Design and preparation of a novel prolinamide-based organocatalyst for the solvent-free asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tet.2019.130855

The preparation of four novel organocatalysts as highly diastereo and enantioselective catalysts for the solvent-free asymmetric aldol reaction was described. These organocatalysts were synthesized in eight steps applying simple and commercially available starting materials. The best results were obtained for the proline-derived catalyst, providing access to the desired adducts in up to 95% yield, 1:19 syn/anti and 98% e.e. Moreover, even sterically bulky aldehydes and substituted cyclohexanones were well tolerated. DFT calculations and control experiments indicated that several hydrogen bonding interactions between the aldehyde and the enamine intermediate are responsible for the stereoselective chiral induction process and that the trifluoroacetate counter-anion is crucial for the attainment of higher stereoselectivities.

Full text of DOI:10.1016/j.tet.2019.130855

Journal Pre-proof
Design and preparation of a novel prolinamide-based organocatalyst for the solvent-
free asymmetric aldol reaction
Rafaela de S. Martins, Mathias P. Pereira, Pedro P. de Castro, Fernanda I.
Bombonato
PII:
S0040-4020(19)31263-3
https://doi.org/10.1016/j.tet.2019.130855
TET 130855
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 October 2019
Revised Date: 25 November 2019
Accepted Date: 30 November 2019
Please cite this article as: Martins RdS, Pereira MP, de Castro PP, Bombonato FI, Design and
preparation of a novel prolinamide-based organocatalyst for the solvent-free asymmetric aldol reaction,
Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2019.130855.
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-Graphical Abstract
Design and Preparation of a Novel
Leave this area blank for abstract info.
Prolinamide-based Organocatalyst for the
Solvent-free Asymmetric Aldol Reaction
Rafaela de S. Martins, Mathias P. Pereira, Pedro P. de Castro and Fernanda I. Bombonato
Chemistry Department, Federal University of Juiz de Fora, Campus Martelos, Juiz de Fora, 36036-900, Brazil.

1
Tetrahedron
journal homepage: www.elsevier.com
Design and Preparation of a Novel Prolinamide-based Organocatalyst for the Solvent-
free Asymmetric Aldol Reaction
Rafaela de S. Martinsa, Mathias P. Pereiraa, Pedro P. de Castroa and Fernanda I. Bombonatoa .
,
a Chemistry Department, Federal University of Juiz de Fora, Campus Martelos, Juiz de Fora, Minas Gerais 36036-900, Brazil.
ARTICLE INFO
ABSTRACT
The preparation of four novel organocatalysts as highly diastereo and enantioselective catalysts
for the solvent-free asymmetric aldol reaction was described. These organocatalysts were
synthesized in eight steps applying simple and commercially available starting materials. The
best results were obtained for the proline-derived catalyst, providing access to the desired
adducts in up to 95% yield, 1:19 syn/anti and 98% e.e. Moreover, even sterically bulky
aldehydes and substituted cyclohexanones were well tolerated. DFT calculations and control
experiments indicated that several hydrogen bonding interactions between the aldehyde and the
enamine intermediate are responsible for the stereoselective chiral induction process and that the
trifluoroacetate counter-anion is crucial for the attainment of higher stereoselectivities.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Aldol
Asymmetric Catalysis
Organocatalysis
Aminocatalysis
Solvent-free
Prolinamide
2019 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +55-32-2102-3310; e-mail: fernanda.bombonato@ufjf.edu.br

2
Tetrahedron
1. Introduction
Reactions involving the formation of carbon-carbon bonds
have always attracted great interest in the organic chemistry
community [1]. Over the last few years, with the great
development of the asymmetric organocatalysis field, elegant
protocols to those transformations were further developed,
especially those involving the simultaneous formation of several
stereogenic centers [2,3]. In this context, the aldol reaction
appears as an important transformation in which two or even
more stereocenters can be generated in a single reaction step [4].
Furthermore, the reagents (aldol acceptor and aldol donor) do not
require any pre-activation step, as occurs in the Mukaiyama aldol
reaction.
Asymmetric protocols for the aldol reaction have presented
great developments since the pioneer studies of List and Barbas
III with L-proline [5–7]. Thus, several catalysts were designed
and applied in this transformation, including peptides [8], metal
catalysts [9], thioureas [10,11], squaramides [12], and
prolinamide organocatalysts [13]. On the other hand, more
efficient chiral catalysts are still required for the enantioselective
aldol reaction, and the development of a general protocol for this
transformation is still a challenge [4].
Prolinamide organocatalysts, in the presence of ketones, are
noteworthy for their capacity to form iminium/enamine
intermediates. These catalysts generally allow the aldol reaction
to proceed at milder reaction conditions [13]. Most of these
catalysts rely on hydrogen bonding interactions for the chiral
induction. For example, Singh’s group described the use of a
prolinamide-based organocatalyst bearing both a gem-diphenyl
substituted side-chain and a hydroxyl group in the asymmetric
aldol reaction (Scheme 1A), affording the desired adducts in
moderate yields and moderate to excellent enantiomeric excesses
[14]. On the other hand, only acetone was used and the reaction
required considerably lower temperatures. Another interesting
study was recently described by Murata and co-workers (Scheme
Scheme 1. Previous reports on prolinamide-catalyzed asymmetric
aldol reaction and this work proposal.
2. Results and Discussion
2.1. Catalysts preparation
We started our study by preparing the chiral amine 6. This
compound was prepared in five steps (21% overall yield)
employing the commercially available
D-mannitol as the initial
substrate (Scheme 2). First, the hydroxyl groups were protected,
affording derivative 2 in 77% isolated yield. Next, the oxidative
cleavage employing sodium periodate was carried out, followed
by the aldehyde reduction into the desired alcohol 3 (63% yield)
using sodium borohydride. For the conversion of the hydroxyl
group into the desired amine, an Appel reaction for the formation
of iodide 4 (73% yield) was initially conducted, followed by a
nucleophilic substitution employing sodium azide as nucleophile
(73% yield) and, finally, the azide reduction through
hydrogenation over palladium on carbon (81% yield). It is worth
mentioning that the optical rotation of all these compounds was
monitored during each reaction step and showed good agreement
with the literature values.
1B), which prepared an unnatural tripeptide bearing an L-proline
residue for the asymmetric aldol reaction between isatins and
acetone [15]. Most interestingly, the catalyst design predicted
stereocontrol by the simultaneous formation of several hydrogen
bonding interactions.
Our research group has recently been studying the influence of
new catalysts bearing polyol moieties derived from glycerol in
organic transformations, such as the Morita-Baylis-Hillman
reaction [16], especially in solvent-free protocols. Thus, we
envisioned that the preparation of a chiral amine with a polyol
side-chain would allow its subsequent coupling with an amino
acid, affording novel chiral organocatalysts with potential
applications in amino-catalyzed transformations (Scheme 1C).
Furthermore, the asymmetric induction by the selective
stabilization of transition states through the formation of
hydrogen bonding interactions might be possible due to the
presence of a side-chain bearing NH and OH groups in these
catalysts.

3
Scheme 4. Preparation of catalysts 9d.
The preparation of the salt-free 9d catalyst was also carried
out employing substrate 8d, trichloroacetic acid (2 equiv.) under
reflux for 12 hours (full details of this reaction are available in
the Supplementary data). However, due the important literature
precedents involving salt catalysts for the aldol reaction [20,21],
we decided to continue our investigation using these compounds
as trifluoroacetate salts.
Scheme 2. Synthetic route to the chiral amine 6.
Next, three different catalysts bearing primary amine moieties
(9a-c) were prepared (Scheme 3). To this purpose, we initially
prepared the Boc-protected amino acids 7a-c based on literature
2.2. Reaction optimization
protocols [17], prepared from the amino acids
L-valine, L-leucine,
and -phenylalanine, respectively. This step was then followed
L
The use of these novel organocatalysts in the asymmetric aldol
reaction between cyclic ketones and aryl-substituted aldehydes
was then studied. To this purpose, the use of these catalysts (15
mol%), employing dimethylsulfoxide (DMSO) as solvent (Table
1) at room temperature, and using 4-nitrobenzaldehyde and
cyclohexanone as substrates was initially investigated.
Unfortunately, the yields and the diastereomeric ratios were poor
for all primary amine catalysts. On the other hand, the
prolinamide-based catalyst led to a more encouraging result
(entry 4). Based on literature reports employing DMSO in the
presence of water as an additive (10 equiv.) [22,23], tests were
also carried out in this reaction condition (entries 1-4). Although
an enhancement in the stereocontrol was achieved for catalyst 9d,
the isolated yield considerably dropped.
by the N,N'-dicyclohexylcarbodiimide (DCC) mediated coupling
between these protected amino acids and the previously prepared
amine 6, resulting in the desired derivatives 8a-c in up to 81%
yield. Finally, the simultaneous deprotection of the Boc and ketal
groups afforded the desired catalysts 9a-c as trifluoroacetate
salts, in isolated yields between 89 and 92%. Moreover, these
three-step protocol resulted in the desired products in 50-63%
overall yields. The chiral purity of these catalysts and their
1
precursors (8a-c) was confirmed by the H NMR analysis of the
crude reaction mixtures, which did not indicate the occurrence of
epimerization during these steps.
By changing the solvent to water, although an increase in
yields was detected, the stereoselectivity slightly dropped (entries
5-8). Once more, the best result was attained for the prolinamide
organocatalyst. Next, tests in the absence of solvents were carried
out and, surprisingly, an excellent isolated yield of 98% was
obtained when employing the catalyst 9d, with
a good
diastereomeric ratio (10:1) and enantiomeric excess (79%) (entry
12). It is also worth mentioning that in the absence of the
catalysts no product was detected.
Scheme 3. Preparation of catalysts 9a-c.
Due to the promising results in the literature employing
proline-based organocatalysts [8,13,18,19], associated with its
capability to form iminium/enamine intermediates through the
condensation with ketones, the preparation of the organocatalyst
9d was carried out employing the same protocol previously
applied and using L-proline as the initial substrate. The desired
organocatalyst was isolated in 44% overall yield after the three-
reaction steps, as depicted in Scheme 4.

