Alternative spiroketalization methods toward purpuromycin: A diketone approach to prevent benzofuran formation

Article abstract of DOI:10.1021/jo200399z

The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the elec

Full text of DOI:10.1021/jo200399z

ARTICLE
pubs.acs.org/joc
Alternative Spiroketalization Methods toward Purpuromycin: A
Diketone Approach To Prevent Benzofuran Formation
Andrew N. Lowell, Michael W. Fennie, 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: The central portion of purpuromycin has been
assembled via a classical spiroketalization reaction. Key to
promoting this reaction mode versus benzofuran formation
was the oxidation state of the spiroketal core. With a higher
oxidation state, even the electron-deficient isocoumarin found
in purpuromycin could be employed directly in the spiroketa-
lization. The two halves of the spiroketalization precursor were
joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A
very mild selenium dioxide oxidation was used to introduce the
required oxidation state of the spiroketal core.
’ INTRODUCTION
The spiroketal purpuromycin (1, Figure 1),1,2 a member of a
unique class of highly oxidized aromatic polyketides, has been
the subject of much inquiry.3 In particular, the inability to
directly form the central portion of the molecule by conven-
tional spiroketalization has driven several innovative alternative
approaches.4ꢀ6 Nonetheless, the central question remains as to
why spiroketalization fails.
The lack of spiroketalization reaction in the rubromycin family
of compounds has been previously attributed primarily to the
nucleophilicity of the two phenols (Figure 2).3,7,8 Namely, the
electron-poor isocoumarin phenol was hypothesized to be a poor
partner in the spiroketalization, rendering the first step of path b
unlikely and also impeding the third step of path a.
Our recent work toward the total synthesis of purpuromycin
(see companion paper, DOI 10.1021/jo200398v),9 however,
produced some new insight into the activity of the two phenols
and other intermediates involved in spiroketalization. Specifi-
cally, we discovered that the more nucleophilic phenol of the
naphthalene does not hemiketalize (top, Figure 3) as judged by
NMR spectroscopy. The less nucleophilic phenol on an isocou-
marin model, however, readily forms the hemiketal (bottom,
Figure 3).9 This result implies that the six-membered hemiketal
ring from the isocoumarin phenol (i.e., intermediate 4 in
Figure 2) forms easily, while the five-membered hemiketal ring
from the naphthalene (i.e., intermediate 3 in Figure 2) is
difficult to achieve. As a consequence, it is clear that the nucleo-
philicities of the phenols are not the sole factor controlling the
spiroketalization.
Furthermore, calculations showed that the pyran oxocarbe-
nium (6) was 11.6 kcal/mol lower in energy than the furan oxo-
carbenium (5). These results are in accord with the NMR observa-
tions illustrated in Figure 3 and indicate that the five-membered ring
Figure 1. Rubromycin family.
compounds (i.e., 3, 5, 10) are generally less stable than the six-
membered ring compounds (i.e., 4, 6, 12), primarily due to ring
strain. However, this finding is not consistent with the observed
preference for formation of naphthofurans similar to 7 in other
systems.7 The controlling factor for the cyclization appears to be
the energy of activation required to convert the oxocarbenium
into a spiroketal or naphthofuran. The transition state from favored
Received: February 22, 2011
Published: June 27, 2011
r
2011 American Chemical Society
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Figure 2. Potential spiroketalization pathways.
oxocarbenium 6 to spiroketal 8 is likely high in energy because
significant steric hindrance and strain evolves as the phenol aligns for
the SN1 closure. If the formation of oxocarbenium 5 is energetically
competitive with this transition state, then the E1 elimination path-
way to naphthofuran 7, which avoids a loss of rotational free-
dom, will predominate over the SN1 closure to spiroketal 8.
Assuming that the manifold in Figure 2 is under equilibrium, it
should be possible to convert naphthofuran 7 into spiroketal 8.
Indeed, Brockmann3 showed that benzofurans are capable of
entering into a spiroketalization with a phenolic group in simple
model systems. The work of Danishefsky, however, showed that
the complete isocoumarin of purpuromycin would not directly
add to a naphthofuran (i.e., 7 to 8 in Figure 2).4 This inability to
spiroketalize is not due to the inability of the isocoumarin phenol
to attack the naphthalene oxocarbenium (5, Figure 2), but rather
because the electron-rich naphthalene is unstable, either decom-
posing or oxidatively demethylating to the naphthoquinone
under strenuous conditions., The spiroketal isolated by Reissig
and co-workers supports this argument, as the isolated product
has also undergone oxidation to the quinone.3,8 This tempering
of the inherent electron-rich nature of the naphthalene is likely
what allowed this compound to be formed and isolated. Support-
ing this electronic argument, Brimble and co-workers show that
an electron-poor phenol is a competent spiroketalizing partner to
a naphthalene phenol under mild conditions.10
Thus, our goals were to stabilize the naphthalene unit by
decreasing its electron-rich character and to prevent benzofuran
formation while using the intact isocoumarin unit to facilitate a
convergent assembly. Using a diketone strategy to prevent elim-
ination to the benzofuran, a method complementary to our other
approaches,9 we intend to show that the isocoumarin of purpur-
omycin can function as a competent nucleophile in a spiro-
ketalization.
’ RESULTS AND DISCUSSION
Diketone Rationale. To prevent elimination of the naphtha-
lene oxocarbenium to naphthofuran (i.e., 7 in Figure 2), we
hypothesized that removal of the acidic protons on the methy-
lene adjacent to the naphthalene ring would suppress the un-
wanted reaction pathway. The group used to replace the protons
had to be easy to install and remove as well as being compatible
with extant functionality. We chose a carbonyl group as we
believed it would meet these requirements and not deleteriously
alter the properties or size of the molecule (13, Figure 4). In fact,
the electron-withdrawing carbonyl group would temper the
electron-rich naphthalene, which is typically very reactive, as
well as enhance the reactivity of the existing carbonyl group.
While the work of Danishesky and co-workers4 indicated that
the neutral form of 13 (i.e., 16, Figure 5A) was accessible,
two concerns remained. First, the indirect route employed by
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Figure 3. Comparison of hemiketalization from the different phenols.
Figure 5. Comparison of strategies using a ketone blocking group.
Figure 4. Diketone to prevent benzofuran formation.
protected intermediate 23 from our original 1,3-dipolar cycload-
dition pathway,7 as outlined in Scheme 1, were explored with
the aim of generating benzyl alcohol 24. Despite extensive
experimentation with a variety of oxidants (including Oxone,
PhNO, O2, OsO4, and m-CPBA), both pentamethoxy naphtha-
lene 23 and its oxidized counterpart naphthoquinone 257 failed
to undergo the requisite benzylic oxidation.
Encouraged by the discovery of a modification to the Riley
reaction (vide infra Scheme 8),11 compound 30 (differing from
the successful candidate 63 in Scheme 11 by only an additional
C4 methoxy group) was targeted for oxidation. Thus, isoxazoline
29 (Scheme 2) was synthesized via 1,3-dipolar cycloaddition and
subjected to nickel cleavage and silylation. However, application
of these new conditions to 30 failed to produce the 1,2-diketone.
Diketone Generation Prior to Fragment Union. We next
attempted to introduce the requisite keto group, or a surrogate
thereof, prior to fragment assembly (Scheme 3). Nitro alcohol
31, which was available from our improved naphthalene syn-
thesis,12 failed to undergo cycloaddition and instead resulted in
decomposition. All attempts to silylate 31 were unsuccessful.12
Ketone 33 would cyclize with isocoumarin 21 to form isoxazoline
Danishefsky and co-workers using a Mitsunobu reaction to
establish the final spirocyclic bond raised questions as to whether
similar intermediates could be achieved via conventional acidic
spirocyclization protocols. As far as we can determine, no
reports directly support the proposed transformation of
diketone 18 (Figure 5B) in this type of system. In addition,
the placement of the alkoxy substituent on the central core
differs in the purpuromycin series, raising the possibility of
ortho-quinone methide generation from intermediates such
as 18 (Figure 5B). With the goal of examining if a diketone
could facilitate the spiroketalization of the intact naphthalene
and isocoumarin units of purpuromycin, and keeping in mind
the considerations outlined above, the synthesis of 19 was
undertaken from penultimate intermediate 18 (Figure 5B).
Strategically, however, it was unclear whether it was better to
install the requisite oxygen functionality on the naphthalene
prior to or after 1,3-dipolar cycloaddition.
Diketone Generation after Fragment Union. With ad-
vanced intermediates in hand, it seemed most logical to intro-
duce the diketone group at a late stage. Accordingly, oxidations of
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Scheme 1. Attempted Oxidation after Fragment Union of
Existing Compounds
Scheme 2. Attempted Oxidation of the Di-ortho Substituted
System with Selenium Dioxide
Scheme 3. Diketone Generation Prior to Fragment Union
34 in moderate yield, but 34 proved highly resistant to selective
reduction, yielding complex mixtures.
Scheme 4. Synthesis of Mono-ortho Aldehyde 38
Construction of Diketones Lacking Naphthazarin C4-Sub-
stitution Prior to Fragment Union. From the above syntheses
(Scheme 3), we concluded that reduction of the isoxazoline was
impossible in the presence of an R-ketone. This seemed to be a
significant setback, as other forms of oxygen functionality on the
nitroethane were incompatible with 1,3-dipolar cycloaddition.
For example, hydroxy nitro 31 would not cyclize, and it could not
be protected.12 We reasoned that our inability to protect 31 arose
from the dense functionality of the naphthalene itself; the seven
substituents prevented silylation of the benzylic alcohol 31,
specifically the C2 and C4 ethers flanking the C3 nitroethane.
Further support for the steric hindrance can be found in the
reluctance of 30 (Scheme 2) to undergo R-oxygenation. To test
this hypothesis, we undertook the synthesis of a naphthalene
without substitution at the C4 position.
produce 36. Further reduction to alcohol 37 followed by oxida-
tion with DessꢀMartin periodinane (DMP)13 proved to be the
most efficient pathway to 38. From aldehyde 38 (Scheme 5),
Toward the construction of a C4 unsubstituted naphthalene,
ortho-quinone 3512 (Scheme 4) was reduced and benzylated to
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Scheme 5. Mono-ortho Naphthalene Elaboration
Scheme 7. Cycloaddition and Elaboration of the Unoxidized,
Mono-ortho Naphthalene
Scheme 6. Reduction with Existing Oxygen Functionality on
the Mono-ortho Naphthalene
when a stronger dehydrating agent (para-nitro phenylisocyanate
versus phenylisocyanate) was used along with more strenuous
reaction conditions (toluene, reflux). With 42 in hand, we again
attempted to reductively cleave the isoxazoline with Raney nickel.
Unfortunately, this material still proved resistant to reduction.
While trace amounts of 43 could be detected, the major product
of this reaction was decomposition. Isoxazoline 42 could be
desilylated, but 44 was likewise incompatible with reduction.
All other reductants such as molybdenum hexacarbonyl also
failed to effect reduction. From the results of this sequence
combined with that described in Scheme 3, we concluded
that any oxygen functionality R to the isoxazoline prohibited
selective reduction.
Diketone Generation after Fragment Union from C4-
Unsubstituted Naphthazarin. With the possibility of including
the oxygen functionality to prevent benzofuran formation prior
to 1,3-dipolar cycloaddition precluded, we again turned to oxida-
tion of the naphthalene benzylic position after isoxazoline forma-
tion and subsequent cleavage. Reasoning that oxidation would be
more facile with a less hindered benzylic position, compound 48,
which lacks C4 substitution, became a target of interest. As
depicted in Scheme 7, naphthalene 41 and isocoumarin 21 were
combined to form isoxazoline 46. Raney nickel catalyzed cleavage
gave 47 which was protected as silyl ether 48.
Treatment of 48 (Scheme 8) with triethylamine and methanol-
d4 showed complete deuterium incorporation at the R positions of
the ketone as well as transesterification of the isocoumarin methyl
ester(49). Satisfiedthat enolization readily occurred, ourattention
turned to identifying a suitable oxidant. Our first approach was to
generate the diketone via the benzylic alcohol (50). As treatment
with sodium hexamethyldisilazane (NaHMDS) and the Davis
oxaziridine caused decomposition instead of forming the requisite
molecule, the search for oxidants broadened. Screening of oxida-
tion conditions revealed a slight conversion to desired product 51
with selenium dioxide. Hypothesizing that the reaction would be
more rapid with the enolate, we added triethylamine. Not only did
this modification enable direct production of the diketone, but also
the base allowed for much milder conditions than are typical for
this reaction.11
hydroxy nitro 39 could be readily produced by means of the Henry
reaction. The highly reactive silylating agent tert-butyldimethylsilyl
imidazole was effective in generating 40, lending support to our
steric hindrance hypothesis. The unsubstituted nitroalkane (41)
could be synthesized as well via the eliminative Henry reaction and
subsequent reduction.
Our first attempt to incorporate a mono-ortho substituted
naphthalene involved 40 (Scheme 6), with the oxidized function-
ality present prior to cycloaddition. Cycloaddition was successful
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Scheme 8. Oxidation to the Diketone
Scheme 9. Hydrogenolysis and Attempted Spiroketalization
of Symmetrically Protected 51
Figure 6. Requirements for a spiroketal precursor.
