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Cite this: Chem. Commun., 2013, 49, 11569 Received 7th October 2013, Accepted 17th October 2013
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Organocatalysed decarboxylative protonation process from Meldrum’s acid: enantioselective synthesis of isoxazolidinones† `re* Tony Tite,z Mohamad Sabbah,z Vincent Levacher and Jean-François Brie
DOI: 10.1039/c3cc47695b www.rsc.org/chemcomm
An asymmetric organocatalysed decarboxylative protonation reaction allowed a straightforward synthesis of a-substituted isoxazolidin5-ones from readily available 5-substituted Meldrum’s acids. This process is initiated by an anionic formal (3+2) cycloaddition– fragmentation, generated in-situ from a sulfone-amide precursor which also served as a latent source of proton.
The enantioselective protonation of stoichiometric enolate derivatives has been proposed as a key technology for the construction of tertiary stereogenic centres, ubiquitous chiral elements within high value organic architectures. A great deal of work has been done since the seminal contribution of Duhamel and Plaquevent,1 but, however, highly stereoselective and organocatalytic versions have emerged only recently.2,3 In that context, the decarboxylative protonation reaction (Scheme 1a), which is easily carried out from stable a-keto carboxylic acids 1 and a catalytic amount of base, holds an important place in asymmetric protonation processes.2a,c,4 This is both a fundamental biochemical process and one of the oldest enantioselective chemical reactions tackled in 1904 by Marckwald.4 Nonetheless, this is not before the 2000s that the groups of Brunner and Rouden developed synthetically more efficient asymmetric sequences making use of cinchona alkaloid organocatalysts.4,5 Despite these decisive and elegant pioneer achievements, only few efficacious organocatalytic and highly enantioselective decarboxylative protonation protocols do exist thus far.4–7 Generally speaking, the difficulty in implementing robust organocatalytic protonation processes may arise from important bottleneck points which have to be overcome in order to control the rapid transfer of a small proton atom, C versus O protonation, the E/Z enolate 2 geometry8 and the preservation of the usually labile absolute chirality of products. The ready availability of the precursors is also a point of importance. For instance, carboxylic acid precursors 1 necessitate a two-step Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnie`re, 76821 Mont Saint Aignan cedex, France. E-mail: [email protected]; Fax: +33 235522464; Tel: +33 235522962 † Electronic supplementary information (ESI) available: Further experimental optimisation, procedures and compound characterisation data. See DOI: 10.1039/c3cc47695b ‡ These two researchers equally contributed to this project.
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Scheme 1
Enantioselective decarboxylative protonation process.
alkylation (R2 introduction) and saponification sequence to be prepared.4 Based on our recent discovery upon native Meldrum’s acid 4 reactivity (Scheme 1b, R1 = H),9 we anticipated that both readily available 5-substituted Meldrum’s acid 4 (R1 a H) and sulfoneamide 5a,10 a convenient N-Boc nitrone 8 precursor,11 might undergo a formal (3+2) cycloaddition event under basic conditions, triggering the domino fragmentation–decarboxylation– protonation reaction (8 to 10). This sequence would both provide a novel enantioselective decarboxylative protonation methodology with chiral organic bases (10), and furnish original access to a-substituted isoxazolidin-5-ones 6. Actually, homologues of 6 are known as useful precursors for both Bode’s chemical ligation process and the synthesis of b2-amino acids.9,12 Since the decisive pioneering studies of Seebach and co-workers, the importance of Chem. Commun., 2013, 49, 11569--11571
