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Three-component, diastereoselective Prins-Ritter reaction for cis-fused-4-amidotetrahydropyrans toward precursor for possible neuronal receptor ligands Manami Chiba, Yuichi Ishikawa, Ryuichi Sakai, and Masato Oikawa ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00046 • Publication Date (Web): 10 May 2016 Downloaded from http://pubs.acs.org on May 11, 2016

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Three-component, diastereoselective Prins-Ritter reaction for cis-fused-4-amidotetrahydropyrans toward precursor for possible neuronal receptor ligands Manami Chiba, Yuichi Ishikawa, Ryuichi Sakai, and Masato Oikawa* Yokohama City University, Seto 22–2, Kanazawa–ku, Yokohama 236–0027, Japan KEYWORDS. amidotetrahydropyran, AMPA receptor ligand, diastereoselective reaction, dysiherbaine, three-component reaction


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ABSTRACT.

Here we report an unprecedented, highly diastereoselective Prins–Ritter reaction of aldehydes, homoallyic alcohols, and nitriles a three-component coupling reaction for synthesis of tetra-cissubstituted 4–amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles, but also for more complex heterotricycles, to show the acceptable levels of conversion yield (42–97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogs of our neuronal receptor ligands, IKM–159 and MC–27. In vivo assay by intracerebroventricular injection in mice suggested that substituent at C9 of the novel analogs interferes with the molecular interactions with the AMPA receptor, which have been originally observed in the complex of IKM–159 and GluA2 ligand binding domain. Our research has thus shown the power of multicomponent coupling reaction for preparation of a structurally diverse compound collection to study structure–activity relationships of biologically active small molecules.


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The Prins reaction1 of aldehydes and homoallylic alcohols mediated by Lewis and Brönsted acids has been used for synthesis of substituted tetrahydropyrans in conventional target-oriented synthesis.2 The reaction has also been used in three-component, combinatorial synthesis and diversity-oriented synthesis for acquiring substituent-based diversity.3 Multi-component coupling reactions4 have been generally considered as a valuable tool for developing biologically active agents.5

We have been particularly interested in the cis-fused heterobicyclic system which can be found in neuronally active agents such as marine-derived dysiherbaine6 and its artificial hybridized analogs, IKM–1597 and MC–278 (Fig. 1). A Prins reaction followed by a Ritter reaction in a nitrile solvent, namely Prins–Ritter reaction,9 had been expected to be a useful three-component coupling reaction for synthesizing structurally diverse 4–amidotetrahydropyrans (Scheme 1a).9h Indeed, such a strategy has been already demonstrated for synthesis of trans-fused bicyclic system (Scheme 1b),9i though no example for “cis-fused” bicyclic ether system related to dysiherbaine6 and MC–278 is reported to date. Prins–Friedel–Crafts reaction, however, was reported for cis-fused, 4–aryltetrahydropyran in 2011 as a close example (Scheme 1c).10 Prins cyclization for cis-fused bicyclic ether system has also been reported in 2010 (scheme not shown).11 Encouraged by these works, we decided to employ the Prins–Ritter reaction for preparation of cis-fused, 4–amidotetrahydropyrans that can be envisioned as a versatile precursor for dysiherbaine6 and MC–278 (Fig. 1). This strategy enables one to introduce aryl or vinyl groups to the tetrahydropyran ring of dysiherbaine or MC-27 conveniently which otherwise requires multi-step procedures. Here, we report a new, Prins–Ritter reaction-based three– component coupling reaction for convenient synthesis of cis-fused heterobicyclic structures


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(Scheme 1d). We found here that the reaction can proceed on structurally complex monocyclic and even bicyclic homoallylic alcohols in combination with various aldehydes and nitriles to afford cis-fused heterobicycles and heterotricycles, respectively, in moderate to excellent yields with exclusive diastereoselectivity. We extended this reaction to prepare analogs of a novel class of AMPA receptor inhibitors IKM–1597 and MC–27,8 which provided us further information on the structure–activity relationships of these ligands.


