Cyclic oligomers (macroaldonolactones) from a protected d-galactonic acid monomer

Article abstract of DOI:10.1016/j.tetlet.2009.07.123

Dicyclohexylcarbodiimide-promoted self-condensation of 2,3:4,5-di-O-isopropylidene-d-galactonic acid (3) led to the macrocyclic oligomeric cyclo[(2,3:4,5-di-O-isopropylidene-(1→6)-d-galactonate)₂ ] (4) and cyclo[(2,3:4,5-di-O-isopropylidene-(1→

Full text of DOI:10.1016/j.tetlet.2009.07.123

Tetrahedron Letters 50 (2009) 5677–5680
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyclic oligomers (macroaldonolactones) from a protected D-galactonic
acid monomer
*
C. Lorena Romero Zaliz, Oscar Varela
CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Pabellón II, Ciudad Universitaria, 1428-Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Dicyclohexylcarbodiimide-promoted self-condensation of 2,3:4,5-di-O-isopropylidene-D-galactonic acid
Received 2 July 2009
Revised 21 July 2009
Accepted 22 July 2009
Available online 26 July 2009
(3) led to the macrocyclic oligomeric cyclo[(2,3:4,5-di-O-isopropylidene-(1?6)-
cyclo[(2,3:4,5-di-O-isopropylidene-(1?6)- -galactonate)3] (5), having, respectively, 14- and 21-mem-
bered rings. The macrocycles 4 and 5 were also synthesized by cyclization of the respective linear dimer
11 and trimer 14 -hydroxy acids precursors prepared by stepwise additions of 3. Compounds 4 and 5
are biomaterials that may be described as macrolactone-cyclodextrins.
D-galactonate)2] (4) and
D
x
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Macrocycle
Macrolactone
Cyclodextrin
Aldonic acid
Biomaterial
Cyclodextrins have attracted considerable attention in recent
years due to their wide range of industrial uses as complexing sys-
tems for environmental remediation,1 fragrance anchoring to fab-
rics,2 or even drug and gene-controlled release systems for the
pharmaceutical industry.3–5 The chirality of cyclodextrins is ap-
plied in asymmetric organic synthesis6,7 and chromatography sep-
arations.8–10
Alternatively, each macrocycle has been selectively prepared by
cyclization of the respective linear dimer or trimer, synthesized by
consecutive addition of the monomer. The resulting oligomeric cy-
clo[(2,3:4,5-di-O-isopropylidene-(1?6)-D-galactonate)2] (4) and
cyclo[(2,3:4,5-di-O-isopropylidene-(1?6)-D-galactonate)3] (5) may
be described as cyclodextrin-macroaldonolactones.
The precursor of the cyclic oligomers, the 2,3:4,5-di-O-isopro-
The versatility of carbohydrate macrocycles relies on the size of
the ring and the chirality that allow the formation of inclusion
complexes with different organic and inorganic molecules. A wide
range of carbohydrate macrocycles have been reported,11 mostly
constituted by monosaccharides linked through glycosidic bonds.
However, there are limited examples of macrocyclic lactones de-
rived from sugars. Monosaccharides conjugated with hydroxy
acids have been employed as precursors of sugar-fatty acid macro-
lactones such as macroviracins, cycloviracins, and others.12 Cyclic
and linear polyesters have been obtained by polycondensation of
isosorbide and suberoyl chloride or other aliphatic dicarboxylic
acid chlorides.13 The ring-opening polymerization of lactones, suc-
cessfully applied for the preparation of cyclic poly(lactide) from
lactide,14 has recently been employed to a racemic derivative of
pylidene-D-galactonic acid (3) was prepared from 1 in two steps
(Scheme 1). Treatment of 1 with 2,2-dimethoxypropane, under
catalysis with p-toluenesulfonic acid (p-TsOH), afforded the
diacetonide 2 as major product.20 Alkaline hydrolysis of the ester
function gave, upon acidification, the hydroxy acid 3. The galacto
configuration was selected for the synthesis of the macrocycles
as the precursor aldonic acid 3 may be obtained in a reasonable
scale and also because the trans–trans-acetonides21 would pre-
clude the formation of the polyhydroxy caprolactone derivative
during the cyclization reaction.
