A concise synthesis of the naphthalene portion of purpuromycin

Article abstract of DOI:10.1021/jo7024114

(Chemical Equation Presented) A concise synthesis of naphthalene compounds for incorporation into a synthetic sequence for the rubromycin family of natural products is presented. These highly substituted naphthalenes are generated in seven and nine steps,

Full text of DOI:10.1021/jo7024114

A Concise Synthesis of the Naphthalene Portion of Purpuromycin
Andrew N. Lowell, Michael W. Fennie, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104-6323
marisa@sas.upenn.edu
ReceiVed NoVember 8, 2007
A concise synthesis of naphthalene compounds for incorporation into a synthetic sequence for the
rubromycin family of natural products is presented. These highly substituted naphthalenes are generated
in seven and nine steps, respectively, from 2,4,5-trimethoxybenzaldehyde. Three ring-forming methods
were explored and the controlled oxygenation of different positions was investigated to yield differentially
substituted/protected systems. Key steps to the final products include a Stobbe condensation to form the
ring system and a novel series of regioselective oxidations to introduce the required oxygen functionality.
These naphthalene products incorporate orthogonal protecting groups and are suitable for combination
with a variety of coupling partners.
Introduction
and heliquinomycin,28-30 and has attracted considerable attention
due to their structural complexity and significant biological
profiles. For example, antibacterial31-36 and antifungal31-35
properties have been reported leading to clinical use.36,37 In
Purpuromycin1,2 (1, Figure 1), a member of the rubromycin
family of bisbenzannulated spiroketals, is a highly functionalized
and oxygenated molecule. This group of natural products,
(Figure 1) also includes the rubromycins,3-8 griseorhodins,9-27
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FIGURE 1. The rubromycin family of bisbenzannulated spiroketals.
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10.1021/jo7024114 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/08/2008
J. Org. Chem. 2008, 73, 1911-1918
1911

Lowell et al.
addition, their activities against reverse transcriptase,38,39 DNA
helicase,40 and human telomerase39 indicate that this unique
structural type has potential as anti-retroviral or anti-cancer
agents.
in the elegant reports of Danishefsky and co-workers58,59 and,
most recently, of Kita and co-workers.60 Even so, a convergent
and broadly applicable synthesis remains elusive and drives
further study of these intriguing compounds.
Construction of the naphthazarin41-44 and isocoumarin45-48
(Figure 1) portions of this family of molecules has been reported
previously by us and others and has recently been reviewed.49
The formation of the spiroketal subunit has been investigated
in several systems.44,50-57 Further, two members of this class
of natural products have succumbed to total synthesis as outlined
In particular, the naphthazarin subunit is challenging due to
its highly substituted and highly oxygenated nature. All ap-
proaches have generated this subunit in the reduced naphthalene
form and then oxidized to the naphthazarin at an appropriate
stage. Surprisingly, general strategies toward highly substituted
naphthalenes remain absent. Rather, specific strategies are
required depending upon the precise position and constitution
of functionality.61-63 Our goal was to develop a synthetic
strategy to the rubromycin naphthalene that is short and efficient.
To maximize convergency and analogue production, we wished
to generate the entire subunit prior to incorporation into the
natural product precursor. Finally, a route that permits produc-
tion of large quantities of material as well as variants for use in
analogue studies is desired.
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Herein we report a concise synthesis that produces the desired
pattern of seven protected substituents on a naphthalene ring
system in 45% yield over seven steps. Further chemistry can
transform a residual ester group into the appropriate functionality
for any coupling mode desired. Our work has focused primarily
on a [3+2] cycloaddition coupling strategy44,50 (Figure 2). This
allows coupling between an isocoumarin bearing a styrene and
a naphthalene with a pendant nitro group giving an isoxazoline.
Cleavage of the isoxazoline ring reveals a â-hydroxyketone,
the functionality needed for the core of purpuromycin. Elucida-
tion to a variety of nitro-derived naphthalenes can easily be
accomplished from the aldehyde (2, Figure 3) by means of a
Henry condensation. Modifications of the Henry protocol can
give different functionality at the benzylic position. This
synthesis is applicable to all members of this family as they
share the same naphthazarin ring system; unveiling the naph-
thazarin from the naphthalene is straightforward and involves
late-stage treatment with a Lewis acid followed by exposure to
air.64,65
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Results and Discussion
Our initial work described a Do¨tz benzannulation42 approach
to the functionalized naphthalene. This, however, proved
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Synthesis of the Naphthalene Portion of Purpuromycin
prepared in 4 steps.66,67 Benzyne generation followed by reaction
with 2-methoxyfuran (5) gives pentamethoxynaphthalene species
6 after protection.68 We now planned to regioselectively install
the desired aldehyde functionality at the C3 position using the
C7 methoxy ether as a directing group as there is good precedent
for reactions of this type.69,70 Gratifyingly, Vilsmeier formylation
gave naphthaldehyde 7.41 In spite of strong precedent,71,72
selective deprotection directed by the aldehyde failed. Instead
of naphthol 8, we saw a mixture of naphthols. As a result, the
quinone intermediate 9 needed for the Michael/oxidation
sequence to introduce the C2 oxygenation is not accessible via
this route.
