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. 2007 Mar 7;129(9):2648-59.
doi: 10.1021/ja067870m. Epub 2007 Feb 6.

Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue

Brian J Albert  1 , Ananthapadmanabhan Sivaramakrishnan, Tadaatsu Naka, Nancy L Czaicki, Kazunori Koide
Affiliations

Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue

Brian J Albert et al. J Am Chem Soc. .

Erratum in

  • J Am Chem Soc. 2007 Jun 6;129(22):7206

Abstract

FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4' stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by beta-elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.

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Figures

Figure 1
Figure 1
Growth inhibition of MCF-7 cells by FR901464 (blue) and meayamycin (97; red)
Scheme 1
Scheme 1
First generation retrosynthetic analysis of FR901464
Scheme 2
Scheme 2
Preparation of ketoaldehyde 2 a aConditions: (a) propargyl alcohol (1.1 equiv), allyl bromide (1.1 equiv), zinc dust (3.1 equiv); then methallyl bromide (1.0 equiv), THF, 23 °C, 93%; (b) (+)-DIPT (9 mol %), Ti(OiPr)4 (8 mol %), tBuOOH (1.9–2.2 equiv), CH2Cl2, -20 °C, 90%, er >97:3; (c) Dess-Martin periodinane (1.5 equiv), CH2Cl2, 0→23 °C, 81%; (d) alkyne 11 or 12 (1.3 equiv), Zn(OTf)2 (1.2 equiv), (−)-N-methylephedrine (1.3 equiv), Et3N (1.3 equiv), toluene, 23→40 °C, 22 h; (e) see table below; (f) 4-O2NPhCO2H (3.0 equiv), diisopropyl azodicarboxylate (2.9 equiv), Ph3P (3.0 equiv), THF, 0→23 °C, 85%; (g) K2CO3 (2.5 equiv), MeOH, 0 °C, 88%; (h) TESCl (1.1 equiv), imidazole (1.4 equiv), THF, 0 °C, quant.; (i) OsO4 (0.05 equiv), NMO (1.0 equiv), THF, 0→23 °C, 58%; then NaIO4 (1.0), THF/H2O (1:1), 23 °C, quant.; (j) O3, CH2Cl2/MeOH (1:1), -78 °C; then Me2S (10 equiv), -78→23 °C, 54–82%.
Scheme 3
Scheme 3
Formation of C4 stereocenter with higher stereocontrol a a Conditions: (a) Ag-C≡C-CO2Me (1.7 equiv), Cp2ZrCl2 (1.3 equiv), AgOTf (0.2 equiv), CH2Cl2, 23 °C, 84% (dr = 6:1); (b) H2 (1 atm), Lindlar's catalyst (1.2 –2.0 mol %), quinoline (0.94–1.5 equiv), EtOH, 23 °C, 7–17 h; (c) TESCl (1.1 equiv), imidazole (1.4 equiv), THF, 0 °C, 74%; (d) Red-Al (2.0 equiv), THF, -72 °C, 81%; (e) TESCl (1.4 equiv), imidazole (1.5 equiv), THF, 0 °C, quant.; (f) O3, CH2Cl2/MeOH (1:1), -78 °C; then Me2S (17 equiv), -78→23 °C, quant. (based on 1H NMR).
Scheme 4
Scheme 4
Preparation of acid 3 a Conditions: (a) cinnamaldehyde (1.1 equiv), TMSCHN2 (1.0 equiv), LDA (1.0 equiv), THF, -78→0 °C, 84%; (b) CH3CHO (2.3 equiv), Zn(OTf)2 (1.0 equiv), (−)-N-methylephedrine (1.0 equiv), Et3N (1.0 equiv), toluene, 23 °C, 41% (86:14 er); (c) Ac2O (5.0 equiv), pyridine, 23 °C, quant.; (d) O3, CH2Cl2, -78 °C; then Me2S (10 equiv), -78→23 °C, 89%; (e) NaClO2 (3.0 equiv), NaH2PO4 (2.0 equiv), 2-methyl-2-butene (15 equiv), tBuOH/H2O (1:1), 23 °C; (f) OsO4 (0.7 mol %), Oxone (4.0 equiv), DMF, 23 °C; (g) H2, Lindlar's catalyst (1 mol %), quinoline (10 mol %), EtOH, 23 °C, 75% (for steps e and g), 60% (for steps f and g).
