Proline-Histidine Dipeptide: A Suitable Template for Generating Ion-Tagged Organocatalysts for the Asymmetric Aldol Reaction

Article abstract of DOI:10.1055/a-1477-4871

Proline-histidine dipeptide laid the foundation for the construction of three new ion-tagged organocatalysts, utilising the imidazole moiety of histidine for generating the quaternary species. A brief comparative investigation of the catalysts in the enam

Full text of DOI:10.1055/a-1477-4871

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–K
paper
A
en
H. Inani et al.
Paper
Synthesis
Proline-Histidine Dipeptide: A Suitable Template for Generating
Ion-Tagged Organocatalysts for the Asymmetric Aldol Reaction
Heena Inani◊a
Avtar Singh◊a
Meeta Bhatia
Kiran Kumaria
Alexander S. Kucherenkob
Sergei G. Zlotin*b
Srinivasan Easwar*a
C-1 (5 mol%)
Ar'CO2H, H2O, 25 °C
O
O
OH
Ar
O
COOMe
Bn
R'
ArCHO
N
R
N
R
NH
C-1
Yields up to 99%
18 examples
H
R'
N
Bn
Tf2N
d.r. up to 99:1
ee up to 98%
a Department of Chemistry, School of Chemical Sciences and
Pharmacy, Central University of Rajasthan, NH-8, Bandarsindri,
Distt. Ajmer, Rajasthan 305817, India
easwar.srinivasan@curaj.ac.in
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy
of Sciences, 119991 Moscow, Russian Federation
◊ These authors contributed equally
Corresponding Authors
Received: 12.11.2020
Accepted after revision: 08.04.2021
Published online: 08.04.2021
may be anticipated, leading to the observed enhancement
in stereoselectivity. The first report of an imidazolium-
tagged proline was by Miao and Chan, who demonstrated
its use in asymmetric aldol addition.4 Following this, signif-
icant contributions have come from the groups of Wang,
Zlotin, Trombini and Lombardo, Liebscher, Cheng and Juar-
isti, to name a few.5–11 An added advantage of ion-tagged
catalysts is the ease of tuning their hydrophilicity/lipo-
philicity by varying the counterion, a feature that is crucial
for the development of aqueous-based protocols. This has
assumed significance owing to: (i) the obvious benefits of
using water as a solvent, and (ii) the intriguing role that wa-
ter has often played in improving the outcome of organo-
catalytic processes.12,13 The research groups of Zlotin6 and
Trombini and Lombardo7 in particular have come up with
several ways of incorporating an ion tag, predominantly
onto proline, to build recyclable catalysts that perform ex-
cellently under aqueous conditions. The former’s ion-
tagged prolinamides6c,6e–h and the trans- and cis-hydroxy-
proline-derived ion-tagged catalysts developed by the lat-
ter7a,d are standout examples of catalysts that have proven
proficient in mediating the asymmetric aldol reaction in
the presence of water.
On a parallel note, it is surprising that peptides, which
form an integral part of living systems and fulfil a multi-
tude of functions, have not been extensively explored as
asymmetric organocatalysts,14 although recent literature
suggests an increase in the use of di- and tripeptide cata-
lysts for asymmetric aldol addition, conjugate addition, the
Stetter and Morita–Baylis–Hillman reactions, hydrogena-
tions, cyanations and numerous other transformations.15
Peptidic catalysts often have unique features such as high
chemoselectivity paired with broad substrate scope, site
selectivity over long distances, and chemical robustness.
DOI: 10.1055/a-1477-4871; Art ID: ss-2020-n0153-op
Abstract Proline-histidine dipeptide laid the foundation for the con-
struction of three new ion-tagged organocatalysts, utilising the imidaz-
ole moiety of histidine for generating the quaternary species. A brief
comparative investigation of the catalysts in the enamine-mediated di-
rect asymmetric aldol reaction brought out their contrasting features,
particularly under aqueous conditions. The best among them was also
utilised in preparing some derivatives and effecting a desymmetrisa-
tion.
Key words dipeptide, ion tag, proline, histidine, asymmetric catalysis,
aldol reaction, aqueous reactions
In the realm of organocatalysis, the advantages of im-
mobilisation of the proline scaffold with an ion tag are re-
nowned.1 The strategy has its genesis in the profitable use
of ionic liquids as solvents in proline-catalysed reactions2
and the successful application of solid-supported ionic liq-
uid phases.3 This triggered the development of new amino
catalysts bearing a quaternary ammonium ion that have
been employed with great success in typical organocatalyt-
ic transformations. Asymmetric aldol addition has been a
huge beneficiary of the ion-tagging strategy; considerable
rate acceleration of the enamine route to aldol adducts has
been achieved, along with exceptional stereocontrol. The
positive influence of the ion tag could be attributed to a
host of factors: with regard to the enhanced efficiency, re-
searchers have concurred upon a better electrostatic stabil-
isation of charged transition states along the path that leads
to the iminium ion intermediate from an uncharged reac-
tant. A high affinity of the ion tag to other ionic moieties
could also be hypothesised, resulting in a more structured
reaction domain; consequently, a ‘tighter’ transition state
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Inani et al.
Paper
Synthesis
Besides, the more structured asymmetric domain of a pep-
tide could also contribute to greater stereocontrol. Owing to
these benefits, peptides are also being explored as candi-
dates for immobilisation, as the research community strives
for the design of ever more efficient catalysts and sustain-
able protocols.16 A majority of known immobilised versions
of peptidic organocatalysts are based on polymer sup-
ports;17 in this context, an immobilisation strategy of ion-
tagging, apart from the beneficial features discussed above,
could allow for a better loading capacity than solid (poly-
meric) supports. However, only a couple of recent reports
by Obregon-Zuniga and Juaristi11 and Zlotin and co-work-
ers6i stand out as examples of this strategy. The former syn-
thesised a proline-based dipeptide, tagged with an imidaz-
olium-bearing side chain at the 4-position of proline, and
employed it with considerable success in the direct asym-
metric aldol reaction in aqueous medium (Scheme 1, I).11
Zlotin and co-workers, on the other hand, used a 4-OH-Pro-
Val tagged to an imidazolium, bearing PF6– as the counteri-
on, also to carry out an asymmetric aldol reaction in an
aqueous environment (Scheme 1, II).6i It is worth noting
that the ionic moiety in both the above catalysts did not
form a part of the dipeptide substructure, necessitating a
linker to tag it to the catalyst framework. We were curious
to find out if the ion tag could be integrated into a dipeptide
framework, thereby circumventing the use of the linker,
without compromising on the efficiency of the resultant
catalyst. Proline, the preeminent catalyst, would form one
half of the proposed dipeptide, whereas the ion tag would
evidently be borne by the other amino acid. The amino ac-
ids bearing a basic side chain present an interesting possi-
bility in this context, since an ionic species can be produced
by a simple protonation.18 We chose histidine, which bears
the imidazole moiety as a suitable platform for generating
an ion tag; we envisaged that marrying the simplicity of
ion-tagging in histidine to the catalytic superiority of pro-
line would lead to a versatile ion-tagged catalyst prototype,
depicted by 1 in Scheme 1. Apart from the ease of introduc-
ing an ion tag, the imidazole moiety in 1 would also allow
for structural modifications to fine-tune the solubility and
lipophilic properties of the catalyst. Thus, based on this
strategy, we synthesised a series of proline-histidine dipep-
tide derived ion-tagged catalysts and studied them in
asymmetric aldol addition under aqueous conditions. The
results obtained from these efforts are described in the fol-
lowing sections.
