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Tetrahedron Lett. Author manuscript; available in PMC 2010 December 9.
Published in final edited form as:
Tetrahedron Lett. 2009 December 9; 50(49): 6755–6757.
doi:  10.1016/j.tetlet.2009.09.074
PMCID: PMC2766076
NIHMSID: NIHMS149218

Total Synthesis of Isoroquefortine E and Phenylahistin

Abstract

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Isoroquefortine E and phenylahistin were synthesized using the Horner-Wadsworth-Emmons reaction as the key step to build the dehydroamino acid moiety. The syntheses provide materials for the biological studies of the roquefortine-phenylahistin molecules.

Keywords: roquefortine E, phenylahistin, dehydroamino acid, Horner-Wadsworth-Emmons reaction

Roquefortine E (1), a natural product isolated from an Australian strain of Gymnoascus reessii Baranetzki, by Capon et al. in 2005, is the first roquefortine to be isolated from a fungus other than Penicillium.1 It combines the main structural features of two classes of natural products: the cyclized isoprenylated tryptophan of the roquefortine C (2), and the isoprenylated dehydrohistidine of the phenylahistin (3).2,3 Both roquefortine C and phenylahistin were reported to have potent biological activities; phenylahistin showed strong binding affinity toward microtubules and potent growth inhibition of various cancer cell lines.3b Roquefortine E (1), however, only showed weak cytotoxic activity to mammalian cells.1 The structure and biological activity relationship among these compounds is still unknown. Phenylahistin has a Z dehydroamino acid moiety, while roquefortine C contains an E structure. The Z isomer of roquefortine C, isoroquefortine C, does not show any significant biological activity. Roquefortine C (2) and phenylahistin (3) have already been synthesized but no total synthesis of roquefortine E (1) has been reported yet.4

Capon reported that roquefortine E should have the E configuration by comparing the 1H and 13C NMR data of roquefortine E to that of roquefortine C and isoroquefortine C. However, the authors failed to convert roquefortine E to isoroquefortine E by treatment with UV light, under the conditions used for the conversion of roquefortine C to isoroquefortine C. A synthesis of roquefortine E and isoroquefortine E should confirm the E/Z configuration of roquefortine E and also provide enough material for further biological studies. Therefore, we began the syntheses of both 1 and 3. The synthesis of aldehyde 9 started from the conversion of amino acid (-)-serine (4) to TBS protected methyl ester 5. Following Baran's protocol, a controlled prenyl magnesium chloride addition, thiourea 7 formation, oxidation-elimination and TBS deprotection converted 6 to imidazole 8.5 Aldehyde 9 was obtained by oxidation of alcohol 8 with manganese dioxide.

Due to the instabilities of Boc, mesyl and tosyl protecting groups on the free nitrogen of imidazole 9, we chose ortho-nitrobenzyl (ONB) as the protecting group.6 After LDA treatment of Boc protected glycine methyl ester, the resulting enolate was added to aldehyde 12 to afford a mixture of diastereomeric aldol addition products (14). Zinc chloride addition was necessary to make the polar dianion enolate of 13 soluble in THF. Subsequent zinc bromide treatment removed the Boc group to afford amine 15.7

Acid 16 8 was coupled with amine 15 under standard conditions to form compound 17, the precursor for the elimination reaction. Unfortunately, all efforts to dehydrate compound 17 were unsuccessful.

The Horner-Wadsworth-Emmons (HWE) reaction is an established method to construct the carbon-carbon double bond of the dehydroamino acid moiety.9 The known phosphonate 19 4c was coupled with aldehyde 9 to give compound 20, which was deprotected and cyclized to give (-)-phenylahistin. Aldehyde 12 and other protected imidazoyl aldehydes failed to give good yields in this HWE reaction. Phosphonate 21 6 was coupled with aldehyde 9 under standard HWE conditions to give product 22. Subsequent treatment with TMSI and triethyl amine afforded isoroquefortine E (23) as the final product.10

In conclusion, a concise total synthesis of isoroquefortine E and phenylahistin was completed and will allow the structure activity relationship of roquefortines and phenylahistin to be investigated. The synthesis and evaluation of the biological activities of the analogs of roquefortines and phenylahistin will be reported in due course.

Figure 1
Roquefortine E, roquefortine C and phenylahistin.
Scheme 1
Synthesis of aldehyde 9.
Scheme 2
Synthesis of amine 13.
Scheme 3
The elimination approach.
Scheme 4
Synthesis of phenylahistin and isoroquefortine E.

Supplementary Material

01

Acknowledgments

We thank NIH (CA-40081) and NSF (0515443) for financial support.

