Towards Enzyme-like, Sustainable Catalysis: Switchable, Highly Efficient Asymmetric Synthesis of Enantiopure Biginelli Dihydropyrimidinones or Hexahydropyrimidinones

Article abstract of DOI:10.1002/chem.201604433

Organocatalysts displaying a network of cooperative hydrogen bonds (NCHB) have been employed in an enzyme-like manner for a direct, switchable synthesis of enantiopure hexahydropyrimidinones (HHPMs) or dihydropyrimidinones (DHPMs), which starts at a common, easily accessible α-ureidosulfone stage. The NCHB organocatalyst exploits all its potential as a pure hydrogen-bond biomimetic catalyst even in the presence of organic bases. This one-pot, diastereo- and enantioselective synthetic procedure has been proven to be robust, scalable, highly efficient, and environmentally benign. A straightforward and truly practical entry to enantiopure HHPMs is reported for the first time.

Full text of DOI:10.1002/chem.201604433

A Journal of
Accepted Article
Title: Towards Enzyme-like, Sustainable Catalysis: Switchable, Highly Efficient
Asymmetric Synthesis of either Enantiopure Biginelli’s Dihydropyrimidinones
or Hexahydropyrimidinones.
´
´
Authors: Jose M. Saa; Victor J. Lillo
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To be cited as: Chem. Eur. J. 10.1002/chem.201604433
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COMMUNICATION
Towards Enzyme-like, Sustainable Catalysis: Switchable, Highly
Efficient Asymmetric Synthesis of either Enantiopure Biginelli’s
Dihydropyrimidinones or Hexahydropyrimidinones.
V.J. Lillo, J.M. Saá*[a]
Dedicated to all members of the Spanish network of Asymmetric Catalysis (Red CASI)
Figure 1. Cartoon-like representation of organocatalysts provided with
Abstract: Organocatalysts displaying a network of cooperative
networks of cooperative hydrogen bonds (NCHB).
hydrogen bonds (NCHB) have been employed in an enzyme-like
Following the pioneering work of Rawal[10] and Ooi[11] who
reported unprecedented organocatalytic capacities of some
hydrogen bond networks (Figure 1),[12] we demonstrated that the
network of cooperative hydrogen bonds present in “salan”
organocatalysts was capable of driving the direct Mannich
addition of acetoacetates (NuH) to preformed arylideneureas (E)
in an enantioselective, enzyme-like manner (Scheme 1)
eventually, after acid treatment, giving rise to Biginelli’s
DHPMs.[13]
manner for
hexahydropyrimidinones
(DHPMs) which starts at
a
direct, switchable synthesis of enantiopure
(HHPMs) or dihydropyrimidinones
common, easily accessible -
a
ureidosulfone stage. The NCHB organocatalyst exploits all its
potential as a pure hydrogen bond biomimetic catalyst even in the
presence of organic bases. This one-pot, diastereo and
enantioselective synthetic procedure has been proved to be robust,
scalable, highly efficient and environmentally benign.
A
straightforward and truly practical entry to enantiopure HHPMs is
reported for the first time.
The most common access to racemic DHPMs is the three-
component reaction named after Pietro Biginelli,[1] who
discovered that the condensation of an aldehyde, urea and an
acetoacetate in acid media leads to this pharmacologically
important class of compounds.[2,3] According to Kappe,[4] DHPMs
result from the easy dehydration of their precursory
hexahydropyrimidine-2-ones (HHPMs),[5] itself derived from the
intramolecular cyclization of the initially formed Mannich adducts.
In spite of the hundred and twenty years elapsed, and the
interesting biological profile unveiled for some specific racemic
HHPM derivatives,[6] we are not aware of a general synthetic
method to enantiopure HHPMs.[7] In fact, none of the Biginelli’s
enantioselective protocols towards DHPMs actually known,[8]
allows for a direct access to HHPMs as these compounds,
having a -hydroxy ester unit, easily dehydrate in acid media to
yield DHPMs, with some exceptions though.[9]
Scheme 1. Enzyme-like NCHB-organocatalyzed synthesis of Biginelli’s
dihydropyrimidinones (DHPMs).
