Bromocyclization of alkynyl guanidine: A new approach to the synthesis of cyclic guanidines of saxitoxin

Article abstract of DOI:10.1055/s-0030-1259546

Bromocyclization of propargyl and homopropargyl guanidines possessing homopropargyl alcohol provides five- and six-membered cyclic guanidines with spiro-hemiaminal, respectively, a candidate of precursors for saxitoxin. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259546

LETTER
651
Bromocyclization of Alkynyl Guanidine: A New Approach to the Synthesis of
Cyclic Guanidines of Saxitoxin
Bromocyclization
u
of
A
lkynyl
G
s
uanidine uke Sawayama, Toshio Nishikawa*
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894111; E-mail: nisikawa@agr.nagoya-u.ac.jp
Received 21 December 2010
involves resolving synthetic issues: the regioselective
Abstract: Bromocyclization of propargyl and homopropargyl
guanidines possessing homopropargyl alcohol provides five- and
six-membered cyclic guanidines with spiro-hemiaminal, respec-
tively, a candidate of precursors for saxitoxin.
halocyclization of alkynylguanidine and the subsequent
cyclization of the resulting haloalkenyl guanidine. In the
halocyclization of alkynyl guanidines, there are two pos-
sible routes for constructing the bicyclic guanidine struc-
ture (Scheme 2): (a) 5-exo-dig cyclization of propargyl
guanidine D to C followed by six-membered cyclization,
or (b) 6-exo-dig cyclization of homopropargyl guanidine
F to E followed by five-membered cyclization. Although
6-endo-dig cyclization of D to a six-membered cyclic
guanidine and 5-endo-dig cyclization of F to a dihydro-
pyrole derivative may be possible,9 we anticipated that the
exo mode of cyclization would proceed preferentially in
both cases to yield the desired cyclic guanidine products
C and E, respectively.
Key words: saxitoxin, cyclic guanidine, alkynyl guanidine, bro-
mocyclization, spiro-hemiaminal
Cyclic guanidine is a common structural motif found in
many biologically active marine natural products.1 Tetro-
dotoxin and saxitoxin (1) are the most famous examples
of these products; both exhibit potent blockage of sodium
ion influx through voltage-gated sodium channels.2 Pres-
ently, our focus has been to develop a subtype selective
blocker of sodium channels on the basis of natural prod-
ucts such as tetrodotoxin3 and saxitoxin. In this context,
we initiated synthetic studies on saxitoxin. The total syn-
thesis of saxitoxin was first achieved by Kishi4 in 1977
and later by Jacobi5 in 1984. Recently, the total syntheses
of saxitoxin and its analogues were reported by Du Bois6
and Nagasawa7 independently. Relatively simple cyclic
guanidine compounds were reported to show some degree
of subtype selectivity in the blockage of the sodium chan-
nels.8 These reports prompted us to disclose our efforts in
regard to the synthesis of saxitoxin and its analogues us-
ing the halocyclization of alkynyl guanidine as a key reac-
tion.
To our knowledge, few example involving the halo-
cyclization of alkynyl guanidine have been reported in the
literature to date.10,11 We first investigated the reactions to
determine the regioselectivities and conditions of halo-
cyclization of alkynyl guanidines such as C and E.
The synthesis of propargyl guanidine 9, a precursor corre-
sponding to D for the cyclization of the five-membered
cyclic guanidine as C, commenced with the reaction of a
lithium acetylide to Garner’s aldehyde (2)12 (Scheme 3).
In the presence of HMPA, the addition of the lithium
acetylide generated from siloxybutyne 3 took place highly
diastereoselectively (>10:1)13 to give 4 in 54% yield.
Mesylation followed by deprotection of all the protective
groups (acetonide, Boc, and TBS) of 5 with TFA yielded
an amino alcohol, which was obtained as an amine hydro-
chloride 6 after treatment with an ion-exchange resin
(Amberlite® IRA-410). Utilization of the amine/HCl was
crucial for achieving reproducible results of the next
Since the pyrolidine ring of saxitoxin (1) would be synthe-
sized by an intramolecular N-alkylation of A (PG2 = Ms,
etc.), we plan to construct bicyclic guanidine as A through
the repeated halocyclization of alkynyl bisguanidine B
(Scheme 1), which could be readily prepared from the
corresponding diamino acetylene. This synthetic strategy
PG1O
PG1O
H2NOCO
H
N
H
H
NH
N
HN
N
HN
HN
NH
NH2
HN
NH2
N
H
N H
HN
N
H2N
N
H2N
H
OH
OH
saxitoxin (1)
X
X+
OPG2
X+
X
PG2O
B
A
Scheme 1 Synthetic strategy for constructing bicyclic guanidine of saxitoxin (1)
SYNLETT 2011, No. 5, pp 0651–0654
x
x.
x
x.
