Convergent assembly of polycyclic ethers via acyl radical addition to unactivated enol ether

Article abstract of DOI:10.1021/ol062349i

(Diagram presented) A new convergent strategy for assembling 6/6- and 6/7-fused ether ring systems was developed. The key features in our method include Ag⁺-promoted facile formation of chemically labile enol ether from 0,S-acetal and addition

Full text of DOI:10.1021/ol062349i

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5801-5804
Convergent Assembly of Polycyclic
Ethers via Acyl Radical Addition to
Unactivated Enol Ether
Masayuki Inoue,*,†,‡ Yuuki Ishihara,† Shuji Yamashita,† and Masahiro Hirama*,†
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, and
Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku UniVersity, Sendai 980-8578, Japan
inoue@ykbsc.chem.tohoku.ac.jp; hirama@ykbsc.chem.tohoku.ac.jp
Received September 25, 2006
ABSTRACT
A new convergent strategy for assembling 6/6- and 6/7-fused ether ring systems was developed. The key features in our method include
+
Ag -promoted facile formation of chemically labile enol ether from O,S-acetal and addition of an acyl radical to unactivated enol ether to
cyclize a six- or seven-membered ether ring.
The trans-fused polyethers, represented by ciguatoxin (1,
Figure 1)1 and brevetoxin B (2),2 are interesting natural
nomena such as seafood poisonings and red tides.3 Their
exquisitely complex structures have served as the inspiration
for the development of new methodologies in organic
synthesis.4
Because the stepwise synthesis of more than 10 rings is
practically impossible due to the large number of transforma-
tions required, the development of powerful methodologies
for coupling substructures has been particularly important
for the construction of gigantic molecules.5 We previously
(1) (a) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.; Yasumoto,
T. J. Am. Chem. Soc. 1990, 112, 4380. (b) Satake, M.; Morohashi, A.; Oguri,
H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J. Am. Chem. Soc.
1997, 119, 11325. (c) Yasumoto, T.; Igarashi, T.; Legrand, A.-M.; Cruchet,
P.; Chinain, M.; Fujita, T.; Naoki, H. J. Am. Chem. Soc. 2000, 122, 4988.
(2) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik,
J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.
(3) (a) Shimizu, Y. Chem. ReV. 1993, 93, 1685. (b) Scheuer, P. J.
Tetrahedron 1994, 50, 3. (c) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897. (d) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589.
(4) For recent reviews on syntheses of polycyclic ethers, see: (a) Alvarez,
E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D. Chem. ReV.
1995, 95, 1953. (b) Nicolaou, K. C.; Sorensen, E. J. Classics in Total
Synthesis: Targets, Strategies, Methods; VCH: Weinheim, 1996; p 731.
(c) Mori, Y. Chem.-Eur. J. 1997, 3, 849. (d) Yet, L. Chem. ReV. 2000,
100, 2963. (e) Marmsa¨ter, F. P.; West, F. G. Chem.-Eur. J. 2002, 8, 4347.
(f) Evans, P. A.; Delouvrie, B. Curr. Opin. Drug DiscoVery DeV. 2002, 5,
986. (g) Nakata, T. Chem. ReV. 2005, 105, 4314.
Figure 1. Representative natural polycyclic ethers.
products by virtue of their unusual ladder-shaped architecture,
biological activity, and association with catastrophic phe-
† Department of Chemistry.
‡ Research and Analytical Center for Giant Molecules.
10.1021/ol062349i CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/07/2006