Previous work: Ionic moiety tagged to the dipeptide using a linker
Obregon-Zuniga & Juaristi (Ref. 11)
R3CHO
I (5 mol%)
O
O
OH
R3
O
Ph
R1
R1
O
p-NBA (5 mol%)
H2O (100 eq.), rt
R2
5
R2
N
N
OMe
O
NH
H
O
N
16 examples; yields up to 94%
PF6
I
d.r. up to 98:2; ee up to 94%
Zlotin & co-workers (Ref. 6i)
O
O
OH
Ar
Ar
O
O
Pri
II (10 mol%)
O
H
N
N
4
H2O (100 eq.), rt
N
NH
X
H
Ph
O
X
N
O
7 examples; conversions up to 99%
d.r. up to 99:1; ee up to 98%
PF6
Me
II
This work: Ionic moiety incorporated within the dipeptide substructure
N
COOH
COOH
Catalytic
proficiency
Ease of
ion-tagging
N
H
HN
H2N
Proline
Histidine
O
R
COOR'
N
+
N
NH
H
N
X–
1
R
Scheme 1 Ion-tagged dipeptide organocatalysts for direct asymmetric
aldol addition
check its effectiveness as an aminocatalyst. The technique
used for the generation of a quaternised species in the syn-
thesis of catalyst A-1 is a simple protonation. On the other
hand, synthesis of the ion-tagged catalysts B-1 and C-1 re-
quired an alkylative quaternisation protocol. To this end,
imidazole 3 was treated with excess benzyl bromide to de-
liver the dibenzylic imidazolium species 4 as a quaternary
bromide salt in good yield. It is evident from these brief re-
sults that the presence of the imidazole-bearing histidine
allows for a relatively easy quaternisation, either by a sim-
ple protonation or by alkylation, resulting in the incorpora-
tion of an ion tag. Further, metathesis of the bromide salt 4
with LiNTf2 gave the bis(trifluoromethanesulfonyl)imide
([NTf2]–) salt 5, which was converted into B-1 upon depro-
tection of the carbamate. Catalyst B-1 is an interesting
bisquaternary species having two counteranions of con-
trasting genesis and character, namely the hydrophilic tri-
fluoroacetate ([CF3COO]–) as a consequence of protonation,
and the lipophilic [NTf2]– born out of an alkylative quaterni-
sation; a 19F NMR scan confirmed the presence of the two
distinct anions. The favourable assistance of the latter in
asymmetric aldol reactions under aqueous conditions has
been well documented. Lastly, the protonated moiety in B-1
was neutralised to afford C-1, a monoquaternary species
that bears only the lipophilic [NTf2]– as the counterion. Sig-
nificantly, unlike A-1 and B-1, catalyst C-1 boasts a free NH
group on the proline moiety, presumably a critical factor for
catalysis.
The synthesis of the proline-histidine dipeptide deriva-
tives was carried out as illustrated in Scheme 2. At the out-
set, coupling of L-histidine methyl ester dihydrochloride (2)
with Boc-L-proline under standard conditions afforded the
protected dipeptide 3.19 Cleaving the carbamate in 3 using
excess TFA delivered the first of the catalysts, the bis-TFA
salt A-1. The protonated proline nitrogen in A-1 is distinct
from a mere depiction of the parent amino acid in a zwitter-
ionic representation; it would therefore be interesting to
With the three catalysts possessing ion tags of varying
nature in hand, we embarked upon comparing their perfor-
mance in the direct asymmetric aldol reaction under aque-
ous conditions. A typical aldol reaction involving 4-nitro-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

C
H. Inani et al.
Paper
Synthesis
COOH
Boc
COOMe
NH2
O
O
N
COOMe
NH
COOMe
NH
TFA, 0 °C
N
N
N
Boc
HN
HN
H
2 h
(98%)
NMM, EDC·HCl
HOBt, THF
rt, 2 d (91%)
·2TFA
N
·2HCl
H
N
N
3
2
A-1
O
O
COOMe
COOMe
LiNTf2, CH2Cl2
BnBr (excess)
N
Boc
3
Bn
N
Boc
Bn
HN
HN
N
N
CH3CN, reflux
(81%)
rt, 15 h
(91%)
N
Bn
N
Bn
4
5
Br–
NTf2
TFA
rt, 2.5 h
CH2Cl2 (98%)
O
O
COOMe
HN
COOMe
NaHCO3
N
Bn
N
Bn
HN
H
N
H
N
H2O, rt
(90%)
·TFA
N
N
Bn
C-1
NTf2
NTf2
B-1
Bn
Scheme 2 Synthesis of the proline-histidine dipeptide derived catalysts
benzaldehyde (6a) and either cyclohexanone (7a) or ace-
tone (7b) as the donor ketone was used for study under
conditions that employed varying amounts of water, to ac-
count for the vastly different hydrophilic quotients of the
three catalysts and the possibility of altered results arising
from it. The results of these comparative studies are collect-
ed in Table 1. An initial reaction between 6a and 7a was car-
ried out using 10 mol% of the bis-TFA salt A-1 in the ab-
sence of water. The results were not very encouraging; a
moderate yield of aldol 8a was obtained along with modest
enantio- and diastereoselectivity (Table 1, entry 1). The ad-
dition of water in the reaction unfortunately had a detri-
mental impact on the yield of the aldol, which worsened
upon increasing the quantity of water; there was not much
improvement in the stereoselectivity either (entries 2 and
3). On the other hand, catalyst B-1, having both hydrophilic
([CF3COO]–) and hydrophobic ([NTf2]–) counterions, gave a
much-improved yield of the aldol along with marginally
better stereoselectivity in a reaction without water. Unfor-
tunately, as with A-1, a drastic drop in the yield resulted
upon the addition of a small amount of water; interestingly
however, the diastereo- and enantioselectivity both re-
ceived a boost under these conditions, and 8a was obtained
in a 95:5 diastereomeric ratio and 95% optical purity (entry
5). The results with A-1 and B-1 reflect the fascinating wa-
ter–counterion interplay in aldol additions mediated by
ion-tagged systems. If one were to attempt to rationalise, in
an aqueous reaction, the highly hydrophilic bis(trifluoroac-
etate) A-1 presumably remains submerged in water, pre-
cluding any possible interaction with the lipophilic sub-
strates; not surprisingly, a steep drop in catalytic activity
ensues with increased quantities of water. On the other
hand, catalyst B-1, bearing two counterions of contrasting
nature, displays enhanced efficiency and selectivity; here,
the positive impact on the stereochemical outcome upon
addition of water, as with similar cases in the literature,
may be thought of as a result of the reaction occurring in
hydrophobic pockets that sequester the transition state
from water. If the counterion indeed plays such an instru-
mental role in influencing the reaction outcome, the mono-
ionic catalyst C-1 bearing just the hydrophobic [NTf2]–
counterion loomed as a potentially superior candidate.
Table 1 Investigating Catalysts A-1, B-1 and C-1 in Direct Asymmetric
Aldol Additiona
CHO
OH
O
O
Catalyst
(10 mol%)
R1
R1
R2
H2O, 8 h
R2
8a/p
O2N
O2N
7a: R1, R2 = -(CH2)4-
7b: R1 = CH3, R2 = H
6a
Entry Ketone Catalyst H2O (L) Yield (%)b 8a/p anti/sync anti ee (%)d
1
2
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7b
A-1
A-1
A-1
B-1
B-1
C-1
C-1
A-1
A-1
A-1
B-1
B-1
C-1
C-1
–
25
100
–
55
36
13
84
42
81
84
10
5
86:14
91:9
84:16
89:11
95:5
77:23
82:18
–
80
89
88
86
95
64
84
30
40
47
80
60
72
44
3
4
5
25
–
6
7
25
–
8
9
25
100
–
–
10
11
12
13
14e
trace
35
17
80
95
–
–
25
–
–
–
25
–
a Reaction conditions: 6a (1 mmol), 7a (5 eq.), rt (25–27 °C).
b Isolated yield.
c Determined by 1H NMR of the crude reaction mixture.
d Determined on the purified product by HPLC on a chiral stationary phase.
e Reaction was carried out for 6 h.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

D
H. Inani et al.
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Synthesis
Pleasingly, the use of C-1 instantly resulted in much better
yields of the aldol in reactions carried out in the absence as
well as in the presence of water (entries 6 and 7). Unfortu-
nately, the stereoselectivity values were rather disappoint-
ing, although a significant spike was observed in the aque-
ous reaction. In the next study, cyclohexanone was replaced
with the hydrophilic acetone (7b) as the donor. The dica-
tionic catalysts A-1 and B-1 once again performed poorly.