Footnotes

Supplementary data: Supplementary data associated with this article can be found, in the online version, at doi:

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References and notes

1. Clark B, Capon RJ, Lacey E, Tennant S, Gill JH. J Nat Prod. 2005;68:1661. [PubMed]
2. Ohmomo S, Sato T, Utagawa T, Abe M. Agric Biol Chem. 1975;39:1333.
3. (a) Kanoh K, Kohno S, Asari T, Harada T, Katada J, Muramatsu M, Kawashima H, Sekiya H, Uno I. Bioorg Med Chem Lett. 1997;7:2847. (b) Kanoh K, Kohno S, Katada J, Takahashi J, Uno I. J Antibiot. 1999;52:134. [PubMed]
4. (a) Shangguan N, Hehre WJ, Ohlinger WS, Beavers MP, Joullié MM. J Am Chem Soc. 2008;130:6281. [PubMed] (b) Hayashi Y, Orikasa S, Tanaka K, Kanoh K, Kiso Y. J Org Chem. 2000;65:8402. [PubMed] (c) Couladouros EA, Magos AD. Mol Diversity. 2005;9:99. [PubMed]
5. Baran PS, Shenvi RA, Mitsos CA. Angew Chem Int Ed. 2005;44:3714. [PubMed]
6. Schiavi BM, Richard DJ, Joullié MM. J Org Chem. 2002;67:620. [PubMed]
7. Nigam SC, Mann A, Taddei M, Wermuth CG. Synth Commun. 1989;19:3139.
8. Depew KM, Marsden SP, Zatorska D, Zatorski A, Bornmann WG, Danishefsky SJ. J Am Chem Soc. 1999;121:11953.
9. Schmidt U, Griesser H, Leitenberger V, Lieberknecht A, Mangold R, Meyer R, Riedl B. Synthesis. 1992:487.
10. Selected data. compound 22: 1H NMR (CDCl3): δ 11.19 (1 H, br), 8.02 (1 H, s), 7.54 (1 H, s), 7.39 (1 H, d, J = 7.9 Hz), 7.26 (1 H, t, J = 7.4 Hz), 7.21 (1 H, d, J = 7.5 Hz), 7.10 (1 H, d, J = 7.5 Hz), 6.92 (1 H, s), 6.19 (1 H, s), 6.13 (1 H, dd, J = 17.5, 10.6 Hz), 5.87 (1 H, dd, J = 17.4, 10.8 Hz), 5.09 (4 H, m), 3.80 (3 H, s), 1.54 (9 H, s), 1.50 (9 H, s), 1.48 (3 H, s), 1.45 (3 H, s), 1.06 (3 H, s), 0.98 (3 H, s); 13C NMR (CDCl3): δ 171.5, 165.8, 155.3, 154.0, 152.4, 147.4, 142.9, 142.8, 137.0, 133.8, 128.6, 125.6, 124.9, 123.7, 120.2, 118.8, 115.2, 114.6, 110.9, 82.7, 81.8, 79.1, 61.9, 61.8, 52.4, 40.4, 39.5, 28.6, 28.5, 28.4, 27.9, 22.9, 22.3; HRMS (ESI) m/z calcd for C20H23N4O2 (M+H)+: 690.3796, Found (M+H)+: 690.3867; IR (cm-1): 3282 (w, br), 2978 (m), 1716 (s), 1480 (m), 1368 (m), 1164 (m), 734 (w); [α]D22 = +49 (c = 0.65, CHCl3). Isoroquefortine E (23): 1H NMR (CDCl3): δ 11.85 (1 H, br), 9.18 (1 H, br), 7.51 (1 H, s), 7.16 (1 H, J =7.5 Hz), 7.08 (1 H, t, J = 7.6 Hz), 6.93 (1 H, s), 6.74 (1 H, t, J = 7.5 Hz), 6.57 (1 H, d, J = 7.7 Hz), 6.02 (1 H, dd, J = 17.5, 10.5 Hz), 5.99 (1 H, dd, J = 17.4, 10.8 Hz), 5.65 (1 H, s), 5.21 (1 H, dd, J = 10.5, 0.7 Hz), 5.17 (1 H, dd, J = 17.4, 0.6 Hz), 5.12 (1 H, dd, J = 10.8, 1.1 Hz), 5.09 (1 H, dd, J = 17.4, 1.1 Hz), 4.94 (1 H, s), 4.10 (1 H, dd, J = 11.5, 5.8 Hz), 2.60 (1 H, dd, J = 12.3, 5.8 Hz), 2.47 (1 H, dd, J = 11.6, 12.0 Hz), 1.50 (6 H, s), 1.14 (3 H, s), 1.03 (3 H, s); 13C NMR (CDCl3): δ 165.5, 158.7, 150.4, 144.6, 143.6, 136.6, 132.4, 132.3, 128.9, 128.9, 125.6, 125.2, 118.8, 114.4, 113.3, 108.9, 105.4, 78.1, 61.6, 59.1, 40.9, 37.5, 37.2, 28.0, 27.9, 23.0, 22.5; HRMS (ESI) m/z calcd for C27H32N5O2 (M+H)+: 458.2485, Found (M+H)+: 458.2556; IR (cm-1): 3234(w, br), 2971 (m), 1661 (s), 1436 (s), 1215 (m), 918 (w), 733 (w); [α]D24= -233 (c = 0.50, CHCl3).