Second Generation Synthesis with Orthogonal Phenol
Protection. The knowledge gained from our earlier routes is
summarized in Figure 6. Orthogonal protection is needed on the
naphthalene to prevent the catechol from oxidizing to the ortho-
quinone. Only one substituent is tolerated adjacent to the naph-
thalene benzylic position if diketone formation is to occur. The
protecting group for the central chain alcohol must be sufficiently
robust to withstand the spiroketalization conditions. Orthogonal
protection of the isocoumarin catechol is preferable.
With these requirements in mind, a new naphthalene synthesis
was undertaken (Scheme 10). Reduction and selective benzylation
of the more acidic position of the catechol found in ortho-quinone
3512 with potassium bicarbonate furnished 55, which could be easily
methylated to give 56. Following a protocol similar to that outlined
in Scheme 4 and Scheme 5, 56 was transformed into 60.
Following our standard protocol (see Scheme 7), orthogonally
protected naphthalene 60 (Scheme 11) was combined with an
orthogonally protected isocoumarin (28)14 and transformed into
63. Fresh selenium dioxide failed to give clean conversion to
diketone 64, but after the addition of 1 equiv of water to the
reaction mixture, high yields of pure product were again obtained.
The likely role of water is to assist in hydrolysis of a selenine
intermediate or to generate a reactive selenous acid species.15
Hydrogenolysis of the benzyl ethers yielded 65 as a mixture of
With 51 in hand, the stage was set for spirocyclization from the
diketone (Scheme 9). Hydrogenolysis furnished 52, which
existed as a mixture of tautomers preventing full characterization.
Further supporting the hypothesis of instability in the electron-
rich naphthalene,4,8 52 spontaneously oxidized to ortho-quinone
53 upon exposure to air. Further, the silyl ether of 52 was labile
under the vigorous conditions needed to effect spiroketalization,
adding additional tautomers (54) to the mixture and opening
a pathway for a retro-Claisen reaction. This combination of
problems from the symmetrically protected system stymied
spiroketal formation by this route.
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Scheme 10. Differentially Protected Naphthalene
Scheme 11. Cycloaddition and Elaboration to the Spiroketal
tautomers. Addition of a small amount of DABCO to the NMR
sample coalesced the tautomers to one signal for easier visu-
alization.16 Treatment of 65 with p-toluenesulfonic acid in
benzene at 100ꢀ105 °C for 1 h gave a diastereomeric mixture
of spiroketal 66 in 50ꢀ86% and a small amount of the eliminated
product 67. This result constitutes the first example of direct
ketalization of two hemispheres to yield the complete carbon
skeleton of a member of the rubromycin family.
Reactions of the Spiroketal. While we were able to introduce
the carbon skeleton necessary for the rubromycin family using a
complete isocoumarin that proved stable under strongly acidic
conditions, two major challenges remain in converting spiroketal
66 (Figure 7) into purpuromycin (1). The challenges are (1)
reduction of the 30 carbonyl, a functionality introduced to
prevent competitive elimination of the oxocarbenium intermedi-
ate, and (2) oxidation of the 40 methine, a functionality needed to
allow installation of the 30 ketone.
We began by attempting the reduction of the ketone (Scheme 12).
Spiroketal 66 could be reduced to alcohol 68 using sodium
borohydride. Alcohol 68 proved resistant to further reduction
under a variety of conditions including hydridic, hydrogenolysis,
trimethylsilyl chloride, trimethylsilyl ioide, and dithionite. In
addition to the stepwise reduction of 66, we attempted a more
direct reduction in two ways: (1) by forming a dithiane and
reducing with Raney nickel and (2) by using trifluoroacetic acid
and triethylsilane. Both of these methods resulted in the reduction of
the ketone but surprisingly also substituted or reduced the methoxy
group conjugated to the isocoumarin lactone (70a and 70b,
respectively). We hypothesize that the isocoumarin ring system
is capable of undergoing a conjugate addition and elimination type
reaction, which accounts for the formation of these products.
Additionally, ketone 66 and alcohol 68 were subjected to
oxidation conditions in the hope of installing oxygen function-
ality at the 40 position (Figure 7). Both of these substrates failed
to oxidize, instead resulting in complex mixtures.
Besides reduction and direct oxidation onto the naphthalene
ring, manipulations of the naphthoquinone were also investi-
gated (Scheme 13). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) readily oxidized 66 to quinone 71. This material, however,
showed the same resistance to oxidation even via nucleophilic addi-
tion into the aromatic ring at the doubly activated 40 position. Light-
induced selective demethylation17 cleaved the 70-methyl ether, but
this did not lend itself to furthering the goals of Figure 7. Boron
trichloride-mediated demethylation gave 72, regardless of the
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Scheme 13. Formation of the Naphthoquinone and Its
Chemistry
Figure 7. Oxidation changes needed to achieve 1.
Scheme 12. Reduction of the 30 Carbonyl
cycloaddition strategy providing a convergent method to easily
couple naphthalene and isocoumarin hemispheres. Here, five
different isoxazolines were constructed allowing us to test
hypotheses and to produce an array of analogs to probe biological
function (e.g., spiroketal compounds 66, 67, 68, 70, 71, 72) in a
straightforward and reliable manner. A key step in this endeavor
was the discovery that water facilitates a mild late-stage selenium
dioxide oxidation to generate a 1,2-diketone. We have unequivocally
shown that the complete isocoumarin is indeed a sufficiently
powerful nucleophile to attack the oxocarbenium intermediate so
long as the competing elimination pathway to the naphthofuran
is suppressed. NMR experiments and calculations showed that
the primary consideration in spiroketalization of phenolic groups
is the ring strain, due to the phenol sp2 centers, generated in the
hemiketal and oxocarbenium intermediates. Extensive experi-
mentation has given us insight into the properties of the com-
pleted spiroketal, which will be useful in the generation of analogs
and other members of this class of natural products. In particular, the
isocoumarin unit is quite electrophilic, undergoing conjugate addi-
tions at the unsaturated ester with thiols and hydride nucleophiles.
Also of interest is product 67 arising from spiroketalization and
elimination, which could offer easy entry to the griseorhodin
structural type if a different isocoumarin were employed.
oxidation state of 71 (quinone or quinol), prior to exposure to
Lewis acid. Diphenol 72 could be reverted to 71 by treatment with
methyl iodide and base. Oxidation of diphenol 72 to 73 also proved
impossible, probably due to the very electron-poor nature of the
ring systems.
’ CONCLUSION
We have shown that the spiroketal skeleton of the rubromycin
family can be synthesized in a convergent manner using classical
ketalization conditions. The synthesis centers on a 1,3-dipolar
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’ EXPERIMENTAL SECTION
(dd, J = 2.2, 17.2 Hz, 1H), 2.80 (dd, J = 9.3, 17.2 Hz, 1H); 13C NMR
(125 MHz, C6D6) δ 208.3, 160.9, 156.8, 155.1, 153.9, 152.7, 151.0,
150.8, 146.8, 146.3, 142.9, 137.6, 136.6, 135.9, 132.8, 128.9, 128.7, 128.5,
125.7, 121.8, 116.5, 114.8, 112.9, 112.5, 75.6, 65.8, 62.4, 62.0, 61.8, 61.7,
56.8, 56.6, 52.1, 49.2, 39.8; IR (film) 3405, 3092, 3073, 3034, 2934, 2841,
1737, 1606, 1451, 1359, 1050 cmꢀ1; HRMS (ES) calcd for C38H39O14
(MH+) 719.2340, found 719.2334.
7-Benzyloxy-8-methoxy-1-oxo-6-{3-[1,4,5,6,8-pentame-
thoxy-3-(triethyl-silanyloxy)-naphthalen-2-ylmethyl]-4,5-di-
hydro-isoxazol-5-yl}-1H-isochromene-3-carboxylic Acid
Methyl Ester (9tes). To triethyl-[1,4,5,7,8-pentamethoxy-3-(2-nitro-
ethyl)-naphthalen-2-yloxy]-silane7 (0.0079 g, 0.016 mmol) and 2814
(0.008 g, 0.02 mmol) dissolved in PhH (5 mL) were added PhNCO
(0.05 mL, 0.46 mmol) and Et3N (0.01 mL, 0.07 mmol). The mixture was
heated (oil bath, 55 °C) and stirred for 40 h when it was cooled and
concentrated to an orange oil containing a white solid. This residue was
purified by flash chromatography18 (33ꢀ50% EtOAc/hexanes, SiO2) to
give 9tes as an off-white solid (0.0095 g, 70%): Rf = 0.55 (50% EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.31ꢀ7.34 (m,
3H), 7.25ꢀ7.29 (m, 3H), 6.60 (s, 1H), 5.60 (dd, J = 7.2, 11.2 Hz, 1H), 5.17
(d, J = 11.2 Hz, 1H), 5.14 (d, J = 11.1 Hz, 1H), 3.99 (s, 3H), 3.950 (s, 3H),
3.947 (s, 3H), 3.94 (s, 3H), 3.85 (d, J = 15.3 Hz, 1H), 3.79 (d, J = 15.3 Hz,
1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.62 (s, 3H), 3.24 (dd, J = 11.3, 17.5 Hz,
1H), 2.65 (dd, J = 7.2, 17.5 Hz, 1H), 0.91 (t, J = 7.8 Hz, 9H), 0.76 (q, J =
7.9 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 160.9, 158.4, 157.2, 155.0,
153.4, 151.7, 150.8, 150.2, 146.4, 145.1, 142.7, 140.4, 136.7, 136.1, 132.6,
128.8, 128.7, 128.5, 125.7, 121.2, 119.1, 116.6, 113.1, 112.5, 95.4, 76.5, 75.8,
62.4, 62.3, 62.2, 61.8, 57.0, 56.8, 53.0, 45.3, 23.5, 7.0, 5.4; IR (film) 3092,
3065, 2953, 2880, 2845, 1741, 1602, 1455, 1413, 1355, 1058 cmꢀ1; HRMS
(ES) calcd for C44H52NO13Si (MH+) 830.3208, found 830.3185.
7-Benzyloxy-6-[3-(3-hydroxy-1,4,5,6,8-pentamethoxy-
naphthalen-2-ylmethyl)-4,5-dihydro-isoxazol-5-yl]-8-meth-
oxy-1-oxo-1H-isochromene-3-carboxylic Acid Methyl Ester
(9isox). To a stirring solution of 9tes (0.103 g, 0.124 mmol) in MeOH
(10 mL) was added concentrated HCl (0.10 mL). After stirring at rt for
4.5 h, the mixture was poured into water (50 mL) and extracted with
CH2Cl2 (3 ꢁ 40 mL). The combined organic fractions were washed
with brine (100 mL), dried with Na2SO4, and concentrated to a yellow
oil. The residue was taken up in PhH and eluted through a plug of SiO2
(CH2Cl2, Et2O, 15 mm, 1 in.) to give 9isox (0.074 g, 83%) from the
Et2O fraction as a yellow oil: Rf = 0.25 (50% EtOAc/hexanes); 1H NMR
(500 MHz, C6D6) δ 7.35 (s, 1H), 7.20ꢀ7.22 (m, 2H), 7.07ꢀ7.12 (m,
3H), 6.90 (s, 1H), 6.34 (s, 1H), 6.33 (s, 1H), 5.65 (dd, J = 7.4, 11.2 Hz,
1H), 4.93 (d, J = 11.1 Hz, 1H), 4.89 (d, J = 11.1 Hz, 1H), 4.04 (d, J = 14.9
Hz, 1H), 4.00 (d, J = 17 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.69 (s, 3H),
3.56 (s, 3H), 3.54 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.14 (dd, J = 11.5,
17.6 Hz, 1H), 2.70 (dd, J = 7.4, 17.4 Hz, 1H); 13C NMR (125 MHz,
C6D6) δ 161.1, 157.8, 156.9, 155.5, 154.4, 153.4, 151.4, 151.2, 147.3,
145.3, 143.3, 137.8, 136.8, 136.1, 133.3, 129.1, 129.0, 128.9, 125.9, 121.7,
117.3, 115.7, 113.3, 112.7, 77.2, 75.9, 62.8, 62.6, 62.11, 62.07, 57.1, 57.0,
52.4, 45.8, 23.5; IR (film) 3381, 3092, 3034, 2937, 2841, 1741, 1606,
1451, 1359, 1050 cmꢀ1; HRMS (ES) calcd for C38H37NO13Na (MNa+)
738.2162, found 738.2189.
4-(tert-Butyl-dimethyl-silanyloxy)-4-(2-hydroxy-phenyl)-
1-(1,4,5,6,8-pentamethoxy-naphthalen-2-yl)-butan-2-one
(11). Benzyl ether 11benz14 (0.046 g, 0.070 mmol) was dissolved in
EtOAc (8 mL), and the solution was combined with 10% Pd/C (0.040 g),
purged with H2, placed under a H2 atmosphere, and stirred for 14 h. The
mixture was filteredthrougha plugof Celite (EtOAc) and concentrated to
give 11 (0.040 g, 99%) as a yellow oil: Rf = 0.55 (50% EtOAc/hexanes).
