The divergent asymmetric synthesis of kalafungin, 5-epi-frenolicin B and related pyranonaphthoquinone antibiotics

Article abstract of DOI:10.1016/j.tet.2012.10.012

A divergent, asymmetric method for the synthesis of pyranonaphthoquinones is reported. The synthetic strategy applies a Staunton-Weinreb annulation between substituted ortho-toluates and the (R)-pyran-2-one 7 to construct the key naphthopyranone intermediates. Stereoselective introduction of either a methyl or propyl C5 alkyl substituent by use of Grignard addition/silane- mediated reduction and a sequence of oxidations gave a series of pyranonaphthoquinones including kalafungin 1, 5-epi-9-methoxykalafungin 34 and 5-epi-frenolicin B 24.

Full text of DOI:10.1016/j.tet.2012.10.012

Tetrahedron 69 (2013) 377e386
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The divergent asymmetric synthesis of kalafungin, 5-epi-frenolicin
B and related pyranonaphthoquinone antibiotics
,b,
Christopher D. Donner a
*
a School of Chemistry, The University of Melbourne, Victoria 3010, Australia
b Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2012
Received in revised form 14 September 2012
Accepted 2 October 2012
Available online 13 October 2012
A divergent, asymmetric method for the synthesis of pyranonaphthoquinones is reported. The synthetic
strategy applies a StauntoneWeinreb annulation between substituted ortho-toluates and the (R)-pyran-
2-one 7 to construct the key naphthopyranone intermediates. Stereoselective introduction of either
a methyl or propyl C5 alkyl substituent by use of Grignard addition/silane-mediated reduction and
a sequence of oxidations gave a series of pyranonaphthoquinones including kalafungin 1, 5-epi-9-
methoxykalafungin 34 and 5-epi-frenolicin B 24.
Keywords:
Kalafungin
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Frenolicin B
StauntoneWeinreb annulation
Pyranonaphthoquinone
1. Introduction
OH
O
O
OH
O
O
The pyranonaphthoquinone family of compounds is a class of
antibiotics widely dispersed in nature1 with the majority of
members of this group of natural products displaying interesting
biological activities.2 For example, kalafungin 1 (Fig.1), first isolated
in 1968 from Streptomyces tanashiensis,3 is an inhibitor of patho-
genic fungi, protozoa, yeasts and Gram-negative bacteria and also
possesses cytotoxic activity. Frenolicin B 2, isolated from a strain of
Streptomyces roseofulvus,4 possesses anticoccidial activity and has
recently been shown to be a potent inhibitor of the serine/threo-
5
7
O
O
3
O
O
O
O
kalafungin 1
frenolicin B 2
OAc
nine kinase AKT (AKT1 IC50¼0.313
m
M),5,6 whilst arizonin B1 37 and
OH
O
HO
Me
griseusin A 48 both exhibit modest Gram-positive activity.
OH
O
MeO
O
O
O
The redox chemistry of quinone-based therapeutics, such as the
anti-cancer agent doxorubicin, is often the basis of their beneficial
properties, however, the one-electron reduction of quinones to
semiquinone radicals (Scheme 1) and the subsequent generation of
reactive oxygen species through redox cycling has been shown to
be responsible for their damaging side-effects.9 Indeed, the major
dose-limiting side-effect in the use of doxorubicin in chemotherapy
is its cardiotoxicity that results from radical formation. Upon two-
electron reduction pyranoquinones such as kalafungin 1 may
form their corresponding hydroquinone (Scheme 1), allowing
O
O
O
O
O
arizonin B1 3
O
griseusin A 4
Fig. 1. Naturally occurring pyranonaphthoquinones.
opening of the g-lactone to take place with resultant generation of
a highly reactive ortho-quinone methide alkylating species.10
Strong support for such a bioreductive alkylation mechanism has
been demonstrated in the case of frenolicin B 2 wherein alkylation
of a cysteine residue at the allosteric T-loop site of an AKT kinase
was observed.6
* Tel.: þ61 3 8344 2411; fax: þ61 3 9347 8189; e-mail address: cdonner@
unimelb.edu.au.
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.012

378
C.D. Donner / Tetrahedron 69 (2013) 377e386
OH
O
O
R
OH
O
R1
OMe OH
O
OH
OH
R
R2
R2
5
7
2e-, 2H+
O
O
O
O
OTBS
3
O
O
O
O
OH
OH
5
O
O
1 R = Me
2 R = Pr
O
R
R
R
1 = Me, R2 = H kalafungin 1
1 = Pr, R2 = H frenolicin B 2
1 = Me, R2 = OMe arizonin B1 3
O2
OH
OH
R
1e-
OMe
O
O2
R
R2
CO2Me
O
O
O
CO2H
+
OTBS
OH
O
O
Me
MeO
OTBS
O
8
NuH
O
6
7
Scheme 2. Retrosynthetic analysis of pyranonaphthoquinones 1e3.
OH
R
O
O
O
structural similarities in that they each contain the same tetracyclic
core with an oxygen substituent at C7 in the aromatic ring. What
differentiates them from one another is the extent of oxygenation
on the aromatic ring and the nature of the substituent at C5, which
ranges from simple alkyl substitution, as seen in 1e3, through to
the more complex spiroacetal system seen in griseusin A 4. It was
reasoned that synthetically a variety of different C5 alkyl groups
could be incorporated by addition of a suitable Grignard reagent
(R1MgX) to the naphthopyranone 5 followed by stereoselective
reduction of the resultant lactol. Further elaboration may then lead
to the pyranoquinones 1e3. Substitution in the aromatic portion of
naphthopyranone 5 (e.g., R2¼H, OMe), and hence the ultimate
naphthoquinone products, would be determined by the choice of
ortho-toluate 6 used in a StauntoneWeinreb annulation21 with the
chiral lactone 7.
CO2H
OH
Nu
Scheme 1. Redox cycling and bioreductive alkylation mechanisms of
pyranonaphthoquinones.
Due to their useful biological activities and interesting structures
many synthetic strategies have been developed for the synthesis of
pyranonaphthoquinone antibiotics,11 however, these have often
been target specific in nature. The first stereospecific synthesis of
kalafungin 1 was achieved by Tatsuta and co-workers12 employing
an enantiodivergent approach that delivered both kalafungin 1 and
nanaomycin D ent-1 from a common carbohydrate-derived in-
termediate. Fernandes and Bruckner reported a stereoselective
synthesis of kalafungin 1 that used an asymmetric dihydroxylation
of an aryl-substituted b,g-unsaturated ester to generate the g-lac-
tone ring, followed by oxa-PicteteSpengler cyclization to complete
the tetracyclic framework. The use of an oxa-PicteteSpengler cy-
clization to form the pyran moiety allows the incorporation of a va-
riety of substituents at C5, as demonstrated by both Salaski and co-
workers6 and Eid and co-workers14 in the preparation of frenolicin B
analogues. Whilst the first asymmetric synthesis of frenolicin B 2
was described by Kraus,15 the recently reported kinase inhibitory
activity of frenolicin B 25,6 has generated renewed synthetic interest
in this compound and its analogues.6,14,16e18
13
€
The first target chosen in order to develop and refine the synthetic
methodology proposed in Scheme 2 was kalafungin 1, the simplest g-
lactone-containing member of the pyranonaphthoquinone family.
The synthesis of kalafungin 1 began with (S)-aspartic acid 9 that was
convertedintothe(R)-epoxide10 (Scheme3)followingthemethodof
Volkmann and co-workers.22 Protection of the hydroxyl group in 10
followed by opening of the epoxide with the anion of methyl pro-
piolate and exposure of the resulting acetylenic ester to sodium
methoxide gave the lactone 7 in 48% yield over the six steps from (S)-
aspartic acid 9, as previously reported.23
Whilst the synthesis of pyranonaphthoquinones using ap-
proaches that allow the incorporation of a variety of substituents on
either the pyran6,14 or aromatic ring19 has been developed, a ver-
satile method that allows structural variation to be readily in-
corporated on both the pyran and aromatic rings, as part of a single
strategy, has not been adequately demonstrated. In pursuit of this
goal we recently reported the synthesis of kalafungin 1 using
a strategy that should be more widely applicable to the synthesis of
a range of pyranonaphthoquinones.20 Reported here are the full
details of our synthesis of kalafungin 1, along with the extension of
this protocol to the synthesis of 5-epi-frenolicin B 24 and 5-epi-9-
methoxykalafungin 34, demonstrating the versatility of this
newly developed strategy for the synthesis of various members of
the pyranonaphthoquinone family.
O
NH2
O
d-f
a-c
O
CO2H
HO2C
OH
MeO
OTBS
9
10
7
Scheme 3. Reagents and conditions: (a) NaNO2, H2SO4, KBr, H2O, 0 ꢁC, 4 h (91%); (b)
BH3$Me2S, THF, ꢀ30 ꢁC to rt, 18 h (97%); (c) K2CO3, CH2Cl2, 72 h (96%); (d) TBSCl, im-
n
idazole, CH2Cl2, 4 h (98%); (e) methyl propiolate, BuLi, BF3$Et2O, THF, ꢀ78 ꢁC, 30 min
(72%); (f) NaOMe, MeOH, 16 h (80%) (Fig. 1).
Applying StauntoneWeinreb annulation conditions, exposure of
toluate 11 to LDA at ꢀ70 ꢁC generates the toluate anion, which upon
addition of lactone
7 undergoes a tandem Michael addi-
tioneDieckmann cyclization reaction to deliver naphthopyranone
12 in 52% yield (Scheme 4). Careful control of temperature and the
use of excess LDA appear crucial for this reaction. Using lower
temperatures or longer periods at low temperature lead to forma-
tion of the side-product 18 (Fig. 2) in significant quantities (w20%),
likely as a result of base-induced elimination.