Having proved the NCHB concept we aimed at moving a step
ahead towards enzyme-like sustainable catalysis, convinced that
the limitations found in using preformed, though unstable,
arylideneureas could be removed by using -ureidosulfones as
precursors.[14] The incoming challenge now being to avoid the
undesirable effects that the incorporation of a preliminary acid-
base step might induce upon stereoselectivity and chemical
yield, as both the organocatalyst and the NuH react with bases.
We now would like to report a “one-pot”, scalable, highly
efficient,[15] and switchable asymmetric synthesis of either
enantiopure
hexahydropyrimidinones
(HHPMs)
or
dihydropyrimidinones (DHPMs) starting from -ureidosulfones,
and based on the organocatalytic job performed by a network of
cooperative hydrogen bonds (NCHB),[16,17] which must do their
work in the presence of suitable organic bases (Scheme 2).
[a]
Dr. V.J. Lillo and Prof. Dr. J.M. Saá
Departamento de Química
Universidad de las Islas Baleares
07122, Palma de Mallorca, Spain
E-mail: jmsaa@uib.es
Support has been provided by the Ministerio de Economía y
Competitividad and Fondo Europeo de Desarrollo Regional (Grant
number CTQ2015-66061-P (MINECO-FEDER), Spain. This grant
also covers Dr. V.J. Lillo’s contract. We would also like to thank Dr.
J. Mansilla for helpful discussions.
Scheme 2. Switchable, enantioselective organocatalyzed synthesis of
DHPM’s or HHPM’s starting from -ureidosulfones.
Supporting information for this article is given via a link at the end of
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Truly efficient synthetic methods require sustainable actions,[18]
as firmly requested by Trost and Sheldon,[19] Noyori,[20] and very
recently by Anastas and Zimmerman.[21] In this regard, we also
would like to highlight that our synthetic method complies with
the well-known 3Rs principles to reduce environmental impact
namely, reduction (of steps), recycling (of materials) and reuse
(of reagents). In fact, in an effort to emulate enzymes,[22] we not
only planned to recourse to non-covalent organocatalysis,[23] but
also focused our efforts in using organic bases only, convinced
that controlling proton transfers is a key issue per se but also for
reaching high levels of sustainability, as metallic bases could
then be avoided, however conscious that the available palette of
bases would then be considerable shrunken.[24]
planned not to isolate the Mannich adduct but, instead, directly
treat the crude product with aqueous HCl so as to proceed to the
desired enantiomerically enriched DHPMs 3 in a "one-pot"
fashion (Scheme 2). This initial screening (Table 1) eventually
led us to select either triethylamine or DIPEA as the ideal
organic bases (a detailed account is given as supporting
information). Stronger bases such as DBU, and TMG were
discarded as they induced formation of the corresponding
ammonium acetoacetates,[30] thereby yielding racemic
products.[29]
-Amidosulfones, but not -ureidosulfones 1,[25] have been used
with great success as surrogates of common N-acyl and N-
sulfonyl imines,[26] for which purpose organic bases B have been
successfully employed sporadically.[27] However, incorporating a
preliminary acid-base step to our enzyme-like mechanism which
involves specific acid catalysis, might induce undesirable effects
upon both stereoselectivity and chemical yield. This is so
because specific acid catalysis involves catalysis by H+ (either
from H3O+ when working in water, from SH+ when working in a
protonatable solvent S, or simply from the acidic NuH when
operating in a nonpolar solvent) but the protonation step is not
rate limiting, the actual rate-determining step being that involving
the resulting protonated species EH+ reacting with Nu-.[22] In
such cases, the reaction is effective only at, or below, the pKa of
the protonated EH+ species. For this reason the reaction is
highly dependent on the pKa of other acidic species present in
the reaction medium. Accordingly, the pKa of NuH should be
somewhat higher than that of the conjugate acid of the organic
base employed (BH+) to deprotonate the sulfone.[28] For the
opposite case, i.e. if pKaEnol < pKaBH+, the enantioselective route
which involves the ion pair EH+.Nu-,[13] could be overdue by the
racemic one as plenty of Nu- would then be available.[29] Also of
great concern was the integrity of the organocatalyst’s network
of cooperative hydrogen bonds under these basic conditions.
