Total synthesis of FR901464. Convergent assembly of chiral components prepared by asymmetric catalysis [17]

Full text of DOI:10.1021/ja0055357

10482
J. Am. Chem. Soc. 2000, 122, 10482-10483
Scheme 1. Retrosynthetic Analysis
Total Synthesis of FR901464. Convergent Assembly
of Chiral Components Prepared by Asymmetric
Catalysis
Christopher F. Thompson, Timothy F. Jamison, and
Eric N. Jacobsen*
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed August 18, 2000
FR901464 (1, Scheme 1) is the most potent member of a new
series of bacterially produced antitumor antibiotics identified by
the Fujisawa pharmaceutical company using a transcriptional
regulation assay.1 This natural product displays pronounced
activity against human solid tumors, and although its precise target
and mechanism of action have not been identified, it has been
shown to induce G1 and G2/M phase arrest in treated cells, cause
changes in chromatin structure, and display strongly differentiated
transcriptional regulatory activity.2 In the latter context, its
regulatory profile is substantially different from those of chromatin
remodeling agents that are known inhibitors of histone deacetyl-
ase,3 suggesting clearly that FR901464 has a fundamentally
different mode of action. In addition to these intriguing biological
properties, only a tentative stereochemical assignment of FR901464
was made, as the absolute configuration of the C4′ position in
the amide side chain has been established unambiguously, but
only the relative stereochemistry within each of the tetrahydro-
pyran units has been elucidated.4 These issues render FR901464
a most interesting target for biological and chemical study, and
we sought to develop a versatile, stereoselective synthetic route
that would provide ready access to 1 and its diastereomers.
From both a structural and retrosynthetic standpoint, 1 can be
divided into three fragments of differing complexity: two highly
functionalized pyran rings connected through a diene system, and
an acyclic side chain joined to the rest of the molecule via an
amide bond. As part of our general effort to effect natural product
synthesis via convergent assembly of chiral building blocks
prepared by asymmetric catalysis,5 we envisioned joining the
fragments by highly reliable and general reactionssin the present
case acylation and Pd-catalyzed cross couplingsand focusing on
the development of efficient methods for the enantioselective
preparation of the requisite chiral components. This strategy would
not only enable the preparation of 1, but would also be readily
adaptable to the synthesis of stereochemical and structural
analogues.
discovery of highly enantio- and diastereoselective chromium-
catalyzed hetero-Diels-Alder (HDA) reactions employing dienes
with a single oxygen substituent (eq 1).6 Application of the new
catalysts to the HDA reaction between diene 6 and ynal 7 could
serve to establish all three stereocenters in 5, with further
elaboration to 3 expected to be relatively straightforward.
Similarly, the HDA reaction between dienyne 9 and aldehyde 10
could provide 8, thereby establishing the complete carbon
framework of the right-hand fragment and the key stereocenter
at C5, from which the other three could be derived. To the extent
that the HDA had never been investigated in the context of
reacting partners as complex as 7 or 9, this approach would also
serve to test the scope of this new catalytic methodology.
The synthesis of chiral fragments required for the assembly of
1 is outlined in Scheme 2. The lone stereocenter in the acyclic
left-hand fragment 2 was established with excellent enantiose-
lectivity using Noyori’s Ru-catalyzed asymmetric transfer hy-
drogenation of commercially available 4-(trimethylsilyl)-3-butyn-
2-one.7 The optically enriched alcohol 12 was then elaborated
by a deprotection/carboxylation8/acetylation sequence to give
carboxylic acid 13. Lindlar reduction afforded the desired cis
alkene 2.
The Z-allylic acetate side chain 2 is the simplest of the
fragments, but its likely sensitivity toward low-valent metal
complexes suggested that it would best be incorporated after the
Pd-catalyzed introduction of the dienyl linkage between the pyran
rings. While identification of efficient routes to pyran units 3 and
4 clearly presented the greatest methodological challenge to this
synthetic exercise, we were encouraged by our group’s recent
(1) Nakajima, H.; Sato, B.; Fujita, T.; Takase, S.; Terano, H.; Okuhara,
M. J. Antibiot. 1996, 49, 1196-1203.
(2) Nakajima, H.; Hori, Y.; Terano, H.; Okuhara, M.; Manda, T.; Matsu-
moto, S.; Shimomura, K. J. Antibiot. 1996, 49, 1204-1211.
(3) (a) Nakajima, H.; Kim, Y. B.; Terano, H.; Yoshida, M.; Horinouchi,
S. Exp. Cell Res. 1998, 241, 126-133. (b) Taunton, J.; Hassig, C. A.;
Schreiber, S. L. Science 1996, 272, 408-411.
