A new process for the synthesis of (2S,3S)-2-ethyl-3-methylvaleramide

Article abstract of DOI:10.3184/174751914X13975731462355

A new process for synthesis of (2S,3S)-2-ethyl-3-methylvaleramide has been developed via the key step of a diastereoselective alkylation reaction using non-cross-linked polystyrene (NCPS) supported (4S)-2-phenylimino-2-oxazolidine as a chiral auxiliary. This method is efficient with the target product obtained in 99.24% ee and 38.4% overall yield and the chiral auxiliaries can be recovered quantitatively by simple filtration.

Full text of DOI:10.3184/174751914X13975731462355

306 RESEARCH PAPER
VOL. 38 MAY, 306–308
JOURNAL OF CHEMICAL RESEARCH 2014
A new process for the synthesis of (2S,3S)-2-ethyl-3-methylvaleramide
Cuifen Lu, Taotao Lu, Qunqi Nie, Guichun Yang and Zuxing Chen*
Hubei Collaborative Innovation Center for Advanced Organochemical Materials & Ministry-of-Education Key Laboratory for the Synthesis and
Application of Organic Functional Molecules, Hubei University, Wuhan 430062, P.R. China
A new process for synthesis of (2S,3S)-2-ethyl-3-methylvaleramide has been developed via the key step of a diastereoselective
alkylation reaction using non-cross-linked polystyrene (NCPS) supported (4S)-2-phenylimino-2-oxazolidine as a chiral auxiliary.
This method is efficient with the target product obtained in 99.24% ee and 38.4% overall yield and the chiral auxiliaries can be
recovered quantitatively by simple filtration.
Keywords: synthesis, (2S,3S)-2-ethyl-3-methylvaleramide, chiral auxiliary, diastereoselective alkylation
Valnoctamide (2-ethyl-3-methylvaleramide, Nirvanil®, VCD),
endowed with anticonvulsant properties, is used clinically as a
mild tranquiliser in several European countries.1 Valnoctamide
contains two stereogenic carbon atoms and exists commercially
as a mixture of four stereoisomers. Bialer and co-workers have
demonstrated that individual VCD stereoisomers exhibits
different pharmacokinetics and/or pharmacodynamics profiles,
and their preclinical testing showed that the (2S,3S)-2-ethyl-3-
methylvaleramide isomer ((2S,3S)-VCD) is more potent and
selective in various pain and antiepileptic models.2–4
a chiral auxiliary through the key step of a diastereoselective
α-alkylation with a stereogenic centre at the β-position which
might have an influence on the stereoselectivity of α-alkylation.
Results and discussion
As shown in Scheme 1, the diastereoselective alkylation reaction
induced by NCPS supported 2-phenylimino-2-oxazolidine was
the key step in the total synthesis of (2S,3S)-VCD. First, NCPS
supported (4S)-2-phenylimino-2-oxazolidine chiral auxiliary 1
reacted with the key intermediate (3S)-methyl valeroyl chloride
2 which was prepared according to a literature procedure, in
the presence of Et3N and DMAP to give NCPS supported (4S)-
N-isovaleryl-2-phenylimino-2-oxazolidine 3. The enolate of
3 was generated by reaction with NaHMDS at –78 °C for 1 h.
followed by the addition of ethyl iodide yielding the alkylated
product 4. The alkylated product 4 was treated with LiOH/H2O2
at 0 °C in THF/H2O to afford (2S,3S)-2-ethyl-3-methylvaleric
acid 5 along with the recovery of the chiral auxiliary 1, while
the endocyclic cleavage problem may be overcome by deploying
the more nucleophilic species LiOOH for hydrolysis.12 (2S,3S)-
2-ethyl-3-methylvaleric acid 5 was treated with SOCl2 and NH3.
H2O respectively as previously reported 6 to afford (2S,3S)-VCD
6 in good overall yield (38.4%) and high enantiomeric purity
(99.24% ee), which was analysed by chiral GC. Moreover,
NCPS supported chiral auxiliary 1 was recovered in 92.4%
yield. The ee (99.24%) is slightly higher than the ee (99.0%) of
(S)-arundic acid, so we deduced that the stereogenic centre at
the β-position may have a positive effect on the stereoselectivity
of α-alkylation.
