Simple chiral auxiliary-assisted resolution of 2-(3,5-di-tert-butyl-4- hydroxyphenyl)propionic acid

Article abstract of DOI:10.1016/j.mencom.2010.09.018

Chiroptical properties and X-ray diffraction were studied for both diastereomers of N-[(R)-1-phenylethyl]-2-(3,5-di-tert-butyl-4-hydroxyphenyl) propanamide, whose acid moiety is a chiral antioxidant.

Full text of DOI:10.1016/j.mencom.2010.09.018

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 291–292
Simple chiral auxiliary-assisted resolution of
2-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid†
Grigory A. Nikiforov,a Orudzh G. Nabiev,b Ivan I. Chervinb and Remir G. Kostyanovsky*b
a N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow,
Russian Federation. Fax: +7 499 137 4101
b N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: + 7 495 651 2191; e-mail: kost@chph.ras.ru
DOI: 10.1016/j.mencom.2010.09.018
Chiroptical properties and X-ray diffraction were studied for both diastereomers of N-[(R)-1-phenylethyl]-2-(3,5-di-tert-butyl-4-
hydroxyphenyl)propanamide, whose acid moiety is a chiral antioxidant.
Synthesis and applications of achiral phenolic antioxidants
(PAO) were broadly studied.1 In the last decades, considerable
attention was focused on the pharmaceutical chiral substances,
including chiral PAO in racemic2 and scalemic3 forms. Several
PAO-based chiral drugs of broad spectrum of action were
devised, e.g., Tazofelone4 and its analogue5 as well as recently
reported antioxidant protector against cigarette smoke.6 Investi-
gations7 dealing with mono-, di-, and three-isobornylphenols7(a)
should be of special note. The works8 on the phenomenon of
‘mitochondria-targeted antioxidants more effective than untargeted
one’ are of particular interest. Studies of natural polyphenolic
antioxidants discovered their antiinflammatory and antiinvasive
activities.9 Natural flavones and their synthetic analogues exhibited
antiviral and antiinvasive activity against solid tumors.9
1 into the racemic PAO 2 followed by simple crystallization to
resolve the diastereomers of amide 3 (Scheme 1).‡
By three-fold crystallization of compound 3 from acetone,
the well-shaped hexahedral plates were obtained; according to
‡
Methyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. 2,6-Di-tert-
butylphenol (20.6 g, 0.1 mol) was added to suspension of NaH (3 g,
0.1 mol) in dry 1,2-dimethoxyethane (200 ml) under argon stream. The
mixture was stirred for 2.5 h at 40 °C, then cooled to 15–20 °C, methyl
2-bromopropionate (11.2 ml, 0.1 mol) was added under stirring. The
mixture was stirred for 1 h at 80–85 °C, cooled to 20 °C, thereafter the
solid residue was filtered off, and the mother liquor was evaporated
in vacuo. The residue was dissolved in CH2Cl2 (100 ml), the solution was
washed with 1% HCl, and the organic layer was separated and evaporated
in vacuo. The residue was dissolved on heating in hexane (20 ml), then
cooled to –5 °C, and the crystals were filtered off to give 20.3 g (69%
A key problem in obtaining chiral PAO is resolution of
racemates into enantiomers. Here, this problem was solved
through incorporation of enantiomerically pure moiety of amine
1
yield) of the title ester, mp 84–85 °C. H NMR (acetone-d6) d: 1.43 (s,
18H, 2Me3C), 1.48 (d, 3H, Me, 3J 6.7 Hz), 3.61 (s, 3H, MeO), 3.67 (q,
1H, CHMe, 3J 6.7 Hz), 6.02 (s, 1H, OH), 7.11 (s, 2H, HAr).
2-(3,5-Di-tert-butyl-4-hydroxyphenyl)propionic acid 2. The corre-
sponding methyl ester (5.84 g, 20 mmol) was added to solution of NaOH
(1 g, 25 mmol) in a mixture of MeOH and water (45 and 5 ml, respec-
tively) under argon stream, and the mixture was boiled for 2 h. After
cooling, 10% HCl was added to reach pH » 5, and the mixture was
diluted with equal amount of water. The residue was separated and
washed with water and hexane to afford 5.7 g of the product, yield 98%,
But
But
i, NaH
ii, MeCH(Br)CO2Me
Me
HO
But
HO
But
CO2Me
1
mp 200–201 °C. H NMR (CDCl3) d: 1.43 (s, 18H, But), 1.48 (d, 3H,
But
i, NaOH (MeOH)
ii, HCl
Me
Me, 3J 6.7 Hz), 3.65 (q, 1H, CH), 5.16 (s, 1H, OH), 7.12 (s, 2H, Ar).
