Approach to tetrodotoxin via the oxidative amidation of a phenol

Article abstract of DOI:10.1021/ol901914u

An approach to tetrodotoxin that relies on the oxidative amidation of methyl 4-hydroxyphenylacetate as a key step Is described. The stereoselective introduction of a β-hydroxynitrile functionality on one of the double bonds of the emerging dienone Is achi

Full text of DOI:10.1021/ol901914u

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4736-4739
Approach to Tetrodotoxin via the
Oxidative Amidation of a Phenol
Brian A. Mendelsohn and Marco A. Ciufolini*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received August 18, 2009
ABSTRACT
An approach to tetrodotoxin that relies on the oxidative amidation of methyl 4-hydroxyphenylacetate as a key step is described. The stereoselective
introduction of a ꢀ-hydroxynitrile functionality on one of the double bonds of the emerging dienone is achieved through an intramolecular
nitrile oxide cycloaddition-fragmentation sequence.
Tetrodotoxin (TTX, 1, Scheme 1),1 a potent neurotoxin,2 is one
of the classical targets in synthetic organic chemistry. Following
Kishi’s historical conquest of 1 in 1972,3 interest in alternative
approaches waned,4 but a resurgence of activity in this domain
has occurred in recent years as a consequence of landmark total
syntheses by Isobe (from carbohydrate educts)5 and DuBois
(through a remarkable C-H insertion of a nitrenoid to install a
key N atom).6 Such accomplishments have inspired additional
syntheses7 and synthetic studies.8
Scheme 1. Retrosynthetic Hypothesis for Tetrodotoxin
(1) Reviews: (a) Narahashi, T. Proc. Jpn. Acad., Ser. B 2008, 84. (b)
Koert, U. Angew. Chem., Int. Ed. 2004, 43, 5572.
(2) Reviews: (a) Hucho, F. Angew. Chem., Int. Ed. 1995, 34, 39. (b)
Kim, Y. H.; Kim, Y. B.; Yotsu-Yamashita, M. J. Toxicol. 2003, 22, 521.
Potential of TTX-like agents for the treatment of pain: (c) Smith, E; St, J.;
Momin, A. J. Physiol. 2008, 586, 2249. (d) Gold, M. S. Exp. Neurol. 2008,
210, 1. (e) Chung, K.; Chung, J. M. Curr. Top. Membr. 2006, 57, 311. (f)
LoGrasso, P.; McKelvy, J. Curr. Opin. Chem. Biol. 2003, 7, 452.
(3) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue,
S.; Tanino, H.; Sugiura, S.; Kakaoi, H. J. Am. Chem. Soc. 1972, 94, 9219.
(4) Representative contribution in this interim period: (a) Keana, J. F. W.;
Bland, J. S.; Boyle, P. J.; Erion, M.; Hartling, R.; Husman, J. R.; Roman,
R. B.; Ferguson, G.; Parvez, M. J. Org. Chem. 1983, 48, 3627. (b) Fraser-
Reid, B.; Alonso, R. A.; McDevitt, R. E.; Rao, B. V.; Vite, G. D.; Zottola,
M. A. Bull. Soc. Chim. Belg. 1992, 101, 617.
Indeed, the intricate structure of TTX provides limitless
opportunity for the exploration of uncharted strategies. In
that respect, we recognized the possibility apparent in the
retrosynthetic diagram of Scheme 1. Compound 3, which is
the product of oxidative amidation9 of phenol 4 (G )
(5) (a) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003,
125, 8798. (b) Nishikawa, T.; Urabe, D.; Isobe, M. Angew. Chem., Int. Ed.
2004, 43, 4782. (c) Urabe, D.; Nishikawa, T.; Isobe, M. Chem. Asian J.
2006, 1, 125. (d) Isobe, M.; Ohyabu, N.; Nishikawa, T. Yuki Gosei Kagaku
Kyokaishi 2007, 65, 492.
(6) Hinman, H.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
(7) (a) Sato, K.-I.; Akai, S.; Shoji, H.; Sugita, N.; Yoshida, S.; Nagai,
Y.; Suzuki, K.; Nakamura, Y.; Kajihara, Y.; Funabashi, M.; Yoshimura, J.
J. Org. Chem. 2008, 73, 1234. (b) Sato, K.; Akai, S.; Sugita, N.; Ohsawa,
T.; Kogure, T.; Shoji, H.; Yoshimura, J. J. Org. Chem. 2005, 70, 7496.
(8) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768.
(9) (a) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175.
(b) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299. Review of
oxidative amidation chemistry: (c) Ciufolini, M. A.; Braun, N. A.; Canesi,
S.; Ousmer, M; Chang, J; Chai, D. Synthesis 2007, 3759.
10.1021/ol901914u CCC: $40.75
Published on Web 09/21/2009
 2009 American Chemical Society

