Asymmetric Synthesis of Adjacent Tri- and Tetrasubstituted Carbon Stereocenters: Organocatalytic Aldol Reaction of an Hydantoin Surrogate with Azaarene 2-Carbaldehydes

Article abstract of DOI:10.1002/chem.201902817

A bifunctional amine/squaramide catalyst promoted direct aldol addition of an hydantoin surrogate to pyridine 2-carbaldehyde N-oxides to afford adducts bearing two vicinal tertiary/quaternary carbons in high diastereo- and enantioselectivity (d.r. up to >20:1; ee up to 98 %) is reported. Acid hydrolysis of adducts followed by reduction of the N-oxide group yields enantiopure carbinol-tethered quaternary hydantoin-azaarene conjugates with densely functionalized skeletons. DFT studies of the potential energy surface (B3LYP/6–31+G(d)+CPCM (dichloromethane)) of the reaction correlate the activity of different catalysts and support an intramolecular hydrogen-bond-assisted activation of the squaramide moiety in the transition state of the catalytic reaction.

Full text of DOI:10.1002/chem.201902817

A Journal of
Accepted Article
Title: Asymmetric Synthesis of Adjacent Tri- and Tetrasubstituted
Carbon Stereocenters. Organocatalytic Aldol Reaction of an
Hydantoin Surrogate with Azaarene 2-Carbaldehydes
Authors: June Izquierdo, Noémie Demurget, Aitor Landa, Tore Brinck,
Jose M. Mercero, Peter Dinér, Mikel Oiarbide, and Claudio
Palomo
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To be cited as: Chem. Eur. J. 10.1002/chem.201902817
Link to VoR: http://dx.doi.org/10.1002/chem.201902817
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10.1002/chem.201902817
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Asymmetric Synthesis of Adjacent Tri- and Tetrasubstituted
Carbon Stereocenters. Organocatalytic Aldol Reaction of an
Hydantoin Surrogate with Azaarene 2-Carbaldehydes.
June Izquierdo,[a] Noémie Demurget,[a] Aitor Landa,[a] Tore Brinck,[b] Jose M. Mercero,[c] Peter Dinér,*[b]
Mikel Oiarbide,*[a] Claudio Palomo*[a]
Abstract: Bifunctional amine/squaramide catalyst promoted
direct aldol addition of an hydantoin surrogate to pyridine 2-
carbaldehyde N-oxides to afford aldol adducts bearing two vicinal
surprisingly, enantio- and diastereoselective 1,2-addition
reactions involving differently disubstituted enolate or equivalent
intermediates are uncommon.3 In particular, to the best of our
tertiary/quaternary
carbons
in
high
diastereo-
and
enantioselectivity (dr up to >20:1; ee up to 98%) is reported. Acid
hydrolysis of adducts followed by reduction of the N-oxide group
yields enantiopure carbinol-tethered quaternary hydantoin-
azaarene conjugates with densely functionalized skeletons. DFT
studies of the potential energy surface (B3LYP/6-31+G(d) +
CPCM (dichloromethane)) of the reaction correlate the activity of
different catalysts and support an intramolecular H-bond-assisted
activation of the squaramide moiety in the transition state of the
catalytic reaction.
Figure 1. A conceivable direct approach to ortho-substituted chiral azaarene
compounds featuring a tertiary/quaternary carbon pattern.
knowledge, direct convergent and enantioselective routes that
satisfy the bond-disconnection of Figure 1 remain reluctant,
despite the resulting ortho-substituted azaarene products would
be interesting from a medicinal chemistry point of view.4,5 In this
context, asymmetric and non-asymmetric modifications at the
ortho position of the azaarene ring were investigated intensively
in the last years.6 Among the ortho-substituted azaarenes, the
chiral 2-(oxymethyl)azaarene skeleton is a frequent structural
Introduction
Molecular complexity, in terms of carbon backbone intricacy
and/or functional group and stereochemical crowding, is inherent
to many natural products and biologically active substances.1
Consequently, the development of direct, catalytic CC bond-
forming reactions leading to densely functionalized,
stereochemically rich motifs enantio- and diastereoselectively is
of significant interest. At the same time, such reactions pose a
number of difficulties, among them (i) the attenuated reactivity of
sterically congested nucleophilic and/or electrophilic reaction
partners, (ii) the propensity of these CC bond-forming reactions
to be reversible, and (iii) the need of stringent control of the facial
selectivity on trisubstituted prostereogenic reactive centers.2 Not
[a]
Prof. C. Palomo, Prof. M. Oiarbide, Dr. A. Landa, J. Izquierdo, N.
Deurget.
Departamento de Química Orgánica I
Universidad del País Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastián, Spain
E-mail: claudio.palomo@ehu.es
[b]
[c]
Assoc. Prof. P. Dinér, Prof. Tore Brinck.
Department of Chemistry, KTH Royal Institute of Technology,
Teknikringen 30, S-100 44 Stockholm, Sweden.
E-mail: diner@kth.se
Prof. J. M. Mercero
Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) &
Donostia International Physics Center (DIPC), Donostia, Spain
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. State of the art of aldol and related addition reactions to azaarene-
2-carbaldehydes and our proposal.
