Univocal syntheses of 2- and 3-hydroxymethyl-2,3-dihydro[1,4]dioxino[2,3-b] pyridine enantiomers

Article abstract of DOI:10.1016/j.tetasy.2005.09.003

The enantiomers of 2- and 3-hydroxymethyl substituted 2,3-dihydro[1,4] dioxino[2,3-b]pyridine 1 and 2, important chiral building blocks for the preparation of several biologically active compounds, were synthesized. (S)- and (R)-1 were obtained from eithe

Full text of DOI:10.1016/j.tetasy.2005.09.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3380–3384
Univocal syntheses of 2- and 3-hydroxymethyl-
2,3-dihydro[1,4]dioxino[2,3-b]pyridine enantiomers
Cristiano Bolchi, Marco Pallavicini, Laura Fumagalli, Barbara Moroni,
Chiara Rusconi and Ermanno Valoti*
`
Istituto di Chimica Farmaceutica e Tossicologica, Universita di Milano, viale Abruzzi 42, I-20131 Milano, Italy
Received 28 July2005; revised 31 August 2005; accepted 21 September 2005
Available online 18 October 2005
Abstract—The enantiomers of 2- and 3-hydroxymethyl substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine 1 and 2, important chiral
building blocks for the preparation of several biologicallyactive compounds, were synthesized. ( S)- and (R)-1 were obtained from
either one or both the enantiomers of benzylglycerol, while (S)- and (R)-2 were obtained from (R)- and (S)-isopropylideneglycerol,
respectively. The novel efficient synthetic strategies, which do not follow routes already reported for the corresponding racemates,
ensure veryhigh regioselectivityand maintenance of the enantiomeric purityof the starting materials. The enantiomeric composition
of the title compounds was determined bychiral HPLC or NMR. The keyintermediate in the synthesis of non-racemic 1, namely
1-benzyl-2-mesyl-3-tritylglycerol, is a new high melting chiral C3 synthon, worth considering for its stability, versatility, easy isola-
tion bysimple crystallization and, potential of configuration inversion through a simple one-pot reaction sequence.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
chloro-3-pyridinol and 1-acetoxy-3-benzyloxy-2-propa-
nol as the starting material, is relativelylong. The latter,
where 2-chloro- or 2-nitro-3-pyridinol is condensed with
epichlorohydrin to give the respective 3-oxiranylmeth-
oxypyridine and oxirane is successively opened by benz-
yl alcohol, is not recommended for the synthesis of
enantiopure derivatives, due to the risk of racemization
deriving from the duplex mechanism of the nucleo-
phile attack on epichlorohydrin. Furthermore, the final
cyclization of the resultant 1-benzyloxy-3-(pyridin-3-
yloxy)propan-2-ols, 2-nitro or 2-chloro substituted at
the pyridine ring, yields the benzyl ether of 1, via a
Smiles rearrangement, always together with the benzyl
ether of 2.4 Otherwise, this positional isomer can only
be the product of the above synthetic route if the ulti-
mate intramolecular cyclization is accomplished under
suitable experimental conditions.4 Syntheses of 2 in opti-
callyactive form have never been reported, but the two
enantiomers have been isolated bypreparative HPLC
The 2,3-dihydro[1,4]dioxino[2,3-b]pyridine system, often
conceived as a 1,4-benzodioxane bioisoster, constitutes
the scaffold or pharmacophoric element of manystruc-
tures of therapeutic agents. Over the course of our
research on peptidomimetic farnesyltransferase inhibi-
tors1 and on a-adrenoceptor ligands2 bearing such a
system in place of a cysteine residue and of a 1,4-
benzodioxane nucleus, respectively, we needed to obtain
both the enantiomers of 2-hydroxymethyl-2,3-dihydro-
[1,4]dioxino[2,3-b]pyridine 1 and of its regioisomer with
the same substituent at the 3-position 2.
