Discovery of the tungsten carbonyl-catalyzed endo-selective alkynyl alcohol cycloisomerization reaction: Applications to stereoselective syntheses of D-olivose, D-olivose disaccharide substructures of landomycin and mithramycin

Article abstract of DOI:10.1016/S0022-328X(00)00643-4

An account of the discovery of the tungsten carbonyl-catalyzed endo-selective cycloisomerization of alkynyl alcohols to dihydropyrans is described. The utility of this new chemical transformation involving tungsten vinylidene catalytic intermediates is de

Full text of DOI:10.1016/S0022-328X(00)00643-4

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 617–618 (2001) 444–452
Discovery of the tungsten carbonyl-catalyzed endo-selective alkynyl
alcohol cycloisomerization reaction: applications to stereoselective
syntheses of
D-olivose,
D-olivose disaccharide substructures of
landomycin and mithramycin
Frank E. McDonald *, K. Subba Reddy
Department of Chemistry, Emory Uni6ersity, 1515 Pierce Dri6e, Atlanta, GA 30322, USA
Received 28 July 2000; accepted 11 September 2000
Abstract
An account of the discovery of the tungsten carbonyl-catalyzed endo-selective cycloisomerization of alkynyl alcohols to
dihydropyrans is described. The utility of this new chemical transformation involving tungsten vinylidene catalytic intermediates
is demonstrated in stereoselective syntheses of disaccharide substructures 26–28 of the landomycin and mithramycin families of
anticancer antibiotics. © 2001 Elsevier Science B.V. All rights reserved.
Keywords: Alkynyl alcohols; Tungsten vinylidenes; Carbohydrate glycals; Disaccharide synthesis
1. Introduction
2. Results and discussion
The interface of organic chemistry with inorganic
chemistry has resulted in the invention of many new
synthetic methods, which in turn have supported the
exploration and application of novel synthetic strategies
for constructing many classes of biologically active
organic compounds. We recently reported the first
examples of a transition-metal catalyzed endo-selec-
tive cycloisomerization reaction in which 5-hydroxy-1-
alkynes are efficiently converted into 3,4-dihydro-2H-
pyrans [1]. Herein we provide a more detailed account
of the discovery of this catalytic transformation which
involves the intermediacy of tungsten vinylidene com-
plexes, and a discussion of our most recent applications
of this novel transformation in the stereoselective
preparation of arabino, arabino-disaccharide substruc-
tures of the anticancer antibiotics landomycin and
mithramycin.
2.1. Early work on alkynol cycloisomerization
In late 1992 we discovered that simple homopropar-
gylic alcohols underwent efficient cycloisomerization to
2,3-dihydrofuran products upon catalytic reaction with
(Et3N)Mo(CO)5 [2]. Over the next few years we opti-
mized this reaction for the preparation of variously
substituted dihydrofurans including compounds 2 and 6
(Scheme 1), and successfully applied this novel transfor-
mation to short syntheses of the biologically active
nucleoside compounds d4T 3 [3], cordycepin 4 [3], and
puromycin aminonucleoside 7 [4].
Although the molybdenum-catalyzed process was not
generally effective for the formation of six-membered
ring products from the corresponding acyclic alkynyl
alcohols [5], in mid-1995 we observed that six-mem-
bered ring products could be formed via a stoichiomet-
ric, tungsten-promoted two-step process [6]. The
reaction sequence required one to three equivalents of
W(CO)6, isolation of the stoichiometric tungsten ox-
acarbene, and conversion of this oxacarbene intermedi-
ate to the endocyclic enol ether by reaction with a
tertiary amine base. The yields for this process rarely
* Corresponding author. Tel.: +1-404-7276102; fax: +1-404-
7276586.
E-mail address: fmcdona@emory.edu (F.E. McDonald).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00643-4

F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
445
Scheme 1.
exceeded 50%, with the modest overall yield of 32%
reported for the two-step conversion of alkynyl alcohol
8 to the moderately functionalized dihydropyran 10 as
a representative example [7] (Scheme 2). Pure samples
of tungsten oxacarbene intermediates such as 9 could
be converted into the corresponding enol ether in
nearly quantitative yield, indicating that the first step to
form the stoichiometric oxacarbene 9 was the problem-
atic transformation in this synthesis. Our initial at-
tempts to combine base-promoted enol ether formation
with the tungsten-promoted alkynyl alcohol cyclization
as a single-step cycloisomerization transformation were
unsuccessful, as the isolated reagent (Et3N)W(CO)5 was
reported to be inert to simple alkynyl alcohol substrates
[8].
reaction was extremely slow and some starting material
11 was still present after 48 h at room temperature. The
1
tungsten oxacarbene 12 could be observed by H-NMR
analysis of an aliquot, but was usually not isolated and
instead the THF solution of unpurified oxacarbene 12
was directly treated with Et3N to provide the glycal 13.
We subsequently discovered that the cyclization reac-
tion of 11 to 12 could be pushed to completion by
heating the reaction mixture to the reflux point of THF
(ca. 65°C). Even better results were obtained when we
photolyzed W(CO)6 in the presence of the alkynyl
alcohol substrate 11 with heating, and the isolated
yields of glycal 13 produced by this stoichiometric
tungsten-promoted procedure were consistently in the
40–45% range, with the first step to tungsten oxacar-
bene 12 judged as the low-yielding operation (Scheme
3).