4
Tetrahedron
carried out employing 5 mol% of catalyst 9d; eReaction carried out
Table 1. Optimization of reaction conditions.
employing 10 mol% of catalyst 9d.
The influence of the catalyst counter-anion was also
investigated. To this purpose, the substitution of trifluoroacetate
moiety for trichloroacetate (catalyst 9d-TCA) was carried out
(the method for its preparation is available in the Supplementary
data). After its use in the optimized reaction conditions, the aldol
adduct was isolated in 80% yield, only 4:1 d.r. and 71% e.e. A
control experiment employing the salt-free 9d catalyst was also
carried out and, although the aldol product was isolated with an
excellent yield (97%), the stereoselectivity drastically dropped
(only 4:1 d.r. and 63% e.e.). These results suggests that the
trifluoroacetate moiety is crucial for the adequate chiral induction
in the desired aldol product. Interestingly, good results for
catalysts bearing fluorinated counter-anions were previously
reported by other groups for the asymmetric aldol reaction [21].
d.r.a
(anti/syn)
2:1/2:1c
Entry Catalyst
Solvent
Yield
e.e.b (%)
9a
DMSO
DMSO
DMSO
DMSO
H2O
H2O
H2O
H2O
-
10/25c
9/23c
9/24c
72/53c
58
ND/81c
ND/74c
ND/51c
75/87c
50
1
2
9b
2:1/3:1c
2:1/2:1c
7:1/14:1c
2:1
3
9c
4
9d
5
9a
6
9b
38
3:1
72
7
9c
40
1:1
40
8
9d
62
10:1
1:1
79
9
9a
38
38
10
9b
Next, aiming to gain further insights of the importance and
extension of the polyol group interactions in the asymmetric
induction process, we prepared an analogue of catalyst 9d
(hereby named 9d-rac) employing glycerol as starting material
(full details of this preparation are available in the Supplementary
data). Thus, the polyol precursor is formed as a racemic mixture
-
44
1:1
47
11
9c
-
77
1:1
24
12
9d
-
98
10:1
79
aCalculated through the 1H NMR the analysis of the crude reaction mixture;
bCalculated through enantiodiscriminationg HPLC; cReaction carried out
using 10 equiv. of water as additive. ND: Not determined.
and, after condensation with the L-proline moiety affords the
catalyst as a mixture of diasteomers. The use of this novel
catalyst (9d-rac) in the optimized reaction conditions resulted in
the desired aldol adduct in 71% yield and with a considerable
drop in the reaction diastereoselectivity (only 4:1 d.r.) and
enantiomeric excess (75%). This suggests that the polyol side-
chain enhance reaction stereocontrol toward the major aldol
isomer through selectively stabilizing the transition state leading
to this isomer.
Since the best overall results were found for the catalyst 9d,
further optimization employing this organocatalyst was carried
out (Table 2). The use of polar protic (entry 1) and aprotic
solvents (entry 2 and 3) failed to considerably enhance the
stereoselectivity. The use of trifluoroacetic acid (TFA) as an
additive (15 mol%) [24] was also evaluated, and significantly
dropped the yield, d.r. and e.e. (entry 4). Interestingly, the use of
catalytic TFA (15 mol%), in the absence of the catalyst 9d,
inverted the diastereocontrol towards the syn isomer (1:2 d.r.)
(entry 5). Noteworthy, by lowering the temperature to 0 °C, in
the absence of solvents and additives, the best overall reaction
condition was accessed (entry 6), with 90% yield, 19:1 d.r. and
98% e.e. Finally, the catalyst loading was evaluated (entries 7
and 8) and, although similar diasteomeric ratios were obtained
when using 5 or 10 mol% of organocatalyst 9d, a considerable
drop in yields and enantiomeric excesses were observed.
Finally, for the determination of the relative and absolute
stereochemistry of the synthesized derivative, an 1H NMR
analysis was carried out and indicated, by comparison with
literature data [25], anti as the major isomer. Moreover,
enantiodiscriminating high-performance liquid chromatography
(HPLC) analysis corroborated with these data and also revealed
(S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one as
the major stereoisomer.
2.3. Reaction scope
Table 2. Optimization of reaction conditions employing the catalyst
9d.
Having established the best reaction conditions and
determined the absolute configuration of the product, the
evaluation of the substrate scope was then carried out. Various
aromatic aldehydes and substituted cyclohexanones were well
tolerated under the optimized reaction conditions (Scheme 5).
Aromatic aldehydes bearing electron-withdrawing groups in
para, meta or even in the sterically bulky ortho-position were
well tolerated, affording the desired compounds 10a-d in 80-90%
yield, 9:1 to 19:1 d.r. and up to 98% e.e.
Solvent/
Additive
d.r.a
(anti/syn) (%)
e.e.b
Entry
Temperature Yield
1
2
Methanol
Toluene
Dichloromethane
-/TFA
r.t.
r.t.
82
59
90
75
67
90
48
73
9:1
5:1
84
53
78
58
0
3
r.t.
9:1
4
r.t.
2:1
5c
-/TFA
r.t.
1:2
6
-/-
0 °C
0 °C
0 °C
19:1
15:1
17:1
98
72
84
7d
8e
-/-
-/-
1
aCalculated through the H NMR the analysis of the crude reaction mixture;
bCalculated through enantiodiscriminationg HPLC; cReaction carried out
using 15 mol% of trifluoroacetic acid in the absence of catalyst 9d; dReaction

5
(compound 10p) in low yield (only 17%) and moderate
diastereoselectivity (4:1 d.r.). This is probably related to the aldol
carbon-carbon bond formation step, in which less electrophilic
aldehyde carbonyl groups are less favored. Finally, acetone was
tested as aldol donor in the presence of 4-nitrobenzaldehyde, but
lead only to the aldol condensation product.
2.4. Computational details
We then turned our attention toward the understanding of the
basics of this reaction by investigating
a plausible key
intermediate and the chiral induction process. To this purpose,
theoretical calculations were then carried out. All calculations
were performed using the Gaussian09 package [26]. Unless
otherwise stated, calculations were performed at a pressure equal
to
1 atm and temperature of 273.15 K. The structural
optimizations at the gas phase of all structures, molecular
complexes (MCs) and transition states (TSs) were carried out
employing the M06-2X functional [27] and the 6-31G(d,p) basis
set. A vibrational analysis was performed to check the identity of
all stationary points and in the attainment of the thermal
corrections to the Gibbs free energy. Transition states were
optimized employing the Berny algorithm or the QST2 method
and confirmed to have only one imaginary frequency (full details
concerning the theoretical data are available in the Electronic
Supplementary Information).
Next, for the attainment of the electronic energy at the desired
level of theory, single-point energy calculations were
subsequently carried out using the previously optimized
geometries at the M06-2X-D3/6-31++G(d,p) level of theory and,
since no solvent was employed during the reactions, the
Solvation Model Based on Density (SMD) for cyclohexanone
(reagent) was employed [28]. The Gibbs Free Energy of each
structure was then calculated by equation 1 [29], in which the
terms are, respectively, the Electronic Energy, the solvation
Gibbs Free Energy, and the thermal correction to enthalpy and
entropy.
ꢀ°ꢁꢂꢃ = ꢄꢀꢅꢁ + ꢀꢆꢂꢃꢇ + ꢀ°ꢈ
(ꢉ)
aDiastereoisomeric ratio of the two anti isomers.
bThe enantiomeric excess of this derivative was not determined.
Scheme 5. Reaction scope.
2.5. Mechanistic investigation
Prolinamide-based organocatalysts are well known for
activating substrates through iminium/enamine formation [13]. In
prolinamide catalyzed aldol reactions, the stereoinduction step
occurs during the addition of the previously in situ formed
enamine to the aldehyde. It is also reported in the literature that,
although the rotation over the C-N bond is possible, enamines
can preferentially adopt a conformation s-cis or s-trans [30]. Due
to that, both conformers were theoretically evaluated (Figure 1)
and it was found that they are very close in energy (ꢀG 0.52
kcal/mol). Although both conformers presented two similar
hydrogen bonding interactions, its distance considerably varied.
For example, the interaction between hydroxyl groups was 2.88
Å for s-cis conformer and 2.68 Å for s-trans; on the other hand,
the hydrogen bonding interaction between the amide carbonyl
and one of the hydroxyl groups was stronger for the s-cis
conformer (2.03 Å against 2.15 Å of the s-trans enamine).
Moreover, the use of aryl groups bearing halides was also
possible. For example, the use of 2-chlorobenzaldehyde resulted
in the derivative 10h in moderate yield (48%) and good
stereoselectivity (7:1 d.r. and 77% e.e.). On the other hand,
although aldehydes with naphthyl and toluyl groups resulted in
the desired adducts (10l and 10j, respectively) in moderate yields
and stereoselectivities (up to 7:1 d.r and 64% e.e.), a considerable
drop in the enantiomeric excess was observed when employing
benzaldehyde (only 20% e.e.).
Most interestingly, the use of substituted cyclohexanones was
also possible, affording the derivatives 10m and 10n, in which a
total of eight stereoisomers are possible to occur. These
compounds were obtained in excellent yields (up to 95%), with a
good selectivity towards the two anti diastereomers (up to 8:1
d.r.), an excellent diastereomeric ratio between these two
stereoisomers (between 12:1 and 15:1 d.r.) and a good
enantiomeric ratio (up to 87% e.e.). Although a good yield was
observed when employing a heteroaryl substituted aldehyde
(compound 10o), only a moderate stereoselectivity was detected
(4:1 d.r and 72% e.e.). Moreover, the use of an electron-donating
group was not well tolerated, affording the desired adduct

