First synthesis of a branched β-C-tetrasaccharide using a triple ring closing metathesis cyclization

Article abstract of DOI:10.1021/jo040203w

The first synthesis of a branched β-C-tetrasaccharide has been carried out through the use of an esterification-ring closing metathesis (RCM) strategy. The precursor triacid 2a was readily prepared via standard chemical methods from a known starting mater

Full text of DOI:10.1021/jo040203w

SCHEME 1. Tr ip le-RCM Ap p r oa ch to
â-C-Tetr a sa cch a r id es
F ir st Syn th esis of a Br a n ch ed
â-C-Tetr a sa cch a r id e Usin g a Tr ip le Rin g
Closin g Meta th esis Cycliza tion
J ared L. Piper1 and Maarten H. D. Postema*,2
Department of Chemistry, Wayne State University,
Detroit, Michigan 48202
mpostema@chem.wayne.edu
Received May 27, 2004
Abstr a ct: The first synthesis of a branched â-C-tetrasac-
charide has been carried out through the use of an esteri-
fication-ring closing metathesis (RCM) strategy. The pre-
cursor triacid 2a was readily prepared via standard chemical
methods from a known starting material, and dehydrative
coupling with an excess of olefin alcohol 1a gave triester 3a
in excellent yield. Methylenation of the triester 3a and
subsequent triple RCM reaction was followed by an in situ
hydroboration-oxidation to furnish the branched â-C-tet-
rasaccharide 6a in good overall yield.
Note, we demonstrate that use of a triple RCM reaction19
allows for efficient access to a â-C-tetrasaccharide. Most
of the published syntheses of C-saccharides20 have fo-
cused on the preparation of C-disaccharides and C-
trisaccharides. Two research groups have synthesized
linear â-C-tetrasaccharides. Dondoni21 relied upon an
iterative Wittig-based approach, and Sinay¨22 employed
the addition of a C-6 acetylide anion addition to anomeric
lactone followed by stereoselective reduction. The syn-
thesis of a branched C-tetrasaccharide has yet to appear.
Our generic approach to â-C-tetrasaccharide synthesis
is shown in Scheme 1. The approach begins with dehy-
drative coupling of 3 equiv of a generic olefin alcohol 1
with a suitable carbohydrate-based triacid, such as 2, to
provide triester 3 (Scheme 1). Methylenation (3 f 4) is
followed by RCM23 with the second generation Grubbs
catalyst 7,24 to furnish the tris-C-glycal 5. Hydroboration
of the formed double bonds should afford the â-C-
tetrasaccharide 6.
The preparation of stable carbohydrate mimetics3 is
of paramount importance given the vast array of biologi-
cal functions in which carbohydrates partake.4-8 The
replacement of the interglycosidic oxygen atom of a
naturally occurring O-glycoside results in the formation
of a stable C-glycoside derivative that should not be prone
to enzymatic or chemical hydrolysis. The field of C-
glycoside synthesis is a mature field that has seen the
use of a wide array of interesting chemistry9-12 for the
attachment of a variety of carbon-based groups to the
anomeric center of carbohydrates.
We have shown that â-C-glycosides,13-15 â-C-disaccha-
rides,16,17 and more recently â-C-trisaccharides18 can be
generated using an esterfication-RCM strategy. In this
(1) Present address: Skaggs Institute for Chemical Biology, BCC-
405 Chemistry, The Scripps Research Institute, 10550 North Torrey
Pines Road, La J olla, CA 92037.
(2) Present address: Department of Internal Medicine, Henry Ford
Health System, One Ford Place, OFP-1D25, Detroit, MI 48202.
(3) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev.
2002, 102, 491-514.
(18) Postema, M. H. D.; Piper, J . L.; Komanduri, V.; Liu, L. Angew.
Chem., Int. Ed. Engl. 2004, 43, 2915-2918.
(19) For examples of double and polycyclization RCM reactions,
see: (a) Grubbs, R. H.; Fu, G. C. J . Am. Chem. Soc. 1992, 114, 7324-
7325. (b) Wallace, D. J .; Bulger, P. G.; Kennedy, D. J .; Ashwood, M.
S.; Cottrell, I. F.; Dolling, U.-H. Synlett 2001, 3, 357-360. (c) Wallace,
D. J .; Cowden, C. J .; Kennedy, D. J .; Ashwood, M. S.; Cottrell, I. F.;
Dolling, U.-H. Tetrahedron Lett. 2000, 41, 2027-2029. (d) Schmidt,
B.; Wildemann, H. J . Chem. Soc., Perkin Trans. 1 2000, 2916-2925.
