A mild, enantioselective synthesis of (R)-salmeterol via sodium borohydride-calcium chloride asymmetric reduction of a phenacyl phenylglycinol derivative

Article abstract of DOI:10.1039/b207068p

A short and efficient enantioselective route to (R)-salmeterol involving asymmetric reduction of a phenylglycinyl ketone derivative followed by reductive amination of the resulting amino alcohol and hydrogenolysis is described.

Full text of DOI:10.1039/b207068p

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A mild, enantioselective synthesis of (R)-salmeterol via sodium
borohydride–calcium chloride asymmetric reduction of a phenacyl
phenylglycinol derivative
1
Robert N. Bream,a Steven V. Ley,a Benjamin McDermottb and Panayiotis A. Procopiou*b
a University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire,
UK SG1 2NY. E-mail: pap1746@gsk.com
Received (in Cambridge, UK) 18th July 2002, Accepted 28th August 2002
First published as an Advance Article on the web 18th September 2002
A short and efficient enantioselective route to (R)-salmeterol involving asymmetric reduction of a phenylglycinyl
ketone derivative followed by reductive amination of the resulting amino alcohol and hydrogenolysis is described.
Salmeterol (Serevent®) 1 is a potent, long acting β2 adreno-
ceptor agonist used as a bronchodilator for the prevention of
bronchospasm in patients with asthma and chronic obstructive
pulmonary disease.1 Recently we have published an efficient
enantioselective route to (S )-salmeterol employing an asym-
metric reduction of an azido ketone to the corresponding azido
alcohol by Pichia angusta.2 Previous to this publication, the
synthesis of non-racemic salmeterol had been described by
Helquist involving enantioselective reduction of a phenacyl
bromide to the corresponding bromohydrin using the CBS–
oxazaborolidine catalyst.3 Other methods required resolution4
or chromatographic separation of diastereoisomeric mixtures.5
We were interested in a practical and efficient synthesis
of (R)-salmeterol using mild and relatively non-hazardous
reagents which would be amenable to scale-up and provide
salmeterol in >95% enantiomeric excess.
by Oshima and Utimoto.7 In the absence of metal chlorides
reduction with borohydride provided the threo-isomer as the
major product. Reduction with NaBH4–CaCl2 or NaBH4–
MnCl2 was fast and required only 10 min, whereas NaBH4–
ZnCl2 was slow and required 15 h to go to completion. The high
stereoselectivities of these reductions have been attributed to
chelation control.
During investigations into the synthesis of the enantiomers
of picumeterol 2, another β2-adrenoceptor agonist that was
being progressed by Glaxo for the treatment of asthma, asym-
metric reduction of a ketone was required. It was envisaged that
a chelation-controlled reduction, directed by a chiral auxiliary
would allow the use of a mild and non-toxic reducing agent,
such as sodium borohydride. Phenylglycinol was examined as
an auxiliary since it is readily available in both enantiomeric
forms and would be cleavable by hydrogenolysis. A non-
selective reduction of the carbonyl group of the tertiary amine
3a by NaBH4 was observed providing a 1:1 diastereoisomeric
mixture which was separable by chromatography.8 However,
when calcium chloride–NaBH4 was used reduction of 3b gave
predominantly one diastereoisomer.8 The very mild conditions
of this reduction prompted us to investigate the reduction of
the analogous ketone 4 in the saligenin series.
The ketone 4 was obtained in 80% yield as a white solid by
condensation of α-bromoketone 52,9 with commercially avail-
able (S )-phenylglycinol 6 in the presence of diisopropylethyl-
amine (Scheme 1). Reduction of 4 with sodium borohydride in
methanol–tetrahydrofuran (5:3) at 0 ЊC gave a mixture of
diastereoisomers 7 and 8 in a 2:1 ratio (98% yield). Repetition
of the reduction with NaBH4 and two equivalents of CaCl2 at
0 ЊC markedly improved the solubility of 4 allowing the reduc-
tion to be performed in methanol alone and afforded a 10:1
mixture of reduction products, which was recrystallised to give
diastereomerically pure 7 in 76% yield.10 The structure of 7
was confirmed by a single crystal X-ray diffraction study indi-
cating that the configuration of the newly formed asymmetric
centre had the required R configuration (Fig. 1), inferred from
the configuration of the starting material (S)-phenylglycinol.