6
Tetrahedron
and thermodynamically favored along all other possible
pathways and perfectly explains the experimental data.
Figure 1. Enamine conformers.
Since no selectivity towards a specific conformer was
observed, the C-C bond formation step involving both enamine
substrates and the formation of all possible products were
evaluated. To this purpose, the 4-nitrobenzaldehyde was chosen
as the aldol acceptor and a total of eight different pathways were
simulated. Interestingly, molecular complexes between the
enamine and the aldehyde are generally thermodynamically
unfavored in comparison with the isolated reagents, especially for
the s-cis enamine (ꢀG 4.76-7.68 kcal/mol). Thus, the
approximation between aldehyde and s-trans enamine (ꢀG -0.90
to 4.33 kcal/mol) is much more probable to occur.
Figure 2. Transition state of the reaction between s-trans enamine
and 4-nitrobenzaldehyde leading to (S)-2-((R)-hydroxy(4-
nitrophenyl)methyl)cyclohexan-1-one.
3. Conclusion
In summary, four novel organocatalysts were synthesized by
the coupling of an amino acid and a chiral amine. These catalysts
were prepared along eight reaction steps and then applied in a
solvent-free asymmetric aldol reaction. The best results were
obtained for the prolinamide catalyst 9d, allowing the access to
the desired adducts in moderate to excellent yields, up to 19:1 d.r.
and 98% e.e. Noteworthy, even sterically bulky aldehydes and
substituted cyclohexanones were successfully employed in the
optimized reaction conditions. The relative and absolute
Moreover, the results concerning the aldol product formation
are summarized in Table 3 and reveal some interesting
conclusions. First, among all possible transition states, six
presented hydrogen bonding interactions between the aldehyde
carbonyl and the enamine side-chain derived from the
prolinamide group (entries 1, 2, 5, 6, 7, and 8), one presented a
hydrogen bonding interaction involving the aldehyde nitro group
(entry 4) and the other did not present any interaction involving
the aldehyde moiety (entry 3).
1
configuration of the products was confirmed through H NMR
and enantiodiscriminating HPLC. Control experiments revealed
that the trifluoroacetate counter-anion is crucial for the
attainment of higher stereoselectivities. Finally, theoretical
calculations were performed to gain insights towards the chiral
induction mechanism and suggested that several hydrogen
bonding interactions between the enamine intermediate and the
aldehyde are responsible for further stabilization of the transition
state that leads to the observed stereoisomer.
Table 3. Reaction pathways towards all possible stereoisomers
(kcal/mol).
Enamine Aldehyde
Final
producta
SS
SR
RS
RR
SS
SR
RS
Entry
Enamine
∆∆G‡
∆∆G
face
Re
Re
Si
face
Si
Re
Si
1
2
3
4
5
6
7
8
s-trans
s-trans
s-trans
s-trans
s-cis
s- cis
s- cis
s- cis
5.78
0.00
8.57
12.41
11.98
5.36
10.18
6.69
2.13
0.00
22.11
26.05
7.24
10.64
3.10
10.17
Si
Re
Si
Re
Si
Re
Re
Si
4. Experimental section
4.1. General remarks
Si
Re
RR
aStereochemistry related to the final product after iminium hydrolysis: first
stereocenter related to the α-carbonyl carbon; second stereocenter related to
the carbon bonded to the hydroxyl group.
All purchased solvents and chemicals were employed without
further purification. The reactions were monitored by thin-layer
chromatography performed on TLC plates (silica gel 60 F254)
and visualized by a UV lamp; column chromatography was
carried out employing 230−400 mesh silica gel. Reported yields
refer to chromatographically purified and spectroscopically pure
Most interestingly, the lower energy transition state (entry 2)
involved the s-trans enamine and, simultaneously, presented
three hydrogen bonding interactions between the enamine side-
chain and the aldehyde carbonyl group (Figure 2). These
interactions are considerably strong (between 1.79 and 2.16 Å),
lowering the transition state barrier to 23.19 kcal/mol.
Noteworthy, the second most accessible transition state (entry 6)
also led to the experimentally observed stereoisomer but through
the s-cis enamine. Moreover, the molecular complex formed right
after the carbon-carbon bond formation also presented lower
energy for the major stereoisomer, with a ꢀG of only 0.06
kcal/mol. Thus, the formation of this stereoisomer is both kinetic
1
compounds. Chemical shifts for H NMR were reported as δ
(parts per million) relative to chloroform signal of at 7.26 ppm
(singlet – solvent CDCl3) or to the water signal at 4.79 ppm
(broad - solvent deuterium oxide). Chemical shifts for 13C {1H}
NMR were reported as δ relative to the central line signal of the
CDCl3 triplet at 77.2 ppm or to methanol (internal standard) at
1
49.5 ppm. The H NMR spectra were recorded at 500 MHz, and
13C {1H} NMR spectra were recorded at 125 MHz. Chemical
shifts are reported employing the following peak abbreviations:
br, broad; s, singlet; d, doublet; dd, doublet of doublet; ddd,
doublet of doublet of doublet; dt, doublet of triplet; dq, doublet of

7
quartet; t, triplet; tdd, triplet of doublet of doublet; q, quartet; oct,
octet; m, multiplet. Melting points were acquired on a melting
were added. The reaction mixture was kept under reflux at 90
°C for 2 hours. Next, the solvent was dried under reduced
pressure and the crude reaction mixture diluted in chloroform. A
liquid-liquid extraction employing a saturated aqueous solution
of Na2S2O3 (two aliquots of 100.0 mL) was then carried out. The
organic phase was then dried under reduced pressure and further
purification by column chromatography (silica gel) employing
isocratic eluent 2:8 ethyl acetate/hexane was carried out.
point apparatus and optical rotations on
a polarimeter.
Enantiodiscriminating HPLC was performed using a 4.6 × 25
cm2 Chiralpak IB column (isocratic elution using
hexane/isopropanol 90:10 or 85:5; flow 0.5 or 0.9 mL/min). The
elemental composition of the catalysts was determined using a
Perkin Elmer 2400 CHNS/O Series II microanalyzer.
4.2. General Procedure for the synthesis of product 2
(R)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (4): Colorless oil,
