Total synthesis of FR901464, an antitumor agent that regulates the transcription of oncogenes and tumor suppressor genes

Article abstract of DOI:10.1021/ja058216u

FR901464 is a potent anticancer agent that regulates the transcription of oncogenes and tumor suppressor genes. A convergent enantioselective synthesis of FR901464 was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cr

Full text of DOI:10.1021/ja058216u

Published on Web 02/11/2006
Total Synthesis of FR901464, an Antitumor Agent that Regulates the
Transcription of Oncogenes and Tumor Suppressor Genes
Brian J. Albert, Ananthapadmanabhan Sivaramakrishnan, Tadaatsu Naka, and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue, Pittsburgh, PennsylVania 15260
Received December 2, 2005; E-mail: koide@pitt.edu
Scheme 1. Retrosynthetic Analysis of FR901464
In search for anticancer natural products with new modes of
action, the Fujisawa group isolated FR901464 (Scheme 1) from
the culture broth of a bacterium of Pseudomonas sp. No.2663 as a
novel transcriptional activator.1 This natural product lowers the
mRNA levels of p53, p21, c-myc, and E2F-1 in MCF-7 cells at 20
nM1b and induces apparent apoptosis in MCF-7 cells with the
impressive LC50 of 0.5 nM. It also exhibits an antitumor activity
in a mouse model at remarkably low concentrations (0.056-0.18
mg/kg).1b This unprecedented pharmacological profile of FR901464
has drawn considerable interest2 and prompted us to further
investigate the biology of FR901464.
Despite the two previous syntheses of FR901464,3 a more concise
synthetic approach was highly desirable to take full advantage of
such biological activities. Scheme 1 illustrates our retrosynthetic
analysis of FR901464, in which the priority was to accomplish a
coupling between A- and B-ring fragments with complete func-
tionality for ultimate convergency. While several intramolecular
diene-ene olefin metathesis reactions have been reported,4 the
corresponding intermolecular version was unprecedented in natural
product synthesis at the outset of this research.5 Nonetheless, we
reasoned that the ruthenium-alkylidene complex with 2 would be
more reactive than that of 1 (if the terminal olefin reacts), the
trisubstituted and electron-deficient olefin would not react with the
ruthenium catalyst due to steric and electronic reasons, and
thermodynamics would favor FR901464 over the homodimer of 2
under reversible conditions. Further retrosynthetic analysis of the
A-ring fragment 1 and B-ring fragment 2 revealed acid 3, amine
4, and selenide 5.
With this strategy in mind, carboxylic acid 3 was prepared as
shown in Scheme 2. We chose to use the styrene unit as a masked
aldehyde because the styryl group significantly suppressed the
volatility of otherwise low molecular weight intermediates. Known
enyne 6 was prepared from cinnamaldehyde according to the
literature (TMSCHN2, LDA, 84%).6 The next step employed a
Carreira asymmetric alkynylation between 6 and acetaldehyde to
generate alcohol 7.7 This alcohol was then converted to acetate 8,
and subsequent ozonolysis afforded aldehyde 9. Further oxidation
of this aldehyde gave 10, which was then partially hydrogenated
with Lindlar’s catalyst to afford 3.
Scheme 3 outlines the preparation of 1. The L-threonine
derivative 11, prepared in one step (2-methoxypropene, CSA;
quant.) from commercially available N-Boc-L-threonine methyl
ester, was transformed to 12 using a one-pot procedure (DIBAL-
H; Ph3PdCH2).8 Removal of the oxazolidine ring of 12 using CSA
in MeOH generated alcohol 13, and subsequent O-methallylation
afforded diene 14. The ring-closing metathesis of 14 was quantita-
tive using 1 mol % of Grubbs’ 2nd generation catalyst9 to provide
15. To prepare lactone 16, we found that allylic oxidation of 15
with PDC was most regioselective and efficient. Subsequent
stereoselective hydrogenation of 16 gave desired lactone 17 and
its C12-epimer in a 10:1 ratio. The allylation of 17 gave hemiketal
Scheme 2. Preparation of 3a
a Conditions: (a) CH3CHO (2.3 equiv), Zn(OTf)2 (1.0 equiv), Et3N (1.0
equiv), (-)-N-methylephedrine (1.0 equiv), toluene, 23 °C, 41% (72% ee);
(b) Ac2O (5.0 equiv), pyridine, 23 °C, quant.; (c) O3, CH2Cl2, -78 °C;
Me2S (10 equiv), -78f23 °C, 89%; (d) NaClO2 (3.0 equiv), NaH2PO4
(3.0 equiv), 2-methyl-2-butene (15 equiv), H2O/tBuOH (1:1), 23 °C; (e)
H2 (1 atm), Lindlar’s catalyst (1 mol %), quinoline (10 mol %), EtOH, 23
°C, 75% (2 steps).
18, which is in equilibrium with an aminal. Due to the presence of
two anomers for both 18 and the aminal, we were not able to
determine the relative ratio among these four compounds. In the
next step, this mixture was subjected to reduction conditions
(BF3‚OEt2, Et3SiH, CF3CH2OH), providing the desired compound
19 along with a pyrrolidine derivative (see Supporting Information).
Subsequent coupling of 3 and 19 (via amine 4) gave amide 20.
Methacrolein and 20 were then subjected to the cross-olefin
metathesis conditions using 5 mol % of catalyst 2210 to form the