As the alkynyl alcohol substrate 11 and tungsten
oxacarbene 12 were observed to be compatible with 350
nm irradiation, we reexplored the idea of a single-step
conversion of compound 11 to cycloisomeric product
glycal 13 by irradiating W(CO)6 and substrate 11 in the
presence of triethylamine, and were gratified to find
2.2. Disco6ery of the tungsten-catalyzed
cycloisomerization at Emory Uni6ersity
We commenced further explorations in this area with
studies of a more highly functionalized substrate 11 in
early 1999. Stoichiometric tungsten-promoted cycliza-
tion of 11 afforded the tungsten oxacarbene 12, but the
Scheme 2.
Scheme 3.

446
F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
working the catalytic loading in the presence of excess
DABCO, we have observed that as little as 10 mol% of
W(CO)6 is sufficient for high-yield cycloisomerization
of 11 to 13 within 6 h provided the reaction tempera-
ture is maintained above 50°C while under continuous
irradiation at 350 nm. W(CO)6 loading below 10 mol%
requires significantly longer reaction times and/or result
in incomplete conversion of alkynyl alcohol substrate.
The mechanism of the catalytic cycloisomerization
transformation probably involves the intermediacy of
the tungsten vinylidene 14, followed by intramolecular
nucleophilic addition of the hydroxyl group to provide
the carbene anion 15 and protonation to afford the
product dihydropyran 13. Note that this mechanism
does not require the neutral oxacarbene 12 as a cata-
lytic intermediate when the reaction is conducted under
basic conditions.
Scheme 4.
2.3. Stereoselecti6e glycosylations and iterati6e
cycloisomerizations in the D-oli6ose series
We previously reported that 2,6-dideoxy glycals of
arabino configuration 16 could be stereoselectively con-
verted into the b-gluco-iodoacetate configuration 17
upon reaction with N-iodosuccinimide (NIS) and acetic
acid, provided that the C3 and C4 oxygen substituents
were substituted with sterically bulky protective groups
such as tert-butyldiphenylsilyl (TBDPS) ethers so that
Scheme 5.
5
reaction from a H4 conformation was preferred [1]. In
contrast, the sterically smaller tert-butyldimethylsilyl
(TBS) ether analog provides a nearly 1:1 mixture of
diastereomeric iodoacetates 17 and 18 under identical
reaction conditions [9] (Scheme 5).
Recognizing that 3-O-linked and 4-O-linked D-
olivose-b-D-olivose disaccharide substructures are
present in the landomycin [10], mithramycin [11], and
olivomycin [12] anticancer natural products, we ini-
tiated a test of our iterative cycloisomerization/glycosy-
lation strategy [1,7] for oligosaccharide synthesis with
these targets in mind. TBSOTf-catalyzed reaction [13]
of the iodoacetate 17 (R=TBDPS) [1,10c] with the
alkynyl diol 19 [1] afforded regioselective glycosylation
of the less hindered propargylic alcohol to provide a
single glycoside 20 (Scheme 6). Preparation of the re-
gioisomeric glycoside 22 required monoprotection of
the propargylic alcohol of diol 19. Although the instal-
lation of a tert-butyldiphenylsilyl protective group did
not exhibit the same level of regioselectivity observed in
the previously described glycosylation with 19, the re-
quired compound 21 could be obtained as the major
silyl ether product in 56% isolated yield. The glycosyla-
tion of iodoacetate 17 (R=TBDPS) and the hindered
secondary alcohol of 21 proceeded better when the
more reactive TMSOTf was used as the glycosylation
catalyst, affording 22 as a single isomer.
Scheme 6.
that near-quantitative isolated yields of the glycal
product 13 were obtained with only 25 mol% of tung-
sten hexacarbonyl (Scheme 4). Control experiments
have demonstrated that continuous irradiation is re-
quired in order to effectively regenerate the
(Et3N)W(CO)5 species, which is attributed to be the
active
transformation.
catalyst
for
this
cycloisomerization
This catalytic protocol is perfectly suitable for small-
scale operations, but on larger scales, (\1 mmol) we
observe that the observed glycal product is accompa-
nied by partial recovery of starting alkynyl alcohol
substrate. We have subsequently explored the use of
other tertiary amine co-reagents, and sublimed 1,4-diaz-
abicyclo[2.2.2]octane (DABCO) is currently the base of
choice of the cycloisomerization transformation. In re-

F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
447
ation required for W(CO)6 catalyzed cycloisomerization
to construct the disaccharide glycals. The b-4-O-linked
disaccharide glycal 26 corresponds with the configura-
tion of both D-olivose-D-olivose disaccharide substruc-
tures of landomycin A, 29 (Scheme 8), and our
synthetic b-3-O-linked disaccharide glycals 27–28 cor-
relate with the D-olivose-O-3-D-olivose disaccharide of
mithramycin, 30.
Reductive removal of the benzoyl protective group
from 22 afforded the corresponding alkynyl alcohol
substrate 23, which efficiently underwent W(CO)6-cata-
lyzed cycloisomerization to provide the corresponding
4-O-linked disaccharide glycal 26 (Scheme 7). Silylation
of the free hydroxyl group in glycoside 20 with either
TBDPSCl or TBSCl and reductive debenzoylation gave
the alkynyl alcohol substrates 24 and 25, which af-
forded the regioisomeric 3-O-linked disaccharide gly-
cals 27–28 upon W(CO)6 catalyzed cycloisomerization.
