Total synthesis of (-)-dysibetaine via a nitrenium ion cyclization-dienone cleavage strategy

Article abstract of DOI:10.1039/b403081h

The diastereoselective total synthesis of the marine natural product (-)-dysibetaine is reported. The key steps in this venture are i) a diastereoselective nitrenium ion spirocyclization, which serves to generate the pyrrolidinone ring and quaternary ster

Full text of DOI:10.1039/b403081h

Total synthesis of (2)-dysibetaine via a nitrenium ion cyclization–dienone
cleavage strategy†
Duncan J. Wardrop* and Matthew S. Burge
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL
60201-7061, USA. E-mail: wardropd@uic.edu; Fax: 1-312-996-0431; Tel: 1-312-355-1035
Received (in Corvallis, OR, USA) 27th February 2004, Accepted 23rd March 2004
First published as an Advance Article on the web 27th April 2004
The diastereoselective total synthesis of the marine natural
product (2)-dysibetaine is reported. The key steps in this
venture are i) a diastereoselective nitrenium ion spirocycliza-
tion, which serves to generate the pyrrolidinone ring and
quaternary stereocenter of the target, and ii) use of the
2-methoxycyclohexa-2,5-dienone ring formed during cycliza-
tion as a masked 2-amino-1,3-dicarbonyl synthon.
ing adalinine,9 lactacystin10 and dysibetaine (5). As outlined in
Scheme 2, we anticipated that oxidative spirocyclization of 8 would
proceed selectively to generate anti dienone 7 as a result of steric
strain between the triisopropylsilyl ether and the o-methoxyl group
on the arene.11 Having thus established the quaternary stereogenic
center and g-lactam of the target molecule, ozonolytic cleavage of
the dienone ring would now reveal b-formyl ester 6, which would
be suitably functionalized to allow introduction of the C-5
(trimethylammonium)methyl group. While substituted cyclohexa-
1,4-dienes (obtained through the Birch reduction of arenes) have
frequently been employed as latent 1,3-dicarbonyl groups,12 the use
of cyclohexa-2,5-dienones to the same end has not been re-
ported.13
Our route to 5 commenced from a,b-unsaturated ester 9 (Scheme
3). Thus, Sharpless asymmetric dihydroxylation14 and regiose-
lective reduction of the resulting diol with triethylsilane in the
presence of trifluoroacetic acid15 provided compound 10 in > 98%
ee.16 The hydroxyl group of 10 was protected as the triisopropylsi-
lyl ether and the methyl ester saponified with potassium hydroxide
in methanol. The resulting carboxylic acid was treated with isobutyl
chloroformate and triethylamine to form the mixed anhydride,
which was coupled in-situ with methoxylamine to provide
compound 8 in excellent overall yield. Following the method
previously reported,6 a solution of 8 in CH2Cl2 was added to a
suspension of PIFA in MeOH at 278 °C and the mixture allowed
to warm to 230 °C over 1 h at which point the reaction was
quenched with aqueous sodium bicarbonate. Spirodienone 7 was
subsequently isolated as a chromatographically inseparable 9 : 1
mixture of C-5 epimers in near quantitative yield. That the major
component of this mixture was the anti diastereomer was apparent
from the NOESY spectrum, which displayed a cross-peak between
the b-hydrogen of the dienone ring at 6.68 ppm and H-4a at 2.03
ppm (Scheme 3).
Excitatory amino acid (EAA) receptors are widely distributed in the
mammalian central nervous system (CNS) and play a role in a range
of brain functions and abnormalities, having been implicated in
such disorders as epilepsy, Alzheimer’s disease, AIDS-related
dementia, and Parkinsonism.1 As a consequence, there is consider-
able interest in the development of synthetic routes to excitatory
amino acids, both natural and otherwise.2 (2)-Dysibetaine (5), an
unusual amino acid isolated by Sakai from the marine sponge
Dysidea herbacea, is a neuroexcitotoxin which may bind to the
glutamate receptors present in the CNS of mice.3 While Sakai
unequivocally established the structure of 5 by X-ray crystallog-
raphy, the absolute stereochemistry of this natural product
remained unknown until Snider reported the first total synthesis in
2001.4,5 Herein, we report the application of a novel nitrenium ion
spirocyclization–dienone cleavage strategy to the total synthesis of
(2)-dysibetaine.
As part of an on-going investigation of the synthetic chemistry of
N-acylnitrenium ions,6,7 we recently reported that nitrenium ions 2,
generated through oxidation of a- and b-substituted 3-aryl-N-
methoxypropionamides 1 with phenyliodine(III) bis(trifluoroace-
tate) (PIFA), undergo spirocyclization to generate azaspiranes 3
with high levels of 1,2- and 1,3-induction (Scheme 1).8 Given the
ability to control the stereochemistry of the spirocenter in 3, we
were interested in the possibility that oxidative cleavage of the
carbon–carbon double bonds of the dienone ring would provide a
convenient route to trisubstituted azetidinone, pyrrolidinone and
piperidinone derivatives 4. Significantly, this structural motif is
found in a number of biologically-active natural products, includ-
Ozonolysis of 7 in CH2Cl2 at 278 °C followed by reductive
workup with dimethyl sulfide generated b-formyl ester 6, together
with a number of other unidentified products. Unfortunately,
attempts to purify 6 proved unsuccessful since this compound was
unstable and underwent decomposition at room temperature in a
matter of hours. Ozonolytic cleavage of 7 in methanol and
subsequent reduction with thiourea,17 on the other hand, proceeded
cleanly to provide the methyl hemiacetal of 6. Since attempts to
purify this material by flash chromatography also resulted in
Scheme 1 Nitrenium ion spirocyclization–dienone cleavage—a ster-
eoselective route to trisubstituted N-heterocycles.
† Electronic supplementary information (ESI) available: experimental
procedures and data including copies of 1H-NMR and 13C-NMR spectra for
5
and all new compounds. See http://www.rsc.org/suppdata/cc/b4/
b403081h/
Scheme 2 Synthetic strategy for (2)-dysibetaine.
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C h e m . C o m m u n . , 2 0 0 4 , 1 2 3 0 – 1 2 3 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

