Design and synthesis of a trans-fused polycyclic ether skeleton as an α-helix mimetic scaffold

Article abstract of DOI:10.1016/j.tetlet.2005.02.039

Inspired by the common skeletal feature of potent marine toxins, a ladder-like polycyclic ether scaffold was designed as the basis for the synthesis of structurally defined α-helix mimics. A synthetic route to trans-fused 6/6/6/6/6 pentacyclic ether skele

Full text of DOI:10.1016/j.tetlet.2005.02.039

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2179–2183
Design and synthesis of a trans-fused polycyclic ether skeleton
as an a-helix mimetic scaffold
Hiroki Oguri,*,ꢀ Akifumi Oomura, Shintaro Tanabe and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, and SORST,
Japan Science and Technology Corporation (JST), Sendai 980-8578, Japan
Received 12 January 2005; revised 31 January 2005; accepted 8 February 2005
Abstract—Inspired by the common skeletal feature of potent marine toxins, a ladder-like polycyclic ether scaffold was designed as
the basis for the synthesis of structurally defined a-helix mimics. A synthetic route to trans-fused 6/6/6/6/6 pentacyclic ether skeletons
is presented, involving the iterative assembly of tetrahydropyran rings via the SmI2-mediated coupling reaction of a-sulfonyl ketones
with aldehydes.
Ó 2005 Elsevier Ltd. All rights reserved.
The potent ladder-like polycyclic ether marine toxins are
based on a common trans/syn-fused cyclic ether array,
with ring sizes ranging from five to nine members.1
Among these potent toxins, brevetoxins2,3 and ciguatox-
ins4,5 (Fig. 1) are believed to bind to a common site (site
5) on the a subunit of voltage-sensitive sodium channels
(VSSCs),6 where the a subunit consists of 24 transmem-
brane helices. Although the three-dimensional structure
of the receptor site in the VSSC remains unknown, and
the extremely limited availability of the toxins has ham-
pered further biological investigation, recent studies
have suggested a relationship between the size of the
polycyclic ether skeleton and the inhibitory activity
against the binding of labeled brevetoxins with the
VSSC.7 It appears that both the length and the relatively
straight conformation of the cyclic ether skeletons are
critical factors in this relationship, and are required
for the binding and modulation of the VSSC function.8
The interactions between the polycyclic ethers and the
receptor site are surmised to be primarily hydrophobic
and to be supplemented by hydrogen bonding between
skeletal oxygen atoms and the OH/NH groups of the
a-helical peptides.8 In addition to this hydrogen bond-
ing, axially oriented CH groups adjacent to the skeletal
oxygen atoms are also expected to play an important
role in molecular recognition of the aromatic amino acid
residues through CH/p interactions, as exemplified by
the crystal structures of complexes between the carbohy-
drate-binding proteins and specific substrates.9,10
Figure 1. Structures of brevetoxin B, ciguatoxin and CTX3C.
Keywords: Polycyclic ether; a-Helix; Scaffold; Samarium iodide.
On analysis of the mode of action of these ladder-like
toxins, it was noticed that the trans-fused cyclic ethers
may be topologically analogous to the a-helical pep-
tides. In the 6/6/6 tricyclic system (Fig. 2a), the distance
*
Corresponding authors. Tel.: +81 22 217 6563; fax: +81 22 217
6566; e-mail addresses: oguri@sci.hokudai.ac.jp; hirama@ykbsc.
chem.tohoku.ac.jp
˚
ꢀ Present address: Division of Chemistry, Graduate School of Science,
Hokkaido University.
between skeletal oxygen atoms on the same side (4.8 A)
in the cyclic ethers is almost identical to the interval
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.039

