Asymmetric synthesis of 2-(α-aminoalkyl)oxazoles, 2-oxazolylpyrrolidines, 2-oxazolylpiperidines: Total synthesis of 4,5-dihydroxypipecolinic acid

Article abstract of DOI:10.1055/s-2000-8719

Asymmetric α-alkylation of 2-aminomethyl-4,5-diphenyloxazole was achieved by formation of azomethines 1 and ent-1 with the enantiomers of 2-hydroxypinan-3-one as chiral auxiliaries, reaction with alkylating reagents and final removal of the chiral auxiliary giving rise to optically active 2-(α-aminoalkyl)oxazoles 3, ent-3, 6 and 9. If α,ω-dihaloalkanes were used the resulting alkylation products could be further cyclized by intramolecular alkylation of the amino group to afford optically active 2-oxazolyl-N-heterocycles 4, ent-4, 7 and 10. The latter could be used for the total synthesis of naturally occurring 4,5-dihydroxypipecolinic acid 13.

Full text of DOI:10.1055/s-2000-8719

PAPER
2051
Asymmetric Synthesis of 2-(a-Aminoalkyl)oxazoles, 2-Oxazolylpyrrolidines,
2-Oxazolylpiperidines: Total Synthesis of 4,5-Dihydroxypipecolinic Acid
Marion Thieme,a Eric Vieira,b Jürgen Liebscher*a
a Institut für Chemie, Humboldt-Universität Berlin, Hessische Straße 1-2, D-10115 Berlin, Germany
Fax +49(30)20938907; E-mail: liebscher@chemie.hu-berlin.de
b Pharma Research Basel, Medicinal Chemistry, F. Hoffmann-La Roche Ltd., CH-4002 Basel, Switzerland
Received 7 March 2000; revised 31 July 2000
We report here the asymmetric synthesis of 2-(a-ami-
Abstract: Asymmetric a-alkylation of 2-aminomethyl-4,5-diphe-
noalkyl)-4,5-diphenyloxazoles 3 and ent-3 starting from
nyloxazole was achieved by formation of azomethines 1 and ent-1
2-aminomethyl-4,5-diphenyl-1,3-oxazole using the enan-
with the enantiomers of 2-hydroxypinan-3-one as chiral auxiliaries,
tiomers of 2-hydroxypinan-3-one as chiral auxiliaries.
reaction with alkylating reagents and final removal of the chiral
auxiliary giving rise to optically active 2-(a-aminoalkyl)oxazoles 3, This concept is extended to the synthesis of oxazolylpyr-
ent-3, 6 and 9. If a,w-dihaloalkanes were used the resulting alkyla-
tion products could be further cyclized by intramolecular alkylation
of the amino group to afford optically active 2-oxazolyl-N-hetero-
cycles 4, ent-4, 7 and 10. The latter could be used for the total syn-
thesis of naturally occurring 4,5-dihydroxypipecolinic acid 13.
rolidines, oxazolylpiperidines 4 and ent-4 and dihydrox-
ypipecolinic acid (13) by further cyclization and oxidative
cleavage of the oxazole ring, respectively.
The starting azomethines 1 and ent-1 could be easily ob-
tained from 2-aminomethyl-4,5-diphenyl-1,3-oxadiazole
and (1S,2S,5S)- or (1R,2R,5R)-2-hydroxypinanone, re-
spectively. Treatment with two equivalents of LDA in
THF and the corresponding alkyl halide afforded the en-
visaged alkylation products 2, ent-2, 5 and 8 (see Schemes
1 and 2, respectively) in high yields and stereoselectivities
(see Tables 1 and 2). In the case of methylation (R = Me),
5% of the corresponding O-methylation products were
obtained as byproducts. The application of BuLi instead
of LDA gave mixtures of inseparable products. The con-
figuration of the new stereogenic center can be governed
by choosing the corresponding enantiomer of hydroxypi-
nanone, i.e. the (S, S, S)-hydroxypinanone generates the
(R)-configuration and vice versa (see Tables 1 and 2, com-
pounds 2a/ent-2a, 2g/ent-2b and 5/8 as well as the corre-
sponding products 3, ent-3, 6 and 9 obtained from these
imines), as also found before in alkylations of a-amino es-
ters or in the aminomethylheterocycle series.1,8,10 It can be
assumed that intermediate azaenolates formed are similar
to the enolate reported by Yamada et al.14 for imines of
a-amino esters, which react with the alkylating reagent in
a SN2-like fashion.
