Synthesis of homochiral 5- and 8-substituted 2-[((2-(2,6-dimethoxyphenoxy)-ethyl)amino)methyl]-1,4-benzodioxanes and electrophoretic determination of their enantiomeric excess

Full text of DOI:10.1021/jo0008340

1018
J . Org. Chem. 2001, 66, 1018-1025
Ch a r t 1
Syn th esis of Hom och ir a l 5- a n d 8-
Su bstitu ted 2-[((2-(2,6-Dim eth oxyp h en oxy)-
eth yl)a m in o)m eth yl]-1,4-ben zod ioxa n es a n d
Electr op h or etic Deter m in a tion of Th eir
En a n tiom er ic Excess
Ermanno Valoti,*,† Marco Pallavicini,† Luigi Villa,† and
Daniele Pezzetta‡
Istituto di Chimica Farmaceutica e Tossicologica,
Universita` di Milano, viale Abruzzi 42, I-20131 Milano,
Italy, and Pharmacia & Upjohn, viale Pasteur 10,
I-20014 Nerviano (MI), Italy
ermanno.valoti@unimi.it
Received May 31, 2000
Among the structures which have the capacity to
interact with R1-adrenoceptors, benzodioxanes are one of
the main classes. In particular, WB4101, which can be
considered the lead compound of such a class, exhibits a
nanomolar affinity toward R1-adrenoceptor, the S enan-
tiomer possessing remarkably higher affinity than the
R enantiomer.1 As part of our ongoing program aimed
at the study of chiral benzodioxane derivatives as type-
selective R-adrenoceptor ligands, we wish to report herein
the synthesis of the enantiomers of the 5-methoxy,
8-methoxy, and 8-fluoro analogues (1-3; see Chart 1) of
WB4101 and, in addition, a practical method to deter-
mine their enantiomeric excess. In fact, an accurate
assessment of the stereoisomeric purity of the optical
isomers of WB4101 and of its analogues is strictly
required for the binding experiments on account of the
known high enantioselectivity displayed by the R1 adreno-
ceptor toward WB4101 and, in general, toward its
derivatives with considerable affinity.
Sch em e 1
To the best of our knowledge, no report on the
synthesis of racemic or homochiral 2-(aminomethyl)-
benzodioxanes substituted at position 5 or 8 has appeared
up to now in the literature. In this regard, the main
challenges are the regioselective introduction of the
substituent into the desired position of the phenyl ring
of benzodioxane and the development of efficient methods
for the synthesis of S and R derivatives with high
enantiomeric excess. In this paper, we report a united
solution to both problems. In fact, our approach for the
construction of the disubstituted benzodioxane skeleton
of the S and R forms of 1-3 was based on the use of the
appropriate 2,6- or 2,3-disubstituted phenol and respec-
tively of (S)- and (R)-glycerol acetonide as building blocks.
The availability of both enantiomers of such a glycerol
derivative is ensured by an easy and efficient resolution
we had previously developed.2 As retrosynthetically il-
lustrated in Scheme 1, the employment of 2,6- and 2,3-
disubstituted phenols circumvented the problem of the
regioselective substitution at the phenyl of benzodioxane
allowing to perform the 2-substituted 1,4-dioxane ring
closure with resultant unambiguous position of the
second benzodioxane substituent in 5 and 8, respectively.
On the other hand, the use of (S)- and (R)-glycerol
acetonide, both with higher than 99.6% enantiomeric
excess, and the consequent possibility of following paral-
lel synthetic routes led to the S and R forms of 1-3 in
analogous optical yields (ee > 99.6%).
As outlined in Scheme 2, the reaction sequence for
preparing the S isomers of 1-3 consisted in the following
steps: (a) displacement of tosylate from the tosyl ester
of (S)-glycerol acetonide [(R)-4] by 2,6-dimethoxy-, 2,3-
dimethoxy- and 2-(benzyloxy)-3-fluorophenoxide, respec-
tively; (b) hydrolysis of the cyclic ketals (S)-5, (S)-12, and
(S)-19; (c) tosylation of the resultant vic-diols (R)-6, (R)-
13, and (R)-20; (d) removal of the two methyl or of the
benzyl from the phenoxy residue of (S)-7, (S)-14, and (S)-
21, respectively; (e) intramolecular nucleophilic substitu-
tion of the tosylate at C2 of the glycerol skeleton by the
ortho-phenoxy moiety to give 1,4-dioxane ring closure
[(R)-9, (R)-16, and (R)-23]; (f) conversion into iodomethyl
† Universita` di Milano.
‡ Pharmacia & Upjohn.
(1) Villa, L.; Valoti, E.; Villa, A. M.; Pallavicini, M.; Ferri, V.; Iuliano,
E.; Brunello, N. Farmaco 1994, 49, 587.
(2) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Tetrahedron:
Asymmetry 1994, 5, 5.
10.1021/jo0008340 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/06/2001

Notes
J . Org. Chem., Vol. 66, No. 3, 2001 1019
Sch em e 2
Sch em e 3
derivatives (R)-11, (R)-18, and (R)-24 after methylating,
in the case of the synthesis of (S)-1 and (S)-2, the residual
phenolic function of (R)-9 and (R)-16; (g) amination with
2-(2,6-dimethoxyphenoxy)ethylamine. The R enantiomers
of 1-3 were synthesized by the same strategy as il-
lustrated in Scheme 1 but starting from the tosyl ester
of (R)-glycerol acetonide [(S)-4]. 2-(Benzyloxy)-3-fluo-
rophenol used in the first step of the syntesis of (S)-3 and
(R)-3 was prepared from 2-fluorophenol as outlined in
Scheme 3. Esterification with acetyl chloride, followed
by Fries rearrangement and benzylation of the resulting
hydroxyketone 26, afforded 2-(benzyloxy)-3-fluoroace-
tophenone (27), which was converted into the corre-
sponding phenyl acetate 28 by the Baeyer-Villiger
reaction and finally submitted to methanolysis.
The enantiomeric purity of the optical isomers of
WB4101 and of its three novel analogues was initially
investigated by applying chromatographic methods. How-
ever, their previous conversion into diastereomeric amides
by reaction with optically pure R-methoxy-R-(trifluoro-
methyl)phenylacetyl chloride was required to obtain
analytical HPLC separation, while attempts at direct
resolution of the enantiomers by HPLC on chiral station-

1020 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
ary phases were ineffective. The alternative use of a more
practical method was therefore planned. Prompted by the
reports on the application of capillary electrophoresis
(CE) to the separation of enantiomeric pairs,3 we con-
sidered the possibility of evaluating the stereoisomeric
purity of the title compounds by cyclodextrin (CD)-
modified CE.
The use of CDs as mobile-phase additives has been
shown to impart enantioselectivity to CE separations.3
Chiral resolution occurs on the basis of differences in the
stability or rate of formation of the analyte-CD inclusion
complex for each enantiomer. With neutral CDs, the
mobility of cationic analytes decreases since the combined
charge/mass ratio of their inclusion complexes with CDs
is lower than that of the same analytes in the free form.
Under such conditions, the enantiomer forming the more
stable complex elutes last. In the present study, the
analyses were performed under acidic conditions employ-
ing phosphate buffer adjusted to pH 2.5 as a running
electrolyte. At this pH value the electroosmotic flow was
minimized and all the analytes were positively charged.
