Tandem intramolecular benzyne-furan cycloadditions. Total synthesis of vineomycinone B2 methyl ester

Article abstract of DOI:10.1016/j.tet.2007.04.031

We have exploited tandem intramolecular benzyne-furan cycloadditions employing three different benzyne precursors to generate substituted bisoxabenzonorbornadienes in a single operation. The regiochemical outcomes in these Diels-Alder reactions were effectively controlled by using disposable silicon tethers to link the reacting benzyne and furan moieties. Two different methods for converting the intermediate bisoxabenzonorbornadienes to substituted anthrarufins were developed. The first tactic entails the initial cleavage of the silicon tethers followed by regioselective ring opening of the oxabicycloheptadienes and oxidation of the central ring giving the target anthrarufin, whereas the second features the regioselective ring opening of the oxabicycloheptadienes followed by protiodesilylation and oxidation. When the starting furans bear carbohydrate substitutents, this new methodology enables the rapid assembly of the glycosyl-substituted aromatic cores of complex C-aryl glycoside antibiotics from simple starting materials. The utility of this novel approach to anthrarufins and C-aryl glycosides is exemplified in a triply convergent synthesis of vineomycinone B₂ methyl ester.

Full text of DOI:10.1016/j.tet.2007.04.031

Tetrahedron 63 (2007) 8619–8635
Tandem intramolecular benzyne–furan cycloadditions.
Total synthesis of vineomycinone B2 methyl ester
y
*
Steven M. Sparks, Chi-Li Chen and Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165,
United States
Received 4 March 2007; revised 7 April 2007; accepted 11 April 2007
Available online 19 April 2007
Abstract—We have exploited tandem intramolecular benzyne–furan cycloadditions employing three different benzyne precursors to gener-
ate substituted bisoxabenzonorbornadienes in a single operation. The regiochemical outcomes in these Diels–Alder reactions were effectively
controlled by using disposable silicon tethers to link the reacting benzyne and furan moieties. Two different methods for converting the
intermediate bisoxabenzonorbornadienes to substituted anthrarufins were developed. The first tactic entails the initial cleavage of the silicon
tethers followed by regioselective ring opening of the oxabicycloheptadienes and oxidation of the central ring giving the target anthrarufin,
whereas the second features the regioselective ring opening of the oxabicycloheptadienes followed by protiodesilylation and oxidation. When
the starting furans bear carbohydrate substitutents, this new methodology enables the rapid assembly of the glycosyl-substituted aromatic
cores of complex C-aryl glycoside antibiotics from simple starting materials. The utility of this novel approach to anthrarufins and C-aryl
glycosides is exemplified in a triply convergent synthesis of vineomycinone B2 methyl ester.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
hydroxylation at the 4-position of specific prolyl residues
in the peptide precursor of collagen.3 Vineomycin A1 has
been shown to be effective for treating hypertrophic scar tis-
sue or keloid in vivo,4 and vineomycin B2 (2) has been used
as a biochemical tool to study collagen prolyl hydroxylase.5
There are a number of natural products that are structurally
similar to those of the vineomycin family. These com-
pounds, which also exhibit significant biological activities,
include: balmoralmycin, an inhibitor of protein kinase
C-a,6 saquaymycins A and B, which are active against
several lines of tumor cells,7 amicenomycins A and B, which
exhibit antimicrobial activity,8 and the antibacterial agents
himalomycins A and B.9
The vineomycins A1, A2, B1, and B2 comprise a group of
antibiotics that were isolated from a culture of Streptomyces
matensis vineus and found to be active against Gram-
positive bacteria and sarcoma-180 solid tumors in mice.1
Although the structures of vineomycins A1 and B2 have
been determined as 1 and 2, respectively, vineomycins A2
and B1 have not been fully characterized. Vineomycin A1
has been shown to be identical with a Streptomyces metabo-
lite P-1894B that was previously reported as a potent inhib-
itor of prolyl hydroxylase (IC50¼2.2 mM),2 which as one
of the key enzymes in collagen biosynthesis catalyzes the
Me
OH
O
O
O
OH O
O
O
Me
O
H
OH
O
O
Me
O
Me
HO
O
O
O
Me
O
Me
Vineomycin A1 (1)
Me
OH
O
O
O
O
O
Me
O
OH
O
O
Me
O
Me
O
Me
O
O
H
Me
CO2H
O
OH
Vineomycin B2 (2)
* Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471 4180; e-mail: sfmartin@mail.utexas.edu
Present address: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
y
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.031

8620
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
Owing to their intriguing structures and biological activities,
a number of studies have been performed with members of
the vineomycin family. The biosynthesis of the vineomycins
methyl ester (3) relies on being able to control the regio-
chemical outcome of two Diels–Alder reactions of unsym-
metrical benzyne and furan substrates to assemble the
substituted aromatic framework. Although unsymmetrical
benzynes are known to undergo regioselective Diels–Alder
reactions, such cycloadditions more typically proceed with
poor regioselectivity,20,21 so our entry to C-aryl glycosides
that involved using disposable silicon tethers to link the
reacting benzyne and furan moieties was of particular inter-
est.16c,22 After considering a number of possibilities, a novel
and highly convergent strategy eventuated for the synthesis
of vineomycinone B2 methyl ester (3) (Scheme 1). The
approach features tandem intramolecular benzyne–furan
cycloadditions originating from the key intermediate 5 to
generate the bisoxabenzonorbornadiene 4, thereby swiftly
assembling the entire skeletal framework in a single opera-
tion. The conversion of 4 into 3 requires cleavage of the
silicon tethers, regioselective ring opening of the oxabenzo-
norbornene core, global removal of the oxygen protecting
groups, and adjustment of the oxidation level in the alkyl
side chain. The precursor 5 for the tandem cycloaddition
sequence would be prepared by the iterative Mitsunobu
coupling of a hydroquinone 7, which would be suitably
substituted to serve as a bis-benzyne precursor, with the
silicon-substituted furans 6 and 8, both of which would be
derived from readily available starting materials.
10
˜
was first studied by Omura and co-workers. In their
pioneering work, they performed feeding experiments with
singly and doubly 13C-labeled acetate and found that the
tetracyclic ring system of vineomycinone A1 (1) and all of
the carbon atoms of the central core of vineomycinone B2
(2) were derived from a single decaketide chain.11
During the course of structural studies of the vineomycins,
it was discovered that when either 1 or 2 was heated in
methanolic HCl, the degradation product vineomycinone
B2 methyl ester (3) was obtained.1b Interestingly, 3 was
also generated from the acid-catalyzed methanolysis of
aquayamycin.12 Vineomycinone B2 methyl ester (3) bears
an olivose residue appended to one ring of the anthrarufin
core and is thus a representative member of the C-aryl
glycoside family of natural products.13 The other ring of
the anthrarufin core is further endowed with a 3(R)-hydroxy-
isovaleryl side chain, thereby making vineomycinone B2
methyl ester an intriguing natural product of modest com-
plexity. Indeed, the structure of 3 coupled with the potential
anticancer activity of the vineomycins and related com-
pounds has rendered vineomycinone B2 methyl ester the
object of a number of investigations, four of which have
culminated in its total synthesis.14,15
OH
HO
OH
HO
OH
O
OH
O
O
Me
O
Me
OH
Me
O
Me
OH
H
H
O
OH
CO2Me
OH
CO2Me
Vineomycinone B2 methyl ester (3)
3
Like many natural products that have been previously pre-
pared, 3 remains an inspiration for the design and develop-
ment of new chemistries. In this context, it is noteworthy
that we recently developed a general entry to the four major
classes of C-aryl glycoside natural products by an approach
that features the ring opening of cycloadducts that are
obtained from Diels–Alder cycloadditions of substituted
benzynes with glycosyl furans.16 We demonstrated the util-
ity of this methodology by its application to a formal synthe-
sis of galtamycinone17 and 2-aryl naphthol derivatives.18
Owing to the unsymmetrical arrangement of carbohydrate
and functionalized side-chain substituents on the anthrarufin
nucleus, it was apparent that vineomycinone B2 methyl ester
(3) posed a significant challenge to our methodology. Hence,
we decided to embark on the total synthesis of 3 as a more
demanding test of the general efficacy of our approach to
C-aryl glycosides, and we now report the details of these
investigations.19
OR
O
Benzyne-furan
cycloaddition
RO
Me
O
Si
Me OR
O
O
H
Si
O
Benzyne-furan
cycloaddition
OR'
4
Mitsunobu
O
Me OR
Y
OR
X
O
Si
RO
Me
OR'
Si
O
X
O
Y
H
O
Mitsunobu
5
OR
Y
Me OR
O
Si
RO
Me
OH
X
X
2. Results and discussion
Si
OH
HO
HO
O
OR'
H
2.1. Development of the synthetic plan
O
Y
8
6
7
The successful application of our methodology for preparing
C-aryl glycosides to the synthesis of vineomycinone B2
Scheme 1. Retrosynthetic analysis.

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8621
2.2. Feasibility of tandem benzyne–furan cycloadditions
give, subsequent to oxidation, the desired anthrarufin 14 or
its undesired isomer 15. Although there was no direct prece-
dent that could be used to predict the regiochemistry of
opening of anthracene-derived oxabicycloheptadienes, there
was information that provided some guidance. Namely, prior
art in our laboratories revealed that the regiochemistry of
acid-catalyzed ring openings of oxabicycloheptadienes
was directed by the orientation of substituents on the bicy-
clic ring.16c The directing effect of bridgehead substituents
in such openings is absolute as only one cleavage mode leads
to a naphthol ring. When the substituent is on the carbon–
carbon double bond, its effect on the direction of ring open-
ing is not as strong, but the product in which the substituent
is ortho to the naphthol hydroxyl group is generally the ma-
jor product.25 Thus, the regiochemistry of ring opening of an
adduct 12 in which the substituents R1 and R2 were located
on the carbon–carbon double bond would be expected to
be different from that of comparably substituted 13. Hence,
we reasoned that the orientation of R1 and R2 on 13 would
be expected to play a significant role in determining whether
14 or 15 was formed preferentially. In the context of the
eventual application of this chemistry to the synthesis of
vineomycinone B2 methyl ester, it appeared likely that the
substitution pattern (e.g., on 4) would lead to the preferential
formation of the anthrarufin core.
Given the somewhat speculative nature of our strategy for the
synthesis of vineomycinone B2 methyl ester, we deemed it
advisable to conduct some simple model studies to evaluate
the underlying efficacy of preparing anthrarufins via tandem
benzyne–furan cycloadditions and ring opening. Several
important issues were to be evaluated in these preliminary
investigations. The first task was to identify a substituted hy-
droquinone derivative 7 that would twice serve as a benzyne
precursor. We and others have found that halohydroquinone
derivatives could be readily converted into benzynes upon re-
gioselective deprotonation with alkyllithium reagents,16,23
so 7 (X¼H; Y¼Cl or Br) emerged as likely candidates.
Hart has shown that tetrabromobenzenes can serve as bis-
benzyne precursors in Diels–Alder reaction,24 so 7 (X¼Y¼
Br) might also be a suitable starting material. In earlier
work, we developed silicon tethers containing one and two
carbon atoms, so a second undertaking would be to ascertain
which of these would be optimal in tandem benzyne–furan
reactions. Hence, we would need to prepare substituted fu-
rans of the general structure 9 and 10 (n¼1, 2; R1, R2¼H,
Me) and couple these with 7 to provide compounds of the
general form 11 (Scheme 2). We would then be in a position
to establish the feasibility of the key tandem benzyne–furan
Diels–Alder reactions to give 12. The specific tactic used to
remove the silicon tethers of 12 to give 13 would depend
upon the nature of the tether itself, but the requisite protocols
had been developed in previous work.16c
We thus first set to the task of determining what kinds of sub-
strates of the general type 11 would undergo efficient tandem
benzyne–furan cycloadditions. Namely, what haloarene
would best serve as a bis-benzyne precursor and what was
the optimal length of the silicon tether. Toward addressing
these questions, we first prepared 17 and 18 by coupling
dicholorohydroquinone (20)26 and 2,3,5,6-tetrabromo-
hydroquinone (21) with furan 16 using K2CO3 and tetra-
n-butylammonium iodide (TBAI) in DMF at 90 ꢀC (Scheme
3). Although we had previously found that acetone was a
good solvent for related alkylations,16c its use in these reac-
tions provided only small quantities of the alkylated phenols.
It is worth noting that the use of acetone as the solvent,
which was successful for the alkylation of 2,6-dichoro-4-
methoxyphenol with alkyl bromides, failed to provide the
coupling products. The methyl group on the furan rings in
17 and 18 would obviate any possible side reactions associ-
ated with deprotonation of the furan ring during the benzyne
generating step(s). When 17 was treated with 2 equiv of
either s-BuLi or n-BuLi at low temperatures in accord with
our prior work,16 only trace amounts at best of the cycload-
duct 19 were isolated, despite considerable experimentation.
Reaction of 18 with n-BuLi in Et2O also produced a complex
mixture, but 19 could be reliably isolated in about 5–10%
yield. However, all attempts to increase the yield by varying
solvent (THF, toluene), temperature (0 ꢀC to room tempera-
ture), or by using additives (TMEDA) were fruitless.
OH
n
LG
R2
X
Y
Y
X
Si
O
O
Coupling
R1
LG
Si
n
OH
7
9
10
n
n
O
Si
O
O
Si
Double benzyne-
furan cycloaddition
X
Y
Y
O
X
R1
R2
R1
R2
O
O
O
Si
O
Si
n
n
11
12
OH
Ring opening
and oxidation
Tether cleavage
R1
R2
O
O
OH
13
OH
O
O
OH
O
OH
R1
R2
R1
R2
and/or
OH
O
These failures naturally led us to query the origin of our
unexpected difficulties. Examination of models of 19 sug-
gested that it might be highly strained, so we decided to
explore the potential of silicon tethers containing two
methylene groups. Toward this objective, we used methods
previously developed in our laboratories to convert 2-methyl-
furan (22) into 24.16c Namely, lithiation of 22 followed by
reaction with commercially available chlorodimethylvinyl-
silane gave 23, which was hydroborated employing 9-BBN
14
15
n = 1, 2; X, Y = H, Cl, Br combinations
R1, R2 = H, Me
Scheme 2. Planning for model studies.
Less predictable was the regiochemical issue related to
opening of the two oxabenzonorbornene rings in 13 to