Key words: 2-(1-aminoalkyl)-1,3-oxazoles, asymmetric synthesis,
2-oxazolylpiperidines, 2-oxazolylpyrrolidines, 4,5-dihydroxypipe-
colinic acid, chiral auxiliaries, heterocycles
Chiral a-aminoalkyl heterocycles are found in natural
products of pharmacological activity such as in dolasta-
tin,1, 2 promothiocine A3, 4 or ibutenic acid5 and were of in-
terest in the synthesis of kinase inhibitors.6 The
asymmetric side chain a-alkylation of aminoalkyl-
heterocycles provided a useful tool for the synthesis of
such moieties.1 Thus adopting a methodology originally
invented by Yamada et al.7 for the synthesis of optically
active a-amino acids and further developed by Viallefont
et al.,8,9 imines of 2-aminomethylthiazole and 2-hydroxy-
pinan-3-ones as chiral auxiliary could be a-benzylated
with high stereoselectivity affording 2-(1-amino-2-phe-
nylethyl)-thiazole as a subunit of dolaphenine after re-
moval of the chiral auxiliary.1 Furthermore, this method
was used in asymmetric a-alkylation of other aminometh-
ylheterocycles and benzylamine.10 Since both enanti-
omers of the hydroxypinanone are commercially
available each enantiomer of the corresponding alkylation
product can be synthesized by this auxiliary technique,
i. e. the (1R,2R,5R)-hydroxypinanone induces the (S)-
configuration of the new stereogenic center while the
enantiomer induces the (R)-configuration.8,10 The same
strategy was applied in the asymmetric alkylation of 2-
aminomethylpyridine used for the synthesis of Ontazo-
last®, a potent LTB4-inhibitor.11 Optically active piperi-
dine and pyrrolidine-2-carboxylic acids could be
synthesized by alkylation of imines of hydroxypinanone
and a-amino ester using a,w-dihaloalkanes, cleaving the
imine and final intramolecular alkylation of the resulting
amino group.12 In the oxazole and oxadiazole series a di-
astereoselective a-alkylation was achieved at prolinolyl-
methyl side chains.13
The chiral auxiliary could smoothly be split off from imi-
nes 2, ent-2, 5 and 8 by hydrolysis in the presence of citric
acid15,16 affording the corresponding 2-(a-aminoalkyl)ox-
azoles 3, ent-3, 6 and 9 (see Schemes 1, 2 and Tables 1, 2).
Hydroxylamine in acetic acid, another known reagent14
for this transformation, gave considerably lower yields.
Assignment of the configuration of the products 2, 3, ent-
2 and ent-3 was based on the X-ray crystal analysis of
compound 2c [see Figure, (R)-configuration] and the in-
dependent synthesis of ent-3a [(S)-configuration] adopt-
ing literature procedures.17 This independent synthesis,
however, gave a partially racemized product thus under-
lining the usefulness of the asymmetric synthesis accord-
ing to Scheme 1.
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

2052
M. Thieme et al.
PAPER
Scheme 1
The a-amino-w-haloalkyloxazoles 3f, 3g, ent-3b, 6 and 9 use of the possibility that the 4,5-diphenyloxazole moiety
survived the removal of the chiral auxiliary without cy- can be degraded to a carboxylic acid by singlet oxygen.20
clization by intramolecular nucleophilic displacement of This methodology was used to develop a new total synthe-
the w-chloro atom by the appearing amino group (see sis of the (2S,4S,5S)-4,5-dihydroxypipecolinic acid (13), a
Schemes 1 and 2). Comparable cases in the a-amino ester natural product isolated from the seed of Derris eliptica, a
series reported by Viallefont gave spontaneous formation legume species.21 The dihydroxypiperidine 10 obtained
of prolines and higher homologues in most cases.12 Cy- starting from the N-(2-aminomethyloxazolyl)hydroxy-
clization of the a-amino-w-haloalkyloxazoles 3f, 3g, ent- pinanoneimine ent-1 with (4R,5R)-4,5-bis(bromomethyl)-
3b, 6 and 9 could be achieved with NaHCO3 in ethanol af- 2,2-dimethyl-1,3-dioxolane was N-protected (see Scheme
fording optically active pyrrolidine 4f and piperidines 4g, 2). The resulting Z-derivative 11 was treated with oxygen
ent-4, 7 and 10 (see Schemes 1 and 2). These products can under irradiation with UV-light in the presence of Rose
be considered as nicotine analogs and are also promising Bengal cleaving the C-C double bond of the oxazole ring
candidates for chiral catalysts.18, 19 Furthermore they can under rearrangement to afford the N,N-dibenzoylamide of
serve as precursors for cyclic a-amino acids by making the pipecolinic acid 12, which was hydrolyzed to the free
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 2-(α-Aminoalkyl)oxazoles, 2-Oxazolylpyrrolidines, 2-Oxazolylpiperidines
2053
Scheme 2
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

2054
M. Thieme et al.
PAPER
Table 1 Imines 1, 2, 5, Aminoalkyloxazoles 3, 6 and Oxazolyl-N-heterocycles 4, 7
R or n
X
–
I
Yield d. r.a
(%)
[a]2D0
(c in g/
100 mL)
in CHCl3
m. p. Molecular
(°C) Formula
1H NMR (CDCl3)
d (ppm), J (Hz)
1b
–
65
75
–
+5.0
(0.42)
122– C26H28N2O2 0.81 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 1.53
125
(400.5)
(d, J = 10.6 Hz, 1 H, CH), 1.99––2.01 (m, 2H, CH2), 2.23–
2.26 (m, 1 H, CH), 2.56–2.58 (m, 3 H, OH, CH2) 4.58 (s, 2 H,
CH2), 7.23–7.30 (m, 6 H, Ph), 7.50–7.59 (m, 4 H, Ph).
2a
Me
>95:5
–
oil
C27H30N2O2 0.83 (s, 3 H, CH3) 1.27 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.58
(414.6)
(d, J = 6.6 Hz, 3 H, CH3), 1.99–2.04 (m, 2 H, CH2), 2.25–2.28
(m, 1 H, CH), 2.53–2.55 (m, 2 H, CH2), 2.61–2.81 (m, 1 H,
CH), 4.90 (q, J = 6.6 Hz, 1 H, CH), 7.18–7.32 (m, 6 H, Ph),
7.49–7.58 (m, 4 H, Ph).