The material exists as a 1:0.66:0.2 mixture of inseparable tautomers: 1H
NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.37 (d, J = 7.6 Hz, 0.2H), 7.22
(dt, J= 1.5, 7.8 Hz, 0.66H), 7.13(s, 1H), 7.13 (dt, J= 1.6, 7.7 Hz, 1H), 7.09
(dd, J = 1.4, 7.5 Hz, 0.66H), 6.97 (dd, J = 1.4, 7.5 Hz, 1H), 6.94 (d, J = 8.3
Hz, 0.66H), 6.93 (t, J = 7.7 Hz, 0.2H), 6.88 (dt, J = 0.9, 7.4 Hz, 0.66H),
6.82 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 7, 0.2H), 6.77 (dt, J = 1.0, 7.2 Hz, 1H),
6.77 (s, 0.2H), 6.75 (t, J = 7 Hz, 0.2H), 6.75 (s, 0.66H), 6.75 (s, 0.2H),
6.73 (s, 1H), 6.72 (s, 1H), 5.33 (dd, J = 5.6, 7.6 Hz, 1H), 5.07 (dd, J = 5.9,
10.5 Hz, 0.2H), 4.83 (dd, J = 2.9, 2.9 Hz, 0.66H), 3.99 (s, 0.6H), 3.98
(s, 2H), 3.97 (coincidental s, 5H), 3.95 (s, 0.6H), 3.94 (s, 3H), 3.91
(s, 2H), 3.88 (s, 3H), 3.83 (s, 0.6H), 3.81 (s, 0.6H), 3.80 (s, 3H), 3.79 (s,
2H), 3.76 (s, 2H), 3.74 (d, J = 16.0 Hz, 1H), 3.68 (d, J =16.0Hz, 1H), 3.62
(s, 3H), 3.43 (d, J = 14.0 Hz, 0.2H), 3.40 (d, J = 13.7 Hz, 0.66H), 3.32 (d, J
= 13.6 Hz, 0.66H), 3.21 (dd, J = 7.7, 16.4 Hz, 1H), 3.16 (d, J = 13.9 Hz,
0.2H), 2.87 (dd, J = 5.6, 16.4 Hz, 1H), 2.33 (dd, J = 6.0, 12.5 Hz, 0.2H),
2.26 (dd, J = 2.6, 14.6 Hz, 0.66H), 1.99 (dd, J = 3.5, 14.6 Hz, 0.66H), 1.94
(dd, J = 10.7, 12.4 Hz, 0.2H), 0.94 (s, 1.8H), 0.85 (s, 9H), 0.83 (s, 4H),
0.18 (s, 0.6H), 0.14 (s, 2H), 0.12 (s, 3H), 0.11 (s, 0.6H), 0.09 (s, 2H),
ꢀ0.2 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 206.3, 155.7, 152.8, 152.3,
152.2, 152.1, 152.0, 151.4, 150.2 (2), 149.9, 148.7, 148.5, 148.2, 138.9 (2),
138.8, 130.2, 129.9, 129.2, 128.5, 127.5, 127.1, 127.0, 126.6, 124.0, 123.9,
123.5, 122.5, 121.5, 120.9, 120.6, 120.0, 117.8, 117.6, 117.4, 116.6, 115.0,
114.3, 111.9, 111.8, 110.1, 110.0, 100.0, 99.9, 99.7, 99.4, 99.3, 98.8, 73.1,
66.4, 63.8, 62.5, 62.1, 62.00, 61.97, 57.8, 57.7, 57.5, 57.3, 57.2, 57.1, 57.04,
56.97, 50.1, 46.0, 42.3, 40.9, 39.8, 36.5, 26.1, 25.80, 25.75, 18.3, 18.2, 18.0,
ꢀ4.0, ꢀ4.1, ꢀ4.5, ꢀ4.6, ꢀ5.08, ꢀ5.09; IR (film) 3389, 2953, 2934, 2903,
2856, 1714, 1602, 1459 cmꢀ1; HRMS (ES) calcd for C31H42O8SiNa
(MNa+) 593.2547, found 593.2525.
7,8-Dibenzyloxy-6-[3-(3,4-dibenzyloxy-5,6,8-trimethoxy-
naphthalen-2-ylmethyl)-4,5-dihydro-isoxazol-5-yl]-1-oxo-
1H-isochromene-3-carboxylic Acid Methyl Ester (29). To 2712
(0.0149 g, 0.033 mmol) and 2814 (0.012 g, 0.033 mmol) dissolved in
PhH (4 mL) were added PhNCO (0.04 mL, 0.37 mmol) and Et3N
(0.030 mL, 0.22 mmol). The mixture was heated (oil bath, 70 °C) and
stirred for 16 h, after which it was cooled, filtered through Celite (PhH),
and concentrated to a brown oil. The residue was purified by flash
chromatography (60% EtOAc/hexanes, SiO2) to give 29 (0.0213 g,
70%) as a yellow oil: Rf = 0.30 (50% EtOAc/hexanes); 1H NMR (500
MHz, CDCl3) δ 7.41ꢀ7.43 (m, 2H), 7.26ꢀ7.35 (m, 9H), 7.22 (s, 1H),
6.67 (s, 1H), 5.57 (dd, J = 7.0, 11.2 Hz, 1H), 5.17 (d, J = 10.9 Hz, 1H),
5.14 (s, 2H), 5.12 (d, J = 11.0 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 9H), 3.86
(s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 3.16 (dd, J = 11.3, 17.5 Hz, 1H), 2.57
(dd, J = 7.0, 17.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 160.8, 158.6,
157.2, 154.9, 153.2, 151.4, 150.8, 150.3, 149.0, 145.0, 143.9, 142.6, 137.8,
137.0, 136.8, 132.6, 128.8, 128.7, 128.6, 128.53, 128.51, 128.2, 126.4,
121.2, 120.3, 116.5, 114.6, 112.5, 96.6, 76.4, 75.7, 75.2, 62.5, 62.2, 62.1,
61.0, 57.1, 57.0, 53.0, 45.5, 23.4; IR (film) 3034, 2934, 2841, 1737, 1602,
1455, 1359, 1328 cmꢀ1; HRMS (ES) calcd for C45H43NO13Na (MNa+)
828.2632, found 828.2627.
7-Benzyloxy-6-[1-hydroxy-4-(3-hydroxy-1,4,5,6,8-penta-
methoxy-naphthalen-2-yl)-3-oxo-butyl]-8-methoxy-1-oxo-
1H-isochromene-3-carboxylic Acid Methyl Ester (9). Isoxazo-
line 9isox (0.074 g, 0.103 mmol) was dissolved in THF (3 mL) and
MeOH (3 mL). B(OH)3 (0.0335 g, 0.542 mmol) was dissolved in water
(1 mL), and the solution was added to the stirring mixture along with
Raney Ni (12 drops). The system was purged and stirred rapidly under
an atmosphere of H2 for 5.5 h. The mixture was diluted with EtOAc
(10 mL) and filtered through a plug of Celite (EtOAc). The eluant was
washed with water (25 mL) and brine (25 mL), dried with Na2SO4, and
concentrated to give 9 (0.071 g, 96%) as a yellow oil: Rf = 0.13 (50%
EtOAc/hexanes); 1H NMR (500 MHz, C6D6) δ 7.40 (s, 1H), 7.37 (d,
J = 7.6 Hz, 2H), 7.20 (t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.7 Hz, 1H), 7.05 (s,
1H), 6.51 (s, 1H), 6.34 (s, 1H), 5.68 (dd, J = 1.4, 9.1 Hz, 1H), 5.10 (d, J =
11.0 Hz, 1H), 4.92 (d, J = 10.9 Hz, 1H), 3.93 (s, 2H), 3.78 (s, 3H), 3.74
(s, 3H), 3.61 (s, 3H), 3.59 (s, 3H), 3.56 (s, 3H), 3.46 (s, 6H), 3.02
6496
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ARTICLE
1
7-Benzyloxy-6-[4-(3-benzyloxy-1,4,5,6,8-pentamethoxy-
naphthalen-2-yl)-1-(tert-butyl-dimethyl-silanyloxy)-3-oxo-
butyl]-8-methoxy-1-oxo-1H-isochromene-3-carboxylic Acid
Methyl Ester (30). Isoxazoline 29 (0.0213 g, 0.026 mmol) was
dissolved in THF (3 mL) and MeOH (3 mL). B(OH)3 (0.0322 g,
0.521 mmol) was dissolved in water (1 mL), and the solution was added
to the stirring mixture along with Raney Ni (12 drops, 50% in water).
The system was purged and stirred rapidly under an atmosphere of H2
for 3 h. The mixture was diluted with EtOAc (10 mL), and the solution
was filtered through a plug of Celite (EtOAc). The eluant was washed
with water (25 mL), washed with brine (25 mL), dried with Na2SO4, and
concentrated, yielding 30alc (0.0165 g, 77%) as a yellow-black oil which
was used immediately in the next reaction.
Alcohol 30alc (0.0165 g, 0.0204 mmol) and imidazole (0.012 g, 0.176
mmol) were dissolved in DMF (2 mL). tert-Butyldimethylsilyl triflate
(TBSOTf) (0.030 mL, 0.131 mmol) was added and the mixture was stirred
under an inert atmosphere (N2) for 4 h, after which the mixture was
dilutedwithEtOAc(10mL) andpouredintosaturatedNH4Cl (10 mL). The
aqueous layer was washed with EtOAc (10 mL). The combined organic
layers were washed with saturated NH4Cl (10 mL), washed with brine
(2 ꢁ 10 mL), dried with Na2SO4, and concentrated to an orange-red oil.
The residue was purified by flash chromatography (35% EtOAc/hexanes
SiO2) to give 30 (0.0040 g, 21%) as a yellow oil: Rf = 0.62 (50% EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.43ꢀ7.44 (m, 2H), 7.41 (s,
1H), 7.27ꢀ7.37 (m, 9H), 6.64 (s, 1H), 5.57 (dd, J = 2.8, 8.3 Hz, 1H),
5.17 (d, J = 10.9 Hz, 1H), 5.13 (m, 2H), 5.08 (d, J = 11.1 Hz, 1H), 3.99
(s, 3H), 3.955 (s, 3H), 3.946 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83
(s, 3H), 3.78 (d, J = 16.7 Hz, 1H), 3.71 (d, J = 16.7 Hz, 1H), 3.62 (s, 3H),
2.79 (dd, J = 8.4, 16.6 Hz, 1H), 2.60 (dd, J = 2.9, 16.6 Hz, 1H), 0.84
(s, 9H), 0.00 (s, 3H), ꢀ0.23 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
205.4, 161.1, 157.3, 155.1, 153.2, 151.4, 150.3, 150.2, 149.0, 148.3, 143.6,
142.6, 138.0, 137.1, 136.8, 132.2, 129.0, 128.9, 128.7, 128.6, 128.4, 128.1,
126.4, 122.0, 120.1, 116.0, 114.7, 112.6, 96.7, 75.6, 75.1, 65.8, 62.3, 62.1,
62.05, 62.00, 57.12, 57.07, 53.0, 51.3, 40.5, 26.0, 18.3, ꢀ4.7, ꢀ4.9; IR
(film) 3034, 2934, 2895, 2860, 1741, 1602, 1455 cmꢀ1; HRMS (ES)
calcd for C51H58O14SiNa (MNa+) 945.3494, found 945.3455.
EtOAc/hexanes) to afford 36 (1.92 g, 92%) as a yellow oil: H NMR
(500MHz,CDCl3) δ8.54 (s, 1H), 7.55 (m, 4H), 7.33 (m, 6H), 6.65 (s, 1H),
5.24(s, 2H), 5.06(s, 2H), 4.39(q, J= 7.8 Hz, 2H), 4.04 (s, 3H), 4.01 (s, 3H),
3.79 (s, 3H), 1.35 (t, J = 7.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
166.1, 153.6, 152.0, 149.4, 147.0, 137.9, 137.6, 136.0, 129.0 (2), 128.4 (2),
128.1 (2), 128.1 (2), 127.7, 127.6, 127.3, 123.2, 122.5, 118.8, 94.3, 76.7, 76.0,
62.1, 61.0, 56.8, 55.8, 14.3; IR (film) 2980, 2937, 2845, 1718, 1613 cmꢀ1
;
HRMS (ES) calcd for C30H31O7 (MH+) 503.2075, found 503.2069.
(7,8-Bis(benzyloxy)-1,2,4-trimethoxynaphthalen-6-yl)-
methanol (37). A solution of 36 (1.92 g, 3.82 mmol) in THF (40 mL)
at 0 °C was treated with LiAlH4 (0.850 g, 22.4 mmol). After stirring for
2 h, the mixture was treated with 0.85 mL of H2O, 0.85 mL of 15%
NaOH/H2O, and then 2.55 mL of H2O. After stirring for 10 min, the
mixture was filtered and concentrated to afford 37 (1.76 g, 99%) as a
yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.61 (m, 2H),
7.35 (m, 8H), 6.64 (s, 1H), 5.27 (s, 2H), 5.06 (s, 2H), 4.70 (q, J = 6.3 Hz,
2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.81 (s, 3H), 2.10 (t, J = 6.3 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 152.7, 150.2, 149.5, 145.6, 137.9, 137.4,
136.4, 131.8, 128.9 (2), 128.5 (2), 128.3, 128.2 (2), 128.2 (2), 127.7,
125.1, 119.7, 118.0, 94.4, 76.7, 75.6, 62.5, 62.1, 57.1, 55.8 ; IR (film)
3439, 2937, 2845, 1602 cmꢀ1; HRMS (ES) calcd for C28H29O6 (MH+),
461.1974, found 461.1964.
