A general method for convergent synthesis of polycyclic ethers based on Suzuki cross-coupling: Concise synthesis of the ABCD ring system of ciguatoxin

Article abstract of DOI:10.1021/ol990885n

(matrix presented) A general method for convergent assembly of polyether structure has been developed based on palladium(0)-mediated Suzuki cross-coupling reaction of alkylboranes with cyclic ketene acetal phosphates. The present method allowed for coupli

Full text of DOI:10.1021/ol990885n

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1075-1077
A General Method for Convergent
Synthesis of Polycyclic Ethers Based on
Suzuki Cross-Coupling: Concise
Synthesis of the ABCD Ring System of
Ciguatoxin
Makoto Sasaki,* Haruhiko Fuwa, Makoto Ishikawa, and Kazuo Tachibana
Department of Chemistry, School of Science, The UniVersity of Tokyo, and
CREST, Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
msasaki@chem.s.u-tokyo.ac.jp.
Received July 28, 1999
ABSTRACT
A general method for convergent assembly of polyether structure has been developed based on palladium(0)-mediated Suzuki cross-coupling
reaction of alkylboranes with cyclic ketene acetal phosphates. The present method allowed for coupling of medium-sized ether rings and thus
a concise synthesis of the ABCD ring system of ciguatoxins has been achieved.
Marine polycyclic ethers, such as brevetoxins, ciguatoxins,
and maitotoxin, present formidable and challenging synthetic
targets due to their structural complexity and exceptionally
potent biological activities.1 One of the most critical issues
in the synthesis of these large natural products is the
development of synthetic methods for convergent coupling
of polyether fragments. Despite recent advances in the
synthesis of medium-sized cyclic ethers,2 only a few methods
for the convergent assembly of polyether structure have been
reported to date.3 In connection with the synthetic studies
on ciguatoxins,4,5 we have recently developed a new strategy
for convergent synthesis of polyether frameworks based on
palladium(0)-catalyzed Suzuki cross-coupling of alkylboranes
with cyclic ketene acetal triflates.6,7 Although this method
has represented a powerful tool for the efficient construction
of trans-fused polytetrahydropyran ring systems via coupling
of six-membered rings, seven-membered ketene acetal tri-
flates could not be utilized as the substrates in this coupling
reaction due to their instability under the aqueous basic
(3) (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M.
E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321. (b) Nicolaou, K. C.;
Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118, 1565.
(c) Oishi, T.; Nagumo, Y.; Hirama, M. Synlett 1997, 980. (d) Oishi, T.;
Nagumo, Y.; Hirama, M. Chem. Commun. 1998, 1041. (e) Nicolaou, K.
C.; Gunzner, J. L.; Shi, G.-q.; Agrios, K. A.; Ga¨rtner, P.; Yang, Z. Chem.
Eur. J. 1999, 5, 646. (f) Very recently, the ABCDE ring framework of
ciguatoxin has been prepared using alkylation-ring-closing metathesis
approach; Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M.; Chem. Commun.
1999, 1063.
(1) For recent reviews on ciguatoxins and related marine toxins, see (a)
Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897. (b) Scheuer, P. J.
Tetrahedron 1994, 50, 3.
(2) For recent reviews on polyether synthesis, see (a) Alvarez, E.;
Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D. Chem. ReV. 1995,
95, 1953. (b) Mori, Y. Chem. Eur. J. 1997, 3, 849.
10.1021/ol990885n CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/14/1999

