Stereoselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type diamines

Article abstract of DOI:10.1016/j.tet.2021.132085

Asymmetric protonation of ketone enolates is a convenient alternative to asymmetric alkylation of enolates that allows to convert racemic ketones into their optically active form. Here, we have reported an efficient enantioselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type diamines. A broad series of salan-type catalysts were synthesized, including several previously unknown, and subsequently tested in the title reaction. For the first time, a chiral amine used as organocatalyst has shown better results than as stoichiometric protonating agent. Application of only 10 mol% of salan allows to obtain the title ketone with high yield and enantiomeric excess up to 75%. The DFT calculations of the structure of the catalyst and its complex with lithium enolate were conducted, which makes it possible to propose a likely reaction mechanism.

Full text of DOI:10.1016/j.tet.2021.132085

Tetrahedron 86 (2021) 132085
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective protonation of 2-methyl-1-tetralone lithium enolate
catalyzed by salan-type diamines
Daniel Łowicki*, Justyna Watral, Maciej Jelecki, Wiktor Bohusz, Marcin Kwit
ꢀ
ꢀ
Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznanskiego 8, 61-614, Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric protonation of ketone enolates is a convenient alternative to asymmetric alkylation of
enolates that allows to convert racemic ketones into their optically active form. Here, we have reported
an efficient enantioselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type
diamines. A broad series of salan-type catalysts were synthesized, including several previously unknown,
and subsequently tested in the title reaction. For the first time, a chiral amine used as organocatalyst has
shown better results than as stoichiometric protonating agent. Application of only 10 mol% of salan
allows to obtain the title ketone with high yield and enantiomeric excess up to 75%. The DFT calculations
of the structure of the catalyst and its complex with lithium enolate were conducted, which makes it
possible to propose a likely reaction mechanism.
Received 13 January 2021
Received in revised form
6 March 2021
Accepted 10 March 2021
Available online 20 March 2021
Keywords:
Organocatalysis
Asymmetric catalysis
Desymmetrization
Density functional calculation
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
for asymmetric protonation of enolate of 1 (Scheme 1). The first
example has been demonstrated by Koga and Yasukata [24], who
Enantioselective protonation of prochiral enolates represents
simple and attractive way to obtain enantiomerically enriched
chiral ketones [1] [e] [7]. Racemic ketones are readily available, and
their conversion into silyl enol ethers or lithium enolates is well-
documented [8] [e] [10]. Desymmetrization of chiral but racemic
ketones can be realized in the two manners. The first approach
requires an excess of chiral protonating agent as an internal proton
source. In the other, an achiral acid acts as an external proton source
and the reaction is conducted in the presence of chiral catalyst. The
most commonly chosen model molecule for asymmetric proton-
ation is 2-methyl-1-tetralone (1). Although the addition of proton
seems to be a simple reaction, in fact not many scientific reports
have been devoted to this topic in contrast to the CeC bond for-
mation [11,12]. Most of the already known applications require a
used slight excess of chiral triamine containing ether moiety in
toluene as a solvent, and with acetic acid as an additional proton
source. The reported enantioselectivities reached 91%. However,
when the catalytic amount of amine (0.1 equiv.) was used in the
same conditions, only 28% ee has been achieved [25]. Koga et al.
obtained better results utilizing a large excess of succinimide (10
equiv.) as a proton source (51% ee) albeit the reaction was carried
out in heterogeneous conditions. The authors also found that
lithium bromide considerably increased the enantioselectivity of
the process, presumably due to disaggregation of the enolate. In
turn, Eames and Weerasooriya applied (1R,2R)-trans-N,N,N0,N0-
tetramethyl-(1,2)-diamino-cyclohexane as chiral amine and
examined different acids as achiral proton sources [26]. Neither
phenol nor CeH acids are relevant reagents in their system, how-
ever, moderate ee’s 48% were obtained using acetic acid. Although
the authors did not provide detailed information on the amount of
reagents used, they referred to Koga’s protocol, in which 1.03
equivalents of chiral diamine was reported. Very interesting results
have been achieved by Levacher and co-workers who tested
modified cinchona alkaloids and latent source of HF via acyl fluo-
rides alcoholysis [27]. The authors found that bis-cinchona alkaloid
(DHQ)2AQN, which in fact is a tertiary amine, provided the best
result in terms of enantioselectivity. In DMF and DMSO as solvents,
2-methyl-1-tetralone was obtained with ee’s of 70% and 84%,
respectively, whereas worse results in the nonpolar solvents eg. in
large excess of chiral proton sources, namely: b-hydroxysulfoxides
(2e3 equiv.) [13e15], carbamates of 1,10-binaphthalene-8,80-diol (3
equiv.) [16], sulfonamides (1e1.3 equiv.) [17,18], aminoborane (3
equiv.) [19], 5-substituted pyrrolidin-2-one (1.5 equiv.) [20], and
TADDOL derivatives (even with 4 equivalents loading) [21]. Sur-
prisingly, among diverse chiral amines effectively and commonly
used in other asymmetric reactions [22,23], only few were applied
* Corresponding author.
E-mail address: lowicki@amu.edu.pl (D. Łowicki).
https://doi.org/10.1016/j.tet.2021.132085
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
Scheme 1. Comparison of the asymmetric protonation of 2-methyl-1-tetralone enolate using homogeneous achiral proton source conducted by an excess of chiral amines and
catalytic amount of chiral amines.
toluene barely 26% ee was obtained. In turn, when the cinchona
alkaloids were modified into tertiary ammonium salts, the title
ketone was obtained with ee of 62% after 4 days [28].
BINAP complexes with silver(I) fluoride in the asymmetric pro-
tonation of silyl enol ether of the model ketone with good selec-
tivity [37]. Yan and Song for the model reaction demonstrated
excellent enantiodiscrimination of cesium and potassium fluoride
complexes with Song’s oligoEG ligand containing two BINOL moi-
eties [38].
Asensio and co-workers have applied
b-hydroxysulfoxides in
the amount of 40 mol% for enantioselective protonation of 2-
methyltetralone enolate [29]. Different alcohols were subjected as
an achiral proton source yielding product 1 with enantioselectiv-
ities ranging from 5% to 84%, in dependence on the alcohol used.
Yanagisawa et al. studied natural amino acids as catalysts for
asymmetric protonation of ketone enolates and employed 2,6-di-
tert-butylcresol as an achiral Brønsted acid [30]. Yamamoto and
Cheon have demonstrated that BINOL-based thio- and seleno-
phosphoramides catalyze asymmetric protonation of silyl enol
ether of cyclohexanone with very good enantioselectivities at
10 mol% loading [31]. The amino acids as well as aspartame
Bearing in mind that chiral amines show promising potential in
the asymmetric protonation of ketone enolates and the alcohol and
phenol hydroxyl groups were used in many of previously reported
studies, we have decided to check catalysts that contain both,
amine and phenol functionalities in this challenging reaction. We
have turned out our attention to cyclic calixsalans and their acyclic
analogs, i.e. salans, which may be easily synthesized from readly
available R,R-diaminocyclohexane and any aldehyde. Metal com-
plexes of both, salans [39e43] and calixsalans [44] have been used
as metalcatalysts in asymmetric reactions. We have assumed that
such complex molecules with two simultaneous functions could
exhibit dual activation similar to ProPhenol catalyst designed by
Trost that posseses diamine and phenol OH groups [45]. Interest-
ingly, the reduced form of well known salen-type ligands, that is
salans, have not reached much attention in their application as
organocatalysts [46].
dipeptide turned out to be ineffective, while the N-b-l-aspartyl-l-
phenylalanine methyl ester dipeptide provided products with
76e80% ee, albeit with the use of DMF that introduces additional
complications with isolation, purification and analysis of the
product. Several catalytic methods applying metal catalysts are
worth mentioning as well. Yamamoto and co-authors used BINOL-
type complexes with tin(IV) chloride. Although they did not test
tetralone derivatives, they provided some insight into the reaction
mechanism, which were based on the DFT calculations of the
structures of the metal complex [32,33]. In turn, 5 mol% of BINAP-
palladium complexes allowed to obtain the reference ketone with
ee of 79% [34]. Stoltz et al. proposed different approach to obtain 1
using Pd2(dba)3 with chiral t-Bu-PHOS ligand, via enantioselective
2. Results and discussion
We have applied to the protonation of 2-methyl-1-tetralone
lithium enolate 3, the chiral amines that contain phenol groups
within the structure. For preliminary studies, we have chosen cyclic
calixsalane 4 and acyclic salan 5 (Scheme 2).
decarboxylative protonation of b-ketoesters [35]. The palladium ion
is engaged in both steps that are decarboxylation of allyl ester
group and subsequently the stabilization of enol formed. Shibasaki
and co-authors described the enantioselective protonation of silyl
enol ethers catalyzed by a chiral polynuclear gadolinium complex
at 10 mol% concentration loading [36]. The studies allowed to
obtain a tetralone derivative with enantniomeric excess reaching
87%. Yanagisawa et al. demonstrated the catalytic activities of
The lithium enolate of 1, obtained one-pot by treating silyl enol
ether
2 with a commercially available ether solution of
methyllithium-lithium bromide complex, was subjected to reaction
with equimolar amount of chiral amines. Similarly to Koga’s pro-
cedure [24] the acetic acid was initially used as external achiral
proton source and toluene as a solvent.
