Enantioselective synthesis of (R)-2-methylalkanoic acids: A convenient approach to α-substituted chiral carboxylic acid derivatives

Article abstract of DOI:10.1081/SCC-200030650

Racemization-free deacylation of N-acylimidazolidine-2-ones using lithium hydroperoxide affords the corresponding α-substituted chiral carboxylic acids in high yield while permitting recovery of the chiral auxiliary.

Full text of DOI:10.1081/SCC-200030650

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Enantioselective Synthesis of
(R)‐2‐Methylalkanoic Acids:
A Convenient Approach
to α‐Substituted Chiral
Carboxylic Acid Derivatives
Shyam Shirali a & Aijun Zhang a
a Chemicals Affecting Insect Behavior Laboratory ,
Beltsville Agricultural Research Center‐West
USDA , ARS, Beltsville, Maryland, 20705, USA
Published online: 10 Jan 2011.
To cite this article: Shyam Shirali & Aijun Zhang (2004) Enantioselective Synthesis
of (R)‐2‐Methylalkanoic Acids: A Convenient Approach to α‐Substituted Chiral
Carboxylic Acid Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:18, 3435-3441, DOI:
10.1081/SCC-200030650
To link to this article: http://dx.doi.org/10.1081/SCC-200030650
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 18, pp. 3435–3441, 2004
Enantioselective Synthesis of (R)-2-
Methylalkanoic Acids: A Convenient
Approach to a-Substituted Chiral
Carboxylic Acid Derivatives
*
Shyam Shirali and Aijun Zhang
Chemicals Affecting Insect Behavior Laboratory, Beltsville
Agricultural Research Center-West USDA, Beltsville, Maryland, USA
ABSTRACT
Racemization-free deacylation of N-acylimidazolidine-2-ones using lithium
hydroperoxide affords the corresponding a-substituted chiral carboxylic
acids in high yield while permitting recovery of the chiral auxiliary.
Key Words: Alkylation; Chiral; Enantioselctive; Lithium hydroper-
oxide.
a-Substituted carboxylic acids are useful chiral synthons for many natural
products,[1] and auxiliary-mediated asymmetric alkylation reactions for the
*
Correspondence: Aijun Zhang, Chemicals Affecting Insect Behavior Laboratory,
Beltsville Agricultural Research Center-West USDA, ARS, Beltsville, MD 20705,
USA; E-mail: zhanga@ba.ars.usda.gov.
3435
DOI: 10.1081/SCC-200030650
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3436
Shirali and Zhang
production of enantiomerically pure a-substituted acid derivatives have
recently received a great deal of attention.[2] In this regard, base-assisted alkyl-
ation[6a,b] of N-acylimidazolidine-2-one has created a lot of interest in this
field. Lithium hydroperoxide has been used in chiral auxiliary removal of
N-acylated-oxazolidin-2-one derivatives,[3] D-xylose-derived N-acylated-
oxazolidin-2-one derivatives,[4] N-acylated-dihydropyprimidin-4-one deriva-
tives,[5a] and N-acyl-imidazolidine-2-ones leading to amino acids[5b–f] with
variable ee of newly created chiral centers. In our hands, a number of reagents
were tried for hydrolysis, and here we report the details of our investigation on
the alkylation of N-acylated-imidazolidine-2-one derivatives[6] and the use of
lithium hydroperoxide at 508C for racemization-free deacylation to provide
a-alkylcarboxylic acids. This approach afforded the desired a-substituted car-
boxylic acids in high chemical yield and high enantiomeric purity with conco-
mitant recovery of the chiral auxiliary. The synthetic route is outlined in
Sch. 1.
At the outset, we chose to prepare (4S,5R)-1,5-dimethyl-4-phenyl imid-
azolidine-2-one, 3 according to the procedure of Close.[7] Treatment of 3
Scheme 1. (a) 1708C–1758C, 1.5 hr, 2008C–2108C, 1 hr. (b) n-Butyllithium, 08C,
1 hr, propanoyl chloride, 08C, 2.5 hr. (c) LDA, –788C, 1 hr alkyl halide, 08C, 12 hr.
(d) LiOH/H2O2, H2O/THF, 508C, 24 hr.

