Asymmetric synthesis of (2S)-1-(3,4-dihydroxyphenoxy)-3-(3,′4′- dimethoxyphenoxy) ethylamino-2-propanol hydrochloride (RO363)

Article abstract of DOI:10.1080/00397910600602651

Enantiomerically pure (S)-RO363 was synthesized by using (R,R) Salen Co(III) complex for the resolution of terminal epoxide. The hydrolytic kinetic resolution process was carried out at room temperature in excellent enantioselectivity. The method can be a

Full text of DOI:10.1080/00397910600602651

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Asymmetric Synthesis of
(2S)‐1‐(3,4‐Dihydroxyphenoxy)‐3‐(3,′4′‐Dimethox
Ethylamino‐2‐propanol hydrochloride
(RO363)
Akkirala Venkat Narsaiah a
a Organic Chemistry Division‐III, Fine Chemicals Laboratory , Indian Institute
of Chemical Technology , Hyderabad, India
Published online: 18 Aug 2006.
To cite this article: Akkirala Venkat Narsaiah (2006) Asymmetric Synthesis of
(2S)‐1‐(3,4‐Dihydroxyphenoxy)‐3‐(3,′4′‐Dimethoxyphenoxy) Ethylamino‐2‐propanol hydrochloride (RO363),
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:13, 1897-1901, DOI: 10.1080/00397910600602651
To link to this article: http://dx.doi.org/10.1080/00397910600602651
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Synthetic Communicationsw, 36: 1897–1901, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602651
Asymmetric Synthesis of (2S)-1-(3,4-
Dihydroxyphenoxy)-3-(3,040-
Dimethoxyphenoxy) Ethylamino-
2-propanol hydrochloride (RO363)
Akkirala Venkat Narsaiah
Organic Chemistry Division-III, Fine Chemicals Laboratory,
Indian Institute of Chemical Technology, Hyderabad, India
Abstract: Enantiomerically pure (S)-RO363 was synthesized by using (R,R) Salen
Co(III) complex for the resolution of terminal epoxide. The hydrolytic kinetic resol-
ution process was carried out at room temperature in excellent enantioselectivity.
The method can be applied for large-scale preparation of (S) RO363.
Keywords: Catecholamine, enantiomers, jacobsen catalyst, resolution, RO363
A synthetic catecholamine, RO363 (1), was first reported in 1978, as a
potent selective b1-adrenoceptor agonist.[1] Recently, it was found that
(+)-1-(3,4-dihydroxyphenoxy)-3-(30,40-dimethoxyphenyl)ethyl-amino-2-pro-
panol (RO363), a partial agonist for b3-adrenoceptor, is able to activate a novel
human atrial b4-adrenoceptor.[2] The original synthesis of (+) RO363 and the
subsequent resolution of the (2S) and (2R) enantiomers was reported.[2d]
Received in India December 19, 2005
IICT Communication No. 050516.
Address correspondence to Akkirala Venkat Narsaiah, Organic Chemistry
Division-III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology,
Hyderabad 500007, India. E-mail: vnakkirala2001@yahoo.com
1897

1898
A. V. Narsaiah
The synthetic approach started from 3,4-dibenzyloxy phenol (3), which was
treated with (+) epichlorohydrin in basic medium to get dibenzyloxyphenoxy
2,3-epoxy-propane (4). The racemic epoxide was treated for hydrolytic kinetic
resolution (HKR)[3] using the Jacobsen catalyst (R,R) [Salen-Co(III) OAc]
(0.5mol%) and water (0.55 eq) at room temperature for 10h and monitored
by HPLC. The reaction mixture was chromatographed on silica gel to give
the selective S epoxide (5) in 44% yield and 95% ee. The optical rotation of
S epoxide shows that [a]2D1 ¼ 6.08 (c 1, CHCl3) and further elution by
increasing the polarity of mobile phase gave the (R)-diol (6) in 48% yield and
97% ee; the optical rotation of (R) diol was [a]2D1 28.08 (c 1, CHCl3).
(Scheme 1)
The enantiomerically rich R diol (6) was treated with triphenylphosphine
(TPP) and diethylazodicarboxylate (DEAD) in benzene for a one-step
Mitsunobu reaction to get optically active R epoxide (7) in 85% yield and
97% ee. The optical rotation of R epoxide was [a]2D1 26.10 (c 1, CHCl3).
The enantiomer excess of all the chiral compounds was determined by
HPLC using chiral column.
The enantioselective (S) epoxide (5) was treated with an equivalent
amount of 3,4-dimethoxyphenylethylamine (8) in ethyl alcohol at 80–858C
for 5 h to obtain the hydroxy amine compound (9), which on hydrogenation
gave the target molecule RO363 (1) in very good yield. (Scheme 2)
CONCLUSION
In summary, we have described the asymmetric synthesis of (2S)-1-(3,4-dihy-
droxyphenoxy)-3-(30,40-dimethoxyphenyl) ethyl amino-2-propanol (RO363) 1
in high enantioselection fashion. The key step involves the HKR of terminal
epoxide using the Jacobsen catalyst. This method can be applied for the
large-scale preparation of (S)-RO363.
Scheme 1. Reagents and conditions: (a) ethanol, KOH, epichlorohydrin; (b) (R,R)
salen Co(III) OAc, water, rt, and (c) TPP, DEAD, benzene, reflux.