In the absence of chiral discriminators, as shown in
Figure 1, a rapid separation, with baseline or near
baseline resolution, of 2-(aminomethyl)-1,4-benzodioxane
hydrochloride, WB4101, 1, and 2 was achieved, while
WB4101 and its 8-fluoro analogue 3 were coeluted. Initial
attempts of enantioseparation were made adding the
most commonly used â-CD to the running electrolyte. As
expected, the addition of â-CD slightly increased migra-
tion times. However, this chiral discriminator gave only
poor resolution of the enantiomers of WB4101 and of
compounds 1 and 3 and failed to resolve those of
2-(aminomethyl)-1,4-benzodioxane hydrochloride. The in-
ability to achieve complete resolution under the above
conditions led to the subsequent use of derivatized CDs,
in particular of the hydroxyalkyl â- and γ-CD, whose
inclusion properties significantly differ from those of the
native counterparts. In fact, they have larger and less
rigid cavities and addtional interactive potentialities with
the analytes due to the hydroxyalkyl moiety. Moreover,
their increased water solubility permits the use of higher
mobile-phase concentrations. Indeed, addition of hy-
droxyethyl â-CD fully resolved the enantiomers of all
investigated compounds except those of 2, causing only
moderate enhancements of the migration times in com-
parison with native â-CD (Figure 2). The high efficiency
of these resolutions is well demonstrated by the electro-
pherogram presented in Figure 3, which shows the
complete separation of the eight stereoisomers of 2-(ami-
nomethyl)-1,4-benzodioxane hydrochloride, WB4101 and
its 5-methoxy and 8-fluoro analogues under a single set
of operating conditions. Finally, the enantiomers of 2
could be resolved only using hydroxypropyl γ-CD (Figure
4). In this case, however, migration times were dramati-
cally increased indicating strong analyte-CD interac-
tions.
F igu r e 1. Electropherogram of a solution containing the
enantiomeric pairs of 2-(aminomethyl)-1,4-benzodioxane hy-
drochloride, WB4101, and 1-3. The running electrolyte con-
sisted of 5 mM phosphate buffer (pH 2.5) without chiral
selector.
excesses. On the contrary, in the case of WB4101 and
2-(aminomethyl)-1,4-benzodioxane hydrochloride, the S
and the R forms, both previously prepared from (S)-
glycerol acetonide by two different synthetic pathways
according to literature methods,1,4,5 showed disparity in
stereoisomeric purity. In fact, only the S isomers proved
to be more than 99.6% enantiomerically pure, while the
enantiomeric excesses of the R forms were 95.95% and
96.97%, respectively. These results indicate the higher
enantioselectivity of the present syntheses, based on the
initial efficient resolution of glycerol acetonide and on the
successive transformations illustrated in Scheme 2, in
comparison with the previously described syntheses of
the R isomers of WB4101 and 2-(aminomethyl)-1,4-
benzodioxane hydrochloride,1,4,5 consisting in using the
same antipod of glycerol acetonide as for the preparation
of the S isomers of the above compounds and in formally
exchanging the attachment site of the functional groups
at the glycerol moiety.
The electophoretic analysis of the optical antipodes of
1-3, under the above specified conditions, allowed one
to determine invariably higher than 99.6% enantiomeric
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR spectra were re-
corded at 60 or 200 MHz. The S and R enantiomers of WB4101
and of 2-(aminomethyl)-1,4-benzodioxane hydrochloride were
synthesized as previously reported.1,4,5 (S)- and (R)-glycerol
acetonide were prepared by chemical resolution of the racemate
as described in the literature 2 and successively transformed into
(3) For example, see: (a) Wren, S. A. C.; Rowe, R. J . Chromatogr.
1993, 635, 113. (b) Lurie, I. S.; Klein, R. F. X.; Dal Cason, T. A.; LeBelle,
M. J .; Brenneisen, R.; Weinberger, R. E. Anal. Chem. 1994, 66, 4019.
(c) Tait, R. J .; Thompson, D. O.; Stella, V. J .; Stobaugh, J . F. Anal.
Chem. 1994, 66, 4013. (d) Szeman, J .; Ganzler, K.; Salgo, A.; Szejtli,
J . J . Chromatogr., A 1996, 728, 423. (e) Williams, R. L.; Vigh, G. J .
Chromatogr., A 1996, 730, 273. (f) Wan, H.; Engstro¨m, A.; Blomberg,
L. G. J . Chromatogr., A 1996, 731, 283.
(4) Nelson, W. L.; Wennerstrom, J . E. J . Med. Chem. 1977, 20, 880.
(5) Nelson, W. L.; Powell, M. L. J . Med. Chem. 1979, 22, 1125.

Notes
J . Org. Chem., Vol. 66, No. 3, 2001 1021
F igu r e 3. Electropherogram of a solution containing the
enantiomeric pairs of 2-(aminomethyl)-1,4-benzodioxane hy-
drochloride, WB4101, 1, and 3. The running electrolyte
consisted of 40 mM hydroxyethyl â-CD in 5 mM phosphate
buffer (pH 2.5).
F igu r e 2. Electropherograms of the solutions of the single
enantiomeric pairs of 2-(aminomethyl)-1,4-benzodioxane hy-
drochloride, WB4101, 3, and 1. The running electrolyte
consisted of 40 mM hydroxyethyl â-CD in 5 mM phosphate
buffer (pH 2.5).
the corresponding tosyl esters (R)-4 and (S)-4 by treatment with
tosyl chloride in pyridine according to standard procedures.
(2S)-3-(2,6-Dim et h oxyp h en oxy)-1,2-p r op a n ed iol Ace-
ton id e [(S)-5]. A mixture of 2,6-dimethoxyphenol (18.96 g, 0.123
mol) and sodium (2.8 g, 0.123 mol) in ethanol (300 mL) was
refluxed for 30 min and, after adding (2R)-3-tosyloxy-1,2-
propanediol acetonide [(R)-4] (31.64 g, 0.110 mol), for 72 h. The
solvent was evaporated and the residue treated with diethyl
ether (400 mL). The resulting suspension was filtered and the
filtrate washed with water, 10% sodium hydroxide, and water
again. The organic layer was dried and concentrated to give a
residue which was chromatographed on silica gel. Elution with
cyclohexane/ethyl acetate (90/10) afforded 19.5 g (57%) of (S)-5
as a white solid: mp 32-35 °C; [R]D25 ) +16.4 (c 1, ethanol); 1H
NMR (60 MHz, CDCl3) δ 1.38 (s, 3 H), 1.43 (s, 3 H), 3.79-3.88
(m, 1 H), 3.84 (s, 6 H), 3.99-4.20 (m, 3 H), 4.39-4.50 (m, 1 H),
6.56 (d, 2 H), 6.99 (t, 1 H). Anal. Calcd for C14H20O5 (268.31):
C, 62.67; H, 7.51. Found: C, 62.44; H, 7.47.
in pyridine (35 mL) at 0 °C. The resulting mixture was stirred
for 18 h at room temperature, diluted with ethyl acetate (300
mL), and washed with 10% HCl and then with water. The
organic phase was dried and concentrated to give the crude
product (38.42 g), which was crystallized from diethyl ether
yielding 34.54 g (97%) of (S)-7 as a white solid: mp 91-92 °C;
[R]D ) +25.0 (c 1, chloroform); 1H NMR (60 MHz, CDCl3) δ
25
2.40 (s, 6 H), 3.78 (s, 6 H), 3.95-4.15 (m, 2 H), 4.24-4.38 (dd, 1
H), 4.42-4.65 (dd, 1 H), 4.80-4.90 (m, 1 H), 6.52 (d, 2 H), 6.98
(t, 1 H), 7.25-7.38 (2d, 4 H), 7.60-7.75 (2d, 4 H). Anal. Calcd
for C25H28O9S2 (536.62): C, 55.96; H, 5.26; S, 11.95. Found: C,
55.67; H, 5.18; S, 11.81.
