Efficient approach to the azaspirane core of FR 901483

Article abstract of DOI:10.1021/ol061538y

(Chemical Equation Presented) An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and a suitably protected enantiopure ketimine as the second component. The resulting dihy

Full text of DOI:10.1021/ol061538y

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4763-4766
Efficient Approach to the Azaspirane
Core of FR 901483
Silvia Kaden and Hans-Ulrich Reissig*
Institut fu¨r Chemie und Biochemie, Freie UniVersita¨t Berlin, Takustraâe 3,
D-14195 Berlin, Germany
hans.reissig@chemie.fu-berlin.de
Received June 22, 2006
ABSTRACT
An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and
a suitably protected enantiopure ketimine as the second component. The resulting dihydropyrrole derivative was smoothly converted into a
spiro keto aldehyde which under acidic conditions provided a novel azanorbornane derivative 15. Under basic reaction conditions, the desired
5-azatricyclo[6.3.1.01,5]dodecane skeleton 16 was generated. The ratio of diastereomers strongly depends on the reaction conditions employed
with L-proline in DMSO providing the highest selectivity in favor of one azaspirane product.
The tricyclic natural product FR 901483 was isolated by
scientists of the Fujisawa group from the fermentation broth
of a Cladobotryum species.1 The compound is a strong
immunosuppressant which inhibits purine nucleotide bio-
synthesis by a mechanism different from that of cyclosporin
A or FK-506. The unique ring junction of FR 901483 and
its biological activity have motivated a number of research
groups to prepare this intriguing natural product. Three total
syntheses of the enantiopure compound2 and two of the
racemate3 have been published so far. In addition, several
attempts to approach the tricyclic core structure are reported.4
compound 1 with base provided the required tricyclic product
2 together with two other diastereomers (Scheme 1).2b
Scheme 1. Intramolecular Aldol Step in Sorensen’s Synthesis
Our approach to the FR 901483 skeleton regards tricyclic
compound 3 as the crucial intermediate, which should be
formed by the aldol reaction of keto aldehyde 4 (Scheme
2). Precursor 5 with suitable protective groups should be
available by addition of lithiated alkoxyallene 6 to ketimine
(2) (a) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778-7786.
(b) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem. 2000, 112, 4783-
4785; Angew. Chem., Int. Ed. 2000, 39, 4593-4596. (c) Ousmer, M.; Braun,
N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001,
123, 7534-7538.
(3) (a) Maeng, J.-H.; Funk, R. L. Org. Lett. 2001, 3, 1125-1128. (b)
Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org.
Lett. 2004, 6, 2729-2731.
An intramolecular aldol reaction is the crucial C-C bond
forming step in four of these syntheses. For example, in
Sorensen’s synthesis of FR 901483, treatment of spiro
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37-44.
10.1021/ol061538y CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/21/2006