conditions. Herein, we report the first Suzuki cross-coupling
of alkylboranes with cyclic ketene acetal phosphates, superior
substrates to the corresponding triflates with respect to their
stability and handling.8,9 The present method allowed for a
general approach to convergent synthesis of polycyclic ethers
containing medium-sized rings, and a concise synthesis of
the ABCD ring system of ciguatoxin analogues (CTX3C 1
and 51-hydroxyCTX3C 2, Figure 1)10,11 has been achieved
accordingly.
Table 1. Suzuki Cross-Coupling of Alkylborane Derived from
exo-Olefin 3 with Cyclic Ketene Acetal Phosphates (eq 1)a
Figure 1. Structure of CTX3C (1) and 51-HydroxyCTX3C (2).
We chose to examine the cross-coupling of the alkylborane
generated in situ via the hydroboration of exo-olefin 312 with
cyclic ketene acetal phosphate 4a13 as a model system to
establish the reaction conditions (eq 1, Table 1). Hydrobo-
(4) (a) Sasaki, M.; Hasegawa, A.; Tachibana, K. Tetrahedron Lett. 1993,
34, 8489. (b) Sasaki, M.; Inoue, M.; Tachibana, K. J. Org. Chem. 1994,
59, 715. (c) Inoue, M.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 1997,
38, 1611. (d) Inoue, M.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed.
Engl. 1998, 37, 965. (e) Sasaki, M.; Inoue, M.; Noguchi, T.; Takeichi, A.;
Tachibana, K. Tetrahedron Lett. 1998, 39, 2783. (f) Sasaki, M.; Noguchi,
T.; Tachibana, K. Tetrahedron Lett. 1999, 40, 1337. (g) Inoue, M.; Sasaki,
M.; Tachibana, K. Tetrahedron 1999, 55, 10949.
(5) For recent synthetic studies from other groups, see (a) Oka, T.;
Fujiwara, K.; Murai, A. Tetrahedron 1996, 52, 12091. (b) Oishi, T.; Shoji,
M.; Maeda, K.; Kumahara, N.; Hirama, M. Synlett 1996, 1165. (c) Alvarez,
E.; Delgado, M.; D´ıaz, M. T.; Hanxing, L.; Pe´rez, R.; Mart´ın, J. D.
Tetrahedron Lett. 1996, 37, 2865. (d) Isobe, M.; Hosokawa, S.; Kira, K.
Chem. Lett. 1996, 473. (e) Atsuta, H.; Fujiwara, K.; Murai, A. Synlett 1997,
307. (f) Oishi, T.; Maeda, K.; Hirama, M. Chem. Commun. 1997, 1289.
(g) Oguri, H.; Hishiyama, S.; Sato, O.; Oishi, T.; Hirama, M.; Murata, M.;
Yasumoto, T.; Harada, N. Tetrahedron 1997, 53, 3057. (h) Oishi, T.; Shoji,
M.; Kumahara, N.; Hirama, M. Chem. Lett. 1997, 845. (i) Oka, T.; Fujiwara,
K.; Murai, A. Tetrahedron Lett. 1997, 38, 8053. (j) Ami, E.; Kishimoto,
H.; Ohrui, H.; Meguro, H. Biosci. Biotech. Biochem. 1997, 61, 2019. (k)
Oka, T.; Murai, A. Tetrahedron 1998, 54, 1. (l) Oka, T.; Fujiwara, K.;
Murai, A. Tetrahedron 1998, 54, 21. (m) Oishi, T.; Nagumo, Y.; Hirama,
M. Chem. Commun. 1998, 1041. (n) Isobe, M.; Nishizawa, R.; Hosokawa,
S.; Nishikawa, T. Chem. Commun. 1998, 2665. (o) Hosokawa, S.; Isobe,
M. J. Org. Chem. 1999, 64, 37. (p) Saeeng, R.; Isobe, M. Tetrahedron
Lett. 1999, 40, 1911. (q) Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M.
Tetrahedron Lett. 1999, 40, 5405 and references therein.
(6) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett.
1998, 39, 9027.
(7) For a review on Suzuki cross-coupling reaction, see Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457.
(8) Cyclic ketene acetal phosphates were successfully used for palladium-
(0)-catalyzed Stille coupling, leading to the total synthesis of brevetoxin
A, see (a) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Ga¨rtner, P.; Yang,
Z. J. Am. Chem. Soc. 1997, 119, 5467. (b) Nicolaou, K. C.; Wallace, P. A.;
Shi, S.; Ouellette, M. A.; Bunnage, M. E.; Gunzner, J. L.; Agrios, K. A.;
Shi, G.-q.; Ga¨rtner, P.; Yang, Z. Chem. Eur. J. 1999, 5, 618.
a exo-Olefin 3 was hydroborated with 9-BBN (2.6 equiv, THF, r.t. f
60 °C) and then treated in situ with aqueous 1 M NaHCO3 (3 equiv),
Pd(PPh3)4 (0.1 equiv), and cyclic ketene acetal phosphate 4 (2 equiv) in
DMF at 50 °C for 20 h. bCyclic ketene acetal phosphates were prepared
from the corresponding lactones [KHMDS, THF-HMPA, (PhO)2P(O)Cl,
-78 °C] following the procedure of Nicolaou et al.8a cThe use of 1 equiv
d
of 4a. The use of 1.4 equiv of 4a.
ration of 3 with 9-BBN (2.6 equiv, THF, r.t. to 60 °C)
provided the corresponding alkylborane, which was in situ
coupled with 1 equiv of 4a under conventional Suzuki
conditions [aqueous K3PO4, Pd(PPh3)4, DMF] to yield the
desired coupling product 5a albeit in moderate yield (46-
(10) Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett. 1993, 34,
1975.
(11) Satake, M.; Fukui, M.; Legrand, A.-M.; Cruchet, P.; Yasumoto, T.
Tetrahedron Lett. 1998, 39, 1197.
(9) Very recently, nickel(0)- and palladium(0)-catalyzed Suzuki cross-
coupling reactions of arylboronic acids with enol phosphates have been
reported, see (a) Huffman, M. A.; Yasuda, N. Synlett 1999, 471. (b) Nan,
Y.; Yang, Z. Tetrahedron Lett. 1999, 40, 3321.
(12) Synthetic scheme for compound 3 is included as Supporting
Information.
(13) The ketene acetal phosphates were prepared from the corresponding
lactones following the procedure of Nicolaou et al., see ref 8.
1076
Org. Lett., Vol. 1, No. 7, 1999

