Asymmetric synthesis of both (R)-and (S)-arundic acid

Article abstract of DOI:10.3184/174751912X13497155982090

The asymmetric synthesis of both (R)-and (S)-arundic acid has been achieved via the key step of a stereoselective alkylation reaction using non-cross-linked polystyrene (NCPS) supported (4R)- and (4S)-2-phenylimino-2- oxazolidine as chiral auxiliaries. This method is efficient (both enantiomers were obtained in 99% ee and 60% overall yield) and the chiral auxiliaries can be recovered quantitatively by simple filtration.

Full text of DOI:10.3184/174751912X13497155982090

678 RESEARCH PAPER
NOVEMBER, 678–679
JOURNAL OF CHEMICAL RESEARCH 2012
Asymmetric synthesis of both (R)-and (S)-arundic acid
Cuifen Lu, Longduo Zhang, Hang Su, Guichun Yang and Zuxing Chen*
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
The asymmetric synthesis of both (R)-and (S)-arundic acid has been achieved via the key step of a stereoselective
alkylation reaction using non-cross-linked polystyrene (NCPS) supported (4R)- and (4S)-2-phenylimino-2-oxazolidine
as chiral auxiliaries. This method is efficient (both enantiomers were obtained in 99% ee and 60% overall yield) and
the chiral auxiliaries can be recovered quantitatively by simple filtration.
Keywords: asymmetric synthesis, arundic acid, chiral auxiliaries, alkylation reaction
(R)-arundic acid (R)-1 (ONO-2506, Fig. 1), which delays the
expansion of cerebral infarcts by modulating the activation
of astrocytes through inhibition of S-100β synthesis, has
been developed as a novel therapeutic agent for stoke and
Alzheimer’s disease.1–3
addition of propyl iodide yielded the alkylated product 4.
Treatment of the alkylated product 4 with LiOH/H2O2 at 0 °C
in THF/H2O, to effect nondestructive removal of the auxiliary
group, gave (R)-arundic acid (R)-1 in good overall yield (62%)
as well as with high enantiomeric purity (99.2% ee), which
was analysed by HPLC, and NCPS supported chiral auxiliary
2 was recovered by simple filtration with 92% yield.
Whereas NCPS supported (4R)-2-phenylimino-2-oxazoli-
dine 2 gave (R)-arundic acid (R)-1, its isomer NCPS supported
(4S)-2-phenylimino-2-oxazolidine 5 should lead to (S)-arundic
acid (S)-1 (Scheme 2). A similar sequence of reactions with 5
also gave (S)-arundic acid (S)-1 in good overall yield (60%)
and high enantiomeric purity (99.0% ee) , and NCPS supported
chiral auxiliary 5 was recovered quantitatively by simple
filtration.
Arundic acid has been a synthetic target in recent years
and a few enantioselective syntheses have been reported.4–16
The strategies employed have been based on resolution of
recemates,4,5 asymmetric alkylation of chiral enolates,6 chiral
auxiliaries,7–10 diastereoselective photodeconjugation,11 metal-
mediated crotylation12 and Johnson–Claisen rearrangement,13,14
asymmetric alkylation of aldehydes by a combination of
transition-metal and chiral amine15 or by the carbenium ion
organocatalyst.16 Although kilogram quantities of (R)-1 have
been prepared by Hasegawa et al.8 through diastereoselective
alkylation of a chiral sulfonamide derived from Oppolzer’s
camphorsultam, the high cost of this auxiliary and the prob-
lems encountered with its recycling are major drawbacks.
Recently, our group has undertaken a research program to
develop a new non-cross-linked polystyrene supported 2-
phenylimino-2-oxazolidine chiral auxiliary and investigated
its applications in asymmetric alkylation reactions.17,18 NCPS
supported 2-phenylimino-2-oxazolidine chiral auxiliary was
found to be a useful tool for asymmetric alkylation with good
yield and stereoselectivity. In addition, this NCPS supported
chiral auxiliary was easily recovered quantitatively by simply
filtration.
Conclusion
In conclusion, both enantiomers of arundic acid were synthe-
sised in 99% ee through the key step of a stereoselective
alkylation using NCPS supported (4R)- and (4S)-2-pheny-
limino-2-oxazolidine as chiral auxiliaries. This method is
efficient and the chiral auxiliaries can be recovered quantita-
tively by simple filtration. In addition to the large availability
of the chiral inductor, the adaptability of the method makes
this approach suitable for the synthesis of various analogues of
arundic acid.
We now report the asymmetric synthesis of both the enan-
tiomers of arundic acid through the key step of a stereoselec-
tive alkylation using our previously prepared NCPS supported
2-phenylimino-2-oxazolidines as chiral auxiliaries.
Experimental
All organic solvents were dried by standard methods. TLCs were
performed on precoated plates of silica gel HF254 (0.5 mm, Yantai,
Results and discussion
Scheme 1 shows our synthesis of (R)-1, and the stereoselective
alkylation reaction induced by NCPS supported 2-pheny-
limino-2-oxazolidine was the key step in the total synthesis
of (R)-1. First, NCPS supported (4R)-2-phenylimino-2-
oxazolidine chiral auxiliary 2, which was prepared starting
from N-Boc D-tyrosine ethyl ester as previously reported,18
reacted with octanoyl chloride in the presence of Et3N and
DMAP to give NCPS supported (4R)-N-octanoyl-2-phenyl-
imino-2-oxazolidine 3. Then 3 was treated with NaHMDS at
–78 °C to generate the sodium enolate and then subsequent
Fig. 1 Arundic acids.
* Correspondent. E-mail: chzux@hubu.edu.cn
Scheme 1 Asymmetric synthesis of (R)-arundic acid.

