Letter Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
An N‑Heterocyclic Carbene-Mediated, Enantioselective and Multicatalytic Strategy to Access Dihydropyranones in a Sequential Three-Component One-Pot Reaction Patrick J. W. Fuchs and Kirsten Zeitler* Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany S Supporting Information *
ABSTRACT: The multicatalytic generation of 3,5,6-trisubstituted 3,4-dihydropyranones with high enantioselectivity using a highly convergent strategy starting from commercially available precursors is reported. The operationally simple three-step, onepot protocol merges H-bond and NHC catalysis to provide crucial, reactive β-unsubstituted enones from nitroalkenes as latent 1,2-biselectrophiles. These intermediates are directly funneled into a further NHC-catalyzed formal hetero-Diels− Alder reaction to deliver manifold chiral C(4)-unsubstituted dihydropyranones (typical ee >98%), allowing aliphatic and heteroaromatic substituents and hence expanding the scope of this Michael addition/lactonization.
D
Scheme 1. Background and Reaction Design: Chiral Multicomponent Strategy toward 3,5,6-Trisubstituted Dihydropyranones
ihydropyranones are important and prevalent structural motifs within natural products and bioactive compounds.1 Aside from being attractive as synthetic targets, these endocyclic enol-type δ-lactones not only represent versatile building blocks en route to a variety of other heterocycles but also can serve as cyclic precursors for linear, polysubstituted, ω-functionalized carboxylic acids. Described simply as a feature of the intermediates’ cyclic nature, stereocontrolled double bond derivatization by a remote, catalytically generated stereocenter, thereby introducing additional chiral centers,2 offers a powerful, more sustainable alternative to classic aldol condensation approaches,3 especially if noncontiguous substitution patterns are targeted. Apart from an array of classical uncatalyzed routes, the use of organocatalytically generated enolate equivalents4 has dramatically expanded access to chiral dihydropyranones with high diastereo- and enantiocontrol. In formal [4 + 2]-cycloadditions N-heterocyclic carbene (NHC)-catalysis5 derived azolium enolates6 are prominent intermediates to access 3,4-dihydro2H-pyran-2-ones with electron-deficient olefins (Scheme 1, upper part). In extended umpolung strategies,7 α-reducible aldehydes, including enals8 and other α-functionalized aldehydes9−11 as well as activated acid derivatives,12 can function as suitable precursors.13 While recent research has mainly focused on expanding the diversity of access modes to such azolium enolates,6 only very little is known about the variation of the Michael acceptor in this reaction. Current strategies mainly utilize chalcones and other simple β-substituted α,β-unsaturated ketones, hence limiting the scope to 3,4,6-trisubstituted dihydropyranones. Recently, a handful of reported processes employ modified, activated enones, allowing access to a range of tetrasubstituted enol lactones.14 Interestingly, despite the importance of such frameworks as building blocks for the synthesis of bioactive and anticarcinogenic compounds such as © XXXX American Chemical Society
MDM2-p53 inhibitors,15 transfomations to a 3,5,6-substitution pattern, also enabling C(5) aryl substituents, are truly rare.16,17 We reasoned that the introduction of an alternative pathway to Received: September 14, 2017
A
DOI: 10.1021/acs.orglett.7b02889 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters generate highly reactive β-unsubstituted enones from easily accessible, stable precursors would allow scaffolds which would be nontrivial to form by other means. Our laboratory recently has introduced the use of nitroalkenes as latent 1,2-biselectrophiles to provide convenient access to catalytically in situ generated, unstable α-substituted/β-unsubstituted enones in a dual catalytic nitro-Stetter/elimination sequence (Scheme 1, lower part).18 Central to the success has been the immediate “trapping” reaction of these Michael acceptors in a subsequent transformation.19 In an effort to demonstrate the wide-ranging applicability of this tactic, we questioned whether an NHC-catalyzed multicomponent approach using in situ generated azolium enolates, together with intermediate enones catalytically derived from acyl anions5 and 1,2-biselectrophile equivalents in a nitro-Stetter/elimination sequence,18 would lead to an alternate, practical access to 