Synthesis of novel and enantiomerically pure epoxypropylamine: A divergent route to the chiral β-adrenergic blocking agents

Article abstract of DOI:10.1016/S0957-4166(99)00248-7

The chiral building block (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine is obtained by means of chlorohydroxylation of allylamine, followed by Jacobsen's hydrolytic kinetic resolution with water. A concise, divergent five-step synthesis of three β-adrenergic blocking agents in high enantiomeric excess using (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine as the key intermediate is described.

Full text of DOI:10.1016/S0957-4166(99)00248-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2319–2326
Synthesis of novel and enantiomerically pure epoxypropylamine:
a divergent route to the chiral β-adrenergic blocking agents
Xue-Long Hou,∗ Bin-Feng Li and Li-Xin Dai
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 6 May 1999; accepted 8 June 1999
Abstract
The chiral building block (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine is obtained by means of chlorohy-
droxylation of allylamine, followed by Jacobsen’s hydrolytic kinetic resolution with water. A concise, divergent
five-step synthesis of three β-adrenergic blocking agents in high enantiomeric excess using (S)-N-benzyl-N-
isopropyl-2,3-epoxypropylamine as the key intermediate is described. © 1999 Published by Elsevier Science Ltd.
All rights reserved.
1. Introduction
The enantiomers of chiral drugs often show different pharmacological and metabolic characteristics.
The synthesis of homochiral drugs has become a key issue not only in academic research but also in
the pharmaceutical industry.1 β-Adrenergic blocking agents of the 3-(aryloxy)-2-hydroxy-N-isopropyl-
propylamine, type 1 (Scheme 1), are such a group of drugs whose biological activity resides almost
exclusively in the S enantiomer. For instance, as a β-blocker with longer plasma half-life, the S isomer of
propranolol 1a is 100-fold more potent than the R form.2
Many syntheses of the homochiral β-adrenergic blocking agents 1 have been published, mainly using
two strategies through the disconnection of bonds a or b (Scheme 2).3–8 The disconnection mode a
of 1 gives the (S)-3-(aryloxy)-2-hydroxypropylamine 2, which can be obtained from the enzymatic
resolution of intermediate compounds,3 asymmetric ring-opening of aryl glycidyl ethers with TMSN3
catalysed by Salen (Cr),4 or nitroaldol reaction.5 With the disconnection mode b, (S)-arylglycidyl ether
3 is obtained. Many methods have been adopted to prepare this chiral aryl glycidyl ether 3, for example,
Sharpless asymmetric epoxidation,6 and asymmetric dihydroxylation7 or from enantiomerically pure
natural products.8
∗
Corresponding author. E-mail: xlhou@pub.sioc.ac.cn
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00248-7

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Scheme 1.
By retrosynthetic analysis, we envisaged that the disconnection mode c is an alternative and convenient
strategy, which gives the (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 and phenols. According to
the Dictionary of Drugs,9 there are more than 30 kinds of β-adrenergic blocking agents, which have
a similar structure. The substituent on the nitrogen atom is always the isopropyl group and they only
differ in the aryloxy group, such as propranolol 1a, moprolol 1b, toliprolol 1c. Gowther et al. have
synthesised 54 kinds of compounds of type 1, varying with different substituted phenoxy groups, to
scan the physiological activity.10 To synthesise this series of β-blockers, we think the third strategy is a
more convenient and effective one, because we can open the epoxide ring of the general intermediate,
(S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 by using different phenols, to give a series of the
corresponding products.
Scheme 2.
Obviously, the key step of the third strategy is how to synthesise the optically active epoxypropylamine
4. To the best of our knowledge, few methods have been reported in the literature that afford this three-
carbon chiral intermediate or its derivatives.11 Our group reported the Pd-catalysed chlorohydroxylation
of allylamine and found that the products were easily converted into 2,3-epoxypropylamines,12 but the
asymmetric induction of an attempted asymmetric chlorohydroxylation from a chiral allylamine was
not very satisfactory. Recently, Jacobsen et al.13a,b reported a convenient method to obtain optically
active terminal epoxides by an efficient hydrolytic kinetic resolution. Afterwards, this procedure was
adopted by other authors to synthesise chiral terminal epoxides.13c–f To date there has been no report
about the kinetic resolution of aminomethyl substituted epoxide. Herein we would like to disclose
the synthesis of the chiral (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 through the Pd-catalysed