2bc iPr
I
I
82
62
>95:5 +83.2
(0.84)
oil
C29H34N2O2 0.82 (s, 3 H, CH3), 0.91(d, J = 5.8 Hz, 6 H CH3), 1.25 (s, 3 H,
(454.6)
CH3), 1.48 (s, 3 H, CH3), 1.94–2.03 (m, 2 H, CH2), 2.21–2.24
(m, 1 H, CH), 2.43–2.50 (m, 1 H, OH, CH) 2.62–2.67 (m, 3 H,
OH, CH2), 4.47 (d, J = 7.6 Hz, 1 H, CH), 7.16–7.30 (m, 6 H,
Ph), 7.48–7.58 (m, 4 H, Ph).
2c
cHex
>95:5 +52.0
(1.5)
159
C32H38N2O2 0.83 (s, 3 H, CH3), 1.10–1.21 (m, 5 H, CH2), 1.25 (s, 3 H,
(482.7)
CH3), 1.43 (d, J = 10.5 Hz, 1 H CH), 1.48 (s, 3 H, CH3), 1.59–
1.69 (m, 5 H, CH2), 1.95–2.02 (s, 3 H, CH3), 1.94–2.03 (m, 2
H, CH2), 2.19–2.24 (m, 2 H, CH2), 2.60–2.62 (m, 3 H, OH,
CH2) 4.50 (d, J = 8.1 Hz, 1 H, CH), 7.17–7.31 (m, 6 H, Ph),
7.49–7.58 (m, 4 H, Ph).
2d
2e
Allyl
Br
72
72
90:10
>95:5
–
–
oil
oil
C29H32N2O2 0.82 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.49
(440.6)
(d, J = 10.6 Hz, 1 H, CH), 1.96–2.01 (m, 2 H, CH2), 2.01–2.03
(m, 1 H, CH), 2.23–2.86 (m, 5 H, OH, CH2), 4.58 (t, J = 5.1
Hz, 1 H, CH) 5.03 (dd, 2 H, CH2), 5.68–5.74 (m, 1 H, CH),
7.16–7.30 (m, 6 H, Ph), 7.48–7.58 (m, 4 H, Ph).
3-Buten-1- Br
yl
C30H34N2O2 0.83 (s, 3 H, CH3), 1.11–1.23 (m, 2 H, CH2), 1.25 (s, 3 H,
(454.6)
CH3), 1.47 (s, 3 H, CH3), 1.94–2.03 (m, 3 H, CH3), 1.94–2.03
(m, 3 H, CH2, CH), 2.10–2.27 (m, 4 H, CH2), 2.60–2.75 (m, 3
H, CH, CH2), 4.78 (t, J = 5.0 Hz, 1 H, CH), 4.90–4.99 (m, 2
H, CH2), 5.77–5.84 (m, 1 H, CH), 7.16–7.30 (m, 6 H, Ph),
7.47–7.57 (m, 4 H, Ph).
2fd
3-Chloro-
propyl
I
85
>95:5
–
–
oil
C29H33ClN2 0.82 (s, 3 H, CH3), 1.11–1.18 (m, 2 H, CH2), 1.25 (s, 3 H,
O2
(482.7)
CH3), 1.46 (s, 3 H, CH3), 1.76–1.85 (m, 2 H, CH2), 1.94–2.04
(m, 2 H, CH2,), 2.23–2.25 (m, 1 H, CH), 2.26–2.28 (m, 1 H,
CH,), 2.57–2.76 99 (m, 2 H, CH2), 3.34–3.54 99 (m, 2 H,
CH2), 4.80 (t, J = 5.5 Hz, 1 H, CH), 7.21–7.30 (m, 6H, Ph),
7.47–7.57 (m, 4 H, Ph).
2g
3a
4-Chloro-
butyl
I
67
63
>95:5
e
oil
55
C30H35ClN2
O2(491.1)
Me
–
+22.2
(1)
C17H13N2O 1.60 (d, J = 6.8 Hz, 3 H, CH3), 1.86 (bs, 2 H, NH2), 4.25 (q, J
(264.3)
= 6.8 Hz, 1 H, CH), 7.30–7.41 (m, 6 H, Ph), 7.58–7.68 (m, 4
H, Ph).
3bf
3c
iPr
–
–
–
80
60
85
+18.8
(1.23)
oil
oil
oil
C19H20N2O 0.95 (d, J = 6.7 Hz, 6 H, CH3), 1.72 (bs, 2 H, NH2), 2.01–2.15
(292.4)
(m, 1 H, CH),3.82 (d, J = 5.8 Hz, 1 H, CH), 7.30–7.41 (m, 6
H, Ph), 7.58–7.68 (m, 4 H, Ph).
cHex
Allyl
+24.5
(0.89)
C27H24N2O 1.08–1.29 (m, 5 H, CH2), 1.53–1.84 (m, 7 H, CH, CH2, NH2),
(332.5)
3.82 (d, J = 6.2 Hz, 1 H, CH), 7.17–7.31 (m, 6 H, Ph), 7.48–
7.58 (m, 4 H, Ph).
3d
+51.1
(0.7)
C19H18N2O
(290.4)
1.74 (bs, 2 H, NH2), 2.47–2.56 (m, 1 H, CH), 4.10 (s, 1 H,
CH), 5.05–5.14 (m, 2 H, CH2), 5.70–5.84 (m, 1 H, CH), 7.16–
7.29 (m, 6 H, Ph), 7.47–7.57 (m, 4 H, Ph).