A titration experiment was performed to ascertain the effect
of varying the amount of CaCl2 on the chemical shift of
1
Zinc borohydride has been used for the chelation-controlled
stereoselective reduction of β-keto esters by Nakata and Oishi.6
The stereoselective reduction of 3-keto-2-methyl esters and
amides to erythro-3-hydroxy-2-methyl esters and amides with
sodium borohydride in the presence of a variety of alkaline
earth, transition or lanthanide metal chlorides was investigated
the α-amino, α-keto, and α-hydroxy protons of 4. H NMR
(600 MHz) spectra of 4 were recorded for samples in CD3OD
with increasing amounts of CaCl2. A marked downfield shift of
one of the α-keto protons was observed indicating strong com-
plexation (Table 1). Smaller shifts were also observed for the
two α-hydroxy and the α-amino protons. Maximum effects were
DOI: 10.1039/b207068p
J. Chem. Soc., Perkin Trans. 1, 2002, 2237–2242
This journal is © The Royal Society of Chemistry 2002
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Scheme 1 Reagents and conditions: i, iPr2NEt, THF, 80%; ii, CaCl2ؒ2H2O, NaBH4, MeOH, 76%.
carbonyldiimidazole (CDI) was also investigated. In this case,
where neither alcohol nor amine is available for complexation
with CaCl2, the ratio of the reduction products 13 and 14 was
1:1. Similarly reduction of the carbonyl group of the tertiary
amine 15 was reported in the patent literature to be non-
selective.5 The selectivity observed in the reduction of ketone 4
is thought to arise via the complex shown in Fig. 2. The calcium
Fig. 1 X-Ray structure of 7.
Fig. 2
Table 1 Effect of addition of CaCl2 to the chemical shift of selected
protons of compound 4 in CD3OD
ion is complexed by the carbonyl oxygen, the amine nitrogen
and the primary alcohol to form two fused five-membered
rings. The borohydride is thus hindered from attacking from the
concave face of the complex by the glycinol bridge, and delivers
a hydride from the less hindered convex face.
Having established an efficient and mild procedure for the
preparation of amino diol 7, attention was focused on com-
pleting the synthesis of (R)-salmeterol. Reaction of 7 with alkyl
bromide 1612 was very slow and on heating or on addition
of sodium iodide, gave a complex mixture of products. The
aldehyde 17, however, was obtained quantitatively from the
bromide 16 by the Kornblum oxidation (Scheme 3).13 Sodium
triacetoxyborohydride-mediated reductive amination14 of 17
with 7 gave the tertiary amine 18 in 87% yield. The chiral
auxiliary was removed by hydrogenolysis of 18 over Pearlman’s
catalyst in ethanol. The crude product was applied to an acidic
SCX-2 ion exchange cartridge to remove the non-amine by-
product from the reaction mixture and concurrently remove the
acetonide protecting group. (R)-Salmeterol free base 19 was
liberated on elution with 10% ammonia in ethanol and con-
verted into the crystalline 1-hydroxynaphthalene-2-carboxylic
acid salt (20). The enantiomeric excess was determined by chiral
HPLC and found to be 97%.
Equiv CaCl2
δ(H1)
δ(H2)
δ(H3)
δ(H4)
δ(H5)
0.00
0.10
0.20
0.30
0.50
0.75
1.00
1.25
1.50
1.75
4.00
4.10
4.18
4.22
4.28
4.30
4.32
4.33
4.33
4.34
3.93
3.96
3.96
3.97
3.95
3.94
3.93
3.93
3.93
3.93
3.87
3.91
3.93
3.95
3.96
3.97
3.97
3.97
3.98
3.98
3.72
3.76
3.79
3.81
3.82
3.83
3.83
3.83
3.84
3.84
3.68
3.72
3.76
3.78
3.79
3.80
3.80
3.80
3.80
3.80
observed when 1 equiv. of CaCl2 was added, indicating the
formation of a 1:1 complex between 4 and CaCl2.
The reduction of the ketone group of the analogue of 4
where the primary hydroxy group was converted into a methoxy
group was of particular interest, as this molecule would not be
as good a ligand as 4. Thus, 6 was alkylated using methyl
iodide and sodium hydride to give 9 in 88% yield (Scheme 2).11
Reaction of 5 with amine 9 gave ketone 10 (64%), which on
reduction with borohydride gave 11 as a mixture of diastereo-
isomers in a ratio of 4.5:1 (91% yield). This indicated that
complexation of calcium ions by amine 10 is not as tight
as in the case of amine 4, allowing greater flexibility and a
lower level of diastereoisomeric selectivity. Reduction of oxazol-
idinone 12, available in 91% yield from 4 by treatment with
In summary we have outlined a short and efficient synthesis
of (R)-salmeterol in 46% overall yield from α-bromoketone 5
and 97% ee. We have also demonstrated a novel and mild
method for the asymmetric reduction of an aromatic α-amino-
ketone suitable for large-scale preparations.
