Synthesis of isochroman-3-ylacetates and isochromane-γ-lactones through rearrangement of aryldioxolanylacetates

Article abstract of DOI:10.1039/a807005i

Lewis acid catalysed rearrangement of methyl 4,5-trans-4-aryldioxolan-5-ylacetates 1 provides a convenient route to substituted methyl isochroman-3-ylacetates 2 and isochromane-γ-lactones 3. The choice of Lewis acid is determined by the substitution pattern of the aromatic ring. The two contiguous isochromane stereocentres are transferred unchanged from the parent dioxolanes, while the configuration of the isochromane methyl group is dependent upon the aryl substitution, the reagent and the reaction conditions. Thus treatment of the C-2 epimeric 3′,5′-dimethoxyphenyldioxolanes 4 and 5 with camphorsulfonic acid afforded a mixture of the C-5 epimeric isochromane lactones 26 and 29, the former being favoured at lower acid concentrations, the latter at higher concentrations. Titanium tetrachloride isomerised the analogous 2′-chloro-5′-methoxyphenyldioxolanes 6 and 7 into the methyl isochroman-3-ylacetate 38, which could be lactonised to the isochromane lactone 27. Phosphoric acid converted the 2′,5′-dimethoxyphenyldioxolanes 8 and 9 into a mixture of the isochromane lactones 28 and 31, while similar treatment of the hydroxylactone 22 in the presence of acetaldehyde afforded the isochromane lactone 28 directly and with complete diastereoselectivity. Oxidative demethylation and annulation of this isochromahe lactone 28 afforded 5-epi-7-deoxykalafungin 41.

Full text of DOI:10.1039/a807005i

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Synthesis of isochroman-3-ylacetates and isochromane-ã-lactones
through rearrangement of aryldioxolanylacetates
Robin G. F. Giles,*a Rodney W. Rickards*b and Badra S. Senanayakeab
a Chemistry Department, Murdoch University, Murdoch, WA 6150, Australia
b Research School of Chemistry, Australian National University, Canberra, ACT 0200,
Australia
Received (in Cambridge) 8th September 1998, Accepted 29th September 1998
Lewis acid catalysed rearrangement of methyl 4,5-trans-4-aryldioxolan-5-ylacetates 1 provides a convenient route to
substituted methyl isochroman-3-ylacetates 2 and isochromane-γ-lactones 3. The choice of Lewis acid is determined
by the substitution pattern of the aromatic ring. The two contiguous isochromane stereocentres are transferred
unchanged from the parent dioxolanes, while the configuration of the isochromane methyl group is dependent upon
the aryl substitution, the reagent and the reaction conditions. Thus treatment of the C-2 epimeric 3Ј,5Ј-dimethoxy-
phenyldioxolanes 4 and 5 with camphorsulfonic acid afforded a mixture of the C-5 epimeric isochromane lacto-
nes 26 and 29, the former being favoured at lower acid concentrations, the latter at higher concentrations. Titanium
tetrachloride isomerised the analogous 2Ј-chloro-5Ј-methoxyphenyldioxolanes 6 and 7 into the methyl isochroman-3-
ylacetate 38, which could be lactonised to the isochromane lactone 27. Phosphoric acid converted the 2Ј,5Ј-dimethoxy-
phenyldioxolanes 8 and 9 into a mixture of the isochromane lactones 28 and 31, while similar treatment of the hydroxy-
lactone 22 in the presence of acetaldehyde afforded the isochromane lactone 28 directly and with complete diastereo-
selectivity. Oxidative demethylation and annulation of this isochromane lactone 28 afforded 5-epi-7-deoxykalafungin
41.
We have recently reported the titanium tetrachloride-promoted
diastereoselective isomerisation of 2,5-dimethyl-4-naphthyl-
dioxolanes into benzoisochromanes in relation to natural
product synthesis.1 The versatility of this novel intramolecular
version of the Mukaiyama reaction2 was further explored by
converting the corresponding 2,5-dimethyl-4-phenyldioxolanes
in high yield into isochromanes.3,4 These studies showed that
the 4,5-stereochemistry of the parent dioxolanes is transferred
intact to the 4,3-positions of the product isochromanes, so that
4,5-trans dioxolanes afford 3,4-cis isochromanes. C-1 of the
isochromanes is derived from C-2 of the dioxolanes with a
diastereoselectivity which depends upon the aryl substitution
and 4,5-stereochemistry of the substrate, and in some cases also
upon the reaction temperature. We now report the extension of
this process to the conversion of methyl 4,5-trans-4-aryl-
dioxolan-5-ylacetates 1 into methyl isochroman-3-ylacetates 2
and the corresponding isochromane-γ-lactones 3 (Scheme 1).