O
O
O
O
*
OH
*
OH
N
N
1
2
5
resolution of the racemate on a chiral stationaryphase
To the best of our knowledge, 1 has never been prepared
in opticallyactive form and onlytwo syntheses have
been reported for the corresponding racemate.3,4
According to the literature, the former, which uses 2-
and their absolute configurations established by
vibrational circular dichroism.6 On the contrary, the
syntheses of the (S)- and (R)-forms of the azido-
methyl analogue of 2 are known. Theywere obtained
from (S)- and (R)-2-chloro-3-oxiranylmethoxypyridine,
in turn prepared bycondensation, under Mitsunobu
conditions, of 2-chloro-3-pyridinol with optically active
*
Corresponding author. Tel.: +39 2 50317553; fax: +39 2 50317565;
e-mail: ermanno.valoti@unimi.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.003

C. Bolchi et al. / Tetrahedron: Asymmetry 16 (2005) 3380–3384
3381
glycidol in place of epichlorohydrin.7 Though applicable
to the preparation of the enantiomers of 1 and 2, we
decided not to exploit either this synthetic route or that
from 1-acetoxy-3-benzyloxy-2-propanol3 and to base
our approach on the alternative use of the enantiomeric
acetonides, 1-ethers and 1,3-diethers of glycerol thus
avoiding both the epoxidic and acetyl intermediates. In
particular, the enantiomers of a new chiral C3 synthon,
that is 1-benzyl-2-mesyl-3-tritylglycerol, were advanta-
geouslyemployed as keyintermediates in the syntheses
of (S)- and (R)-1, herein described together with those
of (S)- and (R)-2.
The 85% mean yield of the six synthetic steps resulted in
an overall 35% yield of the whole synthesis. Only three
of the six steps required chromatographic isolation of
the reaction product, namely the tritylation, detrityl-
ation and intramolecular cyclization. A 99.3% enantio-
meric excess could be attributed to (R)-1 on the basis
of the chiral HPLC analysis of the corresponding mesyl
ester, quantitativelyobtained bytreatment of ( R)-1 with
excess methanesulfonyl chloride and triethylamine in
dichloromethane. These data were consistent with
99.7% enantiomeric excess determined for (S)-3 bychi-
ral HPLC analysis according to a previously reported
method.8
2. Results and discussion
The (S)-enantiomer of 1 was synthesized by the same
strategyas illustrated in Scheme 1 but starting from
(S)-1-benzylglycerol. Alternatively, the configuration of
(S)-4 was inverted displacing the mesylate by the ace-
tate, hydrolyzing the resultant acetate and finally con-
verting the liberated secondaryalcohol into meslyate
(R)-4. Such a three-step conversion was accomplished
without purifying the two crude intermediate products;
the overall yield was 75%.
As outlined in Scheme 1, the synthesis of (R)-1 starts
from (R)-1-benzylglycerol, readily and quantitatively
accessible from (S)-isopropylideneglycerol by standard
methods. The primary hydroxyl group of the diol was
tritylated and the resultant diether (S)-3 mesylated to
give, in near quantitative yield, (S)-1-benzyl-2-mesyl-3-
tritylglycerol (S)-4, a solid intermediate easilyisolated
by extraction and crystallization from diisopropyl ether.
Nucleophilic displacement of mesylate by the sodium
salt of 2-chloro-3-pyridinol afforded, with inversion of
configuration, (R)-1-benzyl-2-(2-chloro-3-pyridinyl)-3-
tritylglycerol (R)-5, which was isolated bysimple
extraction and directlydetritylated bytreatment with
hydrochloric acid. The successive intramolecular cycli-
zation of the primaryalcohol ( S)-6 was carried out
in dimethoxyethane and in the presence of sodium
hydride yielding the (R)-isomer of the 2-benzyloxym-
ethyl substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine
(R)-7. Finally, the benzyl group was quantitatively re-
moved by catalytic transfer hydrogenation under micro-
wave irradiation with cyclohexene as the hydrogen
donor obtaining (R)-1 as a viscous oil, which solidified
upon standing.
As shown in Scheme 2, the reaction sequence for prepar-
ing (R)-2 started from the tosyl ester of (S)-isopropylid-
eneglycerol and consisted of the following steps: (a)
displacement of tosylate by the sodium salt of 2-
chloro-3-pyridinol to give (S)-8; (b) hydrolysis of the
cyclic ketal; (c) tritylation of the primary hydroxyl
group of the resultant diol (R)-9; (d) intramolecular
cyclization of the secondary alcohol (R)-10 immediately
followed bydetritylation.