(2S )-3-(2,6-Dih yd r oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(S)-8]. Boron tribromide (6.42 mL, 68 mmol) was added
dropwise to a solution of (S)-7 (36.5 g, 68 mmol) in dichlo-
romethane (200 mL) at 0 °C. The mixture was stirred for 2 h at
room temperature and then poured into water (500 mL) cooled
at 10 °C. The organic phase was separated and water reextracted
with dichloromethane. The organic extracts were combined,
washed with brine, dried, and concentrated. The resulting
residue was chromatographed on silica gel. Elution with hexane/
ethyl acetate (75/25) afforded 14.7 g (42%) of (S)-8 as a colorless
(2R)-3-(2,6-Dim eth oxyp h en oxy)-1,2-p r op a n ed iol [(R)-6].
A suspension of (S)-5 (19.26 g, 71.7 mmol) in 10% HCl (150 mL)
was heated at 75 °C for 14 h. After cooling, acetone was removed
by vacuum distillation and the residual aqueous phase submitted
to continuous extraction with dichloromethane. The organic
extract was dried and concentrated to give a solid residue (16.62
g), which was chromatographed on silica gel. Elution with
dichloromethane/methanol (95/5) yielded 8.2 g (50%) of (R)-6 as
25
1
oil: [R]D ) +22.5 (c 1, ethanol); H NMR (60 MHz, CDCl3) δ
2.43 (s, 6 H), 4.10-4.25 (m, 3 H), 4.30-4.42 (dd, 1 H), 4.95-
5.10 (m, 1 H), 6.05 (s, 2 H), 6.45 (d, 2 H), 6.83 (t, 1 H), 7.30-
7.40 (2d, 4 H), 7.70-7.85 (2d, 4 H).
a white solid: mp 73-74 °C; [R]D ) -13.3 (c 1, ethanol); 1H
(2R )-2-((Tosyloxy)m e t h yl)-5-h yd r oxy-1,4-b e n zod iox-
a n e [(R)-9]. A mixture of (S)-8 (14.62 g, 28.7 mmol) and K2CO3
(3.97 g, 28.7 mmol) in acetone (100 mL) was refluxed for 24 h.
After evaporation of the solvent, the residue was treated with
diethyl ether (200 mL) and 10% HCl (150 mL). The aqueous
phase was separated and extracted with diethyl ether. The
combined organic extracts were washed with water, dried, and
concentrated. The residue was purified by chromatography on
25
NMR (60 MHz, CDCl3) δ 2.1 (s, 2 H), 3.61-3.80 (m, 2 H), 3.86
(s, 6 H), 3.83-4.09 (m, 2 H), 4.16-4.31 (m, 1 H), 6.60 (d, 2 H),
7.15 (t, 1 H). Anal. Calcd for C11H16O5 (228.25): C, 57.88; H,
7.06. Found: C, 57.86; H, 7.01.
(2S )-3-(2,6-Dim e t h oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(S)-7]. Tosyl chloride (25.24 g, 0.132 mol) was added in
small portions to a stirred solution of (R)-6 (15.12 g, 0.066 mol)

1022 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
ture of (R)-11 (1.5 g, 4.90 mmol) and 2-(2,6-dimethoxyphenoxy)-
ethylamine (1.74 g, 8.82 mmol) in 2-propanol (10 mL) was
refluxed for 48 h. The solvent was evaporated and the residue
treated with ethyl acetate and 10% NaOH. The aqueous phase
was separated and extracted with ethyl acetate twice. The
combined extracts were dried and concentrated to give a residue
which was chromatographed on silica gel. Elution with dichlo-
romethane/methanol (98/2) yielded 780 mg of (2S)-2-[((2-(2,6-
dimethoxyphenoxy)ethyl)amino)methyl]-5-methoxy-1,4-benzo-
25
dioxane: [R]D ) -29.2 (c 1, chloroform). The secondary amine
was dissolved in ethanol (2 mL), and 3.57 N HCl/EtOH (2 mL)
was added. The solvent was evaporated, and the semisolid
residue was crystallized from diisopropyl ether/acetone (90/10)
yielding 380 mg (45%) of (S)-1 as a white solid: mp 128-129 °C;
[R]D25 ) -48.5 (c 1, methanol); 1H NMR (200 MHz, DMSO-d6) δ
3.30-3.50 (m, 4 H), 3.80 (s, 3 H), 3.82 (s, 6), 4.05-4.20 (m, 3 H),
4.44 (dd, 1 H), 4.78 (m, 1 H), 6.55-6.90 (m, 5 H), 7.14 (t, 1 H),
9.54 (br s, 2 H). Anal. Calcd for C20H26ClNO6‚1/2 H2O (420.89):
C, 57.07; H, 6.47; N, 3.33; Cl, 8.42. Found: C, 56.90; H, 6.10; N,
3.22; Cl, 8.59.
(2R)-3-(2,6-Dim et h oxyp h en oxy)-1,2-p r op a n ed iol Ace-
ton id e [(R)-5]. Prepared from (2S)-3-(tosyloxy)-1,2-propanediol
25
acetonide [(S)-4] as described for (S)-5: mp 32-34 °C; [R]D
)
1
-15.3 (c 1, ethanol); H NMR identical to that of (S)-5.
(2S)-3-(2,6-Dim eth oxyp h en oxy)-1,2-p r op a n ed iol [(S)-6].
Prepared from (R)-5 as described for (R)-6: mp 73-74 °C; [R]D
25
1
) +11.9 (c 1, ethanol); H NMR identical to that of (R)-6.
(2R )-3-(2,6-Dim e t h oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(R)-7]. Prepared from (S)-6 as described for (S)-7: mp
91-92 °C; [R]D25 ) -24.7 (c 1, chloroform); 1H NMR identical to
that of (S)-7.
(2R )-3-(2,6-Dih yd r oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
25
p a n e [(R)-8]. Prepared from (R)-7 as described for (S)-8: [R]D
1
) -23.9 (c 1, ethanol); H NMR identical to that of (S)-8.
(2S)-2-((Tosyloxy)m eth yl)-5-h yd r oxy-1,4-ben zod ioxa n e
25
[(S)-9]. Prepared from (R)-8 as described for (R)-9: [R]D
)
1
+28.5 (c 1, chloroform); H NMR identical to that of (R)-9.
F igu r e 4. Electropherogram of a solution containing the
enantiomeric pair of 2. The running electrolyte consisted of
60 mM hydroxypropyl γ-CD in 5 mM phosphate buffer (pH
2.5).
(2S)-2-(Tosyloxy)m et h yl)-5-m et h oxy-1,4-b en zod ioxa n e
25
[(S)-10]. Prepared from (S)-9 as described for (R)-10: [R]D
)
1
+22.6 (c 1, chloroform); H NMR identical to that of (R)-10.
(2S)-2-(Iod om et h yl)-5-m et h oxy-1,4-b en zod ioxa n e [(S)-
11]. Prepared from (S)-10 as described for (R)-11: [R]D25 ) +15.3
1
silica gel eluting with cyclohexane/ethyl acetate (70/30). The pure
(c 1, chloroform); H NMR identical to that of (R)-11.
