Synthesis of a new chiral auxiliary-Non-cross-linked polystyrene-supported oxazolidine-2-selone

Article abstract of DOI:10.1139/V10-162

A new chiral auxiliary, non-cross-linked polystyrene-supported oxazolidine-2-selone was synthesized using N-Boc-l-tyrosine ethyl ester as starting material. The structure of the target product was detected by IR, NMR, elemental analysis, and the spectrum

Full text of DOI:10.1139/V10-162

88
Synthesis of a new chiral auxiliary —
Non-cross-linked polystyrene-supported
oxazolidine-2-selone
Xiping He, Jia Li, Cuifen Lu, Zuxin Chen, and Guichun Yang
Abstract: A new chiral auxiliary, non-cross-linked polystyrene-supported oxazolidine-2-selone was synthesized using N-
Boc-L-tyrosine ethyl ester as starting material. The structure of the target product was detected by IR, NMR, elemental
analysis, and the spectrum result was consistent with the molecular structure.
Key words: non-cross-linked polystyrene, support, oxazoline-2-selone, chiral auxiliary.
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Resume : Faisant appel a l’ester ethylique de la N-Boc-L-tyrosine comme produit de depart, on a realise la synthese d’un
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nouvel auxiliaire chiral, l’oxazolidine-2-selone supportee par du polystyrene non reticule. La structure du produit de syn-
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these a ete confirmee par spectroscopies IR et RMN et par analyse elementaire et les resultats spectraux sont en accord
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avec la structure moleculaire.
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Mots-cles : polystyrene non reticule, support, oxazoline-2-selenone, auxiliaire chiral.
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[Traduit par la Redaction]
the polymer main chain and the resulting tendency toward
crystallization.9,10 We theorized that this solubility versus re-
covery relationship of crystalline polymer — a well-known
phenomenon in polymer chemistry — could lead to a better
recovery yield of the polymer support when precipitated
with a poor solvent.
Introduction
Carbon–carbon bond-forming reactions involving asym-
metric aldol reactions have emerged as powerful tools in or-
ganic synthesis. Chiral oxazolidine-2-selone was found to be
an excellent auxiliary in asymmetric aldol reactions.1–4
However, in most cases, the separation and purification of
the chiral auxiliaries were troublesome. To recycle and reuse
expensive chiral auxiliaries is a challenge in organic synthe-
sis.
Insoluble polymer supports, such as Merrifield resin and
Wang resin provided a simple procedure ‘‘filtration’’ for rap-
idly achieving the isolation of desired compounds or recov-
ering expensive reagents or catalysts attached onto solid
support for recycling.5,6 But several shortcomings were
shown because of nonlinear kinetic behavior, unequal distri-
bution or access to the chemical reaction, and synthetic dif-
ficulties in transferring standard organic reactions to the
solid phase. Soluble polymer supports have been studied
as a way to overcome the problems of insoluble supports.
Soluble polymer supports allow expeditious transfer of
solution-based synthetic protocols, circumventing the exten-
sive optimization process often required in heterogeneous
reactions.7,8 After the addition of an appropriate poor sol-
vent, the polymer support can be precipitated and filtered,
allowing its expeditious recovery.
Our group has undertaken a research program to develop
novel chiral auxiliaries using NCPS as support.11,12 In this
article, we report the synthesis of a new NCPS-supported
oxazolidine-2-selone chiral auxiliary from N-Boc-L-tyrosine
ethyl ester (Scheme 1). Reagents and conditions: (a) K2CO3
(2.0 equiv), BnBr (1.2 equiv), DMF (dimethylformamide),
40 8C, 24 h; (b) LiAlH4 (1.2 equiv), THF, 0 8C ~ RT (RT,
room temperature), 18 h; (c) acetyl chloride (1.1 equiv),
EtOAc–MeOH (1:2, v/v), 0 8C ~ RT, 24 h ; (d) DMF–DMA
(dimethyl acetal) (1.1 equiv), TsOH (catalytic amount), N2,
toluene, reflux, 48 h; (e) 20% Pd(OH)2 (catalytic amount),
THF–MeOH (1:1, v/v), RT, 6 h; (f) K2CO3 (3.5 equiv),
functionalized NCPS (1, 1.05 equiv), 40 8C, 24 h; and (g)
Methyl lithium (1.2 equiv), hexamethyl disilylamine
(1.15 equiv), Se (1.0 equiv), –78 8C ~ RT, 2 h.
Results and discussion
As shown in Scheme 1, NCPS-supported oxazolidine-2-
selone was synthesized using N-Boc-L-tyrosine ethyl ester
as the starting material. A benzylation reaction is used as
the most common way to protect the hydroxy, therefore, N-
Boc-L-tyrosine ethyl ester was first treated with BnBr to
Non-cross-linked polystyrene (NCPS) and functionalized
NCPS show a more restrictive solubility profile because of
their high stereoregular configuration of phenyl rings along
Received 24 July 2010. Accepted 17 October 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 5 January
2011.
X. He, J. Li, C. Lu,1 Z. Chen, and G. Yang. Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic
Functional Molecules, Faculty of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, P.R. China.
1Corresponding author (e-mail: lucuifen0511@yahoo.com.cn).
Can. J. Chem. 89: 88–91 (2011)
doi:10.1139/V10-162
Published by NRC Research Press

