Desymmetrization of cyclic anhydrides using dihydroxy compounds: Selective synthesis of macrocyclic tetralactones

Article abstract of DOI:10.1021/ol060509k

The desymmetrization of cyclic anhydrides is carried out using dihydroxy compounds. A mild route to synthesize fused saturated/unsaturated macrocyclic tetralactones with different ring sizes (20-34) having a wide variety of spacers is described. The structure is confirmed by the representative single-crystal X-ray analysis. The multiple reduction of unsaturated macrocyclic tetralactones is also illustrated. This method is mild, selective, and efficient and achieves high yield.

Full text of DOI:10.1021/ol060509k

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1913-1916
Desymmetrization of Cyclic Anhydrides
Using Dihydroxy Compounds: Selective
Synthesis of Macrocyclic Tetralactones
Sengodagounder Muthusamy,* Boopathy Gnanaprakasam, and
Eringathodi Suresh
Central Salt & Marine Chemicals Research Institute (CSIR),
BhaVnagar, Gujarat 364 002, India
muthu@csmcri.org
Received March 1, 2006
ABSTRACT
The desymmetrization of cyclic anhydrides is carried out using dihydroxy compounds. A mild route to synthesize fused saturated/unsaturated
macrocyclic tetralactones with different ring sizes (20 34) having a wide variety of spacers is described. The structure is confirmed by the
−
representative single-crystal X-ray analysis. The multiple reduction of unsaturated macrocyclic tetralactones is also illustrated. This method
is mild, selective, and efficient and achieves high yield.
Great attention has been focused on the synthesis of
macrolides, particularly dilactones, due to their biological
properties, ability to form complexes and ion carriers, and
application in the perfume industry.1 Since Pederson’s
discovery of macrocyclic polyether (crown) compounds,
extensive research has been carried out toward their synthesis
and ion selectivity.2 Many researchers have been involved
in the synthesis of dilactones because of their potential
importance in ion transports.3 However, only a limited
number of methods for the preparation of macrocylcic
dilactones are currently available. These methods involve
the reaction of the dicesium salts of acids with dibromides,4
reaction of acid chlorides with glycols,5 condensation of
dipotassium salt of acids with dibromides,6 condensation of
dicarboxylic acids with benzyl bromides,7 reaction of acid
chlorides with ω-bromo alcohols,8 condensation of diacid
chlorides with diols under phase-transfer catalysis,9 cycliza-
tion of sulfonium salts in the presence of cesium carbonate,10
or the reaction assisted by alkaline metals.11 Recently,
(5) Asay, R. E.; Bradshaw, J. S.; Nielsen, S. F.; Thompson, M. D.; Snow,
J. W.; Masihdas, D. R. K.; Izatt, R. M.; Christensen, J. J. J. Heterocycl.
Chem. 1977, 14, 85.
(6) (a) Drewes, S. E.; Coleman, P. C.J. Chem. Soc., Perkin Trans. 1
1972, 2148. (b) Drewes, S. E.; Riphagen, B. G. J. Chem. Soc., Perkin Trans.
1 1974, 1908.
(7) Drewes, S. E.; Riphagen, B. G. J. Chem. Soc., Perkin Trans. 1 1974,
323.
(1) Bradshaw, J. S.; Maas, G. E.; Izatt, R. M.; Christensen, J. J. Chem.
ReV. 1979, 79, 37.
(8) Samat, A.; Bibout, M. E. M.; Elguero, J. J. Chem. Soc., Perkin Trans.
1 1985, 1717.
(9) (a) Zhou, Z.; Schuster, D. I.; Wilson, S. R. J. Org. Chem. 2003, 68,
7612. (b) Singh, P.; Kumar, M.; Singh, H. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1987, 26, 64. (c) Singh, H.; Kumar, M.; Singh, P.
J. Chem. Res., Miniprint 1989, 4, 675.
(2) (a) Bogdanova, A.; Perkovic, M. W.; Popik, V. V. J. Org. Chem.
2005, 70, 9867. (b) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
(3) (a) Griesbeck, A. G.; Henz, A.; Hirt, J. Synthesis 1996, 1261. (b)
Masamune, S.; Bates, S. G.; Corcoran, J. W. Angew. Chem., Int. Ed. Engl.
1977, 16, 585. (c) Nicolaou, K. C. Tetrahedron 1977, 33, 683. (d) Paterson,
I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569.
(10) Nakamura, T.; Matsuyama, H.; Kamigata, N.; Iyoda, M. J. Org.
Chem. 1992, 57, 3783.
(4) Piepers, O.; Kellogg, R. M. J. Chem. Soc., Chem. Commun. 1978,
383.
(11) Takahashi, S.; Souma, K.; Hashimoto, R.; Koshino, H.; Nakata, T.
J. Org. Chem. 2004, 69, 4509.
10.1021/ol060509k CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/05/2006

