Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids

Article abstract of DOI:10.1021/jacs.7b09124

The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5-disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C-C bond forming reactions with vinyl ketones or Morita-Baylis-Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.

Full text of DOI:10.1021/jacs.7b09124

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Communication
Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids
Sandra Del Pozo, Silvia Vera, Mikel Oiarbide, and Claudio Palomo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09124 • Publication Date (Web): 12 Oct 2017
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Catalytic Asymmetric Synthesis of Quaternary Barbituric Ac-
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Sandra del Pozo, Silvia Vera, Mikel Oiarbide* and Claudio Palomo*
Departamento de Química Orgánica I, Universidad del País Vasco, Manuel de Lardizabal 3, 2018 San Sebastián, Spain.
Supporting Information Placeholder
a) Known enantioselective approaches to in-ring chiral barbiturates
ABSTRACT: The catalytic asymmetric αꢀfunctionalization of
prochiral barbituric acids, a subtype of pseudosymmetric 1,3ꢀ
O
PdL* (cat)
HN
(Ref. 3 & 4)
O
diamides, to yield the corresponding 5,5ꢀdisubstituted (quaterꢀ
R3
Y
R1
N
O
O
N
nary) derivatives remains essentially unsolved. In this study 2ꢀ
alkylthioꢀ4,6ꢀdioxopirimidines are designed as key 1,3ꢀdiamide
surrogates that perform exceedingly in amineꢀsquaramide cataꢀ
lyzed C–C bond forming reactions with vinyl ketones or Moritaꢀ
BaylisꢀHillmannꢀtype allyl bromides as electrophiles. Mild acid
hydrolysis of adducts affords barbituric acid derivatives with an
in-ring quaternary carbon in unprecedented enantioselectivity,
offering valuable materials for biological evaluations.
Me
O
Y: OAc, OCO2Me
R3
<40% ee
O
N
R2
O
Ph
HN
N
I
Me
Rh(III)L* (cat)
O
(Ref. 5)
Me
Ph
Me
O
11% ee (single entry)
b) Challenges posed by the base-promoted functionalization of prochiral barbiturates II:
R1
N
O
R1
N
O
R1
O
Electrophile (X=Y)
N
X
YH
R
R1
via:
N
Chiral base
(catalyst)
R
N
Barbituric acids and derivatives are very interesting 1,3ꢀdiamide
scaffolds for the development of therapeutic agents and functional
materials.1 Several approaches for the asymmetric synthesis of
chiral barbiturates in which chirality resides outside of the ring (I,
R1=R2) are reported.2 In contrast, the enantioselective synthesis of
chiral barbiturates with inꢀring chirality remains unsolved (Figure
1a). The groups of Brunner3 and Trost,4 independently, described
palladiumꢀcatalyzed asymmetric allylic alkylation reactions of I
(R1= H, R2= Me, R3= alkyl) with allyl acetates or carbonates to
proceed with enantioselectivities from poor to modest. Lam’s
group has described the Rh(III)ꢀcatalyzed oxidative annulations of
cyclic 1,3ꢀdicarbonyl compounds with alkynes,5 including a single
example involving nonsymmetric barbiturates I (R1= H, R2= Me,
R3= Ph) that yields the corresponding spiroindene adduct in 11%
ee. It is thus not surprising that, among the thousands of 5,5ꢀ
disubstituted barbiturates synthesized and selected for clinical
trials, the great majority are racemic,6 even though pharmacologiꢀ
cal profile may be configurationꢀdependent.7 Here we describe a
catalytic highly enantioselective route to barbiturates with an in-
ring allꢀcarbon quaternary stereocenter for the first time. For this
realization 2ꢀalkylthioꢀ4,6ꢀdioxopyrimidines III are designed as
key barbituric acid equivalents that perform exceedingly under
bifunctional Brønsted base/Hꢀbond activation (Figure 1c).