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H. Oguri et al. / Tetrahedron Letters 46 (2005)2179–2183
Figure 2. (a) Structural features of a cyclic ether skeleton and an a-helix; (b) Typical helix–helix interaction, showing projection of the surface defined
by the ridges and grooves of two helices (green and blue); (c) Hypothetical binding model for the cyclic ether with an a-helix; (d) Design of cyclic
ether 1 as an a-helix mimetic scaffold. The water-accessible surface (Connolly surface) for the skeletal cyclic ether part of 1 was generated by Chem
˚
3D Ver. 5.0using a probe radius of 1.4 A .
between side-chains in the a-helical peptides in the
is expected to be analogous to the ridges formed by side-
chains of a-helices in the i, i+4 relationship.
˚
canonical i, i+4 relationship (ca. 5 A). As illustrated in
Figure 2b, a typical mode of packing between a-helices
(green and blue) involves insertion of the ridges of one
helix (blue) into the grooves of an adjacent helix
(green).11 Inspired by this potentially analogous topol-
ogy, the hypothetical binding model shown in Figure
2c was derived. In this model, the ladder-like polycyclic
ether fits into the grooves of the helix.
The strategy for the iterative synthesis of the cyclic ether
scaffolds is outlined in Scheme 1. A SmI2-mediated
Reformatsky-type reaction of a-ketosulfide B with alde-
hyde A was employed for the assembly of the two hyd-
ropyrans.13 Subsequent hydroxy-ketone cyclization of
the compound C would afford tricyclic D.14 After con-
version of D into aldehyde E, the second assembly of
two cyclic ethers E and B followed by the hydroxy-
ketone cyclization would yield the 6/6/6/6/6 cyclic
ether skeleton 2 with two equatorial hydroxy groups.
As a first step in the investigation of this model, a 6/6/6/
6/6 pentacyclic ether skeleton (1) was designed as a
structurally defined a-helix mimetic scaffold12 having
two equatorial hydroxyl groups separated by a distance
˚
of 4.8 A (Fig. 2d). Installation of a variety of substitu-
The key coupling component, a-ketosulfide 8, was syn-
thesized from tri-O-acetyl-D-glucal 3 (Scheme 2). Reduc-
tion of 3 with triethylsilane and BF3ÆEt2O followed by
ents (R1 and R2) is possible via the hydroxyl groups,
and the consequent undulation of the molecular surface
Scheme 1. Strategy for iterative synthesis of cyclic ether skeleton 3.

H. Oguri et al. / Tetrahedron Letters 46 (2005)2179–2183
2181
Scheme 2. Reagents and conditions: (a) Et3SiH, BF3ÆEt2O, CH3CN,
ꢀ20 °C, 78%; (b) K2CO3, MeOH; (c) NaH, BnBr, THF/DMF(1/1),
90% (two steps); (d) RhCl(PPh3)3 (15 mol %), DBU, EtOH, 60 °C,
83%; (e) cat. OsO4, NMO, acetone; (f) Ac2O, pyridine, DMAP, 93%
(two steps); (g) PhSH, SnCl4 (10mol %), CH 2Cl2, ꢀ20to 0 °C, 90%;
(h) K2CO3, MeOH; (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to 0 °C,
92% (two steps); (j) m-CPBA, CH2Cl2, ꢀ40to 0 °C, 88%.
methanolysis and benzylation gave 4. The allylic ether 4
was then converted into enol ether 5 in the presence of
Wilkinsonꢁs catalyst and DBU in 83% yield.15 Dihydr-
oxylation of 5 and subsequent acetylation yielded 6,
which was then subjected to SnCl4-catalyzed thioacetali-
zation to afford 7.16 Conversion of 7 to the a-ketosulfide
8 was achieved by methanolysis and subsequent Swern
oxidation in 92% yield (two steps).
Scheme 3. Reagents and conditions: (a) CSA, MeOH/CH2Cl2 (1:7); (b)
