Biocatalytic asymmetric synthesis of (S)- and (R)-Timolol

Article abstract of DOI:10.1055/s-2004-822395

A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro-1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.

Full text of DOI:10.1055/s-2004-822395

PAPER
1625
Biocatalytic Asymmetric Synthesis of (S)- and (R)-Timolol
Biocatalytic
A
sym
i
m
etric
o
Synthesis of
v
(
S
)- and(
R
)-
a
Timolol nni Tosi, Federica Zironi, Emilia Caselli, Arrigo Forni, Fabio Prati*
Dipartimento di Chimica, Università di Modena e Reggio Emilia, Via G. Campi 183, 41100 Modena, Italy
Fax +39(59)373543; E-mail: prati.fabio@unimore.it
Received 13 November 2003; revised 30 March 2004
O
Cl
O
O
Abstract: A new biocatalytic route for the synthesis of both enan-
tiomers of Timolol (1) is described. Starting from 3,4-dichloro-
OH
O
N
Cl
N
Cl
iii
1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained
in 35% and 30% overall yield, respectively. Asymmetric reduction
of the intermediate haloketone 5 with baker’s yeast afforded the
corresponding halohydrin 6 in the optically active form (87% ee),
which gave the R enantiomer (distomer) of Timolol. The S enan-
tiomer (eutomer) was obtained via inversion of configuration of the
halohydrin following the Mitsunobu procedure.
i,ii
N
N
N
N
N
N
S
S
S
4
2
5
iv
O
Key words: asymmetric synthesis, Mitsunobu reaction, enzymes,
reductions, epoxides
O
HO
Cl
O
O
vii
O
Cl
N
O
N
Timolol (1) is a non-selective b-blocking drug used for the
topical treatment of open-angle glaucoma, an eye disease
characterized by increased intraocular pressure, which re-
sults in defects in the field of vision.1 Like that of most of
the family of aryloxypropanolamines, the b-blocker activ-
ity of 1 is almost entirely due to the S enantiomer, eudis-
mic ratio ER = 50 to 90.2 Nevertheless, the weakly active
isomer (R)-1 maintains a beneficial effect on intraocular
pressure without the undesirable side-effect of bronchial
constriction caused by non-selective action of (S)-1 on b1-
b2 receptors, and has therefore been proposed as an alter-
native for the treatment of glaucoma.2 All of the syntheses
described in the literature refer to the C3 synthon approach
via epichlorohydrin, glycidol and related chirons.3 Taking
into account the increasing interest towards the biocataly-
sis applied to the synthesis of chiral intermediates for
pharmaceuticals,4–7 in this paper we describe a new
chemo-enzymatic approach for the asymmetric synthesis
of both enantiomers of 1 (Scheme 1), where the aryloxy-
propanolic framework is obtained by reaction of dichloro-
acetone with 4-morpholin-4-yl-1,2,5-thiadiazol-3-ol (4)
followed by asymmetric baker’s yeast reduction of the ha-
loketone 5.
N
N
N
N
S
S
(R)-(–)-8
(S)-(–)-6
v
v
O
O
O
O
O
N
O
N
N
N
N
N
S
S
(R)-(-)-7
(S)-(+)-7
vi
vi
HN tBu
HO
HN tBu
HO
O
O
O
N
O
N
N
N
N
N
S
S
(R)-1
(S)-1
Scheme 1 Reagents and conditions: i) morpholine, 98%; ii) 2.5 M
NaOH, DMSO, 93%; iii) dichloroacetone, NaHCO3, DMF, 80%; iv)
baker's yeast, H2O, 57–74%; v) t-BuOK, THF, 97%; vi) t-BuNH2,
Following the procedure described in the literature, 4-
morpholin-4-yl-1,2,5-thiadiazol-3-ol (4) was obtained in 66%; vii) PhCOOH, PPh3, DEAD, THF, 90%.
two steps from commercially available 3,4-dichloro-
1,2,5-thiadiazole (2) in 91% overall yield.
cedure reported herein (see experimental part) the
Reaction of 4 with dichloroacetone (DCA) in dry DMF
proceeded in the presence of NaHCO3, affording the
mono-substituted product, haloketone 5 in 80% yield.
