Synthesis of diyne substituted 2-hydroxy acids, esters, and amides

Article abstract of DOI:10.1071/CH09639

A series of diyne substituted 2-hydroxy acids and derivatives have been prepared and characterized. Alkylation of butane-2,3-diacetal protected glycolic acid with haloalkyl substituted diyne compounds gave the corresponding diacetal protected diyne substi

Full text of DOI:10.1071/CH09639

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 719–722
Synthesis of Diyne Substituted 2-Hydroxy Acids, Esters,
and Amides
Florian H. M. Graichen,A,B Andrew C. Warden,A Stella Kyi,A
and Michael S. O’SheaA
ACSIRO, Division of Molecular and Health Technologies, Bag 10, Clayton South,
Vic. 3800, Australia.
BCorresponding author. Email: florian.graichen@csiro.au
A series of diyne substituted 2-hydroxy acids and derivatives have been prepared and characterized. Alkylation of butane-
2,3-diacetal protected glycolic acid with haloalkyl substituted diyne compounds gave the corresponding diacetal protected
diyne substituted 2-hydroxy acids. Diacetal deprotection through acid mediated hydrolysis, transesterification, or amino-
lysis afforded the 2-hydroxy-diyne acid, ester, or amide derivatives, respectively. A novel class of polydiacetylenes was
produced through topochemical polymerization of a 2-hydroxy diyne acid and compared with the polymerization of
non-hydroxylated diyne acids.
Manuscript received: 9 December 2009.
Manuscript accepted: 9 February 2010.
Alpha or 2-hydroxy fatty acids comprise a unique class of com-
pounds found to occur in a variety of organisms. In vertebrates,
they occur primarily in brain tissues, skin, and nerve tissues[1,2]
but they are also found in many other organisms such as marine
sponges,[3,4,5] crustaceans,[6] sea urchins,[7,8] earthworms,[9]
starfish,[10] sea cucumbers,[11] plant leaves,[12,13] and bacte-
ria including spirillum,[14] thiobacillus,[15] Escherichia coli,[16]
and many others.[16–18] The 2-hydroxy-carboxylic acid motif is
present in many pharmacologically important compounds.[19]
As a part of our ongoing studies into diyne-containing
molecules we recognized a hitherto unreported class of 2-
hydroxy-diyneacidsandderivatives.[20] Conjugateddiacetylenic
compounds and their topochemical polymerization[21] in the
solid state to form polydiacetylenes (PDAs) have been the
subject of intense study since it was first reported by
Wegner in 1969.[22] PDAs have now been incorporated
into a wide variety of chemical systems, including silica
nanocomposites,[23] silver-coated vesicles,[24] liposomes,[25,26]
OMe
O
O
16
O
OMe
(Ϯ)
(1) LHMDS
Y
R
(2) X
12–15
O
O
OMe
TMSCl
R3OH
R1
R3
R1R2NH
R
N
Y
Y
O
Y
O
O
R2 OH
OH
O
OMe
(Ϯ)
R2
25–28
29–32
17–20
R
H2O
CF3COOH
O
HO
Y
OH
21–24
R
Scheme 1. Synthesis 2-hydroxy diyne acid, esters, and amides.
© CSIRO 2010
10.1071/CH09639
0004-9425/10/040719

720
F. H. M. Graichen et al.
Y
X
Y
HO
Y
HO
(a) or (b)
(a)
HO
Y
ϩ
I
R
R
R
R
8–11
12–15
1 Y ϭ
7CH3
4CH3
3CH3
8–11
4 R ϭ
1 Y ϭ
7CH3
4CH3
3CH3
4 R ϭ
5 R ϭ
6 R ϭ
7 R ϭ
2 Y ϭ
3 Y ϭ
3
8
5 R ϭ
6 R ϭ
7 R ϭ
2 Y ϭ
3 Y ϭ
3
8
Product
Y
R
Yield [%]
43
Product
Y
R
X
Yield [%]
85
(CH2)7
CH3
8
(CH2)7
CH3
12
Br
(CH2)8
9
63
(CH2)8
13
I
61
(CH2)4
(CH2)3
(CH2)3
(CH2)8
CH3
CH3
10
11
60
87
(CH2)4
(CH2)3
(CH2)3
(CH2)8
CH3
CH3
14
15
I
I
93
92
Scheme 2. Reagents and conditions: (a) 10% CuI, pyrrolidine, 30 min,
20◦C.