SCHEME 1. The Attempted Synthesis of Target Aldehyde
2 from Vanillin
FIGURE 2. Retrosynthesis to a nitroalkane and styrene.
Our next approach attempted to generate the entire substitu-
tion pattern in the ring-forming reaction to avoid problems
during substituent introduction. A report by Sartori and co-
workers73 showed that related oxygen-rich naphthalene systems
could be formed via a Friedel-Crafts acylation process. In our
hands, acylation of 1,2,4-trimethoxybenzene (10, Scheme 2)
proceeded well to form â-ketoester 11. Lewis acid-catalyzed
condensation of 11 with oxalyl chloride gave intermediate 12,
which then underwent intramolecular acylation to form the
oxygenated naphthalene ring system 13. In contrast to the closely
related dimethoxy analogue,73 the Lewis acid also promoted
cleavage of the methyl ethers. While the desired product 13
did form in approximately 10% yield, the majority of the
material was a mixture of quinones 14a and 14b, the products
of further deprotection.
FIGURE 3. Nitroalkane precursors.
capricious and a more reliable route was sought. In our prior
work,44 a cycloaddition and Claisen condensation provided a
naphthalene with symmetrically protected benzyl alcohols at
the C2 and C3 positions (Figure 3, this numbering system will
the used throughout the paper). Differentiation was affected by
treatment with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),
which oxidized the more electron rich C3 benzylic alcohol as
directed by the C7 methoxy group. Subsequent chemistry at
the C2 position terminated with a Dakin oxidation and protection
of the resulting phenol as a triethylsilyl ether.
Both of our prior approaches exploited electronic aspects of
the naphthalene system to differentiate the C2 and C3 positions.
While successful, the necessary oxidative cleavage of the
undesired carbon substituent to reveal a C2 hydroxyl was
difficult as the material readily oxidized to a naphthaquinone.
Also, protection of the spiroketalizing phenol as the triethylsilyl
ether44 did not prove to be as robust as we had hoped.
Although the above route could not produce the desired
coupling partner, it directed our thinking toward a similar
disconnection. In particular, the use of a facile naphthalene
(66) Dorn, H. W.; Warren, W. H.; Bullock, J. L. J. Am. Chem. Soc.
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To circumvent these problems, we began investigating a late-
stage formylation of an electron-rich naphthalene system
(Scheme 1) wherein the same electronic features are used to
direct substitution of the C2 and C3 positions. Starting from
vanillin (3), 5,6-dibromo-1,2,4-trimethoxybenzene (4) can be
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Org. Chem. 1993, 58, 840-843.
J. Org. Chem, Vol. 73, No. 5, 2008 1913

Lowell et al.
SCHEME 2. Investigation of the Friedel-Crafts Acylation
Method
Initially, direct generation of p-quinone (19) was attempted
as there was precedent for this type of transformation.75
Installation of the necessary oxygenation pattern (18) was
successful using phenyliodonium bis(trifluoroacetate) (PIFA).76
However, further transformation to quinone 19 was unsuccessful.
Tautomerization of 18 is likely slow due to the stable double
conjugation of the alkene in the right-hand ring with the ketone
and ester groups. Apparently, oxidation of the trimethoxy-
substituted ring is competitive with this tautomerization, which
is needed for oxidation to p-quinone 19. Examination of other
oxidants revealed that the cobalt(II) salen complex (Co-salen)77
elicited selective oxidation to o-quinone 20ox in good yield. In
the hope of initiating a Michael addition into the quinone system
and trapping the resultant catechol as the dianion, this material
was treated with basic methanol. While the methanol adduct
21 did form as observed by 1H NMR spectroscopy, dianion 21
could not be achieved, even under more forceful conditions
(reflux).
SCHEME 4. Protected Para Oxidation Attempts
SCHEME 3. Unprotected Para Oxidation Attempts
This dilemma was resolved by first reducing o-quinone 20ox
to catechol 20red (Scheme 4) and selectively protecting in situ.
While methods exist for the selective protection of catechols
adjacent to electron-withdrawing groups,78 we have seen
superior results when using potassium bicarbonate, a weak base
with a noncoordinating counterion. This protocol allowed
selective benzylation of the more acidic C2 position of 20red
yielding naphthol 23. Unfortunately, treatment with PIFA did
not introduce oxidation at C4; only reversion to o-quinone 20ox
occurred (Figure 4).
synthesis was a focus. The synthesis of naphthols from aryl
aldehydes via a Stobbe condensation/cyclization sequence is
such a process and, to our delight, had previously been
elucidated by Green and co-workers.74 A modification of their
protocol readily gave us 17 (Scheme 3) in two steps and up to
81% yield from commercially available 2,4,5-trimethoxyben-
zaldehyde (15). Compound 17 bears the needed methoxy
substitution, an ester where we desire a carbon chain, and, most
importantly, a free C1 naphthol that can be used to direct further
oxidation. The use of a Stobbe product, however, would require
development of selective oxygenation conditions.