25
fractions gave 4.5 g (47%) of (R)-9 as a colorless oil: [R]D
)
(2R)-2-[((2-(2,6-Dim eth oxyph en oxy)eth yl)am in o)m eth yl]-
5-m eth oxy-1,4-ben zod ioxa n e Hyd r och lor id e [(R)-1]. Pre-
1
-27.8 (c 1, chloroform); H NMR (60 MHz, CDCl3) δ 2.43 (s, 3
H), 4.20-4.50 (m, 5 H), 5.30 (s, 1 H), 6.35 (d, 1 H), 6.55 (d, 1 H),
6.75 (t, 1 H), 7.35 (d, 2 H), 7.80 (d, 2 H).
25
pared from (S)-11 as described for (S)-1: mp 128-129 °C; [R]D
25
) +47.4 (c 1, methanol) ([R]D ) +27.0 (c 1, chloroform) for the
1
(2R)-2-(Tosyloxy)-5-m eth oxy-1,4-ben zod ioxa n e [(R)-10].
A solution of (R)-9 (3.6 g, 10.7 mmol) in ethanol (30 mL) and
then iodomethane (2.0 mL, 32.1 mmol) were added dropwise to
a solution of sodium hydroxide (428 mg, 10.7 mmol) in ethanol
(50 mL) at 10 °C. After the solution was stirred for 24 h at room
temperature, the solvent was evaporated and the residue treated
with 10% HCl (80 mL) and ethyl acetate (80 mL). The aqueous
phase was separated and extracted with ethyl acetate. The
organic extracts were combined and washed with an acidic
aqueous solution of sodium bisulfite and then with water. After
drying, ethyl acetate was removed under vacuum and the
residue purified by chromatography on silica gel. Elution with
cyclohexane/acetone (80/20) yielded 2.4 g (64%) of (R)-10 as a
free amine); H NMR identical to that of (S)-1. Anal. Calcd for
C
20H26ClNO6‚1/4 H2O (416.38): C, 57.69; H, 6.41; N, 3.36; Cl,
8.51. Found: C, 57.73; H, 6.14; N, 3.25; Cl, 8.68.
(2S)-3-(2,3-Dim et h oxyp h en oxy)-1,2-p r op a n ed iol Ace-
ton id e [(S)-12]. A mixture of 2,3-dimethoxyphenol (75 g, 0.486
mol) and sodium methoxide (26.25 g, 0.486 mol) in ethanol (600
mL) was refluxed for 30 min and, after adding (2R)-3-(tosyloxy)-
1,2-propanediol acetonide [(R)-4] (125.56 g, 0.438 mol), for 24
h. The solvent was evaporated and the residue treated with
diethyl ether (500 mL). The resulting suspension was filtered
and the filtrate washed with water, 5% potassium hydroxide,
and water again. The organic phase was dried and concentrated
to give a residue which was crystallized from methanol yielding
25
1
25
yellow oil: [R]D ) -24.4 (c 1, chloroform); H NMR (60 MHz,
CDCl3) δ 2.43 (s, 3 H), 3.83 (s, 3 H), 4.00-4.45 (m, 5 H), 6.45
(dd, 2 H), 6.78 (t, 1 H), 7.38 (d, 2 H), 7.80 (d, 2 H).
56.4 g (48%) of (S)-12 as a white solid: mp 95-96 °C; [R]D
)
1
+18.6 (c 1, ethanol); H NMR (60 MHz, CDCl3) δ 1.42 (s, 3 H),
1.48 (s, 3 H), 3.88 (s, 6 H), 3.6-4.8 (m, 5 H), 6.4-7.4 (m, 3 H).
Anal. Calcd for C14H20O5 (268.31): C, 62.67; H, 7.51. Found: C,
62.97; H, 7.56.
(2R)-2-(Iod om eth yl)-5-m eth oxy-1,4-ben zod ioxa n e [(R)-
11]. A mixture of (R)-10 (2.4 g, 7.84 mmol) and sodium iodide
(22.47 g, 0.15 mol) in acetone (80 mL) was refluxed for 3 h. After
evaporation of the solvent, the residue was treated with 10%
HCl (30 mL) and diethyl ether (60 mL). The aqueous layer was
separated and extracted with diethyl ether again. The combined
organic extracts were dried and concentrated to give a residue
which was purified by chromatography on silica gel. Elution with
cyclohexane/ethyl acetate (95/5) afforded 1.6 g (80%) of (R)-11
(2R)-3-(2,3-Dim eth oxyp h en oxy)-1,2-p r op a n ed iol [(R)-13].
Prepared from (S)-12 in quantitative yield as described for (R)-
6: mp 93-96 °C; [R]D25 ) -9.3 (c 1, ethanol); 1H NMR (60 MHz,
acetone-d6) δ 3.6-4.25 (m, 5 H), 3.78 (s, 3 H), 3.82 (s, 3 H), 4.05
(s, 2 H), 6.5-7.27 (m, 3 H). Anal. Calcd for C11H16O5 (228.25):
C, 57.88; H, 7.06. Found: C, 57.99; H, 7.09.
(2S )-3-(2,3-Dim e t h oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(S)-14]. Tosyl chloride (56 g, 0.293 mol) was added in
small portions to a stirred solution of (R)-13 (30 g, 0.131 mol) in
pyridine (100 mL) at 0 °C. The resulting mixture was stirred
for 18 h at room temperature, diluted with dichloromethane
(1500 mL), and washed with 10% HCl and then with water. The
25
as an oil: [R]D ) -16.1 (c 1, chloroform); 1H NMR (60 MHz,
CDCl3) δ 3.36 (d, 2 H), 3.91 (s, 3 H), 4.15-4.38 (m, 2 H), 4.81
(dd, 1 H), 6.10 (d, 1 H), 6.57 (d, 1 H), 6.80 (t, 1 H).
(2S)-2-[((2-(2,6-Dim eth oxyph en oxy)eth yl)am in o)m eth yl]-
5-m eth oxy-1,4-ben zod ioxa n e Hyd r och lor id e [(S)-1]. A mix-

Notes
J . Org. Chem., Vol. 66, No. 3, 2001 1023
organic phase was dried and concentrated to give the crude
product, which was purified by chromatography on silica gel.
Elution with dichloromethane/methanol (98/2) and successive
crystallization from methanol yielded 37 g (52%) of (S)-14 as a
white solid: mp 79-80 °C; [R]D25 ) +13.9 (c 1, ethanol); 1H NMR
(60 MHz, acetone-d6) δ 2.48 (s, 6 H), 3.66 (s, 3 H), 3.84 (s, 3 H),
4.2 (d, 2 H), 4.4 (d, 2 H), 4.8-5.2 (m, 1 H), 6.4-7.1 (m, 3 H), 7.4
(d, 2 H), 7.53 (d, 2 H), 7.75 (d, 2 H), 7.88 (d, 2 H). Anal. Calcd
for C25H28O9S2 (536.62): C, 55.96; H, 5.26; S, 11.95. Found: C,
56.11; H, 5.25; S, 12.07.
(2S )-3-(2,3-Dih yd r oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(S)-15]. A solution of (S)-14 (35 g, 65.22 mmol) in
dichloromethane (100 mL) was added dropwise to a 1 M solution
of boron trichloride in dichloromethane (1755 mL) maintained
at 0 °C under N2. The reaction mixture was stirred at the same
temperature for 1 h and at room temperature for 48 h and then
added dropwise to water (800 mL) at 10 °C. After addition of
10% NaOH (100 mL), the organic layer was separated and the
aqueous one extracted with dichloromethane. The organic phases
H), 3.79 (s, 3 H), 3.83 (s, 6 H), 4.10-4.25 (m, 3 H), 4.48 (dd, 1
H), 4.77 (m, 1 H), 6.55-6.90 (m, 5 H), 7.10 (t, 1 H), 9.60 (br s, 2
H). Anal. Calcd for C20H26ClNO6 (411.88): C, 58.32; H, 6.36; N,
3.40; Cl, 8.61. Found: C, 58.25; H, 6.37; N, 3.43; Cl, 8.33.
