Total synthesis of FR901483

Article abstract of DOI:10.1021/ol015526i

The total synthesis of FR901483, a structurally novel immunosuppressant, has been accomplished by the use of technology recently developed in this laboratory for the oxidative cyclization of phenolic oxazolines to spirolactams. Our approach may reflect th

Full text of DOI:10.1021/ol015526i

ORGANIC
LETTERS
2001
Vol. 3, No. 5
765-767
Total Synthesis of FR901483
Malika Ousmer,† Norbert A. Braun,‡ and Marco A. Ciufolini*
,†,‡
Laboratoire de Synthe`se et Me´thodologie Organiques (LSMO), UniVersite´ Claude
Bernard Lyon 1 and Ecole Supe´rieure de Chimie, Physique, Electronique de Lyon,
43, Bd. du 11 NoVembre 1918, 69622 Villeurbanne Cedex, France, and Department of
Chemistry, Rice UniVersity, 6100 Main Street, Houston, Texas 77005
ciufi@cpe.fr
Received January 8, 2001
ABSTRACT
The total synthesis of FR901483, a structurally novel immunosuppressant, has been accomplished by the use of technology recently developed
in this laboratory for the oxidative cyclization of phenolic oxazolines to spirolactams. Our approach may reflect the biosynthetic pathway
leading to the natural product.
FR901483, 1, is an immunosuppressant produced by a
Cladobotryum species. The compound was described in 1996
by a research team at the Fujisawa Pharmaceutical Com-
pany.1 Its highly novel structure is reminiscent of a family
of muscarinic antagonists reported by Takeda Industries and
known as TAN1251A-D.2 The unique architecture of these
natural products has elicited substantial synthetic activity.3
In particular, important work by Snider has recently led the
first synthesis of 1 and to the elucidation of its absolute
configuration.3c Our own involvement in this area began with
the perception of 1 as being formally derived from two
molecules of tyrosine. This surmise may well reflect the
biogenetic origin of the molecule. Regardless, an especially
concise synthesis might result if a suitably blocked N-
tyrosinyl tyrosine dipeptide might be induced to undergo the
bond-forming processes depicted in Figure 1. One of these
† Universite´ Claude Bernard Lyon 1 and Ecole Supe´rieure de Chimie.
‡ Rice University.
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37.
(2) Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. Int. Patent PCT,
1991, WO91/13887.
(3) FR901483. (a) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem.
1997, 62, 8280 (synthetic studies). (b) Bonjoch, J.; Diaba, F.; Puigbo´, G.;
Sole´, D.; Segarra, V.; Santamar´ıa, L.; Beleta, J.; Ryder, H.; Palacios, J.-M.
Bioorg. Med. Chem. 1999, 7, 2891 (analogues). (c) Snider, B. B.; Lin, H.
J. Am. Chem. Soc. 1999, 121, 7778. (d) Scheffler, G.; Seike, H.; Sorensen,
E. J. Angew. Chem., Int. Ed. 2000, 39, 4593. (e) Funk, R. L.; Maeng, J.-H.
Abstracts of Papers, 220th National Meeting of the American Chemical
Society, Washington, DC, August 20-24, 2000; American Chemical
Society: Washington, DC, 2000; Abstract ORGN 264 (total synthesis).
TAN1251A-D: (f) Nagumo, S.; Nishida, A.; Yamazaki, C.; Murashige,
K.; Kawahara, N. Tetrahedron Lett. 1998, 39, 4493. (g) Snider, B. B.; Lin,
H. Org. Lett. 2000, 2, 643 (total synthesis).
Figure 1. Structure of FR901483 and restrosynthetic logic for the
construction of its ring system.
10.1021/ol015526i CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