extensive decomposition, we sought to reduce the hemiacetal group
in-situ in anticipation that primary alcohol 11 would be more
tractable. Accordingly, after ozonolysis of 7 in methanol and
reduction with thiourea, the reaction mixture was concentrated and
immediately treated with sodium triacetoxyborohydride in acetic
acid18 to furnish 11 in excellent overall yield from 3.
chloride. Since this compound readily underwent ester hydrolysis,
it was immediately converted to the natural product through a
sequence of quaternization, with methyl iodide and ester hydrolysis
using alkaline Dowex 550A resin. In this manner, (2)-dysibetaine
(5) was obtained in 43% yield, over three steps.21 A comparison of
the spectroscopic and chiroptical properties of this material with
that reported by Sakai3 and Snider4 indicated a close match.
In summary, we report the total synthesis of the marine natural
product (2)-dysibetaine (5). The central features of this work
include i) construction of the 5,5-disubstituted pyrrolidinone ring
and C-5 quaternary stereocenter using a diastereoselective acylni-
trenium ion spirocyclization and ii) use of the cyclohexa-
2,5-dienone ring, generated in this transformation, as a latent
2-amino-1,3-dicarbonyl group. Further application of the nitrenium
ion spirocyclization–dienone cleavage strategy disclosed herein is
now underway in this laboratory.
Reductive cleavage of the N–O bond of 11 was accomplished by
heating this compound with Mo(CO)6 in aqueous acetonitrile.19
Exposure of the reaction mixture to air for 24 h prior to isolation
served to oxidize the remaining low-valent molybdenum species
and facilitated the purification of amide 12. Introduction of nitrogen
functionality at the C-5 hydroxymethyl group of 12 was achieved
by exposure of the corresponding mesylate to sodium azide in DMF
at elevated temperature, which provided 13 in moderate yield.20
Attempts to directly install the trimethylammonium group of 5, by
reaction of the mesylate with trimethylamine, were unsuccessful.
After removal of the triisopropylsilyl group from 13 using HF in
acetonitrile, hydrogenation of the azide group over palladium-on-
carbon in the presence of aqueous HCl provided hydrochloride 14.
This compound was now converted to 5 using the three-step
protocol reported by Snider for the corresponding ethyl ester.4
Thus, reductive methylation of 14 by hydrogenation in the presence
of formaldehyde provided the corresponding dimethylamine hydro-
We gratefully thank the National Institutes of Health (GM-
67176) for financial support of this work.
Notes and references
1 J. J. Hansen and P. Krogsgaard-Larsen, Med. Res. Rev., 1990, 10, 55.
2 M. G. Moloney, Nat. Prod. Rep., 2002, 19, 597.
3 R. Sakai, C. Oiwa, K. Takaishi, H. Kamiya and M. Tagawa,
Tetrahedron Lett., 1999, 40, 6941.
4 B. B. Snider and Y. Gu, Org. Lett., 2001, 3, 1761.
5 Synthesis of deoxydysibetaine: B. K. Le Nguyen and N. Langlois,
