Reactions of pyruvates: Organocatalytic synthesis of functionalized dihydropyrans in one pot and further transformations to functionalized carbocycles and heterocycles

Article abstract of DOI:10.1039/c4cc06035k

Concise cascade reactions of pyruvates with aldehydes that generate functionalized dihydropyran derivatives in one pot have been developed. The products, dihydropyrans, were further concisely transformed to various molecules. This journal is

Full text of DOI:10.1039/c4cc06035k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Reactions of pyruvates: organocatalytic synthesis
of functionalized dihydropyrans in one pot and
further transformations to functionalized
carbocycles and heterocycles†‡
Cite this: Chem. Commun., 2014,
50, 14881
Received 2nd August 2014,
Accepted 8th October 2014
Pandurang V. Chouthaiwale and Fujie Tanaka*
DOI: 10.1039/c4cc06035k
www.rsc.org/chemcomm
Concise cascade reactions of pyruvates with aldehydes that generate
functionalized dihydropyran derivatives in one pot have been developed.
The products, dihydropyrans, were further concisely transformed to
various molecules.
The development of synthetic methods that allow access to a
series of functionalized small molecules in concise routes
under mild conditions is important in the search for bioactive
molecules.1 Here we report the development of reactions that
use pyruvates as key reactants to provide a set of functionalized
molecules.
Pyruvates can act as nucleophiles and electrophiles, and
thus are expected to be useful synthons.2,3 For example, pyr-
uvates have been used for enzyme-catalyzed aldol reactions to
generate N-acetylneuraminic acid and related molecules.2 In
non-enzymatic reactions of pyruvates, however, the dual reac-
tivties of pyruvates are difficult to control.3–6 Reactions of
simple pyruvates (such as ethyl pyruvate and methyl pyruvate)
as nucleophiles are especially difficult and have been very
limited.3a–e,4 We hypothesized that with the use of appropriate
Scheme 1 (a) One-pot cascade reaction of pyruvates that afford func-
tionalized dihydropyran derivatives 1 reporting here; (b) various function-
alized molecules synthesized from 1, reporting here.
catalysts and conditions, the dual reactivities of pyruvates could previously reported reactions of pyruvates that yield the self-aldol
be managed for the formation of more than two-bonds in one product3a,b or cross aldol products.3c,d We also report the utility
pot to generate functionalized molecules in non-enzymatic of dihydropyrans 1 as synthons to concisely synthesize a
reactions. Here we report the development of a concise, wide range of functionalized molecules, including molecules
one-pot cascade reaction system to generate functionalized relevant to the search of biofunctional molecules, such
dihydropyran derivatives 1 using pyruvates and aldehydes as as amino group-substituted and fluoro group-substituted
starting materials (Scheme 1a).7–9 Dihydropyran is an impor- dihydropyrans, cyclohexanes, dihydrodiazepines, and pyridines
tant core structure as often found in bioactive natural pro- (Scheme 1b).
ducts and pharmaceuticals.7 Formation of 1 is distinct from
First, catalysts and reaction conditions were evaluated in the
reaction of ethyl pyruvate (2a) and p-nitrobenzaldehyde (3a) to
afford dihydro-2H-pyran derivative 1aa (Table 1). Pyruvate-
dependent aldolases often use an enamine-based mechanism,10
and we tested the use of amine-based catalysts for the formation
of 1 via an enamine-mechanism. It has been reported that proline
forms an oxazolidine derivative with pyruvates and thus cannot
act as a catalyst in the reaction of pyruvates.3a Therefore, amines
other than proline, including pyrrolidine, pyrrolidine bearing acid
functional groups at either 2- or 3-position, and primary amines
Chemistry and Chemical Bioengineeing Unit, Okinawa Institute of Science and
Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan.
E-mail: ftanaka@oist.jp
† This article is dedicated to Prof. Carlos F. Barbas, III, The Scripps Research
Institute, in memoriam, who died in June 2014.