X.-L. Hou et al. / Tetrahedron: Asymmetry 10 (1999) 2319–2326
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chlorohydroxylation of allylamine 6 and the kinetic resolution of the reaction product with water
catalysed by (S,S)-(Salen)Co(III)OAc,13 and provide an example of its application as a chiral building
block in divergent protocol to prepare β-adrenergic blocking agents. The syntheses of (S)-propranolol
1a, (S)-moprolol 1b, (S)-toliprolol 1c can serve as the examples.
2. Results and discussion
By treatment of N-benzyl-N-isopropylallylamine 6 with water in the presence of Li2PdCl4/CuCl2 at
−10°C in DMF, followed by decomplexation of the CuCl2 from the chlorohydroxylation product with
excess Na2S·9H2O,12 N-benzyl-N-isopropyl-2,3-epoxypropylamine 8 was obtained directly with high
yield (Scheme 3). In this step, the reaction temperature was the most important factor. If the reaction was
operated at a higher temperature, for example, 40°C, only 30% yield of the N-benzyl-N-isopropyl-2,3-
epoxypropylamine 8 was obtained. At the same time, 65% yield of benzylisopropylamine 5 was isolated
as a product by deallylation of allylamine 6.14
Scheme 3.
The hydrolytic kinetic resolution of epoxypropylamine 8 was very efficient (Scheme 4). N-Benzyl-
N-isopropyl-2,3-epoxypropylamine 8 was treated with 0.55 equivalents of water catalysed by 0.01
equivalents of (S,S)-(Salen)Co(III)OAc to provide (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4
with 40% yield (>99% ee) and the diol 9 with 51% yield (90.6% ee).13 The absolute configuration of
the diol 9 was determined as (R) by transforming the ring-opened product to the known compound 1015
and thus the configuration of the epoxypropylamine 4 must be (S). We noted that if the benzylcarbonate
protective group (Cbz, COOCH2C6H5) replaced the benzyl group (substituent of the nitrogen atom), the
hydrolytic kinetic resolution was not so good and only 45% yield of epoxypropylamine 4 was afforded
with 47.3% ee. This result means the amino group may play a role in this reaction.
The epoxide ring of the (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 could not be opened
by the aryloxide mediated with Ti(OPri)4.16 We then mixed the epoxypropyl amine 4 and phenol in
refluxing NEt3; (S)-3-(aryloxy)-2-hydroxy-1-(N-benzyl-N-isopropyl)propylamines 11a–c were obtained
with high yield (Scheme 5), and no regioisomers were detected. The enantiomeric excess of the ring-
opened products, for example 11c, were equal to that of the epoxypropylamine 4 (determined by HPLC),
which showed that no racemisation had occurred in this step. Debenzylations of the (S)-3-(aryloxy)-2-
hydroxy-1-(N-benzyl-N-isopropyl)propylamines 11a–c were performed by hydrogenolysis catalysed by
10% Pd/C in ethanol with quantitative yield.17

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X.-L. Hou et al. / Tetrahedron: Asymmetry 10 (1999) 2319–2326
Scheme 4.
Thus, β-adrenergic blocking agents 1a–c were provided in 26.6%, 28.4% and 28.4% overall yields
and >99.0% ee, respectively, from benzylisopropylamine 5 in five steps. It should be pointed out that
the diol 9 obtained in the kinetic resolution procedure is also an important intermediate. It can be easily
transformed by simple manipulation13e to the (R)-epoxypropylamine 4, which could be used to prepare
other molecules of interest, for example, practolol,18 another β-adrenergic blocking agent with biological
activity residing in the R enantiomer.
Scheme 5.
In summary, we have developed a novel and facile method for the synthesis of the enantioenriched
(S)-β-adrenergic blocking agents. It is noteworthy that water was the reagent used in the second and
third steps. This methodology is comparable, if not superior, to the existing repertoire and is attractive
on several accounts: it involves a short synthetic sequence, produces uniformly good overall yields, high
enantiomeric excess and all the reaction conditions are mild and convenient. No moisture-free, oxygen-
free manipulations and hazardous peroxide are involved. Moreover, the synthetic route described here is
a general, divergent procedure to a series of β-adrenergic blocking agents.

