Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue

Article abstract of DOI:10.1016/S0040-4039(01)00910-8

Chiral (E)-arylaldehyde oxime ethers, prepared using (R)-1-phenyl-1,2-ethanediol as a chiral auxiliary, undergo nucleophilic addition with methyllithium to give diastereomerically enriched O-alkyl hydroxylamines which, after reductive N-O bond cleavage, lead to the corresponding (R)-1-(aryl)ethylamines. This methodology has been applied to the enantioselective synthesis of a new type of arylalkylamine calcimimetics (R)-(+)-NPS R-568 and its thio analogue.

Full text of DOI:10.1016/S0040-4039(01)00910-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5029–5032
Nucleophilic addition of methyllithium to chiral oxime ethers:
asymmetric preparation of 1-(aryl)ethylamines and
application to a synthesis of calcimimetics (+)-NPS R-568
and its thio analogue
Naoki Yamazaki, Masakazu Atobe and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 23 April 2001; revised 24 May 2001; accepted 25 May 2001
Abstract—Chiral (E)-arylaldehyde oxime ethers, prepared using (R)-1-phenyl-1,2-ethanediol as a chiral auxiliary, undergo
nucleophilic addition with methyllithium to give diastereomerically enriched O-alkyl hydroxylamines which, after reductive NꢀO
bond cleavage, lead to the corresponding (R)-1-(aryl)ethylamines. This methodology has been applied to the enantioselective
synthesis of a new type of arylalkylamine calcimimetics (R)-(+)-NPS R-568 and its thio analogue. © 2001 Elsevier Science Ltd.
All rights reserved.
Optically active primary amines are frequently encoun-
tered in naturally occurring products and pharmacologi-
cally active compounds and also could serve as chiral
building blocks and chiral auxiliaries in asymmetric
synthesis.1 In this regard, the development of new and
efficient methods for the asymmetric preparation of
enantiopure primary amines and their derivatives is a
matter of considerable significance.1 One of the most
widely used methods for the preparation of such com-
pounds is nucleophilic addition of organometallic
reagents to the CꢁN bond of chiral imines. In the chiral
auxiliary based asymmetric synthesis, the use of chiral
oxime ethers as substrates for the addition reaction of
organometallic reagents is an attractive approach to
primary amines because of the ease of removal of the
chiral auxiliaries by NꢀO bond cleavage. However,
despite numerous studies of imine addition, there have
been only limited examples of this approach reported2,3
mainly due to the low electrophilicity of the carbon
atom of the CꢁN bond in oxime ethers in comparison
with the corresponding imine carbon. To overcome this
problem associated with the low electrophilicity, activa-
tion of oxime ethers by a Lewis acid such as boron
trifluoride etherate is required,3 which has restricted the
synthetic application of this reaction because the Lewis
acid activation is not compatible with substrates having
acid-labile functional groups. In this paper we disclose
a diastereoselective organometallic addition by activa-
tion of oxime ethers via intramolecular lithium chela-
tion leading to 1,4-asymmetric induction to form
optically active 1-(aryl)ethylamines. This methodology
was applied to the enantioselective synthesis of (R)-(+)-
NPS R-568 (1)4,5 and its thio analogue, (R)-N-{1-[3-
(methylsulfanyl)phenyl]ethyl}-3-phenyl-1-propanamime
(2),6 the former of which represents a new class of
calcium receptor agonist (calcimimetics) with potent
and selective activity and has been developed into drug
candidates for the treatment of primary and secondary
hyperparathyroidism.4 The R enantiomer of 1 has been
reported to be 10- to 100-fold more potent than the S
enantiomer.4 The latter compound 2 recently synthe-
sized as a racemate has been proposed to be a potent
calcium receptor modulating agent.6
Me
Me
N
H
N
H
Cl
OMe
(+)-NPS R-568 (1)
SMe
* Corresponding author. Fax.: +81-426-76-4475; e-mail: kibayasi
@ps.toyaku.ac.jp
2
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00910-8