(2R)-3-(2,3-Dim et h oxyp h en oxy)-1,2-p r op a n ed iol Ace-
ton id e [(R)-12]. Prepared from (2S)-3-(tosyloxy)-1,2-propanediol
25
acetonide [(S)-4] as described for (S)-12: mp 95-96 °C; [R]D
)
1
-18.0 (c 1, ethanol); H NMR identical to that of (S)-12.
(2S)-3-(2,3-Dim eth oxyp h en oxy)-1,2-p r op a n ed iol [(S)-13].
Prepared from (R)-12 as described for (R)-13: mp 93-96 °C;
[R]D ) +8.9 (c 1, ethanol); 1H NMR identical to that of (R)-13.
25
(2R)-3-(2,3-Dim e t h oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(R)-14]. Prepared from (S)-13 as described for (S)-14: mp
79-80 °C; [R]D ) -10.6 (c 1, ethanol); 1H NMR identical to
25
that of (S)-14.
(2R )-3-(2,3-Dih yd r oxyp h e n oxy)-1,2-b is(t osyloxy)p r o-
p a n e [(R)-15]. Prepared from (R)-14 as described for (S)-15: mp
25
108-109 °C; [R]D ) -12.3 (c 1, ethanol); 1H NMR identical to
that of (S)-15.
were combined, washed with water, dried, and concentrated to
(2S)-2-((Tosyloxy)m eth yl)-8-h yd r oxy-1,4-ben zod ioxa n e
25
25
give 24.5 g (74%) of (S)-15 as a solid: mp 108-109 °C; [R]D
)
[(S)-16]. Prepared from (R)-15 as described for (R)-16: [R]D
)
1
1
+13.0 (c 1, ethanol); H NMR (60 MHz, CDCl3) δ 2.45 (s, 6 H),
3.9-4.4 (m, 5 H), 4.9-5.2 (m, 1 H), 5.4-5.9 (m, 1 H), 6.2-6.8
(m, 3 H), 7.35 (2d, 4 H), 7.7-7.85 (2d, 4 H). Anal. Calcd for
C23H24O9S2 (508.56): C, 54.32; H, 4.76; S, 12.61. Found: C,
53.95; H, 4.71; S, 12.52.
+6.0 (c 1, ethanol); H NMR identical to that of (R)-16.
(2S )-2-((Tosyloxy)m e t h yl)-8-m e t h oxy-1,4-b e n zod iox-
a n e [(S)-17]. Prepared from (S)-16 as described for (R)-17: mp
25
1
92-94 °C; [R]D ) +7.6 (c 1, chloroform); H NMR identical to
that of (R)-17.
(2R )-2-((Tosyloxy)m e t h yl)-8-h yd r oxy-1,4-b e n zod iox-
a n e [(R)-16]. A mixture of (S)-15 (24 g, 47.2 mmol) and
potassium carbonate (6.52 g, 47.2 mmol) in acetone (150 mL)
was refluxed for 12 h. After cooling, the reaction mixture was
filtered and the filtrate concentrated to yield 7.6 g (48%) of (R)-
(2S)-2-(Iod om et h yl)-8-m et h oxy-1,4-ben zod ioxa n e [(S)-
18]. Prepared from (S)-17 as described for (R)-18: [R]D25 ) +39.2
1
(c 1, chloroform); H NMR identical to that of (R)-18.
(2R)-2-[((2-(2,6-Dim eth oxyph en oxy)eth yl)am in o)m eth yl]-
8-m eth oxy-1,4-ben zod ioxa n e Hyd r och lor id e [(R)-2]. Pre-
25
25
16 as an oil: [R]D ) -6.5 (c 1, chloroform); 1H NMR (60 MHz,
pared from (S)-18 as described for (S)-2: mp 170-171 °C; [R]D
CDCl3) δ 2.4 (s, 3 H), 3.95-4.55 (m, 5 H), 5.0-5.45 (m, 1 H),
6.2-6.8 (m, 3 H), 7.3 (d, 2 H), 7.78 (d, 2 H).
) +66.1 (c 1, chloroform); 1H NMR identical to that of (S)-2.
Anal. Calcd for C20H26ClNO6 (411.88): C, 58.32; H, 6.36; N, 3.40;
Cl, 8.61. Found: C, 58.19; H, 6.38; N, 3.42; Cl, 8.39.
(2R )-2-((Tosyloxy)m e t h yl)-8-m e t h oxy-1,4-b e n zod iox-
a n e [(R)-17]. A solution of (R)-16 (7.5 g, 22.3 mmol) in ethanol
(40 mL) and then iodomethane (3.08 mL, 49.48 mmol) were
added dropwise to a solution of sodium hydroxide (892 mg, 22.3
mmol) in ethanol (40 mL) at 10 °C. After the solution was stirred
for 24 h at room temperature, the solvent was evaporated and
the residue treated with 10% HCl (200 mL) and ethyl acetate
(100 mL). The aqueous phase was separated and extracted with
ethyl acetate. The organic extracts were combined and washed
with an acidic aqueous solution of sodium bisulfite and then with
water. After drying, ethyl acetate was removed under vacuum
and the residue purified by chromatography on silica gel. Elution
with hexane/ethyl acetate (90/10) yielded 3.5 g (45%) of (R)-17
(2S)-3-(2-(Ben zyloxy)-3-flu or op h en oxy)-1,2-p r op a n ed i-
ol Aceton id e [(S)-19]. A mixture of 2-(benzyloxy)-3-fluorophe-
nol (7 g, 0.032 mol) and potassium carbonate (4.5 g, 0.032 mol)
in dimethylformamide (100 mL) was stirred for 30 min. After
dropwise addition of (2R)-3-(tosyloxy)-1,2-propanediol acetonide
[(R)-4] (9.5 g, 0.033 mol), the mixture was heated at 120 °C for
36 h. The solvent was evaporated under vacuum and the residue
treated with dichloromethane. The resulting suspension was
filtered and the filtrate washed with 10% HCl and then with
water. The organic phase was separated, dried, and concentrated
to give a residue, which was purified by chromatography on silica
gel. Elution with cyclohexane/ethyl acetate (80/20) afforded 6.4
25
25
as a white solid: mp 92-94 °C; [R]D ) -6.9 (c 1, chloroform);
g (60%) of (S)-19 as an oil:; [R]D ) +13.69 (c 1, ethanol); 1H
1H NMR (60 MHz, CDCl3) δ 2.43 (s, 3 H), 3.85 (s, 3 H), 3.5-4.1
(m, 5 H), 6.3-7.0 (m, 3 H), 7.35 (d, 2 H), 7.82 (d, 2 H).
NMR (200 MHz, CDCl3) δ 1.39 (s, 3 H), 1.44 (s, 3 H), 3.80-4.20
(m, 4 H), 4.30-4.58 (m, 1 H), 5.1 (s, 2 H), 6.68-6.80 (m 2 H),
6.82-7.00 (m, 1 H), 7.20-7.60 (m, 5 H).
