C-Glycosides to fused polycyclic ethers

Article abstract of DOI:10.1016/S0040-4020(02)00057-1

This manuscript describes the synthesis of fused polycyclic ethers from the coupling of C-glycoside forming reactions with ring closing metathesis and acid mediated annulation reactions.

Full text of DOI:10.1016/S0040-4020(02)00057-1

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1997±2009
C-Glycosides to fused polycyclic ethers
Shawn P. Allwein, Jason M. Cox, Brett E. Howard, Henry W. B. Johnson and Jon D. Rainierp
Department of Chemistry, The University of Arizona, Tucson, AZ 85721, USA
Received 2 November 2001; accepted 4 December 2001
AbstractÐThis manuscript describes the synthesis of fused polycyclic ethers from the coupling of C-glycoside forming reactions with ring
closing metathesis and acid mediated annulation reactions. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The high degree of structural regularity present in the
marine ladder toxins (cf. hemibrevetoxin B and gambierol)
(Fig. 1) has in¯uenced many,1±6 including us,7 to believe
that an iterative approach to their synthesis might be ideal.
With this in mind, over the last several years we have
focused our attention on the development of an iterative
strategy to these agents that couples the formation of
C-glycosides from cyclic enol ethers with acid or metathesis
based cyclizations (Scheme 1).
From our perspective it was clear that the C-glycoside
chemistry (i.e. 1!2) was critical to the success of this
Figure 1.
venture as it would not only incorporate many of the
requisite atoms but it would also result in the generation
of the ring junction stereocenters. Out of a desire to develop
a ¯exible C-glycoside strategy that would also address these
issues, we decided to concentrate on an enol ether oxidation,
nucleophilic addition sequence.8,9 Outlined herein is a full
report of our efforts targeting the formation of C-glycosides
2. Results and discussion
2.1. 1,2-Anhydrosugars in the synthesis of b-C-
glycosides
in model systems and their use in the synthesis of fused
polycyclic ethers.
Since there were a number of questions concerning the
proposal outlined in Scheme 1, we decided to initially
examine the formation of C-glycosides and bicyclic enol
ethers from glucal anhydride 5 as a model substrate. Not
only had Danishefsky utilized 5 in the synthesis of oligo-
saccharides10,11 but Kishi and Czernecki had independently
demonstrated that this and related epoxides were effective
substrates for the synthesis of methyl, phenyl, and allyl-b-
C-glucosides.12 As illustrated in Tables 1 and 2, we have
expanded upon these studies by exploring the scope of the
reactions of nucleophiles with 5.7a,b,13
Following the formation of 5 using Danishefky's conditions
Scheme 1.
and dimethyl dioxirane,11,14 we examined its conversion
into b-C-glycosides (Table 1). We found that careful
attention to the counterion on the nucleophile and the
temperature used during the addition were essential for
Keywords: C-glycosides; polycyclic ethers; annulation reactions.
Corresponding author. Tel.: 11-520-626-2084; fax: 11-520-621-8407;
e-mail: rainier@u.arizona.edu
p
successful b-addition.15 For example, while acetal Grignard
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00057-1

1998
S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
Table 1.
Entry
Nu
Temperature
R
Product
b/a
Yield (%)
1
2
Me2CuLi
08C
08C
Me
6
7
1:0
1:0
82
82
3
4
5
6
7
08C
8
1:0
0:1
1:1
1:1
1:0
78
80
80
08C
9
260!08C
208C
2408C
10
11
11
a
±
57
51
8
208C
13
13
13
15
1:1
9
2408C
2308C
208C
1.7:1
6:1
29
74
65
10
11
5:1
12
13
PhMgCl
Ph2CuLi
2608C
08C
16
16
1:1
1:0
78
84
14
2608C!rt
17
1:0
78
a
Yield was not obtained after the crude 1H NMR spectrum indicated a 1:1 a/b mixture.
1216 gave 1:1 mixtures of a- and b-C-glycosides 13, the
corresponding cuprate gave a 6:1 mixture of products
favoring the b-isomer (entries 8±10). Similar results were
observed with phenyl magnesium chloride and lithium
diphenyl cuprate; phenyl magnesium chloride gave a 1:1
mixture of a- and b-C-glycosides while lithium diphenyl
cuprate gave exclusively b-C-glycoside 16 (entries 12 and
13). With respect to temperature, addition of vinyl
magnesium bromide at 08C resulted in the formation of a
1:1 mixture of a- and b-C-glycosides 11 (entry 6). By
simply lowering the temperature of the addition to 2408C
we were able to isolate a 57% yield of b-vinyl glycoside 11
(entry 7). We propose that the temperature and counterion
dependence of these coupling reactions are related to the
presence of oxocarbenium ions. At higher temperatures
and with some nucleophiles, oxocarbenium ion formation
occurs; apparently the addition of most nucleophiles to the
oxocarbenium ion from 5 is not selective. Particularly
noteworthy is that these coupling reactions are ef®cient
and ¯exible; both the oxidation and nucleophilic additions
are carried out in the same ¯ask. This allows one to avoid
the isolation and handling of potentially labile glycosides
having anomeric leaving groups.
A number of other nucleophiles also coupled with 5 to give
exclusively or predominantly b-C-glycosides. 2-Furyl
lithium in the presence of ZnCl2 (entry 14),17 propenyl
magnesium chloride (entry 2),7,8 propargyl magnesium
chloride (entry 3), lithium dimethyl cuprate (entry 1), and
diethyl acetal cuprate 1418 (entry 11) all underwent stereo-
selective coupling with 5 to give 17, 7, 8, 6, and 15,
respectively. These reactions have proven to be somewhat
dependent upon the substrate used. For example, in contrast
to the nucleophiles mentioned earlier, we have been unable
to selectively generate b-C-glycosides from the coupling of
butenyl and ethynyl nucleophiles with 5. Thus far, these

S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
1999
Table 2.
Entry
1
`Al'
Al (equiv.)
3
Temperature
R
Product
b/a
Yield (%)
82
AlMe3
2958C
Me
6
0:1
2
3
3
3
2958C
2658C
9
0:1
0:1
80
11
24a
4
5
3
3
2658C!rt
2658C!rt
11
11
0:1
0:1
40b
59c
6
7
6
6
2658C!rt
2658C!rt
11
16
0:1
0:1
76d
79
AlPh3
8
6
6
2658C!rt
08C
17
7
0:1
85
73
9
1:2.3
a
Major products were methyl glycoside 6 (40%) and anomeric chloride and/or diol from hydrolysis of the epoxide or anomeric chloride upon workup.
Major by-product was methyl glycoside 6 (44%).
Major by-product was glycosidic dimer resulting from alkoxy transfer.
Inverse addition, see text.
b
c
d
have given either 1:1 mixtures of a- and b-C-glycosides
(butenyl, entry 5) or exclusively a-C-glucoside (ethynyl,
delight, we were also able to couple other aluminum nucleo-
philes with 5. TMS±acetylene was transferred to 5 from
dimethyl aluminum acetylene 1923 at 2958C in high yield
(entry 2). Competitive methyl transfer was not observed at
this temperature. In contrast to this result, methyl transfer
was competitive with vinyl transfer from dimethylvinyl
aluminum 20 at the temperatures required for the reaction
to occur (entries 3 and 4). These problems were circum-
vented by turning to trivinyl aluminum and by using an
inverse mode of addition (addition of epoxide to excess
trivinyl aluminum, entries 5 and 6). By using conditions
optimized for the transfer of vinyl, we were able to also
couple phenyl and furyl aluminum reagents with 5 to give
a-C-glycosides 16 and 17.17 In contrast to the other
reagents, the transfer of allyl from triallyl aluminum was
problematic. When epoxide 5 was exposed to triallyl
aluminum we isolated a 73% yield of an a,b-mixture
favoring a-C-glucoside 7.
entry 4).19
2.2. 1,2-Anhydrosugars in the synthesis of a-C-
glycosides
Having established that a number of carbon nucleophiles are
capable of coupling with 5 to provide b-C-glycosides, we
directed our attention to the formation of the corresponding
a-C-glycosides. It occurred to us that aluminum or boron
nucleophiles might add to 5 in a syn fashion through the
directed transfer of the nucleophile to an oxocarbenium ion
intermediate. Not only would the success of these experi-
ments enable us to tackle the synthesis of cis-fused
polycyclic ethers as are present in a number of interesting
natural products (e.g. the halichondrins20) but they would
also provide us with unprecedented ¯exibility in the
synthesis of C-glycosides. That is, if successful these
experiments would enable us to convert a single glycosyl
donor (glycal anhydride) into a variety a- or b-C-glycosides
by simply changing the counterion on the carbon
nucleophile.21
It was our belief that b-C-allyl glucoside 7 from the triallyl
aluminum reaction was the result of an intermolecular
transfer of allyl from aluminum to the epoxide and that
this was a consequence of our inability to purify triallyl-
aluminum. In an effort to circumvent this problem we turned
to triallylborane (Eq. (1)). Not insigni®cant to the choice of
this reagent was the knowledge that triallylborane can be
puri®ed.24 To our delight, exposure of 5 to triallylborane
With these goals in mind we examined the reaction of
Me3Al with 5 and were pleased to ®nd that they coupled
to provide a-C-glucoside 6 (Table 2, entry 1).22 To our

