Tandem cationic aza-cope rearrangement-Mannich cyclization approach to the core structure of FR901483 via a Bridgehead iminium ion.

Article abstract of DOI:10.1021/ol010029n

[reaction in text] An approach to the potent immunosuppressant FR901483 is described. This route utilizes a tandem cationic aza-Cope rearrangement-Mannich cyclization to generate the core structure of this compound. In addition, this is the first demonstr

Full text of DOI:10.1021/ol010029n

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1347-1349
Tandem Cationic aza-Cope
Rearrangement−Mannich Cyclization
Approach to the Core Structure of
FR901483 via a Bridgehead Iminium Ion
Kay M. Brummond* and Jianliang Lu
Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506-6045
kbrummon@wVu.edu
Received February 19, 2001
ABSTRACT
An approach to the potent immunosuppressant FR901483 is described. This route utilizes a tandem cationic aza-Cope rearrangement−Mannich
cyclization to generate the core structure of this compound. In addition, this is the first demonstration of this tandem reaction passing
through a bridgehead iminium ion.
Researchers at Fujisawa Pharmaceutical Co. Ltd. recently
reported the isolation of FR901483 (1), an immunosuppres-
sant possessing a novel tricyclic structure and a phosphate
residue (Scheme 1).1 This compound is likely to function
associated side effects of either of these drugs. It is thought
that the role of FR901483 in suppressing the immune system
results from an antimetabolite activity whereby adenylosuc-
cinate synthetase and/or adenylosuccinase lyase are inhibited.
These enzymes function as key catalysts in the de novo
purine nucleotide biosynthetic pathway.
FR901483 is also an exciting target in that it possesses a
unique substructure that has not been heretofore observed
in nature. This unprecedented structure has already resulted
in a flurry of interest from the synthetic community.2
Consequently, the biological activity, novel structure, and
the potential for rapid access to FR901483 was the impetus
Scheme 1
(2) For the total synthesis of (-)-FR901483, see: (a) Ousmer, M.; Braun,
N. A.; Ciufolini, M. A. Org. Lett. 2001, 3, 765. (b) Scheffler, G.; Seike,
H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593. (c) Snider, B.
B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778. For the total synthesis of
(()-FR901483, see: (d) Funk, R. L.; Maeng, J.-H. 220th ACS National
Meeting, Washington, DC, Abstract 264; for other approaches to FR901483,
see: (e) Snider, B. B.; Lin, H.; Foxman, B. M. J. Org. Chem. 1998, 63,
6442. (f) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem. 1997, 62,
8280. (g) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667. (h) Quirante, J.; Escolano, C.; Massot,
M.; Bonjoch, J. Tetrahedron 1997, 53, 1391.
by a mechanism that is different from that of cyclosporin A
or tacrolimus (FK 506), an important feature given the drug-
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37.
10.1021/ol010029n CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