described the total synthesis of the three ciguatoxin congeners
including 1 by utilizing a unified convergent strategy.6 The
corresponding two halves of 1 were assembled at the 9/7-
ring system of the central portion (blue highlighting in Figure
1) via four key steps (Scheme 1): (i) coupling of the right
that an acyl radical, generated through homolytic cleavage
of the C-Se bond of 9, would react with the enol ether to
afford the first six- or seven-membered ring of 10.9-11
Reductive etherification12 from 10 would then give the
second six- or seven-membered ring of 8. Reaction from 9
to 10 was a particularly challenging step because of inef-
ficient orbital interaction between the high SOMO of the
nucleophilic acyl radical and the high LUMO of the electron-
rich enol ether.13 To develop the methodology, the tetracyclic
ring systems were selected as target structures.
Scheme 1. Two Radical Routes to Assemble the Polyether
Structure
Synthesis of acyl radical cyclization of substrates 16a-c
began with tetrahydropyrans 11 (n ) 0 or 1) and 13 (m ) 0
or 1) (Scheme 2).14 After treatment of phenylsulfide 11 with
Scheme 2. Formation of Enol Ethers from O,S-Acetals
and left fragments by O,S-acetal formation (3 + 4f5);7 (ii)
introduction of â-alkoxyacrylate (5f6); (iii) seven-mem-
bered ring cyclization using O,S-acetal as a radical donor
(6f7); and (iv) ring-closing olefin metathesis (RCM)8 to
build the nine-membered ring (7f8). Additionally, this
protocol proved to be applicable to other 6/7,8,9/7/6-
tetracyclic ring systems (8: m ) 1-3; n ) 1).7b
To increase the utility of the O,S-acetal coupling strategy,
an alternative method was sought for assembling 6/6-, 7/6-,
and 6/7-membered ring systems [8: m ) 0, 1; n ) 0, 1
(Scheme 1)] that are inaccessible through the radical cy-
clization/RCM sequence. These two methodologies would
be complementary, and their combination would allow the
construction of any typical ring system of natural ladder-
shaped polycyclic ethers. Here, we report the development
of a new method utilizing O,S-acetals as common intermedi-
ates.
NCS,15 the chloride of the resultant 12 was displaced by the
hindered secondary alcohol of 13 by the action of AgOTf
As illustrated in Scheme 1, the mode of the radical
cyclization differentiates the present method from the previ-
ous one. Thus, enol ether 9, prepared from O,S-acetal 5, was
designed to be used as a radical acceptor. It was envisioned
(9) Evans developed the stereoselective methods for construction of the
five-, six-, and seven-membered ether rings through acyl radical addition
to vinylogous carbonates and sulfonates: (a) Evans, P. A.; Roseman, J. D.
Tetrahedron Lett. 1995, 36, 31. (b) Evans, P. A.; Roseman, J. D. J. Org.
Chem. 1996, 61, 2252. (c) Evans, P. A.; Roseman, J. D.; Garber, L. T. J.
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Lett. 1997, 38, 8165. (e) Evans, P. A.; Manangan, T. J. Org. Chem. 2000,
65, 4523. (f) Evans, P. A.; Raina, S.; Ahsan, K. Chem. Commun. 2001,
2504.
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1997, 37, 119. (b) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem.
ReV. 1999, 99, 1991.
(12) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
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Int. Ed. Engl. 1988, 27, 1362. (c) Nicolaou, K. C.; Hwang, C.-K.; Nugiel,
D. A. J. Am. Chem. Soc. 1989, 111, 4136.
(13) Giese, B. Angew. Chem., Int. Ed. 1983, 22, 753.
(14) Compounds 11 and 13 were synthesized from 2-deoxy-D-ribose by
a similar procedure that was described in ref 7b.
(5) (a) Inoue, M. Org. Biomol. Chem. 2004, 2, 1811. (b) Inoue, M. Chem.
ReV. 2005, 105, 4379.
(6) (a) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama,
M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12013. (b) Inoue, M.; Hirama,
M. Acc. Chem. Res. 2004, 37, 961. (c) Hirama, M. Chem. Rec. 2005, 5,
240. (d) Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.;
Kawada, Y.; Komano, K.; Yamashita, S.; Lee, N.; Hirama, M. J. Am. Chem.
Soc. 2006, 128, 9352.
(7) (a) Inoue, M.; Wang, G. X.; Wang, J.; Hirama, M. Org. Lett. 2002,
4, 3439. (b) Inoue, M.; Wang, J.; Wang, G. X.; Ogasawara, Y.; Hirama,
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(8) For reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
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5802
Org. Lett., Vol. 8, No. 25, 2006

