Stereoselective nitrenium ion cyclizations: Asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of fasicularin

Article abstract of DOI:10.1016/j.tetlet.2004.04.028

The asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of the marine natural product fasicularin is reported. The keystone of this divergent synthesis is the diastereoselective azaspirocyclization of an N-methoxy γ-arylbu

Full text of DOI:10.1016/j.tetlet.2004.04.028

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4229–4231
Stereoselective nitrenium ion cyclizations: asymmetric synthesis
of the (+)-Kishi lactam and an intermediate for the preparation
of fasicularin
Duncan J. Wardrop,* Wenming Zhang and Chad L. Landrie
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 27 February 2004;revised 3 April 2004;accepted 7 April 2004
Abstract—The asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of the marine natural product
fasicularin is reported. The keystone of this divergent synthesis is the diastereoselective azaspirocyclization of an N-methoxy
c-arylbutanoamide, which is believed to proceed through the intermediacy of an N-acylnitrenium ion.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The 1-azaspiro[5.5]undecane ring system forms the
substructure of a select number of biologically active
natural products. Histrionicotoxin (1), isolated from the
South American frog, Dendrobates histrionicus, is a
potent noncompetitive blocker of neuromuscular nico-
tinic receptor-gated channels which, together with its
perhydro derivative 2, have been used extensively as a
biochemical probe.1 Fasicularin (3), on the other hand,
was isolated from the Micronesian ascidian Nephteis
fasicularis2 by Patil et al. In addition to displaying
selective activity against strains of yeast, which lack the
double-strand DNA repair gene RAD-52, this tricyclic
alkaloid is cytotoxic toward Vero cells. The biological
activity and novel structures of these natural products
have stimulated extensive investigation.3;4 Total syn-
theses of racemic 3 have been reported by Kibayashi and
co-workers5 and Funk and co-workers,6 while Dake7
recently reported the asymmetric synthesis of a late
stage intermediate common to both of these routes. The
absolute configuration of fasicularin remains to be
established.
As part of an on-going study of the chemistry of nitre-
nium ions,8 we recently developed a novel strategy for
the stereocontrolled preparation of 1-azaspiranes, based
on the p-face selective spirocyclization of N-acylnitre-
nium ions.9 Herein we report the successful application
of this methodology to the asymmetric synthesis of 8, an
intermediate in Kishi’s pioneering synthesis of ( )-per-
hydrohistrionicotoxin (2),4a;10 and compound 7, which
represents a usefully functionalized platform from which
to launch an asymmetric synthesis of fasicularin (3).
As outlined in Scheme 1, we initially envisioned that
azaspirocyclization of N-acyl-N-methoxynitrenium ion
Keywords: Nitrenium ions;Dearomatization;Fasicularin;Polyvalent
iodine;Histrionicotoxin.
* Corresponding author. Tel.: +1-312-355-1035;fax: +1-312-996-0431;
e-mail: wardropd@uic.edu
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.028