Scheme 5
Scheme 5
Alternative methods to prepare acid 3 a a Conditions: (a) HC≡CCH2OTHP (3.0 equiv), nBuLi (3.0 equiv), THF, -78→0 °C, 78–93%; (b) (S)-2-methyl-CBS-oxazaborolidine (0.2 equiv), catecholborane (1.6 equiv), EtNO2, -78 °C; (c) Ac2O (4.6 equiv), pyridine (excess), 23 °C, 97% (2 steps); (d) Na2Cr2O7 (3.5 equiv), H2SO4, H2O, acetone, 0→23 °C, 74%; (e) see Scheme 4.
Scheme 6
Scheme 6
Synthetic approach A-ring formation a a Conditions: (a) 2-methoxypropene (2.0 equiv), CSA (1 mol %), CH2Cl2, 0 °C, quant.; (b) DIBALH (2.0 equiv), CH2Cl2, -78 °C; (c) (EtO)2P(O)CH(CH3)CO2Et (3.3 equiv), NaH (3.0 equiv), solvent, 23 °C, 84% (2 steps); (d) H2 (1 atm), PtO2 (1 mol %), EtOH, 23 °C, quant. (dr = 2:1); (e) AcOH, 58%; (f) DIBALH (2.0 equiv), CH2Cl2, -78 °C; then Ph3PCH3Br (2.1 equiv), KOtBu (2.0 equiv), THF, -78→48 °C, 77%; (g) CSA (10 mol %), MeOH, 23 °C, 95%; (h) methacrylic acid (1.2 equiv), DCC (1.2 equiv), DMAP (0.1 equiv), CH2Cl2, 0 °C, 95%; (i) Ru-3 (10 mol %), ClCH2CH2Cl, 83 °C; (j) methallyl bromide (4.0 equiv), Ag2O (1.5 equiv), DMF, 23 °C, 86%; (k) Ru-1 (1 mol %), benzene, reflux, quant.; (l) PDC (6.0 equiv), ClCH2CH2Cl, reflux, 72%; (m) PCC (2.0 equiv), TBHP (4.0 equiv), Celite, benzene, 23 °C, 67% (n) H2, PtO2 (1 mol %), EtOH, 23 °C, quant. (dr = 10:1); (o) allyl-MgCl (2.0 equiv), THF, -78 °C, 96%.
Scheme 7
Scheme 7
Preparation of 42 a a Conditions: (a) Et3SiH (4.0 equiv), BF3•OEt2 (4.0 equiv), CH2Cl2, -78 °C, 42 (dr = 10:1); (b), Et3SiH (10 equiv), BF3•OEt2 (4.0 equiv), CF3CH2OH (8.0 equiv), CH2Cl2, -78 °C; then Boc2O (0.5 equiv), -78→23 °C, 42 (dr = 10:1).
Scheme 8
Scheme 8
Preparation of 41 using different amine protecting groups a a Conditions: (a) TFA/CH2Cl2 (1:9), 23 °C; then pivaloyl chloride (3.0 equiv), DMAP (0.01 equiv), pyridine, 0→23 °C, 82% (38→44); (b) 6N HCl/THF (2:1), 23 °C; then TsCl (1.3 equiv), K2CO3, 23 °C, 86% (38→45); (c) PDC (4.0 equiv), tBuOOH (4.0 equiv), benzene, 23 °C, 70% (25) or 65% (26); (d) H2, PtO2 (3 mol %), EtOH, 23 °C, 97% (44→46) or 99% (45→47); (e) allyl-MgCl (3.0 equiv), THF, -98 °C, 58% (46→48), or -78 °C, 63% (47→49); (f) Et3SiH (10 equiv), BF3•OEt2 (4.0 equiv), CH2Cl2/MeCN (1:1), -20 °C, 44% (48→50, 61% BORSM; dr = 8:1), or THF, -20 °C, 68% (49→51, dr = 12:1); (g) (from 51) sodium naphthalenide, THF, -78 °C; then Boc2O (2.3 equiv), Et3N (4.0 equiv), DMAP (0.08 equiv), MeCN, 23 °C, 87% (51→42, 2 steps).
Scheme 9
Scheme 9
Failed synthetic attempts using the NHK strategy a a Conditions: (a) Ru-1 (5 mol %), methacrolein (10 equiv), ClCH2CH2Cl, 40 °C, 67%; (b) CHI3 (2 equiv), CrCl2 (6 equiv), THF, 0 °C, 63%; (c) TFA/CH2Cl2 (1:9), 23 °C; then 3 (1.7 equiv), HATU (1.7 equiv), iPr2NEt (3.6 equiv), MeCN, 23 °C, 45%; (d) CrCl2 (7 equiv), NiCl2 (∼5 mol %), DMSO, 23 °C; (e) nBuLi (1–2 equiv), THF, -100→-78 °C.
Scheme 10
Scheme 10
Julia olefination coupling strategy
Scheme 11
Scheme 11