2000
S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
Table 3.
Zna
PbCl2
CH2Br2
21 (M)
CH2Cl2/THF/TMEDA
Time (h)
22
23
a
a
a
Entry
TiCl4
1
2
3
4
16
6
9
36
13
0.045
0.18
0.72
2.2
8.8
6
0.098
0.020
0.006
1:3.5:0.6
1:6:0.3
16:1:1
3.0
0.5
0.5
0
65
30
0
15
50
a
Amounts refer to equivalents relative to 21.
resulted in a 70% yield of 7 as a 13:1 mixture of a- and b-C-
glycosides.
were interested in carrying out the transformation of
C-glycoside 2 into cyclic enol ether 3 through the use of
either ring closing metathesis (RCM) chemistry7a,c,d,25,26
or acid mediated cyclizations and elimination reac-
tions.7b±d,27,28
We initially targeted RCM reactions of the enol ethers from
b-allylglycoside 7 and b-homoallylglycoside 10.29 Follow-
ing the conversion of 7 into the corresponding acetate 21,
we examined acyclic enol ether formation using Takai's
reduced Ti protocol (Table 3).30 Interestingly, the use of
4 equiv. of the reduced Ti reagent resulted in the complete
recovery of starting material (entry 1). From the notion that
the oxygen atoms present in 21 might have been interfering
with the ability of the Ti alkylidene reagent to react with the
ester, we increased the amount of reagent four-fold. This
change led, not only to the formation of the desired acyclic
enol ether 22 in 65% yield, but also to the formation of
cyclic enol ether 23 in 15% yield (entry 2). We subsequently
found that by decreasing the concentration of 21 and
increasing the relative amount of PbCl2 that we could
increase the cyclic enol ether to acyclic enol ether ratio
(entry 3).31 Thus far however, we have been unable to ®nd
conditions to drive the reaction completely to cyclic enol
ether 23.
ꢀ1†
2.3. Ring closing metathesis to bicyclic enol ethers
Having overcome the challenges associated with the
synthesis of C-glycosides, we were prepared to examine
the annulation chemistry. As mentioned previously, we
Table 4.
It was not completely surprising that the use of Takai's
reagent resulted in the formation of 23; ®rst Grubbs32 and
subsequently Nicolaou33 had independently reported that
other reduced Ti reagents (i.e. the Tebbe and Petasis
reagents) gave cyclized material when exposed to ole®ns
having pendant esters. Nicolaou's results were of particular
interest to us as they involved the formation of fused poly-
cyclic enol ethers and were shown to result from an enol
ether±ole®n RCM sequence. In contrast, cyclized products
from the use of the Takai reagent appear to result from ole®n
metathesis, carbonyl ole®nation reactions as all attempts to
convert acyclic enol ether 22 into cyclic enol ether 23
using our revised Takai protocol have failed.34 We
currently believe that the Takai reagent competitively reacts
with either the ole®n or the ester. If the initial coupling
occurs at the ole®n, a metathesis reaction provides the
corresponding titanium alkylidene; a subsequent carbonyl
ole®nation provides cyclic enol ether. On the other hand,
reaction with the ester results in formation of the acyclic
enol ether.
Entry
n
R
Starting material Catalyst Product Yield (%)
1
2
3
4
5
1
1
1
1
2
Me
Me
Me
H
22
22
22
28
26
32
33
34
32
33
23
23
23
29
31
87
85
±
85
78
a
Me
a
Resulted in the recovery of starting material.

S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
2001
Table 5.
Entry
A
Yield (%)
B
Yield (%)
1
2
TMSOTf, CH2Cl2, 2658C
TMSOTf, CH2Cl2, 2658C
56
56
TMSOTf, NEt3, CH2Cl2, 408C, 14 h
PPTS, pyridine, PhCl, 60!1408C, 6 h
50
91
Interestingly, when the homoallyl glycoside 24 was exposed
to the Takai reagent we observed no products resulting from
cyclization and instead isolated enol ether 26 in yields that
varied from 50±76% (Eq. (2)). In an effort to demonstrate
that the capricious nature of this reaction was due to
the presence of the pendant ole®n, we subjected TIPS
ether 2535 to the enol ether forming conditions. This resulted
in the formation of enol ether 27 in a reproducible 78%
yield.
2.4. Acid mediated cyclizations and eliminations to
bicyclic enol ethers
We have also investigated a complementary approach to
cyclic enol ethers that employs acid mediated cyclizations
and eliminations (Table 5).7b±d Our initial experiments
examined the stepwise conversion of 13 into 29. When 13
was exposed to TMSOTf we were able to isolate mixed
acetal 35 in 56% yield.39 In a subsequent reaction, we
found that we could convert the acetal to the enol ether by
40
subjecting 35 to either TMSOTf and NEt3 or PPTS and
pyridine.27
Bicyclic enol ether 29 could be formed more ef®ciently if
both the acetal formation and the elimination reaction were
carried out in a single ¯ask (Table 6). Optimized conditions
involved heating hydroxy acetal 13 to 608C in the presence
of PPTS; following the complete decomposition of starting
material by TLC, pyridine was added to the reaction ¯ask
and the reaction was heated to 1358C. This protocol resulted
in the formation of bicyclic dihydropyran 29 in 91% yield.
Not surprisingly, this reaction was also amenable to the
formation of rings larger than dihydropyrans. For example,
when 15 was subjected to PPTS, pyridine, and heat we
isolated bicyclic oxepene 36 in 72% yield.
ꢀ2†
That the Takai protocol provided a mixture of cyclic and
acyclic enol ethers in the reaction with 21 was of little
consequence as the mixture could be converted into cyclic
enol ether 23 by subjecting the mixture to Schrock's
molybdenum alkylidene catalyst 3236 or to the second
generation Grubbs' Ru alkylidene catalyst 33 (Table 4,
entries 1±3).37 As depicted, we were also able to convert
a-unsubstituted acyclic enol ether 287a into the correspond-
ing a-unsubstituted dihydropyran 29 using 32 (entry 4).
Alkylidene 33 also catalyzed the formation of oxepene 31
from enol ether 26 in 78% yield. This result nicely
illustrates the versatility of 33; we38 and others26b have
had dif®culty using alkylidene 32 to catalyze enol ether±
ole®n RCM to form cyclic enol ethers larger than dihydro-
pyrans having synthetically useful substitution about the
cyclic enol ether.
2.5. C-Glycosides from bicyclic enol ethers
Having established the synthesis of bicyclic enol ethers and
therefore the completion of one iterative cycle, we decided
to further test our strategy by carrying out a second iteration
using 29. While it was not clear to us what the selectivity in
the epoxidation of 29 would be, we were hopeful that
dioxirane would add to the same face as the C5 hydrogen
(Eq. (3)). If this hypothesis proved accurate and we were
subsequently able to add C-nucleophiles to the resulting
Table 6.
Entry
n
Starting material
R
Product
Yield (%)
1
2
1
2
13
15
Me
Et
29
36
91
72

2002
S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
Table 7.
Entry
Reagents
41/42
Yield (%)
Scheme 2.
1
2
3
AD mix-a
AD mix-b
K2OsO4´H2O (cat), KFe(CN)6, K2CO3
12:1
3:1
4:1
88
88
77
epoxide, we would have a direct access to the trans±syn±
trans relative stereochemistry of the marine ladder toxins.
However, when 29 was exposed to dimethyl dioxirane
followed by propenyl magnesium chloride at 2608C we
isolated trans±anti±trans glycoside 37 in relatively low
yield.41
Of particular relevance to our work was a report from the
Nicolaou laboratories that described the use of OsO4 to
overcome an undesired stereochemical outcome in the
hydroboration of a cyclic enol ether.33a Gratifyingly, OsO4
approached 29 from the opposite face of the enol ether when
compared with dimethyl dioxirane. That is, treatment of 29
with OsO4 provided a 4:1 mixture of C2 diastereomers
(Table 7, entry 3). In an attempt to optimize the 41/42
ratio, 29 was exposed to the Sharpless asymmetric
dihydroxylation (AD) protocol.43 Interestingly, both AD
mix-a and AD mix-b gave the trans±syn isomer 41 as the
major product.44 As had also been observed by Nicolaou,
AD mix-a gave the highest selectivity for the formation of
the desired diol 41 (entry 1).
ꢀ3†
The selectivity in the epoxidation of 29 can be rationalized
if one assumes an asynchronous bond forming event where
bond formation at the b-carbon of the enol ether is faster
than bond formation at the a-carbon (Scheme 2). With this,
attack from the upper face proceeds through a `pseudo-
chair' transition state (i.e. 38) to give 39.
Having overcome the oxidation of 29, the next challenge
that we faced was the conversion of 41 into the correspond-
ing C-glycoside. From the various possibilities, we decided
to examine the displacement of an anomeric bromide (e.g.
43) with a carbon nucleophile.45 Towards this end, we set
out to generate the anomeric bromide from 41 (Eq. (5)).
Because of relatively low yields using HOAc, HBr to
generate 43 from 41, we investigated other means of
carrying out this transformation. We were pleased to ®nd
that we could isolate bromide 43 in 85% yield as a single
diastereomer by exposing 41 to TMSBr and CH2Cl2 at
re¯ux.46
Interestingly, the epoxidation and C±C bond forming
chemistry on bicyclic oxepene 36 resulted in the formation
of trans±syn±trans isomer 40 in 72% yield (Eq. (4)).
Presently, the reasons for the discrepancy between the
C-glycoside forming reaction of 29 and 36 are not clear.
ꢀ4†
ꢀ5†
With bromide 43 in hand, we studied its conversion into the
corresponding C-glycoside (Eq. (6)). The displacement of
the bromide in 43 using acetal Grignard 12 provided trans±
syn±trans diastereomer 44 in 72% yield. An added bene®t
to the use of 12 was that the C2 acetate had also been
removed in the course of the reaction. Thus, we were now
In an effort to generate the trans±syn±trans isomer from
bicycle 29 as required by the marine ladder toxin architec-
ture, we investigated other enol ether oxidation protocols.42