X.-L. Hou et al. / Tetrahedron: Asymmetry 10 (1999) 2319–2326
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3. Experimental
3.1. General method
The commercially available reagents were used without further purification. Li2PdCl4 and (Salen)-
Co(II) were prepared according to the literature procedure.19,20 1H NMR spectra were recorded on a
Bruker AMX-300 (300 MHz) spectrometer in CDCl3 at room temperature and chemical shifts were
expressed in ppm from internal TMS. Mass spectra and high-resolution mass spectra were determined
on HP5989A and Finnigan MAT mass spectrometers, respectively. Elemental analyses were performed
on a Foss–Heraeus Vario EL instrument. Optical rotations were measured using a Perkin–Elmer 341
polarimeter (concentration c given as g/100 mL). The enantiomeric excess of (S)-N-benzyl-N-isopropyl-
2,3-epoxypropylamine 4, the (R)-diol 9 and (S)-1-(N-benzyl-N-isopropylamino)-3-(3-methylphenoxy)-
2-propanol 11c were determined by chiral HPLC on a Chiralcel OJ column. Melting points were
uncorrected.
3.2. N-Benzyl-N-isopropylallylamine 6
To a solution of NaOH (2.4 g, 60 mmol) in DMF (10 mL), benzylisopropylamine 5 (4.51 g, 30 mmol)
was added, and the mixture was cooled in an ice-water bath. Allyl bromide (3.3 mL, 3.1 g, 40 mmol)
in DMF (5 mL) was added over 10 min. The mixture was warmed to room temperature and stirred for
1 h. It was then diluted with ether (100 mL), washed with brine (3×20 mL) and the organic layer was
dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography over silica
1
gel to give N-benzyl-N-isopropylallylamine 6 (5.28 g, 93% yield). H NMR (CDCl3/TMS, 300 MHz)
δ (ppm) 1.10 (d, 6.7 Hz, 6H), 3.02–3.15 (m, 3H), 3.63 (s, 2H), 5.11–5.29 (m, 2H), 5.86–5.95 (m, 1H),
7.26–7.45 (m, 5H). EI-MS m/z (%) 189 (M+, 5.1), 174 (71), 91(100). Anal. calcd for C13H19N: C, 82.48;
H, 10.12; N, 7.40. Found: C, 82.46; H, 10.47; N, 7.30.
3.3. N-Benzyl-N-isopropyl-2,3-epoxypropylamine 8
To a solution of Li2PdCl4 (524 mg, 2 mmol) and CuCl2 (8.07 g, 60 mmol) in DMF (100 mL), the
allylamine 6 (3.78 g, 20 mmol) was added at room temperature. After stirring for 15 min, the mixture
was cooled to −10°C and water (10 mL) was added in one portion, then CF3COOH was added to
adjust the reaction mixture to pH 4. After the reaction was complete as monitored by TLC, an excess
of Na2S·9H2O was added. The mixture was stirred at room temperature overnight, filtered through a
pad of Celite and the Celite pad was washed with ether (300 mL). The combined filtrate was washed
with brine (100 mL×3), dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by
flash chromatography provided the N-benzyl-N-isopropyl-2,3-epoxypropylamine 8 (3.42 g, 83% yield).
1H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 1.05 (d, 6.6 Hz, 3H), 1.09 (d, 6.6 Hz, 3H), 2.41–2.43
(m, 1H), 2.54–2.69 (m, 3H), 2.94–2.99 (m, 1H), 3.09 (m, 6.6 Hz, 1H), 3.56, 3.77 (AB, JAB=14.1 Hz,
2H), 7.24–7.27 (m, 5H). EI-MS m/z (%) 205 (M+1, 5.3), 190 (52), 162 (37), 91 (100). Anal. calcd for
C13H19NO: C, 76.04; H, 9.33; N, 6.83. Found: C, 75.81; H, 9.46; N, 6.87.
3.4. Kinetic resolution
A mixture of (S,S)-(Salen)Co(II)20 (60.2 mg, 0.1 mmol) and acetic acid (12 mg, 0.2 mmol) in toluene
(2 mL) was stirred under air for 2 hours at room temperature. The solvent was removed under reduced

