A new synthetic entry to the tricyclic skeleton of FR901483 by palladium-catalyzed cyclization of vinyl bromides with ketone enolates

Article abstract of DOI:10.1016/j.tetlet.2003.09.111

A new synthetic entry to the FR901483 core is described. The Pd-mediated cyclization of amino-tethered vinyl halides and ketone enolates from the azaspiro[4.5]decan-8-ones 5 and 10 gives the functionalized 7,10a-methanoperhydropyrrolo[1,2-a]azocines 1 and 11, respectively.

Full text of DOI:10.1016/j.tetlet.2003.09.111

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8387–8390
A new synthetic entry to the tricyclic skeleton of FR901483 by
palladium-catalyzed cyclization of vinyl bromides with
ketone enolates
Josep Bonjoch,* Fa¨ıza Diaba, Gemma Puigbo´, Emma Peidro´ and Daniel Sole´*
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Received 15 July 2003; revised 8 September 2003; accepted 15 September 2003
Abstract—A new synthetic entry to the FR901483 core is described. The Pd-mediated cyclization of amino-tethered vinyl halides
and ketone enolates from the azaspiro[4.5]decan-8-ones 5 and 10 gives the functionalized 7,10a-methanoperhydropyrrolo[1,2-a]-
azocines 1 and 11, respectively.
© 2003 Elsevier Ltd. All rights reserved.
FR901483, a natural potent immunosuppressant, con-
tains a 2-azabicyclo[3.3.1]nonane framework and a
pyrrolidine ring, which form an azaspirotricyclic skele-
ton (Fig. 1).1 The four total syntheses reported so far
for this natural product use an aldol process,2–5 in
which the C(7)ꢀC(8) bond is formed, for the ring
closure of the azatricyclic core. In this work, we report
a new synthetic entry to the tricyclic skeleton of
FR901483,6–9 involving the formation of the C(7)–C(8)
bond through a Pd-mediated intramolecular coupling
of an amino-tethered vinyl halide and ketone enolate.10–12
posed methodology we required a cyclization precursor
embodying a 1-azaspiro[4.5]decan-8-one framework.
Initially, to assemble this azabicyclic system we decided
to use a protocol inspired by the classical procedure for
preparing spirolactams from nitrocyclohexanes, based
on the a-alkylation of a nitrocycloalkane followed by
the reduction and subsequent lactamization of the nitro
ester obtained (Scheme 1).13,14
The unknown 4-nitrocyclohexanone was achieved by a
Diels–Alder reaction between nitroethylene and 2-
(trimethylsilyloxy)-1,3-butadiene. Treatment of the
resulting Diels–Alder adduct with ethylene glycol in
benzene at reflux in the presence of a catalytic amount
of TsOH furnished the nitro acetal 2,15 which on reac-
tion with tetramethylguanidine (TMG) and methyl
acrylate16 gave the nitro ester 3. This compound was
quite resistant to the reduction process, but Pd/C and
ammonium formate17 provided the corresponding lac-
tam, which after treatment with NaBH4 in acetic acid18
led to spiro compound 4. Alkylation with 2,3-dibromo-
propene followed by hydrolysis of the acetal provided
the amino tethered vinyl halide 5, which was submitted
to the Pd-promoted cyclization in the presence of KOt-
Bu. NMR analysis of spiro compound 5 showed that in
its preferred conformation the bond between the spiro
carbon and the nitrogen atom is equatorial,19 hence a
conformational change is necessary for the success of
this intramolecular vinylation,20 in which a nucleophilic
substitution takes place upon the vinylpalladium inter-
mediate. This ring-forming reaction, involving the treat-
ment of a THF solution of 5 with 0.2 equiv. of
Pd(PPh3)4 and 1.5 equiv. of KOt-Bu at reflux tempera-
Initial investigations to evaluate the feasibility of this
strategy centered around the synthesis of 1. To access
the tricyclic skeleton of FR901483 through the pro-
Figure 1.
Keywords: alkenylation; FR901483; nitrogen heterocycles; palladium;
spiro compounds.
* Corresponding author. Tel.: 34-934024540; fax: 34-934024539;
e-mail: josep.bonjoch@ub.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.111