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 2-(α-Aminoalkyl)oxazoles, 2-Oxazolylpyrrolidines, 2-Oxazolylpiperidines
2055
Table 1 (continued)
R or n
X
Yield d. r.a
(%)
[a]2D0
(c in g/
100 mL)
in CHCl3
m. p. Molecular
1H NMR (CDCl3)
d (ppm), J (Hz)
(°C)
Formula
3e
3-Buten-1-
yl
-
-
66
60
+2.5
(1)
oil
C20H20N2O
(304.4)
1.73 (bs, 2 H, NH2), 1.76 - 1.81 (m, 1 H, CH2), 1.84-1.89
(m, 1 H, CH2), 1.94-2.06 (m, 2H, CH2), 4.03 (t, J = 6.7 Hz,
1 H, CH), 4.90-5.02 (m, 2 H, CH2), 5.69-5.83 (m, 1 H, CH2),
7.16-7.30 (m, 6 H, Ph), 7.47-7.57 (m, 4 H, Ph).
3fg
3-Chloro-
propyl
+17.7
(0.3)
oil
C19H19ClN2 1.73-1.94 (m, 2 H, CH2), 2.02-2.19 (m, 2 H, CH2), 2.45 (bs,
O (326.8)
2 H, NH2), 2.90-2.98 (m, 1 H, CH2), 3.08-3.16 (m, 1 H,
CH2), 4.33 (t, J = 7.3 Hz, 1 H, CH), 7.16-7.29 (m, 6 H, Ph),
7.47-7.56 (m, 4 H, Ph).
3g
4-Chloro-
butyl
-
-
61
98
e
-
oil
oil
C20H21ClN2
O (340.9)
4fh
1
+33.4
(1.27)
C19H18N2O
(290.4)
1.87-2.00 (m, 2 H, CH2), 2.13-2.21 (m, 2 H, CH2), 2.39 (bs,
1 H, NH), 2.98-3.08 (m, 1 H, CH2), 3.20-3.27 (m, 1 H, CH2),
4.42 (t, J = 6.0 Hz, 1 H, CH), 7.25-7.39 (m, 6 H, C6C5), 7.56-
7.66 (m, 4 H, C6C5).
j
4g
5
2
-
-
95
30
i
+22.7
(1)
114- C20H20N2O
116
(304.4)
-
>95:5
-
oil
C33H39BrN2 0.91 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),1.41 (s, 3 H, CH3),1.53
O4 (607.4)
(s, 3 H, CH3), 1.55-1.69 (m, 3 H, CH, CH2), 2.29-2.40 (m, 1
H, CH), 2.64-2.79 (m, 3 H, CH2), 2.82-2.93 (m, 1 H, CH2),
3.52 (dd, J = 1.6 Hz, J = 5.2 Hz, 2 H, CH2Br), 3.99-4.12 (m,
2 H, CH), 5.10 (t, J = 6.7 Hz, 1 H, CH),7.32-7.41 (m, 6 H,
Ph), 7.53-7.64 (m, 4 H, Ph).
6k
-
-
68
71
-
oil
C33H25BrN2 1.42 (s, 3 H, CH2), 1.43 (s, 3 H, CH3), 1.91 (bs, 2 H, NH2),
O3 (457.4)
2.05-2.20 (m, 1 H, CH2), 2.38-2.47 (m, 1 H, CH2), 3.49 (d, J
= 5.8 Hz, 2 H, CH2Br), 3.99-4.13 (m, 2 H, CH), 4.37 (t, J =
8.2 Hz, 1 H, CH), 7.34-7.40 (m, 6 H, Ph), 7.58-7.66 (m, 4 H,
Ph).
7
de =
-20.6
118- C23H24BrN2 1.46 (s, 3 H, CH2), 1.50 (s, 3 H, CH3), 2.07-2.17 (m, 2 H,
120
99.6%l (1)
O3 (376.5)
NH, CH2), 2.89-2.92 (m, 1 H, CH2), 3.16 (t, J = 13 Hz, 1 H,
CH2), 3.39 (dd, J = 6 Hz, J = 12.5 Hz, 1 H, CH2) 3.46-3.51
(m, 1 H, CH), 3.56-3.63 (m, 1 H, CH), 4.55 (dd, J = 2.2 Hz,
J = 8.3 Hz 1 H, CH), 7.33-7.38 (m, 6 H, Ph), 7.57-7.67 (m,
4 H, Ph).
a determined by NMR as far as not otherwise mentioned.
b ee > 99%, determined by HPLC Cliralcel OD; 13C NMR (CDCl3): d = 23.3, 27.1, 28.5, 28.7, 34.2, 38.6, 38.9, 48.5, 50.7, 77.8, 127.0, 128.3,
128.4, 128.9, 129.0, 129.3, 132.8, 135.6, 146.3, 161.1, 180.0.
c 13C NMR (CDCl3): d = 19.3, 19.9, 23.3, 27.7, 28.4, 28.8, 33.8, 33.8, 38.6, 38.7, 50.3, 64.3, 77.8, 126.9, 128.4, 128.8, 128.9, 129.0, 129.3,
132.8, 135.2, 145.8, 162.5, 178.6.
d 13C NMR (CDCl3):d = 23.3, 27.6, 28.4, 28.7, 31.9, 32.1, 338, 38.7, 45.0, 50.4, 57.2, 66.2, 77.9, 126.9, 128.3, 128.5, 128.9, 129.0, 129.2, 132.7,
135.4, 146.1, 162.2, 179.3.
e ee > 99%, determined by HPLC Cliralcel OD.
f 13C NMR (CDCl3): d = 18.5, 19.6, 33.9, 56.3, 126.8, 128.3, 128.4, 128.8, 128.9, 129.0, 129.4, 132.9, 135.3, 145.6, 167.1.