3,5,6-trisubstituted dihydropyranones (Scheme 1). Realization of such a design would be the first example to exploit catalytic in situ generation of highly reactive, unstable enones for a direct subsequent NHC-catalyzed formal heteroDiels−Alder reaction. Herein, we report the successful combination of an initial NHC/H-bond dual-catalytic process with a subsequent, highly enantioselective NHC-mediated synthesis of trisubstituted dihydropyranones. Although this orthogonal tandem catalysis20,21 is particularly attractive from an efficiency point of view, and an NHC-catalytic azolium enolate route does not suffer from potential basepromoted (racemic) background reactions,16 we envisioned a number of challenges inherent to the system at the onset of our investigations. Our planned strategy involves two NHCcatalyzed processes, albeit proceeding with two variant activation modes (acyl anion and chiral azolium enolate intermediate generation) and hence would require the employment of two different, reaction-specific NHC catalysts.22 However, due to the concurrent presence of the aldehydes, numerous side reactions, such as formation of acyloin or acylating acyl azolium species etc.,5−7 are conceivable and may only be suppressed by a subtle fine-tuning of the reaction conditions. Furthermore, we considered the selection of base as well as the control of the reaction mixture’s pH as crucial. While a sufficient amount of base is a prerequisite to generate the corresponding NHC catalyst by deprotonation,23 and base strength may also affect the reaction pathway, such as favoring homoenolate or azolium enolate intermediate formation from enals,8b an excess of base was expected to be detrimental to the reaction outcome either due to decomposition pathways18,24 or racemization of the newly formed α-carbonyl chiral center. We began our study by selecting the three commercially available compounds β-nitrostyrene 1a as well as 3-phenylpropanal (2) and cinnamaldehyde (3) as substrates for our test sequence (Table 1). To limit undesired side reactions, we started our screening as a sequential one-pot protocol with conditions previously established for the in situ formation of the enones (1st step)18 and a subsequent formal cycloaddition. After considerable experimentation, we could identify optimal conditions to yield the desired dihydropyranone 4a with a yield of 72% (entry 1) by employing a set of three different catalysts, K2CO3 as base with acetic acid and 4 Å molecular sieves as moderating additives in the second step, and Et2O as the best solvent (entry 1). Control experiments revealed that product formation indeed requires two different NHC catalysts NHC-1 and NHC-2, specific for the nitro-Stetter and the following cyclization (entries 2 and 3),25 and a further decrease in catalyst loading clearly
Table 1. Optimization Studies for the Multicatalytic, Sequential Synthesis of Dihydropyranone 4aa
entry
variation of “standard” conditions
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d 17d
none no NHC-2 20 mol % NHC-2, instead of NHC-1 5 mol % NHC-1, instead of 10 mol % 10 mol % NHC-2, instead of 20 mol % no thiourea A toluene, instead of Et2O CH2Cl2, instead of Et2O DBU, instead of second portion K2CO3 NEt3, instead of second portion K2CO3 HCOOH, instead of AcOH phenol, instead of AcOH no molecular sieves 4 Å 3 + 0 equiv of aldehyde 3, instead of 2 + 1 2 + 2 equiv of aldehyde 3, instead of 2 + 1 NHC-3, instead of NHC-2 NHC-4, instead of NHC-2
72 (69) 3 0 49 48 48 56 69 54 66 70 65 59 56 73 69 (61) 68 (67)
− − − − − − − − − − − − − − − 81 99
Conditions: β-nitrostyrene 1a (0.20 mmol), aldehyde 2 (0.30 mmol), NHC-1 (10 mol %), thiourea A (20 mol %), K2CO3 (0.4 equiv), Et2O (1.2 mL) for 20 h at rt, then NHC-2 (20 mol %), K2CO3 (1.1 equiv), MS 4 Å, AcOH (50 mol %), aldehyde 3 (0.40 + 0.20 mmol) for 1 day at rt. bYield determined by GC-FID with internal standard; isolated yield in brackets. cEnantiomeric excess determined by chiral HPLC analysis. dThe reaction mixture was stirred for 1.5 days. a
