C-arylglycosides via a benzannulation mediated by fischer chromium carbene complexes

Full text of DOI:10.1021/jo980442h

J . Org. Chem. 1998, 63, 5275-5279
5275
C-Ar ylglycosid es via a Ben za n n u la tion
Med ia ted by F isch er Ch r om iu m Ca r ben e
Com p lexes
Shon R. Pulley* and J ames P. Carey
Department of Chemistry, University of
MissourisColumbia, 123 Chemistry Building,
Columbia, Missouri 65211
Received March 10, 1998
C-arylglycosides, part of the general C-glycoside family,
are carbohydrates with an aromatic ring directly attached
to the anomeric carbon.1 These compounds, with an
inherently stable carbon-carbon glycosidic linkage show
a broad range of useful antitumor, antifungal, and
antibiotic properties that, encourages the development
of synthetic methodologies targeted toward this class of
natural products.2 Vineomycin B2 (1), medermycin (2),
and mederrhodin A (3) represent two of the four classes
of naturally occurring C-arylglycosides each based on the
regiochemistry of the glycosylated aromatic ring (Figure
1).3 In each of these compounds there is an ortho
relationship between a sugar moiety and a phenolic
hydroxyl of the aromatic ring. This is common to many
of the naturally occurring C-arylglygosides and any
synthetic approach toward these compounds must ad-
dress this point.
Methods available for the formation of C-arylglycosides
fall into one of the following categories: (1) activation of
the anomeric center, providing an electrophilic oxonium
ion followed by capture with an aromatic nucleophile,1,2
(2) addition of a metalated aromatic to a glycosyl halide
or lactone,4 (3) addition of an anomeric carbanion to an
electrophilic aromatic equivalent,5 and (4) transition-
metal-mediated cross-coupling between suitably func-
tionalized glycosyl and aromatic coupling partners.6
Each of these involve formation of the C-C bond between
the aromatic and the carbohydrate. In addition, strate-
gies that involve cycloaddition between aromatic alde-
hydes and activated dienes offer de novo approaches to
C-arylglycosides.7 Less common are benzannulation
strategies based on assembling the glycosylated aromatic
ring from suitably functionalized carbohydrate precur-
sors. For example, C-arylglycosides result from the
F igu r e 1. Representative C-arylglycosides.
aromatization of products derived from carbohydrate
â-polyketides,8 addition of carbohydrate C-1 silyl enol
ethers to quinones,9 and Bradsher cyclization of isoquino-
linium salts.10 Recently McDonald and co-workers re-
ported an alkyne cyclotrimerization as an example of a
benzannulation approach for constructing the aromatic
moiety from acyclic precursors.11 In the following report
we describe a strategy toward C-arylglycosides that
utilizes a benzannulation reaction between Fischer alk-
enyl carbene complexes and acetylenic sugars. The
resulting products are envisaged as intermediates in
synthetic approaches to C-arylglycoside antibiotics.
Unsaturated Fischer chromium carbene complexes
undergo what is formally a [3+2+1] cycloaddition (the
Do¨tz reaction) with alkynes. The reaction is key to a
number of natural product syntheses requiring diversely
substituted aromatic rings.12 Theory and experiment
support a mechanism consistent with rate-limiting loss
of CO and insertion into an alkyne resulting in a η1,η3-
vinylcarbene intermediate which after CO insertion and
cyclization affords a phenol after demetalation.13,14 Our
interest in the synthesis of C-arylglycosides led to a
method that involves reacting a C-alkynylglycoside A15
with a alkenyl carbene complex B or reacting a C-
glycosylated carbene complex C with an alkyne to afford
C-arylglycosides (Scheme 1). We are aware of only one
(1) For a general reviews see: (a) Posteme, M. H. D. In C-Glycoside
Synthesis; Rees, C. W., Ed.; CRC Press: Boca Raton, FL, 1995. (b)
Posteme, M. H. D. Tetrahedron 1992, 48, 8545.
(2) For Reviews on the Synthesis and Biological Properties of
C-Arylglycosides see: (a) Hacksell, U.; Daves, G. D., J r. Prog. Med.
Chem. 1985, 22, 1. (b) Suzuki, K.; Matsumoto, T. In Recent Progress
in the Chemical Synthesis of Antibiotics and Related Mircrobial
Products; Lukacs, G., Ed.; Springer-Verlag: New York, 1993; Vol. 2
pp 353-403. (c) J aramillo, C.; Knapp, S. Synthesis 1994, 1. (d) Suzuki,
K.; Matsumoto, T. In Preparative Carbohydrate Chemistry; Hanessian,
S., Ed.; Marcel-Dekker: New York, 1997; pp 527-542.
(3) For classification see: (a) Hosoya, T.; Takashiro, E.; Matsumoto,
T.; Suzuki, K. J . Am. Chem. Soc. 1994, 116, 1004. (b) Parker, K. A.
Pure Appl. Chem. 1994, 66, 2135.
(4) (a) Kraus, G. A.; Molina, M. T. J . Org. Chem. 1988, 53, 752. (b)
Czernecki, S.; Ville, G. J . Org. Chem. 1989, 54, 610. (c) Boyd, V. A.;
Drake, B. E.; Sulikowski, G. A. J . Org. Chem. 1993, 58, 3191.