2. Results and discussion
In order to develop a divergent approach to the pyranonaph-
thoquinone antibiotics we first sought to identify points in the
synthesis at which flexibility needed to be incorporated. Compar-
ison of the naturally occurring compounds 1e3 (Scheme 2), along
with numerous other members of the group, highlights obvious
Addition of methylmagnesium bromide to naphthopyranone 12,
followed by stereoselective reduction of the intermediate lactol

C.D. Donner / Tetrahedron 69 (2013) 377e386
379
OMe
OMe OH
OMe OH
O
O
CO2Me
Me
1
a
O
O
b
O
+
3
OH
OH
OTBS
MeO
OTBS
O
13
7
12
11
c
OR
O
OH
OH
O
O
OH
O
O
1
5
e
5
g
f
O
O
3a
O
O
3a
CO2H
O
O
O
O
14 R = Me
15 R = H
O
16
O
17
d
kalafungin 1
Scheme 4. Reagents and conditions: (a) LDA, THF, ꢀ70 to 0 ꢁC, 1 h (52%); (b) (i) MeMgBr, THF, 0 ꢁC, 4 h; (ii) TFA, Et3SiH, CH2Cl2, ꢀ60 ꢁC to rt, 2 h; (iii) THF, 2 M aq HCl, 16 h (74%,
three steps); (c) (i) NBS, DMF, 18 h; (ii) CAN, H2O, MeCN, 30 min (85%, two steps); (d) AlCl3, CH2Cl2, 2 h (94%); (e) (i) PhI(OAc)2, TEMPO, CH2Cl2, 16 h; (ii) NaClO2, tBuOH, acetone, H2O,
NaH2PO4, 3 h (80%, two steps); (f) (i) O2, MeOH, pyridine, 60 ꢁC, 14 h; (ii) BF3$Et2O, Et3SiH, CH2Cl2, ꢀ45 to 0 ꢁC, 30 min (64%, two steps); (g) H2SO4, PhH, 30 min (81%).
OH
O
OMe
O
respectively. The corresponding signals for the C5 and C3a protons
in 17 appear at 4.79 and 4.35, respectively. These downfield shifts
have been found to be diagnostic features of trans- versus cis-
isomers for closely related
-lactone-containing systems.13,24b,25
CO2H
d
MeO
OTBS
g
O
Importantly, the spectroscopic data for synthetic kalafungin 1,
prepared here from (S)-aspartic acid 9, were in close agreement
with the reported data for (þ)-kalafungin 1.12
O
18
O
19
Fig. 2. Elimination product 18 formed during annulation and acetal 19 formed during
With the synthesis of kalafungin 1 established it was now
possible to expand the scope of this technique towards the syn-
thesis of other members of the pyranonaphthoquinone family. The
synthetic design used for the preparation of kalafungin 1 in-
corporates two potentially divergent steps that are clearly amena-
ble to exploitation. The first is the ability to vary the C5 alkyl group,
introduced by the use of methylmagnesium bromide in the case of
kalafungin 1, by using different Grignard reagents. As a demon-
stration of this idea, we sought to prepare analogues in which the
C5 group has been varied from the commonly seen methyl sub-
stituent, perhaps most significant in this regard being the natural
product frenolicin B 2. Whilst a family of 7-deoxyfrenolicin B ana-
logues possessing a variety of substituents at C5 has been pre-
pared,6 using the naphthopyranone 12 it should be possible to
introduce substituents at C5 whilst retaining the 7-OH group of the
frenolicin B 2 naphthoquinone moiety.
Upon addition of propylmagnesium chloride to naphthopyranone
12, followed by stereoselective reduction of the lactol intermediate,
the naphthopyran 20 (Scheme 5) could be isolated in 47% yield as
a single diastereoisomer. From this point, by applying a slightly
modified reaction sequence to that developed for the synthesis of
kalafungin 1, 5-epi-frenolicin B 24 could be prepared as shown in
Scheme 5. Thus, oxidation of naphthol 20 gave naphthoquinone 21 in
88% yield, however, attempts to cleave the methyl ether in 21 using
aluminiumchloride, aswasusedinthesynthesisofkalafungin 1, were
unsuccessful. Boron tribromide has been reported to selectively
cleave methyl ethers in related pyranoquinones25 and, when used in
excess, effect both demethylation and epimerization at the benzylic
ether position.25,26 Conversely, it has also been reported that the use
of boron tribromide leads to rapid equilibration of cis-/trans-pyran
diastereoisomers.27 We found that attempted demethylation of 21
under boron tribromide conditions led to formation of complex
mixtures. Using the more moderate Lewis acid boron trichloride27 to
form thefreephenol 22from21 provedto bemore effective, however,
this still led to partial epimerization at C1 to the more stable trans-
isomer 25 (Scheme 6).28 The conversion of 22 to 25 is likely to occur
via the dienol intermediate 26, with the final mixture of the cis-22/
trans-25 diastereomers being obtained in a 4:1 ratio.
lactonization.
using Et3SiH/TFA, gave the cis-pyran 13 as a single diastereoisomer.
The 1,3-cis relationship between the C1 and C3 alkyl substituents
was confirmed by the presence of an NOE correlation between the
H-1 and H-3 protons, which adopt a 1,3-pseudo-diaxial arrange-
ment. With the (1S,3S)-naphthopyran 13 in hand, all that remains
to complete the synthesis of kalafungin 1 is to invert the stereo-
chemistry at the benzylic ether position and effect a series of oxi-
dations. The order in which to execute these operations should be
flexible, however, in order to conveniently access stereochemical
diversity ‘correction’ of the stereochemistry at C1 in 13 to that
found in kalafungin 1 was left as the final step.
Using a two-step oxidation procedure, bromination of naphthol
13 using N-bromosuccinimide followed by exposure of the result-
ing p-bromonaphthol to ceric ammonium nitrate (CAN) gave the
naphthoquinone 14. Subsequent cleavage of the O-methyl ether
using aluminium chloride12 delivered 15 in 80% yield over three
steps from 13, with retention of stereochemical integrity. In con-
trast, partial epimerization at the C1 asymmetric centre was ob-
served when boron tribromide was used to effect demethylation of
14. Oxidation of the primary alcohol in cis-pyran 15 gave the re-
quired acid 16 in preparation for lactone formation. The formation
of g-lactones from carboxylic acids such as 16, via an intermediate
quinone methide, is known to proceed in the presence of base and
atmospheric oxygen.24 Exposing a solution of acid 16 in methanol/
pyridine to oxygen formed the desired
g-lactone 17, along with
acetal 19 (Fig. 2) resulting from trapping of solvent. The crude
mixture of 17 and 19 was reduced using BF3$Et2O/Et3SiH to give 5-
epi-kalafungin 17.
Final conversion into kalafungin 1 was achieved by exposure of
17 to concentrated sulfuric acid, conditions that catalyze inversion
of the C5 configuration.13,24a Near complete epimerization at C5 to
the thermodynamically favoured 5,3a-trans-pyran 1 (93:7 mixture
of 1/17) was achieved. Epimerization at C5 was clear from exami-
nation of the 1H NMR spectrum in which the signals associated
with the protons at C5 and C3a in 1 now appear at
d 5.09 and 4.69,

380
C.D. Donner / Tetrahedron 69 (2013) 377e386
OR
O
O
OMe OH
OMe OH
O
1
a
b
O
O
O
OH
OH
OTBS
12
20
21 R = Me
22 R = H (cis:trans 4:1)
c
d
OH
O
O
OH
O
5
O
e
O
CO2H
O
O
O
23 (cis:trans 4:1)
24 (cis,cis:trans,cis 4:1)
Scheme 5. Reagents and conditions: (a) (i) PrMgCl, THF, ꢀ50 ꢁC to 0 ꢁC, 2 h; (ii) TFA, Et3SiH, CH2Cl2, ꢀ60 ꢁC to rt, 2 h; (iii) THF, 2 M aq HCl, 1 h (47%, three steps); (b) (i) NBS, DMF,
18 h; (ii) CAN, H2O, MeCN, 30 min (88%, two steps); (c) BCl3, CH2Cl2, ꢀ50 to 0 ꢁC, 1 h (44%); (d) (i) PhI(OAc)2, TEMPO, CH2Cl2, 7 h; (ii) NaClO2, tBuOH, acetone, H2O, NaH2PO4, 3 h
(72%, two steps); (e) (i) O2, MeOH, pyridine, 65 ꢁC, 10 h; (ii) BF3$Et2O, Et3SiH, CH2Cl2, ꢀ45 ꢁC to 0 ꢁC, 30 min (50%, two steps).
Upon oxidation of 22 (4:1 cis/trans mixture), the acid 23 was
obtained in 72% yield. The spectroscopic data for 23 were in close
OH
O
O
OH
O
agreement with that reported for the corresponding racemic ma-
terial.27,29 Final conversion into the required
g-lactone was ach-
O
O
ieved by heating 23 in a solution of methanol/pyridine in the
presence of oxygen, giving 5-epi-frenolicin B 24.27,30
OH
OH
O
As a final demonstration of the intrinsic flexibility of this strat-
egy we planned to take advantage of the potential to incorporate
additional substituents on the aromatic portion of the core struc-
ture by the use of different ortho-toluates in the StauntoneWeinreb
annulation step. Unfortunately, methyl 2,3-dimethoxy-6-
methylbenzoate 6 (R2¼OMe, Scheme 2) and derivatives thereof
failed to react efficiently with the lactone 7,31 thus precluding direct
access to members of the arizonin family such as 3 using this
technique. However, the 2,4-dimethoxy toluate 27 reacted suc-
cessfully with lactone 7 to give the naphthopyranone 28 in good
yield (Scheme 7).23 From 28, it was expected that the 9-methoxy
analogue 34 could be prepared using the earlier developed se-
quence. However, the presence of the additional methoxy group at
C7 on the aromatic system in 28 resulted in some variation to the
expected reactivity in subsequent transformations. Thus, addition
O
22
25
OH
O
R
O
X
26 X = H / BCl3 / BBr3
Scheme 6. Proposed mechanism for acid-catalyzed epimerization of cis-pyran 22 to
trans-pyran 25.