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b2-amino acids was highlighted either for their bioactivities on their own or for their ability to control the secondary structure of b-peptides.13 To the best of our knowledge, the asymmetric synthesis of these a-substituted isoxazolidin-5-ones 6 was only tackled by the diastereoselective approach.14 On the one hand, this approach may provide a user-friendly decarboxylative protonation approach due to: (1) the in situ formation of the enolate species 10 through a convenient domino C–O and C–C bond formation reaction, (2) the formation of a welldefined cyclic Z-enolate 10 and (3) the use of acidic starting materials 5a and Meldrum’s acids 4 as prerequisites to drive a racemisation-free decarboxylative protonation process towards base sensitive a-substituted carbonyles 6.15 On the other hand, the control of this tandem sequence to enable enantioselective protonation of enolate 10 by R3NH+ necessitates a tedious parameter orchestration dealing with both acidic protons of Meldrum’s acids 4 and nitrone precursor 5a. The purpose is to eventually release a molecule of sodium sulfinate in the presence of a stoichiometric amount of achiral base such as Na2CO3 without a racemic background pathway. The preliminary results of this successful adventure will be discussed herewith. We undertook the identification of a competent chiral promoter by means of 1.2 equivalents of amines 11 and 5-benzyl Meldrum’s acid 4a (Table 1). In principle, the extra equivalent of base 11 neutralises the molecule of sulfinic acid liberated from 5a during nitrone 8 formation. During the screening of organocatalysts
Table 1
Proof of principle and optimization
Cat. Entry Precursor (equiv.) 1 2 3 4 5 6 7 8 9 10 11 12
4a 4a 4a 4a 7b 4a 4a 4a 4ae 4ae 4ae 4ae
1.2 1.2 1.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0
(11a) (11b) (11c) (11c) (11c) (11c) (11c) (11c) (11c) (11d)f (11c)
Na2CO3 (equiv.) — — — — — 1.0 1.0 1.1 1.3 1.3 1.3 1.3
Solvent/ H2O a
100/0 100/0a 100/0a 100/0a 87/13a 87/13a 100/0a 50/50d 50/50d 50/50d 50/50d 50/50d
a
Yieldb (%)
erc (R : S)
99 21 97 30 79 64 56 72 75 74 98g,h 22g,h
83 : 17 41 : 59 90 : 10 82 : 18 87 : 13 87 : 13 84 : 16 90.5 : 9.5 92 : 8 8 : 92 90.5 : 9.5 —
Sulfone-amide 5a (0.1 mmol, 0.1 M), Meldrum’s acid 4a (1.1 equiv.) or 7b (1.0 equiv.), Na2CO3, toluene–H2O, rt, 24 hours. b Isolated yield after silica gel column chromatography. c Determined by chiral HPLC. d m-Xylene as solvent. e 1.3 equivalents of 4a. f Use of 9-epi-aminocinchonidine thiourea 11d. g Yield determined by 1H NMR and an internal standard on the crude product. h After 90 minutes. 11570
Chem. Commun., 2013, 49, 11569--11571
(see ESI†) in toluene at rt, 9-epi-aminoquinidine thiourea 11c (9-epi-QDU) turned out to be a competent asymmetric promoter, as already observed by Rouden and co-workers (entry 1–3).5b Therefore, this original domino reaction was validated, affording a straightforward synthesis of isoxazolidinone 6a with high yield (97%) and 90 : 10 er (entries 3). However, in the presence of 20 mol% 9-epi-QDU 11c both low yield of 30% and a decreased enantiomeric ratio of 82 : 18 were obtained after 24 hours, showing the necessity of neutralising one or both acidic protons of 4a or 5a (entry 4). Pleasingly, starting from the readily available sodium salt of 5-benzyl Meldrum’s acid anion 7b instead of 4a,16 10% of 9-epi-QDU 11c furnished the corresponding isoxazolidinone 6a with an increased 79% yield and 87 : 13 er (entry 5) but in the presence of water.17 For practical reasons, we subsequently sought to perform this organocatalytic process by generating the Meldrum’s acid anion 7b in situ from 4a in the presence of an achiral base. After the screening of various bases (see ESI†), it was shown that Na2CO3 co-base (1 equiv.) provided similar results (entry 6) in the presence of 13% water (entry 6 versus 7) at room temperature. Eventually, an increased amount of water (entry 8) and Meldrum’s acid 4a (entry 9) furnished the desired isoxazolidinone 6a with 75% yield and 92 : 8 er in favour of the R product (vide infra). Importantly, the reverse enantioselectivity (8 : 92 er in favour of the S product) was achieved with the 9-epi-aminocinchonidine thiourea catalyst 11d. Simple test reactions demonstrated the capability of catalyst 11c to accelerate the domino reaction to give a complete conversion into 6a after 1.5 hours (entry 11). In contrast, the uncatalysed reaction furnished only 22% of the product over the same period of time (entries 11 and 12). To our knowledge, we assume