3,4-Bis(benzyloxy)-5,6,8-trimethoxynaphthalene-2-car-
baldehyde (38). A solution of 37 (1.76 g, 3.82 mmol) in CH2Cl2
(50 mL) was treated with a DessꢀMartin periodinane (2 g, 4.7 mmol).13
After stirring for 1 h, the mixture was diluted with H2O, extracted with
CH2Cl2, dried (Na2SO4), concentrated, and chromatographed (25%
EtOAc/hexanes) to afford 38 (1.5 g, 86%) as a yellow resin: 1H NMR
(500 MHz, CDCl3) δ 10.29 (s, 1H), 8.57 (s, 1H), 7.59 (m, 2H), 7.31 (m,
8H), 6.64 (s, 1H), 5.29 (s, 2H), 5.09 (s, 2H), 4.05 (s, 3H), 4.01 (s, 3H),
3.80 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.9, 154.9, 153.1, 151.0,
146.0, 137.7, 136.6, 136.0, 129.0 (2), 128.7 (2), 128.5 (2), 128.3, 128.3
(2), 127.9, 127.8, 126.6, 121.6, 119.0, 94.1, 76.8, 76.7, 62.2, 56.7, 55.9 ;
IR (film) 2937, 2849, 1687, 1610 cmꢀ1; HRMS (ES) calcd for
C28H27O6 (MH+) 459.1796, found 459.1807.
1-(3,4-Dibenzyloxy-5,6,8-trimethoxy-naphthalen-2-yl)-2-
nitro-ethanol (39). THF (10 mL) and CH3NO2 (2.3 mL, 42.5 mmol)
were combined and cooled in an ice bath. n-BuLi (6.0 mL, 6.6 mmol) was
added dropwise over 15 min. After stirring for an additional 15 min, 38
(0.292 g, 0.637 mmol) dissolved in THF (10 mL) was added and the
mixturewasallowedtowarmtortover 26 h. Thereactionwasquenchedby
the addition of saturated NH4Cl (50 mL) and extractedwith CH2Cl2 (2 ꢁ
50 mL). The organic layers were combined, dried with Na2SO4, and
concentrated. The resultant orange oil was purified by flash chromatogra-
phy (25% EtOAc/hexanes, SiO2) to give 39 (0.286 g, 86%) as a yellow oil
or orange foam: Rf = 0.64 (50% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 8.07 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.32ꢀ7.41 (m, 8H),
6.65 (s, 1H), 5.62 (dd, J = 2.7, 9.3 Hz, 1H), 5.39 (d, J = 11.2 Hz, 1H), 5.21
(d, J = 11.2 Hz, 1H), 5.06 (d, J = 9.8 Hz, 1H), 4.99 (d, J = 9.8 Hz, 1H), 4.49
(dd, J =9.4, 13.2 Hz, 1H), 4.43 (dd, J= 3.0, 13.2 Hz, 1H), 4.03 (s, 3H), 3.99
(s, 3H), 3.83 (s, 3H), 2.86 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 152.9,
150.8, 147.8, 145.7, 137.7, 137.1, 136.1, 129.3, 128.9 (2), 128.8, 128.7,
128.5, 128.1, 125.5, 119.6, 117.0, 94.4, 80.3, 77.0, 75.8, 67.6, 62.4, 57.1,
56.0; IR (film) 3432 (br), 3034, 2937, 2883, 2845, 2250, 1718, 1621, 1602,
1552, 1498, 1455, 1420 cmꢀ1; HRMS (ES) calcd for C29H29NO8Na
(MNa+) 542.1791, found 542.1799.
Methyl 7,8-Bis(benzyloxy)-6-(3-(3-(benzyloxy)-1,4,5,6,8-
pentamethoxy-2-naphthoyl)-4,5-dihydroisoxazol-5-yl)-1-
oxo-1H-isochromene-3-carboxylate (34). A solution of R-nitro-
ketone 3312 (0.070 g, 0.15 mmol) and styrene 2114 (0.10 g, 0.23) in PhH
(6 mL) was treated with phenylisocyanate (0.065 g, 0.60 mmol)
followed by Et3N (0.006 g, 0.03 mmol) and heated at 70 °C for 48 h.
The mixture was cooled, diluted with PhH and hexanes, filtered, and
concentrated. Chromatography (25ꢀ40% EtOAc/hexanes) afforded 34
1
(0.075 g, 56%) as a yellow oil: H NMR (500 MHz, CDCl3) δ 7.56
(m, 2H), 7.38 (m, 6H), 7.29 (m, 4H), 7.21 (m, 4H), 7.15 (s, 1H), 6.69
(s, 1H), 5.65 (dd, J = 8.1, 11.7 Hz, 1H), 5.28ꢀ5.11 (m, 6H), 4.02
(s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.76 (s,
3H), 3.35 (dd, J = 11.7, 16.2 Hz, 1H), 2.91 (dd, J = 8.1, 16.2 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 187.7, 160.5, 159.0, 156.9, 153.8, 153.3,
151.2, 150.5, 146.7, 143.1, 142.8, 142.5, 137.6, 136.7, 136.2, 135.8, 132.5,
129.4 (2), 128.7 (2), 128.7, 128.6, 128.4 (2), 128.4 (2), 128.1 (2), 127.8,
127.7, 127.5 (2), 124.7, 120.5, 120.1, 117.1, 113.9, 112.1, 96.0, 79.8, 76.9,
75.7, 75.2, 64.2, 62.0, 61.9, 56.7, 56.6, 52.8, 40.1; IR (film) 3034, 2937,
2845, 1741, 1679, 1602 cmꢀ1; HRMS (ES) calcd for C51H45NO14Na
(MNa+) 918.2747, found 918.2737.
tert-Butyl-[1-(3,4-dibenzyloxy-5,6,8-trimethoxy-naphtha-
len-2-yl)-2-nitro-ethoxy]-dimethyl-silane (40). Alcohol 39 (0.047g,
0.090 mmol) was dissolved in CH2Cl2 (5 mL), and TBSꢀimidazole
(0.070 mL, 0.361 mmol) was added in one portion. The mixture was
heated to reflux (oil bath, 50 °C) and stirred for 16 h, after which
additional TBSꢀimidazole (0.15 mL, 0.773 mmol) was added. After
stirring at reflux (oil bath, 55 °C) for an additional 24 h, the mixture was
partitioned between CH2Cl2 (10 mL) and water (10 mL). The organic
Ethyl 3,4-Bis(benzyloxy)-5,6,8-trimethoxynaphthalene-2-
carboxylate (36). A solution of 3512 (1.33 g, 4.15 mmol) in PhH
(100 mL) was treated with a saturated solution of Na2S2O4 in H2O
(100 mL). After stirring for 5 min, the mixture was extracted with PhH,
dried (Na2SO4), and concentrated. The resultant oil was dissolved in
acetone (65 mL), and the solution was treated with BnBr (2.4 mL, 19.5
mmol) and K2CO3 (4.5 g, 32.5 mmol). After heating at reflux for 6 h,
the mixture was filtered, concentrated, and chromatographed (10ꢀ25%
6497
dx.doi.org/10.1021/jo200399z |J. Org. Chem. 2011, 76, 6488–6502

The Journal of Organic Chemistry
ARTICLE
layer was dried with Na2SO4 and concentrated. The residual orange oil
was purified by flash chromatography (20% EtOAc/hexanes, SiO2) to
give 40 as a clear, faintly yellow oil contaminated with TBS2O. This
material was eluted through a plug of SiO2 (hexanes, CH2Cl2) to give 40
(0.049 g, 86%) as a clear, faintly yellow oil, still with a small amount of
TBS2O: Rf = 0.69 (33% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 8.15 (s, 1H), 7.58 (d, J = 6.7 Hz, 2H), 7.33ꢀ7.42 (m, 8H), 6.65
(s, 1H), 5.66 (dd, J = 2.4, 9.6 Hz, 1H), 5.40 (d, J = 11.3 Hz, 1H), 5.26 (d,
J = 11.3 Hz, 1H), 5.08 (d, J = 9.8 Hz, 1H), 4.98 (d, J = 9.8, 1H), 4.42
(dd, J = 2.5, 11.9 Hz, 1H), 4.34 (dd, J = 9.6, 11.8 Hz, 1H), 4.04 (s, 3H),
3.99 (s, 3H), 3.84 (s, 3H), 0.89 (s, 9H), ꢀ0.04 (s, 3H), ꢀ0.21 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 153.0, 150.6, 147.4, 145.4, 137.8, 137.3,
136.2, 130.0, 129.4, 129.1, 128.8, 128.6, 128.5, 128.1, 125.3, 119.7, 117.5,
94.4, 81.7, 77.0, 75.6, 68.6, 62.4, 57.2, 56.1, 25.8, 18.3, ꢀ4.7, ꢀ5.4; IR
δ 160.9, 160.5, 160.14, 160.11, 157.4, 157.2, 153.5, 153.2, 153.02, 152.95,
150.9, 150.8, 150.51, 150.47, 148.3, 148.1, 145.8, 145.6, 145.1, 144.7,
142.7, 142.5, 137.8, 137.7 (2), 137.6, 136.6, 136.5, 136.4, 136.3, 136.2,
136.1, 132.7, 132.6, 131.3, 131.1, 129.7, 129.6, 129.3, 129.0, 128.93,
128.87, 128.83, 128.77 (6), 128.7 (3), 128.6, 128.5, 128.4 (2), 128.3,
128.2, 128.0, 127.9, 125.4, 125.3, 121.20, 121.17, 119.70, 119.69, 117.2,
117.0, 116.9, 116.8, 112.4, 112.2, 94.5, 94.4, 77.1, 76.9, 76.8, 76.7, 76.6
(2), 75.91, 75.87, 75.3, 75.1, 65.9, 65.8, 62.5, 62.4, 57.3, 57.2, 56.1 (2),
53.1, 52.8, 41.7, 41.5, 25.9, 25.7, 18.5, 18.3, ꢀ4.7 (2), ꢀ4.8, ꢀ4.9; IR
(film) 3092, 3065, 3034, 2953, 2934, 2887, 2856, 1741, 1602, 1498,
1455 cmꢀ1; HRMS (ES) calcd for C62H63NO13SiNa (MNa+)
1080.3966, found 1080.3926.
7,8-Dibenzyloxy-6-[3-{(3,4-dibenzyloxy-5,6,8-trimethoxy-
naphthalen-2-yl)-hydroxy-methyl}-4,5-dihydro-isoxazol-5-
yl]-1-oxo-1H-isochromene-3-carboxylic Acid Methyl Ester
(44). To 42 (0.0235 g, 0.022 mmol) dissolved in CH3CN (2.5 mL)
in a plastic container was added 49% HF (0.60 mL). The mixture was
stirred at rt for 2.5 h, after which it was diluted with water (10 mL) and
extracted with CH2Cl2 (3 ꢁ 10 mL). The organic layers were combined,
dried with Na2SO4, and concentrated. The residual brown oil was
purified by flash chromatography (50% EtOAc/hexanes after treatment
with 1% water in 50% EtOAc/hexanes, SiO2) to give 44 (0.009 g, 43%)
as a 1:1 mixture of diastereomers: a light yellow oil; Rf = 0.43 (50%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 0.5H), 7.95
(s, 0.5H), 7.21ꢀ7.52 (m, 21.5H), 7.17 (s, 0.5H), 6.66 (s, 0.5H), 6.65 (s,
0.5H), 5.76 (d, J = 5.9 Hz, 0.5H), 5.67 (d, J = 6.3 Hz, 0.5H), 5.62 (dd, J =
7.2, 11.4 Hz, 0.5H), 5.59 (dd, J = 6.9, 11.4 Hz, 0.5H), 5.40 (d, J = 10.8 Hz,
0.5H), 5.27 (d, J = 10.8 Hz, 0.5H), 5.20 (d, J = 10.8 Hz, 0.5H),
4.97ꢀ5.17 (m, 6H), 4.03 (coincidental s, 3H), 3.98 (s, 1.5H), 3.97 (s,
1.5H), 3.95 (s, 1.5H), 3.80 (s, 1.5H), 3.79 (s, 1.5H), 3.16 (dd, J = 11.4,
17.7 Hz, 0.5H), 3.10 (dd, J = 11.6, 17.8 Hz, 0.5H), 3.06 (d J = 6.5 Hz,
0.5H), 3.01 (d, J = 6.0 Hz, 0.5H), 2.57 (coincidental dd, J = 7.1, 17.7 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 160.8, 160.72 (2), 160.68, 157.2
(2), 153.6, 153.5, 153.0 (2), 151.1, 151.0, 150.91, 150.86, 148.6 (2),
146.09, 146.07, 144.5, 144.3, 142.7 (2), 137.72, 137.67, 137.5, 137.3,
136.58, 136.55, 136.2, 136.1, 132.8, 132.7, 129.9 (2), 129.6 (2), 129.14,
129.10, 128.8 (3), 128.74 (2, 128.72, 128.71, 128.68, 128.64 (3), 128.60,
128.48, 128.47, 128.4 (2), 128.1 (2), 126.2 (2), 125.7, 125.6, 121.2,
121.1, 119.7, 119.6, 118.0 (2), 117.5 (2), 117.08, 117.05, 112.5, 112.4,
94.54, 94.47, 77.5, 77.4, 77.1, 77.04, 76.95 (2), 75.9 (2), 75.6 (2), 68.1,
67.5, 62.4 (2), 57.2 (2), 56.1, 56.0, 53.0 (2), 42.9 (2); IR (film) 3486,
3092, 3065, 3034, 2941, 2883, 2845, 1741, 1602, 1498 cmꢀ1; HRMS
(ES) calcd for C56H49NO13Na (MNa+) 966.3102, found 966.3093.