Using A-1 in the absence of water, a very poor yield of aldol
8p was obtained (entry 8), which diminished to negligible
levels upon addition of water (entries 9 and 10); the stereo-
chemical results were also rather disappointing through-
out. As expected, catalyst B-1 exhibited an improved per-
formance with respect to both efficiency and stereoselec-
tivity in corresponding reactions; the addition of water
again had an unfavourable effect, proving the limitations of
working with hydrophilic anions in aqueous organocataly-
sis (entries 11 and 12). In sharp contrast, further indica-
tions of the advantages of the lipophilic [NTf2]– counterion
were provided by the superior activity of the monoionic
catalyst C-1 in reactions with acetone; dramatic increase in
the yields were obtained in the absence as well as in the
presence of water, albeit with a huge drop in stereoselectiv-
ity for the latter (entries 13 and 14).
tural feature shared by all three catalysts. The COOH group
is known to play an important role in enhancing both the
efficiency and selectivity of proline-mediated aldol reac-
tions, and the addition of a Brønsted acid, where appropri-
ate, to enhance performance is a common practice.20 To this
end, we undertook further studies using catalyst C-1 in
combination with a Brønsted acid to check for any improve-
ment in the stereoselectivity as an upshot of the latter; the
results are collated in Table 2. It was pleasing to observe an
immediate improvement in the catalytic performance of C-
1 upon adding an equivalent amount of PhCOOH (10 mol%)
in the reaction of 6a with 7a, initially in the absence of wa-
ter; in particular, the spike in the enantioselectivity was
significant (Table 2, entry 1). The addition of water fur-
thered the advantage in terms of both efficiency and selec-
tivity (entry 2). To our delight, replacing PhCOOH with o-
fluorobenzoic acid (OFBA) in the presence of water resulted
in a marked enhancement; a near quantitative yield of aldol
8a was obtained in just 45 minutes, accompanied by a dias-
tereomeric ratio of 93:7 and 93% ee of the major adduct
(entry 3) and excellent results were obtained upon increas-
ing the amount of water (entries 4–6). The results were also
reproduced in a reaction using a large quantity of water,
namely ‘bulk’ water conditions, as it is termed (entry 6).
This is a significant result, since a catalyst that performs
equally well in the presence of ‘micro’ as well as ‘bulk’
quantities of water would certainly be of interest to explore
a variety of transformations. This noteworthy feature of C-1
Having established the superiority of C-1, our curiosity
was aroused by the disparity between its activity and ste-
reocontrol. We pondered whether the poor stereoselectivi-
ty could be attributed to the lack of a COOH group, a struc-
Table 2 Use of Brønsted Acid Additives in Conjunction with Catalyst C-1 for the Aldol Addition of Cyclohexanone (7a) to 4-Nitrobenzaldehyde (6a) in
the Presence of Watera
O
OH
O
OH
O
CHO
C-1, Additive
H2O
O2N
O2N
O2N
6a
7a
8a (anti-isomer)
8a' (syn-isomer)
Yield (%)b 8a
Entry
C-1 (mol%)
7a (eq.)
Additive/mol%
H2O (L)
Time (h)
anti/sync
anti ee (%)d
1
2
10
10
10
10
10
10
10
20
5
5
5
5
3
3
3
3
5
5
5
5
PhCOOH/10
PhCOOH/10
OFBA/10
OFBA/10
OFBA/10
OFBA/10
PhCOOH/10
OFBA/20
OFBA/5
–
25
6
95
99
79:21
85:15
93:7
87
92
93
93
93
93
94
94
93
96
91
6
3
25
0.75
1.5
1.5
1.5
6
99
4
100
450
900
900
25
98
94:6
5
99
93:7
6
99
93:7
7
96
89:11
91:9
8
0.33
2.5
2.5
9
~100
99
9
25
92:8
e
10
11
–
OFBA/5
25
68
88:12
89:11
1
OFBA/1
25
97
a Reaction conditions: 6a (0.5 mmol), rt (25–27 °C); OFBA: o-fluorobenzoic acid.
b Isolated yield.
c Determined by 1H NMR of the crude reaction mixture.
d Determined on the purified product by HPLC on a chiral stationary phase.
e 2nd run.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

E
H. Inani et al.
Paper
Synthesis
could also be observed in a reaction using PhCOOH as the
additive (entry 7). It would be pertinent here to refer to the
contrast in the use of the above acid additives in the context
of the TFA salts A-1 and B-1. The results not only reiterate
the importance of the nature of the counterion as discussed
earlier, but also the significance of the choice of the Brønst-
ed acid additive in the absence of a free COOH moiety in the
catalyst.21 Next, we varied the catalyst loading to further
test the efficacy of C-1. By doubling the loading, a near
quantitative yield of 8a could be obtained in just 20 min-
utes (entry 8), whereas a commendable result could also be
obtained with just 5 mol% (entry 9). Disappointingly, we
were unable to achieve much success with a recycling ex-
periment using these conditions (entry 10). Lastly, we were
pleased to obtain an excellent yield of aldol 8a using just 1
mol% of C-1 in reasonable time (entry 11). In all these cases,
it is worth noting that the stereoselectivity parameters re-
mained consistently very good. Finally, it may be added as a
footnote to the above comparative studies that the perfor-
mance of catalyst C-1 is also far superior to that of proline
itself, alluding to the already well-established benefits of
ion-tagged catalysts for the asymmetric aldol reaction.
The above results with catalyst C-1 were quite satisfy-
ing; we were especially pleased with the strategy of using
an easily generated dipeptide derivative to successfully en-
twine enamine catalysis under aqueous conditions with the
highly effective ion-tagging approach for asymmetric aldol
addition. Synthesis of various aldol adducts was not pur-
sued expansively, as the objective was rather to explore a
simple route to operational ion-tagged dipeptides and us-
ing them to illustrate the peculiar interplay between the
presence of water, the role of the counterion and the pres-
ence of a COOH group in enamine catalysis. Nonetheless,
the scope of the reaction was extended to some other sub-
strates under the deduced optimal conditions. Benzalde-
hydes bearing an electron-withdrawing group unsurpris-
ingly afforded excellent yields of the aldols in short reaction
times, along with good to excellent ee values (Table 3). The
reaction with pentafluorobenzaldehyde was particularly
rewarding as a 99% yield of the aldol was obtained in a rapid
reaction accompanied by near complete diastereoselectivity
and equally impressive enantiocontrol (entry 6), whereas
the heteroaromatic nicotinaldehyde also afforded excellent
results (entry 7). Reactions with other substituted benzal-
dehydes also fared impressively, including ortho-, meta- and
disubstituted ones (entries 8–12). It was pleasing to ob-
serve that C-1 was also able to deliver good yields of the al-
dols with two relatively poorer acceptors (entries 13–15),
although the stereochemical outcome with anisaldehyde in
particular was disappointing (entry 16). Next, using ace-
tone as the donor, an excellent yield of the aldol with 4-ni-
trobenzaldehyde was obtained, but with a modest enantio-
selectivity (Table 4, entry 1). Cyclopentanone proved to be
an exceptionally rapid donor, as the reaction was complete
in just 30 minutes, affording a near quantitative yield of the
aldol, but the diastereo- and enantioselectivity were rather
modest; interestingly though, in a reversal of the usual se-
lectivity, the syn-isomer was favoured over its anti-coun-
terpart (entry 2), which could be worth investigating more
deeply in the future.
Table 3 Asymmetric Aldol Addition of Cyclohexanone (7a) to Various
Aldehydes Catalysed by C-1a
OH
O
O
OH
O
C-1 (5 mol%)
Ar
Ar
ArCHO
OFBA (5 mol%)
H2O (25 µL), rt
6b–o
7a (5 eq.)
8b–o
8b'–o'
Entry Ar
Time (h) Yield (%)b anti/sync anti ee (%)d
1
2
3e
4
5
6
7
8
9
4-CNC6H4 (8b)
4-CF3C6H4 (8c)
4-CF3C6H4 (8c)
4-BrC6H4 (8d)
4-ClC6H4 (8e)
C6F5 (8f)
5
99
99
99
83
90
99
95
99
81
91
98
96
91
99
85
58
85:15
86:14
90:10
89:11
80:20
>99:1
93:7
88
89
94
93
89
98
94
97
90
91
86
93
69
80
60
36
5
3
5
7
2
3-pyridyl (8g)
2-NO2C6H4 (8h)
2-ClC6H4 (8i)
3-NO2C6H4 (8j)
3-ClC6H4 (8k)
4-Cl-3-NO2C6H3 (8l)
C6H5 (8m)
3
Table 4 Asymmetric Aldol Addition of Different Donors to 4-Nitro-
benzaldehyde (6a) Catalysed by C-1a
4
92:8
8
93:7
CHO
OH
O
O
10
2.5
93:7
C-1 (5 mol%)
R2
R1
R1
OFBA (5 mol%)
H2O (25 µL), rt
11
24
88:12
91:9
R2
8p,q
7b,c
5 eq.