and 2,6-di-tert-butyl-4-methyl pyridine (DTBMP),16 leading
to coupling adduct 14 as a diastereomeric mixture. Enol ether
formation then was realized using the same AgOTf in the
presence of more basic i-Pr2NEt.17 Under these conditions,
activation of the phenyl sulfide of 14 occurred to give acid-
labile enol ether 15 in excellent yield. The geometric isomer
ratio of 15 did not reflect the diastereomer ratio at the O,S-
acetal carbon center of 14, indicating an E1-like mechanism
of the reaction. Finally, basic hydrolysis of methyl ester 15,
followed by phenylselenide introduction by the action of
(PhSe)2 and n-Bu3P,18 generated selenoester 16. The high
overall yields of the five-step sequence were indifferent to
the number of the methylenes (m, n ) 0, 1).
amount of aldehyde 19b was obtained. The more reactive
Ph3SnH generated only 19b (entry 2), indicating that the rate
of acyl radical reduction exceeded that of the cyclization.
To suppress premature reduction, (TMS)3SiH (entry 3) and
n-Bu3GeH20 (entry 4) were used because these less-reactive
hydrogen donors can be an advantage when the cyclization
occurs slowly.21 Both reagents produced the tetrahydropyran
in high yield as a mixture of 17b and 18b; n-Bu3GeH gave
the better combined yield (entry 4). The optimized conditions
also were applied successfully to 16a, leading to 17a and
18a in 75% combined yield (entry 7). Importantly, the
R-positions of ketones 18a and 18b were isomerized ef-
fectively with DBU to afford the desired isomers 17a and
17b, respectively.
To evaluate the stereochemical correlation between the
geometrical isomers of 16 and the diastereomers 17 and 18,
chromatographically separated cis-16 and trans-16 were
subjected independently to radical cyclization conditions.
Interestingly, whereas the cis-isomers of 16a and 16b resulted
only in the formation of the desired diastereomers 17a and
17b, respectively (entries 5 and 8), the trans-isomers
generated an approximately 1:1 mixture of the diastereomeric
tetrahydropyrans (entries 6 and 9).
First, six-membered ring cyclization from 16b was un-
dertaken (Table 1). Upon exposure to n-Bu3SnH/Et3B19 in
Table 1. 6-Exo Acyl Radical Cyclization
Because of the success with this radical reaction, the same
reaction conditions were applied to the more entropically
disfavored seven-membered ring cyclization22 (Table 2).
Table 2. 7-Exo Acyl Radical Cyclization
Remarkably, n-Bu3GeH and Et3B converted 16c into cyclized
product 17c in 54% yield with complete stereochemical
control (entry 1). A small amount of tetrahydropyran 20 was
formed in this reaction; competing decarbonylation of the
acyl radical produced the corresponding alkyl radical that
reacted with the enol ether. Despite this minor path,
stereocontrolled intramolecular addition to the electron-rich
a n-Bu3SnH was used as a hydrogen donor in benzene. b cis:trans ) 1.5:1
c Ph3SnH was used as a hydrogen donor in benzene. d cis:trans ) 1.2:1
e (TMS)3SiH was used as a hydrogen donor in toluene.
benzene at room temperature (entry 1), the desired 17b and
its epimer 18b were isolated in low yields, and a significant
(20) (a) Johnston, L. J.; Lusztyk, J.; Wayner, D. D. M.; Abeywickreyma,
A. N.; Beckwith, A. L. J.; Scaiano, J. C.; Ingold, K. U. J. Am. Chem. Soc.
1985, 107, 4594. (b) Pike, P.; Hershberger, S.; Hershberger, J. Tetrahedron
1988, 44, 6295. (c) Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Org.
Biomol. Chem. 2004, 2, 585.
(15) Paquette, L. A. Org. React. 1977, 25, 1.
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Lett. 1982, 1555. (b) McAuliffe, J. C.; Hindsgaul, O. Synlett 1998, 307.
(17) For selected examples of related reactions, see: (a) Nicolaou, K.
C.; McGarry, D. G.; Sommers, P. K. J. Am. Chem. Soc. 1990, 112, 3696.
(b) Iio, H.; Nagaoka, H.; Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7965.
(18) Singh, U.; Ghosh, S. K.; Chadha, M. S.; Mamdapur, V. R.
Tetrahedron Lett. 1991, 32, 255.
(19) (a) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
109, 2547. For a review, see: (b) Ollivier, C.; Renaud, P. Chem. ReV. 2001,
101, 3415.
(21) Rate constants for the reaction of primary alkyl radicals with Group
14 hydrides (M-1 s-1 at 80 °C): Ph3SnH (2.2 × 107) > n-Bu3SnH (6.4 ×
106) > (TMS)3SiH (1.2 × 106) > n-Bu3GeH (3.4 × 105). (a) Chatgilialoglu,
C.; Newcomb, M. AdV. Organomet. Chem. 1999, 44, 67. (b) Chatgilialoglu,
C. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: 2001; Chapter 1.3, pp 28-49.
(22) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
Org. Lett., Vol. 8, No. 25, 2006
5803