7,8-Dibenzyloxy-6-[3-(3,4-dibenzyloxy-5,6,8-trimethoxy-
naphthalen-2-ylmethyl)-4,5-dihydro-isoxazol-5-yl]-1-oxo-
1H-isochromene-3-carboxylic Acid Methyl Ester (46). To 41
(0.272 g, 0.540 mmol) and 2114 (0.207 g, 0.468 mmol) dissolved in PhH
(22 mL) were added PhNCO (0.26 mL, 2.4 mmol) and Et3N (0.020 mL,
0.14 mmol). The mixture was heated (oil bath, 65ꢀ70 °C) and stirred for
17 h, after which it was cooled, filtered through Celite (PhH), and
concentrated to a dark red oil/foam. The residue was purified by flash
chromatography (20ꢀ33% EtOAc/hexanes then 15% MeOH/CH2Cl2,
SiO2) to give 46 (0.218 g, 50%) as a dark orange foam. The highly
colored impure fractions were taken up in CH2Cl2 (∼30 mL), decolor-
ized with charcoal, dried with MgSO4, filtered through a plug of Celite,
and concentrated to give 46 (0.184 g, 42%) as an orange oil: 1H NMR
(500 MHz, CDCl3) δ 7.79 (s, 1H), 7.50 (m, 4H), 7.29 (m, 18H), 6.64 (s,
1H), 5.60 (dd, J = 6.7, 11.2 Hz, 1H), 5.14 (m, 8H), 4.01 (s, 3H), 3.96 (s,
3H), 3.94 (s, 3H), 3.79 (s, 3H), 3.74 (m, 2H), 3.09 (dd, J = 11.2, 17.8 Hz,
1H), 2.48 (dd, J = 6.7, 17.8 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 160.5, 157.7, 156.9, 153.3, 152.2, 150.8, 150.1, 149.4, 146.0, 144.6,
142.4, 137.6, 137.3, 136.4, 136.3, 136.0, 132.5, 129.3 (2), 128.8 (2), 128.5
(2), 128.4 (4), 128.4 (2), 128.3 (4), 128.2 (2), 128.0, 127.7, 126.6, 124.9,
121.0, 119.7, 119.3, 116.2, 112.2, 94.6, 76.8, 76.6, 76.3, 75.6, 75.3, 62.1,
(film) 3066, 2935, 2896, 2858, 1730, 1599, 1552, 1460, 1359 cmꢀ1
;
HRMS (ES) calcd for C35H44NO8Si (MH+) 634.2836, found 634.2834.
1,2-Bis(benzyloxy)-5,7,8-trimethoxy-3-(2-nitroethyl)naph-
thalene (41). A solution of 38 (0.50 g, 1.1 mmol) in MeNO2 (30 mL)
was treated with NH4OAc (0.02 g, 0.4 mmol). After heating at reflux for
30 min, the mixture was diluted with H2O, extracted with CH2Cl2, dried
(Na2SO4), concentrated, and chromatographed (25% EtOAc/hexanes)
to afford 41ene as yellow resin, which was carried directly to the next step:
1,2-Bis(benzyloxy)-5,7,8-trimethoxy-3-((E)-2-nitrovinyl)naphthalene
1
(41ene): H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 8.18 (d, J =
13.6 Hz, 1H), 7.82 (d, J = 13.6 Hz, 1H), 7.60 (m, 2H), 7.33 (m, 8H), 6.65
(s, 1H), 5.23 (s, 2H), 5.08 (s, 2H), 4.05 (s, 3H), 4.02 (s, 3H), 3.80 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 153.8, 152.8, 149.6, 146.6, 137.9, 137.8,
136.5, 136.4, 135.9, 129.2 (2), 129.1 (2), 128.7 (2), 128.7, 128.5 (2),
128.1, 127.4, 122.5, 122.0, 119.5, 94.6, 76.9, 76.4, 62.4, 57.0, 56.1; IR(film)
2937, 2845, 1606 cmꢀ1; LRMS (ES) calcd for C29H27NO7 (M+)
501.1788, found 501.1787.
A solution of unpurified 41ene in MeOH/CHCl3 (30 mL, 1:1) was
treated with NaBH4 (0.166 g, 4.39 mmol). After stirring 5 min, the
mixture was diluted with H2O, acidified with 1 M HCl (pH 3), extracted
with CH2Cl2, dried (Na2SO4), concentrated, and chromatographed
(25% EtOAc/hexanes) to afford 41 (0.54 g, 98%) as a yellow resin; 1H
NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.57 (m, 2H), 7.35 (m, 8H),
6.64 (s, 1H), 5.27 (s, 2H), 5.06 (s, 2H), 4.54 (t, J = 7.4 Hz, 2H), 4.03
(s, 3H), 3.99 (s, 3H), 3.82 (s, 3H), 3.33 (t, J = 7.4 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 152.3, 150.2, 149.5, 145.7, 137.7, 137.4, 136.3, 128.9 (2),
128.5 (2), 128.3 (2), 128.2 (2), 128.1, 127.8, 126.5, 125.0, 119.6, 119.4, 94.5,
76.7, 75.4, 75.0, 62.1, 57.1, 55.8, 29.6 ; IR (film) 2934, 2849, 1602 cmꢀ1
;
HRMS (ES) calcd for C29H30NO7 (MH+) 504.2027, found 504.2022.
7,8-Dibenzyloxy-6-[3-{(tert-butyl-dimethyl-silanyloxy)-
(3,4-dibenzyloxy-5,6,8-trimethoxy-naphthalen-2-yl)-methyl}-
4,5-dihydro-isoxazol-5-yl]-1-oxo-1H-isochromene-3-carbo-
xylic Acid Methyl Ester (42). To a stirring solution of 40 (0.230 g,
0.363 mmol) and 2114 (0.160 g, 0.362 mmol) in PhCH3 (22 mL) were
added p-NO2PhNCO (0.319 g, 1.94 mmol) and NEt3 (0.02 mL,
0.143 mmol). The mixture was heated (oil bath, 130ꢀ135 °C) and
stirred for 15 h, after which the mixture was cooled, filtered through a
plug of Celite (PhH), and concentrated. The residual red oil was purified
by flash chromatography (25% EtOAc/hexanes, SiO2) to give recovered
40 (0.045 g) and 42 (0.237 g, 62%) as a 1:1 mixture of diastereomers: a
dark yellow foam; Rf = 0.43 (33% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 8.17 (s, 0.5H), 8.14 (s, 0.5H), 7.17ꢀ7.54 (m, 21.5H), 6.94 (s,
0.5H), 6.67 (s, 0.5H), 6.62 (s, 0.5H), 5.95 (s, 0.5H), 5.89 (s, 0.5H), 5.59
(dd, J = 7.0, 11.3 Hz, 0.5H), 5.53 (dd, J = 5.9, 11.2 Hz, 0.5H), 4.94ꢀ5.28
(m, 7H), 4.75 (d, J = 9.6 Hz, 0.5H), 4.61 (d, J = 9.6 Hz, 0.5H), 4.04
(s, 1.5H), 4.00 (s, 1.5H), 3.98 (s, 3H), 3.96 (s, 1.5H), 3.85 (s, 1.5H), 3.83
(s, 1.5H), 3.72 (s, 1.5H), 3.23 (dd, J = 11.3, 17.5 Hz, 0.5H), 2.89 (dd, J =
11.3, 17.4 Hz, 0.5H), 2.57 (dd, J = 6.0, 17.4 Hz, 0.5H), 2.26 (dd, J = 7.0,
17.5 Hz, 0.5H), 0.95 (s, 4.5H), 0.80 (s, 4.5H), 0.09 (s, 1.5H), 0.01 (s,
1.5H), ꢀ0.06 (s, 1.5H), ꢀ0.07 (s, 1.5H); 13C NMR (125 MHz, CDCl3)
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ARTICLE
1
57.1, 55.8, 52.7, 44.6, 28.9 ; IR (film) 3034, 2934, 1741, 1598 cmꢀ1
;
yellow oil: Rf = 0.54 (50% EtOAc/hexane); H NMR (500 MHz,
CDCl3) δ 8.36 (s, 1H), 7.52ꢀ7.53 (m, 2H), 7.45ꢀ7.47 (m, 2H), 7.42
(s, 1H), 7.25ꢀ7.34 (m, 14H), 7.18ꢀ7.19 (m, 3H), 6.64 (s, 1H), 5.53
(dd, J = 3.6, 7.7 Hz, 1H), 5.12ꢀ5.17 (m, 4H), 4.97ꢀ5.04 (m, 4H), 4.04
(s, 3H), 4.00 (s, 3H), 3.96 (s, 3H), 3.74 (s, 3H), 3.11 (dd, J = 7.8, 16.0
Hz, 1H), 2.82 (dd, J = 3.6, 16.0 Hz, 1H), 0.85 (s, 9H), 0.03 (s, 3H),
ꢀ0.23 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.6, 192.9, 161.0,
157.3, 154.7, 153.6, 153.3, 150.7, 149.2, 147.3, 145.7, 142.6, 137.6, 136.9,
136.7, 136.3, 136.2, 132.3, 129.6, 129.1, 129.0, 128.81, 128.78, 128.7 (2),
128.6, 128.51, 128.47, 128.4, 128.2, 128.0, 125.7, 123.5, 122.4, 119.2,
116.7, 112.6, 94.3, 77.1, 76.7, 76.1, 75.7, 65.9, 62.4, 57.0, 56.1, 53.0, 47.0,
26.0, 18.3, ꢀ4.7, ꢀ5.0; IR (film) 3092, 3065, 3034, 2953, 2934, 2887,
2856, 1745, 1671, 1606, 1459, 1351, 1258, 1058 cmꢀ1; HRMS (ES)
calcd for C62H63O14Si (MH+) 1059.3987, found 1059.3967.
3-Benzyloxy-4-hydroxy-5,6,8-trimethoxy-naphthalene-2-
carboxylic Acid Ethyl Ester (55). ortho-Quinone 35 (1.56 g, 4.87
mmol) was dissolved in PhH (250 mL) and combined with 10%
Na2S2O4 (250 mL). The mixture was stirred overnight, changing from
red to bright yellow. The layers were separated, and the aqueous layer
was washed with PhH (100 mL). The combined organic layers were
concentrated to a yellow solid that was used immediately.
The residue was dissolved inthoroughly deoxygenatedDMF(75 mL),
and KHCO3 (3.10 g, 31.0 mmol) and BnBr (1.0 mL, 8.4 mmol) were
added. After stirring for 5 d, the mixture was filtered through a plug of
Celite (EtOAc) and poured into 1 N HCl (250 mL). The layers were
separated, and the aqueous layer was washed with EtOAc (3 ꢁ 200 mL).
The combined organic layers were washed with saturated NH4Cl (2 ꢁ
250 mL), washed with brine (250 mL), dried with Na2SO4, and
concentrated to an oily red solid. This residue was taken up in CH2Cl2
and eluted through a plug of SiO2 (CH2Cl2 then EtOAc, 65 mm, 1 in.) to
give a yellow solid and a red solid, respectively.
The yellow CH2Cl2 fraction was purified by flash chromatography
(33% EtOAc/hexanes, SiO2) to give 55 as a yellow crystalline solid. The
red EtOAc fraction was purified by flash chromatography (33% EtOAc/
hexanes, SiO2) to give 55 as a yellow solid. The impure fractions were
combined and resubjected to flash chromatography (33% EtOAc/
hexanes, SiO2) to give further 55 as an orange solid. The spectral data
of 55 (0.982 g, 49%) were in accord with those reported.12 A small
amount of the isomeric phenol 55iso was isolated as well: 4-Benzyloxy-
3-hydroxy-5,6,8-trimethoxy-naphthalene-2-carboxylic acid ethyl es-
ter, a white crystalline or yellow solid; Rf = 0.48 (33% EtOAc/hexanes);
mp 187ꢀ190 °C; 1H NMR (500 MHz, CDCl3) δ 10.7, (s, 1H), 8.65 (s,
1H), 7.70 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.4 Hz,
1H), 6.52 (s, 1H), 5.06 (s, 2H), 4.49 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H),
4.01 (s, 3H), 3.76 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.3, 154.3, 152.9, 151.2, 139.2, 138.4, 135.3, 129.3, 128.9,
128.4, 127.9, 122.4, 115.9, 112.2, 92.4, 76.2, 62.5, 61.8, 56.8, 56.0, 14.5;
IR (film) 3113, 2981, 2935, 2889, 2850, 1676, 1607, 1460, 1336, 1058,
1012 cmꢀ1; HRMS (ES) calcd for C23H25O7 (MH+) 413.1600, found
413.1601.