Tetrahedron Lett., 2003, 44, 5961.
6 (a) D. J. Wardrop and A. Basak, Org. Lett., 2001, 3, 1053; (b) D. J.
Wardrop and W. Zhang, Org. Lett., 2001, 3, 2353.
7 For reviews of nitrenium ion chemistry, see: (a) R. A. Abramovitch and
R. Jeyaraman, in Azides and Nitrenes: Reactivity and Utility, ed. E. F. V.
Scriven, Academic Press, Orlando, 1984, Chapter 6; (b) Y. Kikugawa,
Rev. Heteroatom Chem., 1996, 15, 263; (c) D. E. Falvey, in Reactive
Intermediate Chemistry, ed. R. A. Moss, M. S. Platz and M. Jones, Jr.,
Wiley, New York, 2004, Chapter 13.
8 D. J. Wardrop, M. S. Burge, W. Zhang and J. A. Ortíz, Tetrahedron
Lett., 2003, 44, 2587.
9 D. J. Wardrop, C. L. Landrie and J. A. Ortíz, Synlett, 2003, 1352.
10 S. Omura, K. Matsuzaki, T. Fujimoto, K. Kosuge, T. Furuya, S. Fujita
and A. Nakagawa, J. Antibiot., 1991, 44, 117.
11 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
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and P. D. Woodgate, Aust. J. Chem., 1990, 43, 681.
14 K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung,
K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang, D. Q. Xu and X.
L. Zhang, J. Org. Chem., 1992, 57, 2768.
15 M. Nakajima, K. Tomioka and K. Koga, Tetrahedron, 1993, 49,
10807.
16 Determined by NMR analysis of the (R)-(+)-a-methoxy-a-(trifluor-
omethyl)phenylacetate (MTPA) derivative.
17 D. Gupta, R. Soman and S. Dev, Tetrahedron, 1982, 38, 3013.
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Scheme 3 Reagents and conditions: [i] AD-mix-b, CH3SO2NH2, t-BuOH,
H2O, 0 °C, 24 h, 91%; [ii] Et3SiH, CF3CO2H, CH2Cl2, 0 °C, 10 min, 84%,
> 98% ee; [iii] TIPS-Cl, Im, DMAP, DMF, rt, 36 h, 99%; [iv] KOH,
MeOH, reflux, 16 h, 98%; [v] i-BuOCOCl, Et3N; MeONH2·HCl, CH2Cl2,
rt, 16 h, 88%; [vi] PIFA (1.2 equiv.), CH2Cl2, MeOH, 278 ? 230 °C, 1 h,
99%, dr = 90 : 10; [vii] O3/O2, MeOH, 278 °C, 1 h; thiourea, 278 °C ?
rt, 30 min; NaBH(OAc)3, AcOH, rt, 4 h, 91%; [viii] Mo(CO)6, CH3CN–
H2O (15 : 1), reflux, 24 h; air, rt, 24 h, 90%; [ix] MsCl, Et3N, CH2Cl2, 0 °C,
3 h, 87%; [x] NaN3, DMF, 80 °C, 24 h, 63%; [xi] HF, CH3CN, rt, 4 h, 91%;
[xii] H2 (50 psi), Pd/C (10%), HCl aq., MeOH, rt, 1.5 h, 99%; [xiii] i) H2 (50
psi), CH2O, Pd/C (10%), H2O, rt; ii) MeI, THF, rt, 36 h; iii) Dowex-550A,
MeOH, 55 °C, 24 h, 43% (3 steps).
20 S. Knapp and A. T. Levorse, J. Org. Chem., 1988, 53, 4006.
21 Synthetic (2)-dysibetaine (5): [a]24D 28.0 (c 0.30, H2O), [lit.3 [a]20
D
27.3 (c 0.26, H2O)]; 1H NMR (500 MHz, D2O) d 4.20 (dd, J = 7.8, 5.4
Hz, 1 H, H-3), 3.89 (d, J = 13.9 Hz, 1 H, H-6), 3.59 (d, J = 13.9 Hz,
1 H, H-6), 3.05 (s, 9 H, NMe3), 2.51 (dd, J = 14.0, 7.8 Hz, 1 H, H-4),
1.85 (dd, J = 14.0, 5.4 Hz, 1 H, H-4); 13C NMR (125 MHz, CD3OD/
D2O) d 179.6 (CO), 176.8 (CO), 73.1 (C-3), 69.1 (C-6), 64.1 (C-5), 55.6
(NMe3), 42.4 (C-4).
C h e m . C o m m u n . , 2 0 0 4 , 1 2 3 0 – 1 2 3 1
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