(e) Clark, J . S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372-
374. (f) Zuercher, W. J .; Scholl, M.; Grubbs, R. H. J . Org. Chem. 1998,
63, 4291-4298.
(4) Sasisekharan, R.; Myette, J . R. Am. Sci. 2003, 91, 432-441.
(5) Perkel, J . M. Scientist 2002, 19, 32-34.
(6) Nagai, Y. Glycoconjuguate J . 2002, 19, 161-163.
(7) Roseman, S. J . Biol. Chem. 2001, 276, 41527-41542.
(8) Dwek, R. A. Chem. Rev. 1996, 96, 683-720.
(9) Postema, M. H. D.; Calimente, D. In Glycochemistry: Principles,
Synthesis and Applications; Wang, P. G., Bertozzi, C., Eds.; Marcel
Dekker: New York, 2000; pp 7-131.
(10) Du, Y.; Linhardt, R. J .; Vlahov, I. R. Tetrahedron 1998, 54,
9913-9959.
(11) Postema, M. H. D. C-Glycoside Synthesis, 1st ed.; CRC Press:
Boca Raton, 1995; p 379.
(12) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides, 1st ed.;
Elsevier Science: Oxford, 1995; Vol. 13, p 291.
(13) Postema, M. H. D.; Calimente, D. J . Org. Chem. 1999, 64, 4,
1770-1771.
(14) Postema, M. H. D.; Piper, J . L. Org. Lett. 2003, 5, 1721-1723.
(15) Postema, M. H. D.; Chaulagain, M. R. Tetrahedron Lett. 2004,
45, in press.
(16) Postema, M. H. D.; Calimente, D.; Liu, L.; Behrmann, T. L. J .
Org. Chem. 2000, 65, 6061-6068.
(17) Postema, M. H. D.; Piper, J . L.; Liu, L.; Faust, M.; Andreana,
P. J . Org. Chem. 2003, 68, 4748-4754.
(20) Liu, L.; McKee, M.; Postema, M. H. D. Curr. Org. Chem. 2001,
5, 1133-1167.
(21) Dondoni, A.; Marra, A.; Mizuno, M.; Giovannini, P. P. J . Org.
Chem. 2002, 67, 4186-4199.
(22) Xin, Y.-C.; Zhang, Y.-M.; Mallet, J .-M.; Glaudemans, C. P. J .;
Sinay¨, P. Eur. J . Org. Chem. 1999, 471-476.
(23) For examples of enol ether-olefin metathesis reactions, see: (a)
Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J . Am. Chem.
Soc. 1996, 118, 1565-1566. (b) Nicolaou, K. C.; Postema, M. H. D.;
Yue, E. W.; Nadin, A. J . Am. Chem. Soc. 1996, 118, 10335-10336. (c)
Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 123-126. (d)
Rainier, J . D.; Allwein, S. P. J . Org. Chem. 1998, 63, 5310-5311. (e)
Sturino, C. F.; Wong, J . C. Y. Tetrahedron Lett. 1998, 39, 9623-9626.
(f) Oishi, T.; Nagumo, Y.; Shoji, M.; Le Brazidec, J .-Y.; Uehara, H.;
Hirama, M. J . Chem. Soc., Chem. Commun. 1999, 2035-2036.
10.1021/jo040203w CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/21/2004
J . Org. Chem. 2004, 69, 7395-7398
7395

SCHEME 2. Syn th esis of Tr ia cid 2a
SCHEME 3
Diester 818 was allylated along literature guidelines25
to furnish 9 in 93% yield. Oxidative cleavage26 of the
terminal olefin of 9 gave aldehyde 10 in 91% yield.
Further oxidation27 of 10 to the corresponding carboxylic
acid, followed by saponification of the two alkyl esters,
delivered triacid 2a in 83% overall yield, Scheme 2. The
stereochemistry of the allylation step was established as
R by verification of the H-2 splitting pattern.
With sufficient quantities of triacid 2a in hand, the
esterification-RCM sequence was explored. DCC-medi-
ated coupling of triacid 2a with 3 equiv of alcohol 1a 28
proceeded smoothly to provide ester 3a in 80% yield.