g 13C NMR (CDCl3): d = 25.9, 31.3, 47.3, 55.9, 126.9, 128.3, 128.4, 128.8, 128.9, 129.0, 129.1, 129.4, 132.8, 135.3, 145.9, 165.4.
h 13C NMR (CDCl3): d = 25.8, 31.2, 47.1, 55.9, 126.9, 128.3, 128.4, 128.9, 129.0, 129.2, 132.8, 135.3, 146.0, 165.0.
i ee > 99 % determined by chromatography of the (S)-Trolox-derivatives.
j identical with ent-4, see Table 2.
k 13C NMR (CDCl3): d = 27.5, 27.8, 32.4, 40.1. 48.7, 78.1, 80.4, 110.0, 126.9, 128.3, 128.5, 128.9, 129.0, 129.2, 132.7, 135.4, 145.8, 165.3.
l determined by SFC.
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

2056
M. Thieme et al.
PAPER
Table 2 Imines ent-1, ent-2, 8 Aminoalkyloxazoles ent-3, 9, and Oxazolyl-N-heterocycles ent-4, 10
R or n
X
–
I
Yield d. r.a
(%)
[a]2D0
(c in g/
100 mL)
in CHCl3
m. p. Molecular
(°C) Formula
1H NMR (CDCl3)
d (ppm), J (Hz)
ent-1b
–
74
+5.2
(0.65)
115– C26H28N2O2
0.81 (s, 3 H, CH3) 1.25 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 1.53
(d, J = 10.6 Hz, 1 H, CH), 1.98–2.01 (m, 2 H, CH2), 2.26–
2.29 (m, 1 H, CH), 2.58 (bs, 3 H, OH, CH2), 7.17–7.29 (m, 6
H, Ph), 7.50–7.59 (m, 4 H, Ph).
120
(400.5)
ent-2ac Me
74
77
>95:5 –83.2
oil
C27H30N2O2
(414.6)
0.83 (s, 3H, CH3) 1.27 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.58
(d, J = 6.6 Hz, 3 H, CH3), 1.99–2.04 (m, 2 H, CH2), 2.25–
2.28 (m, 1 H, CH), 2.53–2.55 (m, 2 H, CH2), 2.61–2.81 (m,
1 H, CH), 4.90 (q, J = 6.6 Hz, 1 H, CH), 7.18–7.32 (m, 6 H,
Ph), 7.49–7.58 (m, 4 H, Ph).
(0.84)
ent-2bd 4-Chloro-
I
>95:5
–
oil
C30H35ClN2O2 0.92 (s, 3 H, CH3) 1.34 (s, 3 H, CH3), 1.55 (s, 3 H, CH3),
butyl
(491.1)
1.581–1.60 (m, 2 H, CH2), 1.83–1.87 (m, 2 H, CH2), 2.04–
2.06 (m, 1 H, CH), 2.08–2.10 (m, 1 H, CH), 2.11–2.18 (m, 2
H, CH2), 2.32–2.38 (m, 2 H, CH2), 2.65–2.85 (m, 2 H, CH2),
3.56 (t, J = 6.5 Hz, 2 H, CH2Cl), 4.85 (t, J = 5.2 Hz, 1 H,
CH), 7.26–7.39 (m, 6 H, Ph), 7.55–7.65 (m, 4 H, Ph).
f
f
ent-3ae Me
–
–
79
72
–20.5
(0.95)
58
oil
C17H13N2O
(264.3)
1.60 (d, J = 6.8 Hz, 3 H, CH3), 1.86 (bs, 2 H, NH2), 4.25 (q,
J = 6.8 Hz, 1 H, CH), 7.30–7.41 (m, 6 H, Ph), 7.58–7.68 (m,
4 H, Ph).
ent-3b
4-Chloro-
butyl
–
C20H21ClN2O 1.57–1.76 (m, 2 H, CH2), 1.81–1.89 (m, 4 H, CH2), 1.96 (bs,
(340.9)
2 H, NH2), 3.56 (t, J = 7.8 Hz, 1 H, CH2Cl), 4.11 (t, J = 6.7
Hz, 1 H, CH), 7.34–7.42 (m, 6 H, Ph), 7.57–7.72 (m, 4 H,
Ph).
g
ent-4
–
–
96
30
–22.1
(1)
114– C20H20N2O
1.51–1.64 (m, 3 H, CH2), 1.81 (bs, 1 H, NH),1.83–1.95 (m,
2 H, CH2),2.04–2.17 (m, 1 H, CH2), 2.75–2.83 (m, 1 H,
CH2), 3.17–3.23 (m, 1 H, CH2), 4.03 (dd, J = 3.9 Hz, J = 8.6
Hz, 1 H, CH), 7.31–7.42 (m, 6 H, C6H5), 7.56–7.71 (m, 4 H,
C6H5).
116
(303.4)
8
>95:5
–
–
oil
C33H39BrN2O4 0.93 (s, 3 H, CH3), 1.35 (s, 6 H, CH3), 1.42 (s, 3 H, CH3),
(607.4)
1.56 (s, 3 H, CH3), 1.59–1.64 (m, 3 H, CH, CH2), 2.30–2.43
(m, 2 H, CH2), 2.55–2.69 (m, 2 H, CH2), 3.47–3.51 (m, 1 H,
CH), 3.53–3.59 (m, 2 H, CH2Br), 3.80–3.89 (m, 1 H, CH2),
3.91–4.00 (m, 1 H, CH), 4.17–4.19 (m, 1 H, CH), 5.24 (dd, J
= 3.0 Hz, J = 11.0 Hz, 1 H, CH), 7.34–7.41 (m, 6 H, Ph),
7.53–7.64 (m, 4 H, Ph).