2

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
Scheme 2. Conversion of racemic ketone into silyl enol ether and subsequent one-pot formation of lithium enolate and its stereoselective protonation by achiral acid in the
presence of chiral amines.
Table 2
2.1. Optimization of catalytic process
Effect of achiral proton source on enantioselective protonation of 2-methyltetralone
enolate catalyzed by 5.
At first, we have tested calixsalan 4, but only a racemic 1 and
some amount of unreacted substrate were recovered.
To our surprise, acyclic analogue 5 provided ketone 1 with ee of
22% and 37% yield. This latter result indicates that such a system is
not conducive to the formation of lithium enolate. Changing the
order of solvent addition considerably increased the degree of
conversion. We have found that the addition of toluene not before
lithium enolate is formed is crucial to ensure complete desilylation.
At the beginning of the optimization process, various amounts of
catalyst were studied. Increasing the amount of 5 to two equiva-
lents deteriorates the enantioselectivity (Table 1, entry 1).
In turn, lowering the amine loading increased the enantiomeric
excess of the product. The best result (45% ee) was obtained with
the use of 0.1 equiv. of 5 (Table 1, entry 4). To the best of our
knowledge, this is the first example of utilizing a chiral amine for
asymmetric protonation of lithium enolate of 2-methyltetralone,
which provides considerably better results in the catalytic reaction
than in the stoichiometric one. Note that further decrease of the
catalyst loading reduces the selectivity dramatically.
No.
Achiral acid
pKa
Yield [%]a
Ee [%]b
1
2
3
4
7
6
7
H2O
15.7
9.3
4.8
4.2
3.8
0.2
ꢀ6.2
79
67
88
60
83
67
81
46
14
45
16
72
49
3
(CF3)2CHOH
CH3COOH
PhCOOH
HCOOH
CF3COOH
HCl
a
Isolated yield.
b
Determined by HPLC using a chiral stationary phase column (Lux i-Cellulose-5).
MeLi*LiBr (1.25 eq.), achiral acid (1.21 eq.).
As the second step, we have tested various acids as proton
sources and examined the relationship between the acid strength
and the selectivity of protonation. The resulted ee’s together with
pKa values of the acids used are given in Table 2.
Table 1
To our delight, the employment of formic acid led to a significant
increase of ee, up to 72%. It suggests that stronger formic acid (pKa
3.8) is better than acetic acid (pKa 4.8). Similar tendency is noticed
when acetic acid and trifluoroacetic acid (pKa 0.2) are compared.
Although the latter one is much stronger than formic acid, it gave
(S)-1 with ca. 50% ee. Relatively weak acid, i.e. water also provided
an acceptable result (ee 46%). Considering all above facts, it can be
concluded that not only the acid strength is important for obtaining
good enantioselectivity but also a smaller acid molecule is more
suitable. It is worth mentioning that when the stoichiometric
amount of protonated form of salan 5 was used, no enantiose-
lection was observed.
Encouraged by the above-mentioned results, we check how the
change of solvent will affect efficiency of the process. The studies
clearly demonstrated that no enantiodiscrimination occurs in polar
solvents such as DMSO, DMF, or THF, but in nonpolar solvents, the
catalyst is active. The best result was obtained when toluene was
used as a solvent (Table 3, entry 1).
The effect of the amount of salan
methyltetralone enolate.
5 on enantioselective protonation of 2-
No.
Catalyst loading [eq.]
Yield [%]a
Ee [%]b
1
2
3
4
5
6
2
1
0.5
0.1
0.05
0.01
72
77
83
88
82
67
11
22
37
45
7
3
a
Isolated yield.
b
Determined by HPLC using a chiral stationary phase column (Lux i-Cellulose-5).
MeLi*LiBr (1.25 eq.), CH3COOH (1.21 eq.).
According to Koga’s suggestions [25], that the slow addition of
3

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
Table 3
In the optimized structure of the most abundant conformer of 5,
the oxygen atoms are directed to the interior of the molecule
(Fig. 2) and both are approachable for lithium enolate (Fig. S1,
Supplementary Information). In the lowest-energy conformer of 7,
both arms carrying aromatic fragments are twisted compared to
their arrangement in 5 (Fig. S2, Supplementary Information). When
the structure of 7 is presented in the spacefill projection, it is clearly
visible that all heteroatoms are hindered from both sides of the
molecule (Fig. S3, Supplementary Information). These calculations
are consistent with the experimental observation since ee values
obtained for the processes carried out in the presence of 5 and 7
chiral catalysts are completely different.
To check if the presence of hydroxyl groups is necessary for
efficiency of the process, we have used salan 8, which has a similar
structure to 5 but does not contain OH functionality. Removing of
OH groups deactivates the catalyst completely. Racemic mixture
was also obtained with the use of 9, in which both hydroxyl groups
were converted into methoxy groups. This outcome clearly in-
dicates that OH groups participate in the catalytic process. The
conclusion may be supported by the results obtained for amine 12
that has only one OH group and yielded the desired ketone with
only 5% ee.
In turn, leaving the OH group unchanged but introducing methyl
groups at the nitrogen atoms (10) causes a decreasing of enantio-
selectivity, in comparison to salan 5, to barely 25%. Such deterio-
ration of ee can result from sterical hindrance in the catalytic cavity.
This hypothesis is additionally supported by the result obtained for
catalyst 11, where the two CH3 groups are replaced by one meth-
ylene bridge (-CH2-). The ee value is higher, albeit still unsatisfac-
torily low. The DFT calculations of structure 10 revealed that
additional methyl groups attached to nitrogen atoms significantly
affected the conformation of the molecule (Fig. 2). In the calculated
lowest energy structure of 10, one of the two arms that hold the
aromatic rings is rotated in comparison to its position in the
structure of 5, what effectively obstructs access to oxygen atoms
from one side of the molecule (Fig. S4 and S5, Supplementary
Information).
We also have explored whether the nature of para-located
substituents, in relation to OH groups in the aromatic ring, had
meaning as well. Both electron withdrawing (NO2 and Br) groups as
well as electron donating (OCH3) group were introduced to the
salan core (13, 14, and 15, respectively). Similar to salan 5 having
tert-butyl group of weak electron-donating nature, the catalyst 15
with a much stronger electron-donating methoxy moiety has
provided product with high ee (73%). Such a result being main-
tained when a bromine atom of weak electron-withdrawing char-
acter being present in the aryl ring. In turn, the salan 13 substituted
with a strong electron-withdrawing nitro group in each aryl moiety
failed completely. This observation can be explained by the
considerable increase in the acidity of the phenol proton caused by
the strong electron-withdrawing group.
Solvent effect on enantioselective protonation of 2-methyltetralone enolate cata-
lyzed by 5.
No.
Solvent
Yield [%]a
Ee [%]b
1c
2
3
4
7
Toluene
Hexane
DCM
THF
DMF
84
85
75
94
52
77
75
17
3
0
0
6
DMSO
0
a
Isolated yield.
b
c
Determined by HPLC using a chiral stationary phase column (Lux i-Cellulose-5).
