Efficient large (ca. 40 g) laboratory scale preparation of (S)- and (R)-valine tert-butyl esters

Article abstract of DOI:10.1016/S0957-4166(02)00532-3

A large laboratory scale (ca. 40 g) method for the preparation of enantiomerically pure (S)- and (R)-valine tert-butyl esters has been developed. The method involves three steps: preparation of N-TFA-valines, preparation of valine tert-butyl esters using 2-methylpropene in dioxane in the presence of sulfuric acid, and isolation of the target compounds as the acetate derivative. The overall yield is up to 70% relative to the starting valine, ee being more than 98% (by HPLC).

Full text of DOI:10.1016/S0957-4166(02)00532-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1911–1914
Efficient large (ca. 40 g) laboratory scale preparation of
(S)- and (R)-valine tert-butyl esters
Victor P. Krasnov,a,* Galina L. Levit,a Iraida M. Bukrina,a Alexander M. Demin,a
Oleg N. Chupakhina and Ji Uk Yoob
aInstitute of Organic Synthesis of RAS (Ural Div.), 20, S. Kovalevskoy St., Ekaterinburg 620219, Russia
bSamsung Fine Chemicals Co. Ltd. R&D Center, 103-1 Moonji Yusong, Taejon 305-380, South Korea
Received 23 July 2002; accepted 29 August 2002
Abstract—A large laboratory scale (ca. 40 g) method for the preparation of enantiomerically pure (S)- and (R)-valine tert-butyl
esters has been developed. The method involves three steps: preparation of N-TFA-valines, preparation of valine tert-butyl esters
using 2-methylpropene in dioxane in the presence of sulfuric acid, and isolation of the target compounds as the acetate derivative.
The overall yield is up to 70% relative to the starting valine, ee being more than 98% (by HPLC). © 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
ods for preparation of tert-butyl esters consist of
reaction of the free amino acid with 2-methylpropene in
a mixture of 1,4-dioxane and sulfuric acid,4 where the
yield of the tert-butyl ester is dependant on the solubil-
ity of the amino acid in the dioxane–H2SO4 mixture. In
the case of valine the yield ranged from 454a to
65%.4b,4d
At present we are witnesses of continuing growth in the
production enantiopure compounds, which is caused by
the demands of modern drug industry. However, not all
of the experimental procedures can be extended to
multi-gram processes and solving the problems associ-
ated with large scale preparations of enantiopure com-
pounds sometimes requires the development of special
approaches to provide the target products in a combi-
nation of high yields and high enantiomeric purities.
Synthesis of amino tert-butyl esters also could be per-
formed by reaction of the free amino acid with tert-
BuOAc in the presence of perchloric acid.5 We carried
out the preparation of valine tert-butyl ester as
described in previously,5c the yield being 70%. It should
be noted that although the yield from this method is
rather high, applying this procedure to the large scale
production of valine tert-butyl ester is not promising
due to the high volume of the reaction mixture (ꢀ128
mL of tert-BuOAc per 1 g of valine), which requires a
large-scale process with 50 g valine to be carried out in
a 10 L reactor.
(S)- and (R)-Valine and their alkyl esters are commonly
used as starting materials both in asymmetric synthe-
sis,1 and peptide and peptidomimetic synthesis.2 tert-
Butyl esters are of specific interest since the tert-butyl
ester can be removed easily and selectively in acidic
media, and amino acid tert-butyl esters are stable in the
free base form to N-condensation reactions.
Though the protocols for amino acid tert-butyl esters
are well documented,3 problems arise during large scale
preparation. Usually, tert-butyl esters are prepared
starting from both N-protected (usually N-Cbz or N-
Boc) and free amino acids. The known literature meth-
Some literature methods for preparing amino tert-butyl
esters describe the condensation of N-protected amino
acids with tert-BuOH in the presence of various car-
bodiimides and 4-dimethylaminopyridine as a catalyst
followed by removal of protecting group.6 However,
these methods require an additional protecting group
removal step.
* Corresponding author. Tel.: +7-3432-493057; fax: +7-3432-741189;
e-mail: ca@ios.uran.ru
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00532-3