8622
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
X
20 or 21
O
Si
O
Y
Y
Br
TBAI, K CO
Me
2
3
Me
DMF, 90 °C
81%
Si
O
Me
O
Si
O
X
16
17: X = Cl, Y = H
18: X = Y = Br
Si
O
Me
s-BuLi or n-BuLi
THF or Et O
2
O
O
–95 °C to 0 °C
< 10%
Me
O
Si
19
Br
Cl
HO
Br
Br
OH
HO
H
H
OH
Br
Cl
20
21
Scheme 3. Probing the feasibility of one-carbon silicon tethers.
and oxidized (NaOH, H2O2) to afford 24 in 72% yield over
two steps (Scheme 4).27 We found in ancillary studies that
derivatives of 20 did not serve effectively as precursors of
bis-benzynes, so we focused on alkylated tetrabromohydro-
quinones. Accordingly, 24 was coupled with 21 by a double
Mitsunobu reaction using diisopropylazodicarboxylate and
triphenylphosphine to give 25 in 78% yield. After some
experimentation, we discovered that when 25 was treated
with a slight excess of n-BuLi in Et2O (0.02 M) at room
temperature the bis-cycloadduct 26 could be isolated as a
mixture of diastereomers in 68% yield. To our knowledge,
this constituted the first example of a tandem intramolecular
benzyne–furan Diels–Alder reaction.
hoped to remove the b-dimethylsilylethyl tethers in cycload-
duct 26 to afford the hydroquinone 31 (Scheme 5). However,
treatment of 26 in THF with excess tetra-n-butylammonium
fluoride (TBAF) provided a mixture of diastereomeric phe-
nols 27, arising from removal of only one b-dimethylsilyl-
ethyl tether from 26. When the reaction was run in DMF,
diastereomeric phenols 28 were isolated, even when the so-
lution was warmed. We were thus unable to effect complete
removal of the silicon tethers in a single step. We did find
that exposure of 28 to acid led to anthrarufin 29, presumably
by the facile oxidation of the intermediate anthrol, and we
developed a simple two-step procedure for converting 26
into 29 in up to 50% yield. Because this procedure was
somewhat irreproducible, we turned to an alternative tactic
to cleave bridgehead silicon–carbon bonds using KOH or
KO-t-Bu in DMSO that was reported by Rickborn.28 Indeed,
we found that under the Rickborn conditions 26 underwent
desilylation to give 30, but the reaction was relatively slow
and was accompanied by some decomposition. After exten-
sive screening of various combinations of bases (KOH,
NaOH, K2CO3) and solvents (DMSO, DMF, water), we de-
veloped a modification of the Rickborn protocol and discov-
ered that the use of KOH in DMF/H2O (10:1) was faster and
more effective and provided 30 in 79% yield. Subsequent
ring opening of 30 with HCl in ethanol and aerial oxidation
delivered 29 in 73% yield. We had thus established the via-
bility of our entry to anthrarufins by a procedure that fea-
tured tandem intramolecular benzyne–furan cycloadditions.
n-BuLi, THF, –78 °C;
Me2Si(Cl)CH=CH2
9-BBN, THF;
H2O2, NaOH
Me
Me
Si
O
76%
O
95%
23
22
OH
Me
21, DIAD, PPh3, THF
Si
24
O
78%
Br
O
Br
Me
Si
O
O
Si
Me
Br
O
Br
25
Because the furan rings in intermediates related to 5 lack
substitution at the 5-position, we decided to conduct one
more model study to ascertain whether an acidic proton on
the furan might compromise the efficiency of the key tandem
intramolecular benzyne–furan Diels–Alder reactions. In the
event, furan (32) was converted into 35 in three steps and
65% overall yield following the same procedure used to pre-
pare 25 (Scheme 6). Gratifyingly, the tandem benzyne–furan
cycloadditions were then induced by treating 35 with excess
n-BuLi (2.6 equiv) in Et2O (0.02 M) at ꢁ20 ꢀC to afford 36
in 50% yield, thereby establishing that acidic protons at the
5-position of the furan are compatible with the sequence.
O
Si
Me
2.3 eq n-BuLi
O
O
Et2O, rt
68%
Si
Me
O
26
Scheme 4. Probing the feasibility of two-carbon silicon tethers.
With the cycloadduct 26 in hand, it remained to explore
tactics for its elaboration into an anthraquinone. We initially

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8623
OH
Me
OH
O
Me
Si
Me
TBAF
O
O
O
O
+
O
O
THF or DMF
Me
O
OH
Si
Si
Me
O
Me
O
Si
26
27
28
OH
Me
Me
O
TBAF, DMF, 45 °C;
TFA, DCM, air
50%
O
OH
O
HCl, EtOH, 70 °C
73%
29
Si
HO
Me
KOH, DMF/H2O (10:1)
79%
O
O
Me
O
OH
Si
30
Me OH
O
O
OH Me
31
Scheme 5. Synthesis of a simple anthrarufin.
The conversion of 26 into 29 was accomplished by tether
cleavage, followed by acid-catalyzed rearrangement of the
oxabicycloheptadienes and oxidation. We queried whether
the alternate sequence of rearrangement, followed by tether
cleavage and oxidation might also be a viable protocol for
generating anthrarufins. After screening several conditions
and acids (TMSOTf, 2,6-lutidine, CH2Cl2; CF3CO2H,
CH2Cl2), we discovered that ZnCl2 was an effective catalyst
for converting 36 into 37.29 Because 37 was unstable, it was
methylated to give 38. We anticipated that fluoride would
induce the cleavage of all silicon–carbon bonds in 38, but
were disappointed to find that treatment of 38 with excess
TBAF at 70 ꢀC, followed by oxidation gave 39 in only
22% yield. On the other hand, reaction of 38 with boron
trifluoride–acetic acid complex and chloroacetic acid in
hexanes at room temperature gave 39 in 57% yield;30 yields
were lower when ether or EtOAc was used as solvent.
9-BBN, THF;
H2O2, NaOH
n-BuLi, THF, -78 °C;
Me2Si(Cl)CH=CH2
OH
Si
Si
O
96%
O
O
76%
32
34
33
Br
Br
O
21, DIAD, PPh3, THF
In summary, we had convincingly demonstrated the feasibil-
ity of conducting tandem intramolecular double benzyne–
furan cycloadditions of substrates in which the hydro-
quinone and furan moieties of the precursor were linked
using silicon tethers containing two carbon atoms. The
cycloadducts thus obtained could be converted into anthra-
rufins by two protocols that varied with respect to the order-
ing of the steps involving tether cleavage and ring opening of
the oxabenzonorbornene rings. Based upon these advances,
we turned to the more challenging task of the total synthesis
of vineomycinone B2 methyl ester (3) according to the plan
outlined in Scheme 1.
Si
O
O
Si
89%
O
Br
Br
35
OH
Si
O
O
Si
2.1 eq ZnCl2 in Et2O
2.6 eq n-BuLi
O
O
Et2O, –20 °C
50%
CH2Cl2
71%
Si
O
Si
O
OH
36
37
OMe
OMe
Si
O
O
Si
4 eq BF3·2AcOH
4 eq ClCH2CO2H
MeI, NaH
3. Total synthesis of vineomycinone B2 methyl ester
hexanes, rt
57%
DMF
93%
OMe O
39
OMe O
38
The first phase of the synthesis of vineomycinone B2 methyl
ester (3) was initiated by the preparation of substituted
furans related to 6 and 8. Because we had prepared similar
compounds in other work, the basic chemistry had been
Scheme 6. Alternate route to a simple anthrarufin.

8624
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
established. The basic problem, as in many efforts in total
synthesis of complex natural products, was one of selecting
the proper protecting groups. Inasmuch as our plan involved
a global removal of all hydroxyl protecting groups as the
final step in the synthesis, we envisioned that benzyl ethers
would be well suited to the task. The glycosyl furan 46
thus emerged as an initial subgoal. The synthesis of 46,
which closely followed our previous work,16 commenced
with the addition of 3-lithiofuran to the known lactone
4016c to afford a mixture of lactols 41, which were in equi-
librium with the open chain keto-alcohol 42 as evidenced
provided the enantiomer of 49 in 99% yield and 96% enan-
tiomeric excess.32 Thus, for the specific problem at hand, the
Sharpless asymmetric dihydroxylation appeared to be the
method of choice. Accordingly, 3-methyl-3-butenol 47 was
first protected as its p-methoxyphenyl (PMP) ether 48 and
subjected to Sharpless asymmetric dihydroxylation condi-
tions using AD-mix a to afford diol 49 in 93% yield over
two steps (96% ee) (Scheme 8). Treatment of diol 49 with
tosyl chloride and triethylamine in the presence of a catalytic
amount of DMAP selectively afforded the primary tosylate
50. In initial studies 50 was converted into 51 in two steps
via cyclization to the epoxide 52 (K2CO3, MeOH, 89%;
3-lithiofuran, BF3$OEt2, THF, 89%). However, we discov-
ered a more expeditious one-pot procedure that involved
cyclization of 50 by deprotonation with n-BuLi followed
by facile opening of the intermediate 52 formed in situ
with 3-lithiofuran in the presence of BF3$OEt2 to provide
the tertiary alcohol 51 in 84% yield.
1
by the H NMR spectrum (Scheme 7). When this mixture
was treated with ethanolic HCl, a mixture of ethyl acetals
43 was produced. Subsequent stereoselective reduction of
43 was induced by heating in ethanolic HCl in the presence
of NaCNBH3 to afford 44 in 82% overall yield. Regio-
selective deprotonation of 44 followed by trapping the furyl
anion thus formed with chlorodimethylvinylsilane furnished
the vinylsilane 45, hydroboration and oxidation of which
delivered 46 in 66% yield over two steps.
p-MeO-C6H4OH,
AD-Mix α
DIAD, PPh3, THF
OBn
OBn
OH
OPMP
tert-BuOH, H2O
95%, 96% ee
98%
OBn
BnO
Me
BnO
Me
47
48
BnO
Me
3-lithiofuran
THF, –78 °C
O
O
OH
OH
O
O
O
O
Me OH
Me OH
TsCl, Et3N, DMAP
TsO
41
42
HO
40
OPMP
OPMP
CH2Cl2
90%
OBn
49
50
HCl, EtOH then
NaCNBH3, HCl, 50 °C
BnO
Me
O
82% (2 steps)
n-BuLi, –78 °C, THF
O
EtO
then
Me OH
O
43
3-lithiofuran, BF3·OEt2
84%
OPMP
OBn
OBn
51
BnO
Me
BnO
Me
LDA, THF, –78 °C;
Me2Si(Cl)CH=CH2
Me
Si
O
O
OPMP
O
70%
H
O
H
O
52
44
45
Scheme 8. Synthesis of 3-substituted furan.
OBn
BnO
Me
9-BBN, THF;
H2O2, NaOH
Having established a reliable method for preparing the
3-alkyl furan 51, the next task involved selective introduc-
tion of the silicon-derived tether at the 2-position. We envi-
sioned that selective deprotonation at the 2-position might be
effected through the agency of a suitable directing group that
would also serve as the protecting group for the tertiary
alcohol of 51. Indeed, we had performed related selective
deprotonations in earlier work in the area.16c Because of
the known ability of MOM ethers to direct deprotonations,33
51 was protected accordingly to give 53 (Scheme 9). To our
Si
OH
O
94%
H
O
46
Scheme 7. Synthesis of a glycosyl furan with disposable tether.
The next phase of the synthesis required the synthesis of
a substituted furan related to 8. Toward this objective, the first
task was the enantioselective preparation of the 3-substituted
furan 51, which we envisaged would result from the reaction
of 3-lithiofuran with the epoxide 52. We considered two pos-
sible approaches to 52. The first would rely upon a useful
protocol for the enantioselective epoxidation of homoallylic
alcohols using chiral vanadium catalyst that was reported by
Yamamoto.31 Relevant to the task at hand was the obser-
vation that epoxidation of 3-methyl-3-butenol (47) under
these conditions provided the corresponding epoxy alcohol
in 58% yield and 84% enantiomeric excess. Alternatively,
Corey expanded the scope of Sharpless asymmetric dihydr-
oxylation to homoallylic alcohol derivatives and found
that dihydroxylation of 1-(4-methoxyphenoxy)-3-methyl-
3-butene 48 using (DHQD)2PYDZ$OsO4 as the catalyst
MOMCl, i-Pr2NEt
Me OH
Me OMOM
OPMP
O
O
CH2Cl2, 60 °C
85%
OPMP
51
53
Si
n-BuLi, Et2O, –78 °C
then
Me OMOM
Me OMOM
O
+
O
Me2Si(Cl)CH=CH2
OPMP
OPMP
54:55 = 3:2
Si
54
55
Scheme 9. Attempted selective functionalization of 51.