Experimental
Organic solutions were dried over anhydrous MgSO4 or
Na2SO4. TLC was performed on Merck 0.25 mm Kieselgel 60
F254 plates. Products were visualised under UV light and/or by
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Scheme 2 Reagents and conditions: i, NaH, MeI, DMF, 88%; ii, 5, polystyryldiisopropylethylamine, THF, 64%; iii, CaCl2, MeOH, NaBH4, 0 ЊC,
91%; iv, CDI, CH2Cl2, 91%.
staining with aqueous KMnO4 solution. LCMS was conducted
on an ODS2 column (5 cm × 4.6 mm) eluting with 0.05%
HCO2H in water (solvent A) and 0.05% HCO2H in acetonitrile
(solvent B), using the following elution gradient: 0 min 10% B,
0–12 min 90% B, 12–15 min 90% B, 15–17 min 10% B at a flow
rate of 1 ml minϪ1 detecting at 230 nm. The mass spectra were
recorded on a Fisons VG Platform spectrometer using electro-
spray positive mode (ES ϩ ve). Column chromatography was
performed on Merck Kieselgel 60 (Art. 9385). Optical rotations
were measured with an Optical Activity AA100 or a Perkin
(Ϫ15 to Ϫ20 ЊC) acetonitrile (50 ml). The resulting solid was
collected by filtration and washed with cold acetonitrile to
give 4 (38.5 g, 80%) as a white solid: [α]2D5 ϩ 42.3 (c 1.045 in
MeOH); LCMS tR 5.45 min, 95%; ES ϩ ve m/z 342 (M ϩ H)ϩ;
δH (CDCl3, 400 MHz): 1.54 (6H, s), 2.45–2.80 (2H, br), 3.67
(1H, dd, J 11, 9 Hz), 3.77 (1H, dd, J 11, 4 Hz), 3.88 (1H, dd, J 9,
4 Hz), 3.96 (1H, d, J 18 Hz), 4.05 (1H, d, J 18 Hz), 4.84 (2H, s),
6.81 (1H, d, J 8 Hz), 7.27–7.39 (5H, m), 7.57 (1H, d, J 2 Hz) and
7.69 (1H, dd, J 8, 2 Hz); δC (CDCl3, 100 MHz): 24.7, 24.8, 52.9,
60.6, 64.4, 67.1, 100.6, 117.2, 119.3, 125.2, 127.3, 127.8, 127.8,
128.3, 128.7, 139.9, 156.0 and 196.2.
Elmer 343 digital polarimeter, and are given in 10Ϫ1 deg cm2 gϪ1
.
IR spectra were recorded on neat compounds as thin films. 1H
NMR spectra were recorded at 400 or 600 MHz and 13C NMR
at 100 or 150 MHz.
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(1S )-2-
hydroxy-1-phenylethylamino]ethanol (7)
Calcium chloride dihydrate (38.7 g, 263 mmol) was added in
one portion to a cooled mixture (internal temperature 2 ЊC) of 4
(44.9 g, 132 mmol) in methanol (450 ml) under nitrogen result-
ing in a slight exotherm (max temp ∼12 ЊC). After the resulting
clear solution had cooled to 0 ЊC, sodium borohydride (10.5 g,
277 mmol) was added in four portions over a 50 min period.
After a further 2 h at 0 ЊC the volatile material was removed
in vacuo resulting in a thick white slurry, to which ethyl acetate
(500 ml) was added. The mixture was filtered through a short
plug of Hyflo Supercel and the filtrate was washed with water
and then brine, dried (Na2SO4) and concentrated in vacuo to
give a thick orange oil. The ratio of the diastereoisomers (7:8)
1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(1S )-2-hydroxy-1-
phenylethylamino]ethanone (4)
(S )-Phenylglycinol (28.9 g, 210 mmol) was added in two
portions to a solution of 2-bromo-1-(2,2-dimethyl-4H-1,3-
benzodioxin-6-yl)ethanone (5)2,9 (40 g, 140 mmol) and N,N-
diisopropylethylamine (48.9 ml, 281 mmol) in tetrahydrofuran
(500 ml) under nitrogen. After 4 h the resulting white precipi-
tate was removed by filtration and the filtrate was concentrated
under reduced pressure to give an orange oil. Acetonitrile
(40 ml) was added and then removed in vacuo to give a light
orange solid, which was pulverised and triturated with cold
J. Chem. Soc., Perkin Trans. 1, 2002, 2237–2242
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Scheme 3 Reagents and conditions: i, NaHCO3, DMSO, 150 ЊC, 100%; ii, 7, NaB(OAc)3H, CH2Cl2, 87%; iii, H2, Pd(OH)2–C, EtOH; SCX-2, EtOH,
87%; iv, 1-hydroxy-2-naphthoic acid.
