Enantioselective Synthesis of 5,5-Disubstituted Hydantoins by Br?nsted Base/H-Bond Catalyst Assisted Michael Reactions of a Design Template

Article abstract of DOI:10.1002/chem.201800506

A new method for the enantioselective synthesis of 5,5-disubstituted (quaternary) hydantoins was developed on the basis of an organocatalytic Michael reaction approach involving the use of 2-benzylthio-3,5-dihydroimidazol-4-ones as key hydantoin surrogates. The method is general with respect to the substitution pattern at the hydantoin N¹ (alkyl, aryl, acyl), N³ (aryl), and C⁵ (linear/branched alkyl, aryl) positions and affords essentially single diastereomeric products with enantioselectivities higher than 95 % ee in most cases. Among the bifunctional Br?nsted base/H-bond catalysts examined, a known squaramide–tertiary amine catalyst and a newly prepared squaramide–tertiary amine catalyst provide the highest selectivity so far with either nitroolefins or vinyl ketones as the acceptor components. Kinetic measurements support a first-order rate dependence on both reaction partners, the donor template and the Michael acceptor, whereas competitive ¹H NMR spectroscopy experiments reveal the high ability of the template for catalyst binding.

Full text of DOI:10.1002/chem.201800506

A Journal of
Accepted Article
Title: Enantioselective Synthesis of 5,5-Disubstituted Hydantoins via
Brønsted Base/H-Bond Catalysts Assisted Michael Reactions of
a Design Template
Authors: Joseba Izquierdo, Julen Etxabe, Eider Duñabeitia, Aitor
Landa, Mikel Oiarbide, and Claudio Palomo
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To be cited as: Chem. Eur. J. 10.1002/chem.201800506
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Enantioselective Synthesis of 5,5-Disubstituted Hydantoins via
Brønsted Base/H-Bond Catalysts Assisted Michael Reactions of a
Design Template.
Joseba Izquierdo, Julen Etxabe, Eider Duñabeitia, Aitor Landa, Mikel Oiarbide,* Claudio Palomo*[a]
Abstract: A new method for the enantioselective synthesis of 5,5-
disubstituted (quaternary) hydantoins has been developed based on
an organocatalytic Michael reaction approach using 2-benzylthio-3,5-
dihydroimidazol-4-ones as key hydantoin surrogates. The method is
general with respect to the substitution pattern at the hydantoin N1
(alkyl, aryl, acyl), N3 (aryl) and C5 (linear/branched alkyl, aryl) positions
and affords essentially single diastereomeric products with
enantioselectivities higher than 95% ee in most cases. Among the
Figure 1. Conventional synthesis of optically active 5,5-disubstituted hydantoins
bifunctional Brønsted base/H-bond catalysts examined, the
squaramide-tertiary amine catalyst C2 and the newly prepared C3
provided the highest selectivity so far with either nitroolefins or vinyl
ketones as the acceptor components. Kinetic measurements support
a first order rate dependence on both reaction partners, the donor
template and the Michael acceptor, while competitive 1H NMR
experiments reveal a high ability of the template for catalyst binding.
from the chiral pool.
Although alternative routes from ketones or -dicarbonyl
compounds exist,[11] the main synthetic route to 5-substituted
hydantoins starts from the corresponding -amino acid
derivatives,[17] which is condensed with an isocyanate or
equivalent with the assistance of some highly reactive coupling
reagent (Figure 1).[18] While this route is in principle simple and
straightforward, its realization depends on the availability of the
corresponding -amino acid precursor in enantiomerically pure
form. This is a serious problem, especially when 5,5-disubstituted
(quaternary) hydantoins are targeted.[19]
Introduction
Hydantoins (2,4-imidazolidinediones) constitute
a family of
nitrogen heterocycles that are present in natural products[1] and
comprise a variety of pharmaceutical uses.[2] In particular, 5-
substituted and 5,5-disubstituted hydantoins are important
medicinal compounds.[3] Examples include the anticonvulsant
phenytoin, used for the treatment of epilepsy and cardiac
arrhythmia,[4] and compounds with activity as antidepressant,[5]
antiviral,[6] inhibitors of platelet aggregation,[7] of human aldose
reductase,[8] and of human leukocyte elastase,[9] or antagonist for
use in Hedgehog pathway-dependent malignancies.[10] On the
other hand, hydantoins are also interesting from a purely chemical
point of view.[11] 5-Substituted hydantoins have been employed in
the context of molecular recognition,[12] chiral auxiliaries in organic
synthesis,[13] or constituents of optically active polymers[14] and
metal complexes.[15] Structurally, they can be viewed as masked
-amino acids and, as such, 5-substituted hydantoins also serve
as precursors to unnatural -amino acid derivatives.[16]
Figure 2. Advances in the asymmetric synthesis of 5,5-disubstituted hydantoins
involving C-C bond construction.