synthesis of dilactones was also reported through lipase
catalysis12 or photochemical acylation.13 Even though meth-
ods available in the literature provide a mixture of dilactones
and tetralactones, the reactions give low yields and require
drastic conditions. Thus, in this paper, we report a new high-
yielding, selective method to synthesize macrocyclic tetra-
lactones having various spacers/ring sizes via dicyclohexyl-
carbodiimide (DCC)-mediated double esterification of di-
carboxylic acids.
Table 1. Synthesis of Dicarboxylic Acids 3 via Scheme 1
Toward the objective to synthesize new macrocycles, we
initially proposed performing the desymmetrization14 of
cyclic anhydrides (Figure 1) in the presence of dihydroxy
Figure 1. Anhydrides used for the desymmetrization reactions.
compounds. Therefore, an excess amount of phthalic anhy-
dride 1a was reacted with 1 equiv of tetra(ethylene glycol)
in the presence of triethylamine to furnish the corresponding
dicarboxylic acid 3a in 90% yield (Scheme 1, Table 1). The
product was undoubtedly confirmed on the basis of the
spectral data. This interesting result encouraged us to
investigate this reaction with various dihydroxy compounds.
Toward this end, the anhydride 1a was reacted with several
diols such as tri(ethylene glycol) and 1,2-benzenedimethanol
to afford the respective products 3b,c in good yield.
Scheme 1
a Yields are unoptimized and refer to isolated yields.
To extend this strategy, the reaction was performed with
several cyclic anhydrides. Thus, the reaction was carried with
the racemic anhydrides 1b,c. The anhydride 1b was reacted
with cis-1,4-butenediol in the presence of triethylamine to
(12) (a) Bosch, M. P.; Guerrero, A. Synlett 2005, 17, 2611. (b) Zhi-
Wei, G.; Sih, C. J. J. Am. Chem. Soc. 1988, 110, 1999.
(13) Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791.
(14) Chen, Y.; McDaid, P.; Deng, L. Chem. ReV. 2003, 103, 2965.
1914
Org. Lett., Vol. 8, No. 9, 2006

provide the corresponding dicarboxylic acid 3d in an
excellent yield. The anhydride 1b was also reacted with tri-
(ethylene glycol) or tetra(ethylene glycol) to afford the
dicarboxylic acids 3e,f having oxyethylene moieties as
spacers in very good yield. However, the reaction of
unsymmetrical anhydride 1c with tri(ethylene glycol) pro-
vided the dicarboxylic acid 3g as a mixture of regioisomers.
Similar reaction with anhydride 1d with tetra(ethylene glycol)
provided the dicarboxylic acid 3h.
Table 2. Synthesis of Macrocyclic Tetralactones 5
Next, we investigated the reactions involving cis-cyclic
anhydrides 1e-g. Initially, the reaction of 1,4-butynediol and
an excess cis-cyclic anhydride 1e, in the presence of
triethylamine, afforded the corresponding dicarboxylic acid
3i. Similar reactions were performed with the cis-anhydride
1e and various diols such as cis-2-butene-1,4-diol, di(ethylene
glycol), tri(ethylene glycol), and tetra(ethylene glycol) to
afford the corresponding dicarboxylic acids 3j-m.
The desymmetrization of cyclic anhydride reactions was
successfully carried out with exo- as well as endo-anhydrides.
Thus, the endo-anhydride 1f was reacted with tetra(ethylene
glycol) to furnish the respective endo-dicarboxylic acid 3n.
Similarly, the reaction of exo-anhydride 1g with di(ethylene
glycol) or tetra(ethylene glycol) afforded the respective exo-
dicarboxylic acids 3o,p. All of the above reactions provided
the corresponding dicarboxylic acids 3 in very good yields
(Table 1) except the product 3h. The NMR data character-
istically evidenced a single isomer of the dicarboxylic acids
3 except in the case of 3g. Formation of the corresponding
hydroxy acids 4 was not observed in the above reactions as
confirmed by spectroscopic data.
To synthesize the macrocyclic compounds, we planned
to carry out the double esterification reaction of the above
dicarboxylic acids 3. To this end, the reaction of the
dicarboxylic acid 3a, tetra(ethylene glycol), and an excess
DCC was carried out at 0 °C in the presence of a catalytic
amount of DMAP to furnish the macrocyclic tetralactone
5a in 61% yield (Table 2). The product 5a was characterized
on the basis of detailed spectroscopic studies. Interestingly,
the linear dicarboxylic acid 3a affords the macrocyclic
tetralactone 5a having 34 atoms in the cyclic core. To
generalize the synthesis of macrocyclic tetralactones 5, the
representative dicarboxylic acids 3 were subjected to the
double esterification reaction. To synthesize several tetra-
lactones having different ring sizes, the double esterification
reaction of dicarboxylic acid 3b and tri(ethylene gycol) or
tetra(ethylene glycol) was performed to afford the corre-
sponding macrocyclic tetralactones 5b,c in moderate yield.
The products 5a-c hold several oxyethylene units with 34,
28, and 31 atoms in the cyclic core, respectively (Table 2).
Further, the reaction of dicarboxylic acid 3c and 1,6-
hexanediol provided the tetralactone 5d having 22 atoms in
the cyclic core. The dehydration reactions of dicarboxylic
acids 3e,i,j,l,n and cis-2-butene-1,4-diol, 1,4-butanediol, 1,4-
benzenedimethanol, tri(ethylene glycol), or tetra(ethylene
glycol) were carried out in the presence of DCC/DMAP to
afford the corresponding macrocyclic tetralactones 5e-o in
moderate yield. Notably, this facile method affords many
macrocyclic tetralactones 5 having 20, 22, 23, 24, 27, 28,
a Yields are unoptimized and refer to isolated pure compounds 5.
Org. Lett., Vol. 8, No. 9, 2006
1915