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motif in agrochemicals,7 in biologically active compounds,8 and as
chiral ligand.9 Some asymmetric catalytic aldol and related
addition reactions leading to 2-(oxymethyl)azaarenes with
adjacent tertiary-tertiary stereocenters have been developed,10
but there is virtually not precedent dealing with the construction of
such structures bearing two vicinal tri- and tetrasubstituted carbon
stereocenters enantioselectively (Scheme 1a, entries i-iv).
Krische has reported11 the Ir-catalyzed addition of allyl-transition
metal complexes to pyridyl 2-carbaldehyde (i). Jørgensen
developed12 a Cu-catalyzed Mukaiyama-type addition of silyl enol
ethers to various pyridine carbaldehyde N-oxides (ii).
Chemoenzymatic aldol additions of sodium fluoroacetate to
pyridyl-2-carbaldehyde have been documented to proceed with
variable yields of isolated ethyl ester (iii).13 Finally, Nelson
reported14 the only organocatalytic approach consisting of the
enamine mediated addition of the symmetric cyclohexanone to
pyridyl-2-carbaldehydes (iv). Intrigued by the lack of direct and
asymmetric approaches to 2-(oxymethyl)azaarene skeletons with
adjacent tri- and tetrasubstituted carbon stereocenters, we
envisioned that direct coupling between azaarene-2-
carbaldehydes and -substituted lactam systems that are prone
to Brønsted base-promoted enolization might be conceivable.15
Here, we present initial difficulties during the realization of such
an idea, and how the use of azaarene N-oxides as transiently
activated substrates, in combination with bifunctional catalysts
bearing an additional H-bond donor amide group, allowed to
overcome them.
produced (almost full conversion at 0 ºC overnight), but with
generally low selectivity (Scheme 3). For instance, in the
presence of catalyst C1, a cinchona alkaloid-derived bifunctional
squaramide catalyst previously developed in our laboratory,21
3
was obtained in 79% isolated yield, 4:1 diastereomeric ratio and
enantioselectivities of 65% and 66% ee for each isomer.
Scheme 3. Reaction between 1a and pyridine-2-carbaldehyde 2 and the set of
bifunctional Brønsted base catalysts employed within this work.
At this point we turned our attention to pyridine 2-carbaldehyde N-
oxides (4A) with the expectation that the easy to install20 and
remove N-oxide group would impart higher reactivity22 while
providing a potentially coordinating site for catalyst binding.23
Superior reactivity and stereoselectivity of azaarene N-oxides as
compared to parent azaarenes have been previously observed by
us and others in the realm of metal catalysis24 and
organocatalysis.25 Gratifyingly, (Table 1, entry 1), reaction of 1a
with 4A in CH2Cl2 at 0 ºC in the presence of catalyst C1 proceeded
to completion within less than 16 h, and most significantly,
producing aldol 6Aa in a high (>10:1) diastereomeric ratio and
excellent enantioselectivity (94% ee). None of the other catalysts
tested, including benchmark catalyst C326 (1.7:1 dr, 30% ee, entry
4), the parent cyclohexyldiamine derivatives C516b and C627
(entries 6, 7) and the trimethylsilyl derivative C4, which had been
previously designed by us for the nucleophilic additions of 2-
(cyanomethyl)azaarene N-oxides,26a (entry 5), showed
comparable reactivity. Importantly, by decreasing the reaction
temperature to 10 C the conversion was still complete upon 16
h and the level of dr was further increased to a remarkable >20:1
(entry 2). Control experiment (entry 3) showed that the N-
methylated catalyst C2 was less stereoselective and did not reach
full conversion, demonstrating the crucial role played by the amide
NH group to impart good stereocontrol and reactivity. It is worth
noting that no retroaldol reaction was observed during isolation
and purification of the product through silica gel, and the syn-aldol
product28 could be obtained in high purity as a crystalline solid.
Results and Discussion
Background and working plan. We selected 1H-imidazol-
5(4H)-ones 1, a type of lactam heterocycle easily prepared from
racemic -amino acids and simple aryl isothiocyanates in three-
steps, which has previously been used as an excellent hydantoin
surrogate in Brønsted base-catalyzed conjugate additions to
nitroolefins (Scheme 2).16 Hydantoins can be considered masked
forms of -amino acids, and therefore, serving as precursors of
non-natural amino acids,17 and have in addition revealed some
unique pharmacological uses,18 making them of considerable
practical importance.
Scheme 2. Imidazolinone 1 as hydantoin surrogate in Brønsted base catalysed
conjugate addition reaction.
For initial exploration, the aldol reaction19 between N3-phenyl 2-
benzylthio-3,5-dihydroimidazol-4-one 1a, prepared from DL-
phenylalanine and phenylisothiocyanate,20 and commercially
available pyridine-2-carbaldehyde 2 was evaluated. By using a
range of chiral bifunctional catalysts aldol 3 was efficiently
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Table 1. Catalyst screening for the reaction of hydantoin surrogate 1a with
pyridine 2-carbaldehyde N-oxide 4A.[a]
Entry
Cat
T [ºC]
0
t [h]
Conv [%][b]
dr[c]
ee [%][d]
1
2[e]
C1
C1
C2
C3
C4
C5
C6
16
16
48
16
16
16
16
100
100 (93)
60
>10:1
>20:1
2.5:1
1.7:1
1.8:1
1.5:1
2:1
94
–10
95
3
0
0
0
0
0
45
4
88
30
5
100
82
ND
ND
ND
6
7
100
[a] The reactions were performed using 4A (0.11 mmol), 1a (0.121 mmol) and
catalyst (10 mol%) in CH2Cl2 (0.6 mL). [b] Data in parentheses refer to the yield
after chromatography. [c] dr estimated by 1H NMR spectroscopy and by HPLC.