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N. Yamazaki et al. / Tetrahedron Letters 42 (2001) 5029–5032
The chiral oxime ethers 6a–f were readily prepared
using commercially available 1-phenyl-1,2-ethanediol
(3) as a chiral auxiliary (Scheme 1). Thus, the Mit-
sunobu reaction of (R)-3 with N-hydroxyphthalimide
occurred regioselectively at C-1 of (R)-3 due to its
benzylic nature, affording the alkoxyphthalimide 4 with
clean inversion of the stereochemistry.7 When the free
(S)-alkoxylamine 5, generated from 4 under standard
conditions with hydrazine hydrate, was condensed with
the aryl aldehydes (toluene, reflux) in the presence of a
trace amount of TsOH, the reactions were completed in
15–20 min to form the corresponding oxime ethers 6a–f
as the E isomers in excellent yields.8 The oxime ether 6d
was converted to the O-methyl derivative 7 by treat-
ment with iodomethane and sodium hydride.
With the oxime ethers 6a–f and 7 in hand, diastereo-
selective addition with methyllithium (1.14 M solution in
diethyl ether) was investigated. Thus, after treatment of
a THF solution of 6a with 1 equiv. of methyllithium at
0°C for 5 min, another 1.5 equiv. of methyllithium was
added, and the mixture was stirred at 0°C for 25 min;
however, during the reaction extensive decomposition
was observed without formation of the desired methyl
adduct as seen from Table 1 (entry 1). On the other
hand, when 6a was submitted to the above reaction
conditions, but using diethyl ether instead of THF as
the solvent, the desired methyl adducts 8a and 9a were
obtained in 64% total yield in a 9.8:1 ratio (entry 2) in
favor of the 1%R isomer 8a, along with some decomposi-
tion of the starting material. In the latter case changing
O
O
HO
O
N-hydroxyphthalimide
N2H4•H2O, EtOH, refl.
(99%)
N
OH
OH
H2N
OH
Ph
DEAD, Ph3P
(81%)
Ph
(R)-3
Ph
O
5
4
O
N
OMe
O
ArCHO, TsOH, toluene, refl.
(97–99%)
MeI, NaH, THF, rt
N
OH
Ph
Ph
(85% from 6d)
X
OMe
6a: X = H
6b: X = 4-Me
7
6c: X = 2-OMe
6d: X = 3-OMe
6e: X = 2-OMOM
6f: X = 3-SMe
Scheme 1.
Table 1. Nucleophilic addition of methyllithium to chiral oxime ethersa
Me
Me
O
O
O
MeLi (2.5 equiv.)
N
OR
N
(S)
OR
(R) N
OR
+
H
H
Ph
Ph
9a–f, 11
Ph
X
X
X
6a–f, 7
8a–f, 10
Entry
Oxime ether
R
X
Solvent
Temp. (°C)
Product
Yield (%)b
1R:1Sc
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6b
6b
6c
6c
6d
6d
6d
6e
6f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
THF
Et2O
0
0
0
–
0
64
80
78 (10)
79
76 (11)
84
81 (10)
65
–
8a/9a
8a/9a
8a/9a
8b/9b
8b/9b
8c/9c
8c/9c
8d/9d
8d/9d
8d/9d
8e/9e
8f/9f
10/11
9.8:1
9.8:1
14.0:1
8.4:1
11.6:1
5.1:1
7.6:1
7.4:1
7.6:1
8.1:1
7.5:1
7.1:1
3.0:1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
Toluene
Toluene
Toluene
Toluene
Toluene
−20
0
−20
0
−20
0
4-Me
4-Me
2-OMe
2-OMe
3-OMe
3-OMe
3-OMe
2-OMOM
3-SMe
3-OMe
9
10
11
12
13
14
0
85
−20
−20
−20
0
79 (12)
74 (8)
77 (10)
28
7
Me
a All the reactions in this table were carried out using 1.5 equiv. of MeLi (1.14 M in Et2O) for 25 min after treatment with 1 equiv. of MeLi (1.14
M in Et2O) at 0°C for 5 min.
b Total yield of the chromatographically separated diastereomers. Yields in parentheses are for recovered starting material.
c Determined by 1H NMR of the product mixture.

