A formal asymmetric synthesis of (+)-anatoxin-a using an enantioselective deprotonation strategy on an eight-membered ring

Article abstract of DOI:10.1002/(SICI)1521-3773(19990712)38:13/14<1985::AID-ANIE1985>3.0.CO;2-7

In only seven steps a formal synthesis of enantiomerically enriched (+)- anatoxin-a has been achieved. This was accomplished by utilizing a highly enantioselective desymmetrization of the eight-membered ring ketone 1 to form 2, and a novel cascade reactio

Full text of DOI:10.1002/(SICI)1521-3773(19990712)38:13/14<1985::AID-ANIE1985>3.0.CO;2-7

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obtained from ketone 5. One of the key steps in the synthesis
is the enantioselective deprotonation of cyclooctanone 5.
Desymmetrization of conformationally locked six-mem-
bered rings and bicyclic systems have been well explored over
the last decade, and high levels of asymmetric induction have
been achieved.[5] However, prior to the start of this work
desymmetrization of medium and large rings had not been
reported.[6] This is perhaps because of the commonly held
belief that the greater conformational flexibility of these ring
systems would result in several low-energy conformations that
would lead to low enantioselectivity. However, we were
encouraged by the work of Still and Allinger who showed that
cyclooctanones exist in conformations having as few trans-
annular nonbonded repulsions and high-energy torsional
arrangements as possible (namely chair± boat).[7] Cycloocta-
none 5 should therefore adopt conformation A in which the
carbonyl moiety resides at the position shown (Figure 1) and
the amino group occupies an equatorial position. Several
A Formal Asymmetric Synthesis of
(‡)-Anatoxin-a Using an Enantioselective
Deprotonation Strategy on an Eight-Membered
Ring**
Varinder K. Aggarwal,* Paul S. Humphries, and
Ashley Fenwick
Anatoxin-a (1) is a low molecular weight potent neurotoxin
present in toxic blooms of the filamentous freshwater blue
green algae Anabaena flos-aquae, and has been responsible
for the fatal poisoning of wildlife in North America and
Europe.[1] Anatoxin-a has attracted much synthetic interest,[2]
primarily because of its potent agonist activity at acetylcho-
line receptors,[3] but also because it contains an unusual
9-azabicyclo[4.2.1]nonane skeleton. Herein, we describe a
short formal asymmetric synthesis of this natural product,
which relies on an enantioselective deprotonation of a
cyclooctanone by a chiral lithium amide base (Scheme 1).
Figure 1. Conformational analysis of prochiral ketone 5 and Simpkins base 7.
other conformations are populated at room temperature as a
result of relatively small barriers to pseudorotation and ring
inversion. However, at low temperature one conformation
should be largely favored, which would lead to the possibility
of high asymmetric induction. The enolizable protons of the
low-energy conformation of cyclooctanone 5 are circled in
Figure 1. By correlating the sense of asymmetric induction in
the desymmetrization of 4-tert-butylcyclohexanone with the
Simpkins base 7[8] we predicted that Li-(R,R)-7 would
preferentially abstract H2 and provide the enolate required
for the synthesis of (‡)-anatoxin-a.[9]
Scheme 1. Retrosynthetic analysis of (‡)-anatoxin-a (1).
Our route to key intermediate 10 began with cis-1,5-
cyclooctanediol (6), which was oxidized (PDC, CH2Cl2) to the
intermediate hemiacetal (Scheme 2). Treatment of this hemi-
acetal with hot aqueous benzylamine gave a mixture of the
hemiaminal 8 and aminal 9. Subsequent addition of sulfuric
acid converted this mixture into the required hemiaminal in
high overall yield.[11] Attempted ring opening of hemiaminal 8
and protection of the amine moiety with the benzyl carbamate
group using standard conditions (PhCH2OCOCl, Et3N,
CH2Cl2) was ineffective, returning only starting material.
However, the addition of catalytic quantities of Sc(OTf)3
resulted in rapid protection.
The key desymmetrization step required formation of
enantiomerically enriched enol phosphate 11. It had previ-
ously been shown by Simpkins and Majewski that it was
possible to achieve enantioselective deprotonations utilizing
lithium chloride as an external additive to enhance the
enantioselectivity.[12] This was achieved by treatment of
prochiral ketone 10 with the base-derived (R,R)-7 ´ HCl and
two equivalents of butyllithium at 1008C.[12e] Subsequent
The retrosynthetic analysis of (‡)-anatoxin-a (1) is shown
in Scheme 1. The azabicyclic ketone 2 has previously been
transformed into 1 by Rapoport et al.,[4] and could potentially
be obtained from 3 by intramolecular conjugate addition of
the amine moiety. Enone 3 could be accessed through a Stille
reaction from the vinyl phosphate 4, which itself could be
[*] Prof. V. K. Aggarwal, Dr. P. S. Humphries
Department of Chemistry
University of Sheffield
Brook Hill, Sheffield, S37HF (UK)
Fax: (‡44)114-273-8673
E-mail: v.aggarwal@sheffield.ac.uk
Dr. A. Fenwick
Medicinal Chemistry
SmithKline Beecham Pharmaceuticals
New Frontiers Science Park (North)
Third Avenue, Harlow, Essex, CM195AW (UK)
[**] We thank SmithKline Beecham and Sheffield University for financial
support for this work and Dr. Dash Dhanak (SB) for his interest in this
project.
Angew. Chem. Int. Ed. 1999, 38, No. 13/14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3813-1985 $ 17.50+.50/0
1985