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8625
considerable disappointment, however, sequential reaction
of furan 53 with n-BuLi in Et2O at ꢁ78 ꢀC and then chloro-
dimethylvinylsilane provided a mixture (3:2) of furans 54
and 55 in modest yield.
and imidazole in DMF to give phenol 61. Subsequent reac-
tion of 61 with 59 via Mitsunobu coupling furnished aryl
ether 62 in 75% yield. Removal of the silyl protecting group
with HF$pyridine in THF gave the phenol 60, which was
then coupled with furan 46 via a second Mitsunobu reaction
to deliver 63 in 72% yield over two steps.
Although the directed deprotonation of 53 was not selective,
we discovered that electrophilic bromination was. However,
since protecting the tertiary alcohol in 51 as its MOM ether
would not be compatible with our goal to effect a global
deprotection as the final step of the synthesis, 51 was
converted into 56 by O-benzylation (Scheme 10). Highly
regioselective bromination of 56 was then effected by reac-
tion with NBS to furnish 57 in 86% yield from 51.34 Sub-
jection of 57 to metal–halogen exchange and reaction of
the intermediate anion with chlorodimethylvinylsilane
delivered exclusively the vinylsilane 58 in 87% yield. Sub-
sequent hydroboration and oxidation of the vinyl moiety as
before furnished the furan 59.
The stage was now appropriately set for the pivotal tandem
benzyne–furan cycloaddition of 63. In our initial studies,
we found that dropwise addition of 2.6 equiv of n-BuLi
(0.23 M) to a solution of tetrabromide 63 in Et2O at
ꢁ20 ꢀC afforded the desired bis-cycloadduct 64 as a mixture
of diastereomers in variable and irreproducible yields rang-
ing from 30 to 60% (Scheme 12). It became evident that
these variable yields arose from traces of water remaining
in the tetrabromide 63 that quenched the aryllithium inter-
mediates. In order to ensure that there was no adventitious
€
water to undermine the yield, 63 was dried in a Kugelrohr
oven under vacuum for 2 h at 140 ꢀC. When this dried mate-
rial was treated with 3.0 equiv of n-BuLi (0.23 M) in Et2O at
ꢁ20 ꢀC, the diastereomeric mixture of bis-cycloadducts 64
was obtained in 85% yield. The temperature at which this re-
action was performed was found to be important. For exam-
ple, if 63 was treated with n-BuLi at ꢁ78 ꢀC or ꢁ50 ꢀC, the
yield of 64 plummeted to less than 30%, and other products,
which were not characterized, were also obtained. It thus
appears that the benzyne must be generated at a temperature
where the cycloaddition is sufficiently rapid as to avoid
deleterious side reactions of the intermediate benzynes.24
KH, DMF, 0 °C; BnBr
Me OBn
Me OH
O
O
ca 100%
OPMP
OPMP
56
51
n-BuLi, THF, –78 °C
NBS, DMF, 0 °C
86%
then
Me OBn
O
Me2Si(Cl)CH=CH2
87%
OPMP
Br
57
9-BBN, THF;
H2O2, NaOH
Me OBn
Me OBn
O
O
The tricky task of cleaving the silicon tethers and opening
the two oxabicycloheptadiene rings to unveil the anthrarufin
core was now at hand. As we had observed in our model
studies with 26, complete removal of the tethers from 64
with various fluoride sources (e.g., TBAF, TBAT, CsF,
HF$Py) in different solvents (e.g., DMF, THF, dichloro-
methane, DMSO) at several temperatures (e.g., room
temperature, 45 ꢀC, 60 ꢀC, 80 ꢀC) was problematic. When
these mixtures were then treated with various acids (e.g.,
TFA, TMSOTf, and BF3$Et2O) in several solvents (e.g., THF,
dichloromethane, toluene) to complete the removal of the
tether and open the oxabicycloheptadienes, complex mix-
tures containing isomeric anthraquinones and other uniden-
tified compounds were obtained. Inspection of the 1H NMR
spectra of these mixtures revealed some signals that might
arise from the desired product 67, but these were minor.
However, we again found that the modified Rickborn condi-
tions that we had developed for converting 26 into 29 were
also best suited for cleaving the silyl tethers as the first step
in transforming 64 into 65. In the event, reaction of 64
with KOH in DMF/H2O (10:1) proceeded cleanly to provide
a mixture of diastereomers 65.
96%
OPMP
OPMP
HO
Si
Si
58
59
Scheme 10. Preparing a 3-substituted furan with disposable tether.
With the requisite furans 46 and 59 in hand, it remained to
assemble the appropriate precursor for tandem benzyne–
furan Diels–Alder reaction. In an attempt to assemble 63
from 21, 46, and 59 without any protection steps, 59 was
treated with 4 equiv of 21, triphenylphosphine, and diiso-
propylazodicarboxylate in THF, but a complex mixture of
products was obtained from which little 60 could be isolated
(Scheme 11). In order to circumvent this problem, hydro-
quinone 21 was monoprotected by reaction with TBSCl
Me OBn
O
Br
Br
OH
Br
Br
O
Br
59, DIAD, PPh3
Si
PMPO
THF
RO
Br
RO
Br
Br
HF·py
THF, 0 °C
85%
60: R = H
62: R = TBS (75%)
TBSCl, Im–H
DMF
21: R = H
Optimizing the acid-catalyzed reaction to open the oxabi-
cycloheptadienes present in 65 also required some experi-
mentation. A quick survey of various Lewis acids (e.g.,
ZnCl2, BF3$Et2O, and TiCl4) revealed that they were not
very effective in promoting the desired ring opening of 65
leading to 67. A more promising result was obtained upon
stirring 65 with TFA in CH2Cl2 to give a complex mixture
from which 67 could be isolated in about 7–20% yield.
However, when 65 was heated in ethanolic HCl under
carefully defined conditions the desired anthrarufin 67 was
61: R = TBS
35%
Me OBn
O
Br
OBn
BnO
Br
O
O
46, DIAD, PPh3
Si
PMPO
Si
THF
85%
Br
Me
O
Br
H
O
63
Scheme 11. Setting stage for tandem benzyne–furan cycloaddition.

8626
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
Me OBn
O
Br
OBn
Br
O
O
3.0 eq n-BuLi
Si
BnO
Me
OPMP
Si
ether, –20 °C
85%
Br
O
H
Br
O
63
OBn
BnO
Me
O
Si
KOH, DMF/H O (10:1)
2
O
H
Me OBn
O
O
Si
O
OPMP
64
Si
HO
OBn
BnO
Me
O
HCl, EtOH
65 °C
O
Me OBn
H
O
O
O
OPMP
OH
Si
65
Si
HO
OBn
BnO
Me
OH
O
O
Me OBn
H
34%
O
OH
OPMP
OH
Si
66
OBn
13.1 ppm
BnO
Me
2 doublets, J = 7.9 Hz
OH
O
7.90 ~ 7.71 ppm
O
H
OBn
Me
2 doublets, J = 7.9 Hz
7.90 ~ 7.71 ppm
O
OH
OPMP
13.2 ppm
67
Scheme 12. Construction of substituted anthrarufin core of 3.
reproducibly isolated in 34% overall yield, likely via aerial
oxidation of 66 or a related intermediate.35 An inseparable
mixture of several other products was also obtained, and
although these compounds could not be fully characterized,
an analysis of the 1H NMR spectrum of the mixture
suggested that some of these were isomers of 67. That 67
possessed the requisite substitution pattern on the anthra-
rufin core was supported by its 1H NMR spectrum. Namely,
the ortho relationship of the phenolic hydroxyl groups and the
carbohydrate and alkyl substituents on the two rings was
evident from the appearance of four doublets (J¼7.9 Hz)
at 7.90–7.71 ppm. The downfield chemical shift of the
phenolic protons, which appeared as two singlets at 13.1
and 13.2 ppm, is in accord with their being hydrogen bonded
to the adjacent carbonyl groups.
Completing the synthesis of vineomycinone B2 methyl ester
(3) required adjusting the oxidation level of the aliphatic side
chain to a carboxylic acid, followed by global deprotection
that proceeded largely in accord with our original plan.
Namely, the PMP group was first cleaved from 67 under
oxidative conditions with CAN (20:1 acetonitrile/H2O,
ꢁ15 ꢀC) to give alcohol 68 in 74% yield (Scheme 13). Use
of other typical solvent systems (e.g., 1:1 CH2Cl2/H2O, 4:1
acetonitrile/H2O, and 3:1:1 acetonitrile/pyridine/H2O)
gave lower yields of product. Although we found that oxida-
tion of the primary alcohol function in 68 to give the acid 69
could be achieved in one step using PDC in DMF, the yields
were modest. On the other hand, treatment of 68 with IBX
followed by oxidation of the intermediate aldehyde with
NaClO2 gave 69 cleanly in 70% overall yield.

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8627
OBn
by two different tactics that differed in the order of tether
cleavage and acid-catalyzed opening of the two oxabicyclo-
heptadienes. The practical utility of such constructions
was then established by their incorporation as a key step in
a novel and highly convergent synthesis of vineomycinone
B2 methyl ester (3) via a process that required a longest lin-
ear sequence of 16 steps and proceeded with 2.9% overall
yield in the longest linear sequence. This synthesis thus
represents the first application of our general procedure for
the regioselective synthesis of C-aryl glycosides using
silicon tethers as disposable linkers to control the regio-
chemistry in Diels–Alder reactions of substituted benzynes
and furans. Other applications of this strategy for the rapid
assembly of the glycosyl-substituted aromatic cores found
in complex C-aryl glycoside antibiotics are in progress and
will be reported in due course.
IBX, EtOAc, 80 °C;
NaClO2, NaH2PO4,
2-methyl-2-butene,
tert-BuOH, H2O
BnO
Me
OH
O
O
O
H
Me OBn
70%
OH
OR
67: R = PMP
CAN, CH3CN, H2O, –15 °C
74%
68: R = H
OBn
BnO
OH
OH
OH
O
Me
O
Me OBn
H
O
69
OH
CO2H
MeOH, HCl, rt
74%
OBn
BnO
Me
O
O
5. Experimental
5.1. General
O
H
BBr3, CH2Cl2, –78 °C;
MeOH, HCl, rt
71%
Me OBn
OH
CO2Me
Tetrahydrofuran, dimethylformamide, acetonitrile, and tolu-
ene were dried according to the procedure described by
Grubbs.36 All solvents were determined to contain less
than 50 ppm H2O by Karl Fischer coulometric moisture
analysis. Triethylamine was distilled from calcium hydride
prior to use. Reactions involving air or moisture sensitive
reagents or intermediates were performed under an inert
atmosphere of nitrogen or argon in glassware that was flame
dried. Thin layer chromatography was run on pre-coated
silica gel plates with a 0.25 mm thickness containing
60 F254 indicator (Merck), and the plates were visualized
by staining with AMCAN (ammonium molybdate/cerium
ammonium nitrate), potassium permanganate, or p-anis-
aldehyde. Flash chromatography was performed using the
indicated solvent system on 230–400 mesh silica gel (E.
Merck reagent silica gel 60) according to Still’s protocol.37
Melting points are uncorrected. Infrared (IR) spectra were
obtained as solutions in the solvent indicated. Proton nuclear
magnetic resonance spectra (1H NMR) were obtained in
CDCl3 solutions, and chemical shifts are reported in parts
per million (ppm) referenced to the solvent. Coupling con-
stants (J) are reported in hertz and the splitting abbreviations
used are: s, singlet; d, doublet; t, triplet; app t, apparent trip-
let; q, quartet; m, multiplet; comp, complex multiplet; br,
broad. Carbon nuclear magnetic resonance spectra (13C
NMR) were obtained using CDCl3 as the internal reference.
70
BBr3, CH2Cl2, –78 °C
77%
OH
HO
Me
O
O
O
H
Me
OH
OH
CO2Me
Vineomycinone B2 methyl ester (3)
Scheme 13. Completion of the total synthesis of 3.
Although reaction of 69 with methanolic hydrogen chloride
gave the methyl ester 70 in 74% yield, we were unable to
cleanly remove all of the benzyl protecting groups by hydro-
genolysis with either 10% Pd/C or 10% Pd(OH)2/C at pres-
sures up to 9 atm. On the other hand, reaction of 70 with
BBr3 in dichloromethane at ꢁ78 ꢀC quickly cleaved all of
the benzyl groups and furnished vineomycinone B2 methyl
ester (3) in 77% yield. Alternatively, we developed a one-
step procedure for converting 69 into 3 that involved global
deprotection of all of the O-benzyl groups using BBr3
followed by work-up with methanolic hydrogen chloride
to deliver synthetic vineomycinone B2 methyl ester (3) in
71% yield. The synthetic 3 thus obtained gave H and 13C
1
NMR spectra identical to those of an authentic sample
kindly provided by Professor Tius, and it exhibited an optical
rotation and melting point identical to those reported in the
literature.14d
5.2. Model studies of benzyne–furan cycloadditions
leading to anthrarufins
5.2.1. Bromomethyldimethyl-(5-methyl-furan-2-yl)-
silane (16). n-BuLi (6.6 mL of a 1.5 M solution in hexanes,
10.0 mmol) was added dropwise to a solution of 2-methyl-
furan 22 (0.82 g, 10.0 mmol) in THF (20 mL) at 0 ꢀC, and
the reaction was stirred for 1 h. (Bromomethyl)chlorodi-
methylsilane (1.5 mL, 11.0 mmol) was added dropwise over
3 min and stirring continued for 30 min. The mixture was di-
luted with Et2O (30 mL) and poured onto a mixture of H2O
(15 mL) and brine (15 mL). The organic layer was sepa-
rated, dried (MgSO4), and concentrated. The resulting oil
4. Conclusion
We have demonstrated the feasibility of performing tandem
benzyne–furan intramolecular Diels–Alder cycloadditions
using compounds in which the benzyne precursor and the
reactant furans were linked with silicon tethers containing
two methylene groups. The bisoxabenzonorbornadienes thus
obtained can be converted into substituted anthraquinones