Particular care had to be taken in order to avoid the substi-
tution of both chlorine atoms of DCA. Following the pro-
formation of the disubstituted product, i.e. 1,3-bis(4-mor-
pholin-4-yl[1,2,5]thiadiazol-3-yloxy)-propan-2-one, was
observed in only 15% in the crude reaction mixture and
the side-product was easily separated by chromatography.
The asymmetric reduction of the prochiral haloketone 5
could in principle be performed by a variety of both chem-
ical and biochemical routes. Owing to its low cost and
ease of handling, baker’s yeast was selected as biocata-
lyst.8 The reduction was performed exploring different ra-
SYNTHESIS 2004, No. 10, pp 1625–1628
x
x.
x
x
.
2
0
0
4
Advanced online publication: 26.05.2004
DOI: 10.1055/s-2004-822395; Art ID: T12103SS
© Georg Thieme Verlag Stuttgart · New York

1626
G. Tosi et al.
PAPER
tios for yeast/substrate, as well as the use of glucose or
additives such as allyl alcohol and allyl bromide, which
are known to act as selective inhibitors of the different
oxido-reductases of the multi-enzymatic system.9 Reduc-
tions performed in non-fermenting conditions (entries 2–
7) always showed complete conversions in short reaction
times (3 hours); moreover, as already reported in the liter-
ature, these conditions resulted in easier and higher recov-
ery of the reduction product.10–12 The most representative
results are summarized in Table 1. In all cases, the reduc-
tion invariably afforded the levorotatory enantiomer of
(2S)-1-chloro-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-
yl)oxy]propan-2-ol (6), regardless of the additive used.
Conversely, the enantiomeric excess was affected to some
extent (from 59% to 87% ee) by the experimental condi-
tions adopted: the highest ee was obtained in the presence
of allyl alcohol and with a portion-wise addition of the ha-
loketone (Table 1, entry 7; see experimental part).
Table 1 Baker’s Yeast Reduction of Haloketone 5 to (–)-6
Entry
BY/Substratea
(g/mmol)
Additive
Yield
(%)b
ee
(%)
1
2
3
4
5
6
7
15
23
30
30
30
30
30
glucosec
57
74
69
57
69
65
67
62
59
60
78
62
80
87
none
none
noned
allyl bromidee
allyl alcohole
allyl alcohold,e
a 1 mmol dissolved in 100 mL of water.
b All reductions showed complete conversion of the substrate.
c 7 g/mmol of substrate.
d Portion-wise addition of the substrate.
e 3 g/L.
Figure 1 Chiral HPLC of Timolol: a) commercially available; b,c)
(R)- and (S)-Timolol, respectively, from the asymmetric synthesis.
To the best of our knowledge, the literature describes only
racemic 6,13 while the optical activity of this chlorohydrin
has never been reported. Therefore, the absolute configu-
ration of the synthesized (–)-6, 87% ee, could be deter-
mined only after its conversion to the epoxide (R)-(–)-714
(Scheme 1) which was accomplished by reaction with po-
tassium t-butoxide in THF at 0 °C (97% yield). This reac-
tion, not involving the stereocenter, forces (–)-6 and (–)-7
to have the same stereochemistry, and therefore the de-
scriptor S must be assigned to (–)-6. A further configura-
tional correlation was obtained from the subsequent
nucleophilic ring-opening of (R)-(–)-7 with t-butylamine,
which afforded the distomeric form R of Timolol in 66%
yield and 87% ee, as indicated by HPLC analysis,15 when
compared with an authentic sample of (S)-1, isolated from
commercially available Timolol (Timoptol®, Figure 1).
In order to obtain (S)-(–)-1, we applied to the halohydrin
(S)-(–)-6 the Mitsunobu procedure for the inversion of the
stereochemistry.16 The use of diethyl-azodicarboxylate
(DEAD) and triphenylphosphine (PPh3) on (–)-6 promot-
ed the formation of an ester through a known SN2 mecha-
nism at the carbon atom bearing the hydroxy group.
Therefore, following this procedure, (S)-(–)-6, 87% ee,
was converted into the benzoate (R)-(–)-8 (90% yield).
Subsequent reaction with potassium t-butoxide in THF at
0 °C promptly provided the removal of the acyl group and
the intramolecular alkylation of the in situ-formed alkox-
ide, affording (S)-(+)-7 in nearly quantitative yield. Final-
ly, reaction with t-butylamine afforded (S)-Timolol in
66% yield and in 87% ee like in the starting material.
