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Synlett 2008(16): 2483-2486  
DOI: 10.1055/s-2008-1078263
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of Largazole and Its Biological Evaluation

Yoshitaka Numajiria, Takashi Takahashia, Motoki Takagib, Kazuo Shin-yac, 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;
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Publikationsverlauf

Received 10 June 2008
Publikationsdatum:
22. August 2008 (online)

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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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9

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.

11

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.

16

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).

26

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.

28

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.

30

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.