(5) (a) Parker, K. A.; Su, D.-S. J . Org. Chem. 1996, 61, 2191. (b)
Parker, K. A.; Coburn, C. A.; Koh, Y.-h. J . Org. Chem. 1995, 60, 2938
and references therein.
(7) For an example see: (a) Danishefsky, S. J .; Uang, B. J . Quallich,
G. J . Am. Chem. Soc. 1985, 107, 1285. (b) Schmidt, R. R.; Frick, W.;
Haag-Zeino, B.; Appara, S. Tetraheron Lett. 1987, 28, 4045. (c) For a
related approach also see: Hart, D. J .; Leroy, V.; Merriman, G. H.;
Young, D. G. J . J . Org. Chem. 1992, 57, 5670. (d) For a Ring Closing
Metathesis approach see: Schmidt, B.; Sattelkau, T. Tetrahedron 1997,
53, 12991.
(8) (a) Yamaguchi, M.; Hasebe, K.; Higashi, H.; Uchida, M.; Irie,
A.; Minami, T. J . Org. Chem. 1990, 55, 1611. (b) Yamaguchi, M.;
Horiguchi, A.; Ikeura, C.; Minami, T. J . Chem. Soc. Chem. Commun.
1992, 434.
(9) Kraus, G. A.; Shi, J . J . Org. Chem. 1990, 55, 4922.
(10) Bolitt, V.; Mioskowski, C.; Kollah, R. O.; Manna, S.; Rajapaksa,
D.; Flack, J . R. J . Am. Chem. Soc. 1991, 113, 6320. For a [3 + 2] dipolar
cycloaddition approach see: Kozikowski, A. P.; Cheng, X.-M. J . Chem.
Soc. Chem. Commun. 1987, 680.
(11) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J . Am. Chem.
Soc. 1995, 117, 6605.
(6) For a review see: Frappa, I.; Sinou, D. J . Carbohydr. Chem.
1997, 16, 255.
(12) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644.
S0022-3263(98)00442-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/03/1998

5276 J . Org. Chem., Vol. 63, No. 15, 1998
Notes
Sch em e 1. Tw o Com p lem en ta r y Ap p r oa ch es
Sch em e 2. Syn th esis of Glycosyla ted Ca r ben es
a n d Cycloa d d ition a
previous example of this strategy in which the authors
had limited success in a model reaction directed toward
the synthesis of nogalarol using aryl carbene complexes
and functionalized alkynes.16 The difficulty was at-
tributed to the presence of the propargylic oxygen such
as that found in C-alkynylglycosides. Our methodology
is the first report of the formation of C-arylglycosides
using alkenyl carbene complexes such as B or the novel
glycosylated carbenes C.17
Our initial effort involves the benzannulation between
R,â-unsaturated glycosylated chromium carbene com-
plexes 7 and 8 and trimethylsilylacetylene (Scheme 2).
Metalation of dihydropyran or tri-OTBDPS-D-glucal with
tert-butyllithium followed by the addition of DMF gives
the required C-1 glycosyl aldehydes 5 and 6.18 Aldol
condensation with the anion of [(methyl)(methoxy)car-
bene]pentacarbonylchromium(0) 4 gives the desired gly-
cosylated carbene complexes.19 Complexes 7 and 8 can
be isolated by silica gel chromatography. However, it is
more convenient to carry the crude complexes on to the
a
(a) BF3‚Et2O or TiCl4 1:1 complex with aldehyde (3 equiv), (b)
pyridine followed by SiO2, (c) (trimethylsilyl)acetylene (4 equiv),
(d) Ac2O, pyridine, DMAP.
annulation reaction. Heating a THF solution of the
carbene complexes and TMS-acetylene, followed by air
oxidation to remove the chromium, and subsequent
acetylation result in the desired model C-arylglycosides
as the acetates 9 and 10 in a modest 20% overall yield
from the aldehydes. In each case we observe a single
regioisomer in accordance with the accepted mechanism
for the Do¨tz reaction. It is important to point out that
the observed regiochemistry establishes the phenolic OH
(derived from CO) ortho to the C-C linkage to the
carbohydrate. Incorporation of the trimethylsilyl group
onto the aromatic provides an opportunity to introduce
electrophiles onto the ring for further elaboration.20
Having established precedent for achieving C-arylgly-
cosides via the Do¨tz benzannulation between glycosylated
carbenes and alkynes, we turned our attention to the
benzannulation between chromium carbene complex 11
and alkynylglycosides (eq 1). The advantages of this
(13) For reviews on the chemistry of Fischer carbene complexes
including the Do¨tz reaction see: (a) Do¨tz, K. H. Angew. Chem., Int.
Ed. Engl. 1984, 23, 587. (b) Do¨tz, K. H.; Fischer, H.; Hofmann, P.;
Kreissel, F. R.; Schubert, U.; Weiss, K. Transition Metal Carbene
Chemistry; Verlag-Chemiw: Deerfield Beach, FL. 1984. (c) Wulff, W.
D. In Comprehensive Organic Synthesis; Trost, B. M., Flemming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 1065-1113. (d) Wulff, W. D.
In Comprehensive Organometallic Chemistry II; Abel, A. W.; Stone, F.
