Synthesis of desmethylamino FR901483

Full text of DOI:10.1021/jo981292d

6442
J . Org. Chem. 1998, 63, 6442-6443
hydroxylamine hydrochloride and TsOH in EtOH6 afforded
50% of the oxime ester, which was reduced with BH3‚NMe3
in acidic ethanol7 to give 69% of hydroxylamine 7.
Condensation of hydroxylamine 7 with ketone 8 in EtOH
gave nitrone 5, which was treated with ethyl acrylate in
toluene at reflux for 4 h to give 74% of a 9:1 mixture of
isoxazolidine 4 and the diastereomer. This mixture was
Syn th esis of Desm eth yla m in o F R901483
Barry B. Snider,* Hong Lin, and Bruce M. Foxman
Department of Chemistry, Brandeis University,
Waltham, Massachusetts 02454-9110
Received J uly 6, 1998
FR901483 (1), a novel immunosuppressant, has been
isolated from the fermentation broth of Cladobotrym sp. No.
11231 by a Fujisawa group.1 The structure has been
determined X-ray crystallographically. FR901483 exerts
potent immunosuppressive activity in vitro and significantly
prolongs graft survival time in the rat skin allograft model,
apparently by inhibition of purine nucleotide biosynthesis.
The azatricyclic structure with a phosphate ester is struc-
turally novel and is probably derived biosynthetically from
a tyrosine dimer by oxidative coupling to close the pyrroli-
dine ring and an aldol reaction to form the tricyclic skeleton.
This analysis suggested that 1 could be prepared by an
aldol reaction of keto aldehyde 2. While this should provide
reduced over 10% Pd/C under 45 psi H2 in AcOH for 24 h to
give 91% of a 9:1 mixture of lactam 3 and the diastereomer.
Recrystallization in a mixture of CH2Cl2, hexane, and EtOAc
gave the pure major diastereomer 3. The stereochemistry
was determined to be that needed for elaboration to FR901483
by X-ray crystallographic structure determination.8
The methylamino group was easily introduced by tosyla-
tion of 3 (TsCl, DMAP, Et3N in CH2Cl2, 12 h) to give 99% of
tosylate 9, which was treated with NaN3 in DMF to give
89% of the azide. Hydrogenation of the azide over Pd/C gave
the amine, which was treated with BOC2O to give carbamate
10 quantitatively. Methylation of 10 with NaH and MeI
gave 86% of N-methylcarbamate 11. Because of concerns
about the possible stereochemical complexity of the aldol
reaction of 2, we decided to investigate this step first on
model 13 lacking the protected N-methylamino substituent.
Reaction of tosylate 9 with NaI in acetone at reflux gave
99% of the iodide, which was reduced with SnBu3H and
AIBN in toluene at reflux to give 97% of lactam 12.
Reduction of the ester with LiBH4 in ether/THF afforded the
primary alcohol, which was treated with HCl, AcOH, and
water to cleave the ketal, affording 79% of the keto alcohol
from 12. Oxidation of the primary alcohol with Dess-
Martin reagent provided 82% of the requisite keto aldehyde
13, which can only give four aldol products, rather than the
eight possible from 2. Keto aldehyde 13 has a single chiral
center, so that enolization of the aldehyde will have no effect
in the racemic series.
efficient access to the ring system, there were stereochemical
concerns since the aldol reaction of 2 could give eight
products. Enolization of the ketone can occur at carbons a
or b, addition to the aldehyde can occur to give either the
equatorial or axial alcohol, and enolization of the aldehyde
will convert 2 to a diastereomer that would give four
additional aldol products. Keto aldehyde 2 should be easily
formed from lactam acetal ester 3, which should be readily
available from isoxazolidine 4, which will be constructed by
1,3-dipolar cycloaddition of nitrone 5 with ethyl acrylate.
Although this route to spirocyclic lactams is well-prece-
dented with simple nitrones,2 there are stereochemical
questions in the cycloaddition with 5,3 which will give two
diastereomers. Despite concerns about stereochemical con-
trol in the aldol and cycloaddition steps, the brevity of this
route makes it an attractive approach to FR901483.4
p-Methoxybenzaldehyde and hydantoin were converted to
(p-methoxyphenyl)pyruvic acid (6).5 Reaction of 6 with
We were delighted to find that the aldol reaction9 occurred
readily with acceptable stereocontrol. Cyclization of 13 with
(4) For other approaches to this ring system, see: (a) Quirante, J .;
Escolano, C.; Massot, M.; Bonjoch, J . Tetrahedron 1997, 53, 1391. (b)
Yamazaki, N.; Suzuki, H.; Kibayashi, C. J . Org. Chem. 1997, 62, 8280.
(5) Billek, G. Organic Syntheses; Wiley: New York, 1973; Collect. Vol.
V, p 627.
(6) Ottenheijm, H. C. J .; Plate, R.; Noordik, J . H.; Herscheid, J . D. M. J .
Org. Chem. 1982, 47, 2147.
(7) Plate, R.; Hermkens, P. H. H.; Smits, J . M. M.; Ottenheijm, H. C. J .
J . Org. Chem. 1986, 51, 309.
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J . Antibiot. 1996, 49, 37.
(2) (a) Funk, R. L.; Daggett, J . U. Heterocycles 1987, 26, 2175. (b) Blum,
C.; Hutchison, A. US Pat. US005286860A; Chem. Abstr. 1994, 120, 245160b.
(3) For a review of asymmetric 1,3-dipolar cycloadditions, see: Gothelf,
K. V.; J ørgensen, K. A. Chem. Rev. 1998, 98, 863.
(8) X-ray crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre.
(9) For the synthesis of azabicyclo[3.3.1]nonanes or bicyclo[3.3.1]nonanes
by aldol reactions, see: (a) Kinney, W. A.; Crouse, G. D.; Paquette, L. A. J .
Org. Chem. 1983, 48, 4986. (b) Patir, S.; Rosenmund, P.; Go¨tz, P. H.
Heterocycles 1996, 43, 15.
S0022-3263(98)01292-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/26/1998