[d] ee of major diastereomer as determined by HPLC. [e] Reaction conducted
using 2 equivalents of 1a.
With the established optimal reaction conditions, the scope of the
catalytic
aldol
reaction
with
respect
to
the
2-
benzylthioimidazolinone reagent 1 was investigated using as
azaarene carbaldehyde N-oxides both the pyridine derivative 4A
and the quinoline derivative 5A. As data in Scheme 4 show,
various substitution patterns at the C(sp3) position of the
heterocycle are tolerated well. Thus, the aldol reaction proceeded
smoothly even at –20 ºC with benzyl, p-fluorobenzyl or allyl
substituted 2-benzylthioimidazolinones 1ac affording the syn
aldol product in isolated yields above 93%, diastereomeric ratios
higher than 20:1 and ee’s of 93%, 90% and 94%, respectively
(adducts 6Aa–6Ac). The reaction also tolerated ester groups at
the side chain (products 6Ad, 6Ae) without loss of
enantioselectivity and still high diastereoselectivity (dr >10:1 in
both cases). The enantioselectivity eroded a little bit with
substrates 1f and 1g bearing simple ethyl and isopropyl
substituents (6Af, 6Ag), but both yield and dr remained high.
Finally, the process was not limited to pyridine derivative 4A, and
quinoline-2-carbaldehyde N-oxide 5A also afforded the desired
aldol product 7Aa in 90% isolated yield and a high selectivity (dr
11:1, 94% ee). Although the diastereoselectivity was very high in
most cases, even for the less favourable substrates essentially
single diastereomer was isolated in >80% yield after simple
crushing with Et2O.20
Scheme 4. Scope of the catalytic aldol reaction of azaarene-2-carbaldehyde N-
oxides 4A/5a with hydantoin surrogates 1. (Conditions of entry 2, Table 1.)
The
scope
of
substituted
N3-aryl
2-benzylthio-3,5-
dihydroimidazol-4-ones with a range of azaarene N-oxide
aldehydes was also evaluated (Scheme 5). Various N3-aryl
imidazolinone systems bearing electron-donating (4-Me, 4-MeO)
or electron-withdrawing (4-Br) groups on the N3-aromatic ring
were well tolerated in the reaction with 4A, leading to aldols 6Ah,
6Ai, 6Aj in excellent yields (>90%) and high stereoselectivity (dr
>20:1, >90% ee). Interestingly, the para-, meta- or ortho position
of the substituent does not affect the reaction chemical and
sterechemical efficiency (compare reactions leading to adducts
6Aj, 6Ak and 6Al).
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Scheme 5. Scope of the catalytic aldol reaction of azaarene-2-carbaldehyde N-oxides 4/5 with hydantoin surrogates 1. (Conditions of entry 2, Table 1.)
Most relevant, the reactions involving azaarene systems of
electronically different nature did also proceed satisfactorily. For
instance, 6-Br and 5-Br pyridine systems (4B and 4C) as well as
the 2-Me pyridine system 4D all behaved well affording adducts
6Ba, 6Ca, 6De and 6Dj in high yield and excellent
stereoselectivity. Substitution on the pyridine ring at the most
proximal position (ortho) was also well tolerated, but the reaction
stereoselectivity resulted eroded (3-Cl: 4Ea to give adduct 6Ea,
4:1 dr, 74% ee). Finally, the quinoline-2-carbaldehyde N-oxide 5A
reacted with the phenylalanine-derived heterocycles 1h and 1m
to provide adducts 7Ah and 7Am in good yields, good
diastereomeric ratios (12:1 and 8:1) and excellent
enantioselectivity (98%, 94% ee). The reaction between 5A and
1e, this latter bearing a methylpropanoate appendage, was an
exception leading to 7Ae in eroded diastereoselectivity.29
Elaboration of adducts toward carbinol-tethered new
azaarene-hydantoin conjugates. The experimental study was
complemented by carrying out the final conversion of the N-oxide
functionality into the parent azaarene system and the
regeneration of the hydantoin heterocycle. To that end, treatment
of some aldol adducts 6A with aqueous HCl was examined first,
but unfortunately did not lead to the corresponding hydrolysed
hydantoin products. Instead, products from a retro-aldol reaction
were detected. Shifting the hydrolytic conditions from acidic to
basic (NaOH 6M, 1,4-dioxane, room temperature) did not change
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the result and retroaldol products were again observed. We
squaramide and the maximum is located in between the two
decided to block the hydroxyl group on adducts as a benzoyl ester, hydrogens as best visualized in the front views represented in
which gratifyingly avoided the undesired retro addition.30 Thus,
upon benzoylation of adducts 6Aa to 8Aa and subsequent
treatment with 6M HCl in dioxane at RT for 4 days gave rise to
hydantoin 10Aa in 83% yield over the two steps (Scheme 6).
