Synthesis of non-cross-linked polystyrene supported 5,5-dimethyl oxazolidinone chiral auxiliary

Article abstract of DOI:10.3184/030823407X198212

A new chiral auxiliary, non-cross-linked polystyrene supported 5,5-dimethyl oxazolidinone was synthesised in 25.1% yield using L-tyrosine as the starting material using a six-step method.

Full text of DOI:10.3184/030823407X198212

84 RESEARCH PAPER
FEbRUARY, 84–85
JOURNAL OF CHEMICAL RESEARCH 2007
Synthesis of non-cross-linked polystyrene supported 5,5-dimethyl
oxazolidinone chiral auxiliary
Yadong Wan, Cuifen Lu, Junqi Nie, Guichun Yang, Zuxing Chen*
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules and Faculty of Chemistry
and Chemical Engineering, Hubei University, Wuhan, 430062, P. R China
A new chiral auxiliary, non-cross-linked polystyrene supported 5,5-dimethyl oxazolidinone was synthesised in 25.1%
yield using l-tyrosine as the starting material using a six-step method.
Keywords: non-cross-linked polystyrene, support, chiral auxiliary, 5,5-dimethyloxazolidinone
Oxazolidinone, the most versatile and widely used chiral
auxiliary, was devised by Evans et al.1 This, so called, Evans’
auxiliary has been utilised in a particularly wide variety of
high diastereoselective reactions.2 However, the application
of Evans’ oxazolidinone is limited due to the drawbacks
of the Evans methodology which involves the cleavage of
the auxiliary.3 In order to address fully this troublesome
cleavage problem, a new class of chiral auxiliary, the 5,5-
dimethyloxazolidinone has been developed.4 The improved
auxiliary provides superior performance to many other chiral
auxiliaries currently in common usage. It has proved to be
particulary efficacious in terms of diastereoselectivity, yield
and solubility.5-7
Recently, the attachment of Evans’oxazolidinone to polymer-
support has been reported.8-9 The use of polymer-supported
chiral auxiliaries gives some benefits: (1) easy separation and
recovery of the expensive chiral material; (2) simple isolation
of the desired chiral adduct; and (3) possible extension to a
continuous system. But to the best of our knowledge, polymer-
supported 5,5-dimethyloxazolidinone chiral auxiliary has not
been reported. Our group has undertaken a research program
to develop a new chiral auxiliary using non-cross-linked
polystyrene (NCPS) as support.10 In our study another new chiral
auxiliary based on NCPS was synthesised through six steps
from the material of natural l-tyrosine (Scheme 1). It will be
widely used in asymmetric synthesis, such as chiral alkylation,
Aldol condensation, Diels–Alder and Michael addition.
Experimental
Melting points were measured on a WRS-1A digital melting point
apparatus and uncorrected; polarimetric analysis was recorded
A
on a WZZ-2B polarimeter; IR spectra were recorded on an IR-
spectrum One spectrometer (PE); 1H NMR (600 MHz) and 13C
NMR (150 MHz) spectra were recorded on a Varian Unity INOVA
600 spectrometer using TMS as internal standard; element analysis
was determined by a VarioEL β(Germany) analyser; MS spectra were
recorded on Finnigan LCQ DUO MS system.
Synthesis of l-tyrosine methyl ester hydrochloride 1: Compound
1 was obtained as white crystals in yield (97%). m.p. 189–190°C
(lit.[11]190–191°C),[α]D25=+69.8(c1.06,pyridine)[lit.[11][α]D20=+70.9
(c 1.1, pyridine)].
Synthesis of N-Boc l-tyrosine methyl ester 2: Compound 2 can be
synthesised according to ref.12.Yield 86%. m.p. 104–105°C [lit.[13]
20
20
102°C], [α]D = + 20.4 (c 0.72, THF) [lit.[13] [α]D = -50.0 (c 1.0,
CHCl3)]. IR(NaCl): υ = 3365, 1740, 1689 cm−1; H NMR(600 MHz,
1
CDCl3): 6.96(2H, d, J = 8.4 Hz, Ar–H), 6.72(2H, d, J = 8.4 Hz, Ar–H),
5.03(1H, m, OH), 4.54(1H, m, CH), 3.71(3H, s, O–CH3), 3.01(1H, m,
CH2–Ar), 2.98 (1H, m, CH2–Ar), 1.42(9H, s, C–CH3); 13C NMR (150
MHz, CDCl3): 173.1, 155.8, 155.6, 130.8(2C), 127.9, 115.9(2C), 80.7,
55.0, 52.7, 38.0, 28.7(3C); MS: m/z = 319.9 (M + Na+).
Synthesis of (3S)-3-(N-Boc-amino)-4-(4-hydroxyphenyl)-2-methyl-
butan-2-ol 3: The compound 2 (13.3 g, 45 mmol) in ether (150 ml)
was added dropwise to a solution of methylmagnesium iodide in ether
(300 ml) [From methyl iodide (28 ml, 450 mmol) and magnesium
(12 g, 500 mmol)]. The mixture was stirred at room temperature for
48 h. Then the mixture was hydrolysed with ice and 2M HCl until
the magnesium was consumed. The ether layer was separated and
the aqueous layer was extracted with ether (30 ml × 3). The combined
ether layer was dried over MgSO4 and evaporated to afford a pale
HO
HO
SOCl2
HO
Et3N
COOCH3
CH3MgI
Et2O
COOCH3
COOH
HN
O
CH3OH
(Boc)2O
HCl . H2N
H2N
O
1
2
HO
HO
K2CO3
NaOH
O
HN
HN
O
OH
O
Cl
CH3OH
HN
O
O
O
O
4
3
5
m
n
O
AIBN,70oC
HN
O
6
O
Scheme 1 Synthesis of NCPS supported 5,5-dimethyloxazolidinone.
* Correspondent. E-mail: chzux@hubu.edu.cn.
PAPER: 06/4401