31, and 34 atoms in the cyclic core. The cyclic anhydrides
1 except 1d used in this experimental study provide mac-
rocyclic tetralactones 5 having two fused cyclic/bicyclic ring
systems on the macrocyclic core, which offer conformational
rigidity to some extent. The structure of the tetralactone 5k
having fused cis-cyclohexene ring system was further
confirmed using single-crystal X-ray crystallography (Figure
2).15 The result of the high R value for the tetralactone 5k is
due to the extensive dynamic disorder16 present in the
aliphatic chain even at 100 K.
Scheme 2
hydrogenation was also carried out with the tetralactone 5h
having the alkyne spacer to furnish the tetralactone 7
(Scheme 3). In this process, the triple bond is also reduced
Scheme 3
Figure 2. X-ray crystal structure of macrocyclic tetralactone 5k
(hydrogen atoms are omitted for clarity).
Finally, we were interested in reducing the double bonds
of the unsaturated macrocyclic tetralactones in order to obtain
a more flexible saturated macrocyclic core. Thus, the
macrocyclic tetralactone 5j was reduced by catalytic hydro-
genation in the presence of 5 wt % of palladium on activated
carbon to afford the saturated macrocyclic tetralactone 6
(Scheme 2). In this process, three double bonds are reduced
under mild reaction conditions. This interesting multiple
along with the double bonds. Thus, the unsaturated tetra-
lactones having three double bonds and one triple bond are
simultaneously reduced under mild reaction conditions.
In conclusion, we have developed a novel method to
synthesize macrocyclic tetralactones in a facile manner from
the commercially available materials. This methodology
provides synthesis of medium as well as large interesting
macrocyclic tetralactones having oxyethylene, alkenyl, alky-
nyl, alkyl, and aryl spacers in good yields. Further, the
multiple reduction of unsaturated macrocyclic tetralactones
was successfully performed to afford a fused saturated
macrocyclic core under mild conditions. Work on the detailed
application and chiral version of these crown ethers is under
progress in our laboratory and will be reported in due course.
(15) Crystal data for the compound 5k: C24H19O8, M ) 435.39, 0.24 ×
0.13 × 0.06 mm3, monoclinic, space group P21/c with a ) 13.342(3) Å,
b ) 9.981(3) Å, c ) 16.534(4) Å, R ) 90°, â ) 94.778(4)°, γ ) 90°, V )
2194.2(10) Å3, T ) 100(2) K, R1 ) 0.1286, wR2 ) 0.3586 on observed
data, z ) 4, Dcalcd ) 1.318 g cm-3, F(000) ) 908, absorption coefficient
) 0.100 mm-1, λ ) 0.71073 Å, 7284 reflections were collected on a smart
apex CCD single-crystal diffractometer, 2714 observed reflections (I g 2σ-
(I)). The largest difference peak and hole ) 0.714 and -0.428 e Å-3
,
respectively. The structure was solved by direct methods and refined by
Acknowledgment. This research was supported by DST,
full-matrix least-squares on F2 using SHELXL-97 software.
(16) The data collection was carried out at 100 K using liquid nitrogen
and the extensive dynamic disorder observed in one of the bridging aliphatic
chains with the cyclohexene rings during structure solution. Thus, carbon
atoms C19, C20, C21, C22 and oxygen atoms O5, O6 of the chain are
disordered along with one carbon atom C17 of the cyclohexene ring. The
occupancy factors for these disordered atoms were fixed using FVAR from
the SHELXTL (Sheldrick, G. M. SHELXTL, version 5.10, Bruker AXS,
Madison, WI, 1997) program; all of the disordered atoms were refined only
isotropically. Hydrogen atoms were fixed at geometrical positions for all
of the non-hydrogen atoms refined anisotropically and not for the disordered
atoms.
New Delhi. B.G. thanks CSIR, New Delhi, for a fellowship.
Supporting Information Available: Experimental pro-
cedures, spectral data for all new compounds, copies of
spectra for the compounds 5b-e,h,j-m, 6, and 7, and X-ray
structural data for compound 5k. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL060509K
1916
Org. Lett., Vol. 8, No. 9, 2006