Stereoselective synthesis of the cytotoxic macrolide FD-891

Article abstract of DOI:10.1021/ol060669w

A total synthesis of the naturally occurring, cytotoxic macrolide FD-891 is described. Three fragments were first stereoselectively constructed using mainly asymmetric aldol and allylation reactions. The complete framework was then assembled using two Jul

Full text of DOI:10.1021/ol060669w

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2695-2698
Stereoselective Synthesis of the
Cytotoxic Macrolide FD-891†
Jorge Garc´ıa-Fortanet,‡ Juan Murga,‡ Miguel Carda,*,‡ and J. Alberto Marco*,§
Departamento de Qu´ımica Inorga´nica y Orga´nica, UniVersitat Jaume I, Castello´n,
E-12080 Castello´n, Spain, and Departamento de Qu´ımica Orga´nica, UniVersidad de
Valencia, E-46100 Burjassot, Valencia, Spain
alberto.marco@uV.es
Received March 17, 2006
ABSTRACT
A total synthesis of the naturally occurring, cytotoxic macrolide FD-891 is described. Three fragments were first stereoselectively constructed
using mainly asymmetric aldol and allylation reactions. The complete framework was then assembled using two Julia
−Kocienski olefinations
to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring.
The cytotoxic macrolide FD-891 (1) was isolated from the
fermentation broth of Streptomyces graminofaciens A-8890
and was found to be active against several tumor cell lines.
In addition, it was found to potently prevent both perforin-
and FasL-dependent CTL-mediated killing pathways. In
contrast to the structurally related concanamycin A, however,
it was unable to inhibit vacuolar acidification.1 According
to the results of chemical degradation, NMR studies, and
X-ray diffraction analyses of some degradation products, an
erroneous structure for FD-891 was initially proposed,2 which
was subsequently corrected by the same authors to that
depicted in Scheme 1.3
previous communications, we have published a stereoselec-
tive synthesis of 2,4 as well as of a fragment structurally
Scheme 1. Retrosynthetic Analysis of FD-891
For our synthesis of this bioactive metabolite, we have
chosen the retrosynthetic plan shown in Scheme 1. According
to it, the molecule of macrolide FD-891 is disconnected to
fragments 2 (C1-C12) and 3 (C13-C26) via a macrolac-
tonization and a Julia-Kocienski olefination. A subsequent
disconnection of 3 through a second olefination converts it
into fragments 4 (C13-C18) and 5 (C19-C26). In two
† Dedicated to the memory of Prof. M. Moreno-Man˜as (deceased
February 20, 2006).
‡ Universitat Jaume I.
§ Universidad de Valencia.
(1) Seki-Asano, M.; Tsuchida, Y.; Hanada, K.; Mizoue, K. J. Antibiot.
1994, 47, 1234-1241.
(2) Eguchi, T.; Kobayashi, K.; Uekusa, H.; Ohashi, Y.; Mizoue, K.;
Matsushima, Y.; Kakinuma, K. Org. Lett. 2002, 4, 3383-3386.
(3) Eguchi, T.; Yamamoto, K.; Mizoue, K.; Kakinuma, K. J. Antibiot.
2004, 57, 156-157.
10.1021/ol060669w CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/20/2006