Accordingly, with the above limitations in mind, since the pKa of
common acetoacetates is ca. 11, we initially surmised that
common hindered and unhindered tertiary amines (triethylamine,
diisopropylethylamine (DIPEA), quinuclidine, etc) should work
properly as their published pKa (of the conjugated acids) is
lower than 10.7, whereas stronger bases such as 1,8-
Scheme 3. ”One-pot” enantioselective synthesis of DHPMs 3 with (R,R)-A or
(R,R)-B (results in brackets) as organocatalysts. Product (S)-3aa was
obtained using organocatalyst (S,S)-A.
A considerable number of aryl -ureidosulfones 1 were explored
in their capacity to undergo
a “one-pot” conversion to
enantiomerically enriched DHPMs 3 using organocatalysts A or
B (both easily prepared from commercial sources),[31] as
illustrated in Scheme 3. Standard acid workup led to DHPMs 3
in high chemical yield and enantiomeric excesses (better results
were obtained in some cases using the more flexible catalyst B).
diazabicyclo[5,4,0]undec-7-ene
(DBU)
or
1,1,3,3-
tetramethylguanidine (TMG), should not. In addition, to frame up
the organic bases actually operative only those capable to
induce -elimination upon -ureidosulfones were considered.
Table 1. Screening of bases for the one-pot, enantioselective synthesis of
DHPM 3a from 1a (Scheme 2).[a]
Entry
Base
T [ºC]
25
25
25
25
25
25
0
Yield [%][b]
ee [%][c]
55
78
50
73
0
0
1
2
3
4
5
6
7
8
DIPEA (1 eq.)
DIPEA (4 eq.)
Et3N (1 eq.)
Et3N (4 eq.)
TMG (4 eq.)
DBU (4 eq.)
DIPEA (4 eq.)
DIPEA (4 eq.)
67
99
72
99
99
99
99
96
Scheme 4. Scaled, ”one-pot” enantioselective synthesis of DHPMs 3.
91
97[d]
A further attribute of this one-pot, enantioselective synthesis of
DHPMs worth to be highlighted is that it can be scaled up. For
these scaling experiments, in which 2 mmol of -ureidosulfones
1 were employed, a number of examples besides (R)-3aa were
selected because of their reported relevant pharmacological
activity, namely (S)-3da,[32] (R)-3ea,[33] (S)-3nb,[34,35] and (R)-
3pa.[36] Excellent results were obtained in all cases (Scheme 4).
Moreover, it is important to remark that a simple acid-base
treatment of the crude product allowed us to recover the NCHB
0
[a] Reactions conducted on a 0.2 mmol scale in CH2Cl2 (2 ml) using
organocatalyst (molar ratio -ureidosulfone/ethyl
acetoacetate/organocatalyst 1:1.1:0.1). [b] Isolated yield. [c] Determined
by HPLC analysis (Daicel Chiralpak OD-H column). [d] Reaction
conducted in CH2Cl2 (4 ml).
A
In search for an efficient method to access enantioenriched
DHPMs using "salan" A or B as NCHB organocatalysts, we
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catalyst in high yield (ca. 90%) and purity. This recovered
material was reused in a further small scale operation upon -
ureidosulfone 1a thereby eventually giving rise to 3aa in 96%
yield and 93% ee. Still more, in the same procedure we were
able to recover up to 75% of the DIPEA employed by means of a
simple acid-base extraction.[37] Sodium p-toluensulfinate
recovery by evaporation of the remaining aqueous solution was
however somewhat frustrated by the presence of other salts.[38]
In summary, a direct, “one-pot”, scalable method that can be
switched at will towards either
asymmetric synthesis of Biginelli’s dihydropyrimidinones
(DHPMs) or highly diastereomeric and enantioselective
a highly enantioselective
a
synthesis of hexahydropyrimidinones (HHPMs), is now at hand.