N. Yamazaki et al. / Tetrahedron Letters 42 (2001) 5029–5032
5031
13f11 were obtained in 73–83% yield with recovery of
the antipodal chiral auxiliary (S)-3, which can be uti-
lized as a chiral auxiliary for the preparation of ent-
13a–f. The use of molybdenum hexacarbonyl12 (method
b) for the reductive NꢀO bond cleavage was effective
for 8a–f, and in each case the yield of corresponding
13a–f was noticeably improved to 89–95% (Scheme 2).
The 1-(aryl)ethylamines 13e (X=2-OMOM)11 obtained
was subjected to deprotection of the MOM group
(HCl, MeOH, reflux) to give (1R)-1-(2-hydroxy-
phenyl)ethylamine (14),13 which, together with its (1S)-
enantiomer, was previously demonstrated by us to be a
useful chiral auxiliary in the enantioselective synthesis
of natural alkaloids.14
the solvent from diethyl ether to a very weakly polar
toluene led to an improved total yield of 80% with the
same diastereoselectivity (entry 3). When the addition
to 6a in toluene was employed at lower temperature of
−20°C the diastereomeric ratio increased significantly to
14.0:1 (entry 4). Similar trends in the diastereoselective
addition with methyllithium were observed for other
oxime ethers 6b–f (entries 5–13).
It is interesting to note that the methyl addition to the
methoxy oxime ether 7 in toluene resulted in only poor
yield (28%) and low diastereoselectivity (entry 14), sug-
gesting that the formation of the lithium salt of the
primary alcohol is important in promoting the
diastereoselective methyl additions to the oxime ethers
6a–f. A mechanistic rationale based on a six-membered
chair-like chelate structure 12 is thus proposed as an
intermediate for the observed R selectivity. In this
structure, one molecule of methyllithium would be con-
sumed for the initial formation of the lithium alkoxide
followed by coordination of the lithium atom to the
nitrogen atom of the oxime ether9 which is activated
toward nucleophilic attack. A second molecule of
methyllithium coordinated to the oxygen atom might
occupy an axial position to avoid 1,3-allylic strain,10
and a subsequent internal delivery of the methyl group
would occur to the re face of the imino group. The use
of a non-coordinating solvent such as toluene favors
intramolecular chelation phenomenon associated with
the oxime activation, providing improved yield of the
methyl adducts.
With (1R)-(+)-1-(3-methoxyphenyl)ethylamine (13d)
(obtained in 93% yield from 8d by method b) in hand,
we next examined its conversion into (R)-(+)-NPS R-
568 (1). Thus, coupling of 13d and 2-chlorobenzenepro-
pionic acid (15) was effected with DCC–DMAP
(CH2Cl2, rt) to give the amide 16 in 95% yield. The
DIBAL-H reduction (CH2Cl2, rt) of 16 yielded 1 (71%),
[h]D20 +41.9 (c 1.1, CHCl3) (lit.5b [h]D +38.6 (c 1.1,
CHCl3)). In a similar sequence, coupling of 13f
(obtained in 95% yield from 8f by method b) with
phenylpropionic acid (17) afforded the amide 18 (92%),
which underwent DIBAL-H reduction to provide the
thio analogue of 1, (R)-N-{1-[3-(methylsulfanyl)-
phenyl]ethyl}-3-phenyl-1-propanamime (2), [h]2D0=+44.4
(c 0.3, CHCl3), in 81% yield (Scheme 3).
In summary, we have developed an enantioselective
synthesis of 1-(aryl)ethylamines based on diastereoselec-
tive addition of methyllithium to the chiral oxime ethers
via six-membered ring lithium chelation, which acti-
vates the substrate for the addition, leading to 1,4-
asymmetric induction. The synthetic utility of this
oxime ether-based methodology has been demonstrated
by the application to the enantioselective synthesis of
a new type of arylalkylamine calcimimetics (+)-NPS
R-568 and its thio analogue.
Li
O
Me
N
Li
re
O
Ph
Ar
H
12
When reductive NꢀO bond cleavage was carried out
with 8a–d and 8f by using Zn–AcOH (method a), the
corresponding (R)-1-(aryl)ethylamines 13a–d11 and
Me
(a) Zn, AcOH, THF–H2O, 60 ˚C (for 8a–d, 8f)
(b) Mo(CO)6, MeCN–H2O, refl. (for 8a–f)
O
N
H
OH
Ph
X
8a–f
Me
NH2
HO
OH
+
Ph
X
(S)-3
13a–f method a: 73–83%
method b: 89–95%
Me
NH2
HCl, MeOH, refl.
(from 13e: X = 2-OMOM)
OH
14
(88%)
Scheme 2.

5032
N. Yamazaki et al. / Tetrahedron Letters 42 (2001) 5029–5032
Me
CO2H
DCC, DMAP
CH2Cl2
NH2
+
Y
XMe
15: Y = Cl
17: Y = H
13d: X = O
13f: X = S
Me
O
Me
DIBAL-H
N
H
N
H
CH2Cl2, rt
Y
Y
XMe
XMe
16: X = O, Y = Cl (95%)
18: X = S, Y = H (92%)
1: X = O, Y = Cl (71%)
2: X = S, Y = H (81%)
Scheme 3.
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