Application of intramolecular enyne metathesis to the synthesis of aza[4.2.1]bicyclics: Enantiospecific total synthesis of (+)-anatoxin-a

Article abstract of DOI:10.1021/ol049631e

A concise synthesis of the potent nAChR agonist (4)-anatoxin-a (1) has been completed in a series of only nine chemical operations and 27% overall yield from commercially available D-methyl pyroglutamate (4). The synthesis features a novel procedure for t

Full text of DOI:10.1021/ol049631e

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1329-1331
Application of Intramolecular Enyne
Metathesis to the Synthesis of
Aza[4.2.1]bicyclics: Enantiospecific
Total Synthesis of (+)-Anatoxin-a
Jehrod B. Brenneman and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received February 29, 2004
ABSTRACT
A concise synthesis of the potent nAChR agonist (+)-anatoxin-a (1) has been completed in a series of only nine chemical operations and 27%
overall yield from commercially available D-methyl pyroglutamate (4). The synthesis features a novel procedure for the diastereoselective
preparation of cis-2,5-disubstituted pyrrolidines leading to 10, which underwent an intramolecular enyne metathesis to afford a bridged azabicyclic
intermediate that was transformed into 1.
(+)-Anatoxin-a (1), which was isolated from the toxic
blooms of the blue-green freshwater algae Anabaena flos-
aquae (Lyngb.) de Bre´b, is one of the most potent nicotinic
acetylcholine receptor (nAChR) agonists known.1 Also
referred to as “very fast death factor” (VFDF), 1 has been
shown to resist enzymatic degradation by acetylcholine
esterase, resulting in respiratory paralysis and eventual death.2
Despite its toxicity, 1 has emerged as a valuable chemical
probe for elucidating the mechanism of acetylcholine-
mediated neurotransmission and the disease states associated
with abnormalities in this important signaling pathway.
Consequent to its potent pharmacological profile and unique
9-azabicyclo[4.2.1]nonane skeleton, 1 has remained an
attractive synthetic target since its isolation in 1977.3 A
variety of nonlethal analogues that contain the 9-azabicyclo-
[4.2.1]nonane skeleton have recently been identified as
potential therapeutic targets for treating neurological disor-
ders such as Alzheimer’s and Parkinson’s diseases, schizo-
phrenia, and depression.4
Our interest in (+)-anatoxin-a (1) arose as a result of our
ongoing efforts to develop ruthenium-catalyzed ring-closing
(3) For the most recent syntheses, see: (a) Wegge, T.; Schwarz, S.; Seitz,
G. Tetrahedron: Asymmetry 2000, 11, 1405. (b) Parsons, P. J.; Camp, N.
P.; Edwards, N.; Sumoreeah, L. R. Tetrahedron 2000, 56, 309. (c) Aggarwal,
V. K.; Humphries, P. S.; Fenwick, A. Angew. Chem., Int. Ed. 1999, 38,
1985. (d) Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999, 121, 3057.
(e) Oh, C.-Y.; Kim, K.-S.; Ham, W.-H. Tetrahedron Lett. 1998, 39, 2133.
For a review of earlier syntheses, see: (f) Mansell, H. L. Tetrahedron 1996,
52, 6025.
(4) (a) Karig, G.; Large, J. M.; Sharples, C. G. V.; Sutherland, A.;
Gallagher, T.; Wonnacott, S. Biorg. Med. Chem. Lett. 2003, 13, 2825. (b)
Sutherland, A.; Gallagher, T.; Sharples, C. G. V.; Wonnacott, S. J. Org.
Chem. 2003, 68, 2475. (c) Gohlke, H.; Schwarz, S.; Gu¨ndisch, D.; Tilotta,
M. C.; Weber, A.; Wegge, T.; Seitz, G. J. Med. Chem. 2003, 46, 2031. (d)
Sharples, C. V. G.; Karig, G.; Simpson, G. L.; Spencer, J. A.; Wright, E.;
Millar, N. S.; Wonnacott, S.; Gallagher, T. J. Med. Chem. 2002, 45, 3235.
(e) Gohlke, H.; Gu¨ndisch, D.; Schwarz, S.; Seitz, G.; Tilotta, M. C.; Wegge,
T. J. Med. Chem. 2002, 45, 1064. (f) Gu¨ndisch, D.; Ka¨mpchen, T.; Schwarz,
S.; Seitz, G.; Siegl, J.; Wegge, T. Biorg. Med. Chem. 2002, 10, 1. (g)
Sharples, C. V. G.; Kaiser, S.; Soliakov, L.; Marks, M. J.; Collins, A. C.;
Washburn, M.; Wright, E.; Spencer, J. A.; Gallagher, T.; Whiteaker, P.;
Wonnacott, S. J. Neurosci. 2000, 20, 2783. (h) Wright, E.; Gallagher, T.;
Sharples, C. V. G.; Wonnacott, S. Biorg. Med. Chem. Lett. 1997, 7, 2867.
(i) Sardina, F. J.; Howard, M. H.; Koskinen, A. M. P.; Rapoport, H. J.
Org. Chem. 1989, 54, 4654.
(1) Devlin, J. P.; Edwards, O. E.; Gorham, P. R.; Hunter, N. R.; Pike,
R. K. Can. J. Chem. 1977, 55, 1367.
(2) (a) Carmichael, W. W.; Biggs, D. F.; Gorham, P. R. Science 1975,
187, 542. (b) Spivak, C. E.; Witkop, B.; Albuquerque, E. X. Mol.
Pharmacol. 1980, 18, 384.
10.1021/ol049631e CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/23/2004