FIGURE 4. Competing oxidation pathways.
At this point, a review of the results was instructive. Oxidation
to the p-naphthaquinone could not be achieved on any com-
pound bearing an oxygen functionality at the C2 position;
intramolecular reaction from the C2 position to form the
o-naphthaquinone was more rapid than introduction of an
external nucleophile at C4 (Figure 4). Nor could p-naph-
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1914 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of the Naphthalene Portion of Purpuromycin
thaquinone formation be affected directly from a compound
without C2 oxygenation (that is, naphthol 17); this oxidation
stalled due to the stability of the pseudohydroquinone (18,
Scheme 3) as illustrated above. To circumvent these issues, we
proposed that formation of the methoxy analogue of 18 (25,
Scheme 5) would permit controlled tautomerization at C4 prior
to oxidation. Thus, the PIFA oxidation was reexamined, but
with methanol instead of water.
benzylic alcohol 30 and subsequent Dess-Martin periodinane
(DMP)82 oxidation was undertaken. Treatment of 2 under Henry
conditions provided â-hydroxynitro 31. Notably, a large excess
of the lithium salt of MeNO2 was required. These conditions
limited elimination to 33 and subsequent conjugate addition of
a second molecule of MeNO2. Since the hydroxyl group of 31
was incompatible with the planned [3+2] cycloaddition (Figure
2), protection as a silyl ether (35) was investigated. While we
have seen success on other substrates, elimination or decom-
position was the only product due to the steric hindrance of the
position and the high acidity of the proton adjacent to the nitro
group. Oxidation of 31 to â-ketonitro 32 was successful, but
even with mild conditions (DMP) a small amount (9%) of 33
was produced. The formation of nitroalkene 33 could be
optimized as we have shown previously.44 As such, byproduct
33 was also transformed into a coupling partner (34) by
conjugate reduction with NaBH4.
SCHEME 5. Construction of Ester 29
SCHEME 6. Synthesis of Aldehyde 2 and Completion of
Nitro Coupling Partners
As anticipated, this oxidation installed a methyl ether in the
C4 position to yield 25 (Scheme 5). Over oxidation is typical
in such systems, but did not occur here due to the resistance of
pseudohydroquinones to tautomerization as discussed above.
Screening of tautomerization conditions revealed that t-BuOK
in ethanol provides naphthol 26 in good yield. o-Iodoxybenzoic
acid (IBX),79,80 an oxidant that regioselectively forms o-quinones
via an intramolecular transfer, was examined. Even though IBX
is reported to fail when electron-withdrawing groups are present,
we believed that the four electron-donating alkoxy groups would
offset the ester. Indeed, o-quinone 27 was formed in high yield.
With all needed oxygen functionality in place, selective ben-
zylation, again mediated by potassium bicarbonate, was applied
to furnish 28 in moderate yields. Finally, methylation provided
fully protected naphthalene 29 in 45% yield over seven steps.
With subunit 29 available on scale, we turned toward
introducing the desired nitro group (Figure 3) to enable a [3+2]
cycloaddition (Figure 2). Direct attack on the ester with the
dianion of nitromethane (29, Scheme 6) as demonstrated by
Seebach and co-workers81 was first examined. Ester 29 was
fairly unreactive under these conditions, presumably due to steric
bulk (bis-ortho substitution) around the electrophilic center.
Barring this route, a Henry reaction was investigated to generate
the necessary nitro derivative. Direct formation of aldehyde 2
could not be achieved with DIBAL. Thus, reduction to the
Conclusions
We have shown that the naphthalene portion of purpuromycin
can be efficiently synthesized with orthogonal protection.
Construction of 29 bearing an ester group at the C3 chain
attachment point was affected in seven steps and a 45% yield
permitting facile access to gram quantities of material. Aldehyde
2 was synthesized in two additional steps (overall yield of 27%
for nine steps). Compared to our prior approaches to similar
structures,42,44 this approach is much shorter and provides the
oxygenation pattern without resorting to an oxidative C-C bond
cleavage. This route also offers improvement over alternative
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J. Org. Chem, Vol. 73, No. 5, 2008 1915

Lowell et al.