Scheme 2. Retrosynthetic Analysis of the FR 901483 Core
Scheme 3. Synthesis of Dihydropyrrole 13
7 which is generated by condensation of a L-tyrosine-derived
amine and a cyclohexanone derivative. Lithiated alkoxyal-
lenes 6 have already been successfully employed as func-
tionalized C3 building blocks in stereocontrolled syntheses
of natural products containing functionalized pyrrolidine
rings5 as well as for the preparation of other heterocycles.6
Amino alcohol 8 was smoothly prepared from L-tyrosine
by four routine steps2d and protected as silyl ether to furnish
primary amine 9 in excellent overall yield (Scheme 3).
Ketone 10 containing a thioketal moiety7 was also accessible
according to a known method.8 Under appropriate conditions,
amine 9 and ketone 10 gave ketimine 11 (ca. 85% conver-
sion). Because of its instability toward chromatography,
crude 11 was directly combined with lithiated methoxyallene
(generated in situ from methoxyallene with n-butyllithium),
which provided allenylamine 12 in high efficiacy. Attempts
to purify 12 failed, and therefore, the crude allenylamine was
immediately cyclized in the presence of silver nitrate9 and
K2CO3 in MeCN to afford the desired dihydropyrrole
derivative 13 in 79% overall yield (starting from 9). Our
approach to functionalized spiropyrrolidine derivatives such
as 13 via lithiated alkoxyallenes is therefore very efficient,
and it is potentially very flexible concerning the ketimine
component.10
The thioketal moiety proved to be sufficiently stable during
the formation of spiro compound 13, and after trying a
number of methods, we were able to selectively cleave this
ketal with bis(trifluoroacetate) iodobenzene under optimized
conditions according to a procedure by Stork et al. (Scheme
4).11 Deprotection with TBAF provided a keto alcohol in
good yield which upon oxidation with SO3-pyridine and
triethylamine in DMSO12 furnished the required keto alde-
hyde 14. Alternative methods such as Swern oxidation, DMP,
TEMPO, or TPAP/NMO only resulted in decomposition of
the starting material. With the sequences depicted in Schemes
3 and 4, the crucial aldol precursor 14 was obtained in six
steps and 38% overall yield starting from amine 9 (starting
from L-tyrosine: 10 steps and 24% overall yield).
(4) (a) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353-2356. (b)
Suzuki, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2001, 42, 3013-
3015. (c) Bonjoch, J.; Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron
Lett. 2003, 46, 8387-8390. (d) Brummond, K. M.; Hong, S.-p. J. Org.
Chem. 2005, 70, 907-916. (e) Kropf, J. E.; Meigh, I. C.; Bebbington, W.
P.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2046-2055. (f) Simila, S. T.
M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933-2936.
(5) (a) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002, 4, 2353-
2355. (b) Flo¨gel, O.; Okala Amombo, M. G.; Reissig, H.-U.; Zahn, G.;
Bru¨dgam, I.; Hartl, H. Chem.sEur. J. 2003, 9, 1405-1415. (c) Kaden, S.;
Brockmann, M.; Reissig, H.-U. HelV. Chim. Acta 2005, 88, 1826-1838.
(d) Hausherr, A. Dissertation; Freie Universita¨t Berlin, 2001. (e) Chowdhury,
M. A.; Reissig, H.-U. Synlett 2006, 2383-2386. (f) For a related approach
to substituted pyrrolidines by addition of lithiated methoxyallene to
hydrazones of aldehydes (including SAMP and RAMP hydrazones), see:
Breuil-Desvergnes, V.; Gore´, J. Tetrahedron 2001, 57, 1939-1950. Breuil-
Desvergnes, V.; Gore´, J. Tetrahedron 2001, 57, 1951-1960.
(6) Selected references: (a) Hormuth, S.; Reissig, H.-U. J. Org. Chem.
1994, 59, 67-73. (b) Okala Amombo, M. G.; Hausherr, A.; Reissig, H.-U.
Synlett 1999, 1871-1874. (c) Helms, M.; Schade, W.; Pulz, R.; Watanabe,
T.; Al-Harrasi, A.; Fisˇera, L.; Hlobilova´, I.; Zahn, G.; Reissig, H.-U. Eur.
J. Org. Chem. 2005, 1003-1019. (d) Al-Harrasi, A.; Reissig, H.-U. Angew.
Chem. 2005, 117, 6383-6387; Angew. Chem., Int. Ed. 2005, 44, 6227-
6231. For reviews, see: (e) Zimmer, R.; Reissig, H.-U. Donor-Substituted
Allenes. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, pp 425-492. (f) Zimmer, R.
Synthesis 1993, 165-178. (g) Zimmer, R.; Khan, F. A. J. Prakt. Chem.
1996, 338, 92-94.
(9) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743-745. (b) Marshall,
J. A.; Bartley, G. S. J. Org. Chem. 1994, 59, 7169-7171. (c) Flo¨gel, O.;
Reissig, H.-U. Eur. J. Org. Chem. 2004, 2797-2804.
(10) For selected recently published methods to generate spiropyrrolidine
derivatives, see: (a) El Bialy, S. A. A.; Braun, H.; Tietze, L. F. Synthesis
2004, 2249-2262. (b) Planas, L.; Pe´rard-Viret, J.; Royer, J. J. Org. Chem.
2004, 69, 3087-3092. (c) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem.
2002, 67, 4337-4345.
(7) Other functional groups in this position such as simple ketals or
trialkylsiloxy groups proved not to be easily compatible with the subsequent
steps of our approach. Kaden, S. Dissertation; Freie Universita¨t Berlin, 2006.
(8) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. Synlett 2001, 1641-
1643.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
(12) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
4764
Org. Lett., Vol. 8, No. 21, 2006