The synthesis of the central fragment began with a HDA
reaction between diene 66 and aldehyde 7,9 each accessible in
one or two steps from commercially available materials. Although
the cycloaddition was catalyzed in excellent yield with either the
Cl or the SbF6 complex 11a or 11b, superior enantioselectivity
(4) (a) Nakajima, H.; Takase, S.; Terano, H.; Tanaka, H. J. Antibiot. 1997,
50, 96-99. (b) Nakajima, H., private communication. (c) For previous
synthetic efforts toward the synthesis of FR901464, see: Horigome, M.;
Watanabe, K.; Kitahara, T. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu
1999, 41, 73-78; Chem. Abstr. 2000, 132, 676.
(5) (a) Schaus, S. E.; Brånalt, J. E.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 4876-4877. (b) Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624-
9625.
(6) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 1999, 38, 2398-2400.
(7) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8378-8379.
(8) Getty, S.; Berson, J. J. Am. Chem. Soc. 1991, 113, 4607-4621.
(9) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem.
1996, 61, 2699-2708.
10.1021/ja0055357 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10483
Scheme 3. Fragment Coupling and Completiona
Scheme 2. Fragment Synthesisa
a Conditions: (a) (1) Cp2Zr(H)Cl, THF, 0 °C; (2) ZnCl2, THF, 0 °C;
(3) 3, Pd(PPh3)4 (6.5 mol %). (b) PMe3, THF, rt. (c) H2O. (d) 2, HBTU,
DIPEA, CH3CN/CH2Cl2 (5:1). (e) DBU, DMF, rt, 60 h. (f) TBAF/HOAc,
THF, 0 °C. (g) TsOH, THF/H2O.
step sequence. Deprotection of the secondary alcohol permitted
efficient directed epoxidation of the exo alkene to produce 4 as
a single isomer.
Hindered diene systems of the type found in FR901464 can
be accessed under mild conditions and in good yield by hydrozir-
conation/Negishi coupling sequences,14 and given the high
reactivity of Schwartz’s reagent toward terminal alkynes, we
anticipated that the epoxide functionality in 4 might withstand
hydrozirconation.20 Indeed, the coupling of 4 with 3 proceeded
in excellent yield to afford 20 (Scheme 3). Completion of the
synthesis required azide reduction and acylation with side chain
2, as well as installation of the hemiketal group by an elimination/
hydration sequence. Experimentally, it proved preferable to effect
azide reduction prior to elimination. Thus, Staudinger reaction21
of 20 followed by coupling of the resulting amine to carboxylic
acid 2 afforded 21. The epoxide and primary alkyl iodide moieties
withstood reaction with trimethyl phosphine as well as the
acylation reaction without detectable decomposition. Elimination
of the iodide with DBU, although slow, proceeded to give the
desired enol in good yield. The product of the elimination reaction
was found to be quite unstable and was immediately desilated to
give alcohol 22. Finally, hydration of the enol with p-toluene-
sulfonic acid in THF/H2O afforded 1 with NMR, mass spectral,
and optical rotatory data matching those reported for FR901464.22
a Conditions: (a) Reference 7. (b) TBAF. (c) n-BuLi; CO2. (d) AcCl;
H2O (pH 9). (e) H2, Pd/CaCO3, quinoline, EtOH. (f) (1R,2S)-11b (5 mol
%). (g) m-CPBA, NaHCO3, toluene, 0 °C. (h) TsNHNH2. (i) Na(CN)BH3,
pH 4. (j) NaOAc, EtOH. (k) TBAF. (l) t-BuOK (3 equiv) DMSO
(degassed), 1 min, rt. (m) (1) Cp2Zr(H)Cl (3 equiv); (2) I2. (n)
ClCH2SO2Cl, DMAP, pyridine. (o) LiN3, DMPU. (p) (1R,2S)-11b (5 mol
%). (q) m-CPBA, NaHCO3, CH2Cl2, 0 °C. (r) K2CO3 (cat.), MeOH. (s)
TIPSOTf. (t) Ph3PdCH2. (u) HOAc/THF/H2O. (v) I2, PPh3, imidazole.