CDCl3) δ 9.68 (s, 1H), 8.42 (d, J ) 1.7 Hz, 1H), 7.44 (d, J ) 1.6
Hz, 1H), 6.64 (s, 1H), 4.40 (q, J ) 7.1 Hz, 2H), 4.02 (s, 3H), 4.012
(s, 3H), 4.006 (s, 3H), 1.42 (t, J ) 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 166.7, 154.2, 153.2 (2), 149.2, 126.6, 121.8, 120.5,
116.5, 110.4, 95.4, 62.2, 60.9, 57.0, 55.9, 14.4; IR (film) 3277,
2988, 2949, 2841, 1702, 1613, 1451 cm-1; HRMS (CI) calcd for
C16H19O6 (MH+) 307.1182, found 307.1168.
syntheses where aldehyde 2 was synthesized in 9% yield over
12 steps.43 The high efficiency of this route permits ready entry
into the intermediates needed in our work as well as that of
others.43,52,54-56 For example, 2 g of aldehyde 2 could be
produced from 10 g of 2,4,5-trimethoxybenzaldehyde in less
than two weeks. The synthetic schemes herein are amenable to
many other naphthalene oxygenation patterns. From aldehyde
2, suitable nitro analogues were synthesized. These are easily
coupled to an isocoumarin portion with a pendant styrenyl
moiety via [3+2] cycloaddition chemistry.44,50 The advanced
intermediates generated will be used to further explore spiroket-
alization modes for purpuromycin and other members of this
natural product family.
Ethyl 3,4-Dihydro-5,6,8-trimethoxy-3,4-dioxonaphthalene-2-
carboxylate (20ox). To a solution of 17 (0.500 g, 1.63 mmol) in
CH3CN (160 mL) was added Co-salen77 (0.200 g, 0.615 mmol).
O2 was bubbled through the mixture for 5 min after which it was
stirred for 12 h. The mixture was concentrated and recrystallized
from hot MeOH to afford a red solid in 91% yield (0.476 g, 1.49
1
mmol): mp 189-192 °C; H NMR (500 MHz, CDCl3) δ 8.70 (s,
1H), 6.67 (s, 1H), 4.35 (q, J ) 7.1 Hz, 2H), 3.98 (s, 3H), 3.97 (s,
3H), 3.87 (s, 3H), 1.37 (t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 179.2, 177.8, 164.2, 160.1, 156.6, 148.5, 145.7, 125.7,
123.9, 113.1, 101.6, 61.7, 61.6, 56.8, 56.7, 14.5; IR (film) 2926,
2856, 1729, 1695, 1656 cm-1; HRMS (CI) calcd for C16H16O7Na
(MNa+) 343.0794, found 343.0804.
Experimental Section
1,4,5,6,8-Pentamethoxynaphthalene-2-carbaldehyde (7).41 To
a solution of POCl3 (0.50 mL, 5.4 mmol) and DMF (0.42 mL, 5.4
mmol) in CHCl3 (9 mL) was added 668 (0.27 g, 0.97 mmol) in
CHCl3. After heating at reflux for 12 h, additional POCl3 (0.50
mL, 5.4 mmol) and DMF (0.42 mL, 5.4 mmol) in CHCl3 (9 mL)
were added. Heating at reflux was continued for 6 h after which
the mixture was poured into ice water, extracted with CH2Cl2, dried
(Na2SO4), and concentrated. Chromatography83 (50% EtOAc/
hexanes, SiO2) afforded a yellow solid in 67% yield (0.20 g, 0.65
mmol): 1H NMR (500 MHz, CDCl3) δ 10.48 (s, 1H), 7.13 (s, 1H),
6.78 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.97 (s, 3H), 3.90 (s, 3H),
3.80 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.6, 158.1, 154.8,
153.8, 152.7, 138.8, 127.6, 124.0, 116.6, 101.6, 98.1, 65.6, 62.1,
57.1, 57.0, 56.7; IR (film) 2999, 2934, 2845, 1668, 1594, 1459
cm-1; HRMS (CI) calcd for C16H18O6 (M+) 306.1103, found
306.1107.
Methyl 3-(2,4,5-Trimethoxyphenyl)-3-oxopropanoate (11). 10
(0.50 mL, 3.3 mmol) was added to a solution of AlCl3 (0.65 g, 4.9
mmol) in CH2Cl2 (15 mL) and the solution was stirred for 5 min.
Methyl malonyl chloride (0.43 mL, 4.0 mmol) was added dropwise
and the resulting mixture was stirred at room temperature for 6 h.