metathesis (RCM) strategies for the construction of bridged
azabicycles.5,6 In that context, we envisioned that the
intramolecular enyne metathesis of the cis-2,5-disubstituted
pyrrolidine 3 would generate the 9-azabicyclo[4.2.1]nonene
2 bearing a pendant alkenyl side chain that could be
elaborated to the enone moiety present in 1 (Figure 1). We
now report a concise enantiospecific synthesis of 1 in
accordance with this strategy.
Scheme 1
Figure 1. Retrosynthesis of (+)-anatoxin-a (1): key bond discon-
nections.
The synthesis commenced with N-protection of com-
mercially available D-methyl pyroglutamate (4)7 to provide
the Cbz-lactam 5 (Scheme 1). Addition of 3-butenylmagne-
sium bromide to 5 in the presence of TMEDA afforded the
ring-opened product 6 together with small amounts of 4.8
Premixing excess TMEDA and the Grignard reagent prior
to reaction with 5 minimized the extent to which cleavage
of the N-carbamoyl group occurred to form 4.9
Ketone 6 was subsequently transformed into the cis-2,5-
disubstituted pyrrolidine 7 (dr ) 11:1)10 by a highly
diastereoselective cyclization-reduction strategy recently
discovered and developed in our group.11 In contrast to
conventional hydrogenation techniques that have been em-
ployed for preparing cis-2,5-disubstituted pyrrolidines,12 the
use of triphenylsilane as the reductant allows for the
incorporation of unsaturated side chains. Moreover, the bulky
silane reagent provides a significant steric bias for stereo-
selective reduction of the transient N-acyl iminium ion from
the less-hindered face of the pyrrolidine ring.
(5) (a) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867. (b)
Neipp, C. E.; Martin, S. F. Tetrahedron Lett. 2002, 43, 1779.
(6) For additional examples of bridged azabicycles prepared by RCM,
see: (a) Itoh, T.; Yamazaki, N.; Kibayashi, C. Org. Lett. 2002, 4, 2469.
(b) Bamford, S. J.; Goubitz, K.; van Lingen, H. L.; Luker, T.; Schenk, H.;
Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2000, 345. (c) Grigg, R.; York,
M. Tetrahedron Lett. 2000, 41, 7255. (d) Kim, S. H.; Figueroa, I.; Fuchs,
P. L. Tetrahedron Lett. 1997, 38, 2601. (e) Pandit, U. K.; Borer, B. C.;
Biera¨ugel, H. Pure Appl. Chem. 1996, 68, 659.
(7) Alternatively, 4 may be prepared from D-pyroglutamic acid. See:
Pfaltz, A.; Leutenegger, U.; Siegmann, K.; Fritschi, H.; Keller, W.; Krathy,
C. HelV. Chim. Acta 1988, 71, 1541.
(8) For related examples of reactions of organometallic reagents with
N-alkoxycarbonyl lactams, see: (a) Giovannini, A.; Savoia, D.; Umani-
Ronchi, A. J. Org. Chem. 1989, 54, 228. (b) Ohta, T.; Hosoi, A.; Kimura,
T.; Nozoe, S. Chem. Lett. 1987, 2091.
At this juncture, 7 was converted into the acetylene 9
exploiting a one-pot procedure that was recently reported
by our group.5a In the event, the methyl ester moiety of 7
was reduced with DIBAL-H, and the intermediate aldehyde
was treated with the diazophosphonate reagent 8 in the
presence of Cs2CO3 to give the alkyne 9.13 It was necessary
to perform the alkynylation step in the presence of BnOH
or i-PrOH to prevent epimerization of the intermediate
aldehyde. Alkylation of the sodium anion of 9 with MeOTf
afforded the propynyl intermediate 10 in excellent yield.
The stage was thus set for the intramolecular enyne
metathesis. Exposure of 10 to the Grubbs second-generation
catalyst 11 at room temperature cleanly provided the
9-azabicyclo[4.2.1]nonane 12 in 87% yield. The 1,1-disub-
(9) In the absence of TMEDA, ketoamide 6 was obtained in only 45%
yield together with substantially larger quantities of 4.
(10) Diastereoselectivity was determined by integration of methyl ester
1
signals in the H NMR at 100 °C (DMSO-d6).
(11) Rudolph, A.; Machauer, R.; Martin, S. F. Unpublished results.
(12) (a) Mota, A. J.; Chiaroni, A.; Langlois, N. Eur. J. Org. Chem. 2003,
21, 4187. (b) Li, H.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett. 1997,
38, 6677. (c) Yoda, H.; Yamazaki, H.; Takabe, K. Tetrahedron: Asymmetry
1996, 7, 373. (d) Jegham, S.; Das, B. Tetrahedron Lett. 1989, 30, 2801. (e)
Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229.
(13) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mu¨ller, S.; Liepold,
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
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Org. Lett., Vol. 6, No. 8, 2004