that the role of water is to slow down the background reaction by partitioning the Meldrum’s acid anion 7b (cation = Na+) between aqueous and organic layers (Scheme 1b).18 Therefore, an anion metathesis might take place between sodium salt 7b and 9-epi-QDU-H+ O2SPh, generated from 5a and catalyst R3N 11c in the organic layers (or at the interface with water through a phase transfer catalytic regime), to form the reactive ion pair 7a (Scheme 1b). Overall, this mechanistic proposal outlines an enantioselective protonation sequence to form isoxazolidinone 6a, in which the sulfoneamide 5a serves as an original latent source of hydrogen. Then, we probed the scope of this asymmetric protonation reaction with 10% of 9-epi-QDU catalyst 11c in order to give various a-substituted isoxazoldin-5-ones 6 (Table 2). The N-Boc-nitrone precursor 5a furnished the corresponding isoxazolidinone 6a as a white solid (91 : 09 er) with 74% yield, whose enantiomeric ratio was improved to >99 : 1 after recrystallization (entry 1). The N-Cbz analogue 6b was efficiently synthesized from 5b albeit with lower 79.5 : 20.5 er. Various a-benzyl isoxazolidinone derivatives 6c–f were successfully obtained in good yields with er ranging from 86.5 : 13.5 to 91 : 09 (entries 3–6). The crystalline derivative 6e having a 2-naphthyl CH2 moiety was also enantioenriched to 99 : 1 er after recrystallisation. Furthermore, isoxazolidinones possessing alkyl chains with 2 or 3 carbon atoms flanked by various functional groups such as Ph 6g, alkene 6h and (thio)ethers 6i–j (entries 7–10) were synthesized in good yields and up to 90 : 10 enantiomeric ratios. On the one hand, it was found that an a-branched alkyl chain such as the isopropyl group led to a somewhat lower 82 : 18 er (entry 11). However, a simple 5-methyl Meldrum’s acid 4l furnished the corresponding a-methyl isoxazolidine 6l with 83% yield and This journal is
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Table 2
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Notes and references
Scope of the reactiona
Entry Precursor (R1)
Sulfone-amide (R2) Yieldb (%) erc (R : S)
1 2 3 4 5 6 7 8 9 10 11 12 13
tBu (5a) Bn (5b) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a)
Bn (4a) Bn (4b) pMeOC6H4CH2 (4c) mClC6H4CH2 (4d) 2-NaphthylCH2 (4e) 2-ThienylCH2 (4f) Ph(CH2)3 (4g) CH2QCH(CH2)3 (4h) BnO(CH2)2 (4i) MeS(CH2)3 (4j) iPr (4k) Me (4l) Ph (4m)
74 87 78 85 76 75 79 80 72 83 86 83 38
(6a) (6b) (6c) (6d) (6e) (6f) (6g) (6h) (6i) (6j) (6k) (6l) (6m)
91 : 09d 79.5 : 20.5 91 : 09 89 : 11 86.5 : 13.5d 90 : 10 86.5 : 13.5 89 : 11 87.5 : 12.5 89 : 11 82 : 18e 94 : 06e —
a
Sulfone-amides 5 (0.12–0.5 mmol, 0.1 M), Meldrum’s acids 4 (1.3 equiv.), Na2CO3 (1.3 equiv.), m-xylene–H2O (1/1), rt, 24 hours. b Isolated yield after silica gel column chromatography. c er determined by chiral HPLC. d 99 : 1 er after recrystallization in pentane–ether with 36–37% overall yield. e er determined by chiral GC.
Scheme 2
b2-Amino acid synthesis.
high 94 : 6 er (entry 12). We found a limitation to this process using 5-phenyl Meldrum’s acid precursor 4m (entry 13). In order to evaluate the usefulness of such building blocks for the stereoselective preparation of valuable b-amino acids, we carried out a ring opening hydrogenolysis reaction following the Gellman protocol (Scheme 2).14 Pleasingly, the N-Boc protected 2-homophenylalanine 12 was easily formed in onestep with 76% yield. The b2-amino acid 12 displayed an R absolute configuration with respect to the literature optical rotation value of an enantiopure sample.19 In conclusion, we have reported an original asymmetric organocatalysed synthesis of a-substituted isoxazolidin-5-ones, useful b2-amino acid precursors, based on a practical anionic domino formal (3+2) cycloaddition–fragmentation–decarboxylative– protonation reaction from readily available Meldrum’s acid derivatives. The discovery of more competent and dedicated catalysts is currently under investigation. This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD and Labex SynOrg (ANR-11LABX-0029). This work is part of the Immunochim project (No 34209) and biofluorg project (No 33236) funded by the European Union through a FEDER support engaged in region Haute-Normandie.