(2R)-2-(Iod om eth yl)-8-m eth oxy-1,4-ben zod ioxa n e [(R)-
18]. A mixture of (R)-17 (2 g, 5.71 mmol) and sodium iodide
(18.74 g, 125 mmol) in acetone (80 mL) was refluxed for 12 h,
cooled to room temperature, filtered, and concentrated to give a
residue which was treated with 10% HCl and diethyl ether. The
organic phase was separated, dried, and concentrated. The
resulting residue was purified by chromatography on silica gel.
Elution with hexane/ethyl acetate (90/10) afforded 1.52 g (87%)
(2R)-3-(2-(Ben zyloxy)-3-flu or op h en oxy)-1,2-p r op a n ed i-
ol [(R)-20]. A suspension of (S)-19 (6.4 g, 19.2 mmol) in 10%
HCl (100 mL) was heated at 75 °C for 14 h. After cooling, acetone
was removed by vacuum distillation and brine (50 mL) was
added to the residual aqueous phase which was successively
extracted with ethyl acetate. The organic extract was dried and
concentrated, and the resulting residue was chromatographed
on silica gel. Elution with dichloromethane/methanol (95/5)
25
of (R)-18 as an oil: [R]D ) +39.8 (c 1, chloroform); 1H NMR
25
(60 MHz, CDCl3) δ 3.42 (d, 2 H), 3.9 (s, 3 H), 4.2-4.6 (m, 3 H),
6.4-7.06 (m, 3 H).
yielded 4.5 g (80%) of (R)-20 as an oil: [R]D ) -4.58 (c 0.5,
1
ethanol); H NMR (200 MHz, CDCl3) δ 2.40 (s, 1 H), 3.00 (s, 1
(2S)-2-[((2-(2,6-Dim eth oxyph en oxy)eth yl)am in o)m eth yl]-
8-m eth oxy-1,4-ben zod ioxa n e Hyd r och lor id e [(S)-2]. A mix-
ture of (R)-18 (1.52 g, 4.97 mmol) and 2-(2,6-dimethoxyphenoxy)-
ethylamine (1.96 g, 9.93 mmol) was heated at 130 °C for 2 h
and, after cooling, treated with ethyl acetate (50 mL) and 10%
NaOH (75 mL). The aqueous phase was separated and extracted
with ethyl acetate. The combined extracts were washed with
water, dried, and concentrated to give a residue which was
chromatographed on silica gel. Elution with dichloromethane/
methanol (95/5) yielded 980 mg of (2S)-2-[((2-(2,6-dimethoxyphe-
noxy)ethyl)amino)methyl]-8-methoxy-1,4-benzodioxane. The sec-
ondary amine was dissolved in ethanol (2 mL), and 4 N HCl/
EtOH (1.5 mL) was added. The resulting precipitate was isolated
and twice crystallized from ethanol yielding 540 mg (26%) of
H), 3.60-3.70 (m, 4 H), 3.96-4.13 (m, 3 H), 5.08 (s, 2 H), 6.66-
6.80 (m, 2 H), 6.90-7.00 (m, 1 H), 7.33-7.40 (m, 5 H).
(2S)-3-(2-(Ben zyloxy)-3-flu or oph en oxy)-1,2-bis(tosyloxy)-
p r op a n e [(S)-21]. Tosyl chloride (6 g, 31.5 mmol) was added in
small portions to a stirred solution of (R)-20 (4.5 g, 15.4 mmol)
in pyridine (10 mL) at 0 °C. The resulting mixture was stirred
for 18 h at room temperature, diluted with ethyl acetate, and
washed with 10% HCl and then with water. The organic phase
was dried and concentrated to give the crude product, which was
purified by chromatography on silica gel. Elution with cyclo-
hexane/ethyl acetate (80/20) yielded 6 g (65%) of (S)-21 as a
25
viscous oil: [R]D ) -4.27 (c 1, ethanol); 1H NMR (200 MHz,
CDCl3) δ 2.39 (s, 3 H), 2.42 (s, 3 H), 4.09-4.11 (m, 2 H), 4.14-
4.21 (m, 2 H), 4.85 (m, 1 H), 4.94 (s, 2 H), 6.52-6.74 (m, 1 H),
6.79-6.86 (m, 1 H), 6.90-6.97 (m, 1 H), 7.26-7.55 (m, 9 H),
7.63-7.76 (2d, 4 H).
25
(S)-2 as a white solid: mp 169-171 °C; [R]D ) -67 (c 1,
chloroform); 1H NMR (200 MHz, DMSO-d6) δ 3.30-3.55 (m, 4

1024 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
(2S)-3-(2-H yd r oxy-3-flu or op h en oxy)-1,2-b is(t osyloxy)-
p r op a n e [(S)-22]. A solution of (S)-21 (6 g, 9.99 mmol) in ethyl
acetate (50 mL) was added with 10% Pd/C (50 mg) and
vigorously shaken under hydrogen at room temperature for 6
h. The catalyst was removed by filtration and the filtrate
concentrated to give a residue which was purified by chroma-
(2S)-2-((Tosyloxy)m eth yl)-8-flu or o-1,4-ben zodioxan e [(S)-
23]. Prepared from (R)-22 as described for (R)-23: [R]D25 ) +27.5
1
(c 1, chloroform); H NMR identical to that of (R)-23.
(2S)-2-(Iod om eth yl)-8-flu or o-1,4-ben zod ioxa n e [(S)-24].
25
Prepared from (S)-23 as described for (R)-24: [R]D ) -7.66 (c
1
1, chloroform); H NMR identical to that of (R)-24.
(2R)-2-[((2-(2,6-Dim eth oxyph en oxy)eth yl)am in o)m eth yl]-
8-flu or o-1,4-ben zod ioxa n e Hyd r och lor id e [(R)-3]. Prepared
tography on silica gel. Elution with cyclohexane/ethyl acetate
25
(70/30) afforded 4 g (78%) of (S)-22 as a colorless oil: [R]D
)
25
1
from (S)-24 as described for (S)-3: mp 137 °C; [R]D ) +51.27
-8.54 (c 1, chloroform); H NMR (200 MHz, CDCl3) δ 2.4 (s, 6
H), 4.08-4.22 (m, 4 H), 4.94-5.00 (m, 1 H), 5.8 (s, 1 H), 6.48-
6.51 (m, 1 H), 6.68-6.76 (m, 2 H), 7.26-7.33 (2d, 4 H), 7.69-
7.77 (2d, 4 H).
25
(c 1, methanol) ([R]D ) +23.5 (c 1, chloroform) for the free
amine); 1H NMR identical to that of (S)-3. Anal. Calcd for C19H23
-
ClFNO5 (399.85): C, 57.07; H, 5.80; N, 3.50; F, 4.75; Cl, 8.87.
Found: C, 57.00; H, 5.80; N, 3.48; F, 4.76; Cl, 8.75.