The reaction mixture was cooled to 0 °C and quenched with
saturated NaHCO3, acidified to a pH of 6, extracted with EtOAc,
dried (Na2SO4), and concentrated. Trituration with 10% PhH/
hexanes afforded an off-white solid in 91% yield (0.81 g, 3.0
Ethyl 3-(Benzyloxy)-4-hydroxy-5,6,8-trimethoxynaphthalene-
2-carboxylate (23). To a solution of 20ox (0.20 g, 0.62 mmol) in
PhH (20 mL) in a separatory funnel was added Na2S2O4 (2 g) in
H2O (20 mL). After 3 min of shaking, the layers were separated
and the organic layer was dried and concentrated to afford the
catechol 20red, which was used immediately. This catechol was
dissolved in DMF (6 mL), then treated with BnBr (0.12 mL, 1.0
mmol), KHCO3 (0.10 g, 1.0 mmol), and Na2S2O4 (0.050 g, 0.29
mmol). After 12 h of stirring, the mixture was quenched with
saturated NH4Cl, extracted with EtOAc, dried (Na2SO4), and
concentrated. Chromatography (10-20% EtOAc/hexanes, SiO2)
afforded a yellow oil in 63% yield (0.16 g, 0.39 mmol): 1H NMR
(500 MHz, CDCl3) δ 9.74 (s, 1H), 8.14 (s, 1H), 7.60 (d, J ) 7.3
Hz, 2H), 7.38 (t, J ) 7.3 Hz, 2H), 7.31 (t, J ) 7.3 Hz, 1H), 6.56
(s, 1H), 5.22 (s, 2H), 4.36 (q, J ) 7.3 Hz, 2H), 4.012 (s, 3H),
4.010 (s, 3H), 3.98 (s, 3H), 1.34 (t, J ) 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 166.5, 153.9, 149.1, 145.9, 140.9, 138.0,
135.7, 128.3, 128.2, 127.7, 124.2, 120.9, 118.1, 116.4, 94.3, 74.9,
62.2, 61.0, 57.0, 55.8, 14.3; IR (film) 3296, 2980, 2941, 2849, 1718,
1613, 1459 cm-1; HRMS (ES) calcd for C23H24O7Na (MNa+)
435.1420, found 435.1409.
Ethyl 1,4-Dihydro-1,5,6,8-tetramethoxy-4-oxonaphthalene-2-
carboxylate (25). To a solution of 17 (0.015 g, 0.049 mmol) in
MeOH (1.5 mL) was added PIFA (0.023 g, 0.053 mmol) at room
temperature. After 5 min of stirring, the reaction was quenched
with saturated NaHCO3, extracted with EtOAc, dried (Na2SO4),
and concentrated to afford a yellow oil that was carried on directly
to the next reaction without purification: 1H NMR (500 MHz,
CDCl3) δ 7.06 (s, 1H), 6.79 (s, 1H), 5.74 (s, 1H), 4.35 (q, J ) 7.1
Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.24 (s, 3H), 1.37
(t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 185.5, 165.6,
154.6, 154.3, 143.1, 141.9, 136.3, 126.2, 119.4, 101.9, 65.7, 61.8,
61.5, 56.4, 56.3, 55.1, 14.1; IR (film) 2984, 2937, 2845, 1722, 1671,
1590 cm-1; HRMS (CI) calcd for C17H20O7 (M+) 336.1209, found
336.1217.
1
mmol): mp 107-108 °C; H NMR (500 MHz, CDCl3) δ 7.39 (s,
1H), 6.41 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.78 (s,
3H), 3.63 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 190.4, 168.8,
155.5, 154.6, 143.0, 117.1, 112.1, 95.8, 55.94, 55.90, 55.6, 51.7,
50.2; IR (film) 3003, 2953, 2910, 2841, 1737, 1656, 1606 cm-1
;
HRMS (CI) calcd for C13H16O6 (M+) 268.0947, found 268.0935.
4-Hydroxy-5,6,8-trimethoxynaphthalene-2-carboxylic Acid
Ethyl Ester (17).74 To a solution of 2,4,5-trimethoxybenzaldehyde
(15) (5.52 g, 28.1 mmol) in t-BuOH (105 mL) was added diethyl
succinate (12.3 mL, 73.9 mmol) and t-BuOK (6.3 g, 56 mmol).
After being stirred at rt for 2 h, the mixture was poured into water,
acidified (pH 1) with 1 N HCl, and extracted with EtOAc. The
combined organic layers were washed with aq Na2CO3, dried (Na2-
SO4), and concentrated. The resultant material was dissolved in
Ac2O (100 mL) and NaOAc (5.0 g, 61 mmol) was added. The
mixture was heated to reflux where it was stirred for 4 h. After
cooling, the mixture was poured into a slurry of ice water and
neutralized (pH 7) by the addition of KOH. The mixture was
extracted with EtOAc, dried with Na2SO4, and concentrated giving
16. 16 was dissolved in 1% KOH/EtOH (200 mL), heated to reflux,
and stirred for 10 min. The mixture was cooled, poured into a slurry
of ice water, and acidified (pH 1) with 1 N HCl. The resulting
precipitate was filtered and dried to afford an off-white solid in
81% yield (7.0 g, 23 mmol): mp 150-152 °C; 1H NMR (500 MHz,
Ethyl 4-Hydroxy-1,5,6,8-tetramethoxynaphthalene-2-carbox-
ylate (26). To a solution of 25 from above in EtOH (2 mL) was
added t-BuOK (0.030 g, 0.27 mmol). After 5 min of stirring, the
reaction was quenched with saturated NH4Cl, extracted with EtOAc,
dried (Na2SO4), and concentrated to afford a yellow oil in 99%
yield (0.016 g, 0.048 mmol): 1H NMR (500 MHz, CDCl3) δ 9.78,
(s, 1H), 7.13 (s, 1H), 6.70 (s, 1H), 4.38 (q, J ) 7.1 Hz, 2H), 4.01
(s, 3H), 3.980 (s, 3H), 3.979 (s, 3H), 3.84 (s, 3H), 1.40 (t, J ) 7.2
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.4, 155.3, 150.2, 149.0,
148.9, 136.6, 122.1, 121.0, 117.1, 110.9, 97.6, 63.6, 62.3, 60.9,
57.1, 56.7, 14.3; IR (film) 3308, 2980, 2937, 2845, 1725, 1610
cm-1; HRMS (ES) calcd for C17H20O7Na (MNa+) 359.1107, found
359.1117.
