Synthesis of macrolide-saccharide hybrids by ring-closing metathesis of precursors derived from glycitols and benzoic acids

Article abstract of DOI:10.1021/jo062159l

The benzomacrolactone structural motif is a privileged or evolutionarily selected scaffold that codes properties required for binding to proteins and novel analogues thereof may provide a source of new bioactive compounds. Saccharides are also privileged structures, with (amino)sugars, imino-sugars, and sugar amino acids being applied as scaffolds for the development of nonpeptidal peptidomimetics. The syntheses of novel polyhydroxylated oxamacrolides, structural analogues of natural polyketide derived macrolides, are described herein, providing a basis for their development as scaffolds. The syntheses were carried out from benzoic acids and appropriately protected D-mannitol or D-sorbitol (D-glucitol). Ring-closing metathesis was applied in the macrocyclization step with high E-alkene selectivities being observed. X-ray crystal structures, for two polyhydroxylated derivatives, show that the macrocyclic rings display similar conformations. In addition, intermolecular hydrogen-bonding networks are observed in the lattices.

Full text of DOI:10.1021/jo062159l

CHART 1. Structures of 1-12
Synthesis of Macrolide-Saccharide Hybrids by
Ring-Closing Metathesis of Precursors Derived
from Glycitols and Benzoic Acids
Marie-Christine Matos and Paul V. Murphy*
Centre for Synthesis and Chemical Biology, UCD School of
Chemistry and Chemical Biology, UCD Conway Institute,
UniVersity College Dublin, Belfield, Dublin 4, Ireland
paul.V.murphy@ucd.ie
ReceiVed October 17, 2006
2 and radicicol 35 are both ATPase inhibitors, whereas zearale-
none 4 is an agonist for mammalian estrogen receptors.6 (5Z)-
7-Oxozeaenol7 5 inhibits the kinase TAK-1, whereas LL-
783,2778 6 is a potent inhibitor of MEK. Hypothemycin 7
inhibits the proliferative response, modulates the production of
cytokines during T cell activation,9 and inhibits the ras signal
transduction pathway. Salicylic acid derived lactones such as
salicylihalamides, apicularens (e.g., 8), and lobatamides are also
of interest for their biological properties.10 These diverse
biological effects imply that the benzomacrolactone structural
motif is a privileged scaffold11 or is an evolutionarily selected
scaffold that codes properties required for binding to proteins.12
Novel analogues of such macrolides may provide a source of
new lead compounds or tools for chemical biology. Polyhy-
droxylated sugar derivatives are also privileged structures,13 with
(amino)sugars, iminosugars, and sugar amino acids having been
applied as scaffolds for the development of bioactive com-
pounds, including nonpeptidal peptidomimetics.14 Herein we
describe a synthesis of novel polyhydroxylated oxamacrolides
The benzomacrolactone structural motif is a privileged or
evolutionarily selected scaffold that codes properties required
for binding to proteins and novel analogues thereof may
provide a source of new bioactive compounds. Saccharides
are also privileged structures, with (amino)sugars, imino-
sugars, and sugar amino acids being applied as scaffolds for
the development of nonpeptidal peptidomimetics. The syn-
theses of novel polyhydroxylated oxamacrolides, structural
analogues of natural polyketide derived macrolides, are
described herein, providing a basis for their development as
scaffolds. The syntheses were carried out from benzoic acids
and appropriately protected D-mannitol or D-sorbitol (D-
glucitol). Ring-closing metathesis was applied in the mac-
rocyclization step with high E-alkene selectivities being
observed. X-ray crystal structures, for two polyhydroxylated
derivatives, show that the macrocyclic rings display similar
conformations. In addition, intermolecular hydrogen-bonding
networks are observed in the lattices.
(6) Turcotte, J. C.; Hunt, P. J. B.; Blaustein, J. D. Horm. BehaV. 2005,
47, 178.
