β2, 2-Amino Acid N-Carboxyanhydrides Relying on Sequential Enantioselective C(4)-Functionalization of Pyrrolidin-2,3-diones and Regioselective Baeyer–Villiger Oxidation

Article abstract of DOI:10.1002/chem.201700464

A catalytic enantioselective entry to β^{2, 2}-amino acids enabling their direct coupling with nucleophiles is described. The approach is based upon an effective bifunctional Br?nsted base catalyzed construction of a quaternary carbon stereocenter at C₄ position of pyrrolidin-2,3-diones. Subsequent regioselective Baeyer–Villiger oxidation of the resultant adducts gives β^{2, 2}-amino acid N-carboxyanhydrides as the reactive species, which can further react with nucleophiles. Following this strategy both, β^{2, 2}-amino acid derivatives with different functionalities at the newly created stereocenter, and spirocyclic structures can be efficiently prepared.

Full text of DOI:10.1002/chem.201700464

A Journal of
Accepted Article
Title: beta-2,2-Amino Acid N-Carboxy Anhydrides Relying on
Sequential Enantioselective C(4)-Functionalization of
Pyrrolidin-2,3-diones and Regioselective Baeyer-Villiger
Oxidation
Authors: Claudio Palomo, Antonia Mielgo, Iurre Olaizola, Ana Vázquez,
Eider Badiola, and Silvia Vera
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To be cited as: Chem. Eur. J. 10.1002/chem.201700464
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Amino Acid N-Carboxy Anhydrides Relying on Sequential
Enantioselective C(4)-Functionalization of Pyrrolidin-2,3-diones
and Regioselective Baeyer-Villiger Oxidation
Eider Badiola, Iurre Olaizola, Ana Vázquez, Silvia Vera, Antonia Mielgo and Claudio Palomo*
Abstract: A catalytic enantioselective entry to 2,2-amino acids
enabling their direct coupling with nucleophiles is described. The
approach is based upon an effective bifunctional Brønsted base
catalyzed construction of a quaternary carbon stereocenter at C4
position of pyrrolidin-2,3-diones. Subsequent regioselective Baeyer-
Villiger oxidation of the resultant adducts gives 2,2-amino acid N-
carboxy anhydrides as the reactive species, which can further react
with nucleophiles. Following this strategy both, 2,2-amino acid
derivatives with different functionalities at the newly created
Figure 1. Different types of -amino acids.
stereocenter, and spirocyclic structures can be efficiently prepared.
latter has proven to be effective for the catalytic enantioselective
construction of 2,2-amino acids with an all carbon quaternary
Introduction
streocenter. Whilst the former approach cannot be used to
synthesize 2,2-amino acids, catalytic Mannich reactions have
Construction of tetrasubstituted carbon stereocenters,
particularly all carbon quaternary stereogenic centers is an
been hampered by the usual unstability of formaldehyde derived
imines.[8] A literature search indicates that conjugate addition of
important challenging goal within the domain of asymmetric
nucleophiles to -nitroacrylates,[9,10] and the reaction of -
synthesis.[1]
A
representative example is the catalytic
cyanoacetates with Michael acceptors,[11] are effective catalytic
enantioselective methods for the production of 2,2-amino acids
with a quaternary carbon stereocenter (Scheme 1). Several
other reaction types have also been reported for the synthesis of
2,2-amino acids. For instance, the Henry reaction of
nitromethane with -keto esters,[12] the catalytic asymmetric
acylation of (silyloxy) nitrile anions[13] and Sharpless
enantioselective synthesis of ,-disubstituted -amino acids.
Given their stability and conformational properties when
incorporated into peptides, their synthesis has focused much
attention over the years.[2] -Amino acids, on the other hand,
constitute another example of this interest, not only they are
important building blocks for a wide variety of natural products
and pharmaceutical agents, but also mimics of protein structural
motifs.[3] They are also precursors of -lactams, structural key
units of the most significant class of antibiotics.[4] -Amino acids
may be classified, Figure 1, into 2-, 3-, 2,3-, 2,2- and 3,3
-
amino acids depending upon the position of the R substituent.[5]
To date several methods to synthesize these types of -amino
acids with different substitution patterns exist.[6] However,
despite their interest, catalytic enantioselective entries to 2,2
-
amino acids, the homologous of ,-disubstituted -amino acids,
are currently very limited.[5,7] The most frequently employed
methods to synthesize -amino acids involve the catalytic
asymmetric hydrogenation of -dehydroamino acids, the
Mannich reaction and the conjugate addition of carbon
nucleophiles to ,-unsaturated systems. However, only the
Scheme 1. Catalytic enantioselective approaches to 2,2-amino acid
derivatives through conjugate addition reactions.
dihydroxylation of ,-disubstituted acrylates and subsequent
amino group installation.[14] However, in these cases, -hydroxy
2,2-amino acids may be produced only. Besides this narrow
range of enantioselective methods,[15] there is the fact that they
are generally accompanied by two general drawbacks, i) the
need for functional nitro and cyano group reductions to get the
corresponding -amino acid derivative, and ii) the need for
several protection/deprotection/activation steps for the
incorporation of the resultant 2,2-amino esters into a peptide
segment and/or transformation into a more complex product,
thus complicating somewhat the process. While in this context
there is still much room for improvement, new approaches to
quaternary 2,2-amino acids are also clearly needed. We have
Prof. C. Palomo, Dr . A. Mielgo, Dr. E. Badiola, Dr. I. Olaizola, Dr. S.
Vera and A. Vázquez
Departamento de Química Orgánica I
Universidad del País Vasco
Manuel Lardizábal, 3
20018, Donostia-San Sebastián, Spain
E-mail: Claudio.palomo@ehu.eus
Supporting information for this article is given via a link at the end of
the document.