in the crude product was determined by 1H NMR of the
benzylic OH in DMSO-d6 to be 10:1 respectively. The oil was
dissolved in acetonitrile (150 ml) and cooled to 5 ЊC for 18 h.
The resulting crystals were filtered and washed with acetonitrile
to give 7 (30.8 g, 68%) as a white solid. The filtrate was evapor-
ated and the residue was recrystallised from acetonitrile to
provide a second crop of 7 (3.4 g, 8%): LCMS tR 5.11 min, 98%;
ES ϩ ve m/z 344 (M ϩ H)ϩ; [α]2D5 ϩ52.5 (c 1.01 in MeOH);
δH (CDCl3, 400 MHz): 1.51 (6H, s), 2.63 (1H, dd, J 12, 9 Hz),
2.75 (1H, dd, J 12, 4 Hz), 2.88 (1H, br s), 3.63 (1H, dd, J 11,
9 Hz), 3.74 (1H, dd, J 11, 4 Hz), 3.80 (1H, dd, J 9, 4 Hz), 4.59
(1H, dd, J 9, 4 Hz), 4.79 (2H, s), 6.74 (1H, d, J 8 Hz), 6.92
(1H, d, J 2 Hz), 7.06 (1H, dd, J 8, 2 Hz) and 7.23–7.35 (5H, m);
δC (CDCl3, 100 MHz): 24.6, 24.8, 55.2, 60.9, 65.1, 66.9, 72.6,
99.5, 116.9, 122.2, 125.8, 127.2, 127.7, 128.7, 134.2, 140.2 and
150.7. (Found: C, 69.7; H, 7.3; N, 4.15%. C20H25NO4 requires C,
69.95; H, 7.34; N, 4.08%).
ethyl acetate. The organic solution was dried (MgSO4), filtered
and evaporated to give an inseparable mixture of 7 and 8
(494 mg, 98%) as a white solid in a 2:1 ratio (by NMR).
(1S )-2-Methoxy-1-phenylethanamine (9)
A solution of 6 (1.0 g, 7.3 mmol) in tetrahydrofuran (10 ml)
was added dropwise to a stirred suspension of sodium hydride
(60% oil dispersion, 0.61 g, 15 mmol) in tetrahydrofuran (5 ml)
and stirred for 2 h. Methyl iodide (0.48 ml, 7.7 mmol) was
added dropwise and the solution stirred for 1 h, then heated
to reflux for a further 2 h. The reaction mixture was cooled,
diluted with cold brine, extracted with diethyl ether, dried
(Na2SO4) and evaporated. Distillation afforded 9 (0.97 g,
88%) as a colourless oil:11 bp 75 ЊC/0.5 mmHg; δH (CDCl3, 400
MHz) 1.65 (2H, br), 3.29 (1H, dd, J 9.3, 8.7 Hz), 3.31 (3H, s),
3.43 (1H, dd, J 9.3, 3.8 Hz), 4.11 (1H, dd, J 8.7, 3.8 Hz), 7.18
(1H, t, J 7 Hz), 7.26 (2H, t, J 7 Hz) and 7.31 (2H, d, J 7 Hz);
δC (CDCl3, 100 MHz) 55.8, 59.3, 79.4, 127.1, 127.8, 128.8 and
143.0.
Crystal structure analysis of 7
Suitable crystals were obtained from acetonitrile. Crystal data
for C20H25NO4: M = 343.41, orthorhombic, a = 8.0112(8), b =
9.7580(10), c = 23.019(2) Å, U = 1799.5(3) Å3, T = 160(2) K,
1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(1S )-2-methoxy-
1-phenylethylamino]ethanone (10)
space group P212121 (No. 19), Z = 4, µ(Cu–Kα) = 0.088 mmϪ1
;
8985 unique reflections measured, of which 3164 were
independent and 3024 were observed [>2σ(I)], (Rσ = 0.0367).