S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
2003
positioned to convert 44 into the correponding tricycle (vide
infra).
4.2. Representative procedure for the epoxidation and
the subsequent addition of C-nucleophiles to 5
4.2.1. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-methyl-tetrahydro-pyran-3-ol 6. To a solution
of tri-O-benzyl-d-glucal (0.05 g, 0.12 mmol) and CH2Cl2 at
08C was added dimethyldioxirane (1.8 mL of a 0.1 M solu-
tion in acetone, 0.18 mmol) dropwise. After stirring for
10 min, the reaction mixture was concentrated. The result-
ing white solid was taken up in THF (1.5 mL) and cooled to
08C. To this solution was added Me2CuLi (2.2 mL of a
0.27 M solution in THF, 0.60 mmol; prepared from the
addition of MeLi (1.8 mL of a 1.2 M solution in hexanes,
2.1 mmol) to a slurry of CuI (0.20 g, 1.0 mmol) and THF
(3.9 mL) at 08C). The reaction was allowed to warm to rt
over 1 h and was then quenched with sat. NH4Cl (aq.,
2 mL). After stirring for 0.5 h, the mixture was extracted
with ether (5£5 mL). The extracts were washed with brine
(1£5 mL), dried (Na2SO4), and concentrated. Flash chroma-
tography (5:1 hexanes/ethyl acetate) afforded 44 mg (82%)
of C-glycoside 6 as a white solid. mp 66±688C;
ꢀ6†
2.6. Acid mediated cyclizations to tricylic enol ethers
By simply subjecting bicyclic C-glycoside 44 to PPTS,
pyridine and heat, we were able to ef®ciently convert it
into tricyclic enol ether 45.
ꢀ7†
[a]D ˆ142.51 (cˆ1.70, CHCl3); 1H NMR (500 MHz,
29
CDCl3) 7.37±7.26 (m, 13H), 7.19±7.17 (m, 2H), 4.96 (d,
Jˆ11.6 Hz, 1H), 4.79 (d, Jˆ10.8 Hz, 1H), 4.73 (d,
Jˆ11.6 Hz, 1H), 4.63 (d, Jˆ12.2 Hz, 1H), 4.56 (d,
Jˆ10.3 Hz, 1H), 4.55 (d, Jˆ12.2 Hz, 1H), 3.73±3.66 (m,
2H), 3.62 (dd, Jˆ9.4, 9.4 Hz, 1H), 3.48±3.43 (m, 2H),
3.33±3.28 (m, 1H), 3.23 (dd, Jˆ9.0, 9.0 Hz, 1H), 2.10 (s,
1H), 1.31 (d, Jˆ6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 138.6, 138.1, 138.0, 128.7, 128.4, 128.4, 128.0, 127.8,
127.7, 86.7, 78.9, 78.6, 75.6, 75.5, 75.1, 74.8, 73.5, 69.1,
18.0; IR (neat) 3454, 1109 cm21; MS (FAB1) 449, HRMS
calcd for C28H33O5 (MH1) 449.2328, found 449.2332.
3. Conclusion
To conclude, we have developed a relatively ef®cient and
¯exible approach to fused polycyclic ethers that couples the
synthesis of C-glycosides with enol ether±ole®n RCM
reactions and/or acid mediated cyclizations. We are
continuing to optimize these approaches in model systems
and to apply them in the synthesis of members of the marine
ladder toxin family of natural products.
4.2.2. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-(prop-2-ynyl)-tetrahydro-pyran-3-ol 8. To a
solution of anhydride 5 (0.36 mmol) and CH2Cl2 (4.5 mL)
at 08C was added propargylmagnesium chloride (0.75 mL of
a 1.2 M solution in THF, 0.90 mmol). After stirring for
10 min, the reaction was quenched with sat, aq. NH4Cl
(5 mL). The mixture was extracted with ether (5£5 mL),
washed with brine (1£20 mL), dried (Na2SO4), and concen-
trated. Flash chromatography (5:1 hexanes: ethyl acetate) to
afford 132 mg (78%) of alcohol 8 as a colorless oil.
4. Experimental
4.1. General
NMR spectra were recorded on either a Bruker EM-600,
Bruker EM-500, Bruker AM-250, or a Varian 300 spectro-
meter. Chemical shifts were reported in d, parts per million
(ppm), relative to chloroform (dˆ7.24 ppm) as an internal
standard. Coupling constants, J, were reported in Hertz (Hz)
and refer to apparent peak multiplicities and not true
coupling constants. Optical rotation was recorded on a
JASCO P-1020 spectrometer. Mass spectra were recorded
at the Mass Spectrometry Facility at the Department of
Chemistry of the University of Arizona on a Jeol HX-
110A and are reported as percent relative intensity to the
molecular base peak. IR spectra were recorded on a Nicolet
Impact 410. Ether and THF were distilled from sodium/
benzophenone. CH2Cl2, CHCl3, hexanes, benzene, toluene,
TMEDA, (i-Pr)2NEt, Et3N, and Et2NH were distilled from
CaH2. All other reagents were used without puri®cation.
Unless otherwise stated, all reactions were run under an
atmosphere of argon in ¯ame-dried glassware. Concentra-
tion refers to removal of solvent under reduced pressure
(house vacuum at ca. 20 mmHg) with a BuÈchi Rotavapor.
Characterization data for compounds 6±15, 21±23, 28, 29,
36, and 37 have been reported elsewhere.7,10
[a]D ˆ135.4 (cˆ0.640, CHCl3); 1H NMR (250 MHz,
29
CDCl3) d 7.42±7.24 (m, 13H), 7.22±7.21 (m, 2H), 4.98
(d, Jˆ11.5 Hz, 1H), 4.83 (d, Jˆ11.1 Hz, 1H), 4.78 (d,
Jˆ11.7 Hz, 1H), 4.70 (d, Jˆ12.2 Hz, 1H), 4.62 (d,
Jˆ10.8 Hz, 1H), 4.61 (d, Jˆ12.1 Hz, 1H), 3.78±3.49 (m,
6H), 3.48±3.43 (m, 1H), 2.72 (dddd, Jˆ16.7, 3.2, 3.2,
1.0 Hz, 1H), 2.58 (ddd, Jˆ17.2, 5.8, 2.7 Hz, 1H), 2.38 (br
s, 1H), 2.04 (dd, Jˆ2.6, 2.6 Hz, 1H); 13C NMR (62.5 MHz,
CDCl3) d 138.7, 138.4, 138.2, 128.8, 128.6, 128.5, 128.1,
128.0, 128.0, 127.7, 86.6, 80.7, 79.5, 78.4, 77.8, 77.3, 77.1,
75.4, 75.0, 73.6, 73.1, 70.4, 68.9, 22.2; IR (CCl4) 3571,
3310, 2864, 1448, 1100 cm21; MS (FAB1) 473 (MH1),
HRMS calcd for C30H32O5 (MH1) 473.2328, found
473.2329.
4.2.3. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-vinyl-tetrahydro-pyran-3-ol 11. To a solution
of anhydride 5 (0.24 mmol) and CH2Cl2 at 2608C was
added vinylmagnesium bromide (0.48 mL of a 2.0 M

