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DOI: 10.1055/s-2008-1078263
Total Synthesis of Largazole and Its Biological Evaluation
Publikationsverlauf
Publikationsdatum:
22. August 2008 (online)
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 and Notes
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.
11Compound 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.
16The 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.
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.
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.