O2N
NO2
12
2
18
16
24
36
6a
13
81:19
85:15
70:30
74:26
14e
15e
16e
C6H5 (8m)
Entry
R1, R2
Time (h)
Yield (%)b anti/sync ee (%)d
4-MeC6H4 (8n)
4-MeOC6H4 (8o)
1
2
CH3, H (8p)
-(CH2)3- (8q)
5
95
99
–
65
70
0.5
34:66
a All reactions were performed on 0.5 mmol scale of aldehyde; OFBA:
o-fluorobenzoic acid.
a All reactions were performed on 0.5 mmol scale of aldehyde; OFBA: o-flu-
orobenzoic acid.
b Isolated yield.
b Isolated yield.
c Determined by 1H NMR of the crude reaction mixture.
d Determined on the purified product by HPLC on a chiral stationary phase.
e 10 mol% catalyst was used.
c Determined by 1H NMR of the crude reaction mixture.
d Determined on the purified product by HPLC on a chiral stationary phase.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

F
H. Inani et al.
Paper
Synthesis
To further explore the efficacy of C-1, we undertook the
desymmetrisation of 4-methylcyclohexanone (9) by aldol
addition. This is a challenging yet powerful reaction that
can give rise to four possible diastereomeric product pairs.21
To our delight, 5 mol% of catalyst C-1 mediated an efficient
desymmetrisation of 9 in a reaction with 6a, and delivered
aldol 10 in excellent yield accompanied by good levels of
both diastereo- and enantioselectivity (Scheme 3).
Chemicals and solvents were purchased from commercial suppliers
or purified by standard techniques. Merck 60 F254 precoated silica gel
plates were used for TLC and compounds were visualised by irradia-
tion with UV light and/or by treatment with a solution of KMnO4 fol-
lowed by heating. Column chromatography was performed using sili-
ca gel of mesh 60–120/100–200, procured from Merck. 1H and 13C
NMR spectra were recorded on a Bruker Avance 500 MHz and a JEOL
ECS 400 MHz NMR spectrometers. Mass spectra were obtained using
a HRMS-ESI-Q-time-of-flight LC-MS instrument (Synapt G2, Waters).
Chiral HPLC studies were carried out on a Shimadzu LC-2010CHT
HPLC system. Cyclohexanone, acetone, benzaldehyde and pyridine-3-
/pyridine-4-carboxaldehyde were distilled before use. Commercial
samples of all the other substrates were used without any purifica-
tion.
O
O
OH
CHO
C-1 (5 mol%)
OFBA (5 mol%)
H2O (25 µL), rt, 3 h
O2N
NO2
6a
10 (96% yield)
9 (5 eq.)
d.r. 88:12:0:0; ee 88%
Proline-Histidine Dipeptide Derivative 319
Scheme 3 Desymmetrisation of 4-methylcyclohexanone by aldol addi-
tion mediated by C-1
To a stirred, heterogeneous mixture of N-(tert-butoxycarbonyl)-L-
proline (3.22 g, 15 mmol), 1-hydroxybenzotriazole hydrate (1.77 g, 13
mmol) and L-histidine methyl ester dihydrochloride (2; 3.02 g, 12.5
mmol) in THF (30 mL) was added N-methylmorpholine (2.25 mL, 25
mmol). The resulting mixture was cooled to 0 °C and N-(3-dimethyl-
aminopropyl)-N′-ethylcarbodiimide hydrochloride (2.58 g, 12.5
mmol) was added. The reaction mixture was then allowed to stir in an
ice bath for 2 h, following which it was allowed to warm to rt and
stirred for a further 48 h. The reaction mixture was then cooled to 0
°C and stirred for 30 min. The solid urea formed was filtered off and
the filtrate was concentrated under reduced pressure. The crude resi-
due was dissolved in CH2Cl2 and washed with brine, saturated NaH-
CO3 and brine once again. The organic phase was dried (Na2SO4), fil-
tered and concentrated in vacuo to afford 3 (4.2 g, 91%) as a transpar-
ent yellow sticky compound. The crude product was used as such
without further purification for the next step.
Lastly, a transition state for this dipeptide-mediated al-
dol addition may be proposed as shown in Figure 1, depict-
ing a possibly complex hydrogen-bonded network involving
the aldehyde, benzoic acid and the counterion on the cata-
lyst.22 The favourable addition of the enamine to the Re-face
of the aldehyde has been illustrated, the latter presumably
activated by hydrogen-bonding to the Brønsted acid addi-
tive. The electrostatic stabilisation of such charge-distribut-
ed polar transition states by the presence of an ionic tag has
been well-established in combined experimental and theo-
retical studies by Trombini and Bottoni and co-workers.7,23
[]D25 +80.7 (c 0.51, CHCl3).
IR (neat): 3264, 1665, 1390 cm–1
.
O
N
O
CF3
O
N
O
O
S
F3C
O
S
F3C
Bn
Bn
S
S CF3
O
O
N
N
O
O
N
N
Bn
1H NMR (500 MHz, CDCl3):  = 7.52 (d, J = 19.0 Hz, 1 H), 6.92 (bs, 1 H),
6.75 (d, J = 17.0 Hz, 1 H), 4.79 (s, 1 H), 4.14 (s, 1 H), 3.69 (s, 3 H), 3.51–
3.59 (m, 1 H), 3.40–3.49 (m, 1 H), 3.29–3.37 (m, 1 H), 3.11–3.20 (m, 1
H), 2.42 (bs, 1 H), 2.02–2.20 (m, 2 H), 1.80–1.91 (m, 2 H), 1.48 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 172.09, 171.03, 155.17, 135.73,
135.31, 80.79, 66.92, 61.08, 60.54, 55.42, 53.21, 52.64, 47.22, 46.43,
29.69, 28.49, 24.73.
Bn
N
N
H
H
N
N
H
H
O
O
O
O
Ph
MeO2C
MeO2C
Ar
Ph
O
H
O
Ar
H
Addition to the Re-face (favoured)
Addition to the Si-face (disfavoured)
Figure 1 Plausible transition states for asymmetric aldol addition me-
diated by C-1
HRMS (ESI): m/z [M + H]+ calcd for C17H27N4O5: 367.1976; found:
367.1972.
Thus, a thoughtfully chosen dipeptide provided a suit-
able platform to combine the exceptional catalytic profi-
ciency of proline and the well-established beneficial effects
of incorporating an ion tag in enamine-mediated direct
asymmetric aldol addition. In the process, the endeavour
provided a glimpse into the potential of ion-tagged dipep-
tides, minimally explored to date, as efficient catalysts in
aqueous medium. This could open up an avenue for explor-
ing more ion-tagged small peptides for mediating asym-
metric transformations in water. The results also provide
another illustration of the interesting interplay between
the lipophilic/hydrophilic nature of the ion tag and the
presence of water in enamine-mediated aldol additions.
Catalyst A-1
To dipeptide derivative 3 (500 mg, 1.36 mmol), TFA (10 mL) was add-
ed and the mixture was stirred in an ice bath. Upon consumption of
the starting material (~2 h), the reaction mixture was concentrated
under reduced pressure and the residue was dried under vacuum to
afford bis(trifluoroacetate) A-1 (354 mg, 98%) as a transparent light-
brown sticky compound. No further purification was required and A-
1 was as such for the catalysis study.
[]D25 +18.6 (c 0.86, CHCl3).
IR (neat): 3133, 1660, 1347 cm–1
1H NMR (500 MHz, D2O):  = 8.44 (s, 1 H), 7.13 (s, 1 H), 4.65–4.68 (m,
1 H), 4.15–4.23 (m, 1 H), 3.57 (s, 3 H), 3.14–3.24 (m, 4 H), 3.01–3.09
(m, 1 H), 2.19–2.31 (m, 1 H), 1.79–1.92 (m, 3 H).
