Stereoselective furan-iminium cation cyclization in the construction of the core structure of manzamine A

Article abstract of DOI:10.1021/ol052387m

(Chemical Equation Presented) A new type of furan-iminium cation cyclization was developed and used to construct the ABC ring of manzamine A. The cyclization proceeded at the 2-position with complete regio- and stereoselectivity to give a spiro-center. Th

Full text of DOI:10.1021/ol052387m

ORGANIC
LETTERS
2006
Vol. 8, No. 1
27-30
Stereoselective Furan-Iminium Cation
Cyclization in the Construction of the
Core Structure of Manzamine A
Kazuyuki Tokumaru, Shigeru Arai, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
nishida@p.chiba-u.ac.jp
Received October 3, 2005
ABSTRACT
A new type of furan-iminium cation cyclization was developed and used to construct the ABC ring of manzamine A. The cyclization proceeded
at the 2-position with complete regio- and stereoselectivity to give a spiro-center. The product was efficiently converted to the highly substituted
core structure of manzamine A.
Manzamine alkaloids have attracted considerable attention
because of their unique structure and diverse biological
activities, and new related compounds continue to be isolated
from marine sources.1 Manzamine A, which was the first
manzamine alkaloid isolated by Higa et al.2 contains a 6/6/
5/8/13 diazapentacyclic skeleton with a â-carboline ring and
has shown a variety of biological activities, such as antitu-
mor, antituberculosis, and strong antimalarial activities.
Although many attempts have been made to construct this
attractive molecule,3 only Winkler and Martin have reported
a total synthesis.4
found to be an efficient method for construction of the core
6/5/5/5 structure (Scheme 1). To expand the scope of this
reaction to the synthesis of a 6/6/5 ring system, such as the
ABC core of manzamine A, we have been studying two
cyclization patterns. The cyclization of 1, which has one
carbon linker between a spiro-piperidine ring and a 2-furyl
group, at the 3-position of furan would give tetracyclic furan
2. The cyclization of 3, which has two carbon linkers
connecting the spiro-piperidine ring and 2-furyl group, might
proceed at the 2-position of furan to result in the construction
of the six-membered B ring of 4 with a tetra-substituted
Recently, we achieved the first total synthesis of a
manzamine alkaloid, nakadomarin A, by two different
synthetic pathways.5 In our synthetic study of nakadomarin
A, furan-iminium cation cyclization,6 which is intramolecular
nucleophilic addition of furan to acyl iminium cation, was
(3) For selected studies, see: (a) Pandit, U. K.; Overkleeft, H. S.; Borer,
B. C.; Biera¨ugel, H. Eur. J. Org. Chem. 1999, 959. (b) Magnier, E.; Langlois,
Y. Tetrahedron Lett. 1998, 39, 837. (c) Brands, K. M. J.; DiMichele, L.
M. Tetrahedron Lett. 1998, 39, 1677. (d) Nakagawa, M., Torisawa, Y.,
Uchida, H., Nishida, A. J. Synth. Org. Chem. Jpn. 1999, 57, 1004. (e) Li,
S.; Yamamura, S. Tetrahedron 1998, 54, 8691. (f) Bland, D.; Chambournier,
G.; Dragan, V.; Hart, D. J. Tetrahedron 1999, 55, 8953. (g) Clark, J. S.;
Townsend, R. J.; Blake, A. J.; Teat, S. J.; Johns, A. Tetrahedron Lett. 2001,
42, 3235. (h) Herdemann, M.; Al-Mourabit, A.; Martin, M.-T.; Marazano,
C. J. Org. Chem. 2002, 67, 1890. (i) Magnus, P.; Fielding, M. R.; Wells,
C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947. (j) Coldham, I.; Pih, S. M.;
Rabot, R. Synlett 2005, 1743.
(1) For review, see; Hu, J.-F.; Hamann, M. T.; Hill, R.; Kelly, M. In
The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic
Press: New York, 2003; Vol. 60, p 207.
(2) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
Soc. 1986, 108, 6404.
10.1021/ol052387m CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/08/2005