(2R)-2-((Tosyloxy)m eth yl)-8-flu or o-1,4-ben zodioxan e [(R)-
23]. A mixture of (S)-22 (4 g, 7.83 mmol) and potassium
carbonate (1.08 g, 7.83 mmol) in acetone (25 mL) was refluxed
for 5 h. After cooling, the reaction mixture was concentrated and
the residue treated with ethyl acetate and 10% HCl. The organic
phase was separated, washed with water, dried, and concen-
trated to yield a residue which was chromatographed on silica
2-F lu or op h en yl Aceta te (25). Acetyl chloride (35.3 g, 0.45
mol) was slowly added to a solution of 2-fluorophenol (50 g, 0.45
mol) and pyridine (40 mL) in dichloromethane (300 mL) at 25
°C. After 2 h, 10% HCl (200 mL) was added and the aqueous
layer was separated and extracted with dichloromethane. The
organic phases were combined, washed with water, dried, and
concentrated to give 65 g (94%) of 25 as a yellow oil: 1H NMR
(200 MHz, CDCl3) δ 2.38 (s, 3 H), 7.10-7.29 (m, 4 H).
gel eluting with cyclohexane/ethyl acetate (70/30). The pure
25
fractions gave 2.5 g (94%) of (R)-23 as a yellow oil: [R]D
)
2-Hyd r oxy-3-flu or oa cetop h en on e (26). A solution of 25 (65
g, 0.42 mol) in dichlorobenzene (40 mL) was added dropwise to
a solution of aluminum chloride (56.2 g, 0.42 mol) in dichlo-
robenzene (50 mL). After being warmed to 100 °C for 24 h, the
reaction mixture was allowed to cool to room temperature, added
with dichloromethane, and poured into 10% HCl cooled at 0 °C.
The aqueous layer was separated and extracted with dichlo-
romethane. The organic extracts were combined, rinsed with
water, dried, and concentrated. Column chromatography on
silica gel (eluent: cyclohexane/ethyl acetate, 95/5) of the result-
ing residue allowed to isolate, in sequence, 25 g (38.6%) of 26
and 39 g (60.2%) of 3-fluoro-4-hydroxyacetophenone. 26: 1H
NMR (200 MHz, CDCl3) δ 2.65 (s, 3 H), 6.79-6.89 (dd, 1 H),
7.24-7.34 (dd, 1 H), 7.51-7.55 (dd, 1 H), 12.28 (s, 1 H). 3-Fluoro-
4-hydroxyacetophenone: 1H NMR (200 MHz, CDCl3) δ 2.55 (s,
3 H), 6.5 (br s, 1 H), 7.05-7.15 (m, 1 H), 7.62-7.80 (m, 2 H).
2-(Ben zyloxy)-3-flu or oa cetop h en on e (27). Tetrabutylam-
monium bromide (7.1 g, 22 mmol) and 10% NaOH (200 mL) were
added to a solution of 26 (33.9 g, 0.22 mol) in dichloromethane
(300 mL). Benzyl bromide (28.8 mL, 0.242 mol) was added
dropwise to the mixture while vigorously stirring. After 3 h at
room temperature, the reaction mixture was poured into 10%
HCl (350 mL). The organic layer was separated and the aqueous
phase extracted with dichloromethane. The organic extracts
were combined, washed with water, dried, and concentrated.
Column chromatography on silica gel (eluent: cyclohexane/ethyl
acetate, 95/5) of the resulting residue allowed the isolation of
47 g (87.5%) of 27 as a yellow oil: 1H NMR (200 MHz, CDCl3) δ
2.51 (s, 3 H), 5.29 (s, 2 H), 7.06-7.12 (m, 1 H), 7.21-7.31 (m, 2
H), 7.34-7.40 (m, 5 H).
2-(Ben zyloxy)-3-flu or op h en yl Aceta te (28). 3-Chloroper-
oxybenzoic acid (55%) (150 g, 0.478 mol) was added in small
portions to a solution of 27 (47 g, 0.192 mol) in dichloromethane
at 0 °C. The reaction mixture was stirred for 4 days at room
temperature and then poured into 1 N NaOH (300 mL). The
aqueous layer was separated and extracted with dichlo-
romethane. The organic phases were combined, washed with
water, dried, and concentrated to give 45 g (90%) of 28 as a
yellow oil: 1H NMR (200 MHz, CDCl3) δ 2.25 (s, 3 H), 5.18 (s, 2
H), 6.82-6.92 (m, 1 H), 6.95-7.15 (m, 2 H), 7.35-7.5 (m, 5 H).
2-(Ben zyloxy)-3-flu or op h en ol (29). A solution of 28 (45 g,
0.173 mol) and p-toluenesulfonic acid monohydrate (2 g) in
methanol (300 mL) was refluxed for 24 h. The solvent was
evaporated and the resulting residue treated with ethyl acetate
(200 mL) and 10% HCl (100 mL). The aqueous layer was
separated and extracted with ethyl acetate. The organic phases
were combined, washed with water, dried, and concentrated. The
crude product was purified by chromatography on silica gel
(eluent: cyclohexane/ethyl acetate, 80/20) yielding 27 g (71.5%)
of 29 as a yellow oil: 1H NMR (200 MHz, CDCl3) δ 5.15 (s, 2 H),
5.80 (br s, 1 H), 6.65-6.80 (m, 2 H), 6.82-6.98 (m, 1 H), 7.35-
7.45 (m, 5 H).
1
-24.14 (c 1, chloroform); H NMR (200 MHz, CDCl3) δ 2.45 (s,
3 H), 4.04-4.13 (m, 1 H), 4.20-4.33 (m, 3 H), 4.39-4.45 (m, 1
H), 6.62-6.76 (m, 3 H), 7.35 (d, 2 H), 7.80 (d, 2 H).
(2R)-2-(Iod om eth yl)-8-flu or o-1,4-ben zod ioxa n e [(R)-24].
A mixture of (R)-23 (2.5 g, 7.39 mmol) and sodium iodide (13 g,
86.7 mmol) in acetone (20 mL) was refluxed for 6 h, cooled to
room temperature, and concentrated to give a residue which was
treated with 10% HCl and ethyl acetate. The aqueous phase was
separated and extracted with ethyl acetate. The organic extracts
were combined, washed with an aqueous solution of sodium
metabisulfite, dried, and concentrated. The resulting residue was
purified by chromatography on silica gel. Elution with cyclo-
hexane/ethyl acetate (70/30) afforded 1.53 g (70%) of (R)-24 as
a yellow oil: [R]D25 ) +7.96 (c 1, chloroform); 1H NMR (200 MHz,
CDCl3) δ 3.29-3.47 (m, 2 H), 4.16-4.45 (m, 3 H), 6.66-6.79 (m,
3 H).
(2S)-2-[((2-(2,6-Dim eth oxyph en oxy)eth yl)am in o)m eth yl]-
8-flu or o-1,4-ben zod ioxa n e Hyd r och lor id e [(S)-3]. A mixture
of (R)-24 (1.53 g, 5.20 mmol) and 2-(2,6-dimethoxyphenoxy)-
ethylamine (2 g, 10.1 mmol) in isobutyl alcohol (7 mL) was
refluxed for 24 h. The solvent was evaporated and the residue
treated with ethyl acetate and 10% NaOH. The aqueous phase
was separated and extracted with ethyl acetate. The combined
extracts were washed with water, dried, and concentrated to give
a residue which was chromatographed on silica gel. Elution with
dichloromethane/methanol (98/2) yielded 860 mg of (2S)-2-[((2-
(2,6-dimethoxyphenoxy)ethyl)amino)methyl]-8-fluoro-1,4-benzo-
25
dioxane: [R]D ) -25.8 (c 1, chloroform); 1H NMR (CDCl3) δ
2.15 (br s, 1 H), 2.89-3.03 (m, 4 H), 3.84 (s, 6 H), 4.05-4.16 (m,
3 H), 4.20-4.39 (m, 2 H), 6.52-6.80 (m, 5 H), 7.00 (t, 1 H). The
secondary amine was treated with 3.8 N HCl/EtOH (4 mL). The
solvent was evaporated, and the semisolid residue was crystal-
lized from ethyl acetate yielding 370 mg (18%) of (S)-3 as a white
25
solid: mp 137 °C; [R]D ) -53.2 (c 1, methanol); 1H NMR (200
MHz, DMSO-d6) δ 3.30-3.55 (m, 4 H), 3.82 (s, 6 H), 4.10-4.30
(m, 3 H), 4.54 (dd, 1 H), 4.89 (m, 1 H), 6.70-7.00 (m, 5 H), 7.05-
7.15 (t, 1 H), 9.64 (br s, 2 H). Anal. Calcd for C19H23ClFNO5
(399.85): C, 57.07; H, 5.80; N, 3.50; F, 4.75; Cl, 8.87. Found: C,
56.99; H, 5.81; N, 3.47; F, 4.83; Cl, 8.84.
