A new non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine chiral auxiliary: Synthesis and application in asymmetric alkylation reactions

Article abstract of DOI:10.1002/ejoc.201000981

The synthesis of novel non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine is described, and its use as a chiral auxiliary in asymmetric alkylation reactions is demonstrated by the synthesis of several chiral amides (>96%ee). Furthermore, recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without appreciable reduction in the yield or stereoselectivity. The synthesis of novel non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine is described, and its use as a chiral auxiliary in asymmetric alkylation reactions is demonstrated by the synthesisof several chiral amides (>96%ee). Recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without appreciable reduction in the yield or stereoselectivity.

Full text of DOI:10.1002/ejoc.201000981

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000981
A New Non-Cross-Linked Polystyrene Supported 2-Phenylimino-2-oxazolidine
Chiral Auxiliary: Synthesis and Application in Asymmetric Alkylation
Reactions
Fu-Qiang Hu,[a] De-Xin Xia,[a] Cui-Fen Lu,[a] Zu-Xing Chen,[a] and Gui-Chun Yang*[a]
Keywords: Chiral auxiliaries / Heterocycles / Asymmetric synthesis / Alkylation / Amides
The synthesis of novel non-cross-linked polystyrene sup-
ported 2-phenylimino-2-oxazolidine is described, and its use
as a chiral auxiliary in asymmetric alkylation reactions is
demonstrated by the synthesis of several chiral amides
(Ͼ96%ee). Furthermore, recovery and recycling of the poly-
mer-supported chiral auxiliary were successfully achieved
without appreciable reduction in the yield or stereoselecti-
vity.
shown because of nonlinear kinetic behavior, unequal dis-
tribution or access to the chemical reaction, and synthetic
difficulties in transferring standard organic reactions to the
solid phase. Soluble polymer supports, which combine the
superiorities of insoluble polymer supports with the advan-
tages of classic liquid synthesis, have been extensively
studied by chemists.[14] In previous reports, our group has
undertaken a research program to develop several chiral
auxiliaries by using non-cross-linked polystyrene (NCPS) as
a support and to investigate their applications in asymmet-
ric synthesis.[15] In this article, we wish to report the prepa-
ration of a new soluble NCPS supported 2-phenylimino-2-
oxazolidine chiral auxiliary and the preliminary results of
our investigations concerning the asymmetric alkylation re-
actions on this compound, and the potential for recycling
of the chiral auxiliary.
Introduction
Chiral auxiliary derived asymmetric alkylation reactions
have been studied extensively and are now important and
useful methods for asymmetric carbon–carbon bond forma-
tion.[1] Within this area, the oxazolidinones, so called
Evans’ auxiliary,[2] are arguably the most successful of the
chiral auxiliary systems currently available for asymmetric
transformations based on acyl group reactivity.[3] However,
this auxiliary undergoes endocyclic cleavage rather than the
required exocyclic cleavage in the removal of the auxiliary
with alkaline hydrolysis.[4] The thiazolidinethione chiral
auxiliary,[5] which has been utilized in a wide variety of syn-
thetic transformations such as asymmetric aldol condensa-
tions,[6,7] is also useful for the formation of asymmetric
carbon–carbon bonds. Recently, a new class of chiral auxil-
iary, 2-phenylimino-2-oxazolidine, has been developed.[8]
This improved auxiliary provides superior performance to
many other chiral auxiliaries currently in common usage
and has been proved to be particularly efficient in terms of
stereoselectivity and yields in asymmetric alkylation reac-
tions.[9,10] However, in most case, the expensive chiral auxil-
iaries could not be recovered after the reactions; to recycle
these expensive materials, chiral auxiliaries have been sup-
ported onto polymers.[11–15]
Results and Discussion
As is shown in Scheme 1, we used 2-[(S)-4-(4Ј-vinylbenz-
yloxy)benzyl]amino-1-ol (1) as starting material, which can
be conveniently obtained from N-Boc--tyrosine ethyl es-
ter.[16] Thiourea 2 was readily prepared from the reaction
of 1 with phenyl isothiocyanate, and 2-phenylimino-2-ox-
azolidine 3 was easily obtained from the cyclization of thio-
urea 2 by using p-TsCl and NaOH. One of the remarkable
features of chiral auxiliary 3 is that it has a styrene group,
which is required to act as a “handle” for its coupling to a
suitably functionalized polymer support.
Insoluble polymer supports, such as, Merrifield resin and
Wang resin, only require simple “filtration” to achieve
rapidly the isolation of desired compounds or to recover
expensive reagents or catalysts attached onto solid supports
for recycling.[12,13] However, several shortcomings were