(83) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
1916 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of the Naphthalene Portion of Purpuromycin
Ethyl 3,4-Dihydro-1,5,6,8-tetramethoxy-3,4-dioxonaphthalene-
2-carboxylate) (27). To a solution of 26 (1.14 g, 3.39 mmol) in
DMF (35 mL) was added IBX79 (1.0 g, 3.6 mmol). After 12 h of
stirring, the mixture was filtered through Celite, diluted with EtOAc,
washed with NH4Cl, dried (Na2SO4), and concentrated. Chroma-
tography (50% EtOAc/hexanes, SiO2) afforded a red solid in 82%
yield (0.971 g, 2.77 mmol): mp 120-122 °C; 1H NMR (500 MHz,
CDCl3) δ 6.72 (s, 1H), 4.34 (q, J ) 7.2 Hz, 2H), 3.99 (s, 3H), 3.94
(s, 3H), 3.91 (s, 3H), 3.84 (s, 3H), 1.34 (t, J ) 7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 179.5, 178.3, 170.2, 164.6, 158.1, 156.0,
147.4, 124.5, 116.0, 110.6, 103.9, 61.6, 61.4, 60.7, 57.4, 56.2, 14.1;
IR (film) 2984, 2945, 2845, 1725, 1594 cm-1; HRMS (ES) calcd
for C17H18O8Na (MNa+) 373.0899, found 373.0908.
and concentrated. Chromatography (20%-50% EtOAc/hexanes,
SiO2) afforded a yellow solid in 71% yield (0.022 g, 0.053 mmol):
mp 121-122 °C; 1H NMR (500 MHz, C6D6) δ 10.74 (s, 1H), 7.63
(d, J ) 7.4 Hz, 2H), 7.21 (t, J ) 7.5 Hz, 2H), 7.13 (t, J ) 7.4 Hz,
1H), 6.29 (s, 1H), 5.23 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.71 (s,
3H), 3.47 (s, 3H), 3.39 (s, 3H); 13C NMR (125 MHz, C6D6) δ 188.7,
158.8, 155.4, 153.3, 149.5, 144.8, 138.2, 137.8, 130.3, 128.9, 128.6,
128.5, 121.8, 114.9, 97.7, 76.3, 64.3, 61.9, 61.7, 56.5, 56.3; IR
(film) 3092, 3038, 2934, 2845, 1687, 1598 cm-1; HRMS (ES) calcd
for C23H24O7Na (MNa+) 435.1420, found 435.1417. A crystal
structure was obtained for this compound confirming the aromatic
substitution pattern (see the Supporting Information).
1-(2-(Benzyloxy)-1,4,5,7,8-pentamethoxynaphthalen-3-yl)-2-
nitroethanol (31). To a solution of MeNO2 (0.50 mL) in THF
(5 mL) was slowly added 1.6 M n-BuLi (0.86 mL, 1.4 mmol) at
0 °C. After 15 min of stirring, a solution of 2 (0.057 g, 0.14 mmol)
in THF (5 mL) was added and the mixture was warmed to room
temperature. After 12 h of stirring, the mixture was diluted with
NH4Cl until slightly acidic (pH ∼6), extracted with EtOAc, dried
(Na2SO4), and concentrated. Chromatography (20% EtOAc/hexanes,
SiO2) afforded a clear oil in 86% yield (0.056 g, 0.12 mmol): 1H
NMR (500 MHz, C6D6) δ 7.43 (d, J ) 7.4 Hz, 2H), 7.18 (t, J )
7.3 Hz, 2H), 7.10 (t, J ) 7.5 Hz, 1H), 6.38 (s, 1H), 6.19 (dd, J )
3.1, 9.9 Hz, 1H), 5.24 (d, J ) 10.8 Hz, 1H), 5.15 (d, J ) 10.6 Hz,
1H), 4.98 (dd, J ) 10.2, 12.1 Hz, 1H), 4.05 (dd, J ) 3.1, 12.3 Hz,
1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.57 (s, 3H), 3.52 (s, 3H), 3.42 (s,
3H); 13C NMR (125 MHz, C6D6) δ 153.8, 152.3, 151.6, 148.8,
144.4, 138.0, 137.5, 129.3, 129.1, 128.8, 128.6, 122.5, 115.0, 98.3,
80.8, 76.0, 66.5, 63.3, 61.8 (2), 56.8, 56.6; IR (film) 3475, 2934,
2845, 1602, 1455 cm-1; HRMS (ES) calcd for C24H27NO9Na
(MNa+) 496.1584, found 496.1592.