4.0 g, yield: 73%. [ꢊ]ꢌꢋꢎ + 33.3° (c 1.8, ethanol). IR (ATR) ν (cm-
1): 2984, 2929, 2873, 1371, 1211, 1144, 1040. 1H NMR
(500ꢁMHz, CDCl3) δ: 4.30-4.25 (m, 1H), 4.14 (dd, J 8.6 Hz, J 6.1
Hz, 1H), 3.78 (dd, J 8.6 Hz, J 5.5 Hz, 1H), 3.25 (dd, J 9.8 Hz, J
4.6 Hz, 1H), 3.14 (dd, J 9.8 Hz, J 8.5 Hz, 1H), 1.45 (s, 3H), 1.34
(s, 3H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 110.7, 75.8, 69.8,
27.3, 25.7, 6.8.
In a round-bottom flask, 10.0 g of
D-mannitol (54.9 mmol)
was added, followed by addition of 30 mL of dimethylsulfoxide
(DMSO). The reaction mixture was kept under magnetic stirring
at 0 °C for 30 minutes. Next, 0.2 g of p-toluenesulfonic acid (2
mol%) and 20 mL of acetone were added and the reaction kept at
0 °C for 30 minutes and room temperature for 15 hours. Next, the
crude reaction mixture was diluted in ethyl acetate (30.0 mL) and
a liquid-liquid extraction employing a 5% m/v of an aqueous
solution of NaHCO3 (three aliquots of 100.0 mL) carried out. The
organic phase was then dried under reduced pressure and further
purification by column chromatography (silica gel) employing
isocratic eluent 1:1 ethyl acetate/hexane was carried out.
4.5. General Procedure for the synthesis of product 5
In a round-bottom flask, 3.0 g of product 4 (12.4 mmol) was
added, followed by the addition of 20 mL of dimethylformamide.
Next, 1.1 g of sodium azide (16.1 mmol, 1.3 equiv.) was added.
The reaction mixture was kept under reflux at 60 °C for 6 hours.
The crude reaction mixture was then diluted in hexane (100 mL)
and washed twice with a saturated aqueous solution of NaCl
(2x60 mL). The organic phase was then dried under reduced
pressure and further purification by column chromatography
(silica gel) employing isocratic eluent 1:9 ethyl acetate/hexane
was carried out.
(1S,2S)-1,2-bis((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-
diol (2): White solid, 11.1ꢁg, yield: 77%. m.p.: 118.0-
120.0ꢁ°C. [ꢊ]ꢌꢋꢍ +2.4 (c 1.0, EtOH). IR (ATR) ν (cm-1): 3389,
2978, 2942, 2887, 2849, 1628, 1445, 1402, 1366, 1162, 1076,
1003, 918. 1H NMR (500ꢁMHz, CDCl3) δ: 4.17 (q, J 6.3 Hz, 2H),
4.11 (dd, J 8.6 Hz, J 6.4 Hz, 2H), 3.97 (dd, J 8.6 Hz, J 5.6 Hz,
2H), 3.74 (t, J 6.6 Hz, 2H), 2.69 (d, J 6.5 Hz, 2H), 1.41 (s, 6H),
1.35 (s, 6H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 109.5, 76.4,
71.3, 66.9, 26.9, 25.3.
(S)-4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (5): Colorless oil,
1.4ꢁg, yield: 73%. [ꢊ]ꢋꢌꢎ - 47.1° (c 2.8, CHCl3). IR (ATR) ν (cm-
1): 2984, 2929, 2873, 1371, 1211, 1144, 1040. 1H NMR
(500ꢁMHz, CDCl3) δ: 4.32-4.21 (m, 1H), 4.06 (dd, J 8.5 Hz, J 6.4
Hz, 1H), 3.77 (dd, J 8.4 Hz, J 5.9 Hz, 1H), 3.40 (dd, J 12.8 Hz, J
4.7 Hz, 1H), 3.30 (dd, J 12.8 Hz, J 5.6 Hz, 1H), 1.47 (s, 3H),
1.36 (s, 3H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 110.1, 74.7,
66.8, 53.0, 26.8, 25.4.
4.3. General Procedure for the synthesis of product 3
In a round-bottom flask, 11.0 g of compound 2 (42.1 mmol)
was added, followed by addition of 100 mL of an aqueous
solution of NaHCO3 (5 % m/v). The reaction mixture was kept
under magnetic stirring at 0 °C for 10 minutes. Next, 100 mL of
an aqueous solution containing 18.0 g (84.2 mmol, 2 equiv.) of
sodium periodate was slowly added to the reaction mixture. The
reaction was kept under magnetic stirring for 1 hour, after which
100 mL of ethanol was added. The crude reaction mixture was
then filtered off to remove the unreacted periodate. The
remaining solution was then cooled to 0 °C and 3.2 g (84.2
mmol, 2 equiv.) of sodium borohydride was then added. The
reaction mixture was then kept under magnetic stirring for 2
hours and then filtered off. The solid was diluted in chloroform
and submitted to a liquid-liquid extraction employing distilled
water. Finally, the organic phase was dried and the compound 3
distilled under reduced pressure (5 mmHg).
4.6. General Procedure for the synthesis of product 6
In a round-bottom flask, 1.0 g of product 5 (6.4 mmol) was
added, followed by the addition of 15 mL of methanol. Next,
0.11 g (0.96 mmol, 15 mol%) of Pd/C was added. The
atmosphere was then replaced by hydrogen. The reaction mixture
was kept at room temperature for 24 hours with a balloon of H2.
The reaction mixture was then filtered off to remove the Pd/C
and the solvent removed under reduced pressure. The crude
reaction mixture was then diluted in dichloromethane (50 mL)
and washed twice with a saturated aqueous solution of NaCl
(2x30 mL). The organic phase was then dried under reduced
pressure.
(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (3): Colorless oil,
7.0 g, yield: 63%. [ꢊ]ꢌꢋꢎ + 14.7° (pure). IR (ATR) ν (cm-1): 3414,
2990, 2934, 2887, 1641, 1377, 1261, 1211, 1150, 1046. 1H NMR
(500ꢁMHz, CDCl3) δ: 4.23 (tdd, J 6.5 Hz, J 5.2 Hz, J 3.8 Hz, 1H),
4.03 (dd, J 8.2 Hz, J 6.6 Hz, 1H), 3.78 (dd, J 8.2 Hz, J 6.5 Hz,
1H), 3.72 (dd, J 11.6 Hz, J 3.6 Hz, 1H), 3.58 (dd, J 11.6 Hz, J 5.1
Hz, 1H), 2.10 (br, 1H), 1.43 (s, 3H), 1.36 (s, 3H). 13C {1H}
NMR (125ꢁMHz, CDCl3) δ: 109.5, 76.3, 65.8, 63.1, 26.8, 25.4.
(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (6): Yellow oil,
680ꢁmg, yield: 81%. [ꢊ]ꢌꢋꢎ - 24.0° (c 1.0, ethanol). IR (ATR) ν
(cm-1): 3365, 2984, 2929, 1653, 1598, 1457, 1371, 1248, 1211,
1
1051. H NMR (500ꢁMHz, CDCl3) δ: 4.13-4.06 (m, 1H), 4.02-
3.99 (m, 1H), 3.65-3.62 (m, 1H), 2.81 (dd, J 13.1 Hz, J 4.2 Hz,
1H), 2.75 (dd, J 13.1 Hz, J 6.3 Hz, 1H), 1.61 (s, 2H), 1.39 (s,
3H), 1.33 (s, 3H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 109.3,
77.4, 67.0, 44.8, 27.0, 25.4.
4.4. General Procedure for the synthesis of product 4
4.7. General Procedure for the synthesis of products 7a-d
In a round-bottom flask, 3.0 g of product 3 (22.7 mmol) was
added, followed by addition of 100 mL of toluene. Next, 7.2 g of
triphenylphosphine (27.3 mmol, 1.2 equiv.), 2.3 g (34.1 mmol,
1.5 equiv.) of imidazole and 7.5 g of I2 (29.6 mmol, 1.3 equiv.)
Boc-protected amino acids were prepared following
literature method [17]. Initially, to a solution of water/1,4-
dioxane (3:2 v/v), 5.0 mmol of an amino acid ( -valine, L-
a
L