To summarize, herein we have reported a new asymmetric
synthesis of both enantiomers of Timolol in 87% ee,
which were obtained from 3,4-dichloro-1,2,5 thiadiazole
(2) in six steps for the distomer (35% overall yield), and
in seven steps for the eutomer (30% overall yield).
Synthesis 2004, No. 10, 1625–1628 © Thieme Stuttgart · New York

PAPER
Biocatalytic Asymmetric Synthesis of (S)- and (R)-Timolol
1627
1H and 13C NMR spectra were recorded in CDCl3 solution on a
Bruker DPX-200 MHz spectrometer; chemical shifts are reported in
d values from TMS as internal standard; coupling constants (J) are
given in Hz. For mass spectral determinations a Finnigan MAT SSQ
A mass spectrometer was used (EI, 70 eV). Elemental analyses
were performed with a Carlo Erba Elemental Analyzer 1110. Chro-
matographic purification of compounds was performed on silica gel
(particle size 0.05–0.20 mm). Optical rotations were measured on a
Perkin-Elmer 241 polarimeter at 20 °C. GLC analyses were per-
formed with a Hewlett-Packard 5890A gas chromatograph on a
DB1 column (30 m × 0.53 mm i.d. and 5 m film phase) from J&W
Scientific. The ee of 6 and 1 were determined by HPLC (Jasco PU-
980, UV-1575) on a chiral column Chiralcel OD (0.46 cm × 25 cm,
particle size 10 mm), from Daicel Chemical Industries LTD, eluent:
n-hexane–i-propanol (95:5), UV 295 nm. Fresh baker’s yeast (Fala,
Strasbourg) was purchased in a local shop.
1H NMR (200 MHz, CDCl3): d = 3.49–3.58 (m, 4 H, CH2-N-CH2),
3.78–3.85 (m, 4 H, CH2-O-CH2), 4.2 (s, 2 H, Cl-CH2), 5.3 (s, 2 H,
O-CH2-CO).
13C NMR (50 MHz, CDCl3): d = 46.9, 49.3, 67.8, 73.3, 150.9, 153.8,
197.8 (C=O).
MS (EI): m/z (%) = 277–279 (M+, 100), 184–186 (25), 170 (32), 142
(56), 86 (24).
Anal. Calcd for C9H12ClN3O3S: C, 38.92; H, 4.36; N, 15.13; S,
11.55. Found: C, 38.67; H, 4.54; N, 14.92; S, 11.29.
(2S)-1-Chloro-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]-
propan-2-ol (6)
A suspension of baker’s yeast (110 g) in H2O (380 mL) was pre-in-
cubated at 30 °C for 30 min in the presence of allyl alcohol (3 g/L).
Thereafter, a solution of chloroketone 5 (1 g, 3.6 mmol) in DMSO
(3 mL) was added over a period of 1 h, and the resulting mixture
was magnetically stirred at 30 °C for 3 h, until a GLC analysis
showed >95% conversion. The mixture was centrifuged, the yeast
re-suspended in H2O (100 mL) and re-centrifuged. All the collected
aqueous phases were saturated with NaCl and extracted with EtOAc
(3 × 150 mL). The organic phases were washed with H2O (100 mL),
brine (50 mL), and finally dried (MgSO4). The solvent was removed
under reduced pressure and the residue purified by column chroma-
tography (CH2Cl2–Et2O, 8:2) to afford chlorohydrin 6 as a pale yel-
low solid (675 mg, 67%).
Mp 58–61 °C; [a]D –6.1 (c 1, CHCl3);13 87% ee (HPLC, flow rate
0.3 mL/min, r.t. for the R enantiomer 58.8 min, S enantiomer 61.3).
The ee was confirmed via 1H NMR after esterification of (–)-6 with
(R)-(–)-2-phenyl-propionic acid, following the Mosher procedure;18
the observed different resonances of the diastereotopic methyl
groups of phenylpropionic moiety were observed at d = 1.45 ppm
and d = 1.53 ppm. Several attempts to enhance the enantiomeric
composition of (–)-6 by crystallization failed.
3-Chloro-4-morpholino-1,2,5-thiadiazole (3)
Following the procedure described in the literature,17 starting from
commercially available 3,4-dichloro-1,2,5-thiadiazole (2.4 mL, 26
mmol), compound 3 was obtained as a light yellowish powder (5.67
g, 98% yield).