and 2-chloro-5-methoxyphenyl, have significant synthetic util-
ity and were chosen again for the present investigation. The 3,5-
pattern has symmetry and generates isochromane substitution
typical of polyketide natural products, both 2,5-patterns pro-
vide oxidative access to the para-quinonoid functionality fre-
quently found in natural benzoisochromanes, and the 2-chloro
substituent can also be removed by reduction. The required
substrates were therefore the pairs of diasteromeric dioxolanes
4 and 5, 6 and 7, and 8 and 9.
MeO
MeO
R1
R2
R1
R2
O
O
O
O
MeO
Cl
CO2 Me
CO2 Me
4 R1 = Me, R2 = H
5 R1 = H, R2 = Me
6 R1 = Me, R2 = H
7 R1 = H, R2 = Me
MeO
MeO
MeO
1
4
5
O
O
MeO
3
O
4
5
R
R
3
R
2
OH
CO2Me
O
O
R1
R2
O
O
O
CO2Me
MeO
2
3
1
Scheme 1
CO2 Me
8 R1 = Me, R2 = H
9 R1 = H, R2 = Me
These products contain the key structural elements of a number
of natural naphthopyranquinones.5
3,5-Dimethoxybenzaldehyde 11 was subjected to a Wittig
reaction with the triphenylphosphonium salt 10 of 3-chloro-
propionic acid. The ultraviolet absorption maximum of the
product 12 at 250 nm resembled that of (E)-1-(3Ј,5Ј-dimethoxy-
phenyl)prop-1-ene,3 supporting its assignment as a styrene. In
the 1H NMR spectrum, the coupling constant (J 15.9 Hz)
Results
Synthesis of the dioxolanes
The three different substitution patterns of the 4-phenyl-
dioxolanes previously studied,3,4 3,5- and 2,5-dimethoxyphenyl
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956
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to only one of the C-3 methylene protons and also to 5-H at
δ 5.42 (J 3.8 Hz). An NOE spectrum confirmed the mutual
proximity of the protons 4-H and 5-H, and thus the expected
CO2H
Cl
Ph3P
1
cis stereochemistry of lactone 14. The H NMR data for the
10
heterocyclic ring protons corresponded closely with those
reported for the naphthalenic analogue juglomycin A 25.7
MeO
MeO
MeO
MeO
OMe
MeO
MeO
5
O
O
R
R
MeO
R
3a
O
9b
R1
Cl
R1
MeO
3
O
R2
O
R2
MeO
O
HO
R = CHO
R =
19
11
12
15
O
O
R1 = OMe, R2 = H
R1 = H, R2 = Cl
R1 = H, R2 = OMe
29
30
31
25
26
27
28
16
17
20
21
CO2H
OMe
R =
MeO
MeO
13
O+
CO2Me
O
O
Me
R1
H5
H4
R2
H2
O
O
O
MeO2C
5
R =
O
3
14
22
18
HO
32
33 R1, R2 = H, OMe
between 3-H and 4-H confirmed that the product was the (E)-
stereoisomer. Dihydroxylation of the double bond of acid 12
with osmium tetroxide and N-methylmorpholine N-oxide6
proved troublesome. The acid was therefore converted via the
acid chloride into its methyl ester 13 in 83% yield. Treatment of
this ester with N-methylmorpholine N-oxide and a catalytic
quantity of osmium tetroxide gave in 87% yield the lactone 14
expected7 from ring closure of the intermediate dihydroxy ester.
The mass spectrum of the lactone 14 showed a molecular ion
at m/z 238 and a base peak at m/z 166 through loss of 72 mass
units. The latter ion may arise from the expected initial cleavage
of the lactone carbonyl–oxygen bond in the molecular ion 23
followed by loss of carbon monoxide and the enol of acetalde-
hyde from the resulting intermediate 24 (Scheme 2). Corre-
Treatment of the lactone 14 with 1,1-dimethoxyethane and a
catalytic quantity of camphorsulfonic acid in boiling methylene
dichloride gave the pair of C-2 epimeric dioxolanes 4 and 5 in a
combined yield of 70% and a ratio of approximately 1.3:1.