He et al.
89
Scheme 1. Synthesis of non-cross-linked polystyrene (NCPS)-supported oxazolidine-2-selenone 8.
afford the benzylated product 2 in 80% yield. Then com-
pound 2 was reduced by LiAlH4 to obtain the alcohol 3 in
84% yield. Removal of the Boc group from 3 using acetyl
chloride under MeOH–EtOAc obtained the amino alcohol 4
in 87% yield. Treating 4 with DMF–DMA produced the ox-
azoline 5 through a ring-closing reaction.7 Removal of the
benzyl group of 5 was carried out by 20% Pd(OH)2 under
H2 to provide the chiral oxazoline 6 in 84% yield. Then 6
was linked to 1 to afford NCPS-supported oxazoline 7.
Compound 1 (Fig. 1) was prepared according to ref. 9, by
copolymerizing 4-vinylbenzyl chloride and styrene in a ratio
of 1:4. Finally, 7 was treated with selenium in the presence
of lithium amide to obtain NCPS-supported oxazolidine-2-
selone 8 in 75% yield. The structure of the chiral auxiliary
8 was detected by IR, NMR, elemental analysis, and the
spectrum result was consistent with the molecular structure.
This chiral auxiliary is soluble in typical organic solvents,
such as CHCl3, CH2Cl2, EtOAc, THF, DMF, and benzene,
and insoluble in MeOH, EtOH, and H2O, and this solubility
versus recovery relationship of the crystalline polymer could
lead to better recovery yield of the chiral auxiliary.
Fig. 1. Functionalized non-cross-linked polystyrene (NCPS).
using a sodium D line on a WZZ-2B automatic polarimeter;
IR spectra were recorded on a IR-spectrum one (PerkinElmer)
spectrometer. NMR spectra were recorded on a Varian Unity
INOVA 600 spectrometer in CDCl3 using TMS as the inter-
nal standard; elemental analyses were done on a VarioEL III
(Elementar, Germany) analyzer.
Synthesis of N-Boc-O-benzyl-L-tyrosine ethyl ester (2)
To a solution of N-Boc-L-tyrosine ethyl ester (8.64 g,
27.95 mmol) in dry DMF (50 mL) were added benzyl bro-
mide (3.98 mL, 33.54 mmol), anhyd K2CO3 (7.71 g,
55.90 mmol), and 18-crown-6 (catalytic amount). Then the
resulting mixture was stirred at 40 8C for 24 h. After evapo-
ration of the solvent, the residue was dissolved in ethyl ace-
tate (100 mL) and washed with brine (3 ꢀ 10 mL). The
organic phase was dried over MgSO4, filtered, and concen-
trated to afford a pale yellow solid. Recrystallization from
EtOAc and petroleum ether (PE; 1:5, v/v) gave 2 (8.9 g,
80%); mp 63.2–63.7 8C. ½a2D5ꢁ = +16.2 (c 0.05, THF). IR
(NaCl, cm–1): 3371, 1716, 1611, 1584, 1511. 1H NMR
(CDCl3, 600 MHz) d: 7.43–7.27 (m, 5H), 7.05 (d, J =
7.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.04 (s, 2H), 4.96 (t,
J = 7.8 Hz, 1H), 4.51 (s, 1H), 4.15 (dd, J1 = 7.2 Hz, J2 =
13.8 Hz, 2H), 3.03 (dd, J1 = 6.0 Hz, J2 = 11.4 Hz, 2H),
1.43 (s, 9H), 1.23 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3,
150 MHz) d: 172.1, 158.3, 155.6, 137.7, 131.0, 128.8,
128.6, 128.2, 127.7, 115.2, 80.5, 70.6, 61.3, 54.5, 37.4,
28.3, 14.3.
Conclusions
In conclusion, we have developed a new NCPS-supported
oxazolidine-2-selone chiral auxiliary. This chiral auxiliary
has potential value in asymmetric reactions such as high
stereoselectivity and better recovery yield. Further applica-
tion of this NCPS-supported oxazolidine-2-selone chiral
auxiliary in aldol reactions is currently underway in our lab-
oratory.
Experimental
General
All solvents were obtained from commercial sources and
dried or purified by standard procedures before use. Melting
points were measured on a WRS-1A digital melting point
apparatus and uncorrected; optical rotations were measured
Published by NRC Research Press