for our group initiating a synthetic approach to this com-
pound. Our first retrosynthetic disassembly of the target leads
to the functionalized 3-formyl pyrrolidine 2. Formyl pyrro-
lidines have been accessed in a very efficient manner by
Overman using a tandem cationic aza-Cope rearrangement-
Mannich cyclization strategy.3 Thus, on the basis of elegant
precedents provided by Overman, the formyl pyrrolidine
moiety of 2 can in principle be obtained from the amino
ketone 3 via the tandem reaction, through a bridgehead
iminium ion. This retrosynthetic analysis represents a facile
entry to the synthesis of FR901483 with the potential to set
all the stereochemistry of this target by starting with an amino
aldehyde derived from L-tyrosine.
Scheme 3a
In an effort to quickly establish the feasibility of this route,
we targeted a precursor 4 possessing only the functionality
necessary for the tandem rearrangement-cyclization process
(Scheme 2). The functionally barren precursor, amino
a (a) TMSCHLiCN, THF, 82%; (b) butanediol, PPTS, benzene,
reflux, 92%; (c) LiAlH4, THF, 80%; (d) 1M HCl, acetone, H2O,
95%.
Scheme 2
ketone was then effected (PPTS, butanediol)6 to afford
compound 8 in 92% yield. Reduction of the nitrile using
LAH gives the primary amine 9 (80%).
Initial attempts to effect the monoalkylation of the primary
amine 9 (in excess) with 4-bromo-3-methoxy-1-butene3c gave
poor yields of the desired product 11b. Moreover, a recently
published method for the monoalkylation of primary amines
with alkyl bromides utilizing CsOH‚H2O did not prove to
be successful either.7 Other attempts to improve the amine
alkylation using a reductive amination8 reaction involving
2-(tert-butyldimethylsilyloxy)-but-3-enal9 did afford a 76%
yield of 11a. However, this compound proved unsuitable for
the subsequent tandem aza-Cope/Mannich reaction. Fortu-
nately, Petasis has developed a three-component coupling
method involving amines, aldehydes and organoboronates.10
On the basis of this precedent, amine 9 was treated with
paraformaldehyde and excess allylboronate 1011 in EtOH and
H2O to give amine 11b in 58% isolated yield. Removal of
the ketal of 11b with 1M HCl in acetone furnished the
tandem cyclization precursor, amino ketone 7 in 95% yield.
We were delighted to find that treatment of compound 7
to p-toluenesulfonic acid (PTSA) in refluxing benzene
afforded the amino aldehyde 4 (dr, 2/1) via the tandem
cationic aza-Cope rearrangement-Mannich cyclization se-
quence (Scheme 4). The diastereomeric ratio was determined
by 1H NMR intregration of the corresponding formyl peaks.
The resulting amino aldehyde was then protected as ketal
aldehyde 4, possesses the core structure of 1 with an aldehyde
handle that provides access to the amino methyl group via a
Curtius rearrangement. Amino aldehyde 4 is the product of
a Mannich cyclization of iminium ion 5, which in turn can
be obtained via an aza-Cope rearrangement of the iminium
ion 6. This bridged bicyclic substructure is particularly
interesting, in that it is in violation of Bredt’s rule as applied
to bridging carbocycles. Bridgehead imines have been
prepared, and in fact, Kibayashi has shown that bridgehead
imines can be alkylated.2e,4 Finally, bridgehead iminium ion
6 arises from the intramolecular condensation reaction of
the secondary amine and ketone moieties of 7.
The synthesis of the key cyclization precursor 7 was
initiated (Scheme 3) by addition of the lithium anion of
trimethylsilylacetonitrile to cyclohexenone to give the pro-
todesilylated 1,4-addition product directly after column
chromatography in good yield (82%).5 Protection of the
(3) For reviews, see: (a) Overman, L. E.; Ricca, D. J. Comp. Org. Synth.
1991, 2, 1007. (b) Overman, L. E. Acc. Chem. Res. 1992, 25, 352. (c)
Overman, L. E.; Kakimoto, M.-a.; Okazaki, M. E.; Meier, G. P. J. Am.
Chem. Soc. 1983, 105, 6622.
(4) Yamazaki, N.; Ito, T.; Kibayashi, C. Synlett 1999, 37. For references
concerning bridgehead imines, see: Braje, W. M.; Wartchow, R.; Hoffman,
M. R. Angew. Chem., Int. Ed. 1999, 38, 2540. Wayne, G. S.; Snyder, G. J.
J. Am. Chem. Soc. 1993, 115, 9860. Radziszewski, J. G.; Downing, J. W.;
Wentrup, C.; Kaszynski, P.; Jawdosiuk, M.; Kovacic, P.; Michl, J. J. Am.
Chem. Soc. 1985, 107, 2799. Sheridan, R. S.; Ganzer, G. A. J. Am. Chem.
Soc. 1983, 105, 6158. Toda, M.; Hirata, Y. Yamamura, S. J. Chem. Soc.,
Chem. Commun. 1970, 1597.
(6) The choice of butanediol as the reagent for protection is based on
the facile removal of the resulting dioxepane ketal. Snider, B. B.; Lin, H.
Org. Lett. 2000, 2, 643 and references therein.
(7) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K.-W. Org.
Lett. 1999, 1, 1893.
(8) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. J. Org.
Chem. 1990, 55, 2552
(9) Hayashi, M.; Yoshiga, T.; Nakatani, K.; Ono, K.; Oguni, N.
Tetrahedron 1994, 50, 2821.
(5) Tomioka, K.; Koga, K. Tetrahedron Lett. 1984, 25, 1599.
(10) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
1348
Org. Lett., Vol. 3, No. 9, 2001

In conclusion, we have demonstrated an unprecedented
tandem cationic aza-Cope rearrangement-Mannich cycliza-
tion passing through an anti-Bredt iminium ion intermediate.
This sequence of transformations gives rise to a marked
increase in molecular complexity as evidenced by the
conversion of the monosubstituted cyclohexanone 7 to the
azatricycle 4. In addition, this natural product contains a
particularly well suited structure to serve as a scaffold for a
diversity-based synthesis. Efforts are currently being made
to synthesize FR901483 via the appropriately functionalized
precursor 3 and to prepare a library of analogues.
Scheme 4a
a (a) PTSA, benzene, reflux; (b) (CH2OH)2, PTSA, benzene.
Acknowledgment. We are grateful to the NIH (GM54161)
for generous financial support.
12 for the purpose of isolation and characterization. The yield
for this two-step process (7 f 12) is 72%.
The structural assignments of the azatricycles 4 and 12 is
worth further discussion. Because of the instability of the
aminoaldehyde 4, isolation and characterization was difficult.
In our hands, ketal 12 is the only derivative in which
diastereomers can be separated by HPLC.12 After separation
of the diastereomeric ketals, the structural assignment was
made on the basis of APT and DEPT experiments. The
presence of one quaternary and three tertiary carbons in both
diastereomers clearly matches the structure of 12, the core
structure of FR901483 (1).
Supporting Information Available: Characterization
data and full experimental procedures are provided for
compounds 7, 8, 9, 11b, 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL010029N
(12) We have also shown that treatment of aldehyde 4 with Ag2O affords
the carboxylic acid in a 76% overall yield for the tandem rearrangement
and oxidation steps. We have performed the Curtius rearrangement on this
carboxylic acid using diphenylphosphoryl azide (DPPA), NEt3, and t-BuOH
to afford the desired Boc protected amine in 21% yield. While the yield is
low, this reaction sequence provides support for the successful application
of this approach to FR901483 and will be optimized.
(11) (a) Yamamoto, Y.; Fujikawa, R.; Yamada, A.; Miyaura, N. Chem.
Lett. 1999, 1069. (b) Hoffmann, R. W.; Kemper, B.; Metternich, R.;
Lehmeier, T. Liebigs Ann. Chem. 1985, 2246.
Org. Lett., Vol. 3, No. 9, 2001
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