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1 For leading reviews, see: (a) C. Fehr, Angew. Chem., Int. Ed. Engl., 1996, 35, 2566; (b) L. Duhamel, P. Duhamel and J.-C. Plaquevent, Tetrahedron: Asymmetry, 2004, 15, 3653. 2 For recent reviews, see: (a) J. Rouden, in Cinchona Alkaloids in Synthesis and Catalysis, ed. C. E. Song, Willey, 2009, p. 171; (b) J. T. Mohr, A. Y. Hong and B. M. Stoltz, Nat. Chem., 2009, 1, 359; `re and V. Levacher, in Enantio(c) T. Poisson, S. Oudeyer, J.-F. Brie selective Organocatalyzed Reactions I, ed. R. Mahrwald, Springer, 1st edn, 2011, p. 67; (d) A. Claraz, S. Oudeyer and V. Levacher, Curr. Org. Chem., 2012, 16, 2191; (e) T. Poisson and S. Kobayashi, in Stereoselective Synthesis of Drugs and Natural Products, ed. V. Andrushko and N. Andrushko, Wiley-Blackwell, 2013, p. 961. 3 For recent examples uncovered in reviews, see: (a) L. Dai, H. Yang, J. Niu and F. Chen, Synlett, 2012, 314; (b) F. Capitta, A. Frongia, P. P. Piras, P. Pitzanti and F. Secci, Org. Biomol. Chem., 2012, 10, 490; (c) E. Yamamoto, D. Gokuden, A. Nagai, T. Kamachi, K. Yoshizawa, A. Hamasaki, T. Ishida and M. Tokunaga, Org. Lett., 2012, 14, 6178; (d) N. E. Wurz, C. G. Daniliuc and F. Glorius, Chem.–Eur. J., 2012, 18, 16297; (e) A. Sengupta and R. B. Sunoj, J. Org. Chem., 2012, 77, 10525; ( f ) K. L. Kimmel, J. D. Weaver, M. Lee and J. A. Ellman, J. Am. Chem. Soc., 2012, 134, 9058; ( g) J.-W. Lee and B. List, J. Am. Chem. Soc., 2012, 134, 18245; (h) A. Frongia, F. Secci, F. Capitta, P. P. Piras and M. L. Sanna, Chem. Commun., 2013, 49, 8812; (i) R. A. Unhale, N. K. Rana and V. K. Singh, Tetrahedron Lett., 2013, 54, 1911; ( j) J. Guin, G. Varseev and B. List, J. Am. Chem. Soc., 2013, 135, 2100. 4 For an insightful review on decarboxylative protonation reaction, see: J. Blanchet, J. Baudoux, M. Amere, M.-C. Lasne and J. Rouden, Eur. J. Org. Chem., 2008, 5493. 5 (a) H. Brunner and M. A. Baur, Eur. J. Org. Chem., 2003, 2854; (b) M. Amere, M.-C. Lasne and J. Rouden, Org. Lett., 2007, 9, 2621, and references cited therein. 6 For an alternative enantioselective organometallic approach, see: S. C. Marinescu, T. Nishimata, J. T. Mohr and B. M. Stoltz, Org. Lett., 2008, 10, 1039. 7 For examples of enzymes promoted decarboxylative protonation reactions, see: (a) Y. Terao, Y. Ijima, K. Miyamoto and H. Ohta, J. Mol. Catal. B: Enzym., 2007, 45, 15; (b) K. Miyamoto, S. Hirokawa and H. Ohta, J. Mol. Catal. B: Enzym., 2007, 46, 14. 8 C. H. Cheon, O. Kanno and F. D. Toste, J. Am. Chem. Soc., 2011, 133, 13248. 9 b-Functionalized isoxasolidin-5-ones were prepared from native Meldrum’s acid 4 and an in situ generated unstable substituted N-Boc nitrone: S. Postikova, T. Tite, V. Levacher and `re, Adv. Synth. Catal., 2013, 355, 2513 and references cited J.-F. Brie therein. 10 (a) D. B. Ramachary and G. B. Reddy, Org. Biomol. Chem., 2006, 4, 4463; (b) D. B. Ramachary, M. Kishor and K. Ramakumar, Tetrahedron Lett., 2006, 47, 651. 11 For pioneering developments in the use of N-Boc nitrones, see: ´e and J.-N. Denis, Org. Lett., 2005, 7, 5147; (a) X. Guinchard, Y. Valle (b) C. Gioia, F. Fini, A. Mazzanti, L. Bernardi and A. Ricci, J. Am. Chem. Soc., 2009, 131, 9614. 12 M. E. Juarez-Garcia, S. Yu and J. W. Bode, Tetrahedron, 2010, 66, 4841. 13 For insightful reviews, see: (a) G. Lelais and D. Seebach, Pept. Sci., 2004, 76, 206; (b) D. Seebach, A. K. Beck, S. Capone, G. Deniau, U. Grosˇelj and E. Zass, Synthesis, 2009, 1. 14 H.-S. Lee, J.-S. Park, B. M. Kim and S. H. Gellman, J. Org. Chem., 2003, 68, 1575. 15 pKa = 4.8 (H2O) 4 R1 = H: (a) A. S. Ivanov, Chem. Soc. Rev., 2008, 37, 789; (b) A. M. Dumas and E. Fillion, Acc. Chem. Res., 2009, 43, 440. 16 The stable sodium salt of 5-benzyl Meldrum’s acid anion is easily synthesized by deprotonation with NaOH. 17 Several attempts to perform the same sequence with poorly soluble Meldrum’s acid anion in toluene without water led to inconsistent results with a maximum of 60 : 40 er. 18 5-Benzyl Meldrum’s acid is rapidedly solubilised into water with 1 equivalent of Na2CO3, but not without. 19 A. Tessier, N. Lahmar, J. Pytkowicz and T. Brigaud, J. Org. Chem., 2008, 73, 3970.
Chem. Commun., 2013, 49, 11569--11571
11571
Published on 01 November 2013. Downloaded by St. Petersburg State University on 31/12/2013 11:16:55.