[a]
Prof. C. Palomo, Prof. M. Oiarbide, Dr. Aitor Landa, Joseba
Izquierdo, Julen Etxabe, Eider Duñabeitia
Departamento de Química Orgánica I
Universidad del País Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastián, Spain
Fax: (+34) 943015270
Only very recently have practical syntheses of enantiomerically
enriched quaternary hydantoins involving new carbon-carbon
bond forming reactions been reported. Clayden has developed
an elegant protocol to access quaternary hydantoins and
compounds derived thereof in good diastereoselectivity based on
a substrate-controlled anionic aryl group N→C rearrangement on
lithiated ureas[20] (Figure 2a). On the other hand, Terada has
recently reported a chiral phosphoric acid-catalyzed Friedel-
E-mail: claudio.palomo@ehu.es
Supporting information for this article is given via a link at the end of
the document.
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Crafts-type addition of 2-methoxyfuran to in situ generated
ketimines (Figure 2b).[21] Despite these significant advances, the
scope of available optically active quaternary hydantoins
continues to be rather narrow, essentially restricted to some
particular 5-aryl substituted subfamilies.
Recently we found[22a] that heterocycles I can react smoothly
with some Michael acceptors (i.e., nitroolefins and an acrylate
equivalent) triggered by bifunctional Brønsted base/H-bond
catalysts, thus serving, via the intermediate hydantoin, as N-
substituted -amino acids surrogates. Here we present a full
study on the ability not only of I, but also of the related
heterocycles II and III, to engage in bifunctional Brønsted base/H-
bond catalysed highly enantioselective Michael reactions with
some selected acceptors, including simple vinyl ketones. This
work, which discloses a newly prepared and active squaramide-
tertiary amine catalyst C3, represents the first catalyst-controlled,
enantioselective and broad-scope method for the synthesis of
5,5-disubstituted (quaternary) hydantoins with a variety of
substitution patterns at N1, N3 and C5. (Figure 3).
Scheme 1. Our preliminary finding (ref 22a).
enantioselectivity. In some instances, particularly with aliphatic
nitroolefins (R= alkyl), catalyst C1 led to modest
diastereoselectivities, but using C2[26] instead, both the diastereo-
and the enantioselectivity were high. Importantly, this system
tolerated well a range of dihydroimidazolones 1 with varying
substituents at N1 (R2: alkyl, allyl, aryl) and C5 (R1: linear and
branched alkyl groups), including bicyclic dihydroimidazoles (R1,
R2= (CH2)3). One of the problems of using template 1, or in
general structures I (R2: alkyl or aryl), is their limited thermal
stability as they partially decompose upon storage at room
temperature for several hours, or during standard silica gel
chromatographic purification, making storage in the freezer at –
40 °C necessary.
Figure 3. Template-based catalytic enantioselective synthesis of diversely
substituted quaternary hydantoins.
Results and Discussion
Background and working plan. We have recently
communicated a novel, highly enantioselective approach for the
synthesis of N-substituted -amino acid derivatives via the
corresponding enantioenriched 1,5,5-trisubstituted hydantoins 3
(Scheme 1).[22] A distinguishing feature of this sequence is that
the synthesis of hydantoins 3 no longer relies on the availability
of the precursor -amino acid in enantiopure form; instead, 3 is
prepared through a Brønsted base catalyzed conjugate addition[23,
24] of racemic dihydroimidazolones 1, followed by basic hydrolysis
of the resulting Michael adduct 2. The 1→2 transformation serves
to install a second substituent at C5 of the heterocycle while
creating a new tetrasubstituted carbon stereocenter adjacent to a
tertiary one with high diastereo- and enantioselectivity. To the
best of our knowledge, methods for that goal have not been
described yet.[11] During these preliminary studies we found that
the squaramide/tertiary amine catalysts pioneered by Rawal,[25]
such as C1, efficiently promoted the addition reaction of 1 to
aromatic nitroolefins under very smooth conditions (CH2Cl2 at –
20 ºC) affording the corresponding adducts 3 (EWG=NO2) in
diastereomeric ratios typically higher than 9:1 and excellent
Figure 4. Enolization of templates leading to enolates with aromatic character.