The final wR(F 2) was 0.1225 (observed reflections) and Robs was
0.0646.†
A solution of 9 (359 mg, 2.37 mmol) in tetrahydrofuran (2 ml)
was added dropwise to a mixture of 5 (451 mg, 1.58 mmol)
and polystyryldiisopropylethylamine (830 mg, 3.2 mmol) in
tetrahydrofuran (4 ml) and stirred for 2 h. The reaction mix-
ture was filtered, evaporated and purified by flash column
chromatography eluting with ethyl acetate–light petroleum (1:4)
to give 10 (361 mg, 64%) as a yellow oil: [α]2D5 ϩ44.4 (c 1.09
in MeOH); ν max/cmϪ1 1680, 1609, 1582, 1497, 1266 and 1110;
δH (CDCl3, 600 MHz) 1.52 (6H, s), 2.85 (1H, br s), 3.40 (3H, s),
3.47–3.53 (2H, m), 3.85 (1H, d, J 18.6 Hz), 3.96 (1H, dd, J 8.7,
4.0 Hz), 3.98 (1H, d, J 18.6 Hz), 4.82 (2H, s), 6.78 (1H, d, J 8.6
Hz), 7.27 (1H, t, J 7.4 Hz), 7.33 (2H, t, J 7.4 Hz), 7.38 (2H, d,
J 7.4 Hz), 7.53 (1H, s) and 7.66 (1H, d, J 8.6 Hz); δC (CDCl3,
150 MHz) 24.7, 53.1, 58.9, 60.6, 62.6, 77.8, 100.5, 117.1, 119.2,
125.1, 127.7, 128.1, 128.3, 128.6, 140.2, 155.8 and 196.1;
HRMS (ESI ϩ ve) m/z 356.1864 [(M)ϩ calcd. for C21H26NO4
356.1862].
Reduction of 4 in the absence of CaCl2
Methanol (5 ml) was added to ketone 4 (500 mg, 1.47 mmol)
followed by tetrahydrofuran (3 ml) at 0 ЊC. Sodium borohydride
(116 mg, 3.09 mmol) was added to the resulting clear colourless
solution in two portions over a 10 min period. After 30 min
water (1 ml) was added and the solution allowed to warm to
room temperature. The solvents were removed under reduced
pressure and the residue was partitioned between water and
† CCDC reference number 190192. See http://www.rsc.org/suppdata/
p1/b2/b207068p/ for crystallographic files in .cif or other electronic
format.
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1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(1S )-2-methoxy-
1-phenylethylamino]ethanol (11)
δH (CD3OD, 600 MHz) 1.53 (3H, s), 1.54 (3H, s), 2.82 (1H,
dd, J 14.1, 5.8 Hz), 3.74 (1H, dd, J 14.1, 7.4 Hz), 4.12 (1H, dd,
J 5.8, 3.6 Hz), 4.63 (2H, m), 4.75 (1H, dd, J 7.4, 5.8 Hz), 4.84
(2H, s), 6.79 (1H, d, J 8.4 Hz), 6.98 (1H, s), 7.09 (1H, d,
J 8.4 Hz), 7.25 (2H, d, J 7.2 Hz), 7.42 (1H, t, J 7.2 Hz) and
7.46 (2H, t, J 7.2 Hz); δC (CD3OD, 150 MHz) 24.9, 25.0,
49.9, 61.1, 61.8, 71.1, 71.5, 100.8, 118.0, 121.0, 123.8, 127.2,
128.3, 130.1, 130.3, 135.5, 139.2, 152.4 and 160.9; HRMS
(ESI ϩ ve) m/z 392.1475 [(M ϩ Na)ϩ calcd. for C21H23NNaO5
392.1474].