2
0
1
1
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259546; Art ID: U11310ST
© Georg Thieme Verlag Stuttgart · New York

652
Y. Sawayama, T. Nishikawa
LETTER
PG1O
O
OR
(10:1)
H
N
N
Boc
HN
O
c
a
NH
N H
54%
HN
N
N
H
CHO
(b)
Boc
X
TBSO
(a)
2
X
b
4 R = H
5 R = Ms
OPG2
(quant.)
A
(a)
(b)
HO
TBSO
OMs
PG1O
PG1O
ClH•H2N
HN
d
e
H
NHR2
X
N
R1HN
X
69%
quant.
(2 steps)
HN
HN
NH
HO
TBSO
N H
N
H
6
7
OPG2
OPG2
TBSO
p-NsN
TBSO
C
E
H
N
NBoc
NHBoc
X+
5-exo-dig
X+ 6-exo-dig
PG1O
p-NsHN
f, g
PG1O
R1HN
56%
(2 steps)
H
N
NHR2
TBSO
TBSO
HN
NH
9
8
HN
NH2
NH2
Scheme 3 Synthesis of precursor 9 for five-membered cyclic guani-
dine. Reagents and conditions: (a) H-C≡C(CH2)2OTBS (3), n-BuLi,
HMPA, toluene, –78 °C, 2 h; (b) MsCl, Et3N, CH2Cl2, r.t., 1 h; (c)
TFA, CH2Cl2, H2O, r.t., 2 h, then Amberlite® IRA-410, MeOH, r.t.,
30 min; (d) Et3N, DMF then TBSCl, r.t., 30 min; (e) p-NsCl, Et3N,
Me3N·HCl, toluene, r.t., 40 min; (f) NH3 aq, MeCN, r.t., 15 h; (g)
BocHNC(SMe)=NBoc, HgCl2, Et3N, DMF, r.t., 30 min.
OPG2
OPG2
D
F
Scheme 2 Retrosynthetic analysis of the cyclic guanidine through
halocyclization of alkynyl guanidine (protective groups of guanidine
are omitted)
desilylation of 9 with tetrabutylammonium fluoride
(TBAF), was exposed to three equivalents of pyridinium
tribromide under similar conditions, unexpectedly spiro-
hemiaminal 13 was obtained in 74% yield as ca. 2:1 dias-
tereomeric mixture at the spiro center, and the aromatized
product 12b was not obtained (entry 4). We suggested that
an iminium ion intermediate generated from 11b was
trapped with the intramolecular hydroxy group, which
suppressed the formation of the aminoimidazole product
12b despite the excess use of PyHBr3. The product 13 is
also a potentially useful intermediate for the next guani-
dine ring cyclization.
transformation. The exposure of 6 to triethylamine in
DMF gave an aziridine in which two hydroxy groups were
protected with TBS to afford 7, quantitatively.
After the introduction of a p-nosyl group (p-Ns) to the
aziridine 7,14,15 the treatment of the resulting 7 with aque-
ous ammonia gave rise to regioselective ring opening of
the aziridine at the propargyl position. Guanidinylation
with di-Boc-methylisothiourea in the presence of HgCl2
and Et3N furnished 9, a precursor of the halocyclization,
in a moderate overall yield.
With substrate 9 in our hand, we next examined the con-
ditions for halocyclization that lead to a five-membered
cyclic guanidine as C. Our preliminary experimentation
revealed that bromocyclization was better than iodocy-
clization because of the reactivity and stability of the
products. Representative results of bromocyclization list-
ed in Table 1 shows exclusive exo-mode cyclizations as
we expected. The compound 9 was treated with one
equivalent of NBS in dichloromethane to afford the de-
sired product 11a in 45% yield (entry 1). When two equiv-
alents of NBS were utilized, the product 11a was not
detected; aminoimidazole 12a was obtained instead (entry
2). This result indicates that the compound 11a reacts with
the excess of NBS to afford aminoimidazole 12a through
aromatization.16 Upon treatment of 9 with pyridinium tri-
bromide (PyHBr3) in a biphasic system of CH2Cl2 and
aqueous K2CO3, the yield of 11a was improved to 70%
yield (entry 3). When the substrate 10, derived by the
Next, we sought to establish the synthesis of six-mem-
bered cyclic guanidine as E through a similar bromocy-
clization. A precursor homopropargyl guanidine 16 was
synthesized from the same intermediate 5 in Scheme 4.
Amine hydrochloride salt 6 prepared from 5 was treated
with triethylamine to form aziridine, which was subse-
quently guanidinylated with Boc,Cbz-protected methyl-
isothiourea under similar conditions to the synthesis of 9.