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

G
H. Inani et al.
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Synthesis
13C NMR (125 MHz, D2O):  = 171.51, 169.53, 163.04, 162.75, 162.45,
162.18, 133.47, 128.26, 117.34, 117.08, 115.03, 63.75, 59.46, 53.21,
53.08, 52.04, 48.76, 46.41, 29.56, 25.70, 23.51.
Catalyst B-1
To a solution of bis(trifluoromethanesulfonyl)imide 5 (1.9 g, 2.29
mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The resulting mixture
was allowed to stir at rt until complete consumption of the starting
material (~2 h). The reaction mixture was then concentrated under
reduced pressure, and the residue was washed with Et2O (3 × 2 mL)
and dried under vacuum to afford B-1 (1.88 g, 98%) as a transparent
light-brown sticky solid. The obtained compound was deemed to be
of sufficient purity for the catalysis study.
19F NMR (470 MHz, D2O):  = –75.72.
+
HRMS (ESI): monocationic part: m/z [M]+ calcd for C12H19N4O3
:
267.1452; found: 267.0896.
Bromide Salt 4
To a stirred heterogeneous mixture of dipeptide derivative 3 (1.388 g,
3.79 mmol) and NaHCO3 (12.896 g, 15.35 mmol) in CH3CN (10 mL)
was added BnBr (2.26 mL, 18.95 mmol) and the reaction mixture was
refluxed for 16 h. The mixture was then allowed to cool to rt, filtered
and the filtrate was concentrated under reduced pressure. The crude
residue was washed with Et2O (5 × 2 mL) to remove the excess BnBr,
dissolved in H2O (5 mL) and washed with Et2O (2 × 2 mL) again. The
aqueous layer was then extracted with CH2Cl2 (3 × 15 mL). The com-
bined organic layer was dried (Na2SO4) and concentrated under re-
duced pressure to afford the corresponding quaternised bromide salt
4 (1.92 g, 81%) as a white solid; no further purification was required.
[]D25 –12.68 (c 0.56, CHCl3).
IR (neat): 3392, 1688, 1320 cm–1
.
1H NMR (500 MHz, CDCl3):  = 10.41 (s, 1 H), 8.24 (d, J = 8.43 Hz, NH),
8.16 (s, 1 H), 7.24–7.46 (m, 10 H), 5.28–5.32 (m, 4 H), 4.87 (s, 1 H),
4.52 (s, 1 H), 3.93 (bs, NH), 3.74 (s, 3 H), 3.39–3.55 (m, 2 H), 3.15–3.21
(m, 2 H), 2.49 (s, 1 H), 2.01–2.15 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 169.53, 168.83, 161.91, 134.96,
132.20, 131.55, 131.14, 129.73, 129.59, 128.87, 128.20, 122.13,
120.91, 118.36, 59.84, 53.79, 53.24, 51.42, 50.62, 46.67, 29.44, 25.45,
24.41.
Mp 72 °C; []D25 –17.18 (c 0.36, CHCl3).
19F NMR (234 MHz, CDCl3):  = –75.50, –78.72.
HRMS (ESI): monocationic part: m/z [M]+ calcd for C26H31N4O3
IR (neat): 3433, 1684, 1340 cm–1
.
+
:
1H NMR (500 MHz, CDCl3):  = 9.37 (s, 1 H), 8.30 (d, J = 8.0 Hz, 1 H),
7.29–7.49 (m, 11 H), 5.38–5.63 (m, 4 H), 4.85–4.89 (m, 1 H), 4.42 (d,
J = 4.6 Hz, 1 H), 3.70 (s, 3 H), 3.45–3.58 (m, 1 H), 3.31–3.39 (m, 2 H),
3.02–3.09 (m, 1 H), 2.10–2.17 (m, 1 H), 1.83–1.97 (m, 3 H), 1.43 (s, 9
H).
13C NMR (125 MHz, CDCl3):  = 173.42, 170.79, 135.55, 132.96,
132.76, 131.54, 129.45, 129.20, 128.91, 128.21, 122.08, 79.61, 59.85,
53.50, 52.98, 51.30, 50.22, 47.37, 30.25, 28.51, 25.42, 24.44.
447.2391; found: 447.2412.
Catalyst C-1
Mixed salt B-1 (1.5 g, 2.25 mmol) was dissolved in H2O (2 mL) and the
pH was adjusted to ~8 using 10% aq NaHCO3. The solution was then
extracted with CH2Cl2 (3 × 5 mL). The combined organic layer was
dried (Na2SO4) and concentrated under reduced pressure. The residue
was washed with Et2O (3 × 2 mL) and dried under vacuum to afford
the bis(trifluoromethanesulfonyl)imide salt C-1 (1.47 g, 90%) as a
sticky transparent light-brown compound, which was used as such
for the catalysis studies.
HRMS (ESI): cationic part: m/z [M]+ calcd for C31H39N4O5+: 547.2915;
found: 547.2129.
Bis(trifluoromethanesulfonyl)imide Salt 5
[]D25 –17.7 (c 0.43, CHCl3).
IR (neat): 3133, 1660, 1347 cm–1
.
To a solution of bromide 4 (1.06 g, 1.69 mmol) in CH2Cl2 (4 mL) was
added LiNTf2 (585 mg, 2 mmol). The solution was stirred overnight at
rt, following which it was diluted with CH2Cl2 (15 mL), and washed
with H2O (3 x 15 mL). The organic layer was dried (Na2SO4) and con-
centrated under reduced pressure to afford bis(trifluoromethanesul-
fonyl)imide salt 5 (1.27 g, 91%) as a sticky yellow solid, which was
used as such for the next step.
1H NMR (500 MHz, CDCl3):  = 8.75 (s, 1 H), 8.25 (d, J = 10 Hz, NH),
7.35–7.51 (m, 10 H), 7.13 (s, 1 H), 5.23–5.41 (m, 4 H), 4.58–4.69 (m, 1
H), 3.59–3.64 (m, 4 H), 3.09–3.20 (m, 1 H), 2.91–3.01 (m, 2 H), 2.72–
2.78 (m, 1 H), 2.13 (bs, NH), 1.85–1.99 (m, 1 H), 1.51–1.61 (m, 1 H),
1.38–1.46 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 176.19, 176.16, 170.38, 135.72,
132.30, 132.12, 132.10, 131.96, 129.71, 129.62, 129.58, 128.86,
128.08, 123.62, 121.07, 120.59, 120.56, 118.51, 115.96, 65.90, 60.13,
60.09, 53.65, 53.02, 52.98, 51.34, 49.82, 49.76, 47.10, 30.74, 29.73,
26.91, 26.07.
[]D25 –24.6 (c 0.32, CHCl3).
IR (neat): 3379, 1677, 1348 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.34 (s, 1 H), 7.51 (s, 1 H), 7.23–7.45
(m, 10 H), 7.17 (d, J = 7.5 Hz, NH), 5.25–5.40 (m, 4 H), 4.72 (dd, J = 6.8,
13.6 Hz, 1 H), 4.15–4.28 (m, 1 H), 3.71 (s, 3 H), 3.48 (s, 1 H), 3.35–3.42
(m, 1 H), 3.18–3.23 (m, 2 H), 2.14–2.17 (m, 1 H), 1.78–1.97 (m, 3 H),
1.42 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 173.31, 170.28, 155.04, 134.88,
132.54, 132.20, 131.65, 129.58, 129.54, 129.47, 129.04, 128.74,
128.70, 128.42, 128.12, 128.01, 127.80, 127.02, 123.60, 122.19,
121.04, 118.49, 115.94, 79.95, 67.93, 60.13, 53.65, 53.00, 51.32, 50.57,
47.25, 29.89, 28.36, 25.53, 24.44.
19F NMR (234 MHz, CDCl3):  = –78.73.
HRMS (ESI): cationic part: m/z [M]+ calcd for C26H31N4O3+: 447.2391;
found: 447.2416.
Aldol Adduct 8a; Typical Catalysis Procedure
Cyclohexanone (7a; 0.26 mL, 2.5 mmol) and H2O (25 L, 1.4 mmol)
were added to catalyst C-1 (18.2 mg, 0.025 mmol) and the mixture
was stirred for 5 min at rt. 2-Fluorobenzoic acid (3.5 mg, 0.025 mmol)
was added and the resulting mixture was stirred for a further 15 min
at rt. 4-Nitrobenzaldehyde (6a; 75.5 mg, 0.5 mmol) was then added,
and the reaction mixture was stirred at rt. After 2.5 h of stirring, the
mixture was charged directly onto a silica gel column and eluted with
EtOAc/petroleum ether (~1:3) to isolate pure aldol adduct 8a (123.2
19F NMR (234 MHz, CDCl3):  = –78.74.
