A facile method for synthesis of (R)-(-)- and (S)-(+)-homocitric acid lactones and related α-hydroxy dicarboxylic acids from D- or L-malic acid

Article abstract of DOI:10.1016/j.tetlet.2005.03.180

We report here a simple and convenient route for the stereoselective synthesis of (R)-(-)- and (S)-(+)-homocitric acid lactones, which play very important roles in biochemistry. The method involves only three steps, starting from the readily available met

Full text of DOI:10.1016/j.tetlet.2005.03.180

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3815–3818
A facile method for synthesis of (R)-(ꢀ)- and (S)-(+)-homocitric
acid lactones and related a-hydroxy dicarboxylic acids from
D- or L-malic acid
Peng-Fei Xu,a,b Tsuyoshi Matsumoto,a Yasuhiro Ohkia and Kazuyuki Tatsumia,*
aResearch Center for Materials Science and Department of Chemistry, Graduate School of Science, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
bState Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, 730000, PR China
Received 3 March 2005; revised 25 March 2005; accepted 29 March 2005
Available online 11 April 2005
Abstract—We report here a simple and convenient route for the stereoselective synthesis of (R)-(ꢀ)- and (S)-(+)-homocitric acid
lactones, which play very important roles in biochemistry. The method involves only three steps, starting from the readily available
methyl 3-iodopropionate and D-malic acid or L-malic acid, respectively. The stereoconfiguration of the target molecules has been
achieved via a self-regeneration approach with over 98% diastereoselectivity and significantly improved yield over the previous
methods.
Ó 2005 Elsevier Ltd. All rights reserved.
Homocitrate is an important component of the FeMo-
cofactor in nitrogenase, where nitrogen fixation has
O
O
S
been thought to occur. The FeMo-cofactor was first
identified by Shah and Brill in 1977,1 and its crystallo-
graphic structure was determined by Rees and co-work-
ers.2 Since then, there have been extensive investigations
on the biological functions of FeMo-cofactor,3 and on
the synthetic Mo/Fe/S cluster models.4 However, the
mechanism of fixation/activation of molecular dinitro-
gen remains unclear, and in particular the role of homo-
citrate coordinated to molybdenum has not been well
understood. This is partly due to the lack of convenient
methods to synthesize (R)-(ꢀ)-homocitrate, which is not
commercially available (Fig. 1).
O
O
O
S
Fe
S
S
Fe
O
S
Mo
O
Fe
Cys-S
X
S
Fe
Fe
Fe
Fe
N
N
S
S
S
Figure 1. FeMo-cofactor structure of nitrogenase.
in five steps with an overall yield of 3%.6 The improved
synthesis from D-malic acid was reported thereafter by
Ma and Palmer, but still the overall yield of homocitrate
lactone is 12% and it requires six steps.7 In this paper,
we report a new and facile route for the synthesis of
(R)-(ꢀ)- and (S)-(+)-homocitric acid lactones with much
improved yields (total yields are >30%) and good stereo-
selectivity (>98% ee). The method is based on the work
of Ma and Palmer but we could accomplish the synthe-
sis in only three steps featuring methyl 3-iodopropionate
as the electrophilic reagent by modification of the reac-
tion conditions.
There are two reports on asymmetric synthesis of (R)-
(ꢀ)-homocitrate based on SeebachÕs work,5 which starts
from a-hydroxy carboxylic acid and utilizes pivalalde-
hyde as a protecting group to form a dioxolanone ring
in order to achieve a high regioselectivity created by
the bulkiness of the tert-butyl group. Biellmann started
from L-lactic acid or L-serine and arrived at the target
Keywords: Homocitric acid lactones; a-Hydroxy dicarboxylic acids;
Nitrogenase.
The asymmetric synthetic route to (R)-(ꢀ)-homocitrate
and other corresponding carboxylic acids is summarized
in Scheme 1.
*
Corresponding author. Tel.: +81 52 789 2474; fax: +81 52 789
2943; e-mail: i45100a@nucc.cc.nagoya-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.180