G. A.; Wikinson, G., Eds.; Perganom: Oxford, 1995; Vol. 12, pp 469-
547. (e) Hegedus, L. S. In Comprehensive Organometallic Chemistry
II; Abel, A. W., Stone, F. G. A., Wikinson, G., Eds.; Perganom: Oxford,
1995; Vol. 12, pp 549-576.
(14) For mechanistic considerations see: (a) Gleichmann, M. M.;
Do¨tz, K. H.; Hess, B. A. J . Am. Chem. Soc. 1996, 118, 10551. (b)
Hofmann, P.; Ha¨mmerle, M. Angew. Chem., Int. Ed. Engl. 1989, 28,
908. (c) Wulff, W. D.; Bax, B. M.; Brandvold, T. A.; Chen, K. S.; Gilbert,
A. M.; Hsung, R. P. Organometallics 1994, 13, 102. (d) Bos, M. E.;
Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold, T. A. J . Am.
Chem. Soc. 1991, 113, 9293. (e) Chan, K. S.; Peterson, G. A.; Brandvold,
T. A.; Faron, K. L.; Challener, C. A.; Hyldahl, C.; Wulff, W. D. J .
Organomet. Chem. 1987, 334, 9.
(15) (a) Isobe, M. J . Synth. Org. Chem. J pn. 1994, 968. (b) Tsukiya-
ma, T.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911. (c) For a recent
example of the use of sugar acetylenes in complex syntheses see: J iang,
Y.; Ichikawa, Y.; Isobe, M. Tetrahedron 1997, 53, 5103.
(16) (a) Semmelhack, M. F.; J eong, N. Tetrahedron Lett. 1990, 31,
605. (b) Semmelhack, M. F.; J eong, N.; Lee, G. L. Tetrahedron Lett.
1990, 31, 609.
(17) For recent examples of carbene complex functionalized sugars,
see: (a) Do¨tz, K. H.; Straub, W.; Ehlenz, R.; Peseke, K.; Meisel, R.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1856 and references therein.
(b) Ehlenz, R.; Neub, O.; Teckenbrock, M.; Do¨tz, K. H. Tetrahedron
1997, 53, 5143. (c) Do¨tz, K. H.; Ehlenz, R.; Paetsch, D. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2376.
(18) (a) Friesen, R. W.; Trimble, L. A. J . Org. Chem. 1996, 61, 1165.
(b) Friesen, R. W.; Sturino, C. F.; Daljeet, A. K.; Kolaczewska, A. J .
Org. Chem. 1991, 56, 1944. (b) Paquette, L. A.; Schulze, M. M.; Bolin,
D. G. J . Org. Chem. 1994, 59, 2043.
(19) (a) Wulff, W. D.; Gilbertson, S. R. J . Am. Chem. Soc. 1985, 107,
503. (b) Aumann, R.; Heinen, H. Chem. Ber. 1987, 120, 537.
method are the availability of the alkenyl carbene
complexes and access to a number of alkynylglycosides
with various substitution patterns and stereochemistry.15
We chose alkynylglycosides 12-16 to determine the
generality of the annulation with respect to structural
variation. The preparation of the alkynylglycosides
proceeded according to the following (Scheme 3): React-
(20) (a) Wilbur, D. S.; Stone, W. E.; Anderson, K. W. J . Org. Chem.
1983, 48, 1542. (b) Mills, R. J .; Snieckus, V. Tetrahedron Lett. 1984,
25, 483. (c) J ones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.

Notes
Sch em e 3. Syn th esis of C-Alk yn ylglycosid esa
J . Org. Chem., Vol. 63, No. 15, 1998 5277
Ta ble 1. Rea ction of Ca r ben e 11 w ith Alk yn ylglycosid es
12-16
a
(a) Bis(trimethylsilyl)acetylene, SnCl4; (b) TBAF; (c) (i) K2CO3/
MeOH; (ii) NaH, DMSO, BnCl; (d) 2-(trimethylsilyl)ethynylmag-
nesium bromide; (e) POCl3, pyridine; (f) BnEt3NCl, CH2Cl2/
CH3CN, 50% aq NaOH; (g) Et3SiH, BF3‚Et2O; (h) 2-(trimethyl-
silyl)ethynyllithium.
ing bistrimethylsilylacetylene with tri-O-acetyl-D-glucal
in the presence of SnCl4,15 followed by TBAF-induced
desilylation, or base-induced conjugation, followed by
benzylation, gave alkynylglycosides 12 (R isomer) and 13.
Addition of 2-(trimethylsilyl)ethynylmagnesium bromide
to 2-deoxy-D-glucolactone 17 followed by POCl3/pyridine11
or BF3‚OEt2/Et3SiH4 and selective desilylation gave alky-
nylglycosides 14 and 15. The alkyne 15 was obtained
as a inseparable 5:1 mixture of anomers. Addition of
2-(trimethylsilyl)ethynyllithium to the tetra-O-benzyl-D-
glucolactone 18 followed by reductive deoxygenation and
desilylation yields the â anomer of alkynylglycoside 16.