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addressed these issues and we report here a concise novel
entry for the catalytic asymmetric synthesis of 2,2-amino acid
derivatives that may directly be combined with a nucleophile
coupling step.
even assuming these reasonable hypotheses, successful
implementation of the idea would require effective control of
reaction stereochemistry during the key C-C bond catalytic
forming event. Whilst pyrrolidin-2,3-diones are the core of
several natural products and drugs[21] and are excellent building-
blocks of alkylidene -lactams and derived products,[22] their
general use is hampered by the paucity of existing methodology
to build up chiral products by asymmetric catalysis. In this
context, Xu et al.[23] reported the reaction of 4-unsubstituted
pyrrolidin-2,3-diones with -enals via iminium catalysis but
spontaneous hemiketal formation makes this method unsuitable
for generation of quaternary stereogenic centers at C(4)
(Scheme 3a). To date, methodology for the stereoselective
construction of 4,4-disubstituted pyrrolidin-2,3- diones either
from 4-unsubstituted or 4-alkyl pyrrolidin-2,3- diones has not
been yet described. The most probable reason of this gap is the
tendency of pyrrolidin-2,3-diones to undoergo self aldol
condensation under basic or acid catalysis.[24] Not surprisingly,
pyrrolidin-2,3-diones have been mainly employed in a few
cycloaddition reactions, either racemic or asymmetric, through
their C(4)-alkylidene derivatives. Lin and Feng[25] described a
Diels-Alder reaction of C(4)-alkylidene pyrrolidin-2,3-diones with
The approach is very simple and is founded upon two key
elements, the design and identification of pyrrolidin-2,3-diones,
enabling catalytic enantioselective generation of an all-carbon
quaternary stereocenter at C position of the heterocycle and
their subsequent ring enlargement through a regioselective
oxygen insertion between both carbonyl groups to produce -
amino acid N-carboxy anhydrides (-NCAs).That is, for the first
time, these activated forms of -amino acids may be produced
from a non -amino acid precursor.[16]
Results and Discussion
Background and working plan: Probably, one of the most
direct access to 2,2-amino acids would be the catalytic
enantioselective nucleophilic -functionalization of -branched
-amino acids, (Scheme 2a). However, enolization of a amino
acid derivative by a soft Brønsted base is difficult owing to the
low acidity of the carbon and generally a stoichiometric (or
more) amount of strong base is required. Although only efficient
with reactive alkyl halides (ie, benzylic halides), an attractive
approach, in this context, is the phase-transfer catalytic
alkylation of 2-phenyl-2-imidazoline-4-carboxylic acid esters.[17]
However, only diamino acids may be obtained using this
approach. In fact, given the literature precedents noted above,
the catalytic enantioselective synthesis of 2,2-amino acids is still
underdeveloped. We considered the possibility to address this
deficiency by installing a carbonyl moiety adjacent to the
carboxyl group in the starting -amino acid, Scheme 2b, which
would result in a more reactive 1,2-dicarbonyl compound.[18]
Moreover, forming and intramolecular amide bond would result
in an even more acidic compound, a pyrrolidin-2,3-dione.
cyclopentadiene promoted by
a chiral N,N’- dioxide/Ni(II)
complex to furnish bridged C(4)-spiro pyrrolidin-2,3-diones
(Scheme 3b) and the group of Xu[26] reported the reaction with
allene ketones catalyzed by a cinchona alkaloid (Scheme 3c).
This latter method, however, cannot be employed to generate a
quaternary stereocenter at C4 of the pyrrolidin-2,3-dione ring. In
this regard, two further examples starting from C(4)-alkylidene
pyrrolidin-2,3-diones have also been reported, although in
racemic form[27,28] (Scheme 3d and 3e). We questioned whether
an enantioselective catalytic Brønsted base mediated C(4)-
functionalization of pyrrolidin-2,3-diones could be accomplished
to remediate the above deficiencies whilst broadening the
product scope.
Actually,
C(4)-substituted pyrrolidin-2,3-diones
have
a
pronounced tendency to enolization,[19] and therefore a weak
Scheme 2. Common (a) and designed (b) approaches to 2,2-amino acid N-
carboxy anhydrides.
Brønsted base might be sufficient for enolate generation to
promote the reaction with an electrophile under catalytic
conditions and, moreover, the resultant 4,4-disubstituted
adducts could be transformed, on the basis of previous work
from this laboratory,[20] into N-carboxy anhydrides, thereby
enabling subsequent couplings with nucleophiles. Nonetheless,
Scheme 3. Catalytic reactions of pyrrolidin-2,3-diones.
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






Synthesis of pyrrolidin-2,3-diones: For this study C(4)-
unsubstituted N-benzyl pyrrolidin-2,3-dione
4
and C(4)-
substituted pyrrolidin-2,3-diones 8 were selected (Scheme 4).
Pyrrolidin-2,3-dione 4 was prepared following the protocol[21d, 24b]
shown in Scheme 4a, which implies first the aza-Michael
addition of benzylamine 1 to methyl acrylate 2, followed by
cyclization with ethyl oxalate and further decarboxylation. For
the preparation of C(4)-substituted pyrrolidin-2,3-diones 8 the
same protocol was adapted (Scheme 4b). Thus, -substituted
acrylates 6[29] were reacted with the corresponding amine 5 in
the presence of RuCl3 H2O and PEG (polyethylene glycol).[30]
.
The resulting racemic -amino esters 7 upon treatment with
ethyl oxalate cyclisized and in situ decarboxylated to provide
compounds 8 in good yields. These compounds, in contrast to
pyrrolidin-2,3-dione 4, are essentially in their enolic form 9 as
shown by 1H-NMR spectra in CDCl3 solution.