Given the simplicity and the high selectivity of the method, and
the mild reaction conditions involved, we sought to investigate the
behaviour of the related heterocyclic systems II and III. If
successful, a broad-scope approach for the enantioselective
synthesis of diversely 1,3,5-substituted hydantoins would be at
hand. The effectiveness of template I to react under the above
soft enolization conditions may be ascribed to the aromatic
character of the transiently formed enolate I’ (Figure 4). From a
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similar reasoning, it was envisaged that the related heterocylic
systems II (N1-acyl) and III, would lead, in the presence of a base
promoter, the corresponding aromatic enolates II’ and III’.
against nitroolefins under the same conditions previously reported
for the N-alkyl/aryl congeners 1 was evaluated. Gratifyingly, as
the brief screening in Table 1 shows, the reaction of N-acetyl 8C
Moreover, in view of the structural similarities of the three enolates, with nitrostyrene 25a to afford adduct 26Ca proceeded at room
their interaction with the protonated amine/squaramide catalyst
might be equally productive in affording the Michael addition
adducts.
temperature in the presence of various bifunctional Brønsted
base catalysts with remarkable selectivity, whilst reactivity was
more catalyst-dependent. For instance, both catalysts C1 and C2
were able to afford adduct 26Ca as a 97:3 mixture of
diastereomers in very high (but opposite) enantioselectivity,
although no full conversion could be reached in either case after
24 h (entries 1, 5). As expected, catalyst ent-C1 (entry 2) afforded
the same enantiomer as C2 with reproducible reactivity and
selectivity compared to C1 and was employed from this point on.
Preparation of substrates. The preparation of N-acyl templates
8–11 was carried out by the sequence described in Scheme 2a.
Racemic hydantoins 4–7, prepared in bulk quantities through
classic condensation reactions of the corresponding free or N–
acyl amino acids and suitable reagents,[27, 28, 29] were first silylated
with trimethylchlorosilane and triethylamine, and then treated with
benzyl bromide, to afford, after aqueous work-up, the desired N1-
acyl 2-benzylthioimidazolone 8–11. It is important to note at this
point that these compounds turned out to be solids and
comparatively more stable than the corresponding N-alkyl and
aryl compounds I. For instance, compounds 8–11 showed to be
perfectly stable at room temperature for several days. On the
other hand, the preparation of the N3-aryl templates 19–24
(Scheme 2b) started with the condensation of the respective
amino acid with phenyl(aryl) isothiocyanate 12 and triethylamine
to yield thiohydantoins 13–18. Each one was S-benzylated by
treatment with benzyl bromide and diisopropyl ethyl amine to yield
19–24, which also resulted to be bench-stable compounds.
Table 1. Catalyst screening for the reaction of 8C/9C with nitrostyrene 25a (R:
Ph).[a]
Entry Catal. R2
T [ºC]
t [h]
Conv [%]
dr
ee [%]
1
C1
COMe
RT
RT
RT
–20
RT
RT
–20
RT
RT
–20
RT
RT
24
24
16
96
24
16
96
16
4
80
97:3
97:3
>98:2
--
–98
98
98
--
2
ent-C1 COMe
80
3
COPh
>98
NR
50
4
5
C2
C3
COMe
COPh
97:3
>98:2
>98:2
98:2
98:2
>98:2
90:10
80:20
98
97
98
99
99
98
99
90
6
>98
65
7
8
COMe
COPh
90
9
>98
>98
95
10
11
12
48
16
16
C4
C5
COMe
COMe
60
Scheme 2. Preparation of N1-acyl and N3-aryl 2-benzylthio-3,5-dihydroimidazol-
4-ones.
[a] The reactions were performed using 0.3 mmol of 8C/9C, 0.6 mmol of
nitrostyrene and 10 mol% catalyst in 0.6 mL CH2Cl2. Ee of major diastereomer
as determined by HPLC
Reactions of N1-acyl 2-thiobenzyl-3,5-dihydroimidazol-5-
ones. To assess the viability of these substrates, their behaviour
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Table 2. Scope of the reaction of N1-acyl 2-benzylthio-3,5-dihydroimidazol-4-ones 8–11 with nitroalkenes 25.[a]
[a] Reaction conditions: dihydroimidazolones 8–11 (1 eq, 0.2 mmol), nitroolefins 25 (2 equiv, 0.4 mmol), and C3 (10 mol %) were stirred at 20 °C in 1.0 mL of
CH2Cl2 for 16 h unless otherwise stated. Diastereomeric ratios and ee were determined by HPLC. [b] Reaction run for 48 h. [c] Reaction performed in
deoxygenated dimethoxyethane at 50 °C using 5 equiv. of nitroalkene and 20 mol% catalyst. [d] Reaction run for 72 h.