(7) Ninomiya-Tsuji, J.; Kajino, T.; Ono, K.; Ohtomo, T.; Matsumoto,
M.; Shiina, M.; Mihara, M.; Tsuchiya, M.; Matsumoto, K. J. Biol. Chem.
2003, 278, 18485.
(8) Zhao, A.; Lee, S. H.; Mojena, M.; Jenkins, R. G.; Patrick, D. R.;
Huber, H. E.; Goetz, M. A.; Hensens, O. D.; Zink, D. L.; Vilella, D.;
Dombrowski, A. W.; Lingham, R. B.; Huang, L. J. Antibiot. 1999, 52, 1086.
(9) Camacho, R.; Staruch, M. J.; DaSilva, C.; Koprak, S.; Sewell, T.;
Salituro, G.; Dumont, F. J. Immunopharmacology 1999, 44, 255.
(10) Yet, L. Chem. ReV. 2003, 103, 4283
(11) Molecular structures which bind to more than one type of receptor
are known as “privileged structures”. See: Hirschmann, R. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1278.
Introduction
The naturally occurring resorcylic acid lactones (e.g., 1-7,
Chart 1) have been of interest to chemists because of their
biological properties.1 Aigialomycin D 1 is cytotoxic and inhibits
the malaria parasite;2 its cytotoxicity has recently been attributed
to its inhibition of the kinases CDK and GSK-3.3 Pochonin C4
(12) Koch, M. A.; Waldmann, H. Drug DiscoVery Today 2006, 10, 471.
(13) Hirschmann, R.; Cichy-Knight, M. A.; van Rijn, R. D.; Sprengler,
P. A.; Spoors, P. G.; Shakespere, W. C.; Pietranico-Cole, S.; Barbosa, J.;
Liu, J.; Yao, W.; Roher, S.; Smith, A. B., III. J. Med. Chem. 1998, 41,
1382.
(14) For recent reviews on carbohydrates as scaffolds, see: (a) Dunne,
J. L; Murphy, P. V. Curr. Org. Synth. 2006, 3, 403-37. (b) Velter, I.; La
Ferla, B.; Nicotra, F. J. Carbohydr. Chem. 2006, 25, 97. (c) Becker, B.;
Condie, G. C.; Le, G. T.; Meutermans, W. Mini-ReV. Med. Chem. 2006, 6,
1299-309. (d) Meutermans, W.; Le, G. T.; Becker, B. Chem. Med. Chem.
2006, 1, 1164-94.
(1) Nicolaou, K. C. Tetrahedron 1977, 33, 683.
(2) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(3) Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger,
N. Angew. Chem., Int. Ed. 2006, 45, 3951.
(4) Hellwig, V.; Mayer-Bartschmid, A.; Mueller, H.; Greif, G.; Kley-
mann, G.; Zitzmann, W.; Tichy, H.-V.; Stadler, M. J. Nat. Prod. 2003, 66,
829.
(5) Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881.
10.1021/jo062159l CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/03/2007
J. Org. Chem. 2007, 72, 1803-1806
1803

SCHEME 1. Synthesis of Benzoic Acid Precursors
The carbohydrate precursors were prepared as outlined in
Scheme 2. The allyl ether 19 was obtained after monoallylation
of diol 1822 using sodium hydride (1.4 equiv) and allyl bromide
(1.1 equiv); a small amount of the di-O-allylated product was
also observed. A similar reaction sequence beginning from
D-sorbitol gave a 1:1 mixture of 20 and 21.23 The MOM
derivative 22 was synthesized from D-mannitol 17 in four
steps: regioselective pivaloylation (60%) of the two primary
hydroxyl groups of 17 was followed by introduction of the
MOM protecting groups, removal of the pivaloyl groups was
achieved using sodium methoxide in methanol24 at 40 °C, and
subsequent monoallylation gave 22. In the pivaloylation reaction
some of the 1,2,6-tri-O-pivaloylated product was also obtained.