results in lower yields of 97:3 er, respectively). Electron-poor nitroalkenes (entries 6− 10) generally give lower yields. Most probably due to a rapid decomposition of the intermediate enone, p-cyano substrate 1h only provides the product with a noticeable reduced yield, albeit still with remarkably high ee (entry 8). Since the ester substituted nitroalkene 1i is only poorly soluble in Et2O, we decided to use CH2Cl2 as the solvent of choice for this particular substrate with good success (entry 9). Remarkably, while smaller orthosubstituents are still tolerated in this reaction (entry 10), larger ortho-substituents such as methyl groups (entry 11 compare to entry 4 (para-Me)) are detrimental. Interestingly, as we still observe enone formation for nitro substrate 1k in this inhibited reaction sequence, the subsequent formal cycloaddition seems to be more susceptible to steric effects. As a test for heteroaryl nitroalkenes, 2-(2-nitrovinyl)furan fails to provide any product when using standard conditions as the reaction directly proceeds to the fast formation of the corresponding 1,4-diketone.18 Finally, alkyl-substituted nitroalkenes, such as 1l, are not competent substrates (entry 12); neither enone nor product formation can be detected here. Next, we sought to determine the generality and the scope of our new transformation with respect to the two different
aldehydes being employed in the nitro-Stetter and the formal cycloaddition part of the sequence (Scheme 2). Importantly, while hexanal performs with similar good results as our test aldehyde 2 (product 7a), the multicatalytic transformation is not restricted to the use of aliphatic aldehydes as coupling partners in the initial nitro-Stetter reaction. Heteroaromatic aldehydes, such as furfural and 2-pyridinecarbaldehyde, are also suitable substrates, providing the lactone products in moderate to good yields, albeit with a slightly decreased enantiomeric excess (7b, 7c entry 1). In terms of this lower enantioselectivity we decided to monitor the reaction in more detail, to evaluate potential racemization at the α-carbonyl center during the course of the reaction.11b We found that reducing both reaction time and concentration proves to be beneficial (7c entry 2), thereby supporting our assumption of potential racemization. Aromatic aldehydes (7d, entry 3), however, fail to provide dihydropyranone products, presenting a current limitation of our process. We next turned our attention to study the scope of α,β-unsaturated aldehydes 6 that could be used in the enantioselective transformation. Importantly, alternate electron-rich (products: 7e, 7f) and electron-poor (7g) enals are competent substrates and provide the corresponding products with both good yields and high levels of ee. Notably, the efficiency of the reaction is not impeded by ortho-substituents at the aromatic ring (7f). Similar good results are obtained for enals with heteroaromatic (7h) and aliphatic substituents (7i). Moreover, despite additional possible side reactions, a doubly conjugated α,β,γ,δ-unsaturated aldehyde is tolerated, providing the product 7j with a remarkably good yield of 39% and high ee. As a proof of principle and to highlight the value of our strategy for the synthesis of 3,5,6-substituted dihydropyranones, the C
DOI: 10.1021/acs.orglett.7b02889 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(5) Recent review: (a) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (6) For reviews, see: (a) Vora, H. U.; Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617. (b) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. (7) (a) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506. (b) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (c) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (8) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. Further selected examples using enals as enolate precursors: (b) Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20661. (c) Fu, Z.; Sun, H.; Chen, S.; Tiwari, B.; Li, G.; Chi, Y. R. Chem. Commun. 2013, 49, 261. (9) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088. (10) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817. (11) (a) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47, 373. (b) Attaba, N.; Taylor, J. E.; Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2015, 80, 9728. (12) Esters: (a) Chen, S.; Hao, L.; Zhang, Y.; Tiwari, B.; Chi, Y. R. Org. Lett. 2013, 15, 5822. Acids: (b) Lee, A.; Scheidt, K. A. Chem. Commun. 2015, 51, 3407. (13) For further precursors: (a) Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623. (b) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem. Eur. J. 2008, 14, 8473. (c) Zhao, X.; Ruhl, K. E.; Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 12330. (14) (a) Fang, X.; Chen, X.; Chi, Y. R. Org. Lett. 2011, 13, 4708. (b) Davies, A. T.; Pickett, P. M.; Slawin, A. M. Z.; Smith, A. D. ACS Catal. 