Acid-promoted rearrangement of 2-aryl-2,3-epoxy acylates: Construction of chiral benzylic quaternary carbon centers

Article abstract of DOI:10.1016/S0040-4039(00)00092-7

The reactions of 2-aryl-2,3-epoxy acylates with BF₃·Et₂O were examined in detail. Trans-2-aryl-2,3-epoxy acylates afforded the rearranged products in good yields via the C2-carbocation intermediates. The reaction was used for constructing the optically active benzylic quaternary carbon center. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00092-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2133–2136
Acid-promoted rearrangement of 2-aryl-2,3-epoxy acylates:
construction of chiral benzylic quaternary carbon centers
Yasuyuki Kita,∗ Akihiro Furukawa, Junko Futamura, Kazuhiro Higuchi, Koichiro Ueda and
Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka, 565-0871, Japan
Received 6 December 1999; revised 5 January 2000; accepted 7 January 2000
Abstract
The reactions of 2-aryl-2,3-epoxy acylates with BF3·Et2O were examined in detail. Trans-2-aryl-2,3-epoxy
acylates afforded the rearranged products in good yields via the C2-carbocation intermediates. The reaction was
used for constructing the optically active benzylic quaternary carbon center. © 2000 Elsevier Science Ltd. All rights
reserved.
Recently, we disclosed the Lewis acid-promoted rearrangement of 2,3-epoxy acylates.1 In these cases,
acylates work as electron-withdrawing groups and the 2,3-epoxy acylates rearrange via C3-cleavage of
the oxirane ring. On the other hand, in our synthesis of fredericamycin A, we found that the rearrangement
reactions of the tetrahydrobenz[e]indan systems proceeded via C2-cleavage of the oxirane ring.2 The
phenyl group is known as a cation-stabilizing group, and phenyl epoxides also rearranged via the benzylic
cation intermediates.3 We wondered if a benzo-fused system like fredericamycin A was a special case
or the 2,3-epoxy acylates with a C2-aryl substituent rearranged via the C2-cleavage of oxirane. In other
words, which is more stable, the C2- versus the C3-carbocation during the rearrangement of the 2,3-
epoxy acylates with a C2-aryl substituent? We now present evidence that the cyclic 2-aryl-2,3-epoxy
acylates rearrange via the C2-cleavage of oxirane (Scheme 1).
Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00092-7
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We first investigated the five-membered epoxy acylates (Scheme 2, Table 1). Every reaction occurred
via the C2-cleavage of the oxirane ring. The cis-epoxy acylates 1a–1c rearranged in low yields along with
reasonable side products, orthoesters by neighboring group participation from pivalete 1a and benzoate
1b and the enone via hydride rearrangement and dehydration from p-nitrobenzoate 1c (Entries 1–3).
The trans-epoxy acylates 1d–1f afforded high yields of the corresponding rearrangement products 3d–3f
(Entries 4–6).4 The rearranged products 3 from the trans-epoxy acylates are different from the products
2 of the cis-epoxy acylates. This means that the rearrangements proceeded in a stereospecific manner.
Among the used acyloxy groups, the p-nitrobenzoyloxy group is the best based on the reaction time
and the chemical yield (Entry 6). The effect of the substituent on the aromatic ring was next studied.
The 4-methoxyphenyl group accelerated the rearrangement and a very high yield of the product 3g via
C2-cleavage was obtained for a short reaction time (Entry 7).
Scheme 2.
Table 1
Rearrangement via C2-cleavage of the oxirane ring was also observed in the six-membered ring. 2-
Phenyl trans-epoxy p-nitrobenzoate 4a afforded the ring-contracted five-membered product 5a via C2-
cleavage of the oxirane ring followed by ring-methylene rearrangement. The structure of the product
was unambiguously determined by X-ray analysis. The configuration of the quaternary carbon center
proved to be opposite to the product predicted by the concerted rearrangement. Quite recently, Neef et
al. reported that it is very difficult to predict the configuration of the quaternary carbon center produced