Unexpectedly, a small quantity (7%) of the isochromane-γ-
lactone 26 was also isolated and is discussed below. Further
chromatography of the mixture of dioxolanes 4 and 5 afforded
the major C-2 epimer 4 pure, and the minor epimer 5 enriched
to a ratio of 3:1.
The structure of the major dioxolane 4 was confirmed by 1H
NMR spectroscopy. The dioxolane ring proton 2-H appeared
as a quartet at δ 5.35, with the small coupling constant (4.9 Hz)
typical of 2-H protons in related 2-methyldioxolanes.1,3,4 The
proton 4-H resonated as a doublet at δ 4.59 coupled (J 6.9 Hz)
to 5-H, a doublet of triplets (J 4.9 and 6.9 Hz) at δ 4.26 which
was further coupled (J 6.9 and 4.9 Hz) to the adjacent methy-
lene protons on the pendant acetate. The methylene protons
resonated as doublets of doublets at δ 2.68 (J 15.0 and 6.9 Hz)
and δ 2.63 (J 15.0 and 4.9 Hz). NOE data established the
stereochemistry 4 and the preferred conformation 32 of this
major diastereomer. Irradiation of the proton 4-H and the
acetate methylene protons each provided a 4.2% enhancement
of 2-H, while the reciprocal enhancement of 4-H on irradiation
of 2-H was 2.4%. The 4,5-trans relationship was supported by
a 12.9% enhancement of 4-H on irradiation of the acetate
methylene protons.
MeO
MeO
O
O
O
MeO
MeO
O
HO
HO
23
24
–CO
–C2H4O
MeO
2-Chloro-5-methoxybenzaldehyde 15 was similarly converted
via the intermediates 16, 17 and 18 into the mixture of C-2
epimeric dioxolanes 6 and 7, and 2,5-dimethoxybenzaldehyde
19 via the intermediates 20, 21 and 22 into the dioxolanes 8 and
9. While a small amount of the isochromane lactone 28 (5%)
analogous to 26 was produced in the conversion of lactone 22
into dioxolanes 8 and 9, none of the related isochromane
lactone 27 accompanied the synthesis of dioxolanes 6 and 7
from lactone 18. Evidence will be presented below for the
structures of these minor byproducts 26 and 28. Their
formation probably reflects the higher electrophilicity of the
dimethoxyphenyl rings of the lactones 14 and 22 compared to
the chloromethoxyphenyl ring of 18. They must arise either
directly from the starting lactones 14 and 22 through con-
version into the intermediate oxocarbenium ions 33 with
O
MeO
H
Scheme 2
sponding fragmentations were also observed for the related
hydroxy lactones 18 and 22 discussed below. The infrared spec-
trum of the lactone 14 showed hydroxy and carbonyl stretching
frequencies at 3467 cmϪ1 and 1776 cmϪ1, the latter being typical
of a γ-lactone. Its 1H NMR spectrum showed the two C-3
methylene protons as a doublet (J 17.5 Hz) at δ 2.70 and a
doublet of doublets (J 17.5 Hz and 5.4 Hz) at δ 2.85. The
methine proton 4-H at δ 4.58 showed vicinal coupling (J 5.4 Hz)
3950
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the reagents 1,1-dimethoxyethane and camphorsulfonic acid,
followed by cyclisation,3,4 or from the product dioxolanes
via related oxocarbenium ions of the type 35. We now address
this latter possibility.
MeO
MeO
2O
3'
O
1'
MeO
MeO
H
OH
OH
CO2Me
Conversion of dioxolanes into isochroman-3-ylacetates and
isochromane-ã-lactones
CO2Me
36
37
The 1.3:1 mixture of C-2 epimeric 3Ј,5Ј-dimethoxyphenyl-
dioxolanes 4 and 5 was treated for 18 hours in boiling
methylene dichloride with camphorsulfonic acid in increasing
concentrations, ca. 10–200 times greater than the catalytic
amount (0.02 mol equiv., 4.3 × 10Ϫ4 mol lϪ1) used for the prep-
aration of the dioxolanes themselves from the lactone 14. The
dioxolanes 4 and 5 were converted smoothly into a mixture of
the epimeric isochromane lactones 26 and 29 in a combined
yield of 80–89%. At the lowest catalyst concentration (5.7 ×
10Ϫ3 mol lϪ1) the isochromane lactone 26 predominated in a
ratio of 6.8:1, which was dramatically reversed at higher con-
centrations (5.7 × 10Ϫ2, 8.6 × 10Ϫ2 mol lϪ1) to 1:1.9 and 1:3.6 in
favour of the epimer 29.