Mp 43–45 °C.
IR (KBr): 861, 1120, 1276, 2862, 2966 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.44–3.50 (m, 4 H, CH2-N-CH2),
3.80–3.86 (m, 4 H, CH2-O-CH2).
13C NMR (50 MHz, CDCl3): d = 50.4, 67.7, 136.5, 160.3.
MS (EI): m/z (%) = 205–207 (3:1, M+, 100), 190–192 (3:1, 18), 170
(12), 120–122 (3:1, 8), 86 (30).
Anal. Calcd for C6H8ClN3OS: C, 35.04; H, 3.92; N, 20.43; S, 15.59.
Found: C, 35.33; H, 3.87; N, 20.49; S, 15.32.
4-Morpholin-4-yl-1,2,5-thiadiazol-3-ol (4)
Following the procedure described in the literature,17 starting from
3 (3.07 g, 15 mmol) compound 4 was obtained as a white solid (2.63
g, 93% yield).
IR (KBr): 953, 1113, 1298, 1493, 2854, 2923, 2964, 3563 (br) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.30 (br s, 1 H, OH), 3.47–3.53
(m, 4 H, CH2-N-CH2), 3.65 (dd, 1 H, J = 5.7, 11.3 Hz, Cl-CH2), 3.70
(dd, 1 H, J = 4.9, 11.3 Hz, Cl-CH2), 3.77–3.83 (m, 4 H, CH2-O-
CH2), 4.20–4.34 (m, 1 H, CH-OH), 4.51 (dd, 1 H, J = 5.2, 11.4 Hz,
O-CH2 -CH), 4.59 (dd, 1 H, J = 5.0, 11.4 Hz, O-CH2-CH).
13C NMR (50 MHz, CDCl3): d = 47.4, 49.3, 67.8, 71.1, 72.9, 151.2,
154.8.
Mp 200–204 °C.
IR (KBr): 1117, 1262, 1506, 2702, 2861, 2965, 3225 (br) cm–1.
1H NMR (200 MHz, DMSO-d6): d = 3.38–3.46 (m, 4 H, CH2-N-
CH2), 3.64–3.71 (m, 4 H, CH2-O-CH2), 3.35 (br s, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 49.2, 67.5, 152.0, 159.5.
MS (EI): m/z (%) = 187 (M+, 96), 172 (18), 154 (12), 143 (20), 129
MS (EI): m/z (%) = 279–281 (M+, 84), 230 (24), 187 (76), 154
(100), 129 (66).
(100), 115 (12), 86 (20), 55 (58).
Anal. Calcd for C9H14ClN3O3S: C, 38.64; H, 5.04; N, 15.02; S,
11.46. Found: C, 38.73; H, 5.20; N, 14.80; S, 11.04.
Anal. Calcd for C6H9N3O2S: C, 38.49; H, 4.85; N, 22.44; S, 17.13.
Found: C, 38.46; H, 5.06; N, 22.35; S, 16.91.
4-{4-[(2R)-Oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpho-
line (7)
1-Chloro-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]pro-
pan-2-one (5)
Potassium t-butoxide (184 mg, 1.64 mmol was added at 0 °C to a
stirred solution of (S)-(–)-6 (230 mg, 0.82 mmol, 87% ee), in anhyd
THF (5 mL) and allowed to react at the same temperature for 1 h.
The reaction mixture was diluted with H2O (10 mL) and extracted
with Et2O (3 × 10 mL). The collected organic phases were washed
with brine (10 mL) and dried (Na2SO4). The solvent was removed
under reduced pressure to afford epoxyde (–)-7 as a crystalline
white solid (194 mg, 97%), which was used without further purifi-
cation.
Mp 111–114 °C; [a]D –22.0 (c 0.9, CHCl3) [Lit.14 S enantiomer: mp
113–114 °C; [a]D +24.8 (CHCl3)].
IR (KBr): 537, 643, 855, 906, 1117, 1497, 2865, 2925, 2980 cm–1.