Enantioselective Synthesis of (R)-2-Methylalkanoic Acids
3437
with an equimolar quantity of n-butyllithium in tetrahydrofuran at 08C,
followed by propanoyl chloride gave 4 in quantitative yield. Further alkylation
of 4 with lithium diisopropylamide, alkyl iodide, and hexamethylphosphor-
amine (HMPA) gave the alkylated acylimidazolidinone 5. Compounds 5a–
5d were very easily hydrolyzed with lithium hydroxide monohydrate/hydro-
gen peroxide at 508C for 24 hr to give the corresponding chiral acids in high
yields and enantiomeric purity along with 70%–80% recovery of the chiral
auxiliary (Table 1).
The distereomeric excesses and absolute configurations were determined
1
by H nuclear magnetic resonance (NMR) and 13C NMR spectroscopy by
observing the doublet of the CHPh proton of the auxiliary moiety 5, which
shows a different chemical shift in the two diastereomers. The enantiomeric
excesses of (R)-2-methylalkanoic acids were obtained by gas chromatographic
analyses using a b-cyclodextrin-derived chiral column. Having established a
practical pathway to a-substituted carboxylic acids, we studied the generality
of the method, as shown in the scheme, by making analogs 6a–d.
In summary, N-acylation of chiral imidazolidine-2-one 3, stereoselective
alkylation, and racemization-free deacylation of the alkylated N-acylated-
imidazolidine-2-ones 5a–d using lithium hydroperoxide was accomplished
to provide a-substituted chiral carboxylic acids in high yield and high enan-
tiomeric purity (97%–99%) while permitting recovery of the chiral auxiliary.
EXPERIMENTAL
NMR-spectra were recorded in C6D6 CDC13 (Aldrich) solution on a
Bruker QE Plus spectrometer at 300 MHz for 1H and 75 MHz for 13C, respect-
ively. The chemical shifts are expressed in ppm relative to the residual solvent
for H (CDCl3 at d 7.25 ppm) or to the central peak of CDCl3 13C signal (at
1
Table 1. Alkylation of N-acylated-imidazolidine-2-one derivatives.
Yield
(%)a
ee
(%)
Recovery
(%)c
b
Entry
Substrate
[a]D
a
b
c
R ¼ CH2CH3
76
83
81
80
97
99
99
97
–10.0
–4.1
–6.6
–8.3
75
79
72
78
R ¼ (CH2)4CH3
R ¼ (CH2)3Ph
d
R ¼ CH2CH ¼ C(CH3)2
aIsolated yield of 6.
b(c 0.1, MeOH).
cIsolated yield of chiral auxiliary 3.