2004
S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
solution in THF, 0.96 mmol). After stirring for 10 min, the
reaction was quenched with sat, aq. NH4Cl (2 mL). The
mixture was extracted with ether (5£5 mL), washed with
brine (1£5 mL), dried (Na2SO4), and concentrated. Flash
chromatography (5:1 hexanes/ethyl acetate) gave 69 mg
Jˆ11.0, 2.2 Hz, 1H), 3.74±3.71 (m, 1H), 3.71 (dd,
Jˆ9.3 Hz, 1H), 3.62 (dd, Jˆ8.9 Hz, 1H), 3.59 (partially
obscured ddd, Jˆ9.3, 4.0, 2.3 Hz, 1H), 2.02 (s, 1H); 13C
NMR (125 MHz, CDCl3) d 151.0, 142.9, 138.6, 138.1,
138.0, 128.6, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8,
127.6, 110.4, 109.6, 86.4, 79.4, 77.9, 75.3, 75.0, 73.5,
72.7, 68.9; IR (neat) 3472, 1109 cm21; MS (FAB1) 501,
HRMS calcd for C31H33O6 (MH1) 501.2277, found
501.2289.
(57%) of vinyl-C-glycoside 11 as
a colorless oil.
[a]D ˆ122.0 (cˆ0.415, CHCl3); 1H NMR (500 MHz,
CDCl3) d 7.33±7.24 (m, 13H), 7.14±7.13 (m, 2H), 5.76
(ddd, Jˆ17.3, 10.2, 7.2 Hz, 1H), 5.27 (d, Jˆ17.2 Hz, 1H),
5.19 (d, Jˆ10.8 Hz, 1H), 4.90 (dd, Jˆ9.3, 9.3 Hz, 1H), 4.79
(d, Jˆ11.0 Hz, 1H), 4.77 (d, Jˆ10.0 Hz, 1H), 4.66 (d,
Jˆ11.5 Hz, 1H), 4.60 (d, Jˆ12.2 Hz, 1H), 4.53 (d,
Jˆ10.9 Hz, 2H), 3.74±3.64 (m, 5H), 3.48 (ddd, Jˆ7.3,
3.9, 2.2 Hz, 1H), 1.88 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 169.7, 138.4, 138.1, 138.0, 134.4, 128.4, 128.4,
128.0, 127.8, 127.7, 127.7, 127.6, 119.1, 84.2, 79.9, 79.0,
78.1, 75.1, 73.5, 73.2, 68.8, 21.0; IR (CCl4) 2858, 1758,
1375, 1233, 1110 cm21; MS (FAB1) 503 (MH1), 501, 91
m/z, HRMS calcd for C31H35O6 (MH1) 503.2434, found
503.2439.
29
4.2.6. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-(4,40-diethyloxybutyl)-tetrahydro-pyran-3-ol
15. To a solution of anhydride 5 (0.48 mmol) and THF
(5 mL) at 08C was added a solution of cuprate 14 (prepared
from 1-bromo-4,4-diethoxybutane (0.54 mL, 2.4 mmol),
Mg (0.12 g, 4.8 mmol), CuI (0.23 g, 1.2 mmol), and THF
(10 mL)). After 15 min, the reaction was quenched with
aq. NH4Cl (sat., 15 mL), extracted with ether (3£20 mL),
washed with brine (2£50 mL), dried (Na2SO4), and con-
centrated. Flash chromatography (2:1 hexanes/ethyl
acetate) afforded 0.18 g (65%) of alcohol 15 as a colorless
oil. The alcohol was characterized as the corresponding
acetate.
4.2.4. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-phenyl-tetrahydro-pyran-3-ol 16. To a solution
of anhydride 5 (0.12 mmol), and ether (2.0 mL) at 08C was
added Ph2CuLi (1.3 mL of a 0.23 M solution in ether,
0.30 mmol; prepared from the addition of PhLi (0.33 mL
of a 1.8 M solution in hexanes, 0.6 mmol) to CuI (0.057 g,
0.30 mmol) in ether (1 mL) at 08C). After stirring for
10 min, the reaction was quenched with sat, aq. NH4Cl
(2 mL). After an additional 0.5 h, the mixture was extracted
with ether (5£5 mL), washed with brine (1£5 mL), dried
(Na2SO4), and concentrated. Flash chromatography (5:1
hexanes/ethyl acetate) afforded 52 mg (84%) of phenyl-C-
To a solution of alcohol 15 (0.040 g, 0.069 mmol) and
CH2Cl2 (3.0 mL) was added i-Pr2NEt (0.096 mL,
0.41 mmol), Ac2O (0.039 mL, 0.41 mmol), and DMAP
(ca. 0.005 g). After stirring for 1 h, the reaction mixture
was quenched with sat. NaHCO3 (aq., 5 mL). Following
extraction with CH2Cl2 (3£10 mL), the extracts were
washed with brine (1£10 mL), dried (MgSO4), and concen-
trated. Flash chromatography (5:1 hexanes/ethyl acetate)
gave 38 mg (89%) of acetate 15b as a colorless oil. Acetate
glycoside 16 as a colorless oil. [a]D ˆ122.7 (cˆ1.35,
of 15b: [a]D ˆ15.6 (cˆ0.50, CHCl3); 1H
N MR
29
29
CHCl3); 1H NMR (500 MHz, CDCl3) d 7.46±7.27 (m,
20H), 4.98 (d, Jˆ11.4 Hz, 1H), 4.92 (d, Jˆ10.6 Hz, 1H),
4.91 (d, Jˆ11.4 Hz, 1H), 4.70 (d, Jˆ10.6 Hz, 1H), 4.69 (d,
Jˆ12.2 Hz, 1H), 4.60 (d, Jˆ12.2 Hz, 1H), 4.20 (d,
Jˆ9.2 Hz, 1H), 3.85±3.80 (m, 3H), 3.73 (dd, Jˆ8.8,
8.8 Hz, 1H), 3.67±3.64 (m, 2H), 1.92 (s, 1H); 13C N MR
(125 MHz, CDCl3) d 138.7, 138.5, 138.3, 138.2, 128.5,
128.5, 128.4, 128.4, 128.3, 128.0, 127.8, 127.8, 127.7,
127.5, 127.4, 86.4, 82.1, 79.5, 78.1, 75.8, 75.3, 75.0, 73.5,
69.1; IR (neat) 3446, 1092 cm21; MS (FAB1) 511, HRMS
calcd for C33H35O5 (MH1), 511.2484, found 511.2495.
(500 MHz, CDCl3) d 7.37±7.28 (m, 13H), 7.20±7.18 (m,
2H), 4.89 (dd, Jˆ9.3, 9.3 Hz, 1H), 4.82 (d, Jˆ11.5 Hz, 1H),
4.79 (d, Jˆ10.8 Hz, 1H), 4.67 (d, Jˆ11.4 Hz, 1H), 4.63 (d,
Jˆ12.2 Hz, 1H), 4.57 (d, Jˆ10.8 Hz, 1H), 4.56 (d,
Jˆ12.2 Hz, 1H), 4.46 (t, Jˆ5.4 Hz, 1H), 3.74 (dd,
Jˆ11.0, 2.0 Hz, 1H), 3.71±3.59 (m, 5H), 3.48 (m, 2H),
3.42 (ddd, Jˆ9.3, 4.3, 2.0 Hz, 1H), 3.26 (ddd, Jˆ9.6, 5.7,
5.7 Hz, 1H), 1.94 (s, 3H), 1.62 (m, 3H), 1.49 (m, 2H), 1.41
(m, 1H), 1.19 (ddd, Jˆ7.1, 7.1, 2.0 Hz, 6H); 13C N MR
(125 MHz, CDCl3) d 169.4, 138.4, 138.3, 138.1, 128.4,
128.4, 128.3, 128.0, 127.7, 127.7, 127.6, 127.5, 102.9,
84.7, 79.2, 78.5, 77.8, 75.1, 74.9, 74.1, 73.5, 69.0, 31.1,
60.8, 33.5, 31.3, 20.9, 20.7, 15.3, 15.3; IR (CCl4) 2864,
1758, 1548, 1227, 1091 cm21; MS (FAB1) for 15b 577
(MH1), 91 m/z, HRMS for 15b calcd for C35H45O7 (MH1)
577.3165, found 577.3150.
4.2.5. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-(furan-2-yl)-tetrahydro-pyran-3-ol 17. To a
solution of anhydride 5 (0.12 mmol) and ether (2.0 mL) at
2608C was added ZnCl2 (0.018 g, 0.13 mmol) followed by
2-lithiofuran (1.0 mL of a 0.6 M solution in ether,
0.6 mmol). After warming to rt over 2 h, the reaction was
quenched with 0.5 M HCl (aq., 2 mL). After stirring for
0.5 h, the mixture was extracted with ether (5£5 mL),
washed with brine (1£5 mL), dried (Na2SO4), and concen-
trated. Flash chromatography (5:1 hexanes/ethyl acetate)
afforded 47 mg (78%) of furyl C-glycoside 17 as a colorless
4.2.7.
(2R,3S,4R,5S,6S)-3,4-Dibenzyloxy-2-benzyloxy-
methyl-6-methyl-3,4,4a,8,9,9a-hexahydro-2H-1,5-dioxa-
benzocycloheptene 31. A solution of acetate 21 (0.92 g,
1.8 mmol) and THF (57 mL) at 08C was treated with BH3
(1.9 mL of a 1.0 M solution in THF, 1.9 mmol). After 2 h,
NaOH (1.83 mL of a 3 M solution (aq.), 5.5 mmol) and
H2O2 (0.37 mL of a 30% solution (aq.), 3.9 mmol) were
added to the reaction mixture sequentially. After warming
to rt, H2O (20 mL) was added to the reaction mixture. The
aqueous phase was extracted with ether (3£20 mL), dried
(MgSO4), and concentrated. Flash chromatography (10:1
hexanes/ethyl acetate) afforded 0.70 g (73%) of the alcohol
29
1
oil. [a]D ˆ121.6 (cˆ1.40, CHCl3); H NMR (500 MHz,
CDCl3) d 7.41±7.25 (m, 16H), 7.23±7.17 (m, 1H), 6.42±
6.35 (m, 1H), 4.93 (d, Jˆ11.5 Hz, 1H), 4.85 (d, Jˆ11.5 Hz,
1H), 4.84 (d, Jˆ10.7 Hz, 1H), 4.59 (d, Jˆ12.2 Hz, 1H), 4.58
(d, Jˆ9.0 Hz, 1H), 4.51 (d, Jˆ12.2 Hz, 1H), 4.26 (d,
Jˆ9.8 Hz, 1H), 3.95 (dd, Jˆ9.5, 9.5 Hz, 1H), 3.75 (dd,