HRMS (ESI): cationic part: m/z [M]+ calcd for C31H39N4O5+: 547.2915;
found: 547.2977.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

H
H. Inani et al.
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Synthesis
mg, 99%) as a diastereomeric mixture. The absolute configuration of
the major enantiomer was confirmed based on the optical rotation
and HPLC traces, by comparison with literature data.
2-((4-Chlorophenyl)(hydroxy)methyl)cyclohexan-1-one (8e)26
White solid; yield: 107.4 mg (90%).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 90:10, 0.5
mL·min–1, 40 °C, 220 nm): tR = 15.8 (syn), 18.6 (syn), 23.2 (anti minor),
27.2 (anti major) min; anti/syn 80:20; 89% ee (anti).
Characterisation of the Aldol Adducts24
1H NMR (500 MHz, CDCl3):  = 7.32 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.4
Hz, 2 H), 4.77 (dd, J = 8.7, 2.4 Hz, 1 H), 3.99 (d, J = 2.7 Hz, 1 H), 2.53–
2.59 (m, 1 H), 2.44–2.52 (m, 1 H), 2.32–2.41 (m, 1 H), 2.07–2.14 (m, 1
H), 1.77–1.85 (m, 1 H), 1.61–1.72 (m, 1 H), 1.55–1.61 (m, 2 H), 1.25–
1.35 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 215.44, 139.45, 133.61, 128.57,
128.41, 74.17, 57.37, 42.69, 30.77, 27.75, 24.72.
2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one (8a)25
Yellow solid; yield: 123.2 mg (99%).
[]D20 +13.6 (c 0.6, CHCl3).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 87.5:12.5,
0.8 mL·min–1, 40 °C, 254 nm): tR = 17.1 (syn), 20.5 (syn), 22.3 (anti mi-
nor), 29.0 (anti major) min; anti/syn 92:8; 93% ee (anti).
1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 8.7 Hz, 2 H), 7.51 (d, J = 8.7
Hz, 2 H), 4.91 (d, J = 8.3 Hz, 1 H), 4.07 (m, 1 H), 2.61–2.63 (m, 1 H),
2.51–2.59 (m, 1 H), 2.34–2.49 (m, 1 H), 2.09–2.14 (m, 1 H), 1.82–1.85
(m, 1 H), 1.63–1.72 (m, 1 H), 1.59–1.60 (m, 1 H), 1.34–1.43 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 214.76, 148.35, 147.59, 127.88,
123.59, 74.03, 57.20, 42.68, 30.77, 27.64, 24.69.
2-(Hydroxy(perfluorophenyl)methyl)cyclohexan-1-one (8f)28
Off-white solid; yield: 145.5 mg (99%); mp 82–84 °C (Lit.28 85–87 °C).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 91.5:8.5,
0.5 mL·min–1, 20 °C, 254 nm): tR = 13.0 (syn), 14.1 (syn), 16.0 (anti
major), 21.2 (anti minor) min; anti/syn >99:1; 98% ee (anti).
1H NMR (500 MHz, CDCl3):  = 5.32 (d, J = 9.4 Hz, 1 H), 3.93 (s, 1 H),
2.94–3.08 (m, 1 H), 2.47–2.57 (m, 1 H), 2.32–2.46 (m, 1 H), 2.08–2.21
(m, 1 H), 1.81–1.95 (m, 1 H), 1.60–1.71 (m, 3 H), 1.28–1.39 (m, 1 H).
2-((4-Cyanophenyl)(hydroxy)methyl)cyclohexan-1-one (8b)26
White solid; yield: 113.4 mg (99%).
13C NMR (125 MHz, CDCl3):  = 214.14, 146.69, 144.32, 142.37,
139.99, 138.32, 136.78, 66.05, 54.21, 42.37, 30.16, 27.47, 24.51; note:
C-F coupling could not be assigned from the 13C NMR spectrum.
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 90:10, 0.5
mL·min–1, 40 °C, 230 nm): tR = 28.0 (syn), 33.5 (syn), 38.2 (anti minor),
47.9 (anti major) min; anti/syn 85:15; 88% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.64 (d, J = 8.2 Hz, 2 H), 7.44 (d, J = 8.2
Hz, 2 H), 4.84 (d, J = 8.5 Hz, 1 H), 4.09 (s, 1 H), 2.53–2.63 (m, 1 H),
2.45–2.53 (m, 1 H), 2.36 (td, J = 13.7, 6.3 Hz, 1 H), 2.07–2.15 (m, 1 H),
1.77–1.89 (m, 1 H), 1.52–1.72 (m, 3 H), 1.28–1.42 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 214.90, 146.34, 132.21, 127.79,
118.74, 111.72, 74.26, 57.14, 42.69, 30.75, 27.66, 24.70.
2-(Hydroxy(pyridin-3-yl)methyl)cyclohexan-1-one (8g)18
Brown sticky solid; yield: 98.1 mg (95%).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 92:8, 0.8
mL·min–1, 20 °C, 254 nm): tR = 39.8 (syn), 63.8 (syn), 56.8 (anti major),
67.1 (anti minor) min; anti/syn 93:7; 94% ee (anti).
1H NMR (500 MHz, CDCl3):  = 8.46 (d, J = 14.0 Hz, 2 H), 7.70 (d, J = 7.2
Hz, 1 H), 7.27 (s, 1 H), 6.93 (s, 1 H), 4.85 (d, J = 8.1 Hz, 1 H), 2.53–2.68
(m, 1 H), 2.23–2.46 (m, 2 H), 1.94–2.08 (m, 1 H), 1.72–1.85 (m, 1 H),
1.47–1.72 (m, 3 H), 1.18–1.34 (m, 1 H).
2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one
(8c)26
White solid; yield: 134.6 mg (99%).
13C NMR (125 MHz, CDCl3):  = 215.10, 149.08, 148.55, 136.61,
134.79, 123.65, 72.61, 57.12, 42.66, 30.69, 27.69, 24.66.
HPLC (Daicel Chiralcel OD-H column, hexane/2-propanol 95:5, 0.5
mL·min–1, 40 °C, 217 nm): tR = 14.8 (syn), 15.7 (syn), 17.7 (anti major),
20.9 (anti minor) min; anti/syn 90:10; 94% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.61 (d, J = 8.1 Hz, 2 H), 7.45 (d, J = 8.1
Hz, 2 H), 4.85 (d, J = 8.6 Hz, 1 H), 4.06 (s, 1 H), 2.55–2.64 (m, 1 H),
2.45–2.53 (m, 1 H), 2.31–2.42 (m, 1 H), 2.06–2.16 (m, 1 H), 1.78–1.86
(m, 1 H), 1.65–1.71 (m, 1 H), 1.53–1.61 (m, 2 H), 1.32–1.37 (m, 1 H).
2-(Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one (8h)25
Brown sticky solid; yield: 123.2 mg (99%).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 95:5, 0.5
mL·min–1, 40 °C, 254 nm): tR = 30.5 (syn), 32.4 (syn), 52.6 (anti major),
54.1 (anti minor) min; anti/syn 92:8; 97% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.84 (d, J = 8.1 Hz, 1 H), 7.76 (d, J = 7.8
Hz, 1 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 5.96 (s, 1 H),
5.44 (d, J = 7.8 Hz, 1 H), 2.70–2.82 (m, 1 H), 2.41–2.51 (m, 1 H), 2.33
(td, J = 13.4, 5.95 Hz, 1 H), 2.04–2.15 (m, 1 H), 1.82–1.90 (m, 1 H),
1.72–1.79 (m, 1 H), 1.56–1.72 (m, 3 H).
2
13C NMR (100 MHz, CDCl3):  = 214.91, 144.83, 129.87 (q, JC-F = 32.0
3
1
Hz), 127.19, 125.12 (q, JC-F = 3.7 Hz), 123.92 (q, JC-F = 270.7 Hz),
74.06, 57.19, 42.48, 30.57, 27.52, 24.47.