Calcium chloride (67 mg, 0.60 mmol) was added in one portion
to a solution of 10 (107 mg, 0.30 mmol) in methanol (2 ml) at
0 ЊC and stirred for 10 min. Polystyryl(trimethyl)ammonium
borohydride (241 mg, 0.6 mmol) was added in one portion and
the reaction mixture was allowed to warm to room temper-
ature over 2 h. The reaction mixture was filtered and the
solvent removed under reduced pressure. The residue was dis-
solved in ethyl acetate and the solution was washed with water
and brine, and dried (Na2SO4) to give an inseparable mixture of
isomers of 11 in a 9:2 ratio (98 mg, 91%) as a colourless oil:
νmax/cmϪ1 3405, 1619, 1594, 1498, 1453, 1384, 1373, 1261,
1199, 1142 and 1116; δH (CDCl3, 400 MHz) 1.51 (6H, s), 2.50
(0.18H, dd, J 12.0, 9.9 Hz), 2.69–2.71 (1.64H, m), 2.78 (0.18H,
dd, J 12.0, 3.2 Hz), 2.91 (2H, br s), 3.36 (2.46H, s), 3.38 (0.54H,
s), 3.45–3.47 (2H, m), 3.88 (0.82H, dd, J 7.4, 5.3 Hz), 3.96
(0.18H, dd, J 8.7, 4.0 Hz), 4.47 (0.82H, dd, J 7.6, 4.5 Hz), 4.64
(0.18H, dd, J 9.9, 3.2 Hz), 4.78 (0.36H, s), 4.80 (1.64H, s), 6.73
(0.18H, d, J 8.3 Hz), 6.74 (0.82H, d, J 8.4 Hz), 6.92 (1H, s), 7.04
(1H, d, J 8.4 Hz) and 7.26–7.34 (5H, m); δC (100 MHz, CDCl3)
24.6, 55.3, 58.9, 60.9, 63.2, 72.2, 77.4, 99.4, 116.9, 119.2, 122.1,
125.7, 127.5, 127.7, 128.5, 134.5, 140.6 and 150.6; HRMS
(ESI ϩ ve) m/z 380.1823 [(M ϩ Na)ϩ calcd. for C21H27NNaO4
380.1838].
6-(4-Phenylbutoxy)hexanal (17)
A mixture of dimethyl sulfoxide (100 ml) and NaHCO3
(14.1 g, 167 mmol) was thoroughly de-gassed and then heated
to 150 ЊC under nitrogen. 6-(4-Phenylbutoxy)hexyl bromide12
(16) (10.0 g, 32 mmol) was then added in one portion and the
mixture was stirred at 150 ЊC for 5–6 min before it was cooled to
20 ЊC over a 10 min period. Diethyl ether (100 ml) was added,
followed by water (100 ml). The layers were separated and
the aqueous layer extracted with diethyl ether. The combined
organic layers were washed with water, dried (MgSO4) and
evaporated under reduced pressure to give 17 (7.93 g, 100%)
as a colourless oil: LCMS tR 12.03 min, 99%; ES ϩ ve m/z 249
(M ϩ H)ϩ; δH (CDCl3, 400 Mz): 1.35–1.43 (2H, m), 1.54–1.72
(8H, m), 2.43 (2H, dt, J 2, 7 Hz), 2.63 (2H, t, J 7 Hz), 3.39 (2H,
t, J 7 Hz), 3.41 (2H, t, J 7 Hz), 7.15–7.2 (3H, m), 7.24–7.3 (2H,
m) and 9.76 (1H, t, J 2 Hz); δC (CDCl3, 100 Mz): 21.9, 25.9,
28.1, 29.4, 29.5, 35.7, 43.9, 70.6, 70.8, 125.7, 128.3, 128.4, 142.3
and 202.8.
(4S )-3-[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl]-
4-phenyl-1,3-oxazolidin-2-one (12)
Carbonyldiimidazole (146 mg, 0.90 mmol) was added to a
stirred solution of 4 (154 mg, 0.45 mmol) in dichloromethane
(5 ml). After 15 min, the solution was filtered through a pad
of silica and evaporated to give 12 (151 mg, 91%) as a white
foam: [α]2D5 ϩ135 (c 1.43 in MeOH); νmax/cmϪ1 1755, 1686, 1582,
1499, 1420, 1265, 1221 and 1111; δH (CDCl3, 400 MHz) 1.53
(6H, s), 3.92 (1H, d, J 18 Hz), 4.18 (1H, t, J 8.5 Hz), 4.76 (1H, t,
J 8.5 Hz), 4.83 (2H, s), 4.94 (1H, d, J 18 Hz), 5.14 (1H, t, J 8.5
Hz), 6.81 (1H, d, J 8.6 Hz), 7.28 (2H, dd, J 7.8, 2.0 Hz), 7.35–
7.40 (3H, m), 7.55 (1H, d, J 2 Hz) and 7.67 (1H, dd, J 8.6, 2 Hz);
δC (CDCl3, 100 MHz) 24.7, 24.8, 47.4, 60.2, 60.2, 60.6, 70.3,
100.7, 117.4, 119.5, 125.5, 127.2, 128.5, 129.2, 129.4, 137.3,
156.3, 158.8 and 191.8; HRMS (EI ϩ ve) m/z 367.1417 (Mϩ
calcd. for C21H21NO5 367.1420).