related to 35 but aimed at the synthesis of the wrong structure
initially published for FD-891.2
Scheme 3. Synthesis of Fragment 5a
Aldehyde 4 was synthesized as depicted in Scheme 2. The
known aldehyde 66 was subjected to asymmetric aldol
reaction using the Z enolborane derived from Oppolzer’s
chiral propionate7 equivalent 7. This provided aldol adduct
8 as a single stereoisomer (dr was g98%, as the minor
1
stereoisomer was not detected by means of high-field H/
13C NMR). Introduction of the MOM8 protecting group and
functional manipulation gave nitrile 12, reduction of which
afforded aldehyde 4 (used directly in crude form in the
reaction with 5).
Scheme 2. Synthesis of Fragment 4a
a Acronyms and abbreviations: TPS, tert-butyldiphenylsilyl; Tf,
trifluoromethanesulfonyl; MOM, methoxymethyl; DIBAL, diisobu-
tylaluminum hydride.
a Acronyms and abbreviations: CDI, 1,1′-carbonyldiimidazole;
TBS, tert-butyldimethylsilyl; 2,6-lut, 2,6-lutidine; DIAD, diisopro-
pyl azodicarboxylate.
Intermediate fragment 5 was prepared as shown in Scheme
3 following the methodology previously described by us.5
Thus, the known aldehyde 139 was subjected to asymmetric
aldol reaction with chiral reagent 7 to yield aldol 14 as a
single stereoisomer. Hydroxyl silylation and reductive cleav-
age (DIBAL) of the chiral auxiliary gave an intermediate
aldehyde which was submitted to asymmetric aldol reaction
with Oppolzer’s reagent ent-7.7 This yielded a single
crystalline aldol 16,10 which was converted into the silyl
derivative 17. The latter was then transformed into methyl
ketone 20 via the intermediate acid 18 and the Weinreb11
amide 19.12 Reduction of 20 under chelation control13 and
O-methylation using methyl triflate and Proton Sponge14
(4) Murga, J.; Garc´ıa-Fortanet, J.; Carda, M.; Marco, J. A. Synlett 2004,
2830-2832.
(5) Murga, J.; Garc´ıa-Fortanet, J.; Carda, M.; Marco, J. A. Tetrahedron
Lett. 2004, 45, 7499-7501.
(6) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.;
Somfai, P.; Whritenour, D. C.; Masamune, S. J. Org. Chem. 1989, 54,
2817-2825.
(10) The absolute configuration of aldol 16 has been secured via X-ray
diffraction analysis (see the Supporting Information).
(7) (a) Oppolzer, W. Tetrahedron 1987, 43, 1969-2004. (b) Oppolzer,
W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112,
2767-2772. (c) Reiser, O. Nachr. Chem. Technol. Lab. 1996, 44, 612-
618.
(11) Sibi, M. P. Org. Prep. Proc. Int. 1993, 25, 15-40.
(12) Silylation of 16 required the use of a considerable excess of silylating
agent. Therefore, purification of 17 proved difficult. For this reason, the
overall yield is given for the three steps 16 f 19.
(8) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; pp 27-33.
(9) Kozikowski, A. P.; Stein, P. D. J. Org. Chem. 1984, 49, 2301-2309.
(13) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840-10852. See also: Ooi, T.; Morikawa, J.;
Uraguchi, D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2993-2996.
2696
Org. Lett., Vol. 8, No. 13, 2006

