acetylace-
tone with moderate to very good yields. Finally, for the hydrosily-
lation reactions of N-(1-(4-nitrophenyl)ethylidene)-aniline with
Based on Hoffmann’s method,31 to a stirred solution of cincho-
nidine (10.032 g, 34.08 mmol) in 350 mL of dry THF was added
triethylamine (15 mL, 107.60 mmol) and then the solution was
cooled in an ice bath to 0 °C. Methanesulphonyl chloride (5.3 mL,
68.48 mmol) dissolved in a small volume of THF was added drop-
wise to the previous solution, and then the mixture was allowed to
react at room temperature over 2 h. Next, the reaction was
quenched with saturated aqueous sodium bicarbonate (80 mL)
and then extracted with CH2Cl2 (2 ꢁ 20 mL). The resulting crude
product was purified by column chromatography on silica gel
using ethyl acetate as eluent to give the title compound as a white
solid with a sweet aroma (11.76 g, 93%), mp 107.2–108.0 °C. 1H
NMR (400 MHz, CDCl3): d (ppm) = 8.94 (d, 1H, J = 4 Hz, H20), 8.28
(d, 1H, J = 8 Hz, H50), 8.15 (d, 1H, J = 8 Hz, H80), 7.75 (t, 1H,
J = 8 Hz, H70), 7.66 (t, 1H, J = 8 Hz, H60), 7.52 (br s, 1H, H30), 6.59
(br s, 1H, H9), 5.73 (m, 1H, H10), 5.00 (m, 2H, H11), 3.45–3.32
(m, 2H, H6, H8), 3.11 (br s, 1H, H2), 2.76 (br s, 5H, H6, H2, CH3),
2.38 (br s, 1H, H3), 1.96–1.65 (m, 5H, H7, H5, H4). 13C NMR
trichlorosilane,40
a highest enantioselectivity of 45% ee was
obtained with a yield of 84%.
3. Conclusions
Herein our aim was the synthesis of a new series of organocat-
alysts derived from a combination of various L-amino acids with
cinchonidine and their exploitation in a series of bench-mark
reactions. These organocatalysts were obtained using very simple
strategies and synthesized in overall moderate to high yields
(43–87%).
(100 MHz, CDCl3):
d
(ppm) = 150.0 (C20), 148.8 (C100), 142.4
(C10), 140.1 (C40), 130.8 (C80), 129.9 (C70), 127.9 (C90), 125.0 (C60,
C50), 122.9 (C30), 115.6 (C11), 59.9 (C9), 56.04 (C8, C2), 39.3 (C6,
C3, C-mesyl), 27.2 (C7, C4, C5).
4.3. General procedure for the synthesis of (8S,9S)-9-azide(9-
deoxy)-epi-cinchonidine
We have found that the presence of non-functionalized,
aliphatic and bulky side chains, as well as primary amines are
essential requirements for obtaining high enantiomeric excesses
in the bench-mark aldol reaction of acetone with aromatic alde-
hydes. We also found that using 1e at ꢀ40 °C, in the aldol reaction
gave high enantioselectivities (up to 92% ee).
Other reactions such as the Biginelli and Michael additions and
ketimine hydrosilylations were also investigated, but the results
were less satisfactory.
9-O-Mesylcinchonidine (2.06 g, 5.53 mmol) was dissolved at
room temperature in anhydrous DMF (40 mL); this was followed
by the addition of 2 equiv of NaN3 (0.719 g; 11.06 mmol) and the
mixture was heated to 80 °C over 24 h.15,30 The formation of a yel-
low solution is an indication of azide formation. Monitoring the
reaction by TLC analysis indicated the consumption of the sub-
strate. The solvent was removed by distillation and the residue
was re-suspended in H2O (15 mL) and extracted with CH2Cl2
(3 ꢁ 10 mL), then purified by column chromatography on silica
gel with ethyl acetate to furnish the title compound as a yellowish
dense oil (1.701 g; 96%). 1H NMR (400 MHz, CDCl3): d (ppm) = 8.95
(d, 1H, J = 4 Hz, H20), 8.23 (d, 1H, J = 8 Hz, H50), 8.18 (d, 1H, J = 8 Hz,
H80), 7.77 (t, 1H, J = 8 Hz, H70), 7.65 (t, 1H, J = 8 Hz, H60), 7.41 (d, 1H,
J = 4 Hz, H30), 5.76 (m, 1H, H10), 5.15 (d, 1H, J = 10 Hz, H9), 4.99 (m,
2H, H11), 3.35–3.21 (m, 3H, H6, H2, H8), 2.95–2.83 (m, 2H, H6, H2),
2.30 (br s, 1H, H3), 1.71–1.58 (m, 4H, H4, H7, H5), 0.77–0.72 (m,
4. Experimental
4.1. General
Cinchonidine, L-amino acids and all other reagents and solvents
used herein were purchased from Sigma–Aldrich, Fluka or Acros
Organics and were used as received.
Column chromatography was carried out on silica gel (sds, 70–
200 lm) or on reverse phase C18-silica gel (40–63 lm). Thin-layer
13
1H, H7). C NMR (100 MHz, CDCl3): d (ppm) = 149.9 (C20), 148.7
(C100), 142.2 (C10), 141.3 (C40), 130.6 (C80), 129.4 (C70), 127.2
(C60), 126.6 (C90), 123.0 (C50), 120.2 (C30), 114.4 (C11), 59.5 (C9),
chromatography (TLC) was carried out on aluminium backed
Kieselgel 60 F254 plates (Merck). Plates were visualized either by

930
P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
55.9 (C8), 53.4 (C2), 40.9 (C6), 39.3 (C3), 27.8 (C7), 27.1 (C4), 26.0
(C5).
MS (m/z): 441.27 (M+1), 442.27 (M+2). HRMS (ESI) Found
441.26430, calcd for C28H33N4O, 441.26489. [
MeOH).
a]
28 = +2.1 (c 1.05,
D
4.4. General procedure for synthesis of (8S,9S)-9-amino(9-
deoxy)-epi-cinchonidine
4.5.2. (8S,9S)-9-Glicinylnamide(9-deoxy)-epi-cinchonidine 1b
Using the method described above, 1b was obtained as a yellow
oil (250 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6):d
(ppm) = 8.89 (d, 1H, J = 4 Hz, H20), 8.71 (br s, 1H, NH-COR), 8.48
(d, 1H, H50), 8.04 (d, 1H, J = 8 Hz, H80), 7.77 (t, 1H, J = 8 Hz, H70),
7.67 (t, 1H, J = 8 Hz, H60), 7.60 (br s, 1H, H30), 5.83 (m, 1H, H10),
5.61 (br s, 1H, H9), 5.02–4.92 (m, 2H, H11), 4.51 (m, 2H, NH2),
3.38–3.13 (m, 5H, H6, H2, H8, CH2), 2.67 (m, 2H, H6, H2), 2.24
(br s, 1H, H3), 1.47 (m, 3H, H4, H7, H5), 1.17 (m, 1H, H5), 0.69
(m, 1H, H7). 13C NMR (100 MHz, DMSO-d6): d (ppm) = 168.6
(C@O), 150.3 (C20), 147.9 (C100), 146.8 (C40), 143.0 (C10), 142.0
(C80), 129.7 (C70), 129.2 (C90), 126.9 (C60), 126.7 (C50), 120.0 (C30),
114.3 (C11), 58.7 (C9), 55.3 (C8, C2), 42.2 (CH2), 40.6 (C6), (C3 sig-
nal superimposed with DMSO), 27.2 (C7), 27.1 (C4), 25.8 (C5). ESI-
TOF MS (m/z): 350.20 (M+), 351.23 (M+1), 352.22 (M+2).