NCPS-supported chiral auxiliary 4 was prepared by co-
polymerizing 3 and styrene in a ratio of 1:3, and it showed
good solubility in solvents such as CH2Cl2, CHCl3, and
THF. The loading capacity (1.42 mmolg–1) of chiral auxil-
iary 4 was analyzed by nitrogen elemental analysis.
[a] Ministry-of-Education Key Laboratory for the Synthesis and
Application of Organic Functional Molecules & School of
Chemistry and Chemical Engineering, Hubei University,
Wuhan 430062, China
Fax: +86-27-88663043
E-mail: yangguichun@hubu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000981.
To understand the efficacy of designed NCPS-supported
4 as a new chiral auxiliary, we first studied the asymmetric
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Non-Cross-Linked Polystyrene Supported Chiral Auxiliary
Table 1. Results of asymmetric alkylation reactions.
Entry Product
R1
R2
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
CH3
CH3
CH3
Ph
Ph
Ph
C6H5CH2
CH2=CHCH2
4-NO2C6H4CH2
C6H5CH2
CH2=CHCH2
4-NO2C6H4CH2
67
63
65
68
62
69
99
98
96
99
98
96
[a] Overall yield in three steps starting from 4 (see Scheme 1).
[b] Determined by HPLC analysis.
were obtained in high stereoselectivity (99%ee; Table 2).
Obviously, in these cycles, the stereoselectivity of the prod-
uct was maintained successfully, although the yield de-
creased slightly in each cycle. The results show that the re-
covery of chiral auxiliary 4 was successful.
Table 2. Recycling of NCPS-supported chiral auxiliary 4 in asym-
metric alkylation reactions.
Cycle
Yield [%][a]
ee [%][b]
1
2
3
4
67
65
64
63
99
99
99
99
[a] Overall yield in three steps starting from 4. [b] Determined by
HPLC analysis.
Scheme 1.
Conclusions
In conclusion, we have developed a new NCPS-sup-
ported 2-phenylimino-2-oxazolidine chiral auxiliary and
found it to be a useful tool to perform asymmetric alky-
lation reactions in good yield and stereoselectivity. In ad-
dition, NCPS-supported chiral auxiliary 4 was easily reco-
vered and could be reused more than three times without
appreciable reduction in the yield or stereoselectivity.
alkylation on this compound. Chiral auxiliary 4 was acyl-
ated with phenylacetyl chloride or propionyl chloride to
give the corresponding acylated product 5 (Scheme 1). For-
mation of the lithium enolate at –78 °C by using LDA oc-
curred in THF and then subsequent addition of the alkyl
bromide led to the formation of alkylated products 6. The
identities of purified products 6 were determined by IR and
13C NMR spectroscopic analyses. Treatment of alkylated
Experimental Section
products
6 with benzylamine yielded several chiral
amides[16] 7a–f in good yield as well as high optical purity
(Ͼ96%ee; Table 1), which were analyzed by HPLC.
A higher stereoselectivity was observed by using chiral
auxiliary 4 instead of Merrifield resin supported Evans’
chiral auxiliary,[13b] and the yield was found to be quite
similar. In comparison to the related 2-phenylimino-2-
oxazolidine chiral auxiliary, the stereoselectivity was similar
to those reported for the model alkylation reactions under
classical solution conditions.[9,10] These results show
that NCPS-supported 2-phenylimino-2-oxazolidine chiral
auxiliary 4 is an effective auxiliary for asymmetric alk-
ylation reactions, and it can be recovered by simple fil-
tration.
Preparation of NCPS-Supported 2-Phenylimino-2-oxazolidine (4):
To a solution of monomer 3 (2.0 g, 5.12 mmol) in THF (25 mL)
was added styrene (1.59 g, 15.38 mmol) and AIBN (0.02 g,
0.12 mmol). The mixture was copolymerized at 70 °C for 96 h un-
der a nitrogen atmosphere. Then, most of the solvent was removed
under reduced pressure. The viscous solution was dropped into
cold ethanol (150 mL), and the precipitated solid was filtered and
washed with ethanol (3ϫ10 mL) to remove any micromolecules
(TLC detecting) and dried at 65 °C for 2 h under vacuum to afford
polymer 4 (2.72 g, 70%). IR (NaCl): ν = 3321, 1680 cm–1. 13C
˜
NMR (150 MHz, CDCl3): δ = 157.3, 156.9, 148.5, 146.2, 134.2,
131.0, 129.4, 128.5, 126.8, 120.5, 114.4, 72.9, 70.3, 67.5, 40.2 ppm.
Polymer 4: calcd. C 84.45, H 6.94, N 4.02; found: C 84.50, H 6.97,
N 3.98. Compound 3 was copolymerized with styrene with a radio
of 1:3; the theoretical structural unit of polymer 4 was composed
of 1 mol 3 and 3 mol styrene, so the calculated analysis of polymer
4 was obtained by calculating the contents of C, H, N in the sum
of 1 mol 3 and 3 mol styrene.
To further investigate the ability of recycling NCPS-sup-
ported 4, recovered 4 was washed and dried and then sub-
jected to N-acylation with phenylacetyl chloride and alky-
lation with benzyl bromide to give once again the corre-
sponding alkylation product 6. After the second to fourth
General Procedure for the Synthesis of NCPS-Supported-N-
asymmetric alkylation reactions, the desired chiral amides Propionyl-2-phenylimino-2-oxazolidine (5a): To a solution of poly-
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5553