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Scheme 1. Three-component, tandem-type Prins cyclization: known examples (a–c) and the new example demonstrated for cis-fused 4–amidotetrahydropyran (d, this work)


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Figure 1. Marine-derived neuronally active dysiherbaine6 and the artificial glutamate analogs (IKM–159,7 MC–278) share characteristic cis-fused [4.3.0] heterobicyclic system.

We first examined the Prins–Ritter reaction of glucose-derived enantiomerically pure homoallylic alcohol 112 in combination with three aldehydes and two nitriles, in the presence of BF3･OEt2 at rt. In all runs, reactions were started with 1.2 equiv of aldehyde and 0.3 equiv of BF3 ･OEt2 in the nitrile (as a solvent). Extra amounts of aldehyde and BF3 ･OEt2 were then necessarily added to drive the reaction to completion. The results are shown in Table 1. We first found that the three-component coupling reaction of 1 with benzaldehyde and acetonitrile proceeded at rt in 5 h to give diastereomerically pure tetrahydropyran 2a in acceptable isolated yield (51%, run 1). Changing the nitrile to benzonitrile provided 2b in better yield (60%, run 2). It was also found that the rate of the reaction depends on the aldehyde used. For example,


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reaction of 1 with acrolein in acetonitrile was not completed in 5 h, and 10% of 1 was recovered (run 3). The yield (41%) was thus lower than that with benzaldehyde (51%, run 1). A similar tendency was observed in runs 2 (60% yield) and 4 (54% yield). Cinnamaldehyde was also capable of providing tetrahydropyrans 2e (54% BRSM) and 2f (56% BRSM), while 1 was not fully consumed (runs 5 and 6).

Table 1. Prins–Ritter reaction of glucose-derived homoallylic alcohol 1 for cis-fused heterobicycles 2a–2f

a) Nitriles (Y–CN) were used as a solvent. b) Starting with 0.3 equiv, BF3 ･ OEt2 was necessarily supplemented until the reaction completed. See text. c) In parentheses are the yields based on recovered starting material 1.


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In all entries in Table 1, a single diastereomer, depicted as 2a–2f, was only obtained. The structure was determined by NMR analyses of the derivative (see the Supporting Information). The plausible reaction mechanism is shown in Scheme 2. BF3-mediated condensation of 1 and aldehyde (X–CHO) generates oxocarbenium ion A which spontaneously reacts via chair-like sixmembered mode of cyclization to form carbocation B. The cation B then suffers intermolecular nucleophilic attack by nitrile from the equatorial face of the pseudo-chair tetrahydropyran ring. All cis-arranged tetrahydropyrans 2a–2f would be thereby produced preferentially, and the proposed mechanism is well consistent with the theoretical model for Prins reaction reported by Alder et al.13 Thus it is shown for the first time that the Prins–Ritter reaction is capable of providing cis–fused bicycles with exclusive diastereoselectivity.14

Scheme 2. Plausible mechanism for Prins–Ritter reaction in this study

Next we examined the Prins–Ritter reaction of the more complex, homoallylic alcohol 3 to evaluate its general applicability and versatility (Table 2). The substrate 3 was synthesized over 8 steps

from

benzyl

isocyanide,

2–furaldehyde,

(Z)–3–iodoacrylic

acid,

and

4–

methoxybenzylamine, as previously reported in our synthesis of AMPA receptor inhibitor.3 As compared to 1 in Table 1, 3 was found to react more smoothly to give heterotricycles 4a–4i with


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exclusive diastereoselectivity as well in all runs in Table 2. Of note, the reaction with benzaldehyde in acetonitrile was smoothly completed in 5 h to afford tetrahydropyran 4a in 83% yield (run 1). Vinylic aldehydes (acrolein and cinnamaldehyde) in acetonitrile provided acceptable yields (runs 2, 3) closely comparable to those in Table 1 (runs 3, 5). In benzonitrile (run 4), 4d was obtained in 73% yield (BRSM) which is higher than that for 2f in Table 1. It can be thus estimated that benzaldehyde is the best aldehyde component for Prins–Ritter reaction with 1 or 3.