OMe
OMe OH
O
OMe OH
OMe OH
O
O
CO2Me
a
O
b
O
+
7
+
7
MeO
Me
MeO
OTBS
OH
MeO
MeO
OH
28
27
29
30
c
d
OH
O
O
OR
O
O
O
5
g
f
9
6
O
O
O
9
CO2H
MeO
MeO
OH
MeO
O
O
O
31 R = Me
32 R = H
34
33
e
Scheme 7. Reagents and conditions: (a) LDA, THF, ꢀ70 to 0 ꢁC, 30 min (36%); (b) (i) MeMgBr, THF, 0 ꢁC, 4 h; (ii) TFA, Et3SiH, CH2Cl2, ꢀ60 ꢁC to rt, 2 h; (iii) THF, 2 M aq HCl, 18 h (29
30%, 30 40%, three steps); (c) NaBH4, THF, 2 h (87%); (d) salcomine, MeCN, O2, 23 h (74%); (e) AlCl3, CH2Cl2, 2 h (96%); (f) (i) PhI(OAc)2, TEMPO, CH2Cl2, 6 h; (ii) NaClO2, tBuOH, H2O,
NaH2PO4, 3 h (65%, two steps); (g) (i) O2, MeOH, pyridine, 60 ꢁC, 10 h; (ii) BF3$Et2O, Et3SiH, CH2Cl2, ꢀ45 to 0 ꢁC, 30 min (64%, two steps).

C.D. Donner / Tetrahedron 69 (2013) 377e386
381
of methylmagnesium bromide to naphthopyranone 28 followed by
treatment with Et3SiH/TFA gave, along with the expected cis-
naphthopyran 30 in 40% yield, a second product identified as the
cyclic acetal 29. Formation of 29 may result from the lactol initially
generated from 28 undergoing oxonium ion formation more readily
in the presence of the more electron rich aromatic system, followed
by intramolecular trapping by the primary alcohol. The conversion
of 29 into the required cis-naphthopyran 30 could be effected by
reduction of the acetal using sodium borohydride, with the com-
bined yield of naphthopyran 30 being 66% from lactone 28.
Upon bromination of naphthopyran 30 followed by treatment
with CAN, the naphthoquinone 31 could be isolated in a modest
27% yield. A second product was also isolated, the 1H NMR spec-
trum of which appeared nearly identical to 31 except for the
presence of only a single aromatic signal. The spectroscopic data of
this second product are consistent with formation of a C6 dimer of
31, as has been observed to occur with similar naphthopyran sys-
tems under these conditions.32 No further attempt was made to
optimize formation of either 31 or the C6 dimer using CAN condi-
tions. Instead, naphthopyran 30 was oxidized with salcomine,33
resulting in formation of 31 in 74% yield without any trace of di-
meric products being formed. Selective cleavage of the 9-O-methyl
ether in 31 proceeded smoothly using aluminium chloride to give
32 in 96% yield. Oxidation of the primary alcohol in 32 gave the acid
33, which upon exposure to pyridine and oxygen delivered 5-epi-9-
methoxykalafungin 34, a novel analogue of kalafungin 1.
polarimeter and are given in units of 10ꢀ1 deg cm2 gꢀ1, c values are
given in g 100 mLꢀ1. All moisture sensitive reactions were per-
formed under a dry nitrogen or argon atmosphere in oven-dried or
flame-dried glassware. Anhydrous tetrahydrofuran (THF) and
dichloromethane were pre-dried over activated alumina under
argon. Benzene was distilled from sodium/benzophenone ketyl
prior to use. Thin layer chromatography was performed on pre-
coated silica plates (Merck 60GF254) and compounds were visual-
ized at 254 nm and 365 nm or stained with 20% w/v phosphomo-
lybdic acid in ethanol. Flash column chromatography was
performed on silica gel (Kieselgel 60, 230e400 mesh) using the
indicated solvent system. Melting points were measured using
a Bausch and Lomb hot-stage melting point apparatus and are
uncorrected.
4.2. Experimental procedures
4.2.1. (S)-3,4-Dihydro-10-hydroxy-3-(2-(tert-butyldimethylsilyloxy)
ethyl)-9-methoxy-1H-naphtho[2,3-c]pyran-1-one (12). To a solution
diisopropylamine (0.750 mL, 5.35 mmol) in THF (40 mL) at ꢀ40 ꢁC
was added n-butyllithium (2.1 M in hexane, 2.55 mL, 5.35 mmol).
The reaction mixture was allowed to warm to 0 ꢁC and stirred for
5 min. After cooling to ꢀ70 ꢁC, methyl 2-methoxy-6-
methylbenzoate 11 (482 mg, 2.67 mmol) in THF (5.0 mL) was
added and stirring was continued for 10 min at ꢀ70 ꢁC. To the re-
sultant red solution was added the (R)-lactone 723 (286 mg,
2.67 mmol) in THF (3.0 mL) and the mixture was maintained at
ꢀ70 ꢁC for 30 min then allowed to warm to 0 ꢁC over 45 min. The
reaction was quenched with saturated aq ammonium chloride
(20 mL), extracted with ethyl acetate (3ꢂ15 mL) and the combined
organic layers were washed with brine, dried (MgSO4) and con-
centrated in vacuo. Flash column chromatography (ethyl acetate/
petrol 1:4 to 1:1) gave two main fractions; the first (Rf 0.60 in ethyl
acetate/petrol 1:1) contained a mixture of benzoate 11 and naph-
thalene 12, the second fraction (Rf 0.35 in ethyl acetate/petrol 1:1)
was identified as unchanged lactone 7 (205 mg). The mixed fraction
was further chromatographed (dichloromethane then dichloro-
methane/ethyl acetate 19:1) to afford the benzoate 11 (80 mg) and
3. Summary and conclusions
In conclusion, this work constitutes a novel, stereoselective and
divergent approach to the synthesis of the pyranonaphthoquinones
kalafungin 1, 5-epi-kalafungin 17, 5-epi-9-methoxykalafungin 34
and 5-epi-frenolicin B 24. The late-stage introduction of the C5 alkyl
group in this series, via the key naphthopyranone intermediate 12,
demonstrates the potential to incorporate a variety of other sub-
stituents at this position by appropriate selection of organometallic
reagents. Some flexibility in the choice of ortho-toluate used to
prepare naphthopyranone intermediates, such as 12 and 28, using
the StauntoneWeinreb annulation has also been demonstrated.31
With the more biologically active members of the pyranonaph-
thoquinone family in general possessing the common tetracyclic
the title compound 12 (414 mg, 39%; 52% based on recovered lactone
20
7) as a pale yellow oil; Rf (dichloromethane) 0.20; [
a
]
D
þ16.8 (c
0.94, CHCl3); 1H NMR (500 MHz, CDCl3)
d
0.06 (6H, s, Si(CH3)2), 0.88
framework composed of a fused naphthoquinoneepyrane
g
-lac-
(9H, s, SiC(CH3)3), 1.91e1.97 (1H, m, 3-CHaHb), 2.04e2.09 (1H, m, 3-
CHaHb), 3.00e3.08 (2H, m, 4-H2), 3.80e3.84 (1H, m, CHaHbOSi),
3.86e3.91 (1H, m, CHaHbOSi), 4.02 (3H, s, OCH3), 4.74e4.79 (1H, m,
3-H), 6.83 (1H, d, J 8.1 Hz, 8-H), 6.97 (1H, s, 5-H), 7.23 (1H, d, J 8.1 Hz,
6-H), 7.48 (1H, dd, J 8.1 and 8.1 Hz, 7-H), 13.16 (1H, s, 10-OH); 13C
tone system, the new synthetic strategy demonstrated here, that
allows ready access to this pharmacophore whilst allowing vari-
ability to be introduced into both the aromatic and pyran rings, will
be of significant benefit for accessing many naturally occurring
members and analogues of this class of antibiotics.
NMR (125 MHz, CDCl3)
d
ꢀ5.4, -5.4, 18.2, 25.9, 33.5, 37.8, 56.2, 58.5,
76.6, 102.4, 106.0, 115.3, 116.0, 119.9, 130.7, 133.6, 139.9, 159.2, 164.0,
4. Experimental section
4.1. General
171.0; nmax 2928, 1654, 1635, 1572, 1378, 1259, 1171, 1095, 832 cmꢀ1
;
GCeMS (method A, tR¼26.44 min) m/z 283.0 ([Mꢀ119]þ, 35%), 281
(58), 247.1 (35), 227.0 (29), 193.0 (43), 145.0 (42), 129.1 (46), 101.1
(100), 75.1 (83), 55.1 (66); HRMS (ESI): found 403.1933, C22H31O5Si
([MþH]þ) requires 403.1935.
1H and 13C NMR spectra were recorded using a Varian-500
spectrometer operating at 500 and 125 MHz, respectively. Chem-
ical shifts are given using residual CHCl3 (
d
¼7.26 for 1H and 77.0 for
4.2.2. (1S,3S)-3,4-Dihydro-10-hydroxy-3-(2-hydroxyethyl)-9-
methoxy-1-methyl-1H-naphtho[2,3-c]pyran (13). To the lactone 12
(380 mg, 0.945 mmol) in THF (15 mL) at ꢀ30 ꢁC was added meth-
ylmagnesium bromide (3 M in ether, 0.950 mL, 2.85 mmol) drop-
wise and the solution was allowed to warm to 0 ꢁC. Two further
portions of methylmagnesium bromide (each 0.400 mL,1.20 mmol)
were added at 1 h intervals. After 4 h at 0 ꢁC the reaction was
quenched with saturated aq ammonium chloride (15 mL), extrac-
ted with ethyl acetate (3ꢂ15 mL) and the combined organic layers
were dried (MgSO4) and concentrated in vacuo. The crude residue
was dissolved in dichloromethane (20 mL) and cooled to ꢀ60 ꢁC.
13C) as internal standard. Infrared (IR) spectra were recorded on
a PerkineElmer Spectrum One FT-IR spectrometer. Gas chroma-
tographyemass spectrometry (GCeMS) spectra were recorded on
an Agilent 7890A GC system using an HP-5MS column (30 m, i.d.