Scheme 3. Reagents and conditions: products 13–15 (a) PPh3, imidazole,
I2, CH2Cl2, 1 h, −10◦C, product 12 (b) Ph3PBr2, pyridine, CH3CN, 1 h,
0◦C.
thin films,[27] gels,[28] and nanowires[29] among many others.
The PDA applications currently under development cover
fields such as chemosensors,[30] biosensors,[31,32] picosecond
photoswitches,[33] micropatterning,[34] and strain sensors.[35]
The polymerization of the conjugated diyne units requires the
ordered packing of the diyne monomers to present the acetylenic
moieties in an appropriate spatial arrangement in order to pro-
mote an efficient reaction. Such monomers typically have end
groups (such as carboxylic acids) that facilitate the alignment of
the monomers so that the required packing is achieved.[36,37] The
hydrogen bonding ability of the α-OH acid motif present in 2-
hydroxy-diyne acids has not previously been investigated for this
application and is expected to enhance the self assembly of these
diyne compounds, and lead to polymers with improved proper-
ties. The increased activity in the patent literature with respect
to PDAs demonstrates the demand for novel and versatile PDAs
and other innovative approaches to the pre-organization nec-
essary for topochemical polymerization of the monomers have
been produced.[38]
Diyne substituted 2-hydroxy acids and derivatives have pre-
viously not been described in the open literature. One of the
most commonly adopted strategies for the 2-hydroxylation of
unsaturated acids is the direct oxidation of enolate anions.[39]
Our initial attempts to directly hydroxylate diyne acids via direct
oxidation of the enolate anion were unsuccessful, as the sensitive
diyne functionality is not stable under the highly basic conditions
generally required for the deprotonation step. To avoid degra-
dation of the diyne moiety and to allow easy access to ester
and amide derivatives we adapted an approach described by Ley
et al.[40] for the synthesis of 2-hydroxy acids. In the following we
describe the efficient synthesis of novel 2-hydroxy diyne acid,
ester, and amide derivatives (Scheme 1), as well as results of the
initial polymerization experiments with one of the 2-hydroxy
acid diyne products.
1, 3 diaxial interaction
OMe
OMe H
X
Y
(a)
O
O
O
ϩ
O
Y
R
O
O
OMe
OMe
(Ϯ)
(Ϯ)
12 X ϭ Br
13–15 X ϭ I
R
12–15
16
17–20
Product
Y
R
Yield [%]
88
(CH2)7
CH3
17
18
(CH2)8
39
(CH2)4
(CH2)3
(CH2)3
(CH2)8
CH3
CH3
19
20
39
42
Scheme 4. Reagents and conditions: (a) LHMDS, RX (12–15), AcOH,
3 h, −78◦C to 20◦C.
therefore converted into halides 12–15 with 61–93% yields
(Scheme 3), following the procedures of Sandri et al.[44] and
Liu et al.[45,46]
Protected glycolic acid 16 was deprotonated with lithium
bis(trimethylsilyl)amide (LHMDS) (1.05 eq.) in THF at
−78◦C[47] and the corresponding anion of 16 alkylated with
halo-diyne compounds 12–15 to give the protected hydroxy acid
diynes 17–20, isolated in 39–88% yields (Scheme 4). 1H-NMR
and 13C-NMR spectroscopy performed on the products of these
reactions indicated that in all cases only one diastereoisomer
was formed. The stereochemistry of the phenylene linked prod-
uct 17 was examined in detail using a NOESY experiment. The
results showed that a 1,3-diaxial interaction occurred between
the 5-methoxy group and the proton in position 3, demon-
strating that the substituent bearing the diyne is equatorial.[40]
A modified Cadiot–Chodkiewicz reaction[41] of commer-
cially available terminal alkynols 1–3 with 1-iodoalkynes
4–7[42,43] afforded diyne alcohols 8–11, isolated in 43–87%
yields (Scheme 2).