Based on
a
literature method,30 (8S,9S)-9-azide(9-deoxy)-
epi-cinchonidine (8.37 g, 26.2 mmol) was dissolved in dry THF
(120 mL) followed by the addition of triphenylphosphane
(10.31 g, 39.3 mmol) at room temperature. After the addition was
complete, the mixture was heated to 48–52 °C in an oil bath and
the mixture was allowed to react over 4 h. The mixture was then
cooled to room temperature, H2O (3 mL) was added and left stir-
ring overnight. The crude product was concentrated and purified
by column chromatography on silica gel with ethyl acetate fol-
lowed by AcOEt/MeOH/NEt3 (100:2:3) to furnish the title com-
pound as a yellowish dense oil (7.07 g, 92%). 1H NMR (400 MHz,
CDCl3): d (ppm) = 8.92 (d, 1H, J = 4 Hz, H20), 8.36 (br s, 1H, H50),
8.15 (d, 1H, J = 8 Hz, H80), 7.73 (t, 1H, J = 8 Hz, H70), 7.60 (t, 1H,
J = 8 Hz, H60), 7.54 (br s, 1H, H30), 5.82 (m, 1H, H10), 5.03–4.72
(m, 2H, H11), 4.72 (br s, 1H, H9), 3.33–3.22 (m, 2H, H6, H2), 3.10
(br s, 1H, H8), 2.85–2.82 (m, 2H, H6, H2), 2.42 (s, 2H, NH2), 2.30
(br s, 1H, H3), 1.64–1.58 (m, 3H, H4, H7, H5), 1.43–1.41 (m, 1H,
[a]
28 = +15.9 (c 1.04, MeOH).
D
4.5.3. (8S,9S)-9-
Using the previous method, 1c was obtained as an oily yellow
solid (372 mg, 93%). 1H NMR (400 MHz, DMSO-d6):
d
L-Valinylamide(9-deoxy)-epi-cinchonidine 1c
H5), 0.79–0.74 (m, 1H, H7). 13C NMR (100 MHz, CDCl3):
d
(ppm) = 150.5 (C20), 148.8 (C100), 141.8 (C10, C40), 130.6 (C80),
129.2 (C70), 128.0 (C60), 126.7 (C90), 123.4 (C50), 119.7 (C30), 114.6
(C11), 62.1 (C9), 56.4 (C8), 41.1 (C6), 39.9 (C2), 29.8 (C3), 28.2
(C7), 27.7 (C4), 26.2 (C5). The structure was confirmed by compar-
ison with the literature data30 for the same compound.
(ppm) = 8.88 (d, 1H, J = 4 Hz, H20), 8.52 (d, 1H, J = 8 Hz, H50), 8.48
(br s, 1H, NH-CO), 8.03 (d, 1H, J = 8 Hz, H80), 7.76 (t, 1H, J = 8 Hz,
H70), 7.65 (t, 1H, J = 8 Hz, H60), 7.60 (d, 1H, J = 4 Hz, H30), 5.81 (m,
1H, H10), 5.52 (br s, 1H, H9), 5.00–4.90 (m, 2H, H11), 3.65 (s, 2H,
NH2), 3.23–3.12 (m, 3H, H6, H2, H8), 3.01 (d, 1H, J = 4 Hz, CH-
NH2), 2.68–2.58 (m, 2H, H6, H2), 2.22 (br s, 1H, H3), 1.92–1.86
(m, 1H, CH-(CH3)2), 1.52–1.45 (m, 3H, H4, H7, H5), 1.24 (m, 1H,
H5), 0.83 (d, 3H, J = 8 Hz, CH3), 0.67 (m, 1H, H7), 0.65 (d, 3H,
J = 8 Hz, CH3). 13C NMR (100 MHz, DMSO-d6): d (ppm) = 173.1
(C@O), 150.1 (C20), 147.9 (C100), 147.5 (C40), 142.0 (C10), 129.7
(C80), 129.0 (C70), 127.1 (C90), 126.5 (C60), 124.2 (C50), 119.8 (C30),
114.2 (C11), 59.4 (C8, CH-NH2), 58.9 (C9), 55.3 (C2), 40.6 (C6),
(C3 signal superimposed by DMSO), 31.3 (CH-(CH3)2), 27.3 (C7),
27.1 (C4), 25.7 (C5), 19.3 (CH3), 16.5 (CH3). ESI-TOF MS (m/z):
393.27 (M+1), 394.27 (M+2). HRMS (ESI) Found 393.26424, calcd
4.5. General procedure for the synthesis of the organocatalysts
of subclass A 1
Using the method described by Girgis and Prashad,33 to a stirred
solution of the desired Fmoc-L-amino acid (1.02 mmol) in dry THF
(10 mL) was added NEt3 (0.16 mL, 1.12 mmol). In a two-necked
flask, isobutylchloroformate (0.13 mL, 1.02 mmol) was diluted
with THF (ca. 5 mL) and the solution cooled on an ice bath. The first
mixture prepared was then slowly added via a syringe to the
diluted isobutylchloroformate, after which the resulting mixture
was allowed to react at room temperature for 2 h. (8S,9S)-9-
Amino(9-deoxy)-epi-cinchonidine (0.3 g, 1.02 mmol) was then
added and the reaction was stirred for 1 h at room temperature.
The mixture was concentrated under vacuum and the resulting
crude product was purified by column chromatography on silica
gel with AcOEt/MeOH (4:1). The resulting intermediate was depro-
tected with 20% piperidine in DMF and purified by column chro-
matography on reverse phase silica to furnish the title compound.
for C24H33N4O, 393.26489. [a]
27 = +13.7 (c 1.36, MeOH).
D
4.5.4. (8S,9S)-9-L-Isoleucinylamide(9-deoxy)-epi-cinchonidine 1d
With the aforementioned method, 1d was obtained as a white
solid (211 mg, 51%), 126.2–127.5 °C. 1H NMR (400 MHz, DMSO-
d6): d (ppm) = 8.87 (d, 1H, J = 4 Hz, H20), 8.53 (d, 1H, J = 8 Hz,
H50), 8.40 (s, 1H, NH-CO), 8.03 (d, 1H, J = 8 Hz, H80), 7.76 (t, 1H,
J = 8 Hz, H70), 7.65 (t, 1H, J = 8 Hz, H60), 7.60 (d, 1H, J = 4 Hz, H30),
5.82 (m, 1H, H10), 5.50 (br s, 1H, H9), 5.00–4.90 (m, 2H, H11),
3.23–3.12 (m, 3H, H6, H2, H8), 2.98 (d, 1H, J = 4 Hz, CH-NH2),
2.68–2.59 (m, 2H, H6, H2), 2.50 (s, 2H, NH2), 2.21 (br s, 1H, H3),
1.45 (br s, 3H, H4, H7, H5), 1.24–1.15 (m, 2H, CH2), 1.00–0.93 (m,
1H, CH-CH3), 0.78 (d, 3H, J = 4 Hz, CH3-CH), 0.69 (m, 4H, CH3-CH2,
H7). 13C NMR (100 MHz, DMSO-d6): d (ppm) = 173.9 (C@O), 150.1
(C20), 147.9 (C100), 147.5 (C40), 142.0 (C10), 129.6 (C80), 128.9
(C70), 127.1 (C50), 126.4 (C60), 124.2 (C90), 119.8 (C30), 114.2
(C11), 66.4 (CH-NH2), 59.1 (C8), 58.8 (C9), 55.4 (C2), 40.5 (C6),
(CH-CH3 signal superimposed with DMSO), 38.4 (C3), 27.3 (C4),
27.1 (C7), 25.7 (C5), 23.3 (CH2-CH3), 15.8 (CH3), 11.5 (CH3). ESI-
TOF MS (m/z): 407.30 (M+1), 408.29 (M+2). HRMS (ESI) Found
4.5.1. (8S,9S)-9-L-Phenylalanylamide(9-deoxy)-epi-cinchonidine
1a
Using the method described above, 1a was obtained as a white
powder (395 mg, 88%), mp 98.7–99.1 °C. 1H NMR (400 MHz,
DMSO-d6): d (ppm) = 8.88 (d, 1H, J = 4 Hz, H20), 8.53 (m, 2H, H50,
NH-COR), 8.05 (d, 1H, J = 8 Hz, H80), 7.77 (t, 1H, J = 8 Hz, H70),
7.67 (t, 1H, J = 8 Hz, H60), 7.57 (d, 1H, J = 4 Hz, H30), 7.11 (m, 5H,
Ph), 5.79 (m, 1H, H10), 5.52 (br s, 1H, H9), 4.99–4.89 (m, 2H,
H11), 3.43–3.11 (m, 6H, H6, H2, H8, CH-Ph, NH2), 2.88 (m, 1H,
CH-NH2), 2.63–2.50 (m, 3H, H6, H2, CH-Ph), 1.90 (br s, 1H, H3),
1.57–1.45 (m, 3H, H4, H7, H5), 1.22 (m, 1H, H5), 0.72 (m, 1H,
H7). 13C NMR (100 MHz, DMSO-d6): d (ppm) = 173.4 (C@O), 150.2
(C20), 147.9 (C100), 147.3 (C-Ph), 142.0 (C10), 138.2 (C40), 129.7
(C80), 129.3 (2C-Ph), 129.0 (C70), 128.0 (2C-Ph), 127.1 (C-Ph),
126.5 (C60), 126.0 (C90), 124.1 (C50), 119.8 (C30), 114.2 (C11), 58.8
(C9), 55.7 (C8), 55.2 (C2), 40.5 (C6, CH-NH2), (CH2-Ph and C3 signals
superimposed with DMSO), 27.3 (C7), 27.1 (C4), 25.7 (C5). ESI-TOF
407.28023, calcd for C25H35N4O, 407.28054. [
MeOH).