Asymmetric Synthesis of RO363
1899
Scheme 2. Reagents and conditions: (a) Et-OH, 80–858C, and (b) Pd/C, MeOH,
45 psi.
EXPERIMENTAL
Melting points were recorded in
a Buchi capillary melting-point
(R-535) apparatus and are uncorrected. IR spectra were recorded on a
Perkin-Elmer FT-IR 240C spectrophotometer. 1H NMR spectra were
recorded on Gemini-200 spectrometer with TMS as the internal standard.
Mass spectra were recorded on a Finnigan MAT 1020 mass spectometer
operating at 70 ev. All chemicals or reagents were purchased from standard
commercial suppliers.
(+)-1-(3,4-Dibenzyloxyphenoxy)-2,3-epoxy Propane (4)
To a mixture of 3,4-dibenzyloxy phenol 3 (5 g, 16.3 mmol) in ethyl alcohol
(50 ml), aqueous potassium hydroxide (0.91 g, 16.3 mmol, 5 ml water) and
epichlorohydrin (4.5 g, 49 mmol) were added. The resulting mixture was
stirred for 15 h at room temperature. The solvent was removed under
reduced pressure, and the residue dissolved in water and extracted with
ethyl acetate. The organic extract was washed with brine and dried over
Na2SO4. The solvent was evaporated to afford the crude product, which was
purified by column chromatography (silica gel 60–120 mesh), while eluting
with an ethyl acetate and n-hexane mixture in 2:8 ratio (4.79 g, 81%).
Colorless liquid. IR (KBr). n 3078, 2982, 2841, 1638, 1551, 1372, 1243,
1
1136, 1042, 926 841, 736 cm21. H NMR (CDCl3). d 2.68–2.72 (m, 1H),
2.83–2.87 (m, 1H), 3.22–3.28 (m, 1H), 3.80–3.90 (m, 1H), 4.07–4.13
(m, 1H), 5.12 (s, 2H), 5.18 (s, 2H), 6.35–6.40 (m, 1H), 6.60 (s, 1H), 6.80
(d, 1H, J ¼ 5.0 Hz), 7.25–7.45 (m, 10H). EIMS m/z (%). 362 (mþ 18), 305
(24), 214 (32), 198 (42), 123 (14), 107 (100), 91 (22), 75 (22), 51(31).
Hydrolytic Kinetic Resolution of Racemic Epoxide
The racemic mixture of epoxide 4 (3.0 g, 8.3 mmol) and R,R-Salen-Co-(III)-
OAc (2) (26 mg, 0.414 mmol) was vigorously stirred below 108C for