The newly developed catalyst C3[30] was more active, leading to
essentially full conversion after 24 h (90% conversion after 16 h)
with nearly the same degree of diastereo- and enantiocontrol
(entry 8). Regardless the catalyst employed, the N-benzoyl
analog 9C proved to be more reactive than the N-acetyl derivative
8C and upon reaction with nitrostyrene afforded the
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corresponding adduct 27Ca, again, in essentially perfect
diastereo- and enantioselectivity (entries 3, 6 and 9). This same
order of catalyst activity, namely ent-C1 < C2 < C3, was observed
at subzero temperatures, despite the fact that ent-C1 is perfectly
soluble, while both C2 and C3 were only partially soluble. Thus,
whilst ent-C1 was completely unactive at –20 °C, C2 (entry 7) and
specially catalyst C3 (entry 10), did promote the reaction between
9C and nitrostyrene at that temperature, affording compound
27Ca in very high stereoselectivity. It was also observed that
cinchona-based squaramide catalyst C4[31] was equally active,
albeit less selective (dr 90:10, entry 10), whilst the corresponding
thiourea analog C5[32] was both less active and selective (entry
11). In their turn, quinine and (DHQD)2PYR were completely
ineffective catalyst for this reaction. With these initial results in
hand, the scope of the reaction was explored using catalyst C3,
albeit ent-C1 and C2 could be employed with almost equal
effectiveness. As the data in Table 2 show, the reactions were
performed at room temperature and worked uniformly well for N-
acyl heterocycles 8/9 bearing a variety of substituents at the C5
position of the heterocycle (benzyl, short and large linear alkyl,
At this stage, the efficacy of this catalytic system against simple
vinyl ketones, a less active but yet relevant Michael acceptor
category, was explored. Initial screening of catalysts for the
reaction of 9C with methyl vinyl ketone 30a as representative
reaction model (Scheme 3), showed a trend in catalyst activity
and selectivity similar to that observed with nitroalkenes. Thus,
ent-C1 could promote the addition of 9C to 30a, although the
reaction progressed slowly and with suboptimal enantioselectivity.
In contrast, catalyst C3 and, especially, C2 resulted comparatively
more active (reaction conversion after 48 h at room temperature,
70% and 85%, respectively) and led to ee’s of 95% and 96%.
Table 3. Reaction of N-acyl 2-benzylthioimidazolones 9–11 with vinyl
ketones 30.[a]
branched alkyl, heteroalkyl).
A range of 5,5-disubstituted
cycloadducts 26/27 were isolated in very high yields and
enantioselectivities, and in dr generally 94:6, adduct 27Cd
(dr=74:26) being an exception. The reactions involving the more
problematic aliphatic nitroolefins did also proceed with very good
diastereo- and enantioselectivity (adducts 27Cj and 27Ck).
However, these latter substrates resulted comparatively less
reactive than the aromatic congeners and required 5 equiv. of
nitroalkene and 20 mol% catalyst in DME at 50 ºC for practical
reaction conversions. Under these conditions, deoxygenated
solvent was optimal to prevent -hydroxylation reaction.
Dihydroimidazolone templates with N-Boc and N-Cbz groups (10
and 11) were also competent substrates for this reaction,
affording adducts 28 and 29 with essentially perfect
stereoselectivity and good yields. As formation of product 28Ia in
69% yield and high selectivity proves, the method is also suitable
for templates with an aryl group at the C5 position. It should be
mentioned that in some instances and under extended reaction
times the formation of small amounts (~5%) of overaddition of the
initially formed adduct to a second molecule of nitroolefin was
observed. Adjusting the reaction time was generally enough to
minimize or even cancel this undesired side reaction properly.
[a] The reactions were performed using 0.3 mmol of 9-11, 0.6 mmol of vinyl
ketone 30 and 10 mol% catalyst C2 in 0.6 mL CH2Cl2. Ee determined by
HPLC.
Then the reactions of 9, 10 and 11 with vinyl ketones 30 were
explored, using C2 as the catalyst. As data in Table 3 show,
independently of the substitution pattern, each vinyl ketone 30a-
d was equally competent reaction partner giving rise to the
respective Michael adducts 31-33 in generally good yields and
selectivities. On the other hand, intrinsically less reactive Michael
acceptors, such as -unsaturated esters and, in particular,
acrylates, were not competent reaction partners. However, this
deficiency may be surmounted in part by using the -hydroxy
Scheme 3. Catalyst screening for the reaction of 9C with methyl vinyl ketone
30a.
