The enantioselective synthesis of elecanacin through an intramolecular naphthoquinone-vinyl ether photochemical cycloaddition

Article abstract of DOI:10.1039/b517008g

Elecanacin, an unusual cyclobuta-fused naphthalene-1,4-dione derivative isolated from the bulbs of Eleutherine Americana Merr. et Heyne (Iridaceae) has been obtained, together with its epimer isoelecanacin, by a 2 + 2 cycloaddition resulting from irradiation of 5-methoxy-2-(2-vinyloxypropyl)naphthalene-1,4- dione. The synthesis of enantiopure elecanacin starting with (R)-propylene oxide has established the absolute configuration of the natural product and has revealed that the sample isolated from the bulbs possessed an enantiomeric excess of only 14%. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b517008g

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The enantioselective synthesis of elecanacin through an intramolecular
naphthoquinone-vinyl ether photochemical cycloaddition
Linda B. Nielsen and Dieter Wege*
Received 1st December 2005, Accepted 20th December 2005
First published as an Advance Article on the web 19th January 2006
DOI: 10.1039/b517008g
Elecanacin, an unusual cyclobuta-fused naphthalene-1,4-dione derivative isolated from the bulbs of
Eleutherine Americana Merr. et Heyne (Iridaceae) has been obtained, together with its epimer
isoelecanacin, by a 2 + 2 cycloaddition resulting from irradiation of 5-methoxy-2-(2-vinyloxypropyl)-
naphthalene-1,4-dione. The synthesis of enantiopure elecanacin starting with (R)-propylene oxide has
established the absolute configuration of the natural product and has revealed that the sample isolated
from the bulbs possessed an enantiomeric excess of only 14%.
vinyl ether 8 to 1,4-naphthoquinone 7 is reported to give 9,
Introduction
albeit only in 8% yield.8 However, intramolecular photoadditions
During a search for bioactive constituents from plants of the
within 2-alkenyl-substituted 1,4-naphthoquinones have, to our
Iridaceae family used in traditional medicine, Hara and coworkers
knowledge, not been reported. Here we describe the application of
isolated from the bulbs of Eleutherine Americana Merr. et Heyne
(Iridaceae) a novel dione which they named elecanacin and
whose structure (Fig. 1)was deduced as 1 by means of NMR
such a reaction to the syntheses of racemic and chiral elecanacin;
the latter establishes the absolute configuration of the natural
product.
spectroscopy.1 The absolute stereochemistry was not determined
and was arbitrarily depicted as shown in 1 [systematic name: (2a,
3aa, 4ab, 10aR*)-6-methoxy-2-methyl-1,2,4,4a-tetrahydro-10H-
naphtho[2ꢀ,3ꢀ:2,3]cyclobuta[1,2-b]furan-5,10(3aH)-dione]. Also
isolated from the same plant were the isomeric and well-known2–5
pyranonaphthoquinones eleutherin 2 and isoeleutherin 3.
Fig. 1 Structures of elecanacin (absolute configuration is depicted
arbitrarily), eleutherin and isoeleutherin.
The ring skeleton of 1 is somewhat unusual for a natural
product and has not previously been reported; hence we felt that
confirmation of the structure by synthesis was desirable. Leaving
aside for the moment the question of the configuration of the
Scheme 1 Retrosynthetic analysis for elecanacin and examples of enone
and enedione photocycloadditions.
methyl-substituted carbon of the tetrahydrofuran ring, simple
retrosynthetic considerations suggest that 1 should be accessible
through an intramolecular photochemical cycloaddition of the
vinyl ether moiety to the double bond within the substituted
naphthoquinone 4. This is based on the premise that intramolec-
ular photocycloadditions in cyclohexenones possessing tethered
terminal alkene chains attached to the 2-position are well-known6
(e.g. 5 → 6)7 and that the intermolecular photoaddition of ethyl
Results and discussion
The synthesis of racemic elecanacin was achieved as shown in
Scheme 2.
Allylation of 5-methoxynaphthalen-1-ol 10 followed by Claisen
rearrangement and in situ acetylation afforded acetate 12. Careful
ozonolysis provided aldehyde 13 which was immediately treated
with an excess of methylmagnesium iodide to give the phenolic
School of Biomedical, Biomolecular and Chemical Sciences, University of
Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia.
E-mail: dw@chem.uwa.edu.au
868 | Org. Biomol. Chem., 2006, 4, 868–876
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
the oxabicyclo[3.2.0]heptane framework are displayed in Fig. 2.
The aromatic proton signals in both isomers display second order
characteristics, even at 500 MHz, rather than the first order pattern
implied1 for elecanacin.
Fig. 2 Key NOESY correlations within the 2-oxabicyclo[3.2.0]heptyl
framework of elecanacin (ref. 1) and isoelecanacin (this work).
In the photochemical cycloaddition reaction, compounds 1
and 16 arise by addition of the vinyl ether moiety to the two
diastereotopic faces of the carbon–carbon double bond of the
naphthoquinone system of 4. Monitoring of the reaction showed
that both products were formed at early stages and control
experiments established that 1 and 16 were photostable and not
interconverted under the irradiation conditions.
Our first approach to enantiopure elecanacin (Scheme 3) was
based on the assumption that hydrolytic kinetic resolution of a
racemic epoxide such as 19 or 21 using Jacobsen’s catalyst9,10 20
would provide a chiral epoxide, which on reductive opening with
lithium aluminium hydride and removal of the protecting group
could deliver one enantiomer of the phenolic alcohol 14 depicted
in Scheme 2. In the event, epoxidation of the monosubstituted
ethylene moiety of acetate 12 and benzyl ether 17 with m-
chloroperoxybenzoic acid proceeded sluggishly and appeared to
be accompanied by degradation of the electron-rich naphthalene
ring system. The epoxy acetate 21 could be obtained in poor
yield by treatment of 12 with dimethyldioxirane, while the epoxy
benzyl ether 19 was obtained satisfactorily by reaction of aldehyde
18 with dimethylsulfoxonium methylide. Unfortunately both 19
Scheme 2 (a) allyl bromide, K2CO3, Me2CO, reflux, 97%; (b) Ac2O,
PhNMe2, 170 ◦C, 95%; (c) O3, CH2Cl2–MeOH, −78 ◦C, then (NH2)2CS;
=
(d) MeMgI, THF; (e) Fremy’s salt, 41% for steps c–e; (f) EtOCH CH2,
Hg(OAc)2, 57%; (g) ht at 350 nm, CH2Cl2, 25% 1 and 38% 16.
alcohol 14. Oxidation with Fremy’s salt yielded the hydroxy-
quinone 15 which was converted into the vinyl ether 4 in the usual
fashion. Irradiation of 4 in dichloromethane at 350 nm cleanly gave
two products. These were separated by careful chromatography,
and the slightly more polar product, isolated in 25% yield, was ( )-
1
elecanacin, whose H and 13C NMR spectra were identical with
those of the naturally occurring (+)-enantiomer. The more mobile
component, obtained in 38% yield, we have named isoelecanacin
and is formulated as 16 on the basis of NMR (COSY, HMBC,
HMQC and NOESY) evidence. The NMR spectral data for 1 and
16 are collected in Table 1 and the key NOESY correlations within
Table 1 13C; 1H NMR data for elecanacin and isoelecanacin (300 MHz, CDCl3)
Position
Elecanacin
Isoelecanacin
1
45.3; 2.29, dd, J 12.6, 10.0, Hx;a2.20, dd, J 12.6, 4.7, Hn
45.5; 1.75, dd, J 12.6, 9.6, Hx; 2.86, dd, J 12.6, 5.5, Hn
2
76.6; 4.60–4.48, m
80.9; 4.62–4.58, m
31.0; 2.65–2.50, m
45.3; 3.23–3.17, m
196.2b
124.3
159.2
81.5; 4.38–4.31, m
81.6; 4.46–4.43, m
31.6; 2.52–2.49, m
47.5; 3.30–3.29, m
196.1b
124.4
159.3
3a
4
4a
5
5a
6
7
117.2; 7.29, X part of ABX
134.9c; c. 7.64, B part of ABX
119.3c; c. 7.68, A part of ABX
138.2
117.4; 7.29, X part of ABX
134.8; c. 7.66, B part of ABX
119.4; c. 7.66, A part of ABX
137.5
8
9
9a
10
10a
Me
MeO
195.8b
61.2
195.7b
59.7
19.2; 1.45, d, J 5.9
56.5; 3.96, s
20.6; 1.42, d, J 6.1
56.5; 3.96, s
a Hx is exo within the oxabicyclo[3.2.0]heptane moiety, Hx is endo. b Values can be interchanged within each column. c As assigned in ref. 1 and consistent
with incremental shift calculations.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 868–876 | 869
©

View Article Online
Scheme 3 (a) O3, CH2Cl2–MeOH, −78 ◦C, then (NH2)2CS, 65%;
(b) trimethylsulfoxonium iodide, NaH, Me2SO, 69%; (c) dimethyldioxi-
rane, Me2CO, 23%; (d) Fremy’s salt, 91%; (e) m-Cl–C6H4–CO3H, CH2Cl2,
67%; (f) 20, H2O.