The benzoic acid and carbohydrate derived precursors were
then converted to oxamacrolides (Schemes 3 and 4). The
Mitsunobu coupling reaction of benzoic acids 14a, 14b, and
16 with allyl ether 19, promoted by triphenylphosphine in the
presence of DIAD, gave 23a, 23b, and 23c, respectively. The
lower yields of 23b and 23c were due to increased difficulty in
their chromatographic separation from the byproducts of the
reaction. Ring-closing metathesis25 using the Grubbs’ generation
II catalyst in the presence of 2,6-dichloro-1,4-benzoquinone26
gave the macrocyclic structures in good to excellent yield (62-
92%) with only the E-alkene27 being obtained in each case.
Ring-closing metathesis carried out in the absence of the 2,6-
dichloro-1,4-benzoquinone led only to the isolation of low yields
of mixtures (∼30%) of the E- and Z-alkene containing macro-
cycles, and a major side reaction was the isomerization of the
allyl alkene group to give acyclic vinyl ethers, which can occur
9-12 from benzoic acids and D-mannitol or D-sorbitol (D-
glucitol). These new compounds can be considered hybrids or
novel structural analogues of natural polyketide derived mac-
rolides and saccharides and the work forms a basis for their
investigation as novel scaffolds for bioactive compound dis-
covery.
Our approach combined the Mitsunobu esterification and ring-
closing metathesis which has been successful for synthesis of a
range of resorcylic acid and salicylic acid natural products.15
The synthesis of 9 and 10 was carried out from D-mannitol and
11 and 12 from D-sorbitol. The benzoic acid precursors 14a
and 14b were prepared first (Scheme 1). Esterification of 13a
and 13b, followed by a Stille coupling reaction16 and subsequent
ester hydrolysis, gave 14a17 and 14b,18 respectively. The
esterification of 4-methoxysalicylic acid 15 was carried out
under basic conditions, and subsequent reaction with triflic
anhydride afforded an aryl triflate derivative (90%, two steps).
The exchange of the triflate group of 15 to a vinyl group
according to Nicolaou’s variant of the traditional Stille reac-
tion,19 which was carried out in THF in the presence of LiCl,
proceeded in ∼10% yield. An improvement to this reaction was
observed when the reaction was carried out in toluene instead
(27%), and subsequent hydrolysis of the resulting vinyl deriva-
tive using LiOH gave 16. The reaction was found to occur
slowly, and there was starting material remaining after a few
days. According to Casado et al.,20 the use of LiCl increases
the rate of the oxidative addition step but it can also slow down
the reaction in certain conditions which could explain the low
yield. The tin residues, which were present in the product from
the Stille reactions, were removed by chromatography21 using
a KF/silica (1:9, w/w) packed column with dichloromethane as
eluent. Because of the basicity of the KF-silica column, some
hydrolysis of the ester to give the benzoic acid also occurred.
for allyl derivatives at high temperature, high dilution, and
26
forced high turnovers.
Catalytic hydrogenation of 23a-c,
carried out using the H-Cube hydrogenation flow reaction
system, gave the polyhydroxylated oxamacrolides 9a-c (Scheme
3).28 The lower yield of 9c (47%) was due to losses on
chromatographic purification. The structure assigned to 9b was
confirmed by the determination of its X-ray crystal structure.