S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
2005
24
from 21 as a white solid. Mp 52±548C; [a]D ˆ6.9 (cˆ0.41,
To a slurry of CH3PPh3Br (0.13 g, 0.36 mmol) and THF
(2 mL) at 08C was added BuLi (0.19 mL of a 1.6 M solution
in THF, 0.30 mmol) dropwise. The resulting orange solution
was allowed to warm to rt. After 4 h, the solution was cooled
to 08C and a solution of the aldehyde from above (0.0190 g,
0.036 mmol) and THF (1 mL) was added via cannula. After
0.25 h, the reaction was quenched with sat. NH4Cl (aq.,
10 mL), extracted with CH2Cl2 (3£10 mL), dried
(Na2SO4), and concentrated. Flash chromatography (10:1
hexanes/ethyl acetate) afforded 102 mg (79%) of the alkene
1
THF); H NMR (500 MHz, CDCl3) d 7.36±7.22, (m, 13H,
PhH), 7.19±7.12 (m, 2H, PhH), 4.88 (dd, Jˆ15.0, 7.5 Hz,
1H), 4.78 (dd, Jˆ15.0, 10.0 Hz, 2H), 4.67 (d, Jˆ10.0 Hz,
1H), 4.62±4.48 (m, 3H,), 3.75±3.59 (m, 4H), 3.45±3.35 (m,
1H), 3.35±3.28 (m, 1H), 2.65±2.50 (m, 2H), 1.95 (s, 3H),
1.78±1.62 (m, 2H); 13C NMR (125 MHz, CDCl3) d
202.2, 170.1, 138.7, 187.6, 138.5, 128.9, 128.5, 84.7,
75.1, 78.3, 77.6, 77.3, 77.0, 75.3, 75.1, 69.0, 39.6, 24.2,
21.1; IR (CH2Cl2) 3429, 3048, 2988, 1265 cm21; MS
(FAB1) 533.3, (MH1), 185.1, 93.2 m/z, HRMS calcd for
C32H38O7 (MH1) 535.2696, found 535.2719. Analysis
calcd for C32H38O7: C, 71.89; H, 7.16. Found: C, 71.97;
H, 7.41.
29
as a white solid. Mp 38±398C; [a]D ˆ11.7 (cˆ0.70, THF);
1H NMR (500 MHz, CDCl3) d 7.50±7.23 (m, 13H, PhH),
7.22±7.16 (m, 2H, PhH), 5.79 (ddt, Jˆ17.1, 10.3, 6.8 Hz,
1H), 5.01 (d, Jˆ10.0 Hz, 1H), 4.95 (d, Jˆ5.0 Hz, 1H), 4.89
(t, Jˆ3.0 Hz, 1H), 4.80 (dd, Jˆ15.0, 10.0 Hz, 2H), 4.70±
4.52 (m, 4H), 3.79±3.59 (m, 4H), 3.48±3.39 (m, 1H), 3.32±
3.24 (m, 1H), 2.33±2.23 (m, 1H), 2.16±2.06 (m, 1H), 1.95
(s, 3H), 1.61±1.51 (m, 2H); 13C NMR (125 MHz, CDCl3) d
170.1, 138.5, 138.3, 138.1, 128.6, 128.1, 127.8, 115.1, 85.0,
79.4, 78.8, 77.6, 77.3, 77.0, 75.3, 75.1, 74.2, 73.7, 69.2,
30.9, 29.3, 21.2; IR (CH2Cl2) 3048, 1733, 1413,
1265 cm21; MS (FAB1) 531.28 (MH1), 441.2, 185.1 m/z,
HRMS calcd for C33H38O6 (MH1): 531.2747, found
531.2779.
To a solution of the alcohol from the hydroboration
(0.115 g, 0.220 mmol) and CH2Cl2 (1 mL) was added
i-Pr2NEt (0.15 mL, 0.86 mmol), TIPSCl (0.092 mL,
0.43 mmol), and DMAP (ca. 0.005 g). The reaction mixture
was allowed to warm to rt and was quenched with H2O
(10 mL) after 5 h. The aqueous phase was extracted with
CH2Cl2 (3£10 mL), dried (Na2SO4), and concentrated.
Flash chromatography (5:1 hexanes/ethyl acetate) afforded
104 mg (69%) of TIPS ether 25 as a colorless oil.
24
1
[a]D ˆ4.1 (cˆ2.0, THF); H NMR (500 MHz, CDCl3) d
7.36±7.21 (m, 13H), 7.19±7.12 (m, 2H, PhH), 4.88 (t,
Jˆ7.5 Hz, 1H), 4.78 (t, Jˆ10.0 Hz, 2H), 4.67 (d,
Jˆ10.0 Hz, 1H), 4.62±4.43 (m, 3H), 3.77±3.55 (m, 4H),
3.43±3.33 (m, 1H), 3.33±3.20 (m, 1H), 1.90 (s, 3H),
1.84±1.71 (m, 2H), 1.70±1.51 (m, 2H), 1.50±1.33 (m,
2H), 1.12±0.90 (m, 21H); 13C NMR (125 MHz) d 169.8,
138.7, 138.5, 138.3, 128.3, 127.9, 127.7, 84.8, 79.3, 78.6,
78.0, 77.6, 77.3, 77.0, 75.3, 75.1, 74.2, 73.6, 69.2, 63.2,
63.1, 28.8, 28.0, 21.0, 18.8, 18.2, 17.8, 17.2, 13.6, 12.7,
12.2; IR (CH2Cl2) 3049, 2296, 1750, 1430 cm21; MS
(FAB1) 691.43 (MH1), 307.1, 154.0, m/z, HRMS calcd
for C41H59O7Si (MH1) 691.4030, found 691.4056.
To a yellow solution of TiCl4 (0.35 mL, 1.1 mmol) and
CH2Cl2 (9 mL) at 08C was added THF (0.20 mL,
6.4 mmol) and then TMEDA (0.96 mL, 6.4 mmol) drop-
wise. After stirring for 10 min, Zn (0.16 g, 2.4 mmol) and
PbCl2 (0.035 g, 0.057 mmol) were added. The color of the
reaction mixture changed from brown to green to blue to
greenish blue after 20 min A solution of the acetate 24
(0.030 g, 0.057 mmol), CH2Br2 (0.075 mL, 1.1 mmol), and
CH2Cl2 (1.5 mL) were transferred to the reaction mixture.
The resulting slurry was heated to 658C for 4.5 h. After
cooling to 08C, the reaction was stirred with K2CO3 (sat.,
0.25 mL) for 0.5 h. Following vacuum ®ltration, the
resulting solution was further ®ltered through a plug of
neutral alumina (NEt3/Et2O, 3:100). Concentration provided
19 mg (63%) of enol ether 26 as a yellow oil. Enol ether 26
was immediately subjected to the subsequent RCM
protocol.
4.2.8. (2b,3S,4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxy-
methyl-2-(3-butenyl)-tetrahydro-pyran-3-acetate 24. To
a solution of (COCl)2 (0.45 mL, 5.2 mmol) and CH2Cl2 at
2608C was added DMSO (0.772 mL, 10.9 mmol) dropwise.
To this solution was added a solution of the alcohol from the
hydroboration, oxidation of 21 (1.05 g, 2.0 mmol) and
CH2Cl2 dropwise via cannula. After 0.5 h, NEt3 (3.8 mL,
31.3 mmol) was added and the mixture was allowed to
warm to rt. The reaction mixture was quenched with sat.
NH4Cl (aq., 20 mL), extracted with CH2Cl2 (3£20 mL),
dried (Na2SO4), and concentrated. Flash chromatography
(10:1 hexanes/ethyl acetate) afforded 0.98 g (94%) of the
To a solution of enol ether 26 (0.019 g, 0.036 mmol) and
benzene (4.3 mL) at rt was added Ru catalyst 33 (0.0073 g,
0.0088 mmol). After stirring at rt for 4 h, the reaction
mixture was concentrated. Flash chromatography (20:1,
hexanes/ethyl acetate) gave 16 mg (78%) of bicycle 31 as
24
1
a colorless oil. [a]D ˆ225.7 (cˆ0.110, THF); H N MR
(500 MHz, C6D6) d 7.43 (d, Jˆ7.5 Hz, 2H), 7.29 (d,
Jˆ7.5 Hz, 2H), 7.25 (d, Jˆ7.5 Hz, 2H, PhH), 7.22±7.05
(m, 8H, PhH), 5.13 (d, Jˆ10 Hz, 1H), 4.95 (d, Jˆ10 Hz,
1H), 4.85 (d, Jˆ10 Hz, 1H), 4.68 (t, Jˆ5 Hz, 1H), 4.61 (d,
Jˆ12.5 Hz, 1H), 4.43 (d, Jˆ10.0 Hz, 1H), 4.38 (d,
Jˆ10.0 Hz, 1H), 3.74±3.65 (m, 4H), 3.59±3.51 (m, 1H),
3.49±3.41 (m, 1H), 3.30±3.23, (m, 1H), 2.08±2.01 (m,
1H), 1.95±1.80 (m, 1H), 1.72±1.68 (s, 3H), 1.57±1.48 (m,
2H); 13C NMR (125 MHz, C6D6) d 157.1, 140.3, 139.7,
139.3, 128.0, 108.7, 86.0, 84.8, 80.2, 79.8, 78.8, 76.0,
75.2, 74.1, 70.1, 33.0, 21.5, 21.2; IR (CH2Cl2) 3039, 2918,
1681, 1508 cm21; MS (FAB1) 501.26 (MH1), 185.1, 93.2
m/z, HRMS calcd for C32H37O5 (MH1) 501.2641, found
501.2642.
24
corresponding aldehyde as a colorless oil. [a]D ˆ3.88
(cˆ0.65, THF); 1H NMR (500 MHz, CDCl3) d 9.74
(s, 1H), 7.50±7.22 (m, 13H), 7.19±7.12 (m, 2H), 4.88
(dd, Jˆ15.0, 7.5 Hz, 1H), 4.78 (dd, Jˆ15.0, 10.0 Hz, 2H),
4.67 (d, Jˆ10.0 Hz, 1H), 4.62±4.48 (m, 3H), 3.75±3.59
(m, 4H), 3.45±3.35 (m, 1H), 3.35±3.28 (m, 1H), 2.65±
2.50 (m, 2H), 1.95 (s, 3H), 1.78±1.62 (m, 2H); 13C N MR
(125 MHz, CDCl3) d 202.0, 170.1, 138.7, 138.6, 138.5,
133.5, 128.9, 128.5, 84.7, 75.1, 78.3, 77.6, 77.3, 77.0,
75.3, 75.1, 69.0, 39.6, 24.2, 21.1; IR (CH2Cl2) 3048, 2858,
1750, 1447 cm21; MS (FAB1) 533.25 (MH1), 181.1, 91.2
m/z, HRMS calcd for C32H37O7 (MH1) 533.2461, found
533.2536.

