Total Synthesis of Largazole
and Its Biological Evaluation

Yoshitaka Numajiri; Takashi Takahashi; Motoki Takagi; Kazuo Shin-ya; Takayuki Doi

doi:10.1055/s-2008-1078263

LETTER

Total Synthesis of Largazole and Its Biological Evaluation

Yoshitaka Numajiri^a, Takashi Takahashi^a, Motoki Takagi^b, Kazuo Shin-ya^c, Takayuki Doi*^d
^a Department of Applied Chemistry, Tokyo Institute of Technology, Ookayama, Meguro, Tokyo 152-8552, Japan
^b Biomedicinal Information Research Center (BIRC), Japan Biological Informatics Consortium (JBIC), 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan
^c National Institute of Advanced Industrial Science and Technology, 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan
^d Graduate School of Pharmaceutical Sciences, Tohoku University, Aza-Aoba, Aramaki, Aoba, Sendai 980-8578, Japan
Fax: +81(22)7956864; e-Mail: doi_taka@mail.pharm.tohoku.ac.jp;

Abstract

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Abstract

We achieved a total synthesis of largazole. The optically active β-hydroxycarbonyl unit was prepared from a modified Nagao’s N-acetylthiazolidinethione. A 4-methylthiazoline-thiazole amino ester was prepared by both a step-by-step method and tandem cyclization from Cys-2-MeCys-containing tripeptide. Amidation of the activated β-hydroxycarbonyl unit and 4-methyl-thiazoline-thiazole-containing amino ester, followed by esterification with N-Fmoc valine afforded cyclization precursor after selective removal of the methyl ester at the C-terminus and the Fmoc group at the N-terminus. Macrolactamization, deprotection of thiol, and S-acylation provided largazole. Biological evaluation of its S-modified derivatives as well as the synthetic largazole exhibited strong inhibitory activity against histone deacetylases (HDAC).

Key words

HDAC inhibitor - macrolactamization - natural products - peptides - total synthesis

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References

References and Notes

<A NAME="RU06008ST-1">1</A> Taori K. Paul VJ. Luesch H. J. Am. Chem. Soc. 2008, 130: 1806

For other synthetic approaches of 4-methylthiazoline-thiazole-containing molecules, see:

<A NAME="RU06008ST-2A">2a</A> Han FS. Tokuyama H. Fukuyama T. Chem. Commun. 2007, 3444

<A NAME="RU06008ST-2B">2b</A> Boyce RJ. Pattenden G. Tetrahedron 1995, 51: 7313

<A NAME="RU06008ST-3">3</A> Ueda H. Nakajima H. Hori Y. Fujita T. Nishimura M. Goto T. Okuhara M. J. Antibiot. 1994, 47: 301

<A NAME="RU06008ST-4">4</A> Masuoka Y. Nagai A. Shin-ya K. Furihata K. Nagai K. Suzuki K. Hayakawa Y. Seto H. Tetrahedron Lett. 2001, 42: 41

<A NAME="RU06008ST-5">5</A> Furumai R. Matsuyama A. Kobashi N. Lee K.-H. Nishiyama M. Nakajima H. Tanaka A. Komatsu Y. Nishino N. Yoshida M. Horinouchi S. Cancer Res. 2002, 62: 4916

<A NAME="RU06008ST-6">6</A> During the preparation of this manuscript, another total synthesis of largazole was reported. See: Ying Y. Taori K. Kim H. Hong J. Luesch H. J. Am. Chem. Soc. 2008, 130: 8455

<A NAME="RU06008ST-7">7</A> Doi T. Iijima Y. Shin-ya K. Ganesan A. Takahashi T. Tetrahedron Lett. 2006, 47: 1177

<A NAME="RU06008ST-8">8</A> Li KW. Wu J. Xing W. Simon JA. J. Am. Chem. Soc. 1996, 118: 7237

Thiazole 11 was prepared from commercially available Fmoc-Gly-NH₂ as follows: (i)Lawesson’s reagent, toluene, 80 ˚C;(ii) bromopyruvic acid, 1,4-dioxane, 56% in 2 steps.