Similarly, adducts 6Ae and 7Aa were converted into hydantoin-
azaarene N-oxide conjugates 10Ae and 11Aa in combined yields
of 81% and 79%, respectively. Finally, treatment of adducts 10Aa
Figure 3 (bottom depictions, red region)37 This charge distribution
explains the potential of squaramide group to bind polar groups,
such as carbonyl, through H-bonding. Catalyst C1 has a larger
positive potential at the maximum compared to C2, but the
difference is relatively small (C1: VS,max= 79.8 kcal/mol; C2:
VS,max
=
76.0 kcal/mol). Another consequence of the
intramolecular NHO=C binding38 in catalyst C1 is that the two
extended  systems at the opposite ends of the molecule are
31
and 11Aa with (Bpin)2 afforded the pyridine-hydantoin and
quinoline-hydantoin conjugates 12 and 13 in 88% and 91%
approximately perpendicular one another, leading to
a
isolated yields, respectively, and without loss of enantiopurity.
pseudohelical structure. By contrast, both extended  systems in
C2 adopt a more flexible, roughly antiperiplanar disposition.
Scheme 6. Elaboration of adducts through hydrolysis and reduction to give
carbinol-tethered quaternary hydantoin-azaarene conjugates.
The absolute and relative configurations of the syn adduct 10Ae
(Figure 2) was determined by
a
single-crystal X-ray
crystallographic analysis32 and that of the remaining adducts was
established assuming a uniform reaction mechanism.33
Figure 2. X-ray crystallographic structure of 10Ae. Color code: C gray, H white,
O red, N blue.
Figure 3. Calculated electrostatic potential on the 0.001 a.u. isodensity surface
catalysts C1 and C2. Colour coding in kcal/mol.
Catalyst electronic and conformational features and
mechanistic insights. In an attempt to correlate catalyst
structure with its chemical reactivity, quantum calculations of the
surface electrostatic potential and conformational bias of catalysts
C1 and its N-methyl analogue C2, due to their presumed H-
bonding ability, were performed. We calculated the structures of
C1 and C2 at the B3LYP(D3)/6-31+G(d) level of theory34 in
aqueous phase (by means of the CPCM35 using dichloromethane
as solvent as implemented in the Gaussian 16 code36). The
electrostatic surface potential of the two catalysts shows a
strongly positive potential around the two hydrogens of the
In order to better understand the action of the two catalysts (C1
and C2) the potential energy surface of the reactants,
intermediates and transition states of the aldol reaction was
investigated by optimising all the geometries at the same level of
theory described above. All the energies were recalculated at the
B3LYP/6-311++G(3df,2p) level of theory. The calculations were
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performed with the N-oxide aldehyde
4A and
a simplified 2-methylthio
imidazolone 1n.
As shown in Figures 4 and 5, the
encounter between the imidazolone
1n and the catalyst C1 or C2 leads to
a pre-assemble TS complex (C•1n)
that is stabilized compared to the free
catalyst and the imidazolone (–3.2
and –5.6 kcal mol-1, respectively).
From the pre-assemble complex, the
-CH is deprotonated by the catalyst
quinuclidine nitrogen via TSenolate
leading to the enolate.
The
calculations show that the Gibbs free
energy of activation, calculated from
the pre-assemble complex, is similar
for both catalysts (13.0 and 12.9 kcal
mol-1, respectively) and leads to a
complex between catalyst and the
formed enolate.
Figure 4. Gibbs free energy diagram of the enolization and the aldol reaction of the model imidazolinone
1n and N-oxide aldehyde 4A with catalyst C1 and C2.
Figure 5. Optimised structures of the catalyst, intermediates and transition states of the aldol reaction with catalyst C1.
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[1]
[2]
E. J. Corey, B. Czakó, L. Kürti, Molecules and Medicine, Wiley, New
Jersey, 2007.
The encounter between the aldehyde and catalyst complex leads
to a new pre-assemble TS complex (C•1n•4A) before passing
through the transition state (TSaldol) leading the aldol product. In
this transition state, the new CC bond between the enolate and
the N-oxide aldehyde 4A is forming while the proton from the
ammonium nitrogen is transferred to the oxygen in the aldehyde
in a concerted fashion. The calculated Gibbs free energy of
activation for the various steps shows that this latter (TSaldol) is
the rate-limiting step of the reaction and that the barrier is slightly
lower for catalyst C1 compared to catalyst C2 (10.7 kcal mol-1 vs.
11.6 kcal mol-1). This is in agreement with the experimental
observation that the aldol reaction in the presence of C1 proceeds
faster than with C2 (see Table 1).
Selected reviews on the formation of quaternary stereocenters: a) T. Ling,
F. Rivas, Tetrahedron 2016, 72, 6729–6777; b) K. W. Quasdorf, L. E.
Overman, Nature 2014, 516, 181–191; c) Y. Liu, S. J. Han, W. B. Liu, B.
M. Stoltz, Acc. Chem. Res. 2015, 48, 740–751; d) M. Shimizu, Angew.
Chem. Int. Ed. 2011, 50, 5998–6000; e) J. P. Das, I. Marek, Chem.
Commun. 2011, 47, 4593–4623; f) M. Bella, T. Gasperi, Synthesis 2009,
10, 1583–1614.
[3]
For recent examples relying on Brønsted base activation strategies, see:
a) X. Tian, K. Jiang, J. Peng, W. Du, Y.-C. Chen, Org. Lett. 2008, 10,
2583-3586; b) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem. Soc.