8388
J. Bonjoch et al. / Tetrahedron Letters 44 (2003) 8387–8390
Scheme 1.
iodide 7, which was converted into the corresponding
methylamino derivative 8 either by treatment with a
solution of methylamine in EtOH for one week fol-
lowed by methoxycarbonylation, or by reaction with
sodium azide followed by reduction of the azide inter-
mediate with triphenylphosphine to give the corre-
sponding primary amine (not shown), which
sequentially reacted with methyl chloroformate and
methyl iodide in the presence of sodium hydride. Both
sequences to the 3-methylamino protected azabicyclic
compound 8 gave similar overall yields. Debenzylation
of the latter compound under a slight pressure of
hydrogen rendered the amine 9 which, after deprotec-
tion of the acetal, was alkylated with 2,3-dibromo-
propene to give the vinyl halide 10 required for the key
cyclization step. Treatment of 10 with 0.2 equiv. of
Pd(PPh3)4 and 1.5 equiv. of KO-tBu in refluxing THF
gave 11 in 48% yield as a nearly equimolecular mixture
of stereoisomers. It became clear from this result that
the substituent at C(3) does not influence the regiocon-
ture for 30 min, led to the azatricyclic compound 1 in
54% yield and constitutes a novel approach to the
heterocyclic system found in FR901483.
This promising result prompted us to begin the synthe-
sis of compound 11, which embodies the amino group
at C(3) present in FR901483 and thus could be consid-
ered as an advanced intermediate for the synthesis of
this fungal metabolite.
The synthesis of compound 11 was carried out as
depicted in Scheme 2.21 The required azaspirocyclic
system present in compound 10 was prepared following
our procedure developed in the synthesis of a seco
derivative of FR901483,1a in which the NꢀC(2) bond is
formed by iodoaminocyclization of a homoallylamine.
Thus, reaction of the monoethylene acetal of 1,4-cyclo-
hexanedione and benzylamine followed by the addition
of allylmagnesium bromide upon the initially formed
imine gave 6. Treatment of 6 with iodine provided the
Scheme 2. Synthesis of the azatricyclic core of FR901483.

J. Bonjoch et al. / Tetrahedron Letters 44 (2003) 8387–8390
8389
9. Suzuki, H.; Yamazaki, C.; Kibayashi, C. Tetrahedron
Lett. 2001, 42, 3013–3015.
10. For this methodology in the synthesis of nitrogen hetero-
cycles, see: (a) Sole´, D.; Peidro´, E.; Bonjoch, J. Org. Lett.
2000, 2, 2225–2228; (b) Sole´, D.; Diaba, F.; Bonjoch, J. J.
Org. Chem. 2003, 68, 5746–5749.
11. For a seminal work in the carbocyclic series, see: (a)
Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454–
3455; (b) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58,
11–13.
12. For other examples of this Pd-catalyzed coupling process
in the indole alkaloid field, see: (a) Wang, T.; Cook, J.
Org. Lett. 2000, 2, 2057–2059; (b) Yu, J.; Wearing, X. Z.;
Cook, J. M. Tetrahedron Lett. 2003, 44, 543–547.
13. (a) Moffett, R. B. J. Am. Chem. Soc. 1957, 79, 3186–
3190; (b) Hill, R. K. J. Org. Chem. 1957, 22, 830–832.
14. For the use of this methodology, see: (a) Hill, R. K.;
Sawada, S.; Bock, M. G.; Greene, J. R. Heterocycles
1987, 25, 515–520; (b) Bryce, M. R.; Gardiner, J. M.;
Hursthouse, M. B.; Short, R. L. Tetrahedron Lett. 1987,
28, 577–580; (c) Bryce, M. R.; Gardiner, J. M. Tetra-
hedron 1987, 44, 599–612; (d) Gardiner, J. M.; Bryce, M.
R.; Bates, P. A.; Hursthouse, M. B. J. Org. Chem. 1990,
55, 1261–1266; (e) Hayashi, T.; Senda, T.; Ogasawara, J.
Am. Chem. Soc. 2000, 122, 10716–10717.
Figure 2. NMR (1H and 13C) data of compound 11b.
trol in the formation of the enolate that reacts with the
intermediate vinylpalladium species. The two stereoiso-
mers formed were separated and the relative stereo-
chemistry of compound 11b, elucidated by 2D NMR
spectra (COSY, HSQC, HMBC, NOESY), corre-
sponded to that of FR901483 (Fig. 2).22
In summary, we report a new method for the synthesis
of functionalized 7,10a-methanoperhydropyrrolo[1,2-a]-
azocines embodying the tricyclic core of FR901483,
consisting of Pd-promoted cyclization of vinyl bromides
with ketone enolates. Work is underway to achieve a
regiocontrolled process, install the side-chains and
obtain the oxidation level of the natural product.
15. All yields reported herein refer to isolated, pure materials,
1
which had H and 13C NMR, and elemental combustion
analysis or high-resolution MS characteristics in accor-
dance with the proposed structures. 13C NMR data (75
MHz, DEPT) for selected compounds of Scheme 1: (1).
22.5 (t), 35.2 (t), 35.5 (t), 37.2 (t), 38.6 (t), 52.5 (d), 54.7
(t), 55.4 (t), 57.8 (s), 112.6 (t), 142.0 (s), 210.8 (s). (2) 27.8
(t), 32.0 (t), 64.3 (t), 64.4 (t), 82.2 (d), 106.7 (s). (3) 28.2
(t), 30.8 (t), 31.2 (t), 34.7 (t), 51.6 (q), 64.1 (t), 64.2 (t),
89.3 (s), 106.9 (s), 172.0 (s). (4) 25.4 (t), 32.3 (t), 35.3 (t),
35.4 (t), 45.6 (t), 60.6 (s), 64.2 (t), 64.3 (t), 108.7 (s). (5)
21.1 (t), 31.8 (t), 34.2 (t), 38.9 (t), 50.7 (t), 56.7 (t), 61.8
(s), 116.6 (t), 133.1 (s), 211.1 (s).
Acknowledgements
This research was supported by the MCYT (Spain)
through Grant BQU2001-3551. Thanks are also due to
the DURSI (Catalonia) for Grant 2001SGR-00083.
G.P. was a recipient of a fellowship (MCYT, Spain).
16. Ono, N.; Kamimura, A.; Miyake, H.; Hamamoto, I.;
Kaji, A. J. Org. Chem. 1985, 50, 3692–3698.
17. Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J.
Org. Chem. 1996, 61, 9090–9096.
18. Umino, N.; Iwakuma, T.; Hoh, N. Tetrahedron Lett.
1976, 17, 763–766.
References
19. The NMR data of 5 showed the same pattern of chemical
shifts as other related 1-azaspiro[4.5]decan-8-one deriva-
tives in which the preferred conformation had been estab-
lished by 2D NMR experiments (noted in Ref. 1a). See
also: Fujimoto, R. A.; Boxer, J.; Jackson, R. H.; Simke,
J. P.; Neale, R. F.; Snowhill, E. W.; Barbaz, B. J.;
Williams, M.; Sills, M. A. J. Med. Chem. 1989, 32,
1259–1265.
1. For our previous studies in this field, see: (a) 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, 2891–2897; (b) Puigbo´, G.; Diaba, F.;
Bonjoch, J. Tetrahedron 2003, 59, 2657–2665.
2. Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121,
7778–7786.
3. Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem.,
Int. Ed. 2000, 39, 4593–4596.
20. For intermolecular vinylation of ketone enolates, see:
,
Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.;
4. Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.;
Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534–7538.
5. Maeng, J.-H.; Funk, R. L. Org. Lett. 2001, 3, 1125–1128
(racemic synthesis).
6. Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem.
1997, 62, 8280–8281.
7. Brummond, K. M.; Lu, J. Org. Lett. 2001, 3, 1347–1350.
8. Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353–
2356.
Buchwald, S. L. Org. Lett. 2001, 3, 1897–1900.
21. 13C NMR data (75 MHz, assignment aided by HSQC)
for selected compounds of Scheme 2: (6) 30.2 (t), 32.7 (t),
42.0 (t), 45.7 (t), 53.1 (s), 64.1 (t), 64.2 (t), 109.1 (s), 117.9
(t), 126.7 (d), 128.2 (2 d), 134.1 (d), 141.3 (s). (7, HSQC)
16.8 (C-3), 29.7 (C-10), 30.8 (C-6), 32.2 (C-9), 32.6 (C-7),
47.7 (C-4), 51.1 (CH2Ar), 61.5 (C-2), 63.1 (C-5), 64.2 and
64.3 (OCH2), 108.2 (C-8), 126.7 (p-Ar), 128.1 (o-, m-Ar),
140.0 (ipso-Ar). (8, HSQC) 25.0 (C-10), 28.4 (NMe), 30.9