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by the rearrangement via the benzylic cation intermediates, because the benzylic group prolongs the
lifetime of the cation and the rearrangement proceeds in a non-concerted way.5 However, we rationalized
that our result must be due to the more stable conformation of the cation intermediate ii rather than to
the intermediate i because of the long lifetime of the cation. In fact, the PM3 calculation shows that
intermediate ii is 3.2 kcal/mol more stable than intermediate i. The same rearrangement was observed
in the reaction of 2-(4-methoxyphenyl)trans-epoxy p-nitrobenzoate 4b to give 5b in good yield (Scheme
3).
Scheme 3.
We next determined that our method was applicable to the construction of optically active benzylic
quaternary carbon centers. Optically active epoxy p-nitrobenzoate 9 was prepared by the asymmetric
reduction of the corresponding enone 6 by Corey’s method,6,7 epoxidation with t-BuOOH/VO(acac)2,8
then the Mitsunobu reaction with p-nitrobenzoic acid.9 Treatment of the epoxy p-nitrobenzoate 9 with
BF3·Et2O afforded the optically active product with the same enantiomeric excess value as the starting
epoxy alcohol 710 (Scheme 4).
Scheme 4.
In conclusion, we found that the C2-carbocations are more stable than the C3 ones in the 2-aryl-2,3-
epoxy acylate systems and rearrangement proceeds via C2-cleavage of the oxirane with stereospecificity
and succeed in the construction of the optically active benzylic quaternary carbon center. Since many

2136
natural products contain a chiral benzylic quaternary carbon center, this method would be a useful tool
for constructing them.
References
1. (a) Fujioka, H.; Kitagaki, S.; Imai, R.; Kondo, M.; Okamoto, S.; Yoshida, Y.; Akai, S.; Kita, Y. Tetrahedron Lett. 1995,
36, 3219–3222; (b) Kita, Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.; Fang, D.-F.; Fujioka, H. Tetrahedron Lett. 1997, 38,
1061–1064; (c) Kita, Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.; Fang, D.-F.; Kondo, M.; Okamoto, S.; Imai, R.; Akai, S.;
Fujioka, H. J. Org. Chem. 1997, 62, 4991–4997; (d) Kita, Y.; Yoshida, Y.; Kitagaki, S.; Mihara, S.; Fang, D.-F.; Furukawa,
A.; Higuchi, K.; Fujioka, H. Tetrahedron 1999, 55, 4979–4998.
2. (a) Kita, Y.; Kitagaki, S.; Imai, R.; Okamoto, S.; Mihara, S.; Yoshida, Y.; Akai, S.; Fujioka, H. Tetrahedron Lett. 1996, 37,
1817–1820; (b) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio, K.; Kitagaki, S.; Akai, S.; Fujioka, H. Angew. Chem. Int. Ed. 1999,
38, 683–686.
3. Rana, R. C.; Jana, V. J. Org. Chem. 1998, 63, 8212–8216.
4. The configuration of the quaternary carbon centers was determined by proposing a stereoselective rearrangement of the
starting epoxy acylates.
5. Very recently, some related rearrangements have been reported in preliminary forms. They examined the rearrangement of
the epoxy benzyl ether with a C3-aryl substituent and discussed the lifetime of the benzylic cation: Neef, G.; Baesler, S.;
Depke, G.; Vierhufe, H. Tetrahedron Lett. 1999, 40, 7969–7973.
6. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7526. Absolute
configuration of 7 was deduced by referring to the literature.
7. Enantiomeric excess of 7 was determined by HPLC analysis using the chiral column (Chiralcel OD).
8. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136–6137.
9. Mitsunobu, O.; Kimura, J.; Iizumi, K.; Yanagida, N. Bull. Chem. Soc. Jpn. 1976, 49, 510–513.
10. Enantiomeric excess of 9 was determined by HPLC analysis using the chiral column (Chiralcel OD).