In each case the unoptimized benzannulation between
alkynylglycosides 12-16 and alkenyl carbene complex 11
proceeds smoothly to afford C-arylglycosides 19-23
(Table 1). The reactions are done at 50-55 °C at 0.05 M
with 1.2 equiv of alkynylglycoside followed by simple air
oxidation to give the phenol products. However, it is
generally more convenient to protect the phenol with
Ac2O prior to isolation. Alternatively an oxidative work-
up with Ce(IV) results in the quinone 24 (eq 2).21
a
All reactions were carried out with 1.2 equiv of the alkyne,
b
THF, at 50-55 °C. Isolated purified yield of a single regioisomer
after cycloaddition, air oxidation, and protection of the phenol with
Ac2O. c Single anomer. Isolated as a 7:1 â/R mixture of anomers.
d
consistent with the accepted mechanism and positions
the phenol OH ortho to the carbohydrate portion of the
molecule.13
The most convergent approach to C-arylglycosides with
potential biological activity would involve directly ap-
pending the complete aromatic skeleton to the carbohy-
drate. Semmelhack reported that aryl-substituted car-
bene complexes were inefficient in their reaction with
propargylic ether substituted alkynes to give the desired
4-methoxy-1-naphthols.16 However, given our success
with the alkenyl carbene complexes (vide supra), we
began to investigate the methoxy phenyl carbene complex
25 in the benzannulation of our alkynylglycosides. De-
spite the potential problems, the methoxy phenyl carbene
complex 25 reacts with alkynylglycoside 14 to give the
desired naphthol 26 as a single regioisomer in 62% yield
as the acetate (eq 3). Encouraged by this initial result
Annulations with carbene complex 11 complement the
annulations of complexes 7 and 8 in that the TMS group
is now positioned ortho to the methoxy group instead of
the phenol derived from CO. This regiochemistry is
we pursued the reaction of 25 with alkynylglycosides 12
and 15. However, except for 14, these reactions were
problematic, yielding only limited amounts of the desired
(21) Wulff, W. D.; Chan, K.-S.; Tang, P.-C. J . Org. Chem. 1984, 49,
2293.

5278 J . Org. Chem., Vol. 63, No. 15, 1998
Notes
naphthols. 1H NMR analysis of the crude reaction
mixtures indicated the presence of furan and indene side
products; however, these were not isolated to verify this
point.16 Apparently, the oxygen-substituted eneyne func-
tionality of 14 balances the steric and electronic effects
in the Do¨tz benzannulation to favor formation of the
desired naphthol product. We are currently investigating
the generality of C-alkynylglycals such as 14 in their
reaction with arylcarbene complexes in an effort to
achieve a convergent approach to C-arylglycosides.
In conclusion, we have shown that C-arylglycosides are
available via two complementary approaches utilizing the
Do¨tz benzannulation reaction between Fischer alkenyl
chromium carbene complexes and alkynes. We envisage
that both the phenols and the quinones will allow for
further elaboration of the aromatic moiety of these
molecules. Optimization of the convergent naphthol
approach and application of the methodology to synthetic
efforts are in progress.
1.8 mmol), TiCl4 (0.20 mL, 1.8 mmol), methyl(methoxy)chro-
mium carbene anion (150 mg, 0.6 mmol), pyridine (0.25 mL, 3.1
mmol), and 2 g of dry SiO2 were reacted. The glycosylated
carbene 7 was treated with (trimethylsilyl)acetylene (0.25 mL,
1.8 mmol). The solution was degassed, heated under argon to
55 °C, and stirred for 22 h. Subsequent air oxidation, acetyla-
tion, and purification by radial chromatography (5-10% EtOAc/
hexane) gave 37 mg (19%) of 9 as a single regioisomer: Rf )
0.47 (15% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 6.96
(d, J ) 3.1 Hz, 1H), 6.92 (d, J ) 3.1 Hz, 1H), 5.07 (t, J ) 3.9 Hz,
1H), 4.10 (t, J ) 5.1 Hz, 2H), 3.80 (s, 3H), 2.24 (s, 3H), 2.17 (m,
2H), 1.8 (m, 2H), 0.26 (s, 9H); 13C NMR (125.8 MHz, CDCl3) δ
169.44, 156.64, 150.72, 145.85, 133.93, 130.48, 120.64, 114.77,
100.99, 66.55, 55.51, 22.12, 21.19, 20.80, -0.80; IR (neat) 2956,
2847, 1766, 1658, 1581, 1428, 1176 cm-1; HRMS (EI) m/z calcd
for C17H24O4Si 320.1444, found 320.1445.