0.25 mm, film thickness 0.25
m
m) and 5975C MS system (EI, 70 eꢀV1).
GC heat programs, method A: 1005/2505, heating rate 5 ꢁC min
;
method B: 1005/25030, heating rate 10 ꢁC minꢀ1. The retention
time (tR) and selected fragment ions as their mass/charge ratio (m/
z) are reported. High-resolution ESI mass spectra (HRMS) were
recorded on a Thermo-Finnigan LTQ-FT ICR hybrid mass spec-
trometer. Specific rotations were measured using a JASCO DIP-1000
Trifluoroacetic acid (218 mL, 2.84 mmol) in dichloromethane

382
C.D. Donner / Tetrahedron 69 (2013) 377e386
(1.0 mL) was added dropwise followed by the addition of trie-
thylsilane (483 L, 3.02 mmol). The solution was allowed to warm
4.85e4.88 (1H, m, 1-H), 7.24 (1H, dd, J 8.1 and 1.6 Hz, 8-H), 7.59 (1H,
dd, J 8.1 and 7.7 Hz, 7-H), 7.62 (1H, dd, J 7.7 and 1.6 Hz, 6-H), 11.98
m
slowly to room temperature over 1 h and stirred for a further 1 h.
Water (15 mL) was added and after stirring for 15 min the mixture
was extracted with dichloromethane (3ꢂ10 mL) and the combined
organic layers concentrated in vacuo. The resultant oil was dis-
solved in THF (10 mL) and 2 M aq HCl (2 mL) and stirred at room
temperature for 16 h. The mixture was then diluted with water
(10 mL), extracted with ethyl acetate (3ꢂ15 mL) and the combined
organic layers were dried (MgSO4) and concentrated in vacuo. Flash
column chromatography (ethyl acetate/petrol 2:3) gave the title
(1H, s, 9-OH); 13C NMR (125 MHz, CDCl3)
d 21.1, 28.9, 37.3, 60.6,
69.8, 72.2, 114.9, 119.1, 124.5, 131.7, 136.2, 143.7, 146.0, 161.4, 183.0,
189.0; nmax 3408, 2938, 1659, 1635, 1610, 1455, 1278, 1237,
1055 cmꢀ1; GCeMS (method A, tR¼34.43 min) m/z 288.1 ([M]þ,
100%), 270.1 (50), 255.1 (29), 243.1 (48), 229.1 (39), 227.1 (28), 215.1
(61), 214.1 (84), 213.1 (56), 197.1 (40), 121.1 (34), 115.1 (25); HRMS
(ESI): found 289.1071, C16H17O5 ([MþH]þ) requires 289.1071.
4.2.5. (1S,3S)-3,4,5,10-Tetrahydro-9-hydroxy-1-methyl-5,10-dioxo-
1H-naphtho[2,3-c]pyran-3-acetic acid (16). To alcohol 15 (98.0 mg,
0.340 mmol) in dichloromethane (1.0 mL) were added
[bis(acetoxy)-iodo]benzene (120 mg, 0.361 mmol) and TEMPO
(5.0 mg, 0.032 mmol) and the mixture was stirred at room tem-
perature for 16 h. The reaction mixture was then diluted with aq
sodium thiosulfate (5 mL) and extracted with chloroform (4ꢂ5 mL).
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue, containing the crude intermediate aldehyde,
was dissolved in a mixture of acetone (2.0 mL), tert-butanol
(4.0 mL) and water (1.0 mL). 2-Methyl-2-butene (1.0 mL) was
added followed by sodium dihydrogenphosphate (159 mg,
1.15 mmol) and sodium chlorite (77.0 mg, 0.852 mmol) and the
mixture was stirred vigorously for 3 h. After addition of 2 M aq HCl
(2.0 mL) the mixture was extracted with chloroform (4ꢂ5 mL) and
the combined organic layers were dried (MgSO4) and concentrated
in vacuo. Flash column chromatography (ethyl acetate) gave the
compound 13 (201 mg, 74%) as a pale yellow oil; Rf (ethyl acetate/
25
petrol 1:1) 0.20; [
CDCl3)
a]
ꢀ140 (c 1.44, CHCl3); 1H NMR (500 MHz,
D
d
1.64 (3H, d, J 6.1 Hz, 1-CH3), 1.88e1.95 (2H, m, 3-CH2), 2.71
(1H, dt, J 15.4 and 1.0 Hz, 4-HaHb), 2.95 (1H, dd, J 15.4 and 11.0 Hz, 4-
HaHb), 3.82e3.87 (1H, m, 3-H), 3.89 (2H, t, J 5.6 Hz, CH2OH), 4.04
(3H, s, OCH3), 5.25 (1H, q, J 6.1 Hz, 1-H), 6.71 (1H, d, J 7.6 Hz, 8-H),
7.04 (1H, s, 5-H), 7.24 (1H, dd, J 8.2 and 7.6 Hz, 7-H), 7.30 (1H, d, J
8.2 Hz, 6-H), 9.63 (1H, s, 10-OH); 13C NMR (125 MHz, CDCl3)
d 21.7,
36.0, 37.5, 56.0, 61.6, 71.3, 74.2, 103.2, 113.6, 117.3, 120.9, 121.1, 125.3,
134.9, 135.0, 150.2, 156.0; nmax 3371, 2934, 1634, 1578, 1366, 1352,
1239, 1087, 1064 cmꢀ1; GCeMS (method A, tR¼37.10 min) m/z 288.1
([M]þ, 33%), 273.1 (100), 227.1 (21); HRMS (ESI): found 289.1434,
C17H21O4 ([MþH]þ) requires 289.1434.
4.2.3. (1S,3S)-3,4,5,10-Tetrahydro-3-(2-hydroxyethyl)-9-methoxy-1-
methyl-5,10-dioxo-1H-naphtho[2,3-c]pyran (14). To the naphthol 13
(50.0 mg, 0.173 mmol) in DMF (1.5 mL) was added NBS (32.0 mg,
0.180 mmol) in DMF (0.50 mL) and the solution was stirred in the
dark at room temperature for 18 h. Water (10 mL) was added and
the mixture was extracted with ethyl acetate (4ꢂ5 mL), the com-
bined organic extracts washed with water (4ꢂ10 mL), dried
(MgSO4) and concentrated in vacuo. The residual yellow oil was
dissolved in acetonitrile (2.0 mL) and a solution of ammonium
cerium(IV) nitrate (230 mg, 0.420 mmol) in water (0.75 mL) was
added dropwise. After stirring for 30 min, water (5 mL) was added
and the mixture extracted with chloroform (3ꢂ5 mL) and the
combined organic layers were dried (MgSO4) and concentrated in
vacuo. Flash column chromatography (ethyl acetate/chloroform
95:5) gave the title compound 14 (44 mg, 85%) as a yellow oil; Rf
title compound 16 (82 mg, 80%) as a yellow solid, mp 99e101 ꢁC
23
(dichloromethane/hexane); Rf (ethyl acetate) 0.24; [
a
]
D
ꢀ173 (c
0.32, CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.58 (3H, d, J 6.6 Hz, 1-
CH3), 2.35 (1H, ddd, J 18.5, 10.4 and 3.8 Hz, 4-HaHb), 2.69 (1H, dd,
J 16.1 and 5.2 Hz, 3-CHaHb), 2.77 (1H, dd, J 16.1 and 7.6 Hz, 3-CHaHb),
2.89 (1H, dt, J 18.5 and 2.6 Hz, 4-HaHb), 3.91e3.99 (1H, m, 3-H),
4.87e4.90 (1H, m, 1-H), 7.25 (1H, dd, J 8.2 and 1.5 Hz, 8-H), 7.59 (1H,
dd, J 8.2 and 7.6 Hz, 7-H), 7.63 (1H, dd, J 7.6 and 1.5 Hz, 6-H), 11.97
(1H, s, 9-OH); 13C NMR (125 MHz, CDCl3)
d 20.9, 28.5, 40.1, 68.9,
70.0, 115.0, 119.1, 124.5, 131.7, 136.2, 143.2, 146.2, 161.5, 175.7, 182.9,
188.9; nmax 2938, 1712, 1661, 1636, 1611, 1456, 1273, 1238,
1102 cmꢀ1; GCeMS (method A, tR¼35.87 min) m/z 302.0 ([M]þ,
35%), 284.1 (100), 256.0 (27), 243.1 (51), 242.1 (89), 241.1 (69), 227.1
(51), 214.0 (64), 213.0 (45), 139.1 (27), 128.1 (28), 121.0 (40), 115.0
(29); HRMS (ESI): found 301.0725, C16H13O6 ([MꢀH]ꢀ) requires
301.0718.