Attempts were made to generate cyclic oligomers from 3. We
have previously observed the formation of a cyclic trimer during
the polymerization of an activated analogue of 3, the 6-amino-6-
deoxy-2,3:4,5-di-O-isopropylidene-D
-galactonic acid.19 Moreover,
D
-gluconolactone to yield a functionalized cyclic polyester.15
As continuation of our studies on biodegradable polymers based
Fleet and co-workers21 reported the formation of cyclic oligomers
(being the trimer the main product) during the cyclization reaction
of such a sugar amino acid. It seems reasonable that the formation
of bigger and more flexible cycles would allow liberation of ring
tension compared with the seven-membered lactone having two
dioxolane rings fused.
on the galactose structure,16–19 we describe herein the synthesis of
two macrocyclic oligomers obtained by direct cyclization of a linear
aldonic acid monomer derived from D-galactono-1,4-lactone (1).
A number of activating agents have been employed for macrol-
actonizations of hydroxy acids.22 The use of N,N0-dicyclohexylcar-
bodiimide (DCC) in the presence of 4-(dimethylamino)pyridine
* Corresponding author. Tel.: +54 11 4576 3352; fax: +54 11 4576 3346.
E-mail address: varela@qo.fcen.uba.ar (O. Varela).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.123

5678
C. Lorena Romero Zaliz, O. Varela / Tetrahedron Letters 50 (2009) 5677–5680
H
O
O
O
O
O
KOH,
Me2C(OMe)2
OMe
OH
O
HO
HO
HO
O
O
O
O
O O
MeOH, H2O (95%)
HO
Me2CO, p-TsOH (78%)
HO OH
3
2
1
O
O
O
O
O
O
O
O
O
O
O
DCC, DMAP,
O
O
O
+
O
O
O
O
O
DMAP.HCl, CHCl 3
O
O
O
O
O
O
O
O
O
O
O
4
(20%)
5
(20%)
Scheme 1.
(DMAP)–DMAP hydrochloride led to satisfactory results in the
cyclization of 3. Under these conditions two main products were
obtained together with mixture of oligomers of lower mobility
by TLC. The faster moving components of the mixture (Rf = 0.31
and 0.28, hexane/EtOAc 1.5:1) were isolated by column chroma-
tography, and their structures were established by MS and NMR
spectroscopy as the 14- and 21-membered ring cyclic dilactone 4
and trilactone 5, respectively.23
teristic of coupled protons in a 1,3-dioxolane ring, the J3,4 value
was very sensitive toward conformational changes (Table 1). Thus,
the open-chain aldonic acid 3 exhibited a large J3,4 value (8.5 Hz)
which indicates an anti disposition for H-3 and H-4, as expected
for the extended zigzag conformation typical of galactose deriva-
tives. Interestingly, the J3,4 value is smaller (1.6 Hz) in the cyclic di-
mer 4, in agreement with a gauche disposition of such protons. In
the case of the trimer 5, as some degree of flexibility may be pos-
sible, J3,4 appears as an average value (3.5 Hz) between the linear
monomer and the cyclic dimer.