transformations, the oxidative cyclization of a phenolic amide
to a spirolactam, was regarded as being unfeasible until 1998,
when we demonstrated that spirolactam formation may be
achieved by oxidation of appropriate phenolic oxazolines.4
At the end of 2000, Sorensen reported a variant of this
chemistry that involves a free secondary amine, instead of
an oxazoline, as a nucleophile for oxidative azaspirocyliza-
tion and utilized this transformation in a brilliant total
synthesis of 1.3d We now wish to describe the total synthesis
of FR901483 by the use of our oxazoline-based methodology.
(carbamates, etc.) tends to react with the electrophilic
intermediate produced by DIB activation of the phenol. No
such interference is observed with N-sulfonamido units.
Second, the primary alcohol in 5 readily adds in a 1,4 sense
to the dienone, complicating subsequent manipulations.
Acetylation suppresses this inconvenience. Notice that
exposure of 5 to Ac2O/pyridine results in acetylation of both
primary alcohol and tosylamide, but this is inconsequential.
Hydrogenation of the dienone was effected with PtO2 as the
catalyst, to prevent reductive aromatization back to a phenol.4
Deacetylation and selective N-methylation converted 7 to 9.
The primary alcohol in 9 was oxidized to aldehyde 10
(Scheme 2) with TPAP/NMO.8 Compound 10 appeared to
Commercial L-tyrosine was converted to building blocks
25 and 36 (Scheme 1). The union of 2 and 3 to furnish
Scheme 1a
Scheme 2a
a Key: (a) PPh3, CCl4, Et3N, pyridine, MeCN, 73%; (b)
PhI(OAc)2, CF3CH2OH, then solid NaHCO3; (c) Ac2O, pyridine,
4-DMAP, 41% b-c; (d) H2, PtO2, AcOEt, 96%; (e) K2CO3, MeOH,
79%; (f) MeI, K2CO3, Me2CO, 93%. PAN ) p-anisyl.
oxazoline 4 was achieved in a single step, and without
erosion of stereochemical integrity, by the Vorbru¨ggen
method.7 An advantage of this technique is that no protection
of the phenol in 3 is required. Reaction of 4 with iodobenzene
diacetate (DIB) in trifluoroethanol induced spirocyclization
to 5, which was immediately acetylated to furnish 6. The
reasons for (i) the use of an N-tosyl protecting group in 3
and (ii) the acetylation of 5 have been detailed elsewhere.4
Briefly, the oxygen atom of carbonyl-type N-blocking agents
a Key: (a) TPAP, NMO, CH2Cl2, 77%; (b) NaOMe, 9:1 MeOH-
H2O, 44% of 11; other diastereomers also formed; (c) Ac2O,
pyridine, CH2Cl2, 94%; (d) L-Selectride, THF, -78 °C, 94%; (e)
NsCl, Et3N, 4-DMAP, CH2Cl2, 72%; (f) CsOAc, 18-cr-6, PhH, 80
°C, 72%; (g) LAH, THF, -78 °C to reflux, 6 h; (h) Cbz-Cl, Et3N,
CH2Cl2, 74% g-h; (i) iPr2NP(OBn)2, tetrazole, CH2Cl2, then
tBuOOH; (j) 3 N HCl, MeOH, then H2, Pd(C), MeOH, 29% i-j.
PAN ) p-anisyl.
(4) (a) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667. (b) Braun, N. A.; Bray, J. D.; Ciufolini,
M. A. Tetrahedron Lett. 1999, 40, 4985. (c) Braun, N. A.; Ousmer, M.;
Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E.-M.; Ciufolini, M. A. J. Org.
Chem. 2000, 65, 4397.
(5) The preparation of 2 has been described: Abarbri, M.; Guignard,
A.; Lamant, M. HelV. Chim. Acta 1995, 78, 109. Jung, M. E.; Jachiet, D.;
Rohloff, J. R. Tetrahedron Lett. 1989, 30, 4211. Unfortunately, the product
thus obtained is not optically pure. A short route to 2 that safeguards optical
integrity was developed via (i) double methylation of phenolic and carboxy
units of the N-carbomethoxy-L-tyrosine; (ii) LAH reduction of the ester;
and (iii) carbamate cleavage. Details are provided as Supporting Information.
(6) Fischer, E.; Lipschitz, W. Ber. Dtsch. Chem. Ges. 1915, 48, 360.
(7) Vorbru¨ggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353.
be fairly resistant to epimerization at the starred center, as
first described by Snider.3c Indeed, configurational stability
has been observed in several amino acid-derived aldehydes.9
Stereochemical stability facilitated a subsequent aldol-type
cyclization of 10 to 11 by minimizing the probability of
formation of aldol diastereomers epimeric at C-6.
(8) Ley, S. V.; Normand, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
766
Org. Lett., Vol. 3, No. 5, 2001