Scheme 4 (a) BuLi, THF, −78 ◦C, HMPA, 26, 53% 27 and 13% 28;
=
(b) CBr4, 2-propanol, reflux, 73%; (c) Fremy’s salt, 97%; (d) EtOCH CH2,
Hg(OAc)2, 51%; (e) ht at 350 nm, CH2Cl2, 24% 1 and 40% 16.
and 21 were recovered essentially unchanged when exposed
to the usual conditions for hydrolytic kinetic resolution, even
after long reaction times. Since we felt that the electron-rich
naphthalene moieties of 19 and 21 could possibly interfere in
the catalytic hydrolytic cycle, we prepared the quinonoid epoxide
24 by treatment of quinone 23 with m-chloroperoxybenzoic acid.
However 24 also was recovered unchanged when subjected to
the reaction conditions. Control reactions showed that, using the
same batch of catalyst, simple epoxides such as epichlorohydrin
and propylene oxide were resolved under these conditions, as
described in the literature.9,10 Although the hydrolytic kinetic
resolution of the epoxides 19, 21 and 24 may well be achievable
with further experimentation, particularly in regard to variation of
the organic solvent,10 we adopted instead the approach outlined in
Scheme 4.
Metallation of 1-methoxy-5-(methoxymethoxy)naphthalene11
25 with n-butyllithium followed by sequential addition of HMPA
and (R)-(+)-propylene oxide 26 afforded the desired alcohol
27 (53%) together with alcohol 28 (13%) resulting from met-
allation and alkylation ortho to the methoxy group. Removal
of the MOM protecting group of 27 was achieved by action
of carbon tetrabromide in refluxing 2-propanol.12 The enan-
tiomeric ratio for the resulting alcohol 29 was estimated to be
greater than 95 : 5 by examination of its 1H NMR spectrum
in the presence of the chiral shift reagent europium tris[3-
(heptafluoropropylhydroxymethylene)-(+)-camphorate], indicat-
ing that the enantiomeric excess (ee) within 29 was greater
than 90%. Surprisingly the chiral shift reagent failed to induce
significant chemical shift changes for protons near the stereocentre
and the only significant induced shift was observed for the
aromatic proton 8-H. A more precise upper limit for the ee could
not be ascertained at this stage due to some line-broadening of
this signal.
Oxidation of 29 with Fremy’s salt provided the quinone 30,
which was converted into the vinyl ether 31 as in the racemic series.
Irradiation followed by chromatographic separation gave (2R,
3aR, 4aR, 10aR)-elecanacin 1 having [a]D − 145◦ (CHCl3) after
recrystallisation and an ee of (99.5% as determined by HPLC using
a chiral stationary phase. The optical rotation reported1 for natural
elecanacin is +20.7◦ and thus the major natural enantiomer is the
mirror image of 1, and the configuration is (2S, 3aS, 4aS, 10aS)
(see structure ent-1 in Scheme 6 later). From the magnitude of the
reported rotation, the enantiomeric excess is only 14% and thus
elecanacin is another example of a natural product that does not
occur in enantiopure form.13
Although the biosynthesis of eleutherin 2 and isoeleutherin
3 does not appear to have been investigated, it presumably
involves a polyketide pathway, as has been established for other
pyranonaphthoquinones.14,15 For example, labelling experiments
have revealed that the bacterial metabolite nanaomycin A 33 is
assembled from an octaketide by a folding resulting from orien-
tation 32a (Scheme 5), whereas in the biosynthesis of cardinalin
2 34 in the fruiting bodies of the toadstool Dermocybe cardinalis
the alternative orientation 32b for cyclisation of the octaketide has
been established.15 It has been suggested that this also may be the
pathway for the synthesis of pyranonaphthoquinones in plants.15
Given that eleutherin and isoeleutherin are polyketide-derived,
what is the biogenetic origin of elecanacin? We note that, formally
the vinyl ether 4 can be derived from the Norrish type II cleavage
of 35, the dihydro-derivative of eleutherin and isoeleutherin,
followed by oxidation (Scheme 6). Subsequent intramolecular 2 +
2 cycloaddition would then deliver elecanacin 1. The enantiomeric
ratio of the product 1 would be determined by the configu-
rational ratio at 2-C inherent within 35. Since both eleutherin
and isoeleutherin co-occur in the plant, the involvement of a
biosynthetic precursor such as 35 having both configurations at
870 | Org. Biomol. Chem., 2006, 4, 868–876
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Although we find that in solution 4 undergoes ready cyclisation
when exposed to ambient laboratory light, elecanacin is, as in
the preparative reactions, accompanied by isoelecanacin 16. In
view of the close chromatographic Rf values of these products, we
believe it to be unlikely that 16 would have been missed during
the isolation of 1.1 Thus elecanacin is more likely to be a product
of a diastereoselective enzyme-mediated reaction rather than an
artifact arising from photochemical transformation of 4.
Conclusion
In summary, we have confirmed the nature of the novel ring system
of elecanacin 1 and the absolute configuration and low ee of
the natural product through rational synthesis. The biochemical
pathway that generates 1 in the plant remains to be elucidated.
Experimental
Scheme 5 Incorporation of 1-13C labelled acetate into nanaomycin and of
1,2-13C2 labelled acetate into cardinalin 2 (identified labelled units shown
in bold).
General details have been given previously.21 Irradiations were
carried out through Pyrex in an Oliphant photochemical chamber
reactor equipped with Sylvania F 815/BLB tubes emitting at
350 nm. HPLC was performed using a Chiracel OD column
(Daicel Chemical Industries) fitted to an ICI 1110 pump interfaced
with a Hewlett Packard Series 1050 instrument using UV detection
at 254 nm. The solvent was 2-propanol-hexane 1 : 5 with a flow
rate of 0.5 mL min−1.
5-Methoxy-1-(2-propenyloxy)naphthalene 11
The procedure was adapted from that described by Eisenhuth
and Schmid.4 5-Methoxy-1-naphthol 10 (3.51 g, 20.2 mmol), allyl
bromide (2.8 ml, 3.88 g, 32.1 mmol) and potassium carbonate
(4.28 g, 31.0 mmol) in acetone (90 ml) were refluxed for 3 h
under a nitrogen atmosphere. The reaction mixture was allowed
to cool to room temperature, left to stand overnight and then
poured into water (450 ml) and extracted with ether (3 × 60 ml).
The combined organic extracts were washed successively with
10% sodium hydroxide solution (50 ml), water (50 ml) and
brine (50 ml), then dried and evaporated to give 5-methoxy-1-
(2-propenyloxy)naphthalene ◦as a yellow crystalline solid (4.17 g,
97%), mp 96–98 ◦C (lit.,21 98 C). dH (200 MHz, CDCl3) 7.91 (1H,
d, J 8.5, ArH), 7.85 (1H, d, J 8.5, ArH), 7.43–7.32 (2H, m, 2 ×
ArH), 6.86 (2H, d, J 7.7, 2 × ArH), 6.19 (1H, ddt, J 17.3, 10.5 and
5.1, CH, vinylic), 5.53 (1H, dtd, J 17.3, 1.5 and 1.5, CH, vinylic),
5.34 (1H, dtd, J 10.5, 1.5 and 1.5, CH, vinylic), 4.72 (2H, ddd, J
5.1, 1.5 and 1.5, CH2), 4.00 (3H, s, OCH3).