HRMS (ES) calcd for C56H50NO12 (MH+) 928.3305, found 928.3333.
7,8-Dibenzyloxy-6-[4-(3,4-dibenzyloxy-5,6,8-trimethoxy-
naphthalen-2-yl)-1-hydroxy-3-oxo-butyl]-1-oxo-1H-isochro-
mene-3-carboxylic Acid Methyl Ester (47). Isoxazoline 46 (0.218 g,
0.235 mmol) was dissolved in THF (12 mL) and MeOH (11 mL).
B(OH)3 (0.284 g, 4.59 mmol) was dissolved in water (6 mL), and the
solution was added to the stirring mixture along with Raney Ni (∼1.5 mL,
50% in water). The system was purged and stirred rapidly under an
atmosphere of H2 for 8 h. The mixture was diluted with EtOAc (40 mL)
and filtered through a plug of Celite (EtOAc). The eluant was washed with
water(50 mL) andbrine(50mL), driedwithNa2SO4, and concentrated to
yield 47 as a brown oil, which was carried on directly without further
purification: 1H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.57 (m, 5H),
7.32 (m, 1H), 7.26 (s, 1H), 7.17 (m, 14H), 6.99 (s, 1H), 6.37 (s, 1H), 5.49
(dd, J = 3.3, 8.5 Hz, 1H), 5.12 (m, 8H), 3.86 (s, 3H), 3.63 (s, 3H), 3.54 (m,
2H), 3.44 (s, 3H), 3.43 (s, 3H), 3.38 (s, 1H), 2.81 (dd, J = 3.3, 17.5 Hz,
1H), 2.62 (dd, J = 8.5, 17.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
207.5, 160.7, 156.8, 153.7, 152.5, 150.9, 150.9, 150.0, 146.5, 146.1, 142.9,
138.4, 138.1, 137.8, 137.2, 137.1, 132.8, 129.4 (2), 129.0 (2), 128.7 (2),
128.7 (2), 128.6 (2), 128.5 (2), 128.5 (2), 128.4, 128.3, 128.2 (2), 128.0,
127.7, 126.0, 125.9, 121.8, 120.7, 120.6, 116.8, 112.2, 96.1, 76.9, 76.5, 75.6,
75.4, 65.6, 61.9, 57.4, 55.3, 52.0, 48.8, 46.3; IR (film) 3462, 3034, 2930,
1737, 1602 cmꢀ1; HRMS (ES) calcd for C56H51O13 (MH+) 931.3353,
found 931.3329.
7,8-Dibenzyloxy-6-[1-(tert-butyl-dimethyl-silanyloxy)-4-
(3,4-dibenzyloxy-5,6,8-trimethoxy-naphthalen-2-yl)-3-oxo-
butyl]-1-oxo-1H-isochromene-3-carboxylic Acid Methyl Es-
ter (48). Alcohol 47 (0.219 g, 0.235 mmol) and imidazole (0.099 g,
1.45 mmol) were dissolved in DMF (21 mL). TBSOTf (0.31 mL,
1.35 mmol) was added, and the mixture was stirred under an inert
atmosphere (N2) for 18 h, after which the mixture was diluted with
EtOAc (75 mL) and poured into saturated NH4Cl (75 mL) and water
(50 mL). The aqueous layer was washed with EtOAc (75 mL). The
combined organic layers were washed with saturated NH4Cl (75 mL)
and brine (2 ꢁ 75 mL), dried with Na2SO4, and concentrated to a brown
solid. The residue was purified by flash chromatography (1% Et2O/
CH2Cl2, SiO2) to give 48 (0.134 g, 55%) as a dark yellow oil or a yellow
foam: Rf = 0.66 (50% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.73 (s, 1H), 7.51ꢀ7.54 (m, 4H), 7.39 (s, 1H), 7.24ꢀ7.35 (m, 17H),
6.62 (s, 1H), 5.54 (dd, J = 2.8, 8.5 Hz, 1H), 5.20 (d, J = 11.2 Hz, 1H),
5.16 (d, J = 10.9 Hz, 1H), 5.13 (d, J = 10.9 Hz, 1H), 5.12 (d, J = 11.4 Hz,
1H), 5.09 (d, J = 10.1 Hz, 1H), 5.03, (d, J = 9.9 Hz, 1H), 5.02 (d, J = 9.7
Hz, 1H), 4.99 (d, J = 9.7 Hz, 1H), 4.01 (s, 3H, 3.97 (s, 3H), 3.95 (s, 3H),
3.79 (s, 3H), 3.74 (d, J = 16.3 Hz, 1H), 3.64 (d, J = 16.3 Hz, 1H), 2.75
(dd, J = 8.6, 16.0 Hz, 1H), 2.45 (dd, J = 3.0, 16.0 Hz), 0.85 (s, 9H), 0.00
(s, 3H), ꢀ0.24 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 205.1, 161.0,
157.4, 153.6, 152.5, 150.4, 150.2, 149.8, 148.1, 146.0, 142.6, 138.0, 137.8,
136.6, 136.4, 136.2, 132.3, 129.7, 129.2, 129.0, 128.8, 128.7, 128.6,
128.52, 128.47 (2), 128.4, 128.1, 127.9, 125.8, 125.2, 122.0, 120.5, 119.8,
116.4, 112.5, 94.4, 76.9, 76.8, 75.7, 75.3, 66.1, 62.4, 57.2, 56.0, 53.0, 50.9,
46.8, 26.0, 18.3, ꢀ4.7, ꢀ5.0; IR (film) 3092, 3065, 3034, 2953, 2934,
2887, 2856, 1745, 1602, 1455, 1440, 1351 cmꢀ1; HRMS (ES) calcd for
C62H64O13SiNa (MNa+) 1067.4014, found 1067.4020.
3-Benzyloxy-4,5,6,8-tetramethoxy-naphthalene-2-carbo-
xylic Acid Ethyl Ester (56). To a stirring solution of 55 (0.227 g,
0.549 mmol) in DMF (24 mL) was added K2CO3 (0.943 g, 6.82 mmol)
and CH3I (0.35 mL, 5.6 mmol). The mixture was stirred at rt for 22 h,
after which it was diluted with EtOAc (75 mL) and filtered through a
plug of Celite. The eluant was washed with 1 N HCl (100 mL), saturated
NH4Cl (100 mL), and brine (100 mL), dried with Na2SO4, and
concentrated to a red oil. This oil was azeotroped with EtOAc (3 ꢁ
50 mL) which upon concentration resulted in 56 (0.233 g, 99%) as
amorphous red solid to a light yellow powder: Rf = 0.44 (33% EtOAc/
hexanes); mp 82ꢀ85 °C; 1H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H),
7.59 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H),
6.62 (s, 1H), 5.22 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 4.00
(s, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR
7,8-Dibenzyloxy-6-[1-(tert-butyl-dimethyl-silanyloxy)-4-
(3,4-dibenzyloxy-5,6,8-trimethoxy-naphthalen-2-yl)-3,4-di-
oxo-butyl]-1-oxo-1H-isochromene-3-carboxylic Acid Meth-
yl Ester (51). To 48 (0.0928 g, 0.0888 mmol) in THF (9 mL) were
added Et3N (0.25 mL, 1.79 mmol) and SeO2 (0.0972 g, 0.876 mmol).
The mixture was heated (65ꢀ70 °C, oil bath) for 2.5 h. The mixture was
cooled, diluted with CH2Cl2 (10 mL), eluted through a plug of SiO2
(CH2Cl2, 0.5 in.), and concentrated to an orange solid. The residue was
taken up in CH2Cl2 and eluted through a plug of SiO2 (0ꢀ50% Et2O/
CH2Cl2), which upon concentration yielded 51 (0.0672 g, 71%) as a
6499
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ARTICLE
(125 MHz, CDCl3) δ 166.4, 153.8, 152.2, 149.3, 148.5, 138.1, 136.2,
128.6, 128.5, 128.0, 127.4, 123.3, 122.4, 119.0, 94.6, 76.1, 62.3, 62.2, 61.2,
57.2, 56.0, 14.5; IR (film) 2980, 2937, 2883, 2841, 1718, 1613, 1594,
1455, 1355 cmꢀ1; HRMS (ES) calcd for C24H27O7 (MH+) 427.1757,
found 427.1750.
(3-Benzyloxy-4,5,6,8-tetramethoxy-naphthalen-2-yl)-
methanol (57). To a stirring solution of 56 (0.233 g, 0.546 mmol) in
THF (5 mL) in an ice bath was added LiAlH4 (0.106 g, 2.79 mmol).
After stirring cold for 2 h, the mixture was quenched by the addition of
water (10 mL). The resultant mixture was diluted with 1 N HCl (20 mL)
and extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic layers
were dried (Na2SO4) and concentrated to a yellow oil. The residue was
organic layers were dried with Na2SO4 and concentrated to a red-orange
oil. The residue was eluted through a plug of SiO2 (25% Et2O/CH2Cl2)
to give 60 (0.380 g, 97%) as a yellow-orange foam: Rf = 0.45 (33%
1
EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.47
(dm, J = 7.1 Hz, 2H), 7.39 (tm, J = 7.2 Hz, 2H), 7.35 (tm, J = 7.1 Hz, 1H),
6.61 (s, 1H), 5.27 (s, 2H), 4.55 (t, J = 7.5 Hz, 2H), 4.00 (s, 3H), 3.97
(s, 3H), 3.94 (s, 3H), 3.89 (s, 3H), 3.32 (t, J = 7.6 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 152.4, 150.4, 149.3, 147.2, 137.8, 136.5, 128.8,
128.5, 128.4, 126.6, 125.1, 119.7, 119.3. 94.8, 75.4, 75.3, 62.2, 62.1, 57.4, 56.0,
29.8; IR (film) 3065, 3030, 2934, 2845, 1621, 1602, 1552, 1498, 1455 cmꢀ1
;
HRMS (ES) calcd for C23H26NO7 (MH+) 428.1709, found 428.1707.
7-Benzyloxy-6-[3-(3-benzyloxy-4,5,6,8-tetramethoxy-
naphthalen-2-ylmethyl)-4,5-dihydro-isoxazol-5-yl]-8-meth-
oxy-1-oxo-1H-isochromene-3-carboxylic Acid Methyl Ester
(61). To 60 (1.3 g, 3.0 mmol) and 2814 (1.101 g, 3.005 mmol) dissolved
in PhH (80 mL) were added PhNCO (1.40 mL, 12.9 mmol) and Et3N
(0.060 mL, 0.43 mmol). The mixture was heated (oil bath, 45ꢀ50 °C)
and stirred for 20 h, whereupon additional PhNCO (0.40 mL, 3.68
mmol) was added to the mixture. After stirring an additional 20 h, the
mixture was cooled, filtered through Celite (PhH), and concentrated to
a dark yellow oil. The residue was purified by flash chromatography
(45% EtOAc/hexanes, SiO2) to give 61 (2.026 g, 86%) as a yellow oil or
foam: Rf = 0.42 (50% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.74 (s, 1H), 7.44 (d, J = 6.9 Hz, 2H), 7.25ꢀ7.34 (m, 10H), 6.61 (s, 1H),
5.60 (dd, J = 7.0, 11.3 Hz, 1H), 5.17 (d, J = 11.0 Hz, 1H), 5.15 (d, J = 10.9
Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.12 (d, J = 11.1 Hz, 1H), 4.00 (s,
3H), 3.95 (s, 3H), 3.944 (s, 3H), 3.942 (s, 3H), 3.874 (s, 3H), 3.867 (s,
3H), 3.72 (s, 2H), 3.10 (dd, J = 11.3, 17.6 Hz, 1H), 2.49 (dd, J = 7.1, 17.6
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 160.8, 158.0, 157.1, 154.9,
152.4, 150.7, 150.3, 149.3, 147.4, 144.8, 142.6, 137.7, 136.7, 136.5, 132.6,
128.8, 128.7, 128.65, 128.59, 128.5, 128.3, 126.7, 125.0, 121.1, 119.8,
119.2, 116.6, 112.5, 94.9, 76.6, 75.8, 75.3, 62.2, 62.1, 62.0, 57.4, 56.0,
53.0, 44.9, 29.1; IR (film) 3065, 3034, 2937, 2907, 2841, 2250, 1737,
1621, 1598, 1455 cmꢀ1; HRMS (ES) calcd for C44H41NO12Na (MNa+)
798.2526, found 798.2544.
eluted through a plug of SiO2 (Et2O) to give 57 (0.209 g, 100%) as a
1
yellow oil: Rf = 0.21 (33% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 7.90 (s, 1H), 7.49 (dm, J = 7.1 Hz, 2H), 7.39 (tm, J = 7.2 Hz,
2H), 7.34 (tm, J = 7.2 Hz, 1H), 6.61 (s, 1H), 5.28 (s, 2H), 4.69 (d, J =
4.8 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.95 (s, 3H), 3.89 (s, 3H), 2.18
(t, J = 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 152.8, 150.3, 149.3,
147.0, 137.8, 136.6, 131.9, 128.8, 128.6, 128.4, 125.2, 119.8, 117.8, 94.7,
75.6, 62.7, 62.2, 62.1, 57.4, 56.0; IR (film) 3447, 3065, 3030, 2934, 2841,
1062, 1498, 1455, cmꢀ1; HRMS (ES) calcd for C22H24O6Na (MNa+)
407.1471, found 407.1475.