N
OTs
a
b
Cl
O
O
O
O
(S)-8
O
OBn
OH
OBn
OH
OBn
OMs
N
N
a
b
c
d
c
(R)-2
Cl
O
Cl
O
OH
OTr
OTr
OH
OTr
OH
(S)-3
(S)-4
(R)-9
(R)-10
OH
O
O
Scheme 2. Reagents and conditions: (a) 2-chloro-3-pyridinol, NaH,
DMF, reflux, 90%; (b) 10% aq HCl, 80 ꢁC, 74%; (c) Trityl chloride,
Et3N, t-BuOH, reflux, 75%; (d) NaH, DME, reflux and then 10% aq
HCl, EtOH, room temperature, 63%.
d
OBn
OBn
N
Cl
OTr
N
Cl
OH
(S)-6
(R)-5
The 75% mean yield of the four synthetic steps resulted
in 32% overall yield of the whole synthesis. One of the
four steps, namely the acetonide hydrolysis, did not
require chromatographic isolation of the reaction
product.
O
e
f
OBn
(R)-1
N
O
(R)-7
Scheme 1. Reagents and conditions: (a) trityl chloride, Et3N, t-BuOH,
60 ꢁC, 85%; (b) Mesyl chloride, Et3N, DCM, ꢀ10 ꢁC and then room
temperature, 91%; (c) 2-Chloro-3-pyridinol, NaH, DMF, reflux, 100%;
(d) 10% aq HCl, THF, reflux, 61%; (e) NaH, DME, reflux, 78%;
(f) Cyclohexene, Pd/C, MeOH, MW (200 W), 120 ꢁC, 240 s, 94%.
The (S)-enantiomer of 2 was prepared bythe same
synthetic route as illustrated in Scheme 2 but using
the tosyl ester of (R)-isopropylideneglycerol as a starting
material.

3382
C. Bolchi et al. / Tetrahedron: Asymmetry 16 (2005) 3380–3384
In contrast with the previous case of the mesyl esters of
(R)-1 and (S)-1, attempts at determining the enantio-
meric excess of (R)-2 and (S)-2 bychiral HPLC analysis
of the respective mesylates were not successful. An
almost complete, but not baseline resolution of the
two enantiomers was achieved onlyunder extreme direct
phase HPLC conditions on silica gel coated with cellu-
lose derivatives, such as verypolar mobile phases (water
saturated near 1:1 ethanol/hexane mixtures) at verylow
flow rates.9 Conversely, 1H NMR analysis (300 MHz) in
the presence of chiral shift reagents or chiral solvating
agents proved to be effective. Addition of Eu(hfc)3 or,
better still, of opticallyactive trifluoroanthrlyethanol
split the CH3 singlet into two peaks with a chemical shift
difference of 4 and 18 Hz, respectively. On this basis, the
absence of the methyl signal of the mesyl ester of (R)-1
in the spectrum of the mesyl ester of (S)-1 and vice versa
led us to estimate the enantiomeric excess of the two
mesylates higher than 98%.
4.1. (S)-1-Benzyl-3-tritylglycerol (S)-3
(R)-1-Benzylglycerol was added to a stirred mixture of
trityl chloride (59.6 g, 214 mmol), triethylamine
(32 mL, 230 mmol) and tert-butanol (80 mL) at 60 ꢁC
under an N2 atmosphere. After refluxing for 24 h, the
mixture was concentrated and the resultant residue
chromatographed on silica gel. Elution with cyclohex-
ane/ethyl acetate (80:20) afforded 65.2 g (85%) of (S)-3
25
as a white solid: mp 72 ꢁC; ½aŠ ¼ ꢀ6:45 (c 5, benzene);
D
ee 99.7% (byHPLC on a Chiralcel OD column; hexane/
ethanol/water 90.63:9.06:0.3, v/v/v; 0.2 mL/min; (S)-3:
1
k0 = 1.05; (R)-3: k0 = 0.92); H NMR (CDCl3) d 2.40
(br s, 1H), 3.20 (m, 2H), 3.58 (m, 2H), 3.98 (m, 1H),
4.55 (s, 2H), 7.20–7.45 (m, 20H).