8
Tetrahedron
leucine,
L
-phenylalanine or
L
-proline) and 0.3 g of NaHCO3
Tert-butyl
((S)-1-((((S)-2,2-dimethyl-1,3-dioxolan-4-
(8a):
yl)methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
were added. Next, 7.5 mmol of Boc anhydride (1.5 equiv.) were
added to this mixture. The reaction mixture was stirred at room
temperature for 24 hours. The crude reaction mixture was then
diluted in water (50.0 mL) and a liquid-liquid extraction
employing 40 mL of ethyl acetate was carried out to remove the
residual Boc2O. The pH of the water phase was then adjusted to 1
with an aqueous solution of HCl (2M). Next, a liquid-liquid
extraction employing ethyl acetate was carried out (three aliquots
of 100.0 mL). The organic phase was then dried under reduced
pressure and further purification by column chromatography
White solid, 201ꢁmg, yield: 81%. [ꢊ]ꢌꢋꢏ -16.0° (c 1.0, CHCl3).
m.p.: 101.0-103.0ꢁ°C. IR (ATR) ν (cm-1): 3340, 3309, 2978,
2930, 2868, 1683, 1653, 1518, 1365, 1211, 1169. 1H NMR
(500ꢁMHz, CDCl3) δ: 6.26 (br, 1H), 5.01 (br, 1H), 4.21 (qd, J 6.3
Hz, J 3.7 Hz, 1H), 4.02 (dd, J 8.4 Hz, J 6.5 Hz, 1H), 3.94-3.88
(m, 1H), 3.61 (dd, J 8.4 Hz, J 6.4 Hz, 1H), 3.55 (ddd, J 13.9 Hz,
J 6.0 Hz, J 3.7 Hz, 1H), 3.32 (dt, J 14.0 Hz, J 5.9 Hz, 1H), 2.17
(br, 1H), 1.44 (s, 9H), 1.43 (s, 3H), 1.33 (s, 3H), 0.96 (d, J 6.8
Hz, 3H), 0.91 (d, J 6.8 Hz, 3H). 13C {1H} NMR (125ꢁMHz,
CDCl3) δ: 172.0, 156.0, 109.6, 80.1, 74.6, 66.8, 60.3, 41.5, 30.7,
28.4, 26.9, 25.3, 19.4, 17.8. Anal. calcd. For C16H30N2O5: C
58.16, H 9.15, N 8.48; found: C 58.43, H 8.67, N 8.52.
(silica
gel)
employing
isocratic
eluent
9:1
dichloromethane/methanol was carried out.
(Tert-butoxycarbonyl)-L-valine (7a): Colorless oil, 890ꢁmg, yield:
82%. [ꢊ]ꢌꢋꢍ -10.0° (c 1.0, DMF). IR (ATR) ν (cm-1): 3536, 3325,
2968, 2934, 1718, 1505, 1394, 1368, 1160. H NMR (500ꢁMHz,
CDCl3) δ: 9.45 (br, 1H), 5.04 (d, J 8.5 Hz, 1H), 4.25 (dd, J 9.0
Hz, J 4.7 Hz, 1H), 2.21-2.18 (m, 1H), 1.44 (s, 9H), 0.99 (d, J 6.8
Hz, 3H), 0.92 (d, J 6.8 Hz, 3H). 13C {1H} NMR (125ꢁMHz,
CDCl3) δ: 177.2, 156.0, 80.2, 58.6, 31.2, 28.4, 19.04, 17.6.
Tert-butyl
((S)-1-((((S)-2,2-dimethyl-1,3-dioxolan-4-
(8b):
1
yl)methyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate
White solid, 183ꢁmg, yield: 71%. [ꢊ]ꢌꢋꢏ -20.0 (c 1.0, CHCl3).
m.p.: 96.0-98.0ꢁ°C. IR (ATR) ν (cm-1): 3376, 3328, 2965, 2929,
2873, 1702, 1647, 1501, 1371, 1162. 1H NMR (500ꢁMHz,
CDCl3) δ: 6.48 (br, 1H), 4.91 (d, J 7.3 Hz, 1H), 4.19 (qd, J 6.3
Hz, J 3.9 Hz, 1H), 4.14-4.05 (m, 1H), 4.00 (dd, J 8.3 Hz, J 6.5
Hz, 1H), 3.60 (dd, J 8.4 Hz, J 6.5 Hz, 1H), 3.52-3.49 (m, 1H),
3.31-3.27 (m, 1H), 1.69-1.63 (m, 2H), 1.50-1.46 (m, 1H), 1.42 (s,
12H), 1.32 (s, 3H), 0.93 (d, J 6.4 Hz, 3H), 0.91 (d, J 6.3 Hz,
3H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 173.1, 155.8, 109.5,
80.2, 74.6, 66.8, 53.3, 41.5, 41.4, 28.4, 26.9, 25.4, 24.9, 23.1,
22.1. Anal. calcd. For C17H32N2O5: C 59.28, H 9.36, N 8.13;
found: C 60.27, H 8.67, N 8.34.
(Tert-butoxycarbonyl)-L-leucine (7b): White solid, 1132ꢁmg,
yield: 98%. [ꢊ]ꢌꢋꢍ -29.5° (c 1.0, DMF). m.p.: 67.0-70.0ꢁ°C. IR
(ATR) ν (cm-1): 3448, 3320, 2961, 2876, 1714, 1510, 14. H
1
NMR (500ꢁMHz, CDCl3) δ: 6.71 (br, 1H), 4.90 (d, J 8.1 Hz, 1H),
4.31 (q, J 6.9 Hz, 1H), 1.77-1.72 (m, 1H), 1.70-1.64 (m, 1H),
1.57-1.48 (m, 1H), 1.44 (s, 9H), 0.95 (d, J 6.6 Hz, 6H). 13C {1H}
NMR (125ꢁMHz, CDCl3) δ: 178.1, 155.8, 80.4, 52.1, 41.6, 28.4,
24.9, 23.0, 21.9.
Tert-butyl
((S)-1-((((S)-2,2-dimethyl-1,3-dioxolan-4-
(8c):
(Tert-butoxycarbonyl)-L-phenylalanine (7c): White solid,
1113ꢁmg, yield: 84%. [ꢊ]ꢌꢋꢍ -20.2° (c 1.0, DMF). m.p.: 62.0-
65.0ꢁ°C. IR (ATR) ν (cm-1): 3436, 2986, 2929, 1712, 1505, 1370,
yl)methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
White solid, 185ꢁmg, yield: 65%. [ꢊ]ꢌꢋꢏ -2.0° (c 1.0, CHCl3).
m.p.: 104.0-106.0ꢁ°C. IR (ATR) ν (cm-1): 3340, 3315, 2984,
2929, 2868, 1683, 1659, 1512, 1371, 1205, 1162. 1H NMR
(500ꢁMHz, CDCl3) δ: 7.30 (t, J 7.3 Hz, 2H), 7.25-7.23 (m, 1H),
7.22-7.19 (m, 2H), 6.08 (br, 1H), 5.02 (br, 1H), 4.33 (br, 1H),
4.05 (br, 1H), 3.97-3.94 (m, 1H), 3.52 (dd, J 8.3 Hz, J 6.5 Hz,
1H), 3.43-3.42 (m, 1H), 3.27-3.22 (m, 1H), 3.06-3.05 (m, 2H),
1.40 (s, 9H), 1.35 (s, 3H), 1.30 (s, 3H). 13C {1H} NMR
(125ꢁMHz, CDCl3) δ: 171.6, 155.5, 136.8, 129.4, 128.9, 127.2,
109.5, 80.4, 74.4, 66.8, 56.1, 41.6, 38.7, 28.4, 26.8, 25.3. Anal.
calcd. For C20H30N2O5: C 63.47, H 7.99, N 7.40; found: C 63.85,
H 7.70, N 7.36.
1
1258, 1160. H NMR (500ꢁMHz, CDCl3) δ: 7.31 (t, J 7.2 Hz,
2H), 7.26 (t, J 7.3 Hz, 1H), 7.18 (d, J 7.4 Hz, 2H), 4.96 (d, J 7.4
Hz, 1H), 4.61 (q, J 7.4 Hz, 1H), 3.20 (dd, J 13.9 Hz, J 5.1 Hz,
1H), 3.08 (dd, J 13.9 Hz, J 6.5 Hz, 1H), 1.42-1.30 (s, 9H). 13C
{1H} NMR (125ꢁMHz, CDCl3) δ: 176.4, 155.5, 136.0, 129.5,
128.8, 127.3, 80.5, 54.4, 37.9, 28.4.
(Tert-butoxycarbonyl)-L-proline (7d): White solid, 914ꢁmg,
yield: 85%. [ꢊ]ꢌꢋꢍ -46.0° (c 1.0, DMF). m.p.: 135.0-137.0ꢁ°C. IR
(ATR) ν (cm-1): 3498, 3125, 2976, 2884, 1747, 1697, 1418,
1368, 1166, 1125. 1H NMR (500ꢁMHz, CDCl3) (mixture of
rotamers) δ: 6.61 (br, 1H), 4.35-4.24 (m, 1H), 3.55-3.33 (m, 2H),
2.30-2.28 (m, 1H), 2.09-2.04 (m, 1H), 1.95-1.90 (m, 2H), 1.48-
1.42 (m, 9H). 13C {1H} NMR (125ꢁMHz, CDCl3) (mixture of
rotamers) δ: 178.7, 174.8, 156.8, 154.0, 81.7, 80.5, 59.3, 59.0,
47.2, 46.5, 31.0, 28.5, 28.4, 24.5, 23.8.
Tert-butyl
(S)-2-(2-((((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate
(8d):
White solid, 145ꢁmg, yield: 59%. [ꢊ]ꢌꢋꢏ -80° (c 1.0, CHCl3). m.p.:
155.0-156.0ꢁ°C. IR (ATR) ν (cm-1): 3340; 2984; 2929; 2865;
1
1683; 1647; 1531; 1390; 1365; 1156; 1125. H NMR (500ꢁMHz,
CDCl3) (mixture of rotamers) δ: 6.95 (br, 0.5H), 6.44 (br, 0.5H),
4.24-4.19 (m, 2H), 4.02 (br, 1H), 3.60-3.57 (m, 1H), 3.45 (br,
4H), 2.30-2.14 (m, 2H), 1.87 (br, 2H), 1.45 (s, 9H), 1.42 (s, 3H),
1.32 (s, 3H). 13C {1H} NMR (125ꢁMHz, CDCl3) (mixture of
rotamers) δ: 173.1, 172.6, 155.8, 154.9, 109.4, 80.7, 74.6, 66.7,
61.5, 60.4, 47.2, 41.5, 31.2, 28.4, 26.8, 25.1, 24.6, 23.8. Anal.
calcd. For C16H28N2O5: C 58.52, H 8.59, N 8.53; found: C 58.57,
H 8.31, N 8.56.
4.8. General Procedure for the synthesis of products 8a-d
In a round-bottom flask, 100 mg of product 6 (0.75 mmol) and
0.75 mmol of the Boc protected amino acid 7a-d (1.0 equiv.)
were added, followed by the addition of
dichloromethane. Next, 155 mg
8
of
mL of
N,N'-
dicyclohexylcarbodiimide (0.1 mmol, 1.3 equiv.) and 9 mg of 4-
dimethylaminopyridine (0.08 mmol, 10 mol%) were added. The
reaction mixture was kept under magnetic stirring at room
temperature for 24 hours. The reaction mixture was then filtered
off for to remove the N,N’-dicyclohexylurea and the solvent was
removed under reduced pressure. Further purification by column
chromatography (silica gel) employing isocratic eluent 1:1 ethyl
acetate/hexane was carried out.
4.9. General Procedure for the synthesis of products 9a-d
In a round-bottom flask, 0.3 mmol of product 8a-d, 1.5 mL of
dichloromethane and 6.6 mmol of trifluoroacetic acid (22 equiv.)
were added. The reaction mixture was kept under magnetic
stirring at room temperature for 3 h. Next, the solvent was
removed under reduced pressure.