Figure 2. Catalysts employed in this study.
produced essentially as a single enantiomer. When the N-
methylated catalyst C6 was examined little loss in
a
enantioselectivity was observed. In general, the amination
reaction of 9Aa9Ad with 10 promoted by C5 proceeded at low
Table 1. Catalytic -amination of enols 9 with tert-butylazadicarboxylate 10.[a]
Yield ee
[%][c] [%][d]
Product
Cat
T
t(h)[b]
11Aa R1:Me C1
0
0
0
0
0
0
2
2
1
1
1
1
85
95
92
97
93
92
16
20
80
78
99
90
C2
C3
C4
C5
C6
Scheme 4. Preparation of the starting pyrrolidin-2,3-diones 8.
11Ab R1:Bn
C5
C5
40
1
86
96
-Amination of pyrrolidin-2,3-diones: Considering their
significant advantages in the realm of cooperative asymmetric
catalysis,[31] several bifunctional Brønsted bases[32] were initially
evaluated[33] (Figure 2) for the reaction of the pyrrolidin-2,3-dione
enolic form 9A with tert-butyl azodicarboxylate 10, a highly
reactive acceptor that should provide rapid information about the
feasibility of this plan. Actually, in each case examined, it was
observed that the reaction proceeded cleanly, albeit in variable
levels of enantioselectivity. As the results in Table 1 show, whilst
thiourea (urea)-catalysts C1[34] and C2[34b] were quite unfruitful,
thesquaramides pioneered by Rawal[35,36] were the most
consistent catalysts. For example, using catalysts C3[37] and
C4,[35] product 11Aa was formed in enantioselectivities of 80%
eeand 78% ee, respectively. To improve the enantioselectivity
of the reaction we screened the recently developed new catalyst
C5,[38] which was prepared upon the assumption that an
additional hydrogen bond donor might be beneficial for
stereocontrol.[39] Actually, with this catalyst, product 11Aa was 
11Ac R1:Ph
20
40
1
1
81
77
92
95
11Ad R1:Et
C5
0
1
90
99
11Da[e]
11Ba[e]
11Ca[e,f]
C5 95%, 96% ee
C5 95%, 99% ee
C5 80%, 99% ee
[a]
The reactions were performed on a 0.20 mmol scale in 0.4 mL of CH2Cl2
(mol ratio 9 /tert-butyl azodicarboxylate 10: 1 / 1.5.
[b]
Time needed for total
[c]
[d]
conversion.
Yield of isolated product after chromatography.
Determined
[e]
by chiral HPLC.
Reactions conducted with C5 catalyst at 40 ºC for 1 h
otherwise stated. [f] 16 h were needed for complete conversion.
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Table 2. Conjugate additions to ’-silyloxy enone 15.[a]
temperature (20 ºC, 40 ºC and/or 0 ºC) to give products
11Aad, with very good yields and enantioselectivities between
9599% range. The reaction also seems to be independent on
the N-substituent of the starting pyrrolidin-2,3-dione enol form 9,
as each 9Ba, 9Ca and 9Da led to the respective aminated
products 11Ba, 11Ca and 11Da with good yields and ee´s up to
99%.
Conjugate addition to enones: We next examined the reaction
with the -silyloxy enone 15 (Table 2), an acrylate equivalent
recently documented by us.[40] For these reactions, as Table 2
illustrates, the N-methylated catalyst C6 was found to be the
best in comparison with catalyst C5 as well as catalysts C1-C4
giving products 16 with ee´s up to 96%. Whilst these results
suggest
a strong catalyst/substrate dependence for these
reactions, the advantages of this new modular subfamily of
squaramide catalysts when compared with common catalysts
such as C3 are evident, as several options for better catalyst/
substrate adaptation are easily generated by simple fine tuning
the carboxamide function. As Scheme 5 illustrates, these
catalysts may be prepared by coupling of 12 with (R,R)-9-deoxy-
9-epiaminoquinine 13 to provide intermediate 14. Subsequent
treatment of this squaramide carboxylic acid with N-methyl
imidazol, mesyl chloride[41] and the corresponding amine
provides catalyst C5 and C6 in acceptable yields.
[a] The reactions were performed on a 0.20 mmol scale in 0.4 mL of CH2Cl2 by
using 2 equiv. of silyloxy enone. Isolation of 16 was effected by desilylation
with AcOH in CH3CN/H2O; see S.I. for details. Yield of isolated product after
chromatography. Enantioselectivity determined by chiral HPLC. [b] Reactions
carried out at rt.
revealed that with both catalysts the stereochemical outcome of
the reaction appears to be independent upon the N-substitution
pattern of the pyrrolidin-2,3-dione employed. The N-naphthyl, N-
isopropyl and N-p-methoxyphenyl derivatives 9Ba, 9Bb, 9Ca
and 9Da respectively reacted with MVK to afford the
corresponding adducts 22Ba, 22Bb, 22Ca and 22Da with ee´s
between 9198% range. Furthermore, the reaction seems to be
general with respect to the enone component. For example,
pyrrolidin-2,3-dione enol form 9Ab reacted with ethyl vinyl
ketone 20, Table 3, in the presence of catalysts C3 and C6 to
afford product 23Ab in 82% ee and 88% ee, respectively. Under
same conditions, 4-methylphenyl vinyl ketone 21 provided in the
presence of C6 adduct 24Ab in 87% ee. In this instance,
catalysts, C1 and C3, led to 24Ab in 61% ee and 80% ee
respectively.
Scheme 5. Preparation of catalysts C5 and C6.