Preparation of methyl glycoside 58 a a Conditions: (a) NBS (1.1 equiv), THF, H2O, 0→23 °C, 75%; (b) PPTS (10 mol %), MeOH, CH2Cl2, 23 °C, 40%; (c) NBS (1.5 equiv), 3Å MS, MeOH, MeCN, 0→23 °C, 59%.
Scheme 12
Scheme 12
Preparation of thioethers 61 and 63 a a Conditions: (a) TESCl (1.2 equiv), imidazole (1.4 equiv), THF, 0 °C, quant.; (b) OsO4 (4.5 mol %), NMO (1.0 equiv), THF, H2O, 23 °C; then NaIO4 (1.0 equiv), Et2O, H2O, 23 °C, 60%; (c) NBS (2.0 equiv), acetone, H2O, 23 °C, 95%; (d) PPTS (10 mol %), MeOH, CH2Cl2, 23 °C, 75%; (e) NBS (1.5 equiv), 3Å MS, MeOH, MeCN, 0→23 °C, 47%; (f) 4-phenyltetrazole thiol (1.2 equiv), Et3N (2.0 equiv), MeCN, reflux, 60%; (g) TBAF (1.1 equiv), THF, 0 °C, 80%; (h) 4-phenyltetrazole thiol (1.0 equiv), Et3N (2.0 equiv), MeCN, 50 °C, 74%; (i) 4-O2NPhCO2H (2.1 equiv), DIAD (2.7 equiv), Ph3P (2.2 equiv), THF, 0→23 °C; then K2CO3 (1.0 equiv), MeOH, 23 °C.
Scheme 13
Scheme 13
Diene-ene Cross Metathesis Coupling Strategy
Scheme 14
Scheme 14
Preparation of diene 54 a a Conditions: (a) Ph3PCH3Br (1.4 equiv), tBuOK (1.3 equiv), THF, 0 °C, 80%; (b) TFA/CH2Cl2 (1:9), 23 °C; then 3 (1.7 equiv), HATU (1.7 equiv), iPr2NEt (4.6 equiv), MeCN, 0 °C; (c) TFA/CH2Cl2 (1:9), 23 °C; then 3 (1.2 equiv), HATU (1.2 equiv), iPr2NEt (4.0 equiv), MeCN, 23 °C, 86%; (d) Ru-3 (0.05 equiv), methacrolein (20 equiv), CH2Cl2, 23 °C, 57% (67% based on recovered 75); (e) Ph3PCH3Br (1.4 equiv), KOtBu (1.2 equiv), THF, 0 °C, 86%.
Scheme 15
Scheme 15
Our first synthesis of FR901464 a a Conditions: (a) Ru-1 (0.2 equiv), THF, 40 °C, 22%; (b) HF•pyridine, THF, 0 °C.
Scheme 16
Scheme 16
Preparation of alcohols 81 and 5-epi-81 a a Conditions: (a) DIBALH (3.0 equiv), THF, -78 °C, 95%; (b) ArSeCN (1.2 equiv), nBu3P (1.4 equiv), THF, 0 °C, quant.
Scheme 17
Scheme 17
Preparation of 64 a a Conditions: (a) 2-O2NPhSeCN (1.2 equiv), nBu3P (1.4 equiv), THF, 0 °C; then H2O2 (10 equiv), DMAP (4.0 equiv), -44→23 °C, 91% (dr = 7:1); (b) OsO4 (0.02 equiv), NaIO4 (2.5 equiv), 2,6-lutidine (1.6 equiv), dioxane/H2O (3:1), 0→23 °C, 27%; (c) TESCl (1.4 equiv), imidazole (1.6 equiv), THF, 0 °C, 95%; (d) OsO4 (0.01 equiv), NMO (0.96 equiv), THF/H2O (10:1), 0 to 23 °C; then Pb(OAc)4 (1.2 equiv), benzene, 0→23 °C, 71% (86% based on recovered 82); (e) AcOH/H2O/THF (3:1:3), 0→23 °C, 91%.
Scheme 18
Scheme 18
Final stage of the total synthesis of FR901464 a
Scheme 19
Scheme 19
Summary of the total synthesis of FR901464
Scheme 20
Scheme 20
Decomposition of 64
Scheme 21
Scheme 21
Preparation of the right fragment analog 95 a a Conditions: (a) Hg(OAc)2 (1.1 equiv), THF, 0→23 °C; then NaBH4 (2.0 equiv), Et3B (1.0 equiv), -78→-44 °C, 76%; (b) TBAF (1.2 equiv), THF, 0 °C, 97%; (c) HF•pyr, THF, 0 °C, 73 %.
Scheme 22
Scheme 22
Cross metathesis of 54 and 95 a a Conditions: (a) 54 (1.0 equiv), 95 (1.5 equiv), Ru-3 (0.10 equiv), ClCH2CH2Cl, 40 °C, 59% after 1 recycling of recovered 54 and 95.
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