2-((4-Bromophenyl)(hydroxy)methyl)cyclohexan-1-one (8d)27
White solid; yield: 118.2 mg (83%).
13C NMR (125 MHz, CDCl3):  = 214.87, 148.77, 136.62, 133.04,
129.02, 128.39, 124.06, 69.77, 57.32, 42.82, 31.11, 27.76, 24.98.
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 90:10, 0.5
mL·min–1, 40 °C, 220 nm): tR = 15.5 (syn), 18.4 (syn), 23.1 (anti minor),
27.6 (anti major) min; anti/syn 89:11; 93% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.48 (d, J = 8.3 Hz, 2 H), 7.20 (d, J = 8.3
Hz, 2 H), 4.75 (dd, J = 8.7, 2.2 Hz, 1 H), 3.97 (d, J = 2.65 Hz, 1 H), 2.52–
2.60 (m, 1 H), 2.44–2.52 (m, 1 H), 2.35 (td, J = 13.4, 6.1 Hz, 1 H), 2.06–
2.14 (m, 1 H), 1.76–1.86 (m, 1 H), 1.64–1.74 (m, 1 H), 1.58–1.64 (m, 1
H), 1.23–1.36 (m, 2 H).
2-((2-Chlorophenyl)(hydroxy)methyl)cyclohexan-1-one (8i)27
White solid; yield: 96.3 mg (81%).
HPLC (Daicel Chiralcel OD-H column, hexane/2-propanol 95:5, 1
mL·min–1, 20 °C, 220 nm): tR = 7.7 (anti major), 8.9 (anti minor), 11.0
(syn), 12.1 (syn) min; anti/syn 93:7; 90% ee (anti).
13C NMR (125 MHz, CDCl3):  = 215.40, 139.96, 131.51, 128.76,
121.75, 74.22, 57.32, 42.68, 30.77, 27.74, 24.72.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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1H NMR (500 MHz, CDCl3):  = 7.55 (d, J = 6.9 Hz, 1 H), 7.28–7.36 (m, 2
H), 7.21 (t, J = 7.6 Hz, 1 H), 5.35 (d, J = 8.1 Hz, 1 H), 4.04 (s, 1 H), 2.62–
2.74 (m, 1 H), 2.43–2.52 (m, 1 H), 2.35 (td, J = 13.5, 6.1 Hz, 1 H), 2.03–
2.16 (m, 1 H), 1.77–1.88 (m, 1 H), 1.62–1.72 (m, 2 H), 1.53–1.62 (m, 2
H).
13C NMR (125 MHz, CDCl3):  = 215.33, 139.08, 132.97, 129.22,
128.77, 128.25, 127.27, 70.45, 57.61, 42.75, 30.40, 27.83, 24.93.
2-(Hydroxy(4-methylphenyl)methyl)cyclohexan-1-one (8n)26
Off-white solid; yield: 92.7 mg (85%).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 93:7, 1
mL·min–1, 20 °C, 254 nm): tR = 10.2 (syn), 11.3 (syn), 13.8 (anti major),
16.2 (anti minor) min; anti/syn 70:30; 60% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.20 (t, J = 7.9 Hz, 2 H), 7.15 (d, J = 7.9
Hz, 2 H), 4.76 (d, J = 8.7 Hz, 1 H), 3.92 (s, 1 H), 2.56–2.66 (m, 1 H),
2.42–2.52 (m, 1 H), 2.36–2.41 (m, 1 H), 2.34 (s, 3 H), 2.04–2.13 (m, 1
H), 1.75–1.89 (m, 1 H), 1.48–1.74 (m, 3 H), 1.24–1.35 (m, 1 H).
2-(Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one (8j)25
White solid; yield: 113 mg (91%).
13C NMR (125 MHz, CDCl3):  = 215.64, 138.00, 137.55, 129.06,
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 90:10, 1
mL·min–1, 20 °C, 254 nm): tR = 17.7 (syn), 19.5 (syn), 20.9 (anti major),
26.5 (anti minor) min; anti/syn 93:7; 91% ee (anti).
126.94, 74.53, 57.45, 42.68, 30.88, 27.84, 24.73, 21.16.
2-(Hydroxy(4-methoxyphenyl)methyl)cyclohexan-1-one (8o)26
1H NMR (500 MHz, CDCl3):  = 8.21 (s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H),
7.67 (d, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 1 H), 4.90 (d, J = 8.5 Hz, 1 H),
4.15 (s, 1 H), 2.57–2.68 (m, 1 H), 2.46–2.54 (m, 1 H), 2.38 (td, J = 13.5,
6.0 Hz, 1 H), 2.07–2.18 (m, 1 H), 1.79–1.88 (m, 1 H), 1.63–1.75 (m, 3
H), 1.36–1.45 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 215.00, 148.27, 143.21, 133.24,
129.35, 122.92, 122.05, 74.07, 57.14, 42.69, 30.76, 27.65, 24.67.
Yellow solid; yield: 68.2 mg (58%).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 95:5, 1
mL·min–1, 20 °C, 254 nm): tR = 18.9 (syn), 22.1 (syn), 31.6 (anti minor),
33.6 (anti major) min; anti/syn 74:26; 36% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.23 (t, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.5
Hz, 2 H), 4.74 (d, J = 8.8 Hz, 1 H), 3.93 (bs, 1 H), 3.80 (s, 3 H), 2.54–2.64
(m, 1 H), 2.42–2.51 (m, 1 H), 2.36 (td, J = 13.5, 6.0 Hz, 1 H), 2.04–2.12
(m, 1 H), 1.75–1.82 (m, 1 H), 1.55–1.70 (m, 3 H), 1.27–1.32 (m, 1 H).
2-((3-Chlorophenyl)(hydroxy)methyl)cyclohexan-1-one (8k)27
13C NMR (125 MHz, CDCl3):  = 214.88, 158.64, 133.62, 126.93,
113.59, 70.42, 57.29, 55.26, 42.70, 27.99, 26.20, 24.90.
Pale yellow solid; yield: 117 mg (98%).
HPLC (Daicel Chiralcel OD-H column, hexane/2-propanol 97:3, 0.8
mL·min–1, 40 °C, 210 nm): tR = 12.8 (syn), 14.5 (syn), 15.9 (anti major),
18.6 (anti minor) min; anti/syn 88:12; 86% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.35 (s, 1 H), 7.29 (m, 2 H), 7.20 (t, J =
4.3 Hz, 1 H), 4.77 (d, J = 8.7 Hz, 1 H), 4.76 (s, 1 H), 2.56–2.64 (m, 1 H),
2.46–2.54 (m, 1 H), 2.37 (td, J = 13.4, 6.0 Hz, 1 H), 2.07–2.16 (m, 1 H),
1.79–1.88 (m, 1 H), 1.53–1.74 (m, 3 H), 1.26–1.39 (m, 1 H).
4-Hydroxy-4-(4-nitrophenyl)butan-2-one (8p)25
Yellow solid; yield: 99.3 mg (95%).
HPLC (Daicel Chiralpak IC column, hexane/2-propanol 92.5:7.5, 0.8
mL·min–1, 40 °C, 254 nm): tR = 23.8 (minor), 25.1 (major) min; 65% ee.
1H NMR (500 MHz, CDCl3):  = 8.20 (d, J = 8.7 Hz, 2 H), 7.54 (d, J = 8.1
Hz, 2 H), 5.24–5.30 (m, 1 H), 3.68 (s, 1 H), 2.83–2.89 (m, 1 H), 2.22 (s, 3
H).
13C NMR (125 MHz, CDCl3):  = 215.38, 143.00, 134.35, 129.64,
128.09, 127.16, 125.32, 74.31, 57.27, 42.70, 30.80, 27.75, 24.71.
13C NMR (125 MHz, CDCl3):  = 208.61, 149.98, 147.32, 126.44,
123.80, 68.91, 51.53, 30.75.
2-((4-Chloro-3-nitrophenyl)(hydroxy)methyl)cyclohexan-1-one
(8l)29
2-(Hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one (8q)26
Pale yellow solid; yield: 136 mg (96%).
Yellow solid; yield: 116.3 mg (99%).