<A NAME="RU06008ST-10">10</A> Videnov G. Kaiser D. Kempter C. Jung G. Angew. Chem., Int. Ed. Engl. 1996, 35: 1503

Compound 12 was prepared from previously reported (R)-2-methylcysteine (ref. 12) as follows: (i) TrtCl, DMF, 24 h, 75%; (ii) AcCl, MeOH, 80 ˚C, 15 h.

<A NAME="RU06008ST-12">12</A> Pattenden G. Thom SM. Jones MF. Tetrahedron 1993, 49: 2131

<A NAME="RU06008ST-13">13</A> You S.-L. Razavi H. Kelly JW. Angew. Chem. Int. Ed. 2003, 42: 83

<A NAME="RU06008ST-14">14</A> Sakakura A. Kondo R. Ishihara K. Org. Lett. 2005, 7: 1971

<A NAME="RU06008ST-15">15</A> Raman P. Razavi H. Kelly JW. Org. Lett. 2000, 2: 3289

The tandem dehydrative cyclization of S-trityl derivative 15 did not proceed by the use of either TiCl₄ (ref. 15) or Ph₃PO-Tf₂O (ref. 13).

<A NAME="RU06008ST-17">17</A> Chen Y. Gambs C. Abe Y. Wentworth P., Jr. Janda KD. J. Org. Chem. 2003, 68: 8902

<A NAME="RU06008ST-18A">18a</A> Yurek-George A. Habens F. Brimmell M. Packham G. Ganesan A. J. Am. Chem. Soc. 2004, 126: 1030

<A NAME="RU06008ST-18B">18b</A> Davidson SM. Townsend PA. Carroll C. Yurek-George A. Balasubramanyam K. Kundu TK. Stephanou A. Packham G. Ganesan A. Latchman DS. ChemBioChem 2005, 6: 162

<A NAME="RU06008ST-19">19</A> Nagao Y. Hagiwara Y. Kumagai T. Ochiai M. Inoue T. Hashimoto K. Fujita E. J. Org. Chem. 1986, 51: 2391

<A NAME="RU06008ST-20">20</A> Osorio-Lozada A. Olivo HF. Org. Lett. 2008, 10: 617

<A NAME="RU06008ST-21">21</A> PyAOP = (7-azabenzotriazol-1-yloxy) tripyrrolidino-phosphonium hexafluorophosphate: Albericio F. Cases M. Alsina J. Triolo SA. Carpino LA. Kates SA. Tetrahedron Lett. 1997, 38: 4853

<A NAME="RU06008ST-22A">22a</A> Shiina I. Ibuka R. Kubota M. Chem. Lett. 2002, 31: 286

<A NAME="RU06008ST-22B">22b</A> Shiina I. Kubota M. Oshima H. Hashizume M. J. Org. Chem. 2004, 69: 1822

<A NAME="RU06008ST-23">23</A> Inanaga J. Hirata K. Saeki H. Katsuki T. Yamaguchi M. Bull. Chem. Soc. Jpn. 1979, 52: 1989

<A NAME="RU06008ST-24">24</A> Nicolaou KC. Estrada AA. Zak M. Lee SH. Safina BS. Angew. Chem. Int. Ed. 2005, 44: 1378

<A NAME="RU06008ST-25">25</A> HATU = O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate: Carpino LA. J. Am. Chem. Soc. 1993, 115: 4397