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enone 30e, an acrylate equivalent (vide infra) very easy to
prepare from acetone or commercially available 3-hydroxy-3-
methyl-2-butanone in two steps.[33] Thus, adducts like 31Ce, 32Ce
and 32Ie were obtained in good yield and selectivity, and, as will
be shown later, could be converted into the corresponding
carboxylic acid product through conventional ketol cleavage.
Table 4. Scope of the catalytic reaction of N3-substituted 2-benzylthio-3,5-dihydroimidazol-4-ones with nitroolefins.[a]
Entry
Ar
R1
R
Product
Catalyst
Yield [%]
dr
ee [%]
1
Ph
Me
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-NCC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
4-Me2NC6H4
Ph
34Ab
34Ac
34Ad
34Ae
34Af
C2
C2
C2
C2
C2
C2
C3
C2
C3
C2
C2
C2
C3
C2
C2
C2
C2
C2
C2
C2
C2
95
94
86
90
88
87
83
85
86
94
92
90
92
90
85
90
89
90
86
91
90
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
84:16
95:5
99
99
99
99
96
97
96
90
90
98
99
98
99
99
86
99
97
94
99
94
87
2
Ph
Me
3
Ph
Me
4
Ph
Me
5
Ph
Me
6
Ph
Me
34Ag
34Ag
34Ah
34Ah
34Ai
7
Ph
Me
8
Ph
Me
9
Ph
Me
70:30
>98:2
>98:2
93:7
10
11
12
13
14
15
16
17
18
19
20
21
Ph
Me
Ph
Me
34Ak
34Ca
34Ca
34Da
34Ga
34Ha
35Aa
36Aa
37Aa
38Ae
39Ah
Ph
Bn
Ph
Bn
Ph
91:9
Ph
(CH3)2CHCH2
Ph
>98:2
>98:2
>98:2
93:7
Ph
MeSCH2CH2
Ph
Ph
MeO2CCH2CH2
Ph
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-ClC6H4
Me
Me
Me
Me
Me
Ph
Ph
>98:2
>98:2
>98:2
>98:2
Ph
2-ClC6H4
4-MeOC6H4
[a] Reaction conditions: 19–24 (1 eq, 0.3 mmol), 25 (2 equiv, 0.6 mmol), catalyst (10 mol %) were stirred at ‒20 °C for 15–20 h in 0.6 mL of CH2Cl2. Diastereomeric
ratio and ee for the major diastereomer were determined by HPLC.
Reactions of N3-aryl 2-thiobenzyl-3,5-dihydroimidazol-4-ones
19–24 with nitroolefins. In all examples shown the masked
hydantoins of type I/II were used exclusively. Accordingly, the
hydrolysis of the isothiourea moiety of the resulting adducts would
deliver a route to N3-unsubstituted hydantoins (see below). In
order to develop a similar catalytic approach useful for the
synthesis of the complementary N3-protected N1-unsubstituted
hydantoins, we next studied the behaviour of 2-benzylthio-
dihydroimidazolones 19–24. While it was expected that these
compounds would also provide an extended pseudoaromatic
enolate species III’ upon enolization in the presence of a
bifunctional Brønsted base catalyst (Fig 4), whether or not these
latter would react as efficiently as I’/II’ was unanswered yet. To
begin the study, the reaction of 19A with -nitrostyrene 25a was
carried out in the presence of a base catalyst. As the results in
Scheme 4 show for the titled reaction, catalyst ent-C1 was able to
promote the formation of the contiguous quaternary and tertiary
carbon stereocenters of 34Aa with good isolated yield, moderate
diastereoselectivity (62:38) and very high enantioselectivity for
the major isomer. Under such smooth reaction conditions, among
the catalyst examined, both catalysts C2 and C3 were, once again,
the best in affording product 34Aa in nearly quantitative yield,
diastereoselectivities higher than 95:5 and excellent
enantioselectivity (96% and 95% ee, respectively, for the almost
exclusive diastereomer).
With catalyst C2 selected for further reaction development,
the robustness of the method with respect to structural variation
of both reactants was explored (Table 4). As data in entries 1–11
illustrate, aryl-substituted nitroolefins 25a-k with either electron-
reach, neutral or poor character were equally competent reaction
partners affording upon reaction with 19A the corresponding
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templates I–III under the present soft enolization conditions, the
behavior of 5C, 13A, 42 and 44, four parent thiohydantoins with
comparable substitution patterns at N1 and N3, was explored
(Scheme 6). Initial control experiments showed that, in contrast to
templates I–III (see above), none of these four thiohydantoins
reacted at all with nitrostyrene 25a in the presence of catalyst C3
at low temperature (experiments carried out at –20 °C). This lack
of reactivity was most evident in the case of thiohydantoin 5C
which remained unchanged even after stirring the mixture for 24
h at 0 °C. We ascribe the comparatively higher reactivity of
templates I–III to their tendency towards enolization owing to the
aromatic character of the resulting enol/enolate intermediate
species. At higher temperatures (0 °C) N3-phenyl thiohydantoin
13A reacted with nitrostyrene 25a in the presence of catalyst C3,
but product 41 was obtained as a 1.9:1 mixture of diastereomers.