Ac2O, pyridine, DMAP; (c) Et3SiH, TMSOTf, CH2Cl2, ꢀ20 °C, 16
34% (three steps), 17 9% (three steps); (d) K2CO3, MeOH; (e) (COCl)2,
DMSO, Et3N, CH2Cl2, ꢀ78 to 0 °C, 57% (two steps); (f) NaBH4,
CeCl3, MeOH/THF (4:1), ꢀ20 °C; (g) Ac2O, pyridine, DMAP, 50%
(two steps).
The tetrahydropyran rings were assembled by Refor-
matsky-type coupling of the a-ketosulfide 8 with the
aldehyde 1017 using Mastudaꢁs protocol (Scheme 3).13
A solution of 8 in THF was added dropwise to a solu-
tion of SmI2 (2 equiv) in THF at ꢀ78 °C to generate
the samarium enolate regioselectively, and the resulting
solution was treated with 10 (2 equiv). Unfortunately,
homocoupled 13 was the major product (34% yield),
and the desired coupling products 11 were obtained in
only low yield (18%).18 Thus, the samarium enolate
was trapped immediately after generation by adding a
mixture of 8 and 10 (2 equiv) to a solution of SmI2
(2 equiv) at ꢀ78 °C. Although the yield of the desired
11 was improved (up to ꢁ40%), significant amounts of
13 (ꢁ20%) were still produced.18 To suppress the forma-
tion of 13, sulfone 919 was used in place of sulfide 8 to
accelerate the generation of the samarium enolate.
Treatment of a mixture of 9 and 10 (2 equiv) with
SmI2 (2 equiv) promoted the Reformatsky-type reaction
smoothly at ꢀ78 °C, affording the desired coupling
products without formation of 13. Subsequent in situ
acetylation gave a 3:2 diastereomeric mixture of 14
and 15 in 79% yield (two steps). A highly stereo-con-
trolled addition at C6 occurred in this synthesis, presum-
ably due to 1,2-chelation of 10 with the samarium
species. The mixture of 14 and 15 was subsequently sub-
jected to hydroxy-ketone cyclization followed by reduc-
tive etherification to afford separable tricyclic ethers 1620
and 17. The trans, cis-fused 17 was converted to trans,
trans-fused 16 in four steps involving the epimerization
of ketone 18 under Swern oxidation conditions.14b
manipulation of 16 gave aldehyde 19 via a four-step pro-
cedure involving (i) removal of benzyl groups, (ii) pro-
tection of the hydroxyl groups as TBS ethers, (iii)
selective removal of the primary silyl group, and (iv)
Swern oxidation. The SmI2-mediated coupling reaction
of 19 (1.2 equiv) with sulfone 9 and subsequent acetyla-
tion furnished a 1:1 diastereomeric mixture of 20 and 21
in 72% yield (two steps). Exposure of the mixture to
CSA in MeOH/CH2Cl2 (1:4) effected the removal of
the TBS and in situ methyl ketal formation, as well as
partial deacetylation. The desired methyl ketal 22 was
isolated after acetylation in 52% yield. The products
possessing 13R stereochemistry could not be isolated.
Reduction of 22 with Et3SiH and TMSOTf gave the
trans-fused 6/6/6/6/6 pentacyclic ether 2 in 91% yield.21
Finally, protecting-group manipulation under standard
conditions led to the scaffold 1.
In conclusion, a polycyclic ether scaffold was designed as
an a-helix mimic, inspired by the topological similarity
between ladder-like cyclic ether marine toxins and a-heli-
cal peptides. The synthesis presented here provides an
efficient strategy for the stereo-controlled construction
of trans-fused polycyclic ether skeletons via SmI2-medi-
ated Reformatsky-type coupling of a-sulfonyl ketones
with aldehydes. Further investigation of the synthesis
With tricyclic 16 in hand, iterative assembly with 9 was
performed, leading to 1 (Scheme 4). Functional group