9
54
88
>95:5
oil
oil
C23H25BrN2O3 1.44 (s, 6 H, CH3), 1.96 (bs, 2 H, NH2), 2.16–2.21 (m, 1 H,
(457.4)
CH2), 2.25–2.30 (m, 1 H, CH2), 3.51 (dd, J = 2.0 Hz, J = 6.2
Hz, 2 H, CH2Br), 3.59–4.02 (m, 1 H, CH), 4.24–4.30 (m, 1
H, CH), 4.36 (dd, J = 4.7 Hz, J = 11.5 Hz, 1 H, CH), 7.32–
7.40 (m, 6 H, Ph), 7.56–7.65 (m, 4 H, Ph).
10
>99:1h +12.5
(1)
C23H24N2O3
(376.5)
1.48 (s, 6 H, CH3), 1.57 (bs, 1 H, NH), 2.03–2.09 (m, 1 H,
CH2), 2.64 (t, J = 5 Hz, 0.5 H, CH2), 2,67 (t, J = 5 Hz, 0.5 H,
CH2), 2.89 (t, J = 13 Hz, 1 H, CH2), 3.46–3.49 (m, 1 H, H2),
3.51–3.55 (m, 2 H, CH), 4.07 (dd, J = 4.4 Hz, J = 16.8 Hz,
1 H, CH), 7.33–7.36 (m, 6 H, Ph), 7.56–7.65 (m, 4 H, Ph).
a determined by NMR as far as not otherwise mentioned.
b ee > 98.3%, determined by HPLC Cliralcel OD, 13C NMR (CDCl3): d = 22.8, 27.2, 28.0, 28.2, 33.8, 38.2, 38.5, 48.0, 50.2, 77.4, 126.5, 127.8,
128.0, 128.3, 128.4, 128.5, 128.8, 132.3, 135.1, 145.8, 160.6, 179.6.
c 13C NMR (CDCl3): d = 19.6, 23.2, 27.6, 28.4, 28.8, 33.2, 38.6, 38.7, 50.5, 53.2, 77.0, 126.9, 128.4, 128.8, 128.9, 129.0, 129.3, 132.8, 135.4,
146.0, 163.8, 178.9.
d 13C NMR (CDCl3): d = 5.1, 5.8, 17.8, 25.5, 29.9, 30.7, 31.1, 36.4, 41.1, 41.2, 52.8, 63.5, 80.1, 129.1, 130.6, 130.7, 131.1, 131.2, 131.3, 131.7,
135.2, 137.5, 148.1, 165.2, 181.1.
e 13C NMR (CDCl3): d = 22.2, 46.1, 126.9, 128.3, 128.4, 128.8, 128.9, 129.0, 129.3, 132.8, 135.3, 145.6, 167.1.
f ee > 99%, determined by HPLC Cliralcel OD.
g ee > 99 % determined by chromatography of the (S)-Trolox-derivatives.
h determined by SFC.
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 2-(α-Aminoalkyl)oxazoles, 2-Oxazolylpyrrolidines, 2-Oxazolylpiperidines
2057
and washed with H2O (about 30 mL) The combined filtrates were
basified with NaOH and extracted with Et2O. After drying the or-
ganic phase (Na2SO4) and evaporating the solvent, 15.9 g (98%) of
the 2-aminomethyl-4,5-diphenyl-1,3-oxazole was obtained. The
compound is known, but was prepared by another procedure be-
fore.25
(1S, 2S, 5S)-3-(4,5-Diphenyl-1,3-oxazol-2-ylmethylimino)-2,6,6-
trimethylbicyclo[3.1.1]heptan-2-ol (1)
BF3•OEt2 (0.06 mL) was added to a mixture of (1S,2S,5S)-hydrox-
ypinanone (0.50 g, 30 mmol), 2-aminomethyl-4,5-diphenyl-1,3-ox-
azole (0.75 g, 3 mmol), anhyd toluene (10 mL) and molecular sieves
4Å under argon. After 4 h of reflux, the solution was cooled to r.t.
and filtered. The solvent was evaporated from the filtrate and the
residue was purified by flash chromatography (petroleum ether/
hexane). The product crystallized upon concentrating; yield: 0.78 g
(65%); mp 122-125 °C.
Figure X-ray crystal analysis of the Imine 2c
(1R, 2R, 5R)-3-(4,5-Diphenyl-1,3-oxazol-2-ylmethylimino)-
2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (ent-1)
Prepared analogous to 1 by using (1R,2R,5R)-hydroxypinanone;
yield: 0.90 g (75%); mp 115-120 °C.
acid 12 without prior isolation. Hydrogenolytic N-depro-
tection and acid hydrolysis of the acetonide moiety afford-
ed the (2S,4S,5S)-4,5-dihydroxypipecolinic acid
hydrochloride (13). The overall transformation of 2-ami-
nomethyl-4,5-diphenyloxazole into the (2S,4S,5S)-4,5-di-
hydroxypipecolinic acid (13) represents the first total
synthesis of this natural product, using an auxiliary tech-
nique. The hitherto existing total syntheses of this com-
pound were based on di-O-isopropylidene-a-D-
glucofuranose (18 steps)22 or on D-glucuronolactone
(9 step procedure)23 as enantiopure starting materials
where the original configuration was maintained or the
configuration at position 2 was inverted by elimination/
addition. Since the other enantiomer of these starting ma-
terials does not exist in nature these syntheses are limited
to the (2S,4S,5S)-isomer, while our approach should also
give access to the unnatural (2R,4S,5S)-isomer by analo-
gous degradation of the oxazole ring of the oxazolylpipe-
ridine 7.