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Can. J. Chem. Vol. 89, 2011
Synthesis of N-Boc-O-benzyl-L-tyrosinol (3)
Synthesis of (4S)-4-(4’-p-hydroxy)benzyl-4,5-
dihydrooxazoline (6)
To a solution of compound 2 (8.65 g, 21.65 mmol) in an-
hyd THF (50 mL), LiAlH4 (0.96 g, 25.98 mmol) in THF
(20 mL) was added dropwise at 0 8C. The mixture was al-
lowed to stir at RT for 18 h before acidification to pH 6*7
with 1 N HCl, and the insoluble solid was filtered. After
evaporation of the solvent, the residue was dissolved in
ethyl acetate (100 mL), washed with brine (3 ꢀ 10 mL).
The organic phase was dried over MgSO4, filtered, and con-
centrated to afford a white solid. Recrystallization from
EtOAc and PE (1:3, v/v) gave 3 (6.2 g, 84%); mp 105.0–
105.6 8C. ½a2D5ꢁ = –17.5 (c 0.02, THF). IR (NaCl, cm–1):
3360, 2923, 1816, 1611, 1524, 694. 1H NMR (CDCl3,
600 MHz) d: 7.43–7.26 (m, 5H), 7.12 (d, J = 8.4 Hz, 2H),
6.91 (d, J = 8.4 Hz, 2H), 6.05 (s, 2H), 5.03 (s, 2H), 3.81
(m, 1H), 3.63 (m, 1H), 3.58 (m, 1H), 2.77 (d, J = 7.2 Hz,
2H), 1.42 (s, 9H). 13C NMR (CDCl3, 150 MHz) d: 158.6,
156.5, 137.3, 130.1, 129.4, 128.5, 127.8, 115.6, 80.3, 70.5,
64.7, 60.3, 54.1, 37.5, 29.3.
Compound 5 (1.34 g, 5.0 mmol) was dissolved in THF
(25 mL) and MeOH (25 mL), and 20% Pd(OH)2 (0.27 g)
was added, and the mixture was then stirred under H2 at
room temperature for 6 h. After filtration through Celite,
washing with methanol and THF, and evaporation of the
solvents, the residue was purified by flash column chroma-
tography (EtOAc–PE–Et3N, 1:2:1, v/v) to give 6 (0.74 g,
84%) as a white solid; mp 60.5–60.8 8C. ½a2D0ꢁ = –68.6 (c
0.04, MeOH). IR (NaCl, cm–1): 3197, 1628, 1515, 1380,
1
1244. H NMR (CDCl3, 600 MHz) d: 8.10 (s, 1H), 7.12 (d,
J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 5.40 (s, 1H), 4.24
(t, J = 4.2 Hz, 1H), 3.84 (d, J = 8.4 Hz, 1H), 3.52 (dd, J1 =
4.8 Hz, J2 = 12.4 Hz, 1H), 2.64 (m, 2H). 13C NMR (CDCl3,
150 MHz) d: 160.4, 157.9, 130.6, 130.4, 115.3, 76.2, 70.2,
39.8.
Synthesis of NCPS-supported (4S)-4-substituted 4,5-
dihydrooxazoline (7)
Synthesis of O-benzyl-L-tyrosinol (4)
To a solution of compound 6 (0.66 g, 3.71 mmol) in DMF
(30 mL) were added the functionalized NCPS 1 (2.20 g), an-
hyd K2CO3 (1.80 g, 13.0 mmol), and 18-crown-6 (catalytic
amount). The resulting mixture was stirred at 40 8C for
24 h. Then most of the solvent was removed under reduced
pressure. The viscous solution was dropped into cold EtOH
(100 mL), and the precipitated solid was filtered and dried
to afford polymer 7 (2.43 g, 85%). IR (NaCl, cm–1): 3302,
1629, 1237, 699. 13C NMR (CDCl3, 150 MHz) d: 158.0,
155.0, 145.5, 130.4, 130.1, 128.2, 127.8, 125.9, 115.1, 70.8,
70.2, 66.9, 52.0, 41.0, 40.5. Elementary analysis for polymer
7: C, 86.31%; H, 7.21%; N, 1.89%.
To a solution of compound 3 (5.6 g, 15.68 mmol) in
mixed solvents of EtOAc (30 mL) and MeOH (60 mL) was
added acetyl chloride (3.91 mL, 31.36 mmol) at 0 8C. After
30 min, the reaction mixture was stirred at RT for 24 h.
NaOH (1.5 N) was added to counteract produced acids,
then most of the solvent was removed under reduced pres-