HCOOH (1.21 eq.) was added slowly during 1 h. MeLi*LiBr (1.25 eq.).
proton source is better than its addition in one portion, we have
performed the desymmetrization reaction by adding the solution of
formic acid over 1 h. However, the result was only slightly better
than that obtained when the solution of the acid was added within
1e2 min (Table 3, entry 2). It has been also found that increasing
the temperature to ꢀ50 ꢁC kept the catalyst active while lowering
the temperature to ꢀ98 ꢁC yielded ketone 1 with barely 22% ee.
2.2. Analysis of structural requirements for catalyst activity
Having established the optimal catalytic conditions for this re-
action, we went to explore the catalyst structure requirements that
might shed new light on the mechanism of this process. The aim of
the study was to demonstrate which of the molecular fragments are
essential for catalytic activity. We have examined whether the
presence of OH and NH groups is important for the enantiose-
lectivity of the process as well as the size and nature of substituents
in the aromatic ring, according to Fig. 1.
To perform this task, we have synthesized series of chiral salans,
including new compounds (7, 9, 12 and 14), as it has been shown in
Scheme 3.
We have initiated our study with salan 6, which is devoid of tert-
butyl groups. The enantioselectivity of the reaction has dropped
completely. This suggests a necessity of the bulky group in the
neighborhood of the hydroxyl moiety. On the other hand, com-
pound 7, where these tert-butyl groups were replaced by triphe-
nylmethyl (trityl) groups provided racemic mixture as well.
Inactivation of the catalyst may result from the size of trityl moi-
eties as they are too bulky and change the optimal conformation of
the catalyst. To verify this hypothesis, we have briefly explored the
structures of both molecules (Fig. 2). Initial calculations were car-
ried out with molecular mechanics method in the gas phase, then
the obtained geometries were further fully optimized at the DFT
level using Gaussian software [47e51].
2.3. Mechanistic consideration
For a better understanding of the mechanism of the process, we
have calculated the structure of the complex formed by lithium
enolate 3 and salan 5. Low-energy structure of the complex,
calculated at the B3LYP/6e31þþG(d,p) method is shown in Fig. 2.
Overlapping of the structures of free ligand 5 and complex [3*5]
demonstrates how well the enolate fits to the salan’s cavity, and
how the complexation process changes the conformation of the
latter (Fig. 3). Within the complex, the lithium ion is located inside
the ligand cavity and coordinated by both nitrogen atoms and one
of the oxygen atoms (Fig. S6, Supplementary Information). The
molecule of enolate bound to lithium ion, which is arranged in such
Fig. 1. Structure of the catalyst with indicated places of possible modifications.
4

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
Scheme 3. Structures of the salans tested as catalyst for asymmetric protonation of 2-methyl-1-tetralone lithium enolate. The given ee values were obtained in the optimized
reaction conditions.
a way that Si-face of the double bond is close to the ligand and the
other side is facing outside. The ligand structure ensures a chiral
environment for the protonation process. Additionally, the nucle-
ophilic carbon center is placed in proximity of NeH ligand group
(2.87 Å), what facilitates the stereocontrolled attack on the chiral
quenching agent. However, these studies can be considered pre-
liminary, they provided some important information, which
allowed to propose the mechanism that is depicted in Scheme 4.
Based on the calculations results, it may be assumed that the pro-
tonation takes places via proton transfer from the nitrogen atom of
catalyst located in close proximity to the Si-face of the enolate.
Simultaneously the protonated enolate releases the complex as a
free ketone and the salan catalyst is subsequently regenerated by
formic acid. Such interpretation explains the formation of the S
enantiomer of 1.
mixture was obtained. This clearly shows that salan in protonated
form does not ensure enantiodiscrimination of the process. In the
calculated structure of the complex [3*5] the lone pair of the ni-
trogen atom is involved in the complexation of lithium ion,
ensuring proper orientation of the substrate in the chiral catalytic
cavity. If the nitrogen atom is protonated, the complexation process
could not occur. Moreover, the interaction of nitrogen atom with
lithium cation not only causes the appropriate setting of the re-
actants, but also increases the acidity of the NeH proton in the
catalyst structure. Based on the DFT calculation, the proton transfer
of enolate does not occur from the most acidic phenolic proton. The
distance between the OH proton and nucleophilic
a carbon atom is
too large (4.54 Å) to allow the proton to be transfered from the
phenol group. This hypothesis is supported by the result obtained
for salans containing substituents of different electron affinity. The
salans containing alkyl and methoxy groups or bromine atoms
present in the aromatic ring, which diminish the acidity of the
phenolic proton, led to enantiomeric excess over 70%. In turn, the
salan with a strongly electron-withdrawing nitro group, possessing
The hypothesis that proton transfer arises from the amine group
is consistent with the experimental results obtained for the
ammonium form of salan. When a stoichiometric amount of
diprotonated salan was added to the lithium enolate, the racemic
5

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
Fig. 2. Structures of the lowest energy conformers of 5, 7, and 10 calculated at B3LYP/6-31G(d,p) and complex [3*5] calculated at B3LYP/6e31þþG(d,p) levels of theory. Hydrogen
atoms were omitted for clarity.
suggest that the other mechanism pathway is neither dominant nor
faster.
3. Conclusions
In summary, we have reported a new, efficient and enantiose-
lective method for asymmetric protonation of lithium enolate 3
realized in a catalytic manner. The salan catalysts may be easily
synthesized from readily available (R,R)-1,2-diaminocyclohexane
and appropriate aldehydes. The enantiomeric excesses have
reached 75% using barely 0.1 equivalent of the catalyst that fulfills
the criteria for enantioselective organocatalysis and is comparable
with the results achieved by metal catalysts e.g. palladium ee of 79%
[34] or gadolinium 87% [36]. Studies on the modifications of salans
and their use in catalytic reactions have provided new information
on the mechanism. Phenol groups and tert-butyl groups in ortho
position are essential for the enantioselectivity of the catalytic
process whereas the presence of strong electron withdrawing
substituents deactivates the catalyst. In turn, bulky trityl groups in
Fig. 3. Overlapping of calculated structures of free ligand
5 and complex [3*5].
close proximity to OH group change the catalyst conformation and
make it disable to effective complex of the substrate. Based on DFT
calculations, it is possible to draw conclusion that this process
undergo by the attack of double bond on the hydrogen attached to
the nitrogen atom of salan 5 yielding product of S absolute
configuration. Both, experimental and theoretical studies, revealed
that OH phenol group does not take part in the proton transfer but
in the stabilization and spatial orientation of the substrate within
the catalytic cavity. This finding confirms our assumptions about
the dual role of the catalyst. Detailed mechanistic studies, as well as
further exploration on the scope of other types of carbonyl com-
pounds that may undergo the asymmetric protonation catalyzed by
salan-type amines are in progress in our laboratory.
Hydrogen atoms were omitted for clarity.
a much more acidic phenol proton, failed. Nevertheless, distance
between the OH group and the aromatic ring of the ketone, that is,
2.38 Å, ensures additional spatial orientation of the enolate by non-
…
covalent OeH
p interactions, which stabilizes the geometry of
substrate-catalyst complex.
Although we speculate that the reactions with salan 5, 14, and
15 proceed through proton transfer from NH group, other degen-
erate pathways of this process are also probable, especially for the
catalysts 10 and 11, which do not posses amine protons. Never-
theless, the low enantioselectivities obtained in the later cases
6

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
Scheme 4. Proposed mechanism of asymmetric protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan diamine.
4. Experimental section
2 mL of salan (0.03 mmol, synthesis see Supplementary Informa-
tion) as a solution in dry toluene was added to the reaction previ-
ously cooled to ꢀ20 ꢁC and stirred for additional 10 min. After this
time, the temperature was lowered to ꢀ78 ꢁC and the solution of
4.1. Reagents
Unless otherwise noted, all commercially available compounds
were used as received without further purification. Syntheses of
intermediates were described in Supporting Information.
formic acid (19 mL in 2 mL of toluene) was added dropwise. The
reaction mixture was stirred for 1 h at this temperature and then
was allowed to warm up. The reaction was quenched by adding
aqueous solution of ammonium chloride and extracted with hex-
ane. Organic phase was dried over sodium sulphate and the solvent
was evaporated under vacuum. The resulting residue was purified
by flash chromatography on silica gel (hexane/EtOAc 10:1) to afford
the corresponding product. Absolute configuration of product 1,
that is S, was determined by the comparison the sign of specific
4.2. Characterization
NMR spectra were recorded on a Spectrometer Varian VNMR-S
400 MHz or Varian Mercury 300 MHz using tetramethylsilane as an
internal reference (TMS:
peak as an internal reference (CDCl3:
d
0.00) for 1H NMR spectra and the solvent
d
77.0) for 13C NMR spectra.
optical rotation for the obtained sample with data given in litera-
20
ture [52]. [
a]
¼ ꢀ23 (CHCl3, c. 1.0, for a sample of 45% ee).