COMMUNICATION
Cite this: Chem. Commun., 2013, 49, 11569 Received 7th October 2013, Accepted 17th October 2013
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Organocatalysed decarboxylative protonation process from Meldrum’s acid: enantioselective synthesis of isoxazolidinones† `re* Tony Tite,z Mohamad Sabbah,z Vincent Levacher and Jean-François Brie
DOI: 10.1039/c3cc47695b www.rsc.org/chemcomm
An asymmetric organocatalysed decarboxylative protonation reaction allowed a straightforward synthesis of a-substituted isoxazolidin5-ones from readily available 5-substituted Meldrum’s acids. This process is initiated by an anionic formal (3+2) cycloaddition– fragmentation, generated in-situ from a sulfone-amide precursor which also served as a latent source of proton.
The enantioselective protonation of stoichiometric enolate derivatives has been proposed as a key technology for the construction of tertiary stereogenic centres, ubiquitous chiral elements within high value organic architectures. A great deal of work has been done since the seminal contribution of Duhamel and Plaquevent,1 but, however, highly stereoselective and organocatalytic versions have emerged only recently.2,3 In that context, the decarboxylative protonation reaction (Scheme 1a), which is easily carried out from stable a-keto carboxylic acids 1 and a catalytic amount of base, holds an important place in asymmetric protonation processes.2a,c,4 This is both a fundamental biochemical process and one of the oldest enantioselective chemical reactions tackled in 1904 by Marckwald.4 Nonetheless, this is not before the 2000s that the groups of Brunner and Rouden developed synthetically more efficient asymmetric sequences making use of cinchona alkaloid organocatalysts.4,5 Despite these decisive and elegant pioneer achievements, only few efficacious organocatalytic and highly enantioselective decarboxylative protonation protocols do exist thus far.4–7 Generally speaking, the difficulty in implementing robust organocatalytic protonation processes may arise from important bottleneck points which have to be overcome in order to control the rapid transfer of a small proton atom, C versus O protonation, the E/Z enolate 2 geometry8 and the preservation of the usually labile absolute chirality of products. The ready availability of the precursors is also a point of importance. For instance, carboxylic acid precursors 1 necessitate a two-step Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnie`re, 76821 Mont Saint Aignan cedex, France. E-mail: [email protected]; Fax: +33 235522464; Tel: +33 235522962 † Electronic supplementary information (ESI) available: Further experimental optimisation, procedures and compound characterisation data. See DOI: 10.1039/c3cc47695b ‡ These two researchers equally contributed to this project.
This journal is
c
The Royal Society of Chemistry 2013
Scheme 1
Enantioselective decarboxylative protonation process.
alkylation (R2 introduction) and saponification sequence to be prepared.4 Based on our recent discovery upon native Meldrum’s acid 4 reactivity (Scheme 1b, R1 = H),9 we anticipated that both readily available 5-substituted Meldrum’s acid 4 (R1 a H) and sulfoneamide 5a,10 a convenient N-Boc nitrone 8 precursor,11 might undergo a formal (3+2) cycloaddition event under basic conditions, triggering the domino fragmentation–decarboxylation– protonation reaction (8 to 10). This sequence would both provide a novel enantioselective decarboxylative protonation methodology with chiral organic bases (10), and furnish original access to a-substituted isoxazolidin-5-ones 6. Actually, homologues of 6 are known as useful precursors for both Bode’s chemical ligation process and the synthesis of b2-amino acids.9,12 Since the decisive pioneering studies of Seebach and co-workers, the importance of Chem. Commun., 2013, 49, 11569--11571
11569
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Published on 01 November 2013. Downloaded by St. Petersburg State University on 31/12/2013 11:16:55.