2010, 132, 6286–6287; c) X. Liu, L. Deng, H. Song, H. Jia, R. Wang, Org.
Lett. 2011, 13, 1494-1497; d) Z. Han, W. Yang, C.-H. Tan, Z. Jiang, Adv.
Synth. Catal. 2013, 355, 1505–1511; e) S. Diosdado, J. Etxabe, J.
Izquierdo, A. Landa, A. Mielgo, I. Olaizola, R. Lõpez, C. Palomo, Angew.
Chem. Int. Ed. 2013, 52, 11846–11851; f) Y. Zheng, L. Deng, Chem. Sci.
2015, 6, 6510–6514; g) F. I. Amr, C. Vila, G. Blay, M. C. Muñoz, J. R.
Pedro, Adv. Synth. Catal. 2016, 358, 1583–1588; g) K. Zhao, Y. Zhi, X.
Li, R. Puttreddy, K. Rissanenb, D. Enders, Chem. Commun., 2016, 52,
2249–2252.
Conclusions
Aldol addition reactions between azaarene 2-carbaldehyde N-
oxides and -substituted hydantoin surrogates are promoted
efficiently by a multifunctional Brønsted base/H-bonding chiral
catalyst, furnishing vicinal tertiary/quaternary carbon motifs. The
use of the N-oxide derivatives instead of the parent azaarene
carbaldehydes is crucial, as is the design chiral catalyst, for
attaining high enantio- and diastereoselectivity. Alcohol protection
in adducts followed by acid hydrolysis and diborane reduction of
the N-oxide group afforded carbinol-tethered new azaarene-
hydantoin conjugates as essentially single stereoisomer. DFT
calculations provide some insights on how internal H-bonding in
the catalyst enhances its activity and induces catalyst
preorganization.
[4]
From the 100 most frequently used rings systems from small molecule
drugs in the FDA orange book (2013), 61 were an N-heterocycle: a) R.
D. Taylor, M. Maccoss, A. D. G. Lawson, J. Med. Chem. 2014, 57, 5845–
5859. Moreover, from the 10 most prescribed drugs in the U. S. in 2017,
5 of them also incorporated this structure: b) A. V. Fuentes, M. D. Pineda,
K. C. N. Venkata, Pharmacy 2018, 6, 43.
[5]
[6]
Pyridine is the second (near the first) most commonly used nitrogen
heterocycle among all U.S. FDA approved pharmaceuticals, with the
pyridine C2-position being the preferred position for substitution. E.
Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257–
10274.
a) L. Rupnicki, A. Saxena, H. W. Lam, J. Am. Chem. Soc. 2009, 131,
10386–10387; b) D. Best, S. Kujawa, H. W. Lam, J. Am. Chem. Soc.
2012, 134, 18193–18196; c) M. Meazza, V. Ceban, M- B. Pitak, S. J.
Coles, R. Rios, R. Chem. Eur. J. 2014, 20, 16853–16857; d) M. Meazza,
F. Tur, N. Hammer, K. A. Jørgensen, Angew. Chem. Int. Ed. 2017, 129,
1656 –1660; e) Y. Luo, H. L. Teng, M. Nishiura, Z. Hou, Angew. Chem.
Int. Ed. 2017, 56, 9207–9210; f) K. Wang, C. Chen, X. Liu, D. Li, T. Peng,
X. Liu, D. Yang, L. Wang, Org. Lett. 2018, 20, 5260–5263; g) R. S. J.
Proctor, H. J. Davis, R. J. Phipps, Science 2018, 360, 419–422; h) Y. Yin,
Y. Dai, H. Jia, J. Li, L. Bu, B. Qiao, X. Zhao, Z. Jiang, J. Am. Chem. Soc.
2018, 140, 6083–6087; i) X. Jiang, P. Boehm, J. F. Hartwig, J. Am. Chem.
Soc. 2018, 140, 1239–1242; j) M. T. Qiupeng Hu, A. Kondoh, M. Terada,
Chem. Sci. 2018, 9, 4348–4351; k) C. Xu, C. W. Muir, A. G. Leach, A. R.
Kennedy, A. J. B. Watson, Angew. Chem. Int. Ed. 2018, 11374–11377;
l) X. Jiang, P. Boehm, J. F. Hartwig, J. Am. Chem. Soc. 2018, 140, 1239–
1242; m) K. Cao, S. M. Tan, R. Lee, S. Yang, H. Jia, X. Zhao, B. Qiao,
Z. Jiang, J. Am. Chem. Soc. 2019,141, 5437-5443. For racemic versions
including preliminary asymmetric examples, see: n) H. B. Hepburn, P.
Melchiorre, Chem. Commun. 2016, 52, 3520–3523; o) A. Ponce, I.
Alonso, J. Adrio, J. C. Carretero, Chem. Eur. J. 2016, 22, 4952–4959; p)
H. Suzuki, R. Igarashi, Y. Yamashita, S. Kobayashi, Angew. Chem. Int.
Ed. 2017, 56, 4520–4524.
Experimental Section
For detailed description of the experimental procedures (preparation of
substrates and catalysts, catalytic enantioselective reactions,
transformations of adducts), characterization of compounds, and
spectroscopic/chromatographic information, please see the Supporting
Information.