1912
V. P. Krasno6 et al. / Tetrahedron: Asymmetry 13 (2002) 1911–1914
of the tert-butyl esters 4 as the acetates 55c in 84–88%
2. Results and discussion
yield. The overall yield of the target products in large-
scale preparation (starting from 30–50 g of valine) was
up to 70% (Scheme 1).
Herein, we suggest the trifluoroacetate ester (TFA) as a
useful protecting group: It can be removed smoothly by
alkali treatment of the reaction mixture after interac-
tion with 2-methylpropene. The use of the TFA group
makes it possible to avoid the problems related to the
poor solubility of valine in dioxane–H2SO4 mixture
during esterification with 2-methylpropene, and there-
fore to drastically decrease the reactor volume. Davi-
dovich et al. described the preparation of glycine
tert-butyl ester by the reaction of N-TFA-glycine with
2-methylpropene in the presence of H2SO4 in overall
yield of about 76%.7 However, in the preparation of
valine tert-butyl esters using this approach, the risk of
enantiomeric purity loss exists due to the possibility of
racemization at any of the steps.
The enantiomeric purity of the obtained acetates could
be determined from the specific rotation,5c but actually
this method is not reliable. We therefore applied an
HPLC technique with pre-column derivatization of
acetates 5 with (S)-naproxen chloride9 (Scheme 2).
Previously, we have shown that acylation of sterically
hindered racemic amines by (S)-naproxen acyl chloride
is accompanied by kinetic resolution.10 So, the enan-
tiomeric purity results from the HPLC analysis could
be misjudged if the acylation is not complete. We
performed HPLC determination of de values of amides
6 depending on the duration of the derivatization pro-
cess. At the initial concentration of acetate 5 C0=0.2
M, the reaction proceeds completely in 15 min and the
ratio of (S,S)- and (S,R)-diastereoisomers 6 remains
constant during 24 h. The enantiomeric excess (ee) of
the synthesized acetates 5 was more than 98%.
The (S)- and (R)-N-TFA-valines 2 were obtained from
free valines 1 according to the published procedure8 in
84–90% yield. Esterification of N-TFA-valines by 2-
methylpropene was carried out in dioxane–H2SO4 (10:1
v/v) while shaking the reaction mixture in a glass
pressure bottle during 70–80 h at room temperature.
Then the cooled reaction mixture was treated with 2N
NaOH and stirred for 2 h to remove the N-TFA
protecting group (with yields of ca. 95%). Based on the
1H NMR spectra we have observed that the products
isolated from reaction mixture contain from 5 to 20
mass% of the solvents (1,4-dioxane and hexane) as
impurities. In our hands, further evaporation of the
solvents and drying under reduced pressure resulted in
considerable loss of the product due to its high volatil-
ity. Therefore, purification was performed by isolation
3. Experimental
3.1. General
Solvents were purified according to standard proce-
dures. Routine monitoring of reactions was carried out
using Silufol UV 254 (Kavalier) TLC aluminum plated
silica gel. Melting points were determined on a Boetius
1
melting point apparatus and are uncorrected. H NMR
Scheme 1. Synthesis of (S)- and (R)-valine tert-butyl esters.
Scheme 2. Derivatization of (S)- and (R)-valine tert-butyl ester acetates by (S)-naproxen chloride.