8390
J. Bonjoch et al. / Tetrahedron Letters 44 (2003) 8387–8390
(C-6), 32.3 (C-7), 32.9 (C-9), 38.2 (C-4), 51.9 (C-3),
132.5 (Cꢁ), 156.9 (CO2Me), 210.2 (C-8). (11a) 28.6 (q),
33.4 (t), 35.3 (t), 36.7 (t), 40.8 (t), 51.9 (t), 52.0 (d),
52.5 (q), 54.0 (t), 57.0 (s), 112.8 (t), 140.8 (s), 156.7 (s),
209.7 (s). (11b), see Fig. 2; the 1H NMR data were
recorded at 600 MHz.
52.0 (CH2Ar), 52.4 (OMe), 53.6 (C-2), 62.5 (C-5), 64.1
and 64.2 (OCH2), 108.4 (C-8), 126.5 (p-Ar), 128-0 (o-,
m-Ar), 140.4 (ipso-Ar), 156.8 (CO2Me). (9) 28.9 (t),
29.7 (t), 30.0 (q), 37.4 (t), 38.0 (t), 39.1 (t), 47.4 (t),
52.3 (q), 52.3 (d), 59.8 (s), 156.4 (s), 210.6 (s). (10,
HSQC) 27.4 (C-10), 28.6 (NMe), 35.1 (C-6), 38.2 and
38.4 (C-7 and C-9), 39.2 (C-4), 51.7 (C-3), 52.6 (OMe),
53.5 (C-2), 56.2 (NCH2), 62.1 (C-5), 117.5 (ꢁCH2),
22. The most noteworthy NOESY correlations to deduce
the relative configurations at C-1 and C-3 in compound
11b were those observed between H-2 (l 1.68) and N-
Me and H-11ax.