a]
25 = +17.8 (c 1.11,
D
4.5.5. (8S,9S)-9-L-Leucinylamide(9-deoxy)-epi-cinchonidine 1e
The product 1e was obtained as a white solid (348 mg, 84%), mp
125.9–126.6 °C. 1H NMR (400 MHz, CDCl3): d (ppm) = 8.86 (d, 1H,

P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
931
J = 4 Hz, H20), 8.38 (d, 1H, J = 12 Hz, H50), 8.18 (br s, 1H, NH-CO),
8.10 (d, 1H, J = 8 Hz, H80), 7.69 (t, 1H, J = 8 Hz, H70), 7.58 (t, 1H,
J = 8 Hz, H60), 7.38 (d, 1H, J = 4 Hz, H30), 5.70 (m, 1H, H10), 5.45
(br s, 1H, H9), 4.99–4.93 (m, 2H, H11), 3.38–3.34 (m, 1H, H8),
3.27–3.20 (m, 3H, H6, H2, CH-NH2), 2.76–2.71 (m, 2H, H6, H2),
2.38 (br s, 2H, NH2), 2.28 (br s, 1H, H3), 1.64–1.41 (m, 6H, H5,
H7, H4, CH-NH2, CH(CH3)2, CH), 1.20–1.13 (CH), 0.91–0.86 (m,
1H, H7), 0.81 (m, 6H, 2CH3). 13C NMR (100 MHz, CDCl3): d
(ppm) = 175.6 (C@O), 150.1 (C20), 148.7 (C100), 146.9 (C40), 141.1
(C10), 130.4 (C80), 129.3 (C70), 127.4 (C50), 126.9 (C60), 123.6
(C90), 119.3 (C30), 114.8 (C11), 59.8 (C9), 55.9 (C2), 53.7 (C8), 51.7
(CH-NH2), 41.1 (CH2), 41.0 (C6), 39.4 (C3), 27.6 (C7), 27.4 (C4),
26.2 (C5), 24.8 (CH(CH3)2), 23.3 (CH3), 21.6 (CH3). ESI-TOF MS
127.8 (C60), 127.6 (C90), 127.2 (C-Ar), 123.5 (C50), 118.2 (C30),
115.9 (C11), 115.6 (2C-Ar), 59.5 (C9), 56.4 (C8), 54.9 (C2), 41.3
(CH-NH2), 39.4 (CH2-Ar), 38.2 (C6), 29.8 (C3), 27.1 (C7), 26.4 (C4),
25.8 (C5). ESI-TOF MS (m/z): 457.26 (M+1), 458.27 (M+2).
[a
]
D
24 = ꢀ0.7 (c 0.92, MeOH).
4.6. General procedure for synthesis of the subclass B deriva-
tives 2
Using the method described by Malkov and Kocovsky´42 for con-
ducting N-formylation procedures; formic acid (1 mL, 26.5 mmol)
was carefully added to a cooled mixture of acetic anhydride
(0.450 mL, 4.76 mmol) and the desired compound from subclass
A (0.68 mmol). The mixture was allowed to react at room temper-
ature for 12 h, followed by removal of the volatiles in vacuo. The
product was then purified by column chromatography on reverse
phase silica with methanol.
(m/z): 407.30 (M+1), 408.29 (M+2). [a]
25 = +12.4 (c 1.16, MeOH).
D
4.5.6. (8S,9S)-9-L-Prolinylamide(9-deoxy)-epi-cinchonidine
1f 27b,c
With the aforementioned method, product 1f was obtained as a
white solid (319 mg, 80%), mp 174.3–175.6 °C; (Lit.27c 174.0–
176.0 °C). 1H NMR (400 MHz, CDCl3): d (ppm) = 8.86 (d, 1H,
J = 4 Hz, H20), 8.46 (br s, 1H, NH-CO), 8.33 (d, 1H, J = 8 Hz, H50),
8.09 (d, 1H, J = 8 Hz, H80), 7.69 (t, 1H, J = 8 Hz, H70), 7.58 (t, 1H,
J = 8 Hz, H60), 7.39 (d, 1H, J = 4 Hz, H30), 5.71 (m, 1H, H10), 5.55
(br s, 1H, H9), 5.26 (br s, 1H, NH), 5.02–4.96 (m, 2H, H11), 3.74
(m, 1H), 3.48–3.42 (m, 1H), 3.38–3.32 (m, 2H), 2.97 (m, 1H),
2.83–2.73 (m, 3H), 2.35 (br s, 1H, H3), 1.97–1.93 (m, 1H), 1.72–
1.46 (m, 7H), 0.93–0.88 (m, 1H, H7). 13C NMR (100 MHz, CDCl3):
d (ppm) = 174.9 (C@O), 150.1 (C20), 148.7 (C100), 146.0 (C40),
140.3 (C10), 130.4 (C80), 129.4 (C70), 127.1 (C50), 127.0 (C60),
123.5 (C90), 119.3 (C30), 115.3 (C11), 60.6 (C8), 59.6 (C9), 55.5
(C2), 47.1 (CH2), 44.5 (CH), 41.1 (C6), 38.8 (C3), 30.5 (CH2), 27.3
(C4), 27.0 (C7), 26.0 (C6), 25.9 (CH2). ESI-TOF MS (m/z): 391.25
4.6.1. (8S,9S,
epi-cinchonidine 2a
aS)-9-(N-Formyl)-L-phenylalanylamide(9-deoxy)-
Using the method above and starting with 1a, 2a was obtained
as a yellow oil (312 mg, 98% yield). 1H NMR (400 MHz, CDCl3): d
(ppm) = 8.87 (d, 1H, J = 4 Hz, H20), 8.33 (m, 3H, 2NH-CO, H50),
8.12 (d, 1H, J = 8 Hz, H80), 7.95 (s, 1H, H-CO), 7.72 (t, 1H, J = 8 Hz,
H70), 7.63–7.58 (m, 2H, H60, H30), 6.90 (m, 5H, Ph), 6.04 (br s, 1H,
H9), 5.66 (m, 1H, H10), 5.13–5.08 (m, 2H, H11), 3.64 (m, 1H, H8),
3.51 (m, 1H, CH-NH), 3.12 (m, 3H, H6, H2, CH-Ph), 2.92–2.80 (m,
3H, H6, H2, CH-Ph), 2,63 (br s, 1H, H3), 1.84–1.69 (m, 3H, H4, H7,
H5), 1.05 (m, 1H, H5), 0.79 (m, 1H, H7). 13C NMR (100 MHz, CDCl3):
d (ppm) = 175.3 (C@O), 171.8 (C@O), 150.3 (C20), 148.3 (C100),
143.2 (C-Ph), 136.4 (C10), 135.8 (C40), 130.2 (C80), 129.9 (C70),
129.1 (2C-Ph), 128.7 (C-Ph), 128.4 (2C-Ph), 127.9 (C60), 126.9
(C90), 123.1 (C50), 120.4 (C30), 117.9 (C11), 58.9 (C9), 54.8 (C8),
53.26 (C2), 41.5 (CH-NH), 37.2 (C6, C3), 36.6 (CH2-Ph), 26.7 (C7),
24.4 (C4), 24.1 (C5). ESI-TOF MS (m/z): 469.26 (M+1), 470.26
(M+1), 392.25 (M+2). [
a]
24 = ꢀ3.5 (c 1.12, MeOH).