1-(2-(Benzyloxy)-1,4,5,7,8-pentamethoxynaphthalen-3-yl)-2-
nitroethanone (32). A solution of 31 (0.225 g, 0.475 mmol) in
CH2Cl2 (10 mL) was treated with NaHCO3 (0.84 g, 1.0 mmol)
followed by DMP82 (0.202 g, 0.476 mmol). After 2 h of stirring,
the mixture was concentrated and subjected to chromatography
(20% EtOAc/hexanes, SiO2) affording a yellow oil in 61% yield
(0.137 g, 0.291 mmol): 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J
) 7.1 Hz, 2H), 7.37 (t, J ) 7.2 Hz, 2H), 7.34 (t, J ) 7.2 Hz, 1H),
6.71 (s, 1H), 5.46 (s, 2H), 5.24 (s, 2H), 4.03 (s, 3H), 4.00 (s, 3H),
3.90 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 189.0, 154.0, 152.0, 151.4, 145.5, 143.9, 141.8, 136.6,
133.3, 129.0, 128.6, 128.4, 122.9, 113.6, 96.2, 84.4, 76.1, 64.6,
62.0 (2), 56.7, 56.5; IR (film) 2937, 2845, 1725, 1602, 1559, 1455
cm-1; HRMS (ES) calcd for C24H25NO9Na (MNa+) 494.1427,
found 494.1439.
3-Benzyloxy-1,4,5,6,8-pentamethoxy-2-(2-nitrovinyl)naphtha-
lene (33). Isolated as an orange-red solid in 9% yield (0.019 g,
0.042 mmol) from the above reaction: 1H NMR (500 MHz, CDCl3)
δ 8.42 (d, J ) 13.7 Hz, 1H), 8.11 (d, J ) 13.7 Hz, 1H), 7.45-7.47
(m, 2H), 7.33-7.39 (m, 3H), 6.68 (s, 1H), 5.19 (s, 2H), 4.03 (s,
3H), 4.02 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 156.0, 154.7, 152.7, 148.6, 144.2, 139.8,
136.8, 136.6, 130.8, 129.1, 128.8, 128.7, 128.6, 115.7, 114.1, 96.2,
75.9, 63.2, 62.2, 62.1, 56.9, 56.7; IR (film) 2934, 2845, 1594, 1559,
1509, 1455, 1366, 1320 cm-1; HRMS (ES) calcd for C24H26NO8
(MH+) 456.1658, found 456.1665.
Ethyl 3-(Benzyloxy)-4-hydroxy-1,5,6,8-tetramethoxynaphtha-
lene-2-carboxylate (28). To a solution of 27 (3.8 g, 10.8 mmol)
in PhH (100 mL) in a separatory funnel was added Na2S2O4 (10 g)
in H2O (100 mL). After 3 min of shaking, the layers were separated.
The organic layer was dried and concentrated to afford the catechol,
which was used immediately. This catechol was dissolved in DMF
(100 mL) and treated with BnBr (2.7 mL, 22.7 mmol) and KHCO3
(2.2 g, 22.0 mmol). After 12 h of stirring, the reaction was quenched
with saturated NH4Cl, extracted with EtOAc, dried (Na2SO4), and
concentrated. Chromatography (30% EtOAc/hexanes, SiO2) af-
forded a yellow oil in 71% yield (3.4 g, 7.7 mmol): 1H NMR (500
MHz, CDCl3) δ 9.99 (s, 1H), 7.51 (d, J ) 7.8 Hz, 2H), 7.36 (t, J
) 7.5 Hz, 2H), 7.30 (t, J ) 7.6 Hz, 1H), 6.61 (s, 1H), 5.22 (s, 2H),
4.34 (q, J ) 7.1 Hz, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.97 (s, 3H),
3.81 (s, 3H), 1.29 (t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 166.2, 154.2, 148.2, 145.7, 141.5, 138.3, 137.9, 136.4, 128.2,
128.0, 127.7, 122.7, 120.8, 113.5, 95.9, 74.9, 64.0, 62.3, 61.3, 56.8,
56.6, 14.2; IR (film) 3273, 2980, 2937, 2845, 1729, 1613 cm-1
;
HRMS (ES) calcd for C24H26O8Na (MNa+) 465.1525, found
465.1545.
Ethyl 3-(Benzyloxy)-1,4,5,6,8-pentamethoxynaphthalene-2-
carboxylate (29). A solution of 28 (1.2 g, 2.7 mmol) in DMF (30
mL) at 0 °C was treated with 2 M NaHMDS (4.2 mL, 4.8 mmol)
and MeI (1.0 mL, 16 mmol) and then warmed to room temperature.