(ethyl acetate) 0.35; [
CDCl3)
a
]
22 ꢀ196 (c 1.08, CHCl3); 1H NMR (500 MHz,
D
d
1.53 (3H, d, J 6.6 Hz, 1-CH3), 1.90e1.94 (2H, m, 3-CH2), 2.32
(1H, ddd, J 18.2, 10.4 and 3.6 Hz, 4-HaHb), 2.75 (1H, dt, J 18.2 and
2.4 Hz, 4-HaHb), 3.68e3.73 (1H, m, 3-H), 3.84e3.89 (2H, m, CH2OH),
3.99 (3H, s, OCH3), 4.86e4.90 (1H, m, 1-H), 7.28 (1H, d, J 8.4 Hz, 8-
H), 7.64 (1H, dd, J 8.4 and 7.8 Hz, 7-H), 7.73 (1H, d, J 7.8 Hz, 6-H); 13C
4.2.6. 5-epi-Kalafungin (17). A solution of acid 16 (30.0 mg,
0.099 mmol) in methanol (7.0 mL) and pyridine (0.5 mL) was
maintained at 60 ꢁC whilst oxygen was bubbled through the solu-
tion. After 14 h the solution was concentrated in vacuo then 2 M aq
HCl (2.0 mL) was added and the mixture extracted with chloroform
(4ꢂ5 mL) and the combined organic layers dried (MgSO4) and
concentrated in vacuo. The resultant residue was dissolved in
dichloromethane (4.0 mL) and cooled to ꢀ45 ꢁC. Boron trifluoride
NMR (125 MHz, CDCl3)
d 20.8, 28.2, 37.4, 56.4, 60.6, 70.3, 72.2, 117.8,
119.0, 120.1, 133.8, 134.6, 139.5, 148.2, 159.4, 183.4, 183.8; nmax 3508,
2939, 1651, 1585, 1257, 1057 cmꢀ1
;
GCeMS (method A,
tR¼37.42 min) m/z 302.1 ([M]þ, 100%), 269.1 (23), 257.1 (92), 243.1
(50), 241.1 (26), 229.1 (26); HRMS (ESI): found 303.1227, C17H19O5
([MþH]þ) requires 303.1227.
diethyl etherate (75
mL, 0.592 mmol) was added and stirring was
4.2.4. (1S,3S)-3,4,5,10-Tetrahydro-9-hydroxy-3-(2-hydroxyethyl)-1-
methyl-5,10-dioxo-1H-naphtho[2,3-c]pyran (15). To the methyl
ether 14 (110 mg, 0.364 mmol) in dichloromethane (10 mL) was
added aluminium chloride (388 mg, 2.91 mmol) and the mixture
was stirred at room temperature for 90 min. After addition of water
(15 mL) and chloroform (10 mL) the mixture was stirred vigorously
for 30 min. Extraction with chloroform (5ꢂ10 mL), drying (MgSO4)
and concentration in vacuo gave the title compound 15 (99 mg, 94%)
as a yellow oil that was used without further purification; Rf (ethyl
continued for 10 min. Triethylsilane (144
m
L, 0.902 mmol) was
added and stirring was continued at ꢀ45 ꢁC for 10 min followed by
warming to 0 ꢁC over 15 min. Water (5 mL) was added, the mixture
vigorously stirred (10 min) then extracted with chloroform
(4ꢂ5 mL) and the combined organic layers dried (MgSO4) and
concentrated in vacuo. Flash column chromatography (ethyl ace-
tate) gave the title compound 17 (14 mg, 47%, 64% based on re-
covered acid 16) as a yellow oil, Rf (ethyl acetate) 0.65, and
recovered acid 16 (8 mg). Data for 17: [
a
]
20 ꢀ90.5 (c 0.24, CHCl3). 1H
D
acetate) 0.54; [
a]
23 ꢀ240 (c 0.04, CHCl3); 1H NMR (500 MHz, CDCl3)
NMR (500 MHz, CDCl3)
d
1.64 (3H, d, J 6.7 Hz, 5-CH3), 2.74 (1H, d, J
D
d
1.58 (3H, d, J 6.6 Hz, 1-CH3), 1.89e1.95 (2H, m, 3-CH2), 2.37 (1H,
17.3 Hz, 3-HaHb), 2.89 (1H, dd, J 17.3 and 4.5 Hz, 3-HaHb), 4.35 (1H,
dd, J 4.5 and 2.4 Hz, 3a-H), 4.79 (1H, qd, J 6.7 and 1.6 Hz, 5-H),
5.26e5.27 (1H, m, 11b-H), 7.30 (1H, dd, J 7.9 and 1.6 Hz, 8-H), 7.67
ddd, J 18.6, 10.5 and 3.9 Hz, 4-HaHb), 2.77 (1H, dt, J 18.6 and 2.6 Hz,
4-HaHb), 3.69e3.74 (1H, m, 3-H), 3.83e3.91 (2H, m, CH2OH),

C.D. Donner / Tetrahedron 69 (2013) 377e386
383
(1H, dd, J 7.9 and 7.5 Hz, 9-H), 7.69 (1H, dd, J 7.5 and 1.6 Hz, 10-H),
11.74 (1H, s, 7-OH); 13C NMR (125 MHz, CDCl3)
20.6, 37.2, 68.6,
69.7, 71.1, 115.1, 119.6, 124.8, 131.4, 135.6, 137.0, 150.2, 161.7, 174.2,
181.6, 188.6; nmax 3503, 2927, 1786, 1666, 1644, 1616, 1456, 1283,
1246, 1147, 1037 cmꢀ1; HRMS (ESI): found 299.0568, C16H11O6
([MꢀH]ꢀ) requires 299.0561.
(Method B, tR¼27.45 min) m/z 316.1 ([M]þ, 10%), 273.1 (100); HRMS
(ESI): found 317.1749, C19H25O4 ([MþH]þ) requires 317.1747.
d
4.2.9. (1S,3S)-3-(2-Hydroxyethyl)-9-methoxy-1-propyl-3,4-dihydro-
1H-benzo[g]isochromene-5,10-dione (21). To the naphthol 20
(31.0 mg, 0.098 mmol) in DMF (1.0 mL) was added NBS (18.5 mg,
0.104 mmol) and the solution was stirred in the dark at room tem-
perature for 18 h. Water (10 mL) was added and the mixture was
extracted with chloroform (3ꢂ5 mL), the combined organic extracts
washed with water (3ꢂ10 mL), dried (MgSO4) and concentrated in
vacuo. The residual yellow oil was dissolved in acetonitrile (2.0 mL)
4.2.7. Kalafungin (1). To the cis-pyran 17 (8.0 mg, 0.027 mmol) in
benzene (0.5 mL) at 5 ꢁC was added concentrated H2SO4 (10 drops).
After 5 min the mixture was warmed to room temperature and
stirred for 30 min. After ice (5 g) and ethyl acetate (10 mL) were
added the mixture was stirred vigorously (15 min), washed with
brine (3ꢂ5 mL) and the organic layer dried (MgSO4) and concen-
trated in vacuo. Flash column chromatography (dichloromethane/
and
a solution of ammonium cerium(IV) nitrate (107 mg,
0.196 mmol) in water (0.20 mL) was added dropwise. After stirring
for 30 min, water (10 mL) was added and the mixture extracted with
chloroform (3ꢂ5 mL) and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. Flash column chromatography
chloroform
4:1
then
dichloromethane/chloroform/acetone
80:15:5) gave the title compound 1 (6.5 mg, 81%) as a yellow solid as
a 93:7 diastereoisomeric mixture of trans/cis pyrans 1 and 17; Rf
(dichloromethane/chloroform/acetone 80:15:5) 0.40. Data for 1: 1H
(ethyl acetate/chloroform 4:1) gave the title compound 21 (28 mg,
20
88%) as a yellow oil; Rf (ethyl acetate/chloroform 4:1) 0.40; [a]
D
NMR (500 MHz, CDCl3)
d
1.57 (3H, d, J 6.8 Hz, 5-CH3), 2.71 (1H, d, J
ꢀ167 (c 0.74, CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.92 (3H, t, J 7.5 Hz,
17.7 Hz, 3-HaHb), 2.96 (1H, dd, J 17.7 and 5.1 Hz, 3-HaHb), 4.69 (1H,
dd, J 5.1 and 3.0 Hz, 3a-H), 5.09 (1H, q, J 6.8 Hz, 5-H), 5.26 (1H, d, J
3.0 Hz, 11b-H), 7.31 (1H, dd, J 8.3 and 1.5 Hz, 8-H), 7.67 (1H, dd, J 8.3
and 7.6 Hz, 9-H), 7.71 (1H, dd, J 7.6 and 1.5 Hz, 10-H), 11.84 (1H, s, 7-
CH3), 1.40e1.51 (2H, m, CH2CH3), 1.69e1.76 (1H, m, 1-CHaHb),
1.91e1.94 (2H, m, 3-CH2),1.96e2.03 (1H, m,1-CHaHb), 2.30 (1H, ddd,
J 18.1,10.5 and 3.9 Hz, 4-HaHb), 2.76 (1H, ddd, J 18.1, 2.4 and 2.7 Hz, 4-
HaHb), 3.66e3.71 (1H, m, 3-H), 3.85e3.88 (2H, m, CH2OH), 4.00 (3H,
s, OCH3), 4.84e4.87 (1H, m, 1-H), 7.28 (1H, dd, J 8.6 and 1.1 Hz, 8-H),
7.65 (1H, dd, J 8.6 and 7.6 Hz, 7-H), 7.74 (1H, dd, J 7.6 and 1.1 Hz, 6-H);
OH); 13C NMR (125 MHz, CDCl3)
d 18.6, 36.9, 66.2, 66.4, 68.6, 114.8,
119.8, 124.9, 131.5, 135.1, 137.2, 149.7, 161.9, 173.9, 181.5, 188.0; nmax
2927, 1783, 1650, 1621, 1456, 1284, 1243, 1196, 1150 cmꢀ1; HRMS
(ESI): found 301.0707, C16H13O6 ([MþH]þ) requires 301.0707.
The spectroscopic data (1H and 13C NMR) are in close agreement
with the literature.12
13C NMR (125 MHz, CDCl3)
d 13.8, 18.7, 28.2, 36.2, 37.3, 56.4, 60.9,
72.5, 73.7, 117.8, 119.0, 120.1, 133.9, 134.6, 140.1, 147.6, 159.4, 183.5,
183.6; nmax 3459, 2932, 1723, 1655, 1586, 1271, 1051 cmꢀ1; GCeMS
(method B, tR¼27.25 min) m/z 330.2 ([M]þ, 100%), 287.1 (84), 285.1
(61), 269.1 (46), 256.0 (30), 254.0 (29), 243.0 (37), 241.0 (47), 227.0
(39), 128.1 (26), 115.0 (27), 76.0 (26); HRMS (ESI): found 331.1541,
C19H23O5 ([MþH]þ) requires 331.1540.