Effective alkylation of the butane-2,3-diacetal of glycolic
acid has previously been achieved with iodoalkanes (such as
1-iodo-butane) or benzyl bromide. The alcohols 8–11 were

Synthesis of Diyne Substituted 2-Hydroxy Acids, Esters, and Amides
721
OMe H
O
O
O
Z
Y
(a)–(g)
Y
O
OH
OMe
(Ϯ)
R
R
21–32
17–20
Product
Y
R
Z
Yield [%]
(Conditions)
Overall
yield*
(CH2)7
CH3
OH
OH
21
22
93 (a)
30
14
(CH2)8
93 (a)
91 (a)
91 (a)
(CH2)4
(CH2)3
(CH2)3
(CH2)8
CH3
CH3
20
31
OH
OH
23
24
(CH2)7
CH3
OMe
25
26
95 (b)
86 (c)
31
14
(CH2)8
O
(CH2)4
(CH2)3
(CH2)3
(CH2)8
CH3
CH3
OEt
27
28
96 (d)
95 (b)
21
32
OMe
(CH2)7
CH3
29
47 (e)
83 (f)
78 (g)
73 (g)
15
28
17
11
H
N
(CH2)8
(CH2)3
30
31
N
O
H
N
(CH2)4
(CH2)3
CH3
CH3
H
N
(CH2)8
32
Scheme 5. (a) (21–24) CF3COOH/H2O, 20◦C; (b) (25, 28) HCl, MeOH, 20◦C; (c) (26) HCl, i-PrOH, reflux;
(d) (27) HCl, EtOH, 50◦C; (e) (29) benzylamine, 20◦C, then TFA/H2O; (f) (30) morpholine, 20◦C, then TFA/H2O;
(g) (31, 32) 2-methyl-propaneamine, 20◦C, then TFA/H2O. *Based on 1, 2, or 3.
Diastereoselective alkylation of the protected glycol 16, by
long and highly unsaturated alkyl halides like 12–15 has not
been previously reported, however, the results observed here are
consistent with those obtained with shorter chain halides.[40]
The subsequent diacetal deprotection was accomplished as
shown in Scheme 5. Acid catalyzed hydrolysis yielded 2-
hydroxy-diyne acids 21–24 in 91–93% yields and high purity,
after aqueous workup. Removal of the protecting group through
transesterification was carried out with methanol (room temper-
ature), ethanol (50◦C), or isopropanol (80◦C) giving the esters
25–28 in 86–96% yields. None of the products obtained through
hydrolysis or transesterification required further purification.
Aminolysis reactions were carried out in neat benzylamine, 2-
methyl-propanamine, or morpholine. The desired amides 29–32
were obtained in 47–83% yields.
polymerization reaction, an experiment with the 2-hydroxy-
diyne acid 23 was performed where several single crystals of
23 were prepared, as outlined in the Accessory Publication, and
exposed to UV radiation at 254 nm.After a few seconds the crys-
tals turned a deep blue colour, indicating that the polymerization
of the diacetylene groups had occurred. By comparison, sim-
ilar polymerization experiments with non-hydroxylated diyne
acids produced less intense colour changes and required longer
irradiation times. The hydrogen bonding function of the α-OH
substituent thus does appear to enhance the self assembly and
subsequent polymerization of these compounds. However, X-ray
crystallographic investigations aimed at investigating the unique
multi-dimensional packing arrangements of 21–24 have been
unsuccessful due to the facile thermal polymerization of these
compounds at room temperature.
As indicated above, 2-hydroxy substituted diyne acids 21–
24 are expected to self assemble into a unique two-dimensional
packing array comprising a series of stacked one-dimensional
sheets. In order to determine if the 2-hydroxy substituent on
these long chain diyne compounds enhances the topochemical
Summary
We have described a convenient, high yielding, and stereoselec-
tive methodology for the preparation of 2-hydroxy-diacetylenic

722
F. H. M. Graichen et al.
compounds 21–32 through the hydrolysis, transesterification, or
aminolysis of diacetal protected 2-hydroxy-diyne acids 17–20.
These diacetals can be readily synthesized through the alkylation
of a butane-2,3-diacetal protected glycolic acid 16 with conju-
gated diyne halides 12–15. Preliminary investigations with 23
have shown that the presence of the 2-hydroxy substituent sig-
nificantly enhances its topochemical polymerization. This effect
is being further investigated and results of these studies will be
reported in due course.
[21] S. Penczek, J. Polym. Sci. Part Polym. Chem. 2002, 40, 1665.
doi:10.1002/POLA.10228 Solid-state polymerization of a crystalline
monomer that does not involve significant atomic or molecular
motion; it results in the formation of a polymer having essentially
the same crystal structure as that of the monomer. Note: topochemi-
cal polymerization is typically initiated by irradiation of the crystalline
monomer with, for example, UV light, or γ-rays.
