A new preparation of 2,5-dihydro-1-benzoxepins using Mitsunobu cyclization, and the synthesis of natural radulanins

Article abstract of DOI:10.1016/S0040-4039(00)00676-6

Mitsunobu cyclization of o-[4-hydroxy-3-methyl-2(Z)-butenyl]phenol 2a effected selective seven-membered cyclization to give 3-methyl-2,5-dihydro-1- benoxepin 1a. Using this procedure, natural radulanin A and radulanin A methyl ether were synthesized effec

Full text of DOI:10.1016/S0040-4039(00)00676-6

Tetrahedron Letters 41 (2000) 4787±4790
A new preparation of 2,5-dihydro-1-benzoxepins using
Mitsunobu cyclization, and the synthesis of natural
radulanins
Seiji Yamaguchi,* Katsunori Furihata, Masahiro Miyazawa,
Hajime Yokoyama and Yoshiro Hirai
Department of Chemistry, Faculty of Science, Toyama University, Gofuku, Toyama 930-8555, Japan
Received 21 March 2000; revised 10 April 2000; accepted 21 April 2000
Abstract
Mitsunobu cyclization of o-[4-hydroxy-3-methyl-2(Z)-butenyl]phenol 2a e€ected selective seven-mem-
bered cyclization to give 3-methyl-2,5-dihydro-1-benoxepin 1a. Using this procedure, natural radulanin A
and radulanin A methyl ether were synthesized e€ectively. # 2000 Elsevier Science Ltd. All rights reserved.
Many compounds having a 3-methyl-2,5-dihydro-1-benzoxepin structure (1a) have been iso-
lated from various plants.1 Similar to 2-isopropenyl- 2,3-dihydrobenzofurans and 2,2-dimethyl-
2H-chromenes, they might be biogenetically derived from o-prenylphenols.
In our studies on naturally occurring 2-isopropenyl-2,3-dihydrobenzofurans and 2,2-dimethyl-
2H-chromenes, we found some seven-membered cyclizations (especially in 2,4,6-trihydroxyaceto-
phenone or 2,6-dihydroxyacetophenone)2 and some photo-ring expansions (especially in 6-methoxy-
2,2-dimethyl-2H-chromene or 5-methoxy-2-isopropenyl-2,3-dihydrobenzofuran).3 But there was
no general method for the preparation of 1a until the recent ring-closing metathesis.4 In this
paper, a new method using Mitsunobu cyclization is described.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00676-6

4788
In our new strategy for 1a (Scheme 1), 1a might be prepared from diol 2a, and 2a might be
prepared by Stille coupling of benzyl bromide 3 with stannane 4. This cyclization of Z-methyl-
oxidized o-prenylphenols 2a is a biomimetic procedure, but there are two possibilities: desired
seven-membered cyclization via SN2 to give 1a, and ®ve-membered cyclization via SN20 to give
2-isopropenyl-2,3-dihydrobenzofuran. For a selective seven-membered cyclization, diol 2a was
subjected to Mitsunobu cyclization known as a typical SN2 reaction.5
Scheme 1.
As the substrates of the Stille coupling, (TBS-oxy)benzyl bromide 3a was prepared from o-cresol
in two steps (90%): TBS protection with TBSCl, and bromination with NBS, and (MOM-oxy)-
benzyl bromide 3b was prepared from salicylaldehyde in three steps (83%): MOM protection with
MOMCl, LiAlH4 reduction, and bromination with PBr3. The stannane 4 as the Stille coupling
partner was prepared according to the reported method.6 Diol 2a was obtained from 3a in three
steps (41%): Pd(0)-catalyzed Stille coupling of 3a6,7 with 4 (crude 73%), deprotection of TBS
with TBAF, and deprotection of THP with PPTS (Scheme 2). Diol 2a was also prepared from 3b
in two steps (67%): Pd(0)-catalyzed Stille coupling of 3b with 4 (crude 97%) and deprotection
with conc. HCl.
Scheme 2.
Mitsunobu cyclization of diol 2a by treating with triphenylphosphine and diethyl azo-
dicarboxylate in dry THF at room temperature for 1 h gave 3-methyl-2,5-dihydro-1-benzoxepin
1a in 87% yield. In this cyclization, only the seven-membered cyclization via SN2 was observed,
and none of the ®ve-membered cyclizations via SN20 was observed. Thus, Mitsunobu cyclization
of (Z)-diol might be e€ective for the preparation of some seven-membered 3-methyl-2,5-dihydro-
1-benzoxepins, and this procedure was applied to the synthesis of radulanin A (1c) and its methyl
ether (1b) (Scheme 3), isolated from the Radula species by Asakawa et al.8
Scheme 3.

