A convenient general method for the synthesis of hydroxy diacids

Article abstract of DOI:10.1016/j.tetlet.2007.03.053

Olefinic aldehydes and epoxides with terminal double bonds react with Grignard reagents, and the acetates made from the resulting alcohols undergo double bond cleavage on treatment with RuCl₃·xH₂O in the presence of NaIO₄ to give acetoxy diacids. Hydrolysis with LiOH then affords hydroxy diacids.

Full text of DOI:10.1016/j.tetlet.2007.03.053

Tetrahedron Letters 48 (2007) 3141–3143
A convenient general method for the synthesis of hydroxy diacids
Chandramouli Chiruta, Santosh Jachak and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received 4 January 2007; revised 7 March 2007; accepted 8 March 2007
Available online 13 March 2007
Abstract—Olefinic aldehydes and epoxides with terminal double bonds react with Grignard reagents, and the acetates made from
the resulting alcohols undergo double bond cleavage on treatment with RuCl3ÆxH2O in the presence of NaIO4 to give acetoxy di-
acids. Hydrolysis with LiOH then affords hydroxy diacids.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
is compatible with the presence of acetate groups and so
we have used the corresponding bis olefinic acetates 2 as
precursors of the diacids. These acetates, in turn, are
made from the corresponding alcohols, which are them-
selves readily available by reaction of an appropriate
olefinic Grignard reagent with an olefinic aldehyde or
olefinic epoxide.
During the course of a project aimed at providing a
bank of samples of human metabolites that are present
in body fluids at concentrations above 1lM, we needed
to synthesize a number of hydroxy diacids of general
structure 1, where n = 0–1, and m = 1–10. The purpose
of obtaining these acids—and the other types of com-
pounds we have prepared—is to make available samples
for quantitation, so that levels and ratios of these meta-
bolites can be determined as a diagnostic tool in medical
practice.
The acids we have made and the synthetic routes are
shown in Table 1.
In the particular case of 2-hydroxyhexanedioic acid (5),
cyclohexenyl acetate (3) was the substrate used for the
ruthenium-mediated cleavage. In the other examples, ex-
cept that of entry 7, bis-olefins were used, and they were
made by direct Grignard addition to aldehydes or by
copper-catalyzed addition to epoxides.
We have developed a general method that allows com-
plete control of the values of m and n in 1, although in
the present work we have examined only the range
m = 2–10 and n = 0–1, as the corresponding hydroxy
diacids appear to be the most important for our diag-
nostic studies of fatty acid metabolism. The approach
is experimentally simple and is based on the fact that ter-
minal double bonds are cleaved efficiently by catalytic
amounts of RuCl3ÆxH2O in the presence of stoichiome-
tric NaIO4.1 The cleavage proceeds smoothly at room
temperature in a mixture of MeCN, EtOAc and water
and gives good yields of the required acids, generally
after a 2–12 h reaction period. The reagent combination
It is known that silicon protecting groups are removed
by NaIO4 solutions,11 although this may not be due to
the acidity of the solutions (pH 2.512) because desilyl-
ation (at least of Et3Si-groups) occurs even in a buffered
neutral or slightly basic medium.11 Nonetheless, we find
that the RuCl3ÆxH2O–NaIO4 system removes t-BuMe2-
Si-groups from oxygen and oxidizes the resulting pri-
mary alcohol to a carboxylic acid; this very convenient
feature was used in the synthesis of 35 for which the sub-
strate for reaction with allylmagnesium bromide was x-
siloxy aldehyde 31. In contrast to the present work, tert-
butyldimethylsilyl ethers of secondary alcohols appear
to be reasonably stable to RuCl3ÆxH2O-NaIO4.13–15
The present method is operationally simple and
the precursors are available by standard methods. The
reactions are clean, and it is convenient to use the
*
Corresponding author. Tel.: +1 780 492 3251; fax: +1 780 492
8231; e-mail: derrick.clive@ualberta.ca
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.053