4.2. (S)-1-Benzyl-2-mesyl-3-tritylglycerol (S)-4
Mesyl chloride (17.9 mL, 231 mmol) was added drop-
wise to a solution of (S)-3 (75.6 g, 178 mmol) and trieth-
ylamine (34.5 mL, 248 mmol) at ꢀ10 ꢁC. After stirring
at rt for 3 h, the mixture was added with dichlorometh-
ane (100 mL), washed with 1 M HCl, dried and concen-
trated. The resultant oilyresidue (109 g) was crystallized
3. Conclusion
In summary, we have reported the synthesis and enan-
tiomeric excess assessment of the (S)- and (R)-forms
of 2- and 3-hydroxymethyl substituted 2,3-dihydro-
[1,4]dioxino[2,3-b]pyridine 1 and 2, important chiral
building blocks for the preparation of several biologi-
callyactive compounds. The new syntheses ensure the
maintenance of the enantiomeric purityof the starting
materials and, compared to the synthetic strategies
alreadyreported for the corresponding racemates, a
veryhigh regioselectivitythanks to the unequivocal
course of the reactions of the intermediate glycerol
mono-, di- and triethers. Further advantages are the effi-
ciency(>30% overall iyeld), readyavailabilityof the
starting materials (1-benzylglycerol and isopropylidene-
glycerol tosylate) and reasonable number of synthetic
steps. Finally, a new high melting chiral C3 synthon,
1-benzyl-2-mesyl-3-tritylglycerol, distinguishes itself
from the other intermediates of these syntheses by its
potential due to stability, versatility, easy isolation by
simple crystallization and possibility of inverting its con-
figuration through a Walden inversion.
from diisopropyl ether (500 mL) yielding 81.4 g (91%) of
25
(S)-4 as a white solid: mp 103 ꢁC; ½aŠ ¼ ꢀ8:8 (c 1,
D
CHCl3); 1H NMR (CDCl3) d 3.02 (s, 3H), 3.39 (m,
2H), 3.70 (m, 2H), 4.52 (s, 2H), 4.85 (m, 1H), 7.25–
7.43 (m, 20H).
4.3. (R)-1-benzyl-2-(2-chloro-3-pyridinyl)-3-tritylglycerol
(R)-5
A solution of 2-chloro-3-pyridinol (1.81 g, 14.0 mmol) in
DMF (10 mL) was added to a suspension of 98% NaH
(353 mg, 14.7 mmol) in DMF (20 mL) under an N2
atmosphere. The mixture was heated at 60 ꢁC, added
with a solution of (S)-4 (4.39 g, 8.7 mmol) in DMF
(20 mL), refluxed for 24 h and concentrated. The residue
was treated with water (15 mL) and extracted with
cyclohexane (5 · 20 mL). The organic extracts were
combined, washed with a saturated aqueous solution
of sodium bicarbonate (10 mL) and then with brine
(2 · 10 mL), dried and concentrated to give 5.85 g of
1
crude (R)-5: H NMR (CDCl3) d 3.42 (m, 2H), 3.79
(d, 2H), 4.55 (s, 2H), 4.45–4.62 (m, 1H), 7.10 (dd, 1H),
4. Experimental
7.20–7.50 (m, 21H), 8.00 (dd, 1H).
Melting points were recorded on a Buchi Melting Point
¨
B-450 apparatus and are uncorrected. H NMR spectra
4.4. (S)-1-Benzyl-2-(2-chloro-3-pyridinyl)glycerol (S)-6
1
were recorded on either a Bruker 200 (200 MHz) instru-
ment or on a Varian Gemini 300 (300 MHz) instrument.