Similarly, N1-methyl thiohydantoin 42 also reacted with
nitrostyrene 25a at 0 °C, but, again, led to a roughly equimolecular
mixture of diastereomers with marginal enantioselection. In its
turn, it has been reported by Rios[35] that 13l upon treatment with
nitrostyrene at room temperature gave a complex mixture. Finally,
the N,N-dibenzoyl derivative 44 showed to be completely
unreactive under these conditions.
Scheme 4. Catalyst screening for the reaction of 19A with nitrostyrene.
adducts 34A in very good yields and with nearly perfect diastereo-
and enantioselectivity in most cases. During this substrate
screening, catalyst C3 revealed to be less efficient than C2, as
the inferior diastereoselectivity attained for products 34Ag and
34Ah indicates (compare entries 7/6 and 9/8). Variation of the R1
substituent of the imidazolidinone substrate did not have any
appreciable impact on the reaction outcome. Thus, not only
methyl, but also benzyl (entries 12, 13) and other alkyl (entry 14)
and functionalized chains (entries 15, 16) were tolerated at the
substrate C5 position without affecting the reaction efficiency and
selectivity. On the other hand, as the results in entries 17-21
demonstrate, N3-aryl substrates 20-24 bearing aryl groups other
than phenyl also participate in this reaction satisfactorily.
Scheme 5. Reaction of 2-benzylthiodihydroimidazolones 19A with vinyl
kenones 30a and 30e.
Vinyl ketones also were competent electrophilic partners in the
reactions of N3-substituted 2-benzylthioimidazolones 19–24.
However, in contrast to what was observed with nitroalkenes, the
reactions involving vinyl ketones followed two divergent pathways,
one producing the 5-addition products 40 and the 3-addition path
leading to product 40’ (Scheme 5). Configuration of products 40’
was not determined and that of products 40 was assigned by
assuming a uniform reaction mechanism. Attempts to favour
either reaction pathway were unsuccessful and, regardless the
catalyst and reaction temperature, an essentially equimolar ratio
of either product was formed for the studied cases (Scheme 5).
Similar observations were previously reported in BB-catalyzed
addition reactions involving azlactones as the nucleophile.[34]
Scheme 6. Reactivity profile of the related thiohydantoins 5C, 13A, 13l, 42 and
44. SM: starting material.
Hydrolysis of adducts into 5,5-disubstituted hydantoins.
Removal of the benzylthio adjuvant from adducts obtained
through these series of catalytic conjugate addition reactions
Control experiments using the related thiohydantoins. To put
in context the reactivity and, particularly, selectivity profiles of
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could be carried out by hydrolysis under various convenient
conditions. As shown in Scheme 7, treatment of N1-benzoyl
adduct 27Ca with HCl 6M in dioxane at 65 °C for 6 hours gave
rise to the corresponding N-acyl hydantoin 45 in 80% yield.
Subsequent treatment of 45 with NaOH 6M at 100 °C produced
the free hydantoins 47 in 77% yield. On the other hand, the same
acid hydrolytic conditions applied to N-Boc adduct 28Ca induced
concomitant deprotection of Boc group affording hydantoin 47.
Interestingly, alkylation of imide nitrogen in product 45 under
standard Williamson conditions allowed access to the
corresponding N-benzyl adduct 46 in good yield. In its turn,
hydrolysis of N3-phenylthio-4,5-dihydroimidazol-4-one 34Aa to
the respective hydantoin 48 could be carried out by treatment with
HCl 1M at room temperature. Temperature control for this
reaction is important for clean hydrolysis. The same reaction
carried out at more forcing conditions (65 °C) led to a 1:1 mixture
of compounds 48 and the thio-analog 49. In any event, the
resulting adduct 48 could be fully converted into its thiohydantoin
analog 49 applying Lawesson ’ s reagent, which served to
establish the compound identity and configuration by X-ray
analysis. On the other hand, Nef type oxidation of the nitro group
in 48 under Mioskowski conditions[36] proceeded smoothly to
furnish the carboxylic acid 50 in 79% isolated yield.