3-Benzyloxy-4,5,6,8-tetramethoxy-naphthalene-2-car-
baldehyde (58). To a stirring solution of 57 (0.209 g, 0.544 mmol) in
CH2Cl2 (5 mL) in an ice bath was added DMP (0.246 g, 0.580 mmol) in
one portion. The mixture was stirred cold for 1.1 h, after which it was
filtered through a plug of Celite (CH2Cl2) and concentrated to a red oil.
The residue was suspended in 30% EtOAc/hexanes (5 mL) and
sonicated for 5 min. The resulting suspension was eluted through a
plug of SiO2 (30% EtOAc/hexanes) to give 58 (0.180 g, 87%) as a yellow
crystalline solid: Rf = 0.37 (33% EtOAc/hexanes); mp 120ꢀ124 °C; 1H
NMR (500 MHz, CDCl3) δ 10.29 (s, 1H), 8.53 (s, 1H), 7.47 (dm, J =
6.9 Hz, 2H), 7.38 (tm, J = 7.1 Hz, 2H), 7.33 (tm, J = 7.0 Hz, 1H), 6.62
(s, 1H), 5.29 (s, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.98 (s, 3H), 3.89 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 190.2, 155.1, 153.3, 150.8, 147.4,
137.1, 136.1, 128.83, 128.77 (2), 128.6, 126.7, 121.5, 119.1, 94.3, 76.7,
62.3, 62.2, 57.0, 56.1; IR (film) 3065, 3030, 2937, 2845, 1683, 1606,
1498, 1455, 1351 cmꢀ1; HRMS (ES) calcd for C22H22O6Na (MNa+)
405.1314, found 405.1319.
7-Benzyloxy-6-[4-(3-benzyloxy-4,5,6,8-tetramethoxy-naph-
thalen-2-yl)-1-hydroxy-3-oxo-butyl]-8-methoxy-1-oxo-1H-
isochromene-3-carboxylic Acid Methyl Ester (62). Isoxazoline
61 (0.226 g, 0.291 mmol) was dissolved in THF (9 mL) and MeOH
(9 mL). B(OH)3 (0.0811 g, 1.31 mmol) was dissolved in water (3 mL),
and the solution was added to the stirring mixture along with Raney Ni
(∼1 mL, 50% in water). The system was purged and stirred rapidly
under an atmosphere of H2 for 21 h. The mixture was diluted with
EtOAc (25 mL) and filtered through a plug of Celite (EtOAc). The
eluant was washed with water (70 mL), washed with brine (70 mL),
2-Benzyloxy-1,5,7,8-tetramethoxy-3-(2-nitro-vinyl)-naph-
thalene (59). To a solution of 58 (5.1 g, 13.3 mmol) in CH3NO2
(350 mL) was added NH4OAc (0.381 g, 4.94 mmol). The mixture was
heated to reflux (oil bath, 120 °C) and stirred for 8 h. The mixture was
cooled, and additional NH4OAc (4.22 g, 5.47 mmol) was added. The
mixture was heated to reflux (oil bath, 120 °C) and stirred for 5 h.
The mixture was cooled and partitioned between CH2Cl2 (1.2 L)
and water (1.2 L). The aqueous layer was further extracted with CH2Cl2
(2 ꢁ 600 mL). The combined organic layers were dried with Na2SO4
and concentrated to give 59 (5.6 g, 99%) as a red oil: Rf = 0.37 (33%
dried with Na2SO4, and concentrated to give 62 (0.206 g, 91%) as a
1
yellow oil: Rf = 0.30 (50% EtOAc/hexanes) UV/CAM; H NMR
(500 MHz, CDCl3) δ 7.67 (s, 1H), 7.39ꢀ7.40 (m, 4H), 7.28ꢀ7.35
(m, 8H), 6.60 (s, 1H), 5.29 (dd, J = 2.1, 9.6 Hz, 1H), 5.18 (d, J = 10.9 Hz,
1H), 5.17 (d, J = 11.1 Hz, 1H), 5.13 (d, J = 11.0 Hz, 1H), 5.09 (d, J =
11.1 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 3.88
(s, 3H), 3.87 (s, 3H), 3.63 (d, J = 16.3 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H),
3.53 (s, 1H), 2.76 (dd, J = 2.6, 17.7 Hz, 1H), 2.55 (dd, J = 9.1, 17.8 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 208.9, 160.9, 157.2, 154.8, 152.4,
150.6, 150.3, 149.2, 147.1, 145.8, 142.5, 137.8, 136.7, 136.5, 132.5, 128.9,
128.72, 128.65, 128.6, 128.5, 128.2, 125.3, 125.2, 121.5, 120.1, 119.7,
116.2, 112.6, 94.8, 75.8, 75.1, 65.3, 62.14, 62.08, 62.05, 57.4, 56.0, 53.0,
48.5, 46.3; IR (film) 3478, 3092, 3065, 3034, 2937, 2845, 1733, 1602,
1455 cmꢀ1; HRMS (ES) calcd for C44H42O13Na (MNa+) 801.2523,
found 801.2555.
1
EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 8.15
(d, J = 13.6, 1H), 7.46 (dm, J = 6.9 Hz, 2H), 7.38 (tm, J = 7.1 Hz, 2H),
7.34 (tm, J = 7.0 Hz, 1H), 6.63 (s, 1H), 5.23 (s, 1H), 4.04 (s, 3H), 4.01
(s, 3H), 3.97 (s, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
153.8, 152.8, 149.2, 147.8, 137.9, 136.7, 136.3, 136.0, 129.0, 128.8, 128.7,
127.2, 122.6, 121.8, 119.4, 94.6, 76.0, 62.23, 62.20, 57.0, 56.1; IR (film)
3150, 3107, 3065, 3034, 2937, 2845, 1606, 1509, 1455 cmꢀ1; HRMS
(ES) calcd for C23H24NO7 (MH+) 426.1553, found 426.1598.
2-Benzyloxy-1,5,7,8-tetramethoxy-3-(2-nitro-ethyl)-naph-
thalene (60). To a stirring solution of 59 (0.390 g, 0.917 mmol) in
CH2Cl2 (10 mL) and MeOH (10 mL) in an ice bath, was added NaBH4
(0.0816 g, 2.16 mmol) in one portion. After stirring for 15 min, the now-
yellow mixture was quenched by the addition of 1 N HCl (5 mL) and
partitioned between CH2Cl2 (50 mL) and 1 N HCl (50 mL). The
aqueous layer was washed once with CH2Cl2 (25 mL). The combined
7-Benzyloxy-6-[4-(3-benzyloxy-4,5,6,8-tetramethoxy-naph-
thalen-2-yl)-1-(tert-butyl-diphenyl-silanyloxy)-3-oxo-butyl]-
8-methoxy-1-oxo-1H-isochromene-3-carboxylic Acid Methyl
Ester (63). Alcohol 62 (0.206 g, 0.265 mmol) and imidazole (0.258 g,
6500
dx.doi.org/10.1021/jo200399z |J. Org. Chem. 2011, 76, 6488–6502

The Journal of Organic Chemistry
ARTICLE
3.79 mmol) were dissolved in CH2Cl2 (20mL).tert-Butyldiphenylsilyl triflate
(6.3 mL, 2.5 mmol) in CH2Cl2 and Et3N (0.25 mL, 1.8 mmol) were added,
and the mixture was stirred under an inert atmosphere (N2) and excluded
from light for 21 h. The mixture was filtered through a plug of Celite
(CH2Cl2), washed with 1 N HCl (75 mL) and brine (75 mL), dried with
Na2SO4, and concentrated to a dark orange oil. The residue was purified
by flash chromatography (35% EtOAc/hexanes, SiO2) to give 63 (0.158 g,
59%) as a yellow oil or yellow foam: Rf = 0.61 (50% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ7.54ꢀ7.56 (m, 3H), 7.13ꢀ7.42 (m, 20H), 6.57
(s, 1H), 5.62 (dd, J = 5.6, 5.6 Hz, 1H), 5.07 (d, J = 11.0 Hz, 1H), 5.03 (d,
J = 11.1 Hz, 1H), 4.99 (d, J = 10.8 Hz, 1H), 4.54 (d, J = 10.9 Hz, 1H), 4.00
(s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H),
3.62 (d, J = 16.2 Hz, 1H), 3.50 (d, J = 16.1 Hz, 1H), 2.84 (dd, J = 6.5,
15.6 Hz, 1H), 2.57 (dd, J = 4.5, 15.9 Hz, 1H), 1.05 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 204.7, 161.0, 157.2, 154.9, 152.4, 150.5, 150.2,
149.4, 147.1, 146.5, 142.2, 137.9, 136.9, 136.5, 136.1, 136.0, 133.3, 133.0,
131.9, 130.0, 129.9, 128.6, 128.5, 128.43, 128.37, 128.3, 128.1, 127.8,
127.7, 125.6, 125.0, 122.7, 120.0, 119.7, 115.9, 112.6, 94.6, 75.2, 75.1,
67.1, 62.1, 62.0, 61.9, 57.4, 55.9, 53.0, 50.6, 46.5, 27.2, 19.5; IR (film) 3073,
3034, 2999, 2934, 2895, 2860, 1741, 1602, 1455, 1355, 1073 cmꢀ1; HRMS
(ES) calcd for C60H60O13SiNa (MNa+) 1039.3701, found 1039.3651.
7-Benzyloxy-6-[4-(3-benzyloxy-4,5,6,8-tetramethoxy-naph-
thalen-2-yl)-1-(tert-butyl-diphenyl-silanyloxy)-3,4-dioxo-
butyl]-8-methoxy-1-oxo-1H-isochromene-3-carboxylic Acid
Methyl Ester (64). To 63 (0.482 g, 0.474 mmol) in THF (100 mL)
were added water (0.0847 mL, 4.70 mmol), Et3N (1.30 mL, 9.33 mmol),
and SeO2 (0.519 g, 4.68 mmol). The mixture was heated (55ꢀ60 °C, oil
bath) and stirred for 3 h. The mixture was cooled, diluted with CH2Cl2
(100 mL), eluted through a plug of SiO2 (50% CH2Cl2/Et2O), and
concentrated to a dark yellow oil. The residue was eluted through a plug
of SiO2 (50% Et2O/CH2Cl2) to give 64 (0.466 g, 95%) as a clear yellow
oil: Rf = 0.46 (50% EtOAc/hexanes) UV/CAM; 1H NMR (500 MHz,
CDCl3) δ 8.17 (s, 1H), 7.58ꢀ7.60 (m, 2H), 7.37ꢀ7.43 (m, 6H),
7.27ꢀ7.29 (m, 4H), 7.13ꢀ7.23 (m, 10H), 6.60 (s, 1H), 5.56 (dd, J = 5.4,
5.4 Hz, 1H), 5.00 (d, J = 10.7 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), 4.94 (d,
J = 10.7 Hz, 1H), 4.48 (d, J = 10.9 Hz, 1H), 4.03 (s, 3H), 3.970 (s, 3H),
3.967 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.63 (s, 3H), 3.27 (dd, J = 5.5,
15.4 Hz, 1H), 2.87 (dd, J = 5.3, 15.4 Hz, 1H), 1.08 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 198.9, 193.1, 161.0, 157.2, 154.7, 153.4, 150.7,
148.8, 146.8, 145.6, 142.2, 136.9, 136.2, 136.0, 135.0, 133.3, 132.8, 131.8,
130.1, 129.9, 129.8, 128.8, 128.6, 128.5, 128.4, 128.3, 128.25, 128.21,
127.9, 127.8, 127.7, 125.3, 123.3, 122.9, 119.0, 116.1, 112.8, 94.3, 76.0,
75.2, 67.3, 62.3, 62.2, 61.7, 56.9, 56.0, 53.0, 46.7, 27.2, 19.5; IR (film) 3069,
3034, 2999, 2937, 2891, 2860, 1745, 1606, 1455, 1355, 1069 cmꢀ1; HRMS
(ES) calcd for C60H58O14SiNa (MNa+) 1053.3494, found 1053.3517.
6-[1-(tert-Butyl-diphenyl-silanyloxy)-4-(3-hydroxy-4,5,6,8-
tetramethoxy-naphthalen-2-yl)-3,4-dioxo-butyl]-7-hydroxy-
8-methoxy-1-oxo-1H-isochromene-3-carboxylic Acid Methyl
Ester (65). To a stirring solution of 64 (0.0955 g, 0.0926 mmol) in
EtOAc (11 mL) was added 10% Pd/C (0.0963 g, 0.0905 mmol). The
system was evacuated and purged with H2 and stirred under an atmo-
sphere of the same for 1 h, after which it was eluted through a plug of
packed Celite (EtOAc) and concentrated to yield 65 (0.079 g, 100%) as
an oily yellow-orange foam or a yellow oil: Rf = 0.19 (50% EtOAc/
68.1, 62.4, 62.1, 61.7, 56.8, 56.1, 52.8, 45.4 (DABCO), 42.6, 27.2, 19.5; IR
(film) 3383, 3074, 2943, 2866, 1738, 1622, 1460, 1352, 1074 cmꢀ1; HRMS
(ES) calcd for C46H46O14SiNa (MNa+) 873.2555, found 873.2545.