The Mitsunobu reaction of 14a and 22 followed by ring-
closing metathesis, carried out in the presence of Ti(i-OPr)4,
gave 25, and subsequent removal of the MOM groups under
acidic conditions enabled isolation of the polyhydroxylated
oxamacrolide 10 containing the E-alkene (Scheme 4). The ring-
closing metathesis provided a single stereoisomer in the
macrocyclization reaction, albeit in lower isolated yield than
for benzylated precursors. The metathesis catalyst, in the absence
of Ti(i-OPr)4, is most likely coordinating with the multiple
oxygens of the MOM groups and leads to formation of
complexes which do not go on to cyclize. In the presence of
Ti(i-OPr)4, used to counteract the retarding effect of the oxygen
atoms,29 ring closing metathesis takes place and 25 was isolated
in 28% yield for the reaction carried out in dichloromethane,
(15) For examples of application of Mitsunobu reaction and ring-closing
metathesis in benzomacrolactone synthesis, see: (a) Wu, Y.; Liao, X.; Wang,
R.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem. Soc. 2002, 124, 3245-
53. (b) Barluenga, S.; Moulin, E.; Lopez, P.; Winssinger, N. Chem. Eur. J.
2005, 11, 4935-52. (c) Herb, C.; Dettner, F.; Maier, M. Eur. J. Org. Chem.
2005, 728-39. (d) Yang, Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003,
125, 9602-3. (e) Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004,
15, 81-89. (f) Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem.
Eur. J. 2001, 7, 5286.
(16) Harrowven, D. C., Guy, I. L. Chem. Commun. 2004, 1968.
(17) Mejia-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241.
(18) Couture, A.; Cornet, H.; Grandclaudon, P. Tetrahedron Lett. 1993,
34, 8097.
(22) Ackermann, L.; El Tom, D.; Fu¨rstner, A. Tetrahedron 2000, 56,
2195.
(23) See the Supporting Information for the synthesis of 20 and 21.
(24) Wessel, H. P.; Trumtel, M. Carbohydr. Res. 1997, 297, 163.
(25) Nguyen, S. T.; Trnka, T. M; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18.
(26) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(27) For a recent review on ring-closing metathesis in the synthesis of
natural products, see: Gradillas, A.; Perez-Castells, J. Angew. Chem., Int.
Ed. 2006, 45, 6086.
(19) Nicolaou, K. C.; Kim, D. W.; Baati, R; O’Brate, A.; Giannakakou,
P. Chem. Eur. J. 2003, 9, 6177.
(20) Casado, A. L.; Espinet, P.; Gallego, A. M. J. Am. Chem. Soc. 2000,
122, 11771.
(21) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968.
(28) For a synthesis of other polyhydroxylated macrocycles from our
group, see: Velasco-Torrijos, T.; Murphy, P. V. Org. Lett. 2004, 5, 3961.
(29) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130.
1804 J. Org. Chem., Vol. 72, No. 5, 2007

SCHEME 2. Synthesis of Carbohydrate Precursors
SCHEME 3. Synthesis of Polyhydroxylated Oxamacrolides
9a-c
SCHEME 5. Synthesis of Polyhydroxylated Oxamacrolides
11 and 12
consequent clogging of the hydrogenation flow reactor and was
thus more difficult to isolate.
The conformation of 9b and 12, in the X-ray crystal
structures, was also studied. The lactone group atoms and the
C-3 to C-7 backbone carbon atoms (Figure 1) of 9b and 12
were superimposed using Macromodel 8.5. This showed that
the atoms of the benzene ring and C-1 to C-7 chain in these
two structures adopted closely related conformations in the solid
state. Consequently, the C-4, C-5, and C-6 hydroxyl groups are
similarly oriented in 9b and 12; the 4-OH and 5-OH groups
are axial and the 6-OH group is equatorial; the 7-OH group is
axial for 9a and equatorial for 12. The stereochemical config-
uration of the 7-OH group, different for 9b and 12, thus does
not lead to a change in the conformation of the C-1 to C-7 chain.
