Stereospecific synthesis of α,ω-cis- and α,ω-trans-disubstituted oxepanes

Article abstract of DOI:10.1016/S0040-4039(00)01344-7

An efficient and versatile method for the stereospecific construction of α,ω-cis- and α,ω-trans-disubstituted oxepane skeletons is described. Cyclization of the hydroxy epoxides promoted by a (Bu₃Sn)₂O/ Zn(OTf)₂ system proceeded via an S(N)2 process and exo mode selectivity regardless of the configuration of the hydroxyl and the epoxy groups to provide the corresponding oxepanes in excellent yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01344-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7697–7700
Stereospecific synthesis of a,v-cis- and
a,v-trans-disubstituted oxepanes
Ryuji Matsumura,a Toshio Suzuki,a,* Kohki Sato,a Takashi Inotsume,b
Hisahiro Hagiwara,a Takashi Hoshi,b Vijayendra P. Kamatb and Masayoshi Andob
aGraduate School of Science and Technology, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received 13 July 2000; revised 3 August 2000; accepted 4 August 2000
Abstract
An efficient and versatile method for the stereospecific construction of a,v-cis- and a,v-trans-disubsti-
tuted oxepane skeletons is described. Cyclization of the hydroxy epoxides promoted by a (Bu3Sn)2O/
Zn(OTf)2 system proceeded via an SN2 process and exo mode selectivity regardless of the configuration of
the hydroxyl and the epoxy groups to provide the corresponding oxepanes in excellent yields. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: cyclization; epoxides; oxepanes; regioselection.
Oxepanes constitute a prominent structural feature of many natural products, represented by
2
(+)-isolaurepinnacin (1)1 and (+)-regioloxepane A (2) (Fig. 1), isolated from the marine algae
belonging to a variety of the Laurencia species. Much attention has been focused on efficient
approaches toward this system.3 In particular, the stereoselective introduction of alkyl sub-
stituents into the a- and v-position of a cyclic ether possessing cis- or trans-orientation is an
important synthetic goal. While some efficient methods toward stereoselective synthesis of
a,v-cis-oxepanes were developed,4 few methods have been found for the a,v-trans-oxepane
system.4f,m,5 We described an efficient protocol for the synthesis of oxepane via intramolecular
opening of hydroxy epoxides promoted by a (Bu3Sn)2O/Lewis acid system in the proceeding
article; this reaction proceeded via an SN2 process and exo mode regardless of the geometry of
Figure 1.
* Corresponding author. Tel/fax: +81-25-262-6780; e-mail: suzuki@eng.niigata-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01344-7

7698
the epoxy group. We initiated the present work in an effort to explore the possibility of applying
this methodology to the stereospecific construction of a,v-cis- and a,v-trans-oxepane skeletal
systems.
The requisite key intermediate, hydroxy trans-epoxide 7 leading to a,v-cis-oxepane, was
prepared stereoselectively from the corresponding acetylene derivative 46 and bromoepoxide 6.
The other intermediate 8 required for the preparation of the trans-analogue was obtained from
the epoxy alcohol 7 via a Mitsunobu reaction7 (Scheme 1).
Scheme 1. Reagents and conditions: (a) TBSCl, NaH, THF, 100%; (b) TBHP, (+)-DET, Ti(Oi-Pr)4, 4AMS, CH2Cl2,
93%, 89% ee; (c) TsCl, TEA, DMAP, CH2Cl2, 97%; (d) LiBr, DMF, 50°C, 94%; (e) n-BuLi, HMPA, THF, −30°C;
(f) TBAF, THF, 52% (two steps); (g) H2, PdꢀC, AcOEt, 78%; (h) DEAD, PPh3, p-NO2C6H4CO2H, THF, 98%; (i)
K2CO3, MeOH, 96%
With the desired hydroxy trans-epoxides 7 and 8 in hand, we then proceeded with the
stereospecific cyclization protocol. The tin ether prepared from 7 by reacting it with (Bu3Sn)2O
(0.6 equiv.) in refluxing toluene8 was treated with Zn(OTf)2 (0.4 equiv.) at 90°C. Under the
conditions, the cyclization reaction proceeded smoothly to afford the corresponding a,v-cis-
oxepane 9 in 85% yield as the sole cyclic product. Similarly, the cyclization of the other isomer
8 proceeded with the same reactivity under the same reaction conditions to give the correspond-
ing a,v-trans-derivative 10 in 80% yield. The relative stereochemistry of the cyclized products 9
and 10 at the a,v-positions with respect to each other was ascertained by NOE experiments.
Further, the a,v-cis-oxepane 9 was converted to its epoxide 11 to explore its NOE correlations
1
in view of the overlapping of a-H and v-H signals in the H NMR spectrum (Scheme 2). It may
be noted that the ready formation of terminal epoxide 11 from 9 confirms the earlier
regioselective exo mode cyclization of 7 to the a,v-cis-oxepane derivative 9.
Scheme 2. Reagents and conditions: (a) MsCl, TEA, DMAP, CH2Cl2, 99%; (b) DDQ, CH2Cl2, H2O; (c) K2CO3,
MeOH, CH2Cl2, 85% (two steps)

