Alternative spiroketalization methods toward purpuromycin: A hemiketal conjugate addition strategy and use of an electron-rich isocoumarin precursor

Article abstract of DOI:10.1021/jo200398v

Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a naphthaq

Full text of DOI:10.1021/jo200398v

ARTICLE
pubs.acs.org/joc
Alternative Spiroketalization Methods toward Purpuromycin:
A Hemiketal Conjugate Addition Strategy and Use of an Electron-Rich
Isocoumarin Precursor
Rakeshwar Bandichhor, Andrew N. Lowell, and Marisa C. Kozlowski*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
S Supporting Information
b
ABSTRACT:
Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a
spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a
naphthaquinone electrophile was investigated. Synthesis of the requisite electrophile provided insight into the selective oxidation
and functionalization of the naphthalene portion. Second, the electronic features of the isocoumarin ring system were adjusted, and
the corresponding reactivity further supports the hypothesis that electron-rich isocoumarins are capable of spiroketalization. Robust,
flexible syntheses from simple precursors were developed that allowed multiple reduced isocoumarins to be generated. Combined,
the data presented herein give insight into the sensitivities of this family and illuminate other potential methods of spiroketalization.
In addition, the convergent assembly of substrates containing different naphthaquinone and isocoumarin subunits highlights the
utility of our 1,3-dipolar cycloaddition approach to generate analogs of these structures for SAR, as well as chemical reactivity studies.
’ INTRODUCTION
naphthalene oxidation state was used as a synthon, a method
common to this type of carbocycle.11,17 We have also built vari-
ably substituted isocoumarins.18 While combination of the hemi-
spheres has proceeded well using 1,3-dipolar cycloaddition
methodology,19 spiroketalization of this family has posed a great
challenge.19,20
The rubromycin family of compounds, including purpuromycin,1,2
are interesting from both a structural standpoint and because
of their medicinal activity. In addition to the usual properties of
soil bacterial secondary metabolites, this family shows activity
against cancer,3 DNA helicase,4 reverse transcriptase,5 DNA
polymerase,6 and human telomerase.7 Known since 1953,8 but
structurally undefined for nearly twenty years,9 the rubromycins
were determined with respect to their structure3 and some
stereochemistry,3 and they finally succumbed to total synthesis
in the early 21st century.10À12 While the relative stereochemistry
of purpuromycin has been proposed,13 the absolute configura-
tion remains unknown.
The rubromycin family of compounds, including purpuromy-
cin (1), is shown in Figure 1.14,15 As shown by the labeling, the
molecule can be architecturally divided into three portions, the
naphthazarin, spiroketal, and isocoumarin. Previously, we de-
scribed our investigations into the naphthazarin16 where the
As we have previously reported,19 elimination of penultimate
spiroketal intermediates to form benzofurans has been the major
obstacle in the production of this family (Figure 2). The current
hypothesis is that the electronic differences between the naphtha-
lene and isocoumarin portions are the root of the problem.19,21,22
Specifically, if the isocoumarin phenol is electron-poor it is a poor
nucleophile, and elimination to benzofuran is competitive.19 The
stability of the isocoumarin is also an issue.19,21,23 Some success-
ful approaches by others to synthesize this family have involved
Received: March 2, 2011
Published: June 27, 2011
r
2011 American Chemical Society
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Figure 1. Rubromycin family of compounds.
Figure 3. Strategies for preventing formation of benzofuran.
The second approach (Figure 3b) describes modification of the
isocoumarin to make it more electron-rich and bring it in line
with the nucleophilicity of the naphthalene. Reissig22 and
Brimble11 have seen success with this type of tactic.
Other reasonable approaches to prevent benzofuran elimina-
tion include reducing the nucleophilicity of the naphthalene via a
naphthaquinone (Figure 3c). We have shown previously19 that
such an intermediate does not spiroketalize although Reissig has
successfully isolated a naphthaquinone spiroketal in low yield.21
Another alternative, removal of the acidic benzylic protons, com-
pletely suppresses the undesired pathway (Figure 3d) and is
discussed in a companion paper (DOI 10.1021/jo200399z).25
’ RESULTS AND DISCUSSION
A Conjugate Hemiketal Approach Toward Spiroketals. As
shown in the retrosynthesis in Figure 4, with the proper oxidation
state adjustment of the naphthalene, disconnection of the hemi-
ketal and its tautomer can be envisaged. This material is easily
transformed to an isoxazoline, the product of a 1,3-dipolar
cycloaddition between a naphthalene nitrile oxide and an isocou-
marin styrene.18 The nitrile oxide can be produced from naphthal-
dehydes such as 2 or 3.
There is precedent for this type of conjugate addition cycliza-
tion,26,27 the most recent by Tamura and co-workers,28 who were
successful in adding a pendant nucleophile to a naphthaquinone
electrophile under oxidative conditions (Figure 5). The pro-
posed forward mechanism as catalyzed by base is shown on a
model system in Figure 6.
Of concern was the formal closure type being attempted
(Figure 7). Baldwin’s work29 shows that a 5-endo-trig type cycliza-
tion is disfavored but clearly possible according to the precedents
above.26À28 A formal closure of type 5-exo-trig may also be
possible if the distal quinone acts as a strong electron-with-
drawing group, allowing the nucleophilic addition of the hemi-
ketal to the proximal aromatic ring. Our initial work utilized
a benzene-based model system, but it soon became evident
that this system was inadequate to mimic the reactivity of the
Figure 2. Spiroketal versus benzofuran.
formation of the complete isocoumarin after spiroketalization10,11
or after coupling of the two hemispheres.23 Purpuromycin is a
continuing challenge in spite of the completion of the parent family
member rubromycin10À12 and the aglycon of heliquinomycin.24
Herein, we describe two approaches to circumvent the for-
mation of benzofuran. In the first, the conjugate hemiketal addi-
tion approach (Figure 3a), a new disconnection is used wherein
the nucleophilic phenol is removed from the naphthalene. This
approach prevents benzofuran formation by utilizing a different
pathway to the spiroketal instead of traditional ketalization.
Similar strategies have been successfully illustrated by Kita10 and
Pettus,12 where a Pummerer type reaction or an oxidative cycload-
dition, respectively, are used to circumvent classical spiroketalization.
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Figure 5. Pendant conjugate addition by Tamura and co-workers.28
Figure 6. Base catalyzed hemiketal conjugate approach.
Figure 7. Hemiketal conjugate addition ring closure types.
system. Undeterred, attention focused onusingbenzynechemistry
to synthesize the fully methoxylated naphthalene 5 (Scheme 1).32
Vilsmeier formylation provided the requisite aldehyde (2), validat-
ing distal electronic differentiation of naphthalenes as a general
strategy for selective functionalization.16 The Henry reaction
allowed installation of the nitro group (6) desired for the 1,3-
dipolar cycloaddition and subsequent reduction furnished
naphthalene 7. A dinitro side product (8) resulting from conjugate
addition into the Henry product was isolated and characterized by
X-ray crystallography, assuring that the correct regiochemistry had
been achieved during the earlier formylation.
Coupling of the new naphthalene with an isocoumarin model
(9, Scheme 2) gave isoxazoline 10, which could be reduced to
keto alcohol 11 with Raney nickel. Surprisingly, early attempts at
silylation resulted in low yields of 12 and a byproduct eventually
determined to be aldehyde 2 (Scheme 1). There is scant
precedent for this cleavage, the most likely explanation being
Figure 4. Hemiketal conjugate approach retrosynthetically.
naphthalene/naphthaquinone derivative of the naphthazarin.
Instead, we undertook the synthesis of naphthalenes 2 and 3
(Figure 4).
Initial work on the naphthalene focused on orthogonally
protecting the C5 and C8 phenols (that is, 3, Figure 4) to be
able to selectively generate both possible quinone isomers (see
Scheme 3) via selective deprotection and oxidation. In spite of
good precedent,30 a Hauser type synthesis31 would not proceed,
probably due to the slightly more electron-rich nature of this
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Scheme 1. Synthesis of Naphthalene 7
Scheme 3. CAN Oxidation To Form Quinones
Scheme 4. Variable Hydrogenolysis Products of Benzyl
Ether 13
Scheme 2. Central Chain Creation by 1,3-Dipolar
Cycloaddition
reaction of the enol or silyl enol with singlet oxygen.33 Singlet
oxygen could be produced if the electron-rich naphthalene acts as
a photosensitizer. Oxygen oxidation without cleavage at this
position is known.34,35 The byproduct was suppressed by using a
single equivalent of silylating reagent and rigorous exclusion of
oxygen from the reaction mixture.
With 12 in hand, the next task was to determine oxidative
conditions to release the latent quinone (Scheme 3). With 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ), only the more elec-
tron-rich ring oxidized, resulting in the distal quinone (13). Use
of ceric ammonium nitrate (CAN) as the oxidant, however,
produced both quinone isomers. This result allowed access to
both quinones for testing in the spiroketalization reaction.
Penultimate to the testing of a hemiketal conjugate addition
strategy of spiroketalization was the cleavage of the benzyl group
on the isocoumarin mimic to reveal the phenol nucleophile
(Scheme 4). This cleavage was eventually optimized for the
expected product 15, but initially two byproducts were detected.
Overreduction where the benzylic silyl ether had been cleaved
(17) was easily selected against by using a less activating solvent
(ethyl acetate instead of methanol). The other byproduct, the
unexpected diketone 16, was isolated when the reaction mixture
was not rigorously oxygen free.