Communications
J . Org. Chem., Vol. 63, No. 19, 1998 6443
reflux10 afforded 69% of the desired acetate 20 and 28% of
the readily separable elimination product 21. The stereo-
chemistry of 20 was unambiguously established by the large
NOEs between the three methine hydrogens, which are all
on the endo face of the azabicyclo[3.3.1]nonane.
2.4 equiv of NaOMe in MeOH for 15-30 min at 25 °C
provided 51% of the needed stereoisomer 15, 23% of 14 with
the required equatorial p-methoxybenzyl group but with the
undesired equatorial hydroxyl group, and 13% of 16 with
an axial p-methoxybenzyl group. On the other hand, aldol
reaction with excess KO-t-Bu in toluene for 25 min at 25 °C
afforded 70% of 14 and 22% of the fourth diastereomer 17.
The stereochemistry of the aldol adducts was assigned by
analysis of the COSY and NOESY spectra.
These results indicate that the aldol reaction occurs
mainly from carbon a, presumably because this leads to more
stable products with an equatorial p-methoxybenzyl group.
The required axial alcohol 15 is the major product (51%) with
NaOMe in MeOH, while the undesired equatorial alcohol
14 is isolated in 70% yield as one of only two stereoisomers
with KO-t-Bu in toluene. Fortunately, both 14 and 15 can
be elaborated to desmethylamino FR901483 (23).
Reaction of 15 with LAH in THF at -78 °C to reflux
reduced the ketone and the amide to give 85% of 18
stereospecifically. Reaction of 14 with p-nitrobenzenesulfo-
nyl chloride, DMAP, and Et3N in CH2Cl2 afforded the
nosylate, which was inverted with CsOAc and 18-crown-6
in toluene at reflux10 for 2 h to give the acetate of 15 in 82%
yield from 14. Reaction of this acetate with LAH reduced
the acetate, ketone, and amide, providing 93% of 18. Not
surprisingly, LAH reduced the ketone of 15 from the less
hindered exo face to give 18 with the undesired endo alcohol.
Inversion of the stereochemistry of the hydroxyl group was
accomplished by reaction of 18 with p-nitrobenzenesulfonyl
chloride, DMAP, and Et3N in CH2Cl2 to selectively nosylate
the less hindered equatorial alcohol in 91% yield. The axial
alcohol was protected as the TBDMS ether with TBDMSOTf
and 2,6-lutidine in CH2Cl2, providing 19 in 94% yield.
Reaction of 19 with CsOAc and 18-crown-6 in toluene at
Elaboration of 20 to desmethylamino FR901483 (23) was
accomplished by hydrolysis of the acetate with K2CO3 to give
the alcohol quantitatively, which was treated with tetrazole
and (BnO)2PN(i-Pr)2 to give the dibenzyl phosphite ester,11
which was oxidized to give 69% of the dibenzyl phosphate
with m-CPBA. Hydrolysis of the TBDMS group with TBAF
in THF (98%), followed by hydrogenolysis of the dibenzyl
phosphate (95%), afforded 23. To our surprise, the 1H NMR
spectrum of 23 in CD3OD indicated that a mixture of two
compounds was present. We speculated that protonation
of the tertiary amine by the phosphoric acid can occur on
either face to give a mixture of diastereomers.12 Treatment
of 23 with K2CO3 gave the dipotassium salt of 23 as a single
compound, whose spectral data correspond to those of 1,
except for the expected differences in the pyrrolidine ring.
In conclusion, we have developed an efficient approach
to FR901483 and shown that the 1,3-dipolar cycloaddition
proceeds with 9:1 selectivity and that the model aldol
reaction of 13 gives either 14 or 15 with reasonable selectiv-
ity, depending on the reaction conditions. Both of these aldol
adducts can be elaborated to desmethylamino FR901483,
which has been prepared in 3.3% overall yield from 6 in 18
steps.
Ack n ow led gm en t . We are grateful to the NIH
(GM50151) for generous financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, X-ray data for 3, and 1H and 13C NMR spectral data for
selected compounds (61 pages).
J O981292D
(11) Yu, K.-L.; Fraser-Reid, B. Tetrahedron Lett. 1988, 29, 979.
(12) The formation of diastereomeric ammonium salts by protonation of
tertiary amines is well-known: (a) Glaser, R.; Peng, Q.-J .; Perlin, A. S. J .
Org. Chem. 1988, 53, 2172. (b) Glaser, R.; Charland, J .-P.; Michel, A. J .
Chem. Soc., Perkin Trans. 2 1989, 1875.
(10) (a) Sato, K.-I.; Yoshitomo, A.; Takai, Y. Bull. Chem. Soc. J pn. 1997,
70, 885. (b) Liotta, C. L.; Berkner, J . In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., Ed.; Wiley: Chichester, 1995; pp 1403.