Table 2. Prins–Ritter reaction of complex homoallylic alcohol 3 for cis-fused heterotricycles 4a– 4i

a) Nitriles (Y–CN) were used as a solvent.


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b) Starting with 1.0 equiv, BF3 ･ OEt2 was necessarily supplemented until the reaction completed. c) In parenthesis is the yield based on recovered starting material 3. d) Alcohol 5 was also obtained in 32%.

We therefore, next explored the three-component coupling reaction of 3, benzaldehyde, and various nitriles used as a solvent (Table 2, runs 5–9). It was found that benzonitrile (run 5) and acrylonitrile (run 6) are highly efficient nitriles to give rise to 4e and 4f in excellent yield. Halogenated acetonitriles in runs 7 and 8 also reacted smoothly to provide 4g and 4h in good yield. Only a moderate yield was observed in run 9 where methyl cyanoacetate was employed. In this case, hydroxylated tetrahydropyran 5 (Fig. 2) was also obtained in 32% yield which is apparently due to hydrolysis of the carbocation intermediate B (see Scheme 2). Unfortunately, all attempts to suppress the hydrolysis were unsuccessful. Alcohol 5 was also isolated in 3% yield in run 6. Again, in all runs in Table 2, Prins–Ritter reactions were highly diastereoselective to provide isomer 4a–4i and 5, and no other diastereomer was detected.

Figure 2. Hydroxylated product 5 observed in the Prins–Ritter three-component reaction.


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Heterotricycles 4a–4i shown in Table 2 are protected precursor for C5-oxy analogs8 of IKM– 159 which is the AMPA receptor inhibitor developed by us.7-8 Finally, acidic hydrolysis of 4a–4i and 5 in 6 M hydrochloric acid at 60 °C for 2 h successfully induced deprotection except for 4i to afford compounds 6a–6h and 7 (Fig. 3). We then tested behavioral activity7b of 6a, 6b, 6e, 6f, and 7 in mice. Intracerebroventricular injection (50 µg/mouse) of any analogues, however, did not alter the behaviors of mice. These results indicated that the substitution at C9 substantially attenuate the activity of this class of glutamate analogues, since 1) substitution at C7 had been suggested to have no effect on the inherent activity,7a and 2) MC–278 (Fig. 1) which lacks the substitution at C9 was active. These results can be also reasonably explained by molecular interactions in the complex of IKM–159 with GluA2 ligand binding domain.7b


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Figure 3. Novel glutamate analogs prepared by acidic hydrolysis of Prins–Ritter reaction products 4a–4h and 5.

In conclusion, we demonstrated the Prins–Ritter reaction as a three–component coupling reaction of aldehyde, mono– or bicyclic homoallylic alcohol, and nitrile, for the synthesis of cisfused 4–amidotetrahydropyrans. The reaction was found to proceed in moderate to excellent yields with exclusive cis diastereoselectivity at the newly formed stereogenic centers. The Prins– Ritter reaction is thus expected to serve as a general methodology for synthesis of 4– amidotetrahydropyran bearing three other substituents in the all cis arrangement (see Tables 1, 2), which is not otherwise accessible easily. Though the glutamate analogues prepared here did not show expected activity, important information regarding structure–activity relationships of IKM– 159-type AMPA inhibitors was provided. Works are in progress to develop more potent and/or more selective ligands for understanding and controlling biological functions of AMPA and other neuronal receptors, by virtue of multi-component-based diverted synthesis5 which is apparently powerful methodology for preparation of structurally diverse compound collection.4 Synthetic study of analogs of dysiherbaine,6 the potent agonist for KA receptor, from 2a–2f prepared by the multi-component Prins–Ritter strategy is also underway in our laboratories.