alkene to form oxepane is noteworthy and highlights the
versatility of our reaction. Interestingly, the cis-isomer of
16c (entry 2) gave a greater yield of 17c in comparison to
the trans-isomer (entry 3).
Scheme 3. Synthesis of Tetracyclic Ethers
The stereoselectivity of both the six- and seven-membered
ring cyclizations is explained as shown in Figure 2. The
25b, prepared from 17b, failed to give oxepane 27b. The
main product in this reaction was the reduced, open-chain
diol 26b. In contrast, reductive etherification successfully
produced tetrahydropyran rings in 27a and 27c. Treatment
of 17a with aqueous HF simultaneously removed the TBS
and p-methoxybenzylidene groups to afford the hemiacetal,
which was converted into the 6/6/6/6-ring system 27a by
the action of TMSOTf and Et3SiH. Application of the same
protocol to 17c resulted in synthesis of the 6/7/6/6-ring
system 27c, which is the pseudoenantiomeric compound of
27b. These results provided valuable insights into the
cyclization strategy, revealing the desirability of constructing
the seven-membered ring by radical cyclization rather than
by the reductive etherification for synthesis of the 6/7-ring
systems.
In summary, we have devised the new, efficient convergent
assembly of polycyclic ethers via acyl radical cyclization.
The neutral reaction sequence would enable syntheses of any
6/6- or 6/7-ring system of natural polycyclic ethers with
sensitive functional groups. Furthermore, the use of the
unactivated enol ethers as radical acceptors should find wide
application in organic synthesis.
Figure 2. Mechanistic rationale for the acyl radical cyclization.
exclusive stereoselectivity for 17 observed in the cyclization
of cis-16 (Table 1, entries 5 and 8; Table 2, entry 2) is the
result of the strongly favored transition state 21 with the
s-trans-conformation to alleviate severe A1,3-type allylic
strain of the bulky R group in the transition state 22. In
contrast, both conformational isomers 23 and 24, generated
from trans-16, encounter unfavorable steric interactions; the
interaction between the oxygen and R for 23 and the A1,3-
type allylic strain of the hydrogen for 24. The nonselective
formation of 17a/b and 18a/b from trans-16a/b suggests that
the energy difference between 23a/b and 24a/b is negligible
for the six-membered ring formation (Table 1, entries 6 and
9). In contrast, 23c appears to be more stable than 24c
because of the exclusive formation of 17c from trans-16c,
yet the cyclization from 23c is less efficient than that from
21, presumably due to the steric repulsion in 23c (Table 2,
entry 2 vs 3). The different stereochemical outcomes of trans-
16a/b and trans-16c indicate that the number of the meth-
ylenes influences the three-dimensional interaction of the
radical acceptor and the donor in the transition state.
Acknowledgment. This work was supported financially
by SORST, Japan Science and Technology Agency (JST),
and a Grant-in-Aid for Scientific Research (S) from the Japan
Society for the Promotion of Science (JSPS).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for synthetic compounds
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
To complete our model investigation, our focus turned to
syntheses of the tetracyclic ether systems (Scheme 3).
Disappointedly, reductive etherification of hydroxyketone
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Org. Lett., Vol. 8, No. 25, 2006