3438
Shirali and Zhang
77.0 ppm). Chiral gas chromotography (GC) analyses were carried on a HP
6890 GC equipped with a 30-m ꢀ 0.25-mm ID, 0.25-mm film-thickness
b-DEX 120 [20% permethylated alpha-cyclodextrin in SPB-35 poly (35%
phenyl/65% dimethylsiloxane)] capillary column (Supelco, Inc., Bellefonte,
PA) in the split mode (100 : 1) with hydrogen as carrier (55 cm/sec, 1008C iso-
thermal). Optical rotations were measured on a Perkin-Elmer 241 polarimeter
at 258C. Melting points were determined on a hot stage and are uncorrected.
Flash column chromatography was carried out on silica gel (70–230 mesh,
Aldrich Chemical Company, Milwaukee, WI) unless otherwise stated.
(4S,5R)-1,5-Dimethyl-3-propionyl-4-phenylimidazolidine-2-one, 4.
solution of (4S,5R)-1,5-dimethyl-4-phenylimidazolidine-2-one
A
71.0 g
3
(5.2 mmol) in dry tetrahydrofuran (20 mL) was treated with an equimolar
amount of n-butyllithium (1M) at 08C. After the solid had dissolved, the clear
solution was stirred an additional 0.5 hr at 08C, then propanoyl chloride
0.5mL (5.5mmol) dissolved in tetrahydrofuran (10mL) was added drop-wise
and the mixture was stirred for 1 hr at 08C. Work-up with saturated ammonium
chloride and extraction with dichloromethane (100 mL ꢀ 2) followed by flash
chromatography (ethyl acetate : hexanes 1 : 1) afforded pure 4 1.1 g in 86%
yield. m.p.: 908C–918C (lit.[6a] 908C); GC/MS: 246 (11), 189 (15), 175 (4),
132 (100), 105 (4), 77 (21), 58 (76); optical rotation: [a]D þ 65 (c 1, MeOH).
General procedure for alkylation of 3-propanoylimidazolidine-2-one,
5a–d. To a cooled solution of 3-acylimidazolidine-2-one 4, 4.1 g
(24.4 mmol) lithium diisopropylamide (LDA) (24.4 mmol) in THF was
added drop-wise at 2788C. After 1 hr a solution of the appropriate alkyl
halide (29.28 mmol) and HMPA (29.28 mmol) in THF (15 mL) was slowly
added and the mixture was allowed to warm to 08C in 12 hr. Work-up with
HCl (2M) and extraction with CH2Cl2 (100 mL ꢀ 2) followed by flash chrom-
atography (hexanes : ethyl acetate, 2 : 1) yielded the products 5a–d as distereo-
meric mixtures, the ratios of which were determined on the basis of spectral
1
data. (5a) m.p., 1058C–1078C; H NMR: d 0.78 (t, 3H, J ¼ 7 Hz), 0.79
(d, 3H, J ¼ 7Hz), 1.1 (d, 3H, J ¼ 6 Hz), 2.8 (s, 3H), 1.3 (m, 1H), 1.7 (m, 1H),
2.8 (s, 3H), 3.9 (m, 2H), 5.29 (d, 1H, J ¼ 6.0 Hz), 7.1–7.35 (m, 5H, Ar); 13
C
NMR: d 152.2, 136.9, 128.4, 127.9, 127.0, 126.9, 77.4, 77.0, 76.7, 59.4,
53.7, 39.0, 38.9, 28.2, 27.0, 16.2, 15.0, 11.4; MS m/z: 274 (100), 259 (66),
246 (9), 217 (4), 189 (66), 175 (17), 132 (69), 118 (15), 105 (6), 91 (8), 77
1
(10), 58 (31); [a]D þ 71.8 (c 1, MeOH). (5b) m.p., 708C–728C; H NMR: d
0.8 (d, 3H, J ¼ 6.0 Hz), 0.81 (t, 3H, J ¼ 6.0 Hz), 1.1 (d, 3H, J ¼ 6.0 Hz),
1.15–1.3 (m, 5H), 1.65 (m, 2H), 2.82 (s, 3H), 3.9 (dq, 1H, J ¼ 6.0 Hz), 5.3
(d, 1H, J ¼ 7.0 Hz), 7.3 (m, 5H, Ar); 13C NMR: d 177.6, 155.4, 137.0,
126.5, 125.9, 59.2, 53.7, 37.2, 35.4, 31.2, 28.4, 27.9, 22.6, 16.0, 14.6, 14.0;
MS m/z: 316 (11), 259 (100), 246 (73), 189 (74), 175 (12), 132 (10), 113
1
(15), 77 (2), 58 (43); [a]D þ 41.66 (c 1, MeOH). (5c) m.p., 808C–828C; H
NMR: d 0.84 (d, 3H, J ¼ 6.5 Hz), 1.15 (d, 3H, J ¼ 6.8 Hz), 1.4–1.8 (m, 2H),