Tetramethylnaphthyl Spiroketal Ketone (66). To 65
(0.0064 g, 0.0075 mmol) in PhH (3.8 mL) was added TsOH (0.0183
g, 0.096 mmol). The mixture was heated (oil bath, 100ꢀ105 °C) and
stirred for 1 h. The mixture was cooled and partitioned between CH2Cl2
(10 mL) and water (10 mL). The organic layer was dried (Na2SO4) and
concentrated to a brown solid. The residue was eluted through a plug of
SiO2 (25% Et2O/CH2Cl2) to give 66 (0.0054 g, 86%) as a dark yellow
oil or resin: Rf = 0.45 (50% EtOAc/hexanes); 1H NMR (500 MHz, C6D6
as a 4:1 mixture of diastereomers) δ 8.72 (s, 0.25H), 8.65 (s, 1H),
7.80ꢀ7.82 (m, 0.5H), 7.77ꢀ7.79 (m, 2.5H), 7.69ꢀ7.71 (m, 2H), 7.47
(s, 1H), 7.18ꢀ7.23 (m, 6 H), 7.11ꢀ7.14 (m, 2.5H), 7.02 (s, 0.25H), 6.77
(s, 0.25H), 6.09 (s, 0.25H), 6.07 (s, 1H), 5.60 (dd, J = 5.2, 11.7 Hz, 1H),
5.34 (dd, J = 5.5, 5.5 Hz, 0.25H), 3.94 (s, 0.75H), 3.87 (s, 3.75H), 3.81
(s, 3H), 3.80 (s, 0.75H), 3.70 (s, 3H), 3.46 (s, 0.75H), 3.45 (s, 3H), 3.42
(s, 3.75H), 3.29 (s, 0.75H), 3.27 (s, 3H), 2.66 (dd, J = 12.3, 12.9 Hz, 1H),
2.42 (dd, J = 6.0, 14.2 Hz, 0.25H), 2.39 (dd, J = 5.1, 14.3 Hz, 0.25H), 2.26
(dd, J = 5.5, 13.1 Hz, 1H), 1.22 (s, 2.25H), 1.18 (s, 9H); 13C NMR
(125 MHz, C6D6 for the major diastereomer) δ 193.1, 161.0, 156.4,
155.82, 155.78, 154.6, 150.8, 147.6, 142.8, 138.3, 137.5, 136.41, 136.37,
136.3, 136.2, 135.6, 133.6, 133.1, 131.6, 130.7, 130.6, 130.55, 130.50,
128.6, 128.5, 120.4, 118.5, 112.1, 103.7, 94.1, 64.7, 61.95, 61.90, 61.7,
56.5, 55.4, 52.1, 35.1, 27.3, 19.7; IR (film) 3073, 2934, 2860, 1741, 1625,
1590, 1459 cmꢀ1; HRMS (ES) calcd for C46H44O13SiNa (MNa+)
855.2449, found 855.2424.
Tetramethylnaphthyl Spiroketal Ketone Alkene (67). Iso-
lated as a yellow or orange oil in trace amounts (<5%) from the above
1
protocol: Rf = 0.22 (50% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 8.59 (s, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 7.14 (d, J = 9.8
Hz, 1H), 6.59 (s, 1H), 6.06 (d, J = 9.8 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 3H),
3.95 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 1.53 (water), 1.26
(grease); 13C NMR (125 MHz, CDCl3) δ 193.6, 161.0, 156.9, 156.2,
155.7, 154.7, 150.4, 145.7, 142.5, 137.3, 136.3, 131.3, 130.9, 128.7, 126.7,
121.2, 121.0, 119.9, 119.4, 117.0, 116.0, 112.1, 101.0, 93.3, 62.6, 62.4,
62.2, 56.8, 56.2, 53.1, 29.9 (grease); IR (film) 2957, 2918, 2853, 1733,
1625, 1586, 1459 cmꢀ1; HRMS (ES) calcd for C30H24O12Na (MNa+)
599.1165, found 599.1160.
Hydroxyl Spiroketal (68). To a stirring solution of 66 (0.0096 g,
0.0115 mmol) in MeOH (1.5 mL) and CH2Cl2 (2 mL) in an ice bath
was added NaBH4 (0.0040 g, 0.106 mmol) dissolved in MeOH
(0.5 mL). After stirring for 10 min, the mixture was quenched by the
addition of 1 N HCl (10 mL) and partitioned with CH2Cl2 (10 mL).
The organic layer was dried with Na2SO4 and concentrated to a yellow
film. This residue was purified by flash chromatography (50% EtOAc/
hexanes, SiO2) to give 68 (0.0032 g, 33%) as a faintly yellow film: Rf =
0.77 (2.5% MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3 for the major
diastereomer) δ 8.12 (s, 1H), 7.74ꢀ7.79 (m, 4 H), 7.40ꢀ7.49 (m, 6H),
7.27ꢀ7.29 (m, 2H), 6.58 (s, 1H), 5.45 (dd, J = 6.4, 10.1 Hz, 1H), 5.18
(s, 1H), 3.98 (coincidental s, 6H), 3.95 (s, 3H), 3.77 (s, 3H), 3.66
(s, 3H), 3.64 (s, 3H), 2.46 (dd, J = 10.2, 13.2 Hz, 1H), 2.41 (dd, J = 6.5,
13.3 Hz, 1H), 1.20 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 161.2,
157.1, 152.9, 150.9, 150.1, 146.94, 146.85, 142.0, 136.83, 136.80, 136.2,
136.1 (2C), 133.3, 132.5, 130.6, 130.5, 129.8, 128.3, 128.2, 127.0, 126.1,
121.0, 119.8, 116.1, 114.6, 112.7, 109.0, 93.7, 64.7, 62.1, 62.03, 61.96,
57.1, 56.0, 53.0, 36.7, 29.9, 27.3, 19.7; IR (film) 3429, 2935, 2858, 1746,
1614, 1460, 1336, 1251, 1112 cmꢀ1; HRMS (ES) calcd for C46H47O13Si
(MH+) 835.2786, found 835.2772.
1
hexanes); H NMR (500 MHz, CDCl3 with DABCO17) δ 8.28 (br s,
1H), 7.72 (d, J = 6.7 Hz, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.3 Hz,
1H), 7.41 (br s, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.27 (br t, 1H), 7.17 (br t,
J = 6.8 Hz, 2H), 6.92 (s, 1H), 6.47 (s, 1H), 5.70 (br s, 1H), 4.01 (s, 3H),
3.95 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H), 2.85
(br s, 1H), 2.77 (DABCO), 2.62 (br s, 1H), 1.26 (s, 9H); 13C NMR (125
MHz, CDCl3 with DABCO17) δ 196.8, 160.9, 157.3, 155.6, 154.1, 149.2,
147.9, 140.8, 138.1, 137.8, 136.2, 135.9, 135.8, 135.0, 132.7, 132.4, 130.4, 130.1,
128.0, 127.9, 127.7, 123.3, 118.1, 116.5, 114.7, 112.9, two aromatic carbons
and the hemiketal signal could not be resolved from the baseline, 92.8,
Spiroketal Thiopropane (70a). To a stirring solution of 66
(0.0062 g, 0.0074 mmol) in CH2Cl2 (2.5 mL) in an ice bath were added
propanedithiol (0.0120 mL, 0.120 mmol) and BF3 Et2O (0.0150 mL,
0.118 mmol). The mixture was slowly warmed to rt. After stirring for 1 d,
additional dithiane (0.0120 mL, 0.120 mmol) and BF3 etherate
6501
dx.doi.org/10.1021/jo200399z |J. Org. Chem. 2011, 76, 6488–6502

The Journal of Organic Chemistry
ARTICLE
(0.0300 mL, 0.237 mmol) were added. After another 1 d, the mixture
was diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3
(10 mL) and brine (10 mL). The organic layer was dried overnight with
Na2SO4 and concentrated to a yellow oil.
provided by the NMR and Mass Spectrometry facilities at the
University of Pennsylvania, with partial support from the NIH
(1S10RR023444, 1S10RR022442) and NSF (CHE 0840438).
We thank Scott Allen for assistance with the calculations.
This residue was dissolved in THF (1 mL) and MeOH (1 mL) to
which was added B(OH)3 (0.0112 g, 0.181 mmol) dissolved in water
(0.33 mL), followed by Raney Ni (6 drops, ∼0.3 mL). The system was
evacuated and purged with H2 and stirred under an atmosphere of the
same for 18 h. Additional Raney Ni (3 drops, ∼0.15 mL) was added, and
stirring under H2 was continued for 7 h. The mixture was diluted with
EtOAc (5 mL) and eluted through a plug of Celite (EtOAc). The eluant
was washed with water (10 mL) and brine (10 mL), dried with Na2SO4,
and concentrated to a yellow oil. This residue was purified by flash
chromatography (SiO2, 33% EtOAc/hexanes) to give a single diaster-
eomer of 70a (0.001 g) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ
7.95 (s, 1H), 7.56 (d, J = 6.8 Hz, 2H), 7.46 (d, J = 7.3 Hz, 2H), 7.34 (t, J =
7.4 Hz, 1H), 7.14ꢀ7.22 (m, 6H), 7.10 (d, J = 2.0 Hz, 1H), 6.46 (d, J =
2.2 Hz, 1H), 5.58 (t, J = 6.2 Hz, 1H), 4.06 (s, 3H), 3.99 (s, 3H), 3.96
(s, 3H), 3.92 (s, 3H), 3.89ꢀ4.00 (m, 2H), 3.84 (s, 3H), 3.51 (dd, J = 6.1,
14.1 Hz, 1H), 3.34 (dd, J = 6.3, 14.1 Hz, 1H), 2.55 (t, J = 7.3 Hz, 2H),
1.40 (sextet, J = 7.3 Hz, 2H), 1.08 (s, 9H), 0.86 (t, J = 7.3 Hz, 2H); IR
(film) 3074, 2927, 2858, 1738, 1622, 1460 cmꢀ1; HRMS (ES) calcd for
C48H51O11SSi (MH+) 863.2921, found 863.2906.
Spiroketal Ketone Quinone (71). To a stirring solution of 77
(0.0360 g, 0.0432 mmol) in CH3CN (7 mL) and water (0.7 mL) in an
ice bath was added DDQ (0.0110 g, 0.0485 mmol). The mixture was
warmed to rt over 18 h. Additional DDQ (0.0096 g, 0.0423 mmol) was
added, and after 3 h the mixture was poured into saturated NaHCO3
(25 mL) and extracted with EtOAc (2 ꢁ 20 mL). The combined organic
layers were washed with brine (20 mL), dried with Na2SO4, and
concentrated to a red oil. The residue was purified by flash chromatog-
raphy (60% EtOAc/hexanes, SiO2) to give 71 (0.0184 g, 53%) as a dark
yellow oil: Rf = 0.29 (50% EtOAc/hexanes); 1H NMR (500 MHz, C6D6
as a 4:1 mixture of diastereomers) δ 8.32 (s, 0.25H), 8.19 (s, 1H),
7.65ꢀ7.76 (m, 5H), 7.50 (s, 1H), 7.12ꢀ7.23 (m, 8.5H), 7.00 (s, 0.25H),
6.66 (s, 0.25H), 5.694 (s, 0.25 H), 5.689 (s, 1H), 5.41 (dd, J = 5.4, 11.9
Hz, 1H), 5.14 (dd, J = 4.9, 5.2 Hz, 0.25H), 3.83 (s, 3H), 3.80 (s, 0.75H),
3.78 (s, 0.75H), 3.53 (s, 3H), 3.43 (s, 3H), 3.42 (s, 0.75H), 2.90 (s, 3H),
2.89 (s, 0.75H), 2.45 (dd, J = 12.7, 12.7 Hz, 1H), 2.23 (dd, J = 5.4, 14.6
Hz, 0.25H), 2.18 (dd, J = 4.7, 14.5 Hz, 0.25H), 2.11 (dd, J = 5.4, 13.3 Hz,
1H), 1.17 (s, 11.25H); 13C NMR (125 MHz, CDCl3) δ 193.1, 182.3,
178.1, 166.0, 161.7, 161.4, 156.7, 151.2, 147.3, 147.1, 143.7, 136.81,
136.80, 136.7, 136.6, 135.8, 133.8, 133.1, 131.6, 131.4, 131.2, 130.7,
130.3, 123.1, 120.7, 119.3, 112.3, 109.4, 104.4, 64.7, 62.4, 61.6, 56.1, 52.7,
35.1, 27.7. 20.2; IR (film) 3074, 3012, 2943, 2896, 2858, 1746, 1692,
1653, 1607, 1468, 1205, 1112 cmꢀ1; HRMS (ES) calcd for C44H38O13SiNa
(MNa+) 825.1979, found 825.1999.
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’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data includ-
b
ing H and 13C NMR spectra. Coordinates of calculated struc-
1
tures. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Email: marisa@sas.upenn.edu.
’ ACKNOWLEDGMENT
Financial support was provided by the American Cancer
Society (RSG-02-137-01-CDD). Instrumentation support was
6502
dx.doi.org/10.1021/jo200399z |J. Org. Chem. 2011, 76, 6488–6502