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. Author manuscript; available in PMC: 2012 Aug 3.
Published in final edited form as: Tetrahedron Lett. 2011 Aug 3;52(31):3995–3997. doi: 10.1016/j.tetlet.2011.05.106

Synthesis of the dysiherbaine tetrahydropyran core utilizing improved tethered aminohydroxylation conditions

Christopher L Carroll 1, A Richard Chamberlin 1
PMCID: PMC3148768  NIHMSID: NIHMS301205  PMID: 21822338

Abstract

A concise stereoselective route to the dysiherbaine tetrahydropyran core was achieved in 9 steps and 39% overall yield. Donohoe's improved tethered aminohydroxylation conditions were employed to concurrently install the amino and alcohol groups and construct the tetrahydropyran ring, which features four contiguous cis-stereocenters.

Activation of glutamate receptors (GluRs) is essential to rapid excitatory synaptic transmission and higher order brain functions including memory formation, learning, and pain transmission. Prolonged activation, however, initiates excitotoxicity, which in turn can lead to neurodegenerative disorders such as stroke, depression, Parkinson's disease, and schizophrenia. Structurally unique excitatory amino acids that are potent and selective GluR agonists are essential to studying specific receptor subtypes and elucidating their respective roles in neuronal signaling and neurodegenerative diseases.1 Dysiherbaine (1) (DH) is a novel amino acid isolated from the Micronesian sea sponge, Dysidea herbacea, in 1997 by Sakai and co-workers (Figure 1).2 A potent and selective non-NMDA type ionotropic glutamate receptor (iGluR) agonist, DH is approximately 50-fold selective for KA over AMPA receptors, while also exhibiting agonist activity on a subtype of metabotropic glutamate receptors (mGluRs). DH is also the most potent epileptogenic agent known.1c The unique structure of DH consists of a cis-fused hexahydrofuro[3,2-b]pyran ring substituted with a glutamic acid appendage. Contained in the bicyclic core is a densely functionalized tetrahydropyran (THP) ring that features four contiguous cis-stereocenters, including a methylamino group. The intriguing structure and favorable biological profile coupled with a low natural abundance has made DH a molecule of wide interest, as characterized by several total syntheses including by one our lab.3,4

Figure 1.

Figure 1

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Dysiherbaine

The total synthesis accomplished in our lab was highly convergent and stereocontrolled; however, the overall efficiency suffered due to a low yielding late stage introduction of the methylamino group, therefore our second-generation approach sought to install this moiety at a preliminary stage of the synthesis.3d This was accomplished in the retrosynthetic analysis by utilizing the key ring-contraction transformation from our first-generation synthesis to reveal the lactone 2 (Scheme 1). Dismantling the lactone and removal of the amino acid appendage provides the elaborated THP core, which contains the methyl amino group masked as the oxazolidinone 3. It appeared that a tethered aminohydroxylation of the allylic alcohol 4 would be an ideal strategy for obtaining the desired THP intermediate 3.

Scheme 1.

Scheme 1

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Retrosynthetic Strategy

The initial attempt to install the hydroxy carbamate functionality employed Donohoe's TAH reaction,5 utilizing conditions originally reported by Sharpless6 (Scheme 2). This unexpectedly resulted in a 1:1 mixture of the carbamates 6 and 7. When the isomers were independently re-subjected to basic reaction conditions a 1:1 mixture was again obtained, confirming that a facile thermodynamic equilibration is occurring under the reaction conditions. The mixture was successfully converged to a single isomer over a six-step sequence.7 While employing a TAH reaction to stereoselectively install the amino group and the hydroxyl group concurrently remained an attractive strategy, it was desirable to avoid the observed mixture of isomers.

Scheme 2.

Scheme 2

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Initial tethered aminohydroxylation: (a) t-BuOCl, NaOH, K2[OsO2(OH)4], (DHQ)2PHAL, n-PrOH/H2O.