4789
Dimethoxybenzyl bromide 3aa was prepared from 1,3-dimethoxy-5-(2-phenylethyl)benzene (5)
in four steps: formylation with sec-BuLi and DMF to 6aa (91%), LiAlH4 reduction (86%), and
bromination with PBr3 (93%). Stille coupling of 3aa with stannane 4 gave 7aa in 76% (Scheme 4).
Demethylation of 7aa with sodium ethylthiolate gave mono-demethylated 7ab (49%), which was
readily deprotected to diol 2b with PPTS (82%). Diol 2b was also obtained from methox-
ysalicylaldehyde 6ab, readily prepared by demethylation of 6aa with magnesium iodide etherate
in 87% yield (Scheme 5). Methoxysalicylaldehyde 6ab was converted to methoxy-(TBS-oxy)benzyl
bromide 3ad or methoxy(MOM-oxy)benzyl bromide 3ae in three steps: TBS or MOM protection,
NaBH4 reduction, and bromination with PBr3. Stille coupling of benzyl bromides 3ad and 3ae
gave 7ad (68%) and 7ae (56%), which were readily deprotected to diol 2b: two-steps deprotection
of 7ad with TBAF to 7ab (97%) and followed with PPTS to 2b (82%), one-step deprotection of
7ae with conc. HCl to 2b (58%). Mitsunobu cyclization of diol 2b, thus obtained, caused e€ective
seven-membered cyclization to give 6-methoxy-8-(2-phenylethyl)-2,5-dihydro-1-benzoxepin
(radulanin A methyl ether) 1b in 71% yield.
Scheme 4.
Scheme 5.
Demethylation of dimethoxybenzaldehyde 6aa with boron tribromide e€ectively gave dihydroxy-
benzaldehyde 6bb (Scheme 6). Bis(MOM-oxy)benzyl bromide 3ee was prepared from 6bb in three
steps (66%): MOM protection with MOMCl, LiAlH4 reduction, and bromination with PBr3.
Stille coupling of 3ee with 4 also gave 7ee in 56%, and 7ee was readily deprotected by treating
with conc. HCl to give 2c in 62% yield. Bis(TBS-oxy)benzyl bromide 3dd was also prepared from

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6bb in three steps (63%): TBS protection with TBSCl, NaBH4 reduction, and bromination with
PBr3, but Stille coupling of 3dd with 4 showed a lower yield (21%). Triol 2c was also obtained
from 7ab in three steps, THP protection with DHP-PPTS (80%) to give 7ac, re-demethylation with
NaSEt to 7bc (65%), and THP deprotection with PPTS (84%). Mitsunobu cyclization of triol 2c,
thus obtained, also caused e€ective seven-membered cyclization to give 8-(2-phenylethyl)-2,5-
dihydro-1-benzoxepin-6-ol (radulanin A) 1c in 91% yield.
Scheme 6.
The 1H NMR data of the synthetic 1b and 1c, thus obtained, corresponded well to the data of
natural radulanin A and radulanin A methyl ether.8
References
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J. Chem. Soc. Chem. Comm. 1967, 145. (c) Eshlett, I. T.; Taylor, D. A. H. J. Chem. Soc. (C) 1968, 481. (d)
Takasugi, M.; Nagao, S.; Masamune, T. Tetrahedron Lett. 1979, 4675. (e) Breuer, M.; Leeder, G.; Proksch, P.;
Budzikiewicz, H. Phytochemistry 1986, 25, 495. (f) McCormick, S.; Robson, K.; Bohm, B. Phytochemistry 1986,
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3. Unpublished, but a similar photo-ring expansion of 6-methoxy-2,2,5,7,8-pentamethyl-2H-chromene was reported
by: Dallacker, F.; Reperich, K. Chemiker-Zeitung 1991, 115, 306.
4. Ste®novic, M.; Snieckus, V. J. Org. Chem. 1998, 63, 2808.
5. The selectivity of SN2 in the Mitsunobu reactions was described by: Danishefsky, S.; Berman, E. M.; Ciufolini, M.;
Etheredge, S. J.; Segmuller, B. E. J. Am. Chem. Soc. 1985, 107, 3891, and summarized in Organic Reactions; 1992;
Vol. 42, p. 335.
6. Rayner, C. M.; Astle, P. C.; Paquette, L. A. J. Am. Chem. Soc. 1992, 114, 3926.
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8. Raduranin, A: Asakawa, Y.; Toyota, M.; Takemoto, T. Experimentia 1978, 34, 971; Raduranin A methyl ether:
Asakawa, Y.; Takeda, R.; Toyota, M.; Takemoto, T. Phytochemistry 1981, 20, 858.