8628
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
was purified by flash chromatography eluting with pentane
to provide 1.98 g (85%) of silane 16 as a colorless oil. H
4H), 0.31 (s, 12H); 13C NMR (62.5 MHz) d 156.9, 156.2,
151.9, 121.7, 121.5, 105.8, 71.4, 17.6, 13.7, ꢁ2.9; IR
(NaCl) 2955, 2884, 1347, 1057 cmꢁ1; mass spectrum (CI)
m/z 752.8322 [C24H29Br4O4Si2 (Mꢁ1) requires 752.8338],
731, 621 (base).
1
NMR (400 MHz) d 6.61 (d, J¼2.8 Hz, 1H), 5.96 (dt, J¼
2.8, 0.8 Hz, 1H), 2.60 (s, 2H), 2.31 (d, J¼0.8 Hz, 3H),
0.37 (s, 6H); 13C NMR (100 MHz) d 157.3, 154.4, 122.5,
105.9, 16.1, 13.7, ꢁ4.3; IR (neat) 2961, 2924, 1593, 1494,
1384, 1252, 1215, 1188, 1018, 812 cmꢁ1; mass spectrum
(CI) m/z 233.0009 [C8H14OSiBr (M+1) requires
232.9997], 225 (base).
5.2.5. Cycloadduct 26. n-BuLi (1.1 mL of a 2.6 M solution
in hexanes, 2.8 mmol) was added dropwise at 1.0 mL/h to a
solution of 25 (0.91 g, 1.20 mmol) in Et2O (240 mL) at room
temperature. After the addition was complete, the reaction
mixture was washed with H2O (20 mL), dried (MgSO4),
and concentrated. The residue was purified by flash chroma-
tography on silica gel eluting with hexanes/EtOAc (9:1 to
4:1) to provide 0.36 g (68%) of cycloadduct 26 as a pale yel-
5.2.2. Dimethyl(5-methylfuran-2-yl)vinylsilane (23).
n-BuLi (7.0 mL of
a 2.6 M solution in hexanes,
18.2 mmol) was added dropwise to a solution of 2-methyl-
furan 22 (1.50 g, 18.3 mmol) in THF (8 mL) at 0 ꢀC, and
the reaction was stirred for 1 h. Chlorodimethylvinylsilane
(7.64 mL, 55.3 mmol) was added dropwise over 3 min and
stirring continued for 15 min. The mixture was diluted with
Et2O (30 mL) and poured onto a mixture of H2O (15 mL)
and brine (15 mL). The organic layer was separated, dried
(MgSO4), and concentrated to a volume of 6 mL. The re-
sulting red oil was purified by distillation at atmospheric
pressure to provide 2.30 g (76%) of vinylsilane 23 as a col-
1
low solid; mp 172–173 ꢀC; H NMR (500 MHz) d 7.00 (d,
J¼5.2 Hz, 1H), 6.98 (d, J¼5.2 Hz, 1H), 6.84 (d, J¼5.2 Hz,
1H), 6.82 (d, J¼5.2 Hz, 1H), 4.48 (ddd, J¼12.0, 7.5,
2.2 Hz, 1H), 4.42 (ddd, J¼12.0, 7.5, 2.2 Hz, 1H), 3.90 (dt,
J¼12.0, 4.0 Hz, 1H), 3.76 (dd, J¼12.5, 4.0 Hz, 1H), 1.97
(s, 3H), 1.95 (s, 3H), 1.56–1.44 (m, 2H), 1.10–1.03 (m,
2H), 0.34 (s, 3H), 0.31 (s, 3H), 0.24 (s, 3H), 0.23 (s, 3H);
13C NMR (125 MHz) d 146.9, 146.6, 146.5, 146.3, 146.1,
145.2, 144.8, 144.4, 141.5, 140.6, 91.6, 91.4, 85.0, 84.7,
72.3, 71.5, 17.0, 16.9, 16.7, 16.6, ꢁ3.4, ꢁ4.0, ꢁ4.1, ꢁ4.2;
1
orless oil. H NMR (250 MHz) d 6.54 (d, J¼3.0 Hz, 1H),
6.24 (dd, J¼19.8, 14.7 Hz, 1H), 6.02 (dd, J¼14.7, 4.1 Hz,
1H), 5.95 (d, J¼3.0 Hz, 1H), 5.77 (dd, J¼19.8, 4.1 Hz,
1H), 2.32 (s, 3H), 0.32 (s, 6H); 13C NMR (62.5 MHz)
d 156.9, 156.4, 136.9, 133.0, 121.7, 105.7, 13.7, ꢁ3.3; IR
(NaCl) 3050, 2960, 1493, 1250 cmꢁ1; mass spectrum
(CI) m/z 167.0888 [C9H15OSi (M+1) requires 167.0892],
167 (base), 151.
IR (neat) 2934, 1477, 1448, 1365, 1248, 1108, 1040 cmꢁ1
;
mass spectrum (CI) m/z 438.1677 [C24H30O4Si2 requires
438.1683], 339 (base).
5.2.6. Cycloadduct 30. Potassium hydroxide (two pellets)
and H2O (0.3 mL) were added to a solution of cycloadduct
26 (80 mg, 0.18 mmol) in DMF (3 mL), and the mixture
was stirred for 2 h at room temperature. The mixture was
diluted with 50% Et2O/hexanes (50 mL) and washed with
brine (5ꢂ5 mL). The organic layer was dried (Na2SO4)
and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel eluting with hex-
anes/EtOAc (1:2) to afford 68 mg (79%) of 30 as a yellowish
5.2.3. 2-[Dimethyl-(5-methylfuran-2-yl)silanyl]ethanol
(24). The vinylsilane 23 (2.30 g, 13.8 mmol) was added to
a solution of 9-BBN (2.53 g, 20.7 mmol) in THF (42 mL)
and stirred for 5 h at ambient temperature. The reaction
was cooled to 0 ꢀC and 3 N NaOH (8.2 mL) and 30%
H2O2 (8.2 mL) were added sequentially. The mixture was
stirred for 30 min at 0 ꢀC, the organic layer was separated,
and the aqueous layer was extracted with Et2O (2ꢂ
20 mL). The combined organics were dried (Na2SO4), con-
centrated, and the crude product was purified by flash chro-
matography eluting with hexanes/EtOAc (4:1) to provide
1
oil. H NMR (400 MHz) d 7.02–6.96 (m, 2H), 6.81 (d,
J¼5.6 Hz, 2H), 5.69 (dd, J¼4.0, 2.0 Hz, 2H), 4.05–3.96
(m, 4H), 1.96 (s, 7H, 2CH3 and OH), 1.62–1.57 (br, 1H,
OH), 1.25–1.12 (m, 4H), 0.20 (s, 12H); 13C NMR
(125 MHz) d 146.6, 146.4, 144.1, 144.0, 143.5, 143.3,
142.7, 142.7, 142.1, 141.9, 90.1, 80.2, 80.2, 72.0, 71.6, 19.8,
19.8, 16.9, 16.9, 0.3, 0.3; IR (neat) 3388, 2915, 2853,
1463, 1249 cmꢁ1; mass spectrum (CI) m/z 474.1874
[C24H34O6Si2 requires 474.1894].
1
2.42 g (95%) of alcohol 24 as a colorless oil. H NMR
(250 MHz) d 6.54 (d, J¼3.1 Hz, 1H), 5.95 (d, J¼3.1 Hz,
1H), 3.82–3.72 (comp, 2H), 2.32 (s, 3H), 1.50 (br, 1H),
1.22–1.12 (comp, 2H), 0.26 (s, 6H); 13C NMR (62.5 MHz)
d 156.8, 156.7, 121.4, 105.7, 59.8, 20.7, 13.6, ꢁ3.0;
IR (NaCl) 3434, 2956, 1495, 1035 cmꢁ1; mass spectrum
(CI) m/z 184.0923 [C9H16O2Si requires 184.0920], 184
(base), 139.
5.2.7. 1,5-Dihydroxy-4,8-dimethylanthraquinone (29).
Cycloadduct 30 (68 mg, 0.14 mmol) in MeOH (4 mL) con-
taining concentrated HCl (five drops) was stirred in air for
3 h at 75 ꢀC. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by chromato-
graphy on silica gel eluting with hexanes/EtOAc (10:1) to af-
ford 28 mg (73%) of 29 as a reddish solid; mp 237–238 ꢀC;
1H NMR (500 MHz) d 13.40 (s, 2H), 7.43 (d, J¼8.7 Hz, 2H),
7.19 (d, J¼8.7 Hz, 2H), 2.72 (s, 6H); 13C NMR (125 MHz)
d 190.6, 161.8, 141.0, 134.1, 129.4, 124.8, 117.2, 23.5; IR
(CDCl3) 3155, 2984, 1641, 1470, 1382, 1096 cmꢁ1; mass
spectrum (CI) m/z 269.0816 [C16H13O4 (M+1) requires
269.0814] (base), 253.
5.2.4. 5-Methylfuran-2-yl-dimethyl[2-(2,3,5,6-tetra-
bromo-4-phenoxy)ethyl]-4-(2-dimethylsilanyl-5-methyl-
furan-2-yl)ethoxysilane (25). DIAD (0.16 g, 0.79 mmol)
was added to a solution of tetrabromohydroquinone
(0.17 g, 0.40 mmol), alcohol 24 (0.15 g, 0.81 mmol), and
PPh3 (0.21 g, 0.80 mmol) in THF (3 mL). The reaction
was stirred for 3 h at room temperature and then concen-
trated. The residue was purified by flash chromatography
on silica gel eluting with hexanes/EtOAc (50:1) to afford
0.24 g (78%) of 25 as a pale yellow oil. 1H NMR
(250 MHz) d 6.55 (d, J¼3.0 Hz, 2H), 5.96 (d, J¼3.0 Hz,
2H), 4.13–4.04 (comp, 4H), 2.32 (s, 6H), 1.55–1.46 (m,
5.2.8. 2-[(Furan-2-yl)dimethylsilanyl]ethanol (34). n-BuLi
(27.0 mL of a 2.05 M solution in hexanes, 55.4 mmol) was