JOURNAL OF CHEMICAL RESEARCH 2007 85
yellow solid. Recrystallisation from EtOH–CH3COOEt–H2O (2:3:2,
C, 74.75%, H, 6.87%, N, 4.15%; found: C, 74.85%; H, 6.89%;
N, 3.94%.
v/v) gave 3 as colourless crystals (7.8 g, 58%). m.p. 155.6–156.3°C,
20
[α]D = −39.4 (c 0.91, THF); IR(NaCl): υ = 3355, 1686 cm−1
;
Synthesis of NCPS supported 5,5-dimethyloxazolidinone 6:
To a solution of monomer 5 (3 g, 8.7 mmol) in THF (15 ml) were
added styrene (1.85 g, 17.4 mmol) and AIbN (0.01 g, 0.06 mmol).
The mixture was stirred at 70°C for 48 h under nitrogen atmosphere.
Then most of the solvent was removed under reduced pressure.
The viscous solution was dropped into cold ethanol (200 ml) and the
precipitatedsolidwasfilteredand driedat 65°C for2hundervacuum to
1H NMR (600 MHz, CDCl3): 7.05(2H, d, J = 7.8 Hz, Ar–H), 6.70(2H,
d, J = 7.8 Hz, Ar–H), 5.67(1H, m, OH), 3.65(1H, m, CH), 3.05(1H, m,
CH2–Ar), 2.52(1H, m, CH2–Ar), 1.20-1.18(15H, t, CH3); 13C NMR
(150 MHz, CDCl3): 155.7, 155.6, 130.8, 129.2(2C), 115.8(2C), 80.4,
72.4, 68.2, 37.4, 28.8(3C), 26.7, 21.2; MS: m/z = 318.1 (M + Na+).
Elementary analysis calcd for compound 3: C, 65.06%, H, 8.53%, N,
4.74%; found: C, 65.18%; H, 8.51%; N, 4.59%.
afford solid polymer 6 (4.32 g, 89%). IR(NaCl): υ = 3280, 1752 cm−1
;
1H NMR (600 MHz, CDCl3): 7.25-6.45(m, broad signal due to the
polymer resonance), 4.90 (2H, s, O–CH2), 3.62(1H, s, CH), 2.75
(1H, s, CH2–Ar), 2.60(1H, s, CH2–Ar), 1.81–1.25(m broad signal
due to the polymer resonance); 13C NMR (150 MHz, CDCl3): 158.4,
145.5, 130.4, 129.5, 128.1, 126.2, 115.8, 83.6, 70.5, 63.5, 40.8, 36.6,
28.0, 22.4. Elementary analysis calcd for polymer 6: C, 81.43%; H,
7.20%; N, 2.57%; found: C, 81.83%; H, 7.22%; N, 2.48%.
Synthesis of (S)-4-(4-hydroxybenzyl)-5,5-dimethyloxazolidinone
4: The N-Boc amino alcohol 3 (7.5 g, 25.5 mmol) was suspended
in 5% NaOH (7.2 g, wt%) in MeOH (75 ml), refluxed for 12 h.
The mixture was evaporated and the residue diluted with water
(20 ml) and ethyl acetate (30 ml). The aqueous layer was extracted
with ethyl acetate (30 ml × 3). Then the combined organic phase was
dried over MgSO4, concentrated under vacuum to give 4 (4.5 g, 81%)
as pale yellow solid which was used in the next step without further
20
NCPS supported 5,5-dimethyl oxazolidinone chiral auxiliary
was characterised by IR, 1H NMR, 13C NMR, GPC, TGA and
DSC. The result showed that the obtained polymer has high
loading capacity, remarkable solubility, low molecule and
good thermally stability. The overall yield reached 25.1%.
purification. m.p. 138.2–139.3°C, [α]D = −121.8 (c 0.8, THF);
1
IR(NaCl): υ = 3290, 1729, 1515, 1235 cm−1; H NMR (600 MHz,
CH3OD): 7.00(2H, d, J = 8.4 Hz, Ar–H), 6.70(2H, d, J = 8.4 Hz,
Ar–H), 3.75(1H, m, CH), 2.73(1H, m, CH2–Ar), 2.62(1H, m, CH2–
Ar), 1.34(6H, d, CH3); 13C NMR(150 MHz, CH3OD): 160.0, 156.3,
130.2(2C), 128.3, 115.6(2C), 84.1, 63.5, 36.1, 26.9, 21.1; MS: m/z
= 244.0 (M + Na+). Elementary analysis calcd for compound 4: C,
65.14%, H, 6.83%, N, 6.33%; found: C, 65.19%; H, 6.82%; N, 6.27%.
Synthesis of (S)-4-[4-(4-vinylbenzyloxy)benzyl]-5,5-dimethyl-
oxazolidinone 5: To a solution of 4 (3.3 g, 15 mmol) in dry DMF
(20 ml) were added 4-vinylbenzyl chloride (CMS) (2 ml, 18 mmol),
anhydrous K2CO3 (2 g, 15 mmol) and 18-crown-6 (catalyse amount).
Then the resulting mixture was stirred for 12 h at r.t. The solvent
was removed under vacuum and the residue diluted with H2O
(15 ml) and CH2Cl2 (30 ml). The aqueous layer was extracted with
dichloromethane (25 ml × 3) and the combined organic phase were
dried over MgSO4 and evaporated to afford a pale yellow solid.
Recrystallisation from EtOH–CH3COOEt–H2O (1:2:1, v/v) give
Received 11 January 2007; accepted February 2007
Paper 07/4401
doi:10.3184/030823407X198212
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1
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