3816
P.-F. Xu et al. / Tetrahedron Letters 46 (2005) 3815–3818
Scheme 1.
The first step is the synthesis of protected D-malic acid
by pivalaldehyde, which could be repeated according
to SeebachÕs report.5
also optimized altogether. Compounds 2 are sensitive
to acid and base in the solution. When the acidity was
too high, the protecting group, pivalaldehyde, was easily
removed. The resulting dicarboxylic acid compound
could not be separated by flash column chromatography
using silica gel. The basic solution condition is appar-
ently not suitable because the desired compound would
dissolve in the aqueous phase as carboxylates. Mean-
while, the colour of the solution will turn red even to
black red due to the oxidation of the excess of Iꢀ in
the air, which will be troublesome in the course of sepa-
ration of desired compounds. Thus, we employed the
1 N HCl solution to quench the reaction and adjusted
pH value near to 3. The organic layer was then washed
with saturated solution of sodium sulfite to reduce I2
into Iꢀ.
The following step is alkylation of dianion species of
compound 1. According to the reported method,
(2R,4R)-1 was treated by 2 equiv of LiN(SiMe3)2 at
ꢀ78 °C and then 1.5 equiv of benzyl bromide was added.
The solution was allowed to warm to ꢀ20 °C and
kept for another 5 h to give the corresponding adducts
(2R,4R)-2a in 81% yield (>98% ee, entry 1 in Table 1),
which is almost similar to the reported results.5–7 We
expected 3-iodopropionic acid ester to be the proper
electrophile for a straightforward synthesis of (R)-(ꢀ)-
homocitrate and (S)-(+)-homocitrate. However, the
reaction with methyl 3-iodopropionate did not afford
the adduct by the same procedure. Similarly, the reac-
tion with n-propyl iodide was found unsuccessful (entry
2).8 We examined the reaction with n-propyl iodide
using D,L-1 prepared from D,L-malic acid under various
reaction time and temperature, and we found a clue to
get the adduct although the yield was only 10%, when
the temperature was kept ꢀ10 °C for 10 h (entry 3).
The work-up process after this alkylation reaction was
When the reaction temperature was over 0 °C, the dia-
steroselectivity decreased to 90% (entry 5). Finally the
optimized conditions were to keep the temperature at
ꢀ5 °C for 14 h, and the adduct D,L-2c was obtained in
1
35% (entry 4). H NMR clearly shows that no epimer
exists, and at the same time, we could obtain single crys-
tals of compound D,L-2c and the structure was deter-
Table 1. The alkylation reactions of compound 1
22
½aꢁD
Entry
Substrates
Electrophiles
Reaction conditionsa
Yield (%)
de%b
1
2
(2R,4R)-1
D,L-1
Benzyl bromide
n-Propyl iodide
ꢀ20 °C, 5 h
ꢀ20 °C, 5 h
ꢀ10 °C, 16 h
ꢀ5 °C, 10 h
0 °C, 10 h
ꢀ5 °C, 10 h
ꢀ5 °C, 10 h
ꢀ5 °C, 10 h
ꢀ5 °C, 10 h
ꢀ5 °C, 10 h
81
0
ꢀ64.2
>98
—
>96c
>96c
90
—
—
3
D,L-1
n-Propyl iodide
n-Propyl iodide
10
35
38
35
33
26
30
34
4
D,L-1
—
5
(2R,4R)-1
(2R,4R)-1
(2R,4R)-1
(2R,4R)-1
(2R,4R)-1
(2S,4S)-1
n-Propyl iodide
n-Propyl iodide
—
6
ꢀ24.8
ꢀ20.0
ꢀ17.4
ꢀ12.9
+19.9
>96
>98
>98
>98
>98
7
Methyl 3-iodopropionate
Ethyl 3-iodopropionate
Benzyl 3-iodopropionate
Methyl 3-iodopropionate
8
9
10
a The electrophiles were added at ꢀ78 °C and they were gradually warmed to these temp and stirred.
b The de value were calculated by the integration of 1H NMR from Varian Inova-500M spectrometer.
c One pair of enantiomers, (2R,4R) and (2S,4S), were obtained selectively.