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8629
added dropwise to a solution of furan (8.0 mL, 110.0 mmol)
in ether (160 mL) at ꢁ78 ꢀC and stirred for 1 h. Chlorodime-
thylvinylsilane (7.64 mL, 55.3 mmol) was added dropwise
over 3 min. The reaction was stirred at ꢁ78 ꢀC for 15 min
and then quenched with EtOH (4 mL). The mixture was
diluted with Et2O (200 mL) and washed with brine (2ꢂ
80 mL). The organic layer was separated, dried (Na2SO4),
and concentrated to provide 8.1 g (96%) of 33 as a colorless
oil. A portion of 33 (1.30 g, 8.5 mmol) thus obtained was dis-
solved in THF (34 mL), 9-BBN (2.50 g, 20.5 mmol) was
added, and the solution was stirred at ambient temperature
for 12 h. The reaction was cooled to 0 ꢀC, and 3 N NaOH
(3.90 mL) and 30% H2O2 (3.90 mL) were added. The mixture
was stirred for 25 min at 0 ꢀC, the organic layer was sepa-
rated, and the aqueous layer was extracted with Et2O (2ꢂ
20 mL). The combined organics were dried (Na2SO4), con-
centrated, and the crude product was purified by flash chroma-
tography eluting with EtOAc/hexanes (1:3) to afford 1.13 g
(76%) of alcohol 34 as a colorless oil. 1H NMR (250 MHz)
d 7.66 (d, J¼1.6 Hz, 1H), 6.65 (d, J¼3.3 Hz, 1H), 6.38 (dd,
J¼3.3, 1.6 Hz, 1H), 3.81–3.75 (comp, 2H), 1.39 (br, 1H),
1.23–1.16 (comp, 2H), 0.29 (s, 6H); 13C NMR (62.5 MHz)
d 158.8, 146.8, 120.2, 109.4, 59.6, 20.6, ꢁ3.1; IR (neat)
3364, 2957, 2926, 1412, 1253, 1035 cmꢁ1; mass spectrum
(CI) m/z 170.0766 [C8H14O2Si requires 170.0763], 125, 75
(base).
5.2.11. Anthracenediol (37). A solution of ZnCl2 (2.92 mL
of 1 M solution in Et2O, 2.92 mmol) was added to a solution
of 36 (571 mg, 1.39 mmol) in CH2Cl2 (28 mL) at ꢁ78 ꢀC.
The reaction was allowed to warm to 0 ꢀC over 1 h, and
stirring was continued for 40 min at 0 ꢀC. The mixture was
diluted with hexanes (70 mL), washed with H2O (15 mL)
and brine (15 mL), dried (MgSO4), and concentrated. The
residue was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc (15:1) to afford 403 mg
1
(71%) of 37 as an orange solid; mp 170–171 ꢀC; H NMR
(300 MHz) d 10.53 (s, 2H), 7.58 (d, J¼7.5 Hz, 2H), 6.84
(d, J¼7.5 Hz, 2H), 5.10–3.98 (br, 4H), 1.80–1.38 (br, 4H),
0.44 (s, 12H); 13C NMR (62.5 MHz) d 155.8, 152.0, 135.6,
129.5, 123.2, 117.0, 108.6, 78.3, 19.6, 3–0 (br); IR (NaCl)
3402, 2954, 2897, 1463, 1280, 1251, 1082, 1023 cmꢁ1
;
mass spectrum (CI) m/z 409.1284 [C22H25O4Si2 (Mꢁ1)
requires 409.1291], 397 (base), 367.
5.2.12. Anthracenediol dimethyl ether (38). Sodium
hydride (235 mg of a 60% suspension in mineral oil,
5.88 mmol) was added to a solution of 37 (403 mg,
0.98 mmol) and CH3I (2.90 g, 20.4 mmol) in DMF
(20 mL) at 0 ꢀC. The reaction was allowed to warm to
room temperature over 20 min and stirred for 40 min. H2O
(2 mL) and Et2O (100 mL) were added, and the mixture
was washed with brine (4ꢂ15 mL), dried (MgSO4), and con-
centrated. The residue was purified by flash chromatography
on silica gel eluting with hexanes/EtOAc (15:1) to afford
400 mg (93%) of 38 as a light orange solid; mp 153–
5.2.9. Furan-2-yl-dimethyl[2-(2,3,5,6-tetrabromo-4-
ethoxyphenoxy)ethyl]-4-(2-dimethylsilanylfuran-2-yl)-
ethoxysilane (35). Diisopropylazodicarboxylate (0.24 g,
1.19 mmol) was added to a solution of tetrabromohydroqui-
none (0.25 g, 0.59 mmol), alcohol 34 (0.20 g, 1.17 mmol),
and triphenylphosphine (0.31 g, 1.18 mmol) in THF (6.0 mL).
The reaction was stirred for 2 h at ambient temperature
and then concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with hexanes/
EtOAc (20:1) to provide 0.38 g (89%) of 35 as a colorless
1
154 ꢀC; H NMR (300 MHz) d 7.57 (d, J¼7.5 Hz, 2H),
6.75 (d, J¼7.5 Hz, 2H), 5.00–4.60 (br, 2H), 4.40–4.00 (br,
2H), 4.01 (s, 6H), 1.70–1.30 (br, 4H), 0.41 (s, 12H); 13C
NMR (75 MHz) d 157.3, 150.9, 133.7, 133.5, 127.9, 118.9,
103.9, 74.6, 56.2, 19.5, 2–(ꢁ1) (br); IR (NaCl) 2955,
2896, 1384, 1331, 1073 cmꢁ1; mass spectrum (CI) m/z
438.1686 [C24H30O4Si2 requires 438.1683], 411 (base),
395, 382.
1
oil. H NMR (250 MHz) d 7.62 (d, J¼1.6 Hz, 2H), 6.64
(d, J¼3.1 Hz, 2H), 6.35 (dd, J¼3.1, 1.6 Hz, 2H), 4.09–
4.02 (comp, 4H), 1.53–1.46 (comp, 4H), 0.31 (s, 12H);
13C NMR (62.5 MHz) d 158.1, 151.9, 147.0, 121.5, 120.4,
109.4, 71.2, 17.5, ꢁ3.0; IR (neat) 2955, 1406, 1348, 1252,
1179, 1056 cmꢁ1; mass spectrum (CI) m/z 726.8187
[C22H27Br4O4Si2 (M+1) requires 726.8181], 667, 529
(base), 281.
5.2.13. 1,5-Dimethoxyanthra-9,10-quinone (39).
BF3$2AcOH (17 mg, 0.09 mmol) was added to a solution
of 38 (10 mg, 0.02 mmol) and ClCH2CO2H (8.6 mg,
0.09 mmol) in hexane (0.5 mL). The reaction was stirred
for 40 min at room temperature, whereupon EtOAc (7 mL)
was added. The mixture was washed with brine (3ꢂ1 mL),
dried (MgSO4), and concentrated. The residue was purified
by flash chromatography on silica gel eluting with CHCl3
to afford 3.5 mg (57%) of 39 as a yellowish solid (mp
234–235 ꢀC; lit.38 mp 234–235 ꢀC) whose 1H and 13C
NMR spectral data were consistent with those reported.38
5.2.10. Cycloadduct 36. A solution of n-BuLi (111 mL of a
1.95 M solution in hexanes, 0.22 mmol) was added dropwise
to a solution of 35 (61 mg, 0.08 mmol) in Et2O (14 mL) at
room temperature. Brine (4 mL) was added, and the organic
layer was separated, dried (MgSO4), and concentrated.
The residue was purified by flash chromatography eluting
with hexanes/EtOAc (6:1) to afford 17 mg (50%) of cyclo-
5.3. Synthesis of vineomycinone B2 methyl ester
5.3.1. 3(R),4(R)-Bisbenzyloxy-6(R)-furan-3-yl-2(R)-
methyltetrahydropyran (44). A solution of 3-bromofuran
(0.20 g, 1.36 mmol) in THF (9 mL) was cooled to ꢁ78 ꢀC
and n-BuLi (0.57 mL of a 2.4 M solution in hexanes,
1.36 mmol) was added dropwise. The reaction was stirred
for 10 min, and a solution of lactone 4016c (0.41 g,
1.25 mmol) in THF (3 mL) was added dropwise over
3 min. The reaction was stirred for an additional 30 min
and then poured onto saturated NaHCO3 (2 mL). The
mixture was diluted with H2O (20 mL) and extracted with
EtOAc (30 mL). The organics were dried (MgSO4) and
1
adduct 36 as a yellowish solid; mp 185–186 ꢀC; H NMR
(250 MHz) d 7.10–7.00 (comp, 4H), 5.81–5.77 (comp, 2H),
4.62–4.43 (comp, 2H), 3.91–3.70 (comp, 2H), 1.61–1.41
(comp, 2H), 1.17–1.07 (comp, 2H), 0.33 (s, 3H), 0.30
(s, 3H), 0.24 (s, 3H), 0.21 (s, 3H); 13C NMR (62.5 MHz) d
146.3, 145.1, 145.1, 144.4, 144.1, 143.2, 142.0, 141.1, 139.9,
139.2, 85.7, 85.5, 81.4, 81.2, 72.5, 71.3, 17.1, 16.9, ꢁ3.5,
ꢁ4.0, ꢁ4.1, ꢁ4.1; IR (CDCl3) 2959, 1482, 1035 cmꢁ1
;
mass spectrum (CI) m/z 410.1368 [C22H26O4Si2 requires
410.1370], 411 (base), 383, 355.

8630
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
concentrated to a colorless oil. The oil was dissolved in
EtOH (5 mL) and one drop of HCl in EtOH (prepared
from 0.4 mL of AcCl and 5 mL of EtOH) was added. The
mixture was stirred for 10 min and then poured onto satu-
rated NaHCO3 (20 mL) layered with EtOAc (20 mL). The
organic layer was separated, dried (MgSO4), and concen-
trated to an oil, which solidified upon standing to a colorless
solid. The solid was dissolved in EtOH (13 mL) and heated
to 50 ꢀC. Bromocresol green (1 mg) was added followed by
NaCNBH3 (0.71 g, 11.3 mmol). A solution of HCl in EtOH
(prepared from 0.4 mL of AcCl and 5 mL of EtOH) was
added dropwise until no acetal remained (w2 mL) as deter-
mined by TLC (10% EtOAc/hexanes). The solution was
cooled and poured onto saturated NaHCO3 (20 mL) and
water (20 mL) and extracted with EtOAc (30 mL). The
organics were dried (MgSO4), concentrated, and the result-
ing residue was purified by flash chromatography on silica
gel eluting with hexanes/EtOAc (9:1) to afford 0.39 g
(82%) of glycosyl furan 44 as a colorless oil that was iden-
tical in all respects to that reported.39 1H NMR (250 MHz)
d 7.41–7.25 (comp, 12H), 6.42 (dd, J¼1.6, 0.7 Hz, 1H),
5.00 (d, J¼10.8 Hz, 1H), 4.74 (d, J¼11.6 Hz, 1H), 4.70 (d,
J¼10.8 Hz, 1H), 4.66 (d, J¼11.6 Hz, 1H), 4.38 (dd,
J¼11.7, 2.0 Hz, 1H), 3.74 (ddd, J¼11.4, 8.7, 5.0 Hz, 1H),
3.49 (dq, J¼9.3, 6.2 Hz, 1H), 3.20 (dd, J¼9.3, 8.7 Hz,
1H), 2.37 (ddd, J¼12.8, 5.0, 2.0 Hz, 1H), 1.78 (ddd,
J¼12.8, 11.7, 11.4 Hz, 1H), 1.36 (d, J¼6.2 Hz, 3H); 13C
NMR (75 MHz) d 143.1, 139.2, 138.5, 128.4, 128.4, 128.4,
128.0, 127.7, 127.6, 127.6, 126.1, 108.8, 84.0, 80.6, 75.6,
75.3, 71.5, 70.0, 37.6, 18.5; IR (neat) 3063, 2973, 2922,
2863, 1952, 1875, 1810, 1604, 1498, 1454, 1364, 1300,
1208, 1162, 1113, 1027, 996 cmꢁ1; mass spectrum (CI)
m/z 379.1916 [C24H27O4 (M+1) requires 379.1909].
5.3.3. (2R,4R,5R,6R)-2-{[3-(4,5-Bisbenzyloxy-6-methyl-
tetrahydropyran-2-yl)-furan-2-yl]-dimethylsilanyl}etha-
nol (46). 9-BBN (47 mg, 0.39 mmol) was added to a solution
of vinylsilane 45 (90 mg, 0.19 mmol) in THF (1.0 mL), and
the mixture was stirred at room temperature for 2 h. The re-
action was cooled to 0 ꢀC, and 3 N NaOH (0.40 mL) and
30% H2O2 (0.20 mL) were added sequentially. The mixture
was stirred vigorously for 15 min and then extracted with
Et2O (2ꢂ2 mL). The combined extracts were dried
(MgSO4) and concentrated. The residue was purified by
flash chromatography on silica gel eluting with hexanes/
EtOAc (7:3) to afford 88 mg (94%) of alcohol 46 as a color-
less oil. 1H NMR (250 MHz) d 7.56 (d, J¼1.6 Hz, 1H), 7.40–
7.26 (comp, 10H), 6.40 (d, J¼1.6 Hz, 1H), 5.01 (d, J¼
10.8 Hz, 1H), 4.76–4.64 (comp, 3H), 4.46 (dd, J¼11.6,
1.8 Hz, 1H), 3.81–3.68 (comp, 3H), 3.53–3.44 (comp, 1H),
3.21 (t, J¼8.9 Hz, 1H), 2.31 (ddd, J¼12.9, 5.0, 1.9 Hz,
1H), 1.83 (q, J¼11.6 Hz, 1H), 1.58 (br, 1H), 1.37 (d,
J¼6.1 Hz, 3H), 1.30–1.14 (comp, 2H), 0.32 (s, 6H); 13C
NMR (62.5 MHz) d 155.1, 146.4, 138.5, 138.4, 136.1,
128.4, 128.3, 127.9, 127.7, 127.6, 108.6, 83.9, 80.7, 75.8,
75.3, 71.5, 70.5, 59.6, 37.9, 20.8, 18.5, ꢁ2.5, ꢁ2.5; IR
(CDCl3) 3619, 2930, 2879, 1364, 1253, 1075 cmꢁ1; mass
spectrum (CI) m/z 481.2390 [C28H37O5Si (M+1) requires
481.2410], 435 (base), 379.
5.3.4. (2S)-4-(4-Methoxy-phenoxy)-2-methyl-butane-1,2-
diol (49). A solution of 1-(4-methoxyphenoxy)-3-methyl-
3-butene 4832 (3 g, 15.6 mmol) in tert-BuOH (77 mL) was
added to a solution of DHQ2PHAL (120 mg, 0.16 mmol),
K2OsO2(OH)4 (11 mg, 0.03 mmol), K3Fe(CN)6 (15.4 g,
46.8 mmol), and K2CO3 (6.47 g, 46.8 mmol) in H2O
(77 mL) at 0 ꢀC. The mixture was stirred for 24 h at 0 ꢀC,
and Na2SO3 (2 g, 15.9 mmol) was added. The mixture was
stirred for 20 min, and brine (40 mL) was added. The mix-
ture was extracted with EtOAc/hexanes (2:1, 4ꢂ150 mL).
The combined organic layers were dried (Na2SO4), and con-
centrated under reduced pressure. The residue was purified
by chromatography on silica gel eluting with EtOAc to
afford 3.35 g (95%) of diol 49 as a white solid (mp 57–
58 ꢀC; lit.32 mp 57–58 ꢀC) of 96% ee (determined by
5.3.2. (2R,4R,5R,6R)-[3-(4,5-Bisbenzyloxy-6-methyl-
tetrahydropyran-2-yl)furan-2-yl]dimethylvinylsilane
(45). A solution of furan 44 (0.17 g, 0.45 mmol) in THF
(2.0 mL) was added to a solution of LDA (0.67 mmol)
in THF (3.0 mL) at ꢁ78 ꢀC and stirred for 3.5 h. Freshly dis-
tilled chlorodimethylvinylsilane (81 mg, 0.67 mmol) was
added dropwise, and the mixture was stirred at ꢁ78 ꢀC for
5 min. Saturated NaHCO3 (2 mL) was added, and the mix-
ture was extracted with EtOAc (3ꢂ5 mL). The combined
extracts were dried (MgSO4) and concentrated, and the
residue was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc (9:1) to afford 146 mg (70%)
of furan 45 as a colorless oil and 50 mg (29%) of recovered
44. 1H NMR (500 MHz) d 7.53 (d, J¼1.7 Hz, 1H), 7.35–7.27
(comp, 10H), 6.39 (d, J¼1.7 Hz, 1H), 6.24 (dd, J¼20.4,
14.6 Hz, 1H), 6.01 (dd, J¼14.6, 3.6 Hz, 1H), 5.75 (dd,
J¼20.4, 3.6 Hz, 1H), 4.97 (d, J¼10.9 Hz, 1H), 4.69 (d, J¼
11.6 Hz, 1H), 4.67 (d, J¼10.9 Hz, 1H), 4.62 (d, J¼
11.6 Hz, 1H), 4.43 (dd, J¼11.7, 1.9 Hz, 1H), 3.68 (ddd,
J¼11.3, 8.6, 5.0 Hz, 1H), 3.42 (dq, J¼9.2, 6.2 Hz, 1H),
3.17 (t, J¼8.9 Hz, 1H), 2.23 (ddd, J¼12.9, 5.0, 2.0 Hz,
1H), 1.77 (ddd, J¼12.8, 11.6, 11.6 Hz, 1H), 1.32 (d,
J¼6.2 Hz, 3H), 0.34 (s, 3H), 0.33 (s, 3H); 13C NMR
1
HPLC) whose H and 13C NMR spectral data were consis-
tent with those reported.32
5.3.5. (2S)-Toluene-4-sulfonic acid 2-hydroxy-4-(4-meth-
oxyphenoxy)-2-methylbutyl ester (50). A solution of
p-toluenesulfonyl chloride (1.65 g, 8.65 mmol) in CH2Cl2
(6 mL) was added to a solution of diol 4932 (1.63 g,
7.3 mmol), triethylamine (1.50 mL, 10.76 mmol), and
4,4-dimethylaminopyridine (10 mg, 0.08 mmol) in CH2Cl2
(30 mL) at room temperature. The solution was stirred for
48 h and then washed with saturated aqueous NaHCO3
(20 mL). The organic layer was separated, dried (MgSO4),
and concentrated. The residue was purified by flash chroma-
tography on silica gel eluting with hexanes/EtOAc (7:3) to
1
afford 2.46 g (90%) of tosylate 50 as a colorless oil. H
NMR (250 MHz) d 7.78 (d, J¼8.3 Hz, 2H), 7.34 (d, J¼
8.3 Hz, 2H), 6.83–6.74 (comp, 4H), 4.04 (t, J¼5.9 Hz,
2H), 3.96 (d, J¼9.6 Hz, 1H), 3.88 (d, J¼9.6 Hz, 1H), 3.77
(s, 3H), 2.89 (s, 1H), 2.44 (s, 3H), 1.99 (td, J¼5.8, 2.0 Hz,
2H), 1.25 (s, 3H); 13C NMR (62.5 MHz) d 154.2, 152.2,
145.0, 132.5, 129.9, 128.0, 115.4, 114.6, 75.5, 71.0, 64.9,
55.7, 36.9, 24.5, 21.6; IR (CDCl3) 3525, 2935, 1506,
(125.5 MHz)
d 154.4, 146.5, 138.6, 138.5, 136.9,
136.4, 133.1, 128.4, 128.4, 128.0, 127.7, 127.7, 127.6,
108.6, 84.0, 80.9, 75.7, 75.3, 71.5, 70.4, 38.1, 18.6,
ꢁ2.9, ꢁ2.9; IR (NaCl) 2924, 2861, 1498, 1454, 1366,
1114, 1080 cmꢁ1; mass spectrum (CI) m/z 463.2297
[C28H35O4Si (M+1) requires 463.2304] (base).