Recently optically pure (2S,3S)-VCD has been synthesised
by several researchers.5–9 Bialer and co-workers have reported
a stereoselective synthetic method for both stereoisomers
(2S,3S)-VCD and (2R,3S)-VCD using chiral oxazolidinone
auxiliaries.5 This method required the use of the highly
reactive and expensive alkylating agent ethyl triflate due to
the low nucleophilicity of the enolate. Later Li and co-workers
developed an efficient and scaleable synthesis of (2S,3S)-
VCD using (1S,2S)-pseudoephedrine as a chiral auxiliary.6
Although kilogram quantities of (2S,3S)-VCD can be provided,
the high cost of the auxiliary and the problems encountered
with its recycling are major drawbacks. Analogously, Yang
and co-workers have reported a stereoselective synthetic
method for both stereoisomers (2S,3S)-VCD and (2R,3S)-
VCD using chiral 2-phenylimino-2-oxazolidine auxiliaries,7
but they also encountered difficulties in the recovery of chiral
auxiliaries. Alexakis and co-workers have recently reported a
highly enantioselective synthetic method by the asymmetric
copper-catalysed addition of dialkylzinc to enals followed
by organocatalysed one-pot aldehyde α-functionalisation.8
However, separation of the organocatalyst from the product is
still the issue that needs to be addressed in this method. Chen
and co-workers have reported a synthetic method for (2S,3S)-
VCD by a stereoselective catalytic reaction under the catalysis
of a bio-enzyme.9 A bio-enzyme is a kind of highly effective
biological catalyst, but high temperature, acid, alkali and heavy
metal ions can lead to deactivation.
Conclusion
In conclusion, (2S,3S)-VCD was synthesised in 99.24% ee and
38.4% overall yield through the key step of a diastereoselective
alkylation using NCPS supported (4S)-2-phenylimino-2-
oxazolidine as a chiral auxiliary. This method is efficient and
the chiral auxiliary can be recovered quantitatively by simple
filtration.
The non-cross-linked polystyrene (NCPS) supported
2-phenylimino-2-oxazolidine chiral auxiliary, developed by
our group,10 has proved to be particularly efficient in terms of
stereoselectivity and yield in asymmetric alkylation reactions.
Most importantly, this NCPS supported chiral auxiliary is
easily recovered quantitatively by simply filtration. So it is a
good candidate to synthesise optically pure drugs. In a previous
paper, we have reported asymmetric synthesis of both (R)-and
(S)-arundic acids,11 and we now report the synthesis of (2S,3S)-
VCD using NCPS supported 2-phenylimino-2-oxazolidine as
Experimental
All organic solvents were dried by standard methods. TLCs were
performed on precoated plates of silica gel HF254 (0.5 mm, Yantai,
P.R. China). Separations by flash chromatography were performed
on 300–400 mesh silica gel (Yantai, P.R. China). Melting points were
measured on a WRS-1A digital melting point apparatus. Optical
rotations were measured using a sodium D line on WZZ-2B automatic
polarimeter. IR spectra were recorded with an IR-spectrum one (PE)
1
spectrometer. H 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. GC analyses were carried out on
a Shimadzu GC-2010 chromatograph. The column used was an Agilent
* Correspondent. E-mail: chzux@hubu.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2014 307
NPh
NH
NPh
O
NPh
O
O
O
O
N
O
N
Cl
NaHMDS, THF
CH3CH2I, –78oC
LiOH, H2O2
THF/H2O
2
DMAP, Et3N,
THF, 0oC~rt.
O
O
O
4
1
3
O
O
SOCl2
OH
NH2
NH3.H2O
6
5
(2S,3S)-VCD
Scheme 1 Synthesis of (2S,3S)-2-ethyl-3-methylvaleramide.
Cyclodex-B chiral capillary column (30 mm×0.25 mm×0.25 μm).
The carrier gas was argon, the flow was set at 1.5 mL min–1, injector at
250 °C, column at 120 °C.
(2S,3S)-2-Ethyl-3-methylvalericꢀ acid (5): The polymer 4 (506 g)
was treated with LiOH (26.7 g, 1.1 mol) and 30% H2O2 (0.38 L,
3.3 mol) at 0°C in a 4:1 mixture of THF/H2O (1 L). The reaction was
stirred at room temperature overnight and then concentrated under
reduced pressure. The organic layer was extracted with CH2Cl2
(3×0.5 L), concentrated, precipitated in cold EtOH, filtered to recover
quantitatively the chiral auxiliary 1 (462 g, 92.4% recovered yield).
Acidification of the aqueous layer to pH=1 and extraction with EtOAc
furnished the chiral carboxylic acid 5 as a faint yellow oil (64.5 g,
63% overall yield). [α]2D0 = +2.24 (c 1.45, MeOH), lit.6 [α]2D0 = +2.0 (c
NCPSꢀꢀꢀꢀsupportedꢀꢀꢀꢀ(4S)-N-((3′S)-methyl)-pentyl-2-phenylimino-
2-oxazolidine (3): Et3N (116 mL, 0.85 mol) and DMAP (18 g,
0.142 mol) were added to a stirred solution of NCPS supported (4S)-
2-phenylimino-2-oxazolidine 1 (500 g, 0.71 mol, loading: 1.42 mmol
g–1 polymer) in CH2Cl2 (1 L), and then (3S)-methyl valeroyl chloride
(124 g, 0.92 mol) in CH2Cl2 (0.1 L) was added dropwise to the
reaction mixture at 0 °C. The resulting mixture was warmed to room
temperature and stirred for 3 h. The reaction was quenched with
saturated aqueous NH4Cl (0.1 L), and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3×0.5 L), and then
the organic layers were 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 EtOH and the precipitated solid was filtered
and dried at 65 °C for 2 h under vacuum to afford polymer 3 (515 g).