MeO
MeO
O
OH
OH
Cl
OH
CO2Me
Cl
CO2 Me
39
38
O
O
O
5
5
O
O
3a
3a
The epimers 26 and 29 showed similar mass spectra, with
molecular ions at m/z 264 and base peaks at m/z 249 arising
from loss of a methyl radical as expected for such isochromane
ring systems.3,4 Infrared spectra showed γ-lactone absorption at
9b
11b
O
O
O
O
40
41
O
1
1781 and 1780 cmϪ1 respectively. In the H NMR spectrum of
26 only two meta-coupled aromatic proton resonances (J 2.3
Hz) and two methoxy resonances were observed. The pyran
ring protons 9b-H, 5-H and 3a-H resonated as a doublet (J 2.5
Hz) at δ 5.07, a quartet (J 6.5 Hz) at δ 4.79 and a doublet of
doublets (J 2.5 and 4.6 Hz) at δ 4.35. The methylene protons
of the γ-lactone ring appeared at δ 2.88 and δ 2.74 coupled
geminally (J 17.5 Hz), and only the former resonance showed
additional vicinal coupling (J 4.6 Hz) to 3a-H.
ature and maintained for two hours, only the dihydroiso-
benzofuran ester 37 was obtained. Its mass spectrum showed a
structurally distinctive base peak at m/z 193 corresponding to
loss of the CH(OH)CH2CO2Me radical from the molecular ion
at m/z 296, as has been observed in analogous dihydroisobenzo-
1
furans.3 The H NMR spectrum of this sole product 37 estab-
lished the trans arrangement of the heterocyclic substituents
from the long range coupling constant (J 3.0 Hz) between the
protons 1Ј-H and 3Ј-H at δ 5.26 and δ 5.40.3,8
The only major differences between the 1H NMR spectra of
the isochromane lactone 26 and its C-5 epimer 29 were the
chemical shifts of the protons 3a-H and 5-H, which appeared at
δ 4.35 and 4.79 for the former and δ 4.77 and 5.10 for the latter.
The chemical shifts of the 3a-H protons suggest the 1,3-cis and
1,3-trans stereochemistry for the epimers 26 and 29 respectively,
consistent with the observation that the corresponding 3-H
proton in 1,3-cis dimethylisochromanes appears at significantly
higher field than in the 1,3-trans compounds.1,3,4 A lesser differ-
ence between the spectra was the chemical shift of the C-5
methyl substituent, which appeared at δ 1.56 for the all-cis iso-
chromane lactone 26 and 1.46 for the C-5 epimer 29. For each
epimer the small coupling constant (J 2.5 and 3.0 Hz) between
3a-H and 9b-H,3,4 and the mutually enhanced intensities (5–
12%) observed on irradiation of 3a-H and 9b-H, verified the
expected 3a,9b-cis relationship derived from the parent lactone
14. Assignment of the all-cis stereochemistry to isochromane 26
was confirmed by mutual 7–10% NOE enhancements between
the ring protons 3a-H and 5-H, which are thus axial and
pseudoaxial, respectively.3,4 In contrast, irradiation of the C-5
methyl group of 3a,5-trans epimer 29 enhanced 3a-H (15%).
Since titanium tetrachloride had proved so effective in previ-
ous isomerisation studies,1,3,4 the effect of this Lewis acid on the
1.3:1 mixture of epimeric 3Ј,5Ј-dimethoxyphenyldioxolanes 4
and 5 was also investigated at various temperatures. After 30
min in methylene dichloride at Ϫ78 ЊC the starting materials
were recovered in the altered ratio of 1:1.8, suggesting that the
epimer 5 was favoured under those conditions. When the
reaction temperature was raised from Ϫ78 ЊC to Ϫ30 ЊC and
maintained for 30 minutes, a mixture of products was obtained.