D
Mass spectra (ESI MS) were recorded with a Waters/Micromass
(Manchester, UK) ZQ mass spectrometer equipped with a Harvard
Apparatus syringe pump at the cone voltage 30 V. All reactions
were monitored by thin-layer chromatography using Merck silica
gel plates 60 F254; visualization was accomplished with UV light. A
Jasco P-2000 polarimeter was used for optical rotation measure-
ments (at 20 ꢁC). Melting points were measured on Büchi Melting
Point B-545 and uncorrected. Enantiomeric excesses were deter-
mined by HPLC analysis using Hitachi Elite LaChrom HPLC System
with UV detector L-2400.
4.4. Computational details
Conformational searches for compounds 5, 7, and 10 were car-
ried out using Scigress software (SCIGRESS 2.5, Fujitsu Ltd.) using
the MM3 molecular mechanics force field. The obtained con-
formers were optimized at the DFT-level using B3LYP/6-31G(d,p)
and subsequently B3LYP/6e31þþG(d,p) methods as implemented
in Gaussian 09 package [47e51]. The conformer of the lowest
electronic and the Gibbs free energy without any imaginary fre-
quencies was assumed as the global minimum structure. Graphical
images were produced by the Mercury software [53].
4.3. Catalytic procedure
To a dry reaction flask equipped with a magnetic stirring bar, the
silyl enol ether (0.30 mmol) and methyllithium-lithium bromide
4.5. Synthesis of salans
complex (250
mL, 1.5 M solution in Et2O) were added, and the
mixture was stirred for 2 h, at room temperature. Subsequently,
In a round bottomed flask filled with argon, (1R,2R)-trans-1,2-
7

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
diaminocyclohexane (R,R-DACH) (1 equiv.) and potassium carbon-
ate (0.9 equiv.) were dissolved in 3 mL of distilled water and heated
for 30 min at 80e85 ꢁC. The exact amounts are given below. Sub-
sequently, a solution of aldehyde (2 equiv.) in 45 mL of ethanol was
added dropwise and the reaction mixture was stirred for 3 h. The
solution turned yellow. After this time, ethanol was evaporated and
10 mL of distilled water was added. Water solution was extracted
with dichloromethane 3 times with 30 mL of the solvent. The
combined extracts were washed with brine and dried with anhy-
drous Na2SO4. After filtration of the drying agent, solution was
evaporated to dryness. The resulting salens were subsequently
reduced without purification.
2.51e2.35 (m, 1H), 2.15 (d, J ¼ 11.4 Hz, 1H), 1.78e1.60 (m, 1H),
1.29e1.05 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3)
128.3, 122.9, 119.2, 116.4, 59.7, 49.7, 30.5, 24.2 ppm; [
1.0, CHCl3).
d: 158.0, 128.9,
20
a
]
¼ ꢀ32.5 (c
D
(1R,2R)-N,N0-di[(2-hydroxy-3-triphenylmethyl-5-tert-butyl)
benzyl]-1,2-diaminocyclohexane (7, new compound):
The resulting salens were dissolved in methanol (300 mL or
more if it was necessary for complete dissolution). To the salen
solution, sodium borohydride (4 equiv.) was added in portions at
room temperature. After addition of NaBH4, the reaction mixture
was stirred for 3 h and then 30 mL of water was added and stirred
for 15 min. The alcohol was evaporated under vacuum and the
water residue was extracted with DCM three times for 30 mL.
Organic phase was dried with Na2SO4 and after removing of the
desiccant, the solvent was evaporated.
Substrates: (R,R)-DACH (96 mg, 0.84 mmol), 3-tert-butyl-5-
triphenylmethyl-2-hydroxybenzaldehyde (synthesis described
below) (710 mg,1.69 mmol). Overall isolated yield: 0.200 g, 26% as a
violet solid, m.p. 140e147 ꢁC. Formula: C66H70N2O2, calculated
molecular weight: 923.30 g/mol; ESI-MS: [MþH] m/z ¼ 924; 1H
Experimental procedures for modification of salan
described for appropriate products, respectively.
(1R,2R)-N,N0-di[(2-hydroxy-3,5-di-tert-butyl)benzyl]-1,2-
diaminocyclohexane (5) [54].
5 are
NMR (400 MHz, CDCl3) d: 11.30e9.00 (broad signal, 1H), 7.19e7.14
(m, 12H), 7.11 (ddd, J ¼ 6.9, 5.3, 2.0 Hz, 3H), 7.05 (d, J ¼ 2.4 Hz, 1H),
6.83 (d, J ¼ 2.2 Hz, 1H), 3.72 (dd, J ¼ 51.4, 13.9 Hz, 2H), 1.78 (d,
J ¼ 12.9 Hz, 1H), 1.49 (d, J ¼ 7.9 Hz, 2H), 1.13 (s, 9H), 0.83 (t,
J ¼ 9.8 Hz, 1H), 0.53 (dd, J ¼ 19.2, 11.4 Hz, 1H) ppm; 13C NMR
(101 MHz, CDCl3) d: 153.9, 146.2, 140.0, 133.2, 131.2, 127.3, 126.8,
125.3, 124.1, 121.7, 63.4, 57.8, 49.2, 34.0, 31.5, 29.8, 24.5 ppm;
20
[
a
]
D
¼ ꢀ10.1 (c 1.0, CHCl3).
(1R,2R)-N,N0-di(3,5-di-tert-butylbenzyl)-1,2-
diaminocyclohexane (8) [56].
Substrates: (R,R)-DACH (540 mg, 4.7 mmol), 3,5-di-tert-butyl-2-
hydroxybenzaldehyde (purchased from: Apollo Scientific) (2.198 g,
9.4 mmol); Overall isolated yield: 1.550 g, 60% as pale yellow solid,
m.p. 124e127 ꢁC. Formula: C36H58N2O2, calculated molecular
weight: 550.87 g/mol, ESI-MS: [MþH] m/z ¼ 552. 1H NMR
(300 MHz, CDCl3)
d
: 7.21 (d, J ¼ 2.3 Hz, 2H), 6.86 (d, J ¼ 2.2 Hz, 2H),
4.04 (d, J ¼ 13.3 Hz, 2H), 3.90 (d, J ¼ 13.3 Hz, 2H), 2.47 (d, J ¼ 5.7 Hz,
Substrates: (R,R)-DACH (460 mg, 4 mmol), 3,5-di-tert-butyl-
benzaldehyde (purchased from: FluoroChem) (1.800 g, 8 mmol).
Overall isolated yield: 1.50 g, 72% as an oil. Formula: C36H58N2,
calculated molecular weight: 518.87 g/mol; ESI-MS: [MþH] m/
2H), 2.17 (d, J ¼ 10.2 Hz, 2H), 1.70 (s, 2H), 1.36 (t, J ¼ 22.1 Hz, 42H)
ppm; 13C NMR (75 MHz, CDCl3)
d: 154.4, 140.6, 136.0, 123.2, 123.1,
20
122.4, 59.9, 50.9, 34.9, 34.2, 31.7, 30.8, 29.6, 24.2 ppm; [
a
]
¼ ꢀ27.2
D
z ¼ 520; 1H NMR (300 MHz, CDCl3)
: 7.28 (t, J ¼ 1.7 Hz, 1H), 7.14 (d,
d
(c 1.0, CHCl3).
(1R,2R)-N,N0-di(2-hydroxybenzyl)-1,2-diaminocyclohexane (6)
J ¼ 1.7 Hz, 2H), 3.90 (d, J ¼ 12.9 Hz,1H), 3.65 (d, J ¼ 12.9 Hz,1H), 2.29
(dd, J ¼ 5.3, 3.6 Hz, 1H), 2.19 (d, J ¼ 13.0 Hz, 1H), 1.95 (s, 1H), 1.73 (d,
[55].