On the other hand, adducts 16Aa and 16Ba could be
transformed into the corresponding esters 17 and 18
respectively, by simple oxidative cleavage of the acyloin moiety
with NaIO4 and subsequent esterification. In each case acetone
is the only carbon byproduct formed which facilitates product
isolation. Interest in this transformation stems by the fact that
attempted formation of adducts 17 and 18 by reaction of the
corresponding pyrrolidin-2,3-dione with methyl acrylate failed
regardless the catalyst employed. The reaction with other
carbon-centered Michael acceptors further illustrates the
feasibility of the proposal. Thus, the reaction of 9Aa with methyl
vinyl ketone (MVK) 19 carried out at –10 ºC using catalyst C5
led to the product 22Aa in 75% yield and 88% ee (Table 3). For
this reaction, however, both C3 and C6 were found to be equally
effective giving the adduct 22Aa in 92% ee and 90% ee
respectively. Likewise, 22Ab was obtained from 9Ab and MVK
in good yield and 93% ee using catalyst C6 whilst catalyst C3
led to the adduct with almost same ee. Further experiments
The absolute configuration of the products from these reactions
was determined for compounds 11Ad and 16Ba by X-ray single
crystal structure analysis[42] and that of the remaining adducts
was established by assuming an uniform reaction mechanism.
Conjugate addition to nitroolefins: The conjugate addition
was next extended to nitroolefins with the aim to broaden the
pool of available 2,2-amino acids. In particular, we studied the
reaction of pyrrolidin-2,3-dione 4 with nitroolefins 25, Scheme 6,
wherein the resulting adducts would be attractive intermediates
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Table 3. Catalytic conjugate addition of pyrrolidin-2,3-dione derived enols 9 to
enones 19‒21.[a]
Scheme 6. Conjugate additions to nitroolefins.
We next focused on the reaction scope of the nitroalkene
counterpart using C7. As the results in Table 5 show, the
reaction was equally effective with nitrostyrenes bearing either
electron-poor or electron-rich substituents which afforded the
corresponding Michael adducts in 96‒97% ee. Significantly, the
reaction was also efficient with the more recalcitrant -alkyl
nitroalkenes 26e-h, as in these cases the corresponding adducts
were obtained in very good yields (78–98%) and excellent
enantioselectivity (96% ee). Attempts to extend this reaction
using pyrrolidin-2,3-dione enolic form 9A were disappointing.[44]
Table 4. Catalyst screening for the reaction of 4 with 25a (R = Ph) to give
26a.[a]
Cat (%)
T(ºC)
t(h)[b]
Conv.
(%)[c]
Yield
[%][d]
ee
[%][e]
C1 (5 mol%)
C3 (5 mol%)
C3 (5 mol%)
C3 (5 mol%)
C5 (5 mol%)
C6 (10 mol%)
C6 (10 mol%)
C6 (10 mol%)
C7(5 mol%)
0
rt
10
20
0
40
3
100
100
85
82
77
59
62
83
86
89
83
88
58
75
80
84
87
82
84
87
98
40
40
16
16
16
16
16
89
100
100
100
100
100
0
[a] The reactions were performed on a 0.20 mmol scale in 0.4 mL of CH2Cl2 by
using 2 equiv. of enone. Yield of isolated product after chromatography.
Enantioselectivity determined by chiral HPLC.
10
20
0
[a] The reactions were performed on a 0.20 mmol scale in 0.4 mL of CH2Cl2 by
using 1.1 equiv. of the nitroalkene. [b] Reaction time. [c] Conversion
determined in the reaction crude by 1H-NMR analysis. [d] Yield of isolated
product after chromatography. [e] Enantioselectivity determined by chiral
HPLC.
or precursors of unprecedented spirocyclic amino acid N-
carboxy-anhydrides. In a first instance, we explored the reaction
of pyrrolidin-2,3-dione 4 with nitrostyrene 25a (Scheme 6, Table
4) and found that whilst thiourea based catalyst C1 afforded
after 40
h at 0 ºC the Michael adduct 26a in poor
With these results in hand, we next investigated the
transformation of the previous Michael adducts in spirocyclic
derivatives[45] by treating them with acrolein in the presence of
pyrrolidine (Scheme 7a). At the onset, three possible spirocycles
could be generated from this approach. However, fortunately,
the reaction of 26a under these conditions revealed the
formation of only the diastereomeric spirocycles 27/28 in 80:20
ratio (55% isolated yield for 27) and neither A nor B were
observed. Similar results were obtained from nitro derivatives
26b and 26g, being in this latter case 27g the only diastereomer
observed. Lowering the temperature did not led to any change in
diastereoselectivity, but these data show that the reaction occurs
through a cascade Michael-Henry sequence,[46] involving first the
enantioselectivity (58% ee), the squaramide-type catalysts C3,
C5, C6 and C7 were more effective. For instance, catalyst C3
provided adduct 26a in 75% ee after 3 h reaction at rt, and
lowering the temperature to –20 ºC led to an improvement of
enantioselectivity up to 84% ee. Similarly, with both C5 and C6
the ee’s could be improved up to 87%, being C5 slightly superior
to C6. Thus, we then replaced the cinchona portion in C5 by a
tert-leucine derived diamine scaffold[43] and envisaged catalyst
C7.[29] It was gratifying to observe that this catalyst provided the
product in 98% ee.
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absolute configuration and that of the major diastereomer 27a
was assigned by NOE experiments and analysis of coupling
constants.[29] The configuration of the remaining adducts was
established by assuming an uniform reaction mechanism.

Table 5. Reaction scope of 4 with different nitroalkenes 25 catalyzed by C7. [a]

2,2-Amino acid N-carboxyanhydrides: Given the precedents
from this laboratory,[20] we questioned whether these 4,4-
disubstituted adducts upon Baeyer-Villiger oxidation could be
regioselectively transformed into the respective N-carboxy
anhydrides, that is, a carboxyl activated form of 2,2-amino acids
which would provide the opportunity to perform further couplings,
for instance, with -amino acid esters. We were pleased to find
that reaction of pyrrolidin-2,3-diones 11Aa, 16Ba, 22Da, 17 and
18, with m-chloroperbenzoic acid (m-CPBA)[49] proceeds with
complete regio- and chemoselectivity to give the respective -
amino acid derived N-carboxyanhydrides (-NCAs) 29‒33,
almost quantitatively and without products from oxidation of the
exocyclic carbonyl group (Scheme 8). To the best of our
knowledge, this is the first approach to a carboxyl activated form
of ,-disubstituted -amino acids instead of the most common
[a] The reactions were performed at 0 ºC on a 0.20 mmol scale in 0.4 mL of
CH2Cl2 by using 1.1 equiv. of the nitroalkene and catalyst C7 (5 mol%). The
resulting mixture was stirred at 0 ºC until total comsuption of the starting -
ketoamide (monitored by 1H-NMR). Yield of isolated product after
chromatography. Enantioselectivity determined by chiral HPLC.