4.2.8. (1S,3S)-3-(2-Hydroxyethyl)-9-methoxy-1-propyl-3,4-dihydro-
1H-benzo[g]isochromen-10-ol (20). To the lactone 12 (206 mg,
0.510 mmol) in THF (10 mL) at ꢀ50 ꢁC was added propylmagne-
sium chloride (2 M in ether, 1.00 mL, 2.00 mmol) dropwise and the
solution was allowed to warm to 0 ꢁC over 1 h. A further portion of
propylmagnesium chloride (0.50 mL, 1.00 mmol) was added and
after 1 h at 0 ꢁC the reaction was quenched with saturated aq am-
monium chloride (10 mL), extracted with ethyl acetate (3ꢂ10 mL)
and the combined organic layers were washed with brine (15 mL),
dried (MgSO4) and concentrated in vacuo. The crude residue was
dissolved in dichloromethane (10 mL) and cooled to ꢀ60 ꢁC. Tri-
4.2.10. (1S,3S)-9-Hydroxy-3-(2-hydroxyethyl)-1-propyl-3,4-dihydro-
1H-benzo[g]isochromene-5,10-dione (22). To the methyl ether 21
(28 mg, 0.085 mmol) in dichloromethane (1.5 mL) at ꢀ50 ꢁC was
added boron trichloride (1.0 M in dichloromethane, 0.45 mL,
0.45 mmol) and the mixture was allowed to warm slowly to 0 ꢁC
over 1 h. After addition of ice (5 g), water (5 mL) and chloroform
(5 mL) the mixture was stirred vigorously for 30 min. Extraction
with chloroform (3ꢂ5 mL), drying (MgSO4) and concentration in
vacuo gave a yellow residue. Flash column chromatography (ethyl
acetate/chloroform 1:1) gave the title compound 22 (12 mg, 44%) as
a yellow oil as a 4:1 mixture of cis-/trans-diastereoisomers; Rf (ethyl
acetate/chloroform 4:1) 0.50; 1H NMR (500 MHz, CDCl3, major di-
fluoroacetic acid (114
was added dropwise followed by the addition of triethylsilane
(262 L, 1.64 mmol). The solution was allowed to warm slowly to
mL, 1.54 mmol) in dichloromethane (1.0 mL)
m
room temperature over 1 h and stirred for a further 1 h. Water
(10 mL) and 2 M aq HCl (5 mL) were added and after stirring for
15 min the mixture was extracted with chloroform (3ꢂ10 mL) and
the combined organic layers concentrated in vacuo. The resultant
oil was dissolved in THF (5.0 mL) and 2 M aq HCl (1.0 mL) and
stirred at room temperature for 1 h. The mixture was then diluted
with water (10 mL), extracted with chloroform (3ꢂ10 mL) and the
combined organic layers were dried (MgSO4) and concentrated in
vacuo. Flash column chromatography (ethyl acetate/petrol 1:2)
gave the title compound 20 (76 mg, 47%) as a pale yellow oil; Rf
astereoisomer)
d 0.93 (3H, t, J 7.5 Hz, CH3), 1.36e1.58 (2H, m,
CH2CH3), 1.76e1.82 (1H, m, 1-CHaHb), 1.88e1.95 (2H, m, 3-CH2),
2.02e2.09 (1H, m,1-CHaHb), 2.34 (1H, ddd, J 18.5,10.3 and 4.0 Hz, 4-
HaHb), 2.78 (1H, ddd, J 18.5, 2.6 and 2.6 Hz, 4-HaHb), 3.67e3.71 (1H,
m, 3-H), 3.86e3.89 (2H, m, CH2OH), 4.82e4.86 (1H, m, 1-H), 7.24
(1H, dd, J 8.0 and 1.5 Hz, 8-H), 7.59 (1H, dd, J 8.0 and 7.5 Hz, 7-H),
7.62 (1H, dd, J 7.5 and 1.5 Hz, 6-H), 11.98 (1H, s, 9-OH); 13C NMR
(125 MHz, CDCl3, major diastereoisomer)
d 14.0, 18.6, 29.0, 36.6,
37.3, 60.9, 72.3, 73.1, 114.9, 119.1, 124.5, 131.7, 136.2, 144.4, 145.3,
161.5, 182.8, 189.0; nmax 3460, 2927, 1660, 1637, 1612, 1456, 1279,
1241, 1057 cmꢀ1; GCeMS (method A, tR¼36.67 min) m/z 316.1
([M]þ, 62%), 273.1 (94), 255.1 (100), 229.1 (56), 227.1 (45), 213.1
(32), 121.0 (28); HRMS (ESI): found 317.1384, C18H21O5 ([MþH]þ)
requires 317.1384.
(ethyl acetate/petrol 1:2) 0.25; [
(500 MHz, CDCl3)
a
]
19 ꢀ200 (c 0.62, CHCl3); 1H NMR
D
d
0.92 (3H, t, J 7.3 Hz, CH3), 1.32e1.39 (1H, m,
CHaHbCH3), 1.45e1.51 (1H, m, CHaHbCH3), 1.83e1.90 (1H, m, 1-
CHaHb), 1.91e1.96 (2H, m, 3-CH2), 2.09e2.16 (1H, m, 1-CHaHb),
2.69 (1H, dd, J 15.4 and 1.9 Hz, 4-HaHb), 2.93 (1H, dd, J 15.4 and
11.0 Hz, 4-HaHb), 3.82e3.87 (1H, m, 3-H), 3.88e3.90 (2H, m,
CH2OH), 4.05 (3H, s, OCH3), 5.22e5.24 (1H, m, 1-H), 6.71 (1H, dd, J
7.6 and 1.0 Hz, 8-H), 7.04 (1H, s, 5-H), 7.23e7.26 (1H, m, 7-H), 7.31
(1H, dd, J 8.3 and 1.0 Hz, 6-H), 9.62 (1H, s, 10-OH); 13C NMR
4.2.11. 2-((1S,3S)-9-Hydroxy-5,10-dioxo-1-propyl-3,4,5,10-
tetrahydro-1H-benzo[g]isochromen-3-yl)acetic acid (23) (1-epi-de-
oxyfrenolicin). To alcohol 22 (12.0 mg, 0.038 mmol) in dichloro-
methane (0.5 mL) were added [bis(acetoxy)-iodo]benzene (14.0 mg,
0.043 mmol) and TEMPO (1.0 mg, 0.006 mmol) and the mixture was
stirred at room temperature for 7 h. The reaction mixture was then
(125 MHz, CDCl3) d 14.1, 18.6, 36.2, 37.2, 37.5, 56.0, 61.8, 74.39, 74.41,
103.3, 113.6, 117.1, 119.7, 121.1, 125.3, 134.9, 135.6, 150.0, 156.1; nmax
3379, 2928, 1578, 1368, 1353, 1236, 1087, 1065 cmꢀ1; GCeMS

384
C.D. Donner / Tetrahedron 69 (2013) 377e386
diluted with aq sodium thiosulfate (5 mL) and extracted with chlo-
roform (3ꢂ5 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo. The residue, containing the crude in-
termediate aldehyde, was dissolved in a mixture of acetone (0.2 mL),
tert-butanol (0.5 mL) and water (0.2 mL). 2-Methyl-2-butene
(0.1 mL) was added followed by sodium dihydrogenphosphate
(18.0 mg, 0.114 mmol) and sodium chlorite (9.0 mg, 0.100 mmol)
and the mixture was stirred vigorously for 3 h. After addition of 2 M
aq HCl (2.0 mL) the mixture was extracted with chloroform
(4ꢂ5 mL) and the combined organic layers were dried (MgSO4) and
concentrated in vacuo. Flash column chromatography (ethyl ace-
tate/chloroform 2:1) gave the title compound 23 (9.0 mg, 72%) as
a yellow solid; Rf (ethyl acetate) 0.63; 1H NMR (500 MHz, CDCl3,
bromide (each 0.35 mL, 1.05 mmol) were added at 1 h intervals.
After 4 h at 0 ꢁC the reaction was quenched with saturated aq
ammonium chloride (20 mL), extracted with ethyl acetate
(3ꢂ10 mL) and the combined organic layers were dried (MgSO4)
and concentrated in vacuo. The crude residue was dissolved in
dichloromethane (15 mL) and cooled to ꢀ60 ꢁC. Trifluoroacetic acid
(160
mL, 2.08 mmol) in dichloromethane (1 mL) was added drop-
wise followed by the addition of triethylsilane (355
mL, 2.22 mmol).
The solution was allowed to warm slowly to room temperature over
1 h and stirred for a further 1 h. Water (15 mL) was added and after
stirring for 15 min the mixture was extracted with dichloro-
methane (3ꢂ10 mL) and the combined organic layers concentrated
in vacuo. The resultant oil was dissolved in THF (10 mL) and 2 M aq
HCl (5 mL) and stirred at room temperature for 18 h. The mixture
was then diluted with water (10 mL), extracted with chloroform
(3ꢂ10 mL) and the combined organic layers were dried (MgSO4)
and concentrated in vacuo. Flash column chromatography (ethyl
acetate/petrol 1:2) gave the title compound (pyran) 30 (88 mg, 40%)
as a pale yellow oil, Rf (ethyl acetate/petrol 1:2) 0.17, and the title
major diastereoisomer) d 0.92 (3H, t, J 7.5 Hz, CH3),1.31e1.41 (1H, m,
CHaHbCH3), 1.43e1.52 (1H, m, CHaHbCH3), 1.77e1.84 (1H, m, 1-
CHaHb), 2.02e2.07 (1H, m, 1-CHaHb), 2.29e2.36 (1H, m, 4-HaHb),
2.70 (1H, dd, J 15.8 and 5.8 Hz, CHaHbCO2H), 2.76 (1H, dd, J 15.8 and
7.6 Hz, CHaHbCO2H), 2.90 (1H, ddd, J 18.4, 2.5 and 2.5 Hz, 4-HaHb),
3.89e3.93 (1H, m, 3-H), 4.84e4.86 (1H, m, 1-H), 7.25 (1H, dd, J 8.2
and 1.3 Hz, 8-H), 7.59 (1H, dd, J 8.2 and 7.6 Hz, 7-H), 7.62 (1H, dd, J 7.6
and 1.3 Hz, 6-H), 11.98 (1H, s, 9-OH); 13C NMR (125 MHz, CDCl3,
compound (acetal) 29 (65 mg, 30%) as a pale yellow oil, Rf (ethyl
20
acetate/petrol 1:2) 0.24. Data for pyran 30: [
a
]
D
ꢀ105 (c 1.60,
major diastereoisomer)
d
13.9,18.3, 28.5, 36.4, 40.0, 68.7, 73.3,114.9,
CHCl3); 1H NMR (500 MHz, CDCl3)
d 1.62 (3H, d, J 6.3 Hz, 1-CH3),
119.1, 124.5, 131.7, 136.2, 143.9, 145.4, 161.5, 175.0, 182.6, 188.9; nmax
2926, 1712, 1661, 1637, 1612, 1456, 1274, 1243 cmꢀ1; HRMS (ESI):
found 329.1022, C18H17O6 ([MꢀH]ꢀ) requires 329.1031.