D
4.5.7. (8S,9S)-9-(N-Methyl)-
epi-cinchonidine 1g
L-phenylalaninylamide(9-deoxy)-
(M+2). HRMS (ESI) Found 469.25982, calcd for
C29H33N4O2,
In the same manner, 1g was obtained as an oily yellow solid
(450 mg, 97% yield). 1H NMR (400 MHz, CDCl3): d (ppm) = 8.87
(d, 1H, J = 4 Hz, H20), 8.42 (br s 1H, H50), 8.14 (m, 2H, H80, NH-
CO), 7.71 (m, 1H, H70), 7.60 (m, 1H, H60), 7.33 (br s, 1H, H30), 7.16
(m, 3H, Ph), 7.05 (m, 2H, Ph), 5.70 (m, 1H, H10), 5.38 (br s, 1H,
H9), 4.98–4.91 (m, 2H, H11), 3.26–3.06 (m, 5H, H6, H2, H8, CH-
Ph, NH), 2.86 (m, 1H, CH-NH2), 2.72–2.62 (m, 3H, H6, H2, CH-Ph),
2.29 (s, 3H, CH3-NH), 1.82 (br s, 1H, H3), 1.64–1.58 (m, 3H, H4,
H7, H5), 1.39 (m, 1H, H5), 0.90 (m, 1H, H7). 13C NMR (100 MHz,
CDCl3): d (ppm) = 173.7 (C@O), 150.1 (C20), 148.7 (C100), 147.0
(C-Ph), 141.5 (C10), 137.5 (C40), 130.5 (C80), 129.2 (2C-Ph), 128.6
(C70, C-Ph), 126.8 (2C-Ph), 123.6 (C60, C90, C50), 119.6 (C30), 114.6
(C11), 66.3 (C9), 60.0 (C8), 56.1 (C2), 44.7 (C6), 41.0 (CH-NH2),
39.6 (CH2-Ph), 39.1 (C3), 35.2 (CH3-NH), 27.9 (C7), 27.5 (C4), 26.3
(C5). ESI-TOF MS (m/z): 455.29 (M+1), 456.29 (M+2).
469.26035. [
a
]
24 = ꢀ16.1 (c 1.28, MeOH).
D
4.6.2. (8S,9S)-9-(N-Formyl)glicinylamide(9-deoxy)-epi-cinchoni-
dine 2b
Using the method described above and starting with 1b, 2b was
obtained as a yellow oil (250 mg, 97%). 1H NMR (400 MHz, CDCl3):
d (ppm) = 8.94 (d, 1H, J = 4 Hz, H20), 8.80 (br s, 2H, 2NH-CO), 8.42 (s,
1H, H-CO), 8.37 (d, 1H, J = 8 Hz, H50), 8.15 (m, 1H, H80), 7.76 (t, 1H,
J = 8 Hz, H70), 7.69–7.2 (m, 2H, H60, H30), 6.15 (br s, 1H, H9), 5.71
(m, 1H, H10), 5.20–5.15 (m, 2H, H11), 4.33 (m, 1H, H8), 4.05–
3.62 (m, 4H, H6, H2, CH2), 3.31–3.19 (m, 2H, H6, H2), 2.70 (br s,
1H, H3), 1.97 (m, 2H, H5, H7), 1.81 (m, 1H, H4), 1.12 (m, 1H, H5),
0.85–0.81 (m, 1H, H7). 13C NMR (100 MHz, CDCl3):
d
(ppm) = 169.4 (C@O), 167.7 (C@O), 150.3 (C20), 148.5 (C100),
142.9 (C40), 136.6 (C10), 130.5 (C80), 130.1, (C70), 128.1 (C60),
126.8 (C90), 122.9 (C50), 120.0 (C30), 117.9 (C11), 59.3 (C9), 53.7
(C8, C2), 41.8 (C6, C3), 41.5 (CH2), 26.7 (C5), 24.5 (C7, C4). ESI-
[a]
24 = +17.4 (c 1.03, MeOH).
D
4.5.8. (8S,9S)-9-
L
-Tyrosinylamide(9-deoxy)-epi-cinchonidine 1h
TOF MS (m/z): 379.21 (M+1), 380.21 (M+2). [
MeOH).
a
]
D
23 = ꢀ8.6 (c 1.09,
Using the previous method, 1h was obtained as an oily yellow
solid (433 mg, 93%). 1H NMR (400 MHz, CDCl3): d (ppm) = 8.75
(d, 1H, J = 4 Hz, H20), 8.42 (d, 1H, J = 8 Hz, H50), 8.13 (d, 1H,
J = 8 Hz, H80), 7.73 (t, 1H, J = 8 Hz, H70), 7.65 (t, 1H, J = 8 Hz, H60),
7.33 (d, 1H, J = 4 Hz, H30), 6.67 (d, 2H, J = 8 Hz, Ar), 6.42 (d, 2H,
J = 8 Hz, Ar), 5.84 (br s, 1H, H9), 5.76–5.67 (m, 1H, H10), 5.06–
5.02 (m, 2H, H11), 3.66 (m, 1H, H8), 3.54 (m, 1H, H6), 3.46 (m,
1H, H2), 2.93–2.88 (m, 3H, H6, H2, CH-Ar), 2.51–2.45 (m, 2H, H3,
CH-Ar), 1.97 (m, 1H, CH-NH2), 1.64–1.60 (m, 4H, H4, H7, H5),
4.6.3. (8S,9S)-9-(N-Formyl)-L-valinylamide(9-deoxy)-epi-cincho-
nidine 2c
Using the same method and starting with 1c, 2c was obtained as
a
yellow oil (269 mg, 94%). 1H NMR (400 MHz, CDCl3):
d
(ppm) = 8.92 (s, 1H, H20), 8.39 (br s, 3H, H50, H80, NH-CO), 8.13
(m, 2H, H70, NH-CO), 7.74–7.66 (m, 3H, H60, H30, H-CO), 6.61 (br
s, 1H, H9), 5.74 (m, 1H, H10), 5.19–5.15 (m, 2H, H11), 4.49 (br s,
1H, H8), 4.10 (m, 1H, CH-NH2), 3.79 (br s, 1H, H6), 3.61 (m, 1H,
H2), 3.27 (m, 2H, H6, H2), 2.69 (br s, 1H, H3), 2.05 (m, 1H,
CH(CH3)2), 1.98–1.82 (m, 3H, H5, H7, H4), 1.13 (m, 1H, H5), 0.92
0.93–0.90 (m, 1H, H7). 13C NMR (100 MHz, CDCl3):
d
(ppm) = 174.7 (C@O), 155.9 (C-OH), 150.1 (C20), 148.4 (C100),
145.4 (C40), 139.3 (C10), 130.4 (2C-Ar), 130.2 (C80), 129.9 (C70),

932
P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
(m, 1H, H7), 0.75–0.70 (m, 6H, 2CH3). 13C NMR (100 MHz, CDCl3): d
(ppm) = 175.4 (C@O), 171.9 (C@O), 150.3 (C20), 148.3 (C100), 143.1
(C40), 136.5 (C10), 130.3 (C80), 129.9 (C70), 127.8 (C60), 126.8 (C90),
123.1 (C50), 120.2 (C30), 117.9 (C11), 59.5 (C8, C9), 59.0 (CH-NH),
53.7 (C2), 41.7 (C6), 36.7 (C3), 30.1 (CH-(CH3)2), 26.7 (C7), 24.4
(C4), 24.2 (C5), 19.2 (CH3), 17.9 (CH3). ESI-TOF MS (m/z): 421.26
4.6.7. (8S,9S)-9-(N-Formyl)amino(9-deoxy)-epi-cinchonidine 2g
Using the same method and starting with (8S,9S)-9-amino(9-
deoxy)-epi-cinchonidine, 2g was obtained as
a yellow oil
(217 mg, 99%). 1H NMR (400 MHz, CDCl3): d (ppm) = 8.93 (d, 1H,
J = 4 Hz, H20), 8.38 (m, 1H, H50), 8.15–8.11 (m, 2H, H80, NH-CO),
7.75 (t, 1H, J = 8 Hz, H70), 7.66 (m, 1H, J = 8 Hz, H60), 7.62 (d, 1H,
J = 4 Hz, H30), 6.16 (br s, 1H, H9), 5.69 (m, 1H, H10), 5.16–5.10
(m, 2H, H11), 4.22 (m, 1H, H8), 3.77–3.61 (m, 2H, H6, H2), 3.39–
3.21 (m, 1H, H6), 3.11–3.07 (m, 1H, H2), 2.69 (br s, 1H, H3),
2.09–1.96 (m, 3H, H4, H5, H7), 1.77 (m, 1H, H5), 1.14 (m, 1H,
H7). 13C NMR (100 MHz, CDCl3): d (ppm) = 167.7 (C@O), 150.2
(C20), 148.4 (C100), 143.3 (C40), 136.6 (C10), 130.3 (C80), 130.1
(C70), 128.0 (C60), 126.6 (C50), 123.0 (C90), 120.0 (C30), 117.8
(C11), 58.9 (C8), 53.2 (C9), 46.8 (C2), 41.0 (C6), 36.5 (C3), 26.8
(C7), 24.5 (C5), 24.3 (C4). ESI-TOF MS (m/z): 322.19 (M+1),
(M+1), 422.26 (M+2). [
a]
D
23 = ꢀ9.4 (c 1.23, MeOH).
