Efficient Synthesis of Chiral α- and β-Hydroxy Amides: Application to the Synthesis of (R)-Fluoxetine

Article abstract of DOI:10.1002/anie.200352431

Four flavors for epoxide openings: The regioselective openings of epoxy amides obtained by asymmetric epoxidation yields all types of aryl- and alkyl-substituted hydroxy amides sometimes counter to the reactivity of the α- and β-positions.

Full text of DOI:10.1002/anie.200352431

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 Š) more effec-
[10]
À
tively than the Ca O bond (Da = 0.0092Š).
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
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 317 –320
DOI: 10.1002/anie.200352431
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317

Communications
Table 1: Selective epoxide-opening reaction of b-aryl a,b-epoxy amides (Scheme 1, path B).
sponding b-hydroxy amides 6a–g in excel-
lent yields and selectivities.[7]
The transformation of b-alkyl-substi-
tuted a,b-epoxy amides into a-hydroxy
amides (Scheme 1, path D) is extremely
challenging because the b-position is much
less reactive than the a-position. After
intensive examination, we obtained a-hy-
droxy amide 7a with moderate selectivity
(2.7:1) by using LiAlH4.[11] To obtain a-
hydroxy amides efficiently, we used a new
synthetic strategy with a,b,g,d-unsaturated
amides, as shown in Scheme 2. In this
process, the a,b-selective epoxidation of
a,b,g,d-unsaturated amides through the
intramolecular transfer of peroxide from
La to the b-position and hydrogenolysis of
the corresponding g,d-unsaturated a,b-
epoxy amides were key steps.
Entry
Substrate[a]
R1
[15]crown-5
[equiv]
Solvent
T
[8C]
Yield
[%][b]
5:4[c]
R2NR3
1
2
3
4
5
6
7
8
9
10
11
12
13
14[e]
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
MeNH
BnNH
0
DME
DME
DME
DME
DME
DME
DME
DME
THF
toluene
CH2Cl2
DME
DME
DME
4
4
4
4
4
72
78
91
89
86
84
87
87
80
73
88
85
90
87
2:1
4:1
7:1
8:1
8:1
0.5
1.0
1.2
1.2[d]
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
4
8:1
À20
À40
4
16:1
18:1
6:1
3:1
3:1
10:1
14:1
5:1
Ph
Ph
Ph
4
4
4-Me-C6H4
4-F-C6H4
Ph
À20
À20
À20
We first investigated the catalytic asym-
metric epoxidation of a,b,g,d-unsaturated
=
amides 10a using Sm–(S)-binol–Ph3As O
1
[a] Substrate purity in all cases 99% ee. [b] Yield of 4 and 5. [c] The ratio was determined by H N MR
analysis of the crude sample. [d] [18]Crown-6 was used instead of [15]crown-5. [e] Reaction time was
5.0 h.
(1:1:1) complex 13 (binol = 2,2’-dihydroxy-
1,1’-binaphthyl), which is a useful catalyst
for the asymmetric epoxidation of a,b-
unsaturated amides.[3] The reaction pro-
ceeded to afford 11a with complete a,b-
selectivity; however, the reactivity was not
satisfactory (Table 3, entry 1). Thus, we
further tested a number of other lanthanum
complexes.[11] Finally, the Gd–(S)-binol–
=
Ph3As O complex 14 was determined to
be the best in this system (entry 2), and
activation of 4-Š molecular sieves was
necessary to improve the reactivity
(entry 3). This catalytic system was applica-
ble to various a,b-selective epoxidations
of a,b,g,d-unsaturated amides 10a–f
À
Figure 1. The effects of a sodium ion on the C O bonds of a,b-epoxy amides 2a during reduction
with Red-Al.
Table 2: Selective epoxide-opening reaction of b-alkyl a,b-epoxy amides
(Scheme 1, path C).
Entry
Substrate[a]
t [h]
Yield [%][b]
6:7[c]
R1
R2NR3
Scheme 2. Strategy to obtain b-alkyl,a-hydroxy amides (Scheme 1, path D)
1[d]
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
3 f
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)4
cHex[e]
MeNH
MeNH
BnNH
AllylNH
cHexNH[e]
tBuNH
MeNH
BnNH
2.5
1.0
1.5
1.5
1.5
1.5
1.5
1.5
95
94
88
89
89
92
93
89
40:1
22:1
21:1
20:1
28:1
>50:1
12:1
11:1
=
(entries 5–9). When 10 to 20 mol% of Gd–(S)-binol–Ph3As
O complex 14 was used, amides prepared from primary
amines (10a,b,e,f), a secondary amine (10c), and an a-
branched primary amine (10d) were epoxidized to afford g,d-
unsaturated a,b-epoxy amides in good yield and excellent
selectivity.[12]
Moreover, these g,d-unsaturated a,b-epoxy amides 11a–f
were easily converted into g,d-unsaturated a-hydroxy amides
12a–f via a p-allyl palladium intermediate (Table 4).[13]
3g