F.-Q. Hu, D.-X. Xia, C.-F. Lu, Z.-X. Chen, G.-C. Yang
SHORT COMMUNICATION
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mer 4 (2.01 g) in CH2Cl2 (30 mL) was added DMAP (0.074 g,
0.60 mmol), Et3N (0.49 mL, 3.32 mmol), and then propionyl chlo-
ride (0.32 mL, 3.62 mmol) in CH2Cl2 (10 mL) was added dropwise
to the reaction mixture at 0 °C. The resulting mixture was stirred
at 25 °C for 1 h. The reaction was quenched with saturated aqueous
NH4Cl, and the organic layer was separated. The aqueous layer
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combined, washed with saturated aqueous NaHCO3 and brine,
dried with MgSO4, filtered, and most of the solvent was removed
under reduced pressure. The viscous solution was dropped into
cold ethanol and the precipitated solid was filtered and dried at
65 °C for 2 h under vacuum to afford polymer 5.
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General Procedure for the Synthesis of Compounds 6: To a dry
round-bottomed flask under a nitrogen atmosphere was added 7
(1.50 g) in anhydrous THF (30 mL). The solution was cooled to
–78 °C and 2.0  LDA (2.25 mL, 4.5 mmol) was added in THF
(10 mL), and the solution was allowed to stir at –78 °C for 1 h.
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6.75 mmol). After stirring for 30 min at –78 °C and 1 h at 0 °C, the
reaction was quenched with saturated aqueous NH4Cl (10 mL) and
extracted with CH2Cl2 (3ϫ30 mL). The combined organic layers
were dried with MgSO4 and filtered. Then, most of the solvent
was removed under reduced pressure, and the viscous solution was
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General Procedure for the Synthesis of Compounds 7: To a solution
of polymer 6 (1.20 g) and acetic acid (0.05 mL, catalytic amount)
in CH2Cl2 was added benzylamine (0.59 mL, 5.40 mmol), and the
reaction mixture was heated at reflux for 12 h at 40 °C. After evap-
oration of the solvent, The viscous solution was dropped into cold
ethanol (150 mL), and the precipitated solid was filtered. The fil-
trate was concentrated, and the crude was purified by column chro-
matograph (ethyl acetate/petroleum ether, 1:20) to give 7.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, additional experimental procedures, and
characterization data of all compounds prepared.
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Acknowledgments
We gratefully acknowledge the National Natural Sciences Founda-
tion of China (No. 20772026, 20372019).
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Received: July 12, 2010
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Published Online: September 10, 2010
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