A simple and efficient synthesis of optically pure 4-alkylisoxazolidin-4-ols

Article abstract of DOI:10.1016/j.tetlet.2006.08.054

The reaction between N-hydroxyphthalimide and optically pure epichlorohydrin followed by addition of methanol represents a straightforward procedure for the synthesis of isoxazolidin-4-ols in high enantiomeric purity. Under the same conditions, the reacti

Full text of DOI:10.1016/j.tetlet.2006.08.054

Tetrahedron Letters 47 (2006) 7635–7639
A simple and efficient synthesis of optically pure
4-alkylisoxazolidin-4-ols
Barrie P. Martin,* Martin E. Cooper,ꢀ David K. Donald and Simon D. Guile
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
Received 30 May 2006; revised 4 August 2006; accepted 17 August 2006
Available online 7 September 2006
Abstract—The reaction between N-hydroxyphthalimide and optically pure epichlorohydrin followed by addition of methanol rep-
resents a straightforward procedure for the synthesis of isoxazolidin-4-ols in high enantiomeric purity. Under the same conditions,
the reaction of glycidyl arenesulfonates can lead to different products depending on the nature of the sulfonate. This property
allowed the synthesis of both enantiomers of 4-methylisoxazolidin-4-ol from the same chiral epoxide starting material.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Small hydrophilic heterocycles are often the key constit-
uents in biologically interesting compounds. Further-
more, the introduction of polar substituents and small
alkyl groups to improve potency and aid metabolic sta-
bility are strategies often employed in the drug discovery
process. Therefore, short asymmetric syntheses of such
compounds, in high enantiomeric purity, are of great
importance to the medicinal chemist. During our
research we became interested in heterocycles such as
isoxazolidine and of particular interest were those
containing sterically hindered hydroxyl groups. Very
few syntheses of these interesting fragments have been
reported. We now report the asymmetric syntheses of
both optically pure enantiomers of 4-methylisoxazoli-
din-4-ol, S-1 and R-1 (Fig. 1).
followed by opening of the oxirane ring with hydrochlo-
ric acid affords chlorohydrin rac-2. Treatment of rac-
2 with t-butylamine in methanol furnishes methyl
2-[(4-hydroxyisoxazolidin-2-yl)carbonyl]benzoate, rac-3
via nucleophilic attack of methoxide on the phthalimide
carbonyl followed by intramolecular N-alkylation. The
desired heterocycle, rac-4, can then be isolated as the
hydrochloride salt by acidic hydrolysis of the amide
(Scheme 1).1,2
Buchalska and Plenkiewicz, as well as reporting the first
chiral resolution of this system via a lipase catalysed
O
O
O
R=Br
It has been demonstrated that alkylation of N-hydrox-
yphthalimide (NHP) with racemic epibromohydrin
O
N
a
R
O
b
HO CH3
HO CH3
R=Cl
e
OH
O N
H
O N
H
OH
S-1
R-1
OH
O
O
N
c
d
Cl
O
O
Figure 1. 4-Methylisoxazolidin-4-ols.
MeO2C
N
O NH.HCl
O
Keywords: Isoxazolidin-4-ol; 4-Methylisoxazolidin-4-ol; Asymmetric
rac-4
synthesis; Epoxide.
rac-3
rac-
2
*
Corresponding author. Tel.: +44 1509 645457; fax: +44 1509
645507; e-mail: Barrie.Martin@AstraZeneca.com
Scheme 1. Reagents and conditions: (a) NHP, DMF, Et3N, 35%; (b)
HCl, CHCl3, 100%; (c) t-BuNH2, MeOH, 100%; (d) HCl, H2O, 100%;
(e) NHP, MeOH, Et3N, 80%.