IR (NaCl): υ=1705, 1683, 1510, 757, 699 cm–1; 13C NMR (CDCl3,
150 MHz): δ 172.9, 158.1, 145.0, 139.2, 130.5, 130.0, 129.2, 128.9, 128.5,
127.9, 125.6, 115.1, 69.9, 56.0, 44.1, 40.3, 31.8, 31.4, 29.3, 29.1, 19.2, 11.1.
NCPSꢀꢀꢀsupportedꢀꢀꢀ(4S)-N-((2′S)-ethyl-(3′S)-methyl)-pentyl-2-
1
1.0, MeOH); IR (NaCl): υ=1704, 1416, 940 cm–1; H NMR (CDCl3,
600 MHz): δꢀ2.23–2.19 (m, 1H), 1.66–1.65 (m, 2H), 1.56–1.53 (m, 2H),
1.24–1.19 (m, 1H), 0.95–0.89 (m, 9H); 13C NMR (CDCl3, 150 MHz):
182.2, 52.0, 36.4, 26.5, 22.4, 16.2, 12.1, 11.1.
(2S,3S)-2-Ethyl-3-methylvaleramide (6): The chiral carboxylic acid
5 (64.5 g, 0.45 mol) was added dropwise to SOCl2 (36 mL, 0.5 mol) at
room temperature, and the reaction mixture was stirred for 1.5 h. After
evaporation under reduced pressure to get rid of the excess SOCl2, 25%
NH3.H2O (0.28 L, 2.0 mol) was added to the residue at 0 °C, and the
reaction mixture was warmed to room temperature and stirred for 1 h.
The slurry was dissolved in a 1:1 mixture of acetone/water (0.4 L) at
65 °C and cooled to 0 °C over 12 h. The solid was collected by filtration
and recrystallised from a mixture of petroleum ether and EtOAc (20/1,
V1/V2) to give (2S,3S)-VCD 6 as a white crystalline solid (39.2 g, 38.4%
overall yield). Chiral GC indicated 99.24% (2S,3S), 0.34% (2R,3S)
and 0.42% (2S,3R) isomers. M.p. 130 °C, lit.6 131.5 °C; [α]2D0 = –11.2
(c 1.0, MeOH), lit.6 [α]2D0 = –12.1 (c 1.0, MeOH); IR (NaCl): υ=3373,
phenylimino-2-oxazolidineꢀ (4): Polymer
3 (515 g) in anhydrous
THF (1 L) was added to a dry round-bottomed flask under a nitrogen
atmosphere was added. The solution was cooled to –78°C and 2.0 M
NaHMDS (0.42 L, 0.84 mol) was added, and the solution was allowed
to stir at –78°C for 1 h. Then, ethyl iodide (137 mL, 1.7 mol) was added
and the solution was stirred for 2 h at –78°C and progressively warmed
to room temperature overnight. The reaction was quenched with
saturated aqueous NH4Cl (0.1 L) and extracted with CH2Cl2 (3×0.5 L).
The combined organic layers were 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 inꢀvacuo to afford polymer 4 (506 g).
IR (NaCl): υ=1715, 1674, 1510, 758, 701 cm–1; 13C NMR (CDCl3,
150 MHz): δ 172.9, 158.0, 145.2, 145.1, 130.2, 129.3, 129.1, 128.8, 128.5,
127.9, 127.6, 125.5, 113.6, 112.5, 69.9, 56.5, 44.1, 40.3, 31.8, 31.4, 31.3,
29.2, 29.0, 19.1, 11.1.
1
3188, 2966, 1634 cm–1; H NMR (CDCl3, 600 MHz): δ 6.29 (s, 1H),
5.72 (s, 1H), 1.91–1.87 (m, 1H), 1.60–1.51 (m, 4H), 1.20–1.16(m, 1H),
0.94–0.87 (m, 9H); 13C NMR (CDCl3, 150 MHz): δ 178.2, 53.9, 36.6,
26.4, 23.0, 16.6, 12.2, 10.9.
We gratefully acknowledge the National Natural Sciences
Foundation of China (No. 20772026 and 21042005) and the
Natural Sciences Foundation of Hubei Province in China (No.
2010CDA019) for financial support.
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308 JOURNAL OF CHEMICAL RESEARCH 2014
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Receivedꢀ15ꢀJanuaryꢀ2014;ꢀacceptedꢀ17ꢀMarchꢀ2014
Paperꢀ1402403ꢀdoi:ꢀ10.3184/174751914X13975731462355
Publishedꢀonline:ꢀ6ꢀMayꢀ2014
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