‡ Electronic supplementary information (ESI) available: Synthesis and character-
ization of compounds, X-ray crystal structures of 1ab and 7aa. CCDC 1012430
(compound 1ab) and 1012431 (compound 7aa). For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c4cc06035k
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 14881--14884 | 14881

View Article Online
Communication
ChemComm
Table 1 Screening of catalysts in the reaction of ethyl pyruvate (2a) and
aldehyde 3a to form 1aaa
Table 2 Scope of the b-proline-catalyzed reaction to form dihydropyransa
Yieldb
Time (h) (%)
Entry Catalyst
1
2
3
4
5
6
Pyrrolidine
Pyrrolidine–CH3COOH (1 : 1)
CH3COOH
(S)-5-Pyrrolidin-2-yl-1H-tetrazole
(S)-Prolinamide
3-(Trifluoromethanesulfonylamino)pyrrolidine 48
48
48
48
48
48
4
27
nd
2
nd
9
7
(S)-b-Proline
(S)-b-Proline
(S)-b-Prolinamide
(S)-b-Proline-Et3N
b-Alanine
(S)-L-Alanine, valine, histidine, or tryptophan 48
O-tBu-(S)-L-threonine
Et3N, DBU, or DMAP
24
24
24
48
48
49
72
46
nd
nd
nd
nd
nd
8c
9c
10
11
12d
13
14d
48
48
a
Reaction was performed using 2a (2.2 mmol) and 3a (1.0 mmol) in
the presence of catalyst (0.1 mmol) in CH3CN (1.0 mL) at 25 1C except
a
Reaction conditions: pyruvate (3.0 mmol), aldehyde (1.0 mmol), and
b
(S)-b-proline (0.2 mmol) in CH3CN (1.0 mL) at 25 1C for 24 h. Yields
were the isolated yields; the cyclic form and the linear form were
combined. The main product was 1 for all cases. The reaction time
where indicated. Isolated yield (the cyclic form and the linear form
were combined11); nd = formation of 1aa was not detected by TLC
c
analyses. Reaction using 2a (3.0 mmol) and 3a (1.0 mmol) in the
presence of catalyst (0.2 mmol). Each catalyst was tested in a separate
b
d
was not optimized for each aldehyde substrate. 4na (30%) was
c
obtained with 1na. 4oa (11%) was obtained with 1oa.
reaction.
such as a-amino acids, were tested as catalysts for the formation
of 1aa. We found that pyrrolidine-3-carboxylic acid (b-proline) was
the best catalyst of those tested (entries 7 and 8).11,12 Reactions
using non-enamine-forming bases, such as DBU,13 as catalysts
were also tested, but did not afford 1aa (entry 14). With optimiza-
tion, when the reaction was performed using ethyl pyruvate (2a)
(3 equiv.), aldehyde 3a (1 equiv.), and b-proline (0.2 equiv.) in
CH3CN at 25 1C for 24 h, 1aa (including the linear form) was
obtained in 72% yield (entry 8).14
Next, the scope of the b-proline-catalyzed reaction was
examined under the optimized conditions to afford 1aa, and
various dihydropyran derivatives were synthesized (Table 2).11
The use of b-proline catalysis efficiently provided various
dihydropyrans 1; the main product was 1 for all cases. In the
reactions to generate 1na and 1oa, aldol condensation products
4na and 4oa, respectively, were also obtained. In most cases,
Scheme 2 Reactions using preformed intermediate 4ab.
however, significant formation of the aldol condensation pro- sp2 or sp3 carbon of the dihydropyran ring was obtained
duct was not detected during the reaction. The generated (Scheme 2). That is, no significant discrimination between
dihydropyran product (i.e., the cyclic form) was mostly a single the two ketoester groups was observed in the reaction to form
diastereomer (dr 4 10 : 1). The relative stereochemistry of 1ab was the dihydropyran ring. This result suggests that the formation
determined to be as drawn in Table 2 by X-ray crystal structural of 6 is likely via a Michael addition–cyclization, i.e., via the
analysis (see ESI‡).