sure. The residue was dissolved in CH2Cl2 (100 mL) and
washed with brine (3 ꢀ 10 mL). The organic phase was
dried over MgSO4, filtered, and concentrated to afford a yel-
low solid. The crude product was further purified by column
chromatography (MeOH–CH2Cl2, 1:20, v/v) to give 4 (3.5 g,
87%); mp 174.4–174.8 8C. ½a2D5ꢁ = –12.0 (c 0.04, CH3OH).
IR (NaCl, cm–1): 3704, 3360, 3032, 1609, 1580, 748. H
1
Synthesis of NCPS-supported (4S)-4-benzyloxyl
oxazolidine-2-selenone (8)
NMR (CDCl3, 600 MHz) d: 7.45–7.35 (m, 5H), 7.19 (d, J =
8.4 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H), 5.13 (s, 2H), 3.74–
3.55 (m, 2H), 3.47 (m, 1H), 2.89 (d, J = 6.6 Hz, 1H), 2.77
(t, J = 6.9 Hz, 1H), 1.85 (s, 3H). 13C NMR (CDCl3,
150 MHz) d: 157.3, 137.5, 131.1, 130.6(2C), 129.7, 128.3,
127.8, 115.6, 70.1, 66.2, 54.7, 40.1.
Methyllithium (2.26 mL, 3.17 mmol) and hexamethyl di-
silylamine (0.63 mL, 3.04 mmol) were added to dry THF
(15 mL) under N2 at 0 8C. The solution was stirred for
10 min and then cooled to –78 8C. Compound 7 (1.50 g,
2.64 mmol) in dry THF (30 mL) was added dropwise to the
solution and the mixture was stirred for 30 min at –78 8C.
Se (0.24 g, 2.68 mmol) was added in batches, stirred for an
additional 2 h at RT, and then the pH was adjusted to 4–5
by aq saturated citric acid. After filtrating through Celite,
the filtrate was concentrated under reduced pressure. The
viscous solution was dropped into cold EtOH (50 mL), and
the precipitated solid was filtered and dried to afford poly-
mer 8 (1.30 g, 75%). IR (NaCl, cm–1): 3340, 1510, 1261,
698. 13C NMR (CDCl3, 150 MHz) d: 188.2, 158.1, 137.6,
136.4, 136.3, 130.1, 127.7, 127.1, 126.5, 126.3, 115.7,
114.2, 75.5, 68.8, 56.9, 52.2, 39.2. 77Se NMR (CDCl3,
150 MHz) d: –319.80 (relative to (R)-4-benzyloxazolidine-
2-selenone at –328.70). Elementary analysis for polymer 8:
C, 77.71%; H, 6.58%; N, 1.69%.
Synthesis of (4S)-4-(4’-benzyloxy)benzyl-4,5-
dihydrooxazoline (5)
DMF–DMA (1.16 mL, 8.79 mmol) and TsOH (0.06 g)
under N2 were added to a solution of 4 (2.06 g, 8.0 mmol)
in toluene (85 mL). The solution was refluxed for 48 h in a
flask equipped with a Soxhlet extraction device containing
˚
20 g of 4 A molecular sieves under N2. The reaction mixture
was washed with 10% NaHCO3 (30 mL) and brine (30 mL)
and dried over Na2SO4. The residue was purified by flash
column chromatography (EtOAc–PE–Et3N, 1:4:1, v/v) to
give 5 (1.71 g, 80%) as a white solid; mp 117.9–118.3 8C.
1
IR (NaCl, cm–1): 3035, 1630, 1513, 1114. H NMR (CDCl3,
600 MHz) d: 8.10 (s, 1H), 7.30–7.42 (5H, m), 7.09 (d, J =
9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 5.01 (s, 2H), 4.18 (t,
J = 3.0 Hz, 1H), 3.70 (d, J = 7.2 Hz, 1H), 3.58 (dd, J1 =
3.6 Hz, J2 = 10.2 Hz, 1H), 2.82 (m, 2H). 13C NMR (CDCl3,
150 MHz) d: 161.8, 157.9, 137.2, 130.6, 130.4, 129.7, 128.8,
127.7, 115.3, 70.2, 63.8, 52.2, 36.2.
Acknowledgments
We gratefully acknowledge the National Natural Sciences
Foundation of China (grant Nos. 20772026 and 20372019).
Published by NRC Research Press

He et al.
91
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