Scheme 4. Generation of Keto Aldehyde 14 Followed by
Acid-Promoted Reaction to 15
Table 1. Base-Promoted Intramolecular Aldol Reactions of
Keto Aldehyde 14 Leading to Tricyclic Compounds 16a-d
entry reaction conditions 16a [%] 16b [%] 16c [%] 16d [%]
1
2
3
4
5
6
7
8
NaOMe, MeOH
KOtBu, tBuOH
33
16
2
20
6
16
20
34
18
36
55
14
44
9
KOtBu, toluene
L-proline, MeOH
L-proline, toluene
L-proline, DMSO
D-proline, MeOH
D-proline, toluene
4
26
13
4
17
28
6
19
as the major component (Table 1, entries 4-6). The
configuration of the amino acid in these organo-catalyzed
reactions seems to have a minor influence because D-proline
induced rather similar product ratios (Table 1, entries 7 and
8). On the other hand, the nature of solvents is of great
importance for these organo-catalyzed aldol reactions. L-
Proline in DMSO provided the highest selectivity and yield
for any of the four diastereomers (Table 1, entry 6) delivering
compound 16c in satisfying 55% yield. It is too early and
speculative to interpret these results in detail; however, it
should be noted that our precursor 14 behaves remarkably
differently from the related compound 1 used by Sorensen
et al. during their studies (see Scheme 1).
Treatment of keto aldehyde 14 with camphor sulfonic acid
in analogy to conditions applied by Fukuyama et al.3 resulted
in an aldol-type reaction involving the enol ether moiety,
which exclusively furnished tricyclic spiro compound 15 as
a single diastereomer (64% yield based on the keto alcohol
precursor of 14). The configuration of the novel tricyclic
skeleton 15 was established by analysis of the coupling
constants and the NOESY spectrum.
In contrast, reactions of keto aldehyde 14 under basic
conditions led to the desired aldol reaction of the cyclohex-
anone enolates, thus generating the tricyclic compound 16
with the FR 901483 skeleton. Using sodium methoxide in
methanol, we isolated diastereomer 16a as the major
component, whereas with potassium tert-butoxide, diaster-
eomer 16c was the major product (Scheme 5, Table 1, entries
First attempts to invert the configuration of the secondary
alcohol of major isomer 16c were not successful. Under
Mitsunobu conditions or by treatment of 16c with nosyl
chloride followed by cesium acetate14 (Scheme 6), we almost
Scheme 6. Attempt to Invert the Configuration of Alcohol 16c
Scheme 5. Base-Promoted Aldol Reactions
of Keto Aldehyde 14
exclusively obtained substitution products with retained
configuration such as chloro compound 17 or acetate 18.
This may be due to the neighboring group participation of
the nucleophilic dihydropyrrole nitrogen which probably
leads to an aziridinium ion 19 as an intermediate (Scheme
7). The nucleophiles open this species and provide substitu-
tion products with overall retention of configuration.15 The
1-3). Only L-proline13 in methanol afforded reasonable
amounts of 16d with the correct FR 901483 configuration,
whereas in toluene or DMSO, diastereomer 16c was obtained
(13) Reviews: (a) List, B. Tetrahedron 2002, 58, 5573-5590. (b) Notz,
W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591. (c)
Moisan, L.; Dalko, P. I. Angew. Chem. 2004, 116, 5248-5286; Angew.
Chem., Int. Ed. 2004, 43, 5138-5175.
(14) For an example, see: Snider, B. B.; Lin, H.; Foxman, B. M. J.
Org. Chem. 1998, 63, 6442-6443.
Org. Lett., Vol. 8, No. 21, 2006
4765

steps, five purifications, 21% overall yield). However, the
crucial aldol reaction needs to be modified to obtain the
correct diastereomer 16d in excess. Attempts to achieve this
objective as well as experiments to convert the enol ether
moiety of type 3 compounds into the methylamino-
substituted pyrrolidine function as required for the natural
product will be reported in due course.
Scheme 7. Neighboring Group Participation Leading to
Retention of Configuration
Acknowledgment. Generous support by the Deutsche
Forschungsgemeinschaft, the Fonds der Chemischen Indus-
trie, and the Schering AG is most gratefully acknowledged.
We thank Dr. Oliver Flo¨gel for preliminary experiments in
this field and Dr. Shahla Yekta for help during the prepara-
tion of this manuscript.
constitutions and configurations of compounds 16-18 were
unequivocally determined by NOESY spectra.
In summary, we have demonstrated that the alkoxyallene
approach to functionalized pyrrolidine derivatives allows for
a very fast and efficient generation of compound 16c with
the FR 901483 skeleton in enantiopure form (seven synthetic
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Audia, J. E.; Colocci, N. Tetrahedron Lett. 1991, 32, 3779-
3782. (b) Freedman, J.; Vaal, M. J.; Huber, E. W. J. Org. Chem. 1991, 56,
670-672. (c) Pfister, J. R. Synthesis 1984, 969-970.
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