4.6.4. (8S,9S)-9-(N-Formyl)-L-isoleucinylamide(9-deoxy)-epi-
cinchonidine 2d
Using the same method and starting with 1d, 2d was obtained
as a yellow oil (283 mg, 96%). 1H NMR (400 MHz, CDCl3): d
(ppm) = 8.93 (d, 1H, J = 4 Hz, H20), 8.39 (m, 2H, H50, NH-CO),
8.16–8.11 (m, 2H, H80, CH-CO), 7.74 (t, 1H, J = 8 Hz, H70), 7.68–
7.63 (m, 2H, H60, H30), 6.10 (br s, 1H, H9), 5.73 (m, 1H, H10),
5.20–5.16 (m, 2H, H11), 4.47 (m, 1H, H8), 4.16 (m, 1H, CH-NH),
3.79 (m, 1H, H6), 3.63–3.57 (m, 1H, H2), 3.29–3.20 (m, 2H, H6,
H2), 2.70 (m, 1H, H3), 1.32–1.00 (m, 3H, H4, H5, H7), 0.95–0.81
(m, 2H, CH2), 0.78–0.75 (m, 1H, H7), 0.73–0.68 (m, 6H, 2CH3). 13C
NMR (100 MHz, CDCl3): d (ppm) = 171.8 (C@O), 167.7 (C@O),
150.4 (C20), 148.5 (C100), 143.1 (C40), 136.6 (C10), 130.4 (C80),
129.9 (C70), 127.8 (C60), 126.9 (C50), 123.1 (C90), 120.3 (C30), 117.9
(C11), 60.5 (CH-NH2), 59.1 (C9), 58.6 (C8), 53.8 (C2), 41.7 (C6),
36.8 (CH-CH3), 36.5 (C3), 26.7 (CH2-CH3), 25.1 (C4), 24.5 (C5),
24.3 (C7), 15.5 (CH3), 11.1 (CH3). ESI-TOF MS (m/z): 435.28
323.19 (M+2). [
a
]
D
23 = ꢀ28.5 (c 1.15, MeOH).
4.7. General procedure for synthesis of subclass C derivatives 3
Using the same method as described for the synthesis of
subclass A, compound 1a (0.3 g, 0.68 mmol) was coupled with a
second amino acid furnishing the dipeptide hybrid compounds.
4.7.1. (8S,9S)-9-(
oxy)-epi-cinchonidine 3a
Using Fmoc- -phenylalanine (263 mg, 0.68 mmol), 3a was
L-Phenylalanyl-L-phenylalanineamide)-(9-de-
(M+1), 436.28 (M+2). [
a]
D
23 = ꢀ6.8 (c 1.24, MeOH).
L
obtained as an oily yellow solid (400 mg, 90%). 1H NMR
(400 MHz, CDCl3): d (ppm) = 8.82 (d, 1H, J = 4 Hz, H20), 8.29 (m,
1H, NH-CO),8.09 (d, 1H, J = 8 Hz, H50), 7.69–7.56 (m, 4H, NH-CO,
H80, H70, H60), 7.31 (d, 1H, J = 4 Hz, H30), 7.26–7.08 (m, 10H, 2Ph),
5.66–5.57 (m, 1H, H10), 5.20 (br s, 1H, H9), 4.93–4.87 (m, 2H,
H11), 4.69–4.64 (m, 1H, CH), 3.45 (m, 1H, H8), 3.17–3.11 (m, 1H,
CH), 3.06–2.96 (m, 4H, H2, H6, CH2, CH2), 2.60 (m, 2H, H2, H6),
2.42 (m, 1H, CH), 2.24 (br s, 1H, H3), 1.60–1.55 (m, 4H, H4, H5,
H7, CH), 1.23 (m, 1H, H5), 0.87–0.85 (m, 2H, H7, CH). 13C NMR
(100 MHz, CDCl3): d (ppm) = 174.4 (C@O), 170.8 (C@O), 150.1
(C20), 148.6 (C100), 146.7 (C-Ph), 141.0 (C10), 137.6 (aromatic),
136.6 (aromatic), 130.5 (aromatic), 129.4 (2C), 129.3 (2C), 129.2
(aromatic), 128.7 (2C), 128.5 (2C), 126.9 (2C), 126.7 (aromatic),
123.3 (aromatic), 119.7 (aromatic), 114.8 (C11), [60.2, 56.4, 55.8,
53.8, 40.8, 40.7, 39.4, 37.6, 29.8, 27.7, 27.3, 25.9 (8C quinuclidine,
4.6.5. (8S,9S)-9-(N-Formyl)-L-leucinylamide(9-deoxy)-epi-cincho-
nidine 2e
Using the same method and starting with 1e, 2e was obtained
as a yellow oil (294 mg, 99%). 1H NMR (400 MHz, CDCl3): d
(ppm) = 8.92 (d, 1H, J = 4 Hz, H20), 8.39–8.35 (m, 3H, H50, 2NH-
CO), 8.13 (d, 1H, J = 8 Hz, H80), 8.05 (s, 1H, CH-CO), 7.73 (t, 1H,
J = 8 Hz, H70), 7.67–7.62 (m, 2H, H60, H30), 6.08 (br s, 1H, H9),
5.73 (m, 1H, H10), 5.19–5.14 (m, 2H, H11), 4.44 (m, 1H, H8), 4.27
(m, 1H, CH-NH), 3.77 (m, 1H, H6), 3.61 (m, 1H, H2), 3.30–3.19
(m, 1H, H6, H2), 2.69 (m, 1H, H3), 2.08–2.06 (m, 1H, CH(CH3)2),
1.83–1.77 (m, 1H, H4), 1.56–1.53 (m, 2H, H5, H7), 1.43–1.41 (m,
2H, CH2), 0.93–0.91 (m, 1H, H5), 0.85–0.83 (m, 1H, H7), 0.80–
0.76 (m, 6H, 2CH3). 13C NMR (100 MHz, CDCl3): d (ppm) = 173.0
(C@O), 163.7 (C@O), 150.3 (C20), 148.3 (C100), 143.1 (C40), 136.5
(C10), 130.3 (C80), 129.9 (C70), 127.9 (C60), 126.9 (C50), 123.0
(C90), 120.3 (C30), 117.9 (C11), 59.1 (C9), 53.7 (C2), 52.7 (C8), 48.7
(CH-NH), 41.7 (CH2), 40.3 (C6), 36.7 (C3), 26.7 (C7), 24.7 (C4),
24.4 (C5), 24.2 (CH(CH3)2), 22.9 (CH3), 21.4 (CH3). ESI-TOF MS (m/
4C
(ESI) Found 588.33229, calcd for C37H42N5O2, 588.33330.
24 = +24.6 (c 1.4, MeOH).
L-Phe)]. ESI-TOF MS (m/z): 588.33 (M+1), 589.33 (M+2). HRMS
[a]
D
z): 435.28 (M+1), 436.28 (M+2). [a]
24 = +29.8 (c 1.8, MeOH).