2006
S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
4.2.9. Preparation of [3-(4,5-bis-benzyloxy-6-benzyloxy-
methyl-3-isopropenyloxy-tetrahydro-pyran-2-yl)-pro-
poxy-[triisopropylsilane] 27. 27 was synthesized using the
protocol used for the synthesis of 26 and TiCl4 (0.32 mL,
1.0 mmol), CH2Cl2 (7.7 mL), THF (0.17 mL, 1.0 mmol),
TMEDA (0.87 mL, 5.8 mmol), Zn (0.14 g, 2.2 mmol),
PbCl2 (0.032 g, 0.12 mmol), acetate 25 (0.036 g,
0.052 mmol), CH2Br2 (0.068 mL, 1.0 mmol), and CH2Cl2
(1.4 mL) gave 29 mg (81%) of enol ether 27 as a colorless
oil. [a]D ˆ224.5 (cˆ0.530, THF); H NMR (500 MHz,
C6D6) d 7.40 (d, Jˆ7.5 Hz, 2H), 7.30 (d, Jˆ7.5 Hz, 2H),
7.25 (d, Jˆ7.5 Hz, 2H), 7.20±7.16 (m, 7H), 7.10 (t,
Jˆ7.5 Hz, 2H), 4.91 (d, Jˆ11.0 Hz, 1H), 4.72 (d,
Jˆ10.5 Hz, 1H), 4.62 (d, Jˆ11.0 Hz, 1H), 4.48 (d,
Jˆ12.3 Hz, 1H), 4.42 (d, Jˆ12.3 Hz, 1H), 4.30 (br s, 1H),
4.08 (t, Jˆ9.0 Hz, 1H), 4.02 (br s, 1H), 3.78±3.62 (m, 4H),
3.42±3.40 (m, 1H), 3.34±3.31 (m, 1H), 2.03±1.94 (m, 2H),
1.78 (s, 3H), 1.65±1.57 (m, 1H), 1.52±1.43 (m, 1H), 1.38±
0.98 (m, 23H); 13C NMR (125 MHz, C6D6) d 159.5, 139.9,
139.8, 139.5, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2, 128.0, 87.1, 84.6, 80.1, 79.9, 79.7, 79.7,
78.9, 75.6, 75.4, 74.0, 70.1, 64.1, 63.9, 30.5, 30.0, 29.2,
21.8, 19.3, 18.7, 18.4, 17.9, 14.2, 13.4, 12.8; IR (CH2Cl2)
3049, 2919, 1663, 1456 cm21; MS (FAB1) 690 (MH1), 632,
91 m/z, HRMS calcd for C42H61O6Si (MH1) 689.4237,
found 689.4238.
(2.7 mL of a 0.1 M solution, 0.27 mmol). A solution of
the anhydride and THF (5.4 mL) at 08C was treated with a
solution of acetal Grignard 12 (1.12 mL of a 0.48 M solution
in THF, 0.54 mmol). After stirring for 0.33 h, the reaction
was quenched with aq. NH4Cl (sat., 10 mL). The mixture
was extracted with ether (3£10 mL), dried (MgSO4), and
concentrated. Flash chromatography (5:1 hexanes/ethyl
acetate) afforded 73 mg (67%) of alcohol 40 as a 10:1 b/a
mixture. The alcohols were characterized as the
corresponding acetates.
24
1
The mixture of alcohols from above (0.024 g, 0.040 mmol)
were treated with i-Pr2NEt (0.06 mL, 0.32 mmol), Ac2O
(0.024 mL, 0.24 mmol), and DMAP (ca. 0.005 g). After
stirring for 1 h, the reaction mixture was quenched with
aq. NaHCO3 (sat., 5 mL). The aqueous phase was extracted
with CH2Cl2 (3£10 mL), washed with brine (1£10 mL),
dried (MgSO4), and concentrated. Flash chromatography
(10:1 hexanes/ethyl acetate) provided 19 mg (73%) of
acetate 40b along with 2 mg (8%) of acetate 40a Acetate
of 40b: [a]D ˆ28.25 (cˆ0.65, CHCl3); 1H N MR
29
(500 MHz, CDCl3) d 7.35±7.24 (m, 13H), 7.11±7.10 (m,
2H), 4.91±4.89 (m, 2H), 4.78 (d, Jˆ10.9 Hz, 2H), 4.58 (d,
Jˆ12.3 Hz, 1H), 4.52 (d, Jˆ12.3 Hz, 1H), 4.48 (d,
Jˆ10.8 Hz, 1H), 4.29 (t, Jˆ5.5 Hz, 1H), 3.69 (dd,
Jˆ10.6, 1.3 Hz, 1H), 3.63±3.60 (m, 2H), 3.56±3.50 (m,
2H), 3.45±3.42 (m, 1H), 3.37 (dd, Jˆ8.9, 8.9 Hz, 1H),
3.21 (s, 6H), 3.17 (part. obs. dd, Jˆ9.7, 4.4 Hz, 1H), 2.06
(s, 3H), 1.95±1.90 (m, 2H), 1.85±1.72 (m, 3H), 1.67±1.52
(m, 3H); 13C NMR (125 MHz, CDCl3) d 170.3, 138.7,
138.2, 138.1, 128.4, 128.4, 128.4, 127.9, 127.9, 127.7,
127.6, 127.6, 104.3, 85.8, 83.9, 83.1, 79.0, 78.1, 76.6,
75.7, 75.1, 73.5, 69.2, 52.9, 52.6, 29.8, 28.8, 26.7, 23.9,
21.4; IR (CCl4) 2944, 1740, 1245, 1073 cm21; MS
(FAB1) 647 (MH1), 618, 91 m/z, HRMS calcd for
4.2.10. (4S,5R,6S,7S,8R)-1,2-Anhydro-6,7,9-tribenzyloxy-
pyrano-[4,5]-pyran 36. To a solution of alcohol 15
(0.025 g, 0.043 mmol) and chlorobenzene (2 mL) at 08C
was added PPTS (0.066 g, 0.264 mmol). The solution was
heated to 608C until all of the starting material was
consumed (TLC). After cooling, pyridine (0.009 mL,
0.11 mmol) was added and the resulting mixture was heated
to 1358C for 4 h. The reaction was quenched with NaOH
(1 M, 2 mL), extracted with ether (3£3 mL), washed with
brine (2£15 mL), dried (Na2SO4), and concentrated. Flash
chromatography (10:1 hexanes/ethyl acetate) afforded
15 mg (72%) of bicyclic enol ether 36 as a colorless oil.
C38H47O9 (MH1) 647.3220, found 647.3203. Acetate of
40a: [a]D ˆ10.63 (cˆ0.39, CHCl3); 1H
N
MR
28
(500 MHz, CDCl3) d 7.34±7.24 (m, 13H), 7.20±7.00 (m,
2H), 4.91 (d, Jˆ11.8 Hz, 1H), 4.88 (d, Jˆ11.8 Hz, 2H), 4.68
(d, Jˆ10.6 Hz, 1H), 4.67 (part. obs. m, 1H), 4.59 (d,
Jˆ12.3 Hz, 1H), 4.52 (d, Jˆ12.3 Hz, 1H), 4.46 (d,
Jˆ10.6 Hz, 1H), 4.04 (t, Jˆ5.4 Hz, 1H), 3.67 (dd,
Jˆ10.6, 1.6 Hz, 1H), 3.64±3.59 (m, 2H), 3.54 (dd, Jˆ9.4,
9.4 Hz, 1H), 3.41 (ddd, Jˆ9.7, 4.2, 1.7 Hz, 1H), 3.31 (dd,
Jˆ9.1, 9.1 Hz, 1H), 3.25±3.20 (m, 1H), 3.12 (s, 3H), 3.03
(s, 3H), 2.17 (ddd, Jˆ13.7, 5.9, 5.9 Hz, 1H), 2.01 (s, 3H),
1.83 (ddd, Jˆ11.8, 11.8, 11.8 Hz, 1H), 1.76±1.47 (m, 6H);
13C NMR (125 MHz, CDCl3) d 170.2, 138.9, 138.1, 137.9,
128.4, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 127.1,
126.8, 104.1, 85.3, 79.3, 78.6, 78.5, 77.5, 76.1, 75.4, 75.0,
73.5, 68.9, 52.9, 52.2, 30.9, 29.1, 27.5, 26.9, 21.3; IR (CCl4)
2938, 1740, 1233, 1079 cm21; MS (FAB1) 647 (MH1), 618,
91 m/z, HRMS calcd for C38H47O9 (MH1) 647.3220, found
647.3203.
[a]D ˆ27.76 (cˆ0.795, CHCl3); 1H NMR (500 MHz,
30
CDCl3) d 7.42±7.24 (m, 13H), 7.15±7.13 (m, 2H), 6.35
(dd, Jˆ6.3, 1.5 Hz, 1H), 4.98 (dd, Jˆ11.7, 6.2 Hz, 1H),
4.96 (d, Jˆ11.1 Hz, 1H), 4.83 (d, Jˆ10.8 Hz, 1H), 4.79
(d, Jˆ11.2 Hz, 1H), 4.58 (d, Jˆ12.3 Hz, 1H), 4.53 (d,
Jˆ12.7 Hz, 1H), 4.50 (d, Jˆ10.8 Hz, 1H), 3.71 (dd,
Jˆ11.0, 1.6 Hz, 1H), 3.67 (d, Jˆ8.8 Hz, 1H), 3.62 (dd,
Jˆ10.8, 4.9 Hz, 1H), 3.57±3.51 (m, 2H), 3.47 (ddd,
Jˆ9.9, 4.8, 1.5 Hz, 1H), 3.43±3.41 (m, 1H), 2.43±2.13
(m, 2H), 2.07±1.99 (m, 1H), 1.63±1.58 (m, 1H); 13C
NMR (62.5 MHz, CDCl3) d 147.4, 139.1, 138.3, 138.2,
128.3, 128.0, 127.8, 127.7, 127.6, 127.5, 112.7, 85.2, 84.6,
79.5, 78.9, 77.9, 75.5, 75.0, 73.5, 69.4, 67.3, 65.9, 32.4,
20.6; IR (CCl4) 1647, 1449, 1208, 1073 cm21; MS
(FAB1) 487 (MH1), 91 m/z, HRMS calcd for C31H35O5
(MH1) 487.2484, found 487.2488.
4.2.12.
(2R,4S,5R,6S,7S,8R)-1,2-Diacetoxy-6,7,9-tri-
4.2.11.
(1S,2R,5S,6R,7S,8S,9R)-2-Hydroxy-1-(3,3-di-
benzyloxypyrano-[4,5]-pyran 41. A mixture of AD
mix-a (0.40 g), NH2SO2Me (0.041 g, 0.43 mmol), t-BuOH
(0.65 mL), and H2O (0.65 mL) was stirred at rt for 0.25 h
before a solution of bicyclic enol ether 29 (0.068 g,
0.14 mmol) and THF (0.65 mL) was added. After 20 h,
the reaction was quenched with sat. Na2SO4 (aq., 3 mL).
The mixture was extracted with ether (3£3 mL), washed
methoxypropyl)-7,8,10-tribenzyloxypyrano-[5,6]-oxa-
pane 40b and (1R,2S,5S,6R,7S,8S,9R)-2-hydroxy-1-(3,3-
dimethoxypropyl)-7,8,10-tribenzyloxypyrano-[5,6]-
oxepane 40a. The anhydride from 36 was prepared accord-
ing to the procedure used for the preparation of 5 using enol
ether 36 (0.088 g, 0.18 mmol) and dimethyldioxirane