Optical rotations were measured in a 1 dm cell of 1 mL
capacityusing a Perkin–Elmer 241 polarimeter. HPLC
analyses were performed on a Chiralcel OD column
(250 · 4.6 mm i.d.) from Daicel using a Hitachi 7100
pump, a Hitachi L-7400 UV detector and a Hitachi
D-7000 HPLC System Manager software. (S)- and
(R)-glycerol acetonide were prepared by chemical reso-
lution of the racemate as described in the literature10
and successivelytransformed into the corresponding
tosyl esters or 1-benzylglycerols according to standard
procedures.
A mixture of (R)-5 (3.1 g, 5.8 mmol) and 10% HCl
(20 mL) in THF (30 mL) was refluxed for 12 h. After
cooling to room temperature, the precipitate was filtered
off and THF evaporated. The acidic aqueous residue
was washed with cyclohexane and this latter with 10%
HCl. The aqueous phases were combined, made alkaline
(pH 9) bythe addition of sodium carbonate and
extracted with ethyl acetate (2 · 50 mL). The organic
extracts were dried and concentrated. The residue was
purified bychromatographyon silica gel. Elution with
cyclohexane/ethyl acetate (60:40) afforded 1.07 g (61%)
25
of (S)-6 as a whitish wax: ½aŠ ¼ þ7:3 (c 0.5, EtOH);
D
1H NMR (CDCl3) d 2.16 (br s, 1H), 3.75 (d, 2H,

C. Bolchi et al. / Tetrahedron: Asymmetry 16 (2005) 3380–3384
3383
J = 4.9 Hz), 3.90 (m, 2H), 4.50 (m, 1H), 4.56 (s, 2H),
7.15 (dd, 1H, J = 8.4, 4.7 Hz), 7.30–7.37 (m, 5H), 7.43
(dd, 1H, J = 8.4, 1.6 Hz), 8.00 (dd, 1H, J = 4.7, 1.6 Hz).
acetone (70 mL) and added with 3 M KOH (7 mL).
After stirring at room temperature overnight, the sol-
vent was evaporated and the residue treated with dichlo-
romethane and water again. The organic layer was
separated, dried and concentrated to give 9.66 g of crude
(R)-3. 1H NMR analysis indicated that the product was
unitaryand could be directlymesylated without previ-
ous chromatographic purification as described for the
conversion of (S)-3 into (S)-4. Crystallization of the
crude mesyl ester from diisopropyl ether afforded 8 g
(75% of the starting (S)-4) of (R)-4: mp 103 ꢁC;
4.5. (R)-2-Benzyloxymethyl-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine (R)-7
A solution of (S)-6 (5.6 g, 19 mmol) in DME (20 mL)
was added to a suspension of 98% NaH (480 mg,
19 mmol) in DME (20 mL) under an N2 atmosphere.
The mixture was refluxed for 12 h, concentrated, added
with water (100 mL) and extracted with dichlorometh-
ane (3 · 100 mL). The organic phases were combined,
washed with water (20 mL), dried and concentrated.
The resultant residue (5.8 g) was purified bychromato-
25
1
½aŠ ¼ þ8:7 (c 1, CHCl3); H NMR identical to that
of D(S)-4.
4.9. (S)-1-Benzyl-2-(2-chloro-3-pyridinyl)-3-tritylglycerol
(S)-5
graphy on silica gel. Elution with cyclohexane/ethyl
25
D
acetate (1:1) afforded 3.75 g (78%) of (R)-7: ½aŠ
¼
þ24:9 (c 0.5, EtOH); 1H NMR (CDCl3) d 3.68 (m,
2H), 4.26 (dd, 1H, J = 11.3, 7.3 Hz), 4.35 (m, 1H),
4.47 (dd, 1H, J = 11.3, 2.2 Hz), 4.60 (s, 2H), 6.86 (dd,
1H, J = 7.7, 4.8 Hz), 7.20 (dd, 1H, J = 7.7, 1.5 Hz),
7.33 (m, 5H), 7.81 (dd, 1H, J = 4.8, 1.5 Hz).
Prepared from (R)-4 as described for (R)-5: H NMR
1
identical to that of (R)-5.
4.10. (R)-1-Benzyl-2-(2-chloro-3-pyridinyl)glycerol (R)-6
25
Prepared from (S)-5 as described for (S)-6: ½aŠ ¼ ꢀ7:0
D
1
4.6. (R)-2-Hydroxymethyl-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine (R)-1
(c 0.5, EtOH); H NMR identical to that of (S)-6.