appropriate oxygen functionality or precursor thereof), nicely
maps onto intermediate 2, which emerges upon release of
the ortholactone and guanidine moieties in 1. The elaboration
of 3 into 2 requires, inter alia, the stereocontrolled introduc-
tion of an OH group at C-2 and of a CHO group (or an
equivalent functionality) at C-3. The work of Fukuyama10
suggests that such a goal may be attained via an intramo-
lecular nitrile oxide cycloaddition (INOC) reaction11 followed
by isooxazoline fragmentation, leading to the installation of
a cyano group as a formyl equivalent.
produce 7, which we imagined to progress to 8 and hence
to 2 via a stereocontrolled osmylation of the diene system.
In this paper, we describe exploratory studies that defined a
method to elaborate an intermediate of the type 3 into one
such as 7 according to the format of Scheme 2. For the
purpose of this model investigation, group G was chosen as
H.
The starting point of this research was phenol 13, the
reaction of which with I,I-(diacetoxy)iodobenzene (“DIB”)
in MeCN containing 1.5 equiv of trifluoroacetic acid9b
afforded 14 in 70% yield (Scheme 3). In preparation for the
The implementation of such a strategy in the context of 3
entails the seemingly straightforward sequence seen in
Scheme 2. In fact, this planned course of action comports a
Scheme 3. Preparation of a Nitroketone Substrate for INOC
Scheme 2. Strategy for the Elaboration of 3 into 7
advancement of the ester function to an R-nitroketone,15
a
precursor of reactive intermediate 5 (Scheme 2), the dienone
carbonyl was selectively reduced (DIBAL) and alcohol 15
was silylated. Such a maneuver suppressed the possibility
of later Michael cyclization of the nitroketone. Compound
16 emerged as the major component of an 11:1 mixture of
C-1 epimers. Its relative configuration was assigned on the
basis of an X-ray crystallographic study of a later intermedi-
ate (vide infra).
nettlesome issue relating to the viability of the keto-
isooxazoline 6. The CAS database records no examples of
substructures 9 or 10 (Figure 1), although 19 occurrences of
Saponification of the ester and careful acidification (AcOH)
afforded acid 17, a sensitive material that cyclized readily
to lactone 19 (Scheme 4), a synthetic dead end, in media
with a pH lower than about 2. Activation of the acid with
carbonyldiimidazole (“CDI”)16 and condensation of the
(12) Representative examples: ref 10 as well as: (a) Mendelsohn, B. A.;
Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett.
2009, 11, 1539. (b) Tsantali, G. G.; Dimtsas, J.; Tsoleridis, C. A.; Takakis,
I. M. Eur. J. Org. Chem. 2007, 258. (c) Gao, S.; Tu, Z.; Kuo, C.-W.; Liu,
J.-T.; Chu, C.-M.; Yao, C.-F. Org. Biomol. Chem. 2006, 4, 2851. (d)
Fernandez-Mateos, A.; Pascual Coca, G.; Rubio Gonzalez, R. Tetrahedron
2005, 61, 8699. (e) Yeh, M.-C. P.; Jou, C.-F.; Yeh, W.-T.; Chiu, D.-Y.;
Reddy, N. R. K. Tetrahedron 2005, 61, 494. (f) Souza, F. E. S.; Rodrigo,
R. Chem. Commun. 1999, 1947. (g) Toyota, M.; Asoh, T.; Fukumoto, K.
Heterocycles 1997, 45, 147. (h) Stannsen, D.; De Keukeleire, D.; Vander-
walle, M. Tetrahedron: Asymmetry 1990, 1, 547. (i) Knight, J.; Parsons,
P. J. J. Chem. Soc., Perkin Trans. 1 1989, 979. (j) Curran, D. P.; Jacobs,
P. B. Tetrahedron Lett. 1985, 26, 2031.
Figure 1. CAS search for substructures 9-12.
its “des-keto” analogue 11 are found12 and more than 200
keto-isooxazolines of the general type 12 are known. Concern
regarding 6 emanates from the fact that its CdO group is
forced into a nearly eclipsed orientation relative to the CdN
bond.13 The ensuing repulsive electrostatic interactions14 may
well engender unusual reactivity and possibly instability. In
any event, nucleophilic cleavage of the isooxazoline should
(13) The NdC-CdO dihedral angle in an MM+-optimized structure 6
where G ) H is q ) -17.0°.
(14) Similar (but not identical) electrostatic forces seemingly define the
unusual conformational properties of N-acyl piperazic acids: (a) Xi, N.;
Alemany, L. B.; Ciufolini, M. A. J. Am. Chem. Soc. 1998, 120, 80. (b)
Ciufolini, M. A.; Xi, N. Chem. Soc. ReV. 1998, 437.
(10) Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002, 1323.
(11) Reviews: (a) Mulzer, J. In Organic Synthesis Highlights; Mulzer,
J., Altenbach, H. J., Braun, M., Krohn, K., Reissig, H. U., Eds.; VCH:
Weinheim, Germany, 1990; Vol. I, p 77. (b) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247. See especially p 12255-12259.
(15) Chemistry of R-nitroketones: Ballini, R.; Bosica, G.; Fiorini, D.;
Palmieri, A. Tetrahedron 2005, 61, 8971.
Org. Lett., Vol. 11, No. 20, 2009
4737