Configurational integrity of adducts was not affected during all
these transformations and the final products were obtained as
essentially single enantiomer (99% ee).
sequence. Both amides 53 and 54 have been reported to present
significant inhibitory activity as ADAMTS (A disintegrin and
metalloproteinase inhibitors).[37] Starting from adduct 32le (Table
2, 82%, 91% ee), an acid hydrolysis of the S-benzylisothiourea
moiety in dioxane at 65 °C, followed by ketol oxidative scission
with HIO4, provided carboxylic acid 52 in 74% yield over two steps.
Final coupling of acid 52 with piperidine and N-phenyl piperazine
using EDC/HOBt coupling reagent led to amides 53 and 54 in
65% and 70% yield, respectively. These examples show that
adducts can be manipulated easily, with minimum production of
waste organic materials (e.g. acetone is obtained as byproduct in
the 5152 transformation) and, most important, with preserved
configurational integrity.
Scheme 8. Synthesis of ADAMTS (A disintegrin and metalloproteinase)
inhibitors 53 and 54.
Mechanistic insights. Several experiments were carried out in
order to get insights on the reaction mechanism. In a first set of
experiments (Figure 5), the conversion for the reaction between
10C and 25a was measured as a function of time, maintaining the
concentration of 25a pseudoconstant (15 equiv.) and in the
presence of 10 mol% of catalyst C3. The plotting in of –
ln([10C]/[10C]ₒ) versus time gave a straight line (R2=0.996) which
indicates first-order dependence in the nucleophile.
R² = 0,981
3
2,5
2
1,5
1
R² = 0,996
0,5
0
0
100
200
300
Time, min
400
500
600
Scheme 7. Hydrolysis of cycloadducts to 5,5-disubstituted hydantoins and
further elaborations.
Figure 5. Plot of reaction conversion vs. time for the C3-catalyzed reaction
between 10C and 25a under pseudoconstant concentration of 25a () and 10C
(■).
Scheme 8 shows a specific application to the synthesis of
pharmacologically active constituents based on a three-step
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The reaction order in the electrophilic component was determined
similarly by measuring the reaction conversion as a function of
time under pseudoconstant concentration of nucleophile 10C (15
mol equiv.) and in the presence of 10 mol% of catalyst C3. In this
instance, plotting ln([25a]/[25a]ₒ) versus time afforded again a
straight line (R2=0.9815) indicating first-order reaction with
respect to the acceptor component too. Unfortunately, the
reaction order in the catalyst could not be determined by this
means due to the limited solubility of the catalyst.
chemical shifts when admixing the template 9C and the catalyst
(compare spectra 2, 3 and 5) seemed to be less pronounced, with
only a slight downfield shift of Hb. However, spectrum 6, in which
both substrates 25a and 9C must compete for best catalyst
binding, reveals that the molecular affinity between 9C and ent-
C1 is relatively high. Indeed, the chemical shift pattern of ent-C1
in 6, in particular the chemical shifts of both Ha and Hb, remained
essentially that of spectrum 5 and distinct from spectrum 4. These
observations reinforce the idea that the new hydantoin template
upon enolization would remain tightly bound to the catalyst during
the key C–C bond-forming event, allowing an efficient transfer of
chiral information.
100
90
80
70
60
50
40
30
20
10
0
0
20
40
60
80
100
Time (min)
Figure 6. Insets of 1H NMR spectra corresponding to individual samples of 9C,
25a, ent-C1, and three 1:1 combinations of them taken in CDCl3 at rt
(concentration ~0.1 M).
Figure 7. Conversions for the reaction between 9C and 25a catalyzed by C3
(▲) and its N-Me derivative (), respectively, under standard conditions.