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S )-2-
hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}ethanol
(18)
Sodium triacetoxyborohydride (433 mg, 2 mmol) was added in
one portion under nitrogen to a cloudy mixture of 7 (500 mg,
1.45 mmol) and crude 17 (400 mg, 1.6 mmol) in CH2Cl2 (3 ml).
A gelatinous mixture formed initially which thinned over a
15 min period. The resulting light yellow solution was stirred
for 18 h before it was partitioned between ethyl acetate and
saturated aqueous NaHCO3. The aqueous layer was extracted
with ethyl acetate and the combined organic layers were dried
(MgSO4), concentrated and purified by column chromato-
graphy eluting with ethyl acetate–light petroleum (1:8) to give
18 (725 mg, 87%) as a colourless gum: LCMS tR 7.92 min,
100%; ES ϩ ve m/z 576 (M ϩ H)ϩ; [α]2D0 Ϫ9.0 (c 1.6 in CHCl3);
δH (CDCl3, 400 Mz): 1.18–1.38 (5H, m), 1.53 (6H, s), 1.40–1.71
(9H, m), 2.33–2.42 (1H, m), 2.59–2.70 (4H, m), 2.82 (1H, dd,
J 13, 5 Hz), 3.37 (2H, t, J 7 Hz), 3.41 (2H, t, J 7 Hz), 3.80 (1H,
dd, J 9, 4 Hz), 3.90–4.00 (2H, m), 4.60 (1H, dd, J 9, 5 Hz), 4.83
(2H, s), 6.79 (1H, d, J 8 Hz), 6.96 (1H, d, J 2 Hz), 7.09 (1H, dd,
J 8, 2 Hz), 7.15–7.2 (3H, m) and 7.21–7.37 (7H, m); δC (CDCl3,
100 Mz): 24.6, 24.8, 26.1, 27.1, 28.1, 28.4, 29.4, 29.7, 35.7, 51.3,
60.1, 61.0, 61.8, 67.0, 70.7, 70.8, 72.0, 99.5, 117.0, 119.4, 122.2,
125.7, 125.8, 127.8, 128.3, 128.4, 128.5, 134.5, 137.7, 142.5 and
150.8.
(4S )-3-[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-
hydroxyethyl]-4-phenyl-1,3-oxazolidin-2-one (13) and (4S )-3-
[(2S )-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-
ethyl]-4-phenyl-1,3-oxazolidin-2-one (14)
Calcium chloride (54 mg, 0.48 mmol) was added to a stirred
solution of 12 (89 mg, 0.24 mmol) in methanol (2 ml) at 0 ЊC.
After 10 min, polystyryl(trimethyl)ammonium borohydride
(194 mg, 0.48 mmol) was added and the mixture stirred for 2 h,
warming slowly to room temperature. The reaction mixture was
filtered through a pad of silica to give a 1:1 mixture of diastereo-
isomers 13 and 14 (49 mg, 87%). Purification by flash column
chromatography, eluting with ethyl acetate–petroleum ether
(3:7) yielded isomer A (18 mg, 32%) as a white crystalline solid:
[α]2D5 ϩ29.8 (c 1.21 in CD3OD); νmax/cmϪ1 3427, 1732, 1620 and
1594; δH (CD3OD, 600 MHz) 1.52 (6H, s), 2.92 (1H, dd, J 14.3,
8.4 Hz), 3.51 (1H, dd, J 14.3, 4.3 Hz), 4.18 (1H, dd, J 8.8, 6.3
Hz), 4.71 (1H, t, J 8.8 Hz), 4.84 (1H, m), 4.84 (2H, s), 5.15 (1H,
dd, J 8.8, 6.3 Hz), 6.75 (1H, d, J 8.4 Hz), 7.00 (1H, s), 7.12 (1H,
d, J 8.4 Hz), 7.33 (2H, d, J 7.3 Hz), 7.41 (1H, t, J 7.3 Hz) and
7.46 (2H, t, J 7.3 Hz); δC (CD3OD, 150 MHz) 24.9, 25.0, 50.5,
61.8, 62.7, 71.6, 73.0, 100.7, 117.8, 120.9, 123.4, 126.9, 128.4,
130.0, 130.3, 135.5, 139.7, 152.2 and 160.9; HRMS (ESI ϩ ve)
m/z 392.1465 [(M ϩ Na)ϩ calcd. for C21H23NNaO5 392.1474]
and isomer B (9 mg, 16%) as an amorphous white solid: [α]2D5
ϩ60.4 (c 0.57 in CD3OD); νmax/cmϪ1 3430, 1731, 1619 and 1593;
(R)-(–)-2-Hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenylbutoxy)-
hexylamino]ethyl}phenol (19)
A solution of 18 (110 mg, 0.19 mmol) in ethanol (75 ml), was
hydrogenated over Pearlman’s catalyst [Pd(OH)2–C, 60% H2O,
55 mg) for 18 h. The catalyst was removed by filtration through
a short plug of Celite and the residue was washed with ethanol.