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EXPERIMENTAL PROCEDURES

General methods have been summarized elsewhere.15

Typical procedure for Prins–Ritter reaction (3→ →4f) To a stirred solution of homoallylic alcohol 3 (4.2 mg, 0.014 mmol) and benzaldehyde (0.005 mL, 0.05 mmol) in acrylonitrile (0.500 mL) at 0 °C under Ar atmosphere was added boron trifluoride diethyl ether complex (0.005 mL, 0.04 mmol). After stirring at rt for 1 h, additional boron trifluoride diethyl ether complex (0.010 mL, 0.080 mmol) was supplemented at 0 °C. After stirring at rt for further 16 h, additional boron trifluoride diethyl ether complex (0.020 mL, 0.16 mmol) was supplemented at 0 °C. After stirring at rt for further 1 h, the mixture was diluted with EtOAc (1 mL) and poured into saturated aqueous NaHCO3 (1.5 mL) at 0 °C. Organic layer was separated and aqueous layer was extracted with EtOAc (3 × 1.5 mL). Combined organic layer was washed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (BW-300, 0.6 g, CHCl3/acetone = 7:3) to give tetrahydropyran 4f (6.2 mg, 97%) as a white oil and hydroxytetrahydropyran 5 as a colorless oil (0.2 mg, 3%). Data for tetrahydropyran 4f: IR (neat) 2954, 2925, 1711, 1540, 1216, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 6.50 (brs, 1H), 6.30 (d, J = 16.8 Hz, 1H), 6.11 (dd, J = 16.8, 10.0 Hz, 1H), 6.06 (d, J = 8.9 Hz, 1H), 5.67 (d, J = 10.0 Hz, 1H), 4.57 (m, 1H), 4.54 (s, 1H), 4.47 (d, J = 12.1 Hz, 1H), 4.46 (s, 1H), 4.06 (s, 1H), 3.73 (s, 3H), 3.63 (s, 3H), 3.36 (AB, J = 16.5 Hz, 1H), 3.34 (s, 1H), 3.02 (AB, J = 16.5 Hz, 1H), 2.08 (dd, J = 12.1, 3.3 Hz, 1H), 1.73 (ddd, J = 12.1, 12.1, 12.1 Hz, 1H);

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C NMR (100 MHz, CDCl3) δ 173.2, 170.4, 170.1, 164.9,


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140.4, 130.3, 128.5 (× 2), 128.0, 127.5, 125.8 (× 2), 87.2, 79.5, 65.6, 65.2, 57.0, 52.8, 51.9, 46.6, 40.1, 33.7, 29.7; HRMS (ESI, positive) calcd for C23H27N2O8 [(M+H)+] 459.1762, found 459.1762. Data for hydroxytetrahydropyran 5: IR (neat) 3330, 2954, 2927, 1706, 1215, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 6.19 (brs, 1H), 4.49 (s, 1H), 4.49 (s, 1H), 4.34 (d, J = 11.1 Hz, 1H), 4.16 (brs, 1H), 4.04 (m, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 3.38 (AB, J = 16.9 Hz, 1H), 3.37 (s, 1H), 3.03 (AB, J = 16.9 Hz, 1H), 2.06 (dd, J = 12.0, 4.4 Hz, 1H), 1.86 (dd, J = 12.0, 12.0, 11.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 173.0, 170.4, 170.1, 140.4, 128.6 (× 2), 126.1, 125.9 (× 2), 87.1, 79.6, 78.6, 77.7, 67.8, 65.0, 56.8, 52.8, 51.9, 40.1, 36.6; HRMS (ESI, negative) calcd for C20H22NO8 [(M–H)–] 404.1351, found 404.1342.