Scheme 4
.
Undesired Reactions of Intermediates 17 and 18
Scheme 5. Cyclization of Reduced Derivatives of 18
resultant acid imidazolide with CH3NO2/tert-BuOK17 pro-
vided nitroketone 18.18
The dehydration of 18 to the corresponding R-keto-nitrile
oxide19 proved to be troublesome. Various reagents com-
monly used for this purpose, such as 4-chlorophenyl isocy-
anate20 and BOC2O,21 performed poorly, affording the
desired INOC product as a minor component of a complex
mixture. Exposure of 18 to Et3N22 also failed to induce
cycloaddition, promoting instead conversion into 20 (Scheme
4; structure ascertained by X-ray crystallography), a com-
pound that formally arises through O-alkylation of the enolate
of the nitroketone via allylic displacement of the OTBDPS
group.
Sensing that such obstacles may be a consequence of the
difficulties alluded to earlier, we sought to alleviate the
problem by reducing the keto group prior to the INOC step.
Accordingly, NaBH4 treatment of 18 provided alcohol 22
(Scheme 5), a sensitive material that was prone to undergo
retro-Henry fragmentation, especially upon attempted puri-
fication. Therefore, crude 22 was immediately O-silylated
(TBSCl/imidazole/Et3N). This step occurred with a con-
comitant Torssell-type cyclization23 to a 1:1 mixture of
isooxazolines 23 and 24. Such a lack of diastereoselectivity
signals that the steric demand of an OTBS group is
insufficient to exert stereocontrol during the cycloaddition
step. This is contrary to the case of a tosylamide.12a It is
worthy of note that a mixture of diastereomeric nitroso
acetals24 27 and 28 was also isolated as a minor product of
the reaction (flash chromatography). Upon standing, 27 and
28 underwent spontaneous conversion into 23 and 24. A
sample of nearly pure diastereomer 28 (6% yield) was
secured by flash chromatography and characterized. This
material was converted into 24 upon standing. Such observa-
tions implicate the intermediacy of siloxy nitronate25 29 en
route to the isooxazolines, i.e, product formation via an
intramolecular siloxynitronate-olefin cycloaddition (ISOC)
process. It remains unclear whether the ISOC pathway
operates exclusively or in parallel with the INOC one.
Release of the silyl ethers from 23 and 24 afforded a 1:1
mixture of diols 25 and 26. Crystals of pure 26 slowly
separated from this mixture, enabling an X-ray structural
study that ascertained the relative configuration between C-1
and C-4. Recall that this stereochemical relationship had been
established upon DIBAL reduction of 14 (Scheme 3).
The success of the TBSCl-mediated cyclization of 22
induced us to attempt the same reaction with ketone 18.
Treatment with 1 equiv each of TBSCl and imidazole
induced slow cyclization to 30, which was obtained in 38%
yield after chromatography. At this time, we are unable to
resolve the question of whether 30 forms via an ISOC or an
(16) (a) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351. Review:
(b) Armstrong, A.; Li, W. N,N’-Carbonyldiimidazole. In e-EROS Ency-
clopedia of Reagents for Organic Synthesis; Wiley, 2006. http://www.m-
rw.interscience.wiley.com/eros/articles/rc024/frame.html; DOI 10.1002/
047084289X.rc024.pub2.
(17) Baker, D. C. Putt, S. R. Synthesis 1978, 478. See also ref 15.
(18) The synthesis of 18 detailed herein was devised by Dr. Cyril
Benhaim during his tenure as a postdoctoral fellow in this group. We thank
Dr. Benhaim for his efforts in this area.
(19) These species are documented; e.g.: (a) Paul, R.; Tchelitcheff, S.
Bull. Soc. Chim. Fr. 1962, 2215. (b) Martin, S. F.; Dappen, M. S.; Dupre´,
B.; Murphy, C. J.; Colapret, J. A. J. Org. Chem. 1989, 54, 2209. For the
ester and nitrile analogues, see: Kozikowski, A. P.; Adamcz, M. J. Org.
Chem. 1983, 48, 366.
(20) (a) Confalone, P. N.; Ko, S. S. Tetrahedron Lett. 1984, 25, 947.
(b) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
(21) Basel, Y.; Hassner, A. Synthesis 1997, 309.
(22) Cecchi, L.; De Sarlo, F.; Marchetti, F. Tetrahedron Lett. 1985, 46,
7877.
(24) Chemistry of nitroso acetals: Denmark, S. E.; Baiazitov, R. Y. J.
Org. Chem. 2006, 71, 593, and refs cited therein.
(23) (a) Andersen, S. H.; Das, N. B.; Joergensen, R. D.; Kjeldsen, G.;
Knudsen, J. S.; Sharma, S. C.; Torssell, K. B. G. Acta. Chem. Scand. B
1982, 36, 1. (b) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; VCH: New York, 1988.
(25) See ref 23 as well as (a) Klebe, J. F. J. Am. Chem. Soc. 1964, 86,
3399. (b) Shitkin, V. M.; Ioffe, S. L.; Kashutina, M. V.; Tartakovskii, V. A.
IzV. Akad. Nauk SSSR, Ser. Khim. 1977, 2266. (c) Namboothiri, I. N. N.;
Hassner, A.; Gottlieb, H. E. J. Org. Chem. 1997, 62, 485.
4738
Org. Lett., Vol. 11, No. 20, 2009