P.-F. Xu et al. / Tetrahedron Letters 46 (2005) 3815–3818
3817
mined by X-ray analysis.9 It is clear that there is a pair
of enantiomers in the unit cell, since space group is P-1
and Z = 2 (Fig. 2).10 The relative configuration is the
predicted one, which is in agreement with the results
Seebach referred to as the self-regeneration of stereocen-
tres (SRS) approach.11
Under these optimized conditions, the reaction of
(2R,4R)-1 and methyl 3-iodopropionate as an electro-
phile afforded (2R,4R)-3-(2-tert-butyl-5-carboxymethyl-
4-oxo-[1,3]dioxolan-5-yl)-propionic acid methyl ester
[(2R,4R)-2c] in 33% yield (entry 7). Similarly,
(2S,4S)-2c was obtained in 34% from (2S,4S)-1 (entry
10). Their optical rotation values match well except for
the direction. When the reaction of (2R,4R)-1 was
performed over 0 °C, a diastereomer, (2R,4S)-2c, was
also isolated, whose X-ray structural analysis clearly
shows that methyl propionate group is located on the
same side as tert-butyl group (Fig. 3).9 Other spectro-
scopic data are consistent with the X-ray structure.12
When ethyl 3-iodopropionate and benzyl 3-iodopropio-
nate were used as an electrophilic reagent, the corres-
ponding adducts were obtained in 26% and 30% yield,
respectively (entries 8 and 9).
Figure 3. The ORTEP3 structure of (2R,4S)-2c.
tion. Homocitric acid is not a stable form and hence a
five member lactone ring was spontaneously formed
after removing pivalaldehyde protection to give (R)-
(ꢀ)-homocitric acid lactone in 98% yield. (S)-(+)-homo-
citric acid lactone was also synthesized in the same pro-
cedure. The overall yields of (R)-(ꢀ)- and (S)-(+)-
homocitric acid lactone are 32% and 33% from D- and
L-malic acid, respectively.
The last step is to remove the protecting group (Scheme
2). We tried using formic acid or trifluoroacetic acid in
various concentrations to remove pivalaldehyde protec-
The optical rotations were measured. (R)-(ꢀ)- and (S)-
(+)-homocitric acid lactone were already synthesized
by Biellmann6 and their optical rotations were reported
in a complicated system.13 We measured the optical
rotations of (R)-(ꢀ)- and (S)-(+)-homocitric acid lac-
tone in methanol, and also in the presence of molybdate
complex according to the reported method.13 The results
22
D
are as following; (R)-(ꢀ)-homocitric acid lactone: ½aꢁ
22
D
ꢀ21.2 (c 1.22, CH3OH), ½aꢁ ꢀ51.8 (c 0.25, condition
22
22
D
see Ref. 13); (S)-(+)-homocitric acid lactone: ½aꢁ
+21.3 (c 1.12, CH3OH). ½aꢁ +52.2 (c 0.22, condition
D
see Ref. 13).
In conclusion, we have developed a new and simple
method for the synthesis of (R)-(ꢀ)- and (S)-(+)-homo-
citric acid lactone with high stereoselectivity in higher
yield. We believe such a facile method will significantly
Figure 2. The ORTEP3 structure of D,L-2b.
Scheme 2.

