Angewandte
Chemie
Regioselective Epoxide Opening
Efficient Synthesis of Chiral a- and b-Hydroxy
Amides: Application to the Synthesis of
(R)-Fluoxetine**
Hiroyuki Kakei, Tetsuhiro Nemoto, Takashi Ohshima,
and Masakatsu Shibasaki*
Chiral a- and b-hydroxy amides are useful building blocks for
the synthesis of biologically active compounds.[1] The syn-
thesis of these intermediates in both a regio- and stereo-
selective manner, however, is difficult. There are only a few
methods for the synthesis of such chiral units, and their
substrate scope and selectivity remain unsatisfactory.[2] The
regioselective epoxide-opening reaction of optically active
a,b-epoxy amides is one of the most attractive approaches to
this problem. We[3] and Aggarwal's group[4] recently suc-
ceeded in developing efficient strategies to obtain a,b-epoxy
amides in a highly enantioselective manner. There are no
reports, however, on regioselective epoxide-opening reac-
tions of a,b-epoxy amides,[3,5] in contrast to the success with
a,b-epoxy ketones.[6] We report herein a new synthesis of
nearly enantiomerically pure a- and b-hydroxy amides with
high substrate generality, which consists of a novel highly
regioselective epoxide opening of both b-alkyl- and b-aryl-
substituted a,b-epoxy amides (Scheme 1). An efficient enan-
tioselective synthesis of (R)-fluoxetine, using the newly
developed method, is also described.
To realize the highly regioselective epoxide-opening
reactions of a,b-epoxy amides, it is important to control the
relative reactivity of the a- and b-positions, which depends on
the b-substituent. Thus, we discuss the reactions of the b-aryl-
substituted amide (paths A and B) and of the b-alkyl-
substituted amide (paths C and D).
We recently described the highly enantio- and regioselec-
tive synthesis of b-aryl a-hydroxy amides using a one-pot,
tandem process consisting of catalytic asymmetric epoxida-
tion and a Pd-catalyzed epoxide opening (path A). The
selectivity was based on the higher reactivity of the b-position
(benzyl position) over that of the a-position.[3] The higher
reactivity of the b-position, however, make it difficult to
Scheme 1. Strategy to obtain a- and b-hydroxy amides from a,b-epoxy
amides by regioselective epoxide opening.
products. To overcome this difficulty, we examined a so-called
intramolecular hydride transfer using Red-Al (sodium bis(2-
methoxyethoxy)aluminum hydride),[1c,8] which might react
À
À
with N H first to produce a N Al species; the remaining
hydride attacks the a-position of the epoxy amide (see
Figure 1). As we expected, the reduction of 2a with Red-Al
gave b-hydroxy amide 5a[7] as the major product in moderate
yield (Table 1, entry 1). This result prompted us to optimize
the reaction conditions.
To gain insight into the reaction mechanism, especially for
the counterion effects, calculations were performed by means
of the hybrid density functional method (B3LYP[9]) using a
6-31G(d) basis set. As shown in Figure 1, the coordination
of a sodium ion to the epoxide and carbonyl oxygen atoms
À
should weaken the Cb O bond (Db = 0.0315 ) more effec-
[10]
À
tively than the Ca O bond (Da = 0.0092).
In an attempt
to overcome this drawback, we added [15]crown-5 to trap
sodium ions. Both regioselectivity and reactivity improved
(entries 2–4, and 6). The best selectivity was obtained with a
1:1 ratio of Red-Al and [15]crown-5 (entry 4). The use of
[18]crown-6 gave a comparable result (entry 5). Solvents and
temperatures were also investigated; the use of dimethoxy-
ethane (DME) and a lower reaction temperature gave much
better results (entries 7 and 8).[11] This mixture of reagents,
Red-Al and crown ether, was applicable to the selective
conversion of various b-aryl a,b-epoxy amides 2b–d into
b-aryl b-hydroxy amides 5b–d (entries 12–14).[7]
À
obtain b-hydroxy amides through cleavage of the Ca O bond
(path B). Indeed, the general conditions for selective cleavage
À
of the Ca O bond in a,b-epoxy ketones, such as SmI2 and
The Red-Al/crown ether strategy was applicable to the
regioselective epoxide-opening reaction of b-alkyl-substi-
tuted amides (Scheme 1, path C). In contrast to b-aryl-
substituted amides, these substrates have higher reactivity at
the a-position than at the b-position, and b-hydroxy amides
were obtained with much higher regioselectivity (Table 2,
entry 1). Thus, satisfactory selectivity was achieved even when
simple reaction reagents, such as DIBAL (diisobutylalumi-
num hydride, entry 2), were employed. The scope and
limitations of this reaction were also examined with various
substrates prepared from primary amines 3b,c,f,g (entries 3, 4,
7, and 8) and a-branched primary amines 3d,e (entries 5 and
6). When two equivalents of DIBAL were used, b-alkyl a,b-
epoxy amides were successfully converted into the corre-
[Cp2TiCl2]/Zn,[6,7] gave unsatisfactory results (trace amounts)
with a,b-unsaturated and -saturated amides as the major
[*] H. Kakei, T. Nemoto, Dr. T. Ohshima, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113–0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
[**] This work was supported by RFTF and by a Grant-in-Aid for the
Encouragement of Young Scientists (A) from the Japan Society for
the Promotion of Science (JSPS).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2004, 43, 317 –320
DOI: 10.1002/anie.200352431
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
317