Scheme 6 Formal derivation of vinyl ether 4 and elecanacin 1 from the
dihydro derivative 35 of eleutherin and isoeleutherin.
the methyl-substituted carbon would explain the low ee observed
for elecanacin.
Of the pericyclic reactions possibly involved in biological
systems,16 the Diels–Alder reaction has attracted considerable
attention and evidence has been presented for the existence
of Diels–Alderases.17,18 Although the suggestion that elecanacin
could possibly be generated in vivo by a sequence involving peri-
cyclic reactions as shown in Scheme 6 must be regarded as highly
speculative, we note that ethylene has been reported to arise from
a Norrish type II fragmentation of enzymatically generated triplet
butanal, providing an example of a photobiochemical reaction
without light.19 The cleavage step a in Scheme 6 therefore has
some precedence. Furthermore, very recently evidence has been
presented that the conversion of isochorismate to salicylate and
pyruvate, catalysed by the enzyme isochorismate pyruvate lyase,
involves a one-step pericyclic retro-ene process.20 However, at this
stage there appear to be no enzyme-mediated analogies for the 2 +
2 cycloaddition. We consider it unlikely that the vinyl ether 4 is in
fact a natural product and that elecanacin then arises as an artifact
through photochemical cyclisation during isolation and workup.
5-Methoxy-2-(2-propenyl)naphthalen-1-yl acetate 12
A stirred solution of 5-methoxy-1-(2-propenyloxy)naphthalene
(4.17 g, 19.5 mmol) in acetic anhydride (31.0 ml, 33.5 g, 328 mmol)
and N,N-diethylaniline (100 ml, 93.3 g, 625 mmol) was heated
at 165–170 ◦C (bath) for 6 h under an argon atmosphere, then
allowed to cool to room temperature and left to stir for 24 h. The
solution was diluted with water (250 ml) and extracted with ether
(3 × 60 ml). The combined ether extracts were washed with 2 M
hydrochloric acid solution (3 × 100 ml), followed by saturated
sodium carbonate solution (80 ml) and brine (80 ml), dried
and evaporated to give 5-methoxy-2-(2-propenyl)naphthalen-1-yl
acetate as a yellow-brown oil (4.74 g, 95%), which was pure by
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 868–876 | 871
©

View Article Online
1H NMR. dH (200 MHz, CDCl3) 8.11 (1H, d, J 8.8, ArH), 7.46–
7.29 (3H, m, ArH), 6.80 (1H, d, J 7.4, ArH), 6.06–5.82 (1H, m,
CH, vinylic), 5.18–5.04 (2H, m, 2 × CH, vinylic), 3.97 (3H, s,
OCH3), 3.43 (2H, ddd, J 6.6, 1.5 and 1.5, CH2), 2.45 (3H, s, CH3).
dC (75.5 MHz, CDCl3) 155.1 (C), 150.9 (C), 129.0 (CH), 126.8 (C),
126.0 (C), 125.0 (CH), 118.9 (C), 114.6 (CH), 113.5 (CH), 103.8
(CH), 70.9 (CH), 55.5 (OCH3), 40.5 (CH2), 23.2 (CH3).
2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dione 15
5-Methoxy-2-(2-formylmethyl)naphthalen-1-yl acetate 13
A solution of 1-(1-hydroxy-5-methoxynaphthalen-2-yl)propan-2-
ol (3.48 g, 15.0 mmol) in ethyl acetate (80 ml) was added to a
separating funnel containing Fremy’s salt (8.25 g, 30.8 mmol)
dissolved in an aqueous borax buffer solution (0.025 M sodium
tetraborate, 250 ml; 0.1 M sodium hydroxide, 121 ml). The
resulting mixture was shaken until TLC indicated that the starting
material had been consumed (ca 40 min). The mixture was diluted
with brine (50 ml) and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (4 × 60 ml). The
combined organic extracts were washed with brine (80 ml), dried
and evaporated to give a yellow oil, which was subjected to silica
gel filtration. Elution with 30% ethyl acetate-light petroleum gave
2-(2-hydroxypropyl)-5-methoxynaphthalene-1,4-dione as a yellow
oil (1.54 g, 41% over 3 steps) which solidified upon refrigeration.
A small sample recrystallised from ethyl acetate-light petroleum
as fine yellow needles, mp 95–96 ◦C (lit.,4 96–97 ◦C). (Found M+,
246.0894. C14H14O4 requires 246.0892). Mass Spectrum m/z: 246
(M, 23%), 230 (27), 204 (73), 203 (54), 202 (100), 187 (15), 175
(17), 174 (32), 173 (38), 159 (25), 144 (15), 131 (23), 115 (34). ( H
(300 MHz, CDCl3) 7.75 (1H, dd, J 7.7 and 1.2, ArH), 7.66 (1H,
dd, J 8.4 and 7.7, ArH), 7.29 (1 H, dd, J 8.4 and 1.1, ArH), 6.78
(1H, t, J 1.0, CH, vinylic), 4.15–4.03 (1H, m, CH), 4.00 (3H, s,
OCH3) 2.74 (1H, ddd, J 13.8, 4.1 and 1.0, CH of methylene), 2.59
(1H, ddd, J 13.8, 8.0 and 1.0, CH of methylene), 1.29 (3H, d, J
Ozone was bubbled through
a solution of 5-methoxy-2-
(2-propenyl)naphthalen-1-yl acetate (3.87 g, 15.1 mmol) in
dichloromethane/methanol (4 : 1, 180 ml) at −78 ◦C until TLC in-
dicated that all the starting material had been consumed (45 min).
The solution did not turn blue. Oxygen, followed by nitrogen
was bubbled through the solution in order to displace the ozone.
The cold solution was added dropwise to a stirred suspension of
thiourea (1.41 g, 18.5 mmol) and sodium bicarbonate (826 mg,
9.84 mmol) in dichloromethane (50 ml) at ice bath temperature
and stirred for 1.5 h under a nitrogen atmosphere. The resulting
reaction mixture was diluted with water (350 ml) and the organic
layer was separated. The aqueous layer was extracted with
dichloromethane (2 × 40 ml) and the combined organic extracts
were washed with brine, dried and evaporated to give the aldehyde
as a yellow oil (4.03 g), which was refrigerated overnight. dH
(200 MHz, CDCl3) 9.69 (1H, t, J 2.4, CHO), 8.20 (1H, d, J 8.8,
ArH), 7.48–7.30 (3H, m, ArH), 6.85 (1H, d, J 7.5, ArH), 4.00
(3H, s, OCH3), 3.70 (2H, d, J 2.4, CH2), 2.46 (3H, s, CH3). Due to
its instability, the aldehyde was used directly in the next reaction
without purification or further characterisation.
1-(1-Hydroxy-5-methoxynaphthalen-2-yl)propan-2-ol 14
=
=
A solution of methyl iodide (6.2 ml, 14.1 g, 99.7 mmol) in anhy-
drous tetrahydrofuran (35 ml) was added dropwise to magnesium
turnings (2.28 g, 93.8 mmol) at room temperature under an argon
atmosphere. The mixture was stirred and diluted by the dropwise
addition of anhydrous tetrahydrofuran (70 ml). Upon completion
of the reaction, the Grignard reagent was cooled in an ice bath and
a solution of crude 5-methoxy-2-(2-formylmethyl)naphthalen-1-yl
acetate (4.03 g, 15.6 mmol) in anhydrous tetrahydrofuran (100 ml)
was added dropwise. Then the resulting mixture was allowed
to warm to room temperature and stirring was continued for a
further 2 h. The reaction mixture was carefully quenched with
water (300 ml), acidified with concentrated hydrochloric acid, and
extracted with ethyl acetate (3 × 70 ml). The combined organic
extracts were washed with water (70 ml) followed by brine (70 ml),
dried and evaporated to give 1-(1-hydroxy-5-methoxynaphthalen-
2-yl)propan-2-ol as an orange oil (3.55 g), which was used directly
in the next reaction. A small sample was subjected to radial chro-
matography. Elution with 10% ethyl acetate-light petroleum gave
a clear oil, which solidified upon refrigeration and recrystallised
from dichloromethane-light petroleum as white plates, mp 83–
84 ◦C (Found: C, 72.4; H, 7.0. C14H16O3 requires C, 72.4; H,
6.9%). (Found M+, 232.1103. C14H16O3 requires 232.1099). Mass
Spectrum m/z: 232 (M, 25%), 214 (100), 212 (28), 199 (47), 187
(18), 186 (29), 171 (28), 169 (21), 128 (21), 115 (43). dH (300 MHz,
CDCl3) 7.88 (1H, dt, J 8.5 and 0.8, ArH), 7.74 (1 H, dd, J 8.5 and
0.6, ArH), 7.37 (1 H, dd, J 8.5 and 7.7, ArH), 7.12 (1H, d, J 8.5,
ArH), 6.80 (1H, d, J 7.7, ArH), 4.36–4.27 (1H, m, CH), 3.99 (3H, s,
OCH3) 3.01 (1H, dd, J 14.7 and 2.5, CH of methylene), 2.90 (1H,
dd, J 14.7 and 7.1, CH of methylene), 1.27 (3H, d, J 6.2, CH3).