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8631
1227 cmꢁ1; mass spectrum (CI) m/z 380.1305 [C19H24O6S
requires 380.1294], 380, 209, 191 (base).
dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel
eluting with hexanes/EtOAc (9:1) to afford 0.39 g (100%)
of benzyl ether 56 as a pale yellow oil. 1H NMR
(500 MHz) d 7.35–7.24 (comp, 7H), 6.84–6.78 (comp, 4H),
6.33 (dd, J¼2.0, 1.0 Hz, 1H), 4.52 (s, 2H), 4.13–4.05 (m,
2H), 3.75 (s, 3H), 2.76 (s, 2H), 2.14–2.02 (m, 2H), 1.31 (s,
3H); 13C NMR (100 MHz) d 153.8, 153.1, 142.4, 140.8,
139.2, 128.4, 127.2, 127.2, 120.3, 115.4, 114.7, 112.6, 76.4,
64.6, 63.6, 55.8, 37.2, 34.5, 23.5; IR (CDCl3) 2935, 1508,
1230 cmꢁ1; mass spectrum (CI) m/z 366.1827 [C23H26O4 re-
quires 366.1831], 366, 259, 177 (base).
5.3.6. (2S)-1-Furan-3-yl-4-(4-methoxyphenoxy)-2-methyl-
butan-2-ol (51). Method A. A solution of n-BuLi (0.87 mL
of a 2.5 M solution in hexanes, 2.18 mmol) was added
dropwise to a solution of tosylate 50 (0.83 g, 2.18 mmol)
in THF (16 mL) at ꢁ78 ꢀC. The reaction mixture was stirred
for 10 min, and a solution of 3-lithiofuran (5.45 mmol) in
THF (12 mL) at ꢁ78 ꢀC was transferred to the mixture via
cannula. BF3$Et2O (0.60 mL, 4.74 mmol) was then added,
and the reaction was stirred for 1 h. The reaction was
quenched by addition of saturated NaHCO3 (5 mL) and
extracted with EtOAc (20 mL). The organic layer was washed
with brine (2ꢂ15 mL), dried (MgSO4), and concentrated. The
residue was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc (3:1) to afford 0.50 g (84%)
of furan 51 as a pale yellow oil. 1H NMR (250 MHz) d 7.38
(t, J¼1.5 Hz, 1H), 7.31 (s, 1H), 6.90–6.80 (comp, 4H), 6.36
(s, 1H), 4.15 (t, J¼6.3 Hz, 2H), 3.77 (s, 3H), 2.70 (d,
J¼14.3 Hz, 1H), 2.63 (d, J¼14.3 Hz, 1H), 2.37 (br, 1H),
2.07–1.86 (comp, 2H), 1.26 (s, 3H); 13C NMR (62.5 MHz)
d 154.0, 152.7, 142.7, 140.8, 120.1, 115.4, 114.7, 112.6,
71.7, 65.5, 55.7, 39.7, 38.0, 26.7; IR (CDCl3) 3550, 2935,
1508, 1227 cmꢁ1; mass spectrum (CI) m/z 276.1368
[C16H20O4 requires 276.1362], 276, 177 (base). Method B.
Potassium carbonate (0.58 g, 4.20 mmol) was added to a solu-
tion of tosylate 50 (0.20 g, 0.53 mmol) in MeOH (10 mL) at
room temperature. The reaction was stirred for 45 min and
then poured onto Et2O (80 mL) and water (20 mL). The or-
ganic layer was separated and washed with brine (20 mL),
dried (MgSO4), and concentrated. The residue was purified
by flash chromatography on silica gel eluting with hexanes/
EtOAc (4:1) to afford 97 mg (89%) of epoxide 52 as a color-
less solid; mp 51–53 ꢀC; 1H NMR (250 MHz) d 6.82 (s, 4H),
4.07–3.93 (comp, 2H), 3.76 (s, 3H), 2.73 (d, J¼4.9 Hz, 1H),
2.63 (d, J¼4.9 Hz, 1H), 2.14–1.93 (comp, 2H), 1.40 (s,
3H); 13C NMR (62.5 MHz) d 153.9, 152.7, 115.4, 114.6,
64.8, 55.7, 55.2, 53.9, 36.1, 21.6; IR (CDCl3) 2957, 1508,
1230, 1039 cmꢁ1; mass spectrum (CI) m/z 208.1095
[C12H16O3 requires 208.1099], 191 (base). A solution of
3-bromofuran (0.21 g, 1.43 mmol) in THF (4 mL) was cooled
to ꢁ78 ꢀC, and n-BuLi (0.68 mL of a 2.1 M solution,
1.43 mmol) was added dropwise. The solution was stirred
for 15 min, and then a solution of epoxide 52 (0.10 g,
0.48 mmol) in THF (1.0 mL) was added dropwise. The solu-
tion was stirred for 5 min and BF3$Et2O (0.11 g, 0.76 mmol)
was added. The solution was stirred for 1.5 h, whereupon
saturated aqueous NaHCO3 (2 mL) was added. The mixture
was extracted with Et2O (2ꢂ5 mL), and the combined organic
layers were dried (MgSO4) and concentrated. The residue was
purified by flash chromatography on silica gel eluting with
hexanes/EtOAc (3:1) to afford 116 mg (88%) of 51.
5.3.8. 3-[2-Benzyloxy-4-(4-methoxyphenoxy)-2(S)-methyl-
butyl]-2-bromofuran (57). A solution of furan 56 (0.68 g,
1.86 mmol) in DMF (37 mL) was cooled to 0 ꢀC, and freshly
recrystallized N-bromosuccinimide (0.33 g, 1.85 mmol) was
added. The reaction was stirred for 1 h, and saturated aqueous
NaHCO3 (40 mL) was added. The mixture was extracted with
EtOAc (3ꢂ100 mL), and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel
eluting with hexanes/EtOAc (9:1) to afford 0.72 g (86%) of
57 as a colorless oil. 1H NMR (250 MHz) d 7.38–7.23
(comp, 6H), 6.85–6.78 (comp, 4H), 6.42 (d, J¼2.0 Hz, 1H),
4.52 (s, 2H), 4.09 (app t, J¼6.9 Hz, 2H), 3.75 (s, 3H), 2.70
(s, 2H), 2.14–2.04 (m, 2H), 1.32 (s, 3H); 13C NMR
(62.5 MHz) d 153.8, 153.0, 143.6, 139.1, 128.3, 127.3,
127.2, 121.9, 119.9, 115.4, 114.6, 114.5, 76.8, 64.5, 63.7,
55.7, 37.3, 34.9, 23.3; IR (NaCl) 2934, 1508, 1231,
1040 cmꢁ1; mass spectrum (CI) m/z 444.0932 [C23H25O4Br
(M+1) requires 444.0936], 444, 177 (base).
5.3.9. {3-[2-Benzyloxy-4-(4-methoxyphenoxy)-2(S)-
methylbutyl]furan-2-yl}dimethylvinylsilane (58). A solu-
tion of bromofuran 57 (0.38 g, 0.84 mmol) in THF (13 mL)
was cooled to ꢁ78 ꢀC, and n-BuLi (0.43 mL of a 2.4 M
solution, 1.03 mmol) was added dropwise. The solution
was stirred for 25 min, and freshly distilled chlorodimethyl-
vinylsilane (150 mL, 1.09 mmol) was added. The reaction
was stirred for 25 min at ꢁ78 ꢀC and then poured onto satu-
rated NaHCO3 (20 mL). The mixture was extracted with
EtOAc (2ꢂ30 mL), and the combined organics were dried
(MgSO4) and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel eluting
with hexanes/EtOAc (95:5) to furnish 0.34 g (88%) of vinyl-
1
silane 58 as a colorless oil. H NMR (250 MHz) d 7.54 (d,
J¼1.5 Hz, 1H), 7.38–7.23 (comp, 5H), 6.83–6.78 (comp,
4H), 6.43 (d, J¼1.5 Hz, 1H), 6.28 (dd, J¼20.0, 14.5 Hz,
1H), 6.03 (dd, J¼14.5, 3.8 Hz, 1H), 5.77 (dd, J¼20.0,
3.8 Hz, 1H), 4.51 (s, 2H), 4.08 (t, J¼7.1 Hz, 2H), 3.75
(s, 3H), 2.87 (d, J¼14.7 Hz, 1H), 2.78 (d, J¼14.7 Hz,
1H), 2.20–1.99 (m, 2H), 1.26 (s, 3H), 0.36 (s, 6H); 13C
NMR (62.5 MHz) d 154.0, 153.7, 153.0, 146.4, 139.2,
137.2, 133.1, 131.8, 128.3, 127.3, 127.2, 115.3, 114.6,
112.5, 76.6, 64.6, 63.6, 55.7, 37.8, 34.7, 23.5, ꢁ2.7; IR
(CDCl3) 3051, 2959, 1508, 1230 cmꢁ1; mass spectrum
(CI) m/z 450.2233 [C27H34O4Si requires 450.2226], 451,
343 (base).
5.3.7. 3-[2-Benzyloxy-4-(4-methoxyphenoxy)-2(S)-methyl-
butyl]furan (56). A solution of furan 51 (0.29 g, 1.05 mmol)
in DMF (3 mL) was added dropwise to a suspension of
KH (0.24 g of a 35% suspension, 2.09 mmol) in DMF
(5 mL) at 0 ꢀC. The mixture was stirred for 10 min, and
benzyl bromide (0.27 g, 1.58 mmol) was added. After
45 min, saturated aqueous NaHCO3 (15 mL) was added,
and the mixture was extracted with Et2O (2ꢂ20 mL). The
combined organic layers were washed with brine (15 mL),
5.3.10. 2-({3-[2-Benzyloxy-4-(4-methoxyphenoxy)-2(S)-
methylbutyl]furan-2-yl}dimethylsilanyl)ethanol (59).
9-BBN (0.36 g, 2.95 mmol) was added to a solution of