1900
A. V. Narsaiah
20 min, and water (0.082 ml, 4.55 mmol) was introduced over a period of 1 h.
The reaction mixture was stirred at room temperature for 20 h, and the
progress of the reaction was monitored by using chiral HPLC (ODS
column, UV; 225 nm, 60% CH3CN in water). The reaction mixture was
diluted by adding ethyl acetate, dried over Na2SO4, and concentrated
to afford the crude product, which was chromatographed on silica gel
(60–120 mesh) by eluting with a mixture of ethyl acetate–hexane (2:8) to
gave the pure S-epoxide 5 (1.32 g, 44%) as colorless oil.
[a]2D1 ¼ 6.08 (c 1, CHCl3). IR (KBr). n 3079, 2982, 2841, 1636, 1551,
1
1372, 1227, 1137, 1042, 928 841, 736 cm21. H NMR (CDCl3). d 2.62–2.68
(m, 1H), 2.82–2.86 (m, 1H), 3.22–3.28 (m, 1H), 3.80–3.90 (m, 1H),
4.07–4.13 (m, 1H), 5.08 (s, 2H), 5.15 (s, 2H), 6.35–6.40 (m, 1H), 6.60
(s, 1H), 6.80 (d, 1H, J ¼ 7.0 Hz), 7.25–7.45 (m, 10H).
On further elution with a mixture of ethyl acetate–hexane in a 4:6 ratio
gave the R-diol (6) (1.44 g, 48%). [a]2D1 ¼ 28.08 (C 1, CHCl3).
1-(30,40-Dibenzyloxyphenoxy)-2,3-epoxy Propane (7)
A mixture of R-diol compound 6 (1.4 g, 3.7 mmol), triphenylphosphene
(1.45 g, 5.5 mmol), and DEAD (5.5 mmol) was refluxed in benzene (15 ml)
for 15 h. The solvent was removed and diluted with ether to precipitate
Ph3PO. The filtrate was concentrated and chromatographed on silica gel
(60–120 mesh) by eluting with ethyl acetate–n-hexane mixture (2:8) to get
the pure R-epoxide (1.13 g, 85%). [a]2D1 ¼ 26.18 (c 1, CHCl3).
(2S)-1-(30,40-Dibenzyloxyphenoxy)-3-(30, 40-
dimethoxyphenyl)ethylamino-2-propanol (9)
A mixture of S-epoxy propane 5 (1.0 g, 2.76 mmol) and phenyl ethylamine 8
(0.5 g, 2.76 mmol) in ethyl alcohol (10 ml) was heated to 80–858C for 5 h. The
solvent from the reaction mixture was removed under reduced pressure, and
the residue was adsorbed on silica gel (60–120 mesh) and eluted with ethyl
acetate–hexane in a 4:6 ratio. The product was obtained as a thick syrup
and yield 1.3 g (87%).
[a]2D1 ¼ 7.08 (C 1, CHCl3); IR (KBr). n 3496, 3251, 3127, 3068, 2979,
1
2831, 1618, 1583, 1451, 1384, 1143, 1071, 953, 847, 738 cm21. H NMR
(CDCl3). d 1.90–1.98 (m, 2H), 2.02–2.14 (m, 2H), 2.80–2.90 (m, 2H),
3.40 (brs, 1H), 3.78 (s, 3H), 3.88 (s, 3H), 3.98–4.10 (m, 2H), 4.53–4.73
(m, 1H), 5.18 (s, 2H), 5.22 (s, 2H), 5.58 (br s, 1H), 6.75–6.97 (m, 6H),
7.35–7.50 (m, 10H). EIMS m/z (%). 543 (mþ 21), 452 (23), 436 (12), 345
(10), 329 (12), 289 (100), 254 (31), 165 (43), 134 (10), 119 (73), 107 (51),
91 (37), 75 (21), 51 (23).

Asymmetric Synthesis of RO363
1901
(2S)-1-(3,4-Dihydroxyphenoxy)-3-(30,40-dimethoxyphenyl) Ethyl
Amino-2-propanol (RO363) (1)
To a mixture of (2S)-1-(3,4-dibenzyloxyphenoxy)-3-(30,40-dimethoxy phenyl)
ethyl amino-2-propanol 9 (1.0 g, 1.8 mmol) in methanol (10 ml) was added
10% Pd/C (100 mg). The resulting reaction mixture was stirred under
hydrogen atmosphere (45 psi) at room temperature for 10 h. The reaction
mixture was filtered on a Celitew bed to remove the Pd/C. The filtrate was
concentrated under reduced pressure; the obtained residue was dissolved in
dry diethyl ether (15 ml) and bubbled HCl gas. The precipitated RO363
hydrochloride solid was filtered. Yield was 0.66 g (90%).
Mp 70–728C. [a]2D1 ¼ 11.08 (c 1, 1N HCl). IR (KBr). n 3583, 3268, 3147,
3079, 2951, 2832, 1619, 1573, 1349, 1163, 1028, 963, 857, 739 cm21
.
1H NMR (CDCl3). d 1.94–2.00 (m, 2H), 2.05–2.20 (m, 2H), 2.90–3.00
(m, 2H), 3.50 (brs, 1H), 3.80 (s, 3H), 3.84 (s, 3H), 3.90–4.00 (m, 2H),
4.68–4.80 (m, 1H), 5.60 (brs, 1H), 6.55–7.15 (m, 6H), 7.35–7.50 (m, 6H).
EIMS m/z (%). 365 (mþ 10), 363 (36), 254 (18), 165 (22), 134 (14), 119
(51), 107 (100), 91 (22), 75 (19), 51 (31).
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