J ¼ 8.3 Hz, 1H), 1.32 (dd, J ¼ 6.6, 2.7 Hz, 2H), 1.28 (s, 16H) ppm; 13
C
NMR (75 MHz, CDCl3) d: 150.6, 140.1, 122.3, 120.8, 61.1, 51.7, 34.8,
20
31.7, 31.5, 25.1 ppm; [
a]
¼ ꢀ40.6 (c 1.0, CHCl3).
D
(1R,2R)-N,N’-bis(3,5-di-tert-butyl-2-methoxybenzyl)cyclo-
hexane-1,2-diamine (9, new compound):
Substrates: (R,R)-DACH (600 mg, 5.3 mmol), salicylaldehyde
(purchased from: Sigma-Aldrich) (1.30 g, 10.6 mmol); Overall iso-
lated yield: 1.460 g, 85% as pale yellow oil solidified in a fridge m.p.
96e98 ꢁC. Formula: C20H26N2O2, calculated molecular weight:
326.44 g/mol, ESI-MS: [MþH] m/z ¼ 327. 1H NMR (300 MHz, CDCl3)
d
: 7.20e7.11 (m, 1H), 6.97 (d, J ¼ 6.4 Hz, 1H), 6.86e6.73 (m, 2H),
6.50e5.00 (broad signal, 1H), 3.98 (dd, J ¼ 36.8, 13.9 Hz, 2H),
Substrates: (R,R)-DACH (450 mg, 4.0 mmol), 3,5-di-tert-butyl-2-
8

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
methoxybenzaldehyde (Sigma-Aldrich) (2.00 g, 8.1 mmol). Overall
isolated yield: 1.91 g, 83% as a pale yellow oil solidifying in a fridge,
m.p. 95e97 ꢁC. Formula: C38H62N2O2, calculated molecular weight:
578.93 g/mol; ESI-MS: [MþH] m/z ¼ 579; 1H NMR (300 MHz,
z ¼ 563; 1H NMR (300 MHz, CDCl3)
d
: 10.71 (s, 1H), 7.19 (d,
J ¼ 2.3 Hz, 1H), 6.79 (d, J ¼ 2.2 Hz, 1H), 4.15 (d, J ¼ 13.6 Hz, 1H),
3.57e3.41 (m, 2H), 2.34 (d, J ¼ 8.8 Hz, 1H), 2.01 (d, J ¼ 11.2 Hz, 1H),
1.82 (d, J ¼ 8.1 Hz, 1H), 1.40 (s, 11H), 1.25 (s, 11H) ppm; 13C NMR
CDCl3)
d
: 7.19 (dd, J ¼ 6.7, 2.5 Hz, 2H), 3.95 (d, J ¼ 13.0 Hz, 1H), 3.77
(75 MHz, CDCl3) d: 153.9, 140.7, 135.6, 123.1, 123.0, 120.9, 75.5, 69.5,
57.4, 34.85, 34.1, 31.6, 29.6, 29.0, 24.2 ppm; [
CHCl3).
2,4-di-tert-butyl-6-((((1R,2R)-2-((3,5-di-tert-butyl-2-
methoxybenzyl)(methyl)amino)cyclohexyl)-(methyl)amino)
methyl)phenol (12, new compound):
20
(s, 3H), 3.71 (d, J ¼ 13.0 Hz, 1H), 2.23 (dd, J ¼ 15.8, 10.3 Hz, 2H), 2.06
a]
¼ ꢀ40.2 (c 1.0,
D
(s,1H),1.72 (d, J ¼ 8.6 Hz,1H),1.36 (s, 9H),1.25 (s, 9H) ppm; 13C NMR
(75 MHz, CDCl3)
61.4, 46.6, 35.3, 34.4, 31.6, 31.1, 25.1 ppm; [
d
: 155.8, 145.4, 141.6, 133.2, 125.2, 122.8, 61.9, 61.9,
20
a
]
¼ ꢀ35.0 (c 1.0,
D
CHCl3).
(1R,2R)-N,N0-dimethyl-N,N0-di[(2-hydroxy-3,5-di-tert-butyl)
benzyl]-1,2-diaminocyclohexane (10) [57].
Synthesis: In
a round-bottomed flask, salan 10 (210 mg,
0.36 mmol) and cesium carbonate (473 mg, 1.45 mmol) were dis-
solved in 4 mL of DMF. To the flask, a solution of methyl iodide
(103 mg, 0.73 mmol) in 2 mL of DMF was added from a syringe via
septum. The reaction mixture was stirred at ambient temperature
overnight. Subsequently, 10 mL of 2 M sodium hydroxide solution
was added and after 15 min the white precipitate was dissolved by
adding hexane. The two layers were separated and the water/DMF
phase was extracted with hexane 3 ꢂ 15 mL. Combined hexane
extracts were collected and washed with water twice and with
brine. After drying over sodium sulphate, the solution was evapo-
rated and the white foam solid was obtained. The product was
purified by flash chromatography on silica gel (DCM-100%, then
DCM/MeOH/NH3 aq. 200:10:0.1), m.p. 119e120 ꢁC. Yield 156 mg,
73%. Formula: C39H64N2O2, calculated molecular weight: 592.95 g/
Synthesis: Compound 5 (750 mg, 1.36 mmol) was dissolved in
35 mL of acetonitrile and glacial acetic acid (4.5 mL) was slowly
added. To a stirred solution, the aqueous formaldehyde (1.08 mL of
37%, 13.2 mmol) was added and stirring was maintained for 20 min
at room temperature. After this time, sodium borohydride (225 mg,
6.76 mmol) was added in portions and the reaction was stirred
overnight. A white solid precipitated in the mixture. Acetonitrile
was evaporated in vacuo and a 10% solution of sodium hydroxide
(15 mL) was added. Whole suspension was extracted with DCM (5
times) and the organic phase was washed with water and brine and
dried over sodium sulphate. After removal of solvent, 764 mg of
product was obtained (yield 97%) as a white solid m.p. 89e93 ꢁC.
Formula: C38H62N2O2, calculated molecular weight: 578,93 g/mol;
mol; ESI MS m/z ¼ 594; 1H NMR (300 MHz, CDCl3)
d: 11.18 (dd,
ESI-MS: [MþH] m/z ¼ 579; 1H NMR (400 MHz, CDCl3)
d: 10.45 (s,
J ¼ 53.6, 44.7 Hz, 2H), 7.45 (s, 3H), 7.19 (dd, J ¼ 12.3, 2.4 Hz, 6H), 6.76
(d, J ¼ 2.0 Hz, 3H), 4.03e3.58 (m, 20H), 2.65 (dd, J ¼ 14.3, 6.7 Hz,
3H), 2.53 (t, J ¼ 9.4 Hz, 3H), 2.23 (s, 9H), 2.13 (s, 7H), 2.03 (d,
J ¼ 12.1 Hz, 4H), 1.90 (d, J ¼ 10.1 Hz, 3H), 1.75 (d, J ¼ 9.3 Hz, 6H), 1.40
(d, J ¼ 7.9 Hz, 52H), 1.33e0.98 (m, 65H) ppm; 13C NMR (75 MHz,
1H), 7.19 (d, J ¼ 2.5 Hz, 1H), 6.82 (d, J ¼ 2.4 Hz, 1H), 3.79 (q,
J ¼ 13.4 Hz, 2H), 2.72e2.62 (m, 1H), 2.21 (s, 3H), 2.00 (d, J ¼ 12.5 Hz,
1H), 1.79 (d, J ¼ 7.6 Hz, 1H), 1.37 (s, 8H), 1.28 (s, 8H), 1.23e1.07 (m,
2H) ppm; 13C NMR (101 MHz, CDCl3)
d: 154.4, 140.1, 135.5, 123.5,
122.7, 121.3, 61.3, 58.7, 34.8, 34.1, 31.7, 29.6, 25.3, 22.6 ppm;
20
CDCl3) d: 156.3, 155.1, 145.3, 141.4, 139.5, 135.09, 131.3, 126.4, 123.5,
[
a
]
¼ þ54.9 (c 1.0, CHCl3).
