Synthesis of (R)-lactic acid and (2R,5R)-2-tert-Butyl-5-methyl-1,3-dioxolan-4-one

Article abstract of DOI:10.1055/s-0034-1380511

Abstract A convenient procedure for the synthesis of very expensive (R)-lactic acid from relatively inexpensive (R)-alanine is described. Its subsequent conversion into a chiral dioxolanone can be carried out by using an inexpensive pivalaldehyde-tert-butanol mixture.

Full text of DOI:10.1055/s-0034-1380511

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1557–1559
psp
1557
R. A. Aitken et al.
PSP
Synthesis
Synthesis of (R)-Lactic Acid and (2R,5R)-2-tert-Butyl-5-methyl-1,3-
dioxolan-4-one
R. Alan Aitken*
Anna Meehan
Lynn A. Power
EaStCHEM School of Chemistry, University of St Andrews,
North Haugh, St Andrews, Fife KY16 9ST, UK
raa@st-and.ac.uk
Received: 23.02.2015
Accepted after revision: 07.03.2015
Published online: 02.04.2015
DOI: 10.1055/s-0034-1380511; Art ID: ss-2015-t0121-psp
aq NaNO2,
dillute H2SO4
Me
Me
OH
OH
H2N
HO
58% yield
O
O
Abstract A convenient procedure for the synthesis of very expensive
(R)-lactic acid from relatively inexpensive (R)-alanine is described. Its
subsequent conversion into a chiral dioxolanone can be carried out by
using an inexpensive pivalaldehyde–tert-butanol mixture.
2
1
Scheme 1
Key words chiral pool, stereoselective synthesis, (R)-lactic acid, (R)-al-
anine, diazotization, 1,3-dioxolan-4-one
The diazotisation of alanine is one of the oldest reac-
tions in organic chemistry and was first reported in 1850 by
Strecker in the same paper in which he first prepared and
named the (racemic) amino acid alanine.4 Once chiral ami-
no acids were obtained from natural sources, their conver-
sion into the corresponding chiral α-hydroxy acids emerged
as a useful general method. Reaction with sodium nitrite in
dilute acetic, hydrochloric or sulfuric acid is followed by a
range of different work-up procedures to separate the prod-
uct from the inorganic salts present. However, as recently
noted by Ley and co-workers in the course of adapting the
process to flow chemistry,5 lactic acid is exceptionally wa-
ter soluble, so general methods described for a range of hy-
droxy acids may not be suitable for this particular case. The
reports of conventional (i.e., non-flow) lactic acid synthesis
from alanine may be divided into those for which formation
of (R)-lactic acid,6,7 or (S)-lactic acid8,9 has been carried out
but the detailed procedure reported is either general or for
another amino acid, and those for which (R)-lactic acid10,11
or (S)-lactic acid10,12 has been prepared but no detailed pro-
cedure is given at all. After considerable experimentation,
we have been able to combine certain features of these pro-
cedures to develop a convenient and reliable method that
has been used to produce over 100 grams of the product.
We started by using a reported method,6 involving
treatment of alanine in 1 M sulfuric acid with six equiva-
lents of aqueous sodium nitrite, which claimed a yield of
82–92%. At the end of the reaction the pH was adjusted first
In the appropriate section of a prestigious reference
work published in 1996,1 the following statement appears:
‘Both enantiomers of lactic acid (2-hydroxypropanoic acid)
are natural products and easily obtained by biotechnologi-
cal methods, so there is no need for their synthesis in the
laboratory’. While this may be true of the natural S-enan-
tiomer, it is certainly not the case for the R-enantiomer,
with major chemical suppliers currently offering (R)-lactic
acid at up to 104 times the price of the S-enantiomer. Thus,
while (S)-lactic acid has found widespread application as a
chiral building block and auxiliary for asymmetric synthe-
sis,2 extension of these methods to obtain products of the
opposite enantiomeric series by using the commercially
available (R)-lactic acid is completely uneconomic. Fortu-
nately, diazotisation of alanine in an aqueous medium pro-
ceeds with complete retention of absolute configuration,3
and since the two enantiomers of alanine differ in cost by a
factor of only 2–3, diazotisation of (R)-alanine (1) is the
method of choice to obtain (R)-lactic acid (2). We were
therefore surprised to discover that a detailed experimental
procedure for this process does not appear to have been
published. The optimised method described here produces
(R)-lactic acid (2) directly in 58% yield on a multi-gram
scale and in a purity comparable to that of the commercial-
ly available S-enantiomer (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1557–1559