1-O-Acetyl-2-(2′-d eoxy-3′,4′,6′-tr i-O-t-bu tyld ip h en ylsilyl-
1′-D-glu ca l)-4-m eth oxy-6-tr im eth ylsilylben zen e (10). Fol-
lowing general procedure A, 6 (232 mg, 0.216 mmol), BF3‚Et2O
(0.027 mL, 0.216 mmol), and methyl(methoxy)chromium carbene
anion (33 mg, 0.131 mmol) in 2.5 mL of THF were reacted. In
this case the reaction mixture was quenched after 15 min with
a pH 7 buffer and extracted with ether (2 × 10 mL). The
combined organic layers were dried over MgSO4, and concentra-
tion gave an orange oil that was dissolved in ether and stirred
with dry SiO2 (2 g). The glycosylated carbene 8 was treated with
(trimethylsilyl)acetylene (0.055 mL, 0.393 mmol). This solution
was degassed, heated under argon to 55 °C, and stirred for 28
h. Subsequent air oxidation, acetylation, and purification by
radial chromatography (5% EtOAc/hexane) gave 26 mg (20%)
of 10 as a single regioisomer: Rf ) 0.36 (5% EtOAc/hexanes);
1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 6H), 7.45-7.17 (m,
24H), 6.95 (m, 2H), 4.89 (dd, J ) 5.5, 1.3 Hz, 1H), 4.41-4.38
(m, 1H), 4.19 (dd, J ) 11.5, 7.8 Hz, 1H), 4.06 (d, J ) 1.7 Hz,
1H), 3.92-3.90 (m, 1H), 3.83 (dd, J ) 11.5, 4.3 Hz, 1H), 3.66 (s,
3H), 1.91 (s, 3H), 1.00 (s, 9H), 0.92 (s, 9H), 0.75 (s, 9H), 0.24 (s,
9H); 13C NMR (125.8 MHz, CDCl3) δ 169.65, 161.67, 148.02,
141.36, 135.74, 135.72, 135.64, 135.63, 135.55, 135.50, 133.73,
133.67, 133.50, 133.48, 133.39, 133.23, 130.85, 129.76, 129.66,
129.59, 129.56, 129.51, 129.48, 129.15, 127.63, 127.57, 127.56,
127.48, 110.14, 100.36, 80.52, 69.74, 66.15, 62.33, 55.36, 26.87,
26.74, 20.75, 19.17, 19.15, 18.88, -1.17; IR (neat) 3071, 3052,
Exp er im en ta l Section
Gen er a l. All air- or moisture-sensitive reactions were carried
out in oven-dried (at 120 °C) or flame-dried glassware under an
argon atmosphere. Solvents were degassed and purified by
distillation under nitrogen from standard drying reagents. Flash
chromatography was carried out using 230-400 mesh silica gel
with technical grade solvents distilled prior to use. Radial
chromatography was performed on plates prepared from silica
gel 60 with PF254 indicator. NMR chemical shifts are reported
in δ vs Me4Si assigning the CDCl3 resonance in 13C spectra to
be at 77.00 ppm. Elemental analyses were performed by
M-H-W Laboratories (Phoenix, AZ). High-resolution mass
spectra were obtained in-house or from Washington University
Resource for Biomedical/Bio-organic Mass Spectrometry (St.
Louis, MO). Compounds 5,18b 11,22 12,15 14,11 16,23 17,24 18,25
and 2526 were all prepared from literature procedures.
Gen er a l Ben za n n u la tion P r oced u r e A. To a THF (0.2 M)
solution of methyl(methoxy)chromium carbene (1.0 equiv), at
-78 °C, was added n-BuLi (1.0 equiv), and the mixture stirred
for 20 min. This solution was cannulated to a CH2Cl2 (0.2 M)
solution of a 1:1 complex of the aldehyde and Lewis acid (3.0
equiv) at -78 °C. Reaction progress was monitored by TLC, and
when starting carbene was consumed, dry pyridine (5 equiv) was
added dropwise. After stirring for 45 min, SiO2 (1 g/100 mg
carbene) was added and the mixture stirred for another 15 min.
The reaction was filtered through Celite and the filtrate washed
with water. The organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure to give the glycosy-
lated carbene as a red/orange oil. This crude carbene complex
was dissolved in THF (0.05 M) and TMS-acetylene (4 equiv) was
introduced. The solution was freeze-thaw-degassed (-196 to
25 °C, three cycles) and then heated to 55 °C and stirred under
positive argon pressure. When the starting carbene was con-
sumed (TLC) the reaction flask was cooled to room temperature
and subsequently stirred in the open air for 0.5 h. Removal of
the solvent under reduced pressure and redissolving in CH2Cl2
(0.1 M based on starting carbene) preceded the treatment with
Ac2O (2 equiv), pyridine (2 equiv), and a catalytic amount of
DMAP. The reaction mixture was stirred at room temperature
(16-24 h) until acetylation was complete. The crude reaction
was filtered through Celite, and solvents were removed under
reduced pressure. Chromatography by standard methods on
silica gel gave the pure acetylated phenols.
2960, 2933, 2895, 2859, 1657, 1607, 1478, 1769, 1210, 1116 cm-1
;
[R]20 -80.3° (c ) 0.66, CH2Cl2); HRMS m/z calcd for C66H80O7-
D
Si4 1096.4981, found 1096.4979.
Gen er a l Ben za n n u la tion P r oced u r e B. A Schlenk reac-
tion vessel was charged with the carbene complex and C-
alkynylglycoside and diluted with THF to make the concentra-
tion 0.05 M (based on carbene). The solution was freeze-thaw-
degassed (-196 to 25 °C, three cycles) and the reaction vessel
filled with dry argon. The reaction mixture was heated to 55
°C while being stirred under positive argon pressure. When the
starting carbene was consumed (TLC, 16-36 h), the reaction
flask was cooled to room temperature and stirred in the open
air for 0.5 h. The solvent was removed under reduced pressure
and the residue dissolved in CH2Cl2 (0.1 M based on starting
carbene), treated with Ac2O (2 equiv), pyridine (2 equiv), and a
catalytic amount of DMAP, and stirred under argon at room
temperature (16-24 h). The crude reaction was filtered through
Celite, and were solvents removed under reduced pressure.