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b2-amino acids was highlighted either for their bioactivities on their own or for their ability to control the secondary structure of b-peptides.13 To the best of our knowledge, the asymmetric synthesis of these a-substituted isoxazolidin-5-ones 6 was only tackled by the diastereoselective approach.14 On the one hand, this approach may provide a user-friendly decarboxylative protonation approach due to: (1) the in situ formation of the enolate species 10 through a convenient domino C–O and C–C bond formation reaction, (2) the formation of a welldefined cyclic Z-enolate 10 and (3) the use of acidic starting materials 5a and Meldrum’s acids 4 as prerequisites to drive a racemisation-free decarboxylative protonation process towards base sensitive a-substituted carbonyles 6.15 On the other hand, the control of this tandem sequence to enable enantioselective protonation of enolate 10 by R3NH+ necessitates a tedious parameter orchestration dealing with both acidic protons of Meldrum’s acids 4 and nitrone precursor 5a. The purpose is to eventually release a molecule of sodium sulfinate in the presence of a stoichiometric amount of achiral base such as Na2CO3 without a racemic background pathway. The preliminary results of this successful adventure will be discussed herewith. We undertook the identification of a competent chiral promoter by means of 1.2 equivalents of amines 11 and 5-benzyl Meldrum’s acid 4a (Table 1). In principle, the extra equivalent of base 11 neutralises the molecule of sulfinic acid liberated from 5a during nitrone 8 formation. During the screening of organocatalysts
Table 1
Proof of principle and optimization
Cat. Entry Precursor (equiv.) 1 2 3 4 5 6 7 8 9 10 11 12
4a 4a 4a 4a 7b 4a 4a 4a 4ae 4ae 4ae 4ae
1.2 1.2 1.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0
(11a) (11b) (11c) (11c) (11c) (11c) (11c) (11c) (11c) (11d)f (11c)
Na2CO3 (equiv.) — — — — — 1.0 1.0 1.1 1.3 1.3 1.3 1.3
Solvent/ H2O a
100/0 100/0a 100/0a 100/0a 87/13a 87/13a 100/0a 50/50d 50/50d 50/50d 50/50d 50/50d
a
Yieldb (%)
erc (R : S)
99 21 97 30 79 64 56 72 75 74 98g,h 22g,h
83 : 17 41 : 59 90 : 10 82 : 18 87 : 13 87 : 13 84 : 16 90.5 : 9.5 92 : 8 8 : 92 90.5 : 9.5 —
Sulfone-amide 5a (0.1 mmol, 0.1 M), Meldrum’s acid 4a (1.1 equiv.) or 7b (1.0 equiv.), Na2CO3, toluene–H2O, rt, 24 hours. b Isolated yield after silica gel column chromatography. c Determined by chiral HPLC. d m-Xylene as solvent. e 1.3 equivalents of 4a. f Use of 9-epi-aminocinchonidine thiourea 11d. g Yield determined by 1H NMR and an internal standard on the crude product. h After 90 minutes. 11570
Chem. Commun., 2013, 49, 11569--11571
(see ESI†) in toluene at rt, 9-epi-aminoquinidine thiourea 11c (9-epi-QDU) turned out to be a competent asymmetric promoter, as already observed by Rouden and co-workers (entry 1–3).5b Therefore, this original domino reaction was validated, affording a straightforward synthesis of isoxazolidinone 6a with high yield (97%) and 90 : 10 er (entries 3). However, in the presence of 20 mol% 9-epi-QDU 11c both low yield of 30% and a decreased enantiomeric ratio of 82 : 18 were obtained after 24 hours, showing the necessity of neutralising one or both acidic protons of 4a or 5a (entry 4). Pleasingly, starting from the readily available sodium salt of 5-benzyl Meldrum’s acid anion 7b instead of 4a,16 10% of 9-epi-QDU 11c furnished the corresponding isoxazolidinone 6a with an increased 79% yield and 87 : 13 er (entry 5) but in the presence of water.17 For practical reasons, we subsequently sought to perform this organocatalytic process by generating the Meldrum’s acid anion 7b in situ from 4a in the presence of an achiral base. After the screening of various bases (see ESI†), it was shown that Na2CO3 co-base (1 equiv.) provided similar results (entry 6) in the presence of 13% water (entry 6 versus 7) at room temperature. Eventually, an increased amount of water (entry 8) and Meldrum’s acid 4a (entry 9) furnished the desired isoxazolidinone 6a with 75% yield and 92 : 8 er in favour of the R product (vide infra). Importantly, the reverse enantioselectivity (8 : 92 er in favour of the S product) was achieved with the 9-epi-aminocinchonidine thiourea catalyst 11d. Simple test reactions demonstrated the capability of catalyst 11c to accelerate the domino reaction to give a complete conversion into 