[22] G. A. Wegner, Naturforsch. Teil B 1969, 24, 824.
[23] Y. Lu, Y. Yang, A. Sellinger, M. Lu, J. Huang, H. Fan, R. Haddad,
G. Lopez, A. R. Burns, D. Y. Sasaki, J. Shelnutt, C. J. Brinker, Nature
2001, 410, 913. doi:10.1038/35073544
[24] X. Chen, G. Zou, Y. Deng, Q. Zhang, Nanotechnology 2008, 19, 1.
[25] U. Jonas, K. Shah, S. Norvez, D. Charych, J. Am. Chem. Soc. 1999,
121, 4580. doi:10.1021/JA984190D
[26] J. Lee, H.-J. Kim, J. Kim, J. Am. Chem. Soc. 2008, 130, 5010.
doi:10.1021/JA709996C
Accessory Publication
Full experimental details and characterization data for all new
compounds are available on the Journal’s website.
[27] R. Volinsky, M. Kliger, T. Sheynis, S. Kolusheva, R. Jelinek, Biosens.
Bioelectron. 2007, 22, 3247. doi:10.1016/J.BIOS.2006.12.024
[28] O. J. Dautel, M. Robitzer, J.-P. Lère-Porte, F. Serein-Spirau,
J. J. E. Moreau, J. Am. Chem. Soc. 2006, 128, 16213. doi:10.1021/
JA065434U
Acknowledgement
We thank the GRDC (Grains Research and Development Corporation),
Australia for financial support and Drs Jack Ryan and Peter Duggan for
critical comments on the manuscript.
[29] H. Gan, H. Liu,Y. Li, Q. Zhao,Y. Li, S. Wang, T. Jiu, N. Wang, X. He,
D. Yu, D. Zhu, J. Am. Chem. Soc. 2005, 127, 12452. doi:10.1021/
JA053352K
[30] D. J. Ahn, J.-M. Kim, Acc. Chem. Res. 2008, 41, 805. doi:10.1021/
AR7002489
[31] M. A. Reppy, B. A. Pindzola, Chem. Commun. 2007, 4317.
doi:10.1039/B703691D
[32] Y. K. Jung, H. G. Park, J.-M. Kim, Biosens. Bioelectron. 2006, 21,
1536. doi:10.1016/J.BIOS.2005.07.010
[33] H. Abdeldayem, D. O. Frazier, M. S. Paley, Appl. Phys. Lett. 2003, 82,
1120. doi:10.1063/1.1543251
[34] J. H. Baek, H. Ahn, J. Yoon, J.-M. Kim, Macromol. Rapid Commun.
2008, 29, 117. doi:10.1002/MARC.200700693
[35] C. J. Pollock, J. S. Kauffman, W. T. Pennington, Abstracts of Papers,
234th ACS National Meeting, Boston, MA, USA, August 19–23,
2007.
References
[1] Y. Kishimoto, N. S. Radin, J. Lipid Res. 1964, 5, 94.
[2] Y. Kishimoto, N. S. Radin, J. Lipid Res. 1963, 4, 139.
[3] G. Barnathan, J. M. Kornprobst, P. Doumeno, J. Miralles, N. Boury-
Esnault, J. Nat. Prod. 1993, 56, 2104. doi:10.1021/NP50102A012
[4] N. M. Carballelra, A. Emiliano, J. Rodriguez, E. D. Reyes, Lipids
1992, 27, 681. doi:10.1007/BF02536024
[5] F. Cafieri, E. Fattorusso, A. Mangoni, O. Taglialatela-Scafati, Gazz.
Chim. Ital. 1996, 126, 711.
[6] N. Asai, N. Fusetani, S. Matsunaga, J. Nat. Prod. 2001, 64, 1210.
doi:10.1021/NP010177M
[7] N. M. Carballeira, F. Shalabi, M. Reyes, J. Nat. Prod. 1994, 57, 614.
doi:10.1021/NP50107A008
[8] H. Kubo, G. J. Jiang, A. Irie, M. Morita, T. Matsubara, M. Hoshi,
J. Biochem. 1992, 111, 726.
[36] M. D. Mowery, H. Menzel, M. Cai, C. E. Evans, Langmuir 1998, 14,
5594. doi:10.1021/LA980331D
[9] P. W. Albro, J. L. Schroeder, J. T. Corbett, Lipids 1992, 27, 136.
doi:10.1007/BF02535813
[37] M. D. Mowery, C. E. Evans, J. Phys. Chem. B 1997, 101, 8513.
doi:10.1021/JP971209A
[38] J. W. Lauher, F. W. Fowler, N. S. Goroff, Acc. Chem. Res. 2008, 41,
1215. doi:10.1021/AR8001427
[39] D. A. Konen, L. S. Silbert, P. E. Pfeffer, J. Org. Chem. 1975, 40, 3253.
doi:10.1021/JO00910A020
[10] A. Irie, H. Kubo, F. Inagaki, M. J. Hoshi, J. Biochem. 1990, 108, 531.