A possible mechanism for the formation of 16 is shown in
Figure 8. In the hydrogenolysis mixture, the naphthaquinone
is first reduced to the naphthaquinol. However, if oxygen is
present in the mixture, this process can be reversed; naphtha-
quinone is still present. Lewis acid complexation allows
the formation of a tautomeric extended quinone methide.
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Figure 9. Reduction approach to an electron-rich isocoumarin.
Lewis acid complexation again generates an extended quinone
methide, which is a tautomer of the protonated diketone. Oxidation
generates the naphthaquinone, terminating the sequence. This
discovery points to a facile method for oxidation of benzylic sites
in naphthaquinones and anthraquinones using a combination of
Pd/C and air.
Once formation of 16 was prevented by scrupulous removal of
oxygen, the extended quinone methide was no longer available as
an electrophile. All of these products in Scheme 4 (15À17) were
isolated as an interconverting mixture of the hemiketal and the
open chain tautomers.
The investigation now turned to the hemiketal addition. The
distal quinone 15 was analyzed first (Scheme 5) under a variety of
basic conditions. As depicted in Figure 6, the intention was to
equilibrate the mixture from the open chain phenolate to the
spiroketalized diphenolate or to trap the diphenol as the quinone.
None of the conditions screened delivered the desired product
18; only slow decomposition was observed. Diketone 16 from
Scheme 4 also failed to react under basic conditions. Scandium
triflate was screened as an acid catalyst but was ineffective. As per
the protocol of Tamura and co-workers,28 the proximal quinone
14 was screened against a variety of oxidants after successful
debenzylation. These conditions showed the same pattern as
observed with 15: no reaction and eventual decomposition upon
heating except for DDQ, which caused decomposition immedi-
ately. It appears either that the basic conditions favor the
phenolate form over the hemiketal anion (see Figure 6) or that
reoxidation is very slow, such that the cyclic form undergoes
retro-conjugate addition more quickly than oxidation. Regard-
less, these results caution against the design of tandem reactions
terminating with an oxidative conjugate addition to a quinone if
the initial steps are reversible.
Figure 8. Mechanism for diketone formation.
Scheme 5. Hemiketal Conjugate Addition Attempts
Use of an Electron-Rich Isocoumarin Surrogate. With an
oxidative cyclization disconnection having proved ineffective, we
next turned to an electron-rich isocoumarin surrogate, with the
aim of putting the isocoumarin nucleophilicity on par with the
nucleophilicity of the naphthalene. Specifically, we sought to
reduce the isocoumarin in such a manner as to disconnect the
electron-withdrawing groups from the nucleophilic phenol
(Figure 9) while keeping the carbon skeleton intact and readily
convertible into the complete isocoumarin.
The synthesis of the first generation isocoumarin surrogate is
shown in Scheme 6. Starting from aldehyde 23, selective
methylation18,36 and bromination produced 24.37 Mannich
reaction and subsequent displacement of the N-acylated species
with acetate furnished 25.18 After hydrolysis of the acyl groups
(26), the phenol was chemoselectively benzylated (27). Reduc-
tion of the aldehyde and bisacylation afforded Stille precursor 28.
Intermolecular addition of water produces the R-hydroxy
ketone. Oxidation returns the molecule to the naphthaquinone.
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Scheme 6. First Generation Synthesis of an Electron-Rich
Isocoumarin Surrogate
Scheme 7. 1,3-Dipolar Cycloaddition and Attempted Spiro-
ketalization of the First Generation Surrogate
Scheme 8. Second Generation Isocoumarin Surrogate
mimic.13 Surrogate 21 and 35 underwent facile cycloaddition,
affording 36 in good yield. Reductive cleavage of the isoxazoline
ring was accomplished using Raney nickel and of the benzyl
ethers using palladium on carbon to provide 37, predominantly
in its hemiketal form. Finally, spiroketalization of the isocoumarin
surrogate was attempted by treating 37 with p-toluenesulfonic
(tosic) acid. While desired spiroketal 38 was detected in the
reaction mixture by mass spectroscopy, it could not be separated
from the complex reaction mixture that was produced due to the
presence of the acid labile methyl ketal.
This encouraging result stimulated us to develop a new
surrogate without an acid sensitive group. As shown in Scheme 8,
advanced intermediate 22 was readily modified with catalytic
sulfuric acid to provide alkene 39. Oxidation with DMP pro-
duced benzaldehyde 40, which was efficiently converted into
styrene 41 through Wittig olefination. With a second generation
isocoumarin surrogate in hand, work toward a spiroketal continued.
Coupling of second generation isocoumarin surrogate 41
(Scheme 9) with naphthalene mimic 35 successfully provided
isoxazoline 42. We next employed a sequence analogous to that
described in Scheme 7: reductive cleavage of isoxazoline 42 with
a buffered Raney nickel solution provided keto alcohol 43.
With tributyl allyl tin as the coupling agent, the Stille reaction
produced 29. Oxidation with osmium tetroxide and N-methyl
morpholine oxide (NMO) generated diol 30. Attempts to
oxidize 30 to the R-ketoacid resulted in decarboxylation. Accord-
ingly, the primary alcohol of diol 30 was selectively silylated with
tert-butyldiphenylsilyl chloride (TBDPSCl) and 31 was subse-
quently oxidized with DessÀMartin periodinane (DMP),38
yielding R-keto silyl ether 32. Base mediated deacylation gave
the diol, which existed predominantly as the hemiketal 22.
Treatment with pyridinium p-toluenesulfonate (PPTS) in
methanol selectively generated the methyl ether by SN1 displace-
ment of the tertiary alcohol, providing ketal 33. Finally, oxidation
with DMP gave benzaldehyde 34 which could easily be con-
verted to desired styrene 21 via Wittig olefination.
Our attention now turned to utilization of the 1,3-dipolar
cycloaddition strategy19 for the coupling of the isocoumarin
surrogate with a model naphthalene (Scheme 7). The previously
reported aromatic nitroalkane 35 was selected as the naphthalene
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Scheme 9. Cycloadditions of the Second Generation
Surrogate
hydrogenation of 42 was subjected directly to tosic acid and
spirocyclized to a mixture of four diastereomers of 47, one of
which could be separated from the others.
The successful spiroketalization verified our hypothesis and
the observations of others11,22 that increasing the nucleophilicity
of the isocoumarin allows competitive spiroketal formation at the
expense of benzofuran formation. While providing an expedi-
tious and convergent route to purpuromycin analogs for further
study, the removal of double bond functionality to avoid quinone-
methide reactivity greatly complicated the conversion of 47 to
authentic isocoumarin.
’ CONCLUSION
We outline two alternative routes to circumvent the propen-
sity for benzofuran formation during spiroketalization in the
synthesis of the rubromycin family of compounds. These routes
illustrate how our 1,3-dipolar cycloaddition approach permits the
rapid and convergent assembly of structures with variable eastern
and western hemispheres to probe different hypotheses and
ultimately to generate analogs rapidly.13 While precedent exists
for an oxidative conjugate addition to naphthaquinone type
systems,28 a hemiketal conjugate addition did not prove effective.
These results caution against the design of tandem reactions
terminating with an oxidative conjugate addition if the initial
steps are reversible. The discovery of oxidation via quinone-
methide type intermediates in this route points to a facile method
for oxidation of benzylic sites in naphthaquinones and anthra-
quinones under conventional hydrogenolysis conditions. In
addition, we demonstrate the utility of remote electronic control
for the efficient regioselective substitution of naphthalenes (5 to 7).
We used an isocoumarin surrogate that lacked the electron-
withdrawing groups of the isocoumarin moiety found in the
natural product, and thus spiroketalization could be favored over
benzofuran formation. Robust, flexible syntheses from simple
precursors were developed that allowed multiple reduced iso-
coumarin analogs to be generated (e.g., 21 and 41). There was a
predilection for formation of extended quinone methides in
reduced isocoumarins, indicating that the reactivity of hydroxy-
methylene groups conjugated to phenols needs to be considered
in synthetic ventures. Although the reduced isocoumarin
approach was successful and provides an efficient route to many
purpuromycin analogs to explore the SAR of the isocoumarin
portion, an alternate diketone method under exploration to
prevent benzofuran formation25 became the focus because it
permitted introduction of the intact isocoumarin unit.
Scheme 10. Successful Creation of a Apiroketal Using an
Isocoumarin Surrogate
Unfortunately, the benzyl ether hydrogenolysis resulted in a
complex mixture instead of giving rise to phenol 44. It is likely
that the unmasking of the phenol on the isocoumarin surrogate
allowed the formation of an extended quinone methide such as
45 by elimination of the tert-butyldiphenylsilylether group, which
could react further to form a variety of compounds other than the
desired spiroketal.
To investigate this hypothesis, isocoumarin 46 (Scheme 10)
was targeted because the lack of the enol ether double bond
would insulate it from quinone methide formation as outlined in
Scheme 9. Thus, a method was sought to first reduce the enol
ether double bond without causing hydrogenolysis of the benzyl
groups (Scheme 10). While a difficult proposition, treatment of
the isoxazoline 42 instead of the β-hydroxy ketone 43 with
palladium on carbon under a hydrogen atmosphere was found to
result in a different order of reactivity. Under these conditions,
enol ether reduction occurred prior to hydrogenolysis of the
benzyl ethers. Upon prolonged stirring, hydrogenolysis and
isoxazoline ring cleavage occurred. The mixture obtained from
’ EXPERIMENTAL SECTION
General procedures can be found in the Supporting Information.
1,2,4,5,8-Pentamethoxy-6-(2-nitro-ethyl)-naphthalene (8).