6.2, CH3). d (75.5 MHz, CDCl3) 186.1 (C O), 184.3 (C O),
C
159.4 (C), 145.6 (C), 139.2 (CH), 134.7 (CH), 134.3 (C), 119.8 (C),
119.5 (CH), 117.8 (CH), 66.7 (CH), 56.4 (OCH3), 39.1 (CH2), 23.7
(CH3). kmax (CH2Cl2) (log e) 247 (4.14), 268 (3.22), 354 (4.06), 396
(3.54). mmax(CH2Cl2)/cm−1 1658 (C O).
=
5-Methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 4
A solution of 2-(2-hydroxypropyl)-5-methoxynaphthalene-1,4-
dione (1.43 g, 5.80 mmol) and mercuric acetate (351 mg,
1.10 mmol) in ethyl vinyl ether (35 ml, 26.4 g, 366 mmol) and
dichloromethane (10 ml) in a foil-covered flask was refluxed
for 6 h under an argon atmosphere. The solution was kept
at room temperature for 2 days, then poured into water and
extracted with dichloromethane (3 × 40 ml). The combined
organic extracts were washed with brine, dried and evaporated
to give a yellow residue, which was subjected to silica gel filtration.
Elution with 15% ethyl acetate-light petroleum gave 5-methoxy-2-
(2-vinyloxypropyl)naphthalene-1,4-dione (903 mg, 57%) as a yellow
oil. (Found M+, 272.1054. C16H16O4 requires 272.1049). Mass
Spectrum m/z: 273 (M(1, 17%), 272 (M, 97), 243 (16), 230 (34),
229 (100), 228 (36), 227 (18), 215 (15), 213 (31), 211 (19), 205
(19), 202 (27), 201 (19), 188 (27), 187 (36). dH (300 MHz, CDCl3)
7.74 (1H, dd, J 7.7 and 1.2, ArH), 7.66 (1H, dd, J 8.3 and 7.7,
ArH), 7.28 (1 H, dd, J 8.3 and 1.2, ArH), 6.75 (1H, t, J 1.0, CH,
vinylic), 6.27 (1H, dd, J 6.7 and 14.2, CH, vinylic), 4.30 (1H, dd,
J 14.2 and 1.7, CH, vinylic), 4.26–4.15 (1H, m, CH), 4.00–3.99
(1H, m, CH, vinylic), 3.99 (3H, s, OCH3) 2.79 (1H, ddd, J 13.9,
7.4 and 1.1, CH of methylene), 2.67 (1H, ddd, J 13.9, 5.3 and
872 | Org. Biomol. Chem., 2006, 4, 868–876
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
1.1, CH of methylene), 1.27 (3H, d, J 6.2, CH3). d C (75.5 MHz,
unreacted starting material as a yellow oil (89 mg). Further elution
with 10% ethyl acetate-light petroleum gave a yellow oil (348 mg),
which was subjected to radial chromatography. Elution with 5%
ethyl acetate-light petroleum gave the epoxide as a colourless
oil (279 mg, 23%). (Found: M+, 272.1042. C16H16O4 requires
272.1049). Mass spectrum (FAB) m/z: 273 (M ( 1, 74%), 272 (M,
100), 231 (32), 230 (88), 213 (64), 212 (32), 187 (35). dH (300 MHz,
CDCl3) 8.15 (1H, d, J 8.7, ArH), 7.44–7.39 (2H, m, ArH), 7.30
(1H, d, J 8.5, ArH), 6.82 (1H, d, J 7.1, ArH), 3.99 (3H, s, OCH3),
3.22–3.18 (1H, m, CH, X of ABX), 3.01 (1H, dd, J 14.6 and
5.5, CH of methylene), 2.88–2.79 (2H, m, 2 × CH of methylene),
2.59 (1H, m, CH of methylene), 2.49 (3H, s, CH3). dC (75.5 MHz,
=
=
CDCl3) 185.4 (C O), 184.3 (C O), 159.4 (C), 150.3 (CH), 144.7
(C), 139.3 (CH), 134.7 (CH), 134.2 (C), 119.4 (CH), 117.7 (CH),
88.8 (CH2), 77.2 (C), 73.2 (CH), 56.4 (OCH3), 36.1 (CH2), 20.0
(CH3). kmax (CH2Cl2) (log e) 230 (4.10), 238 (4.15), 262 (4.06), 333
(3.22), 249 (3.24), 393 (3.46). mmax (CH2Cl2)/cm−1 1658 (C O).
=
( )-Elecanacin 1 and and ( )-isoelecanacin 16
A deoxygenated solution of 5-methoxy-2-(2-vinyloxypropyl)-
naphthalene-1,4-dione 4 (122 mg, 0.45 mmol) in anhydrous
dichloromethane (50 ml) was irradiated at 350 nm through Pyrex
for 65 min, when TLC indicated that all the starting material
had been consumed. The solvent was evaporated and the yellow
residue was subjected to careful radial chromatography. Elution
with 20% ethyl acetate-light petroleum gave ( )-isoelecanacin 16
(46 mg, 38%) as a yellow oil, which solidified upon refrigeration
and recrystallised from dichloromethane-light petroleum as white
needles, mp 114–115 ◦C. (Found M+, 272.1048. C16H16O4 requires
272.1049). Mass Spectrum m/z: 273 (M + 1, 16%), 272 (M, 100),
270 (22), 244 (22), 243 (87), 242 (20), 241 (16), 229 (41), 228 (20),
227 (30), 217 (19), 211 (19), 201 (15), 189 (19), 187 (22), 153 (65),
136 (57), 135 (17), 128 (16), 115 (27), 108 (19), 107 (71), 106 (55),
105 (39), 104 (17), 90 (19), 89 (96). The 13C and 1H NMR spectral
=
CDCl3) 169.3 (C O), 155.6 (C), 144.3 (C), 128.1 (C), 127.0 (CH),
126.8 (CH), 126.4 (C), 125.9 (C), 120.5 (CH), 113.2 (CH), 104.1
(CH), 55.6 (OCH3), 51.4 (CH), 47.0 (CH2), 33.5 (CH2), 20.7 (CH3).