[11] K. Yamada, Y. Harada, Y. Nagaregawa, T. Miyamoto, R. Isobe,
R. Higuchi, Eur. J. Org. Chem. 1998, 2519. doi:10.1002/(SICI)1099-
0690(199811)1998:11<2519::AID-EJOC2519>3.0.CO;2-V
[12] M. Hamberg,A. Sanz, C. Castresana, J. Biol. Chem. 1999, 274, 24503.
doi:10.1074/JBC.274.35.24503
[40] S.V. Ley, E. Diez, D. J. Dixon, R.T. Guy, P. Michel, G. L. Nattrass,T. D.
Sheppard, Org. Biomol. Chem. 2004, 2, 3608. doi:10.1039/B412788A
[41] M. Alami, F. Ferri, Tetrahedron Lett. 1996, 37, 2763. doi:10.1016/
0040-4039(96)00414-5
[13] I. Prost, S. Dhondt, G. Rothe, J. Vicente, M. J. Rodriguez,
N. Kift, F. Carbonne, G. Griffiths, M.-T. Esquerre-Tugaye, S. Rosahl,
C. Castresana, M. Hamberg, Plant Physiol. 2005, 139, 1902.
doi:10.1104/PP.105.066274
[42] L. Brandsma, Preparative Acetylenic Chemistry 1988 (Elsevier:
Amsterdam).
[43] B. E. Coleman, V. Cwynar, D. J. Hart, F. Havas, J. M. Mohan,
S. Patterson, S. Ridenour, M. Schmidt, E. Smith, A. J. Wells, Synlett
2004, 8, 1339.
[14] C. W. Moss, M. A. Lambert, Microbios Lett. 1976, 3, 207.
[15] H. W. Knoche, J. M. Shively, J. Biol. Chem. 1969, 244, 4773.
[16] J. H. Parker, G. A. Smith, H. L. Fredrickson, J. R. Vestal, D. C. White,
Appl. Environ. Microbiol. 1982, 44, 1170.
[17] P. Drigues, D. Lafforgue, J. Asselineau, Biochim. Biophys. Acta
Lipids and Lipid Metabolism 1981, 666, 504. doi:10.1016/0005-
2760(81)90312-X
[44] J. Sandri, J. Viala, Synth. Commun. 1992, 22, 2945. doi:10.1080/
00397919208021119
[45] J. Liu, J. J. Swidorski, S. D. Peters, R. P. Hsung, J. Org. Chem. 2005,
70, 3898. doi:10.1021/JO0501846
[18] J.-F. Rontani, S. Christodoulou, M. Koblizek, Lipids 2005, 40, 97.
doi:10.1007/S11745-005-1364-6
[46] The conversions into the halides were carried out under very mild
conditions, which had no impact on the sensitive diyne functionality.
[47] After 15 min the reaction mixture was warmed to −50◦C to −40◦C,
prior to addition of the halo-diyne compounds. The excess of base did
not lead to dialkylation of 16 and had no impact on the sensitive diyne
functionality of our electrophiles. The slightly increased temperature
was necessary to avoid the precipitation of the halides in the reaction
mixture at −78◦C.
[19] (a) G. M. Coppola, H. F. Schuster, in α-Hydroxy Acids in Enantio-
selective Synthesis 1997 (VCH: Weinheim).
(b) Y. Murakami, Y. Oshima, Y. Yasumoto, Bull. Jpn. Soc. Sci. Fish.
1982, 48, 69.
(c) L. M. West, P. T. Northcote, C. N. Battershill, J. Org. Chem. 2000,
65, 445. doi:10.1021/JO991296Y
[20] A. C. Warden, F. H. M. Graichen, M. S. O’Shea, WO/2008/031157
2008, Acetylenic Compounds.