Takai methylenation29 of triester 3a to the corresponding
triacyclic enol ether 4a was followed by a triple RCM
reaction in the presence of 50 mol % of catalyst 7,24 added
portion-wise in hot toluene, to provide the intermediate
tris-glycal 5a . Hydroboration30,31 of the crude tris-glycal
5a with an excess of BH3‚THF (followed by H2O2, NaOH,
THF-H2O) afforded the target â-C-tetrasaccharide 6a in
44% yield over three steps, Scheme 3. The intermediate
tris-glycal 5a was stable for brief periods of time, but not
long enough to be fully characterized. The stereochem-
istry of hydroboration was verified by acetylation (6a f
11, Ac2O, pyridine, 4-DMAP) of 6a and examination of
the H2 coupling constants in the proton NMR spectrum.32
These results show that triple RCM sequences can now
be applied for the synthesis of carbohydrate mimics of
greater complexity and biological relevance.
quenched with saturated sodium bicarbonate (5 mL) and ex-
tracted with diethyl ether (3 × 20 mL). The combined ethereal
extracts were washed with saturated ammonium chloride (1 ×
20 mL), dried, filtered, and concentrated. Flash chromatography
of the residue over silica using 15% f 20% EtOAc-hexanes gave
9 (118 mg, 93%) as a pure (Rf ) 0.37, TLC silica, 20% EtOAc-
hexanes; 1H NMR, 500 MHz) clear oil: [R]D ) +39.3 (c ) 1.0,
CHCl3); FT-IR (neat) 3066, 3030, 2978, 2947, 1732, 1453, 1436,
1370, 1259, 1208, 1170, 1084, 1028, 913, 737, 698 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.36-7.26 (m, 10 H, ArH), 5.76 (dddd, 1 H,
J ) 16.5, 10, 6.5, 6.5 Hz, H-10), 5.06 (dd, 1 H, J ) 17.5, 1.5 Hz,
H-11trans), 5.04 (dd, J ) 10, 1.0 Hz, H-11cis), 4.67 (d, 1 H, J )
11.5 Hz, OCH2Ph), 4.53 (d, 1 H, J ) 12.5 Hz, OCH2Ph), 4.51 (d,
1 H, J ) 12 Hz, OCH2Ph), 4.47 (d, 1 H, J ) 12 Hz, OCH2Ph),
4.11 (q, 2 H, J ) 7.0 Hz, OCH2CH3), 3.90 (ddd, 1 H, J ) 8.5, 4.5,
4.5 Hz, H-1), 3.78-3.72 (m, 2 H, H-3, H-5), 3.61 (s, 3 H, OCH3),
3.43 (dd, 1 H, J ) 5.5, 3.5 Hz, H-2), 2.83 (dddd, 1 H, J ) 6.5,
6.5, 4.0, 4.0 Hz, Hz, H-4), 2.50 (dd, 1 H, J ) 16.5, 7.5 Hz, H-8),
2.47-2.38 (m, 2 H, H-7, H-9), 2.38-2.27 (m, 3 H, H-7, H-8, H-9),
2.18-2.08 (bm, hump, 1 H, H-6), 1.63 (dddd, 1 H, J ) 15, 7.5,
7.5, 2.5 Hz, H-6), 1.25 (t, 3 H, J ) 7.0 Hz, OCH2CH3); 13C NMR
(100 MHz, CDCl3) δ 173.6, 173.1, 138.2, 135.1, 128.3, 127.9,
127.7, 127.6, 116.8, 75.7, 73.9, 72.7, 72.0, 60.1, 51.6, 36.1, 33.3,
30.9, 30.2, 24.3, 14.2; HRMS (ES) calcd for C30H38O7Na (M)+
533.2510, found 533.2513.