Michael addition of the C(4) carbon of pyrrolidin-2,3-dione to
acrolein.[47] Significantly, treatment of 4 with nitrostyrene at 0 ºC
in the presence of C7 followed by addition of acrolein and further
Scheme 8. -amino acid N-carboxy anhydrides (2,2-NCAs) from 2,3-
dioxopyrrolidines and reaction couplings. PMP: p-methoxyphenyl, Naph:
Naphthyl.
Scheme 7. Synthesis of spirocyclic pyrrolidin-2,3-diones. a) Sequential
protocol. b) One-pot protocol.
free acids or esters,[50] and therefore products of relatively more
complexity may be made readily feasible by coupling of these
NCAs with appropriate nucleophiles. For example, 30, after
treatment with L-phenylalanine tert-butyl ester, furnished product
34 in 77% yield. Similarly, 33 reacted with benzylamine to
provide 35 in 72% yield, and the coupling of -NCA 29, prepared
reaction at rt for 16 h provided spirocyclic compounds 27a and
28a in the same diastereomeric ratio but better yield (Scheme
7b), thus showing that it is possible to carry all three reactions
(Michael to nitrostyrene/Michael to acrolein/Henry) without
isolation of intermediate 26a and by using only C7 as catalyst.
X-Ray analysis of the minor diastereomer 28a[48] provided its
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7.56 (m, 5H), 7.32 (dd, J = 9.2, 2.5 Hz, 1H), 6.40 (bs, 1H), 5.86 (ddd, J =
17.2, 10.4, 6.8 Hz, 1H), 5.32 – 4.97 (m, 2H), 4.50 (s, 1H), 4.05 – 3.53 (m,
5H), 3.51 – 3.11 (m, 2H), 2.84 (d, J = 9.0 Hz, 1H), 2.25 – 1.97 (m, 4H),
1.78 (t, J = 12.4 Hz, 1H), 1.22 (d, J = 13.9 Hz, 1H). 13C NMR (75 MHz,
Acetonitrile-d3) δ 185.7, 181.9, 171.9, 169.0, 166.5, 159.5, 149.0, 145.6,
142.4, 140.6, 139.6, 138.4, 132.8, 131.7 (q), 127.9, 127.0, 123.2, 122.7,
120.7, 120.6, 117.4, 117.0, 102.2, 60.4, 56.3, 55.3, 54.3, 42.2, 37.3, 27.6,
24.7, 24.2. UPLC-DAD-QTOF: C32H30N4O5F3 [M+H]+ calcd.: 607.2168,
found: 607.2175.
from 11Aa as above, with glycine ethyl ester afforded the -
tetrasubstituted -amino -hydrazino acid derived peptide 36 in
75% yield.[51] This coupling reaction also tolerates dipeptides,
even with relatively bulky groups, as shown in the preparation of
product 37 through coupling of 32 with the corresponding
dipeptide H2N-Val-Phe-OtBu.
Coupling of 14 with the corresponding amine: Obtention of C5 and
C6. 1-Methylimidazole (0.2 mL, 2.5 mmol, 2.5 equiv.) was added to a
slurry of 14 (606 mg, 1 mmol, 1 equiv.) in CH3CN (2.5 mL) at 0 °C, and
the mixture was stirred for 10 min. MsCl (0.12 mL, 1.5 mmol, 1.5 equiv.)
in CH3CN (0.5 mL) was added to the mixture under –5 °C. After stirring at
that temperature for 20 min, the corresponding amine (1 mmol, 1 equiv.)
was added. The mixture was then stirred at room temperature overnight.
H2O (10 mL) was added to the mixture and a solid precipitated. This solid
was solved with EtOAc (10 mL) and the organic layer was washed with
brine (3 x 50 mL) and dried over anhydrous MgSO4. The solvent was
evaporated under reduced pressure and the crude was purified by silica
flash column chromatography to afford the desired catalyst.
Scheme 9. -amino acid N-carboxy anhydrides (2,2-NCAs) from spirocyclic
derivative 27a and ring opening with glycine tert-butyl ester hydrochloride.
Catalyst C5: This catalyst was synthesized starting from 3,5-
bis(trifluoromethyl)aniline (0.16 mL, 1 mmol, 1 equiv.) and following the
above general procedure. The reaction crude was purified by column
chromatography (eluting with CH2Cl2:MeOH, 98:2). Yellow solid. Yield:
To further prove the efficiency of this protocol, spirocyclic
derivative 38 was subjected to Baeyer-Villiger oxidation under
the previous conditions (Scheme 9). For this purpose 27a was
transformed into the acetylated derivative 38, which upon
treatment with m-CPBA provided NCA 39. Subsequent coupling
of 39 with glycine tert-butyl ester chlorohydrate afforded
compound 40 in 72% yield.