8632
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
vinylsilane 58 (0.84 g, 1.86 mmol) in THF (9 mL) at room
temperature. The reaction was stirred for 3 h and then cooled
to 0 ꢀC, whereupon 3 N NaOH (5 mL) and 30% H2O2
(5 mL) were added sequentially. The mixture was stirred
for 30 min and then extracted with EtOAc (3ꢂ30 mL).
The combined organic layers were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The res-
idue was purified by chromatography on silica gel eluting
with hexanes/EtOAc (7:3) to afford 0.84 g (96%) of alcohol
2,3,5,6-tetrabromophenol (60). HF$pyridine (0.2 mL, 65–
70%) was added to a solution of silyl ether 62 (0.32 g,
0.32 mmol) in THF (4.5 mL) at 0 ꢀC in a Teflon vial. The
reaction was stirred for 1 h and then poured into a mixture
of saturated NaHCO3 (10 mL) and EtOAc (15 mL). The
organic layer was separated, washed with brine (10 mL),
dried (MgSO4), and concentrated. The residue was purified
by flash chromatography on silica gel eluting with hexanes/
EtOAc (4:1) to afford 0.25 g (89%) of phenol 60 as a color-
less oil. 1H NMR (400 MHz) d 7.53 (d, J¼2.0 Hz, 1H), 7.36–
7.25 (m, 5H), 6.84–6.78 (comp, 4H), 6.43 (d, J¼2.0 Hz, 1H),
5.98 (s, 1H), 4.52 (s, 2H), 4.10 (t, J¼7.0 Hz, 2H), 4.08–4.02
(m, 2H), 3.76 (s, 3H), 2.88 (d, J¼14.4 Hz, 1H), 2.80 (d,
J¼14.4 Hz, 1H), 2.19–2.05 (m, 2H), 1.53–1.50 (m, 2H),
1.30 (s, 3H), 0.36 (s, 3H), 0.35 (s, 3H); 13C NMR
(100 MHz) d 153.9, 153.7, 153.0, 148.9, 148.0, 146.5,
112.6, 112.3, 76.5, 71.4, 64.5, 63.6, 55.7, 37.8, 35.0,
23.6, 18.0, ꢁ2.0; IR (CDCl3) 3490, 2956, 1508, 1363,
1230, 1040 cmꢁ1; mass spectrum (CI) m/z 871.9028
[C33H36O6Br4Si requires 871.9015], 876, 741, 483, 423
(base).
1
59 as a colorless oil. H NMR (250 MHz) d 7.49 (d, J¼
1.5 Hz, 1H), 7.34–7.22 (comp, 5H), 6.83–6.76 (comp, 4H),
6.39 (d, J¼1.5 Hz, 1H), 4.49 (s, 2H), 4.07 (t, J¼7.1 Hz,
2H), 3.72 (s, 3H), 3.69 (app t, J¼8.2 Hz, 2H), 2.84 (d,
J¼14.6 Hz, 1H), 2.75 (d, J¼14.6 Hz, 1H), 2.13–2.04 (m,
2H), 1.26 (s, 3H), 1.18–1.12 (m, 2H), 0.28 (s, 6H); 13C
NMR (62.5 MHz) d 154.4, 153.8, 153.0, 146.3, 139.2,
131.6, 128.3, 127.3, 127.2, 115.4, 114.6, 112.6, 64.6, 63.7,
59.7, 55.7, 37.9, 35.0, 23.6, 21.2, ꢁ2.1; IR (NaCl) 3417,
2953, 1504, 1230, 1039 cmꢁ1; mass spectrum (CI) m/z
468.2339 [C27H36O5Si requires 468.2332], 469, 423, 259
(base).
5.3.11. 2,3,5,6-Tetrabromo-4-(tert-butyl-dimethylsilanyl-
oxy)-1-phenol (61). Imidazole (0.19 g, 2.79 mmol) and
TBSCl (0.17 g, 1.13 mmol) were added to a solution of 21
(0.6 g, 1.41 mmol) in DMF (1 mL) at room temperature. Af-
ter stirring for 50 min, the mixture was loaded onto column
and purified by chromatography on silica gel eluting with
hexanes/EtOAc (9:1) to furnish 274 mg (35%) of phenol
5.3.14. 3(R),4(R)-Bisbenzyloxy-6(R)-{2-[(2-{4-[2-({3-[2-
benzyloxy-4-(4-methoxyphenoxy)-2(S)-methylbutyl]-
furan-2-yl}dimethylsilanyl)ethoxy]-2,3,5,6-tetrabromo-
phenoxy}ethyl)dimethylsilanyl]furan-3-yl}-2(R)-methyl-
tetrahydropyran (63). DIAD (65 mg, 0.32 mmol) was
added to a solution of phenol 60 (230 mg, 0.26 mmol), alco-
hol 46 (140 mg, 0.29 mmol), and PPh3 (84 mg, 0.32 mmol)
in THF (10 mL) and the reaction was stirred for 4 h at room
temperature. The mixture was concentrated under reduced
pressure and the residue was purified by chromatography
on silica gel eluting with hexanes/EtOAc/Et3N (93:5:2) to
furnish 299 mg (85%) of aryl ether 63 as a colorless oil.
1H NMR (400 MHz) d 7.55 (d, J¼1.6 Hz, 1H), 7.53 (d,
J¼1.6 Hz, 1H), 7.39–7.24 (m, 15H), 6.84–6.80 (comp,
4H), 6.44 (d, J¼2.0 Hz, 1H), 6.38 (d, J¼2.0 Hz, 1H), 4.99
(d, J¼10.8 Hz, 1H), 4.72 (d, J¼11.6 Hz, 1H), 4.69 (d,
J¼10.8 Hz, 1H), 4.66 (d, J¼11.6 Hz, 1H), 4.53 (s, 2H),
4.46 (dd, J¼11.6, 2.0 Hz, 1H), 4.15–4.04 (comp, 6H), 3.76
(s, 3H), 3.75–3.70 (m, 1H), 3.52–3.45 (m, 1H), 3.20 (t,
J¼8.8 Hz, 1H), 2.88 (d, J¼14.4 Hz, 1H), 2.81 (d, J¼
14.4 Hz, 1H), 2.31 (ddd, J¼12.8, 4.8, 1.6 Hz, 1H), 2.19–
2.06 (m, 2H), 1.80 (dd, J¼12.8, 11.6 Hz, 1H), 1.59–1.51
(m, 4H), 1.36 (d, J¼6.0 Hz, 3H), 1.30 (s, 3H), 0.36 (s,
3H), 0.36 (s, 9H); 13C NMR (100 MHz) d 154.2, 153.9,
153.7, 153.0, 151.9, 146.5, 139.1, 138.5, 138.4, 136.6,
131.8, 128.4, 128.4, 128.3, 128.0, 127.7, 127.7, 127.6,
127.3, 121.5, 115.3, 114.6, 112.6, 108.7, 83.9, 80.8, 76.5,
75.8, 75.3, 71.5, 71.3, 71.2, 70.8, 64.5, 63.6, 55.7, 38.2,
37.8, 35.0, 23.6, 18.6, 18.0, 17.7, ꢁ2.0, ꢁ2.3; IR (CDCl3)
3032, 2953, 2887, 1508, 1348, 1230, 1088 cmꢁ1; mass
spectrum (CI) m/z 1338.1149 [C61H70O10Br4Si2 requires
1338.1200], 1338, 655, 555 (base).
1
61 as a yellowish oil. H NMR (400 MHz) d 5.85 (s, 1H,
OH), 1.02 (s, 9H), 0.32 (s, 6H); 13C NMR (100 MHz)
d 145.9, 145.8, 118.3, 112.4, 26.2, 19.0, ꢁ1.8; IR (CDCl3)
3493, 2929, 2857, 1652, 1424, 1364, 1258, 1179 cmꢁ1
mass spectrum (CI) m/z 536.7726 [C12H17O2Br4Si (M+1)
requires 536.7731], 483 (base), 404.
;
5.3.12. 3-[2-Benzyloxy-4-(4-methoxyphenyl)-2(S)-meth-
ylbutyl]-2-(dimethyl-{2-[2,3,5,6-tetrabromo-4-(tert-butyl-
dimethylsilanyloxy)phenoxy]ethyl}silanyl)furan (62).
DIAD (9.1 mg, 0.05 mmol) was added to a solution of phe-
nol 61 (24 mg, 0.04 mmol), alcohol 59 (21 mg, 0.05 mmol),
and PPh3 (11.8 mg, 0.05 mmol) in THF (0.5 mL), and the
solution was stirred for 3 h at room temperature. The reac-
tion mixture was concentrated under reduced pressure, and
the residue was purified by chromatography on silica gel
eluting with hexanes/EtOAc (95:5) to furnish 33 mg (75%)
1
of 62 as a colorless oil. H NMR (400 MHz) d 7.52 (d,
J¼1.2 Hz, 1H), 7.35–7.24 (comp, 5H), 6.83–6.77 (comp,
4H), 6.42 (d, J¼1.6 Hz, 1H), 4.52 (s, 2H), 4.10 (t, J¼
6.8 Hz, 2H), 4.05 (t, J¼6.8 Hz, 2H), 3.75 (s, 3H), 2.88 (d,
J¼14.8 Hz, 1H), 2.80 (d, J¼14.8 Hz, 1H), 2.19–2.03
(comp, 2H), 1.54 (app t, J¼8.4 Hz, 2H), 1.30 (s, 3H), 1.04
(s, 9H), 0.36 (s, 3H), 0.36 (s, 3H), 0.35 (s, 3H), 0.34 (s,
3H); 13C NMR (100 MHz) d 153.8, 153.5, 152.8, 149.4,
148.6, 146.3, 139.0, 131.7, 128.2, 127.1, 127.1, 121.3,
118.4, 115.2, 114.5, 112.4, 76.5, 71.1, 64.6, 63.7, 55.8,
37.9, 35.1, 26.3, 23.8, 19.1, 18.1, ꢁ1.5, ꢁ1.6,ꢁ1.8; IR
5.3.15. Preparation of bis-cycloadduct 64. Tetrabromide
63 (800 mg, 0.60 mmol), which had been dried in the bꢀulb
(CDCl3) 2930, 1508, 1419, 1368, 1252, 1230, 1041 cmꢁ1
;
€
of a Kugelrohr apparatus under vacuum for 2 h at 140 C,
mass spectrum (CI) m/z 985.9865 [C39H50O6Br4Si2 requires
985.9879], 597, 483, 403 (base).
was dissolved in Et2O (30 mL), and a solution of n-BuLi
(7.8 mL of a 0.23 M solution, 1.84 mmol, which was pre-
pared by diluting 0.8 mL of 2.3 M n-BuLi in hexanes with
7.0 mL Et2O) was added dropwise over 30 min at ꢁ20 ꢀC.
Once addition was complete, the reaction was stirred for
5.3.13. 4-[2-({3-[2-Benzyloxy-4-(4-methoxyphenoxy)-
2(S)-methylbutyl]furan-2-yl}dimethylsilanyl)ethoxy]-