Exp er im en ta l Section
Allyl Diester (9). The procedure of Hosomi25 was followed
with slight modifications. TMSOTf (20 µL, 0.001 mmol) was
added dropwise over 1 min to a cool (0 °C) solution of ester 818
(125 mg, 0.25 mmol) and allyltrimethylsilane (79 µL, 0.5 mmol)
in dry acetonitrile (2 mL). The ice-water bath was left in place,
and the resulting solution was stirred for 12 h. The solution was
Diester Ald eh yd e (10). Osmium tetroxide (∼10 mg) was
added to a slurry of 9 (700 mg, 1.37 mmol) and sodium
metaperiodate (645 mg, 3.01 mmol) in THF-H2O (4:1, 12 mL),
and the resulting mixture was stirred at room temperature for
3 h at which point TLC (silica, 20% Et2O-hexanes) showed no
starting material remaining. The reaction was quenched by the
addition of saturated sodium thiosulfate (5 mL) and partitioned
between EtOAc (10 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic extracts were washed with brine (1 × 10 mL),
dried, and filtered. The solution was concentrated, and flash
chromatography of the residue over silica gel using 10% f 20%
EtOAc-hexanes gave aldehyde 10 (639 mg, 91%) as a pure (Rf
) 0.19, TLC silica, 10% EtOAc-hexanes; 1H NMR, 500 MHz)
oil: [R]D ) +10.0 (c ) 1, CHCl3); FT-IR (neat) 3061, 3029, 2980,
(24) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
(25) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25,
2383-2386.
(26) Pappo, R.; Allen, D., J r.; Lemieux, R.; J ohnson, W. J . Org. Chem.
1956, 21, 478-479.
(27) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(28) Freeman, F.; Robarge, K. D. Carbohydr. Res. 1987, 171, 1-11.
(29) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J . Org. Chem.
1994, 59, 2668-2670.
(30) Hanessian, S.; Martin, M.; Desai, R. C. J . Chem. Soc., Chem.
Commun. 1986, 926-927.
2905, 1727, 1454, 1372, 1257, 1171, 1088, 739, 699 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 9.69 (dd, 1 H, J ) 2.5, 1.5 Hz, CHO),
7.36-7.26 (m, 10 H, ArH), 4.64 (d, 1 H, J ) 11.5 Hz, OCH2Ph),
4.52 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.46 (d, 1 H, J ) 12.5 Hz,
(31) Schmidt, R. R.; Preuss, R.; Betz, R. Tetrahedron Lett. 1987, 28,
6591-6594.
(32) See Supporting Information.
7396 J . Org. Chem., Vol. 69, No. 21, 2004

OCH2Ph), 4.45 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.47-4.43 (buried
m, 1 H, H-1), 4.10 (q, 2 H, J ) 7.0 Hz, OCH2CH3), 3.78-3.72
(m, 2 H, H-3, H-5), 3.61 (s, 3 H, OCH3), 3.43 (dd, 1 H, J ) 5.5,
3.5 Hz, H-2), 2.82 (dddd, 1 H, J ) 7.0, 7.0, 4.5, 4.5 Hz, H-4),
2.69 (ddd, 1 H, J ) 16.5, 7.5, 2.5 Hz, H-9), 2.55 (dd, 1 H, J )
16.5, 5.0 Hz, H-9), 2.48 (dd, 1 H, J ) 16.5, 8.0 Hz, H-8), 2.41-
2.23 (m, 3 H, 2 × H-7, H-8), 2.18 (dddd, 1 H, J ) 14, 14, 6.5, 6.5
Hz, H-6), 1.63 (dddd, 1 H, J ) 14.5, 7.0, 7.0, 2.5 Hz, H-6), 1.23
(t, 3 H, J ) 7.0 Hz, OCH2CH3); 13C NMR (125 MHz, CDCl3) δ
200.6, 173.4, 172.9, 137.8, 137.6, 128.4, 128.3, 128.1, 127.9, 127.7,
127.6, 75.2, 73.4, 72.9, 72.8, 72.1, 65.0, 60.2, 51.6, 43.8, 35.6,
30.9, 30.3, 24.0, 14.1; HRMS (ES) calcd for C29H36O8Na (M)+
535.2302, found 535.2305.