JOURNAL OF CHEMICAL RESEARCH 2012 679
mixture of THF/H2O (100 mL). The reaction was stirred overnight at
room temperature and then concentrated under reduced pressure. The
organic layer was extracted with CH2Cl2 (3×100 mL), concentrated,
precipitated in cold EtOH, filtered to recover quantitatively the chiral
auxiliary 2 (6.45 g, 92% recovery yield). Acidification of the aqueous
layer to pH = 1 and extraction with EtOAc furnished the desired acid
(R)-1 (1.65 g, 62% overall yield). 99.2% ee [HPLC, Chiralcel OJ-RH;
MeCN/H2O = 60/40; flow rate, 0.5 mL min−1; detection, 244 nm;
retention time, 22.73 min (S), 24.29 min (R)] after conversion into
the corresponding phenacyl ester (phenacyl bromide, Et3N, CH2Cl2);
[α]2D5 = –6.5 (c 1.2, EtOH), lit.9 [α]2D5 = –6.8 (c 0.82, EtOH) for
1
(R)-arundic acid; IR (NaCl): υ = 1706, 1419, 944 cm−1; H NMR
(600 MHz, CDCl3): δ 2.38–2.34 (1H, m), 1.64–1.59 (2H, m), 1.49–
1.43 (2H, m), 1.38–1.26 (10H, m), 0.91 (3H, t, J = 7.2 Hz), 0.87 (3H,
t, J = 6.6 Hz); 13C NMR (150 MHz, CDCl3): δ 183.0, 45.2, 34.2, 32.0,
31.5, 29.1, 27.2, 22.5, 20.4, 13.9, 13.7.
Synthesis of (S)-arundic acid (S)-1
Following the same procedures described above for its enantiomer
(R)-1, from NCPS supported (4S)-2-phenylimino-2-oxazolidine 5
(10.0 g, 14.2 mmol, loading: 1.42 mmol g−1 polymer) via three steps
to obtain (S)-arundic acid (S)-1 (1.60 g, 60% overall yield). 99.0% ee
[HPLC, Chiralcel OJ-RH; MeCN/H2O = 60/40; flow rate, 0.5 mL
min−1; detection, 244 nm; retention time, 22.73 min (S), 24.29 min
(R)] after conversion into the corresponding phenacyl ester (phenacyl
bromide, Et3N, CH2Cl2); [α]2D5 = +6.2 (c 1.2, EtOH), lit.9 [α]2D5 = +6.6
(c 0.54, EtOH) for (S)-arundic acid; IR (NaCl): υ = 1706, 1419,
Scheme 2 Asymmetric synthesis of (S)-arundic acid.
China). Optical rotations were determined with a Perkin–Elmer Model
241 MC polarimeter. IR spectra were recorded with an IR-spectrum
one (PE) spectrometer. 1H NMR (600 MHz) and 13C NMR (150 MHz)
spectra were recorded with a Varian Unity INOVA 600 spectrometer
in CDCl3 by using TMS as an internal standard. HPLC analyses were
carried out on a Dionex chromatograph (Chiralcel OJ-RH; CH3CN/
H2O=60:40; flow rate, 0.5 mL min−1; detection, 244 nm).