N
R2
R2
O
R2
O
O
II
Pseudosymmetrical
(difficult face discrimination)
Relatively low
carbon acidity
= quaternary carbon
c) 2-Alkylthio-4,6-dioxopirimidines (III) as efficient barbituric acid equivalents (this work):
1.
O
O
O
O
Brønsted
base cat.
H
N
EWG
N
N
N
EWG
R1
R'S
R1
R'S
O
R1
N
N
2. H3O+
R
R
O
R
O
III
- pseudoaromatic
- enhanced disymmetry
- facilitates enantiocontrol
high ee
Figure 1. Asymmetric αꢀfunctionalization of 1,3ꢀdiamides toward
barbituric acid derivatives with an inꢀring stereogenic carbon.
concerns the pseudosymmetrical structure of the 1,3ꢀdiamide
moiety (Figure 1b) which makes enantioface discrimination comꢀ
plicated,10 a situation that would be critical during generation of a
quaternary stereocenter.11 For example (Scheme 1), at the outset
of our investigation barbiturates 1 and 2, as well as their thioꢀ
analogues 3/4Aa, were treated with vinyl ketone 6a in the presꢀ
ence of 10 mol% catalyst C1 (Figure 2) to give, respectively,
adducts 7–10 as essentially racemic material (<20% ee at best).12
Reaction reversibility (retroMichael process)2d,9 as a cause of the
low enantiocontrol could be discarded as no crossover products
were detected when adducts 7 and 8 were admixed with vinyl
ketone 6b in the presence of a base catalyst.12 We then questioned
whether 2ꢀbenzylthioꢀ4,6ꢀdioxopyrimidines 5 (Figure 2), which as
far as we know have never been employed in asymmetric catalyꢀ
sis, could be used to solve this problem, considering: (i) the ready
conversion into the target barbituric acids upon standard hydrolytꢀ
ic conditions, (ii) the enhancement of structural dissymmetry as
compared to the nearly symmetric diamides 1ꢀ4, and (iii) the
Chiral organobase catalysis is recognized as one of the operationꢀ
ally simplest approach for the enantioselective functionalization
of acidic CH proꢀnucleophiles.8 Recently, while our work was in
progress, Rawal and coꢀworkers reported the enantioselective
conjugate addition of symmetrically N,N’ꢀdisubstituted barbituric
acids to prochiral nitroalkenes triggered by a bifunctional amineꢀ
thiosquaramide organocatalyst.2d Whereas N,N’ꢀdisubstituted
barbituric acids thus seems to be suitable for a mild Brønsted base
deprotonation,9
the
asymmetric
organocatalytic
C(5)ꢀ
functionalization of prochiral barbiturates of general structure II
(R1≠R2, Figure 1b) has not yet been realized. A major problem
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Table 1. Catalyst screening for the reaction of 5Aa with
1
2
3
6a to give 11.a
entry catalyst yield (%)a ee (%) entry catalyst yield (%) ee (%)
4
5
6
7
8
9
1
2
3
4
5
67
71
60b
66
36
6
7
59
66
72
60
62
54
75
80
96
78
C1
C2
C3
C4
C5
C6
C7
C8
C8c
C9
n.d.
32
8
69
9
67
73
10
aReactions carried out at r.t. using 0.2 mmol of 5Aa, 0.6 mmol
of enone 6a and 10 mol% catalyst in 0.5 mL of CH2Cl2.; yields of
isolated product after chromatography; ee determined by chiral
HPLC. bConversion. cReaction run at 0 ºC.
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17
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25
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58
59
60
Table 2. Scope of the reaction of 2-benzylthio-4,6-
dioxopyrimidines 5 with aryl vinyl ketones 6.a
Figure 2. Barbituric substrates and catalysts used in this study.