for 5 h at ambient temperature, at which point TLC (silica, 30%
EtOAc-hexanes) showed the reaction was complete. The reac-
tion mixture was diluted with ether (20 mL) and filtered by
gravity through cotton to remove most of the formed dicyclo-
hexylurea. The resulting organic solution was washed with
saturated NH4Cl (1 × 20 mL), dried, and concentrated. Flash
chromatography over silica gel using 30% EtOAc-hexanes gave
ester 3a (833 mg, 80%) as a pure (Rf ) 0.32, TLC silica, 30%
1
EtOAc-hexanes; H NMR, 500 MHz) oil: [R]D ) -1.60 (c ) 1,
CHCl3); FT-IR (neat) 3062, 3029, 2868, 1733, 1496, 1453, 1352,
1256, 1203, 1170, 1090, 1027, 932, 735, 696 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.33-7.22 (m, 55 H, ArH), 5.91-5.80 (m, 3 H,
H-1′, H-1”, H-1′′′), 5.33-5.21 (m, 9 H, 2 × H-1′, 2 × H-1”, 2 ×
H-1′′′, H-5′, H-5′′, H-5′′′), 4.66 (d, 1 H, J ) 11 Hz, OCH2Ph), 4.64
(d, 1 H, J ) 12.5 Hz, OCH2Ph), 4.64 (d, 1 H, J ) 12 Hz, OCH2-
Ph), 4.63 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.59 (d, 1 H, J ) 12.5
Hz, OCH2Ph), 4.58 (d, 1 H, J ) 11 Hz, OCH2Ph), 4.57 (d, 1 H,
J ) 11 Hz, OCH2Ph), 4.56 (d, 1 H, J ) 11 Hz, OCH2Ph), 4.55 (d,
1 H, J ) 11.5 Hz, OCH2Ph), 4.54 (d, 1 H, J ) 12 Hz, OCH2Ph),
4.52 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.45 (d, 1 H, J ) 11.5 Hz,
OCH2Ph), 4.43 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.43 (d, 1 H, J )
11.5 Hz, OCH2Ph), 4.41 (d, 1 H, J ) 13 Hz, OCH2Ph), 4.40 (d, 1
H, J ) 13 Hz, OCH2Ph), 4.40 (d, 1 H, J ) 13 Hz, OCH2Ph), 4.40
(d, 1 H, J ) 13 Hz, OCH2Ph), 4.41-4.39 (m, 1 H, H-1), 4.37 (d,
1 H, J ) 12.5 Hz, OCH2Ph), 4.34 (d, 1 H, J ) 12 Hz, OCH2Ph),
4.30 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.29 (d, 1 H, J ) 11.5 Hz,
OCH2Ph), 4.26 (d, 1 H, J ) 12 Hz, OCH2Ph), 3.91-3.84 (m, 3
H, H-3′, H-3′′, H-3′′′), 3.78-3.67 (m, 11 H, H-3, H-5, H-4′, H-4′′,
H-4′′′, 2 × H-6′, 2 × H-6′′, 2 × H-6′′′), 3.36 (dd, 1 H, J ) 5.5, 3.5
Hz, H-2), 2.75 (dddd, 1 H, J ) 9.0, 9.0, 5.0, 5.0 Hz, H-4), 2.56
(dd, 1 H, J ) 17, 8.5 Hz, H-9), 2.40 (dd, 1 H, J ) 17, 8.0 Hz,
H-8), 2.35-2.27 (m, 2 H, H-9, CH2), 2.25-2.17 (m, 2 H, H-8,
CH2), 1.59-1.50 (m, 2 H, 2 × CH2); 13C NMR (125 MHz, CDCl3)
δ 172.8, 171.6, 170.4, 138.4, 138.3, 138.2, 138.2, 138.2, 138.1,
138.1, 138.0, 138.0, 135.2, 135.1, 135.0, 128.3, 128.3, 128.3, 128.2,
128.2, 128.1, 128.0, 128.0, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6,
127.5, 127.4, 119.4, 119.3, 119.2, 81.1, 80.9, 80.8, 80.7, 80.7, 75.0,
74.9, 74.9, 73.0, 72.5, 72.5, 72.4, 72.4, 72.2, 70.4, 70.3, 70.3, 68.1,
68.1, 68.0, 65.9, 35.2, 23.7; HRMS (ES) calcd for C107H114O18Na
(M)+ 1710.7931, found 1710.7903.
â-C-Tetr a sa cch a r id e (6a ). A solution of titanium tetrachlo-
ride (1.0 mL, 2 M in CH2Cl2, 2.0 mmol) was added to cool (0 °C)
THF (3 mL). The resulting mixture was stirred for 30 min, at
which point TMEDA (0.58 mL, 3.87 mmol) was added in one
portion. The resulting yellow-brown suspension was allowed to
warm to ambient temperature and stirred for 30 min. At this
point, zinc dust (285 mg, 4.37 mmol) and lead(II) chloride (3 mg,
10.7 µmol) were added in portion, and stirring at ambient
temperature was continued for 10 min. A solution of ester 3a
(100 mg, 0.059 mmol) and dibromomethane (0.77 µL, 10.9 µmol)
in THF (1 mL plus 1 mL rinse) was then added via cannula to
the reaction flask in one portion. The mixture was stirred at 60
°C for 1 h, cooled to 0 °C, and then quenched by the addition of
saturated potassium carbonate (1 mL). The resulting mixture
was stirred for 30 min (while warming to ambient temperature),
diluted with ether (20 mL), and stirred vigorously for 15 min.