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D. J. Wardrop et al. / Tetrahedron Letters 45 (2004) 4229–4231
5, generated through oxidation of amide 4 with phenyl-
iodine(III) bistrifluoroacetate (PIFA), would provide
2,4-dienone 6.11 Given the findings of our previous
study,9 we anticipated that nonbonding interactions
between the triisopropylsilyloxy substituent on the side
chain and the ortho position of the aromatic ring would
favor the formation of anti-6 during the spirocyclization
of 5. Reduction of 6 would then offer an ingress to both
())-perhydrohistrionicotoxin (2) and fasicularin (3), by
way of common intermediate 7.
12, without the necessity of proceeding through 6, we
attempted to reduce the diene system. However, sub-
mission of 12 to catalytic hydrogenation over a range of
heterogeneous catalysts, including Adams catalyst
(PtO2),15 served only to trigger rearomatization and
formation of amide 4.
Given our inability to access 2,4-dienone 6, we now
shifted our attention to the preparation of 2,5-dienone 16
in the expectation that this cross-conjugated system
would be more stable. As shown in Scheme 3, the req-
uisite precursor 15 was prepared from iodoarene 13 in a
similar fashion to 4, with the exception that the conver-
sion of 14 to the corresponding carboxylic acid was
accomplished in one step, using Jones reagent. Gratify-
ingly, spirocyclization of 15 now proceeded smoothly to
generate 16 as a 9:1 mixture of diastereomers. That the
major product was the anti diastereomer was established
through a combination of COSY, HMQC, and homo-
nuclear 1H NOE experiments;the salient NOE
enhancements for anti-16 are illustrated in Figure 1. This
Our route to 4 commenced from 2-bromoanisole (9) and
(10),12
(R)-4-benzyloxy-3-hydroxy-1-butyne
which
underwent Sonogashira cross-coupling to provide the
corresponding alkynylarene in high yield (Scheme 2).
Protection of this secondary alcohol, as the triisoprop-
ylsilyl ether, then concomitant de-O-benzylation and
reduction of the acetylene gave 11 in high overall yield.
Not withstanding the apparently trivial nature of this
task, conversion of 11 to amide 4, through two oxida-
tions and an amine coupling, proved to be quite prob-
lematic. The low overall yield of this transformation is a
reflection of the proclivity with which the intermediate
carboxylic acid underwent rearrangement to the corre-
sponding triisopropylsilyl ester.
Treatment of 4 with PIFA in a mixture of CH2Cl2 and
MeOH9 generated an intractable mixture of products.
Suspecting that the trifluoroacetic acid generated in this
reaction might trigger dienone–phenol rearrangement of
the desired product,13 triethylamine was added to the
reaction mixture prior to workup. This modification
failed to provide 6, but instead generated a chromato-
graphically inseparable mixture of acetals 12, which
presumably arise through interception of the Wheland
intermediate generated upon attack of the acylnitrenium
ion on the arene ring.14 Disappointingly, attempts to
convert 12 to dienone 6, through acidic hydrolysis lead
only to decomposition. In an attempt to access 7 from
Scheme 3. Reagents and conditions: (a) PdCl2 (3 mol %), Ph3P
(3 mol %), CuI (2 mol %), Et3N, ultrasonication, 40 ꢁC, 4 h (81%);(b)
TIPSCl, Im, DMAP, DMF, rt, 24 h;(c) H (1 atm), Pd(C) (10%),
2
EtOAc, rt, 28 h (86%, two steps);(d) CrO 3, H2SO4, acetone, 25 ꢁC,
30 min;(e) i-BuOCOCl, Et3N, )20 ꢁC, 1 h, then NH2OMeÆHCl, Et3N,
)20 ꢁC fi rt, 18 h (67%, two steps);(f) PhI(OCOCF 3)2, CH2Cl2,
MeOH, )78 fi 20 ꢁC, 1 h (90%, dr 9:1);(g) H (1 atm), PtO2, EtOAc,
2
7 min, rt (17, 20%; 18, 67%);(h) (i) NaBH 4, CeCl3Æ7H2O, MeOH,
15 min, 0 ꢁC;(ii) 1 M HCl, THF, rt, 30 min (87%);(i) H (1 atm), 10%
2
Pd(C), EtOAc, rt, 30 min (99%).
Scheme 2. Reagents and conditions: (a) PdCl2 (6 mol %), Ph3P
(6 mol %), CuI (4 mol %), Et3N, ultrasonication, 40 ꢁC, 17 h (83%);(b)
TIPSCl, Im, DMAP, DMF, rt, 16 h;(c) H (1 atm), Pd(C) (10%),
2
EtOAc, rt, 3 h (92%, two steps);(d) (COCl) 2, DMSO, CH2Cl2, )60 ꢁC,
then Et3N, )60 ꢁC fi rt, 2 h;(e) NaClO 2, NaH2PO4ÆH2O, t-BuOH,
2-methyl-2-butene, 5 h (39%, two steps);(f) NH 2OMeꢀHCl, EDCꢀHCl,
Et3N, rt, 14 h (55%);(g) PhI(OCOCF 3)2, CH2Cl2–MeOH (1:1),
)78 fi )10 ꢁC, then Et3N, )10 fi 0 ꢁC, 10 min (76%);(h) H (1 atm),
2
10% Pd(C), EtOAc, 20 min, rt (99%).
Figure 1. NOE enhancements observed for compound anti-16.