Acknowledgements
Financial support was provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(Grant No IT-1236-19), and Ministerio de Economía
y
Competitividad (MEC, Grant CTQ2016-78487-C2), Spain. We
thank SGiker (UPV/EHU) for providing NMR, HRMS, X-Ray and
Computational resources. T.B. and P.D. thank KTH–Royal
Institute of Technology for financial support and the National
Supercomputer Center (NSC) in Linköping for computational
resources.
[7]
[8]
G. Li, X. Qian, J. Cui, Q. Huang, R. Zhang, H. Guan, J. Agric. Food Chem.
2006, 54, 125–129.
a) G. Luo, L. Chen, C. M. Conway, R. Denton, D. Keavy, M. Gulianello,
Y. Huang, W. Kostich, K. A. Lentz, S. E. Mercer, R. Schartman, L. Signor,
M. Browning, J. E. Macor, G. M. Dubowchik, ACS Med. Chem. Lett. 2012,
16, 337–341; b) S. Ananthan, S. K. Saini, C. M. Dersch, H. Xu, N.
Mcglinchey, D. Giuvelis, E. J. Bilsky, R. B. Rothman, J. Med. Chem. 2012,
55, 8350−8363; c) A. Gomtsyan, R. G. Schmidt, E. K. Bayburt, G. A.
Gfesser, E. A. Voight, J. F. Daanen, D. L. Schmidt, M. D. Cowart, H. Liu,
R. J. Altenbach, et al., J. Med. Chem. 2016, 59, 4926–4947; d) E. A.
Hallinan, T. J. Hagen, R. K. Husa, S. Tsymbalov, S. N. Rao, M. F.
Keywords: hydantoins • azaarenes • quaternary stereocenters •
asymmetric catalysis • Brønsted bases
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Rafferty, A. Stapelfeld, M. A. Savage, M. Reichman, J. Med. Chem. 1993,
36, 3293–3299; e) F. Clemence, O. Le Martret, F. DeleVallee, J.
Benzoni, A. Jouanen, S. Jouquey, M. Mouren, R. Deraedtt, J. Med.
Chem. 1988, 31, 1453–1462; f) A. M. Haidle, S. L. Knowles, S. D. Kattar,
D. Deschenes, J. Burch, J. Robichaud, M. Christopher, M. D. Altman, J.
P. Jewell, A. B. Northrup, M. Blouin, J. M. Ellis, H. Zhou, C. Fischer, A.
J. Schell, M. H. Reutershan, B. M. Taoka, A. Donofrio, PCT Int. Appl.,
2013192098, 27 Dec 2013. g) W. Xu, D. L. Gray, S. A. Glase, N. S. Barta,
Bioorg. Med. Chem. Lett. 2008, 18, 5550–5553; h) S. Kolczewski, H.-P.
Marty, R. Narquizian, E. Pinard, H. Stalder, H. U.S. Pat. Appl.
20100210592 A1, 2010.
Drug Discovery Today 2007,12, 241−248; 4-(Hydroxymethyl)diaryl
hydantoin (SARM) d) F. Nique, S. Hebbe, N. Triballeau, C. Peixoto, J. M.
Lefrançois, H. Jary, L. Alvey, M. Manioc, C. Housseman, H. Klaassen,
K. Van Beeck, D. Guꢀdin, F. Namour, D. Minet, E. Van der Aar, J. Feyen,
S. Fletcher, R. Blanquꢀ, C. Robin-Jagerschmidt, P. Deprez, J. Med.
Chem. 2012, 55, 8236–8247; Aryl hydantoins (antischistosomal efficacy)
e) C. Wang, Q. Zhao, M. Vargas, J. O. Jones, K. L. White, D. M.
Shackleford, G. Chen, J. Saunders, A. C. F. Ng, F. C. K. Chiu, Y. Dong,
S. A. Charman, J. Keiser, J. L. Vennerstrom, J. Med. Chem. 2016, 59,
10705–10718,
[19] For reviews on aldol reaction, see: a) C. Palomo, M. Oiarbide, J. M.
García, Chem. Soc. Rev. 2004, 33, 65–75; b) M. M. Heravi, S. Asadi,
Tetrahedron Asymmetry 2012, 23, 1431–1465; c) U. Scheffler, R.
Mahrwald, Chem. Eur. J. 2013, 19, 14346–14396; d) Y. Yamashita, T.
Yasukawa, W. Yoo, T. Kitanosono, S. Kobayashi, Chem. Soc. Rev. 2018,
47,4388–4480; e) T. Engesser, R. Brückner, Synthesis 2019, 51, 1715–
1745.
[9]
For reviews on chiral pyridine-containing ligands in asymmetric catalysis,
see: a) H.-L. Kwong, H.-L. Yeung, C.-T. Yeung, W.-S. Lee, C.-S. Lee,
W.-L. Wong, Coord. Chem. Rev. 2007, 251, 2188–2222; b) G. Yang, W.
Zhang, Chem. Soc. Rev. 2018, 47, 1783–1810. Selected examples: c)
C. Bolm, M. Zehnder, D. Bur, Angew. Chem. Int. Ed. 1990, 29, 205–207;
d) W. J. Drury, N. Zimmermann, M. Keenan, M. Hayashi, S. Kaiser, R.
Goddard, A. Pfaltz, Angew. Chem. Int. Ed. 2004, 43, 70–74; e) G. Chen,
W. Gong, Z. Zhuang, Y. Chen, X. Hong, Y. Yang, T. Liu, K. N. Houk, J-
Q. Yu, Science 2016, 353, 1023–1027.
[20] See the Supporting Information for details.