1558
R. A. Aitken et al.
PSP
Synthesis
to 6 with NaHCO3 then to 3 with HCl before freeze-drying. A
sequence of extraction with acetone, evaporation and ex-
traction with Et2O, drying and evaporation was used.6,9 In
our hands, this gave a maximum yield of 37% and the prod-
uct contained up to 20% of the cyclic dimer. On scaling up
the same procedure, various unidentified contaminants
were formed and separation of the product from the large
amount of inorganic salts became increasingly problematic.
Attempted purification by vacuum distillation led to in-
creased formation of cyclic dimer and polymer, and re-
placement of acetone in the procedure by tetrahydrofuran
(THF) was also ineffective. With many of the problems be-
ing caused by the excess of inorganic salts, we reduced the
amount of NaNO2 to 1.5 equiv but retained the pH adjust-
ment sequence from before. After this, the solution was re-
duced in volume by evaporation under reduced pressure
with the minimum of heating to minimise formation of di-
mer and polymer. The residual aqueous phase was then ex-
tracted exhaustively with ethyl acetate, following the meth-
od reported for norleucine,7 and also based upon the use of
isopropyl acetate in the large-scale formation of phenyllac-
tic acid.13 This approach was successful in separating the
product from the inorganic salts, which remained in the
aqueous phase, and drying and evaporation of the com-
bined extracts gave the product. The use of diethyl ether for
this extraction, as reported for lactic acid8,10 and other hy-
droxy acids,8 was not effective in our hands because it
proved to be too weak a solvent to extract the highly polar
lactic acid from water.
tion, both with reported values17 and with the enantiomer-
ic product 4 made by using commercially available (S)-lactic
acid.
t-BuCHO–t-BuOH (3:1)
cat. p-TsOH, H2SO4
Me
Me
pentane, Dean–Stark
O
OH
OH
O
HO
HO
38% yield
97:3 dr
O
O
O
t-Bu
3
2
t-BuCHO–t-BuOH (3:1)
cat. p-TsOH, H2SO4
pentane, Dean–Stark
Me
Me
O
O
36% yield
98:2 dr
O
t-Bu
4
Scheme 2
Pure pivalaldehyde is rather expensive but, fortunately,
we were able to source a mixture of 75% pivalaldehyde/25%
tert-butanol at less than 1/8 of the cost and found that it can
be used just as well in the preparation of 3 and 4. The tert-
butanol does not affect the condensation process and is re-
moved in the aqueous wash.
NMR data were recorded in CDCl3 with a Bruker instrument at 400
MHz (1H) and 100 MHz (13C) and are referenced to internal Me4Si. (R)-
Alanine, (S)-lactic acid (85–90% aq solution) and pivalaldehyde (75%
in t-BuOH) were obtained from Alfa Aesar.
The final product obtained was a very pale green or yel-
low liquid, which was suitable for use directly in further
transformations. Very small amounts of two impurities
were visible by 1H NMR spectroscopy; these were the cyclic
dimer, (R,R)-lactide or 3,6-dimethyl-1,4-dioxane-2,5-dione
[1H NMR: δ = 1.62 (d, J = 7.0 Hz, 3 H, CH3), 5.29 (q, J = 7.0 Hz,
1 H, CHCH3)14] (<3%) and polylactic acid [1H NMR: δ = 1.55
(d, J = 7.0 Hz, 3 H, CH3), 5.11 (q, J = 7.0 Hz, 1 H, CHCH3)15]
(<2%) but neither of these were detrimental to its use in
further reactions and their concentrations were similar to
those present in all commercial samples of lactic acid.
One of the most useful applications of lactic acid as a
chiral auxiliary is in the formation of the 1,3-dioxolan-4-
one by condensation with pivalaldehyde (Scheme 2). This
was first described in 1984 by Seebach and co-workers,16
and the two enantiomeric dioxolanones 3 and 4, derived re-
spectively from (R)- and (S)-lactic acid, have been used in
the synthesis of various natural products,17,18 as well as in
developing new asymmetric synthetic methodologies, in-
cluding their use as chiral acyl anion equivalents.19 To
demonstrate the purity of the (R)-lactic acid formed by our
method, it was converted into dioxolanone 3 by using a re-
ported procedure,16 and the resulting product showed good
agreement in terms of yield, NMR spectra and optical rota-
Preparation of (R)-Lactic Acid (2)
A solution of NaNO2 (23.35 g, 338 mmol) in H2O (200 mL) was added
to a stirred solution of (R)-alanine 1 (20.0 g, 225 mmol) in 0.5 M
H2SO4 (344 mL, 172 mmol) over a 2 h period, with the temperature
kept at 0–5 °C. The reaction mixture was then stirred and warmed to
r.t. overnight. Solid NaHCO3 was then added to the reaction mixture
to achieve pH 6, then conc. HCl was added until pH 3 was reached.
The solution was then concentrated to roughly a fifth of its original
volume (120 mL) under reduced pressure and then extracted with
EtOAc (9 × 100 mL). The combined organic extracts were dried with
MgSO4 and the solvent was removed under reduced pressure to give
(R)-lactic acid.
Yield: 11.83 g (58%); pale-yellow oil; [α]D +14.6 (c 2.5, 1.5 M NaOH)
[Lit.21 for (S)-lactic acid [α]D –14.3 (c 2.5, 1.5 M NaOH)].
1H NMR: δ = 1.49 (d, J = 7.0 Hz, 3 H, CH3), 4.40 (q, J = 7.0 Hz, 1 H,
CHCH3) [Lit.5 δ = 1.48 (d, J = 6.8 Hz, 3 H), 4.38 (q, J = 6.8 Hz, 1 H)].
13C NMR: δ = 20.0, 66.6, 179.9 (Lit.20 δ = 20.5, 66.9, 180.0).
Preparation of (2R,5R)-2-tert-Butyl-5-methyl-1,3-dioxolan-4-one
(3)
A solution of (R)-lactic acid (8.49 g, 95 mmol), pivalaldehyde (75% in
t-BuOH, 20.3 g, 177 mmol), p-toluenesulfonic acid monohydrate
(0.005 g, 0.025 mmol) and conc. H2SO4 (0.25 mL) in pentane (85 mL)
was heated to reflux with azeotropic removal of H2O under Dean–
Stark conditions for 24 h. The mixture was then washed with H2O
(2 × 100 mL), dried over MgSO4 and the solvent was removed under
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1557–1559