For the preparation of glycals 26 and 27, we found that
the cycloisomerization reaction proceeded much better
when DABCO was used instead of triethylamine. Note
that the potentially light-sensitive iodide substituents of
23–25 are compatible with the continuous photo-irradi-
3. Conclusions
These results demonstrate the efficacy of the W(CO)6
catalyzed endo-selective alkynyl alcohol cycloisomeriza-
tion reaction in the synthesis of functionally and stereo-
Scheme 7.
Scheme 8.

448
F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
chemically complex organic compounds, exemplified by
the effective construction of the disaccharide glycals
26–28. Notable features include the compatibility with
sensitive functional groups, including glycoside link-
ages, silyl ethers, and iodide substituents. This method
has been applied to the stereoselective synthesis of
disaccharide substructures of the landomycin and
mithramycin families of antitumor antibiotic natural
products. Applications of this methodology to the total
synthesis of various families of natural products are in
progress.
mmol, dried under vacuum) and alkynol substrate 11
(150 mg, 0.42 mmol, azeotropically dried twice from
toluene). The mixture was dissolved in freshly distilled
dry THF (2 ml) and triethylamine (0.5 ml). The solu-
tion was irradiated under argon atmosphere for 5 h at
350 nm (Rayonet photoreactor) without cooling, so
that the solvent reflux point was reached. Volatile com-
ponents were removed under reduced pressure, and the
product was purified by silica gel chromatography us-
ing an eluent mixture of pentane–triethylamine (99:1)
to afford the product glycal 13 (147 mg, 98%).
4.2.3. Procedure C: catalytic single-step
cycloisomerization, with DABCO and 10 mol%
W(CO)6
4. Experimental
The procedure is essentially the same as procedure B
(Section 4.2.2) except sublimed DABCO and 10 mol%
W(CO)6 were utilized. Thus a mixture of alkynol 11
(716 mg, 2 mmol), W(CO)6 (70 mg, 0.2 mmol, 10
mol%), DABCO (448 mg, 4 mmol), and THF (10 ml)
was irradiated under argon for 6 h at a temperature of
50–60°C. The solvent was then removed to give the
crude product mixture, which was purified by SiO2
(pretreated with 2.5% v/v Et3N) column chromatogra-
phy (n-hexanes eluent) to afford glycal 13 (680 mg,
95%) as a colorless liquid, which solidified to a white
solid upon standing. M.p. 38–40°C; [a]2D3 +231
(CHCl3, C=1.66); IR (KBr) 3037, 2957, 2930, 2858,
4.1. General information
See Ref. [1].
4.2. Cycloisomerization of alkynyl alcohol (11) to
D-ribo-2,6-dideoxyglycal (13)
4.2.1. Procedure A: stoichiometric two-step
cycloisomerization
An oven-dried 50 ml Schlenk flask was fitted with a
reflux condenser and a magnetic stir bar, under a
nitrogen atmosphere, and was charged with tungsten
hexacarbonyl (320 mg, 0.91 mmol, dried under vac-
uum), THF (10 ml), and the alkynyl alcohol 11 (296
mg, 0.827 mmol). The mixture was photolyzed for 5 h
at 350 nm (Rayonet photoreactor) without external
cooling so that the reaction temperature reached the
reflux point (approximately 65°C). The crude oxacar-
bene–THF solution (yellow color) was cooled to 0°C,
freshly distilled Et3N (1 ml) was added, and the reac-
tion mixture was allowed to warm to room temperature
(r.t.) while stirring for 4 h. The reaction mixture was
then concentrated in vacuo, and purified by flash chro-
matography with silica which was pretreated 2.5% v/v
with Et3N, to provide the glycal 13 (118 mg, 40% yield).
A sample of the tungsten oxacarbene intermediate 12
was isolated by silica gel column chromatography (gra-
dient elution, pure pentane to 19:1 pentane–Et2O) as a
1
1642, 1256, 1141, 1127, 1088, 999, 903 cm−1; H-NMR
(400 MHz, CDCl3): l 6.28 (app. d, J=6.0 Hz, 1H),
4.76 (app. t, J=6.0 Hz, 1H), 4.12 (dq, J=8.1, 3.0 Hz,
1H), 3.98 (dd, J=6.0, 3.2 Hz, 1H), 3.50 (dd, J=9.6,
3.3 Hz, 1H), 1.28 (d, J=6.0 Hz, 1H), 0.91 (s, 9H), 0.88
(9H), 0.08 (s, 6H), 0.063 (s, 3H), 0.06 (s, 3H); 13C-NMR
(100 MHz, CDCl3): l 145.0, 102.3, 73.8, 70.5, 64.5,
26.0, 18.2, 18.1, −3.3, −3.6, −4.1, −4.1, −4.6;
HRMS (FAB+) Anal. Calc. for C18H38LiO3Si2 [(M+
Li)+] 365.2520. Found 365.2505. Anal. Calc. for
C18H38O3Si2, C, 60.28; H, 10.68. Found C, 60.11; H,
10.53%.