Aldehyde 2 (0.302 g, 0.986 mmol) and NH4OAc (0.0181 g, 0.231
mmol) were combined in CH3NO2 (12.0 mL) and heated in a sealed
tube (oil bath, 120 °C) for 21.5 h. The mixture was cooled, poured into
water (90 mL), and extracted with CH2Cl2 (1 Â 90 mL, 1 Â 40 mL).
Brine (∼40 mL) was added to the extraction to clarify an emulsion. The
organic layers were combined, dried with Na2SO4, and concentrated,
giving 6 contaminated with 8 as a dark red solid. A small amount of 6 was
purified for characterization purposes: a red-orange solid; mp
1
178.5À180.5 °C; H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 13.7
Hz, 1H), 7.67 (d, J = 13.7 Hz, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 4.011 (s,
3H), 4.008 (s, 3H), 3.96 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 154.6, 153.9, 153.3, 152.8, 138.9, 136.8, 134.8,
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126.6, 117.8, 116.8, 103.8, 98.6, 64.1, 62.1, 57.2, 57.1 (2); IR (film) 3107,
2999, 2937, 2845, 1590, 1498, 1455 cmÀ1; HRMS (CI) calcd for
C17H19NO7 (M+) 349.1162, found 349.1147.
4-(2-Benzyloxy-phenyl)-4-(tert-butyl-dimethyl-silany-
loxy)-1-(1,4,5,6,8-pentamethoxy-naphthalen-2-yl)-butan-2-
one (12). Hydroxyketone 11 (0.359 g, 0.657 mmol) was dissolved in
CH2Cl2 (12 mL) and thoroughly deoxygenated by subjection to three
freezeÀpumpÀthaw cycles. The mixture was cooled in an ice bath, and
Et3N (0.20 mL, 1.44 mmol) and tert-butyldimethylsilyl triflate (0.15 mL,
0.653 mmol) were added to the mixture, the latter in a dropwise fashion.
The mixture was stirred for 1.4 h, at which time it was quenched by the
addition of water (2 mL). The mixture was paritioned between water
(170 mL) and CH2Cl2 (170 mL). The organic layer was dried (Na2SO4)
and concentrated to a yellow oil. The residue was purified by flash
chromatography (33À70% EtOAc/hexanes) to give recovered starting
material 11 (0.061 g, 17%) as a yellow oil and 12 as a yellow oil (0.202 g,
47%): Rf = 0.66 (50% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ
7.49 (dd, J = 1.5, 7.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.4 Hz,
2H), 7.27 (t, J = 7.2 Hz, 1H), 7.17 (dt, J = 1.5, 8.0 Hz, 1H), 6.95 (t, J = 7.5
Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.72 (s, 1H), 6.54 (s, 1H), 5.74 (dd, J =
2.9, 8.9 Hz, 1H), 5.09 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.89 (d, J = 16.2
Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.75 (d, J = 16.2 Hz, 1H), 3.61 (s,
3H), 2.96 (dd, J = 9.0, 15.4 Hz, 1H), 2.73 (dd, J = 3.0, 15.4 Hz, 1H), 0.89
(s, 9H), 0.07 (s, 3H), À0.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
206.9, 154.4, 152.8, 152.1, 150.0, 148.2, 138.9, 137.4, 133.3, 128.7, 128.1,
127.8, 127.3, 127.0, 123.7, 122.3, 120.9, 117.9, 111.7, 110.4, 99.3, 69.9,
66.1, 62.2, 62.0, 57.8, 57.2, 57.1, 51.3, 45.8, 26.1, 18.4, À4.6, À4.9; IR
(film) 2953, 2930, 2856, 1718, 1602, 1451 cmÀ1; HRMS (ES) calcd for
C38H48O8SiNa (MNa+) 683.3016, found 683.3025.
To a stirring solution of the mixture of 6 and 8 (0.685 g, 1.96 mmol)
in MeOH (60 mL) and CH2Cl2 (65 mL) was added NaBH4 (0.188 g,
4.97 mmol) in one portion. Stirring was continued for 1 h when the
mixture was poured into 0.5 M HCl (260 mL) and partitioned with
CH2Cl2 (130 mL). The organic layer was dried (Na2SO4) and con-
centrated. The resultant brown oil was purified by flash chromato-
graphy39 (17% hexanes/Et2O, SiO2), affording 7 (0.420 g, 61%) and 8
(0.187 g, 23%) as off-white crystalline solids. 7: mp 115.5À117.5 °C; 1H
NMR (500 MHz, CDCl3) δ 6.75 (s, 1H), 6.63 (s, 1H), 4.68 (dd, J = 7.5,
7.7 Hz, 2H), 3.98 (s, 6H), 3.92 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.40
(dd, J = 7.7, 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 152.6, 152.4,
150.3, 148.5, 138.7, 123.9, 122.8, 117.6, 109.7, 98.9, 75.5, 62.5, 62.0, 57.7,
57.3, 56.9, 29.2; IR (film) 2991, 2934, 2841, 1602, 1548 cmÀ1; HRMS
(CI) calcd for C17H21NO7 (M+) 351.1318, found 351.1325. 8: mp
133À136 °C; 1H NMR (500 MHz, CDCl3) δ 6.77 (s, 1H), 6.53 (s, 1H),
4.89 (m, 4H), 4.80 (m, 1H), 3.98 (s, 6H), 3.91 (s, 3H), 3.803 (s, 3H),
3.798 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 153.0, 152.8, 151.1,
148.6, 138.7, 124.6, 120.7, 117.3, 105.8, 99.1, 76.5, 63.2, 62.0, 57.5, 57.4,
57.0, 36.8; IR (film) 2934, 2845, 1598, 1556 cmÀ1; HRMS (ES) calcd for
C18H22N2O9Na (MNa+) 433.1223, found 433.1219.
5-(2-Benzyloxy-phenyl)-3-(1,4,5,6,8-pentamethoxy-
naphthalen-2-ylmethyl)-4,5-dihydro-isoxazole (10). To a stir-
ring solution of 7 (0.362 g, 1.03 mmol) and 9 (0.249 g 1.18 mmol) in
PhH (30 mL) were added PhNCO (0.63 mL, 5.80 mmol) and NEt3
(3 drops, ∼0.02 mL). The mixture was heated (oil bath, 70À80 °C)
and stirred for 44 h. The mixture was cooled, filtered through Celite,
and concentrated to a brown oil. This residue was purified by flash
chromatography (50% hexanes/EtOAc, SiO2) to give 10 as an orange oil
or a red foam (0.449 g, 80%): Rf = 0.42 (50% hexanes/EtOAc); 1H NMR
(500 MHz, CDCl3) δ 7.46 (dd, J = 1.5, 7.6 Hz, 1H), 7.28À7.34 (m, 5H),
7.21 (dt, J = 1.6, 7.8 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.1 Hz,
1H), 6.74 (s, 1H), 6.56 (s, 1H), 5.84 (dd, J = 7.0, 11.0 Hz, 1H), 5.04 (d,
J = 11.7 Hz, 1H), 5.01 (d, J = 11.8 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H),
3.88 (d, J = 15.0 Hz, 1H), 3.79, (d, J = 14.4 Hz, 1H), 3.79 (s, 3H), 3.77 (s,
3H), 3.70 (s, 3H), 3.30 (dd, J = 11.1, 17.3 Hz, 1H), 2.75 (dd, J = 7.0, 17.3
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 158.1, 155.2, 152.8, 152.4,
150.2, 147.9, 138.9, 137.0, 130.3, 128.9, 128.7, 128.1, 127.4, 126.3, 123.6,
123.1, 121.0, 117.8, 111.8, 108.6, 99.2, 77.6, 70.1, 62.5, 62.0, 57.8, 57.1,
57.0, 44.4, 27.5; IR (film) 3065, 3034, 2991, 2930, 2841, 2250, 1745,
1602, 1490, 1451 cmÀ1; HRMS (ES) calcd for C32H33NO7Na (MNa+)
566.2155, found 566.2145.
4-(2-Benzyloxy-phenyl)-4-hydroxy-1-(1,4,5,6,8-penta-
methoxy-naphthalen-2-yl)-butan-2-one (11). To a stirring so-
lution of 10 (0.503 g, 0.925 mmol) in MeOH (45 mL) and THF
(25 mL) was added B(OH)3 (0.061 g, 0.987 mmol) dissolved in water
(5 mL). Raney Nickel (∼0.5 mL, 50% in water) was added to the
mixture, and it was stirred under an atmosphere of H2 for 13 h and then
filtered through Celite (CH2Cl2). The filtrate was partitioned between
water (50 mL) and CH2Cl2 (50 mL). The organic layer was dried
(Na2SO4) and concentrated giving 11 as a yellow foam (0.481 g, 95%):
Rf = 0.32 (50% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.45
(dd, J = 1.5, 7.5 Hz, 1H), 7.29À7.34 (m, 5H), 7.17 (dt, J = 1.6, 7.9 Hz,
1H), 6.96 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.72 (s, 1H), 6.50
(s, 1H), 5.49 (dd, J = 3.0, 8.8 Hz, 1H), 5.02 (s, 2H), 3.97 (s, 3H), 3.92 (s,
3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.78 (s, 2H), 3.61 (s, 3H), 3.06 (dd, J =
3.2, 17.1 Hz, 1H), 2.89 (dd, J = 8.9, 17.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 209.9, 155.1, 152.8, 152.2, 150.2, 148.2, 138.9, 137.0, 131.4,
128.8, 128.4, 128.1, 127.3, 126.8, 123.9, 121.8, 121.1, 117.8, 111.7, 110.1,
99.2, 70.1, 66.2, 62.1, 62.0, 57.8, 57.2, 57.0, 48.7, 45.4; IR (film) 3447
(br), 3038, 2991, 2934, 2841, 1710, 1602, 1451 cmÀ1; HRMS (ES) calcd
for C32H34O8Na (MNa+) 569.2151, found 569.2160.