Alkylation Products 2, ent-2, 5 and 8; General Procedure
A LDA-solution, prepared from absolute THF (3 mL), (i-Pr)2NH
(0.3 mL, 2 mmol) and 1.6 M BuLi in hexane (1.5 mL, 2.4 mmol) at
-78 °C was slowly added to a solution of the azomethine 1 or ent-
1 (400 mg, 1 mmol) in THF (1 mL) at -78 °C. After about 10 min,
the alkylating reagent R-X (3 mmol) was added. The mixture was
allowed to warm up to r.t. overnight. It was quenched with satd aq
NH4Cl solution (about 10 mL) and extracted with Et2O (4 × 15 mL).
The combined organic phases were dried (MgSO4), filtered and
concentrated. The remaining material was purified by flash chroma-
tography. This material was used for further transformation into the
aminoalkyloxazoles 3, ent-3, 6 and 9 by hydrolytic cleavage of the
imine moiety without further purification.
2-(a-Aminoalkyl)-4,5-diphenyl-1,3-oxazoles 3, ent-3, 6 and 9;
General Procedure
A solution of 15% aq citric acid (6 mL) was added to a solution of
the corresponding azomethine 2, ent-2, 5 or 8 (1 mmol) in THF
(7 mL). The mixture was stirred at r.t. for 3 to 4 days (TLC). The
organic solvent was evaporated and the hydroxypinanone removed
by extraction with Et2O. The remaining aqueous solution was bas-
ified with solid Na2CO3 and extracted with Et2O (3 × 15 mL). After
drying (MgSO4) and concentration the product was purified by flash
chromatography (MeOH/CH2Cl2).
1H NMR and 13C NMR spectra were recorded at 300 and 75.5 MHz,
respectively, with a Bruker AC-300 with TMS as internal standard.
Optical rotations were determined with a Perkin Elmer polarimeter
241. Mass spectra (HP 5995 A) were measured at 70eV. An external
tungsten 500 W halogen lamp was used to generate singlet oxygen
from dioxygen. Silica gel (0.04-0.063 mm, Merck) was used for
preparative column chromatography. If not otherwise mentioned,
chemicals were purchased from Aldrich. (4R,5R)-4,5-Bis(bromom-
ethyl)-2,2-dimethyl-1,3-dioxolane as reactant for the synthesis of 5
and 8 was prepared using a known procedure modified by adding an
equimolar quantity of Li2CO3 in the last step.24
2-(Pyrrolidin-2-yl)-1,3-oxazole (4f) and 2-(Piperidin-2-yl)-1,3-
oxazoles 4g, ent-4, 7 and 10; General Procedure
A mixture of the corresponding a-amino-w-haloalkyloxazole 3, ent-
3, 6 or 9 (0.5 mmol) and NaHCO3 (84 mg) in EtOH (20 mL) was
stirred at r. t. overnight. After the addition of H2O (20 mL), the mix-
ture was extracted with EtOAc (3 × 20 mL). The combined organic
phases were dried (MgSO4), the solution was concentrated and the
remainder was purified by column chromatography (EtOAc or
CH2Cl2/MeOH/NH3, 25:1:0.1).
2-Aminomethyl-4,5-diphenyl-1,3-oxazole
A solution of 2-bromomethyl-1,3-oxazole (31.4 g, 0.1 mol) and po-
tassium phthalimide (18.6 g, 0.1 mol) in anhyd EtOH (500 mL) was
refluxed for 5 h. After cooling to r.t., the precipitate was filtered off
and dissolved in CHCl3 (~ 300 mL). The solution was washed with
H2O (3 × 100 mL) and dried (Na2SO4). After evaporation of the sol-
vent, 4,5-diphenyl-2-phthalimidoethyl-1,3-oxazole (24.81 g, 0.066
mol, 66%) was obtained. This material was combined with EtOH
(250 mL) and hydrazine hydrate (3.3 g, 0.066 mol). The mixture
was refluxed until all 4,5-diphenyl-2-phthalimidoethyl-1,3-oxazole
disappeared (TLC, about 2 h). The cold reaction mixture was slight-
ly acidified with aq HCl (half-concentrated) and shortly heated to
reflux. After cooling to r. t. precipitated phthalazine was filtered off
Benzyl (2S,4S, 5S)-2-(4,5-Diphenyl-1,3-oxazol-2-yl)-4,5-isopro-
pylidenedioxypiperidine-1-carboxylate (11)
K2CO3 (97 mg, 0.7 mmol) and benzyl chloroformate (136.5 mg, 0.8
mmol) were added to a solution of the oxazolylpiperidine 10 (245
mg, 0.65 mmol) in dioxane/H2O (10 mL, 1:1) at 0 °C under stirring.