Chromatography on silica gel gave the pure acetylated phenols.
1-O-Acetyl-2-(4′,6′-d i-O-a cetyl-2′,3′-d id eoxy-r-D-er yth r o-
h ex-2-en op yr a n osyl)-4-m et h oxy-5-t r im et h ylsilylb en zen e
(19). Following general procedure B, 12 (120 mg, 0.50 mmol),
11 (152 mg, 0.46 mmol), THF (1 mL), 55 °C for 24 h, air
oxidation, acetylation, and radial chromatography (25% EtOAc/
hexane) gave 134 mg (59%) of 19: Rf ) 0.5 (33% EtOAc/hexanes);
1H NMR (250 MHz, CDCl3) δ 7.01 (s, 1H), 6.85 (s, 1H), 6.12-
5.98 (m, 2H), 5.39 (dd, J ) 3.8, 1.9 Hz, 1H), 5.30-5.26 (m, 1H),
4.34 (dd, J ) 12.0, 5.7 Hz, 1H), 4.03 (dd, J ) 12.0, 3.4 Hz, 1H),
3.92 (ddd, J ) 9.6, 3.4, 3.4 Hz, 1H), 3.81 (s, 3H), 2.30 (s, 3H),
2.09 (s, 3H), 2.07 (s, 3H), 0.25 (s, 9H); 13C NMR (62.9 MHz,
CDCl3) δ 170.73, 170.32, 170.07, 161.70, 142.60, 132.14, 131.18,
129.98, 129.17, 125.10, 110.00, 70.04, 69.02, 64.75, 62.39, 55.47,
21.00, 20.88, 20.75, -1.22; IR (neat) 2958, 2905, 1747, 1607,
1465, 1371, 1239 cm-1; HRMS (EI) m/z calcd for C22H30O8Si
1-O-Acetyl-2-(1′-d ih yd r op yr a n yl)-4-m eth oxy-6-tr im eth -
ylsilylben zen e (9). Following general procedure A, 5 (200 mg,
(22) Wulff, W. D.; Bax, B. Tetrahedron 1993, 49, 5531.
(23) Lancelin, J .-M.; Zollo, P. H. A.; Sinay¨, P. Tetrahedron Lett. 1983,
24, 4833. Vasella, A.; Alzeer, J . Helv. Chim. Acta 1995, 78, 177.
(24) Rollin, P.; Sinay¨, P. Carbohydr. Res. 1981, 98, 139.
(25) Benhaddou, R.; Czernecki, S.; Farid, W.; Ville, G.; Xie, J .; Zegar,
A. Carbohydr. Res. 1994, 260, 243.
(26) Fischer, E. O.; Aumann, R. Chem. Ber. 1968, 101, 960.
450.1710, found 450.1728; [R]20 -30.0° (c ) 2.28, CH2Cl2).
D

Notes
1-O-Acet yl-2-(4′,6′-d i-O-b en zyl-3′-d eoxy-1′-D-glu ca l)-4-
J . Org. Chem., Vol. 63, No. 15, 1998 5279
) 11.9 Hz, 1H), 4.49 (m, 2H), 4.22 (d, J ) 9.5 Hz, 1H), 3.95 (d,
J ) 10.5 Hz, 1H), 3.89-3.82 (m, 2H), 3.80-3.70 (m, 3H), 3.66
(s, 3H), 3.49-3.47 (m, 1H), 2.16 (s, 3H), 0.27 (s, 9H); 13C NMR
(125.8 MHz, CDCl3) δ 170.13, 161.66, 142.58, 138.60, 138.28,
138.09, 137.57, 131.85, 129.69, 129.56, 128.50, 128.47, 128.43,
128.31, 128.11, 127.89, 127.83, 127.75, 127.69, 127.64, 127.56,
111.20, 86.98, 81.59, 80.16, 79.32, 78.00, 75.82, 75.10, 74.81,
73.49, 68.92, 55.31, 21.00, -1.17, -1.18; IR (neat) 3089, 3034,
m eth oxy-5-tr im eth ylsilylben zen e (20). Following general
procedure B, 13 (50 mg, 0.15 mmol), 11 (45 mg, 0.14 mmol), THF
(1 mL), 55 °C for 24 h, air oxidation, acetylation, and radial
chromatography (5%EtOAc/hexane) gave 41 mg (53%) of 20: Rf
) 0.2 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.35-
7.27 (m, 10H), 6.94 (s, 1H), 6.89 (s, 1H), 5.06 (dd, J ) 5.0, 3.0
Hz, 1H), 4.68-4.57 (m, 4H), 4.03 (ddd, J ) 12.5, 8.1, 3.9 Hz,
1H), 3.90-3.85 (m, 3H), 3.75 (s, 3H), 2.52 (ddd, J ) 17.1, 5.5,
5.5 Hz, 1H), 2.26 (ddd, J ) 17.1, 8.3, 3.0 Hz, 1H), 2.18 (s, 3H),
0.23 (s, 9H); 13C NMR (125.8 MHz, CDCl3) δ 169.95, 161.69,
149.45, 141.14, 138.29, 138.27, 130.40, 129.60, 128.98, 128.38,
128.30, 127.70, 127.68, 127.52, 109.86, 98.49, 77.76, 73.51, 71.24,
70.25, 69.20, 55.41, 27.91, 20.98, -1.19; IR (neat) 3031, 2956,
2902, 2864, 1763, 1603, 1397, 1372, 1207, 1177 cm-1; HRMS
2956, 2904, 2865, 1766, 1610, 1457, 1368, 1199, 1069 cm-1; [R]20
D
-4.70° (c ) 2.00, CH2Cl2). Anal. calcd for C46H52O8Si C, 72.60;
H, 6.89. Found: C, 72.56; H, 6.76.