desired aldehyde 21, which was then converted to diene 1 upon
addition of Ph3PdCH2.
B-ring fragment 2 was prepared according to Scheme 4. Through
the three-step sequence that we previously reported, aldehyde 23
was prepared from methallyl bromide and propargyl alcohol.11 The
subsequent C4-C5 bond formation was most stereoselective and
efficient using the Zr/Ag-promoted alkynylation method developed
in our laboratory to afford 24 and C4-epimer in a ratio of 6:1 in
favor of 24.12 While the partial hydrogenation of 24 or its TES
ether failed, the Red-Al reduction protocol from our laboratory
successfully afforded allylic alcohol 25.13 This alcohol was protected
as the TES ether 26, which was then reduced by DIBAL-H to
furnish the primary alcohol 27. Transformation of the hydroxy group
of 27 to the o-nitrophenylselenide gave 5. Despite the lack of closely
related Mislow-Evans-type [2,3]-sigmatropic rearrangements of
9
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J. AM. CHEM. SOC. 2006, 128, 2792-2793
10.1021/ja058216u CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Preparation of 1a
Scheme 5. Final Stage
raphy3a partly accounts for the loss of the material. Only 5% of
homodimers of 2 were detected, and diene 1 did not form its
homodimer under the reaction conditions. The fragile nature of 2
(thermal decomposition at g47 °C) precluded more forcing reaction
conditions.
In summary, we completed the total synthesis of FR901464 in
the 13 longest linear steps with 31 total steps, which features Zr/
Ag-promoted alkynylation using electron-deficient methyl propi-
olate, mild Red-Al reduction, stereoselective [2,3]-sigmatropic
rearrangement via a selenoxide, and diene-ene cross olefin metath-
esis without protecting groups. Biological studies of FR901464 and
its analogs are underway in our laboratory.
a Conditions: (a) DIBAL-H (2.0 equiv), CH2Cl2, -78 °C; Ph3PCH3Br
(2.1 equiv), tBuOK (2.0 equiv), THF, -78f48 °C, 77%; (b) CSA (10 mol
%), MeOH, 23 °C, 95%; (c) methallyl bromide (4.0 equiv), Ag2O (1.5
equiv), DMF, 23 °C, 86%; (d) Grubbs’ 2nd cat. (1 mol %), PhH, reflux,
quant.; (e) PDC (6.0 equiv), (ClCH2)2, reflux, 72%; (f) H2 (1 atm), PtO2 (1
mol %), EtOH, 23 °C; quant.; (g) allyl-MgBr (2.0 equiv), THF, -78 °C,
96%; (h) Et3SiH (10 equiv), BF3‚OEt2 (4.0 equiv), CF3CH2OH (8.0 equiv),
-78 °C, 38%; (i) TFA/CH2Cl2 (1:9), 23 °C, 3 (1.2 equiv), HATU (1.2
Acknowledgment. We wish to dedicate this paper to the 60th
birthday of Professor K. C. Nicolaou. This work was supported by
the University of Pittsburgh, the American Chemical Society (PRF
No. 38542-G1), The American Cancer Society George Heckman
Institutional Research Grant, and The Competitive Medical Re-
search Fund. B.J.A. is thankful for a Graduate Excellence Fellow-
ship.
i
equiv), Pr2NEt (4.0 equiv), 23 °C, 86%; (j) 22 (5 mol %), methacrolein
(20 equiv), CH2Cl2, 23 °C, 57% (67% based on recovered 20); (k)
t
Ph3PCH3Br (1.4 equiv), BuOK (1.2 equiv), THF, 0 °C, 86%.
Scheme 4. Preparation of 2a
Supporting Information Available: Experimental procedures and
spectroscopic data for all the new compounds and FR901464. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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A.; Koide, K. 228th ACS National Meeting, Philadelphia, PA, Aug 22-
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a Conditions: (a) Ag-CtC-CO2Me (1.7 equiv), Cp2ZrCl2 (1.3 equiv),
AgOTf (0.2 equiv), CH2Cl2, 23 °C, 84%; (b) Red-Al (2.0 equiv), -72 °C,
81%; (c) TESCl (1.4 equiv), imidazole (1.5 equiv), THF, 0 °C, quant.; (d)
DIBAL-H (3.0 equiv), THF, -78 °C, 95%; (e) o-O2N-PhSeCN (1.2 equiv),
nBu3P (1.4 equiv), THF, 0 °C, quant.; (f) H2O2 (30% v/v in H2O, excess),
DMAP (5.0 equiv), THF, -44f23 °C, 96%; (g) TESCl (1.4 equiv),
imidazole (1.6 equiv), THF, 0 °C, 95%; (h) OsO4 (1 mol %), NMO (0.96
equiv), THF/H2O (10:1), 0f23 °C; Pb(OAc)4 (1.2 equiv), PhH, 0f23 °C,
71% (86% based on recovered 29); (i) AcOH/THF/H2O (3:3:1), 0f23 °C,
91%.
chiral E-allylselenides, we proceeded to treat substrate 5 with H2O2
and DMAP, which promoted a rearrangement via the putative
selenoxide to provide the desired allylic alcohol 28 and its
diastereomer with a pleasantly surprising diastereomeric ratio of
7.5:1.14 Alcohol 28 was protected as the TES ether 29, which
dramatically improved the regioselectivity of the oxidative cleavage
sequence (OsO4-NMO; Pb(OAc)4), giving ketone 30. Finally, both
TES groups were hydrolyzed under carefully optimized conditions
to form the fully functionalized B-ring fragment 2.
The stage was set to test the cross diene-ene metathesis between
1 and 2 (Scheme 5). Gratifyingly, despite the absence of protecting
groups, the coupling of these two fragments in the presence of
catalyst 22 furnished FR901464 in 40% yield after subjecting the
unreacted 1 and 2 to the same conditions without a detectable cis
isomer. The decomposition of FR901464 during column chromatog-
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