1-Benzyloxy-5-methoxy-2-(2-propenyl)naphthalene 17
Benzyl bromide (6.13 g, 35.8 mmol) was added to a mechanically
stirred suspension of 5-methoxy-2-(2-propenyl)naphthalen-1-ol
(6.40 g, 29.9 mmol) and potassium carbonate (6.52 g, 47.2 mmol)
in acetone (200 ml) and the mixture was refluxed for 3 h under an
argon atmosphere. The mixture was diluted with water (400 ml)
and extracted with ether (3 × 60 ml). The combined organic
extracts were washed with 10% sodium hydroxide solution (60 ml)
followed by brine (70 ml), dried and evaporated to give a yellow oil
(9.70 g). Kugelrohr distillation under a vacuum gave 1-benzyloxy-
5-methoxy-2-(2-propenyl)naphthalene (7.63 g, 84%) as a pale yel-
low oil, which solidified upon refrigeration. A sample recrystallised
from light petroleum as white plates, mp 46–47 ◦C. (Found: M+,
304.1455. C21H20O2 requires 304.1463). Mass spectrum m/z: 304
(M, 60%), 214 (18), 213 (100), 198 (20), 153 (20), 115 (18), 91 (90),
77 (23). dH (300 MHz, CDCl3) 8.03 (1H, d, J 8.7, ArH), 7.73 (1H,
d, J 8.5, ArH), 7.59–7.56 (2H, m, ArH), 7.48–7.32 (5H, m, ArH),
6.82 (1H, d, J 7.3, ArH), 6.10–5.96 (1H, m, CH, vinylic), 5.14–5.06
(2H, m, 2 × CH, vinylic), 5.02 (2H, s, OCH2), 4.01 (3H, s, OCH3),
3.61 (2H, ddd, J 5.0, 1.4 and 1.4, CH2). dC (75.5 MHz, CDCl3)
155.8 (C), 151.8 (C), 137.5 (C), 137.2 (CH), 129.4 (C), 129.1 (C),
128.6 (CH), 128.0 (CH), 127.7 (CH), 127.5 (CH), 126.0 (CH),
125.9 (C), 118.2 (CH), 115.9 (CH2), 114.4 (CH), 103.6 (CH), 76.2
(CH2), 55.5 (OCH3), 34.0 (CH2).
data are given in Table 1. mmax (CH2Cl2)( cm−1 1683(C O). Analysis
=
on the Chiracel OD column showed two peaks in a ratio of 48 :
52 at retention times 19.2 and 22.6 min. Further elution with 30%
ethyl acetate-light petroleum gave ( )-elecanacin 1 (31 mg, 25%)
as a yell◦ow oil which could not be induced to crystallise (lit.,1
mp 198 C for optically active material). (Found M+, 272.1050.
C16H16O4 requires 272.1049). Mass Spectrum m/z: 273 (M + 1,
17%), 272 (M, 100), 244 (22), 243 (88), 229 (30), 228 (19), 227 (21),
217 (15), 215 (15), 211 (15), 202 (16), 201 (15), 189 (17), 187 (17),
135 (18), 128 (16), 115 (23). The 13C and 1H NMR spectral data are
shown in Table 1 and are identical with those of natural elecanacin.
mmax (CH2Cl2)/cm−1 1684 (C O). Analysis on the Chiracel OD
=
column showed two peaks in the ratio of 52 : 48 at retention times
26.5 and 39.2 min.
When the irradiation was repeated and the reaction was inter-
rupted at low conversion of reactant, elecanacin and isoelecanacin
were found to be present in the same ratio as at complete
conversion (TLC and NMR analysis). Irradiation of pure samples
of elecanacin and isoelecanacin in dichloromethane led to no
change.
2-(1-Benzyloxy-5-methoxynaphthalen-2-yl)ethanal 18
Conversion of the vinyl ether 4 into elecanacin and isoelecancin
also was observed when a solution of 4 in dichloromethane was
kept in ambient laboratory light.
Ozone was bubbled through a solution of 1-benzyloxy-5-
methoxy-2-(2-propenyl)naphthalene 17 (2.31 g, 7.60 mmol) in
◦
dichloromethane(methanol (4 : 1, 180 ml) at −78 C, until TLC
indicated that the starting material had been consumed (ca.
20 min). The solution did not turn blue. Oxygen, followed by argon
was bubbled through the solution in order to displace the ozone.
The cold solution was added dropwise to a stirred suspension of
thiourea (687 mg, 9.02 mmol) and sodium bicarbonate (457 mg,
5.44 mmol) in dichloromethane (60 ml) at ice bath temperature
and stirred for 1.5 h under an argon atmosphere. The reaction
mixture was then diluted with water (300 ml), the organic
layer was separated and the aqueous layer was extracted with
dichloromethane (2 × 60 ml). The combined organic extracts were
washed with brine (80 ml), dried and evaporated to give a yellow
oil, which was subjected to silica gel filtration. Elution with 5%
2-(2,3-Epoxypropyl)-5-methoxynaphthalen-1-yl acetate 21
A cold solution of an excess of dimethyldioxirane in acetone
(60 ml), prepared according to the procedure described by
Murray and Singh,22 was added to a solution of 5-methoxy-2-(2-
propenyl)naphthalen-1-yl acetate (1.16 g, 453 mmol) in acetone
(10 ml) and left to stir for 16 h at room temperature. The solution
was diluted with water (350 ml) and extracted with ethyl acetate
(3 × 70 ml). The extracts were washed with brine, dried and
evaporated to give a brown oil, which was subjected to silica gel
filtration. Elution with 5% ethyl acetate-light petroleum returned
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 868–876 | 873
©

View Article Online
ethyl acetate-light petroleum gave the aldehyde as a faint yellow oil
(1.51 g, 65%). (Found: M+, 306.1251. C20H18O3 requires 306.1256).
Mass spectrum m/z: 306 (M, 24%), 288 (54), 215 (43), 198 (26),
187 (54), 155 (25), 149 (29), 127 (19), 115 (22), 91 (100), 84 (20), 83
(17), 77 (18), 71 (20), 69 (21), 57 (36). dH (300 MHz, CDCl3) 9.70
(1H, t, J 2.2, CHO), 8.09 (1H, dd, J 8.6 and 0.4, ArH), 7.73 (1H, d,
J 8.5, ArH), 7.50–7.36 (6H, m, ArH), 7.26 (1H, d, J 8.6, ArH), 6.86
(1H, d, J 7.3, ArH), 5.02 (2H, s, OCH2), 4.02 (3H, s, OCH3), 3.78
22.9 mmol) was heated at 160–185 ◦C (oil bath) for 2 h 15 min
under an argon atmosphere, affording almost pure 4-methoxy-2-
(2-propenyl)naphthalen-1-ol 22 as a pale brown waxy solid (4.62
g). dH (200 MHz, CDCl3) 7.80 (1H, d, J 8.5, ArH), 7.73 (1H, d,
J 8.5, ArH), 7.38 (1H, dd, J 8.5, 7.7, ArH, 7.21 (1H, d, J 8.5,
ArH), 6.81 (1H, d, J 7.7, ArH), 6.18–5.99 1H, (m, CH, vinylic),
5.50 (1H, s, br, OH), 5.30–5.20 (2H, m, 2 × CH, vinylic), 3.99
(3H, s, OCH3), 3.58 (2H, ddd, J 6.2, 1.6, 1.6, CH2). A solution
of the phenol 22 (1.49 g, 6.96 mmol) in ether (30 ml) was added
to a separating funnel containing Fremy’s salt (5.23 g, 19.5 mmol)
dissolved in an aqueous borax buffer solution (0.025 M sodium
tetraborate, 148 ml; 0.1 M sodium hydroxide, 72 ml). The resulting
mixture was shaken until TLC indicated that all the starting
material had been consumed (ca 1.5 h). Argon was bubbled
through the solution to evaporate most of the ether, during
which time a yellow-brown precipitate separated. The solid was
collected and dried over phosphorus pentoxide to give 5-methoxy-
2-(2-propenyl)naphthalene-1,4-dione 23 (1.44 g, 91%), which was
=
(2H, d, J 2.2, CH2). dC (75.5 MHz, CDCl3) 199.7 (C O), 155.9
(C), 152.9 (C), 136.8 (C), 129.2 (C), 128.6 (CH), 128.3 (CH), 128.0
(CH), 127.4 (CH), 126.8 (C), 126.5 (CH), 122.1 (C), 118.9 (CH),
114.3 (CH), 104.2 (CH), 76.2 (CH2), 55.6 (OCH3), 45.3 (CH2).
