Resolution of 1-arylalkylamines with 6-(1,2:3,4-di-O-isopropylidene- α-D-galactopyranosyl)hydrogen phthalate

Article abstract of DOI:10.1016/j.tetasy.2003.12.038

The resolving ability of a new acidic resolving agent, the hydrogen phthalate of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 1, against various 1-arylalkylamines 2a-k is described. Treatment of 1 with amines 2a-f to obtain diastereomeric salts 1·(S)2a-f in 2-propanol allowing the corresponding (S)-amines 2a-f to be recovered in good yield and 61-89% ee. Recrystallization in dichloromethane/hexane, and regeneration gave the amines in enhanced enantiomeric purity (>98% ee). 1 resolved 1-phenylpropylamine 2f in high enantiomeric purity (99% ee) than 1-phenylethylamine 2g (11% ee) and o- and m-methoxy 2h-i, o-chloro-2j and p-fluoro-2k substituted 1-arylamines (11-19% ee). A possible chiral recognition mechanism based on the ability of 1 to exist in two conformations is described.

Full text of DOI:10.1016/j.tetasy.2003.12.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 585–587
Resolution of 1-arylalkylamines with 6-(1,2:3,4-di-O-
isopropylidene-a- -galactopyranosyl)hydrogen phthalate
D
Hari Babu Mereyala,* Liyakat Fatima and Pallavi Pola
Speciality, Gas Based Chemicals and Processes Division, Indian Institute of Chemical Technology, Hyderabad 500-007, India
Received 28 November 2003; accepted 19 December 2003
Abstract—The resolving ability of a new acidic resolving agent, the hydrogen phthalate of 1,2:3,4-di-O-isopropylidene-a-D-galac-
topyranose 1, against various 1-arylalkylamines 2a–k is described. Treatment of 1 with amines 2a–f to obtain diastereomeric salts
1Æ(S)2a–f in 2-propanol allowing the corresponding (S)-amines 2a–f to be recovered in good yield and 61–89% ee. Recrystallization
in dichloromethane/hexane, and regeneration gave the amines in enhanced enantiomeric purity (>98% ee). 1 resolved 1-phenyl-
propylamine 2f in high enantiomeric purity (99% ee) than 1-phenylethylamine 2g (11% ee) and o- and m-methoxy 2h–i, o-chloro-2j
and p-fluoro-2k substituted 1-arylamines (11–19% ee). A possible chiral recognition mechanism based on the ability of 1 to exist in
two conformations is described.
Ó 2004 Published by Elsevier Ltd.
Resolution through diastereomeric salt formation is the
most widely used method for separating enantiomers of
a given racemic acid or base.1 This classical technique
still constitutes the most important methodology for the
industrial manufacture of pure enantiomers.2 Systematic
investigation studies on the resolution of 1-arylalkyl-
amines have identified the following criteria for rational
design of acidic resolving agents3 (i) similarity in
molecular length between a target racemate and a
resolving reagent,3d (ii) presence of hydrogen-bonding
and van der Waals interactions,3c;e;j;k (iii) hydrophobic
water insoluble carboxylic acids to facilitate isolation of
uncontaminated liberated base.3a The acidic resolving
agents tried for this purpose contained the carboxylic
group attached to the stereogenic carbon.
substituent.4d Despite the design of resolving agents
there is a need to develop newer ones to understand the
criterion for chiral descrimination.
Here, we describe our studies concerning the resolution
of 1-arylalkylamines by the use of carbohydrate derived
acidic resolving agent.5 We have chosen the hydrogen
phthalate of
D
-galactopyranose bearing two a,a-di-
methyldioxolane rings because of its ability to exist in at
least two conformations due to flipping of the pyranose
ring. In each one of the conformers the phthalate group
is perhaps aligned over one of the dioxolane rings. The
recognition mechanism if operated would lead to pref-
erential crystallization of (R)- and (S)-isomers by the
two conformers.
Highly efficient chiral discrimination exhibited by
enantiomerically pure isopropylidene glycerol hydrogen
phthalate4 bearing a stereogenic carbon remote from the
carboxylic acid has been attributed to conformational
restriction of the dioxolane in line with proven empirical
guidelines. The success of the resolutions presented
indicated the versatility of isopropylidene glycerol
hydrogen phthalate in the resolution of monosubstituted
1-phenylethylamines irrespective of the position of the
Reaction of 1,2:3,4-di-O-isopropylidene-a-D-galacto-
pyranose 36 [100 g, 0.38 mol] and phthalic anhydride
[56.0 g, 0.38 mol] in dry pyridine [62 mL] according to
the usual procedure and work up gave 6-(1,2:3,4-di-O-
isopropylidene-a-D-galactopyranosyl)hydrogen phthal-
25
D
ate 1 in quantitative yield as a syrup; ½aꢀ ¼ +8.4 [c 2.0,
CHCl3] [98.9% de by HPLC] (Scheme 1). Compound 1
was characterized from 1H NMR spectrum by the
appearance of H-10 at d 5.65 (d, 1H, J1;2 ¼ 5:8 Hz) and
aromatic protons at d 7.50–7.75 (m, 4H); FAB-MS, m=z
409 (Mþ+H).
Keywords: 1-Arylalkylamines; Hydrogenphthalate; Diacetone galac-
tose.
We first sought to understand the effect of substitutents
at the para position of 1-arylethylamines. Thus
treatment of p-alkyl-(methyl, ethyl), p-halo-(Cl, Br)
* Corresponding author. Tel.: +91-40-27193137; fax: +91-40-271603-
87/27160757; e-mail: mereyalahb@rediffmail.com
0957-4166/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2003.12.038