1
556 mg, 0.68 mmol, 68%. [α]D25 = – 52.7° (c=0.5, MeOH). H NMR (300
MHz, DMSO-d6) 10.94 (s, 1H), 10.16 (s, 1H), 8.80 (d, J = 4.5 Hz, 1H),
8.47 (d, J = 1.8 Hz, 2H), 8.27 (s, 1H), 8.17 (s, 1H), 7.97 (t, J = 4.5 Hz,
3H), 7.84 (s, 1H), 7.76 (s, 1H), 7.67 (d, J = 4.6 Hz, 1H), 7.45 (dd, J = 9.2,
2.4 Hz, 1H), 6.22 – 5.82 (m, 2H), 5.30 – 4.81 (m, 2H), 3.96 (s, 3H), 3.56
– 3.06 (m, 3H), 2.85 – 2.55 (m, 2H), 2.28 (q, J = 8.0, 7.2 Hz, 1H), 1.84 –
1.34 (m, 4H), 0.68 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ184.6, 180.1,
168.5, 164.4, 163.0, 157.9, 147.8, 144.3, 143.1, 142.1, 140.7, 140.3,
136.0, 131.5, 130.9, 130.5, 127.5, 125.1, 121.2, 120.0, 118.0, 117.5,
116.8, 114.3, 101.5, 58.9, 55.8, 55.7,40.2, 39.4, 38.3, 38.0, 27.3, 26.0.
UPLC-DAD-QTOF: C40H33N5O4F9 [M+H]+ calcd.: 818.2389, found:
818.2398.
Conclusions
In summary, we have reported a new subclass of easily tunable
squaramide-Brønsted base catalysts that promote the reaction
of pyrrolidin-2,3-diones or their enolic form with a survey of
different electrophiles generating either quaternary or
tetrasubstituted carbon stereocenters with very high
Catalyst C6: This catalyst was synthesized starting from 1-(3,5-
bis(trifluoromethyl)phenyl)-N-methylmethanamine[29] (257 mg, 1 mmol, 1
equiv.) and following the general procedure. The reaction crude was
purified by column chromatography (eluting with CH2Cl2:MeOH, 98:2).
enantioselectivity, including enantioenriched unprecedented 2,2
-
spyrocyclic compounds. Smooth ring enlargement of the
adducts with m-CPBA provides a quick entry to the synthesis of
-amino acid N-carboxy anhydrides enabling subsequent
direct couplings with nucleophiles en route to relatively more
complexity. This approach thus may serve to increase not only
the chemical space of pyrrolidin-2,3-diones for new bioactive
compounds, but also their synthetic applications in asymmetric
catalysis and peptidic synthesis.
25
Yellow solid. Yield: 573 mg, 0.69 mmol, 69%. [α]D = – 115.9° (c=1.0,
CH2Cl2). 1H NMR (300 MHz, Acetone-d6) δ 8.77 (d, J = 4.5 Hz, 1H), 8.01
(d, J = 9.6 Hz, 4H), 7.93 (s, 2H), 7.86 (s, 1H), 7.77 (s, 1H), 7.69 (d, J =
4.0 Hz, 1H), 7.42 (dd, J = 9.2, 2.5 Hz, 1H), 7.23 (s, 1H), 6.31 (s, 1H),
5.87 (m , 1H), 4.97 (m, 2H), 4.04 (s, 3H), 3.59 (s, 3H), 3.36 – 3.20 (m,
1H), 2.82 (d, J = 12.4 Hz, 2H), 2.36 (s, 1H), 2.08 (m, 1H), 1.65 (d, J =
15.0 Hz, 4H), 0.89 (s, 1H). 13C NMR (75 MHz, Acetone-d6) δ 185.8,
181.4, 169.7, 169.1, 164.1, 159.3, 148.4, 146.8, 145.8, 143.9, 142.4,
141.1, 138.9, 132.6, 132.4, 131.9, 129.3, 128.8, 128.5, 126.1, 125.7,
123.0, 122.5, 122.1, 120.7, 119.3, 118.4, 116.6, 114.8, 102.2, 60.7, 56.7,
56.3, 54.9, 41.5, 40.4, 38.3, 30.3, 28.5, 28.1, 26.7. UPLC-DAD-QTOF:
C42H36N4O4F9 [M+H]+ calcd.: 831.2593, found: 831.2596.
Experimental Section
General procedure for the synthesis of catalysts C5 and C6.
Synthesis of catalysts C7. This catalyst was synthesized from 3-amino-
N-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)benzamide, 3,4-dime-
thoxy-3-cyclobutane-1,2-dione and (S)-3,3-dimethyl-1-(piperidin-1-yl)
butan-2-amide.[29] Thus, to a solution of 3,4-dimethoxy-3-cyclobutane-1,2-
dione (711 mg, 5.0 mmol, 1 equiv.) in MeOH (10 mL), 3-amino-N-(3,5-
bis(trifluoromethyl)phenyl)-5-(trifluoro-methyl)benzamide (2.3 g, 5.5 mmol,
1.1 equiv.) was added at room temperature. The mixture was stirred at
room temperature for 15 h. The white precipitate was filtered, washed
with MeOH, dried in vacuum and used as such in the next step. Yield: 2.3
g, 4.4 mmol, 88%. 1H NMR (300 MHz, Acetone-d6) δ 10.71 (s, 1H), 10.52
(s, 1H), 8.03 (s, 2H), 7.73 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H),
3.96 (s, 3H).
Squaramide based catalysts C5 and C6 were synthesized from 3-((2-
methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzoic
acid 12.[29] Triethylamine (0.67 mL, 4.8 mmol, 1 equiv.) and (R,R)-9-
deoxy-9-epiaminoquinine 13 (1.55 g, 4.8 mmol, 1 equiv.) were added to a
suspension of 12 (1.51 g, 4.8 mmol, 1 equiv.) in CH3CN (5 mL) at room
temperature. The reaction mixture was stirred vigorously at room
temperature for 16 h and then was directly purified by flash column
chromatography (DCM/ MeOH, 99:1) to give product 14 as a yellow solid.