The resulting mixture was filtered through neutral alumina
using 3% triethylamine-ether as the eluent. The greenish-blue
precipitate that resulted was crushed (mortar and pestle) and
thoroughly extracted by vigorous stirring over diethyl ether (15-
20 mL) for 30 min. The combined ethereal extracts were then
concentrated in vacuo to give the acyclic enol ether 4a .
Tr ia cid (2a ). 2-Methyl-2-butene (660 µL, 7.84 mmol), potas-
sium phosphate monobasic (207 mg, 1.52 mmol), and sodium
chlorite (tech., 80%, 169 mg, 1.52 mmol) were added to a
t-BuOH-water (4:1, 20 mL) solution of aldehyde 10 (600 mg,
1.17 mmol). The resulting mixture was stirred at room temper-
ature for 6 h, concentrated, and diluted with water (10 mL). The
resulting mixture was acidified with HCl (∼5 mL, 2 M) to
approximately pH ) 2-3 (litmus red). The mixture was ex-
tracted with EtOAc (5 × 20 mL), and the combined organic
extracts were dried, filtered, and concentrated. The residue was
passed through a short plug of silica gel using 40% EtOAc-
hexanes-1/2% AcOH as the eluent to give the monoacid (585
mg, 95%) as a fairly pure (Rf ) 0.23, TLC silica, 40% EtOAc-
hexanes-1/2% AcOH; 1H NMR, 500 MHz) waxy solid: [R]D
)
+16.9 (c ) 1, CHCl3); FT-IR (neat) 3030 (br), 1728, 1715, 1454,
1437, 1372, 1261, 1173, 1075, 1027, 738, 699 cm-1; 1H NMR (500
MHz, CDCl3) δ 11.14 (br s, 1 H, CO2H), 7.36-7.23 (m, 9 H, ArH),
7.18-7.13 (m, 1 H, ArH), 4.67 (d, 1 H, J ) 11.5 Hz, OCH2Ph),
4.54 (d, 1 H, J ) 12.5 Hz, OCH2Ph), 4.51 (d, 1 H, J ) 12 Hz,
OCH2Ph), 4.48 (d, 1 H, J ) 13 Hz, OCH2Ph), 4.24 (dddd, 1 H, J
) 4.5, 4.5, 4.5, 4.5 Hz, H-1), 4.10 (q, 2 H, J ) 7.5 Hz, OCH2-
CH3), 3.78 (ddd, 1 H, J ) 11.5, 3.0, 3.0 Hz, H-5), 3.75 (dd, 1 H,
J ) 5.5, 3.5, H-3), 3.61 (s, 3 H, OCH3), 3.43 (dd, 1 H, J ) 6.0,
3.5 Hz, H-2), 2.82 (dddd, 1 H, J ) 6.5, 6.5, 4.0, 4.0 Hz, Hz, H-4),
2.71 (dd, 1 H, J ) 16, 9.0 Hz, H-9), 2.60 (dd, 1 H, J ) 16, 5.0 Hz,
H-9), 2.50 (dd, 1 H, J ) 16.5, 7.0 Hz, H-8), 2.38-2.28 (m, 3 H,
2 × H-7, H-8), 2.22-2.10 (bm, 1 H, H-6), 1.63 (dddd, 1 H, J )
15.5, 8.0, 8.0, 3.0 Hz, H-6), 1.22 (t, 3 H, J ) 7.5 Hz, OCH2CH3);
13C NMR (125 MHz, CDCl3) δ 176.7, 173.5, 172.9, 137.8, 137.6,
128.2, 128.2, 127.8, 127.6, 127.6, 127.5, 75.1, 73.3, 72.6, 71.9,
69.8, 65.5, 60.1, 51.5, 35.7, 34.5, 30.4, 29.9, 24.1, 14.0; HRMS
(ES) calcd for C29H36O9Na (M)+ 551.2251, found 551.2239.