Scheme 1. Initial experiments with (thio)barbiturates 1ꢀ4.
entry
1
R
R1
R’’
product yield (%)b ee (%)c
Me
Me
Me
Me
Me
Me
Me
Me
FAr
Bn
Me
Me
Me
Me
Me
Et
4ꢀMe
4ꢀBr
H
72
63
61
72
62
71
75
65
65
67
73
96
95
92
85
96
97
94
92
90
90
92
11
12
13
14
15
16
2
3
4
2ꢀMe
3ꢀMe
4ꢀBr
5
6
7
Bn
3ꢀMe 17d
8
Allyl
Me
Me
H
18
19
20
21
suitability towards deprotonation (pseudoaromatic enolate would
be formed) promoted by a weak base.
9
H
10
4ꢀBr
The preparation of compounds 5 was afforded in one benzylaꢀ
tion step from the easily available thiobarbiturates 4 (Figure
2).12,13 Initial assessment of the behavior of these compounds in
conjugate additions was gratifying as the reaction of 5Aa with
enone 6a under the catalytic conditions of Scheme 1 afforded
adduct 11 with a promising 66% ee (Table 1, entry 1). The enanꢀ
tioselectivity could not be improved when other known catalysts,
such as bifunctional thiourea C214 or squaramides C315 and C416
(entries 2ꢀ4), or modified analogs C5, C6 and C717 (entries 5ꢀ7)
were employed. Eventually, the sterically more congested cataꢀ
lysts C8 and C9, which can be prepared easily through Grignard
technology, performed the best.12 Thus, catalyst C8 provided
product 11 with 80% ee at room temperature and a remarkable
96% ee by running the reaction at 0 °C (entries 8, 9). The silyl
analog C9 provided similar selectivities, but slower reaction. To
the best of our knowledge, this realization constitutes the first
catalytic asymmetric Michael reaction of αꢀbranched 1,3ꢀ
diamides.18
11
nꢀPent Me
4ꢀBr
aReactions carried out at 0.2 mmol scale in 0.5 mL of CH2Cl2.b
c
Yields of isolated product after chromatography. Ee determined
F
by chiral HPLC. dXꢀray. Ar: 3,5ꢀ(CF3)2C6H3.
acrylates and, by extension, α,βꢀunsaturated esters, were not
competent reaction partners. In the opposite direction, the more
reactive but less sterically demanding acrolein, upon reaction with
5Aa, led, after hydrolysis, to adduct 22, but with a poor 48% ee.
In order to surmount these difficulties, we next examined the
reactions with αꢀsilyloxy enone 23, an acrylate and acrolein
equivalent very easy to prepare from acetone.19 As before, initial
experiments using enone 23 in combination with
(thio)barbiturates 1 and 4 provided the corresponding addition
adduct as essentially racemic material independently of the cataꢀ
lyst employed.12 Gratifyingly, however, the reaction of 23 with
various 2ꢀbenzylthioꢀ4,6ꢀdioxopyrimidines 5 proceeded smoothly
and with very high enantioselectivity (Table 3). Adducts from
these reactions were isolated after acidic hydrolysis leading to
barbituric acids 24. As data in the table show, products 24 bearing
As the results in Table 2 show, several aryl vinyl ketones with
electron donating (Me) or withdrawing (Br) substituents on the
aromatic ring were equally competent reaction partners, apparentꢀ
ly irrespective of the oꢀ, mꢀ, or pꢀ substitution pattern (compounds
11–15). Also, the method tolerates substrates 5 with a range of
substituents at both the N(3) (methyl, pentyl, benzyl, aryl) and the
C(5) (methyl, ethyl, benzyl, allyl) position of the heterocycle to
give the respective adducts 11–21 in ee’s generally above 90%.
However, intrinsically less reactive Michael acceptors, such as
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(entry 2). Among the bases examined, K3PO4 provided a similar
Table 3. Scope of nucleophiles for the reaction with acry-
late equivalent 23.a
1
2
3
4
5
6
7
8
(97% ee) selectivity, whereas Cs2CO3 led to a reduced 77% ee
and tertiary amines were completely ineffective in terms of
enantioselectivity.12As data in Table 4 show, the allylic alkylation
with 25 resulted suitable for a variety of substrates 5, affording
adducts 28 with short and long alkyl, allyl or aryl groups installed
at the C(5) and N(1) positions in generally good yields and selecꢀ
tivities of 89% ee or higher.