6-[4-(2-Benzyloxy-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-
2-oxo-butyl]-2,5,8-trimethoxy-[1,4]naphthaquinone (13) and
2-[4-(2-Benzyloxy-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-2-
oxo-butyl]-5,6,8-trimethoxy-[1,4]naphthaquinone (14). To a
stirring solution of 12 (0.202 g, 0.306 mmol) in CH3CN (40 mL) in a
saltÀice bath (À10 to À15 °C) was added CAN (0.424 g, 0.773 mmol)
dissolved in water (4 mL). The mixture was stirred, still cold, for 10 min
when it was diluted with water (160 mL) and extracted with CH2Cl2 (1
 160 mL, 1  80 mL). The organic layers were combined, dried
(Na2SO4), and concentrated. The residual red-yellow oil was purified by
flash chromatography (50À66% EtOAc/hexanes) to give 13 (0.126 g,
65%) and 14 (0.058 g, 30%) as yellow-red oils. 13: Rf = 0.27 (50%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz,
1H), 7.41 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.2 Hz,
1H), 7.21 (t, J = 7.4 Hz, 1H), 6.99 (s, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.90
(d, J = 8.2 Hz, 1H), 5.98 (s, 1H), 5.70 (dd, J = 2.8, 8.4 Hz, 1H), 5.11 (s,
2H), 3.90 (s, 3H), 3.88 (d, J = 16.8 Hz, 1H), 3.83 (s, 3H), 3.72 (d, J =
16.8 Hz, 1H), 3.64 (s, 3H), 2.99 (dd, J = 8.6, 15.2 Hz, 1H), 2.81 (dd, J =
2.9, 15.2 Hz, 1H), 0.88 (s, 9 H), 0.04 (s, 3H), À0.13 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 204.8, 184.7, 178.9, 160.0, 156.5, 154.5, 152.1,
139.7, 137.2, 132.8, 128.8, 128.4, 128.0, 127.2, 127.1, 125.1, 121.1 (2C),
119.5, 111.8, 109.7, 70.1, 66.1, 62.1, 56.9, 56.4, 52.0, 45.9, 26.1, 18.4,
À4.6, À5.0; IR (film) 3069, 3034, 2953, 2930, 2856, 1722, 1652, 1629,
1590, 1455 cmÀ1; HRMS (ES) calcd for C36H42O8SiNa (MNa+)
1
653.2547, found 653.2544. 14: Rf = 0.05 (50% EtOAc/hexanes); H
NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 7.9 Hz,
2H), 7.35 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 7.1 Hz, 1H), 7.21 (t, J = 7.0 Hz,
1H), 6.98 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.87 (s, 1H), 5.91
(s, 1H), 5.70 (dd, J = 2.9, 8.5 Hz, 1H), 5.11 (s, 2H), 3.95 (s, 3H), 3.88 (s,
3H), 3.83 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 16.8 Hz, 1H), 3.55 (s, 3H),
2.98 (dd, J = 8.6, 15.2 Hz, 1H), 2.80 (dd, J = 3.1, 15.2 Hz, 1H), 0.88 (s,
9H), 0.04 (s, 3H), À0.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
204.5, 180.2, 179.3, 170.1, 158.5, 154.5, 150.8, 140.5, 137.2, 132.7, 128.7,
128.5, 128.0, 127.2, 127.0, 124.9, 121.1, 119.4, 118.7, 111.8, 103.2, 70.0,
66.1, 62.6, 57.1, 56.7, 51.9, 46.5, 26.0, 18.3, À4.6, À5.0; IR (film) 3069,
3038, 3011, 2953, 2934, 2856, 1722, 1687, 1652, 1602, 1575,
1451 cmÀ1; HRMS (ES) calcd for C36H42O8SiNa (MNa+) 653.2547,
found 653.2541.
6482
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The Journal of Organic Chemistry
ARTICLE
6-[4-(tert-Butyl-dimethyl-silanyloxy)-4-(2-hydroxy-phenyl)-
2-oxo-butyl]-2,5,8-trimethoxy-[1,4]naphthaquinone (15).
Quinone 13 (0.0167 g, 0.026 mmol) was dissolved in MeOH (5 mL)
and combined with 10% Pd/C (0.013 g) in a flask stoppered with a
three-way stopcock. House vacuum was attached to one arm of the
stopcock and a balloon of hydrogen to the other. The flask was evacuated
until the solvent boiled and filled with hydrogen gas. This purging
procedure was repeated five times. The mixture was stirred for 1 d before
it was filtered through a plug of Celite (MeOH) and concentrated. The
residue was taken up in EtOAc (5 mL) and stirred exposed to air for
5 min, after which it was concentrated. The resultant dark yellow oil was
purified by flash chromatography (66% EtOAc/hexanes) to give 15
(0.009 g, 63%) as a yellow film: Rf = 0.21 (50% EtOAc/hexanes); the
183.6, 178.9, 178.6, 178.5, 160.0 (2), 159.9, 156.62, 156.57 (2), 156.0,
155.8, 153.3, 151.2, 150.8, 149.9, 141.5, 141.1, 136.3, 130.6, 129.9, 129.5,
128.9, 127.2, 127.1, 127.0, 126.8, 125.81, 125.78, 125.7, 124.3, 122.4,
122.1, 121.9, 121.8, 121.4, 120.1, 118.8, 118.4, 118.2, 118.0, 117.6, 116.7,
116.2, 110.0, 109.94, 109.87, 98.6, 98.4, 72.0, 65.7, 64.3, 63.9, 63.4, 63.1,
57.2, 57.01, 56.97, 56.7, 56.6, 56.5, 45.9, 36.9, 34.5, 26.0, 25.8 (2), 18.3,
18.2, 18.1, À4.15, À4.17, À4.5, À4.7, À5.0, À5.1; IR (film) 3374, 3080,
2953, 2934, 2856, 1776, 1725, 1679, 1652, 1629, 1586, 1463 cmÀ1
;
HRMS (ES) calcd for C29H34O9SiNa (MNa+) 577.1870, found
577.1883.
6-Bromo-3-hydroxy-2-methoxy-4-morpholin-4-ylmethyl-
benzaldehyde (24morph). To a solution of 37% aqueous formal-
dehyde (0.323 mL, 4.32 mmol) and morpholine (0.377 mL, 4.32 mmol)
in EtOH (2 mL) was added 2437 [500 mg (77% pure), 2.16 mmol] in
one portion at rt. After heating at reflux for 15 h, the reaction mixture was
concentrated and chromatographed (83% hexanes/EtOAc) to afford
24morph (282 mg, 51%) as a semisolid: Rf = 0.30 (50% hexanes/
EtOAc); 1H NMR (500 MHz, CDCl3) δ 10.29 (s, 1H), 7.06 (s, 1H),
3.97 (s, 3H), 3.90 (s, 4H), 3.80 (s, 2H), 2.61 (s, 4H); 13C NMR (125
MHz, CDCl3) δ 190.1, 150.8, 150.4, 128.5, 127.9, 127.6, 110.8, 66.3,
61.7, 60.9, 50.7; IR (neat) 3374, 2853, 1698 cmÀ1; HRMS (CI) calcd for
C13H16BrNO4 (M+) 329.0263, found 329.0247.
Acetic Acid 2-Acetoxy-5-bromo-4-formyl-3-methoxy-
benzyl Ester (25). To Ac2O (25 mL, 260 mmol) was added 24morph
(1.00 g, 3.03 mmol) in one portion at rt. After heating at reflux for 48 h,
the reaction mixture was concentrated. Chromatography (90% hexanes/
EtOAc) afforded 25 (1.03 g, 99%) as a semisolid: Rf = 0.50 (50%
hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 10.21 (s, 1H), 7.44 (s,
1H), 4.97 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H), 2.04 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 189.2, 169.9, 167.7, 154.2, 142.3, 136.0, 129.2,
128.3, 121.0, 63.1, 60.0, 20.4, 20.0; IR (neat) 2945, 1776, 1745,
1702 cmÀ1; HRMS (CI) calcd for C13H14BrO6 (MH+) 344.9974, found
344.9985.
6-Bromo-3-hydroxy-4-hydroxymethyl-2-methoxy-ben-
zaldehyde (26). To a solution of 25 (1.0 g, 2.9 mmol) in THF was
added 1 N NaOH (17.4 mL, 17.4 mmol). After stirring 30 min at rt, the
reaction mixture was neutralized with 1 N HCl (21 mL, pH ∼5) and
extracted three times with CH2Cl2. The combined organic layers were
dried over Na2SO4, filtered, and concentrated to afford 26 (713 mg,
94%) as a semisolid: Rf = 0.40 (50% hexanes/EtOAc); 1H NMR (500
MHz, CDCl3) δ 10.33 (s, 1H), 7.40 (s, 1H), 6.42 (s, 1H), 4.80 (s, 2H),
3.96 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 190.8, 149.0, 148.0, 134.2,
128.0, 126.0, 115.0, 63.2, 61.0; IR (neat) 3316, 2953, 1679 cmÀ1; HRMS
(CI) calcd for C9H8BrO4 (MHÀ) 258.9606, found 258.9604.