S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
2007
with brine (10 mL), dried (MgSO4), and concentrated. The
resulting diols were immediately acetylated using Ac2O
(0.048 mL, 0.5 mmol), i-Pr2NEt (0.10 mL, 0.58 mmol),
and DMAP (ca. 0.005 g). Following workup, ¯ash chroma-
tography afforded 65 and 9.6 mg (12:1 mixture, 88%) of
acetates 41 and 42 respectively. 41 (white solid): mp 93±
CHCl3); 1H NMR (500 MHz, CDCl3) d 7.34±7.24 (m,
13H), 7.12±7.11 (m, 2H), 4.95 (d, Jˆ11.1 Hz, 1H), 4.83
(d, Jˆ10.7 Hz, 1H), 4.73 (d, Jˆ11.1 Hz, 1H), 4.68 (ddd,
Jˆ5.7, 5.7, 2.1 Hz, 1H), 4.59 (d, Jˆ12.3 Hz, 1H), 4.51 (d,
Jˆ13.1 Hz, 1H), 4.59±4.52 (m, 2H), 4.49 (d, Jˆ12.4 Hz,
1H), 4.47 (d, Jˆ10.9 Hz, 1H), 4.35 (t, Jˆ5.5 Hz, 1H), 3.69
(dd, Jˆ10.7, 1.5 Hz, 1H), 3.64 (dd, Jˆ10.8, 4.3 Hz, 1H),
3.61±3.56 (m, 2H), 3.46 (m, 1H), 3.32 (ddd, Jˆ9.4, 9.4,
2.0 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H), 3.21±3.14 (m,
2H), 2.52±2.49 (m, 1H), 2.04 (s, 3H), 1.91±1.86 (m, 1H),
1.72±1.62 (m, 2H), 1.55 (ddd, Jˆ11.1, 11.1, 11.1 Hz, 1H),
1.43±1.39 (m, 1H); 13C NMR (62.5 MHz, CDCl3) d 169.9,
138.6, 138.2, 138.1, 128.4, 128.3, 128.0, 127.9, 127.8,
127.7, 127.6, 104.2, 84.0, 82.4, 79.4, 78.8, 77.5, 75.2,
75.1, 73.5, 73.4, 70.6, 69.0, 52.9, 52.4, 35.1, 28.4, 26.7,
21.1; IR (CCl4) 1740, 1456, 1245, 1098 cm21; MS
(FAB1) 633 (M2H1), 91 m/z, HRMS calcd for C37H45O9
(M2H1) 633.3064, found 633.3077.
29
1
968C; [a]D ˆ11.3 (cˆ1.56, CHCl3); H NMR (250 MHz,
CDCl3) d 7.35±7.25 (m, 13H), 7.14±7.04 (m, 2H), 6.22 (d,
Jˆ3.4 Hz, 1H), 5.66 (d, Jˆ8.3 Hz, 1H), 4.98±4.81 (m, 3H),
4.69±4.43 (m, 4H), 3.72±3.42 (m, 6H), 3.43 (ddd, Jˆ10.4,
10.4, 6.4 Hz, 1H), 2.56 (ddd, Jˆ11.4, 4.5, 4.5 Hz, 1H), 2.29
(ddd, Jˆ11.4, 4.5, 4.5 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H),
2.05 (s, 3H), 2.04 (s, 3H), 1.99 (ddd, Jˆ11.8, 11.8, 11.8 Hz,
1H), 1.70 (ddd, Jˆ11.7, 11.7, 11.7 Hz, 1H); 13C N MR
(125 MHz, CDCl3) d 169.9, 169.5, 169.2, 169.1, 138.4,
138.4, 138.1, 138.0, 137.9, 137.9, 128.3, 128.3, 128.3,
128.2, 128.0, 127.9, 127.8, 127.7, 127.7, 127.6, 93.6, 88.2,
83.3, 83.1, 80.5, 79.5, 79.4, 77.4, 77.1, 75.2, 75.1, 75.0,
74.8, 73.5, 73.4, 72.8, 72.8, 72.4, 68.8, 68.8, 68.2, 67.3,
33.6, 29.6, 21.0, 20.9, 20.8; IR (CCl4) 1750, 1746, 1554,
1208, 1073 cm21; MS (FAB1) 591 (MH1), 589, 531, 441,
451, 91 m/z, HRMS calcd for C34H39O9 (MH1) 591.2594,
found 591.2606.
4.2.15. (2R,4S,5R,6S,7S,8R)-1,2-Dianhydro-9,10,12-tri-
benzyloxy-[4,5]-pyrano-[7,8]-pyran 45. According to the
procedure for the preparation of 29, acetal 43 (0.025 g,
0.038 mmol) was treated with PPTS (0.058 g, 0.23 mmol),
pyridine (0.0083 mL, 0.099 mmol), and PhCl (1.1 mL) to
afford 15 mg (72%) of tricyclic enol ether 45 as a colorless
4.2.13. (2R,4S,5R,6S,7S,8R)-2-Acetoxy-1-bromo-6,7,9-
tribenzyloxypyrano-[4,5]-pyran 43. To a solution of
diacetate 41 (0.018 g, 0.030 mmol) and CH2Cl2 (0.5 mL)
at rt was added TMSBr (0.12 mL, 1.1 mmol), dropwise.
The resulting solution was heated to re¯ux for 18 h and
then concentrated. Flash chromatography afforded 16 mg
(85%) of bromide 43 as a colorless oil. 1H N MR
(500 MHz, CDCl3) d 7.35±7.25 (m, 13H), 7.12±7.10 (m,
2H), 6.65 (d, Jˆ3.5 Hz, 1H), 4.86 (d, Jˆ11.2 Hz, 1H), 4.82
(d, Jˆ10.8 Hz, 1H), 4.70 (ddd, Jˆ11.8, 4.2, 4.2 Hz, 1H),
4.65 (d, Jˆ11.1 Hz, 1H), 4.58 (d, Jˆ12.2 Hz, 1H), 4.51 (d
Jˆ12.2 Hz, 1H), 4.47 (d, Jˆ10.5 Hz, 1H), 3.88, (dd, Jˆ9.4,
9.4 Hz, 1H), 3.70±3.60 (m, 4H), 3.48 (m, 1H), 3.28 (ddd,
Jˆ10.6, 10.6, 4.3 Hz, 1H), 2.20 (ddd, Jˆ11.7, 4.6, 4.6 Hz,
1H), 2.12 (ddd, Jˆ11.6, 11.6, 11.6 Hz, 1H), 2.11±2.09 (m,
1H), 2.09 (s, 3H); 13C NMR (125 MHz, CDCl3) d 169.9,
138.4, 138.0, 137.9, 128.4, 128.3, 128.0, 128.0, 127.9,
127.7, 127.7, 127.6, 89.0, 82.7, 79.6, 77.5, 76.8, 75.3,
74.7, 73.5, 72.2, 68.9, 68.7, 30.1, 20.9; IR (CCl4)1752,
1554, 1227, 1098 cm21; MS (FAB1) 611 (MH1), 609,
441, 91 m/z, HRMS calcd for C32H35O7Br (MH1),
609.1488, found 609.1505.
oil. [a]D ˆ152.1 (cˆ0.575, CHCl3); 1H NMR (250 MHz,
29
CDCl3) d 7.38±7.24 (m, 13H), 7.15±7.08 (m, 2H), 6.30 (d,
Jˆ6.0 Hz, 1H), 4.94 (d, Jˆ11.3 Hz, 1H), 4.84 (d,
Jˆ10.7 Hz, 1H), 4.75 (d, Jˆ13.1 Hz, 1H), 4.46 (d, Jˆ5.7,
5.7, 2.1 Hz, 1H), 3.73±3.25 (m, 8H), 3.19 (dd, Jˆ9.3,
4.0 Hz, 1H), 2.51 (ddd, Jˆ11.5, 3.9, 3.9, 1H), 2.30 (ddd,
Jˆ16.6, 5.1, 5.1 Hz, 1H), 2.10±1.99 (m, 1H), 1.67 (ddd,
Jˆ11.1, 11.1, 11.1 Hz, 1H); 13C NMR (62.5 MHz, CDCl3)
d 138.9, 138.2, 138.0, 128.4, 128.0, 127.9, 127.7, 127.5,
98.6, 84.0, 82.3, 79.4, 77.6, 75.2, 75.0, 74.6, 73.9, 73.5,
73.3, 69.0, 34.9, 26.8; IR (CCl4) 1647, 1449, 1239,
1067 cm21; MS (FAB1) 529 (MH1), 527, 91 m/z, HRMS
calcd for C33H35O6 (MH1) 527.2434, found 527.2450.
Acknowledgements
We graciously thank the National Institutes of Health,
General Medical Sciences (GM56677), Research Corpora-
tion, the Petroleum Research Fund, administered by the
American Chemical Society, and Gencorp for their support
of this work. Support of the NMR facility in the Department
of Chemistry at the University of Arizona by the National
Science Foundation under Grant No. 9729350 is also
gratefully acknowledged. The authors would like to thank
Professors Robin Polt (University of Arizona) and Keith
Woerpel (U. C. Irvine) for helpful discussions. We are
indebted to Dr Arpad Somagyi and Dr Neil Jacobsen for
help with mass spectra and NMR experiments, respectively.
4.2.14. (2R,4S,5R,6S,7S,8R)-2-Hydroxy-1-(3,3-dimethoxy-
propyl)-6,7,9-tribenzyl-oxypyrano-[4,5]-pyran 44. To a
solution of bromo acetate 43 (0.019 g, 0.031 mmol) and
THF (2 mL) at 2508C was added Grignard 12 (0.65 mL
of a 0.48 M solution, 0.31 mmol) dropwise. After warming
to 08C the reaction was quenched with NH4Cl(sat., 2 mL),
extracted with ether (3£3 mL), washed with brine
(2£10 mL), dried (MgSO4), and concentrated. Flash chro-
matography (2:1, hexanes/ethyl acetate) afforded 13 mg
(72%) of alcohol 44 as a colorless oil.
References
For characterization purposes 44 was converted into the
corresponding acetate using 44 (0.13 g, 0.022 mmol),
CH2Cl2 (1 mL), i-Pr2NEt (0.032 mL, 0.18 mmol), Ac2O
(0.015 mL, 0.13 mmol), and DMAP (ca. 0.005 g) to provide
the acetate of 44 as a colorless oil. [a]D ˆ28.47 (cˆ0.220,
1. Evans, P. A.; Roseman, J. D.; Garber, L. T. J. Org. Chem.
1996, 61, 4880.
2. Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158.
29