However, there was not a similar conformation for the C-9 to
SCHEME 4. Synthesis of Polyhydroxylated Oxamacrolide
10
1
C-12 chain of the two structures. The vicinal H-1H coupling
constants (Table 1, MeOD) for protons of the C-3 to C-7 chain
and corresponding dihedral angles measured from the crystal
structures of 9b and 12 correlate with that predicted by the
Karplus relationship to a degree which indicates that the
orientations of the C-4 to C-7 OH groups in solution do not
deviate largely from that in the solid state. The vicinal 1H-1H
coupling constants for 9a and 9c agree well with 9b, indi-
cating these analogues have the same conformations. The vicinal
1H-1H coupling constants for 10 indicate that a minor distortion
of the macrocyclic ring is brought about by having the alkene
group in the ring, although no major difference in conformation
of these derivatives is apparent from this analysis (Table 1). It
is worth noting that the macrocyclic hydroxyl groups form part
of extensive hydrogen-bonding networks in the crystal lattices
of 9a and 12 (not shown herein).30
with an equal proportion of the starting material also being
recovered. The conversion to the ring closed product was higher
(∼60%) when the reaction was carried out at 80 °C in toluene.
In addition, the yield of 10 after removal of the MOM protecting
groups (35%) was low due to difficulty in chromatographic
separation of the product from unidentified byproducts.
The Mitsunobu reaction followed by ring-closing metathesis
(not shown) of the D-sorbitol derivatives 20 and 21 gave a
mixture of macrolactones 26 and 27, and these were separated
by column chromatography. Subsequent removal of the benzyl
groups of 26 and 27 with concomitant reduction of the alkene
groups gave the macrolactones 11 and 12, respectively (Scheme
5). The structural assignment was confirmed by the determi-
nation of the X-ray crystal structure of 12. The lower yield
obtained in the hydrogenolysis of 26 is explained by the low
solubility of the product 11, which led to its precipitation and
In summary, the syntheses of novel polyhydroxylated oxam-
acrolides, inspired by recent natural product and carbohydrate
research, are described from simple precursors. Conformational
J. Org. Chem, Vol. 72, No. 5, 2007 1805

NMR (CDCl3) δ 168.4 (CdO), 139.1, 138.2, 138.1, 137.9, 137.5
(each s), 132.1, 131.9, 131.2 (each s), 129.5 (s), 128.4, 128.3, 128.2,
128.13, 128.10, 127.9, 127.8, 127.7, 127.4, 127.3, 127.2 (each d),
82.9, 78.9, 77.4, 77.3, 75.5, 74.6, 71.8, 71.3, 69.6, 68.7, 61.0 (each
t); IR (film, CHCl3) νmax 3062, 3029, 2917, 2865, 2358, 2341, 1712,
1598, 1454, 1392, 1373, 1288, 1261, 1027, 908, 809, 744, 698
cm-1; ES-HRMS found 707.2980, C44H44O7Na requires 707.2985
[M + Na]+.
FIGURE 1. Superimposition of the X-ray crystal structures of 9b and
12. The hydrogen atoms are not shown.
(4R,5R,6R,7R)-Tetrakis(benzyloxy)-3,4,5,6,7,8,10,11,12-non-
ahydro-1H-2,9-benzdioxacyclotetradecin-1-one (9a). Catalytic
hydrogenation of a solution of 24a in ethanol (152 mg in 9 mL,
0.22 mmol, 25 mM) in EtOH over 5% Pd-C using a H-cube flow
reactor (pressure ) 80 bar, temperature ) 60 °C, flow rate ) 1
mL/min) followed by removal of excess ethanol under reduced
pressure and subsequent purification of the residue by chromatog-
raphy (19:1, CH2Cl2-MeOH) gave 9a as a colorless oil (51 mg,
71%): Rf 0.48 (9:1, CH2Cl2-MeOH)); [R]20D -21 (c 0.94, CHCl3);
1H NMR (600 MHz, CD3OD) δ 7.81 (d, 1H, J 7.8 Hz), 7.49 (t,
1H, J 7.5 Hz), 7.39 (d, 1H, J 7.8 Hz), 7.30 (t, 1H, J 7.6 Hz), 4.66
(dd, 1H, J 11.4, 2.2 Hz), 4.49 (dd, 1H, J 7.7, 3.3 Hz), 4.46 (dd,
1H, J 11.4, 4.8 Hz), 4.13 (m, 1H), 4.04 (t, 1H, J 3.0 Hz), 3.93 (m,
1H), 3.71 (dd, 1H, J 9.4, 7.0 Hz), 3.57 (m, 3H), 3.21 (dt, 1H, J
14.5, 8.3 Hz), 3.10 (m, 1H), 1.90 (m, 2H); 13C NMR (400 MHz,
CD3OD) δ 170.9 (CdO), 143.5 (s), 133.1 (d), 132.1 (s), 131.9,
131.3, 127.0, 74.1 (each d), 72.8 (t), 72.6 (d), 71.8 (t), 71.7 (d),
71.0 (d), 67.3 (t), 33.0 (t), 32.2 (t); IR (film, CH3OH) νmax 3386,
2921, 2871, 2360, 2341, 1704, 1600, 1446, 1371, 1284, 1263, 1132,
1076, 860, 750 cm-1; ES-HRMS found 349.1259, C16H22O7Na
requires 349.1263 [M + Na]+.