Improved TAH conditions were recently reported by Donohoe et al., which featured base free reaction conditions that appeared to be amenable to our synthetic strategy (Scheme 3).8 The allylic alcohol 4, which was previously reported by our lab, is readily obtained in a high yielding three step sequence from tri-O-acetyl-D-galactal.7 Subjecting the alcohol 4 to CDI in pyridine, with the ensuing addition of hydroxylamine, produced the hydroxy carbamate 8 in 60% yield (27% recovered alcohol 4). The resultant hydroxy carbamate was then treated with PFBCl, in the presence of Et3N, to obtain the requisite O-substituted hydroxy carbamate 9 in 96% yield. Upon mixing the carbamate 9 with potassium osmate, clean conversion to the oxazolidinone 6 was effected in 63 to 100% yield. While the amino hydroxylation gave complete conversion by TLC, the oxazolidinone 6 proved difficult to purify due to high polarity and low solubility, which may account for the moderate 63% isolated yield when column chromatography was applied. The oxazolidinone 6 was also insoluble in both acetonitrile and water, including mixtures thereof, which precluded HPLC reverse phase purification. Favorably, the improved NaOH free conditions provided the oxazolidinone 6 as a single isomer, without any observed migration of the cyclic carbamate that proved detrimental when employing the original TAH conditions. The hydroxyl group was then protected as the TBS ether to give the oxazolidinone 10 in 50 to 72% yield with the remainder of the mass balance accounted for by the recovered alcohol 6. The yield was comparable whether purified or crude oxazolidinone was subjected to silyl protection conditions. Silylation of the secondary alcohol proved surprisingly tricky; employment of TBSOTf as the silylation reagent only lead to N-TBS formation and not the desired O-TBS product, while using N-TBS-N-methylacetamide showed no significant improvement in yield.9 Treatment of the carbamate 10 with methyl iodide in the presence of t-BuOK afforded the N-methyl oxazolidione 11 in 98% yield, with subsequent chemoselective cleavage of the primary TBS to complete construction of the advanced THP core 12.

Scheme 3.

Scheme 3

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Synthesis of Alcohol 12: (a) i. CDI, pyridine, 40 °C ii. NH2OH•HCl; (b) Et3N, F5C6COCl, CH2Cl2, −8 °C; (c) K2[OsO2(OH)4] (1 mol%), t-BuOH/H2O; (d) TBSCl, imidazole, DMF; (e) t-BuOK, MeI, THF; (f) DOWEX, MeOH.

A concise and stereoselective route to the dysiherbaine THP core employing Donohoe's improved TAH conditions was successfully completed. The alcohol 12 was synthesized in 39% yield over nine steps from commercially available material, featuring four contiguous stereocenters including the methyl amino group. The improved conditions avoided the mixture of alcohol isomers previously observed, and obviated the need for a chiral amine additive in the TAH reaction. The THP intermediate could potentially be applied to a concise total synthesis of dysiherbaine.

Supplementary Material

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Acknowledgements

The authors are grateful for support from the National Institutes of Health (NINDS, NS27600 to ARC).

Footnotes

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Supplementary Information Complete experimental procedures, product characterization, and spectral data associated with this article can be found at doi:

References and Notes

  • 1.(a) Michaelis EK. Prog. Neurobio. 1998;54:369–415. doi: 10.1016/s0301-0082(97)00055-5. [DOI] [PubMed] [Google Scholar]; (b) Sakai R, Sasaki M, Shimamoto K, Kamiya H. Nerv. Sys. Agents Med. Chem. 2006;6:83–108. [Google Scholar]; (c) Sakai R, Swanson G, Shimamoto K, Green T, Contractor A, Ghetti A, Tamura-Horikawa Y, Owia C, Kamiya H. J. Pharmacol. Exp. Ther. 2001;296:650–655. [PubMed] [Google Scholar]; (d) Swanson G, Green T, Sakai R, Contractor A, Che W, Kamiya H, Heinemann SF. Neuron. 2002;34:589–598. doi: 10.1016/s0896-6273(02)00676-1. [DOI] [PubMed] [Google Scholar]; (e) Trist DG. Pharma. Acta Helv. 2000;74:221–229. doi: 10.1016/s0031-6865(99)00053-9. [DOI] [PubMed] [Google Scholar]
  • 2.Sakai R, Kamiya H, Murata M, Shimamoto K. J. Am. Chem. Soc. 1997;119:4112–4116. [Google Scholar]
  • 3.Total syntheses: Snider BB, Hawryluk NA. Org. Lett. 2000;2:635–638. doi: 10.1021/ol991393d.; Sasaki M, Koike T, Sakai R, Tachibana K. Tetrahedron Lett. 2000;41:3923–3926.; Masaki H, Maeyama J, Kamada K, Esumi T, Iwabuchi Y, Hatakeyama S. J. Am. Chem. Soc. 2000;122:5216–5217.; Phillips D, Chamberlin AR. J. Org. Chem. 2002;67:3194–3201. doi: 10.1021/jo0107610.; Sasaki M, Akiyama N, Tsubone K, Shoji M, Oikawa M, Sakai R. Tetrahedron Lett. 2007;48:5697–5700.; Sasaki M, Tsubone K, Aoki K, Akiyama N, Shoji M, Oikawa M, Sakai R, Shimamoto K. J. Org. Chem. 2008;73:264–273. doi: 10.1021/jo702116c.; Takahashi K, Matsumura T, Ishihara J, Hatakeyama S. Chem. Commun. 2007:4158–4160. doi: 10.1039/b709627e.
  • 4.Partial and formal syntheses: Miyata O, Iba R, Hashimoto J, Naito T. Org. Biomol. Chem. 2003;7:993–994. doi: 10.1039/b212556k.; Kang SH, Lee YM. Synlett. 2003;7:993–994.; Huang J, Xu K, Loh T. Synthesis. 2003;5:755–764. Naito T, Nair JS, Nishiki A, Yamashita K, Kiguchi T. Heterocycles. 2000;53:2611–2615.
  • 5.(a) Donohoe TJ, Johnson PD, Helliwell M, Keenan M. Chem. Commun. 2001:2078–2079. doi: 10.1039/b107253f. [DOI] [PubMed] [Google Scholar]; (b) Donohoe TJ, Johnson PD, Pye RJ. Org. Biomol. Chem. 2003;1:2025–2028. doi: 10.1039/b305189g. [DOI] [PubMed] [Google Scholar]; (c) Donohoe TJ, Johnson PD, Pye RJ, Keenan M. Org. Lett. 2004;6:2583–2585. doi: 10.1021/ol049136i. [DOI] [PubMed] [Google Scholar]; (d) Donohoe TJ, Chughtai MJ, Klauber DJ, Griffin D, Campbell AD. J. Am. Chem. Soc. 2006;128:2514–2515. doi: 10.1021/ja057389g. [DOI] [PubMed] [Google Scholar]
  • 6.(a) Li G, Chang HT, Sharpless KB. Angew. Chem. Int. Ed. Engl. 1996;35:451–454. [Google Scholar]; (b) O'Brien P. Angew. Chem. Int. Ed. 1999;38:326–329. doi: 10.1002/(SICI)1521-3773(19990201)38:3<326::AID-ANIE326>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  • 7.Cohen JL, Chamberlin AR. Tetrahedron. Lett. 2007;48:2533–2536. doi: 10.1016/j.tetlet.2007.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Donohoe TJ, Bataille CJR, Gattrell W, Kloesges J, Rosignol E. Org. Lett. 2007;9:1725–1728. doi: 10.1021/ol070430v. [DOI] [PubMed] [Google Scholar]
  • 9.Mawhinney TP, Madson MA. J. Org. Chem. 1982;47:3336–3339. [Google Scholar]

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