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C. Chiruta et al. / Tetrahedron Letters 48 (2007) 3141–3143
Table 1. Synthesis of hydroxy diacids
Superscript numbers 2–9 refer to references. (a) RuCl3ÆxH2O, NaIO4, 2:2:3 MeCN–EtOAc–water, 2 h; (b) LiOH, 1:10 water–THF, 12 h; (c)
allylmagnesium bromide, THF, À78 ꢁC, 2 h; (d) AcCl, pyridine, CH2Cl2, 3 h; (e) RuCl3ÆxH2O, NaIO4, 2:2:3 MeCN–EtOAc–water, 12 h; (f)
allylmagnesium bromide, Et2O, À78 ꢁC, 2 h; (g) Ac2O, Et3N, CH2Cl2, 3 h; (h) vinylmagnesium bromide, THF, À78 ꢁC, 2 h; (i) vinylmagnesium
bromide, CuI, THF, À78 ꢁC, 1.5 h; (j) allylmagnesium bromide, Et2O, À78 ꢁC, 5 h.
crude acetates directly for hydrolysis, to liberate the
desired hydroxy acids. Representative procedures are as
follows.
oxydecanedioic acid (1.20 g, 83%) as an oil which was
used directly in the next step.
3. ( )-2-Hydroxydecanedioic acid (20)
2. ( )-2-Acetoxydecanedioic acid (19)10
LiOH (332 mg, 13.84 mmol) was added to a stirred solu-
tion of ( )-2-acetoxydecanedioic acid (1.20 g, 4.61
mmol) in 10:1 THF–water (15 mL) and stirring was
continued overnight. Most of the organic solvent was
evaporated and the aqueous phase was acidified with
1 N hydrochloric acid and extracted with EtOAc
(5 · 20 mL). The combined organic extracts were dried
(Na2SO4) and evaporated to give 2-hydroxydecanedioic
RuCl3Æ3H2O (50 mg, 0.24 mmol) and NaIO4 (9.69 g,
45.34 mmol) were added to a stirred mixture of acetic
acid 1-vinyldec-9-enyl ester (1.24 g, 5.53 mmol) and
3:2:2 water–MeCN–EtOAc (35 mL), and stirring was
continued for 12 h. The mixture was then diluted with
EtOAc (50 mL) and the organic layer was washed with
brine, dried (Na2SO4) and evaporated to give ( )-2-acet-

C. Chiruta et al. / Tetrahedron Letters 48 (2007) 3141–3143
3143
acid (800 mg, 80%) as a solid: mp 118–121 ꢁC (from
(t), 28.5 (t), 28.7 (t), 28.9 (t), 28.9 (t), 29.0 (t), 33.6 (t),
36.9 (t), 42.7 (t), 67.0 (d), 173.0 (s), 174.4 (s); exact mass
m/z calcd for C14H25O5 (MÀH) 273.16965. Found:
273.17045.
EtOAc); FTIR (DMSO cast) 3510 (sharp), 3400–2000
(br), 1677 cmÀ1 1H NMR (300 MHz, CDCl3 plus
;
DMSO-d6) d 1.15–1.39 (m, 8H), 1.40–1.60 (m, 3H),
1.60–1.71 (m, 1H), 2.13 (t, J = 7.7 Hz, 2H), 3.99 (dd,
J = 7.2, 4.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 24.4 (t), 24.6 (t), 28.4 (t), 28.6 (t), 33.6 (t), 33.9 (t),
69.5 (d), 174.4 (s), 175.9 (s); exact mass m/z calcd for
C10H17O5 (MÀH) 217.10705. Found: 217.10655.
Acknowledgements
We thank Genome Canada and Genome Prairie for
financial support.
4. ( )-3-Acetoxytetradecanedioic acid (34)
References and notes
RuCl3Æ3H2O (27.6 mg, 0.133 mmol) and NaIO4 (2.33 g,
10.91 mmol) were added to a stirred mixture of 1-[(11-
(t-butyldimethylsilyl)oxy]undecyl]but-3-enyl ester (530
mg, 1.33 mmol) in 3:2:2 H2O–MeCN–EtOAc (14 mL),
and stirring was continued for 12 h. The mixture was
then extracted with EtOAc (3 · 20 mL) and the com-
bined organic extracts were dried (Na2SO4) and evapo-
rated. The resulting residue was neutralized with
saturated aqueous NaHCO3 (10 mL) and extracted with
Et2O (2 · 20 mL). The aqueous phase was acidified with
20% hydrochloric acid and extracted with EtOAc (3 ·
20 mL). The combined organic extracts were dried
(Na2SO4) and evaporated to give ( )-3-acetoxytetra-
decanedioic acid (320 mg, 76%) as a white solid, which
was used directly for the next step.
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5. ( )-3-Hydroxytetradecanedioic acid (35)
LiOH (95 mg, 3.98 mmol) was added to a stirred solu-
tion of ( )-3-acetoxytetradecanedioic acid (315 mg,
0.99 mmol) in 1:1 THF–water (5 mL) and stirring was
continued overnight. Most of the organic solvent was
evaporated and the aqueous phase was acidified with
1 N hydrochloric acid and extracted with EtOAc
(5 · 10 mL). The combined organic extracts were dried
(Na2SO4) and evaporated to give ( )-3-hydroxy-
tetradecanedioic acid (260 mg, 95.2%) as a white solid:
mp 113–116 ꢁC; FTIR (DMSO cast) 3565 (sharp),
3400–2000 (br), 1689 cmÀ1; 1H NMR (300 MHz, CDCl3
plus DMSO-d6) d 1.15–1.59 (m, 18H), 2.19 (t, J =
7.2 Hz, 2H), 2.29 (dd, JAB = 16.3, JBX = 8.8 Hz, 1H),
2.41 (dd, JAB = 16.3, JAX = 3.4 Hz, 1H), 3.84–3.95 (m,
1H); 13C NMR (100 MHz, DMSO-d6) d 24.5 (t), 25.0
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