The product distribution observed in the aldol step proved
to be sensitive to the nature of the solvent employed.3c Thus,
protic solvents favored formation of the aldol diastereomer
displaying the correct C-7-(S) configuration, while conduct
of the reaction in aprotic media, e.g., DBU/CH2Cl2, promoted
formation of the incorrect C-7-(R) diastereomer as the major
product. Optimal conditions for the production of the desired
11 entailed treatment of 10 with NaOMe in 10% aqueous
methanol, but other diastereomers were also obtained.
The secondary alcohol in 11 was acetylated prior to
L-Selectride reduction of the cyclohexanone, which occurred
highly stereoselectively from the Si face, thereby affording
exclusively the equatorial alcohol 13.10 While this result may
seem to be in conflict with principles governing the reactivity
of selectride agents,11 it is apparent that the shape of the
molecule precludes approach from the Re face of the
carbonyl. Inversion of C-9 configuration a` la Snider3c
afforded 15.10 LAH reduction of 15 engendered release of
the acetyl groups, deoxygenation of the amide, and cleavage
of the sulfonamide to afford diol 16. This substance amounts
to the dephosphorylated form of 1. As of yet, compound 16
is not a known natural product, but it is reported to be a
biologically inactive metabolite of 1.1 The secondary amine
was blocked as a Cbz derivative, setting the stage for
phosphorylation of the C-9 alcohol. This transformation was
achieved by phosphitylation-oxidation.12 Significant differ-
ences in steric environment between C-7 and C-9 permitted
selective phosphitylation of the C-9 alcohol in 17 without
protection of the C-7 OH group. The presumed phosphite
intermediate was oxidized in situ to 18, which was treated
with excess 3 N aqueous HCl prior to hydrogenolysis of all
benzyl groups. The emerging, fully synthetic bis-hydrochlo-
ride salt of 1 was identical in all respects (1H, 13C, MS, TLC,
[R]D) to a sample of natural material, prepared from the
monohydrochloride of 1, kindly provided by the Fujisawa
Co., by treatment with excess 3 N aqueous HCl.
The key step in the present synthesis of FR901483, the
transformation of 4 to 5, amounts to an oxidative dearoma-
tization leading to the formation of a C-N bond. Analogous
reactions involving formation of C-O bonds have enjoyed
widespread use in organic chemistry.13 We thus feel that the
“aza” variant of this process holds considerable potential for
the chemical synthesis of many complex nitrogenous sub-
stances. Work in the area continues, and additional results
will be disclosed in due course.
Acknowledgment. We thank the NIH (CA-55268), the
NSF (CHE 95-26183), the R. A. Welch Foundation (C-1007),
the MENRT (Fellowship to M. O.), the CNRS, and the
Re´gion Rhoˆne-Alpes for support of our research. M.A.C. is
a Fellow of the A. P. Sloan Foundation (1994-1998) and
the recipient of a Merck & Co. Academic Development
Award (2000). We also thank Dr. Denis Bouchu and
Laurence Rousset for the mass spectral measurements.
Supporting Information Available: Description of ex-
perimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) (a) Myers, A. G.; Kung, D. W.; Zhong, B. J. Am. Chem. Soc. 2000,
122, 3236. (b) Myers, A. G.; Zhong, B.; Kung, D. W.; Movassaghi, M.;
Lanman, B. A.; Kwon, S. Org. Lett. 2000, 2, 3337. (c) Myers, A. G.; Kung,
D. W. Org. Lett. 2000, 2, 3019. (d) Myers, A. G.; Kung, D. W. J. Am.
Chem. Soc. 1999, 121, 10828. (e) Garner, P. Tetrahedron Lett. 1984, 25,
5855. See also ref 3d.
(10) Structure confirmed by X-ray crystallography. Compound 13:
Ousmer, M.; Braun, N. A.; Ciufolini, M. A.; Perrin, M. Z. Kristallogr. NCS
2000, 215, 597. Compound 15: Ousmer, M.; Braun, N. A.; Ciufolini, M.
A.; Perrin, M.; Bavoux, C. Z. Kristallogr. NCS. Submitted.
(11) Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159.
(12) (a) Yu, K.-L.; Fraser-Reid, B. Tetrahedron Lett. 1998, 29, 979. (b)
Dreef, C. E.; Tuinman, R. J.; Elie, C. J. J.; van der Marel, G. A.; van Boom,
J. H. Recl. TraV. Chim. Pays-Bas 1988, 107, 395.
OL015526I
(13) The opportunities offered by such processes, in their manifold
incarnations, are exemplified by the following: (a) Cox, C.; Danishefsky,
S. J. Org. Lett. 2000, 2, 3493. (b) Wipf, P.; Li, W. J. Org. Chem. 1999, 64,
4576. (c) Kita, Y.; Egi, M.; Okajima, A.; Ohtsubo, M.; Takada, T.; Tohma,
H. J. Chem. Soc., Chem. Commun. 1996, 1491. (d) Wipf, P.; Kim, Y.;
Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (e) Kita, Y.; Tohma,
H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org. Chem. 1991, 56, 435. (f)
Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987, 52,
3927. (g) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256.
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