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[1] a) W. W. Carmichael, D. F. Biggs, P. R. Gorham, Science 1975, 187,
542; b) N. A. Mahmood, W. W. Carmichael, Toxicon 1987, 25, 1221.
[2] For a review of recent total syntheses of anatoxin-a, see H. L. Mansell,
Tetrahedron 1996, 52, 6025.
[3] P. Thomas, M. Stephens, G. Wilkie, M. Amar, G. G. Lunt, P. Whiting,
T. Gallagher, E. Pereira, M. Alkondon, E. X. Alburquerque, S. J.
Wannacott, J. Neurochem. 1993, 60, 2308.
[4] J. S. Petersen, G. Fels, H. Rapoport, J. Am. Chem. Soc. 1984, 106, 4539.
[5] a) P. J. Cox, N. S. Simpkins, Tetrahedron: Asymmetry 1991, 2, 1; b) P.
OꢁBrien, J. Chem. Soc. Perkin Trans. 1 1998, 1439.
[6] In the course of our work an enantioselective deprotonation of an
eight-membered ring was reported. See W. F. Berkowitz, Y. Wu, J.
Org. Chem. 1997, 62, 1536.
[7] a) W. C. Still, I. Galynker, Tetrahedron 1981, 37, 3981; b) N. L.
Allinger, M. T. Tribble, M. A. Miller, Tetrahedron 1972, 28, 1173.
[8] C. M. Cain, R. P. C. Cousins, G. Coubarides, N. S. Simpkins, Tetrahe-
dron 1990, 46, 523.
[9] Newcombe and Simpkins have described an asymmetric synthesis of
(
)-anatoxin-a with an enantioselective deprotonation of a tropa-
none. See N. J. Newcombe, N. S. Simpkins, J. Chem. Soc. Chem.
Commun. 1995, 831.
[10] Abbreviations: AcOH ˆ acetic acid; Bn ˆ benzyl; Boc ˆ tert-butoxy-
carbonyl; p-TsOH ˆ para-toluenesulfonic acid; PDC ˆ pyridinium
dichromate; Tf ˆ trifluoromethanesulfonyl; THF ˆ tetrahydrofuran;
Z ˆ benzyloxycarbonyl.
Scheme 2. Formal total synthesis of (‡)-anatoxin-a (1). See reference [10]
for abbreviations. a) PDC, CH2Cl2, 100%; b) 1. aq PhCH2NH2 (40%), p-
[11] For the synthesis of the N-methyl analogue of hemiaminal 8, see J. R.
Wiseman, S. Y. Lee, J. Org. Chem. 1986, 51, 2485.
~
TsOH (30 mol%), ; 2. H2SO4 (10%), 81% over two steps; c) PhCH2-
[12] a) B. J. Bunn, N. S. Simpkins, Z. Spavold, M. J. Crimmin, J. Chem. Soc.
Perkin Trans. 1 1993, 3113; b) B. J. Bunn, N. S. Simpkins, J. Org. Chem.
1993, 58, 533; c) M. Majewski, G.-Z. Zheng, Synlett 1991, 173; d) M.
Majewski, G.-Z. Zheng, Can. J. Chem. 1992, 70, 2618; e) M. Majewski,
R. Lazny, P. Nowak, Tetrahedron Lett. 1995, 36, 5465.
[13] The enantiomeric excess was determined by HPLC analysis on a
Chiralcel OD column (hexane:iPrOH 98:2). Retention times: (R)-11:
16.8 min, (S)-11: 18.7 min.
OCOCl, Sc(OTf)3 (5 mol%), iPr2NEt, MeCN, 95%; d) (R,R)-7 ´ HCl,
nBuLi (2 equiv), (PhO)2POCl, THF, 1008C, 89%, 89% ee; e) [Pd(PPh3)4],
ˆ
~
CH2 CH(OEt)SnBu3, LiCl, THF, , 84%; f) 45% HBr in AcOH, 95%;
g) Pd/C, H2, MeOH, (tBuCO)2O, 89%.
quenching of the reaction mixture with diphenyl chlorophos-
phate gave the enol phosphate 11 with high enantioselectivity
(89% ee).[13]