On the other hand, the collective experimental data shown in
Tables 1–4 reveal the unique reactivity profile of templates I–III,
as opposite to the variable results attained with the parent
thiohydantoins (see Scheme 6). An interesting aspect of this high
reactivity is that it appears quite general regardless the catalyst
employed, and therefore it should be ascribed to an inherent
feature of the template design. As shown in the introductory
section (Fig 4), the pseudoaromatic character of the enolic forms
I’–III’ would facilitate the enolization process, but this effect alone
would not necessarily justify the subsequent reactivity against the
electrophilic acceptor. In order to get additional insights in this
respect, and more specifically with regard to the affinity of the
templates for these type of bifunctional catalysts, we performed
competitive 1H NMR experiments involving template 9C,
nitroolefin 25a and catalyst ent-C1 (Figure 6). Catalyst ent-C1 was
chosen because its complete solubility in halogenated solvents as
noted above. As the comparison of spectra 1, 2 and 4 shows,
admixing 25a and ent-C1 caused a slight downfield shift of the
olefinic protons Hc/Hd of 25a along with an upfield shift of Ha and
Hb of ent-C1, quite significant ( 0.1 ppm) in the former case,
clearly indicating some degree of molecular recognition between
nitrostyrene 25a and the catalyst. In its turn, variation of the
In order to get more insights on the structural/functional
requirements of these catalysts for optimal activity and selectivity,
the performances of catalyst C3, featuring a free NH amide, and
its N-Me derivative were compared. As the conversion profiles in
Figure 7 show for the reaction between 9C and 25a, catalyst C3
resulted significantly more active than its N-methylated form. For
instance, with C3 the reaction conversion was over 70% after 30
min at RT (over 90% after 1 h), whilst with C3-NMe barely reached
27% after 30 min (45% after 1 h). While erosion of the
stereoselectivity was less important (C3, dr=98:2, 99% ee, Table
1, entry 9; C3-NMe, dr>98:2, 90% ee), the difference in catalyst
activity is significant, especially considering that, unlike C3, C3-
NMe is completely soluble, and may be attributable to the ability
of the free amide in C3 for additional H-bonding. Although the
number of individual H-bond interactions within the substrate-
catalyst complex in the transition state, and their precise
orientation, are unknown yet, and based on previous studies in
the literature for related catalytic systems,[38] a simultaneous
activation of both reactants as in stereomodels A/A’ (Figure 8)
may be proposed tentatively for the reactions catalyzed by C3.
The free amide NH would be H-bonded internally as in A, to assist
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catalyst preorganization, or intermolecularly as in A’ to better fix
one of the approaching reactants. Similar models are conceivable
for the remaining templates and catalysts in which the
approaching trajectory of both reactants correctly explains the
observed configuration, both relative and absolute, of adducts.
Experimental Section
For detailed description of the experimental procedures (preparation of
templates, catalytic enantioselective reactions, transformations of adducts,
kinetic measurements), characterization of compounds, and
spectroscopic/chromatographic information, please see the Supporting
Information.
CCDC 1581118 and 1581122 contain the supplementary crystallographic
data for this paper. These data are provided free of charge by the
Cambridge Crystallographic Data Centre.
Acknowledgements
Finantial support was provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(Grant No IT-628-13), and Ministerio de Economía
y
Competitividad (MEC, Grant CTQ2016-78487-C2), Spain. J.I.
thanks UPV/EHU, and J.E. to MEC, for fellowship. We also thank
SGiker (UPV/EHU) for providing NMR, HRMS, and X-Ray
resources.
Figure 8. Plausible TS stereomodels for the C3-catalyzed reaction between
templates II and nitroolefins.
Conclusions
Keywords: hydantoins •-amino acids
•
quaternary
A new, quick entry to the enantioselective synthesis of 5,5-
disubstituted hydantoins has been developed based on an
organocatalytic Michael reaction approach using easy to prepare
and handle 2-benzylthio-3,5-dihydroimidazol-4-ones as key
hydantoin surrogates. The method is general with respect to the
substitution pattern at the N1 (alkyl, aryl, acyl), N3 (aryl) and C5
(linear/branched alkyl, aryl) positions of the resulting hydantoins
and affords essentially single diastereomeric products with
enantioselectivities higher than 95% ee in most cases. These
hydantoin surrogates demonstrate to be clearly superior to the
parent thiohydantoins which were inefficient in terms of reactivity
and/or selectivity under similar catalytic conditions. Among the
catalysts examined, C2 and the newly prepared squaramide-
tertiary amine catalyst C3 provided the highest selectivity in the
reactions with either nitroolefins or vinyl ketones as the acceptor
component. One designing advantage of C3 is its adaptability to
particular reaction needs owing to the easy modification of the
carboxamide unit. Kinetic studies of these catalytic Michael
reactions support a first order rate dependence on both donor and
stereocenters • asymmetric catalysis • Brønsted bases
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Entry for the Table of Contents
Layout 2:
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Joseba Izquierdo, Julen Etxabe, Eider
Duñabeitia, Aitor Landa, Mikel Oiarbide,*
Claudio Palomo*
Page No. – Page No.
Enantioselective Synthesis of 5,5-
Disubstituted Hydantoins via
Brønsted Base Catalyzed Michael
Reactions of a Design Template.
Hydantoins made easy: a general, catalytic and asymmetric procedure to access
5,5-disubstituted (quaternary) hydantoins is developed relying on the Brønsted
base catalyzed enantioselective C-functionalization of a design dihydroimidazolone
template with Michael acceptors.
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