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pressure. The N-benzyl-N-isopropyl-2,3-epoxypropylamine 8 (2.05 g, 10 mmol) was added in one
portion, and to the stirred mixture cooled in an ice-water bath, water (99 mg, 5.5 mmol) was slowly
added over 0.5 hour. Then the reaction was stirred at room temperature for 36 hours. The reaction mixture
was diluted with ethyl acetate (50 mL), dried over anhydrous Na2SO4, and filtered through a pad of
activated carbon to remove the colour. The filtrate was concentrated and purified by flash chromatography
to give the (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 (0.826 g, 40% yield) and the (R)-diol 9
(1.142 g, 51% yield). Compound 4: [α]20=+20.8 (c, 1.0, CHCl3), >99.0% ee (HPLC). Compound 9:15
D
20
1
[α] =+54.8 (c, 1.45, CHCl3), 90.6% ee (HPLC). H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 1.01
D
(d, 6.6 Hz, 3H), 1.05 (d, 6.7 Hz, 3H), 2.43 (dd, 13.0 Hz, 4.3 Hz, 1H), 2.62 (dd, 13.0 Hz, 8.2 Hz, 1H),
2.92–3.01 (m, 1H), 3.41 (dd, 11.1 Hz, 4.1 Hz, 1H), 3.51–3.70 (m, 4H), 7.22–7.34 (m, 5H). EI-MS m/z
(%) 223 (M+, 31), 162 (100), 91 (60).
3.5. Amino diol diacetate 1015
To a solution of amino diol 9 (213 mg, 1 mmol) in pyridine (1 mL), Ac2O (245 mg, 2.4 mmol) was
added, and the mixture was stirred for 30 minutes at 60°C. The reaction was diluted with ether (30 mL),
washed with 10% NaOH (10 mL), water (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated.
Flash chromatography afforded 10 (283 mg, 92% yield). [α]20=−39.5 (c, 1.248, EtOH) (lit. [α]20=−39.8
D
D
(c, 1.25, EtOH, ›90% ee). 1H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 0.96 (d, 6.6 Hz, 3H), 0.99 (d, 6.6
Hz, 3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.51 (dd, 5.6 Hz, 13.4 Hz, 1H), 2.61 (dd, 7.8 Hz, 13.4 Hz, 1H), 3.54
(d, 14.1 Hz, 1H), 3.65 (d, 14.1 Hz, 1H), 4.06 (dd, 6.0 Hz, 11.9 Hz, 1H), 4.28 (dd, 3.0 Hz, 11.9 Hz, 1H),
7.20–7.28 (m, 5H). EI-MS m/z (%) 308 (M+1, 11), 162 (100), 91 (55).
3.6. General procedure for ring-opening of (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 with
phenols
To a solution of (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 4 (205 mg, 1 mmol) in NEt3 (5 mL),
phenol (1 mmol) was added, and the mixture was refluxed overnight. The solvent was removed under re-
duced pressure and the residue was purified by flash column chromatography to furnish the corresponding
products 11a–c. Compound 11a:21 (86% yield) [α]20=+28.8 (c, 3.24, EtOH) (lit. [α]20=+9.2 (c, 3.13,
D
D
EtOH, about 32% ee). 1H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 1.08 (d, 6.6 Hz, 3H), 1.16 (d, 6.7 Hz,
3H), 2.78 (d, 6.4 Hz, 2H), 3.06–3.10 (m, 1H), 3.62, 3.82 (AB, JAB=13.6 Hz, 2H), 4.08–4.16 (m, 3H),
6.79 (dd, 0.9 Hz, 7.5 Hz, 1H), 7.26–7.51 (m, 9H), 7.80 (d, 7.0 Hz, 1H), 8.19 (d, 9.7 Hz, 1H). EI-MS m/z
(%) 350 (M+1, 3.3), 162 (100), 91 (69).
20
1
Compound 11b: (92% yield) [α] =+35.7 (c, 2.12, EtOH). H NMR (CDCl3/TMS, 300 MHz): δ
D
(ppm) 1.04 (d, 6.6 Hz, 3H), 1.09 (d, 6.7 Hz, 3H), 2.66–2.68 (m, 2H), 2.96–3.05 (m, 1H), 3.59, 3.73 (AB,
JAB=13.7 Hz, 2H), 3.84 (s, 4H), 3.99 (s, 2H), 6.89–6.94 (m, 4H), 7.25–7.33 (m, 5H). EI-MS m/z (%) 330
(M+1, 16.2), 162 (100), 91 (34). EI-HRMS calcd for C20H27NO3: 329.1991; found: 329.1992.
Compound 11c: (92% yield) [α]20=+28.7 (c, 1.2, EtOH). 1H NMR (CDCl3/TMS, 300 MHz): δ (ppm)
D
1.02 (d, 6.6 Hz, 3H), 1.07 (d, 6.7 Hz, 3H), 2.30 (s, 3H), 2.56–2.63 (m, 2H), 2.96–3.00 (m, 1H), 3.55, 3.70
(AB, JAB=13.7 Hz, 2H), 3.86–3.92 (m, 3H), 6.66–6.75 (m, 3H), 7.10–7.31 (m, 6H). EI-MS m/z (%) 313
(M+, 10.0), 162 (100), 91 (85). EI-HRMS calcd for C20H27NO2: 313.2042; found: 313.2024.