9
(S)-1-(((S)-2,3-dihydroxypropyl)amino)-3-methyl-1-oxobutan-2-
aminium 2,2,2-trifluoroacetate (9a): Yellow oil, 81ꢁmg, yield:
89%. [ꢊ]ꢌꢋꢏ +73.0° (c 0.3, CH3OH). IR (ATR) ν (cm-1): 3351,
1341, 1291. 1H NMR (500ꢁMHz, CDCl3) (syn/anti 2:3) δ: 8.20-
8.19 (m, 2H), 7.51-7,47 (m, 2H), 5.48 (s, 0.4H, syn), 4.89 (d, J =
8.0 Hz, 0.6H, anti), 4.08 (d, J = 2.2 Hz, 0.6H, anti), 3.19 (d, J =
2.2 Hz, 0.4H, syn), 2.65-2.56 (m, 1H), 2.51-2.46 (m, 1H), 2.42-
2.33 (m, 1H), 2.13-2.08 (m, 1H), 1.87-1.81 (m, 1H), 1.72-1.51
(m, 4H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 214.9, 214.2,
149.2, 148.5, 147.7, 147.2, 128.0, 126.7, 123.7, 123.6, 74.1, 70.2,
57.3, 56.9, 42.8, 42.7, 30.9, 28.0, 27.8, 26.0, 24.9, 24.8.
1
2965, 2923, 2849, 1659, 1438, 1187, 1131. H NMR (500ꢁMHz,
D2O) δ: 3.80-3.76 (m, 1H), 3.73 (d. J 6.1 Hz, 1H), 3.56 (dd, J
11.8 Hz, J 4.3 Hz, 1H), 3.48 (dd, J 11.8 Hz, J 6.2 Hz, 1H), 3.40
(dd, J 14.0 Hz, J 4.4 Hz, 1H), 3.23 (dd, J 14.1 Hz, J 7.6 Hz, 1H),
2.16 (oct, J 6.8 Hz, 1H), 0.98 (d, J 6.8 Hz, 3H), 0.97 (d, J 6.9 Hz,
3H). 13C {1H} NMR (125ꢁMHz, D2O) δ: 170.5, 163.5 (q, J 34
Hz), 116.9 (q, J 290 Hz), 70.7, 63.9, 59.3, 42.4, 30.5, 18.2, 17.4.
Anal. calcd. For C10H18F3N2O4: C 39.48, H 6.29, N 9.21; found:
C 38.72, H 5.97, N 8.03.
2-(hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one
(10b):
Reaction time: 3 days. White solid, 30ꢁmg, yield: 80%, 10:1 d.r.,
79% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 1:9) δ: 8.21-8.18
1
(m, 1H), 8.17-8.11 (m, 1H), 7.68-7.66 (m, 1H), 7.54-7.50 (m,
1H), 5.48 (s, 0.1H, syn), 4.89 (d, J = 8.5 Hz, 0.9H, anti), 4.11 (s,
0.9H, anti), 3.17 (s, 0.1H, syn), 2.67-2.59 (m, 1H), 2.52-2.47 (m,
1H), 2.44-2.34 (m, 1H), 2.14-2.09 (m, 1H), 1.85-1.81 (m, 1H),
1.76-1.51 (m, 3H), 1.44-1.35 (m, 1H). 13C {1H} NMR (125ꢁMHz,
CDCl3) δ: 215.0, 214.3, 148.4, 143.9, 143.4, 133.3, 132.1 129.4,
129.3, 123.0, 122.2, 121.0, 74.2, 70.6, 57.3, 56.9, 42.8, 42.7,
30.9, 28.0, 27.8, 26.0, 24.9, 24.8.
(S)-1-(((S)-2,3-dihydroxypropyl)amino)-4-methyl-1-oxopentan-2-
aminium 2,2,2-trifluoroacetate (9b): Yellow oil, 86ꢁmg, yield:
90%. [ꢊ]ꢌꢋꢏ +18.0° (c 1.0, CH3OH). IR (ATR) ν (cm-1): 3221,
1
2929, 2855, 1659, 1413, 1193, 1139. H NMR (500ꢁMHz, D2O)
δ: 3.94-3.92 (m, 1H), 3.83-3.81 (m, 1H), 3.61 (dd, J 11.7 Hz, J
4.2 Hz, 1H), 3.53 (dd, J 11.7 Hz, J 6.2 Hz, 1H), 3.44 (dd, J 14.0
Hz, J 4.5 Hz, 1H), 3.29 (dd, J 14.1 Hz, J 7.5 Hz, 1H), 1.71-1.70
(m, 2H), 1.46-1.36 (m, 1H), 0.97-0.95 (m, 6H). 13C {1H} NMR
(125ꢁMHz, D2O) δ: 172.7, 163.6 (q, J 35 Hz), 117.0 (q, J 291
Hz), 70.7, 63.9, 52.4, 42.6, 40.9, 24.6, 22.4, 21.5. Anal. calcd.
For C11H20F3N2O4: C 41.51, H 6.65, N 8.80; found: C 40.72, H
6.54, N 8.09.
2-(hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one
(10c):
Reaction time: 3 days. White solid, 30ꢁmg, yield: 81%, 9:1 d.r.,
1
88% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 1:9) δ: 8.01-7.83
(m, 1H), 7.77-7.76 (m, 1H), 7.66-7.62 (m, 1H), 7.44-7.41 (m,
1H), 5.96 (d, J = 1.6 Hz, 0.1H, syn), 5.44 (d, J = 7.1 Hz, 0.9H,
anti), 2.89-2.73 (m, 1H), 2.46-2.41 (m, 1H), 2.37-2.30 (m, 1H),
2.12-2.07 (m, 1H), 1.86-1.83 (m, 1H), 1.80-1.73 (m, 1H), 1.71-
1.55 (m, 3H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 215.1, 214.2,
148.9, 147.3, 137.1, 136.8, 133.3 133.2, 129.8, 129.1, 128.5,
128.1, 124.8, 124.2, 69.9, 66.8, 57.4, 55.0, 43.0, 42.7, 31.3, 28.1,
27.9, 26.6, 25.1, 25.0.
(S)-1-(((S)-2,3-dihydroxypropyl)amino)-1-oxo-3-phenylpropan-2-
aminium 2,2,2-trifluoroacetate (9c): Yellow oil, 97ꢁmg, yield:
92%. [ꢊ]ꢌꢋꢏ +37.5° (c 0.8, CH3OH). IR (ATR) ν (cm-1): 3340,
1
2959, 2929, 2855, 1666, 1438, 1192, 1131. H NMR (500ꢁMHz,
D2O) δ: 7.44-7.35 (m, 3H), 7.28 (d, J 7.6 Hz, 2H), 4.19 (t, J 7.3
Hz, 1H), 3.57-3.65 (m, 1H), 3.46 (dd, J 11.8 Hz, J 4.1 Hz, 1H),
3.39 (dd, J 11.8 Hz, J 6.3 Hz, 1H), 3.29 (dd, J 14.0 Hz, J 4.5 Hz,
1H), 3.22-3.13 (m, 3H). 13C {1H} NMR (125ꢁMHz, D2O) δ:
171.5, 163.6 (q, J 36 Hz), 134.9, 129.9, 129.7, 128.5, 116.9 (q, J
289 Hz), 70.6, 63.8, 54.9, 42.5, 38.0. Anal. calcd. For
C14H18F3N2O4: C 47.73, H 5.44, N 7.95; found: C 48.73, H 5.91,
N 6.83.
2-(hydroxy(4-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one
(10d): Reaction time: 3 days. White solid, 33ꢁmg, yield: 81%,
1
13:1 d.r., 87% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 1:9) δ:
7.61-7.59 (m, 2H), 7.45-7.42 (m, 2H), 5.44 (s, 0.1H, syn), 4.84
(dd, J = 8.6 Hz, J = 2.8 Hz, 0.9H, anti), 4.03 (d, J = 3.0 Hz, 0.9H,
anti), 3.11 (d, J = 3.3 Hz, 0.1H, syn), 2.62-2.56 (m, 1H), 2.51-
2.45 (m, 1H), 2.42-2.32 (m, 1H), 2.13-2.08 (m, 1H), 1.83-1.80
(m, 1H), 1.74-1.62 (m, 1H), 1.59-1.50 (m, 2H), 1.39-1.29 (m,
1H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 215.3, 214.6, 145.7,
145.1, 130.2 (q, J = 32.1 Hz), 127.5, 126.2, 125.4 (q, J = 3.8 Hz),
125.3, 124.2 (q, J = 270.4 Hz), 74.4, 70.4, 57.4, 57.1, 42.8, 30.9,
28.0, 27.8, 26.0, 25.0, 24.9.
(S)-2-(2-(((S)-2,3-dihydroxypropyl)amino)-2-oxoethyl)pyrrolidin-
1-ium 2,2,2-trifluoroacetate (9d): Yellow oil, 79ꢁmg, yield:
87%. [ꢊ]ꢌꢋꢏ -30.0° (c 1.0, CH3OH). IR (ATR) ν (cm-1): 3359,
3266, 2959, 2923, 2855, 1666, 1567, 1426, 1187, 1125. 1H NMR
(500ꢁMHz, D2O) (mixture of rotamers) δ: 4.38 (t, J 7.3 Hz, 1H),
3.82 (ddd, J 11.1 Hz, J 6.8 Hz, J 4.6 Hz, 1H), 3.61 (dd, J 11.8
Hz, J 4.3 Hz, 1H), 3.53 (dd, J 11.8 Hz, J 6.3 Hz, 1H), 3.49-3.36
(m, 3H), 3.30 (dd, J 14.0 Hz, J 7.4 Hz, 1H), 2.49-2.43 (m, 1H),
2.09-2.06 (m, 3H). 13C {1H} NMR (125ꢁMHz, D2O) (mixture of
rotamers) δ: 170.3, 162.8 (q, J 36 Hz), 116.6 (q, J 290 Hz), 70.7,
63.8, 60.4, 47.1, 42.6, 30.3, 24.4. Anal. calcd. For C10H16F3N2O4:
C 39.74, H 5.67, N 9.27; found: C 40.00, H 4.98, N 8.08.
2-((4-fluorophenyl)(hydroxy)methyl)cyclohexan-1-one
(10e):
Reaction time: 5 days. White solid, 29ꢁmg, yield: 88%, 5:1 d.r.,
1
79% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 3:7) δ: 7.30-7.25
(m, 2H), 7.05-7.00 (m, 2H), 5.36 (s, 0.3H, syn), 4.77 (dd, J = 8.8
Hz, 0.7H, anti), 3.99 (s, 0.7H, anti), 3.05 (s, 0.3H, syn), 2.59-2.54
(m, 1H), 2.51-2.44 (m, 1H), 2.40-2.32 (m, 1H), 2.12-2.07 (m,
1H), 1.87-1.79 (m, 1H), 1.74-1.54 (m, 4H). 13C {1H} NMR
(125ꢁMHz, CDCl3) δ: 215.6, 214.9, 162,5 (d, J = 244.4 Hz),
162,0 (d, J = 243.1 Hz), 137,3 (d, J = 3.0 Hz), 136,9 (d, J = 3.1
Hz), 128,8 (d, J = 8.0 Hz), 127.5 (d, J = 7.94 Hz), 115,4 (d, J =
21.3 Hz), 115,1 (d, J = 21.2 Hz), 145.1, 130.2 (q, J = 32.1 Hz),
127.5, 126.2, 125.4 (q, J = 3.8 Hz), 125.3, 124.2 (q, J = 270.4
Hz), 74.3, 70.3, 57.6, 57.3, 42.8, 30.9, 29.8, 28.1, 27.9, 26.2,
25.0, 24.9.
4.10. General Procedure for the synthesis of products 10a-p
In a 2 mL vial, 0.75 mmol of cyclohexanone (5 equiv.) was
added, followed by 0.02 mmol of catalysts 9a-d (15 mol%) and
0.15 mmol of aldehyde. The reaction mixture was kept at 0 °C
for 3-7 days. Next, the crude reaction mixture was then diluted in
water (10.0 mL) and a liquid-liquid extraction employing 10 mL
of dichloromethane (2x10 mL). The organic phase was dried
under reduced pressure and further purification by column
chromatography (silica gel) employing hexane to 3:1
hexane/ethyl acetate was carried out.
2-((4-chlorophenyl)(hydroxy)methyl)cyclohexan-1-one
(10f):
Reaction time: 5 days. White solid, 19ꢁmg, yield: 52%, 9:1 d.r.,
1
73% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 2:3) δ: 7.33-7.28
2-(hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
(10a):
(m, 2H), 7.27-7.23 (m, 2H), 5.35 (s, 0.4H, syn), 4.76 (d, J = 8.7
Hz, 0.6H, anti), 3.98 (d, J = 2.4 Hz, 0.6H, anti), 3.05 (d, J = 2.6
Reaction time: 3 days. White solid, 34ꢁmg, yield: 90%, 19:1 d.r.,
98% e.e. IR (ATR) ν (cm-1): 3505, 2923, 2849, 1683, 1598, 1506,