3-Benzyloxy-6-bromo-4-hydroxymethyl-2-methoxy-ben-
zaldehyde (27). To a solution of 26 (700 mg, 2.70 mmol) in dry DMF
(35 mL) was added K2CO3 (1.12 g, 8.09 mmol). After stirring 15 min at
rt, BnBr (0.962 mL, 8.09 mmol) was added under N2. After stirring 17 h
at rt, the reaction mixture was neutralized with 1 N HCl (35 mL), diluted
with water (35 mL), and extracted four times with Et2O. The combined
organic layers were dried over MgSO4, filtered, and concentrated.
Chromatography (83% hexanes/EtOAc) afforded 27 (755 mg, 80%)
as a semisolid: Rf = 0.60 (50% hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3) δ 10.30 (s, 1H), 7.46 (s, 1H), 7.34À7.37 (m, 5H), 5.05 (s, 2H),
4.55 (s, 2H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 190.2, 155.2,
148.7, 142.5, 136.3, 128.5, 128.4, 128.3, 128.2, 127.6, 118.4, 75.1, 62.2,
59.6; IR (neat) 3439, 2941, 1698 cmÀ1; HRMS (CI) calcd for
C16H15BrO4 (M+) 350.0154, found 350.0142.
1
material exists as a 1:0.25:0.25 mixture of inseparable tautomers, H
NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.60 (s, 0.25H), 7.37 (d, J = 7.6
Hz, 0.25H), 7.25 (s, 0.25H), 7.23 (dt, J = 1.6, 7.7 Hz, 0.25H), 7.16 (dt,
J = 1.6, 7.7 Hz, 1H), 7.14 (t, J = 7 Hz, 0.25H), 7.12 (dt, J = 1.5, 7.6 Hz,
0.25H), 6.97 (dd, J = 1.5, 7.5 Hz, 1H), 6.95 (t, J = 1.0, 7 Hz, 0.25H), 6.92
(dd, J = 1.0, 7.3 Hz, 0.25H), 6.92 (coincidental s, 1.25H), 6.90 (s,
0.25H), 6.89 (d, J = 8.2 Hz, 0.25H), 6.86 (dd, J = 0.6, 8.1 Hz, 1H), 6.81
(s, 0.25H), 6.79 (dt, J = 1.0, 7.4 Hz, 1H), 6.71 (d, J = 7.5 Hz, 0.25H), 6.01
(s, 0.25H), 6.00 (s, 0.25H), 5.99 (s, 1H), 5.29 (dd, J = 6.3, 7.0 Hz, 1H),
5.06 (dd, J = 5.9, 10.1 Hz, 0.25H), 4.85 (dd, J = 2.8, 2.9 Hz, 0.25H), 4.23
(s, 0.25H), 3.95 (s, 0.75H), 3.94 (s, 0.75H), 3.913 (s, 3H), 3.905 (s,
0.75H), 3.85 (s, 0.75H), 3.831 (coincidental s, 3.75H), 3.828 (s, 0.75H),
3.70 (d, J = 16.6 Hz, 1H), 3.67 (s, 3H), 3.66 (d, J = 16.6 Hz, 1H), 3.45 (d,
J = 13.6 Hz, 0.25H), 3.35 (d, J = 13.5 Hz, 0.25H), 3.32 (d, J = 13.5 Hz,
0.25H), 3.21 (dd, J = 7.4, 16.2 Hz, 1H), 3.18 (d, J = 13.6 Hz, 0.25H), 2.98
(dd, J = 6.0, 16.2 Hz, 1H), 2.32 (dd, J = 5.9, 12.6 Hz, 0.25H), 2.23 (dd, J =
2.5, 14.5 Hz, 0.25H), 1.97 (dd, J = 3.4, 14.4 Hz, 0.25H), 1.89 (ddd, J =
1.7, 10.2, 12.2 Hz, 0.25H), 0.94 (s, 2.25H), 0.86 (s, 9H), 0.83 (s, 2.25H),
0.19 (s, 0.75H), 0.16 (s, 0.75H), 0.14 (s, 0.75H), 0.12 (s, 3H), 0.11 (s,
0.75H), À0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.1, 185.0,
184.6, 184.5, 179.1, 179.0, 178.9, 160.0 (2), 159.9, 156.5, 156.2, 155.7,
152.4, 151.94, 151.91, 151.5, 141.0, 140.0, 138.8, 130.4, 130.1, 129.4 (2),
128.8, 127.20, 127.15, 127.1, 126.3, 125.5, 125.2, 125.0, 124.1, 122.7,
122.3, 122.2, 121.3, 121.1, 120.9, 120.1, 119.8, 119.7, 119.3, 117.7, 117.5,
116.5, 109.80, 109.75, 109.7, 99.0, 98.9, 73.1, 66.2, 63.6, 62.3, 62.2, 62.0,
56.94, 56.87, 56.8, 56.51, 56.48, 56.4, 50.7, 46.16, 42.4, 40.6, 40.1, 36.9,
26.1, 25.8, 25.7, 18.3, 18.2, 18.0, À4.0, À4.1, À4.5, À4.6, À5.1 (2); IR
(film) 3397, 3076, 2953, 2934, 2903, 2856, 1722, 1675, 1648, 1629,
1586, 1552, 1459 cmÀ1; HRMS (ES) calcd for C29H36O8SiNa (MNa+)
563.2077, found 563.2060.
6-[4-(tert-Butyl-dimethyl-silanyloxy)-4-(2-hydroxy-phenyl)-
2-oxo-butyryl]-2,5,8-trimethoxy-[1,4]naphthaquinone (16).
Isolated as a byproduct (<49%) from the above experiment: a yellow
film; Rf = 0.58 (66% EtOAc/hexanes); the material exists as a 1:1:1
mixture of inseparable tautomers, 1H NMR (500 MHz, CDCl3) δ 7.82
(s, 0.33H), 7.69 (s, 0.33H), 7.54 (s, 0.33H), 7.39 (d, J = 7.6 Hz, 0.67H),
7.32 (s, 0.33H), 7.25 (dt, J = 1.6, 8.0 Hz, 0.33H), 7.19 (dd, J = 1.5, 7.5 Hz,
0.33H), 7.18 (dt, J = 1.7, 8.4 Hz, 0.33H), 7.14 (dt, J = 1.3, 7.7 Hz, 0.33H),
7.08 (s, 0.33H), 7.07 (dd, J = 1.6, 7.6 Hz, 0.33H), 7.00 (dt, J = 1.1, 7.4 Hz,
0.33H), 6.98 (dt, J = 1.0, 7.4 Hz, 0.33H), 6.89 (dd, J = 0.9, 8.1 Hz,
0.33H), 6.86 (d, J = 8.2 Hz, 0.33H), 6.83 (dt, J = 1.1, 7.4 Hz, 0.33H), 6.71
(dd, J = 0.9, 8.1 Hz, 0.33H), 6.05 (s, 0.33H), 6.043 (s, 0.33H), 6.038 (s,
0.33H), 5.43 (dd, J = 5.3, 7.3 Hz, 0.33H), 5.34 (d, J = 1.6 Hz, 0.33H),
5.14 (dd, J = 5.4, 10.4 Hz, 0.33H), 5.04 (dd, J = 3.1, 3.1 Hz, 0.33H), 3.99
(s, 2H), 3.91 (s, 1H), 3.87 (s, 1H), 3.858 (s, 1H), 3.855 (s, 2H), 3.851 (s,
1H), 3.58 (dd, J = 7.4, 17.8 Hz, 0.33H), 3.55 (s, 1H), 3.21 (dd, J = 5.2,
17.8 Hz, 0.33H), 2.58 (dd, J = 2.9, 14.4 Hz, 0.33H), 2.43 (dd, J = 3.4, 13.7
Hz, 0.33H), 2.40 (dd, J = 5.5, 12.9 Hz, 0.33H), 2.08 (ddd, J = 1.6, 10.6,
12.6 Hz, 0.33H), 0.96 (s, 3H), 0.88 (s, 3H), 0.87 (s, 3H), 0.26 (s, 1H),
0.22 (s, 1H), 0.18 (s, 1H), 0.17 (s, 1H), 0.16 (s, 1H), 0.01 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 198.5, 197.7, 195.6, 193.4, 184.0, 183.8,
(3-Benzyloxy-6-bromo-4-hydroxymethyl-2-methoxy-
phenyl)-methanol (27red). To a solution of 27 (735 mg, 2.09
mmol) in MeOH (22 mL) was added NaBH4 (277 mg, 7.32 mmol).
After stirring 12 h at rt, the resulting suspension was neutralized with 1 N
HCl (35 mL, pH ∼5), diluted with water (35 mL), and extracted five
times with CH2Cl2. The combined organic layers were dried over
6483
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The Journal of Organic Chemistry
ARTICLE
Na2SO4, filtered, and concentrated. Chromatography (83% hexanes/
EtOAc) afforded 27red (547 mg, 74%) as a viscous solid: Rf = 0.50 (50%
hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.35À7.40 (m, 5H),
170.9 (2C), 153.0, 148.9, 137.4, 135.7, 135.2, 133.2, 131.3, 130.0, 129.8,
128.7, 128.4, 128.3, 128.0, 126.9, 75.3, 72.9, 67.7, 61.5, 61.6, 58.5, 36.0,
27.0, 26.7, 21.1, 19.4; IR (neat) 3462, 2934, 2860, 1741, 1722 cmÀ1
;
7.34 (s, 1H), 5.03 (s, 2H), 4.85 (s, 2H), 4.50 (s, 2H), 3.96 (s, 3H); 13
C
HRMS (ES) calcd for C39H46O8SiNa (MNa+) 693.2860, found
693.2832.