The mixture was allowed to warm up to r.t. and stirring was contin-
ued for 1 h. After dilution with H2O (about 20 mL), the mixture was
extracted with EtOAc (3 × 20 mL). The organic phase was dried
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

2058
M. Thieme et al.
PAPER
(MgSO4), concentrated and purified by flash chromatography
(EtOAc/hexane); yield: 97%; colorless oil.
structure refinement: SHELXL-93 (Sheldrick, 1993), Computing
molecular graphics: XSTEP-2.16 (Stoe, 1997), Computing publica-
tion material: SHELXL-93 (Sheldrick, 1993). Refinement on F2 for
all reflections except for 0 with very negative F2 or flagged by the
user for potential systematic errors. Full details have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-141584. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK
1H NMR (CDCl3): d = 1.44 (s, 3 H, CH3), 1.46 (s, 3 H, CH3), 1.57,
2.31-2.53 (m, 1 H, CH2), 2.80-2.89 (m, 1 H, CH2), 3.55-3.67 (m,
1 H, CH2), 3.57-3.86 (m, 2 H, CH, CH2), 4.14-4.21 (m, 1 H, CH),
5.16 (s, 2 H, CH2Ph), 5.45-5.53 (m, 1 H, CH), 7.28-7.38 (m, 11 H,
C6H5), 7.49-7.65 (m, 4 H, C6H5).
MS (70eV): m/z (%) = 510 (M+, 62), 419 (70), 375 (100), 91 (64).
(2S,4S, 5S)-1-Benzyloxycarbonyl-4,5-isopropylidenedioxypipe-
ridine-2-carboxylic Acid (12)
Acknowledgement
A solution of the oxazole 11 (153 mg, 0.3 mmol) in CH2Cl2 (10 mL)
was saturated with oxygen at 0 °C for 20 min. After the addition of
Bengal Rose (30 mg) the solution was irradiated with a 500 W
tungsten halogen lamp for 4 h while the supply of oxygen was con-
tinued. The solvent was evaporated under vacuum and the remain-
ing material was dissolved in dioxane/H2O (20 mL, 1:1). After
stirring at r.t. for 3 h, H2O was added (about 20 mL) and the mixture
was extracted with EtOAc (3 ¥ 20 mL). The organic phases were
dried (MgSO4), concentrated under vacuum and purified by flash
chromatography (hexane/EtOAc/AcOH); yield 48%; colorless oil.
1H NMR (CDCl3): d = 1.43 (s, 6 H, CH3), 2.67-2.71 (m, 1 H, CH2),
3.35-3.37 (m, 1 H, CH2), 3.57-3.59 (m, 2 H, CH), 4.15-4.19 (m,
1 H, CH2), 4.59 (dd, J = 3, 10 Hz, 1 H, CH), 5.14 (m, 2 H, CH2Ph),
7.30-7.36 (m, 5 H, C6H5).
We acknowledge the financial support by Fonds der Chemischen
Industrie and thank Dr. Burkhard Ziemer, Institut für Chemie,
Humboldt-Universität Berlin for the X-ray crystal analysis.
References
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(2S,4S,5S)-4,5-Dihydroxypiperidine-2-carboxylic Acid Hydro-
chloride (13)
A mixture of Pd/C (20 mg), the acetonide 12 (67 mg, 0.2 mmol) and
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from EtOH/Et2O; yield: 77%; mp >219 °C (dec.); [a]D20 +20.4
(c = 0.11, 2 N HCl) {Lit.21 [a]D20 +19.5 (c = 0.15, 2 N HCl), Lit.26
[a]D20 +24.4 (c = 0.64, 2 N HCl)}.
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1H NMR (400 MHz/D2O): d = 1.75-1.91 (m, 1 H, CH2), 2.55 (dt,
J = 3.5, 14 Hz, 1 H, CH2), 2.93 (dt, J = 9, 12.5 Hz, 1 H, CH2), 3.57
(dd, J = 4, 12.5 Hz, 1 H, CH2), 3.70-3.83 (m, 2 H, CH), 3.98 (dd,
J = 3.7, 11 Hz, 1 H, CH).
MS (ESI): m/z = 160[M− - H]
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X-Ray Crystal Structure Analysis of the Imine 2c
Crystal data: C32 H38 N2 O2, Mr = 482.64, monoclinic, P 21,
a = 9.887(2) A, a = 90°, b = 8.2380(10) Å, ß = 95.19(2)°,
c = 16.336(3) Å, g = 90°. T = 180(2) K, l(Mo Ka) = 0.71073 Å,
V = 1325.2(3) Å3, Z: 2, Dx (calculated): 1.210 Mg/m3, m = 0.075
mm−1, F(000): 520.
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Data collection and reduction: Crystal size: 0.92 × 0.56 × 0.40 mm,
2.32 to 26.10°, Index ranges: -12< = h< = 12, -10< = k< = 10, -
19< = l< = 20, Reflections collected: 8613, Independent reflec-
tions: 5127 [R(int) = 0.0264], Absorption correction: None, Refine-
ment method: Full-matrix least-squares on F2, Data/restraints/
parameters: 5127/1/328, Goodness-of-fit on F2: 1.060, Final R indi-
ces [I>2s(I)]: R1 = 0.0311, wR2 = 0.0769, R indices (all data):
R1 = 0.0329, wR2 = 0.0779, Absolute structure parameter: 0.0(8),
Largest diff. peak and hole: 0.180 and -0.126 e.Å−3. IPDS-2.75
(Stoe, 1997), Computing cell refinement: IPDS-2.75 (Stoe, 1997),
Computing data reduction: IPDS-2.75 (Stoe, 1997), Computing
structure solution: SHELXS-86 (Sheldrick, 1990), Computing
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 2-(α-Aminoalkyl)oxazoles, 2-Oxazolylpyrrolidines, 2-Oxazolylpiperidines
2059
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Article Identifier:
1437-210X,E;2000,0,14,2051,2059,ftx,en;H01600SS.pdf
Synthesis 2000, No. 14, 2051–2059 ISSN 0039-7881 © Thieme Stuttgart · New York