HPLC (Daicel Chiralpak IC column, hexane/2-propanol 90:10, 1.5
mL·min–1, 20 °C, 210 nm): tR = 9.6 (syn), 10.8 (syn), 15.7 (anti major),
16.5 (anti minor) min; anti/syn 91:9; 93% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.85–7.89 (m, 1 H), 7.52 (d, J = 8.2 Hz, 1
H), 7.46–7.50 (m, 1 H), 4.84 (d, J = 8.3 Hz, 1 H), 4.10 (s, 1 H), 2.53–2.64
(m, 1 H), 2.45–2.53 (m, 1 H), 2.36 (td, J = 13.7, 6.0 Hz, 1 H), 2.07–2.18
(m, 1 H), 1.80–1.92 (m, 1 H), 1.53–1.72 (m, 3 H), 1.32–1.46 (m, 1 H).
HPLC (Daicel Chiralpak AD-H column, hexane/2-propanol 95:5, 0.5
mL·min–1, 40 °C, 254 nm): tR = 49.4 (syn), 66.1 (syn), 80.2 (anti minor),
84.4 (anti major) min; anti/syn 34:66; 70% ee (syn).
1H NMR (500 MHz, CDCl3):  = 8.18–8.25 (m, 2 H), 7.52 (t, J = 8.8 Hz, 2
H), 4.84 (d, J = 9.2 Hz, 1 H), 4.78 (s, 1 H), 2.43–2.52 (m, 1 H), 2.34–2.43
(m, 1 H), 2.10–2.33 (m, 1 H), 1.98–2.07 (m, 1 H), 1.66–1.76 (m, 2 H),
1.49–1.61 (m, 1 H).
13C NMR (125 MHz, CDCl3):  (characteristic peaks of both diastereo-
mers) = 222.30, 219.52, 150.17, 148.64, 147.65, 147.18, 127.37,
126.38, 123.75, 123.67, 74.44, 70.48, 56.09, 55.10, 38.95, 38.62, 26.86,
22.42, 20.38, 20.34.
13C NMR (125 MHz, CDCl3):  = 214.68, 147.81, 141.78, 131.72,
131.69, 126.17, 124.08, 73.43, 57.05, 42.65, 30.68, 27.60, 24.64.
2-(Hydroxy(phenyl)methyl)cyclohexan-1-one (8m)25
Pale yellow sticky solid; yield: 101 mg (99%).
HPLC (Daicel Chiralcel OD-H column, hexane/2-propanol 90:10, 0.5
mL·min–1, 20 °C, 220 nm): tR = 14.0 (syn), 15.5 (syn), 17.2 (anti major),
22.0 (anti minor) min; anti/syn 85:15; 80% ee (anti).
1H NMR (500 MHz, CDCl3):  = 7.24–7.38 (m, 5 H), 4.79 (d, J = 8.8 Hz, 1
H), 4.10 (s, 1 H), 2.57–2.67 (m, 1 H), 2.46–2.52 (m, 1 H), 2.36 (td, J =
13.4, 7.0 Hz, 1 H), 2.05–2.14 (m, 1 H), 1.74–1.84 (m, 1 H), 1.62–1.73
(m, 1 H), 1.49–1.61 (m, 2 H), 1.23–1.36 (m, 1 H).
2-(Hydroxy(4-nitrophenyl)methyl)-4-methylcyclohexan-1-one
(10)21
White solid; yield: 125.8 mg (96%).
HPLC (Daicel Chiralpak IC column, hexane/2-propanol 80:20, 1
mL·min–1, 40 °C, 254 nm): tR = 16.7 (major), 18.6 (minor) min; d.r.
88:12:0:0; 88% ee.
13C NMR (125 MHz, CDCl3):  = 215.49, 141.03, 128.37, 127.88,
127.05, 74.67, 57.43, 42.62, 30.83, 27.82, 24.66.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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H. Inani et al.
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1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 8.6 Hz, 2 H), 7.50 (d, J = 8.6
Hz, 2 H), 4.92 (d, J = 8.4 Hz, 1 H), 3.89 (s, 1 H), 2.71–2.79 (m, 1 H),
2.50–2.60 (m, 1 H), 2.36–2.44 (m, 1 H), 2.01–2.15 (m, 1 H), 1.89–2.0
(m, 1 H), 1.75–1.85 (m, 1 H), 1.55–1.66 (m, 1 H), 1.24–1.37 (m, 1 H),
1.06 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 214.85, 148.39, 147.68, 127.82,
123.66, 74.17, 52.82, 38.15, 36.06, 32.87, 26.65, 18.17.
J. Curr. Org. Chem. 2009, 13, 1259. (g) Kucherenko, A. S.;
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Chem. Bull. 2012, 61, 1313.
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Recycling Procedure for the Aldol Reaction between 4-Nitrobenz-
aldehyde (6a) and Cyclohexanone (7a)
Cyclohexanone (7a; 0.50 mL, 5 mmol) and H2O (50 L, 2.78 mmol)
were added to catalyst C-1 (36.3 mg, 0.05 mmol) and the mixture was
stirred at rt for 5 min. To this biphasic mixture, 2-fluorobenzoic acid
(7 mg, 0.05 mmol) was added and the resulting mixture was stirred
for 15 min at rt. 4-Nitrobenzaldehyde (6a; 151 mg, 1.0 mmol) was
then added and the reaction mixture was stirred at rt for 2.5 h. The
reaction mixture was then extracted with Et2O (4 × 2 mL). The com-
bined organic extract was concentrated under reduced pressure and
the residue was purified by silica gel column chromatography EtOAc/
petroleum ether (~1:3) to afford pure aldol adduct 8a (246 mg, 99%).
The reaction flask containing catalyst C-1 was dried under vacuum for
1 h and then charged with the reactants again in identical amounts
and order as above.
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Conflict of Interest
The authors declare no conflict of interest.
Funding Information
The work was supported by a collaborative project between the De-
partment of Science and Technology (DST), Ministry of Science and
Technology, India (Grant No. INT/RFBR/P-170) and the Russian Foun-
dation for Basic Research (Grant No. 14-03-92701), research grant
from the Science and Engineering Research Board (SERB), India (Grant
No. EMR/2017/ 005350), a research grant from the Council of Scientif-
ic and Industrial Research (CSIR), India (Grant No. 02(0316)/17/EMR-
II), and a DST-Fund for Improvement of S&T Infrastructure in Univer-
sities and Higher Educational Institutions (FIST) research grant to the
Department of Chemistry, CURAJ [Grant No. SR/FST/CSI-257/2014
(C)]. H.I. and M.B. thank the University Grants Commission (UGC), In-
dia, and K.K. thanks CSIR, India, for research fellowships. S.E. thanks
(11) Obregon-Zuniga, A.; Juaristi, E. Tetrahedron 2017, 73, 5373.
(12) For a review on the role of water in organocatalytic reactions,
see: Giacalone, F.; Gruttadauria, M. Water in Organocatalytic
Reactions, In Comprehensive Enantioselective Organocatalysis:
Catalysts, Reactions, and Applications, 1st ed; Dalko, P. I., Ed.;
Wiley-VCH: Germany, 2013, 673–717.
the Central University of Rajasthan for support.
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(13) For some mechanistic studies related to the role of water, see:
(a) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492.
(b) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G.
J. Am. Chem. Soc. 2007, 129, 15100. (c) Rulli, G.; Duangdee, N.;
Baer, K.; Hummel, W.; Berkessel, A.; Gröger, H. Angew. Chem. Int.
Ed. 2011, 50, 7944.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1477-4871. Su
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ortingInformatio
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Su
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ortingInformatio
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(14) (a) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev.
2007, 107, 5759. (b) Wennemers, H. Chem. Commun. 2011, 47,
12036. (c) Lewandowski, B.; Wennemers, H. Curr. Opin. Chem.
Biol. 2014, 22, 40. (d) Freund, M.; Tsogoeva, S. B. In Catalytic
Methods in Asymmetric Synthesis: Advanced Materials, Tech-
niques, and Applications, 1st ed; Gruttadauria, M.; Giacalone, F.,
Ed.; John Wiley & Sons: New York, 2011, 529, and references
cited therein.
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Wennemers, H. Angew. Chem. Int. Ed. 2008, 47, 1871.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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Paper
Synthesis
(c) Rodríguez-Llansola, F.; Miravet, J. F.; Escuder, B. Chem.
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