586
H. B. Mereyala et al. / Tetrahedron: Asymmetry 15 (2004) 585–587
O
O
OH
O
O
O
O
O
O
Pyridine
+
O
O
°
90 C, 4 h
O
O
O
O
O
O
OH
9
1
2a) R= H, Ar=p-Me-C6H4
2b) R= H, Ar=p-Et-C6H4
2c) R= H, p-Cl-C6H4
NH2
2d) R= H, Ar=p-Br-C6H4
2e) R= H, Ar=p-OMe-C6H4
1.(S)-salt
less soluble
(S)-amine
+1
Ar
CH2
2f) R=Me, Ar=C6H5
2g) R=H, Ar=C6H5
2a-2f
R
2h) R=H, Ar=o-OMe-C6H4
2i) R=H, Ar=m-OMe-C6H4
2j) R=H, Ar=o-Cl-C6H4
2k) R=H, Ar=p-F-C6H4
Scheme 1.
p-methoxy substituted 1-arylethylamines 2a–e and 1-
phenylpropylamine 2f, respectively, with stoichiometric
amount of 1 in boiling 2-propanol and cooling to )15 °C
yielded white crystalline precipitates 1Æ(S)2a–f, which
after usual extractive procedures afforded the corre-
sponding amines (S)2a–f in moderate enantiomeric
purity (61–88% ee) and in good yield (Table 1, entries
i–vi). However, a similar treatment of 1-phenylethyl-
amine and amines bearing o-, m-substituents 2g–k with 1
in 2-propanol did not result in the formation of any
salts, the solvent was removed to obtain a thick syrup,
which was partitioned into two phases by addition of
dichloromethane/hexane (2:3) to isolate insoluble and
soluble fractions containing 1Æ(S)2g–k and 1Æ(R)2g–k
salts, respectively, which on decomposition gave the
corresponding amines (S)2g–k and (R)2g–k, respec-
tively, in low enantiomeric purity (11–25% ee) (Table 1,
entries vii–xi). Recrystallization of salts 1Æ(S)2a–f from
CH2Cl2/n-hexane at rt (1:1, 4 mL/g) or 2-propanol
(6 mL/g) followed by decomposition resulted in the
recovery of their corresponding amines (S)2a–f with
increased enantiomeric purity (>98% ee).
A possible chiral discrimination mechanism might
involve the following steps. The resolving agent 1 rec-
ognizes the (R)- and (S)-amines by approaching them by
columbic attraction. The process requires a favourable
conformation of the galactopyranose ring possessing
two dioxolane rings and a phthalate group. The con-
formers could be present in chair/boat forms with
alignment of phthalate over one of the dioxalane rings
thereby facilitating recognition phenomena. These
Table 1. Resolution of 1-arylalkylamines 2a–k by 6-(1,2:3,4-di-O-isopropylidene-a-
D
-galactopyranosyl)hydrogen phthalate (1)a
1Æ(S)-salt (% yield)b, ½aꢀ
(S)-Aminee, Eec (% yield)b, ½aꢀ
Reference
d
d
Entry
(RS)-Amine
D
D
2
Resolution
Recrystallization
Resolution
Recrystallization
i
a
b
c
d
e
f
(99.0), )40.9
(91.4), )42.6