Amide 3. Thionyl chloride (1.2 ml, 17 mmol) was added to a suspension
of acid 2 (2.78 g, 10 mmol) in heptane (30 ml), and the mixture was stirred
for 3 h at 90–95 °C, cooled down and evaporated in vacuo. The chloro-
anhydride thus obtained (mp 40–42 °C) was dissolved in benzene (75 ml),
and a solution of Et3N (1.4 ml, 10 mmol) and (R)-(+)-PhCH(Me)NH2 1
(1.3 ml, 10 mmol) in benzene (10 ml) was added at 20 °C. The mix-
ture was stirred for 0.5 h under argon stream, the precipitate of Et3N·HCl
was separated, and the filtrate was evaporated in vacuo. Crystallization
of the residue from hexane gave 3.5 g of yellowish crystals of amide 3
(92% yield). Upon three-fold crystallization from acetone the diastereomer
(R,R)-(+)-3 was obtained, yield 92%, mp 188–189 °C, [a]D20 +21.8
(c 0.49, MeOH). HRMS, m/z: 382.2763 [M+] (calc. 381.5597). 1H NMR
(benzene-d6) d: 1.07 (d, 3H, MeCHAr, 3J 6.9 Hz), 1.62 (d, 3H, MeCHN,
SOCl2
heptane
HO
But
CO2H
2
But
HO
(R)-(+)-PhCH(Me)NH2
Me
1
Et3N–benzene
Cl
But
O
But
Crystallization from
Me2CO–hexane
3
3J 7.1 Hz), 1.35 (s, 18H, 2Me3C), 3.33 (q, 1H, CHAr, J 6.9 Hz), 5.27
(R,R)-(+)-3
Me Me
NH
3
and
HO
But
Ph
(dq, 1H, MeCHNH, J 7.1 and 8.0 Hz), 5.02 (s, 1H, OH), 5.45 (d, 1H,
3
NH, J 8.0 Hz), 7.06 (m, 5H, Ph), 7.2 (s, 2H, HAr). Upon evaporation
(S,R)-(+)-3
of mother liquor, three-fold crystallization of the residue from acetone–
O
hexane mixture (1:9 v/v) gave the diastereomer (S,R)-(+)-3, yield 91%,
3
mp 143–144 °C, [a]D20 +57.4 (c 0.76, MeOH). H NMR (benzene-d6) d:
1
Scheme 1
To the memory of Grigory Nikiforov, our long-time friend and colleague.
3
1.06 (d, 3H, MeCHAr, J 7.0 Hz), 1.38 (s, 18H, 2Me3C), 1.58 (d, 3H,
MeCHN, 3J 7.1 Hz), 3.21 (q, 1H, CHAr, 3J 7.1 Hz), 5.25 (dq, 1H, MeCHNH).
†
– 291 –
© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 291–292
The authors are grateful to Professor K. A. Lyssenko (A. N.
C(20)
C(19)
C(20)
C(17)
C(7)
Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences) for performing X-ray diffraction analysis.
This work was supported by the Russian Academy of
Sciences and the Russian Foundation for Basic Resarch (grant
no. 09-03-00537a).
C(3)
C(6)
C(2)
C(1)
C(18)
C(4)
C(5)
C(2S)
O(1)
C(21)
C(8)
H(1N)
C(23)
H(1O)
O(2)
C(22)
C(1S)
N(1)
C(9)
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O(1S)
C(25)
C(3S)
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Figure 1 General view of the molecule of (R,R)-(+)-3.
results of X-ray diffraction they have the (R,R)-(+) configura-
tion.§ This compound crystallizes as the solvate with acetone
molecule that participates in the formation of hydrogen bond
with hydroxy group [O(1)···O(1S) 2.826(2) Å]. In the crystal, the
molecules are assembled into infinite chains by means of weak
N–H···O hydrogen bonds [N···O 3.298(2) Å] (Figure 1).§ This
diastereomer was characterized by the CD spectrum (Figure 2).
Upon evaporation of the mother liquor, three-fold crystallization
of the residue from acetone–hexane mixture (1:9 v/v) afforded
fine needles of another diastereomer (S,R)-(+)-3.
To conclude, a simple and efficient method has been developed
to synthesize (yields 69–92%) and resolve diastereomers of the
described chiral PAO.
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–0.14
180 200 220 240 260 280 300 320 340 360
l/nm
8
9
Figure 2 CD spectrum of (R,R)-(+)-3.
§
Crystal data for (R,R)-(+)-3. Crystals (C25H35NO2, C3H6O, M = 439.62)
are trigonal, space group P3221, at 100 K: a = b = 10.519(5) and c =
= 40.33(4) Å, V = 3865(4) Å3, Z = 6 (Z' = 1), dcalc = 1.133 g cm–3,
m(MoKα) = 0.72 cm–1, F(000) = 1440. All measurements were performed
with a Bruker SMART APEX2 CCD diffractometer [l(MoKα) =
= 0.71073 Å, w-scans]. 15781 reflections were measured (2q < 58°),
from which 3950 are independent (Rint = 0.0332), wR2 = 0.1004 and
GOF = 1.062 for all independent reflections [R1 = 0.0407 for 3626
observed reflections with I > 2s(I)]. All calculations were performed
using SHELXTL-Plus 5.0.10
10 G. M. Sheldrick, Acta Crystallogr., Sect. A, 2008, 64, 112.
CCDC 791361 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
Received: 30th March 2010; Com. 10/3498
– 292 –