formation of acyclic intermediate 5 or its iminium ion with
To understand the mechanism of the formation of dihydro- b-proline, rather than a [4+2] reaction15 between 4ab and an
pyrans 1 from pyruvates and aldehydes, reactions using a enol of the pyruvate.
possible intermediate b,g-unsaturated a-ketoester and pyruvates
It is expected that the synthesized dihydropyran derivatives 1
were examined. When the reaction began with preformed have features of a-ketoesters and thus are useful for further
b,g-unsaturated a-keto methyl ester 4ab with ethyl pyruvate transformations to synthesize various functionalized molecules.16
(2a) or benzyl pyruvate (2c), a mixture of dihydropyran deri-
Reactions of 1 with nitromethane gave functionalized cyclo-
vatives in which the methyl ester group was either at the hexanes 7 in high yields (Table 3). In all cases, the isolated
14882 | Chem. Commun., 2014, 50, 14881--14884
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
Table 3 Transformation of the dihydropyrans 1 to functionalized cyclo-
hexanes 7a
Scheme 4 Reactions of 1 with amines.
Table 5 Transformation of 1 to pyridines
a
Reaction conditions: 1 (0.1 mmol), CH3NO2 (1.0 mmol), and Et3N
b
(0.15 mmol) in CH2Cl2 (0.5 mL) at 25 1C. 7abc was synthesized from 6abc.
Scheme 3 Transformations of 7.
Table 4 Transformations of 1 to fluorodihydropyrans
molecules.20 Previously reported synthesis of substituted
pyridine-2,6-dicarboxylic acids often requires long routes
including steps that require severe conditions.20 Here, start-
ing from pyruvates and aldehydes, pyridine-2,6-dicarboxylic
acid derivatives bearing various substitutions at the 4-position
of the pyridine were concisely synthesized under mild
conditions.
In conclusion, we have developed concise cascade reactions
cyclohexane product was a single diastereomer. The relative of pyruvates that provide various functionalized dihydropyrans
stereochemistry of 7aa was determined to be as shown in in one pot under mild conditions. We have demonstrated that
Table 3 by X-ray crystal structural analysis (see ESI‡).
the use of b-proline catalysis can provide the dihydropyrans
Debenzylation of 7gc gave diacid 8gc and reduction of the that were not obtained in previously reported reactions of
nitro group of 7da gave amino acid derivative 9da (Scheme 3). A pyruvates. Our strategy enabled harnessing of the reactivity of
highly functionalized amino acid derivative was obtained in a the pyruvates to synthesize complex, functionalized products in
concise route via the use of the cascade reaction of pyruvates. one pot. Furthermore, we have demonstrated that the cascade
Reactions of 1 with diethylaminosulfur trifluoride (DAST) reaction products, dihydropyrans, can be readily transformed
afforded fluorinated pyran derivatives 10 (Table 4).17,18
Reactions of 1 with amines afforded amino group substi- as bioactive candidates.
to various molecules under mild conditions, which can be used
tuted dihydropyrans 11 and 12, dihydrodiazepines 13 and 14,
We thank Dr Takashi Matsumoto, Rigaku for X-ray crystal
and quinoxalinone derivative 15 depending on the amine under analyses and Dr Michael Chandro Roy, Research Support Divi-
mild conditions (Scheme 4).19
sion, Okinawa Institute of Science and Technology Graduate
Reactions of 1 with ammonium acetate afforded pyridine University for mass analyses. This study was supported by the
derivatives 16 (Table 5). Pyridine-2,6-dicarboxilic acids and Okinawa Institute of Science and Technology Graduate Uni-
their derivatives are important as ligands for metals, small versity and by the MEXT (Japan) Grant-in-Aid for Scientific
organic molecules, and biomolecules, and have been used Research on Innovative Areas ‘‘Advanced Molecular Transfor-
as building blocks in the synthesis of bioactive and biofunctional mations by Organocatalysts’’
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 14881--14884 | 14883

View Article Online
Communication
ChemComm
C. Rodriguez-Escrich and K. A. Jorgensen, Angew. Chem., Int. Ed.,
2012, 51, 13109; (e) J. Feng, X. Fu, Z. Chen, L. Lin, X. Liu and X. Feng,
Org. Lett., 2013, 15, 2640.