After 12 h of stirring, the reaction was quenched with 1 M HCl,
extracted with EtOAc, dried (Na2SO4), and concentrated. Chroma-
tography (20% EtOAc/hexanes, SiO2) afforded a yellow oil in 97%
yield (1.2 g, 0.26 mmol): 1H NMR (500 MHz, CDCl3) δ 7.49 (d,
J ) 7.5 Hz, 2H), 7.38 (t, J ) 7.5 Hz, 2H), 7.31 (t, J ) 7.1 Hz,
1H), 6.67 (s, 1H), 5.23 (s, 2H), 4.34 (q, J ) 7.1 Hz, 2H), 4.00 (s,
3H), 3.97 (s, 3H), 3.89 (s, 3H), 3.84 (s, 6H), 1.30 (t, J ) 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 166.2, 153.7, 150.9, 150.2,
146.5, 143.6, 137.7, 136.7, 128.3, 128.0, 127.8, 127.3, 121.7, 114.1,
96.4, 75.8, 63.8, 62.1, 61.9, 61.4, 56.82, 56.75, 14.1; IR (film) 2934,
2845, 1729, 1602, 1455 cm-1; HRMS (ES) calcd for C25H28O8Na
(MNa+) 479.1682, found 479.1701.
(2-(Benzyloxy)-1,4,5,7,8-pentamethoxynaphthalen-3-yl)metha-
nol (30). A solution of 29 (0.10 g, 0.22 mmol) in THF (3 mL) was
treated with LiAlH4 (0.084 g, 2.2 mmol) at 0 °C and then warmed
to room temperature. After 6 h of stirring, the reaction was quenched
with a saturated solution of NaKtartrate, extracted with EtOAc, dried
(Na2SO4), and concentrated. Chromatography (50% EtOAc/hexanes,
SiO2) afforded a clear, colorless oil in 85% yield (0.077 g, 0.19
mmol): 1H NMR (500 MHz, C6D6) δ 7.44 (d, J ) 8.1 Hz, 2H),
7.17 (m, 3H), 6.45 (s, 1H), 5.23 (s, 2H), 5.01 (s, 2H), 3.98 (s, 3H),
3.88 (s, 3H), 3.73 (s, 3H), 3.57 (s, 3H), 3.46 (s, 3H), 2.42 (s, 1H);
13C NMR (125 MHz, C6D6) δ 154.0, 152.6, 151.1, 150.0, 144.4,
138.4, 129.1, 128.8, 128.7, 128.6, 127.6, 126.2, 115.8, 98.7, 76.0,
63.2, 61.9, 61.8, 56.98, 56.95, 56.3; IR (film) 3486, 2934, 2841,
1602, 1455 cm-1; HRMS (ES) calcd for C23H26O7Na (MNa+)
437.1576, found 437.1608.
3-Benzyloxy-1,4,5,6,8-pentamethoxy-2-(2-nitroethyl)naphtha-
lene (34). To a solution of 33 (0.010 g, 0.022 mmol) dissolved in
CH2Cl2 (1 mL) and MeOH (1 mL) was added NaBH4 (0.0073 g,
0.193 mmol) in one portion. After 0.5 h of stirring, the mixture
was poured into 1 N HCl (10 mL) and partitioned with CH2Cl2
(10 mL). The organic layer was dried (Na2SO4) and concentrated.
Chromatography (4% Et2O/CH2Cl2, SiO2) afforded a light yellow
oil in 83% yield (0.0083 g, 0.018 mmol): 1H NMR (500 MHz,
CDCl3) δ 7.45-7.46 (m, 2H), 7.33-7.40 (m, 3H), 6.67 (s, 1H),
4.42 (m, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H),
3.74 (s, 3H), 3.38 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 153.1,
3-(Benzyloxy)-1,4,5,6,8-pentamethoxynaphthalene-2-carbal-
dehyde (2).43 A solution of 30 (0.031 g, 0.075 mmol) in CH2Cl2
(1 mL) at 0 °C was treated with DMP82 (0.039 g, 0.092 mmol) and
then the mixture was stirred for 0.5 h. The mixture was filtered
J. Org. Chem, Vol. 73, No. 5, 2008 1917

Lowell et al.
151.7, 150.4, 148.9, 143.8, 137.6, 136.9, 128.8, 128.7, 128.5, 126.5,
119.8, 114.4, 96.4, 75.4, 74.4, 62.7, 62.1, 61.0, 57.1, 56.9, 23.4;
IR (film) 2934, 2841, 1606, 1548, 1455,1359, 1339 cm-1; HRMS
(ES) calcd for C24H27NO8Na (MNa+) 480.1634, found 480.1636.
instead of vanillin in the version published ASAP February 8,
2008; the corrected version was published ASAP February 12,
2008.
Supporting Information Available: Characterization data
including 1H and 13C NMR spectra and X-ray crystal structure data
for compound 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
American Cancer Society (RSG-02-137-01-CDD).
Note Added after ASAP Publication. In the text and in the
title of Scheme 1, compound 3 was referred to as isovanillin
JO7024114
1918 J. Org. Chem., Vol. 73, No. 5, 2008