ꢀ Present address: 7TM Pharma A/S, Fremtidsvej 3, 2970 Horsholm,
Denmark.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.054

7636
B. P. Martin et al. / Tetrahedron Letters 47 (2006) 7635–7639
OH
Cl
OH
O
N
c
HO
N
O
O
OH
O
OH
CO2Me
HN
O
O
S-3
b
c
a
CO2Me
OH
e
d
rac-2
S-7
N OH
Cl
N
Cl
Cl
5
CO2Me
HO
O
Cl
6
OH
O
N
f
O
c
HN
O
g
O
Cl
O
O
CO2Me
CO2Me
Et3N.HCl
R-3
S-2 O
S-8
Scheme 2. Reagents and conditions: (a) Et3NÆHCl; (b) NHP, Et3N; (c) Et3N; (d) MeOH, Et3N; (e) (S)-epichlorohydrin, Et3N; (f) NHP, Et3N, 1,4-
dioxane, 50 ꢁC, 48 h; (g) MeOH, Et3N, 50 ꢁC, 2 h, 44%.
acetylation of both rac-2 and rac-3, were also able signif-
icantly to shorten the synthesis. They demonstrated that
the preparation of rac-3 could be achieved in a one-pot
process by reaction of NHP with racemic epichloro-
hydrin and triethylamine in methanol (Scheme 1).3,4
We believed that this short synthetic route could be
exploited in the asymmetric synthesis of 4-methylisox-
azolidin-4-ol stereoisomers by making use of suitably
substituted optically pure epoxides.
N-alkylation to be the minor reaction pathway, the con-
sequence of ring closure of S-7 would be the formation
of enantiomer S-3. Although no experimental attempt
was made to determine which hypothesis was correct,
we reasoned that only in the presence of methanol could
either side reaction occur leading to an overall reduction
in the enantiomeric excess of R-3. Thus, we elected to
explore an alternative procedure employing an aprotic,
nonnucleophilic solvent.
For our initial investigations we elected to focus on the
synthesis of isoxazolidines containing a secondary
hydroxyl group by employing optically pure epichloro-
hydrin, expecting to produce optically pure 3 in a single
step (cf. Scheme 1). Unfortunately, these experiments
gave disappointing results. For example, reaction of
NHP with (S)-epichlorohydrin and triethylamine in
methanol afforded R-3 in good yield but with an enan-
tiomeric excess of only 74% (as determined by chiral
HPLC).ꢁ This level of enantiomeric purity could not
be significantly improved by recrystallisation and only
moderate improvements were achieved with alternative
bases.
Using 1,4-dioxane as solvent, reaction of NHP with (S)-
epichlorohydrin and triethylamine proceeded smoothly
to furnish S-2. Upon addition of methanol to the reac-
tion mixture, R-3 was formed quickly (Scheme 2). Fol-
lowing the isolation of this product we were gratified
to find that chiral HPLC analysis revealed excellent
optical purity with an ee of >99%. The expected abso-
lute stereochemistry was confirmed by NMR analysis
of the (S)-a-methoxyphenylacetate.7 Acidic hydrolysis
yielded the hydrochloride salt of (4R)-isoxazolidin-4-ol
(R-4) with no loss of enantiomeric purity.8
Encouraged by this success we turned our attention to
the synthesis of 4-methylisoxazolidin-4-ols S-1 and R-
1. We hoped that a similar approach could be employed,
however, the lack of commercial availability or suitable
routes to enantiomerically pure 2-(chloromethyl)-2-
methyloxirane precluded this. We believed that glycidyl
arenesulfonates, readily available via Sharpless asym-
metric epoxidation of allylic alcohols followed by
in situ derivatisation, would provide an alternative strat-
egy.9 Nucleophilic substitution of compounds of this
type can result in displacement of the sulfonate or open-
ing of the oxirane ring with high selectivity. Thus, reac-
tion of glycidyl tosylate with a variety of nucleophiles
leads to selective epoxide opening, while direct displace-
ment of the arenesulfonate moiety can be attained with
glycidyl 3-nitrobenzenesulfonate.10 We recognised that
good C-1 versus C-3 selectivity offered a possible meth-
od for the preparation of S-1 and R-1 from a single
enantiomer of (2-methyloxiran-2-yl)methanol.
We considered a number of possible side reactions to ex-
plain these unsatisfactory results. For example the
known reaction between tertiary or quaternary ammo-
nium salts and epoxides would result in the formation
of a symmetrical alkylating agent 5.5 The consequence
of reaction of 5 with NHP would be the generation of
rac-2 and subsequently rac-3 (Scheme 2). Another possi-
bility is the premature reaction between NHP and meth-
oxide to reveal hydroxamic acid 6. Subsequent
alkylation of this ambident species with (S)-epichlorohy-
drin could then result in a mixture of N- and O-alkyl
hydroxamates S-7 and S-8.6 Although one would expect
ꢁ Although IUPAC nomenclature rules require a change in stereo-
chemical descriptor no inversion of chiral centre had occurred.