4.11. (S)-2-Benzyloxymethyl-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine (S)-7
A solution of (R)-7 (1 g, 3.9 mmol) in methanol (3.5 mL)
was added with 5% Pd/C (120 mg) and cyclohexene
(1.5 mL) and irradiated for 4 min in a microwave oven
at 200 W and 120 ꢁC. The catalyst was removed by fil-
tration and the filtrate concentrated, dissolved in dichlo-
romethane (10 mL), washed with a saturated solution of
sodium bicarbonate (2 · 10 mL), dried and concentrated
25
D
Prepared from (R)-6 as described for (R)-7: ½aŠ
¼
ꢀ24:0 (c 0.5, EtOH); 1H NMR identical to that of
(R)-7.
4.12. (S)-2-Hydroxymethyl-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine (S)-1
again to give 610 mg (94%) of (R)-1 as a viscous oil,
25
which solidified upon standing: mp 91 ꢁC; ½aŠ
¼
þ32:6 (c 0.5, EtOH); ee 99.3% (byHPLC of a samDple
of the mesyl ester on a Chiralcel OD column; hexane/
2-propanol 60:40; 1 mL/min; mesyl ester of (R)-1:
k0 = 7.8; mesyl ester of (S)-1: k0 = 11.3); 1H NMR
(CDCl3) d 3.01 (br s, 1H), 3.89 (m, 2H), 4.30 (m,
2H), 4.49 (m, 1H), 6.87 (dd, 1H, J = 8.2, 4.8 Hz), 7.19
(dd, 1H, 1H, J = 8.2, 1.7 Hz), 7.79 (dd, 1H, J = 4.8,
1.7 Hz).
Prepared from (S)-7 as described for (R)-1: ½aŠ ¼ ꢀ31:8
25
D
(c 0.5, EtOH); ee 99.2% [byHPLC of a sample of the
mesyl ester under the conditions reported for the mesyl
1
ester of (R)-1]; H NMR identical to that of (R)-1.
4.13. (S)-1-(2-Chloro-3-pyridinyl)-2,3-isopropylidene-
glycerol (S)-8
A solution of 2-chloro-3-pyridinol (10 g, 77.2 mmol) in
DMF (40 mL) was added dropwise to a stirred suspen-
sion of 90% NaH (2.06 g, 77.2 mmol) under N2
atmosphere. After 30 min, a solution of (R)-1-tosyl-
2,3-isopropylideneglycerol (22.1 g, 77.2 mmol) was
added dropwise. The reaction mixture was heated at
100 ꢁC for 24 h. DMF was evaporated and the residue
treated with dichloromethane (80 mL) and water
(80 mL). The organic phase was separated, dried and
concentrated and the residue purified bychromatogra-
phy on silica gel. Elution with cyclohexane/ethyl acetate
4.7. (R)-1-Benzyl-3-tritylglycerol (R)-3
Prepared from (S)-1-benzylglycerol as described for
25
(S)-3: mp 72 ꢁC; ½aŠ ¼ þ6:4 (c 5, benzene); ee 99.6%
D
1
(byHPLC under the conditions reported for ( S)-3); H
NMR identical to that of (S)-3.
4.8. (R)-1-Benzyl-2-mesyl-3-tritylglycerol (R)-4
Method A: From (R)-3. The procedure was identical to
that described for the conversion of (S)-3 into (S)-4:
(70:30) afforded 16.9 g (90%) of (S)-9 as a colourless oil:
25
25
mp 103 ꢁC; ½aŠ ¼ þ8:6 (c 1, CHCl3); 1H NMR identical
½aŠ ¼ þ20:1 (c 0.5, EtOH); 1H NMR (CDCl3) d 1.40 (s,
D
D
to that of (S)-4. Method B: From (S)-4. Potassium ace-
tate (29.4 g, 0.3 mol) was added to a solution of (S)-4
(10.7 g, 21.3 mmol) in isobutanol (150 mL). The mixture
was refluxed for 20 h. The solvent was evaporated and
the residue treated with dichloromethane and water.