3818
P.-F. Xu et al. / Tetrahedron Letters 46 (2005) 3815–3818
Sunada, Y.; Honda, M.; Katada, M.; Tatsumi, K. J. Am.
Chem. Soc. 2003, 125, 4052–4053; (d) Zhang, Y.; Zuo,
J.-L.; Zhou, H.-C.; Holm, R. H. J. Am. Chem. Soc. 2002,
124, 14292–14293.
facilitate the research of nitrogenase and nitrogenase
models.
5. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313–1324.
Acknowledgements
´
6. Rodrıguez, R. G. H.; Biellmann, Jean-Francois J. Org.
Chem. 1996, 61, 1822–1824.
This work was financially supported by Grant-in-Aid
for Science Research on Priority Areas (No. 14078211,
14078101) from Ministry of Education, Culture, Sports,
Science and Technology of Japan, which is gratefully
acknowledged.
7. Ma, G.; Palmer, D. R. J. Tetrahedron Lett. 2000, 41, 9209–
9212.
8. Palmer also reported that the reactions with less activated
electrophiles were unsuccessful. See Ref. 7.
9. X-ray data for D,L-2b and (2R,4S)-2c; the data collection
was made with a Rigaku-AFC8 diffractometer equipped
with a Rigaku Saturn CCD detector. The structure was
solved by direct methods and refined by full-matrix least-
squares on F by teXsan software package of Rigaku/MSC.
Crystal data for D,L-2b: C12H20O5, M = 244.29, tric-
Supplementary data
Experimental details and spectroscopic data for all new
compounds are included in Supplementary data which
can be obtained on-line at doi:10.1016/j.tetlet.
2005.03.180.
ꢀ
linic, space group P1, a = 5.964(1), b = 9.246(2), c =
˚
12.610(3) A,
a = 98.848(10),
b = 103.231(9),
c =
91.11(1)°, V = 667.7(2) A , Z = 2, Dcalcd = 1.215 g/cm3,
3
˚
T = 173 K, l(Mo-Ka) = 0.94 cmꢀ1
0.071, GOF = 1.91, 158 variables, 2856 unique reflections
,
R = 0.054, Rw
=
[I > 0r(I)]. For (2R,4S)-2c: C13H20O7, M = 288.30, mono-
clinic, space group P21, a = 10.06(1), b = 6.346(5),
References and notes
3
˚
˚
c = 12.77(1) A, b = 112.09(2)°, V = 755.2(10) A , Z = 2,
1. Shah, V. K.; Brill, W. J. Proc. Natl. Acad. Sci. U.S.A.
1977, 74, 3249–3253.
Dcalcd = 1.268 g/cm3, T = 173 K, l(Mo-Ka) = 1.03 cmꢀ1
,
R = 0.036, Rw = 0.046, GOF = 1.31, 184 variables, 2816
unique reflections [I > 0r(I)]. Crystallographic data have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
265287 for D,L-2b and CCDC 265288 for (2R,4S)-2c.
10. Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565–571.
11. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2708–2748.
2. (a) Georgiadis, M. M.; Komiya, H.; Chakrabarti, P.;
Woo, D.; Kornuc, J. J.; Rees, D. C. Science 1992, 257,
1653–1659; (b) Kim, Jongsun; Rees, D. C. Science 1992,
257, 1677–1682; (c) Einsle, O.; Tezcan, F. A.; Andrade, S.
L. A.; Schmid, B.; Yoshida, M.; Howard, J. B.; Rees, D.
C. Science 2002, 297, 1696–1700.
3. (a) Hinnemann, B.; Nørskov, J. K. J. Am. Chem. Soc.
2003, 125, 1466–1467; (b) Lovell, T.; Li, J.; Case, D. A.;
Noodleman, L. J. Am. Chem. Soc. 2002, 124, 4546–4547;
(c) Durrant, M. C. Biochemistry 2002, 41, 13934–13945;
1
12. (2R,4R)-2c: H NMR (500 MHz, CDCl3): d 5.20 (s, 1H),
3.71 (s, 3H), 2.89 (d, 1H, J = 16.5 Hz), 2.86 (d, 1H,
J = 16.5 Hz), 2.43–2.52 (m, 2H), 2.26–2.32 (m, 1H), 2.08–
(d) Sanakis, Y.; Power, P. P.; Stubna, A.; Munck, E.
¨
22
2.14 (m, 1H), 0.96 (s, 9H); mp: 75–77 °C. ½aꢁD ꢀ20.0.
Inorg. Chem. 2002, 41, 2690–2696; (e) Lovell, T.; Li, J.;
Liu, T.; Case, D. A.; Noodleman, L. J. Am. Chem. Soc.
2001, 123, 12392–12410; (f) Benton, P. M. C.; Mayer, S.
M.; Shao, J.; Hoffman, B. M.; Dean, D. R.; Seefeldt, L. C.
Biochemistry 2001, 40, 13816–13825; (g) Sorlie, M.;
Christiansen, J.; Lemon, B. J.; Peters, J. W.; Dean, D.
R.; Hales, B. J. Biochemistry 2001, 40, 1540–1549.
1
(2R,4S)-2c: H NMR (500 MHz, CDCl3): d 5.32 (s, 1H),
3.72 (s, 3H), 2.94 (d, 1H, J = 17 Hz), 2.88 (d, 1H,
J = 17 Hz), 2.54–2.60 (m, 1H), 2.42–2.48 (m, 1H), 2.22–
2.28 (m, 1H), 2.12–2.18 (m, 1H), 0.99 (s, 9H); mp: 108–
22
110 °C. ½aꢁD +26.2.
13. Krebs, H. A.; Eggleston, L. V. Biochemistry 1943, 37, 334,
According to their method, we prepared the media from
2.5 mL of Na3-citrate (1 M), 0.5 mL of glacial acetic acid,
4.5 mL (NH4)2MoO4 (29%) and 2.5 mL distilled water.
4. (a) Lee, S. C.; Holm, R. H. Chem. Rev. 2004, 104, 1135–
1158; (b) Dos Santos, P. C.; Dean, D. R.; Hu, Y.; Ribbe,
M. W. Chem. Rev. 2004, 104, 1159–1174; (c) Ohki, Y.;