Typical procedure for synthesis of glutamate analog by acidic hydrolysis of Prins–Ritter reaction product (4d→ →6d) A suspension of dimethyl ester 4d (4.4 mg, 0.0082 mmol) in hydrochloric acid (6 M, 0.400 mL) was stirred at 60 ºC for 3.5 h. The mixture was then cooled to rt and concentrated by blowing of air. The residue was purified by column chromatography on reversed-phase silica gel (0.6 g, H2O/MeOH = 8:2) to give dicarboxylic acid 6d (4.0 mg, 95%) as a white solid: IR (neat) 3328, 2924, 2852, 1714, 1219, 772 cm-1; 1H NMR (400 MHz, D2O) δ 7.62-7.51 (m, 4H), 7.487.10 (m, 6H), 6.57 (d, J = 16.0 Hz, 1H), 6.18 (dd, J = 16.0, 7.0 Hz, 1H), 4.39 (m, 1H), 4.36 (s, 1H), 4.21 (s, 1H), 4.15 (m, 1H), 4.00 (s, 1H), 3.10 (s, 1H), 2.96 (AB, J = 15.7 Hz, 1H), 2.77 (AB, J = 15.7 Hz, 1H), 1.70 (m, 1H), 1.53 (m, 1H); 13C NMR (100 MHz, D2O) δ 175.7, 175.4, 175.4, 170.8, 136.4, 133.5, 132.5, 128.8, 128.6 (× 2), 128.5 (× 2), 128.5 (× 2), 127.2 (× 2), 126.5, 126.5,


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87.0, 78.6, 77.6, 76.7, 68.0, 56.9, 49.7, 40.6, 30.5; HRMS (ESI, negative) calcd for C27H25N2O8 [(M–H)–] 505.1605, found 505.1625.


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ASSOCIATED CONTENT Supporting Information. The supporting information is available free of charge via the Internet at http://pubs.acs.org. General methods, synthetic procedures, and characterization data for intermediates and final products (PDF) AUTHOR INFORMATION Corresponding Author *[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. All authors contributed equally to this work. Funding Sources This work was financially supported by Grant-in-Aid for Scientific Research (26282216 to M.O.; 15H0454605 to R.S.) from the Ministry of Education, Science, Sports, Culture and Technology, Japan. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This paper is dedicated to Prof. Stuart L. Schreiber on the occasion of his 60th birthday.


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ABBREVIATIONS BF3･OEt2, boon trifluoride diethyl ether complex; BRSM, based on recovered starting material; NMR, nuclear magnetic resonance; AMPA, (S)–2–amino–3–(3–hydroxy–5–methyl–4– isoxazolyl)propionic acid.


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REFERENCES (1) (a) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Synthesis of tetrahydropyrans and related heterocycles via prins cyclization; extension to aza-prins cyclization. Tetrahedron 2010, 66, 413-445. (b) Greco, S. J.; Fiorot, R. G.; Lacerda, V.; dos Santos, R. B. Recent Advances in the Prins Cyclization. Aldrichimica Acta 2013, 46, 59-67. (2) (a) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Synthesis of (-)-centrolobine by prins cyclizations that avoid racemization. Org. Lett. 2002, 4, 3919-3922. (b) Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. L. Stereloselective synthesis of the tetrahydropyran core of polycarvernoside A. Org. Lett. 2005, 7, 2683-2686. (c) Chan, K. P.; Loh, T. P. Prins cyclizations in silyl additives with suppression of epimerization: Versatile tool in the synthesis of the tetrahydropyran backbone of natural products. Org. Lett. 2005, 7, 4491-4494. (d) Bahnck, K. B.; Rychnovsky, S. D. Rapid stereocontrolled assembly of the fully substituted C-aryl glycoside of kendomycin with a Prins cyclization: a formal synthesis. Chem. Commun. 2006, 2388-2390. (e) Chio, F. K.; Warne, J.; Gough, D.; Penny, M.; Green, S.; Coles, S. J.; Hursthouse, M. B.; Jones, P.; Hassall, L.; McGuire, T. M.; Dobbs, A. P. On the choice of Lewis acids for the Prins reaction; two total syntheses of (+/-)-Civet. Tetrahedron 2011, 67, 5107-5124. (f) Li, B.; Lai, Y.C.; Zhao, Y.; Wong, Y.-H.; Shen, Z.-L.; Loh, T.-P. Synthesis of 3-Oxaterpenoids and Its Application in the Total Synthesis of (+/-)-Moluccanic Acid Methyl Ester. Angew. Chem. Int. Ed. 2012, 51, 10619-10623. (3) Wender, P. A.; Billingsley, K. L. Lead diversification through a Prins-Driven macrocyclization strategy: application to C13-diversified bryostatin analogues. Synthesis 2013, 45, 1815-1824.