2-(4′,6′-d i-O-a cet yl-2′,3′-d eoxy-r-D-er yth r o-h ex-2-en op y-
r a n osyl)-5-tr im eth ylsilyl-1,4-ben zoqu in on e (24). Following
general procedure B, 12 (260 mg, 1.09 mmol), 11 (331 mg, 0.991
mmol), and THF (20 mL) were freeze-thaw-degassed and then
reacted at 55 °C for 18 h. Upon completion of the reaction (TLC),
7.0 mL of CAN (3.5 mmol, 0.5 M in HNO3) was added and
stirring continued for 0.5 h at room temperature. The reaction
mixture was diluted with brine and extracted with Et2O (2 ×
20 mL), and the combined organic layers were dried over MgSO4.
The volatiles were removed under reduced pressure followed by
flash chromatography (25% EtOAc/hexane) to give 228 mg (61%)
(EI) m/z calcd for C32H38O6Si 546.2438, found 546.2409; [R]20
92.1° (c ) 0.33, CH2Cl2).
D
1-O-Acet yl-2-(3′,4′,6′-t r i-O-t-b u t yld ip h en ylsilyl-1′-D-glu -
cal)-4-m eth oxy-5-tr im eth ylsilylben zen e (21). Following gen-
eral procedure B, 14 (51 mg, 0.057 mmol), 11 (18 mg, 0.054
mmol), THF (1 mL), 55 °C for 24 h, air oxidation, acetylation,
and radial chromatography (2% EtOAc/hexane) gave 33 mg
(56%) of 21: Rf ) 0.42 (5% EtOAc/hexane); 1H NMR (250 MHz,
CDCl3) δ 7.58-7.15 (m, 30H), 6.96 (s, 2H), 4.89 (dd, J ) 5.4,
1.4 Hz, 1H), 4.39 (m, 1H), 4.19 (dd, J ) 11.3, 7.7 Hz, 1H), 4.07
(d, J ) 1.7 Hz, 1H), 3.92 (m, 1H), 3.83 (dd, J ) 11.3, 4.2 Hz,
1H), 3.66 (s, 3H), 1.91 (s, 3H), 1.01 (s, 9H), 0.92 (s, 9H), 0.75 (s,
9H), 0.24 (s, 9H); 13C NMR (62.9 MHz, CDCl3) δ 169.61, 161.68,
148.04, 141.38, 135.73, 135.64, 135.54, 135.50, 133.74, 133.68,
133.52, 133.50, 133.41, 133.25, 130.85, 129.76, 129.65, 129.55,
129.50, 129.15, 127.62, 127.57, 127.48, 110.16, 100.37, 80.54,
69.76, 66.17, 62.35, 55.37, 26.88, 26.75, 20.74, 19.16, 18.87,
-1.17; IR (neat) 3073, 2961, 2930, 2860, 1757, 1433, 1210, 1117
cm-1; [R]20D -65.2° (c ) 1.46, CH2Cl2). Anal. calcd for C66H80O7-
Si4 C, 72.22; H, 7.35. Found: C, 71.99; H, 7.53.
1
of 24 as a deep orange oil: Rf ) 0.62 (25% EtOAc/hexanes); H
NMR (250 MHz, CDCl3) δ 6.88 (m, 2H), 6.13 (ddd, J ) 10.4, 2.9,
1.5 Hz, 1H), 5.93 (ddd, J ) 10.4, 2.7, 2.7 Hz, 1H), 5.33 (ddd, J )
6.6, 4.4, 2.3 Hz, 1H), 5.19 (m, 1H), 4.31-4.18 (m, 2H), 3.97 (ddd,
J ) 10.5, 4.0, 4.0 Hz, 1H), 2.13 (s, 3H), 2.09 (s, 3H), 0.25 (s, 9H);
13C NMR (62.9 MHz, CDCl3) δ 190.90, 185.93, 170.63, 170.18,
152.35, 144.47, 143.55, 133.39, 129.21, 125.64, 70.85, 68.06,
64.56, 62.69, 20.92, 20.73, -1.84; IR (neat) 2961, 2905, 1747,
1656, 1586, 1368, 1242 cm-1; HRMS (EI) m/z calcd for C19H24O7-
Si 392.1291, found 392.1234; [R]20 -49.1° (c ) 1.64, CH2Cl2).