NMR (125 MHz, CDCl3) δ 152.9, 149.0, 137.1, 136.9, 134.3, 128.9,
128.8 (2C), 127.9, 119.0, 75.4, 62.0, 60.9, 60.6; IR (neat) 3331,
2968 cmÀ1; HRMS (ES) calcd for C16H17BrO4Na (MNa+) 375.0208,
found 375.0223.
Acetic Acid 4-Acetoxymethyl-2-benzyloxy-5-[3-(tert-bu-
tyldiphenylsilanyloxy)-2-oxopropyl]-3-methoxy-benzyl Es-
ter (32). To a solution of 31 (32 mg, 0.048 mmol) in CH2Cl2
(15 mL) was added DMP38 (122 mg, 0.29 mmol). After stirring 12 h
at rt, the reaction mixture was filtered through a short pad of SiO2 with
CH2Cl2, concentrated, and chromatographed (83% hexanes/EtOAc) to
afford 32 (25 mg, 78%) as a liquid: Rf = 0.40 (83% hexanes/EtOAc); 1H
NMR (500 MHz, CDCl3) δ 7.66À7.68 (m, 4H), 7.36À7.46 (m, 11H),
6.86 (s, 1H), 5.09 (s, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 4.31 (s, 2H), 3.94
(s, 2H), 3.90 (s, 3H) 2.01 (s, 3H), 1.98 (s, 3H), 1.13 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 207.2, 170.9, 170.8, 153.0, 149.5, 137.4, 135.7,
132.7, 131.4, 130.6, 130.3, 129.8, 128.7, 128.4, 128.3, 128.1, 127.7, 75.3,
69.8, 61.6, 61.5, 58.6, 43.1, 27.0, 21.2, 21.0, 19.4; IR (neat) 2934, 2856,
1741 cmÀ1; HRMS (ES) calcd for C39H44O8SiNa (MNa+) 691.2703,
found 691.2691.
3-Benzyloxy-6-bromo-4-hydroxymethyl-2-methoxy-phenyl)-
methanol (28). To a solution of 27red (537 mg, 1.52 mmol) in
CH2Cl2 (40 mL) were added pyridine (3 mL, 36.5 mmol) and Ac2O
(1.8 mL, 18 mmol). After stirring 5 d at rt, the reaction mixture was
concentrated and chromatographed (83% hexanes/EtOAc) to afford 28
(520 mg, 78%) as a liquid: Rf = 0.70 (50% hexanes/EtOAc); 1H NMR
(500 MHz, CDCl3) δ 7.31À7.41 (m, 6H), 5.27 (s, 2H), 5.04 (s, 2H),
5.02 (s, 2H), 3.89 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 170.3, 170.1, 153.5, 149.2, 136.5, 132.9, 129.9, 128.3
(2C), 128.2, 128.1, 119.0, 74.9, 61.5, 60.9, 60.4, 20.6, 20.5; IR (neat)
3034, 2945, 1741 cmÀ1; HRMS (ES) calcd for C20H21BrO6Na (MNa+)
459.0420, found 459.0441.
Acetic Acid 4-Acetoxymethyl-5-allyl-2-benzyloxy-3-
methoxy-benzyl Ester (29). In a sealed, flame-dried tube Pd-
(PPh3)4 (0.1 g), 28 (0.69 g, 1.58 mmol), toluene (6 mL), and
allyltributyltin (0.63 mL, 2.03 mmol) were combined. The solution
was stirred in an oil bath at 115À120 °C for 18 h. The reaction mixture
was chromatographed (25% EtOAc/hexanes, SiO2) giving 29 (0.39 g,
62%) as a liquid: Rf = 0.30 (83% hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3) δ 7.32À7.46 (m, 5H), 6.99 (s, 1H), 5.92À5.97 (m, 1H), 5.23 (s,
2H), 5.09 (s, 2H), 5.00À5.07 (m, 4H), 3.90 (s, 3H), 3.42À3.44 (m, 2H),
2.06 (s, 3H), 2.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.4, 170.3,
152.7, 148.4, 137.1, 136.6, 136.1, 131.1, 128.5, 128.3, 128.1, 127.9, 125.9,
7-Benzyloxy-3-(tert-butyldiphenylsilanyloxymethyl)-6-
hydroxymethyl-8-methoxy-isochroman-3-ol (22). To a solu-
tion of 32 (25 mg, 0.37 mmol) in HPLC grade MeOH (12 mL) was
added dry K2CO3 (48 mg, 0.35 mmol). After 4 h at 0 °C, the reaction
mixture was quenched with a saturated solution of NH4Cl (5 mL) and
water (8 mL). The mixture was concentrated, and the resultant solution
was extracted five times with CH2Cl2. The organic layers were com-
bined, dried over Na2SO4, filtered, and concentrated. Chromatography
(83% hexanes/EtOAc) afforded 22 (20 mg, 91%) as a liquid: Rf = 0.70
(50% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.71À7.76 (m,
4H), 7.39À7.45 (m, 11H), 6.80 (s, 1H), 5.05À5.06 (m, 2H), 4.90 (d,
1H, J = 15.5 Hz), 4.97 (d, 1H, J = 15.5 Hz), 4.49À4.55 (m, 2H), 3.93 (s,
3H), 3.88 (d, 1H, J = 11.4 Hz), 3.67 (d, 1H, J = 11.4 Hz), 3.63 (s, 1H),
2.67À2.75 (m, 2H), 1.12 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
148.5, 147.4, 137.4, 135.9, 135.8, 133.8, 133.2, 132.9, 130.1 (2C), 128.8,
128.7, 128.5, 128.1, 128.0, 127.9, 127.6, 124.4, 94.9, 75.3, 69.5, 61.5, 60.4,
115.9, 74.9, 61.2, 61.1, 57.9, 36.6, 20.7, 20.6; IR (neat) 2961, 1741 cmÀ1
;
HRMS (ES) calcd for C23H26O6Na (MNa+) 421.1627, found 421.1622.
Acetic Acid 6-(2,3-Dihydroxy-propyl)-4-ethyl-2,3-dimeth-
yl-benzyl Ester (30). To a solution of 29 (0.39 g, 0.98 mmol) in
acetone (17 mL) and water (6 mL) were added NMO (0.128 g, 1.09
mmol) and a small crystal of OsO4 (∼10 mg). The solution was stirred
at rt for 12 h. The reaction mixture was diluted with water (40 mL), and
the aqueous layer was extracted with CH2Cl2 (4 Â 40 mL). The organic
layers were combined, dried with MgSO4, and concentrated. The
resultant material was chromatographed (EtOAc, SiO2), giving 30
58.9, 33.9, 27.0, 19.5; IR (neat) 3412, 2930, 2856, 1455, 1428 cmÀ1
;
HRMS (ES) calcd for C35H40O6SiNa (MNa+) 607.2492, found
607.2485.
[7-Benzyloxy-3-(tert-butyldiphenylsilanyloxymethyl)-3,8-
dimethoxy-isochroman-6-yl]-methanol (33). To a solution of
22 (46 mg, 0.079 mmol) in MeOH (15 mL) was added PPTS (67 mg,
0.24 mmol). After stirring 42 h at rt, the reaction mixture was directly
adsorbed onto SiO2 and chromatographed (90% hexanes/EtOAc) to
afford 33 (27 mg, 57%) as a liquid: Rf = 0.70 (60% hexanes/EtOAc); 1H
NMR (500 MHz, CDCl3) δ 7.69À7.72 (m, 4H), 7.38À7.44 (m, 11H),
6.86 (s, 1H), 5.06 (d, 1H, J = 11.0 Hz), 5.01 (d, 1H, J = 11.0 Hz), 4.85 (d,
1H, J = 15.4 Hz), 4.65 (d, 1H, J = 15.4 Hz), 4.51À4.59 (m, 2H), 3.90 (d,
1H, J = 11.0 Hz), 3.93 (s, 3H), 3.61 (d, 1H, J = 11.0 Hz), 3.25 (s, 3H),
2.92À3.02 (m, 2H), 1.10 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
148.3, 147.2, 137.4, 135.8 (2C), 133.9, 133.5 (2C), 129.9 (2C), 128.8
(2C), 128.6, 128.5, 128.2, 127.9, 127.8, 124.3, 98.8, 75.4, 65.1, 61.6, 60.4,
59.0, 49.2, 34.6, 27.0, 19.6; IR (neat) 3451, 2934, 2860, 1455,
1428 cmÀ1; HRMS (ES) calcd for C36H42O6SiNa (MNa+) 621.2648,
found 621.2652.
7-Benzyloxy-3-(tert-butyldiphenylsilanyloxymethyl)-3,8-
dimethoxy-isochroman-6-carbaldehyde (34). To a solution of
33 (27 mg, 0.045 mmol) in CH2Cl2 (25 mL) was added DMP38 (33 mg,
0.078 mmol). After stirring 1 h at rt, the reaction mixture was directly
adsorbed onto SiO2 and chromatographed (90% hexanes/EtOAc) to
afford 34 (22 mg, 80%) as an oil: Rf = 0.50 (60% hexanes/EtOAc); 1H
NMR (500 MHz, CDCl3) δ 10.18 (s, 1H), 7.26À7.71 (m, 16H),
5.08À5.14 (m, 2H), 4.65 (d, 1H, J = 20.0 Hz), 4.88 (d, 1H, J = 20.0 Hz)
3.92 (s, 3H), 3.89 (d, 1H, J = 10.0 Hz), 3.60 (d, 1H, J = 10.0 Hz), 3.25 (s,
1
(0.353 g, 83%) as a liquid: Rf = 0.40 (EtOAc); H NMR (500 MHz,
CDCl3) δ 7.29À7.43 (m, 5H), 7.04 (s, 1H), 5.25 (s, 2H), 5.06 (s, 2H),
5.01 (s, 2H), 3.84À3.89 (m, 1H), 3.86 (s, 3H), 3.65À3.66 (m, 1H),
3.62À3.63 (m, 1H), 3.30 (br, 2H), 2.79À2.83 (m, 2H), 2.04 (s, 3H),
2.01 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.9, 170.7, 152.7, 148.5,
137.0, 134.7, 131.0, 129.0, 128.3, 128.0, 127.9, 126.7, 74.9, 72.7, 65.7,
61.3, 61.2, 58.2, 35.9, 20.8, 20.7; IR (neat) 3439, 2964, 1737 cmÀ1
;
HRMS (ES) calcd for C23H28O8Na (MNa+) 455.1682, found 455.1666.