In order to confirm the structure of 4 and 5 and to explore the
feasibility to synthesize cyclic oligomers with different sizes, we
designed a route based in the stepwise addition of the monomer
3 to yield a linear dimer (11) and trimer (14). The cyclization of
these two compounds to the respective macrocycles 4 and 5 was
conducted. Protection of the free hydroxyl group at C-6 of methyl
Analysis of coupling constant values from the 1H NMR spectra
of compounds 3, 4, and 5 showed variations that were attributed
to conformational changes. While J2,3 and J4,5 show values charac-
Table 1
1H NMR Coupling constant values for compounds 3, 4, and 5
0
0
Compound
J2,3
J3,4
J4,5
J5,6
J5,6
J6,6
2,3:4,5-di-O-isopropylidene-D-galactonate (2) as tert-butyldimeth-
3
4
5
5.8
7.6
6.6
8.5
1.6
3.5
7.7
7.2
7.4
3.7
2.8
5.3
4.3
8.9
5.0
12.0
10.5
11.6
ylsilyl (TBS) ether gave 6, which upon hydrolysis of the ester gave 7
(Scheme 2). In addition, esterification of the carboxylic acid 3 with
benzyl bromide gave the hydroxyester 8, having the hydroxyl
O
O
O
O
OMe
OH
KOH
MeOH - H2O (96%)
RO
TBSO
O
O
O
O
2
O
7
O
TBSCl-Im,
R = H
DMF
(98%)
6 R = TBS (Me3CSiMe2)
O
O
O
O
Cs2CO3, BrBn
DMF (92%)
O
OH
HO
HO
O
O
O
O
8
O
O
3
O
O
O
O
O
O
R
O
DMAP, DMAP.TFA
DCC, CHCl3 (72%)
8
7
+
O
O
O
O
O
9
R = OTBS
TBAF, THF
10 R = OH (74%)
O
O
O
DMAP, DMAP.HCl,
DCC, CHCl3 (20%)
O
O
O
O
O
O
O
O
H2/Pd-C
(72% from 9)
O
10
HO
OH
or
O
O
O
O
O
O
O
O
DCC, HOBt, DMF
11
(85%)
O
O
O
4
Scheme 2.

C. Lorena Romero Zaliz, O. Varela / Tetrahedron Letters 50 (2009) 5677–5680
5679
O
O
O
O
O
O
O
DMAP, DMAP.TFA
OR2
O
R1O
10
7
+
O
DCC, CHCl3
(55%)
O
O
O
O
O
O
O
= TBS, R2 = Bn
O
1
12
R
TBAF, THF
H2/ Pd-C
1
2
13
R = H, R = Bn (85%)
14 R1 = H, R2 = H (81%)
O
O
O
O
O
DMAP, DMAP.HCl,
DCC, CHCl3 (26%)
O
O
O
O
14
or
O
DCC, HOBt, DMF
O
O
O
O
(87%)
O
O
O
O
5
Scheme 3.
group at C-6 free for the dimerization. The condensation reaction
between 7 and 8 took place using DCC as condensing agent in
the presence of DMAP–DMAPꢀTFA to give the protected linear di-
mer 9 (72% yield). This compound was treated with tetrabutylam-
monium fluoride (TBAF) in THF to release the terminal hydroxyl
group. The resulting product 10 reacted with hydrogen in the pres-
ence of 10% Pd/C with removal of the benzyl ester to produce the
dimeric hydroxy acid 11 (72% yield from 9).24
Acknowledgments
Support of this work by the University of Buenos Aires (project
X059), the National Research Council of Argentina (CONICET, pro-
ject PIP 5011), and the National Agency for Promotion of Science
and Technology (ANPCyT-FONCyT, project PICT-13922) is grate-
fully acknowledged. O.V. is a Research Member of CONICET.
Cyclization of 11 (0.5 mmol) promoted by DCC (1.0 mmol) in
the presence of DMAP (1.5 mmol) and DMAPꢀHCl (1.0 mmol) affor-
Supplementary data
ded crystalline cyclo [(2,3:4,5-di-O-isopropylidene-(1?6)-D-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.123.
galactonate)2] (4) in 20% yield. However, the analogous reaction
of 11 (0.2 mmol) with 1-hydroxybenzotriazole (HOBt, 0.4 mmol)
and DCC (0.4 mmol) in DMF afforded the macrocycle 4 in 85% yield.