Spectral Data for 20
Mp 97-99 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.76 (s, 1 H), 7.37 (m, 6 H), 7.28 (m, 6 H), 7.17-7.26 (m, 4 H), 6.55 (dd, J = 9.3, 3.0 Hz, 1 H), 5.73 (dt, J = 15.6, 6.8 Hz, 1 H), 5.62 (m, 1 H), 5.41 (dd, J = 15.6, 6.3 Hz, 1 H), 5.21 (dd, J = 17.6, 9.3 Hz, 1 H), 4.56 (dd, J = 9.3, 3.9 Hz, 1 H), 4.13 (dd, J = 17.6, 3.0 Hz, 1 H), 4.05 (d, J = 11.7 Hz, 1 H), 3.29 (d, J = 11.7 Hz, 1 H), 2.82 (dd, J = 16.1, 9.3 Hz, 1 H), 2.65 (dd, J = 16.1, 2.9 Hz, 1 H), 2.16-2.27 (m, 2 H), 1.99-2.12 (m, 3 H), 1.85 (s, 3 H), 0.69 (d, J = 6.8 Hz, 3 H), 0.53 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.3, 169.5, 168.7, 168.1, 165.3, 147.2, 144.9, 133.2, 129.7, 128.1, 128.0, 126.7, 124.6, 84.1, 72.0, 66.7, 58.1, 43.4, 41.1, 40.8, 34.1, 31.5, 31.3, 24.1, 18.9, 16.9. IR (neat): 3373, 2930, 1734, 1674, 1511, 1245, 751, 701 cm^-¹. [α]_D ^²5 +4.0 (c 0.25, CHCl₃). HRMS (ESI-TOF): m/z calcd for [C₄₀H₄₂N₄O₄S₃ + H]⁺: 739.2446; found: 739.2447.

<A NAME="RU06008ST-27">27</A> Nishino N. Jose B. Okamura S. Ebisusaki S. Kato T. Sumida Y. Yoshida M. Org. Lett. 2003, 5: 5079

Spectral Data for 1
^¹H NMR (400 MHz, CDCl₃): δ = 7.77 (s, 1 H), 7.16 (d, J = 9.3 Hz, 1 H), 6.47 (dd, J = 9.8, 2.9 Hz, 1 H), 5.83 (dt, J = 15.6, 6.8 Hz, 1 H), 5.66 (m, 1 H), 5.52 (dd, J = 15.6, 6.8 Hz, 1 H), 5.29 (dd, J = 17.6, 9.8 Hz, 1 H), 4.60 (dd, J = 9.3, 3.4 Hz, 1 H), 4.27 (dd, J = 17.6, 2.9 Hz, 1 H), 4.06 (d, J = 11.2 Hz, 1 H), 3.28 (d, J = 11.2 Hz, 1 H), 2.90 (t, J = 7.3 Hz, 2 H), 2.87 (dd, J = 16.6, 10.2 Hz, 1 H), 2.68 (dd, J = 16.6, 2.9 Hz, 1 H), 2.53 (t, J = 7.8 Hz, 2 H), 2.32 (dt, J = 7.3, 6.8 Hz, 2 H), 2.10 (m, 1 H), 1.87 (s, 3 H), 1.64 (m, 2 H), 1.25-1.28 (m, 8 H), 0.87 (t, J = 6.8 Hz, 3 H), 0.68 (d, J = 6.8 Hz, 3 H), 0.51 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 199.4, 173.5, 169.6, 168.9, 168.1, 165.1, 147.4, 132.8, 128.5, 124.5, 84.3, 72.2, 57.9, 44.2, 43.4, 41.2, 40.6, 34.2, 32.4, 31.7, 29.0, 29.0, 28.0, 25.7, 24.2, 22.7, 18.9, 16.8, 14.1. IR (neat): 3374, 2927, 2855, 1735, 1681, 1507, 1258, 1031 cm^-¹. [α]_D ^²4 +39 (c 0.38, MeOH) {lit.^¹ [α]_D ^²0 +22 (c 0.1, MeOH), lit.⁶ [α]_D ^²³.5 +37.8 (c 0.027, MeOH)}. HRMS (ESI-TOF): m/z calcd for [C₂₉H₄₂N₄O₅S₃ + H]⁺: 623.2396; found: 623.2396.

<A NAME="RU06008ST-29">29</A> Dressel U. Renkawitz R. Baniahmad A. Anticancer Res. 2000, 20: 1017

Hong and Luesch also concluded that the thiol group is the pharmacophore of largazole by SAR studies based on the biological evaluation of its thiol-free and S-acetyl derivatives and the hydroxy analogue instead of the S-octanoyl group. See ref. 6.