Acetic Acid 4-Acetoxymethyl-2-benzyloxy-5-[3-(tert-bu-
tyldiphenylsilanyloxy)-2-hydroxypropyl]-3-methoxy-ben-
zyl Ester (31). To a solution of 30 (50 mg, 0.116 mmol) in dry DMF
(0.5 mL) were added imidazole (40 mg, 0.58 mmol) and TBDPSCl
(0.1 mL, 0.4 mmol). After stirring 2.5 h at rt, the reaction mixture was
diluted with CH2Cl2 and washed with H2O (10 mL) and saturated
NaHCO3 (10 mL). The combined aqueous layers were extracted five
times with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated. Chromatography (90% hexanes/
EtOAc) afforded 31 (52 mg, 68%) as a liquid: Rf = 0.15 (83% hexanes/
EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.65À7.68 (m, 4H),
7.38À7.45 (m, 11H), 7.02 (s, 1H), 5.20À5.26 (m, 2H), 5.07 (s, 2H),
5.05 (s, 2H), 3.88À3.93 (m, 1H), 3.88 (s, 3H), 3.71 (dd, 1H, J = 4.0 Hz,
J = 10.0 Hz), 3.63 (dd, 1H, J = 6.7 Hz, J = 10.0 Hz) 2.79À2.81 (m, 2H),
2.02 (coincidental s, 6H), 1.09 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
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ARTICLE
3H), 2.99 (s, 2H), 1.10 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 189.7,
152.1, 148.7, 138.2, 137.1, 136.4, 135.8 (2C), 135.7, 135.6, 133.4, 133.3,
130.0, 129.4, 128.9 (2C), 128.8, 127.9, 123.4, 98.7, 76.8, 65.0, 60.7, 59.1,
49.2, 34.6, 27.0, 19.6; IR (neat) 3080, 1671 cmÀ1; HRMS (ES) calcd for
C36H40O6SiNa (MNa+) 619.2492, found 619.2487.
124.4, 122.8, 121.9, 120.8, 118.2, 100.0, 98.7, 65.1, 60.6, 49.2, 43.8, 32.4,
27.0, 26.5, 23.6, 19.6; IR (neat) 3447, 2926, 1737 cmÀ1; HRMS (ES)
calcd for C38H44O8SiNa (MNa+) 679.2703, found 679.2707.
Spiroketal (38). To a solution of 37 (0.002 g, 0.003 mmol)
dissolved in CH2Cl2 (1 mL) was added p-toluenesulfonic acid (0.2
mg, 0.001 mmol). The mixture was stirred at rt for 1 h and concentrated.
The residue was dissolved in 50% EtOAc/hexanes, eluted through a
short pad of SiO2 (50% EtOAc/hexanes), and concentrated. LRMS
(ES) 661 (MNa+).
(7-Benzyloxy-3,8-dimethoxy-6-vinyl-isochroman-3-yl-
methoxy)-tert-butyldiphenylsilane (21). To a solution of 34
(22 mg, 0.036 mmol) in dry THF (2 mL) was added a freshly prepared
solution of the Wittig ylid (115 μL, 0.11 mmol) in THF. After stirring
10 min at rt, the reaction mixture was quenched with water (1 mL) and
extracted with CH2Cl2. The combined organic portions were dried over
Na2SO4, filtered, and concentrated. Chromatography (90% hexanes/
EtOAc) afforded 21 (20 mg, 98%) as a liquid: Rf = 0.50 (83% hexanes/
EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.69À7.73 (m, 4H),
7.33À7.48 (m, 11H), 7.06 (s, 1H), 6.99 (dd, 1H, J = 17.5 Hz, J = 11.0
Hz), 5.72 (d, 1H, J = 17.5 Hz), 5.24 (d, 1H, J = 11.0 Hz), 4.89À4.95 (m,
2H), 4.84 (d, 1H, J = 15.0 Hz), 4.65 (d, 1H, J = 15.0 Hz), 3.87 (s, 3H),
3.90 (d, 1H, J = 10.0 Hz), 3.61 (d, 1H, J = 10.0 Hz), 3.25 (s, 3H),
2.94À3.04 (m, 2H), 1.11 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
148.7, 147.2, 137.6, 135.9, 135.8, 134.0, 133.8, 133.5, 131.4, 131.3, 130.0,
129.9, 128.6, 128.4, 128.2, 128.0, 127.9, 127.5, 121.4, 114.9, 98.8, 75.5,
[7-Benzyloxy-3-(tert-butyldiphenylsilanyloxymethyl)-8-
methoxy-1H-isochromen-6-yl]-methanol (39). To a solution of
22 (260 mg, 0.44 mmol) in H2SO4/dry acetone (25 mL, 0.179 N) was
added activated 4 Å molecular sieves (∼100 mg). After stirring 84 h at rt,
the reaction mixture was diluted with water (25 mL). After concentra-
tion, the aqueous portion was extracted with EtOAc. The combined
organic layers were dried over Na2SO4, filtered, and concentrated.
Chromatography (90% hexanes/EtOAc) afforded 39 (150 mg, 60%)
1
as a liquid: Rf = 0.30 (83% hexanes/EtOAc); H NMR (500 MHz,
CDCl3) δ 7.76À7.77 (m, 4H), 7.36À7.48 (m, 11H), 6.77 (s, 1H), 5.98
(s, 1H), 5.20 (s, 2H), 5.12 (s, 2H), 4.57 (s, 2H), 4.21 (s, 2H), 3.90 (s,
3H), 1.16 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.2, 148.2, 148.0,
137.3, 135.7, 134.8, 133.4, 129.9, 128.7, 128.6, 128.5, 128.3, 127.9, 121.3,
118.9, 100.3, 75.5, 63.9, 62.9, 61.3, 61.0, 27.0, 19.4; IR (neat) 3428, 2930,
2856, 1455, 1428 cmÀ1; HRMS (ES) calcd for C35H38O5SiNa (MNa+)
589.2386, found 589.2402.
65.1, 60.7, 59.1, 49.2, 34.7, 27.1, 19.6; IR (neat) 2930, 1455, 1428 cmÀ1
;
HRMS (ES) calcd for C37H42O5SiNa (MNa+) 617.2699, found
617.2701.
3-(2-Benzyloxy-benzyl)-5-[7-benzyloxy-3-(tert-butyldi-
phenylsilanyloxymethyl)-3,8-dimethoxy-isochroman-6-
yl]-4,5-dihydroisoxazole (36). To a solution of 21 (20 mg, 0.034
mmol) in benzene (2.5 mL) were added 35 (19.3 mg, 0.075 mmol),
phenyl isocyanate (0.055 mL, 0.51 mmol), and Et3N (0.020 mL, 0.14
mmol). After stirring 18 h at rt, the reaction mixture was filtered and
concentrated. Chromatography (90% hexanes/EtOAc) afforded 36
(25 mg, 89%, dr = 1.5:1) as a liquid: Rf = 0.35 (75% hexanes/EtOAc);
1H NMR (500 MHz, CDCl3) δ 7.69À7.83 (m, 4H), 7.32À7.43 (m, 15H),
7.10À7.19 (m, 2H), 6.80À6.92 (m, 4H), 5.59À5.67 (m, 1H), 5.03
(minor), 5.02 (major) (s, 2H), 4.88À4.97 (m, 2H), 4.76À4.82 (m, 1H),
4.56À4.61 (m, 1H), 3.84À3.87 (m, 1H), 3.79 (major), 3.78 (minor) (s,
3H), 3.63À3.76 (m, 2H), 3.55À3.58 (m, 1H), 3.22 (minor), 3.19
(major) (s, 3H), 3.09À3.19 (m, 1H), 2.86À2.96 (m, 2H), 2.64À2.70
(m, 1H), 1.12 (minor), 1.10 (major) (s, 9H); 13C NMR (125 MHz,
CDCl3) (major diastereomer) δ 158.0, 156.6, 148.4, 146.5, 137.6, 137.1,
135.7, 135.9, 134.3, 133.5, 133.4, 130.8, 129.9, 129.2, 128.7, 128.6, 128.5,
128.4, 128.3, 128.1, 127.9, 127.8, 127.5, 127.4, 124.9, 122.2, 122.0, 121.3,
112.1, 98.7, 75.2, 75.1, 70.2, 65.3, 60.4, 58.9, 49.2, 44.6, 34.6, 28.3, 27.1,
19.6; IR (neat) 2934, 1737 cmÀ1; HRMS (ES) calcd for C52H55NO7-
SiNa (MNa+) 856.3646, found 856.3652.