Enantioselective Synthesis of (R)-2-Methylalkanoic Acids
3439
2.55 (m, 2H, CH2Ph), 2.86 (s, 3H), 3.9 (m, 1H), 5.3 (d, 1H, J ¼ 7.0 Hz), 7.3
(m, 10H, 2Ar); 13C NMR: d 176.9, 155.4, 148.3, 137.0, 128.8, 128.5, 126.5,
125.9, 59.2, 53.7, 38.2, 36.2, 34.6, 28.5, 16.6, 14.6; MS m/z: 364 (11), 321
(2), 273 (2), 259 (17), 246 (9), 189 (100), 175 (6), 132 (26), 117 (8), 91 (90),
1
77 (10), 58 (25); [a]D þ 30.0 (c 1, MeOH). (5d) m.p., 1508C–1538C; H
NMR: d 1.16 (d, 3H, J ¼ 6.8 Hz), 1.6 (s, 3H), 2.1–2.5 (m, 1H), 3.85 (m, 1H),
5.0 (m, 1H), 5.3 (d, 1H, J ¼ 9 Hz), 7.3 (m, 5H, Ar); 13C NMR: d 169.8, 156.3,
134.5, 137.0, 126.5, 125.9, 124.4, 54.1, 53.7, 40.0, 28.4, 28.1, 25.6, 17.6, 15.8,
14.6; MS m/z: 314 (2), 246 (5), 189 (61), 175 (7), 132 (39), 113 (53), 104 (11),
91 (17), 81 (24), 69 (32), 58 (100), 41 (29); [a]D þ 65.0 (c 1, MeOH).
General procedure for the preparation of (R)-2-methylalkanoic acids,
6a–6d. To a solution of (4S,5R,20R)-1,5-dimethyl-4-phenyl-3-[(20alkyl)]
imidazolidine-2-one, 5, 2.2 g (8.33 mmol) in THF : H2O (20 mL, 3 : 1) was
added 30% H2O2 11.33 g (12 eq, 99.9 mmol) and LiOH, 1.05 g (3 eq,
24.99 mmol) at ice-bath temperature. The reaction mixture was heated to
508C in an oil bath for 24 hr. After the reaction was complete, it was quenched
with 10% Na2S2O3 at 08C and the pH was adjusted to 9–10. THF was removed
with a rotary evaporator and the residual oil was extracted with petroleum
ether (50 mL ꢀ 3) to obtain (R)-2-methyl alkanoic acids 6a–d. The chiral
auxiliary was recovered in quantitative yield by filtering the colorless solid.
1
(6a) b.p. 708C–728C/12 mm (lit.[9a] 748C–758C/12 mm). H NMR: d 0.9
(t, 3H, J ¼ 7.0 Hz), 1.17 (3H, J ¼ 7 Hz), 1.7 (m, 2H), 2.39 (m, 1H), 10.3
(bs, 1H); 13C NMR: d 183.4, 41.0, 26.6, 16.4, 11.4; MS m/z: 102 (12), 87
(33), 74 (100), 57 (51), 50 (1), 41 (36). (6b) b.p. 1248C–1268C/12 mm
(lit.[9b] 1288C/12 mm); 1H NMR: d 0.87 (t, 3H, J ¼ 7 Hz), 1.18 (d, 3H,
J ¼ 6.0 Hz), 1.3–1.7 (m, 8H), 2.45 (m, 1H); 13C NMR: d 182.8, 34.0, 32.1,
27.3, 22.5, 16.2, 14.0; MS m/z: 144, 101 (12), 87 (29), 74 (100), 69 (6), 57
(18), 45 (18), 41 (32). (6c) b.p. 1408C–1438C/12 mm (lit.[9c] 1418C–
1
1438C/12 mm); H NMR: d 1.2 (d, 3H, J ¼ 7.0 Hz), 1.5–1.7 (m, 4H), 2.5
(m, 1H), 2.65 (t, 2H, CH2Ph, J ¼ 7.0 Hz), 7.1–7.4 (m, 5H); 13C NMR: d
182.1, 140.7, 129.4, 128.5, 125.8, 39.1, 35.1, 33.1, 28.2, 16.8; MS m/z: 192
(15), 174 (21), 146 (3), 131 (9), 117 (15), 104 (38), 91 (100), 74 (32), 65
(17), 45 (16). (6d) b.p. 1208C–1228C/15 mm (lit.[9d] 124–1258C/15 mm);
1H NMR: d 1.15 (d, 3H, J ¼ 7.0 Hz), 1.6 (s, 3H), 1.69 (s, 3H), 2.16 (m, 1H),
2.36 (m, 1H), 2.5 (m, 1H), 5.1 (m, 1H, HC55C); 13C NMR: d 182.9, 131.9,
121.2, 40.5, 28.9, 25.6, 17.8, 16.0; MS m/z: 142 (11), 96 (3), 87 (4), 81 (7),
74 (17), 69 (100), 55 (17), 45 (11), 41 (71).
ACKNOWLEDGMENTS
We thank Ms. Junying Nie of the Chemicals Affecting Insect Behavior
Laboratory for assistance with syntheses. Mention of tradenames or

3440
Shirali and Zhang
commercial products are solely for the purpose of providing specific infor-
mation and do not imply recommendation or endorsement by the U.S. Depart-
ment of Agriculture.
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Received in the USA May 27, 2004