Unexpectedly, the product obtained was a 1:1 diastereo-
meric mixture. The structure was proposed to be 14,
where the proximate hydroxy group participated to the
guanidine carbon.17,18 The unique structure of the product
made it possible to discriminate the two hydroxy groups:
the remaining hydroxy group was protected with TBSCl
and triethylamine, whereas the condition of acetic anhy-
dride and triethylamine acetylated the hidden alcohol to
afford 15 in a high yield.
Synlett 2011, No. 5, 651–654 © Thieme Stuttgart · New York

LETTER
Bromocyclization of Alkynyl Guanidine
653
Table 1 Bromocyclization of Propargyl Guanidine 9 and 10
TBSO
TBSO
TBSO
TBSO
H
NBoc
H
N
H
N
N
N
p-NsHN
Br
p-NsHN
p-NsHN
Br
p-NsHN
conditions
r.t.
NBoc
NBoc
NBoc
H
O
NHBoc
+
+
N
N
N
Boc
Boc
Boc
OR
HO
Br
Br
13
OR
9
R = TBS
TBAF, THF
(73%)
11a R = TBS
11b R = H
12a R = TBS
12b R = H
10 R = H
Entry Substrate
Conditions
Products (%)
R
Reagents, solvents
Time (min)
11a
45
0
12a
0
13
1
2
3
4
9
TBS
TBS
TBS
H
NBS (1 equiv), CH2Cl2
NBS (2 equiv), CH2Cl2
210
120
50
0
0
0
9
40
0
9
PyHBr3 (1.5 equiv), K2CO3 (4 equiv), CH2Cl2–H2O
PyHBr3 (3 equiv), K2CO3 (6 equiv), CH2Cl2–H2O
70
0
10
20
0
74 (66:34)
CbzHN
BocHN
O
vealed that mono-Cbz-protected guanidine 18 derived
from 16 in two steps underwent bromocyclization with
three equivalents of pyridinium tribromide in the biphasic
solvent system to form six-membered cyclic guanidine 19
as a single diastereomer in good overall yield. In this case,
exo-mode bromocyclization took place exclusively as ex-
pected. Although the bromoenamide corresponding to E
in Scheme 2 has not been obtained by treatment with one
equivalent of pyridinium tribromide in this case, the spiro
product 19 will also be an important intermediate for the
next guanidine cyclization.
N
H
H
c, d
a
b
6
5
90%
(2 steps)
95%
(3 steps)
HO
14
AcO
HN
AcO
N3
N
e
g
BocN
BocN
CbzHN
CbzHN
87%
In summary, we have developed bromocyclization of pro-
pargyl and homopropargyl guanidines. This cyclization
strategy utilizing a simple alkynyl guanidine as a precur-
sor should provide a variety of cyclic guanidine, which are
possible scaffolds for the development of a subtype-selec-
tive blocker of sodium channels. Because the five- and
six-membered cyclic guanidine compounds 11a, 13, and
19 synthesized in this study are fully functionalized for
saxitoxin, these compounds are potentially important in-
termediates for saxitoxin and its analogues. Further syn-
thetic studies on saxitoxin and its analogues according to
Scheme 1 are currently under way in our laboratory. On
the other hand, since the strucuture of guanidine spiro-
hemiaminal of 19 is found in crambescin B, an ichthyo-
toxic marine natural product (Figure 1),19 synthetic efforts
towards crambescin B on the basis of the bromocycliza-
tion strategy are also in progress.
TBSO
RO
15
f
16 R = TBS
17 R = H
(43%)
AcO
HN
AcO
HN
N3
N3
h
CbzN
Br
Br
NH2
HO
71%
(2 steps)
CbzN
N
H
O
18
19
Scheme 4 Synthesis of six-membered guanidine 19. Reagents and
conditions: (a) TFA, CH2Cl2, H2O, r.t., 2 h, then Amberlite® IRA-410,
MeOH, 30 min; (b) Et3N, DMF, r.t., then HgCl2, Et3N,
BocHNC(SMe)=NCbz, DMF, r.t., 30 min; (c) TBSCl, Et3N, CH2Cl2,
DMF, r.t., 16.5 h; (d) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 3.5 h; (e)
NaN3, DMF, r.t., 3.5 h; (f) TBAF, THF, r.t., 10 min; (g) TFA, CH2Cl2,
r.t., 2 h, then Amberlite® IRA-410, MeOH, 30 min; (h) PyHBr3,
K2CO3, CH2Cl2, H2O, r.t., 1 h.
CH3(CH2)9
O
NH2
NH2
Ring opening of the aziridine with sodium azide took
place in a highly regioselective manner to provide 16, a
precursor for cyclization. In sharp contrast to the bro-
mocyclization for the five-membered cyclic guanidine de-
scribed above, the bromocyclization of 16 did not proceed
under the same conditions. Extensive examination re-
(CH2)7
HN
O
N
H
H2N
N
H
O
Figure 1 Structure of crambescin B
Synlett 2011, No. 5, 651–654 © Thieme Stuttgart · New York

654
Y. Sawayama, T. Nishikawa
LETTER
(8) Mao, H.; Fieber, L. A.; Gawley, R. E. ACS Med. Chem. Lett.