D
122.8, 122.4, 121.8, 62.5, 61.8, 61.3, 58.3, 35.9, 35.3, 34.9, 34.4, 34.1,
6,6’-(((3aR,7aR)-hexahydro-1H-benzo[d]imidazole-1,3(2H)-
20
31.8, 31.6, 31.1, 29.7, 25.7, 25.5, 22.9 ppm; [
CHCl3).
a]
¼ þ40.9 (c 1.0,
diyl)bis(methylene))bis(2,4-di-tert-butylphenol) (11):
D
(1R,2R)-N,N0-di[(2-hydroxy-3-tert-butyl-5-nitro)benzyl]-1,2-
diaminocyclohexane (13) [54].
Synthesis analogous to published in the literature [58]: To round-
bottom flask filled with argon, the (R,R)-DACH (600 mg, 5 mmol),
3,5-di-tert-butylphenol (2.06 g, 10 mmol), and 2 mL of aqueous
formaldehyde (37%, 25 mmol) were added. Reaction mixture was
heated at 78 ꢁC overnight. The white solid was filtrated and dis-
solved in hexane and dried over sodium sulphate. After removal of
the drying agent, the solvent was evaporated under reduced
pressure. Resulted solid was crystallized from methanol yielding
2.12 g (75%) of white powder, m.p. 87e91 ꢁC. Formula: C37H58N2O2,
calculated molecular weight: 562.88 g/mol; ESI-MS: [MþH] m/
Substrates: (R,R)-DACH (512 mg, 4.48 mmol), 3-(tert-butyl)-2-
hydroxy-5-nitrobenzaldehyde (synthesis described in Supporting
Information) (2.00 g, 8.96 mmol); Overall isolated yield: 1.76 g, 74%
as yellow powder m.p. 98e105 ꢁC.; Formula: C28H40N4O6, calcu-
lated molecular weight: 528.65 g/mol; ESI MS m/z ¼ 529 [MþH],
551 [MþNa], 567 [MþK], 1080 [2 M þ Na], 1096 [2 M þ K]; 1H NMR
(400 MHz, CDCl3)
d
: 8.11 (d, J ¼ 2.8 Hz, 1H), 7.83 (d, J ¼ 2.7 Hz, 1H),
9

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
ꢃEnantioselective protonation of prochiral lithium enolate pro-
vides enantiomerically enriched ketone.
ꢃStructures of salan ligand and its complex with lithium enolate
of 2-methyl-1-tetralone have been calculated by DFT methods.
ꢃ Four new salan-type compound have been efficiently
synthesized.
4.12 (dd, J ¼ 55.8, 14.2 Hz, 2H), 2.45 (dd, J ¼ 10.6, 7.0 Hz, 1H), 2.24 (d,
J ¼ 13.0 Hz, 1H), 1.77 (d, J ¼ 8.2 Hz, 1H), 1.36 (s, 9H), 1.31e1.11 (m,
3H) ppm; 13C NMR (100 MHz, CDCl3)
d: 163.6, 139.5, 138.0, 122.7,
20
122.5, 122.4, 59.9, 49.7, 34.9, 30.6, 29.0, 24.2 ppm; [
1.0, CHCl3).
a
]
¼ þ38.7 (c
D
(1R,2R)-N,N0-di[(2-hydroxy-3-tert-butyl-5-bromo)benzyl]-1,2-
diaminocyclohexane: (14, new compound).
Acknowledgments
This work was supported by the National Science Centre in
Poland, grant no DEC-2018/02/X/ST5/01757.
All calculations were performed in Poznan Supercomputing and
Networking Center.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132085.
Substrates: (R,R)-DACH (1.636 g, 14.3 mmol), 5-bromo-3-(tert-
butyl)-2-hydroxybenzaldehyde (synthesis described in Supporting
Information) (7.386 g, 28.7 mmol); Overall isolated yield: 7.944 g,
42% as a white power m.p. 158e160 ꢁC. Formula: C28H40Br2N2O2,
calculated molecular weight: 596.45 g/mol; ESI-MS: [MþH] m/
References
[1] L. Duhamel, P. Duhamel, J.-C. Plaquevent, Enantioselective protonations:
fundamental insights and new concepts, Tetrahedron: Asymmetry 15 (2004)
3653e3691, https://doi.org/10.1016/j.tetasy.2004.09.035.
[2] C. Fehr, Enantioselective protonation of enolates and enols, Angew. Chem. Int.
Ed. 35 (1996) 2566e2587, https://doi.org/10.1002/anie.199625661.
[3] A. Yanagisawa, K. Ishihara, H. Yamamoto, Asymmetric protonations of enol
derivatives, Synlett 1997 (1997) 411e420, https://doi.org/10.1055/s-1997-
6131.
[4] J. Eames, N. Weerasooriya, Recent advances into the enantioselective pro-
tonation of prostereogenic enol derivatives, Tetrahedron: Asymmetry 12
(2001) 1e24, https://doi.org/10.1016/S0957-4166(00)00496-1.
[5] J.T. Mohr, A.Y. Hong, B.M. Stoltz, Enantioselective protonation, Nat. Chem. 1
(2009) 359e369, https://doi.org/10.1038/nchem.297.
z ¼ 595/597/699; 1H NMR (300 MHz, CDCl3)
d: 10.99 (s, 1H), 7.25 (d,
J ¼ 2.5 Hz, 2H), 6.97 (d, J ¼ 2.5 Hz, 2H), 3.94 (dd, J ¼ 42.0, 13.8 Hz,
4H), 2.44e2.30 (m, 2H), 2.16 (d, J ¼ 12.7 Hz, 2H), 1.79e1.63 (m, 2H),
1.48e0.99 (m, 22H) ppm; 13C NMR (76 MHz, CDCl3)
d: 156.0, 139.3,
129.0, 128.8, 124.8, 110.67, 59.8, 49.7, 34.8, 30.9, 29.2, 24.3 ppm;
20
[
a
]
¼ þ5.8 (c 1.0, CHCl3).
D
(1R,2R)-N,N0-di[(2-hydroxy-3-tert-butyl-5-methoxy)benzyl]-
1,2-diaminocyclohexane (15) [59].
[6] F. Legros, S. Oudeyer, V. Levacher, New developments in chiral cooperative ion
pairing organocatalysis by means of ammonium oxyanions and fluorides:
from protonation to deprotonation reactions, Chem. Rec. 17 (2017) 429e440,
https://doi.org/10.1002/tcr.201600111.
ꢁ
[7] S. Oudeyer, J.-F. Briere, V. Levacher, Progress in catalytic asymmetric proton-
ation, Eur. J. Org. Chem. 2014 (2014) 6103e6119, https://doi.org/10.1002/
ejoc.201402213.
[8] L.R. Liou, A.J. McNeil, A. Ramirez, G.E.S. Toombes, J.M. Gruver, D.B. Collum,
Lithium enolates of simple Ketones: structure determination using the
method of continuous variation, J. Am. Chem. Soc. 130 (2008) 4859e4868,
https://doi.org/10.1021/ja7100642.
[9] W.P. Weber, Preparation of silyl enol ethers, in: W.P. Weber (Ed.), Silicon
Reagents for Organic Synthesis, Springer, Berlin, Heidelberg, 1983,
pp. 255e272, https://doi.org/10.1007/978-3-642-68661-0_16.
[10] D. Seebach, Structure and reactivity of lithium enolates. From pinacolone to
selective C-alkylations of peptides. Difficulties and opportunities afforded by
complex structures, Angew. Chem. Int. Ed. 27 (1988) 1624e1654, https://
doi.org/10.1002/anie.198816241.
[11] M. Perez, M. Fananas-Mastral, P.H. Bos, A. Rudolph, S.R. Harutyunyan,
B.L. Feringa, Catalytic asymmetric carbonecarbon bond formation via allylic
alkylations with organolithium compounds, Nat. Chem. 3 (2011) 377e381,
https://doi.org/10.1038/nchem.1009.