The organic phase was separated, dried and concen-
trated to give an oilyresidue, which was dissolved in
3H), 1.46 (s, 3H), 3.98–4.23 (m, 4H), 4.45–4.56 (m, 1H),
7.15–7.27 (m, 2H), 8.01 (dd, 1H, J = 5.0, 1.7 Hz).
4.14. (R)-1-(2-Chloro-3-pyridinyl)glycerol (R)-9
A stirred mixture of (S)-9 (16.8 g, 69 mmol) and 10%
HCl (100 mL) was heated at 80 ꢁC for 2 h, cooled to

3384
C. Bolchi et al. / Tetrahedron: Asymmetry 16 (2005) 3380–3384
room temperature and, after adjusting the pH to 8 by
the addition of 10% NaOH, submitted to continuous
extraction with dichloromethane. The organic extract
4.18. (S)-1-(2-Chloro-3-pyridinyl)glycerol (S)-9
Prepared from (R)-8 as described for (R)-9: mp
25
D
1
was dried and concentrated to give 10.4 g (74%) of
124 ꢁC; ½aŠ ¼ þ3:1 (c 0.5, EtOH); H NMR identical
25
(R)-10 as a white solid: mp 125 ꢁC; ½aŠ ¼ ꢀ3:8 (c 0.5,
to that of (R)-9.
D
EtOH); 1H NMR (DMSO-d6) d 3.46 (t, 2H, J =
5.7 Hz), 3.81 (m, 1H), 4.00 (dd, 1H, J = 10.1, 5.7 Hz),
4.10 (dd, 1H, J = 10.1, 5.7 Hz), 4.69 (t, 1H, J =
5.7 Hz), 5.00 (d, 1H, J = 5.1 Hz), 7.36 (dd, 1H, J =
8.1, 4.8 Hz), 7.57 (d, 1H, J = 8.1 Hz), 7.94 (d, 1H,
J = 4.8 Hz).
4.19. (S)-1-(2-Chloro-3-pyridinyl)-3-tritylglycerol (S)-10
25
D
Prepared from (S)-9 as described for (R)-10: ½aŠ
¼
ꢀ11:1 (c 0.5, EtOH); 1H NMR identical to that of
(R)-10.
4.15. (R)-1-(2-Chloro-3-pyridinyl)-3-tritylglycerol (R)-10
4.20. (S)-3-Hydroxymethyl-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine (S)-2
A mixture of (R)-10 (5.13 g, 25.2 mmol), trityl chloride
(9.8 g, 35 mmol), triethylamine (5.6 mL, 40 mmol) and
tert-butanol (50 mL) was refluxed for 12 h under an
N2 atmosphere. The solvent was evaporated and the res-
idue treated with ethyl acetate (50 mL) and water
(20 mL). The organic phase was separated, washed with
water (20 mL), dried and concentrated. The residue was
purified bychromatographyon silica gel. Elution with
25
D
Prepared from (S)-10 as described for (R)-2: ½aŠ
¼
ꢀ27:9 (c 0.5, EtOH); ee >98% (by 1H NMR of a sample
of the mesyl ester under the conditions reported for
1
the mesyl ester of (R)-2); H NMR identical to that of
(R)-2.
cyclohexane/ethyl acetate (60:40) afforded 8.4 g (75%)
Acknowledgements
25
of (R)-10 as a low melting solid: ½aŠ ¼ þ11:7 (c 0.5,
D
EtOH); 1H NMR (CDCl3) d 2.55 (d, 1H), 3.35–3.50
(m, 2H), 4.10–4.30 (m, 3H), 7.10–7.50 (m, 17H), 8.00
(dd, 1H).
This work was supported bythe Ministero dell ÕIstruzi-
`
one, dellÕUniversita e della Ricerca of Italy.
References
4.16. (R)-3-Hydroxymethyl-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine (R)-2
1. Bolchi, C.; Di Pumpo, R.; Fumagalli, L.; Pallavicini, M.;
Pedretti, A.; Valoti, E.; Villa, L.; Vistoli, G. Book of
Abstracts, Joint Meeting on Medicinal Chemistry, Kra-
A solution of (R)-10 (8.2 g, 18.4 mmol) in DME (40 mL)
was added to a suspension of 90% NaH (530 mg,
20 mmol) in DME (50 mL) under an N2 atmosphere.