10
Tetrahedron
Hz, 0.4H, syn), 2.58-2.53 (m, 1H), 2.50-2.43 (m, 1H), 2.40-
(m, 3H), 7.76 (s, 1H), 7.50-7.35 (m, 3H), 5.57 (s, 0.2H, syn), 4.97
(dd, J = 8.8 Hz, J = 2.0 Hz 0.8H, anti), 4.06 (d, J = 2.6 Hz, 0.8H,
anti), 3.16 (d, J = 3.0 Hz, 0.2H, syn), 2.75-2.69 (m, 1H), 2.53-
2.47 (m, 1H), 2.43-2.35 (m, 1H), 2.11-2.06 (m, 1H), 1.84-1.64
(m, 3H), 1.57-1.48 (m, 1H), 1.39-1.29 (m, 1H). 13C {1H} NMR
(125ꢁMHz, CDCl3) δ: 215.7, 215.0, 139.0, 138.4, 133.4, 133.3,
133.2, 132.8, 128.4, 128.2, 128.1, 128.0, 127.8, 127.7, 126.4,
126.3, 126.2, 126.1, 125.8, 124.8, 124.7, 124.0, 75.1, 70.9, 57.5,
57.2, 42.9, 31.1, 28.1, 27.9, 26.2, 25.0, 24.9.
2.32 (m, 1H), 2.12-2.07 (m, 1H), 1.87-1.78 (m, 1H), 1.72-1.50
(m, 3H), 1.33-1.27 (m, 1H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ:
215.5, 214.8, 140.1, 139.6, 133.7, 132.8, 128.7, 128.5, 128.4,
127.3, 74.3, 70.3, 57.5, 57.2, 42.8, 30.9, 28.1, 27.9, 26.1, 25.0,
24.9.
2-((3-chlorophenyl)(hydroxy)methyl)cyclohexan-1-one
Reaction time: 5 days. White solid, 23ꢁmg, yield: 65%, 10:1 d.r.,
73% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 1:9) δ: 7.34-7.32
(10g):
1
(m, 1H), 7.29-7.25 (m, 2H), 7.24-7.16 (m, 1H), 5.36 (s, 0.1H,
syn), 4.76 (dd, J = 8.7 Hz, J = 2.7 Hz, 0.9H, anti), 3.99 (d, J = 2.8
Hz, 0.9H, anti), 3.05 (d, J = 3.2 Hz, 0.1H, syn), 2.60-2.55 (m,
1H), 2.51-2.44 (m, 1H), 2.41-2.32 (m, 1H), 2.13-2.07 (m, 1H),
2-(hydroxy(4-nitrophenyl)methyl)-4-methylcyclohexan-1-one
(10m): Reaction time: 3 days. White solid, 37ꢁmg, yield: 94%,
8:1 anti/syn, 12:1 d.r. (d.r. of the anti isomers), 87% e.e. 1H
NMR (500ꢁMHz, CDCl3) (syn/anti 1:4) δ: 8.23-8.21 (m, 2H),
7.51-7.50 (m, 2H), 5.49-5.47 (m, 0.2H, syn), 4.92 (d, J = 8.5 Hz,
0.8H, anti), 3.90 (s, 0.8H, anti), 3.12 (s, 0.2H, syn), 2.77-2.72 (m,
1H), 2.58-2.51 (m, 1H), 2.46-2.37 (m, 1H), 2.10-2.04 (m, 1H),
1.96-1.92 (m, 1H), 1.82-1.78 (m, 1H), 1.63-1.58 (m, 1H), 1.33-
1.26 (m, 1H), 1.07-1.04 (m, 3H). 13C {1H} NMR (125ꢁMHz,
CDCl3) δ: 215.1, 148.5, 147.8, 128.0, 127.9, 126.7, 126.6, 123.8,
123.7, 123.6, 123,5, 74.3, 74.1, 70.5, 70.1, 56.2, 55.9, 53.0, 52.1,
42.2, 41.9, 38.7, 38.3, 36.2, 35.8, 35.6, 33.8, 33.0, 32.9, 31.7,
31.6, 31.5, 26.8, 21.3, 21.2, 18.3, 18.2.
1.88-1.79 (m, 1H), 1.73-1.52 (m, 3H), 1.36-1.26 (m, 1H). 13
C
{1H} NMR (125ꢁMHz, CDCl3) δ: 215.4, 214.7, 143.8, 143.2,
134.5, 134.4, 129.8, 129.6, 128.2, 127.3, 126.2, 125.4, 124.0,
74.4, 70.2, 57.4, 57.1, 42.9, 42.8, 30.9, 28.1, 27.9, 26.1, 25.0,
24.9.
2-((2-chlorophenyl)(hydroxy)methyl)cyclohexan-1-one
(10h):
Reaction time: 5 days. White solid, 17ꢁmg, yield: 48%, 7:1 d.r.,
77% e.e. 1H NMR (500ꢁMHz, CDCl3) (anti) δ: 7.56-7.54 (m, 1H),
7.34-7.29 (m, 2H), 7.23-7.19 (m, 1H), 5.35 (dd, J = 8.1 Hz, J =
6.6 Hz, 1H), 4.02 (d, J = 3.9 Hz, 1H), 2.70-2.65 (m, 1H), 2.48-
2.45 (m, 1H), 2.38-2.31 (m, 1H), 2.11-2.07 (m, 1H), 1.84-1.81
(m, 1H), 1.73-1.53 (m, 4H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ:
215.4, 139.2, 133.1, 129.4, 128.9, 128.4, 127.4, 70.6, 57.7, 42.9,
30.5, 28.0, 25.1.
4-ethyl-2-(hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
(10n): Reaction time: 3 days. White solid, 40ꢁmg, yield: 95%, 6:1
1
anti/syn, 15:1 d.r. (d.r. of the anti isomers), 83% e.e. H NMR
(500ꢁMHz, CDCl3) (syn/anti 1:4) δ: 8.22-8.20 (m, 2H), 7.51-7.47
(m, 2H), 5.48 (s, 0.2H, syn), 4.92 (d, J = 8.6 Hz, 0.8H, anti), 3.92
(s, 0.8H, anti), 3.15 (s, 0.2H, syn), 2.70-2.65 (m, 1H), 2.52-2.45
(m, 1H), 2.41-2.36 (m, 1H), 1.93-1.85 (m, 1H), 1.76-1.70 (m,
1H), 1.57-1.35 (m, 4H), 0.82-0.79 (m, 3H). 13C {1H} NMR
(125ꢁMHz, CDCl3) δ: 215.2, 148.5, 147.8, 128.0, 127.9, 126.7,
126.6, 123.8, 123.6, 74.3, 70.5, 70.2, 55.9, 53.1, 52.2, 42.0, 41.8,
38.5, 38.1, 38.0, 33.8, 33.7, 33.2, 33.0, 31.7, 30.6, 30.5, 29.0,
28.7, 28.6, 24.9, 24.8, 12.1, 11.8, 11.7.
2-((4-bromophenyl)(hydroxy)methyl)cyclohexan-1-one
(10i):
Reaction time: 5 days. White solid, 26ꢁmg, yield: 61%, 9:1 d.r.,
1
69% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 1:9) δ: 7.48-7.45
(m, 2H), 7.21-7.17 (m, 2H), 5.34 (s, 0.1H, syn), 4.75 (dd, J = 8.7
Hz, J = 2.6 Hz, 0.9H, anti), 3.97 (d, J = 2.8 Hz, 0.9H, anti), 3.04
(d, J = 3.3 Hz, 0.1H, syn), 2.58-2.52 (m, 1H), 2.50-2.46 (m, 1H),
2.38-2.32 (m, 1H), 2.12-2.07 (m, 1H), 1.87-1.78 (m, 1H), 1.72-
1.64 (m, 1H), 1.60-1.50 (m, 2H), 1.33-1.25 (m, 1H). 13C {1H}
NMR (125ꢁMHz, CDCl3) δ: 215.4, 214.8, 140.6, 140.2, 131.6,
131.4, 128.9, 127.7, 121.9, 120.9, 74.3, 70.3, 57.5, 57.1, 42.8,
30.9, 28.1, 27.9, 26.1, 25.0, 24.9.
2-(furan-2-yl(hydroxy)methyl)cyclohexan-1-one (10o): Reaction
time: 7 days. White solid, 20ꢁmg, yield: 70%, 4:1 d.r., 72% e.e.
1H NMR (500ꢁMHz, CDCl3) (syn/anti 3:7) δ: 7.39-7.34 (m, 1H),
6.34-6.27 (m, 2H), 5.27 (s, 0.3H, syn), 4.83 (dd, J = 8.4 Hz, J =
2.6 Hz, 0.7H, anti), 3.88 (d, J = 3.5 Hz, 0.7H, anti), 3.01 (s, 0.3H,
syn), 2.94-2.80 (m, 1H), 2.48-2.44 (m, 1H), 2.41-2.34 (m, 1H),
2.13-2.08 (m, 1H), 2.97-2.78 (m, 2H), 1.71-1.63 (m, 2H), 1.39-
1.28 (m, 1H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 215.1, 213.9,
154.8, 153.8, 142.5, 141.6, 110.4, 110.2, 108.1, 106.7, 68.4, 66.9,
55.0, 54.7, 42.8, 42.6, 30.8, 28.0, 27.8, 27.4, 24.9, 24.8.
2-(hydroxy(p-tolyl)methyl)cyclohexan-1-one (10j): Reaction
time: 7 days. White solid, 137ꢁmg, yield: 39%, 6:1 d.r., 64% e.e.
1H NMR (500ꢁMHz, CDCl3) (syn/anti 1:4) δ: 7.21-7.18 (m, 2H),
7.16-7.14 (m, 2H), 5.35 (d, J = 2.3 Hz 0.2H, syn), 4.75 (d, J = 8.8
Hz, 0.8H, anti), 2.63-2.58 (m, 1H), 2.50-2.43 (m, 1H), 2.40-2.32
(m, 4H), 2.10-2.05 (m, 1H), 1.79-1.75 (m, 1H), 1.69-1.49 (m,
3H), 1.32-1.24 (m, 1H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ:
215.8, 215.0, 138.6, 138.1, 137.7, 136.7, 129.2, 129.0, 127.1,
125.8, 74.7, 70.7, 57.6, 57.4, 42.8, 31.0, 28.1, 28.0, 26.2, 25.0,
24.9, 21.3.
2-(hydroxy(4-methoxyphenyl)methyl)cyclohexan-1-one
(10p):
1
Reaction time: 7 days. White solid, 6ꢁmg, yield: 17%, 4:1 d.r. H
NMR (500ꢁMHz, CDCl3) (syn/anti 3:7) δ: 7.25-7.21 (m, 2H),
6.89-6.86 (m, 2H), 5.33 (s, 0.3H, syn), 4.74 (d, J = 8.9 Hz, 0.7H,
anti), 3.92 (s, 0.7H, anti), 3.80 (s, 3H), 2.98 (s, 0.3H, syn), 2.62-
2.54 (m, 1H), 2.50-2.42 (m, 1H), 2.39-2.32 (m, 1H), 2.11-2.06
(m, 1H), 1.87-1.75 (m, 2H), 1.73-1.50 (m, 3H). 13C {1H} NMR
(125ꢁMHz, CDCl3) δ: 215.9, 215.1, 159.4, 158.8, 133.7, 133.3,
128.3, 127.1, 113.9, 113.7, 74.4, 70.6, 57.7, 57.4, 55.4, 42.9,
42.8, 31.0, 28.1, 28.0, 26.3, 25.0, 24.9.
2-(hydroxy(phenyl)methyl)cyclohexan-1-one (10k): Reaction
time: 7 days. White solid, 18ꢁmg, yield: 60%, 8:1 d.r., 20% e.e.
1H NMR (500ꢁMHz, CDCl3) (syn/anti 2:3) δ: 7.36-7.23 (m, 5H),
5.39 (s, 0.4H, syn), 4.79 (d, J = 8.8 Hz, 0.6H, anti), 3.95 (s, 0.6H,
anti), 3.01 (s, 0.4H, syn), 2.65-2.58 (m, 1H), 2.50-2.44 (m, 1H),
2.41-2.33 (m, 1H), 2.10-2.06 (m, 1H), 1.86-1.50 (m, 4H), 1.35-
1.28 (m, 1H). 13C {1H} NMR (125ꢁMHz, CDCl3) δ: 215.7, 215.0,
141.6, 141.1, 128.5, 128.3, 128.1, 127.2, 127.1, 125.9, 74.9,
70.8, 57.6, 57.3, 42.8, 31.0, 28.1, 28.0, 26.2, 25.0, 24.9.
Conflicts of interest
2-(hydroxy(naphthalen-2-yl)methyl)cyclohexan-1-one
(10l):
The authors declare no conflicts of interest.
Reaction time: 7 days. White solid, 18ꢁmg, yield: 46%, 7:1 d.r.,
1
62% e.e. H NMR (500ꢁMHz, CDCl3) (syn/anti 1:4) δ: 7.85-7.81