Notes and references
1 T. E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed., 2008, 47, 48
and references cited therein.
2 M.-J. Kim, W. J. Hennen, H. M. Sweers and C.-H. Wong, J. Am. Chem.
Soc., 1988, 110, 6481; H. J. M. Gijsen, L. Qiao, W. Fitz and C.-
H. Wong, Chem. Rev., 1996, 96, 443.
10 A. D. Daniel, I. Campeotto, M. W. van der Kamp, A. H. Bolt, C. H.
Trinh, S. E. V. Phillips, A. R. Pearson, A. Nelson, A. J. Mulholland
and A. Berry, ACS Chem. Biol., 2014, 9, 1025.
11 Product 1aa obtained in Table 1 was mainly (470%) the cyclic forms
after initial isolation/purification. The ratio of the cyclic form to the
corresponding acyclic, C2 symmetric, achiral linear form varied
depending on the aldehyde used in the reaction and on other
factors such as time kept after isolation. (See ESI‡). Cyclic hemi-
acetals are often in equilibrium with the corresponding open chain,
linear forms.
12 b-Proline has been used for Mannich-type reactions of ketones via
in situ-generation of enamines, but has not been used in reactions of
pyruvates. See: (a) H. Zhang, M. Mifsud, F. Tanaka and C. F. Barbas
III, J. Am. Chem. Soc., 2006, 128, 9630; (b) H. Zhang, S. Mitsumori,
N. Utsumi, M. Imai, N. Garcia-Delgado, M. Mifsud, K. Albertshofer,
P. H.-Y. Cheong, K. N. Houk, F. Tanaka and C. F. Barbas III, J. Am.
Chem. Soc., 2008, 130, 875.
13 D. Zhang, S. Johnson, H.-L. Cui and F. Tanaka, Asian J. Org. Chem.,
2014, 3, 391.
14 For the b-proline-catalysis to give 1aa, CH3CN was the best solvent
among those tested. Solvent screen results under the conditions of
Table 1, entry 7: 1aa was obtained in a range of 6–15% in toluene,
CH2Cl2, CHCl3, DMSO, DMF, THF, 1,4-dioxane, and 2-PrOH; no
formation of 1aa was detected in CH3CN–H2O (3 : 1).
15 Z. Xu, L. Liu, K. Wheeler and H. Wang, Angew. Chem., Int. Ed., 2011,
50, 3484.
16 Note that for many of 6-membered hemiacetals (such as carbo-
hydrates including glucose), the cyclic form is stable and they do not
behave as typical aldehydes: (a) B. Voigt, U. Scheffler and R. Mahrwald,
Chem. Commun., 2012, 48, 5304; (b) B. Voigt, A. Anastassia and
R. Mahrwald, Tetrahedron, 2013, 69, 4302.
17 Fluoropyran derivatives include enzyme inhibitors and other bio-
functional molecules: (a) C.-S. Tsaai, H.-Y. Yen, M.-I. Lin, T.-I. Tsai,
S.-Y. Wang, W.-I. Huang, T.-L. Hsu, Y.-S. E. Cheng, J.-M. Fang and
C.-H. Wong, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 2466; (b) J.-H.
Kim, R. Resende, T. Wennekes, H.-M. Chen, N. Bance, S. Buchini,
A. G. Watts, P. Pilling, V. A. Streltsov, M. Petric, R. Liggins, S. Barrett,
J. L. McKimm-Breschkin, M. Niikura and S. G. Withers, Science,
2013, 340, 71.