Substrates: (R,R)-DACH (219 mg, 1.90 mmol), 3-(tert-butyl)-2-
hydroxy-5-methoxybenzaldehyde (synthesis described in Sup-
porting Information) (800 mg, 3.8 mmol); Overall isolated yield:
724 mg, 76% as a pale brown solid m.p. 120e125 ꢁC. Formula:
C
30H46N2O4, calculated molecular weight: 498.71 g/mol; ESI-MS:
ꢀ
~
ꢀ
[MþH] m/z ¼ 499; 1H NMR (400 MHz, CDCl3)
d: 10.41 (s, 2H),
6.79 (d, J ¼ 3.1 Hz, 7H), 6.43 (d, J ¼ 3.0 Hz, 7H), 3.96 (dd, J ¼ 49.6,
13.6 Hz, 14H), 3.74 (s, 21H), 2.44e2.36 (m, 7H), 2.16 (d, J ¼ 12.9 Hz,
7H), 1.69 (dd, J ¼ 5.4, 3.2 Hz, 8H), 1.36 (s, 65H), 1.24e1.09 (m, 16H)
[12] C.-J. Li, Organic reactions in aqueous media with a focus on CarbonꢀCarbon
bond Formations:
A decade update, Chem. Rev. 105 (2005) 3095e3166,
ppm; 13C NMR (100 MHz, CDCl3)
d: 151.7, 150.7, 138.1, 123.4, 112.7,
https://doi.org/10.1021/cr030009u.
[13] H. Kosugi, K. Hoshino, H. Uda, -Hydroxy sulfoxide derivatives as a powerful
20
110.9, 59.9, 55.7, 50.6, 34.79, 30.9, 29.4, 24.3 ppm; [
1.0, CHCl3).
a
]
¼ ꢀ14.3 (c
b
D
chiral protonating reagent, phosphorus, sulfur, and silicon and the related
elements 95 (1994) 401e402, https://doi.org/10.1080/10426509408034251.
ꢀ
ꢀ
[14] G. Asensio, P. Aleman, A. Cuenca, J. Gil, M. Medio-Simon, Efficient asymmetric
protonation of enolates with readily accessible chiral -sulfinyl alcohols,
Declaration of competing interest
a
Tetrahedron: Asymmetry
S0957-4166(98)00426-1.
[15] G. Asensio, P.A. Aleman, L.R. Domingo, M. Medio-Simon, Remarkable effect of
9
(1998) 4073e4078, https://doi.org/10.1016/
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Highlights
ꢀ
lithium bromide in the enantioselective protonation with a-sulfinyl alcohols,
Tetrahedron Lett. 39 (1998) 3277e3280, https://doi.org/10.1016/S0040-
4039(98)00469-9.
[16] K. Fuji, T. Kawabata, A. Kuroda, T. Taga, Enantioselective protonation of eno-
lates: novel chiral proton sources and remarkable effects of the countercation,
J. Org. Chem. 60 (1995) 1914e1915, https://doi.org/10.1021/jo00112a002.
[17] E. Boyd, G.S. Coumbarides, J. Eames, A. Hay, R.V.H. Jones, R.A. Stenson,
M.J. Suggate, Reversal of enantioselectivity on protonation of enol(ate)s
derived from 2-methyl-1-tetralone using C2-symmetric sulfonamides, Tetra-
ꢃDesymmetrization of racemic ketones has been achieved with
75% of ee.
ꢃCatalytic amount of salan provides better result in enantiose-
lective protonation than stoichiometric amount.
hedron
Lett.
45
(2004)
9465e9468,
https://doi.org/10.1016/
10

D. Łowicki, J. Watral, M. Jelecki et al.
Tetrahedron 86 (2021) 132085
j.tetlet.2004.10.087.
with non-planar ONNO ligands: salen, salalen and salan, Chem. Commun.
(2007) 3619e3627, https://doi.org/10.1039/B701431G.
[41] L.-S. Zheng, Y.-L. Wei, K.-Z. Jiang, Y. Deng, Z.-J. Zheng, L.-W. Xu, Enantiose-
[18] G.S. Coumbarides, J. Eames, J.E.W. Scheuermann, K.F. Sibbons, M.J. Suggate,
M. Watkinson, Enantioselective protonation of a lithium enolate derived from
2-Methyl-1-tetralone using chiral sulfonamides, Bull. Chem. Soc. Jpn. 78
(2005) 906e909, https://doi.org/10.1246/bcsj.78.906.
[19] A. Yanagisawa, H. Inanami, H. Yamamoto, Chiral aminoborane as a chiral
proton source for asymmetric protonation of lithium enolates derived from 2-
arylcycloalkanones, Chem. Commun. (1998) 1573e1574, https://doi.org/
10.1039/A803756F.
lective fluorination of b-ketoamides catalyzed by Ar-BINMOL-derived salan-
copper complex, Adv. Synth. Catal. 356 (2014) 3769e3776, https://doi.org/
10.1002/adsc.201400603.
[42] J.L. Jat, S.R. De, G. Kumar, A.M. Adebesin, S.K. Gandham, J.R. Falck, Regio- and
enantioselective catalytic monoepoxidation of conjugated dienes: synthesis of
chiral allylic cis-epoxides, Org. Lett. 17 (2015) 1058e1061, https://doi.org/
10.1021/acs.orglett.5b00281.
[43] Z. Wang, J. He, Y. Mu, Synthesis of chiral salan ligands with bulky substituents
and their application in Cu-catalyzed asymmetric Henry reaction,
J. Organomet. Chem. 928 (2020) 121546, https://doi.org/10.1016/
j.jorganchem.2020.121546.
[20] H. Fujihara, K. Tomioka, Asymmetric protonation of lithium enolate using 5-
substituted pyrrolidin-2-one as a chiral proton source, J. Chem. Soc., Perkin
Trans. 1 (1999) 2377e2381, https://doi.org/10.1039/A901581G.
ꢀ
[21] A. Cuenca, M. Medio-Simon, G.A. Aguilar, D. Weibel, A.K. Beck, D. Seebach,
Highly enantioselective protonation of the 3,4-dihydro-2- methylnaphthalen-
1(2H)-one Li-enolate by TADDOLs, Helv. Chim. Acta 83 (2000) 3153e3162,
https://doi.org/10.1002/1522-2675(20001220)83:12<3153::AID-
HLCA3153>3.0.CO;2-R.
[44] J. Gao, R.A. Zingaro, J.H. Reibenspies, A.E. Martell, Direct observation of
enantioselective synergism at trimetallic centers, Org. Lett.
6 (2004)
2453e2455, https://doi.org/10.1021/ol049156k.
[22] S. France, D.J. Guerin, S.J. Miller, T. Lectka, Nucleophilic chiral amines as cat-
alysts in asymmetric synthesis, Chem. Rev. 103 (2003) 2985e3012, https://
doi.org/10.1021/cr020061a.
[23] L.-W. Xu, J. Luo, Y. Lu, Asymmetric catalysis with chiral primary amine-based
organocatalysts, Chem. Commun. (2009) 1807e1821, https://doi.org/10.1039/
B821070E.
[45] B.M. Trost, C.-I. (Joey) Hung, G. Mata, Dinuclear metal-ProPhenol catalysts:
development and synthetic applications, Angew. Chem. Int. Ed. 59 (2020)
4240e4261, https://doi.org/10.1002/anie.201909692.
ꢀ
[46] V.J. Lillo, J. Mansilla, J.M. Saa, Organocatalysis by networks of cooperative
hydrogen bonds: enantioselective direct mannich addition to preformed
arylideneureas, Angew. Chem. Int. Ed. 55 (2016) 4312e4316, https://doi.org/
10.1002/anie.201511555.
[24] T. Yasukata, K. Koga, Enantioselective protonation of achiral lithium enolates
using
a
chiral amine in the presence of lithium bromide, Tetrahedron:
[47] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
J.R. Cheeseman, G. Scalmani, V. Barone, G.A. Petersson, H. Nakatsuji, X. Li,
M. Caricato, A. Marenich, J. Bloino, B.G. Janesko, R. Gomperts, B. Mennucci,
H.P. Hratchian, J.V. Ortiz, A.F. Izmaylov, J.L. Sonnenberg, D. Williams-Young,
F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson,
D. Ranasinghe, V.G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, K. Throssell, J.A. Montgomery Jr., 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, J.M. Millam, M. Klene, C. Adamo, R. Cammi,
J.W. Ochterski, R.L. Martin, K. Morokuma, O. Farkas, J.B. Foresman, D.J. Fox,
Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT, 2016. https://
gaussian.com/citation/. (Accessed 10 July 2020).
Asymmetry 4 (1993) 35e38, https://doi.org/10.1016/S0957-4166(00)86011-
5.