11
[17]
[18]
P.P. de Castro, D.L. Campos, F.R. Pavan, G.W. Amarante,
Acknowledgments
Dual-protected amino acid derivatives as new antitubercular agents,
Chem. Biol. Drug Des. 92 (2018) 1576–1580.
The authors acknowledge the generous financial support from
FAPEMIG, CAPES (Finance Code 001), CNPq and Rede
Mineira de Química.
doi:10.1111/cbdd.13315.
C. Cruz-Hernández, P. Hernández-González, E. Juaristi, Proline-
Glycine Dipeptidic Derivatives of Chiral Phosphoramides as
Organocatalysts for the Enantiodivergent Aldol Reaction of Aryl
Aldehydes and Isatins with Cyclohexanone in the Presence of
Water, Synthesis (Stuttg). 50 (2018) 3445–3459. doi:10.1055/s-
0036-1592005.
C. Cruz-Hernández, J.M. Landeros, E. Juaristi, Multifunctional
phosphoramide-( S )-prolinamide derivatives as efficient
organocatalysts in asymmetric aldol and Michael reactions, New J.
Chem. 43 (2019) 5455–5465. doi:10.1039/C9NJ00300B.
K. Zumbansen, A. Döhring, B. List, Morpholinium
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/
[19]
[20]
[21]
Trifluoroacetate-Catalyzed Aldol Condensation of Acetone with
both Aromatic and Aliphatic Aldehydes, Adv. Synth. Catal. 352
(2010) 1135–1138. doi:10.1002/adsc.200900902.
References and notes
[1]
[2]
K.W. Quasdorf, L.E. Overman, Catalytic enantioselective synthesis
of quaternary carbon stereocentres, Nature. 516 (2014) 181–191.
D.W.C. MacMillan, The advent and development of
organocatalysis., Nature. 455 (2008) 304–308.
J.-H. Lin, C.-P. Zhang, J.-C. Xiao, Enantioselective aldol reaction
of cyclic ketones with aryl aldehydes catalyzed by a
cyclohexanediamine derived salt in the presence of water, Green
Chem. 11 (2009) 1750. doi:10.1039/b916583e.
Y. Hayashi, In Water or in the Presence of Water?, Angew. Chemie
Int. Ed. 45 (2006) 8103–8104. doi:10.1002/anie.200603378.
J. Mlynarski, S. Baś, Catalytic asymmetric aldol reactions in
aqueous media – a 5 year update, Chem. Soc. Rev. 43 (2014) 577–
587. doi:10.1039/C3CS60202H.
L. Li, Z. Fang, J. Fang, J. Zhou, Y. Xiang, d-Fructose-derived β-
amino alcohol catalyzed direct asymmetric aldol reaction in the
presence of p-nitrophenol, RSC Adv. 3 (2013) 21084.
doi:10.1039/c3ra42029a.
N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka, C.F.
Barbas, Organocatalytic Direct Asymmetric Aldol Reactions in
Water, J. Am. Chem. Soc. 128 (2006) 734–735.
doi:10.1038/nature07367.
[22]
[23]
[3]
[4]
[5]
[6]
[7]
T. Chanda, J.C.-G. Zhao, Recent Progress in Organocatalytic
Asymmetric Domino Transformations, Adv. Synth. Catal. 360
(2018) 2–79. doi:10.1002/adsc.201701059.
Y. Yamashita, T. Yasukawa, W.-J. Yoo, T. Kitanosono, S.
Kobayashi, Catalytic enantioselective aldol reactions, Chem. Soc.
Rev. 47 (2018) 4388–4480. doi:10.1039/C7CS00824D.
B. List, R.A. Lerner, C.F. Barbas, Proline-Catalyzed Direct
Asymmetric Aldol Reactions, J. Am. Chem. Soc. 122 (2000) 2395–
2396. doi:10.1021/ja994280y.
[24]
[25]
[26]
W. Notz, B. List, Catalytic Asymmetric Synthesis of anti- 1,2-
Diols, J. Am. Chem. Soc. 122 (2000) 7386–7387.
doi:10.1021/ja001460v.
doi:10.1021/ja0573312.
K. Sakthivel, W. Notz, T. Bui, C.F. Barbas, Amino Acid Catalyzed
Direct Asymmetric Aldol Reactions: A Bioorganic Approach to
Catalytic Asymmetric Carbon−Carbon Bond-Forming Reactions, J.
Am. Chem. Soc. 123 (2001) 5260–5267. doi:10.1021/ja010037z.
E. Machuca, Y. Rojas, E. Juaristi, Synthesis and Evaluation of ( S )-
Proline-Containing α,β-Dipeptides as Organocatalysts in Solvent-
Free Asymmetric Aldol Reactions Under Ball-Milling Conditions,
Asian J. Org. Chem. 4 (2015) 46–53. doi:10.1002/ajoc.201402170.
H. Inoue, M. Kikuchi, J. Ito, H. Nishiyama, Chiral Phebox–
rhodium complexes as catalysts for asymmetric direct aldol
reaction, Tetrahedron. 64 (2008) 493–499.
M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A.
Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A.
Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F.
Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, J.J.E.
Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N.
Kudin, V.N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M.
Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O.
Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L.
Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador,
J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B.
Foresman, J. V. Ortiz, J. Cioslowski, F. D. J., Gaussian 09,
Revision D.01, (2013).
Y. Zhao, D.G. Truhlar, The M06 suite of density functionals for
main group thermochemistry, thermochemical kinetics,
noncovalent interactions, excited states, and transition elements:
two new functionals and systematic testing of four M06-class
functionals and 12 other function, Theor. Chem. Acc. 120 (2008)
215–241. doi:10.1007/s00214-007-0310-x.
G. Scalmani, M.J. Frisch, Continuous surface charge polarizable
continuum models of solvation. I. General formalism, J. Chem.
Phys. 132 (2010) 114110. doi:10.1063/1.3359469.
[8]
[9]
doi:10.1016/j.tet.2007.11.022.
[10]
[11]
[12]
P. Wang, H.-F. Li, J.-Z. Zhao, Z.-H. Du, C.-S. Da, Organocatalytic
Enantioselective Cross-Aldol Reaction of o -Hydroxyarylketones
and Trifluoromethyl Ketones, Org. Lett. 19 (2017) 2634–2637.
doi:10.1021/acs.orglett.7b00828.
S. Konda, Q.-S. Guo, M. Abe, H. Huang, H. Arman, J.C.-G. Zhao,
Organocatalyzed Asymmetric Aldol Reactions of Ketones and β,γ-
Unsaturated α-Ketoesters and Phenylglyoxal Hydrates, J. Org.
Chem. 80 (2015) 806–815. doi:10.1021/jo502254e.
N. Hara, S. Nakamura, Y. Funahashi, N. Shibata, Organocatalytic
Enantioselective Decarboxylative Addition of Malonic Acids Half
Thioesters to Isatins, Adv. Synth. Catal. 353 (2011) 2976–2980.
doi:10.1002/adsc.201100410.
[27]
[28]
[29]
[13]
[14]
[15]
G.D. Yadav, Deepa, S. Singh, Prolinamide‐Catalysed Asymmetric
Organic Transformations, ChemistrySelect. 4 (2019) 5591–5618.
doi:10.1002/slct.201900764.
M. Raj, Vishnumaya, S.K. Ginotra, V.K. Singh, Highly
Enantioselective Direct Aldol Reaction Catalyzed by Organic
Molecules, Org. Lett. 8 (2006) 4097–4099. doi:10.1021/ol0616081.
K. Kon, Y. Kohari, M. Murata, Unnatural tripeptide as highly
enantioselective organocatalyst for asymmetric aldol reaction of
isatins, Tetrahedron Lett. 60 (2019) 415–418.
I.F.S. Marra, A.M. de Almeida, L.P. Silva, P.P. de Castro, C.C.
Corrêa, G.W. Amarante, Stereoselective Intermolecular [2 + 2]
Cycloadditions of Erlenmeyer–Plöchl Azlactones Using Visible
Light Photoredox Catalysis, J. Org. Chem. 83 (2018) 15144–15154.
doi:10.1021/acs.joc.8b02430.
J. Burés, P. Dingwall, A. Armstrong, D.G. Blackmond,
Rationalization of an Unusual Solvent-Induced Inversion of
Enantiomeric Excess in Organocatalytic Selenylation of Aldehydes,
Angew. Chemie Int. Ed. 53 (2014) 8700–8704.
[30]
doi:10.1016/j.tetlet.2018.12.049.
[16]
M.P. Pereira, R. de Souza Martins, M.A.L. de Oliveira, F.I.
Bombonato, Amino acid ionic liquids as catalysts in a solvent-free
Morita–Baylis–Hillman reaction, RSC Adv. 8 (2018) 23903–
23913. doi:10.1039/C8RA02409J.
doi:10.1002/anie.201404327.

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Highlights
- Preparation of four novel organocatalysts for the solvent-free asymmetric aldol
reaction.
- Aldol adducts prepared in up to 95% yield, 1:19 syn/anti and 98% e.e.
- Sterically bulky aldehydes and substituted cyclohexanones were well
tolerated.
- Up to three stereogenic centers formed in a single reaction step.
- Chiral induction through several simultaneous hydrogen bonding interactions.

Design and Preparation of a Novel Prolinamide-based Organocatalyst
for the Solvent-free Asymmetric Aldol Reaction
Rafaela de S. Martins, Mathias P. Pereira, Pedro P. de Castro, and Fernanda I.
Bombonato.
Declarations of interest: none