stituted olefin in 12 was selectively dihydroxylated in the
presence of the endocyclic olefin using the complex of OsO4
and Et3N followed by reduction of the intermediate osmate
esters to afford the diol 13 along with 13% of an undesired
diol that resulted from osmylation of the endocyclic alkene.
The mixture of diols was readily separated by flash chro-
matography to afford pure 13. Cleavage of the diol unit with
periodate ion cleanly delivered 14.4i Removal of the N-
carbamoyl function was effected with TMSI at -10 °C to
afford 1 in near quantitative yield. The spectral data of the
synthetic 1 thus obtained were consistent with those reported
in the literature.14 To prevent light-induced decomposition
of 1,15 the free base was converted to its hydrochloride salt
with methanolic HCl at 0 °C. The hydrochloride salt of 1
also exhibited 1H and 13C NMR spectral properties consistent
with those reported by Rapoport,16 and it gave an optical
In summary, a concise and practical synthesis of the
9-azabicyclo[4.2.1]nonane skeleton has been achieved by a
strategy that features the intramolecular enyne metathesis of
a cis-2,5-disubstituted pyrrolidine. The utility of this con-
struction was demonstrated by its use in a concise enan-
tiospecific total synthesis of (+)-anatoxin-a (1). The strategy
is inherently flexible, thereby providing an entry to related
compounds by simply modifying the nature of the side chains
on the 2- and 5-positions of the pyrrolidine ring prior to
metathesis. Applications of RCM reactions to the syntheses
of other alkaloids constitutes the subject of a number of
current investigations in our laboratories, the results of which
will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health, Pfizer, Inc., Merck Research Laboratories, and the
Robert A. Welch Foundation for their generous support of
this research. We additionally thank Mr. Alexander Rudolph
and Drs. Rainer Machauer and Christopher Straub for helpful
discussions.
rotation ([R]27 +37.3 (c 2.08, abs. EtOH)) in accord with
D
values previously reported in the literature.17
(14) Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106,
4539 and references therein.
Supporting Information Available: Copies of 1H NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Stevens, D. K.; Krieger, R. I. Toxicon 1991, 29, 167.
(16) Koskinen, A. M. P.; Rapoport, H. J. Med. Chem. 1985, 28, 1301.
(17) Campbell, H. F.; Edwards, O. E.; Kolt, R. Can. J. Chem. 1977, 55,
1372: [R]24 +36 (c 0.85, EtOH). See also in ref 14: [R]24 +43.2 (c
D
D
0.676, abs. EtOH).
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