3-(tert-Butyldiphenylsilanyloxymethyl)-6-[1-hydroxy-2-
(2-hydroxy-2,3-dihydrobenzofuran-2-yl)-ethyl]-3,8-dimethoxy-
isochroman-7-ol (37). To a solution of 36 (15 mg, 0.018 mmol) in
MeOH (3 mL), THF (3 mL), and H2O (1.2 mL) were added boric acid
(12 mg, 0.201 mmol) and Raney Ni (a 50% suspension in water, 7 drops,
∼0.4 mL). After stirring 3.75 h at rt, the reaction mixture was filtered
through a short pad of silica, diluted with H2O (10 mL), and extracted
five times with CH2Cl2. The organic layers were dried over Na2SO4 and
concentrated. The residue was dissolved in EtOAc (15 mL), and 10%
Pd/C (25 mg) was added. After stirring 18 h at rt under a hydrogen
atmosphere, the reaction mixture was filtered through a short pad of
Celite, concentrated, and chromatographed (50% hexanes/EtOAc) to
afford 37 as a mixture of diastereomers (4 mg, 34%) as a liquid: Rf = 0.45
(50% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.67À7.75 (m,
4H), 7.37À7.43 (m, 6H), 7.82À7.25 (m, 5H), 4.78À4.88 (m, 1H),
4.62À4.64 (m, 1H), 3.75À3.89 (m, 5H), 3.40À3.63 (m, 2H),
3.21À3.24 (m, 3H), 3.14À2.92 (m, 3H), 2.04À2.44 (m, 2H), 1.10 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 156.4, 135.8 (2C), 135.4, 133.4,
132.9, 129.9 (2C), 129.4 (2C), 128.8 (2C), 127.9, 126.9, 125.8, 125.2,
7-Benzyloxy-3-(tert-butyldiphenylsilanyloxymethyl)-8-
methoxy-1H-isochromene-6-carbaldehyde (40). To a solution
of 39 (167 mg, 0.30 mmol) in CH2Cl2 (60 mL) was added DMP38 (318
mg, 0.75 mmol). After stirring 50 min at rt, the reaction mixture was
filtered through a short pad of Celite and washed with CH2Cl2.
Concentration afforded 40 (141 mg, 85%) as a liquid: Rf = 0.70 (50%
hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 10.18 (s, 1H),
7.73À7.74 (m, 4H), 7.40À7.46 (m, 11H), 7.20 (s, 1H), 6.00 (s, 1H),
5.21 (s, 2H), 5.16 (s, 2H), 4.23 (s, 2H), 3.93 (s, 3H), 1.14 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 189.7, 157.0, 153.3, 148.6, 136.1, 135.7,
134.9, 133.3, 130.3, 130.0, 129.7, 128.8 (2C), 128.7 (2C), 128.6, 127.9
(2C), 127.8, 117.0, 99.6, 76.9, 63.9, 62.8, 61.2, 26.9, 19.4; IR (neat) 2930,
2860, 1687 cmÀ1; HRMS (ES) calcd for C35H36O5SiNa (MNa+)
587.2230, found 587.2211.
(7-Benzyloxy-8-methoxy-6-vinyl-1H-isochromen-3-yl-
methoxy)-tert-butyldiphenylsilane (41). To a solution of 40
(140 mg, 0.25 mmol) in dry THF (30 mL) was added freshly prepared
Wittig ylid (0.557 mL, 0.625 mmol). After stirring 10 min at rt, the
reaction mixture was quenched with water (10 mL) and extracted with
CH2Cl2. The combined organic portions were dried over Na2SO4,
filtered, and concentrated. Chromatography (66% hexanes/EtOAc)
afforded 41 (110 mg, 79%) as a liquid: Rf = 0.70 (83% hexanes/EtOAc);
1H NMR (500 MHz, CDCl3) δ 7.78À7.80 (m, 4H), 7.37À7.52 (m,
11H), 7.04 (dd, 1H, J = 17.5 Hz, J = 11.0 Hz), 7.09 (s, 1H), 6.02 (s, 1H),
5.78 (d, 1H, J = 17.5 Hz), 5.30 (d, 1H, J = 11.0 Hz), 5.21 (s, 2H), 5.00 (s,
2H), 4.28 (s, 2H), 3.92 (s, 3H), 1.19 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 156.2, 148.7, 148.1, 137.5, 135.7, 134.0, 133.8, 133.4, 132.0,
131.3, 129.9, 128.8, 128.6 (2C), 128.4, 128.2, 128.1, 127.9, 121.3, 115.8,
115.1, 100.2, 75.6, 63.9, 63.0, 61.2, 27.0, 19.5; IR (neat) 2934, 1451,
1428 cmÀ1; HRMS (ES) calcd for C36H38O4SiNa (MNa+) 585.2437,
found 585.2441.
3-(2-Benzyloxy-benzyl)-5-[7-benzyloxy-3-(tert-butyl-
diphenylsilanyloxymethyl)-8-methoxy-1H-isochromen-6-yl]-
4,5-dihydroisoxazole (42). To a solution of 41 (108 mg, 0.20
mmol) in benzene (20 mL) were added 35 (129 mg, 0.50 mmol), phenyl
isocyanate (0.217 mL, 2 mmol), and Et3N (0.050 mL, 0.36 mmol). After
stirring 36 h at rt, the reaction mixture was filtered and concentrated.
Chromatography (94% hexanes/EtOAc) afforded 42 (108 mg, 70%) as
a liquid: Rf = 0.30 (80% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3)
6485
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ARTICLE
δ 7.74À7.76 (m, 4H), 7.34À7.45 (m, 16H), 7.18À7.26 (m, 2H),
6.94À6.96 (m, 2H), 6.77 (s, 1H), 5.92 (s, 1H), 5.64 (dd, 1H, J = 8.0
Hz, 11.0 Hz), 5.12À5.20 (m, 2H), 5.08 (s, 2H), 4.97À5.02 (m, 2H) 4.23
(s, 2H), 3.82 (s, 3H), 3.73À3.79 (m, 2H), 3.10 (dd, 1H, J = 11.0 Hz, 17.5
Hz), 2.68 (dd, 1H, J = 8.0 Hz, 17.4 Hz) 1.15 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 158.0, 156.6, 156.1, 148.2, 147.3, 137.4, 137.0, 135.7,
135.4, 133.4 (2C), 129.9, 129.2, 128.7, 128.6, 128.5, 128.4 (2C), 128.3,
128.0, 127.9, 127.3, 124.8, 121.3, 121.2, 116.5, 112.1, 100.4, 77.0, 75.3,
70.2, 63.8, 62.9, 61.0, 44.7, 27.0, 19.4; IR (neat) 2934, 1737, 1660, 1602,
1494, 1451 cmÀ1; HRMS (ES) calcd for C51H51NO6SiNa (MNa+)
824.3383, found 824.3413.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental informa-
b
tion, characterization data including 1H and 13C NMR spectra,
and X-ray crystal structure data for compound 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Email: marisa@sas.upenn.edu.
4-[7-Benzyloxy-3-(tert-butyldiphenylsilanyloxymethyl)-8-
methoxy-1H-isochromen-6-yl]-1-(2-benzyloxy-phenyl)-4-hy-
droxybutan-2-one (43). To a solution of 42 (15 mg, 0.02 mmol) in
MeOH (4 mL), THF (4 mL), and H2O (1 mL) were added boric acid
(12 mg, 0.22 mmol) and Raney Ni (2 drops, ∼0.1 mL). After stirring for
2 h at rt, the reaction mixture was filtered through a short pad of Celite,
diluted with H2O (2 mL) and brine solution (5 mL), and extracted with
CH2Cl2. The organic layers were combined, dried over Na2SO4, and
concentrated. Chromatography (90% hexanes/EtOAc) afforded 43 (11
mg, 73%) as a liquid: Rf = 0.25 (80% hexanes/EtOAc); 1H NMR (500
MHz, CDCl3) δ 7.71À7.72 (m, 4H), 7.32À7.43 (m, 16H), 7.22À7.31
(m, 1H), 7.08À7.09 (m, 1H), 6.90À6.92 (m, 2H), 6.79 (s, 1H), 5.95 (s,
1H), 5.31 (dd, 1H, J = 4.0 Hz, 8.0 Hz), 5.10 (d, 1H, J = 13.3 Hz), 5.16 (d,
1H, J = 13.3 Hz), 5.01 (s, 2H), 4.92À5.01 (m, 2H), 4.20 (s, 2H), 3.81 (s,
3H), 3.61À3.69 (m, 2H), 3.28 (br s, 1H), 2.67À2.75 (m, 2H), 1.11 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 209.6, 156.6, 156.1, 148.1, 146.8,
137.4, 136.9, 136.6, 135.7, 133.6, 133.4, 131.5, 129.9, 128.8 (2C), 128.7,
128.4, 128.3, 128.1, 127.9, 127.5, 125.6, 121.2, 120.9, 116.8, 112.0, 100.4,
75.3, 70.3, 65.0, 63.9, 62.9, 61.0, 49.5, 45.5, 27.0, 19.5; IR (neat) 3501,
2956, 1710 cmÀ1; HRMS (ES) calcd for C51H52O7SiNa (MNa+)
827.3380, found 827.3358.
’ ACKNOWLEDGMENT
Financial support was provided by the American Cancer
Society (RSG-02-137-01-CDD). We thank Dr. Patrick Carroll
for determination of the crystal structure. Instrumentation
support was provided by the NMR, Mass Spectrometry, and
X-ray Diffraction facilities at the University of Pennsylvania, with
partial support from the NIH (1S10RR023444, 1S10RR022442)
and NSF (CHE 0840438).
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