Dichloroacetone (1.35 g, 10.6 mmol) was added portion-wise with-
in 1 h to a solution of NaHCO3 (0.52 g, 6.2 mmol) and hydroxythia-
diazole (4, 1.0 g, 5.2 mmol) in anhyd DMF (40 mL) at 0 °C. The
reaction mixture was stirred at this temperature for 1 h, and then at
r.t. for further 22 h. The reaction mixture was diluted with H2O (400
mL) and extracted with EtOAc (3 × 100 mL). The collected organic
phases were washed with H2O (100 mL), brine (30 mL) and dried
(MgSO4). The solvent was removed under reduced pressure and the
residue was purified by column chromatography (CH2Cl2–Et2O,
8:2) affording 5 as a white solid (1.19 g, 80%).
Mp 131–133 °C.13
IR (KBr): 944, 1116, 1262, 1500, 1745, 2859, 2969, 3443 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.71 (dd, 1 H, J = 2.6, 4.7 Hz, CH2-
ring), 2.91 (dd, 1 H, J = 4.2, 4.7 Hz, CH2-ring), 3.34–3.43 (m, 1 H,
CH-O), 3.49–3.56 (m, 4 H, CH2-N-CH2), 3.77–3.84 (m, 4 H, CH2-
Synthesis 2004, No. 10, 1625–1628 © Thieme Stuttgart · New York

1628
G. Tosi et al.
PAPER
O-CH2), 4.26 (dd, 1 H, J = 6.4, 11.7 Hz, O-CH2-CH), 4.75 (dd, 1 H,
J = 4.2, 11.7 Hz, O-CH2-CH).
Anal. Calcd for C16H18ClN3O4S: C, 50.06; H, 4.74; N, 10.94; S,
8.35. Found: C, 49.84; H, 4.62; N, 10.82; S, 8.27.
13C NMR (50 MHz, CDCl3): d = 44.6, 47.9, 49.3, 66.4, 71.2, 149.8,
4-{4-[(2S)-Oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpho-
line (7)
Following the procedure described for the synthesis of (R)-(–)-7
from (S)-(–)-6, starting from (R)-(–)-8 (200 mg, 0.523 mmol),
(S)-(+)-7 was obtained (120 mg, 95%).
152.3.
MS (EI): m/z (%) = 243 (M+, 100), 210 (55), 187 (18), 154 (22), 129
(30), 57 (43).
Anal. Calcd for C9H13N3O3S: C, 44.43; H, 5.39; N, 17.27; S, 13.18.
Found: C, 44.59; H, 5.60; N, 17.08; S, 12.97.
[a]D +22.3 (c 0.7, CHCl3).
(2R)-1-(tert-Butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-
3-yl)oxy]propan-2-ol [1, (R)-Timolol]
(2S)-1-(tert-Butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-
3-yl)oxy]propan-2-ol [1, (S)-Timolol]
Few crystals of KI were added to a solution of (R)-(–)-7 (0.23 g,
0.95 mmol, 87% ee), in t-butylamine (5 mL, 47.6 mmol), and the
mixture was refluxed for 72 h. Thereafter, the solution was cooled,
the solvent removed under reduced pressure and the residue purified
by column chromatography (Et2O–MeOH, 8:2) to afford (R)-1 as a
low-melting, hygroscopic solid (66%).
According to the procedure described for the synthesis of (R)-1
from (R)-(–)-7, starting from (S)-(+)-7 (100 mg, 0.412 mmol),
(S)-1 was obtained (66%).
[a]D 0.0 (c 1.0, CHCl3); 87% ee (HPLC).
[a]D 0.0 (c 1, CHCl3); 87% ee (HPLC, flow rate 0.7 mL/min, r.t. for
the R enantiomer 18.9 min, S enantiomer 24.2 min).15
Acknowledgment
The authors thank Ministero della Università e della Ricerca Scien-
tifica e Tecnologica (Rome) for financial support, Dr Giuseppe
Cannazza for precious help in HPLC analyses, Dr Giuseppe Tosi for
Timoptol sample and Centro Interdipartimentale Grandi Strumenti
(University of Modena and Reggio Emilia) for instrumental mea-
surements.
IR (neat): 768, 957, 1122, 1228, 1311, 1497, 2855, 2964, 3295 (br),
3412 (br) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.10 [s, 9 H, C-(CH3)3], 2.40 (br
s, 1 H, -NH), 2.61 (dd, 1 H, J = 7.9, 12.0 Hz, CH2-NH), 2.80 (dd, 1
H, J = 4.1, 12.0 Hz, CH2-NH), 3.50–3.57 (m, 4 H, CH2-O-CH2),
3.76–3.84 (m, 4 H, CH2-N-CH2), 3.94 (ddt, 1 H, J = 7.9, 5.7, 4.2 Hz,
CH-OH), 4.38 (dd, 1 H, J = 5.7, 11.1 Hz, -O-CH2-CH), 4.49 (dd, 1
H, J = 4.2, 11.1 Hz, -O-CH2-CH).