V. P. Krasno6 et al. / Tetrahedron: Asymmetry 13 (2002) 1911–1914
1913
spectra were measured on a Bruker DRX 400 spec-
trometer. All signals are given in ppm (l) with TMS as
an internal standard. Optical rotations were measured
on a Perkin–Elmer 241 polarimeter. The de values of
amides 6 were measured by HPLC on a Merck–Hitachi
chromatograph with L-4000A Intelligent Pump, L-
4000A UV Detector, and D-2500A Chromato-Integra-
tor [Hibar Pre-packed Column RT250-4, Lichrosorb
Si-60]; mobile phase: hexane: i-PrOH=80:1, flow rate 1
mL/min; UV detection 230 nm; ~SS 8.6 min, ~SR 10.1
min.
CH3,), 0.97 (d, J=7.1 Hz, 3H, CH3,), 1.47 (s, 9H,
(CH3)3), 2.00 (sept d, J=6.9 and 4.9 Hz, 1H, CH,), 3.17
(d, J=4.8 Hz, 1H, CaH).
3.5. (R)-Valine tert-butyl ester, 4
Following the above procedure, and starting with N-
TFA-(R)-valine 2 (50.0 g, 0.234 mol) the title com-
pound was obtained as a light yellow oil (43.8 g, 95%).
1
Dioxane content according to H NMR spectrum was
1
12%. For H NMR, see: (S)-4 (Section 3.4).
3.6. (S)-Valine tert-butyl ester acetate, 5
2-Methylpropene was obtained according to the litera-
ture procedure11 and was used as such in the subse-
quent step. (S)- and (R)-Valines were purchased from
Lancaster Synthesis (UK). (S)-2-(6-Methoxynaphthyl-
2)propionyl chloride [(S)-naproxen acyl chloride] was
prepared from commercially available (S)-(+)-naproxen
and oxalyl chloride.12
To a solution of tert-butyl ester (S)-4 (39.8 g, 0.211
mol) in hexane (200 mL) was added glacial AcOH (12.1
mL, 0.211 mol). The acetate was precipitated almost
immediately. After stirring overnight at rt the precipi-
tate was filtered off, and washed with hexane (2×15
mL). Drying the product gave (S)-5 as colorless crystals
1
(41.8 g, 85%). Mp 88–90°C; [h]2D0 +20.2 (c 2, EtOH); H
3.2. N-Trifluorocetyl (S)-valine, 2
NMR (CDCl3): 0.92 (d, J=6.7 Hz, 3H, CH3), 0.99 (d,
J=6.9 Hz, 3H, CH3), 1.48 (s, (9H, (CH3)3), 2.05 (s, 3H,
CH3COO−), 2.06 (sept d, J=6.8 and 4.6 Hz, 1H, CH),
N-TFA-(S)-Valine 2 was prepared from (S)-valine
(31.8 g, 0.271 mol), trifluoroacetic anhydride and TFA
as previously described in literature12 (51.9 g, 90%). It
was obtained as white crystals. Mp 84–86°C; [h]2D0 −15
+
3.28 (d, J=4.7 Hz, 1H, CaH), 4.75 (br. s, 3H, NH3 ).
Anal. calcd for C11H23NO4: C, 56.63; H, 9.94; N, 6.00.
Found: C, 56.68; H, 9.93; N, 5.98%. Enantiomeric
purity: 98.1% (HPLC, de after pre-column derivatiza-
tion with (S)-naproxen acyl chloride).
1
(c 2, H2O); H NMR (CDCl3): 1.01 (d, J=7.0 Hz, 3H,
CH3), 1.03 (d, J=7.0 Hz, 3H, CH3), 2.35 (sept d,
J=6.9 and 4.8 Hz, 1H, CH), 4.64 (dd, J=8.6 and 4.5
Hz, 1H, CaH), 6.83 (br. d, J=8.3 Hz, 1H, NH), 8.29
(br. s, COOH). Anal. calcd for C7H10F3NO3: C, 39.44;
H, 4.73; N, 6.57; F, 26.74. Found: C, 39.61; H, 4.77; N,
6.68; F, 26.70%.
3.7. (R)-Valine tert-butyl ester acetate, 5
Following the above procedure, and starting with tert-
butyl ester (R)-4 (43.8 g, 0.222 mol) the title compound
(45.6 g, 88%) was obtained as colorless crystals. Mp
90–91°C; [h]2D0 −20.4 (c 2, EtOH). Anal. calcd for
C11H23NO4: C, 56.63; H, 9.94; N, 6.00. Found: C,
56.62; H, 9.95; N, 6.00%. Enantiomeric purity: 98.8%
(HPLC, de after pre-column derivatization with (S)-
3.3. N-Trifluorocetyl (R)-valine, 2
Following the above procedure, and starting with (R)-
valine (35.8 g, 0.306 mol) the title compound was
obtained as white crystals (55.4 g, 85%). Mp 85–87°C;
[h]2D0 +15 (c 2, H2O). Anal. calcd for C7H10F3NO3: C,
39.44; H, 4.73; N, 6.57; F, 26.74. Found: C, 39.71; H,
1
naproxen acyl chloride). For H NMR, see: (S)-5 (Sec-
tion 3.6).
1
4.87; N, 6.67; F, 26.77%. H NMR see (S)-2.
3.8. Derivatization with (S)-naproxen acyl chloride.
General procedure
3.4. (S)-Valine tert-butyl ester, 4
To a solution of acetate (S)-5 or (R)-5 (117 mg, 0.5
mmol) and pyridine (0.080 mL, 1.0 mmol) in dry
dichloromethane (2.5 mL) was added a solution of
(S)-naproxen acyl chloride (124 mg, 0.5 mmol) in the
same solvent (2.5 mL). The reaction mixture was then
stirred at rt for 15 min, filtered through silica gel and
analyzed by HPLC.
A solution of N-TFA-(S)-valine 2 (50 g, 0.234 mol) in
a mixture of dry 1,4-dioxane (250 mL) and concen-
trated H2SO4 (25 mL) was placed in a 750 mL glass
pressure bottle and cooled to −5 to 10°C, then freshly
prepared 2-methylpropene (340 mL) was added to the
reaction mixture. The reaction bottle was tightly sealed
and then shaken in a shaking machine at rt for 70 h.
The bottle was cooled before opening and cold 2N
NaOH (630 mL) was carefully added to the reaction
mixture under stirring. The mixture was stirred for 2 h
at rt. The product was extracted with hexane (3×125
mL). The combined hexane solutions were dried
(Na2SO4). Evaporation under reduced pressure (the
bath temperature was maintained at about 30°C) fol-
lowed by drying to constant weight at rt gave the title
compound as a light yellow oil (39.8 g, 90%). The
product contains dioxane (8.3%) according to 1H NMR
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