Yield: 1.46 g, 2.4 mmol, 50%. 1H NMR (300 MHz, Acetonitrile-d3) δ 11.51
(bs, 1H), 10.17 (bs, 1H), 8.85 (d, J = 4.5 Hz, 1H), 8.38 (s, 1H), 8.07 –
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10.1002/chem.201700464
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Obtention of C7. To a suspension of the abvove product (1.05 g, 2
mmol, 1 equiv.) in MeOH (10 mL) was added (S)-3,3-dimethyl-1-
(piperidin-1-yl)butan-2-amine (369 mg, 2 mmol, 1 equiv.) at room
temperature. The reaction mixture was stirred at room temperature for 2
days. Solvents were then evaporated and the resulting crude was
purified by silica column chromatography (CH2Cl2:MeOH, 98:2) to give
the pure C7 catalyst as a yellow solid. Yield: 1.17 g, 1.72 mmol, 86%.
obtained nitroketone 26 (1.0 mmol, 1 equiv.) in dichloromethane (2 mL)
and the resulting solution was stirred at room temperature for 16 h. The
reaction mixture was directly purified by flash column chromatography
(Hex:EtOAc 40:60) separating both diastereomers.
Procedure for the one-pot synthesis of spirocycle 27a: To a mixture
of 1-benzylpyrrolidine-2,3-dione 4 (38 mg, 0.2 mmol, 1 equiv.) and the
corresponding nitroalkene 25 (0.22 mmol, 1.1 equiv.) in dichloromethane
(0.4 mL), catalyst C7 (5 mg, 0.01 mmol, 5 mol%) was added. The mixture
was stirred for 16 h at 0 ºC until completion of the first conjugate addition
(monitored by 1H-NMR). Then acrolein (26 L, 0.4 mmol, 2 equiv.) was in
situ added at the same temperature and the resulting solution was stirred
at room temperature for 16 h. The reaction mixture was directly purified
by flash column chromatography (Hex:EtOAc 40:60) separating both
diastereomers. Yield 27a: 52 mg, 0.13 mmol, 66%. [α]D25 = – 40.2° (c=1,
acetone). m.p. 233–234 ºC. 1H NMR (300 MHz, Acetone-d6) δ 7.40 –
7.11 (m, 6H), 7.09 – 6.90 (m, 2H), 6.85 – 6.57 (m, 2H), 5.48 (dd, J = 12.0,
9.6 Hz, 1H), 4.81 (d, J = 6.5 Hz, 1H), 4.53 (d, J = 14.9 Hz, 1H), 4.17 (d, J
= 14.9 Hz, 2H), 3.58 – 3.40 (m, 2H), 3.32 (d, J = 11.4 Hz, 1H), 2.21 –
2.09 (m, 2H), 2.04 – 1.96 (m, 2H). 13C NMR (75 MHz, Acetone-d6) δ
204.9, 158.9, 135.8, 134.9, 129.9, 129.7, 129.6, 129.4, 128.4, 128.3,
93.4, 72.7, 52.8, 52.4, 48.2, 47.0, 32.7, 29.3. UPLC-DAD-QTOF:
C22H23N2O5 [M+H]+ calcd.: 395.1607, found: 395.1612. Yield 28a: 13 mg,
[α]D25 = + 7.8° (c=0.5, MeOH). H NMR (500 MHz, DMSO-d6) δ 10.99 (s,
1
1H), 10.06 (s, 1H), 8.50 (t, J = 2.1 Hz, 2H), 8.32 (s, 1H), 8.05 (t, J = 1.9
Hz, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.58 (dd, J = 10.4, 5.5 Hz, 1H), 4.02
(d, J = 10.4 Hz, 1H), 2.49 – 2.39 (m, 2H), 2.40 – 2.29 (m, 2H), 2.26 –
2.13 (m, 2H), 1.50 – 1.24 (m, 6H), 0.94 (s, 9H). 13C NMR (126 MHz,
DMSO-d6) δ 184.4, 180.1, 170.5, 164.4, 161.8, 140.7, 140.6, 136.1,
130.7 (q), 130.4 (q), 124.3, 122.1, 120.8, 120.1, 117.6, 117.1, 116.9.
UPLC-DAD-QTOF: C31H32N4O3F9 [M+H]+ calcd.: 679.2331, found:
679.2327.
General procedure for the α-amination: To
a mixture of the
corresponding enol 9 (0.2 mmol, 1 equiv.) and catalyst C5 (16 mg, 0.02
mmol, 10 mol%) in dichloromethane (0.4 mL), di-tert-butyl
azodicarboxylate 10 (69 mg, 0.3 mmol, 1.5 equiv.) was added. The
resulting mixture was stirred until consumption of the enol 9 (monitored
by 1H-NMR). The mixture was then directly purified by flash column
chromatography on silica gel (eluent hexane/ ethyl acetate 80/20) without
previous work-up to afford the expected adducts.
25
0.03 mmol, 16%. [α]D = – 41.1° (c=0.5, CH2Cl2). m.p. 130–135 ºC. 1H
NMR (300 MHz, CDCl3) δ 7.29 – 7.12 (m, 6H), 7.05 – 6.96 (m, 2H), 6.80
– 6.73 (m, 2H), 5.84 (dd, J = 12.2, 2.4 Hz, 1H), 4.68 (q, J = 2.7 Hz, 1H),
4.50 (d, J = 14.6 Hz, 1H), 4.25 (d, J = 14.7 Hz, 1H), 3.73 (d, J = 12.2 Hz,
1H), 3.49 (d, J = 11.2 Hz, 1H), 3.12 (d, J = 11.2 Hz, 1H), 2.36 (tdd, J =
13.7, 3.7, 2.2 Hz, 1H), 2.21 (td, J = 13.8, 3.5 Hz, 1H), 2.01 – 1.82 (m, 1H),
1.75 – 1.60 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 203.1, 158.3, 133.9,
133.7, 129.3, 129.1, 129.0, 128.7, 128.2, 127.9, 88.1, 67.4, 52.2, 48.2,
46.9, 45.6, 28.2, 26.6. UPLC-DAD-QTOF: C22H23N2O5 [M+H]+ calcd.:
395.1607, found: 395.1606.