Scheme 1. Synthesis of Manzemine Alkaloids Using Furan-Iminium Cation Cyclization
Scheme 2. Synthesis of Cyclization Precursors
asymmetric center. In both reactions, the furan unit would
give 7 in 87% yield. The ketone was reduced to increase
the nucleophilicity of furan. After protection of the hydroxyl
and lactam groups, N-Boc-lactam 8 was converted to
hemiaminal 9, an iminium cation precursor, by reduction
using LiBEt3H.9
Both precursors, 13 and 14, which have two carbon linkers
between a spiro-piperidine ring and a 2-furyl group, were
also synthesized from 5. Wittig reaction and diastereoselec-
tive hydrogenation10 gave ester 11, which was converted to
2-furyl ketone 12 via Weinreb amide.11 After this ketone
was converted to a thioketal or siloxy group, the same
transformation of lactam as described above gave hemiami-
nals 13 and 14.
be useful for constructing the D ring of manzamine A. Since
the regio- and stereoselectivity of these cyclizations have
not been clearly demonstrated before, we decided to start
an initial model study using substrates that have no sub-
stituent at C34.
The synthesis of cyclization precursors is outlined in
Scheme 2. Compound 57 was converted to the enol triflate
6, and one carbon linker and a 2-furyl group were then
introduced by a carbonylative Stille coupling reaction8 to
(4) (a) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425.
(b) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem.
Soc. 1999, 121, 866. (c) Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong,
Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002,
124, 8584.
(5) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003,
125, 7484. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int.
Ed. 2004, 43, 2020.
(6) For selected examples of furan-iminium cation cyclization, see: (a)
Cassidy, M. P.; O¨ zdemir, A. D.; Padwa, A. Org. Lett. 2005, 7, 1339. (b)
Tanis, S. P.; Deaton, M. V.; Dixon, L. A.; McMills, M. C.; Raggon, J. W.;
Collins, M. A. J. Org. Chem. 1998, 63, 6914. (c) Martin, S. F. Acc. Chem.
Res. 2002, 35, 895.
(7) Nagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42,
8345.
Hemiaminals 9, 13, and 14 were then exposed to acidic
media (Scheme 3). Depending on the structure of the
substrates, cyclization conditions were modified slightly and
cyclization occurred under mild acidic conditions without
(9) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carren˜o, M. C.; Ruano, J.
L. G. Tetrahedron Lett. 1994, 35, 2053.
(10) The diastereoselectivity of hydrogenation was catalyst- and solvent-
dependent. For example, hydrogenation using Pd/C as a catalyst in AcOEt
gave the product in 84% yield and R-H:â-H ratio was 1:1.5.
(11) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(8) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1997; Vol. 50, p 1.
28
Org. Lett., Vol. 8, No. 1, 2006

Scheme 3. Furan-Iminium Cation Cyclizations
Figure 2. Transition state model of simplified substrate.
an acyl group attached to the iminium nitrogen.6c,13 Several
types of intramolecular furan-iminium cation cyclizations
have been reported, for example, cyclization of 3-substituted
furan at the 2-position,6b cyclization of 2-substituted furan
at the 3-position,6a,b and cyclization of 2-substituted 5-siloxy
furan at the 2-position.6c However, intramolecular furan-
iminium cation cyclization of 2-monosubstituted furan at the
2-position has not been reported, and the high level of
diastereoselectivity in this reaction is noteworthy.
We also studied the introduction of a C1 unit at the B
ring, which is a key functional group for preparing â-car-
boline (Scheme 4). Unfortunately, the thioketal group of 18
could not be deprotected effectively. Deprotection of the TBS
group of 17 followed by hydrogenation of olefin in the
lactone ring gave secondary alcohol 19 quantitatively as a
1:1 mixture of diastereomeres. Thus, a secondary alcohol of
19 at C11 was oxidized to ketone 20, whose structure was
determined by X-ray analysis. However, all attempts to
introduce a C1 unit by R-acylation of 20 were unsuccessful.14
We next synthesized epoxide 23 from 19b by dehydration
to give 22 followed by epoxidation using DMDO. Although
19a could not be directly used to synthesize 23, 19a could
be converted to 19b via 20 by an oxidation-reduction
sequence. Regioselective nucleophilic epoxide opening was
accomplished using the method reported by Utimoto15 to give
â-cyanohydrin 24. Finally, usual dehydration gave R,â-
unsaturated nitrile 25, which has all of the functional groups
necessary to synthesize the manzamine A structure except
for the E ring.
deprotection of acid-sensitive TBS and Boc groups. All of
these reactions proceeded in a regioselective manner com-
pletely at the 2-position of furan regardless of the length of
the carbon tether to generate new spiro-centers. Furthermore,
the stereochemistry of the newly formed tetrasubstituted
spiro-centers was also completely controlled and consistent
with the corresponding stereocenter of manzamine A (C12).
The structure of each cyclized product was determined by
X-ray or NMR analysis.12
In summary, we have developed a new synthetic pathway
to the ABC core skeleton of manzamine A. A noteworthy
feature of this synthesis is the highly regio- and stereose-
lective furan-iminium cation cyclization under mild acidic
Figure 1. ORTEP Presentation of compound 16.
The observed stereoselectivity could be explained by
Diels-Alder-type transition states (Figure 2). The face
selectivity of furan might be controlled by interaction with
(13) Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1987, 109, 7881.
(14) Both Winkler and we successfully introduced C1 unit at C10 by
R-acylation. See refs 3e and 4a. These unsuccesssful results might be
attributed to the bulkiness of the tetrasubstituted center at C12.
(15) Matsubara, S.; Onishi, H.; Utimoto, K. Tetrahedron Lett. 1990, 31,
6209.
(12) The structure of 15 and 17 were determined by X-ray analysis after
conversion to 16 and 20 (Figure 1 and Scheme 4). The structure of 18 was
determined by NMR analysis (see Supporting Information).
Org. Lett., Vol. 8, No. 1, 2006
29

Scheme 4. Functionalization of the B Ring
conditions. The reaction was used to construct two contigu-
Note Added after ASAP Publication. There was an error
in Figure 2 in the version published ASAP December 8,
2005; the corrected version was published ASAP December
13, 2005.
ous stereocenters including a tetrasubstituted stereocenter
corresponding to the B ring of manzamine A. The total
synthesis of manzamine A using this methodology is now
under investigation.
Supporting Information Available: Experimental pro-
cedures, X-ray analysis data (11, 16, and 20) in CIF format,
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas
(17035014) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
OL052387M
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