The cyclic trimer 5 was prepared following a procedure similar
to the one employed for the synthesis of 4. Condensation of the al-
donic acid derivative 7 with the dimer alcohol 10 gave the trimer
12 (Scheme 3). Deprotection of the silyl ether of 12 with TBAF
led to 13, which was subjected to hydrogenolysis to afford the lin-
References and notes
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11. Gattuso, G.; Nepogodiev, S. S.; Stoddart, J. F. Chem. Rev. 1998, 98, 1919–1958.
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R. M.; Olesker, A.; Cleophax, J. Tetrahedron Lett. 2003, 44, 9151–9153.
13. Kricheldorf, H. R.; Chatti, S.; Schwarz, G.; Krüger, R.-P. J. Polym. Sci., Part A:
Polym. Chem. 2003, 41, 3414–3424.
14. (a) Culkin, D. A.; Jeong, W.; Csihony, S.; Gomez, E. D.; Balsara, N. P.; Hedrick, J.
L.; Waymouth, R. M. Angew. Chem., Int. Ed. 2007, 46, 2627–2630; (b) Chisholm,
M. H.; Galucci, J. C.; Yin, H. Proc. Natl. Acad. U.S.A. 2006, 103, 15315–15320 and
references therein.
15. Tang, M.; White, A. J. P.; Stevens, M. M.; Williams, C. K. Chem. Commun. 2009,
941–943.
16. Romero Zaliz, C. L.; Varela, O. J. Carbohydr. Chem. 2001, 20, 689–701.
17. Romero Zaliz, C. L.; Varela, O. Tetrahedron: Asymmetry 2003, 14, 2579–2586.
18. Romero Zaliz, C. L.; Varela, O. Tetrahedron: Asymmetry 2005, 16, 97–103.
19. RomeroZaliz, C. L.; Erra-Balsells, R.; Nonami, H.; Sato, Y.; Varela, O. ARKIVOC
2005, Part xii, 76–87.
20. Long, D. D.; Stetz, R. J. E.; Nash, R. J.; Marquess, D. G.; Lloyd, J. D.; Winters, A. L.;
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21. Mayes, B. A.; Stetz, R. J. E.; Watterson, M. P.; Edwards, A. A.; Ansell, C. W. G.;
Tranter, G. E.; Fleet, G. W. J. Tetrahedron: Asymmetry 2004, 15, 627–638.
ear
presence of DCC, DMAP–DMAPꢀHCl gave crystalline cyclo
[(2,3:4,5-di-O-isopropylidene-(1?6)- -galactonate)3] (5) in 26%
x
-hydroxy acid 14 (69% from 12).24 Cyclization of 14 in the
D
yield; whereas the use of HOBt and DCC resulted, as observed in
the cyclization of 11, in a considerable increment in the yield of
5 (87%). In the DCC–DMAP protocol the formation of unreactive
N-acyl urea byproducts decreases the yield of macrolactones.
This side reaction may be prevented by adding a proton source,
such as DMAPꢀHCl25 or DMAPꢀTFA,26 to the reaction mixture. How-
ever, even with these additives, the formation of the N-acyl urea
was detected in the cyclization of 11 and 14. In contrast, the use
of HOBt–DCC gave good yields of the expected macrolactones.
These reagents have been employed for rather difficult
macrolactonizations.27
In conclusion, two 14- and 21-membered ring macrocycles,
having the galacto configuration for the constituent units, have
been synthesized using a straightforward approach from a selec-
tively acetonide-protected aldonic acid. This compound was also
employed as key precursor of a linear dimer and trimer
x-hydro-
xy acids, which have been successfully converted into macrocy-
cles. The macrolactonization promoted by DCC–HOBt gave a
higher yield than that performed with DCC, DMAP–DMAPꢀHCl.
The resulting carbohydrate-based macrocycles are biomaterials
that may be described as macrolactone–cyclodextrins. They are
soluble in organic solvents of varied polarity, and they are ex-
pected to be able to complex a variety of organic and inorganic
species.