1
TABLE 1. Selected H--H Vicinal Coupling Constants (Hz) for
Oxamacrolidesa
9a
9b
9c
10
12
J3a,4
J3b,4
J4,5
J5,6
J6,7
2.1 (68)
4.7 (51)
7.8 (167)
3.2 (66)
3.2 (68)
7.1 (49)
n.d. (68)
2.2
4.8
7.7
3.2
3.2
7.0
n.d.
2.1
4.6
7.8
3.6
2.8
7.1
n.d
1.8
3.2
9.0
2.3
2.3
n.d
2.9
2.4 (62)
4.6 (58)
7.8 (177)
1.2 (67)
8.6 (161)
6.1 (49)
2.6 (69)
J7,8a
J7,8b
a Dihedral angles (deg) measured using Macromodel 8.5 from the X-ray
crystal structures of 9a and 12 are provided in parentheses.
(4R,5R,6R,7R)-Tetrahydroxy-3,4,5,6,7,8,10-heptahydro-(11E)-
1H-2,9-benzodioxacyclotetradecin-1-one (10). To a solution of
(4R,5R,6R,7R)-tetrakis(methoxymethoxy)-3,4,5,6,7,8,10-heptahydro-
(11E)-1H-2,9-benzodioxacyclotetradecin-1-one (53 mg, 0.11 mmol)
in MeOH (10.6 mL, 0.01 M solution of the precursor) was added
at room temperature concd HCl (1.05 mL). The reaction mixture
was stirred at that temperature for 19 h, the solvent then removed,
and the residue purified by chromatography (19:1, CH2Cl2-MeOH)
analysis indicates the macrolides adopt structures in the solid
state which are similar to that in solution. A preliminary
screening of the hydroxylated products against a panel of 45
kinases has shown that they are not potent inhibitors of kinases,
and suggests that structures based on a resorcyclic acid or
salicylic acid, as suggested by one reviewer, might be required
for potent compounds. The synthesis of salicylic acid analogues
is currently being investigated as are efforts to apply saccha-
ride-macrolide scaffolds to the identification of novel lead
compounds or provision of tools for biological research, and
the outcomes of this research will be reported in due course.