18 Fluoropyran derivatives as building blocks: (a) Y. Zhang, J. Gaekwad,
M. A. Wolfert and G.-J. Boons, Chem. – Eur. J., 2008, 14, 558;
(b) D. Solomon, M. Fridman, J. Zhang and T. Baasov, Org. Lett.,
2001, 3, 4311; (c) S. B. Cohen and R. L. Halcomb, J. Org. Chem., 2000,
65, 6145.
3 (a) P. Dambruoso, A. Masai and A. Dondoni, Org. Lett., 2005, 7, 4657;
(b) K. Juhl, N. Gathergood and K. A. Jorgensen, Chem. Commun.,
2000, 2211; (c) H. Torii, M. Nakadai, K. Ishihara, S. Saito and
H. Yamamoto, Angew. Chem., Int. Ed., 2004, 43, 1983; (d) J. El-Sepelgy
and O. Mlynarski, Adv. Synth. Catal., 2013, 355, 281; (e) K. Juhl,
N. Gathergood and K. A. Jorgensen, Angew. Chem., Int. Ed., 2001,
40, 2995; ( f ) M. Raj, G. S. Parashari and V. K. Singh, Adv. Synth. Catal.,
2009, 351, 1284; (g) C. Luo and Y. Huang, J. Am. Chem. Soc., 2013,
135, 8193.
4 Reaction methods used on a-ketoacid derivatives that are equal or
larger than 2-ketobutanoic acid derivatives often do not work for the
reactions of 2-ketopropionic acid (i.e., pyruvic acid) derivatives. See:
J.-M. Vincent, C. Margottin, M. Berlande, D. Cavagnat, T. Buffeteau
and Y. Landais, Chem. Commun., 2007, 4782.
5 Because of the difficulty to control the nucloephilic and electrophilic
reactivities of pyruvates, pyruvate surrogates and precursors have
often been used. See: (a) D. Enders and T. Gasperi, Chem. Commun.,
2007, 88; (b) R. Winzar, J. Philip and M. J. Kiefel, Synlett, 2010, 583.
6 Reactions of a-ketoacid derivatives that are equal or larger than
2-ketobutanoic acid derivatives: (a) D. Lee, S. G. Newman and
M. S. Taylor, Org. Lett., 2009, 11, 5486; (b) G. Lu, H. Morimoto,
S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2008,
47, 6847; (c) Y. Xu, G. Lu, S. Matsunaga and M. Shibasaki, Angew.
Chem., Int. Ed., 2009, 48, 3353; (d) A. Nakamura, S. Lectard,
D. Hashizume, Y. Hamashima and M. Sodeoka, J. Am. Chem. Soc.,
2010, 132, 4036; (e) O. El-Sepelgy and J. Mlynarski, Adv. Synth. Catal.,
2013, 355, 281; ( f ) L. C. Akullian, M. L. Snapper and A. H. Hoveyda,
J. Am. Chem. Soc., 2006, 128, 6532; (g) J. Sedelmeier, T. Hammerer
and C. Bolm, Org. Lett., 2008, 10, 917; (h) V. B. Gondi, K. Hagihara
and V. H. Rawal, Chem. Commun., 2010, 46, 904; (i) H. Li, B. Wang
and L. Deng, J. Am. Chem. Soc., 2006, 128, 732; ( j) L. Gremaud and
A. Alexakis, Angew. Chem., Int. Ed., 2012, 51, 794; (k) A. Lee and
K. A. Scheidt, Angew. Chem., Int. Ed., 2014, 53, 7594; (l) See also
ref. 4.
7 Selected reports on the synthesis of dihydro- and tetrahydropyrans:
(a) J. Magano, Chem. Rev., 2009, 109, 4398; (b) H. Ishikawa,
S. Sawano, Y. Yasui, Y. Shibata and Y. Hayashi, Angew. Chem., Int.
Ed., 2011, 50, 3774; (c) L.-J. Dong, T.-T. Fan, C. Wang and J. Sun, Org.
Lett., 2013, 15, 204; (d) A. G. Dossetter, T. F. Jamison and E. N.