4.3. Preparation of glycoside (20)
A mixture of iodoacetate 17 [1] (R=TBDPS, 284
mg, 0.36 mmol, 9:1 mixture of b-17: a-18), alkynyl diol
1
yellow oil. H-NMR (400 MHz, CDCl3): l 4.82 (app.
quintet, J=8.8 Hz, 1H), 3.98 and 3.92 (dd, J=26.8,
6.4 Hz, 1H), 3.70 (app. septet, J=2.4 Hz, 1H), 3.54
and 3.52 (dd, J=9.8, 2.8 Hz, 1H), 3.12 and 3.05 (dd,
J=26.8, 4.8 Hz, 1H), 1.60 (d, J=8.8 Hz, 3H), 0.90 (s,
9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s,
3H), 0.08 (s, 3H).
,
19 [1] (84 mg, 0.36 mmol), and 4A molecular sieves (284
mg) was stirred in dry CH2Cl2 (2 ml) for 30 min, and
cooled to −75°C. tert-Butyldimethylsilyl triflate (41 ml,
0.18 mmol) was added, and the reaction was stirred for
20 min at −75°C. The reaction was quenched with
Et3N (0.2 ml) at low temperature. The cold bath was
removed and saturated aqueous NaHCO3 (2 ml) was
added. The mixture was extracted with CH2Cl2, and the
combined organic layers were washed with brine and
dried. The solvent was removed under reduced pressure
to give a crude product, which was purified by flash
silica gel chromatography (gradient elution 19:1–9:1,
4.2.2. Procedure B: catalytic single-step
cycloisomerization, with triethylamine
An oven-dried 25 ml Schlenk flask fitted with a reflux
condenser and a stir bar, under argon atmosphere, was
charged with tungsten hexacarbonyl (37 mg, 0.11

F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
449
n-hexanes–EtOAc) to afford the desired glycoside 20
(251 mg, 73%) as a white flocculent material. IR (neat):
3479, 33054, 3070, 2932, 1721, 1427, 1274, 1110, 1082,
(app. q, J=2.0 Hz, 1H), 1.49 (d, J=6.4 Hz, 3H), 1.42
(d, J=6.0 Hz, 1H), 1.13 (s, 9H); 13C-NMR (100 MHz,
CDCl3): l 165.2, 136.1, 135.9, 132.9, 132.8, 132.6,
130.1, 129.9, 129.8, 129.6, 128.2, 127.7, 127.6, 81.8,
77.6, 75.0, 72.2, 63.9, 29.7, 27.1, 19.6, 14.9; HRMS
(FAB+) Anal. Calc. for C29H32LiO4Si [(M+Li)+]
479.2230. Found 479.2221. Anal. Calc. for C29H32O4Si,
C, 73.69; H, 6.82. Found C, 73.47; H, 6.74%.
1
1030, 702 cm−1. H-NMR (400 MHz, CDCl3): l 8.06–
8.04 (m, 2H), 7.60–7.24 (series of m, 23H), 5.52 (d,
J=8.4 Hz, 1H), 5.37 (app. quintet, J=6.4, Hz, 1H),
4.61 (d, J=3.6 Hz, 1H), 4.59 (dd, J=6.0, 2.4 Hz, 1H),
4.00 (app. q, J=5.2 Hz, 3H), 3.82 (d, J=8.0 Hz, 1H),
3.72 (app, q, J=6.4 Hz, 1H), 3.58 (d, J=3.2 Hz, 1H),
2.85 (d, J=4.8 Hz, 1H), 2.85 (d, J=4.8 Hz, 1H), 2.57
(d, J=2.0 Hz, 1H), 1.47 (d, J=6.4 Hz, 1H), 1.03 (s,
9H), 0.96 (s, 9H), 0.64 (d, J=6.8 Hz, 3H); 13C-NMR
(100 MHz, CDCl3): l 165.5, 136.0, 135.9, 135.8, 132.9,
132.8, 132.7, 132.6, 130.5, 129.9, 129.9, 129.8, 129.7,
128.2, 127.8, 127.7, 127.6, 99.9, 80.1, 79.2, 78.4, 76.7,
75.1, 74.3, 70.8, 68.4, 28.0, 27.0, 26.9, 19.5, 19.0, 18.9,
15.5.
4.5. Preparation of glycoside (22)
A mixture of iodoacetate 17 [1] (R=TBDPS, 200
mg, 0.25 mmol, 9:1 mixture of b-17: a-18), alkynyl
,
alcohol 21 (120 mg, 0.25 mmol), and 4A molecular
sieves (100 mg) was stirred in dry CH2Cl2 (4 ml) for 30
min, and cooled to −75°C. Trimethylsilyl triflate (20
ml, 0.13 mmol) was added, and the reaction was stirred
for 1.5 h at −75°C. The reaction was quenched by
adding Et3N (0.2 ml) at low temperature. The cold bath
was removed and saturated aqueous NaHCO3 (5 ml)
was added. The mixture was extracted with CH2Cl2,
and the combined organic layers were washed with
brine and dried. The solvent was removed under re-
duced pressure to give crude product, and was purified
by flash silica gel chromatography (gradient elution
98:2–19:1, n-hexanes–EtOAc) to afford the desired
glycoside 22 (0.252 g, 83%) as a white flocculent mate-
rial. M.p. 50–52°C; [a]2D3 +2.5 (CHCl3, C, 1.71); IR
(neat): 3307, 3071, 3049, 2931, 2858, 1716, 1427, 1111,
4.4. Preparation of alkynyl alcohol (21)
Alkynyl diol 19 [1] (234 mg, 1 mmol) and imidazole
(170 mg, 2.5 mmol) were dissolved in dry DMF (1 ml),
and tert-butyldiphenylsilyl chloride (260 ml, 1 mmol)
was added. The resulting mixture was stirred at r.t. for
1 h and then quenched with water (2 ml). The reaction
mixture was diluted with EtOAc (100 ml), washed with
water (20 ml), brine (20 ml), dried over Na2SO4, and
then concentrated under reduced pressure to give the
crude product as a mixture of 21 and the regioisomeric
1
1
monosilyl ether (69:31 by H-NMR) as well as a small
702 cm−1; H-NMR (400 MHz, CDCl3): l 8.17–7.19
amount of bissilyl ether byproduct. The product mix-
ture was separated by silica gel chromatography (gradi-
ent elution 19:1–9:1, n-hexanes–EtOAc) to afford 21
(265 mg, 56%) as a thick colorless liquid, and the
regioisomeric monosilyl ether (140 mg, 30%) as a white
solid.