Initial attempts to induce conversion of 30 into 31 by the
action of NaOMe/MeOH or K2CO3 in alcohols (MeOH,
EtOH, BnOH) gave disappointing results. Methanolic imi-
dazole or 4-dimethylaminopyridine had no effect on the
substrate. It ultimately transpired that a catalytic amount of
Li2CO3 in MeOH performed best, promoting conversion of
30 into 31 in 68% yield after chromatography.
Scheme 6. Preparation and Methanolysis of Keto-Isooxazolines
Finally, compound 33, an analogue of 6 where G ) H,
was prepared by desilylation of 30 and ensuing Dess-Martin
oxidation. Substance 30 was quite intolerant of TBAF or
the HF-pyridine complex: either reagent, especially the basic
TBAF, rapidly degraded it. Conversely, it readily withstood
the action of aqueous HF in MeCN, which provided 32 in
70% yield. Diketone 33 was not amenable to chromato-
graphic purification (poor recovery), and it was best advanced
to the next step in crude form. Thus, exposure to cat. Li2CO3
in MeOH furnished the target 34 in 38% yield after
chromatography (Scheme 6).
This work demonstrates the feasibility of the planned
approach to TTX building blocks of type 7 along the lines
of Scheme 2. It also provides information concerning the
reactivity of a number of structurally novel intermediates.
Ongoing research aims to parlay these findings into a total
synthesis of 1. Results of such investigations will be disclosed
in due course.
INOC mechanism. Remarkably, attempts to accelerate this
reaction by the use of excess reagents (10 equiv each)
resulted in the unexpected formation of the noteworthy
dihydropyridone 21 as the major product (Scheme 4, 65%
after chromatography) and in a concomitant decrease in the
yield of 30 (5% after chromatography). The structure of this
architecturally unique material (the CAS database contains
no records of like substances) was ascertained by X-ray
crystallography. The compound formally arises through an
unusual Knoevenagel-type condensation of the nitroketone
with the acetamide, proceeding in all likelihood via an O-silyl
imino ether derivative of the latter unit.
Acknowledgment. We thank the University of British
Columbia, NSERC, CIHR, BCKDF, the Canada Research
Chair program, and Merck-Frosst Canada for financial
support.
Supporting Information Available: Experimental pro-
cedures and characterization data for the compounds de-
scribed herein. This material is available free of charge via
the Internet at http://pubs.acs.org.
At this juncture, we refocused our attention on the
development of a procedure for keto-isooxazoline ring
fragmentation. Once again, the execution of the desired
transformation required a good deal of experimentation.
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