1-Benzyloxy-2-(2,3-epoxypropyl)-5-methoxynaphthalene 19
Trimethylsulfoxonium iodide (999 mg, 4.54 mmol) was added
portionwise over 20 min to sodium hydride (60% oil dispersion,
186 mg, 4.65 mmol) in anhydrous dimethyl sulfoxide (4 ml) under
an argon atmosphere and the resulting suspension was stirred
for 30 min. 2-(1-Benzyloxy-5-methoxynaphthalen-2-yl)ethanal 18
(526 mg, 1.72 mmol) in anhydrous dimethyl sulfoxide (4 ml) was
added dropwise and the resulting mixture was stirred at room
temperature for 1 h 45 min. The mixture was quenched with ice,
diluted with water (80 ml) and extracted with ether (4 × 40 ml). The
combined organic extracts were washed with brine (50 ml), dried
andevaporatedto giveayellow oil, which was subjected to silica gel
filtration. Elution with 5% ethyl acetate-light petroleum afforded
the epoxide 21 as a colourless oil (383 mg, 69%). (Found: M+,
320.1422. C21H20O3 requires 320.1412). Mass spectrum m/z: 321
(M+1, 20%), (M, 89), 230 (23), 229 (28), 201 (15), 199 (57), 187
(22), 186 (24), 171 (37), 155 (20), 128 (20), 127 (22), 115 (23), 91
(100), 77 (24), 69 (17), 57 (23). dH (300 MHz, CDCl3) 8.04 (1H, d,
J 8.9, ArH), 7.72 (1H, d, J 8.5, ArH), 7.57–7.39 (7H, m, ArH),
6.83 (1H, d, J 7.3, ArH), 5.05 (2H, s, OCH2), 4.01 (3H, s, OCH3),
3.24–3.18 (1H, m, CH, X of ABX), 3.10 (1H, dd, J 14.3 and 5.3,
CH of methylene), 3.00 (1H, dd, J 14.3 and 5.4, CH of methylene),
2.85 (1H, m, CH of methylene), 2.60 (1H, m, CH of methylene).
dC (75.5 MHz, CDCl3) 155.8 (C), 152.3 (C), 137.4 (C), 129.3 (C),
128.6 (CH), 128.1 (CH), 127.7 (CH), 127.4 (CH), 126.7 (C), 126.3
(C), 126.2 (CH), 118.5 (CH), 114.3 (CH), 103.8 (CH), 76.3 (CH2),
55.6 (OCH3), 52.1 (CH), 47.1 (CH2), 32.9 (CH2).
1
pure by H NMR and used in the next reaction without further
purification. A sample recrystallised from dichloromethane-light
◦
petroleum as yellow needles, mp 95–96 C (lit.,4 96–97 ◦C). dH
(200 MHz, CDCl3) 7.76–7.57 (2H, m, ArH), 7.26 (1H, d, J 7.7,
ArH), 6.68 (1H, s, 3-CH, vinylic), 5.96–5.76 (1H, m, CH, vinylic),
5.22–5.12 (2H, m, 2 × CH, vinylic), 3.98 (3H, s, OCH3), 3.58 (2H,
ddd, J 6.8, 1.9 and 1.3, CH2).
2-(2,3-Epoxypropyl)-5-methoxynaphthalen-1,4-dione 24
m-Chloroperoxybenzoic acid (70%, 278 mg, 1.13 mmol) was added
to a stirred solution of 5-methoxy-2-(2-propenyl)naphthalen-1,4-
dione 23 (212 mg, 0.93 mmol) in dichloromethane (10 ml) at
ice bath temperature under an argon atmosphere. After 3 h, the
mixture was allowed to warm to room temperature and left to stir
for a further 21 h. The mixture was diluted with dichloromethane
(50 ml) and washed with 2.5% sodium bisulfite solution (20 ml),
followed by saturated sodium bicarbonate solution (2 × 25 ml)
and brine (30 ml), dried and evaporated to give a yellow-orange
solid (257 mg), which was subjected to radial chromatography.
Elution with 40% ethyl acetate-light petroleum returned unreacted
starting material (21 mg). Further elution with 70% ethyl acetate-
light petroleum gave the epoxide 24 as an orange crystalline solid
(152 mg, 67%, 74% based on recovered starting material). A
sample recrystallised from ethyl acetate-light petroleum as orange
plates, mp 159–160 ◦C. (Found: C, 68.9; H, 5.0. C14H12O4 requires
C, 68.85; H, 4.95%). (Found: M+, 244.0731. C14H12O4 requires
244.0736). Mass spectrum m/z: 246 (M + 2, 35%), 245 (M ( 1,
16), 244 (M, 100), 228 (15), 227 (23), 216 (27), 215 (42), 214 (32),
213 (32), 202 (73), 201 (52), 200 (31), 199 (24), 198 (43), 197 (29),
187 (30), 186 (117), 185 (56), 184 (20), 183 (31), 174 (15), 173
(45), 171 (23), 169 (24), 168 (24), 159 (21), 157 (48), 156 (26), 155
(25), 145 (22), 144 (21), 143 (21), 141 (22), 133 (16), 131 (20), 129
(42), 128 (90), 127 (39), 116 (25), 115 (77), 105 (23), 104 (39), 102
(20), 91 (18), 89 (16), 77 (29), 76 (71), 75 (21), 64 (15), 63 (26). dH
(300 MHz, CDCl3) 7.75 (1H, dd, J 7.6 and 1.1, ArH), 7.67 (1H,
dd, J 8.3 and 7.6, ArH), 7.30 (1H, dd, J 8.3 and 1.1, ArH), 6.84
(1H, t, J 1.2, 3-CH, vinylic), 4.00 (3H, s, OCH3), 3.22–3.16 (1H,
m, CH, X of ABX), 2.91–2.82 (2H, m, CH of methylene and CH
of oxirane methylene), 2.66–2.57 (2H, m, CH of methylene and
5-Methoxy-2-(2-propenyl)naphthalene-1,4-dione 23
The procedure was adapted from that of Eisenhuth and Schmid.4
5-Methoxy-1-naphthol (4.21 g, 24.2 mmol), allyl bromide (3.4 ml,
4.6 g, 38 mmol) and potassium carbonate (5.14 g, 37.2 mmol) in
acetone (110 ml) were refluxed for 3 h under a nitrogen atmosphere.
The reaction mixture was allowed to cool, then poured into
water and extracted with ether (3 × 60 ml). The extracts were
washed with 10% aqueous sodium hydroxide solution (40 ml)
followed by brine, dried and evaporated to give 5-methoxy-1-(2-
propenyloxy)naphthalene as a pale brown solid (4.89 g, 94%),
1
which was pure by H NMR. dH (200 MHz, CDCl3) 7.91 (1H,
d, J 8.5, ArH), 7.85 (1H, d, J 8.5, ArH), 7.43–7.32 (2H, m, 2 ×
ArH), 6.86 (2H, d, J 7.7, 2 × ArH), 6.19 (1H, ddt, J 17.3, 10.5,
5.1, CH, vinylic), 5.53 (1H, dtd, J 17.3, 1.5, 1.5, CH, vinylic),
5.34 (1H, dtd, J 10.5, 1.5, 1.5, CH, vinylic), 4.72 (2H, ddd, J 5.1,
1.5, 1.5, CH2), 4.00 (3H, s, OCH3). The foregoing ether (4.89 g,
=
CH of oxirane methylene). dC (75.5 MHz, CDCl3) 185.1 (C O),
874 | Org. Biomol. Chem., 2006, 4, 868–876
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
=
184.1 (C O), 159.5 (C), 144.4 (C), 138.5 (CH), 134.8 (CH), 134.2
(C), 119.8 (C), 119.4 (CH), 117.9 (CH), 56.5 (OCH3), 50 (CH), 47
in CH2Cl2). (Found: M+, 276.1366. C16H20O4 requires 276.1362).