B. P. Martin et al. / Tetrahedron Letters 47 (2006) 7635–7639
7637
Reaction between [(2R)-2-methyloxiran-2-yl]methyl 4-
methylbenzenesulfonate (R-9) and NHP formed tosylate
R-10. Subsequent addition of methanol and triethyl-
amine furnished isoxazolidine S-11 in good yield and
high enantiomeric excess (ee >99%). The formation of
R-10 as a single enantiomer must occur as a conse-
quence of selective nucleophilic attack on the oxirane
ring. Therefore the absolute stereochemistry of R-10
can be assigned. Acidic hydrolysis completed the synthe-
sis of target heterocycle S-1 (Scheme 3).
chloric acid. Chlorohydrin S-14 then underwent cycli-
sation with triethylamine in methanol to furnish the
desired 4-methylisoxazolidin-4-ol, R-11, again in excel-
lent enantiomeric excess (ee >99%). Chiral HPLC
confirmed this product, R-11, to be the enantiomer of
that obtained from tosylate R-9 (i.e., S-11) thus
selective displacement of the nosylate rather than an
epoxide opening-Payne rearrangement sequence had
occurred.
In summary, our investigations into the reaction be-
tween NHP and optically pure epichlorohydrin have
led to the development of a short synthetic route to
isoxazolidin-4-ols 3 with excellent enantiomeric excess.
Furthermore, exploitation of the differences in the
mode of reaction of different glycidyl arenesulfonates
led to the synthesis of both stereoisomers of 4-methyl-
isoxazolidin-4-ol (1), again in excellent enantiomeric
excess. Both stereoisomers were derived from a single
enantiomer of (2-methyloxiran-2-yl)methanol. This pro-
cedure has been successfully employed in the synthesis
of other 4-alkylisoxazolidin-4-ols.
Under similar conditions, the reaction between [(2R)-
2-methyloxiran-2-yl]methyl
3-nitrobenzenesulfonate
(R-12) and NHP afforded epoxyphthalimide R-13 in
accordance with direct displacement of the arenesulfo-
nate (Scheme 4). Conversion of R-13 to chlorohydrin
S-14 was achieved by the action of concentrated hydro-
HO CH3
O
a
O
CH3
OTos
O
N
TosO
R-
R-10
9
O
General procedure for the synthesis of {[4-hydroxy-
isoxazolidin-2-yl]carbonyl}benzoates from epichloro-
hydrins or glycidyl tosylates
b
HO CH3
O N
Methyl 2-{[(4R)-4-hydroxyisoxazolidin-2-yl]carbonyl}-
benzoate (R-3)
HO CH3
O NH.HCl
c
O
Triethylamine (0.56 ml, 4.0 mmol) was added to a solu-
tion of N-hydroxyphthalimide (5.0 g, 31 mmol) and
(S)-epichlorohydrin (2.6 ml, 34 mmol) in anhydrous
1,4-dioxane (10 ml) under nitrogen and the mixture
stirred at 50 ꢁC for 48 h. Methanol (10 ml) and triethyl-
amine (4.3 ml, 31 mmol) were then added to the reaction
mixture and stirring at 50 ꢁC was continued for a further
2 h. The mixture was evaporated under reduced pres-
sure, and partitioned between ethyl acetate and satu-
rated sodium bicarbonate solution. The organics were
dried and the residue recrystallised from ethyl acetate
to give R-3 as a white solid (3.4 g, 44%).
CO2Me
S-
1
S-11
Scheme 3. Reagents and conditions: (a) NHP, Et3N, 1,4-dioxane,
50 ꢁC, 48 h; (b) MeOH, Et3N, 50 ꢁC, 2 h, 41%; (c) HCl, H2O, 95 ꢁC,
4 h, 72%.