[a] Substrate purity in all cases 99% ee except for substrate 3c (98% ee).
[b] Yield of 6 and 7. [c] The ratio was determined by H NMR analysis of the
crude sample. [d] Red-Al/crown ether conditions shown in Table 1 (entry 6)
were used. [e] cHex=cyclohexyl.
1
318
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Chemie
À
Table 3: Catalytic asymmetric epoxidation of a,b,g,d-unsaturated amides.
Finally, reduction of the C C
double bonds proceeded smoothly
with Pd/C and H2, producing b-alkyl
a-hydroxy amides 7a–f efficiently.[7]
To demonstrate the usefulness
of our methodology, an asymmetric
synthesis of (R)-fluoxetine (17) was
Entry
Substrate
R6
Cond.[a]
14
[mol%]
t [h]
Yield [%]
ee [%]
executed on
a multigram scale
(Scheme 3). Fluoxetine (Prozac,
Eli Lilly Co.), marketed as a race-
mate, is an antidepressant drug and
many groups have intensively stud-
ied an efficient synthesis of the
enantiomerically pure form.[14,15]
Catalytic asymmetric epoxidation
of 15 (5-g scale) gave enantiomeri-
cally pure a,b-epoxy amides 2a in
91% yield and 99% ee. The Red-
R5
R2NR3
1[b]
2
3
4
5
6
7
8
10a
10a
10a
10a
10b
10c
10d
10e
10 f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
MeNH
MeNH
MeNH
MeNH
BnNH
MeNMe
cHexNH
BnNH
A
A
B
B
B
B
B
B
B
10
10
10
15
10
10
15
20
20
48
48
48
48
21
12
48
48
48
48
61
78
85
89
90
94
85
76
97
99
99
96
99
99
99
99
99
Me
H
9
-(CH2)4-
BnNH
[a] Conditions A: TBHP in decane, 4-Š molecular sieves not dried. Conditions B: TBHP in toluene, 4-Š Al/crown ether strategy was used to
molecular sieves dried for 3 h at 1808C under reduced pressure. [b] Sm was used as a central metal.
convert this epoxide into b-hydroxy
amide 5a.[16] The resulting amide
was reduced to the known key
intermediate 16 with LiAlH4, and
Table 4: Conversion to b-alkyl a-hydroxy amides (Scheme 1, path D).
16 was coupled with 4-chlorobenzo-
trifluoride to give 17 as the hydro-
chloride salt.[15d,e]
In summary, regioselective
epoxide-opening processes for a,b-
Entry
Substrate
R6
t [h]
Yield [%]
step B
epoxy amides to give both a- and b-
hydroxy amides have been devel-
oped. Moreover, this reaction was
successfully applied to an asymmet-
ric synthesis of (R)-fluoxetine, dem-
onstrating the power of the newly
R5
R2NR3
step A
step B
step A
1
2
3
4
5
6
11a
11b
11c
11d
11e
11 f
Ph
Ph
Ph
Ph
Me
H
H
H
H
H
MeNH
BnNH
MeNMe
cHexNH
BnNH
BnN
1
1
1
1
2
1
1
1
1
1
91
90
87
95
95
94
92
94
94
94[c]
-(CH2)4-
H
12
12
94
86
developed reaction. We are cur-
rently investigating more detailed
mechanisms of the epoxide-opening
reaction and more difficult tasks
such as the regioselective epoxide
opening of a,b-epoxy amides by
[a] Conditions: [Pd2(dba)3]·CHCl3 (2.6 mol%), Bu3P (2.6 mol%), Et3N(2 equiv), HCO 2H (5 equiv), THF,
RT. [b] Conditions: Pd/C (5 mol%), H2 (1 atm), THF/MeOH (2:1), RT. [c] A mixture of three olefin
isomers was obtained.
carbon nucleophiles and other nucleophiles.
Received: July 21, 2003 [Z52431]
Keywords: asymmetric synthesis · epoxides · regioselectivity ·
.
synthetic methods
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Scheme 3. Asymmetric synthesis of (R)-fluoxetine hydrochloride (17).
=
a) Sm–(S)-binol–Ph3As O (13) (10 mol%), TBHP (1.2 equiv), THF,
4-Š molecular sieves, RT, 91%, 99% ee; b) Red-Al (1.2 equiv),
[15]crown-5 (1.2 equiv), DME (0.2m), À408C to RT, 80% (yield of
b-OH product isolated), b-OH/a-OH >20:1; c) LiAlH4, THF, reflux,
quantitative; d) NaH, DMSO, 4-chlorobenzotrifluoride; HCl, 92%
(lit.[14e]). DMSO=dimethyl sulfoxide, RT=room temperature,
TBHP=tert-butyl hydroperoxide.
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Communications
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[8] Red-Al was used for the transformation of allylic alcohol
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These results also support our hypothesis.
[11] See the Supporting Information for details.
[12] The absolute configuration of 11a was determined to be 2R,3S.
See the Supporting Information for details.
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in 87% yield. See the Supporting Information. Alternatively,
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320
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