(series of m, 35H), 5.83 (dq, J=7.4, 2.0 Hz, 1H), 5.09
(d, J=7.6 Hz, 1H), 4.82 (dd, J=5.2, 2.8 Hz, 1H), 4.52
(d, J=3.2 Hz, 1H), 3.85 (d, J=7.6 Hz, 1H), 3.72 (dd,
J=5.0, 2.4 Hz, 1H), 3.50 (d, J=7.6 Hz, 1H), 3.31
(app. q, J=6.8 Hz, 1H), 2.36 (d, J=2.0 Hz, 1H), 1.63
(d, J=6.8 Hz, 1H), 1.08 (s, 9H), 0.96 (s, 9H), 0.92 (s,
9H), 0.49 (d, J=7.2 Hz, 3H); 13C-NMR (100 MHz,
CDCl3): l 165.6, 136.1, 136.0, 135.9, 135.9, 135.8,
135.8, 133.2, 133.1, 133.0, 132.9, 132.9, 132.7, 132.6,
130.7, 130.0, 129.9, 129.8, 129.7, 128.2, 127.8, 127.8,
127.7, 127,.6, 127.5, 127.4, 104.7, 82.4, 82.0, 79.5, 79.2,
74.7, 74.3, 70.9, 64.9, 28.1, 27.0, 26.9, 26.9, 19.8, 19.2,
19.0, 18.7, 15.1; HRMS (FAB+) Anal. Calc. for
Data for 21: [a]2D3 −21.6 (CHCl3, C, 2.5); IR (neat):
3528, 3302, 3071, 3050, 2932, 1719, 1427, 1275, 1113,
1
1069, 709 cm−1; H-NMR (400 MHz, CDCl3): l 7.97–
7.19 (series of m, 15H), 5.29 (app. quintet. J=6.4 Hz,
1H), 4.46 (dd, J=3.6, 1.6 Hz, 1H), 3.90 (app. q, J=6.0
Hz, 1H), 2.70 (dd, J=6.4, 1.2 Hz, 1H), 2.30 (d, J=2.4
Hz, 1H), 1.42 (d, J=6.0 Hz, 3H), 1.09 (s, 9H); 13C-
NMR (100 MHz, CDCl3): l 165.4, 136.1, 135.7, 132.9,
132.6, 131.9, 130.2, 129.9, 129.8, 129.6, 128.2, 127.7,
127.3, 81.6, 76.7, 75.4, 70.6, 63.9, 26.9, 19.3, 15.7.
HRMS (FAB+) Anal. Calc. for C29H32LiO4Si [(M+
Li)+] 479.2230. Found 479.2221. Anal. Calc. for
C29H32O4Si, C, 73.69; H, 6.82. Found C, 73.02; H,
6.77%.
C67H77ILiO7Si3
[(M+Li)+]
1107.3920.
Found
1107.3933. Anal. Calc. for C67H77IO7Si3, C, 66.76; H,
6.44. Found C, 67.02; H, 6.70%.
4.6. Preparation of glycosylated alkynyl alcohol
substrates 23–25
Data for the regioisomeric monosilyl ether: M.p.
4.6.1. Preparation of alkynyl alcohol (23)
83–85°C, [a]2D3 −30.9 (CHCl3, C, 1.81) IR (neat): 3466,
Benzoate 22 (190 mg, 0.16 mmol) was dissolved in
dry CH2Cl2 (2 ml) and cooled to −70°C. DIBAL-H (1
M solution in CH2Cl2, 395 ml, 0.4 mmol) was added at
−70°C and the reaction mixture was stirred for 30 min.