This straightforward and robust methodology operates in rather
simple reaction conditions which involve the direct combination
of a -ureidosulfone 1 with an alkyl -ketoester in the presence
of a suitable organic base compatible with the substoichiometric
amount of an organocatalyst provided with a network of
cooperative hydrogen bonds (NCHB). Eventual treatment of the
crude Mannich mixture with acid leads to DHPMs 3. Alternatively,
treatment of the crude Mannich mixture with an organic base
(TMG) yields HHPMs 2.[41] As an additional value-added benefit,
it is worth remarking that the NCBH catalyst and the amine
employed can be recovered and reused, thus qualifying it as a
truly practical, enzyme-like and, at least in part, sustainable
synthetic procedure. We keep working on other reactions to
widen the non-trivial goal of designing fully sustainable, enzyme-
like, enantioselective synthetic methodology.
1
In examining by means of H NMR the reaction crude from 1a
prior to acid treatment (species between brackets in Scheme 2),
we discovered it was composed by a ca. 6:4 diastereomeric
mixture of Mannich adducts, together with a small amount of the
cyclized HHPM in which two (out of four) diastereoisomeric pairs
predominated. Fortunately, longer reaction time (24 h.) induced
further cyclization thereby giving rise to HHPM as the only
products in the crude mixture. Still more gratifying was the fact
that adding an extra amount of organic base to the original
Mannich mixture not only promoted cyclization but also
accelerated epimerization (Scheme 5). As the base employed
could also induce the retro-Mannich reaction and therefore lower
the enantiomeric purity of the major diastereomer, extreme care
need to be enforced for a successful access to enantiopure
HHPMs 2.
Keywords: organocatalysis • sustainable chemistry • network of
cooperative hydrogen bonds • enantiopure dihydropyrimidinones
• enantiopure hexahydropyrimidinones
[1]
[2]
P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
See, “Patented Catalysts for the Synthesis and Biological Applications
of Dihydropyrimidones: Recent Advances of the Biginelli Reaction” by R.
A. W. Neves Filho, M. C. N. Brauer, M. A. T. Palm-Forster, R. N. de
Oliveira, L.A. Wessjohann, “Recent Patents on Catalysis”, Bentham
Science, 2012, p.51-73.
[3]
a) C. O. Kappe, Acc. Chem. Res. 2000, 33, 879; b) C. O. Kappe, Eur.
J. Med. Chem. 2000, 35, 1043.
[4]
[5]
C. O. Kappe, F. Falsone, Synlett 1998, 718.
Both hexahydropyrimidine-2-ones (HHPMs) and tetrahydropyrimid-
2(1H)-ones are synonyms, the former being the most frequently used.
O. C. Agbaje, O. O Fadeyi, S. A. Fadeyi, L. E. Miles, C. O. Okoro, Biol.
Scheme 5. “One-pot” diastereo and enantioselective synthesis of HHPMs 2.
Product 2qa was obtained using organocatalyst (R,R)-B.
[6]
[7]
[8]
Med. Chem. Lett. 2011, 21, 989.
For racemic syntheses, see A. D. Shutalev, V.A. Kuksa, Chem.
Heterocycl. Comp. 1995, 31, 97; ibid. 1997, 33, 91.
On the basis of the above behaviour, we explored a divergent
operation over the original Mannich mixture aiming at
enantiopure HHPMs. To that purpose an organic base was
added to the Mannich crude reaction mixture to promote
cyclization and epimerization at C4 and C5 in a one-pot
fashion,[39] though nevertheless trying to avoid the lethal
retroMannich that would otherwise affect C6. Actually, best
results were obtained when 2 equivalents of TMG were
employed, thus leading to enantioselectively enriched HHPMs 2
in good overall yield, in ca. 9:1 diasteromeric ratio, and quite
a) L-Z. Gong, X-H. Chen, X-Y. Xu, Chem. Eur. J. 2007, 13, 8920; b) M.
M. Heravi, S. Asadi, B. M. Lashkariani Mol. Divers. 2013, 19, 389.
The use of CF3COCH2COOR leads to HHPMs hardly capable of
dehydration to DHPMs. See: a) C. O Kappe, F. Falsone, W. M. F.
Fabian, F. Belaj, Heterocycles 1999, 51, 77; b) Y. Ma, C. Quian, L.
Wang, M. Yang, J. Org. Chem. 2000, 65, 3864; c) P. A. Solovyev, A. A.