The combined filtrate and washings were concentrated and then
applied to a 10 g SCX-2 ion exchange cartridge. The cartridge
was eluted with ethanol and then with 10% aqueous 880 NH3
in ethanol. The ammoniacal eluent was concentrated under
reduced pressure to give 19 (69 mg, 87%) as a colourless gum:
LCMS tR 6.27 min, 100%; ES ϩ ve m/z 416 (M ϩ H)ϩ; [α]2D0
J. Chem. Soc., Perkin Trans. 1, 2002, 2237–2242
2241

View Online
Ϫ18.5 (c 0.81 in MeOH); δH (CD3OD; 400 MHz) 1.28–1.41
(4H, m), 1.45–1.73 (8H, m), 2.60 (2H, t, J 7 Hz), 2.63–2.87 (4H,
m), 3.38 (2H, t, J 7 Hz), 3.40 (2H, t, J 7 Hz), 4.63 (2H, s), 4.70
(1H, dd, J 8, 4 Hz), 6.75 (1H, d, J 8 Hz) and 7.07–7.30 (7H, m).
Chiral HPLC conducted on a 25 cm × 0.46 cm Chiralcel OJ
column, eluting with ethanol–heptane [20:80] at a flow rate of
1 ml minϪ1 at 0 ЊC and detecting at 215 nm: tR 9.70 min, >98%
(R-isomer).
Acknowledgements
We thank Mr. E. Hortense for performing the chiral HPLC,
Mr. S. M. Lynn for providing the X-ray crystallographic details
and Dr. P. Grice for the NMR complexation experiment.
References
1 A. T. Nials, R. A. Coleman, M. Johnson and C. Vardey, J. Am. Rev.
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(12 Feb 1991).
(R)-(–)-2-Hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenylbutoxy)-
hexylamino]ethyl}phenol, 1-hydroxynaphthalene-2-carboxylic
acid salt (20)
A solution of 19 (53 mg, 0.13 mmol) in MeOH (2 ml) was
treated with 1-hydroxy-2-naphthoic acid (24 mg, 0.13 mmol).
The solution was evaporated to dryness to give 20 (77 mg) as a
solid: δH (CD3OD, 400 MHz) 1.36–1.42 (4H, m), 1.50–1.74 (8H,
m), 2.60 (2H, t, J 7 Hz), 2.99 (2H, t, J 8 Hz), 3.05–3.14 (2H, m),
3.38 (2H, t, J 7 Hz), 3.40 (2H, t, J 7 Hz), 4.65 (2H, s), 4.87 (1H,
shoulder to CD3OH), 6.78 (1H, d, J 8 Hz), 7.18–7.26 (7H, m),
7.34 (1H, d, J 2 Hz), 7.40 (1H, m), 7.48 (1H, m), 7.72 (1H, br d,
J 8 Hz), 7.85 (1H, d, J 8 Hz) and 8.28 (1H, br d, J 8 Hz). Chiral
HPLC conducted on a 25 cm × 0.46 cm Sumichiral OA-
4100 column, eluting with hexane–dichloromethane–ethanol–
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trifluoroacetic acid [240:130:30:1] at a flow rate of 1 ml minϪ1
:
tR 18.79 min, 98.5% (R-isomer) and tR 16.42 min, 1.5%
(S-isomer).
14 A. F. Abdel-Magid, C. A. Maryanoff and K. G. Carson,
Tetrahedron Lett., 1990, 31, 5595.
2242
J. Chem. Soc., Perkin Trans. 1, 2002, 2237–2242