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(4) (a) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity. Angew. Chem. Int. Ed. 2011, 50, 6234-6246. (b) Brauch, S.; van Berkel, S. S.; Westermann, B. Higher-order multicomponent reactions: beyond four reactants. Chem. Soc. Rev. 2013, 42, 4948-4962. (c) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small Heterocycles in Multicomponent Reactions. Chem. Rev. 2014, 114, 83238359. (d) Zarganes-Tzitzikas, T.; Chandgude, A. L.; Dömling, A. Multicomponent Reactions, Union of MCRs and Beyond. Chem. Rec. 2015, 15, 981-996. (5) (a) Slobbe, P.; Ruijter, E.; Orru, R. V. A. Recent applications of multicomponent reactions in medicinal chemistry. Med. Chem. Commun. 2012, 3, 1189-1218. (b) Dömling, A.; Wang, W.; Wang, K. Chemistry and Biology of Multicomponent Reactions. Chem. Rev. 2012, 112, 30833135. (6) (a) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. Dysiherbaine: A new neurotoxic amino acid from the Micronesian marine sponge Dysidea herbacea. J. Am. Chem. Soc. 1997, 119, 4112-4116. (b) Sakai, R.; Swanson, G. T.; Shimamoto, K.; Green, T.; Contractor, A.; Ghetti, A.; Tamura-Horikawa, Y.; Oiwa, C.; Kamiya, H. Pharmacological properties of the potent epileptogenic amino acid dysiherbaine, a novel glutamate receptor agonist isolated from the marine sponge Dysidea herbacea. J. Pharmacol. Exp. Ther. 2001, 296, 650-658. (7) (a) Gill, M. B.; Frausto, S.; Ikoma, M.; Sasaki, M.; Oikawa, M.; Sakai, R.; Swanson, G. T. A series of structurally novel heterotricyclic α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor-selective antagonists. Br. J. Pharmacol. 2010, 160, 1417-1429. (b) Juknaite, L.; Sugamata, Y.; Tokiwa, K.; Ishikawa, Y.; Takamizawa, S.; Eng, A.; Sakai, R.; Pickering, D. S.; Frydenvang, K.; Swanson, G. T.; Kastrup, J. S.; Oikawa, M. Studies on an (S)-2-amino-3-(3-


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hydroxy-5-methyl-4-isoxazolyl)propionic

acid

(AMPA)

receptor

antagonist

IKM-159:

asymmetric synthesis, neuroactivity, and structural characterization. J. Med. Chem. 2013, 56, 2283-2293. (c) Oikawa, M.; Kasori, Y.; Katayama, L.; Murakami, E.; Oikawa, Y.; Ishikawa, Y. Biology- and diversity-oriented domino reactions for synthesis of AMPA receptor antagonist IKM-159 and analogs. Synthesis 2013, 45, 3106-3117. (8) Chiba, M.; Fujimoto, C.; Sakai, R.; Oikawa, M. Structure–activity relationships of IKM159: Diverted synthesis and biological evaluation of a series of C5-oxy analogs. Bioorg. Med. Chem. Lett. 2015, 25, 1869–1871. (9) (a) Yadav, J. S.; Reddy, B. V. S.; Kumar, G.; Reddy, G. M. CeCl3·7H2O/AcCl-catalyzed Prins-Ritter reaction sequence: a novel synthesis of 4-amido tetrahydropyran derivatives. Tetrahedron Lett. 2007, 48, 4903-4906. (b) Yadav, J. S.; Reddy, B. V. S.; Aravind, S.; Kumar, G.; Madhavi, C.; Kunwar, A. C. Three-component, one-pot diastereoselective synthesis of 4amidotetrahydropyrans via the Prins-Ritter reaction sequence. Tetrahedron 2008, 64, 3025-3031. (c) Sabitha, G.; Bhikshapathi, M.; Nayak, S.; Yadav, J. S. Molecular Iodine–Catalyzed, One-Pot, Diastereoselective Synthesis of 4-Amido Tetrahydropyrans. Synth. Commun. 2010, 41, 8-15. (d) Srinivasan, P.; Perumal, P. T.; Raja, S. Iodine/AcCl-catalyzed Prins-Ritter reaction: Synthesis of 4-amido tetrahydropyrans. Indian J. Chem., Sect B 2011, 50B, 1083-1091. (e) Yadav, J. S.; Reddy, Y. J.; Reddy, P. A. N.; Reddy, B. V. S. Stereoselective Synthesis of anti-1,3Aminoalcohols via Reductive Opening of 4-Amidotetrahydropyrans Derived from the Prins/Ritter Sequence. Org. Lett. 2013, 15, 546-549. (f) Reddy, B. V. S.; Ghanty, S.; Kishore, C.; Sridhar, B. B(C6F5)3-catalyzed Prins/Ritter reaction: a novel synthesis of hexahydro-1H-furo[3,4c]pyranyl amide derivatives. Tetrahedron Lett. 2014, 55, 4298-4301. (g) Reddy, B. V. S.; Ghanty, S. o-Benzenedisulfonimide as a Recyclable Homogeneous Organocatalyst for an