O
HO CH3
CH3
O
1H (CDCl3) 3.66 (1H, d, J = 6 Hz), 3.79 (1H, d,
a
b
O
d
CH3
Cl
O
O
N
J = 6 Hz), 3.89–3.99 (4H, m), 3.99–4.10 (2H, m), 4.74–
4.81 (1H, m), 7.46 (1H, d, J = 7 Hz), 7.49 (1H, t,
O
N
NosO
R-12
O
J = 7 Hz), 7.62 (1H, t, J = 7 Hz), 7.99 (1H, d,
O
S-14
21
J = 7 Hz). ½aꢀD +28.73 (c 0.1, CH3OH). Chiral HPLC
rt = 12.71 min, ee >99%.11
R-13
c
HO CH3
Methyl 2-{[(4S)-4-hydroxyisoxazolidin-2-yl]carbonyl}-
benzoate (S-3)
N O
O
HO CH3
Prepared using (R)-epichlorohydrin in 44% yield.
d
MeO2C
d
1H (CDCl3) 3.66 (1H, d, J = 6 Hz), 3.79 (1H, d,
HCl.HN O
R-1
J = 6 Hz), 3.89–3.99 (4H, m), 3.99–4.10 (2H, m), 4.74–
4.81 (1H, m), 7.46 (1H, d, J = 7 Hz), 7.49 (1H, t,
R-11
J = 7 Hz), 7.62 (1H, t, J = 7 Hz), 7.99 (1H, d,
Scheme 4. Reagents and conditions: (a) NHP, Et3N, CH2Cl2, 24 h,
62%; (b) concd HCl, 1 h, 95%; (c) MeOH, Et3N, 50 ꢁC, 2 h, 59%; (d)
HCl, H2O, 95 ꢁC, 3 h, 75%.
21
J = 7 Hz). ½aꢀD ꢁ30.24 (c 0.1, CH3OH). Chiral HPLC
rt = 12.89 min, ee >99%.11

7638
B. P. Martin et al. / Tetrahedron Letters 47 (2006) 7635–7639
Methyl 2-{[(4S)-4-hydroxy-4-methylisoxazolidin-2-yl]-
carbonyl}benzoate (S-11)
d 1H (CDCl3) 1.52 (3H, s), 3.59 (1H, d, J = 11 Hz), 3.81
(1H, d, J = 8 Hz), 3.88 (1H, d, J = 8 Hz), 3.92 (3H, s),
4.03 (1H, s), 4.35 (1H, d, J = 11 Hz), 7.45 (1H, d,
Prepared using [(2R)-2-methyloxiran-2-yl]methyl 4-meth-
ylbenzenesulfonate (R-9) in 41% yield.
J = 8 Hz), 7.49 (1H, dt, J = 8, 1 Hz), 7.62 (1H, t,
21
J = 7 Hz), 8.00 (1H, d, J = 8 Hz). ½aꢀD +2.88 (c 0.12,
CHCl3). Chiral HPLC rt = 6.48 min, ee >99%.12
d 1H (CDCl3) 1.52 (3H, s), 3.59 (1H, d, J = 11 Hz), 3.81
(1H, d, J = 8 Hz), 3.88 (1H, d, J = 8 Hz), 3.92 (3H, s),
4.03 (1H, s), 4.35 (1H, d, J = 11 Hz), 7.45 (1H, d,
General procedure for the hydrolysis of {[4-hydroxy-
isoxazolidin-2-yl]carbonyl}benzoates
J = 8 Hz), 7.49 (1H, dt, J = 8, 1 Hz), 7.62 (1H, t,
25
J = 7 Hz), 8.00 (1H, d, J = 8 Hz). ½aꢀD ꢁ7.23 (c 0.1,
CHCl3). Chiral HPLC rt = 4.97 min, ee >99%.12
(4R)-Isoxazolidin-4-ol (R-4)
A solution of R-3 (1.9 g, 7.4 mmol) in 4 M hydrochloric
acid (15 ml) was heated at reflux for 3 h. The mixture
was filtered and the filtrate concentrated to dryness.
The residue was recrystallised from propan-2-ol to give
R-4 as a colourless solid (0.78 g, 84%).
General procedure for the synthesis of {[4-hydroxy-
isoxazolidin-2-yl]carbonyl}benzoates from glycidyl
nosylates
2-{[(2R)-2-Methyloxiran-2-yl]methoxy}-1H-iso-indole-1,
3(2H)-dione (R-13)
1
d H (DMSO-d6) 3.35 (1H, d, J = 11 Hz), 3.47 (1H, dd,
J = 11.5 Hz), 4.03 (1H, dd, J = 9, 4 Hz), 4.07 (1H, d,
21
A solution of R-12 (5.9 g, 22 mmol), N-hydroxyphthal-
imide (5.3 g, 33 mmol) and triethylamine (10.6 ml,
76 mmol) in dichloromethane (15 ml) was stirred at
ambient temperature for 24 h. The mixture was then
concentrated to dryness and the residue purified by
SiO2 chromatography, eluting with dichloromethane to
yield R-13 as a white solid (3.1 g, 62%).