D
4.7.2. (8S,9S)-9-(
epi-cinchonidine 3b
Using Fmoc- -proline (229 mg, 0.68 mmol), 3b was obtained as
L-Prolinyl-L-phenylalanineamide)-(9-deoxy)-
4.6.6. (8S,9S)-9-(N-Formyl)-L-prolinylamide(9-deoxy)-epi-cincho-
L
nidine 2f
a white solid (303 mg, 83% yield), mp 138.0–140.2 °C. 1H NMR
(400 MHz, CDCl3): d (ppm) = 8.83 (d, 1H, J = 4 Hz, H20), 8.32 (m,
1H, NH-CO), 8.10 (d, 1H, J = 8 Hz, H50), 7.91 (d, 1H, J = 8 Hz, H80),
7.68 (m, 2H, H70, NH-CO), 7.57 (m, 1H, H60), 7.31 (s, 1H, H30),
7.23–7.11 (m, 5H, Ph), 5.68–5.60 (m, 1H, H10), 5.23 (br s, 1H,
H9), 4.94–4.87 (m, 2H, H11), 4.63–4.61 (m, 1H, CH), 3.17 (m, 1H,
CH), 3.07–3.03 (m, 2H, H2, H6), 3.66–3.60 (m, 3H, H2, H6, CH),
2.23 (m, 2H, CH, H3), 1.98–1.93 (m, 1H, CH), 1.66–1.54 (m, 6H,
H4, H5, H7, CH2, CH), 1.35–1.29 (m, 2H, H5, CH), 0.86 (m, 2H, H7,
CH). 13C NMR (100 MHz, CDCl3): d (ppm) = 175.5 (C@O), 170.9
(C@O), 150.1 (C20), 148.6 (C100), 146.8 (C-Ph), 141.3 (C10), 136.8
(C40), 130.5 (C80), 129.3 (2C-Ph), 129.1 (C70), 128.5 (2C-Ph), 126.8
(C90), 127.2 (CH-Ph), 126.7 (C60), 123.4 (C50), 119.6 (C30), 114.6
(C11), [60.3, 55.9, 53.6, 47.1, 40.8, 39.6, 37.2, 30.6, 29.8, 27.9,
Using the same method and starting with 1f, 2f was obtained as
a
yellow oil (176 mg, 62%). 1H NMR (400 MHz, CDCl3):
d
(ppm) = 8.94 (d, 1H, J = 4 Hz, H20), 8.42 (d, 1H, J = 8 Hz, H50), 8.19
(m, 2H, H80, NH-CO), 7.98 (s, 1H, CH-CO), 7.93 (br s, 1H, H70),
7.74 (m, 1H, H60), 7.66 (m, 1H, H30), 6.12 (br s, 1H, H9), 5.75 (m,
1H, H10), 5.19–5.12 (m, 2H, H11), 4.10–4.05 (m, 1H, H8), 3.80
(m, 2H, H6, H2), 3.54 (m, 2H, CH2), 3.44 (m, 1H, CH), 3.29 (m, 2H,
H6, H2), 2.70 (br s, 1H, H3), 1.96–1.64 (m, 7H, H4, H5, H7, CH2,
CH2), 1.53–1.50 (m, 1H, H5), 1.10–1.07 (m, 1H, H7). 13C NMR
(100 MHz, CDCl3): d (ppm) = 172.5 (C@O), 164.2 (C@O), 150.2
(C20), 147.8 (C100), 143.9 (C40), 136.8 (C10), 130.4 (C80), 129.7
(C70), 128.3 (C60), 127.4 (C50), 123.5 (C90), 121.2 (C30), 118.1
(C11), 59.8 (C8), 59.2 (C9), 54.0 (C2), 47.6 (CH2), 42.2 (CH), 41.2
(C6), 37.0 (C3), 29.9 (CH2), 27.1 (C7), 24.6 (C5, CH2), 24.5 (C4).
27.4, 25.9 (8C quinuclidine, 2C L-Phe, 4C L-Pro)]. ESI-TOF MS
ESI-TOF MS (m/z): 419.25 (M+1), 420.25 (M+2). [
1.01, MeOH).
a]
24 = +65.2 (c
(m/z): 538.32 (M+1), 539.32 (M+2). HRMS (ESI) Found 538.31705,
D
calcd for C33H40N5O2, 538.31765. [
a]
23 = ꢀ40.4 (c 1, MeOH).
D

P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
933
4.7.3. (8S,9S)-9-(
cinchonidine 3c
L
-Valinyl-
L
-phenylalanineamide)-(9-deoxy)-epi-
stir at room temperature for 10 min. The aldehyde (0.53 mmol)
was then added to the reaction mixture and allowed to stir for
24–72 h. The volatiles were removed under reduced pressure and
the product was purified by column chromatography on silica gel
eluted with hexane/AcOEt (5:1), to furnish the desired aldol
product 6.
Using Fmoc-L-valine (231 mg, 0.68 mmol), 3c was obtained as
an oily solid (323 mg, 88% yield). 1H NMR (400 MHz, CDCl3): d
(ppm) = 8.82 (br s, 1H, H20), 8.30 (m, 1H, NH-CO), 8.10 (br s, 1H,
H50), 7.97 (br s, 1H, H80), 7.68 (m, 1H, H70), 7.57 (m, 2H, H60, NH-
CO), 7.29 (br s, 1H, H30), 7.22–7.13 (m, 5H, Ph), 5.67–5.59 (m, 1H,
H10), 5.17 (br s, 1H, H9), 4.93–4.87 (m, 2H, H11), 4.63 (m, 1H,
CH), 3.42 (s, 1H, CH), 3.18–3.12 (m, 1H, CH), 3.06–3.00 (m, 3H,
H2, H6, CH), 3.65–3.56 (m, 2H, H2, H6), 2.22 (br s, 1H, H3), 2.09
(br s, 1H, CH), 1.59 (m, 4H, H4, H5, H7, CH), 1.28–1.23 (m, 1H,
H5), 0.85–0.80 (m, 4H, H7, CH3), 0.53–0.52 (m, 3H, CH3). 13C
NMR (100 MHz, CDCl3): d (ppm) = 174.6 (C@O), 170.9 (C@O),
150.0 (C20), 148.6 (C100), 146.9 (C-Ph), 141.3 (C10), 136.8 (C40),
130.5 (C80), 129.3 (2C-Ph), 129.1 (C70), 128.6 (2C-Ph), 127.2 (CH-
Ph), 126.8 (C90), 126.6 (C60), 123.3 (C50), 119.5 (C30), 114.6 (C11),
[60.2, 55.9, 53.8, 40.8, 39.6, 37.4, 30.8, 29.8, 27.8, 27.4, 26.0 (8C
4.8.1.1. 4-Hydroxy-4-(4-nitrophenyl)butan-2-one27 6a
This was obtained as a brown oil (47 mg, 42% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 8.15 (d, 2H, J = 4 Hz, Ar), 7.51 (d, 2H,
J = 8 Hz, Ar), 5.23 (br s, 1H, OH), 3.75 (s, 1H, CH), 2.84 (d, 2H,
J = 4 Hz, CH2), 2.19 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
(ppm) = 208.5 (C@O), 150.3 (Ar), 147.3 (Ar), 126.5 (2C-Ar), 123.8
(2C-Ar), 68.9 (CH), 51.6 (CH2), 30.7 (CH3). HPLC (Daicel Chirapak
AD-H, hexane/EtOH = 70:30, flow rate 0.7 mL/min), k = 254 nm:
tr = 12.2 min (S), tr = 13.1 min (R).
quinuclidine, 2C
L
-Phe, CH)], 19.5 (iPr), 19.1 (iPr), 15.8 (iPr). ESI-
4.8.1.2. 4-Hydroxy-4-phenylbutan-2-one43–45 6b
TOF MS (m/z): 540.33 (M+1), 541.32 (M+2). HRMS (ESI) Found
This was obtained as an orange oil (22 mg, 25% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.33–7.25 (m, 5H, Ph), 5.12 (m, 1H,
CH), 3.31 (br s, 1H, OH), 2.89–2.73 (m, 2H, CH2), 2.15 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): d (ppm) = 209.1 (C@O), 142.9
(Ar), 128.5 (2C-Ar), 127.7 (Ar), 125.7 (2C-Ar), 69.8 (CH),
52.0 (CH2), 30.8 (CH3). HPLC (Daicel Chirapak AD-H, hexane/
isopropanol = 90:10, flow rate 1 mL/min), k = 230 nm: tr = 5.4 min
(R), tr = 6.6 min (S).
540.33285, calcd for
1.28, MeOH).
C
33H42N5O2, 540.33330.