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Efficient and Facile Synthesis of 4-Amidotetrahydropyran Derivatives through Prins-Ritter Reaction. Synth. Commun. 2014, 44, 2545-2554. (h) Reddy, B. V. S.; Ghanty, S.; Reddy, N. S. S.; Reddy, Y. J.; Yadav, J. S. Stereoselective synthesis of 2-(2-hydroxyalkyl)piperidine alkaloids through Prins-Ritter reaction. Synth. Commun. 2014, 44, 1658-1663. (i) Sarmah, B.; Baishya, G.; Baruah, R. K. First example of a Prins-Ritter reaction on terpenoids: a diastereoselective route to novel 4-amido-octahydro-2H-chromenes. RSC Advances 2014, 4, 22387-22397. (10) Reddy, B. V. S.; Chaya, D. N.; Yadav, J. S.; Chatterjee, D.; Kunwar, A. C. BF3·OEt2catalyzed tandem Prins Friedel–Crafts reaction: a novel synthesis of sugar fused diarylhexahydro-2H-furo[3,2-b]pyrans. Tetrahedron Lett. 2011, 52, 2961-2964. (11) Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.; Chaya, D. N.; Chatterjee, D.; Kunwar, A. C. First example of carbohydrate-based Prins cyclization: a novel class of sugar-annulated tetrahydropyrans. Tetrahedron Lett. 2010, 51, 1475-1478. (12) (a) Song, J.; Hollingsworth, R. I. Homochiral 4-hydroxy-5-hexenoic acids and their derivatives and homologues from carbohydrates. Tetrahedron: Asymmetry 2001, 12, 387-391. (b) Fernandes, R. A.; Kattanguru, P. A Protecting-Group-Free Synthesis of Hagen's Gland Lactones. J. Org. Chem. 2012, 77, 9357-9360. (13) Alder, R. W.; Harvey, J. N.; Oakley, M. T. Aromatic 4-Tetrahydropyranyl and 4Quinuclidinyl Cations. Linking Prins with Cope and Grob. J. Am. Chem. Soc. 2002, 124, 49604961. (14) Nevertheless, however, the isolated yields shown in Table 1 are not satisfactory. We have observed, in some runs, decomposition of the substrate 1 and/or the product 2a–2f during the


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reaction. Since the decomposition is now supposed to cause diminishment of the yield, we are currently investigating more mild conditions for the Prins–Ritter reaction. (15) Oikawa, M.; Sasaki, S.; Sakai, M.; Ishikawa, Y.; Sakai, R. Total synthesis of (±)dysibetaine CPa and analogs. Eur. J. Org. Chem. 2012, 2012, 5789-5802.

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