stereoselectively afforded compound 22. Hydrogenolytic
O-debenzylation to 23, introduction of the tetrazolylthio15
moiety via Mitsunobu reaction using PBu3,16 and Mo(VI)-
catalyzed sulfide-sulfone oxidation17 gave rise to the desired
aryl sulfone 5.
Scheme 5. Final Steps of the Synthesis of 1a
With all key fragments in hand, the synthesis proceeded
as shown in Scheme 4. Connection between 4 and 5 was
Scheme 4. Synthesis of Fragment 3a
a Acronyms and abbreviations: HMDS, hexamethyldisilazide;
HMPA, hexamethylphosphortriamide; DME, 1,2-dimethoxyethane.
performed using the Julia-Kocienski18 olefination protocol,
which yielded olefin 24 in good yield (75%, based on
recovered 5) as a single E stereoisomer. Selective cleavage
of the TPS group19 gave alcohol 25, which was converted
into aryl sulfone 3 via Mitsunobu reaction (PPh3 performed
better here than PBu3) and Mo(VI)-catalyzed oxidation.
The final attack toward macrolide 1 was carried out as
depicted in Scheme 5. Connection of fragments 2 and 3 was
performed as above with the aid of the Julia-Kocienski
olefination protocol and gave 26. The yield was, however,
not as high as in Scheme 4, and the reaction was not
stereoselective. Changes in various reaction conditions did
not lead to improvements.20 Separation of the E and Z
stereoisomers of 26 was not feasible but could be done after
a Acronyms and abbreviations: TASF, tris(dimethylamino)sul-
fonium difluorotrimethylsilicate.
selective cleavage of the MOM group,21 which yielded E-27
and Z-27. Hydrolysis of the ethyl ester group of E-27 was
achieved under mild, anhydrous conditions using TMSiOK.22
Macrolactonization of the resulting hydroxyl acid was
performed at high dilution (0.006M) using the Yamaguchi
procedure23 and yielded lactone E-28. Cleavage of all silyl
groups with TASF24 finally gave macrolide E-1 (FD-891).25,26
(14) Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem.
Soc., Perkin Trans. 1 1999, 955-968.
(15) Voitekhovich, S. V.; Gaponik, P. N.; Koldobskii, G. I. Russ. J. Org.
Chem. 2005, 41, 1565-1582.
(20) Under the standard conditions for the Julia-Kocienski reaction
(KHMDS, THF), we obtained an 80:20 E/Z mixture but in only 23% yield,
even when using a 4-fold excess of aldehyde 2.
(16) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656. (c) Valentine, D. H., Jr.; Hillhouse, J. H.
Synthesis 2003, 317-334.
(21) (a) Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983,
24, 3969-3972. (b) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem.
1984, 49, 3912-3920.
(17) Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1,
941-944.
(22) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831-
(18) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585.
(19) Hatakeyama, S.; Irie, H.; Shintani, T.; Noguchi, Y.; Yamada, H.;
Nishizawa, M. Tetrahedron 1994, 50, 13369-13376.
5834.
(23) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
Org. Lett., Vol. 8, No. 13, 2006
2697

Following the same series of reactions, lactone Z-27 was
transformed into Z-1, a stereoisomer of the natural macrolide.
Its biological properties will also be investigated and
compared with those of the natural product.
In summary, a convergent synthesis of the cytotoxic
macrolide FD-891 has been achieved. We are presently
investigating how to improve the unsatisfactory yield of some
of the final steps.27
projects BQU2002-00468, CTQ2005-06688-C02-01, and
CTQ2005-06688-C02-02), by the Conseller´ıa de Educacio´
(projects Grupos03/180 and GV05-52), and by the BAN-
CAJA-UJI foundation (projects P1-1B2005-30). J.M. thanks
the Spanish Ministry of Science and Technology for a
contract of the Ramo´n y Cajal program. J.G.-F. thanks the
Spanish Ministry of Education and Science for an FPU
predoctoral fellowship. We also thank Prof. T. Eguchi,
Department of Chemistry and Material Science, Tokyo
Institute of Technology, and Dr. K. Mizoue, Taisho Phar-
maceutical Co., Saitama, Japan, for kindly providing an
authentic sample of FD-891.
Acknowledgment. Financial support has been granted by
the Spanish Ministry of Education and Science (DGICYT
(24) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-6437.
(25) The identity of the final desilylation product 1 was confirmed
through comparison with an authentic sample of the natural product (see
the Acknowledgment).
(26) Cleavage of the silyl groups at C-7 and C-10 takes place with ease.
In contrast, those allocated at C-21 and C-23 proved unexpectedly reluctant
to cleavage under various mild conditions (too harsh conditions caused
decomposition). These two groups are thus responsible for the low yield in
the final desilylation step. We are presently investigating how to eliminate
this unfavorable feature.
Supporting Information Available: Experimental pro-
cedures for the preparation and tabulated spectral data of all
new compounds. Graphical NMR spectra of all new com-
pounds. Crystallographic data of aldol 16 (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(27) While this manuscript was being prepared, a stereoselective total
synthesis of macrolide FD-891 (E-1) appeared: Crimmins, M. T.; Caussanel,
F. J. Am. Chem. Soc. 2006, 128, 3128-3129.
OL060669W
2698
Org. Lett., Vol. 8, No. 13, 2006