The mixture was refluxed for 12 h and concentrated.
The residue was added with 10% HCl (20 mL) and eth-
anol (25 mL) and the resultant mixture stirred at room
temperature for 4 h, washed with dichloromethane
(30 mL), made alkaline with 10% NaOH (25 mL) and
extracted with ethyl acetate (3 · 30 mL). The organic
extracts were combined, washed with water (30 mL), dried
and concentrated. The residue was purified bychroma-
tographyon silica gel. Elution with dichloromethane/
methanol (95:5) afforded 1.94 g (63%) of (R)-2 as an
´
kow, Poland, 15–18 October 2003, P129.
2. Bolchi, C.; Di Pumpo, R.; Fumagalli, L.; Mennini, T.;
Pallavicini, M.; Pedretti, A.; Valoti, E.; Villa, L.; Vistoli,
G. Atti del XVI Convegno Nazionale della Divisione di
`
Chimica Farmaceutica della Societa Chimica Italiana,
Sorrento, 18–22 September 2002, L18.
3. Benarab, A.; Guillaumet, G. Heterocycles 1993, 36, 2327.
4. (a) Soukri, M.; Lazar, S.; Akssira, M.; Guillaumet, G.
Org. Lett. 2000, 2, 1557; (b) Lazar, S.; Soukri, M.; Leger,
J. M.; Jarry, C.; Akssira, M.; Chirita, R.; Grig-Alexa, I.
C.; Finaru, A.; Guillaumet, G. Tetrahedron 2004, 60, 6461.
´
5. Van Emelen, K.; De Bruyn, M. F. L.; Alcazar-Vaca, M. J.;
´
´
Andres-Gil, J. I.; Fernandez-Gadea, F. J.; Mattesanz-
25
1
oil: ½aŠ ¼ þ28:1 (c 0.5, EtOH); ee >98% (by H NMR
D
´
Ballesteros, M. E.; Bartolome-Nebreda, J. M.
of a sample of the mesyl ester in CDCl3 and in the pres-
WO0198306A1, 2001.
1
ence of (R)-(ꢀ)-1-(9-anthryl)-2,2,2-trifluoroethanol); H
6. Kuppens, T.; Langenaeker, W.; Tollenaere, J. P.; Bultinck,
P. J. Phys. Chem. A 2003, 107, 542.
7. Comoy, C.; Benarab, A.; Monteil, A.; Leinot, M.;
Massingham, R.; Guillaumet, G. Med. Chem. Res. 1996,
392.
NMR (CDCl3+D2O) d 3.88 (dd, 1H, J = 12.4, 4.4 Hz),
4.00 (dd, 1H, J = 12.4, 4.4 Hz), 4.14 (dd, 1H, J = 11.7,
8.1 Hz), 4.33 (d, 1H, J = 11.7), 4.42 (m, 1H), 6.88 (dd,
1H, J = 7.7, 4.8 Hz), 7.20 (d, 1H, J = 7.7 Hz), 7.81 (d,
1H, J = 4.8 Hz).
8. Pallavicini, M.; Villa, L.; Cesarotti, E. J. Chromatogr.
1992, 604, 197.
9. The best separation and resolution factors (a = 1.13,
Rs = 0.8) were obtained on a Chiralcel OB column,
eluting with hexane/ethanol/water 37.2:60.7:2.1 at 0.15 mL/
min (mesyl ester of (R)-2: k0 = 1.65; mesyl ester of (S)-2:
k0 = 1.87).
4.17. (R)-1-(2-Chloro-3-pyridinyl)-2,3-isopropylidene-
glycerol (R)-8
Prepared from (S)-1-tosyl-2,3-isopropylideneglycerol
25
as described for (S)-8: ½aŠ ¼ ꢀ19:5 (c 0.5, EtOH);
10. Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Tetra-
hedron: Asymmetry 1994, 5, 5.
D
1H NMR identical to that of (S)-8.