[21] E. Badiola, I. Olaizola, A. Vázquez, S. Vera, A. Mielgo, C. Palomo, Chem.
Eur. J. 2017, 23, 8185–8195.
[10] Asymmetric transfer hydrogenation of 2-acylazaarenes is still limited
because few chiral ligands only have proven effective for a wide range
of substrates and substrate availability problems. For a recent example,
see: a) L.-S. Zheng, C. Férard, P. Phansavath, V. Ratovelomanana-
Vidal, Chem. Commun. 2018, 54, 283–286. For photoredox 2-
acylazaarene reduction, see: b) B. Qiao, C. Li, X. Zhao, Y. Yin, Z. Jiang,
Chem. Commun. 2019, DOI: 10.1039/c9cc03661j.
[22] 2-Alkylpyridine N-oxides are more acidic than the parent 2-alkylpyridines
by about 3−4 pKa units in DMSO: a) F. G. Bordwell, Acc. Chem. Res.
1988, 21, 456−463; b) http://www.chem.wisc.edu/areas/reich/pkatable/.
[23] a) N. M. Karayannis, Coord. Chem. Rev. 1973, 11, 93−159; b) X. Liu, L.
Lin, X. Feng, Acc. Chem. Res. 2011, 44, 574−587; c) A. V. Malkov, P.
Kočovský, P. Eur. J. Org. Chem. 2007, 29−36.
[24] a) ref 12a; b) M. Holmquist, G. Blay, M. C. Muñoz, J. R. Pedro, Org. Lett.
2014, 16, 1204–1207.
[11] a) X. Gao, Y. J. Zhang, M. J. Krische, Angew. Chem. Int. Ed. 2011, 50,
4173–4175; b) R. Tsutsumi, S. Hong, M. J. Krische, Chem. Eur. J. 2015,
21, 12903–12907.
[25] a) J. Izquierdo, A. Landa, I. Bastida, R. López, M. Oiarbide, C. Palomo,
J. Am. Chem. Soc. 2016, 138, 3282–3285; b) I. Bastida, M. San Segundo,
R. López, C. Palomo, Chem. Eur. J. 2017, 23, 13332–13336; c) Q. Hu,
A. Kondoh, M. Terada, Chem. Sci. 2018, 9, 4348–4351.
[12] a) A. Landa, A. Minkkila, G. Blay, K. A. Jørgensen, Chem. Eur. J. 2006,
12, 3472–3483. Also, see: b) W. Zhuang, T. B. Poulsen, K. A. Jørgensen,
Org. Biomol. Chem. 2005, 3, 3284–3289; c) T. Hamada, K. Manabe, S.
Ishikawa, S. Nagayama, M. Shiro, S. Kobayashi, J. Am. Chem. Soc.
2003, 125, 2989–2996; d) Y. Mei, D. J. Averill, M. J. Allen, J. Org. Chem.
2012, 77, 5624–5632.
[26] a) L. Dai, S.-X. Wang, F.-E. Chen, Adv. Synth. Catal. 2010, 352, 2137-
2141; b) W. Yang, D.-M. Du, Org. Lett. 2010, 12, 5450-5453.
[27] K. Hu, A. Lu, Y. Wang, Z. Zhou, C. Tang, Tetrahedron: Asymmetry 2013,
24, 953-957.
[13] a) S. Saha, J. N. Moorthy, Tetrahedron Lett. 2010, 51, 912–916; b) V.
Liautard, D. Jardel, C. Davies, M. Berlande, T. Buffeteau, D. Cavagnat,
F. Robert, J. M. Vincent, Y. Landais, Chem. Eur. J. 2013, 19, 14532–
14539; c) N. Fanjul-Mosteirín, C. Concellón, V. Del Amo, Org. Lett. 2016,
18, 4266–4269.
[28] The syn-diastereoselectivity observed here is in contrast to the BB-
catalyzed anti-selective aldol reaction of -substituted azlactones with
aliphatic aldehydes reported by Deng. See reference 3f.
[29] Some adducts 6/7 were not fully stable at room temperature and
decomposed over time. Stored in the fridge at 30 C they were stable
for >3 months. Alternatively, they were transformed into stable
compounds 8/9.
[14] J. K. Howard, M. Müller, A. Berry, A. Nelson, Angew. Chem. Int. Ed. 2016,
55, 6767–6770.
[15] Selected reviews on Brønsted base-promoted asymmetric reactions: a)
S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. McDaid, L. Deng, Acc. Chem.
Res. 2004, 37, 621–631; b) C. Palomo, M. Oiarbide, R. López, Chem.
Soc. Rev. 2009, 38, 632–653; c) A. Ting, J. M. Goss, N. T. McDougal, S.
E. Schaus, Top. Curr. Chem. 2010, 291, 145–200; d) R. P. Singh, L.
Deng, in Asymmetric Organocatalysis 2: Brønsted Base and Acid
Catalysts, and Additional Topics (Ed.: K. Maruoka), Thieme, Stuttgart,
2012, pp. 41–118; e) H. B. Jang, J. S. Oh, C. E. Song in ref. [15d], pp.
119–168.