Jacobsen, Angew. Chem., Int. Ed., 1999, 38, 2398; (e) Y. Yamashita,
S. Saito, H. Ishitani and S. Kobayashi, J. Am. Chem. Soc., 2003, 19 Synthesis of diazepines: (a) B. Elger, A. Huth, R. Neuhaus, E. Ottow,
125, 3793; ( f ) A. K. Unni, N. Takenaka, H. Yamamoto and V. H.
Rawal, J. Am. Chem. Soc., 2005, 127, 1336; (g) N. Momiyama,
H. Tabuseand and M. Terada, J. Am. Chem. Soc., 2009, 131, 12882;
(h) J. Guin, C. Rabalakos and B. List, Angew. Chem., Int. Ed., 2012,
51, 8859; (i) H. Cui and F. Tanaka, Chem. – Eur. J., 2013, 19, 6213.
H. Schneider, B. Seilheimer and L. Turski, J. Med. Chem., 2005,
48, 4618; (b) M. Zappala, G. Postorino, N. Micale, S. Caccamese,
N. Parrinello, G. Grazioso, G. Roda, F. Menniti, G. De Sarro and
S. Grasso, J. Med. Chem., 2006, 49, 575; (c) K. Sugimoto, R. Hayashi,
H. Nemoto, N. Toyooka and Y. Matsuya, Org. Lett., 2012, 14, 3510.
8 Selected cascade reactions: (a) C. Grondal, M. Jeanty and D. Enders, 20 (a) A. Picot, A. D’Aleo, P. L. Baldeck, A. Grichine, A. Duperray,
Nat. Chem., 2010, 2, 167 and references cited therein; (b) X. Zeng,
Q. Ni, G. Raabe and D. Enders, Angew. Chem., Int. Ed., 2013,
52, 2977; (c) K. E. Ozboya and T. Rovis, Chem. Sci., 2011, 2, 1835;
(d) C. M. R. Volla, I. Atodiresei and M. Ruping, Chem. Rev., 2014,
114, 2390 and cited therein.
9 Reactions of b,g-unsaturated a-ketoesters with aldehydes or ketones
to afford dihydropyrans: (a) S.-L. Zhao, C.-W. Zheng, H.-F. Wang and
G. Zhao, Adv. Synth. Catal., 2009, 351, 2811; (b) Z. Xu, L. Liu,
K. Wheeler and H. Wang, Angew. Chem., Int. Ed., 2011, 50, 3484;
(c) J. Shen, D. Liu, Q. An, Y. Liu and W. Zhang, Adv. Synth. Catal.,
2012, 354, 3311; (d) L. Albrecht, D. Dickmeiss, C. F. Weise,
C. Andraud and O. Maury, J. Am. Chem. Soc., 2008, 130, 1532; (b) A. T.
Parsons and J. S. Johnson, J. Am. Chem. Soc., 2009, 131, 3122; (c) C. J.
van Staveren, V. M. L. J. Aart, P. D. J. Grootenhuis, W. J. H. Droppers,
J. van Eerden, S. Harkema and D. N. Reinhoudt, J. Am. Chem. Soc.,
1988, 110, 8134; (d) R. Tang, Q. Zhao, Z. Yan and Y. Luo, Synth.
Commun., 2006, 36, 2027; (e) D. Wang, P. Y. Zavalij and A. N.
Vedernikov, Organometallics, 2013, 32, 4882; ( f ) L. L. Zhu,
T. Kawate, X. Liu, Y. B. Kim, Y. Zhao, G. Feng, J. Banerji, H. Nash,
C. Whitehurst, S. Jindal, A. Siddiqui, B. Seed and J. L. Wolfe, Bioorg.
Med. Chem., 2012, 20, 750; (g) P. Hommes, C. Fischer, C. Lindner,
H. Zipse and H.-U. Ressing, Angew. Chem., Int. Ed., 2014, 53, 7647.
14884 | Chem. Commun., 2014, 50, 14881--14884
This journal is ©The Royal Society of Chemistry 2014