6a after 1.5 hours (entry 11). In contrast, the uncatalysed reaction furnished only 22% of the product over the same period of time (entries 11 and 12). To our knowledge, we assume that the role of water is to slow down the background reaction by partitioning the Meldrum’s acid anion 7b (cation = Na+) between aqueous and organic layers (Scheme 1b).18 Therefore, an anion metathesis might take place between sodium salt 7b and 9-epi-QDU-H+ O2SPh, generated from 5a and catalyst R3N 11c in the organic layers (or at the interface with water through a phase transfer catalytic regime), to form the reactive ion pair 7a (Scheme 1b). Overall, this mechanistic proposal outlines an enantioselective protonation sequence to form isoxazolidinone 6a, in which the sulfoneamide 5a serves as an original latent source of hydrogen. Then, we probed the scope of this asymmetric protonation reaction with 10% of 9-epi-QDU catalyst 11c in order to give various a-substituted isoxazoldin-5-ones 6 (Table 2). The N-Boc-nitrone precursor 5a furnished the corresponding isoxazolidinone 6a as a white solid (91 : 09 er) with 74% yield, whose enantiomeric ratio was improved to >99 : 1 after recrystallization (entry 1). The N-Cbz analogue 6b was efficiently synthesized from 5b albeit with lower 79.5 : 20.5 er. Various a-benzyl isoxazolidinone derivatives 6c–f were successfully obtained in good yields with er ranging from 86.5 : 13.5 to 91 : 09 (entries 3–6). The crystalline derivative 6e having a 2-naphthyl CH2 moiety was also enantioenriched to 99 : 1 er after recrystallisation. Furthermore, isoxazolidinones possessing alkyl chains with 2 or 3 carbon atoms flanked by various functional groups such as Ph 6g, alkene 6h and (thio)ethers 6i–j (entries 7–10) were synthesized in good yields and up to 90 : 10 enantiomeric ratios. On the one hand, it was found that an a-branched alkyl chain such as the isopropyl group led to a somewhat lower 82 : 18 er (entry 11). However, a simple 5-methyl Meldrum’s acid 4l furnished the corresponding a-methyl isoxazolidine 6l with 83% yield and This journal is
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Table 2
Communication
Notes and references
Scope of the reactiona
Entry Precursor (R1)
Sulfone-amide (R2) Yieldb (%) erc (R : S)
1 2 3 4 5 6 7 8 9 10 11 12 13
tBu (5a) Bn (5b) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a) tBu (5a)
Bn (4a) Bn (4b) pMeOC6H4CH2 (4c) mClC6H4CH2 (4d) 2-NaphthylCH2 (4e) 2-ThienylCH2 (4f) Ph(CH2)3 (4g) CH2QCH(CH2)3 (4h) BnO(CH2)2 (4i) MeS(CH2)3 (4j) iPr (4k) Me (4l) Ph (4m)
74 87 78 85 76 75 79 80 72 83 86 83 38
(6a) (6b) (6c) (6d) (6e) (6f) (6g) (6h) (6i) (6j) (6k) (6l) (6m)
91 : 09d 79.5 : 20.5 91 : 09 89 : 11 86.5 : 13.5d 90 : 10 86.5 : 13.5 89 : 11 87.5 : 12.5 89 : 11 82 : 18e 94 : 06e —
a
Sulfone-amides 5 (0.12–0.5 mmol, 0.1 M), Meldrum’s acids 4 (1.3 equiv.), Na2CO3 (1.3 equiv.), m-xylene–H2O (1/1), rt, 24 hours. b Isolated yield after silica gel column chromatography. c er determined by chiral HPLC. d 99 : 1 er after recrystallization in pentane–ether with 36–37% overall yield. e er determined by chiral GC.
Scheme 2
b2-Amino acid synthesis.
high 94 : 6 er (entry 12). We found a limitation to this process using 5-phenyl Meldrum’s acid precursor 4m (entry 13). In order to evaluate the usefulness of such building blocks for the stereoselective preparation of valuable b-amino acids, we carried out a ring opening hydrogenolysis reaction following the Gellman protocol (Scheme 2).14 Pleasingly, the N-Boc protected 2-homophenylalanine 12 was easily formed in onestep with 76% yield. The b2-amino acid 12 displayed an R absolute configuration with respect to the literature optical rotation value of an enantiopure sample.19 In conclusion, we have reported an original asymmetric organocatalysed synthesis of a-substituted isoxazolidin-5-ones, useful b2-amino acid precursors, based on a practical anionic domino formal (3+2) cycloaddition–fragmentation–decarboxylative– protonation reaction from readily available Meldrum’s acid derivatives. The discovery of more competent and dedicated catalysts is currently under investigation. This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD and Labex SynOrg (ANR-11LABX-0029). This work is part of the Immunochim project (No 34209) and biofluorg project (No 33236) funded by the European Union through a FEDER support engaged in region Haute-Normandie.