Scheme 1. Synthesis of the ABCD Ring System of CTX3Ca
a Reagents and conditions: (a) Thexylborane, THF, -20 f 0 °C, then H2O2, NaOH; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C f r.t.;
(c) TsOH, MeOH-CH2Cl2 (4:1), r.t. f 55 °C; (d) SO3‚Pyr, Et3N, DMSO, CH2Cl2, 0 °C f r.t.; (e) Ph3P+CH3Br-, NaHMDS, THF, 0 °C;
(f) Et3SiH, BF3‚OEt2, CH2Cl2-CH3CN (5:3), r.t.; (g) I2, CH2Cl2, 0 °C f r.t.; (h) Zn, AcOH, Et2O-MeOH, r.t.; (i) NaHMDS, allyl bromide,
DMF, 0 °C f r.t.; (j) RuCl2(dCHPh)(PCy3)2, CH2Cl2, r.t.
56%). Presumably, hydrolysis of 4a would occur competi-
tively under these conditions due to the slow rate of oxidative
addition of less reactive 4a to the palladium(0) complex. The
yield of 5a was improved by carrying out the reaction with
aqueous NaHCO3 as a milder base instead of K3PO4 (Table
1, entry 1). Finally, the best result was obtained when excess
4a (2 equiv) was employed, giving 5a in nearly quantitative
yield (entry 3). Other phosphine-free palladium catalysts such
as Pd2(dba)3‚CHCl3 proved ineffective, which is consistent
with the results of cross-coupling of phenylboronic acid with
an enol phosphate.9a
It is noteworthy that this coupling reaction can be applied
to not only six-membered ketene acetal phosphates but also
medium-sized rings (Table 1, entries 4-8), including eight-
membered ring where the corresponding triflates are known
to be difficult to prepare.14 Since the seven-membered ketene
acetal triflate decomposed even under these mild conditions,15
use of the phosphate leaving group is essential for this
coupling reaction. The present method therefore appears to
be quite general and efficient for synthesis of polycyclic
ethers containing medium-sized rings.
the TBS and MOM groups and concomitant acetal formation
giving hydroxy methyl acetal 7 in 82% overall yield. Further
oxidation to the corresponding aldehyde followed by Wittig
reaction provided terminal olefin 8 in 79% yield for the two
steps. Reduction of 8 with Et3SiH-BF3‚OEt2 proceeded
smoothly to give tricyclic ether 9 as a single stereoisomer
in 86% yield. Regioselective debenzylation of 9 was carried
out according to the method of Cipolla et al.16 to provide
alcohol 10, which was allylated giving bisolefin 11 in 65%
overall yield. Finally, ring-closing metathesis of 11 by using
Grubbs’ catalyst [RuCl2(dCHPh)(PCy3)2]17 furnished the
desired ABCD ring system 1218 in quantitative yield. Thus,
a concise and rapid synthesis of 12 was achieved in 10 steps
and 30% overall yield from 3.
In conclusion, we have demonstrated Suzuki cross-
coupling of alkylboranes with cyclic ketene acetal phosphates
to be a powerful tool for the construction of polycyclic ethers
containing medium-sized rings. The present methodology is
thus believed to allow a general approach to convergent
syntheses of polyether marine toxins. Further studies toward
the total synthesis of ciguatoxins and their simplified
analogues based on the present strategy are currently
underway and will be reported in due course.
The usefulness of the described method has been dem-
onstrated in the concise synthesis of the ABCD ring system
of CTX3C series (1, 2) (Scheme 1). Hydroboration of 5c
with thexylborane proceeded regio- and stereoselectively to
give, after oxidative workup, alcohol 6 in 73% yield (86%
based on recovered 5c). Oxidation under Swern conditions
followed by acidic treatment in MeOH effected removal of
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid for Scientific Research on Priority
Area 08245103 from the Ministry of Education, Science,
Sports and Culture, Japan.
(14) (a) Tsushima, K.; Araki, K.; Murai, A. Chem. Lett. 1989, 1313. (b)
Tsushima, K.; Murai, A. Chem. Lett. 1990, 761. (c) Barber, C.; Jarowicki,
K.; Kocienski, P. Synlett 1991, 197.
(15) Reaction of the seven-membered ketene acetal triflate corresponding
to 4c [aqueous 1 M NaHCO3 (3 equiv), Pd2(dba)3‚CHCl3 (0.05 equiv), Ph3-
As (0.4 equiv), DMF, r.t. 20 h] gave 5c in only 29% yield.
(16) Cipolla, L.; Lay, L.; Nicotra, F. J. Org. Chem. 1997, 62, 6678.
(17) Schwab, R. R.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
Supporting Information Available: Synthetic schemes
for compounds 3 and 4a-e, typical experimental procedures
for synthesis of 4 and Suzuki cross-coupling reaction,
spectroscopic data for compounds 5a-f, experimental pro-
cedures and spectroscopic data for compounds 6-12, and 1H
and 13C NMR spectra for compound 12 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) The relative stereochemistry of 22 was firmly established by
prominent NOEs between H-8/H-12, H-9/H-5 and H-9/H-11 (CTX3C
numbering).
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