References
13C NMR (50 MHz, CDCl3): d = 29.0, 44.3, 47.9, 50.5, 66.5, 68.1,
72.9, 151.0, 153,8.
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Drugs 1979, 38.
(2) Crossley, R. Chirality and the Biological Activity of Drugs;
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(3) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D.
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MS (EI): m/z (%) = 316 (1), 301 (9), 130 (20), 86 (100), 74 (16), 57
(20).
(1R)-2-Chloro-1-{[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]-
methyl}ethyl Benzoate (8)
Diethyldiazodicarboxylate (0.297 mL, 1.89 mmol) in anhyd THF
(0.5 mL) was slowly added to a cooled solution (0 °C) of (S)-(–)-6
(192 mg, 0.69 mmol, 87% ee), benzoic acid (253 mg, 2.07 mmol)
and PPh3 (495 mg, 1.89 mmol) in anhyd THF (1.5 mL), and the re-
sulting solution magnetically stirred at the same temperature for 30
min. Thereafter, the cooling bath was removed, and the mixture al-
lowed to react at r.t. for further 2 h, when a TLC analysis showed
complete conversion. The solvent was removed in vacuo and the
residue purified by column chromatography (light petroleum–Et2O,
7:3) to afford (R)-(–)-8 as a white solid (237 mg, 90%).
Mp 59–61 °C; [a]D +2.5 (c 5, CHCl3).
(10) Bucciarelli, M.; Forni, A.; Moretti, I.; Torre, G. Synthesis
1983, 897.
IR (KBr): 708, 956, 1114, 1266, 1513, 1725, 2831, 2872, 2924,
2971, 3063 cm–1.
(11) Seebach, D.; Roggo, S.; Maetzke, T.; Braunschweiger, H.;
Cercus, J.; Krieger, M. Helv. Chim. Acta 1987, 71, 1605.
(12) Zhang, B. L.; Pionnier, S. Chem.–Eur. J. 2003, 9, 3604.
(13) Bodor, N.; ElKoussi, A.; Kano, M.; Nakamura, T. J. Med.
Chem. 1988, 31, 100.
(14) McClure, D. E.; Engelhardt, E. L.; Mensler, K.; King, S.;
Saari, W. S.; Huff, J. R.; Baldwin, J. J. J. Org. Chem. 1979,
44, 1826.
1H NMR (200 MHz, CDCl3): d = 3.40–3.47 (m, 4 H, CH2-N-CH2),
3.65–3.72 (m, 4 H, CH2-O-CH2), 3.84 (dd, 1 H, J = 5.2, 12.0 Hz,
CH2Cl), 3.87 (dd, 1 H, J = 5.4, 12.0 Hz, CH2Cl), 4.75 (dd, 1 H, J =
6.4, 11.4 Hz, -O-CH2-CH-O), 4.81 (dd, 1 H, J = 4.0, 11.4 Hz, -O-
CH2-CH-O), 5.72 (ddt, 1 H, J = 4.0, 6.4, 5.3 Hz, CH-O), 7.38–7.52
(m, 2 H, arom. meta), 7.56–7.65 (m, 1 H, arom. para), 8.01–8.06
(m, 2 H, arom. ortho).
(15) Aboul-Enein, H. Y.; Islam, M. R. J. Chromatogr., A 1990,
511, 109.
(16) Mitsunobu, O. Synthesis 1981, 1.
13C NMR (50 MHz, CDCl3): d = 42.3, 47.8, 66.4, 68.9, 70.7, 128.5,
129.2, 129.7, 133.6, 149.7, 152.9, 165.4 (C=O).
(17) Weinstock, L. M.; Mulvey, D. M.; Tull, R. J. Org. Chem.
1976, 41, 3121.
(18) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
MS (EI): m/z (%) = 383–385 (M+, 8), 197–199 (100), 186 (2), 144
(4), 105 (92), 77 (36).
Synthesis 2004, No. 10, 1625–1628 © Thieme Stuttgart · New York