Entry
R1
R
Product
Yield (%)
ee (%)
9
24Aa
24Ab
24Ac
24Adc
24Ba
24Ca
24Da
24Ea
24Fa
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Et
Me
Bn
82
61
63
62
71
70
68
--
90
81(87)b
83(87)b
90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
nPent
Ph
Me
Me
Me
Me
Me
94
Bn
92
iBu
iPr
93
--
Allyl
72
92
aReactions carried out at 0.2 mmol scale in 0.5 mL of CH2Cl2.
bReactions run at room temperature using 10 mol% C9.cXꢀray.
linear/branched alkyl or allyl R1 substituents are produced in good
yields and enantioselectivities typically above 90%, with isoproꢀ
pyl being an exception (entry 8). The absolute configuration of
adduct 24Ad was established by single crystal Xꢀray structural
analysis20 and that of the remaining adducts by analogy and by
assuming a uniform reaction mechanism. To further illustrate the
potential of templates 5 to buildꢀup quaternary barbiturates
through modification at C(5), the alkylation reaction with allyl
bromides derived from MoritaꢀBaylisꢀHillmann adducts was
examined. It was found that the reaction of 5 with allyl bromides
25/26 in the presence of 1 equivalent of K2CO3 and 10 mol%
catalyst C8 proceeded smoothly at 0 °C (Table 4).21 Curiously,
these reactions were sensitive to both the nature of the ester group
and the base employed. For example, while ethyl ester 25 led to
adduct 27Aa using K2CO3 as base with moderate enantioselectiviꢀ
ty (entry 1, 54% ee), the tertꢀbutyl congener 25 afforded 28Aa in
a remarkable 99% ee under the same conditions
Scheme 2. Elaboration of adducts.
Transformations in Scheme 2 give an idea of the versatility of the
present method for the preparation of 5,5ꢀdisubstituted chiral
barbituric acid derivatives. Thus oxidative ketol cleavage in 24Aa
furnished the acid 30 almost quantitatively, while applying a
reduction/1,2ꢀdiol cleavage sequence, aldehyde 22 was produced
in 88% overall yield. Subsequent Wittig olefination gave rise to
elongated barbiturates 31–33. Eventually, conversion of both
24Aa and 11 into the same ketone 29 served to further corroborate
the stereochemical assignments. On the other hand, ring closing
metathesis of tethered diene 28Fa and subsequent hydrolysis of
the resulting adduct 34 provided spiranic barbiturate 35 as essenꢀ
tially enantiopure compound. Finally, Nꢀalkylation/arylation of
imide 31 using standard protocols gave rise fully substituted
barbiturates 36, 37 and 38 which are products otherwise difficult
to obtain in enantioenriched form.
Table 4. Allylic alkylation with MBH bromides 25/26.a
Entry
R1
R
Product
Yield (%)
ee (%)
1
2
3
4
5
6
7
Me
Me
Me
Me
Et
Me
27Aa
28Aa
28Ab
28Ac
28Ba
28Ca
28Fa
62
63
61
73
67
63
65
54
99
90
99
96
86
92
Me
Bn
nPent
Me
Bn
Me
Allyl
Me
On the other hand, according to recent proposals for this type of
catalysis where the squaramide is doubly Hꢀbonded to the nucleꢀ
philic component (enolate) and the protonated quinuclidine actiꢀ
aReactions carried out using 0.2 mmol of 5 and 1 equiv. of each
bromide 25/26 and K2CO3 in 0.5 mL of CH2Cl2.
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vates the electrophile,22 model A could be invoked which would
correctly explain the observed stereochemistry.
5 Chidipudi, S. R.; Burns, D. J.; Khan, I.; Lam, H. W. Angew. Chem. Int.
Ed. 2015, 54, 13975ꢀ13979.