General procedure for the conjugate addition to α’-silyloxy enones:
To a mixture of the corresponding enol 9 (0.2 mmol, 1 equiv.) and the α’-
silyloxy enone 15 (74 mg, 0.4 mmol, 2 equiv.) in dichloromethane (0.4
mL) catalyst C6 (17 mg, 0.02 mmol, 10 mol%) was added. The mixture
was stirred until consumption of the starting enol 9 (monitored by 1H-
NMR). The reaction mixture was then quenched with 1M HCl (10 mL)
and the aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The
combined organic layers were dried over MgSO4, filtered and the solvent
was evaporated under reduced pressure. For the desilylation step, the
reaction crude was dissolved in CH3CN (1 mL) and, H2O (0.5 mL) and
glacial acetic acid (0.3 mL) were added. The reaction mixture was stirred
for 1 h at room temperature and it was quenched with NaHCO3 saturated
aqueous solution (20 mL). The organic solvent was evaporated under
reduced pressure and the aqueous layer was extracted with CH2Cl2 (3 x
20 mL). The combined organic layers were dried over MgSO4, filtered
and the solvent was evaporated under reduced pressure. The crude was
purified by flash column chromatography on silica gel to afford the
expected adducts.
General procedure for 2,2-NCA synthesis: To a solution of the starting
adduct (0.2 mmol, 1 equiv.) in CH2Cl2 (1 mL), mCPBA (67 mg, 0.3 mmol,
1.5 equiv.) was slowly added at –20 ºC. The reaction mixture was stirred
at –20 ºC or warmed up to room temperature. The reaction was
quenched with aqueous 10% NaHSO3 and it was extracted with CH2Cl2
(x 3). All organic phases were combined, washed with NaOH 1N, dried
over MgSO4 and evaporated under reduced pressure to afford the
corresponding NCAs in quantitative yield.
General procedure for ring opening of the NCAs:
METHOD A: Amino ester hydrochlorides as nucleophiles:
A
General procedure for the conjugate addition to vinyl ketones: To a
mixture of the α-ketoamide enol form 9 (0.2 mmol, 1 equiv.) and the vinyl
ketone 19‒21 (0.4 mmol, 2 equiv.) in dichloromethane (0.4 mL) catalyst
C6 (17 mg, 0.02 mmol, 10 mol%) was added. The mixture was stirred
until consumption of the enol 9 (monitored by 1H-NMR). The reaction
mixture was then quenched with 1M HCl (10 mL) and the aqueous layer
was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers
were dried over MgSO4, filtered and the solvent was evaporated under
reduced pressure. The crude was purified by flash column
chromatography on silica gel to afford the expected adducts.
suspension of the amino ester hydrochloride (1.2 equiv.) in CH2Cl2 (2
mL/mmol) was treated with Et3N (2.0 equiv.) for 30 min. The mixture was
then cooled to –20 ºC and the corresponding NCA (1.0 equiv.) solution in
CH2Cl2 (1 mL/mmol) was added at this temperature. The reaction mixture
was warmed to room temperature and stirred overnight. The reaction
was quenched with HCl 1N, and the mixture was extracted with CH2Cl2 (x
3). The combined organic layers were washed with NaHCO3, dried over
MgSO4 and evaporated under reduced pressure.
METHOD B: Amines as nucleophiles: The amine nucleophile (1.2
equiv.) was added to a solution of the crude NCA (1 equiv.) in CH2Cl2 (2
mL/mmol) at –20 ºC. The reaction mixture was warmed to room
temperature and stirred overnight. The reaction was quenched with HCl
1N, and the mixture was extracted with CH2Cl2 (x 3). The combined
organic layers were washed with NaHCO3, dried over MgSO4 and
evaporated under reduced pressure.
General procedure for the conjugate addition to nitroalkenes: To a
mixture of 1-benzylpyrrolidine-2,3-dione 4 (38 mg, 0.2 mmol, 1 equiv.)
and the corresponding nitroalkene 25 (0.22 mmol, 1.1 equiv.) in
dichloromethane (0.4 mL), catalyst C7 (5 mg, 0.01 mmol, 5 mol%) was
added. The mixture was stirred for 16 h at 0 ºC. The reaction mixture was
then directly purified by flash column chromatography on silica gel
(eluent hexane/ethyl acetate 70/30) without previous work-up to afford
the expected adducts in the enolized form.
Acknowledgements
General procedure for the synthesis of spirocycles 27 starting from
nitroalkanes 26: Pyrrolidine (7 mg, 0.1 mmol, 10 mol%) was added to a
solution of acrolein (0.13 mL, 2 mmol, 2 equiv.) and the previously
Support has been provided by the University of The Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
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10.1002/chem.201700464
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FULL PAPER
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Asymmetric Organocatalysis 2, Brønsted Base and Acid Catalysis and
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Entry for the Table of Contents (Please choose one layout)
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Eider Badiola, Iurre Olaizola, Ana
Vázquez, Silvia Vera, Antonia Mielgo
and Claudio Palomo *
Page No. – Page No.
2,2-Amino Acid N-Carboxy
Anhydrides Relying on Sequential
C(4)-Functionalizaton of Pyrrolidin-
2,3-diones and Regoslective Baeyer-
Villiger Oxidation
Looking for reagents: N-Carboxyanhydrides of 2,2-amino acids, instead of their
corresponding free amino acids, may now be prepared thanks to an effective
stereocontrolled construction of a quaternary or tetrasubstituted carbon
stereocenter in a pyrrolidin-2,3-dione scaffold, promoted by a new subclass of
easily tunable bifunctional Brønsted base catalysts.
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