[30] For a previous example where the hydroxyl group of the aldol adduct is
acylated to avoid the retro aldol reaction, see reference 3b.
[31] H. P. Kokatla, P. F. Thomson, S. Bae, V. R.Doddi, M. K. Lakshman, J.
Org. Chem. 2011, 76, 7842−7848.
[32] CCDC 1922664 (compound 10Ae) contains the supplementary
crystallographic data for this paper. These data are provided free of
charge by The Cambridge Crystallographic Data Centre. See the
Supporting Information for details.
[33] Homochirality of adducts is supported by the good correlation of the
optical rotation sign and the uniform order of elution on the HPLC
chromatograms, except for the ethyl-substituted adduct 6Af, whose
configuration remains uncertain so far.
[16] a) J. Etxabe, J. Izquierdo, A. Landa, M. Oiarbide, C. Palomo, Angew.
Chemie Int. Ed. 2015, 54, 6883–6886; b) J. Izquierdo, J. Etxabe, E.
Duñabeitia, A. Landa, M. Oiarbide, C. Palomo, Chem. Eur. J. 2018,
7217–7227.
[34] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648-5652; b) C. Lee, W. Yang,
R. G. Parr, Phys. Rev. B 1988, 37, 785-789; c) S. Grimme, J. Antony, S.
Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104-1-19.
[35] a) V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995-2001; b) M.
Cossi, N. Rega, G. Scalmani, V. Barone, J. Comp. Chem. 2003, 24, 669-
281.
[17] C. Slowka, U. Engel, C. Syldatk, J. Rudat in Science of Synthesis,
Biocatalysis in Organic Synthesis, Vol 1 (K. Faber, W.-D. Fessner, N. J.
Turner, Eds.), Georg Thieme Verlag, Stuttgart, Germany, 2015, pp 373–
414.
[18] Pharmacologically active N3-aryl hydantoins: Nilutamide (used in the
treatment of prostate cancer) a) W. Kassouf, S. Tanguay, A. G. Aprikian,
J. Urol. 2003,169, 1742−1744; BIRT-377 (LFA-1 Antagonist) b) N. S.
Chowdari, C. F. Barbas, Org. Lett. 2005, 7, 867–870. BMS-564929
(selective androgen receptor modulator (SARM)) c) W. Gao, J. T. Dalton,
[36] Gaussian 16, Revision D.01, M. J. Frisch et al., Gaussian, Inc.,
Wallingford CT, 2016 (for complete reference, see the SI).
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FULL PAPER
[37] a) J. S. Murray, T. Brinck, M. E. Grice, P. Poltzer, J. Mol. Struct.
(Theochem) 1992, 88, 29–45; b) T. Brinck, J. H. Stenlid, Adv. Theory
Simul. 2019, 2, 1800149/1-1800149/20.
[38] For strategies to enhance the H-bond donor ability of organocatalysts,
see: (Reviews) a) T. J. Auvil, A. G. Schafer, A. E. Mattson, Eur. J. Org.
Chem. 2014, 2014, 2633–2646; b) T. James, M. Van Gemmeren, B. List,
Chem. Rev. 2015, 115, 9388–9409. (Representative examples) c) Y.
Huang, A. K. Unni, A. N. Thadani, V. H. Rawal, Nature 2003, 424, 146;
d) A. K. Unni, N. Takenaka, H. Yamamoto, V. H. Rawal, J. Am. Chem.
Soc. 2005, 127, 1336–1337; e) S. Rashdan, M. E. Light, J. D. Kilburn,
Chem. Commun. 2006, 3, 4578–4580; f) A. Hasegawa, Y. Naganawa, M.
Fushimi, K. Ishihara, H. Yamamoto, Org. Lett. 2006, 8, 3175–3178; g) M.
Ganesh, D. Seidel, J. Am. Chem. Soc. 2008, 130, 16464–16465; h) C.
R. Jones, G. Dan Panto, A. J. Morrison, M. D. Smith, Angew. Chem. Int.
Ed. 2009, 48, 7391–7394; i) N. Probst, Ú. Madarász, A. Valkonen, I.
Pápai, K. Rissanen, A. Neuvonen, P. M. Pihko, Angew. Chem. Int. Ed.
2012, 51, 8495–8499; j) D. M. Nickerson, V. V. Angeles, T. J. Auvil, S. S.
So, A. E. Mattson, Chem. Commun. 2013, 49, 4289–4291; k) L. Ratjen,
M. Van Gemmeren, F. Pesciaioli, B. List, Angew. Chem. Int. Ed. 2014,
53, 8765–8769.
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Entry for the Table of Contents
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J. Izquierdo, N. Demurget, A. Landa, T.
Brinck, J. M. Mercero, P. Dinér,* M.
Oiarbide,* C. Palomo*
Page No. – Page No.
Asymmetric Synthesis of Adjacent
Tri- and Tetrasubstituted Carbon
Stereocenters. Organocatalytic Aldol
Reaction of an Hydantoin Surrogate
with Azaarene 2-Carbaldehydes
Assembled by aldol: a highly diastereo- and enantioselective direct aldol reaction
between an hydantoin surrogate and azaarene 2-carbaldehyde N-oxides is enabled
by a multifunctional amine-squaramide-amide catalyst. The process serves to
assemble carbinol-tethered hydantoin-azaarene conjugates featuring vicinal
tertiary/quaternary carbon stereocenters.
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