D
1-O-Acet yl-2-(3′,4′,6′-t r i-O-t-b u t yld ip h en ylsilyl-1′-D-glu -
ca l)-4-m eth oxyn a p h th a len e (26). Following general proce-
dure B, 14 (60 mg, 0.068 mmol), 25 (18 mg, 0.058 mmol), THF
(1 mL), 55 °C for 36 h, air oxidation, acetylation, and flash
chromatography (5% EtOAc/hexane) gave 42.5 mg (62%) of 26:
1-O-Acetyl-2-(2′-d eoxy-3′,4′,6′-tr i-O-t-bu tyld ip h en ylsilyl-
1′-â-D-glu cose)-4-m eth oxy-5-tr im eth ylsilylben zen e (22). Fol-
lowing general procedure B, 15 (65 mg, 0.073 mmol), 11 (22 mg,
0.066 mmol), THF (1.3 mL), 55 °C for 22 h, air oxidation,
acetylation, and radial chromatography (5% EtOAc/hexane) gave
23 mg (32%) of 22 as a 7:1 mixture of anomers enriched during
chromatography. The anomeric ratio was determined by inte-
gration of the methyl resonance of the acetate at 2.26 ppm for
the minor and 2.12 ppm for the major. The following data is
for the major â anomer: Rf ) 0.28 (5% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3) δ 7.70-7.16 (m, 30H), 6.88 (s, 1H), 6.85 (s,
1H), 4.70 (dd, J ) 10.6, 4.2 Hz, 1H), 4.19 (dd, J ) 11.1, 5.5 Hz,
1H), 4.02 (appt, J ) 4.4 Hz, 1H), 3.96-3.92 (m, 1H), 3.78 (dd, J
) 10.5, 6.3 Hz, 1H), 3.63 (dd, J ) 10.5, 4.3 Hz, 1H), 3.55 (s, 3H),
2.12 (s, 3H), 2.03 (ddd, J ) 13.9, 6.0, 4.2 Hz, 1H), 1.64 (ddd, J
) 16.0, 10.7, 5.5 Hz, 1H), 0.96 (m, 18H), 0.77 (s, 9H), 0.23 (s,
9H); 13C NMR (125.8 MHz, CDCl3) δ 169.64, 162.17, 140.51,
136.71, 135.81, 135.73, 135.68, 135.66, 135.42, 134.37, 134.03,
133.73, 133.67, 133.62, 129.60, 129.36, 129.33, 129.30, 127.98,
127.85, 127.61, 127.57, 127.53, 127.44, 127.41, 107.78, 82.87,
72.54, 71.95, 68.59, 65.48, 55.34, 38.55, 31.59, 27.00, 26.92, 26.83,
22.65, 20.89, 19.37, 19.22, 18.97, 11.71, -1.14; IR (neat) 3073,
1
Rf ) 0.32 (10% EtOAc/hexanes); H NMR (250 MHz, CDCl3) δ
8.23-8.19 (m, 1H), 7.72-7.69 (m, 1H), 7.61-7.16 (m, 32H), 6.92
(s, 1H), 4.99 (d, J ) 4.9 Hz, 1H), 4.44-4.41 (m, 1H), 4.28 (dd, J
) 11.3, 7.9 Hz, 1H), 4.08 (s, 1H), 4.01-3.98 (m, 1H), 3.86-3.81
(m, 4H), 2.07 (s, 3H), 1.02 (s, 9H), 0.94 (s, 9H), 0.76 (s, 9H); 13
C
NMR (62.9 MHz, CDCl3) δ 169.40, 153.03, 148.37, 137.59,
135.76, 135.67, 135.56, 135.51, 133.74, 133.66, 133.51, 133.41,
133.26, 129.68, 129.58, 129.53, 128.00, 127.65, 127.60, 127.50,
127.09, 126.23, 125.95, 125.56, 122.23, 121.73, 103.88, 100.96,
80.63, 69.91, 66.32, 62.34, 55.59, 32.59, 26.89, 26.78, 22.65, 20.60,
19.19, 18.89, 14.11; IR (neat) 3071, 2960, 2932, 2894, 1771, 1657,
1599, 1462, 1430, 1111 cm-1; HRMS m/z calcd for C67H74O7Si3
1074.4742, found 1074.4721; [R]20 -63.5° (c ) 1.39, CH2Cl2).
D
Ack n ow led gm en t. This work has been supported
by the University of MissourisColumbia, and acknowl-
edgment is made to the donors of the Petroleum
Research Fund, administered by the ACS, for partial
support of this research.
2960, 2933, 2860, 1765, 1609, 1477, 1430, 1200, 1114 cm-1
;
HRMS m/z calcd for C66H82O7Si4 1098.5138, found 1098.5136.
1-O-Acet yl-2-(2′,3′,4′,6′-t et r a -O-b en zyl-1′-â-D-glu cose)-4-
m eth oxy-5-tr im eth ylsilyl ben zen e (23). Following general
procedure B, 16 (163 mg, 0.297 mmol), 11 (90 mg, 0.27 mmol),
THF (1 mL), 55 °C for 16 h, air oxidation, acetylation, and radial
chromatography (5% EtOAc/hexane) gave 111 mg (54%) of 23:
Rf ) 0.32 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ
7.38-7.14 (m, 18H), 7.02 (s, 1H), 6.85 (s, 1H), 6.84 (s, 1H), 6.71
(s, 1H), 4.97-4.90 (m, 3H), 4.69 (d, J ) 10.7 Hz, 1H), 4.58 (d, J
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for compounds 6, 13, and 15 and H/ 13C NMR spectra
of compounds 6, 9, 10, 13, 15, 19, 20, 22, 24, and 26 (23 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1
J O980442H