Mass spectrum m/z: 276 (M, 41%), 258 (36), 226 (18), 214 (56),
212 (19), 201 (15), 200 (40), 199 (34), 198 (17), 187 (23), 185
(24), 171 (23), 169 (15), 157 (17), 155 (24), 153 (20), 149 (37),
141 (18), 139 (16), 129 (18), 128 (31), 127 (23), 121 (15), 115 (37),
109 (17), 107 (20), 105 (17), 98 (16), 97 (24), 96 (16), 95 (29), 93
(18), 91 (19), 86 (49), 85 (20), 84 (78), 83 (38), 82 (23), 81 (45),
79 (19), 78 (40), 77 (33), 71 (36), 70 (33), 69 (100), 68 (24), 67
(34), 63 (62), 61 (15), 60 (32), 57 (67), 56 (34). (H (300 MHz,
CDCl3) 8.03 (1H, dd, J 8.6 and 0.4, ArH), 7.73 (1H, dt, J 8.4
and 0.8, ArH), 7.44 (1H dd, J 8.4 and 7.7, ArH),7.33 (1H, d,
J 8.6, ArH), 7.09 (1H, dd, J 7.7 and 0.8, ArH), 5.39 (2H, s,
OCH2O), 4.16 (1H, m, CH), 3.94 (3H, s, OCH3), 3.54 (3H, s,
OCH3), 2.96 (2H, d, J 6.2, CH2), 2.29 (1H, s, br, OH), 1.28 (3H,
d, J 6.2, CH3). dC (75.5 MHz, CDCl3) 153.8 (C), 153.2 (C), 129.2
(C), 128.2 (CH), 127.5 (C), 126.5 (C), 126.1 (CH), 118.3 (CH),
115.4 (CH), 107.7 (CH), 94.6 (OCH2O), 68.6 (CH), 61.8 (OCH3),
56.2 (OCH3), 39.9 (CH2), 23.2 (CH3). Further elution with 10%
ethyl acetate-light petroleum gave a fraction containing a 15 :
85 mixture of (2R)-1-(1-methoxy-5-methoxymethoxynaphthalen-
2-yl)propan-2-ol 28 and the title alcohol, (2R)-1-(5-methoxy-1-
methoxymethoxynaphthalen-2-yl)propan-2-ol 27 as a pale yellow
oil (1.13 g), which was used directly in the next reaction. The crude
oil obtained from a second reaction was subjected to careful radial
chromatography. Elution with 5% ethyl acetate-light petroleum
allowed the isolation of a small analytical sample of (2R)-1-
(5-methoxy-1-methoxymethoxynaphthalen-2-yl)propan-2-ol 27 as
(CH2), 32.2 (CH2). mmax (CH2Cl2) 1660 cm−1 (C O).
Attempted hydrolytic kinetic resolution of the epoxides 19, 21
and 24 under standard conditions9,10 in each case returned starting
material exhibiting no significant optical rotation.
=
5-Methoxy-1-methoxymethoxynaphthalene 25
This was prepared as described11 and obtained in 86% yield as
◦
◦
colourless needles mp 74–75 C (lit.,11 75–76 C). dH (200 MHz,
CDCl3) 7.91 (2H, m, ArH), 7.45–7.35 (2H, m, ArH), 7.14 (1H,
d, J 7.6, ArH), 6.86 (1H, d, J 7.6, ArH), 5.40 (3H, s, CH2), 4.01
(3H, s, OCH3), 3.56 (3H, s, CH3).
(R)-Propylene oxide 26
The procedure described by Jacobsen and coworkers was
followed.9,10
The
precatalyst,
(R,R)-N,Nꢀ-bis(3,5-di-tert-
butylsalicalidene)-1,2-cyclohexanediaminocobalt(II) (604 mg,
1.00 mmol) and glacial acetic acid (123 mg, 2.05 mmol) in toluene
(5 ml) were stirred for 2 h at room temperature while exposed
to the atmosphere. The solvent was evaporated under reduced
pressure leaving the crude (R,R)-(salen)Co(III)(OAc) catalyst as a
dark brown residue. Anhydrous propylene oxide (35 ml, 29.0 g,
499 mmol) was added and the resulting solution was cooled
in an ice-water bath. Water (4.90 ml, 272 mmol) was added
slowly to the stirring solution, ensuring the temperature stayed
between 15–20 ◦C. After the addition was complete (ca 0.5 h),
the solution was allowed to warm to room temperature and left
to stir for 18 h. Distillation gave (R)-propylene oxide bp 35 ◦C,
a colourless oil. [a]D + 8.7 (c 0.078 in CH2Cl2). (Found: M+,
21
276.1359. C16H20O4 requires 276.1362). Mass spectrum m/z: 276
(M, 21%), 244 (24), 215 (30), 214 (100), 199 (41), 187 (49), 115
(20). dH (300 MHz, CDCl3) 8.03 (1H, d, J 8.6, ArH), 7.59 (1H,
d, J 8.6, ArH), 7.41 (1H, dd, J 8.6, 7.6, ArH), 7.33 (1H, d, J 8.6,
ArH), 6.81 (1H, d, J 7.6, ArH), 5.18 (1H, d, J 5.9, CH), 5.16 (1H,
d, J 5.9, CH), 4.23 (1H, m, CH), 3.99 (3H, s, OCH3), 3.70 (3H, s,
OCH3), 3.10–2.94 (2H, m, CH2), 2.32 (1H, d, J 4.6, OH), 1.30 (3H,
d, J 6.2, CH3). dC (75.5 MHz, CDCl3) 155.7 (C), 151.6 (C), 129.4
(C), 128.3 (C), 127.7 (C), 126.3 (CH), 126.1 (CH), 118.8 (CH),
114.2 (CH), 103.8 (CH), 100.3 (CH2), 68.6 (CH), 57.6 (OCH3),
55.6 (OCH3), 40.1 (CH2), 23.6 (CH3).
20
31
(12.0 g, 41%), [a]D + 14.0 (neat) (lit.,23 [a]D + 13.8 (neat)),
followed by 1,2-propanediol bp 46 ◦C( 0.7 mm Hg (16.9 g, 45%).
The remaining residue was diluted with methanol and the red
precatalyst (563 mg) was recovered by filtration.
(2R)-1-(5-Methoxy-1-methoxymethoxynaphthalen-2-yl)propan-
2-ol 27
n-Butyllithium in hexane (1.6 M, 5.4 ml, 8.6 mmol) was
added dropwise to a stirred solution of 5-methoxy-1-methoxy-
methoxynaphthalene (1.43 g, 6.56 mmol) in anhydrous tetrahy-
drofuran (30 ml) cooled in an ice-water bath under an argon
atmosphere. After 2 h the mixture was treated with hexam-
ethylphosphoramide (3.54 ml, 20.3 mmol), followed by the
immediate dropwise addition of (R)-propylene oxide (491 mg,
8.45 mmol) in anhydrous tetrahydrofuran (2 ml). The resulting
yellow solution was allowed to warm to room temperature and
left to stir for17 h. The solution was diluted with saturated
ammonium chloride (70 ml) and extracted with ether (3 × 50 ml).
The combined organic extracts were washed with water (40 ml),
followed by brine (50 ml), dried and evaporated to give a
yellow oil (2.18 g), which was subjected to silica gel filtration.
Elution with 1% ethyl acetate-light petroleum returned unreacted
starting material as a white crystalline solid (293 mg). Further
elution with 10% ethyl acetate-light petroleum gave (2R)-1-
(1-methoxy-5-methoxymethoxynaphthalen-2-yl)propan-2-ol 28 (66
mg) as a colourless oil, which became a white crystalline solid
upon refrigeration and recrystallised from dichloromethane-light
(2R)-1-(1-Hydroxy-5-methoxy-2-naphthalenyl)propan-2-ol 29
A 15 : 85 mixture of (2R)-1-(1-methoxy-5-methoxymethoxy-
naphthalen-2-yl)propan-2-ol and (2R)-1-(5-methoxy-1-methoxy-
methoxynaphthalen-2-yl)propan-2-ol (1.13 g) in anhydrous 2-
propanol (20 ml) was treated with carbon tetrabromide (141 mg,
0.425 mmol) and refluxed for 1.5 h under an argon atmosphere.
The solution was concentrated under reduced pressure and the
resulting yellow oil was subjected to silica gel filtration. Elution
with 5% ethyl acetate-light petroleum gave (2R)-1-(1-hydroxy-
5-methoxy-2-naphthalenyl)propan-2-ol 29 as a white crystalline
solid (696 mg, 73%), which recrystallised from ethyl acetate-light
petroleum as white plates, mp 85–86 ◦C. [a]D − 6.7 (c 0.009
21
in CH2Cl2). The NMR spectral properties of this material were
identical with those of the (2R,S) compound prepared previously.