X.-L. Hou et al. / Tetrahedron: Asymmetry 10 (1999) 2319–2326
2325
3.7. General procedure for debenzylation
A solution of (S)-3-(aryloxy)-2-hydroxy-1-(N-benzyl-N-isopropyl)propylamine 11a–c (1 mmol) and
10% Pd/C catalyst (40 mg) in ethanol (10 mL) was shaken in a Parr series 3900 hydrogenation apparatus
at 4 kg/cm2 hydrogen pressure and 25°C for 24 h. The mixture was filtered through a pad of Celite and
concentrated under reduced pressure to provide the corresponding product 1a–c (100% yield).
Compound 1a:22 [α]20=−9.9 (c, 0.5, EtOH) (lit. [α]20=−10.2 (c, EtOH)); mp: 72–73°C (lit. 72–73°C);
D
D
1H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 1.07 (d, 6.0 Hz, 6H), 2.82–2.94 (m, 4H), 4.10–4.18 (m, 3H),
6.80 (d, 7.4 Hz, 1H), 7.34–7.48 (m, 4H), 7.77–7.80 (m, 1H), 8.23–8.26 (m, 1H). EI-MS m/z (%) 260
(M+1, 48.7), 72 (100).
Compound 1b:23 [α]20=−5.6 (c, 4.5, EtOH) (lit. [α]20=−5.3–5.7 (c, 5.0, EtOH)); mp: 80–81°C (lit.
D
D
1
82–83°C); H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 1.06 (d, 1.1 Hz, 3H), 1.09 (d, 1.1 Hz, 3H),
1.80–2.87 (m, 5H), 3.85 (s, 3H), 3.98–4.07 (m, 3H), 6.89–6.98 (m, 4H). EI-MS m/z (%) 240 (M+1, 100),
72 (77.7).
Compound 1c:24 [α]20=−9.9 (c, 0.83, EtOH) (lit. [α]20=−9.9 (c, 0.99, EtOH); mp: 76–78°C (lit.
D
D
76–77°C); 1H NMR (CDCl3/TMS, 300 MHz): δ (ppm) 1.09 (d, 6.3 Hz, 6H), 2.32 (s, 3H), 2.68–3.20 (m,
5H), 3.90–4.03 (m, 3H), 6.71–6.79 (m, 3H), 7.13–7.18 (m, 1H). EI-MS m/z (%) 223 (M+, 31), 72 (100).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Projects 29790127
and 29872045) and the Chinese Academy of Sciences.
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