LiOH (795 mg, 18.9 mmol, 20 equiv) was added to a 0 °C
solution of the diester-acid (500 mg, 0.95 mmol) in THF (6 mL).
Water (6 mL) was added, and the resulting suspension was
vigorously stirred at 0 °C for 1 h, allowed to warm to ambient
temperature, and then stirred overnight (12 h). The mixture was
cooled to 0 °C and acidified by the addition of HCl (∼5 mL, 2 M)
until litmus red was obtained. The resulting solution was
extracted with EtOAc (5 × 20 mL), dried, and concentrated.
Flash chromatography over silica gel using 5% f 10% MeOH-
CH2Cl2-1/2% AcOH gave 2a (400 mg, 83% over 2 steps) as a
fairly pure (Rf ) 0.25, TLC silica, 70% EtOAc-hexanes; 1H
NMR, 500 MHz) white solid: mp ) 139-140 °C; [R]D ) +51.3
(c ) 1, CHCl3); FT-IR (neat) 3031 (br), 1698, 1453, 1413, 1360,
1281, 1176, 1073, 698 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33-
7.24 (m, 10 H, ArH), 4.62 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.50-
4.44 (m, 3 H, 3 × OCH2Ph), 4.24 (dddd, 1 H, J ) 8.5, 3.5, 3.5,
3.5 Hz, H-1), 3.78 (ddd, 1H, J ) 11.5, 3.0, 3.0 Hz, H-5), 3.71 (dd,
1 H, J ) 6.0, 4.0, H-3), 3.43 (dd, 1 H, J ) 5.5, 3.5 Hz, H-2), 2.77
(dddd, 1 H, J ) 7.0, 7.0, 4.5, 4.5 Hz, H-4), 2.64 (dd, 1 H, J ) 16,
9.0 Hz, H-9), 2.49-2.38 (m, 3 H, H-7, H-8, H-9), 2.37-2.26 (m,
2 H, H-7, H-8), 2.18-2.05 (bm, 1 H, H-6), 1.68-1.58 (m, 1 H,
H-6); 13C NMR (125 MHz, CDCl3) δ 176.7, 175.5, 174.3, 137.9,
137.7, 128.3, 128.0, 127.8, 127.6, 127.6, 75.5, 73.7, 72.8, 72.5,
72.0, 35.8, 34.6, 30.4, 30.1, 24.1; HRMS (ES) calcd for C26H30O9-
Na (M)+ 509.1728, found 509.1772.
Ruthenium-based metathesis catalyst 7 (25 mg, 0.30 mmol,
50 mol %) was added in five equivalent portions over 2.5 h (10
mol % every 30 min) to a dry and degassed toluene (6 mL)
solution of crude 4a from the above experiment. The resulting
mixture (0.01 M in substrate) was heated to 60 °C for 3 h, at
which point TLC (silica, 30% Et2O-hexanes) showed the reac-
tion was complete. The resulting solution was concentrated,
diluted with THF (3 mL), and cooled to 0 °C. BH3‚THF (0.59
mL, 1 M in THF, 0.59 mmol) was added to the cooled solution,
and the resulting mixture was allowed to warm to room
temperature and stirred overnight. The solution was cooled back
down to 0 °C, and NaOH (20 mL, 1 M, 20 mmol) and hydrogen
Tr iester (3a ). 4-DMAP (75 mg, 0.62 mmol) and DCC (395
mg, 1.91 mmol) were added in one portion to a solution of triacid
2a (300 mg, 0.62 mmol) and alcohol 1a 28 (774 mg, 1.85 mmol)
in dry CH2Cl2 (5 mL). The resulting solution was then stirred
J . Org. Chem, Vol. 69, No. 21, 2004 7397

peroxide (20 mL, 30% in water) were added in one portion. The
solution was allowed to warm to room temperature over 2 h.