The spectroscopic data (1H and 13C NMR) are in close agreement
with the literature.27,29
1.89e1.94 (2H, m, 3-CH2), 2.67 (1H, dd, J 15.4 and 2.0 Hz, 4-HaHb),
2.92 (1H, dd, J 15.4 and 11.2 Hz, 4-HaHb), 3.82e3.86 (1H, m, 3-H),
3.87 (3H, s, OCH3), 3.89 (2H, t, J 5.5 Hz, CH2OH), 4.02 (3H, s, OCH3),
5.21 (1H, q, J 6.3 Hz, 1-H), 6.39 (1H, d, J 2.2 Hz, 8-H), 6.61 (1H, d, J
2.2 Hz, 6-H), 6.93 (1H, s, 5-H), 9.40 (1H, s, 10-OH); 13C NMR
(125 MHz, CDCl3)
d 21.8, 36.0, 37.5, 55.2, 56.0, 61.4, 71.2, 74.0, 97.1,
4.2.12. 5-epi-Frenolicin B (24). A solution of acid 23 (8.0 mg,
0.024 mmol) in methanol (4.0 mL) and pyridine (0.3 mL) was
maintained at 65 ꢁC whilst oxygen was bubbled through the solu-
tion. After 10 h the solution was concentrated in vacuo then 1 M aq
HCl (5.0 mL) was added and the mixture extracted with chloroform
(4ꢂ5 mL) and the combined organic layers dried (MgSO4) and
concentrated in vacuo. The resultant residue was dissolved in
dichloromethane (1.5 mL) and cooled to ꢀ45 ꢁC. Boron trifluoride
98.5, 109.4, 116.4, 118.9, 135.5, 135.6, 150.3, 157.1, 157.4; nmax 3380,
2928, 1630, 1594, 1357, 1264, 1205, 1160 cmꢀ1; GCeMS (method A,
tR¼33.76 min) m/z 318.2 ([M]þ, 25%), 303.1 (100); HRMS (ESI):
found 341.1359, C18H22O5Na ([MþNa]þ) requires 341.1359; Data for
19
acetal 29: [
d
a]
ꢀ24.6 (c 0.060, CHCl3); 1H NMR (500 MHz, CDCl3)
D
1.37 (1H, dd, J 13.7 and 3.0 Hz, 10-HaHb), 2.05 (3H, s, 1-CH3),
2.44e2.51 (1H, m, 10-HaHb), 2.73 (1H, d, J 17.1 Hz, 4-HaHb), 3.55 (1H,
dd, J 17.1 and 7.3 Hz, 4-HaHb), 3.57e3.63 (1H, m, 20-HaHb), 3.76 (1H,
dd, J 11.8 and 6.7 Hz, 20-HaHb), 3.87 (3H, s, 7-OCH3), 4.01 (3H, s, 9-
OCH3), 4.49e4.52 (1H, m, 3-H), 6.40 (1H, d, J 2.1 Hz, 8-H), 6.60
(1H, d, J 2.1 Hz, 6-H), 6.96 (1H, s, 5-H), 9.82 (1H, br s, 10-OH); 13C
diethyl etherate (15.0
mL, 0.119 mmol) was added and stirring was
continued for 10 min. Triethylsilane (30.0
m
L, 0.188 mmol) was
added and stirring was continued at ꢀ45 ꢁC for 10 min followed by
warming to 0 ꢁC over 15 min. Water (5 mL) was added, the mixture
vigorously stirred (10 min) then extracted with chloroform
(4ꢂ5 mL) and the combined organic layers dried (MgSO4) and
concentrated in vacuo. Flash column chromatography (ethyl ace-
tate/chloroform 1:1) gave the title compound 24 (4.0 mg, 50%) as
a yellow oil; Rf (ethyl acetate/chloroform 1:1) 0.64; 1H NMR
NMR (125 MHz, CDCl3) d 27.0, 29.2, 33.3, 55.3, 56.2, 59.1, 66.2, 97.3,
98.4, 109.7, 115.7, 115.9, 136.5, 136.6, 152.2, 157.7, 158.1 (1 signal
obscured); nmax 3370, 2939, 1630, 1586, 1364, 1204, 1159, 1100,
1044 cmꢀ1; GCeMS (method A, tR¼33.95 min) m/z 316.1 ([M]þ,
54%), 301.1 (100), 255.1 (54), 254.1 (35), 240.1 (22), 239.1 (25);
HRMS (ESI): found 317.1383, C18H21O5 ([MþH]þ) requires 317.1384.
(500 MHz, CDCl3, major diastereoisomer)
d 0.91 (3H, t, J 7.4 Hz,
CH3), 1.28e1.35 (1H, m, CHaHbCH3), 1.43e1.49 (1H, m, CHaHbCH3),
1.91e1.98 (1H, m, 1-CHaHb), 2.04e2.10 (1H, m, 1-CHaHb), 2.75 (1H,
d, J 17.5 Hz, 3-HaHb), 2.88 (1H, dd, J 17.5 and 4.5 Hz, 3-HaHb), 4.32
(1H, dd, J 4.5 and 2.3 Hz, 3a-H), 4.75e4.78 (1H, m, 5-H), 5.27 (1H,
dd, J 2.3 and 2.3 Hz, 11b-H), 7.30 (1H, dd, J 8.1 and 1.6 Hz, 8-H), 7.67
(1H, dd, J 8.1 and 7.5 Hz, 9-H), 7.70 (1H, dd, J 7.5 and 1.6 Hz, 10-H),
11.74 (1H, s, 7-OH); 13C NMR (125 MHz, CDCl3, major di-
4.2.14. (1S,3S)-3,4-Dihydro-10-hydroxy-3-(2-hydroxyethyl)-7,9-
dimethoxy-1-methyl-1H-naphtho[2,3-c]pyran (30) (from reduction of
acetal 29). To the acetal 29 (15.0 mg, 0.047 mmol) in THF at 0 ꢁC
was added NaBH4 (40 mg, 1.06 mmol) and the solution was stirred
for 1 h. After addition of further NaBH4 (20 mg, 0.53 mmol) the
solution was allowed to warm to room temperature and stirred for
2 h. Water was then added followed by 2 M aq HCl and the mixture
was extracted with chloroform (3ꢂ5 mL) and the combined organic
layers were dried (MgSO4) and concentrated in vacuo. Flash column
chromatography (ethyl acetate/petrol 1:2) gave the title compound
30 (13.0 mg, 87%) as a pale yellow oil. The spectroscopic data were
identical to that described above.
astereoisomer)
d 13.9, 18.2, 36.0, 37.3, 69.7, 70.8, 71.8, 115.0, 119.6,
124.8, 131.4, 136.2, 137.1, 149.7, 161.7, 174.3, 181.4, 188.7; nmax 2960,
1787, 1665, 1644, 1617, 1456, 1284, 1247, 1148 cmꢀ1; HRMS (ESI):
found 327.0878, C18H15O6 ([MꢀH]ꢀ) requires 327.0874.
The spectroscopic data (1H and 13C NMR) are in close agreement
with the literature.27,30
4.2.15. (1S,3S)-3,4,5,10-Tetrahydro-3-(2-hydroxyethyl)-7,9-
4.2.13. (1S,3S)-3,4-Dihydro-10-hydroxy-3-(2-hydroxyethyl)-7,9-
dimethoxy-1-methyl-1H-naphtho[2,3-c]pyran (30) and cyclic acetal
(29). To the naphthopyranone 2823 (300 mg, 0.690 mmol) in THF
(15 mL) at ꢀ40 ꢁC was added methylmagnesium bromide (3.0 M in
ether, 0.70 mL, 2.10 mmol) dropwise and the solution was allowed
to warm to 0 ꢁC. Two further portions of methylmagnesium
dimethoxy-1-methyl-5,10-dioxo-1H-naphtho[2,3-c]pyran
(31). To
the naphthol 30 (35.0 mg, 0.11 mmol) in MeCN (2.5 mL) was added
salcomine (7.0 mg, 0.022 mmol) and the mixture was stirred under
an atmosphere of oxygen for 23 h. The mixture was filtered through
Celite and concentrated in vacuo. Flash column chromatography
(ethyl acetate/chloroform 4:1) gave the title compound 31 (27.0 mg,

C.D. Donner / Tetrahedron 69 (2013) 377e386
385
20
74%) as a yellow solid; Rf (ethyl acetate/chloroform 4:1) 0.40; [
a
]
was maintained at 60 ꢁC whilst oxygen was bubbled through the
solution. After 10 h the solution was concentrated in vacuo then
2 M aq HCl (2.0 mL) was added and the mixture extracted with
chloroform (4ꢂ5 mL) and the combined organic layers dried
(MgSO4) and concentrated in vacuo. The resultant residue was
dissolved in dichloromethane (2.0 mL) and cooled to ꢀ45 ꢁC. Boron
D
ꢀ161 (c 0.22, CHCl3); 1H NMR (500 MHz, CDCl3)
d 1.53 (3H, d, J
6.6 Hz, 1-CH3), 1.84e1.93 (2H, m, 3-CH2), 2.31 (1H, ddd, J 18.2, 10.5
and 3.8 Hz, 4-HaHb), 2.72 (1H, dt, J 18.2 and 2.6 Hz, 4-HaHb),
3.68e3.72 (1H, m, 3-H), 3.85e3.88 (2H, m, CH2OH), 3.94 (3H, s,
OCH3), 3.95 (3H, s, OCH3), 4.86e4.88 (1H, m, 1-H), 6.71 (1H, d, J
2.4 Hz, 8-H), 7.24 (1H, d, J 2.4 Hz, 6-H); 13C NMR (125 MHz, CDCl3)
trifluoride diethyl etherate (25
mL, 0.199 mmol) was added and
d
21.0, 28.3, 37.4, 55.9, 56.4, 60.8, 70.5, 72.5, 103.1, 104.2, 114.7, 135.6,
stirring was continued for 10 min. Triethylsilane (50 m
L,
139.0, 148.4, 161.7, 164.5, 182.3, 183.9; nmax 3478, 2924, 1647, 1593,
1564, 1318, 1267, 1156, 1048 cmꢀ1; HRMS (ESI): found 333.1331,
C18H21O6 ([MþH]þ) requires 333.1333.