(w) TBAF/HOAc. (x) VO(acac)2, TBHP. (y) TESOTf, Et3N.
was achieved using the SbF6 counterion (95 vs 86% ee).10
Rubottom oxidation of the silyl enol ether afforded the desired
R-hydroxy ketone 14. The ketone functionality was then reduced
via the tosylhydrazone by a three-step sequence.11 The terminal
acetylene 15 obtained upon desilylation underwent rapid and
quantitative isomerization to the thermodynamically more stable
internal alkyne 16 in the presence of KOt-Bu in DMSO.12,13
Treatment of 16 with Schwartz’s reagent under equilibrating
conditions followed by quenching of the vinylzirconium inter-
mediate with I2 gave the desired vinyl iodide 17.14 Installation of
the azide by SN2 displacement proved difficult, as might be
anticipated given the steric and conformational properties of this
ring system. After careful optimization, it was found that
conversion of the alcohol to the monochloromethanesulfonate
leaving group15 followed by displacement with LiN3 in DMPU
gave an acceptable yield of 4, thereby completing the synthesis
of the central fragment.16
The synthesis of the right-hand fragment began with the
cycloaddition of commercially available 10 with the novel dienyne
9,17 catalyzed by 11b in 98% ee.18 Rubottom oxidation of 8 gave
a mixture of epimeric R-hydroxy ketones which could be
equilibrated to the desired stereoisomer 18 in good yield using
catalytic K2CO3 in MeOH.19 Elaboration to the primary iodide
19 was then effected in excellent yield by a straightforward four-
The synthesis of the antitumor antibiotic FR901464 highlights
the successful application of asymmetric catalytic reactions to
access building blocks of varying complexity, along with the use
of powerful established coupling strategies for the convergent
assembly of the target structure. This strategy is readily adapted
to the preparation of analogues, and the synthesis of such
compounds and their evaluation along with FR901464 in biologi-
cal systems are now underway.
Acknowledgment. We are grateful to Prof. Stuart L. Schreiber for
stimulating discussions. This work was supported by the NIH (GM-59316)
and by a postdoctoral fellowship to T.F.J. from the Cancer Research Fund
of the Damon Runyon-Walter Winchell Foundation (DRG-1431). We
thank Dr. H. Nakajima (Fujisawa) for providing spectra of 1, and D.
Lehsten for experimental contributions.
(10) The protiodesilylated analogue of aldehyde 7 underwent cycloaddition
with similar ee’s, but its reactivity was greatly diminished. The absolute
stereochemistry of HDA adducts was assigned by analogy to assignments made
in ref 6.
(11) Nair, V.; Sinhababu, A. J. Org. Chem. 1978, 43, 5013-5017.
(12) Takano, S.; Shimazaki, Y.; Iwabuchi, Y.; Ogasawara, K. Tetrahedron
Lett. 1990, 31, 3619-3622.
(13) Although 3-pentyn-1-al would have provided a cycloaddition adduct
with proper placement of the alkyne functionality, this aldehyde was found
to be quite unstable and was not compatible with the conditions for HDA
reactions.
(14) (a) Hu, T.; Panek, J. S. J. Org. Chem. 1997, 62, 4912-4913. (b)
Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121, 456-457.
None of the undesired vinyl iodide regioisomer was obtained.
(15) Shimizu, T.; Ohzeki, T.; Hiramoto, K.; Hori, N.; Nakata, T. Synthesis
1999, 1373-1385.
(16) Approximately 35% of the corresponding elimination product was also
obtained. Standard displacement conditions such as NaN3 in DMF or DMSO
gave much lower yields of the desired product.
(17) Diene 9 is available from trimethylsilyl propynal in three steps with
an overall yield of 50%. See Supporting Information.
Supporting Information Available: Experimental section and NMR
spectra of synthetic and natural FR901464 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0055357
(19) On preparative scale (5-10 mmol), the best results were obtained by
subjecting the HDA reaction mixture to quick filtration through a pad of silica
gel to remove sieves and catalyst. The crude HDA adduct was then subjected
to Rubottom oxidation and equilibration with K2CO3. Using this procedure,
a 30% yield for the three-step sequence could be obtained reproducibly.
(20) Epoxides are generally considered to be incompatible with Schwartz’s
reagent: Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853-12909.
(21) Knapp, S.; Jaramillo, C.; Freeman, B. J. Org. Chem. 1994, 59, 4800-
4804.
(22) We are currently undertaking the synthesis of diastereomers of 1
derived from ent-2 and ent-3. While this is required for the unambiguous
confirmation of the relative stereochemistry of FR901464, the fact that all
physical data of 1 match those of the natural product provides compelling
support for the original, tentative stereochemical assignment (ref 4b).
(18) With the chloride catalyst 11a, the HDA adduct 8 was obtained in
>99% ee. However, product yields did not exceed 30-40%.