Fesenko, A. D. Shutalev, J. Fluorine Chem. 2016, 182, 28.
[9]
[10] a) Y. Huang, A. K. Unni, A. V. Thadani, V. H. Rawal, Nature 2003, 424,
146; b) A. N. Thadani, A. N. Stankovic, V. H. Rawal, Proc. Natl. Acad.
Sci. 2004, 101, 5846.
high
enantiomeric
excesses
(Scheme
5).
Relative
[11] D. Uraguchi, Y. Ueki, T. Ooi, Science 2009, 326, 120.
[12] C. D. Anderson, T. Dudding, R. Gordillo, K. N. Houk, Org. Lett. 2008,
10, 2749.
stereochemistry of the major diastereomer was inferred from
their ROESY spectra,[40] and its absolute (4R, 5R, 6S)
stereochemistry deduced from that of the corresponding DHPMs
3 that result by treatment of 2 with aqueous acid.[13] The ROESY
spectra also revealed that the minor stereoisomer was the (4S,
5R, 6S) epimer. This is the first time a one-pot, synthetic route of
diastereo and enantioselectively enriched HHPMs 2 is reported
in the literature.[41]
[13]
V. J. Lillo, J. Mansilla, J. M. Saá, Angew. Chem. Int. Ed. 2016, 55,
4312; Angew. Chem. 2016, 128, 4384.
[14] None of the most cited reviews on -amidosulfones pays attention to -
ureidosulfones. See ref. 26.
[15] H. Yan, J. S. Oh, J-W. Lee, C. E. Song, Nat. Commun. 2012, 3, 1212.
[16] A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713.
[17] a) G. A. Jeffrey, W. Saenger in “Hydrogen Bonding in Biological
Structures”, Springer, Berlin, 1991; b) T. Steiner, Chem. Commun.
1997, 727.
As for the case of DHPMs, we have also explored the
preparation of HHPMs in up to a 2 mmol scale. In this regard it is
worth remarking that compound 2aa could be obtained in 96%
yield, as a 9:1 diastereomeric mixture, the enantiomeric excess
of the major stereoisomer being 92% ee, as determined by chiral
HPLC, in excellent agreement with data in Scheme 5.
[18] N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2011, 50, 4760;
Angew. Chem. 2011, 123, 4856.
[19] a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost, Angew. Chem.
Int. Ed. 1995, 34, 259; Angew. Chem. 1995, 107, 285; c) R.A. Sheldon,
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Chemistry - A European Journal
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COMMUNICATION
Chem. Ind. (London) 1992, 903; d) R. A. Sheldon, Chem. Ind. (London)
1997, 12.
[33] DHPM 3ea is the chiral scaffold of a patented anti HIV. See C. W.
Andrews, P. Cao, G. A. Freeman, J. Qu, (Smithkline Beecham
Corporation), WO 2009 020457 A2.
[20] R. Noyori , Chem. Commun. 2005, 1807.
[21] P. T. Anastas, J. B. Zimmerman, Chem 2016, 1, 10.
[22] a) E. V. Anslyn, D. A. Dougherty in Modern Physical Organic Chemistry,
University Science Books, Sausalito, CA, 2006; b) R. B. Silverman in
The Organic Chemistry of Enzyme-Catalyzed Reactions, Academic
Press, San Diego, CA, 2002.
[34] 1a Adrenoreceptor antagonists are useful for the treatment of benign
prostatic hypertrophy. See: a) B. E. Evans, K. F. Gilbert, J. M. Hoffman,
K. E. Rittle, (Merck), GB2355457A, 2001; b) D. Cui, M.R. Davis, H. P.
Kari, K. P. Vyas, K. Zhang, B. Evans, M. Dunn, D. Nagarathnam, B.
Lagu, (Synaptic Pharmaceutical Corporation, Merck & Co., Inc.), WO
2000 037026 A1; c) J. Barrow, (Merck & Co., Inc.), WO 1999 025345
A1.
[23] a) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520;
Angew. Chem. 2006, 118, 1550; b) T. Akiyama, J. Itoh, K. Fuchibe, Adv.