7699
Next, we turned our investigation to probe the reactivity of cis-epoxy substrates under the
same reaction conditions. The desired cyclization precursors 15 and 16 were prepared by the
protocol shown in Scheme 3. Epoxide 13 derived from 2,3-O-isoropylidene- -threitol 12 was
D
coupled with the acetylene derivative 4 by following the Yamaguchi method.9 The resulting
intermediate 14 was transformed to the hydroxy cis-epoxides 15 and 16 via standard procedures.
Repeating the above-mentioned cyclization protocol on cis-epoxides 15 and 16 under identical
reaction conditions provided, respectively, the corresponding a,v-cis-oxepane 17 (68%) and its
trans-isomer 19 (79%). It may also be noted that compared to the trans-epoxides 7 and 8, there
is a decrease in the reactivity of cis-epoxides 15 and 16, and this property is reflected in the
isolation of rearranged ketones 18 and 20 as minor products during the cyclization reaction
(Scheme 4).
Scheme 3. Reagents and conditions: (a) MPMCl, NaH, DMF; (b) TsCl, TEA, DMAP, CH2Cl2, 72% (two steps); (c)
Amberlyst 15, MeOH; (d) K2CO3, CH2Cl2, MeOH, 52% (two steps); (e) 4, n-BuLi, BF3·OEt2, THF, −78°C, 60%; (f)
H2, PdꢀC, AcOEt, 78%; (g) MsCl, TEA, DMAP, CH2Cl2; (h) TBAF, THF, 97% (two steps); (i) DEAD, PPh3,
p-NO2C6H4CO2H, THF, 95%; (j) K2CO3, MeOH, 95%
Scheme 4.
In conclusion, a highly efficient methodology for the stereospecific construction of a,v-cis-
and a,v-trans-oxepanes, the fundamental structural unit of several important bioactive marine
natural products, has been developed. Interestingly, the cyclization reaction proceeded via an
SN2 process and exo mode selectivity and independently of the hydroxyl and epoxide groups
configuration in the substrate. Furthermore, the newly generated asymmetric centers are
stereospecifically inducted in the product molecule. The oxepane derivatives 9, 10, 17 and 19

7700
inherited the requisite carbon skeleton and stereochemistry for its application to the synthesis of
natural products (+)-isolaurepinnacin (1) and (+)-rogioloxepan A (2). Further efforts in this
direction are in progress in our laboratory.
Acknowledgements
This work was financially supported in part by the Grant-in-Aid for Scientific Research on
Priority Area No. 08245101 from the Ministry of Education, Science, Sports and Culture of the
Japanese Government.
References
1. Fukuzawa, A.; Masamune, T. Tetrahedron Lett. 1981, 41, 4081–4084.
2. Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. Helv. Chim. Acta 1992, 75, 310–322.
3. For a review of synthetic investigation in this area, see: Albizati, K.; Martin, V. A.; Agharahimi, M. R.; Stolze,
D. A. In Bioorganic Marine Chemistry; Scheuer, P. J., Ed.; Springer-Verlag: Berlin, 1992; Vol. 6, pp. 69–84.
4. (a) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999, 1, 1099–1101. (b) Mori, Y.; Yaegashi, K.; Furukawa,
H. J. Am. Chem. Soc. 1997, 119, 4557–4558. (c) Isobe, M.; Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473–474. (d)
Nakata, T.; Nomura, S.; Matsukura, H.; Morimoto, M.; Tetrahedron Lett. 1996, 37, 217–220. (e) Oishi, T.; Shoji,
M.; Maeda, K.; Kumahara, N.; Hirama, M. Synlett 1996, 1165–1167. (f) Palazo´n, J. M.; Mart´ın, V. S. Tetrahedron
Lett. 1995, 36, 3549–3552. (g) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.; Reddy,
K. B.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc.
1995, 117, 10227–10238. (h) Kadota, I.; Matsukawa, Y.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1993,
1638–1641. (i) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Soc., Perkin Trans. 1 1992, 83–94. (j) Feng,
F.; Murai, A. Chem. Lett. 1992, 1587–1590. (k) Davies, M. J.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1991,
9–12. (l) Yamada, J.; Asano, T.; Kadota, I.; Yamamoto, Y. J. Org. Chem. 1990, 50, 6066–6068. (m) Kotsuki, H.;
Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989, 54, 5153–5161. (n) Castan˜eda, A.; Kucera, D. J.; Overman,
L. E. J. Org. Chem. 1989, 54, 5698–5707.
5. (a) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Tetrahedron Lett. 1994, 35, 3401–3404. (b)
Davies, M. J.; Moody, C. J.; Taylor, R. J. Synlett 1990, 93–96.
6. Takano, S.; Sekiguchi, Y.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1987, 555–557.
7. (a) Mitsunobu, O. Synthesis, 1981, 1–28. (b) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017–3020.
8. Ogawa, T.; Matsui, M. Carbohydr. Res. 1977, 56, C1–C6.
9. Yamaguchi, M.; Hirano, I. Tetrahedron Lett. 1983, 24, 391–394.
.