[25] P. Riviere, K. Koga, An approach to catalytic enantioselective protonation of
prochiral lithium enolates, Tetrahedron Lett. 38 (1997) 7589e7592, https://
doi.org/10.1016/S0040-4039(97)01790-5.
[26] J. Eames, N. Weerasooriya, Investigations into the enantioselective proton-
ation of enolates derived from 2-methyl-1-tetralone using a chiral diamine
ligand, Tetrahedron Lett. 41 (2000) 521e523, https://doi.org/10.1016/S0040-
4039(99)02109-7.
[27] T. Poisson, V. Dalla, F. Marsais, G. Dupas, S. Oudeyer, V. Levacher, Organo-
catalytic enantioselective protonation of silyl enolates mediated by cinchona
alkaloids and
7090e7093, https://doi.org/10.1002/anie.200701683.
a latent source of HF, Angew. Chem. Int. Ed. 46 (2007)
[28] A. Claraz, G. Landelle, S. Oudeyer, V. Levacher, Asymmetric organocatalytic
protonation of silyl enolates catalyzed by simple and original betaines derived
from cinchona alkaloids, Eur. J. Org. Chem. 2013 (2013) 7693e7696, https://
doi.org/10.1002/ejoc.201301345.
[48] W.J. Hehre, R. Ditchfield, J.A. Pople, Selfdconsistent molecular orbital
methods. XII. Further extensions of Gaussiandtype basis sets for use in mo-
lecular orbital studies of organic molecules, J. Chem. Phys. 56 (1972)
2257e2261, https://doi.org/10.1063/1.1677527.
[29] J. Gil, M. Medio-Simon, G. Mancha, G. Asensio, Enantioselective protonation of
the lithium transient enolate of2-methyltetralone with 2-sulfinyl alcohols,
Eur. J. Org. Chem. 2005 (2005) 1561e1567, https://doi.org/10.1002/
ejoc.200400812.
[30] K. Mitsuhashi, R. Ito, T. Arai, A. Yanagisawa, Catalytic asymmetric protonation
of lithium enolates using amino acid derivatives as chiral proton sources, Org.
Lett. 8 (2006) 1721e1724, https://doi.org/10.1021/ol0603007.
[31] C.H. Cheon, H. Yamamoto, A brønsted acid catalyst for the enantioselective
protonation reaction, J. Am. Chem. Soc. 130 (2008) 9246e9247, https://
doi.org/10.1021/ja8041542.
[32] K. Ishihara, S. Nakamura, M. Kaneeda, H. Yamamoto, First example of a highly
enantioselective catalytic protonation of silyl enol ethers using a novel lewis
acid-assisted brønsted acid system, J. Am. Chem. Soc. 118 (1996)
12854e12855, https://doi.org/10.1021/ja962414r.
[33] S. Nakamura, M. Kaneeda, K. Ishihara, H. Yamamoto, Enantioselective pro-
tonation of silyl enol ethers and ketene disilyl acetals with lewis acid-assisted
chiral brønsted Acids: reaction scope and mechanistic insights, J. Am. Chem.
Soc. 122 (2000) 8120e8130, https://doi.org/10.1021/ja001164i.
[34] M. Sugiura, T. Nakai, Asymmetric catalytic protonation of silyl enol ethers
with chiral palladium complexes, Angew. Chem. Int. Ed. 36 (1997)
2366e2368, https://doi.org/10.1002/anie.199723661.
[35] S.C. Marinescu, T. Nishimata, J.T. Mohr, B.M. Stoltz, Homogeneous Pd-
catalyzed enantioselective decarboxylative protonation, Org. Lett. 10 (2008)
1039e1042, https://doi.org/10.1021/ol702821j.
[36] M. Morita, L. Drouin, R. Motoki, Y. Kimura, I. Fujimori, M. Kanai, M. Shibasaki,
Two methods for catalytic generation of reactive enolates promoted by a
chiral poly Gd complex: application to catalytic enantioselective protonation
reactions, J. Am. Chem. Soc. 131 (2009) 3858e3859, https://doi.org/10.1021/
ja9005018.
[49] A.D. Becke, Density-functional thermochemistry. III. The role of exact ex-
change, J. Chem. Phys. 98 (1993) 5648e5652, https://doi.org/10.1063/
1.464913.
[50] C. Lee, W. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-en-
ergy formula into a functional of the electron density, Phys. Rev. B 37 (1988)
785e789, https://doi.org/10.1103/PhysRevB.37.785.
[51] S.H. Vosko, L. Wilk, M. Nusair, Accurate spin-dependent electron liquid cor-
relation energies for local spin density calculations: a critical analysis, Can. J.
Phys. 58 (1980) 1200e1211, https://doi.org/10.1139/p80-159.
[52] A. Yanagisawa, T. Sugita, K. Yoshida, Enantioselective protonation of alkenyl
trifluoroacetates catalyzed by chiral tin methoxide, Chem. Eur J. 19 (2013)
16200e16203, https://doi.org/10.1002/chem.201302975.
[53] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor,
M. Towler, J. van de Streek, Mercury: visualization and analysis of crystal
structures, J. Appl. Crystallogr. 39 (2006) 453e457, https://doi.org/10.1107/
S002188980600731X.
[54] K.P. Bryliakov, E.P. Talsi, Titanium-salan-catalyzed asymmetric oxidation of
sulfides and kinetic resolution of sulfoxides with H2O2 as the oxidant, Eur. J.
Org. Chem. 2008 (2008) 3369e3376, https://doi.org/10.1002/ejoc.200800277.
€ €
ꢀ
[55] T. Kylmala, N. Kuuloja, Y. Xu, K. Rissanen, R. Franzen, Synthesis of chlorinated
biphenyls by suzuki cross-coupling using diamine or diimine-palladium
complexes, Eur. J. Org. Chem. 2008 (2008) 4019e4024, https://doi.org/
10.1002/ejoc.200800119.
[56] K. Ishimaru, K. Ono, Y. Tanimura, T. Kojima, Novel chiral bisformamide-
promoted asymmetric allylation of benzaldehyde with allyltrichlorosilane,
Synth. Commun. 41 (2011) 3627e3634,
https://doi.org/10.1080/
00397911.2010.519841.
[57] A. Yeori, I. Goldberg, M. Shuster, M. Kol, Diastereomerically-specific zirconium
complexes of chiral salan Ligands: isospecific polymerization of 1-hexene and
4-Methyl-1-pentene and cyclopolymerization of 1,5-hexadiene, J. Am. Chem.
Soc. 128 (2006) 13062e13063, https://doi.org/10.1021/ja0647654.
[58] X. Xu, Y. Yao, Y. Zhang, Q. Shen, Synthesis, reactivity, and structural charac-
terization of sodium and ytterbium complexes containing new imidazolidine-
bridged bis(phenolato) ligands, Inorg. Chem. 46 (2007) 3743e3751, https://
doi.org/10.1021/ic0701054.
[59] R.C. Pratt, C.T. Lyons, E.C. Wasinger, T.D.P. Stack, Electrochemical and spec-
troscopic effects of mixed substituents in bis(phenolate)ecopper(II) galactose
oxidase model complexes, J. Am. Chem. Soc. 134 (2012) 7367e7377, https://
doi.org/10.1021/ja211247f.
[37] A. Yanagisawa, T. Touge, T. Arai, Enantioselective protonation of silyl enolates
catalyzed by
a Binap,AgF complex, Angew. Chem. Int. Ed. 44 (2005)
1546e1548, https://doi.org/10.1002/anie.200462325.
[38] S. Paladhi, Y. Liu, B.S. Kumar, M.-J. Jung, S.Y. Park, H. Yan, C.E. Song, Fluoride
anions in self-assembled chiral cage for the enantioselective protonation of
silyl enol ethers, Org. Lett. 19 (2017) 3279e3282, https://doi.org/10.1021/
acs.orglett.7b01429.
[39] H. Egami, T. Katsuki, Fe(salan)-Catalyzed asymmetric oxidation of sulfides
with hydrogen peroxide in water, J. Am. Chem. Soc. 129 (2007) 8940e8941,
https://doi.org/10.1021/ja071916þ.
[40] K. Matsumoto, B. Saito, T. Katsuki, Asymmetric catalysis of metal complexes
11