[
a]
24 = ꢀ17.9 (c
D
4.7.4. (8S,9S)-9-(Glycinyl-L-phenylalanineamide)-(9-deoxy)-epi-
cinchonidine 3d
Using Fmoc-glycine (202 mg, 0.68 mmol), 3d was obtained as
an oily white solid (291 mg, 86% yield). 1H NMR (400 MHz, CDCl3):
d (ppm) = 8.81 (br s, 1H, H20), 8.30 (m, 1H, H50), 8.08 (br s, 1H, H80),
8.00 (br s, 1H, NH-CO), 7.68 (m, 2H, H70, NH-CO), 7.56 (m, 1H, H60),
7.45 (br s, 1H, H30), 7.14–7.08 (m, 5H, Ph), 5.65–5.62 (m, 1H, H10),
5.43 (br s, 1H, H9), 4.99–4.92 (m, 2H, H11), 4.58 (m, 1H, CH), 3.23–
2.97 (m, 6H, H2, H6, H8, CH2, CH), 2.68 (m, 2H, H2, H6), 2.30 (br s,
1H, H3), 1.65 (m, 4H, H5, H4, H7, CH), 1.37 (m, 1H, H5), 0.86–0.80
(m, 1H, H7). 13C NMR (100 MHz, CDCl3): d (ppm) = 173.9 (C@O),
170.9 (C@O), 150.2 (C20), 148.4 (C100), 145.7 (C-Ph), 140.1 (C10),
136.4 (C40), 130.3 (C80), 129.2 (C70, 2C-Ph), 128.5 (2C-Ph), 127.4
(C-Ph), 126.9 (C60, C90), 123.3 (C50), 119.9 (C30), 115.3 (C11), 59.6
(C8), 55.2 (C9), 54.4 (CH), 50.4 (C2), 41.0 (C6), 38.8 (CH2), 37.6
(C3), 29.7 (CH2), 27.1 (C7), 26.9 (C4), 25.5 (C5). ESI-TOF MS (m/z):
498.28 (M+1), 499.29 (M+2). HRMS (ESI) Found 498.28622, calcd
4.8.1.3. 4-Hydroxy-4-(4-methoxyphenyl)butan-2-one45 6c
This was obtained as an orange oil (2 mg, 2% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.29 (m, 2H, Ar), 6.90 (m, 2H, Ar),
6.89, 5.14–5.11 (m, 1H, CH), 3.86 (s, 3H, CH3), 2.94–2.78
(m, 2H, CH2), 2.21 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
(ppm) = 198.5 (C@O), 161.7 (Ar), 143.3 (2C-Ar), 127.1 (Ar), 125.1
(2C-Ar), 60.5 (CH), 29.8 (OCH3), 21.1 (CH2), 14.3 (CH3). HPLC
(Daicel Chirapak AD-H, hexane/isopropanol = 90:10, flow rate
1 mL/min), k = 230 nm: tr = 14.5 min (R), tr = 16.6 min (S).
4.8.1.4. 4-Hydroxy-4-(2-methoxyphenyl)butan-2-one 6d
This was obtained as yellow oil (73 mg, 71% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.44 (d, 1H, J = 8 Hz, Ar), 7.25 (t, 1H,
J = 8 Hz, Ar), 6.97 (t, 1H, J = 8 Hz, Ar), 6.86 (d, 1H, J = 8 Hz, Ar),
5.41 (d, 1H, J = 8 Hz, CH), 3.82 (s, 3H, CH3), 3.61 (br s, 1H, OH),
2.93–2.74 (m, 2H, CH2), 2.17 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d (ppm) = 209.3 (C@O), 155.7 (Ar), 130.9 (Ar), 128.3
(Ar), 126.3 (Ar), 120.7 (Ar), 110.2 (Ar), 65.4 (CH), 55.2 (OCH3),
50.4 (CH2), 30.5 (CH3). HPLC (Daicel Chirapak AD-H, hexane/
isopropanol = 85:15, flow rate 1 mL/min), k = 230 nm: tr = 9.9 min,
tr = 11.3 min.
for C30H36N5O2, 498.28635. [
a
]
D
24 = ꢀ14.5 (c 1.3, MeOH).
4.7.5. (8S,9S)-9-(
oxy)-epi-cinchonidine 3e
Using Fmoc- -methionine (253 mg, 0.68 mmol), 3e was
L-Methioninyl-L-phenylalanineamide)-(9-de-
L
obtained as an oily yellow solid (370 mg, 95% yield). 1H NMR
(400 MHz, CDCl3+DMSO-d6): d (ppm) = 8.61 (br s, 1H, H20), 8.11
(m, 1H, H50), 7.82 (br s, 1H, H80), 7.73 (br s, 2H, 2NH-CO), 7.45
(m, 1H, H70), 7.35 (m, 1H, H60), 7.16 (m, 1H, H30), 6.94–6.90 (m,
5H, Ph), 5.43 (m, 1H, H10), 5.09 (br s, 1H, H9), 4.72–4.65 (m, 2H,
H11), 4.39 (m, 1H, CH), 3.06–2.4 (m, 6H), 2.43–2.31 (m, 3H),
2.16–2.01 (m, 3H), 1.81 (m, 1H), 1.58 (m, 2H), 1.44–1.32 (m, 4H),
0.99 (m, 1H), 0.63–0.59 (m, 3H, CH3). 13C NMR (100 MHz, CDCl3+-
DMSO-d6): d (ppm) = 174.4 (C@O), 170.3 (C@O), 149.5 (C20), 147.9
(C100), 146.5 (C-Ph), 140.6 (C10), 136.5 (C40), 129.7 (C80), 128.8 (2C-
Ph), 128.6 (C70), 127.8 (2C-Ph), 126.7 (C-Ph), 126.2 (C60, C90), 123.0
(C50), 119.2 (C30), 114.1 (C11), 59.2 (C8), 55.1 (CH), 53.7 (C9), 53.3
(CH), 43.8 (C2), 37.1 (C6), 33.5 (C3), 29.9 (CH2), 29.8 (CH2), 29.1
(CH2), 27.0 (C7), 26.8 (C4), 25.3 (C5), 14.7 (CH3). ESI-TOF MS (m/
z): 572.31 (M+1), 573.31 (M+2). HRMS (ESI) Found 572.30486,
4.8.1.5. 4-(2,4-Dimethoxyphenyl)-4-hydroxybutan-2-one 6e
This was obtained as yellow oil (6 mg, 5% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.27 (d, 1H, J = 8 Hz, Ar), 6.45–6.40
(m, 2H, Ar), 5.30 (d, 1H, J = 4 Hz, CH), 3.76 (s, 6H, 2CH3), 3.43 (br
s, 1H, OH), 2.85–2.72 (m, 2H, CH2), 2.14 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d (ppm) = 209.4 (C@O), 160.1 (Ar), 156.9 (Ar),
127.1 (Ar), 123.5 (Ar), 104.2 (Ar), 98.4 (Ar), 65.4 (CH), 55.3
(OCH3), 55.2 (OCH3), 50.6 (CH2), 30.6 (CH3). HPLC (Daicel
Chirapak AD-H, hexane/isopropanol = 85:15, flow rate 1 mL/min),
k = 230 nm: tr = 13.9 min, tr = 19.1 min.
calcd for C33H42N5O2S, 572.30537. [
a]
24 = ꢀ19.6 (c 1.13, MeOH).
D
4.8.1.6. 4-(4-Bromophenyl)-4-hydroxybutan-2-one45 6f
4.8. Catalytic reactions
This was obtained as yellow oil (25 mg, 19% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.43 (d, 2H, J = 8 Hz, Ar), 7.19 (d, 2H,
J = 8 Hz, Ar), 5.07 (m, 1H, CH), 3.73 (br s, 1H, OH), 2.85–2.71 (m,
4.8.1. General procedure for the aldol reaction27
The organocatalyst (0.053 mmol) was dissolved in 1 mL of ace-
tone in a 10 mL round bottom flask and the solution was allowed to
2H, CH2), 2.15 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d
(ppm) = 208.7 (C@O), 142.0 (Ar), 131.5 (2C-Ar), 127.4 (2C-Ar),

934
P. Barrulas et al. / Tetrahedron: Asymmetry 25 (2014) 923–935
121.3 (Ar), 69.1 (CH), 51.8 (CH2), 30.7 (CH3). HPLC (Daicel Chirapak
AD-H, hexane/isopropanol = 95:5, flow rate 1 mL/min), k = 262 nm:
tr = 18.2 min (R), tr = 19.9 min (S).
4.8.3. General procedure for the Michael addition48
Organocatalyst 3d (0.1 equiv) and 2,4-pentadione (2 equiv)
were dissolved in CH2Cl2 (2 mL) in a 10 mL round bottom flask.
After 10 min, trans-b-nitrostyrene (1 equiv) was added and the
reaction was allowed to proceed at room temperature for 24 h
under an atmosphere of nitrogen, after which the product was
purified by column chromatography with silica gel and eluted with
a mixture of hexane/ethyl acetate (5:1) to furnish the product.