5680
C. Lorena Romero Zaliz, O. Varela / Tetrahedron Letters 50 (2009) 5677–5680
0
0
22. Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106, 911–939.
1H, J3 ,4 = 6.7 Hz, H-30), 4.36 (t, 1H, J2,3 ꢄ J3,4 = 6.0 Hz, H-3), 4.32–4.26 (m, 2H,
J5,6b = 5.5 Hz, H-5,6b), 4.10 (dt, 1H, J4 ,5 = 7.8, J5 ,6 a = 4.2, J5 ,6 b = 4.5 Hz, H-50),
0
0
0
0
0
0
23. Compound 3: mp 121–122 °C; ½a D
ꢁ
ꢂ11.3 (c 1.0, CHCl3). Anal. Calcd for C12H20O7:
C, 52.17; H, 7.30. Found: C, 52.09; H, 7.14. 1H NMR (200 MHz, CDCl3) d: 5.14 (sa,
1H, COOH), 4.62 (d, 1H, J2,3 = 5.8 Hz, H-2), 4.36 (dd, 1H, J3,4 = 8.5 Hz, H-3), 4.14
4.01 (dd, 1H, H-4), 3.98 (dd, 1H, H-40), 3.85 (dd, 1H, J6 a,6 b = 11.9 Hz, H-60a),
3.75 (dd, 1H, H-60b), 1.48 (ꢃ2), 1.45, 1.45, 1.44, 1.43 (ꢃ2), 1.42 (6s, 24H,
C(CH3)2). 13C NMR (CDCl3, 125.7 MHz): 170.6 (ꢃ2) (C-1,10), 112.4, 112.3, 110.7,
110.0 (C(CH3)2), 79.7, 79.6, 79.2, 77.7, 77.6, 76.8, 76.6, 76.5 (C-2,20,3,30,4,40,5,50),
64.8, 62.5 (C-6,60), 27.1, 27.0, 26.8, 26.0, 25.9 (C(CH3)2). Compound 14: 1H NMR
0
0
0
(ddd, 1H, J4,5 = 7.7, J5,6 = 3.7, J5,6 = 4.3 Hz, H-5), 4.00 (dd, 1H, H-4), 3.88 (dd, 1H,
J6,6 = 12.0, H-6), 3.74 (dd, 1H, H-60), 1.49, 1.45 (ꢃ2), 1.43 (4s, 12H, C(CH3)2). 13C
0
NMR (50.3 MHz, CDCl3) d: 173.1 (C-1), 112.6, 110.3 (C(CH3)2), 79.9, 79.3, 77.7,
76.9 (C-2–C-5), 62.2 (C-6), 27.0 (ꢃ2), 26.8, 25.9 (C(CH3)2). Compound 4: mp 190–
0
0
0 0 ,300
(CDCl3, 500 MHz): 4.60 (d, 1H, J2
= 5.4 Hz, H-200), 4.59 (d, 1H, J2 ,3 = 5.6 Hz,
191 °C; ½a D
ꢁ
ꢂ15.7 (c 0.9, CHCl3). Anal. Calcd for C24H36O12: C, 55.81; H, 7.02.