[14] K. C. Nicolaou, G.-Q. Shi, J. L. Gunzner, P. Gärtner, Z. Yang, J. Am.
Chem. Soc. 1997, 119, 5467.
[15] A single diastereomer at C2 was formed. This observation is in keeping
with a report that acid catalysis results in equilibration of the system,
in favor of ketone 13.[4]
Completion of the formal synthesis was achieved by a Stille
reaction of enol phosphate[14] 11 with CH2 CH(OEt)SnBu3 in
ˆ
the presence of [Pd(PPh3)4] and LiCl in THF, followed by a
novel cascade reaction. This sequence entailed unmasking the
enone moiety with concomitant nitrogen deprotection and
intramolecular conjugate addition to give the required
bridged azabicycle.[15] Changing the protecting group from
benzyl to tert-butoxycarbonyl gave ketone 13, which was
2,2'-commo-Bis[2-ruthena-nido-1-(h5-pentame-
thylcyclopentadienyl)ruthenahexaborane(12)]:
An Unusual Ruthenaborane Related to
Ruthenocene and Exhibiting a Linear
Triruthenium Fragment**
1
identical, by H and 13C NMR, and IR spectroscopy and MS,
to that reported by the group of Rapoport.[4] The [a]D22 value
we obtained (‡47.2, c ˆ 0.8 in CH2Cl2) is consistent with the
production of the natural enantiomer ([a]2D2 ˆ ‡51.9, c ˆ 0.795
in CH2Cl2).[4] Ketone 13 has been converted into (‡)-
anatoxin-a (1) by Rapoport et al. in three steps.
Xinjian Lei, Maoyu Shang, and Thomas P. Fehlner*
In conclusion, this paper describes one of the most concise
and efficient routes (34% overall yield, including the final
literature steps) to enantiomerically enriched (‡)-anatoxin-a.
Key steps in our synthesis include a highly enantioselective
desymmetrization of an eight-membered ring ketone, and a
novel cascade reaction to set up the 9-azabicyclo[4.2.1]nonane
skeleton. Such desymmetrization reactions of medium and
perhaps large ring ketones could find wide applications in
synthesis.
The intimate connection between metallaborane chemistry
and organometallic chemistry is expressed in the existence of
isoelectronic pairs of compounds, for example, [(CO)4-
[1, 2]
FeB2H5]
versus [(CO)4Fe(h2-C2H4)] and [(h5-C5H5)-
CoB4H8][3] versus [(h5-C5H5)Co(h4-C4H4)].[4±8] One of the
fascinating aspects of these inorganic analogues of organo-
[*] Prof. T. P. Fehlner, Dr. X. Lei, Dr. M. Shang
Department of Chemistry and Biochemistry
University of Notre Dame
Received: January 14, 1999 [Z12911IE]
German version: Angew. Chem. 1999, 111, 2178 ± 2180
Notre Dame, IN 46556 (USA)
Fax: (‡1)219-631-6652
Keywords: anatoxin ´ enantioselective deprotonation ´ nat-
ural products ´ total synthesis
E-mail: fehlner.1@nd.edu
[**] This work was supported by the National Science Foundation.
1986
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3813-1986 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 13/14