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1 For leading reviews, see: (a) C. Fehr, Angew. Chem., Int. Ed. Engl., 1996, 35, 2566; (b) L. Duhamel, P. Duhamel and J.-C. Plaquevent, Tetrahedron: Asymmetry, 2004, 15, 3653. 2 For recent reviews, see: (a) J. Rouden, in Cinchona Alkaloids in Synthesis and Catalysis, ed. C. E. Song, Willey, 2009, p. 171; (b) J. T. Mohr, A. Y. Hong and B. M. Stoltz, Nat. Chem., 2009, 1, 359; `re and V. Levacher, in Enantio(c) T. Poisson, S. Oudeyer, J.-F. Brie selective Organocatalyzed Reactions I, ed. R. Mahrwald, Springer, 1st edn, 2011, p. 67; (d) A. Claraz, S. Oudeyer and V. Levacher, Curr. Org. Chem., 2012, 16, 2191; (e) T. Poisson and S. Kobayashi, in Stereoselective Synthesis of Drugs and Natural Products, ed. V. Andrushko and N. Andrushko, Wiley-Blackwell, 2013, p. 961. 3 For recent examples uncovered in reviews, see: (a) L. Dai, H. Yang, J. Niu and F. Chen, Synlett, 2012, 314; (b) F. Capitta, A. Frongia, P. P. Piras, P. Pitzanti and F. Secci, Org. Biomol. Chem., 2012, 10, 490; (c) E. Yamamoto, D. Gokuden, A. Nagai, T. Kamachi, K. Yoshizawa, A. Hamasaki, T. Ishida and M. Tokunaga, Org. Lett., 2012, 14, 6178; (d) N. E. Wurz, C. G. Daniliuc and F. Glorius, Chem.–Eur. J., 2012, 18, 16297; (e) A. Sengupta and R. B. Sunoj, J. Org. Chem., 2012, 77, 10525; ( f ) K. L. Kimmel, J. D. Weaver, M. Lee and J. A. Ellman, J. Am. Chem. Soc., 2012, 134, 9058; ( g) J.-W. Lee and B. List, J. Am. Chem. Soc., 2012, 134, 18245; (h) A. Frongia, F. Secci, F. Capitta, P. P. Piras and M. L. Sanna, Chem. Commun., 2013, 49, 8812; (i) R. A. Unhale, N. K. Rana and V. K. Singh, Tetrahedron Lett., 2013, 54, 1911; ( j) J. Guin, G. Varseev and B. List, J. Am. Chem. Soc., 2013, 135, 2100. 4 For an insightful review on decarboxylative protonation reaction, see: J. Blanchet, J. Baudoux, M. Amere, M.-C. Lasne and J. Rouden, Eur. J. Org. Chem., 2008, 5493. 5 (a) H. Brunner and M. A. Baur, Eur. J. Org. Chem., 2003, 2854; (b) M. Amere, M.-C. Lasne and J. Rouden, Org. Lett., 2007, 9, 2621, and references cited therein. 6 For an alternative enantioselective organometallic approach, see: S. C. Marinescu, T. Nishimata, J. T. Mohr and B. M. Stoltz, Org. Lett., 2008, 10, 1039. 7 For examples of enzymes promoted decarboxylative protonation reactions, see: (a) Y. Terao, Y. Ijima, K. Miyamoto and H. Ohta, J. Mol. Catal. B: Enzym., 2007, 45, 15; (b) K. Miyamoto, S. Hirokawa and H. Ohta, J. Mol. Catal. B: Enzym., 2007, 46, 14. 8 C. H. Cheon, O. Kanno and F. D. Toste, J. Am. Chem. Soc., 2011, 133, 13248. 9 b-Functionalized isoxasolidin-5-ones were prepared from native Meldrum’s acid 4 and an in situ generated unstable substituted N-Boc nitrone: S. Postikova, T. Tite, V. Levacher and `re, Adv. Synth. Catal., 2013, 355, 2513 and references cited J.-F. Brie therein. 10 (a) D. B. Ramachary and G. B. Reddy, Org. Biomol. Chem., 2006, 4, 4463; (b) D. B. Ramachary, M. Kishor and K. Ramakumar, Tetrahedron Lett., 2006, 47, 651. 11 For pioneering developments in the use of N-Boc nitrones, see: ´e and J.-N. Denis, Org. Lett., 2005, 7, 5147; (a) X. Guinchard, Y. Valle (b) C. Gioia, F. Fini, A. Mazzanti, L. Bernardi and A. Ricci, J. Am. Chem. Soc., 2009, 131, 9614. 12 M. E. Juarez-Garcia, S. Yu and J. W. Bode, Tetrahedron, 2010, 66, 4841. 13 For insightful reviews, see: (a) G. Lelais and D. Seebach, Pept. Sci., 2004, 76, 206; (b) D. Seebach, A. K. Beck, S. Capone, G. Deniau, U. Grosˇelj and E. Zass, Synthesis, 2009, 1. 14 H.-S. Lee, J.-S. Park, B. M. Kim and S. H. Gellman, J. Org. Chem., 2003, 68, 1575. 15 pKa = 4.8 (H2O) 4 R1 = H: (a) A. S. Ivanov, Chem. Soc. Rev., 2008, 37, 789; (b) A. M. Dumas and E. Fillion, Acc. Chem. Res., 2009, 43, 440. 16 The stable sodium salt of 5-benzyl Meldrum’s acid anion is easily synthesized by deprotonation with NaOH. 17 Several attempts to perform the same sequence with poorly soluble Meldrum’s acid anion in toluene without water led to inconsistent results with a maximum of 60 : 40 er. 18 5-Benzyl Meldrum’s acid is rapidedly solubilised into water with 1 equivalent of Na2CO3, but not without. 19 A. Tessier, N. Lahmar, J. Pytkowicz and T. Brigaud, J. Org. Chem., 2008, 73, 3970.
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