1
944 cm−1; H NMR (600 MHz, CDCl3): δ 2.38–2.34 (1H, m), 1.64–
1.59 (2H, m), 1.49–1.43 (2H, m), 1.38–1.26 (10H, m), 0.91 (3H, t,
J = 7.2 Hz), 0.87 (3H, t, J = 6.6 Hz); 13C NMR (150 MHz, CDCl3):
δ 183.0, 45.2, 34.2, 32.0, 31.5, 29.1, 27.2, 22.5, 20.4, 13.9, 13.7.
We gratefully acknowledge the National Natural Sciences
Fundation of China (No. 20772026 and 21042005) and the
Natural Sciences Foundation of Hubei province in China (No.
2010CDA019) for financial support.
Synthesis of NCPS supported (4R)-N-octanoyl-2-phenylimino-2-
oxazolidine 3
Et3N (2.9 mL, 21.3 mmol) and DMAP (0.36 g, 2.84 mmol) were
added to NCPS supported (4R)-2-phenylimino-2-oxazolidine 2
(10.0 g, 14.2 mmol, loading: 1.42 mmol g−1 polymer) in CH2Cl2
(100 mL) and then octanoyl chloride (7.3 mL, 42.6 mmol) in CH2Cl2
(20 mL) was added dropwise to the reaction mixture at 0 °C. The
resulting mixture was stirred at room temperature for 3 h. The reaction
was quenched with saturated aqueous NH4Cl (20 mL), and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(3×100 mL). The organic layers were combined, washed with satu-
rated 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 EtOH and the precipitated solid was
filtered and dried at 65 °C for 2 h under vacuum to afford polymer 3
(10.6 g, 90%). IR (NaCl): υ = 1715, 1678, 1510, 787, 699 cm−1; 13C
NMR (CDCl3, 150 MHz): δ 173.3, 158.5, 147.8, 139.2, 130.5, 130.0,
129.6, 127.6, 127.3, 125.6, 122.4, 113.4, 112.5, 67.9, 56.2, 38.1, 36.5,
34.3, 31.5, 29.2, 24.7, 22.8, 14.0.
Received 30 August 2012; accepted 20 September 2012
Paper 1201489 doi: 10.3184/174751912X13497155982090
Published online: 12 November 2012
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4 (8.7 g, 78%). IR (NaCl): υ = 1716, 1675, 1511, 789, 701 cm−1; 13
NMR (CDCl3, 150 MHz): δ 173.5, 158.7, 147.7, 139.6, 130.7, 130.0,
129.5, 127.7, 127.3, 125.6, 122.8, 113.6, 112.5, 67.8, 56.5, 42.4, 37.8,
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C
Synthesis of (R)-arundic acid (R)-1
The polymer 4 (8.7 g, 10.06 mmol) was treated at 0 °C with LiOH
(0.48 g, 20.12 mmol) and 30% H2O2 (6.15 mL, 60.36 mmol) in a 4:1

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