(2R)-3-(2-(Ben zyloxy)-3-flu or op h en oxy)-1,2-p r op a n ed i-
ol Aceton id e [(R)-19]. Prepared from (2S)-3-(tosyloxy)-1,2-
25
propanediol acetonide [(S)-4] as described for (S)-19: [R]D
)
1
-13.63 (c 1, ethanol); H NMR identical to that of (S)-19.
(2S)-3-(2-(Ben zyloxy)-3-flu or op h en oxy)-1,2-p r op a n ed i-
25
ol [(S)-20]. Prepared from (R)-19 as described for (R)-20: [R]D
1
) +6.39 (c 0.5, ethanol); H NMR identical to that of (R)-20.
(2R)-3-(2-(Ben zyloxy)-3-flu or oph en oxy)-1,2-bis(tosyloxy)-
p r op a n e [(R)-21]. Prepared from (S)-20 as described for (S)-
21: [R]D ) +5.93 (c 1, ethanol); 1H NMR identical to that of
25
(S)-21.
(2R)-3-(2-H yd r oxy-3-flu or op h en oxy)-1,2-b is(t osyloxy)-
p r op a n e [(R)-22]. Prepared from (R)-21 as described for (S)-
22: [R]D ) +9.26 (c 1, chloroform); H NMR identical to that
of (S)-22.
Ca p illa r y Electr op h or esis An a lyses. All runs were done
with a CE Perkin-Elmer 270A-HT instrument. The electro-
phoretic separations were performed on a fused-silica capillary
of 72 cm (50 cm effective length) × 50 µm i.d. Detection was
25
1

Notes
J . Org. Chem., Vol. 66, No. 3, 2001 1025
done by UV absorbance recording at 200 nm. Sample injection
was performed hydrodynamically at 127 mmHg for 0.2 s. For
CE analysis at the optimum conditions, the applied voltage was
25 kV. The capillary temperature was controlled at 30 °C. The
running electrolyte was 5 mM phosphate buffer (pH 2.5). The
following chiral selectors (Sigma) were used: â-CD (10 mM),
hydroxyethyl â-CD (40 mM) and hydroxypropyl γ-CD (60 mM).
The capillary was conditioned with 1 M NaOH for 20 min
followed by 0.1 M NaOH for 5 min and then by water (18 MΩ)
for 5 min, prior to use. After each run, the capillary was washed
with 0.1 M NaOH and then with water for 1 min, respectively,
and finally with running buffer for 4 min before the next run.
The following samples for injection were prepared: (i) aqueous
solution containing (S)-WB4101, (R)-WB4101, (S)-2-(aminom-
ethyl)-1,4-benzodioxane hydrochloride, (R)-2-(aminomethyl)-1,4-
benzodioxane hydrochloride, (S)-1, (R)-1, (S)-2, (R)-2, (S)-3, and
(R)-3 at respective concentrations of 5 µg mL-1; (ii) 0.02% w/v
solutions of the enantiomeric pairs of WB4101, 2-(aminomethyl)-
1,4-benzodioxane hydrochloride, and 1-3 obtained by prepara-
tion of aqueous solutions (10 mL) containing 10 mg of both the
enantiomers of the above pairs and successive 10-fold dilution
with the same CD-added running buffer as used for the elec-
trophoretic run; (iii) 0.01% w/v solutions of (S)-WB4101, (R)-
WB4101, (S)-2-(aminomethyl)-1,4-benzodioxane hydrochloride,
(R)-2-(aminomethyl)-1,4-benzodioxane hydrochloride, (S)-1, (R)-
1, (S)-2, (R)-2, (S)-3, and (R)-3 obtained by diluting the respective
0.1% w/v aqueous solutions with the same CD-added running
buffer as selected for the electrophoretic run.
) 11.63 and 11.91 min, respectively; running electrolyte, 40 mM
hydroxyethyl â-CD in 5 mM phosphate buffer); (b) (R)-WB4101
and (S)-WB4101 (tr ) 16.10 and 16.84 min, respectively; running
electrolyte, 40 mM hydroxyethyl â-CD in 5 mM phosphate
buffer); (c) (S)-3 and (R)-3 (tr ) 16.08 and 16.70 min, respectively;
running electrolyte, 40 mM hydroxyethyl â-CD in 5 mM phos-
phate buffer); (d) (S)-1 and (R)-1 (tr ) 14.85 and 15.60 min,
respectively; running electrolyte, 40 mM hydroxyethyl â-CD in
5 mM phosphate buffer); (e) (S)-2 and (R)-2 (tr ) 45.80 and 46.67
min, respectively; running electrolyte, 60 mM hydroxypropyl
γ-CD in 5 mM phosphate buffer) (see Figures 2 and 4). Under
the above conditions, which had produced complete enantiosepa-
ration, the analysis of the 10 single enantiomers, namely of the
corresponding solution prepared as described in sample iii,
allowed us to determine the following enantiomeric excesses:
99.99 ((S)-2-(aminomethyl)-1,4-benzodioxane); 96.97 ((R)-2-(ami-
nomethyl)-1,4-benzodioxane); 99.95 ((S)-WB4101); 95.95 ((R)-
WB4101); 99.74 ((S)-1); 99.62 ((R)-1); 99.81 ((S)-2); 99.72 ((R)-
2); 99.83 ((S)-3); 99.66 ((R)-3).
Finally, an aqueous solution, prepared as in sample i but
excluding (S)-2 and (R)-2, was submitted to electrophoretic
analysis using 40 mM hydroxyethyl â-CD in 5 mM phosphate
buffer as a running electrolyte. The corresponding electrophero-
gram, which shows the complete resolution of the four enantio-
meric pairs contained in the sample, is presented in Figure 3.
Ack n ow led gm en t. This work was supported by the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica of Italy. Thanks are due to Perkin-Elmer
Italia SpA, in whose laboratories the authors performed
the electrophoretic separations.
In the absence of chiral selector, i.e., using the mere 5 mM
phosphate as a running electrolyte, injection of sample i gave
four peaks corresponding, in sequence, to (S)- and (R)-2-
(aminomethyl)-1,4-benzodioxane (retention time (tr) ) 6.81 min),
to the coeluted enantiomers of WB4101 and of 3 (tr ) 10.14 min),
to (S)- and (R)-2 (tr ) 10.31 min), and, finally, to (S)- and (R)-1
(tr ) 10.72 min) (see Figure 1).
Injection of the solutions of the single enantiomeric pairs,
prepared as described in sample ii, produced two completely
separated peaks in the following cases: (a) (R)-2-(aminomethyl)-
1,4-benzodioxane and (S)-2-(aminomethyl)-1,4-benzodioxane (tr
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds (S)-1, (R)-1, (S)-2, (R)-2, (S)-3, (R)-3, (S)-19, (R)-
20, (S)-21, (S)-22, (R)-23, (R)-24, and 25-29. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0008340