The solution was then extracted with EtOAc (3 × 10 mL), and
the combined organic extracts were washed with saturated
sodium thiosulfate (1 × 20 mL) and brine (1 × 10 mL), dried,
and filtered. The solution was concentrated, and flash chroma-
tography of the residue over silica using 40% f 50% EtOAc-
hexanes gave 6a (43 mg, 44% over 3 steps) as a pure (Rf ) 0.41,
TLC silica, 45% EtOAc-hexanes; 1H NMR, 500 MHz) waxy
solid: mp ) 47-48 °C; [R]D ) +6.2 (c ) 1.0, CHCl3); FT-IR (neat)
3454 (br), 3030, 2921, 2853, 1496, 1454, 1256, 1098, 737, 698
3.17 (m 2 H, 1 × OCH and also contains dd at 3.19, J ) 9.5, 9.5
Hz, 1 H, H-2′′), 3.07 (dd, 1 H, J ) 9.0, 9.0 Hz, H-2′′′), 2.97 (ddd,
1 H, J ) 9.5, 9.5, 1.5 Hz, H-1′′′), 2.87 (ddd, 1 H, J ) 9.0, 9.0, 2.0
Hz, H-1′′), 2.63 (dddd, 1 H, J ) 9.5, 6.5, 3.5, 3.5 Hz, H-4), 2.30-
2.23 (m, 1 H, H-9), 2.18-2.08 (m, 2 H, 2 × H-6 or H-6, H-7),
2.00-1.94 (m, 1 H, H-8), 1.91-1.85 (m, 1 H, H-9), 1.80-1.69
(m, 1 H, H-7 or H-6), 1.35-1.20 (m, 2 H, H-8, H-6); 13C NMR
(100 MHz, CDCl3) δ 139.1, 138.8, 138.4, 138.4, 138.3, 138.2,
138.1, 138.1, 128.6, 128.6, 128.4, 128.3, 128.3, 128.2, 128.2, 128.0,
127.9, 127.9, 127.9, 127.8, 127.8, 127.8, 127.7, 127.6, 127.6, 127.5,
127.3, 86.7, 86.3, 80.7, 79.2, 79.0, 78.9, 78.3, 78.2, 78.0, 75.6,
75.1, 74.9, 74.8, 74.1, 73.5, 73.4, 73.2, 72.8, 72.0, 69.5, 69.3, 68.9,
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.40-7.13 (m, 43 H, ArH),
7.11-7.07 (m, 2 H, ArH), 4.95 (d, 1 H, J ) 11 Hz, OCH2Ph),
4.93 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.82 (d, 1 H, J ) 11.5 Hz,
OCH2Ph), 4.79 (d, 1 H, J ) 11 Hz, OCH2Ph), 4.78 (d, 1 H, J )
10.5 Hz, OCH2Ph), 4.77 (d, 1 H, J ) 10.5 Hz, OCH2Ph), 4.75 (d,
1 H, J ) 11.5 Hz, OCH2Ph), 4.73 (d, 1 H, J ) 12 Hz, OCH2Ph),
4.71 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.60 (d, 1 H, J ) 12 Hz,
OCH2Ph), 4.57 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.57 (d, 1 H, J )
11.5 Hz, OCH2Ph), 4.56 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.55 (d, 1
H, J ) 10 Hz, OCH2Ph), 4.55 (d, 1 H, J ) 10.5 Hz, OCH2Ph),
4.52 (d, 1 H, J ) 12.5 Hz, OCH2Ph), 4.50 (d, 1 H, J ) 10.5 Hz,
OCH2Ph), 4.49 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.46 (d, 1 H, J )
11.5 Hz, OCH2Ph), 4.45 (d, 1 H, J ) 12 Hz, OCH2Ph), 4.44 (d, 1
H, J ) 12 Hz, OCH2Ph), 4.28 (d, 1 H, J ) 12.5 Hz, OCH2Ph),
4.24 (m, 1 H, H-1′), 2.23 (ddd, 1 H, J ) 4.0, 2.0, 0 Hz, H-5), 3.80-
3.55 (m, 10 H, 10 × OCH), 3.47-3.44 (m, 2 H, 2 × OCH), 3.43-
3.38 (m, 2 H, 2 × OCH), 3.38-3.30 (m, 4 H, 4 × OCH), 3.25-
63.0, 61.4, 30.3, 30.0, 29.7, 29.2; HRMS (ES) calcd for C104H114O18
-
Na (M)+ 1674.7931, found 1674.7916.
Ack n ow led gm en t. We gratefully acknowledge the
NSF (CHE-0132770) for support of this research. Mr.
J ared Piper gratefully held a David H. Green Memorial
Fellowship and a Willard R. Lenz Memorial Fellowship.
Su p p or tin g In for m a tion Ava ila ble: Stereochemical as-
1
signment information for 6a and H and GCOSY NMR spectra
of 2a , 3a , 6a , and 9-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O040203W
7398 J . Org. Chem., Vol. 69, No. 21, 2004