The reaction mixture was quenched with a −70°C
3304, 3071, 2931, 1715, 1427, 1277, 1111, 708 cm−1
;
1H-NMR (400 MHz, CDCl3): l 7.82–7.28 (series of m,
15H), 5.42 (dq, J=6.8, 2.8 Hz, 1H), 4.38 (ddd, J=8.0,
6.4, 2.0 Hz, 1H), 4.02 (dd, J=5.6, 2.8 Hz, 1H), 2.46

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F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
solution of EtOAc (0.5 ml) and stirred for an additional
30 min at low temperature. The mixture was then
poured into a cold solution of 1M aqueous HCl (30
ml). Extractive workup (EtOAc–H2O) and silica gel
chromatography (n-hexanes–EtOAc, 19:1) afforded
compound 23 (129 mg, 74%). [a]2D3 +18.7 (CHCl3, C,
2.11); IR (neat): 3534, 3306, 3071, 3049, 2957, 2932,
[a]2D3 +27.6 (CHCl3, C, 1.35); IR (neat): 3582, 3306,
1
3071, 3049, 2931, 1427, 1111, 701 cm−1; H-NMR (600
MHz, CDCl3): l 7.76–7.75 (m, 2H), 7.73–7.71 (m,
2H), 7.55–7.53 (m, 2H), 7.49–7.48 (m, 2H), 7.43–7.20
( series of m, 22H), 5.48 (d, J=8.4 Hz, 1H), 4.64 (d,
J=3.0 Hz, 1H), 4.55 (dd, J=4.2, 2.4 Hz, 1H), 4.15
(app. q, J=6.6 Hz, 1H), 3.81 (app. sextet, J=4.2 Hz,
1H), 3.78 (d, J=8.4 Hz, 1H), 3.60 (app. q, J=6.6 Hz,
1H), 3.50 (d, J=3.0 Hz, 1H), 2.66 (d, 4.2 Hz, 1H), 2.43
(d, J=1.8 Hz, 1H), 1.25 (br, s, 1H), 1.23 (d, J=6.0
Hz, 3H), 1.10 (s, 9H), 1.00 (s, 9H), 0.97 (s, 9H), 0.69 (d,
J=7.2 Hz, 3H). 13C-NMR (150 MHz, CDCl3): l 136.3,
136.0, 135.9, 135.9, 135.8, 133.6, 133.0, 132.9, 132.8,
132.7, 129.9, 129.9, 129.8, 129.7, 129.7, 127.8, 127.7,
127.6, 127.6, 127.5, 98.9, 80.0, 79.9, 76.7, 74.4, 69.4,
69.1, 28.0,.27.2, 27.0, 26.9, 19.6, 19.10, 19.0, 18.9.
HRMS (FAB+) Anal. Calc. for C60H73ILiO6Si3 [(M+
Li)+] 1107.3920. Found 1107.3866. Anal. Calc. for
C60H73O6Si3 C, 66.75; H, 6.44. Found C, 65.63; H,
6.68%.
2859, 1427, 1110, 1033, 703 cm−1 1H-NMR (400
;
MHz, CDCl3): l 7.79–7.23 (series of m, 30H), 5.07 (d,
J=7.6 Hz, 1H), 4.98 (app. dd, J=5.0, 2.0 Hz, 1H),
4.48 (d, J=3.6 Hz, 1H), 4.39 (app. q, J=6.4 Hz, 1H),
3.73 (d, J=8.0 Hz, 1H), 3.67 (br, s, 1H), 3.55 (d,
J=3.2 Hz, 1H), 3.35–3.30 (m, 2H), 2.39 (d, J=1.6 Hz,
1H), 1.43 (d, J=6.0 Hz, 1H), 1.11 (s, 9H), 1.05 (s, 9H),
0.91 (s, 9H), 0.47 (d, J=6.8 Hz, 3H); 13C-NMR (100
MHz, CDCl3): l 136.1, 135.9, 135.8, 135.7, 133.2,
132.9, 132.9, 132.6, 132.6, 132.1, 130.0, 130.0, 129.8,
129.6, 127.8, 127.8, 127.7, 127.6, 127.5, 104.7, 82.6,
81.6, 79.7, 79.1, 75.1, 74.2, 68.5, 67.5, 67.6, 28.1, 27.1,
26.9, 26.8, 19.9, 19.8, 19.2, 19.0, 18.9; HRMS (FAB+)
Anal. Calc. for C60H73ILiO6Si3 [(M+Li)+] 1107.3920.
Found 1107.3933. Anal. Calc. for C67H77IO7Si3, C,
66.76; H, 6.44. Found C, 67.02; H, 6.70%.
4.6.3. Preparation of alkynyl alcohol (25)
The procedure for 25 is essentially the same as de-
scribed for 24 (Section 4.6.2) except tert-
butyldimethylsilyl chloride was used instead of
TBDPSCl. Thus a mixture of 20 (135 mg, 0.14 mmol),
imidazole (45 mg, 0.66 mmol), tert-butyldimethylsilyl
chloride (32 mg, 0.21 mmol), and DMF (2 ml) was
stirred for 48 h to give O-TBS protected product (141
mg, 94%). IR (neat): 3306, 3071, 3049, 2930, 1719,
4.6.2. Preparation of alkynyl alcohol (24)
Glycoside 20 (205 mg, 0.21 mmol) and imidazole (72
mg, 1.1 mmol) were dissolved in dry DMF (2 ml), and
tert-butyldiphenylsilyl chloride (110 ml, 0.42 mmol) was
added. The resulting mixture was stirred for 48 h and