4.8.1.7. 4-Hydroxy-4-m-tolylbutan-2-one43 6g
This was obtained as a red oil (10 mg, 11% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.26–7.09 (m, 4H, Ar), 5.10 (m, 1H,
CH), 3.65 (s, 1H, OH), 2.91–2.74 (m, 2H, CH2), 2.37 (m, 3H, CH3),
2.17 (m, 3H, CH3). 13C NMR (100 MHz, CDCl3): d (ppm) = 208.9
(C@O), 142.9 (Ar), 138.0 (Ar), 128.3 (Ar), 128.3 (Ar), 126.3 (Ar),
122.6 (Ar), 69.7 (CH), 52.0 (CH2), 30.6 (CH3), 21.3 (CH3). HPLC (Dai-
cel Chirapak AD-H, hexane/isopropanol = 95:5, flow rate 1 mL/
min), k = 257 nm: tr = 16.5 min (R), tr = 17.8 min (S).
4.8.3.1. 3-[1-(1-Phenyl-2-nitroethyl)]-2,4-pentanedione49–52
This was obtained as a white solid (mp 102.3–102–9 °C). 1H
NMR (400 MHz, CDCl3): d (ppm) = 7.35–7.19 (m, 5H, Ph), 4.66–
4.64 (m, 2H, CH2), 4.40–4.37 (m, 1H, CH), 4.28–4.22 (m, 1H, CH),
2.29 (s, 3H, CH3), 1.95 (s, 3H, CH3). 13C NMR (400 MHz, CDCl3): d
(ppm) = 201.9 (C@O), 201.1 (C@O), 136.1 (Ph), 129.4 (2C-Ph),
128.6 (Ph), 128.0 (2C-Ph), 78.3 (CH2), 70.7 (CH), 42.9 (CH),
30.5 (CH3), 29.7 (CH3). HPLC: (Daicel Chirapak AD-H, hexane/
isopropanol = 85:15, flow rate 0.8 mL/min), k = 210 nm; tr =
12.2 min (S), tr = 16.3 min (R).
4.8.1.8. 4-Hydroxy-4-o-tolylbutan-2-one 6h
This was obtained as yellow oil (2 mg, 2% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.28–7.10 (m, 4H, Ar), 5.37 (m, 1H,
CH), 3.41 (br s, 1H, OH), 2.86–2.69 (m, 2H, CH2), 2.31 (s, 3H,
CH3), 2.19 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d
(ppm) = 208.8 (C@O), 133.5 (Ar), 131.6 (Ar), 130.2 (Ar), 127.2
(Ar), 126.1 (Ar), 125.1 (Ar), 66.2 (CH), 50.6 (CH2), 30.6 (CH3), 18.8
(CH3). HPLC (Daicel Chirapak AD-H, hexane/isopropanol = 90:10,
flow rate 1 mL/min), k = 257 nm: tr = 8.6 min, tr = 11.4 min.
4.8.4. General procedure for the ketimine hydrosilylation
reaction53
To a 10 mL round bottom flask were added 0.1 equiv of the
organocatalyst 3d and 1 equiv of N-(1-(4-nitrophenyl)ethyli-
dene)-aniline (100 mg, 0.42 mmol) in CH2Cl2 (2 mL) at 0 °C. After
4.8.1.9. 4-(2-Chlorophenyl)-4-hydroxybutan-2-one43,45 6i
This was obtained as yellow oil (15 mg, 14% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.28–7.14 (m, 4H, Ar), 5.55–5.46 (m,
1H, CH), 3.80 (br s, 1H, OH), 2.96–2.61 (m, 2H, CH2), 2.17 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): d (ppm) = 209.0 (C@O), 129.3
(Ar), 129.3 (Ar), 128.5 (Ar), 127.2 (Ar), 127.2 (Ar), 127.1 (Ar), 66.5
(CH), 50.1 (CH2), 30.5 (CH3). HPLC (Daicel Chirapak AD-H, hexane/
isopropanol = 95:5, flow rate 1 mL/min), k = 262 nm: tr = 13.0 min
(R), tr = 14.9 min (S).
15 min, 3 equiv of HSiCl3 (176 lL) was added dropwise, and after
the addition was complete, the mixture was allowed to react at
room temperature for over 21 h. The reaction was then quenched
with a saturated solution of NaHCO3 (2 mL) and extracted with
CH2Cl2 (10 mL ꢁ 3) and then MgSO4 to remove the vestigial water
that was present. The crude product was purified by column chro-
matography on silica gel and eluted with CH2Cl2 to furnish the
desired chiral amine.
4.8.4.1. N-(1-(4-Nitrophenyl)ethyl)aniline54
4.8.1.10. 4-(4-(Benzyloxy)phenyl)-4-hydroxybutan-2-one 6j
This was obtained as an orange oil (16 mg, 11% yield). 1H NMR
(400 MHz, CDCl3): d (ppm) = 7.41–6.96 (m, 9H, Ar), 5.05 (m, 3H,
CH, CH2), 3.37 (br s, 1H, OH), 2.90–2.88 (m, 2H, CH2), 2.17 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): d (ppm) = 209.1 (C@O), [158.3,
137.0, 135.3, 128.6 (2C), 128.0, 127.5 (2C), 127.0 (2C), 114.9 (2C)
(aromatics)], 70.0 (CH), 52.0 (CH2), 30.8 (CH3). HPLC (Daicel Chirapak
AD-H, hexane/ethanol = 80:20, flow rate 0.8 mL/min), k = 257 nm:
tr = 19.9 min, tr = 25.9 min.
This was obtained as an orange oil. 1H NMR (400 MHz, CDCl3): d
(ppm) = 8.18 (d, 2H, J = 8 Hz, Ar), 7.55 (d, 2H, J = 8 Hz, Ar), 7.10 (m,
2H, Ph), 6.68 (t, 1H, J = 8 Hz, Ph), 6.45 (d, 2H, J = 8 Hz, Ph), 4.57 (d,
1H, J = 8 Hz, CH), 4.13 (br s, 1H, NH), 1.55 (d, 3H, J = 4 Hz, CH3). 13
C
NMR (100 MHz, CDCl3): d (ppm) = [153.3, 147.1, 146.6, 129.3 (2C),
126.8 (2C), 124.1 (2C), 118.0, 113.4 (2C) (aromatics)], 53.4 (CH),
25.0 (CH3). HPLC (Daicel Chirapak OD-H, hexane/isopropanol =
80:20, flow rate 1 mL/min), k = 254 nm: tr = 15.6 min (R), tr = 18.6
min (S).
4.8.2. General procedure for the Biginelli reaction46
Urea (0.116 g, 1.93 mmol) was dissolved in THF (2 mL) and to
this solution were added benzaldehyde (0.197 mL, 0.206 g,
1.93 mmol), methyl acetoacetate (0.139 mL, 0.149 g, 1.29 mmol),
Acknowledgements
We are grateful for the award of a PhD Grant to P.B. (SFRH/BD/
61913/2009) from the Science and Technology Foundation,
Ministry of Science and Education (FCT) 2010. We also thank the
FCT for funding through the strategic program PEst-OE/QUI/
UI0619/2011. Dr. Olivia Furtado Burke, LNEG, Lisbon is acknowl-
edged for performing the optical rotation measurements. The
University of Vigo (Spain) is gratefully acknowledged for MS
analysis. The NMR spectrometers are part of The National NMR
Facility, supported by Science and Technology Foundation, Ministry
of Science and Education (RECI/BBB-BQB/0230/2012).
0.1 equiv of the organocatalyst 3d and 0.1 equiv of HCl (65 lL of
a 4 M solution in dioxane). The reaction was allowed to take
place at room temperature over 6 days and then was quenched
by evaporation of all the volatile compounds under reduced
pressure.
4.8.2.1. Methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate46,47
This was obtained as a white solid (mp 197.3–198.0 °C). 1H
NMR (400 MHz, DMSO-d6) d (ppm) = 9.23 (s, 1H, NH), 7.77 (s, 1H,
NH), 7.33–7.23 (m, 5H, Ph), 5.16 (s, 1H, CH), 3.52 (s, 3H, CH3),
2.26 (s, 3H, CH3). 13C NMR (400 MHz, DMSO-d6) d (ppm) = 165.9
(C@O), 152.3 (C@O), [148.7, 144.7, 128.5 (2C), 127.3, 126.2
(2C), 99.1 (phenyl and olefin)], 53.9 (CH), 50.8 (CH3), 17.9
(CH3). HPLC (Daicel Chirapak OD-H, hexane/isopropanol =
80:20, flow rate 0.5 mL/min), k = 254 nm: tr = 15.8 min (S),
tr = 20.9 min (R).
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