2008
S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
È
3. Marmsater, F. P.; West, F. G. J. Am. Chem. Soc. 2001, 123,
5144.
21. To the best of our knowledge, there are no existing methods
that would enable one to utilize a single glycosyl donor in the
synthesis of both a- and b-C-glycosides.
22. We have successfully used this protocol in our formal
synthesis of hemibrevetoxin B. See Ref. 7c. We are aware
of one other report of the addition of trimethyl aluminum to
glycal epoxides giving the product from syn-facial epoxide
opening. See: Bailey, J. M.; Craig, D.; Gallagher, P. T. Synlett
1999, 132.
4. Alvarez, E.; Diaz, M. T.; Perez, R.; Ravelo, J. L.; Regueiro,
A.; Vera, J. A.; Zurita, D.; Martin, J. D. J. Org. Chem. 1994,
59, 2848.
5. Clark, J. S.; Kettle, J. G. Tetrahedron 1999, 55, 8231.
6. Bowman, J. L.; McDonald, F. E. J. Org. Chem. 1998, 63, 3680.
7. (a) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310.
(b) Rainier, J. D.; Allwein, S. P. Tetrahedron Lett. 1998, 39,
9601. (c) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org.
Chem. 2001, 66, 1380. (d) Cox, J. M.; Rainier, J. D. Org. Lett.
2001, 3, 2919.
23. The aluminum reagents were prepared by coupling commmer-
cially available aluminum chlorides (Me2AlCl or AlCl3) with
the appropriate Grignard or lithium reagent. See Ref. 13 and
Paley, R. S.; Snow, S. R. Tetrahedron Lett. 1990, 31, 5853.
24. Brown, H. C.; Racherla, U. S. J. Org. Chem. 1986, 51, 427.
8. After we had begun our work, Evans and Stick independently
demonstrated that a similar strategy employing allylic nucleo-
philes could be accomplished. See: (a) Best, W. M.; Ferro, V.;
Harle, J.; Stick, R. V.; Tilbrook, D. M. G. Aust. J. Chem. 1997,
25. For reviews describing RCM see: (a) Fu
Èrstner, A. Angew.
Chem., Int. Ed. Engl. 2000, 39, 3013. (b) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (c) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(d) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34,
1833.
à Â
50, 463. (b) Evans, D. A.; Trotter, B. W.; Cote, B. Tetrahedron
Lett. 1998, 39, 1709. (c) Evans, D. A.; Trotter, B. W.;
à Â
Coleman, P. J.; Cote, B.; Dias, L. C.; Rajapakse, H. A.;
Tyler, A. N. Tetrahedron 1999, 55, 8671.
9. For monographs on the synthesis of C-glycosides see:
(a) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier: Tarrytown, NY, 1995. (b) Postema, M. H. D.
C-Glycoside Synthesis; CRC: Boca Raton, FL, 1995. For
recent review of C-glycosides see: (c) Postema, M. H. D. In
Glycochemistry Principles, Synthesis and Applications,
Bertozzi, C., Wang, P. G., Eds.; Marcel Dekker: New York,
2000; pp. 77±131. (d) Du, Y.; Lindhart, R. J.; Vlahov, I. R.
Tetrahedron 1998, 54, 9913.
26. For examples of enol ether±ole®n RCM see Refs. 5,7,37 and:
(a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994,
59, 4029. (b) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997,
38, 123. (c) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997,
38, 127. (d) Postema, M. H. D. J. Org. Chem. 1999, 64, 1770.
(e) Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. Engl.
2000, 39, 372. (f) Postema, M. H. D.; Calimente, D.; Liu,
L.; Behrmann, T. J. Org. Chem. 2000, 65, 6061. (g) Rainier,
J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron Lett. 2001, 42,
179. (h) Liu, L.; Postema, M. H. D. J. Am. Chem. Soc. 2001,
123, 8602.
10. Danishefsky, S. J.; McClure, K. F.; Randolph, J. T.; Ruggeri,
R. B. Science 1993, 260, 1307.
11. Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661.
27. See Refs. 7b±d,16, and Corey, E. J.; Kang, M.; Desai, M. C.;
Ghosh, A. K.; Houpis, J. N. J. Am. Chem. Soc. 1988, 110, 649.
28. The combination of RCM reaction, C-glycoside synthesis and
acid mediated cyclization provides a particularly ef®cient
approach to fused polycyclic ether natural products. See
Ref. 7c,d.
12. (a) Klein, L. L.; McWhorter Jr, W. W.; Ko, S. S.; Pfaff, K.-P.;
Kishi, Y.; Uemura, D.; Hirata, Y. J. Am. Chem. Soc. 1982,
104, 7362. (b) Bellosta, V.; Czernecki, S. J. Chem. Soc.,
Chem. Commun. 1989, 199.
13. Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2, 2707.
14. Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377.
29. 10 either came from the separation of the a- and b-C-glyco-
sides from the addition of butenyl magnesium chloride to 5 or
from 21 via a three step protocol: (a) hydroboration, oxidation,
(b) oxidation, (c) Wittig methylenation.
15. For anti selective epoxide openings see Refs. 7,8,12, and
(a) Timmers, C. M.; Dekker, M.; Buijsman, R. C.; van der
Marel, G. A.; Ethell, B.; Anderson, G.; Burchell, B.; Mulder,
G. J.; Van Boom, J. H. Bioorg. Med. Chem. Lett. 1997, 7,
1501. (b) Guo, J. S.; Duffy, K. J.; Stevens, K. L.; Dalko,
P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew.
Chem., Int. Ed. Engl. 1998, 37, 187.
30. Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org.
Chem. 1994, 59, 2668.
31. The ratio of acyclic to cyclic enol ethers from the Takai proto-
col shows a substrate dependence. For example see Ref. 7c,d.
32. (a) Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108,
855. (b) Stille, J. R.; Santarsiero, B. D.; Grubbs, R. H. J. Org.
Chem. 1990, 55, 843.
16. Kozikowski, A. P.; Ghosh, A. K. J. Org. Chem. 1985, 50,
3017.
33. (a) Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A.
J. Am. Chem. Soc. 1996, 118, 10335. (b) Nicolaou, K. C.;
Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc.
1996, 118, 1565.
17. C-Aryl glycosides are important subunits in a number of
interesting bioactive molecules. For example see: Hansen,
M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249.
18. Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200.
19. Van Boom has generated a-alkynyl glycosides from alkynyl
zinc additions. See: Leeuwenburgh, M. A.; Timmers, C. M.;
van der Marel, G. A.; van Boom, J. H.; Mallet, J.-M.; Sinay,
P. G. Tetrahedron Lett. 1997, 38, 6251.
34. This reaction leads to a relatively low yield (15%) of an as yet
unidenti®ed product. The majority of the reaction consists of
intractable material.
35. 25 comes from the hydroboration of 21 followed by TIPS
ether formation.
20. For the isolation of halichondrin B see: (a) Uemura, D.;
Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.;
Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796.
(b) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.;
Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero,
D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162.
36. Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
DiMare, M.; O'Regan, M. B. J. Am. Chem. Soc. 1990, 112,
3875. For the use of the Schrock alkylidene in enol ether±
ole®n ring closing metathesis reactions see Refs.
5,7a,c,d,26a±d,f,g.
37. For other examples of the use of the Grubbs Ru alkylidene in

S. P. Allwein et al. / Tetrahedron 58 (2002) 1997±2009
2009
enol ether±ole®n metathesis see Ref. 26g,h, and Chatterjee,
A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783.
Spilling's conditions. See Ref. 7a and Marzabadi, C. H.;
Spilling, C. D. J. Org. Chem. 1993, 58, 3761. Unfortunately,
these conditions were not successful in our hands with 29.
43. Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
38. In the course of our work on hemibrevetoxin B, we were
unable to generate one of the oxepane rings using enol
ether±ole®n RCM chemistry. Allwein, S. P.; Rainier, J. D.,
unpublished results.
44. Nicolaou reported that the reaction of his substrates with AD-
mix were under thermodynamic control. The reaction of 29
with AD-mix appears to be under kinetic control, when 41 and
42 were individually resubjected to the reaction conditions
equilibration did not occur.
39. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357.
40. Gassman, P. G.; Burns, S. J.; P®ster, K. B. J. Org. Chem. 1993,
58, 1449.
45. For an example of the displacement of an anomeric bromide
using a carbon nucleophile see: Hanessian, S.; Pernet, A. G.
Can. J. Chem. 1974, 52, 1266.
41. We isolated a low yield of an analogous trans±anti±trans
glycoside when 23 was subjected to similar conditions. See
Ref. 7a.
46. Thiem, J.; Meyer, B. Chem. Ber. 1980, 113, 3075.
42. We utilized a double inversion epoxidation on 23 using