then quenched with water (1 ml). The reaction mixture
was diluted with EtOAc (100 ml), washed with water
(20 ml), brine (20 ml), dried over Na2SO4, and then
concentrated under reduced pressure to give the crude
product. The mixture was purified by silica gel chro-
matography (gradient elution 98:2–19:1, n-hexanes–
EtOAc) to afford O-TBDPS protected product (212
mg, 83%) as a white solid. M.p. 62–64°C; [a]2D3 −6.95
(CHCl3, C, 3.2); IR (neat): 3304, 3071, 2931, 2858,
1
1276, 1111, 702 cm−1; H-NMR (400 MHz, CDCl3): l
8.07–8.05 (m, 2H), 7.58–7.18 (series of m, 23H), 5.64
(d, J=8.4 Hz, 1H), 5.61 app. sextet, J=7.2, 2.4 Hz,
1H), 4.18 (dd, J=7.4, 2.4 Hz, 1H, 3.92, (d, J=8.0 Hz,
1H), 3.70 (app. q, J=7.2 Hz, 1H), 3.50 (d, J=2.8 Hz,
1H), 1.40 (d, J=6.8 Hz, 1H), 1.04 (s, 9H), 1.00 (s, 9H),
0.93 (s, 9H), 0.68 (d, J=6.8 Hz, 1H), 0.14 (s, 3H), 0.07
(s, 3H); 13C-NMR (100 MHz, CDCl3): l 165.9, 136.1,
136.0, 135.9, 135.8, 133.1, 133.0, 132.7, 132.7, 130.6,
129.9, 129.8, 129.7, 128.2, 127.8, 127.6, 127.5, 98.8,
79.8, 79.5, 78.6, 75.43, 74.3, 72.4, 68.9, 28.4, 27.1, 27.0,
25.9, 19.6, 19.0, 18.9, 18.3, 14.1, −3.6, −4.8; HRMS
(FAB+) Anal. Calc. for C60H73ILiO6Si3 [(M+Li)+]
1087.3869. Found 1087.3821. The benzoate ester of this
product was removed by DiBAL-H reduction as de-
scribed for 23 (Section 4.6.1), to provide compound 25
(114 mg, 89%). IR (neat): 3568, 3480, 3307, 3071, 3049,
1
1717, 1427, 1274, 1111, 1032, 702 cm−1; H-NMR (400
MHz, CDCl3): l 7.77–7.19 (series of m, 35H), 5.57
(app. br. d, J=8.4 Hz, 1H), 4.73 (app. d, J=2.8 Hz,
1H), 4.55 (dd, J=6.2, 2.0 Hz, 1H), 4.18 (dd, J=6.2,
2.0 Hz, 1H), 3.88 (d, J=8.0 Hz, 1H), 3.61 (app. q,
J=6.8 Hz, 1H), 3.48 (d, J=3.6 Hz, 1H), 2.48 (d,
J=2.0 Hz, 1H), 1.58 (d, J=6.8 Hz, 3H), 1.12 (s, 9H),
1.04 (s, 9H), 1.00 (s, 9H), 0.67 (d, J=6.4 Hz, 3H);
13C-NMR (100 MHz, CDCl3): l 165.6, 136.5, 136.2,
136.1, 136.1, 135.9, 135.9, 135.8, 133.1, 133.0, 132.9,
132.8, 132.7, 132.4, 130.5, 129.8, 129.7, 129.6, 129.4,
127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.4, 98.9,
79.8, 79.7, 78.9, 77.4, 75.6, 74.4, 72.2, 68.6, 28.2, 27.2,
27.0, 19.6, 19.0, 18.9, 14.9. HRMS (FAB+) Anal. Calc.
for C67H77ILiO7Si3 [(M+Li)+] 1211.4182. Found
1211.4207. The benzoate ester of this product was
removed by DIBAL-H reduction as described for 23, to
provide compound 24 (192 mg, 100%). M.p. 55–60°C;
2930, 2858, 1471, 1427, 1110, 1084, 1032, 702 cm−1
;
1H-NMR (400 MHz, CDCl3): l 7.58–7.19 (series of m,
20H), 5.64 (d, J=8.4 Hz, 1H), 4.72 (d, J=3.2 Hz, 1H),
4.55 (d, J=4.0, 2.0 Hz, 1H), 4.13 (app. quintet, J=6.4
Hz, 1H), 3.88 (d, J=8.0 Hz, 1H), 3.76 (d, J=5.6 Hz,
1H), 3.74 (app. q, J=6.0 Hz, 1H), 3.55 (d, J=2.8 Hz,
1H), 2.52 (d, J=2.4 Hz, 1H), 1.22 (d, J=6.4 Hz, 3H),
1.04 (s, 9H), 0.99 (s, 9H), 0.92 (s, 9H), 0.74 (d, J=6.8
Hz, 3H), 0.16 (s, 3H), 0.13 (s, 3H); 13C-NMR (100

F.E. McDonald, K.S. Reddy / Journal of Organometallic Chemistry 617–618 (2001) 444–452
451
MHz, CDCl3): l 136.1, 136.0, 135.9, 135.8, 133.1,
132.9, 132.9, 132.6, 129.9, 129.9, 129.8, 127.8, 127.7,
127.7, 127.6, 98.8, 80.0, 79.4, 78.8, 76.8, 76.7, 76.6, 74.4,
69.7, 68.5, 28.3, 27.0, 26.9, 25.9, 19.6, 19.0, 18.9, 18.3,
18.2, −3.8, −4.6; HRMS (FAB+) Anal. Calc. for
C50H69ILiO6Si3 [(M+Li)+] 983.3607. Found 983.3642.
Calc. for C60H73ILiO6Si3 [(M+Li)+] 1107.3920. Found
1107.3893.