0.313 mmol) was added and stirring was continued at ꢀ45 ꢁC for
10 min followed by warming to 0 ꢁC over 15 min. Water (5 mL) was
added, the mixture vigorously stirred (10 min) then extracted with
chloroform (4ꢂ5 mL) and the combined organic layers dried
(MgSO4) and concentrated in vacuo. Flash column chromatography
(ethyl acetate) gave the title compound 34 (7.0 mg, 41%, 64% based
4.2.16. (1S,3S)-3,4,5,10-Tetrahydro-9-hydroxy-3-(2-hydroxyethyl)-7-
methoxy-1-methyl-5,10-dioxo-1H-naphtho[2,3-c]pyran (32). To the
methyl ether 31 (27.0 mg, 0.081 mmol) in dichloromethane (2 mL)
at 0 ꢁC was added aluminium chloride (85 mg, 0.637 mmol) and the
mixture was stirred for 30 min, warmed to room temperature and
stirred for a further 45 min. After addition of water (5 mL) and
chloroform (5 mL) the mixture was stirred vigorously for 30 min.
Extraction with chloroform (3ꢂ5 mL), drying (MgSO4) and con-
centration in vacuo gave the title compound 32 (25.0 mg, 96%) as
a yellow oil that was used without further purification; Rf (ethyl
acetate) 0.60; [
CDCl3)
(1H, ddd, J 18.6, 10.4 and 3.9 Hz, 4-HaHb), 2.74 (1H, dt, J 18.6 and
2.6 Hz, 4-HaHb), 3.67e3.70 (1H, m, 3-H), 3.85e3.89 (2H, m, CH2OH),
3.90 (3H, s, OCH3), 4.83e4.86 (1H, m, 1-H), 6.63 (1H, d, J 2.6 Hz, 8-
H), 7.18 (1H, d, J 2.6 Hz, 6-H), 12.22 (1H, s, 9-OH); 13C NMR
on recovered acid 33) as a yellow oil, and recovered acid 33
20
(6.0 mg). Data for 34: Rf (ethyl acetate) 0.50; [
a
]
ꢀ60.0 (c 0.06,
D
CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.63 (3H, d, J 6.7 Hz, 5-CH3),
2.73 (1H, d, J 17.5 Hz, 3-HaHb), 2.88 (1H, dd, J 17.5 and 4.5 Hz, 3-
HaHb), 3.94 (3H, s, OCH3), 4.33 (1H, dd, J 4.5 and 2.5 Hz, 3a-H),
4.77 (1H, qd, J 6.7 and 1.7 Hz, 5-H), 5.24e5.25 (1H, m, 11b-H), 6.67
(1H, d, J 2.5 Hz, 8-H), 7.23 (1H, d, J 2.5 Hz, 10-H), 12.01 (1H, s, 7-OH);
13C NMR (125 MHz, CDCl3)
d 20.8, 37.3, 56.2, 68.7, 69.8, 71.0, 106.5,
20
a
]
D
ꢀ199 (c 0.046, CHCl3); 1H NMR (500 MHz,
108.4, 109.8, 133.0, 134.9, 150.8, 164.7, 166.6, 174.3, 181.6, 186.5; nmax
2925, 1790, 1610, 1303, 1265, 1205, 1150 cmꢀ1; HRMS (ESI): found
329.0670, C17H13O7 ([MꢀH]ꢀ) requires 329.0667.
d
1.58 (3H, d, J 6.6 Hz, 1-CH3), 1.91e1.95 (2H, m, 3-CH2), 2.36
Acknowledgements
(125 MHz, CDCl3) d 21.2, 28.9, 37.3, 56.0, 60.5, 69.9, 72.1, 106.2, 107.7,
Financial support from the Australian Research Council through
the Centres of Excellence program is gratefully acknowledged.
Professor Carl Schiesser, The University of Melbourne, is acknowl-
edged for useful discussions.
109.5, 133.2, 142.8, 146.4, 164.3, 165.8, 182.9, 187.2; nmax 3435, 2928,
1635, 1608, 1387, 1313, 1272, 1207 cmꢀ1; GCeMS (method A,
tR¼39.80 min) m/z 318.1 ([M]þ, 100%), 300.1 (28), 273.1 (50), 259.0
(38), 257.0 (24), 245.0 (38), 244.0 (53), 243.0 (40), 151.0 (30); HRMS
(ESI): found 317.1031, C17H17O6 ([MꢀH]ꢀ) requires 317.1031.
Supplementary data
1H NMR and 13C NMR spectra for compounds 1, 12e17, 20e24,
29e31 and 33e34. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.10.012.
4.2.17. (1S,3S)-3,4,5,10-Tetrahydro-9-hydroxy-7-methoxy-1-methyl-
5,10-dioxo-1H-naphtho[2,3-c]pyran-3-acetic acid (33). To alcohol
32 (25.0 mg, 0.079 mmol) in dichloromethane (1 mL) were added
[bis(acetoxy)-iodo]benzene (28.0 mg, 0.086 mmol) and TEMPO
(2.0 mg, 0.013 mmol) and the mixture was stirred at room tem-
perature for 6 h. The reaction mixture was then diluted with aq
sodium thiosulfate (2 mL) and extracted with chloroform (4ꢂ5 mL).
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue, containing the crude intermediate aldehyde,
was dissolved in a mixture of tert-butanol (1.0 mL) and water
(0.25 mL). 2-Methyl-2-butene (0.25 mL) was added followed by
sodium dihydrogenphosphate (37 mg, 0.24 mmol) and sodium
chlorite (18 mg, 0.16 mmol) and the mixture was stirred vigorously
for 3 h. After addition of 2 M aq HCl (1.0 mL) the mixture was
extracted with chloroform (4ꢂ5 mL) and the combined organic
layers were dried (MgSO4) and concentrated in vacuo. Flash column
chromatography (ethyl acetate/chloroform 2:1) gave the title
References and notes
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Chapman and Hall: London, New York, 1987; (b) Thomson, R. H. Naturally
Occurring Quinones IV: Recent Advances, 4th ed.; Blackie Academic and
Professional: London, 1997.
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3. Bergy, M. E. J. Antibiot. 1968, 21, 454e457.
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Omura, S. J. Antibiot. 1978, 31, 959e965.
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L. R.; Ding, W.-D.; Krishnamurthy, G.; Hu, Y. B.; Lucas, J.; Bernan, V. S.; Cai, P.;
Levin, J. I.; Mansour, T. S.; Gibbons, J. J.; Abraham, R. T.; Yu, K. Mol. Cancer Ther.
2007, 6, 3028e3038.
6. Salaski, E. J.; Krishnamurthy, G.; Ding, W.-D.; Yu, K.; Insaf, S. S.; Eid, C.; Shim, J.;
Levin, J. I.; Tabei, K.; Toral-Barza, L.; Zhang, W.-G.; McDonald, L. A.; Honores, E.;
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J. Med. Chem. 2009, 52, 2181e2184.
7. Hochlowski, J. E.; Brill, G. M.; Andres, W. W.; Spanton, S. G.; McAlpine, J. B. J.
Antibiot. 1987, 40, 401e407.
8. Tsuji, N.; Kobayashi, M.; Wakisaka, Y.; Kawamura, Y.; Mayama, M.; Matsumoto,
K. J. Antibiot. 1976, 29, 7e9.
9. Powis, G. Free Radical Biol. Med. 1989, 6, 63e101.
compound 33 (17.0 mg, 65%) as a yellow solid; Rf (ethyl acetate)
0.45; [
a]
ꢀ157 (c 0.33, CHCl3); 1H NMR (500 MHz, CDCl3)
d 1.53
23
D
(3H, d, J 6.4 Hz, 1-CH3), 2.32 (1H, ddd, J 18.3, 10.4 and 3.8 Hz, 4-
HaHb), 2.67 (1H, dd, J 16.1 and 5.2 Hz, 3-CHaHb), 2.76 (1H, dd, J 16.1
and 7.7 Hz, 3-CHaHb), 2.84 (1H, dt, J 18.3 and 2.6 Hz, 4-HaHb), 3.89
(3H, s, OCH3), 3.92e3.96 (1H, m, 3-H), 4.85e4.88 (1H, m, 1-H), 6.62
(1H, d, J 2.4 Hz, 8-H), 7.16 (1H, d, J 2.4 Hz, 6-H), 12.20 (1H, s, 9-OH);
10. Moore, H. W. Science 1977, 197, 527e531.
13C NMR (125 MHz, CDCl3)
d 21.1, 28.5, 40.1, 56.0, 68.9, 70.1, 106.3,
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107.8, 109.5, 133.2, 142.3, 146.6, 164.3, 165.9, 175.0, 182.8, 187.1; nmax
2918, 1708, 1636, 1607, 1299, 1262, 1205, 1150, 1101 cmꢀ1; HRMS
(ESI): found 331.0822, C17H15O7 ([MꢀH]ꢀ) requires 331.0823.
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