2010, 1, 135.
(9) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734. (b) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
736.
(10) The iodocyclization of alkynyl imidazolinone was reported.
See: Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.;
Nakamura, O. Tetrahedron 1996, 52, 6581.
(11) During preparation of this manuscript, transition-metal-
catalyzed cyclizations of alkynyl guanidines were reported:
(a) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.; Looper,
R. E. Angew. Chem. Int. Ed. 2011, 50, 684. (b) Ermolat’ev,
D. S.; Bariwal, J. B.; Steenackers, H. P. L.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was financially supported by a Grant-in-Aid for Scienti-
fic Research and G-COE grant from JSPS, SUNBOR Scholarship
(to Y.S.), the Naito Foundation, and the Nagase Foundation.
References and Notes
(1) Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva,
A. E.; Romminger, S.; Morais, R. P.; Bandeira, K.; Mizuno,
C. M. Nat. Prod. Rep. 2010, 27, 1871; and references cited
therein.
(2) Llewellyn, L. E. Nat. Prod. Rep. 2006, 23, 200.
(3) For synthetic studies on tetrodotoxin from this laboratory,
see: Urabe, D.; Nishikawa, T.; Isobe, M. Chem. Asian J.
2006, 1, 125; and references cited therein.
(4) (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am.
Chem. Soc. 1977, 99, 2818. (b) Kishi, Y. Heterocycles
1980, 14, 1477. (c) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc.
1992, 114, 7001.
(5) (a) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem.
Soc. 1984, 106, 5594. (b) Martinelli, M. J.; Brownstein, A.
D.; Jacobi, P. A.; Polanc, S. Croat. Chem. Acta 1986, 59,
267. (c) Jacobi, P. A. In Strategies and Tactics in Organic
Synthesis, Vol. 2; Lindberg, T., Ed.; Academic Press: New
York, 1989, 191–219.
De Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew.
Chem. Int. Ed. 2010, 49, 9465. (c) Perl, N. R.; Ide, N. D.;
Prajapati, S.; Perfect, H. H.; Durón, S. G.; Gin, D. Y. J. Am.
Chem. Soc. 2010, 132, 1802. (d) Giles, R. L.; Sullivan, J. D.;
Steiner, A. M.; Looper, R. E. Angew. Chem. Int. Ed. 2009,
48, 3116.
(12) Garner, P.; Park, J. M. Org. Synth., Coll. Vol. IX 1998, 300.
(13) Fujisawa, T.; Nagai, M.; Koike, Y.; Shimizu, M. J. Org.
Chem. 1994, 59, 5865.
(14) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(15) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183.
(16) In fact, when 11a was exposed to NBS in CH2Cl2,
aminoimidazole 12a was obtained.
(17) The structure of 14 was supported by extensive NMR
analysis of the di-Boc analogue of 14 (as a single product)
prepared from 6 with di-Boc-methylisothiourea in a similar
manner. See Supporting Information.
(18) (a) Disadee, W.; Ishikawa, T.; Kawahata, M.; Yamaguchi,
K. J. Org. Chem. 2006, 71, 6600. (b) White, J.; Baker, D. C.
Synthesis 1990, 151. (c) Fromm von, E.; Arbeiten, N.;
Barrenscheen, H.; Frieder, J.; Pirk, L.; Kapeller, R. Justus
Liebigs Ann. Chem. 1925, 442, 130.
(6) (a) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128,
3926. (b) Fleming, J. J.; McReynolds, M. D.; Du Bois, J.
J. Am. Chem. Soc. 2007, 129, 9964. (c) Mulcahy, J. V.;
Du Bois, J. J. Am. Chem. Soc. 2008, 130, 12630.
(d) Andresen, B. M.; Du Bois, J. J. Am. Chem. Soc. 2009,
131, 12524.
(19) Isolation and structure reassignment of crambescin B:
(a) Berlinck, R. G. S.; Braekman, J. C.; Daloze, D.;
Hallenga, K.; Ottinger, R.; Riccio, I. B. R. Tetrahedron Lett.
1990, 31, 6531. (b) Snider, B. B.; Shi, Z. J. Org. Chem.
1993, 58, 3828.
(7) (a) Iwamoto, O.; Koshino, H.; Hashizume, D.; Nagasawa, K.
Angew. Chem. Int. Ed. 2007, 46, 8625. (b) Iwamoto, O.;
Shinohara, R.; Nagasawa, K. Chem. Asian J. 2009, 4, 277.
(c) Iwamoto, O.; Nagasawa, K. Org. Lett. 2010, 12, 2150.
Synlett 2011, No. 5, 651–654 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.