D. J. Wardrop et al. / Tetrahedron Letters 45 (2004) 4229–4231
4231
lactam (8) has also been prepared in 14 steps with an
overall yield of 16%, which compares favorably with
Luzzio’s synthesis of this target molecule (15 steps, 9%
yield).4a Since the transformation of 8 into ( )-perhy-
drohistrionicotoxin (2) has previously been reported,10
our synthesis of (+)-8 also constitutes a formal synthesis
of ())-perhydrohistrionicotoxin.
Acknowledgements
We thank the National Institutes of Health (GM-67176)
for financial support. W.Z. thanks the University of
Illinois for a University Graduate Fellowship.
Scheme 4. Reagents and conditions: (a) NaBH4, MeOH, CH2Cl2,
0 ꢁC, 15 min (99%);(b) SmI 2, THF–HMPA (25:1), rt, 30 min;(c)
TBAF, THF, rt, 20 min;(d) SmI 2, EtCO2H, THF, ultrasonication, rt,
28 h (80%, three steps);(e) (COCl) 2, DMSO, CH2Cl2, )60 ꢁC, then
Et3N, )60 ꢁC fi rt, 2 h (81%).
References and notes
mixture of spirodienones was then hydrogenated over
PtO2 to provide vinylogous ester 18, again, as a mixture
of diastereomers. Cyclohexanone 17 was also generated
in this reaction and found to be a single diastereomer by
1H NMR spectroscopy. In order to prevent formation of
this undesired product, it was necessary to strictly limit
the duration of this reaction. Luche reduction of 18 and
exposure of the resulting allylic alcohol to aqueous HCl
then provided the transposed enone, which was hydro-
genated to provide ketone 7 as a single diastereomer.
This ketone is suitably functionalized to allow intro-
duction of the second piperidine ring and the C-2 n-hexyl
side chain of fasicularin (3) and as such represents a
useful platform from which to complete the asymmetric
synthesis of this natural product.
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J. Tetrahedron Lett. 1997, 38, 363.
3. For recent approaches to the 1-azaspiro[5.5]undecane ring
system, see: (a) Davison, E. C.;Fox, M. E.;Holmes, A. B.;
Roughley, S. D.;Smith, C. J.;Williams, G. R. M.;Davies,
J. E.;Raithby, P. R.;Adams, J. P.;Forbes, I. T.;Press, N.
J.;Thompson, M. J. J. Chem. Soc., Perkin Trans. 1 2002,
1494;(b) Jachak, S. M.;Karche, N. P.;Dhavale, D. D.
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H.;Vanucci-Bacque, C.;Lhommet, G. Heterocycles 2001,
55, 941;(d) Ciblat, S.;Canet, J. L.;Troin, Y. Tetrahedron
Lett. 2001, 42, 4815;(e) Stockman, R. A. Tetrahedron
Lett. 2000, 41, 9163.
4. For recent synthetic work and leading references on the
histrionicotoxins, see: (a) Luzzio, F. A.;Fitch, R. W. J.
Org. Chem. 1999, 64, 5485;(b) Williams, G. M.;Roughley,
S. D.;Davies, J. E.;Holmes, A. B. J. Am. Chem. Soc.
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X. L. J. Chem. Soc., Chem. Commun. 1998, 2509;(d)
Tanner, D.;Hagberg, L. Tetrahedron 1998, 54, 7907.
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2000, 122, 4583.
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8. (a) Wardrop, D. J.;Basak, A. Org. Lett. 2001, 3, 1053;(b)
Wardrop, D. J.;Zhang, W. Org. Lett. 2001, 3, 2353;(c)
Wardrop, D. J.;Landrie, C.;Ortz, J. A. Synlett 2003, 9,
1352.
9. Wardrop, D. J.;Burge, M. S.;Zhang, W.;Ortz, J. A.
Tetrahedron Lett. 2003, 43, 2587.
10. Aratani, M.;Dunkerton, L. V.;Fukuyama, T.;Kishi, Y.;
Kakoi, H.;Sugiura, S.;Inoue, S. J. Org. Chem. 1975, 40,
2009.
11. Kikugawa, Y. Rev. Heteroatom Chem. 1996, 15, 263.
12. Kanger, T.;Niidas, P.;Mrisepp, A.-M.;Pehk, T.;Lopp,
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13. Whiting, D. A. In Comprehensive Organic Synthesis:
Selectivity, Strategy, and Efficiency in Modern Organic
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Oxford, 1991;Vol. 3, pp 803–820.
In order to access the (+)-Kishi lactam (8), it was now
necessary to expunge the N-methoxy and a-triisoprop-
ylsilyloxy groups from compound 7 (Scheme 4). To
avoid the reductive cleavage of the N–C6 bond, the ke-
tone group of 7 was reduced with sodium borohydride to
provide the corresponding alcohol as a 3:1 mixture of
anti and syn diastereomers. While a priori, we envisioned
that cleavage of the N–O bond and the a-triisopropyl-
silyloxy group could be accomplished in one pot, using
samarium diiodide, treatment of the alcohol mixture
derived from 7 with SmI2 mediated only N–O bond
cleavage and provided 19 in high yield. Nevertheless,
after removal of the TIPS protecting group, treatment
with SmI2 in the presence of propionic acid now fur-
nished 20 as a single diastereomer in excellent overall
yield. Finally, Swern oxidation of 20 provided crystalline
(+)-8 in good yield. A comparison of the spectroscopic
and physical data collected for this material with that
previously reported confirmed its identity. Significantly,
the optical rotation of 8 {½aꢁ25 +60.4 (c 0.48, CHCl3)} was
D
25
close to the value reported by Luzzio and Fitch {½aꢁ
D
+60.3 (c 0.54, CHCl3)}.4a This observation therefore
confirms that the spirocyclization of amide 14 proceeded
with anti selectivity, as anticipated.
14. For examples of the trapping of arenium intermediates,
generated upon ipso nitration, see: Fischer, A.;Henderson,
G. N.;Iyer, L. M. Can. J. Chem. 1985, 63, 2390.
15. Braun, N. A.;Ousmer, M.;Bray, J. D.;Bouchu, D.;
Peters, K.;Peters, E. M.;Ciufolini, M. A. J. Org. Chem.
2000, 65, 4397.
In summary, we report the application of a stereose-
lective nitrenium ion cyclization to the asymmetric
preparation of a useful intermediate for the synthesis of
the marine natural product fasicularin. The (+)-Kishi