4.7.3. Preparation of disaccharide glycal (28)
The procedure described for 26 (Section 4.7.1) was
followed. Thus a mixture of alkynol 25 (90 mg, 90
mmol), W(CO)6 (9 mg, 23 mmol), Et3N (0.3 ml) and
THF (1.2 ml) was irradiated for 5 h under N2 to
provide disaccharide 28 (51 mg, 61%). [a]2D3 −4.7
(CHCl3, C, 1.27); IR (neat): 3070, 3050, 2930, 2858,
4.7. Synthesis of disaccharide glycals 26–28 6ia
catalytic cycloisomerization of alkynyl alcohols 23–25
1647, 1427, 1111, 1076, 701 cm−1 1H-NMR (400
;
4.7.1. Preparation of disaccharide glycal (26)
The procedure described for 13 under procedure C
(Section 4.2.3) was followed except 25 mol% W(CO)6
loading was used. A mixture of alkynol 23 (70 mg, 64
mmol), W(CO)6 (6 mg, 16 mmol), DABCO (14 mg, 0.12
mmol) and THF (1 ml) was irradiated at 350nm for 5
h. Removal of volatiles and basic silica gel (2.5% v/v
SiO2–Et3N) chromatography afforded disaccharide 26
(46 mg, 66%) as a white solid. M.p. 46–48°C; [a]D23
+4.8 (CHCl3, C=2.0); IR (neat): 3070, 3049, 2930,
MHz, CDCl3): l 7.60–7.19 (series of m, 20H), 6.40 (dd,
J=6.0, 0.8 Hz, 1H), 5.29 (d, J=8.0 Hz, 1H), 4.88 (dd,
J=6.0, 2.0 Hz, 1H), 4.76 (d, J=3.2 Hz, 1H), 4.2 (dt,
J=3.2, 1.6 Hz, 1H), 3.90 (d, J=8.0 Hz, 1H), 3.84
(app. sextet, J=6.4 Hz, 1H), 3.65 (d, J=6.8 Hz, 1H),
3.62 (app. q, J=6.8 Hz, 1H), 3.51 (d, J=2.8 Hz, 1H),
1.34 (d, J=6.8 Hz, 3H), 1.04 (s, 9H), 1.02 (s, 9H), 0.90
(s, 9H), 0.22 (s, 3H), 0.10 (s, 3H); 13C-NMR (100 MHz,
CDCl3): l 144.7, 136.1, 136.0, 135.9, 135.8, 133.2,
132.9, 132.7, 129.9, 129.9, 129.8, 129.7, 127.8, 127.7,
127.6, 127.6, 99.7, 98.9, 79.9, 79.3, 75.5, 74.7, 74.4, 73.0,
30.1, 29.1, 27.1, 27.0, 25.0, 19.6, 19.0, 18.8, 18.1, 17.8,
−3.2, −4.5; HRMS (FAB+) Anal. Calc. for
C50H69ILiO6Si3 [(M+Li)+] 983.3607. Found 983.3644.
Anal. Calc. C50H69IO6Si3 C, 61.45; H, 7.12. Found: C,
61.75; H, 7.30%.
1
2858, 1647, 1427, 1110, 1080, 702 cm−1; H-NMR (400
MHz, CDCl3): l 7.73–7.17 (series of m, 30H), 6.23 (d,
J=6.0 Hz, 1H), 5.35 (d, J=7.6 Hz, 1H), 4.68 (d,
J=3.2 Hz, 1H), 4.40 (dd, J=3.4 Hz, 1H), 4.37–4.34
(app. m, 2H), 3.92 (d, J=7.6 Hz, 1H), 3.86 (dd,
J=3.8, 3.6 Hz, 1H), 3.65 (app. q, J=6.8 Hz, 1H), 3.52
(d, J=3.2 Hz, 1H), 1.61 (d, J=6.8 Hz, 3H), 1.08 (s,
9H), 1.05 (s, 9H), 0.96 (s, 9H), 0.68 (d, J=6.8 Hz, 3H);
13C-NMR (100 MHz, CDCl3): l 142.8, 136.1, 136.0,
135.9, 135.9, 134.5, 133.7, 133.1, 132.9, 132.8, 132.7,
129.9, 129.8, 129.7, 129.5, 127.7, 127.6, 127.5, 102.2,
101.5, 80.0, 79.6, 79.6, 74.5, 72.1, 65.8, 29.7, 29.6, 27.1,
27.0, 26.9, 19.9, 19.2, 19.0, 18.9, 17.1; HRMS (FAB+)
Anal. Calc. for C60H73ILiO6Si3 [(M+Li)+] 1107.3920.
Found 1107.3945. Anal. Calc. for C67H77IO7Si3, C,
66.76; H, 6.44. Found C, 67.18; H, 7.28%.
Acknowledgements
This research is supported by the US National Insti-
tutes of Health (CA-59703). Unrestricted funding from
Novartis Pharmaceuticals (Grant Program for the Sup-
port of Academic Research in Synthetic Organic Chem-
istry, to F.E.M.) is also greatly appreciated. The 600
MHz NMR spectrometer was purchased with a grant
from the Georgia Research Alliance.
4.7.2. Preparation of disaccharide glycal (27)
The procedure described for 26 (Section 4.7.1) was
followed. Thus a mixture of alkynol 24 (150 mg, 0.14
mmol), W(CO)6 (12 mg, 34 mmol), DABCO (31 mg,
0.27 mmol) and THF (1.5 ml) was irradiated for 6 h
under Ar to provide disaccharide 27 (94 mg, 62%) as a
white flocculent solid. M.p. 50–54°C; [a]2D3 −11.4
(CHCl3, C, 1.45); IR (neat): 3069, 2932, 1646, 1427,
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1108, 702 cm−1; H-NMR (400 MHz, CDCl3): l 7.72–
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