Treatment of a sample of the (2R,S)-alcohol with the chiral shift
reagent europium tris[3-heptafluoropropylhydroxymethylene)-
(+)-camphorate] (7.5 mol%) separated the 8-H proton doublet sig-
nal into two doublets in the 1H NMR spectrum. The enantiomeric
petroleum as white plates, mp 74–75 ◦C. [a]D −26.9 (c 0.015
21
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 868–876 | 875
©

View Article Online
excess within the (2R)-alcohol was estimated to be greater than
90% by examination of the H-8 signal in the 1H NMR spectrum
of a sample of 29 which had been treated with 7.5 mol% of the
chiral shift reagent.
for this material. The NMR spectral properties of this sample
were identical with those of the (2R,S) compound prepared
previously. Further elution with 30% ethyl acetate-light petroleum
gave (−)-elecanacin 1 as a pale yellow crystalline solid (31 mg,
24%), which recrystallised from dichloromethane-light petroleum
as faint yellow plates, mp 167–168 ◦C (lit.,1 198 ◦C for material of
(2R)-2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dione 30
low ee). [a]D − 145.2 (c 0.004 in CHCl3) (lit.,1 + 20.7 in CHCl3).
21
A
solution of (2R)-1-(1-hydroxy-5-methoxy-2-naphthalenyl)-
Analysis on the Chiracel OD column showed a single peak at
retention time 26.1 min. Under these conditions <0.5% of the
other enantiomer (expected retention time 39.2 min) could have
been detected. The ee of this sample was thus >99%. The NMR
spectral properties of this material were identical with those of
(2R,S) compound prepared previously.
propan-2-ol 29 (696 mg, 3.00 mmol) in ether (15 ml) was added to
a separating funnel containing Fremy’s salt (1.718 g, 6.11 mmol)
dissolved in an aqueous borax buffer solution (0.025 M sodium
tetraborate, 84 ml; 0.1 M sodium hydroxide, 41 ml). The resulting
mixture was shaken until TLC indicated that the starting material
had been consumed (ca 30 min). The mixture was extracted with
chloroform (4 × 50 ml) and the combined organic extracts were
washed with brine (60 ml), dried and evaporated to give (2R)-2-
(2-hydroxypropyl)-5-methoxynaphthalene-1,4-dione 30 as a yellow
Acknowledgements
We thank Dr Lindsay Byrne for 2D NMR spectra and chiral
shift reagent experiments. Dr Tony Reader recorded the mass
spectra while Professor Robin Giles (Murdoch University) kindly
provided the chiral HPLC column and Dr Gavin Flematti
assisted with the HPLC analyses. Professor Y. Imakura (Naruto
University, Takashima) supplied 13C and 1H NMR spectra of
natural elecanacin.
1
crystalline solid (717 mg, 97%), which was pure by H NMR. A
sample recrystallised from ethyl acetate-light petroleum as bright
yellow needles, mp 116–117 ◦C. [a]D − 25.3 (c 0.015 in CH2Cl2).
20
The NMR spectral properties of this material were identical with
those of the (2R,S) compound prepared previously.
(2R)-5-Methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 31
A solution of (2R)-2-(2-hydroxypropyl)-5-methoxynaphthalene-
1,4-dione 30 (692 mg, 2.81 mmol) and mercuric acetate (212 mg,
0.66 mmol) in ethyl vinyl ether (17 ml, 12.8 g, 178 mmol) and
dichloromethane (4.5 ml) in a foil-covered flask was heated under
reflux for 5.5 h under an argon atmosphere. The solution was
allowed to left to stand at room temperature overnight and was
then diluted with dichloromethane (40 ml) and washed with water
(80 ml). The organic layer was separated and the aqueous layer
was extracted with dichloromethane (3 × 40 ml). The combined
organic extracts were washed with brine (50 ml), dried and
evaporated to give a yellow oil, which was subjected to silica gel
filtration. Elution with 15% ethyl acetate-light petroleum gave the
vinyl ether 31 as a yellow oil (393 mg, 51%, 81% based on recovered
References
1 H. Hara, N. Maruyama, S. Yamashita, Y. Hayashi, K.-H. Lee, K. F.
Bastow, Chairul, R. Marumoto and Y. Imakura, Chem. Pharm. Bull.,
1997, 45, 1714.
2 H. Schmid, Th. M. Meijer and A. Ebno¨ther, Helv. Chim. Acta, 1950,
33, 595.
3 H. Schmid, A. Ebno¨ther and Th. M. Meijer, Helv. Chim. Acta, 1950,
33, 1751.
4 W. Eisenhuth and H. Schmid, Helv. Chim. Acta., 1958, 41, 2021.
5 R. H. Thomson, Naturally Occurring Quinones III. Recent Advances,
Chapman and Hall, London, New York, 1987, p. 277.
6 M. T. Crimmins, Chem. Rev., 1988, 88, 1453.
7 R. L. Cargill, J. R. Dalton, S. O’Connor and D. G. Michels, Tetrahedron
Lett., 1978, 4465.
8 D. Bryce-Smith, E. H. Evans, A. Gilbert and H. S. McNeill, J. Chem.
Soc., Perkin Trans. 1, 1992, 485.
9 M. Tokunaga, J. F. Larrow, F. Kakiuchi and E. N. Jacobsen, Science,
1997, 277, 936.
10 S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen,
A. E. Gould, M. E. Furrow and E. N. Jacobsen, J. Am. Chem. Soc.,
2002, 124, 1307.
11 T. Kamikawa and I. Kubo, Synthesis, 1986, 431.
12 A. S.-Y. Lee, Y.-J. Hu and S.-F. Chu, Tetrahedron, 2001, 57, 2121.
13 K. Mori, in Comprehensive Natural Products Chemistry, ed. D. Barton
and K. Nakanishi, Elsevier Science, Oxford, 1999, vol. 8, p. 7.
14 M. A. Brimble, L. J. Duncalf and M. R. Nairn, Nat. Prod. Rep., 1999,
16, 267 and references therein.
15 M. Gill and C. Elsworth, Nat. Prod. Lett., 2000, 14, 411.
16 U. Pindur and G. H. Schneider, Chem. Soc. Rev., 1994, 23, 409.
17 E. M. Stocking and R. M. Williams, Angew. Chem., Int. Ed. Engl.,
2003, 42, 3078.
18 H. Oikawa, Bull. Chem. Soc. Jpn., 2005, 78, 537.
19 F. Da Silva Knudsen, A. Campa, H. A. Stefani and G. Cilento, Proc.
Natl. Acad. Sci. U. S. A, .1994, 91, 410.
20 M. S. DeClue, K. K. Baldridge, D. E. Ku¨nzler, P. Kast and D. Hilvert,
J. Am. Chem. Soc., 2005, 127, 15002.
21
starting material). [a]D − 15.6 (c 0.010 in CH2Cl2). The NMR
spectral properties of this material were identical with those of the
(2R,S) compound prepared previously. Further elution with 40%
ethyl acetate-light petroleum returned unreacted starting material
as a yellow crystalline solid (255 mg).
(−)-Elecanacin 1 and (+)-isoelecanacin 16
A
deoxygenated solution of (2R)-5-methoxy-2-(2-vinyloxy-
propyl)naphthalene-1,4-dione 31 (131 mg, 0.482 mmol) in anhy-
drous dichloromethane (50 ml) was irradiated at 350 nm through
Pyrex for 65 min, when TLC indicated that all the starting material
had been consumed. The solvent was evaporated and the yellow
residue was subjected to careful radial chromatography. Elution
with 20% ethyl acetate-light petroleum gave (+)-isoelecanacin 16
(53 mg, 40%) as a yellow crystalline solid, which recrystallised
from dichloromethane/light petroleum as pale yellow plates, mp
21 A. D. Payne and D. Wege, Org. Biomol. Chem., 2003, 1, 2383.
22 R. W. Murray and M. Singh, Org. Synth., 1997, 74, 91.
23 D. E. White and E. N. Jacobsen, Tetrahedron: Asymmetry, 2003, 14,
3633.
138–139 ◦C. [a]D + 110.4 (c 0.010 in CH2Cl2). Analysis on
21
the Chiracel OD column showed two peaks in the ratio of 1 :
99 at retention times 20.1 and 23.4 min, giving an ee of 98%
876 | Org. Biomol. Chem., 2006, 4, 868–876
This journal is
The Royal Society of Chemistry 2006
©