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R. A. Aitken et al.
PSP
Synthesis
reduced pressure without heating to afford the crude product.
Kugelrohr distillation (20 Torr) followed by recrystallisation from
pentane at –78 °C with collection of the crystalline product in a
cooled filtration funnel gave the product as colourless crystals, which
melted to a colourless liquid below r.t.
Yield: 5.67 g (38%); [α]D –41.5 (c 1.87, CHCl3) [Lit.17 –44.7 (c 1.89,
CHCl3)].
1H NMR: δ = 0.98 (s, 9 H, C(CH3)3), 1.49 (d, J = 6.7 Hz, 3 H, CH3), 4.37
(qd, J = 6.7, 1.2 Hz, 1 H, CHCH3), 5.15 (d, J = 1.2 Hz, 1 H, OCHO) (Lit.17
δ = 0.98, 1.48, 4.36, 5.15).
(4) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 28.
(5) Hu, D. X.; O’Brien, M.; Ley, S. V. Org. Lett. 2012, 14, 4246.
(6) Jia, C.; Yang, K.-W.; Liu, C.-C.; Feng, L.; Xiao, J.-M.; Zhou, L.-S.;
Zhang, Y.-L. Bioorg. Med. Chem. Lett. 2012, 22, 482.
(7) Raddatz, P.; Minck, K.-O.; Rippmann, F.; Schmitges, C.-J. J. Med.
Chem. 1994, 37, 486.
(8) Yang, D.; Li, B.; Ng, F.-F.; Yan, Y.-L.; Qu, J.; Wu, Y.-D. J. Org. Chem.
2001, 66, 7303.
(9) Winitz, M.; Bloch-Frankenthal, L.; Izumiya, N.; Birnbaum, S. M.;
Baker, C. G.; Greenstein, J. P. J. Am. Chem. Soc. 1956, 78, 2423.
(10) Williams, P. G.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J. J. Nat.
Prod. 2002, 65, 29.
(11) Arimoto, H.; Oishi, T.; Nishijima, M.; Kinumi, T. Tetrahedron Lett.
2001, 42, 3347.
Preparation of (2S,5S)-2-tert-Butyl-5-methyl-1,3-dioxolan-4-one
(4)
The method described above was used but with commercially avail-
able (S)-lactic acid. The procedure gave enantiomeric product 4.
(12) Pitt, N.; Gani, D. Tetrahedron Lett. 1999, 40, 3811.
(13) Storz, T.; Dittmar, P.; Fauquex, P. F.; Marschal, P.; Lottenbach,
W. U.; Steiner, H. Org. Process Res. Dev. 2003, 7, 559.
(14) Leemhuis, M.; van Steenis, J. H.; van Uxem, M. J.; van Nostrum,
C. F.; Hennink, W. E. Eur. J. Org. Chem. 2003, 3344.
(15) Fedushkin, I. L.; Morozov, A. G.; Chudakova, V. A.; Fukin, G. K.;
Cherkasov, V. K. Eur. J. Inorg. Chem. 2009, 4995.
(16) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313.
(17) Matsuo, K.; Sakaguchi, Y. Chem. Pharm. Bull. 1997, 45, 1620.
(18) (a) Naef, R.; Seebach, D. Liebigs Ann. Chem. 1983, 1930.
(b) Boeckman, R. K. Jr.; Yoon, S. K.; Heckendorn, D. K. J. Am.
Chem. Soc. 1991, 113, 9682. (c) Kanda, Y.; Fukuyama, T. J. Am.
Chem. Soc. 1993, 115, 8451.
Yield: 36%; mp 5–6 °C (Lit.16 5 °C); [α]D +46.8 (c 1.82, CHCl3) [Lit.16
+44.8 (c 1.83, CHCl3)].
1H NMR: δ = 0.98 (s, 9 H, C(CH3)3), 1.48 (d, J = 6.6 Hz, 3 H, CH3), 4.36
(qd, J = 6.6, 1.2 Hz, 1 H, CHCH3), 5.15 (d, J = 1.2 Hz, 1 H, OCHO) (Lit.16
δ = 0.98, 1.48, 4.45, 5.14).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1557–1559