(94.5), )38.2
(96.2), )36.2
(95.4), )42.2
(94.5), )35.3
(91.6), )26.7
(87.8), )31.6
(82.3), )29.8
(83.6), )28.7
(41.8), )31.9
(78.7), )43.4
(73.4), )45.1
(62.5), )42.3
(77.9), )38.5
(76.2), )45.3
(79.1), )39.1
––
84.3, (88.1), )27.5f
88.3, (81.2), )15.6g
61.0, (93.0), )14.6f
64.1, (94.0), )16.0g
60.3, (86.0), )17.1f
84.7, (89.0), )16.0f
11.7, (90.2), ) 3.5f
13.6, (85.7), )8.0g
15.2, (80.8), )3.4g
18.6, (82.3), )10.3h
25.3, (89.6), )4.8f
98.7, (65.7), )32.4f
4b
––
4b
4a
4a
4b
4a
4b
4d
4d
––
ii
99.4, (74.4), )18.9g
iii
iv
v
98.9, (64.1), )23.4f
99.2, (78.3), )24.8g
98.1, (64.1), )28.8f
vi
vii
viii
ix
x
99.1, (77.8), )18.8f
g
h
i
––
––
––
––
––
––
––
j
––
––
xi
k
a All crystallizations were carried out using equivalent amounts of racemic amines and 1.
b Yield of the crystallized diastereomeric salt based on half amount of the racemic amine.
c % Enantiomeric excess of the amines determined by reverse-phase chiral HPLC analysis on Crownpak CR(+) column from Daicel (elutant aq
HClO4 at pH 1.5).7
d At 25 °C.
e Specific rotation was determined and the value at concentrations and temperatures comparable to those in the literature.
f c 2.0, MeOH.
g c 1.0, MeOH.
h c 1.5, MeOH.

H. B. Mereyala et al. / Tetrahedron: Asymmetry 15 (2004) 585–587
587
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observations are similar to those observed for hydrogen
phthalate of isopropylidene glycerol4c;8 except the
dioxolane rings present on 1 are not flexible.
In summary, we have investigated the applicability of
carbohydrate derived, new acidic resolving agent 1 for
the resolution of ten 1-arylalkylamines 2a–k. A common
chiral discrimination mechanism seems to work allowing
to obtain the (S)-isomer.3 1-Arylethylamines bearing
alkyl (methyl, ethyl), halo-(Cl, Br) and methoxy substitu-
tents at para position of the phenyl group were resolved
to obtain the corresponding (S)-amines in good enan-
tiomeric purity. The amines bearing electron donating
substituents in the ortho and meta positions were
resolved less efficiently. Rational design of carbohydrate
derived resolving agents by modification of the pyranose
and dioxolane rings to understand the conformer based
chiral recognition phenomena is in progress.
Acknowledgements
L.F. thanks CSIR, New Delhi and P.P. the UGC, New
Delhi for financial support in the form of a Senior
Research Fellowship.
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