J = 9 Hz), 4.78–4.81 (1H, m). ½aꢀD ꢁ29.29 (c 0.15,
CH3OH).
(4S)-Isoxazolidin-4-ol (S-4)
Prepared using methyl 2-{[(4S)-4-hydroxyisoxazolidin-
2-yl]carbonyl}benzoate (S-3) in 80% yield.
1
1
d H (CDCl3) 1.03 (3H, s), 2.63 (1H, d, J = 5 Hz), 2.77
d H (DMSO-d6) 3.35 (1H, d, J = 11 Hz), 3.47 (1H, dd,
(1H, d, J = 5 Hz), 4.17 (1H, d, J = 11 Hz), 4.21 (1H, d,
J = 11 Hz), 7.73–7.78 (2H, m), 7.82–7.87 (2H, m).
J = 11, 5 Hz), 4.03 (1H, dd, J = 9, 4 Hz), 4.07 (1H, d,
21
J = 9 Hz), 4.78–4.81 (1H, m). ½aꢀD +21.11 (c 0.22,
CH3OH).
2-{[(2S)-3-Chloro-2-hydroxy-2-methylpropyl]oxy}-1H-
isoindole-1,3(2H)-dione (S-14)
(4S)-4-Methylisoxazolidin-4-ol (S-1)
Prepared from methyl 2-{[(4R)-4-hydroxy-4-methylisox-
azolidin-2-yl]carbonyl}benzoate (S-11) in 72% yield.
Compound R-13 (3.1 g, 13 mmol) was treated with
concd hydrochloric acid (12 ml) and the resulting
solution stirred at ambient temperature for 1 h. The
reaction mixture was partitioned between water and
dichloromethane, the organics were washed with satu-
rated sodium bicarbonate solution then dried over mag-
nesium sulfate, filtered and concentrated to dryness.
The residue was purified by SiO2 chromatography, elut-
ing with ethyl acetate to afford S-14 as a white solid
(3.3 g, 95%).
1
d H (DMSO-d6) 1.42 (3H, s), 3.29 (1H, d, J = 11 Hz),
3.41 (1H, dd, J = 11, 0.3 Hz), 3.87 (1H, d, J = 8 Hz),
25
4.05 (1H, dd, J = 8, 0.5 Hz). ½aꢀD +5.20 (c 0.31, H2O).
(4R)-4-Methylisoxazolidin-4-ol (R-1)
Prepared from methyl 2-{[(4R)-4-hydroxy-4-methylisox-
azolidin-2-yl]carbonyl}benzoate (R-11) in 75% yield.
1
d H (CDCl3) 1.39 (3H, s), 3.01 (1H, s), 3.67 (1H, d,
1
d H (DMSO-d6) 1.42 (3H, s), 3.29 (1H, d, J = 11 Hz),
J = 11 Hz), 3.76 (1H, d, J = 11 Hz), 4.09 (1H, d,
J = 11 Hz), 4.47 (1H, d, J = 11 Hz), 7.77–7.80 (2H,
m), 7.84–7.87 (2H, m).
3.41 (1H, dd, J = 11, 0.3 Hz), 3.87 (1H, d, J = 8 Hz),
25
4.05 (1H, dd, J = 8, 0.5 Hz). ½aꢀD ꢁ10.64 (c 0.30, H2O).
Acknowledgement
Methyl 2-{[(4R)-4-hydroxy-4-methylisoxazolidin-2-yl]-
carbonyl}benzoate (R-11)
The authors thank S. Bodill for assistance with chiral
HPLC method development.
A solution of S-14 (3.3 g, 12 mmol) in methanol (25 ml)
was treated with triethylamine (3.4 ml, 24 mmol) and the
mixture heated at reflux for 2 h. The reaction mixture
was then concentrated to dryness and purified by SiO2
chromatography, eluting with 95:5 dichloromethane:
methanol and then recrystallised from acetonitrile to
give R-11 as a white solid (1.92 g, 59%).
References and notes
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B. P. Martin et al. / Tetrahedron Letters 47 (2006) 7635–7639
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