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H. Oguri et al. / Tetrahedron Letters 46 (2005)2179–2183
Scheme 4. Reagents and conditions: (a) H2, Pd(OH)2/C, MeOH/AcOEt (1/4); (b) TBSCl, imidazole, DMF, 99% (two steps); (c) CSA, MeOH, ꢀ5 °C,
75%; (d) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N, 0 °C; (e) 19 (1.2 equiv), 9, SmI2 (2 equiv), THF, ꢀ100 °C; (f) Ac2O, pyridine, DMAP,
20:21 = 1:1, 72% (two steps); (g) CSA, MeOH/CH2Cl2 (1:4); (h) Ac2O, pyridine, DMAP, 22 52% (two steps); (i) Et3SiH, TMSOTf, CH2Cl2, ꢀ20 °C,
91%; (j) H2, Pd(OH)2/C, MeOH/AcOEt (1/4); (k) p-MeOC6H4CH(OMe)2, CSA, DMF, 71% (two steps); (l) DIBAL, CH2Cl2, ꢀ78 to ꢀ15 °C, then
Ac2O, pyridine, DMAP, 80%; (m) K2CO3, MeOH/THF (4/1), 99%.
Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett.
of a variety of a-helix mimics based on cyclic ether scaf-
1993, 34, 1975; (c) Satake, M.; Morohashi, A.; Oguri, H.;
folds and evaluation of the interaction with a-helical
Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J. Am.
peptides will be presented in future reports.
Chem. Soc. 1997, 119, 11325; (d) Satake, M.; Fukui, M.;
Legrand, A.-M.; Cruchet, P.; Yasumoto, T. Tetrahedron
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Acknowledgements
The authors thank Professors K. Tsumoto and M.
Umetsu for valuable discussions. This work was
supported by the Core Research for Evolutional Science
and Technology (CREST) programs of the Japan
Science and Technology Agency (JST), and by a
Grant-in-Aid for Scientific Research (S) from the
Japanese Society for the Promotion of Science (JSPS).
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H. Oguri et al. / Tetrahedron Letters 46 (2005)2179–2183
2183
10. Our recent studies indicated a high content (more than
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tricyclic polyether fragment of CTX3C, see: Nagumo,
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18. Unfortunately, diastereomeric coupling products such as
12 could not be detected, presumably due to a retro-aldol
reaction. In situ acetylation was thus conducted to prevent
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´
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20. Data for 16: 1H NMR (500 MHz, CDCl3) d 1.46–1.58 (m,
1H), 1.49 (dt, 1H, J = 12.0, 9.0 Hz), 1.65–1.76 (m, 2H), 2.09
(s, 3H), 2.11–2.12 (m, 1H), 2.57 (dt, 1H, J = 12.0, 4.0 Hz),
3.04 (t, 1H, J = 9.0Hz), 3.13 (t, 1H, J = 9.0Hz), 3.23 (td,
2H, J = 9.0, 4.5 Hz), 3.30 (td, 1H, J = 11.5, 3.5, Hz), 3.40
(ddd, 1H, J = 9.0, 5.5, 2.0 Hz), 3.49 (td, 1H, J = 9.0,
4.5 Hz), 3.62 (dd, 1H, J = 11.0, 5.5 Hz), 3.80 (dd, 1H,
J = 11.0, 2.0 Hz), 3.95 (ddd, 1H, 11.0, 3.5, 1.0 Hz), 4.44 (d,
1H, J = 11.0Hz), 4.52 (d, 1H, J = 11.0Hz), 4.58 (d, 2H,
J = 11.0Hz), 5.11 (t, 1H, J = 9.0Hz), 7.23–7.34 (m, 10H);
13C NMR (125 MHz, CDCl3) d 21.00, 24.90, 29.06, 35.03,
67.80, 68.93, 71.05, 71.97, 73.05, 73.17, 73.93, 75.94,
79.41, 80.13, 80.92, 127.28, 127.42, 127.57, 127.71,
127.86, 128.10, 128.17, 128.30, 137.71, 138.42, 170.32; IR
(neat) mÅ3030, 2948, 1741, 1454, 1367, 1237, 1099 cmꢀ1
;
MALDI-TOFMS calcd for C28H34O7Na [M+Na]+
26
505.220; found 505.218; ½aꢂD +26.4 (c 1.00, CHCl3).
21. Data for 2: 1H NMR (500 MHz, CDCl3) 1H NMR
(500 MHz, CDCl3) d 1.37–1.48 (m, 1H), 1.46 (dt, 1H,
J = 11.5, 9.5 Hz), 1.51 (dt, 1H, J = 11.5, 9.5 Hz), 1.59–1.70
(m, 2H), 1.97 (s, 3H), 2.01 (s, 3H), 2.01–2.08 (m, 1H), 2.38
(dt, 1H, J = 11.5, 4.5 Hz), 2.51 (dd, 1H, J = 11.5, 4.5 Hz),
2.98 (t, 1H, J = 9.5 Hz), 3.02 (t, 1H, J = 9.5 Hz), 3.03 (t,
1H, J = 9.5 Hz), 3.07 (t, 1H, J = 9.5 Hz), 3.12–3.20(m,
2H), 3.21–3.30(m, 3H), 3.34 (ddd, 1H, J = 9.5, 5.5,
1.5 Hz), 3.44 (td, 1H, J = 9.5, 4.5 Hz), 3.57 (dd, 1H,
J = 11.0, 5.0 Hz), 3.71 (dd, 1H, J = 11.0, 1.5 Hz), 3.89
(m, 1H), 4.38 (d, 1H, J = 11.5 Hz), 4.49 (d, 1H,
J = 12.0Hz), 4.52 (d, 1H, J = 11.5 Hz), 4.52 (d, 1H,
J = 12.0Hz), 5.04 (t, 1H, J = 9.5 Hz), 5.07 (t, 1H,
J = 9.5 Hz), 7.17–7.28 (m, 10H); 13C NMR (125 MHz,
CDCl3) d 20.66, 20.75, 24.98, 29.09, 34.91, 35.03, 67.90,
68.97, 71.22, 71.98, 72.40, 72.72, 73.29, 74.00, 74.31, 74.56,
76.33, 79.23, 79.99, 80.04, 80.08, 81.02, 127.42, 127.56,
127.82, 127.84, 128.29, 128.42, 137.72, 138.42, 169.43,
169.75; MALDI-TOFMS calcd for C36H44O11Na
[M+Na]+ 675.273; found 675.289.
´
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