S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
8633
10 min at ꢁ20 ꢀC. The mixture was quenched with EtOH
(1 mL) and then poured onto saturated NaHCO3 (30 mL)
and Et2O (300 mL). The organic layer was separated, washed
with saturated NaHCO3 (3ꢂ30 mL), dried (Na2SO4), and
concentrated. The residue was purified by flash chromato-
graphy on silica gel eluting with hexanes/EtOAc (1:4) to
afford 517 mg (85%) of a mixture of diastereomeric
cycloadducts 64 as a yellowish oil. 1H NMR (400 MHz) of
an enriched diastereomer d 7.35–7.20 (m, 15H), 6.99 (s,
1H), 6.82–6.70 (m, 5H), 5.74–5.71 (m, 2H), 4.98 (d, J¼
11.0 Hz, 1H), 4.69 (d, J¼11.6 Hz, 1H), 4.66 (d, J¼
11.0 Hz, 1H), 4.59 (d, J¼11.6 Hz, 1H), 4.60–4.45 (m, 3H),
4.37 (d, J¼10.8 Hz, 1H), 4.25 (d, J¼10.8 Hz, 1H), 4.00–
3.81 (m, 4H), 3.76 (s, 3H), 3.66–3.58 (m, 1H), 3.42–3.35
(m, 1H), 3.14 (t, J¼9.0 Hz, 1H), 2.76 (d, J¼18.4 Hz, 1H),
2.49 (d, J¼18.6 Hz, 1H), 2.26 (dd, J¼11.8, 4.2 Hz, 1H),
2.12–1.98 (m, 2H), 1.68 (dd, J¼12.4, 11.6 Hz, 1H), 1.53–
1.43 (m, 1H), 1.40 (s, 3H), 1.36 (d, J¼6.0 Hz, 3H), 1.27–
1.17 (m, 1H), 1.12–1.03 (m, 2H), 0.36 (s, 3H), 0.33 (s,
3H), 0.16 (s, 3H), 0.06 (s, 3H); IR (NaCl) 2936, 2878,
1507, 1454, 1229, 1109, 1038 cmꢁ1; mass spectrum (CI)
m/z 1019.4559 [C61H70O10Si2 (M+1) requires 1019.4585]
(base), 992, 885, 694.
at ꢁ15 ꢀC, and the reaction was stirred for 20 min. Et2O
(20 mL) was added, and the solution was washed with brine
(4ꢂ3 mL). The organic layer was dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography
on silica gel eluting with hexanes/EtOAc (2:1) to afford
16 mg (74%) of 68 as a yellowish oil. 1H NMR
(500 MHz) d 13.22 (s, 1H, OH), 13.09 (s, 1H, OH), 7.91
(d, J¼7.8 Hz, 1H), 7.85 (d, J¼7.8 Hz, 1H), 7.75 (d, J¼
7.8 Hz, 1H), 7.63 (d, J¼7.8 Hz, 1H), 7.36–7.24 (comp,
15H), 4.99 (d, J¼11.3 Hz, 1H), 4.86 (dd, J¼11.4, 1.9 Hz,
1H), 4.72 (d, J¼7.1 Hz, 1H), 4.70 (d, J¼7.1 Hz, 1H), 4.64
(d, J¼11.3 Hz, 1H), 4.61 (d, J¼11.1 Hz, 1H), 4.58 (d, J¼
11.1 Hz, 1H), 3.91–3.80 (comp, 3H), 3.57 (dq, J¼9.1,
6.1 Hz, 1H), 3.21 (t, J¼9.1 Hz, 1H), 3.18 (d, J¼13.6 Hz,
1H), 3.12 (d, J¼13.6 Hz, 1H), 2.69 (ddd, J¼13.0, 5.1,
1.9 Hz, 1H), 2.62 (t, J¼4.8 Hz, 1H, OH), 1.98–1.90 (m,
1H), 1.88–1.82 (m, 1H), 1.48–1.39 (m, 1H), 1.39 (s, 3H),
1.38 (d, J¼6.1 Hz, 3H); 13C NMR (125 MHz) d 188.2,
161.5, 158.9, 139.2, 138.6, 138.5, 138.4, 138.3, 135.1, 133.3,
131.8, 131.6, 128.5, 128.4, 128.3, 128.1, 127.7, 127.6,
127.5, 127.4, 127.3, 119.4, 118.7, 115.6, 115.5, 84.0, 80.8,
79.6, 75.8, 75.3, 71.4, 71.2, 64.1, 59.4, 40.3, 37.3, 36.9,
22.8, 18.6; IR (NaCl) 3428 (br), 2930, 2872, 1626, 1606,
1582, 1475, 1431, 1372, 1318, 1279, 1260, 1109, 1090,
1071 cmꢁ1; mass spectrum (CI) m/z 741.3059 [C46H45O9
(Mꢁ1) requires 741.3064] (base), 633.
5.3.16. Anthraquinone 67. Potassium hydroxide (10 pel-
lets) and H2O (1 mL) were added to a solution of cycload-
duct 64 (225 mg, 0.22 mmol) in DMF (10 mL), and the
mixture was stirred for 24 h at room temperature. A mixture
of 50% Et2O/hexanes (300 mL) was added, and the solution
was washed with brine (5ꢂ20 mL). The organic layer was
dried (Na2SO4) and concentrated. The residue was dissolved
in EtOH (30 mL), and concentrated hydrochloric acid (40
drops) was added. The reaction was stirred for 4 h at 65 ꢀC
and then concentrated under reduced pressure. The residue
was purified by chromatography on silica gel eluting with
hexanes/EtOAc (8:1) to afford 64 mg (34%) of 67 as a
5.3.18. Anthraquinone 69. IBX (9 mg, 0.03 mmol) was
added to a solution of alcohol 68 (8.0 mg, 0.01 mmol) in
EtOAc (1 mL), and the resulting suspension was heated
for 3 h at 80 ꢀC with vigorous stirring. The reaction was al-
lowed to cool to room temperature, and Et2O (5 mL) was
added. The mixture was filtered through a pad of Celite,
and the filtrate was concentrated under reduced pressure.
The crude aldehyde thus obtained was dissolved in
t-BuOH/H2O (3.5:1, 2 mL), and the solution was cooled
to 0 ꢀC. NaH2PO4$2H2O (28 mg, 0.18 mmol), 2-methyl-
2-butene (0.16 mL, 1.51 mmol), and NaClO2 (21 mg,
0.23 mmol) were then added, and the mixture was stirred
for 90 min at room temperature. The mixture was diluted
with Et2O (20 mL) and washed with brine (3ꢂ2 mL). The
organic layer was dried (Na2SO4) and concentrated. The
residue was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc (1:2) to afford 5.7 mg (70%)
1
yellowish oil. H NMR (500 MHz) d 13.19 (s, 1H, OH),
13.11 (s, 1H, OH), 7.90 (d, J¼7.9 Hz, 1H), 7.85 (d, J¼
7.9 Hz, 1H), 7.74 (d, J¼7.8 Hz, 1H), 7.71 (d, J¼7.9 Hz,
1H), 7.36–7.24 (comp, 15H), 6.83–6.76 (comp, 4H), 4.99
(d, J¼11.2 Hz, 1H), 4.86 (dd, J¼11.5, 1.7 Hz, 1H), 4.72
(d, J¼8.0 Hz, 1H), 4.70 (d, J¼8.0 Hz, 1H), 4.64 (d, J¼
11.2 Hz, 1H), 4.55 (s, 2H), 4.17–4.08 (comp, 2H), 3.85
(ddd, J¼13.5, 8.9, 4.7 Hz, 1H), 3.74 (s, 3H), 3.57 (dq,
J¼8.9, 6.2 Hz, 1H), 3.21 (t, J¼8.9 Hz, 1H), 3.19 (d, J¼
13.6 Hz, 1H), 3.11 (d, J¼13.6 Hz, 1H), 2.69 (ddd, J¼12.8,
4.7, 1.7 Hz, 1H), 2.21–2.07 (comp, 2H), 1.48–1.39 (m, 1H),
1.39 (d, J¼6.2 Hz, 3H), 1.34 (s, 3H); 13C NMR
(125 MHz) d 188.3, 188.2, 161.5, 158.9, 153.8, 153.0,
139.4, 139.1, 138.6, 138.5, 138.4, 138.3, 135.5, 133.3,
131.9, 131.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8,
127.7, 127.6, 127.5, 127.3, 127.1, 125.5. 119.4, 118.6,
115.5, 114.7, 84.0, 80.9, 77.5, 75.8, 75.3, 71.4, 71.2, 64.6,
63.8, 55.7, 37.7, 37.4, 37.3, 23.1, 18.6; IR (NaCl) 2918,
2848, 1625, 1507, 1431, 1372, 1284, 1261, 1231, 1107,
1090, 1072 cmꢁ1; mass spectrum (CI) m/z 849.3634
[C53H53O10 (M+1) requires 849.3639], 742 (base), 726,
419, 293, 267.
1
of acid 69 as a yellowish oil. H NMR (500 MHz) d 13.24
(s, 1H, OH), 13.05 (s, 1H, OH), 9.80 (br, 1H), 7.91 (d,
J¼7.9 Hz, 1H), 7.85 (d, J¼7.8 Hz, 1H), 7.78 (d, J¼7.8 Hz,
1H), 7.63 (d, J¼7.8 Hz, 1H), 7.38–7.25 (comp, 15H), 4.99
(d, J¼11.0 Hz, 1H), 4.86 (dd, J¼11.3, 1.3 Hz, 1H), 4.74–
4.62 (comp, 5H), 3.85 (ddd, J¼13.6, 8.8, 4.9 Hz, 1H), 3.57
(dq, J¼8.8, 6.1 Hz, 1H), 3.29 (d, J¼13.6 Hz, 1H), 3.21 (t, J¼
8.8 Hz, 1H), 3.18 (d, J¼13.6 Hz, 1H), 2.71 (d, J¼15.3 Hz,
1H), 2.71–2.67 (comp, 1H), 2.66 (d, J¼15.3 Hz, 1H), 1.49
(s, 3H), 1.48–1.40 (m, 1H), 1.39 (d, J¼6.1 Hz, 3H); 13C
NMR (125 MHz) d 188.2, 188.1, 171.1, 161.4, 159.0,
139.2, 138.7, 138.6, 138.5, 137.2, 133.6, 133.4, 132.1,
131.7, 128.7, 128.5, 128.4, 128.2, 128.1, 127.8, 127.7,
127.6, 119.6, 118.8, 115.8, 115.4, 83.9, 80.8, 78.2, 75.8,
75.3, 71.4, 71.2, 64.9, 44.1, 37.3, 36.8, 22.7, 18.6; IR
(NaCl) 2919, 2860, 1702, 1619, 1431, 1366, 1320, 1290,
1255, 1114, 1091, 1073 cmꢁ1; mass spectrum (CI) m/z
757.3013 [C46H45O10 (M+1) requires 757.3013], 689, 621,
502 (base), 458, 355.
5.3.17. Anthraquinone 68. A solution of ceric ammonium
nitrate (48 mg, 0.09 mmol) in H2O (0.1 mL) was added to
a solution of 67 (25 mg, 0.03 mmol) in CH3CN (2.9 mL)

8634
S. M. Sparks et al. / Tetrahedron 63 (2007) 8619–8635
11. (a) Vederas, J. C. Nat. Prod. Rep. 1987, 277; (b) Simpson, T. J.
Chem. Soc. Rev. 1987, 16, 123.
12. Sezaki, M.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M.
Tetrahedron 1970, 26, 5171.
5.3.19. Vineomycinone B2 methyl ester (3). BBr3 in
CH2Cl2 (0.2 mL of 1 M solution, 0.2 mmol) was added
to a solution of acid 69 (5.5 mg, 7.27 mmol) in CH2Cl2
(2 mL) at ꢁ78 ꢀC. The mixture was stirred for 10 min
at ꢁ78 ꢀC, and methanolic HCl (2 mL, prepared from
0.2 mL of AcCl and 5 mL MeOH) was added. The mixture
was stirred for 6 h at room temperature and then concen-
trated under reduced pressure. The residue was purified by
flash chromatography on silica gel eluting with EtOAc to af-
ford 2.6 mg (71%) of vineomycinone B2 methyl ester (3) as
an orange solid; mp 183–184 ꢀC (lit.14b,d mp 183–184 ꢀC);
[a]D24 +109.8 (c 0.00091, CDCl3) (lit.14b [a]D +109.1 (c
13. For general reviews of C-aryl glycosides, see: (a) Jaramillo, C.;
Knapp, S. Synthesis 1994, 1; (b) Levy, D. E.; Tang, C. The
Chemistry of C-Glycosides; Elsevier Science: Tarrytown, NY,
1995; (c) Nicotra, F. Top. Curr. Chem. 1997, 187, 55; (d) Du,
Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913;
(e) Liu, L.; McKee, M.; Postema, M. H. D. Curr. Org. Chem.
2001, 5, 1133.
14. For total syntheses of vineomycinone B2 methyl ester, see: (a)
Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. Am. Chem. Soc.
1984, 106, 2453; (b) Danishefsky, S. J.; Uang, B. J.; Quallich,
G. J. Am. Chem. Soc. 1985, 107, 1285; (c) Tius, M. A.; Gu,
X.-q.; Gomez-Galeno, J. J. Am. Chem. Soc. 1990, 112, 8188;
(d) Tius, M. A.; Gomez-Galeno, J.; Gu, X.-q.; Zaidi, J. H.
J. Am. Chem. Soc. 1991, 113, 5775; (e) Bolitt, V.;
Mioskowski, C.; Kollah, R. O.; Manna, S.; Rajapaksa, D.;
Falck, J. R. J. Am. Chem. Soc. 1991, 113, 6320; (f)
Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. J. Am.
Chem. Soc. 1991, 113, 6982.
15. For related investigations of synthesis of vineomycinone B2
methyl ester, see: (a) Cambie, R. C.; Rutledge, P. S.;
Woodgate, P. D. Aust. J. Chem. 1992, 45, 483; (b) Pausler,
G. M.; Rutledge, P. S. Tetrahedron Lett. 1994, 35, 3345; (c)
Bercich, M. D.; Cambie, R. C.; Howe, T. A.; Rutledge, P. S.;
Thomson, S. D.; Woodgate, P. D. Aust. J. Chem. 1995,
48, 531; (d) Beauregard, D. A.; Cambie, R. C.; Dansted,
P. C.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1995,
48, 669.
16. (a) Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem.
Soc. 2001, 123, 6937; (b) Martin, S. F. Pure Appl. Chem. 2003,
75, 63; (c) Kaelin, D. E., Jr.; Sparks, S. M.; Plake, H. R.;
Martin, S. F. J. Am. Chem. Soc. 2003, 125, 12994.
1
0.00066, CDCl3)); H NMR (500 MHz) d 13.20 (s, 1H,
OH), 13.09 (s, 1H, OH), 7.90 (d, J¼7.9 Hz, 1H), 7.85 (d,
J¼7.9 Hz, 1H), 7.80 (d, J¼7.8 Hz, 1H), 7.68 (d, J¼7.9 Hz,
1H), 4.94 (dd, J¼11.3, 1.8 Hz, 1H), 3.87 (s, 1H, OH),
3.86–3.81 (m, 1H), 3.70 (s, 3H), 3.52 (dq, J¼9.0, 6.1 Hz,
1H), 3.21 (dt, J¼9.0, 3.5 Hz, 1H), 3.09 (d, J¼13.4 Hz,
1H), 3.01 (d, J¼13.4 Hz, 1H), 2.57 (d, J¼16.0 Hz, 1H),
2.53 (d, J¼16.0 Hz, 1H), 2.52 (ddd, J¼12.7, 4.8, 1.8 Hz,
1H), 2.20 (d, J¼3.5 Hz, 1H, OH), 2.10 (d, J¼3.7 Hz, 1H,
OH), 1.51–1.42 (m, 1H), 1.41 (d, J¼6.1 Hz, 3H), 1.29 (s,
3H); 13C NMR (125 MHz) d 188.2, 188.2, 173.3, 161.4,
159.0, 139.6, 138.3, 134.7, 133.3, 131.9, 131.8, 119.4,
118.9, 115.6, 115.5, 78.1, 75.9, 73.1, 71.8, 71.3, 51.7,
44.4, 40.5, 39.4, 27.3, 18.1; IR (NaCl) 3400 (br), 2930,
2860, 1733, 1626, 1433, 1374, 1260, 1090, 1070, 993,
971 cmꢁ1; mass spectrum (CI) m/z 501.1757 [C26H29O10
(M+1) requires 501.1761] (base), 326.
Acknowledgements
We thank the National Institutes of Health (GM 31077), the
Robert A. Welch Foundation, Pfizer, Inc., and Merck
Research Laboratories for their generous support of this
research. C.-L. Chen is grateful to Bristol-Myers Squibb
for a graduate fellowship. We are also grateful to Prof. Mar-
cus A. Tius (University of Hawaii) for providing an authentic
sample of vineomycinone B2 methyl ester (3).
17. Apsel, B.; Bender, J. A.; Escobar, M.; Kaelin, D. E., Jr.; Lopez,
O. D.; Martin, S. F. Tetrahedron Lett. 2003, 44, 1075.
18. (a) Chen, C.-L.; Martin, S. F. Org. Lett. 2004, 6, 3581; (b)
Chen, C.-L.; Martin, S. F. J. Org. Chem. 2006, 71, 4810.
19. For a preliminary account of portions of this work, see: Chen,
C.-L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128,
13696.
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