Synth. Catal. 2006, 348, 999; c) R. R. Knowles, E. N. Jacobsen Proc.
Natl. Acad. Sci. 2010, 107, 20678.
[35] SNAP7541 is an antagonist of melanin concentrating hormone receptor,
thus promoting weight loss and anxiety in animals. See, B. Lagu, J.
Wetzel, M. R. Marzabadi, J. E. Deleon, C. Gluchowski, S. Noble, D.
Nagarathnam, G. Chiu (Synaptic Pharmaceutical Corporation), WO
2002006245 A1. For an enantioselective synthesis see J. M. Goss, S.
E. Schaus, J. Org. Chem. 2008, 73, 7651.
[24] a) W. P Jencks, Chem. Rev. 1972, 72, 705; b) A. J. Kirby, Angew.
Chem. Int. Ed. Engl. 1996, 35, 706; Angew. Chem. 1996, 108, 770; c) K.
B. Schowen, H.-H. Limbach, G. S. Denisov, R. L. Schowen, Biochim.
Biophys. Acta 2000, 1458, 43.
[25] A systematic entry to -ureidosulfones has been described. See ref. 13.
[26] a) M. Petrini, Chem. Rev. 2005, 105, 3949; b) B. Yin, Y. Zhang, L-W Xu,
Synthesis 2010, 21, 3385; c) J. Vesely, R. Rios, Chem. Soc. Rev. 2014,
43, 611.
[36] A patent has been filed on racemic 3pa due to its nitric oxide synthase
inhibitory activity (EC50 ≤ µM). See J. R. Roppe, H. Zhuang, X. Chen, C.
Bonnefous, J. E. Payne, N. D. Smith, C. A. Hassig, S. A. Noble,
(Kalipsis Inc.) WO 2007 101213 A2.
[27] S. M. Mennem, J. D. Gibson, Y. R Kim, S. J. Miller, J. Am. Chem. Soc.
2005, 127, 1654.
[37] “Chemistry of Waste Minimization”, by J. H. Clark, Springer Science &
Business Media 2012, p. 39.
[28] This reasoning should be taken as a crude approximation as the
reaction takes place not in water but in methylene chloride.
[29] We have actually carried out the reaction of the sodium salt of ethyl
acetoacetate (commercially available) with the -ureido sulfone 1a in
the presence of our NCHB organocatalyst A under otherwise ordinary
reaction conditions. DHPM 3a was obtained in good chemical yield
(98%) though as a racemic mixture.
[38] F. C. Whitmore, F. H. Hamilton, Org. Synth. 1922, 2, 89.
[39] A number of inorganic solid bases were assayed for comparison,
namely sodium, potassium and cesium carbonates, as well as sodium
ethoxide.
In
all
cases
lower
enantioselectivities
and/or
diastereoselectivities were found.
[40] In full agreement with the NMR data of trifluoromethyl analogs whose
structure has been supported by X-ray data. See ref. 9.
[41] European patent (EP-07286) pending.
[30] R. J. Clemens, F. D. Rector, J. Coat. Technol. 1989, 61, 83.
[31] Alkyl -ureidosulfones yielded complex reaction mixtures.
[32] Inhibitors of GRKs are expected to have clinical importance. See, K. T.
Homan, K. M. Larimore, J. M. Elkins, M. Szklarz, S. Knapp, J. J. G.
Tesmer, ACS Chem. Biol. 2015, 10, 310.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Witched switch: Devising
Dr. Victor J. Lillo and Prof. José M.
Saá*
straightforward, environmentally
sustainable and practical chemical
synthesis is a must (Noyori). We
have conceived a switchable
synthetic method to access either
enantiopure DHPMs or HHPMs. It is
not magic, but just the right
combination of players conducted by
the catalytic job performed by “salan”
NCHB organocatalysts in an
enzyme-like manner.
Page No. – Page No.
Towards Enzyme-like, Sustainable
Catalysis: Switchable, Highly
Efficient Asymmetric Synthesis of
either Enantiopure Biginelli’s
Dihydropyrimidinones or
Hexahydropyrimidinones.
Layout 2:
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Author(s), Corresponding Author(s)*
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