2014, 4, 2696. (c) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Org. Lett. 2009, 11, 3934. (15) (a) Zhao, Y.; Aguilar, A.; Bernard, D.; Wang, S. J. Med. Chem. 2015, 58, 1038. (b) Rew, Y.; Sun, D. J. Med. Chem. 2014, 57, 6332. (16) For an isothiourea based approach with C(5)-ester substituents: Stark, D. G.; Morrill, L. C.; Cordes, D. B.; Slawin, A. M. Z.; O’Riordan, T. J. C.; Smith, A. D. Chem. - Asian J. 2016, 11, 395. (17) Bicyclic dihydropyranones: Ren, Q.; Li, M.; Yuan, L. Org. Biomol. Chem. 2017, 15, 1329. (18) Fuchs, P. J. W.; Zeitler, K. J. Org. Chem. 2017, 82, 7796. (19) For further examples of catalytic in situ trapping of reactive Michael acceptors, see: (a) Franz, J. F.; Fuchs, P. J. W.; Zeitler, K. Tetrahedron Lett. 2011, 52, 6952. (b) Padmanaban, M.; Biju, A. T.; Glorius, F. Org. Lett. 2011, 13, 5624. (c) Reference 12b. (20) Lohr, T. L.; Marks, T. J. Nat. Chem. 2015, 7, 477. (21) Hayashi, Y. Chem. Sci. 2016, 7, 866. (22) For studies describing the impact of N-aryl residues in NHC organocatalysis, see: (a) Mahatthananchai, J.; Bode, J. W. Chem. Sci. 2012, 3, 192. (b) Collett, C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.; O’Donoghue, A. C.; Smith, A. D. Chem. Sci. 2013, 4, 1514. (c) Levens, A.; An, F.; Breugst, M.; Mayr, H.; Lupton, D. W. Org. Lett. 2016, 18, 3566. (d) Reference 7b. (23) pKa values of N-C6F5 vs. N-Mes triazolium salts differ considerably: Li, Z.; Li, X.; Cheng, J.-P. J. Org. Chem. 2017, 82, 9675. (24) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932. (25) For a multipurpose zwitterionic carborane NHC precatalyst, see: Selg, C.; Neumann, W.; Lönnecke, P.; Hey-Hawkins, E.; Zeitler, K. Chem. - Eur. J. 2017, 23, 7932. (26) Kotke, M.; Schreiner, P. R. (Thio)urea Organocatalysts In Hydrogen Bonding in Organic Synthesis; Pihko, P. M., Ed.; Wiley-VCH: Weinheim, 2009. (27) Due to the slow in situ generation of the Michael system, too high concentrations of the aldehyde partner 3 favor side reactions. (28) Based on the series of previous reports on formal hetero Diels− Alder reactions with catalyst NHC-4 (refs 8a, c, 9, 10, 13b), all providing products with S-selectivity, we also assume the formation of the Senantiomers in our sequence. (29) For details, see Supporting Information.
Scheme 3. Derivatization of Dihydropyranone 7c
a
Yield of isolated product. bDetermined by 1H NMR spectra analysis.
utility and further elaboration of these products in a substratecontrolled, stereoselective reaction was explored (Scheme 3). We selected a catalytic Pd/C-catalyzed hydrogenation to control the two new remote stereocenters at C(5) and C(6). Dihydropyranone 7c was smoothly transformed into all-cis δ‑lacone 8 in good yield with high diastereoselectivity, providing a novel substitution pattern with aryl/hetaryl substituents as an interesting, versatile building block. The relative configuration was determined by 1H NMR NOESY analysis.29 In summary, we have successfully developed a highly enantioselective, convergent, multicatalytic, three-step one-pot strategy to access dihydropyranones. Our approach specifically addresses the previously limited generation of important (C4)unsubstituted products with C(5)-aryl and various aliphatic and heteroaromatic C(6)-substituents and is tolerant of a broad range of substituents. Unlike former methods, this operationally simple process uses only commercially available starting material and catalysts and relies on the catalytic in situ generation of reactive enones from nitroalkenes as latent 1,2-biselectrophiles without requiring their presynthesis.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02889. Experimental procedures and characterization data for all compounds, including copies of 1H, 13C NMR (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kirsten Zeitler: 0000-0003-1549-5002 Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS We gratefully acknowledge the generous funding by the Deutsche Forschungsgemeinschaft (DFG, FOR 1296). REFERENCES
(1) (a) Natural Lactones and Lactams: Synthesis, Occurrence and Biological Activity; Janecki, T., Ed.; Wiley-VCH: Weinheim, 2014. (b) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007, 63, 2929. (2) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (3) (a) Davies, S. G.; Nicholson, R. L.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 3385−3400. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (4) Robinson, E. R. T.; Fallan, C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. Chem. Sci. 2013, 4, 2193. D
DOI: 10.1021/acs.orglett.7b02889 Org. Lett. XXXX, XXX, XXX−XXX