to afford the title compound 10 as a colorless oil (12 mg, 35%):
1
Rf 0.39 (9:1, CH2Cl2-MeOH); [R]20 -23 (c 0.61, CH3OH); H
D
NMR (500 MHz, CD3OD) δ 7.85 (dd, 1H, J 8.1, 1.3 Hz), 7.61
(dd, 1H, J 7.9, 1.1 Hz), 7.50 (ddd, 1H, J 15.2, 1.4, 0.5 Hz), 7.48
(dt, 1H, J 15.3, 1.9 Hz), 7.33 (td, 1H, J 7.6, 1.2 Hz), 6.23 (ddd,
1H, J 16.0, 4.3, 4.0 Hz), 4.77 (dd, 1H, J 9.0, 2.3 Hz), 4.60 (dd,
1H, J 11.5, 1.8 Hz), 4.51 (dd, 1H, J 11.5, 3.2 Hz), 4.29 (dq, 1H, J
14.5, 1.9 Hz), 4.20 (ddd, 1H, J 14.5, 4.5, 2.0 Hz), 4.13 (m, 1H),
4.11 (t, 1H, J 2.3 Hz), 3.87 (m, 2H), 3.66 (dd, 1H, J 10.5, 2.9 Hz);
13C NMR (CD3OD) δ 170.5 (CdO), 139.1 (s), 133.3 (s), 132.3
(d), 131.2 (d), 130.8 (d), 129.6 (d), 128.3 (d), 128.0 (d), 75.7 (d),
73.2 (t), 71.7 (d), 71.5 (t), 71.2 (d), 70.8 (d), 67.8 (t); IR (film,
CH3OH) νmax 3342, 2915, 2861, 2362, 2329, 1702, 1598, 1477,
1448, 1371, 1292, 1268, 1176, 1133, 1079, 1045, 966, 929, 836,
742, 561 cm-1; ES-HRMS found 323.1145, C16H19O7 requires
323.1131 [M - H]-.
Experimental Section
(4R,5R,6R,7R)-Tetrakis(benzyloxy)-3,4,5,6,7,8,10-heptahydro-
(11E)-1H-2,9-benzodioxacyclotetradecin-1-one (24a). To a de-
gassed solution of 23a (384 mg, 0.54 mmol) and 2,6-dichloro-1,4-
benzoquinone (38 mg, 0.22 mmol) in dry toluene (269 mL, 2 mM
solution of 23a) was added Grubbs’catalyst II generation (43 mg,
0.05 mmol) under N2. The reaction mixture was heated and stirred
at 80 °C for 18 h. The solution was then filtered through silica and
washed with diethyl ether, and the solvent was removed. The residue
was purified by chromatography (9:1 cyclohexane-EtOAc) to give
24a (311 mg, 84%, colorless oil): Rf 0.48 (4:1 cyclohexane-
EtOAc); [R]20D -11 (c 0.545, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.88 (d, 1H, J 5.8 Hz), 7.47-7.04 (m, 24H), 6.08 (d, 1H, J 13.9
Hz), 5.00 (m, 1H), 4.86 (d, 1H, J 10.4 Hz), 4.72 (m, 3H), 4.47 (m,
Acknowledgment. This investigation was supported by
Science Foundation Ireland (03/IBN/B352) and the Programme
for Research in Third Level Institutions administered by the
HEA. We thank Dr. D. Rai for mass spectrometry, Dr. H.
Mu¨ller-Bunz for X-ray crystal structure determination, and Dr.
J. Muldoon and the UCD NMR Centre for high-field NMR.
3H), 4.38-4.03 (m, 5H), 4.03 (d, 1H, J 7.3 Hz), 3.70 (m, 2H); 13
C
Supporting Information Available: Full experimental proce-
dures, 1H and 13C NMR spectra, NMR assignments, X-ray
structures, and crystallographic information files. This material is
available free of charge via the Internet at http://pubs.acs.org.
(30) The networks of hydrogen bonding can be viewed using the
crystallographic information files (see the Supporting Information). For
selected publications where hydrogen bonding networks have been of
interest, see (a) Jeffrey, G. A.; Saenger, W. Hydrogen bonding in biological
structures; Springer-Verlag: Berlin, 1991. (b) Murphy, P. V.; Mueller-
Bunz, H.; Velasco-Torrijos, T. Carbohydr. Res. 2005, 340, 1437.
JO062159L
1806 J. Org. Chem., Vol. 72, No. 5, 2007