6 For more details, see: (a) Ref 1. (b) Savechenkov, P. Y.; Zhang, X.;
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B.; Forman, S. A.; Miller, K. W.; Bruzik, K. S. J. Med. Chem. 2012,
55, 6554ꢀ6565.
1
2
3
4
5
6
7
8
In summary, we report here the first highly enantioselective
construction of chiral barbiturates with an inꢀring quaternary
stereogenic center, based on the catalytic αꢀfunctionalization of 2ꢀ
alkylthio 4,6ꢀdioxopyrimidines as key barbituric acid equivalents.
Squaramideꢀtertiary amine bifunctional catalysts are able to trigꢀ
ger the reaction of these templates with Michael acceptors effiꢀ
ciently, being the highest selectivities attained with the new bulky
catalyst C8. While extension of this approach (i.e. using different
acceptors) can be foreseen, chemical elaboration of adducts proꢀ
vides a route to structurally diverse, quaternary barbituric acid
derivatives hitherto inaccessible in optically active form.
7 (a) Towin, S. L.; Jenking, A.; Lieb, W. R.; Franks, N. P. Anesthesiolo-
gy 1999, 90, 1714ꢀ1722. (b) Ref. 6b.
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McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621ꢀ631. (b) Palomo,
C.; Oiarbide, M.; López, R. Chem. Soc. Rev. 2009, 38, 632ꢀ653. (c)
Ting, A.; Goss, J. M.; McDougal, N. T.; Schaus, S. E. Top. Curr.
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Organocatalysts. In Asymmetric Organocatalysis 2: Brønsted Base and
Acid Catalysts, and Additional Topics; Maruoka, K., Ed.; Thieme:
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functional Cinchona Alkaloid Organocatalysts. In ref 8d, pp 119ꢀ168.
9 Schade, A.; Tchernook, I.; Bauer, M.; Oehlke, A.; Breugst, M.; Frieꢀ
drich, J.; Spange, S. J. Org. Chem. 2017, 82, 8476ꢀ8488.
9
10
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12
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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ASSOCIATED CONTENT
10 This reason could also explain the difficulty associated with enantioseꢀ
lective allylations and spiroannulations, see: ref 3ꢀ5.
The Supporting information is available free of charge via the
Internet at http://pubs.acs.org: Crystallographic data for 17, 24Ad
(CIF).
11 Reviews on quaternary carbon stereocenters: (a) Hong, A. Y.; Stoltz, B.
M. Eur. J. Org. Chem. 2013, 2745ꢀ2759. (b) Das, J. P.; Marek, I.
Chem. Commun. 2011, 47, 4593ꢀ4623. (c) Bella, M.; Caspery, T. Syn-
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Eur. J. Org. Chem. 2007, 5969ꢀ1614. (e) Trost, B. M.; Jiang, C. Syn-
thesis 2006, 369ꢀ396. (f) Quaternary Stereocenters, Christoffers, J.;
Baro, A., Eds.; WileyꢀVCH: Weinheim, 2005.
12 See the Supporting Information for details.
13 Rakhimov, A. I.; Avdeev, S. A.; Chang, L. T. D. Russ. J. Gen. Chem.
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14 (a) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. 2005, 44,
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Chem. Soc. 2010, 132, 2775ꢀ2783. For pioneering work on squaraꢀ
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18 Selected reviews on asymmetric organocatalytic conjugate additions:
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Experimental details, NMR spectra, HPLC chromatograms (PDF).
AUTHOR INFORMATION
Corresponding Author
*claudio.palomo@ehu.es; mikel.oiarbide@ehu.eus.
Notes
The authors declare no competing financial interest
.
ACKNOWLEDGMENT
Finantial support was provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(Grant No ITꢀ628ꢀ13), and Ministerio de Economía y Competiꢀ
tividad (MEC, Grant CTQ2016ꢀ78487ꢀC2), Spain, S.P. thanks
UPV/EHU for fellowship. We also thank SGiker (UPV/EHU) for
providing NMR, HRMS, and XꢀRay resources.
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