H-20), 4.58 (d, 1H, J2,3 = 5.2 Hz, H-2), 4.54–4.44 (m, 2H, H-6a,60a), 4.40 (dd, 1H,
Found: C, 55.85; H, 7.26. 1H NMR (500 MHz, CDCl3) d: 4.60 (dd, 1H, J5,6 = 2.8,
J3
= 6.9 Hz, H-300), 4.37 (dd, 1H, J3 ,4 = 7.6 Hz, H-30), 4.36 (dd, 1H, J3,4 = 6.1 Hz,
0
0
00 ,400
0 0 ,50 0
= 7.4,
0
J6,6 = 10.5 Hz, H-6), 4.48 (d, 1H, J2,3 = 7.6 Hz, H-2), 4.38 (dd, 1H, J3,4 = 1.6 Hz, H-3),
H-3), 4.30–4.21 (m, 4H, H-5,50,6b,60b), 4.08 (m, 1H, J4
4.27 (dd, 1H, J4,5 = 7.2 Hz, H-4), 4.16 (dd, 1H, J5,6 = 8.9 Hz, H-60), 4.13 (ddd, 1H, H-
J5 a = 4.2, = J5 b = 4.3 Hz, H-500), 4.00 (t, 1H, J4,5 = 6.7 Hz, H-4), 3.97 (t, 1H,
00 ,600 0 0 ,60 0
0
5), 1.51, 1.48, 1.47, 1.44 (4s, 12H, C(CH3)2). 13C NMR (125.7 MHz, CDCl3) d: 169.6
(C-1), 112.1, 110.6 (C(CH3)2), 79.2, 78.2, 74.2, 72.9 (C-2–C-5), 65.1 (C-6), 27.3,
26.6 (ꢃ2), 25.8 (C(CH3)2). MALDI-MS: 539.2 (M+Na). Compound 5: mp 74–75 °C;
H-400), 3.93 (t, 1H, J4 ,5 = 7.0 Hz, H-40), 3.83 (dt, 1H, J6
b = 11.9 Hz, H-600a),
0
0
0 0 a,60 0
3.74 (m, 1H, H-600b), 1.48 (ꢃ2), 1.45, 1.44 (ꢃ2), 1.43, 1.42 (ꢃ4), 1.41, 1.40 (7s,
36H, C(CH3)2). 13C NMR (CDCl3, 125.7 MHz): 172.5 (C-1), 170.5, 170.4 (C-10,100),
112.5 (ꢃ2), 112.4, 110.8, 110.6, 109.9 (C(CH3)2), 79.8, 79.7 (ꢃ2), 79.1
(C-3,30,300,500), 77.8, 77.7, 77.5, 77.4, 77.3, 77.1, 76.8, 76.3 (C-
2,20,200,4,40,400,5,50), 64.8, 64.7 (C-6,60), 62.5 (C-600), 27.3, 27.2, 27.1, 27.0 (ꢃ3),
26.9, 26.8, 26.7, 26.1, 26.0, 25.9 (C(CH3)2).
½aꢁD ꢂ9.1 (c 0.5, CHCl3). Anal. Calcd for C36H54O18: C, 55.81; H, 7.02. Found: C,
56.43; H, 7.05. 1H NMR (500 MHz, CDCl3) d: 4.57 (d, 1H, J2,3 = 6.6 Hz, H-2), 4.42
0
(dd, 1H, J3,4 = 3.5 Hz, H-3), 4.38 (dd, 1H, J5,6 = 5.3, J6,6 = 11.6 Hz, H-6), 4.33 (dd,
1H, J5,6 = 5.0 Hz, H-60), 4.25 (ddd, 1H, J4,5 = 7.4 Hz, H-5), 4.11 (dd, 1H, H-4), 1.48,
0
1.44, 1.43, 1.41 (4s, 12H, C(CH3)2). 13C NMR (125.7 MHz, CDCl3) d: 170.5 (C-1),
112.4, 110.5 (C(CH3)2), 79.1, 78.5, 75.4, 74.9 (C-2–C-5), 65.1 (C-6), 27.1, 26.7,
26.6, 25.8 (C(CH3)2). MALDI-MS: 797.3 (M+Na).
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2000, 10, 775–778; (b) Nakagawa, Y.; Irie, K.; Nakamura, Y.; Ohigashi, H. Bioorg.
Med. Chem. Lett. 2001, 11, 723–728.
24. Compound 11: 1H NMR(CDCl3, 500 MHz): 4.61 (d, 1H, J2 ,3 = 5.5 Hz, H-2), 4.60
(d, 1H, J2,3 = 6.0 Hz, H-2), 4.51 (m, 1H, J5,6a = 5.3, J6a,6b = 11.5 Hz, H-6a), 4.40 (dd,
0
0