GC-MS analysis of this mixture indicated the starting diox-
olanes 4 and 5 in a ratio of 1:1.5 (55%), together with two other
isomers. These were an isochromane ester (20%), presumed to
have the structure 36 by analogy with that of ester 38 discussed
below, and the dihydroisobenzofuran ester 37 (25%). If the
reaction temperature was raised from Ϫ78 ЊC to room temper-
Reaction of the 1:1 mixture of C-2 epimeric 2Ј-chloro-5Ј-
methoxyphenyldioxolanes 6 and 7 with camphorsulfonic acid in
boiling methylene dichloride for extended periods afforded no
isochromane lactones, the dioxolanes being recovered. With
titanium tetrachloride in methylene dichloride at Ϫ78 or
Ϫ30 ЊC the dioxolanes were again recovered in high yield, but
substantially enriched in one epimer (unidentified). At the
higher temperatures of 0 ЊC and room temperature, no dioxo-
lanes were recovered and the observed products were the
rearranged isochromane ester 38 and the diol ester 39 from
dioxolane cleavage, isolated in yields of 64 and 12% after 5
hours at room temperature. The mass spectrum of isochromane
ester 38 provided the expected molecular ion isotope pair at m/z
302/300, with a base peak at m/z 198 arising through loss of
methyl 3-oxopropanoate in a retro Diels–Alder process.4 The
1H NMR spectrum showed the isochromane to be a single
diastereomer, which was assigned the all-cis stereochemistry
from the mutual 10% NOE enhancements between the protons
1-H and 3-H, a quartet and a doublet of triplets at δ 4.94 and
4.02, respectively. The expected cis relationship between 3-H
and 4-H followed from their small coupling constant (J 1.3 Hz),
and the enhanced intensity (11%) of the 4-H doublet at δ 4.69
on irradiation of 3-H.
When the isochromane ester 38 was boiled in methylene
dichloride with camphorsulfonic acid the isochromane lactone
27 was obtained in 83% yield. The chemical shifts and coupling
constants of the heterocyclic ring protons of this lactone
matched closely those of its analogue 26. Together with NOE
data which indicated the mutual proximity of 3a-H and 5-H,
this confirmed the all-cis stereochemistry of isochromane
lactone 27 and also, therefore, of the isochromane ester 38.
None of the C-5 epimer 30 of 27 was observed in this reaction.
The rearrangement conditions above were extended to the
1:1 epimeric mixture of 2Ј,5Ј-dimethoxyphenyldioxolanes 8
and 9, where the para substituents provide latent quinonoid
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956
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functionality.4 The mixture was recovered unchanged after
treatment with camphorsulfonic acid in dichloromethane at
reflux, while reaction with titanium tetrachloride gave rise to
inseparable mixtures of products which were not further
investigated. When the dioxolanes 8 and 9 were treated with
phosphoric acid at room temperature, however, the epimeric
isochromane lactones 28 and 31 were formed in good yield
(70%) as an inseparable mixture in a 1:1 ratio. Distinctive
NMR signals for 3a-H, 5-H and the C-5 methyl protons in each
component, assigned from their close correspondence in shift
and coupling to the signals of the analogues 26 and 29 dis-
cussed above, occurred at δ 4.28, 4.85 and 1.57 for the all-cis
isochromane lactone 28, and at 4.69, 5.14 and 1.46 for its
epimer 31.
Previous syntheses of 1-methylisochromanes involved the
reaction of 2-(2Ј-hydroxypropyl)-1,4-naphthoquinols with
acetaldehyde in the presence of acid catalysts.9,10 The hydroxy-
lactone 22 was therefore reacted with acetaldehyde in neat
phosphoric acid at room temperature, whereupon the isochro-
mane lactone 28 was isolated as a single stereoisomer in 76%
yield. Its mass spectrum showed the expected molecular ion at
m/z 264 and base peak at 249 arising from loss of a methyl
radical. The all-cis stereochemistry inferred earlier was con-
firmed by reciprocal NOE enhancements of 8–15% between
3a-H and 5-H, and between 3a-H and 9b-H.
These undergo an allowed 6-enolendo-endo-trig type electro-
philic cyclisation16 to afford isochromanes in which the two
contiguous pyran stereocentres are transferred unchanged from
the parent dioxolanes. Attack at O-1 of the dioxolanes and
cleavage of the C(2)–O(1) bond no doubt also occurs giving rise
to the alternative oxocarbenium ions 34, but these cannot
achieve the disallowed 5-enolendo-endo-trig type cyclisation to
dihydroisobenzofurans and so reform the parent dioxolanyl
acetates.
When the reagent is a Brønsted acid, lactonisation accom-
panies isochromane ring closure to give directly the iso-
chromane lactones. With the Lewis acid titanium tetrachloride,
lactonisation does not occur and the products remain as the
γ-hydroxy esters, perhaps because the reagent is complexed to
the γ-hydroxy group as in the intermediate 35. Lactonisation
can be effected subsequently by treatment with acid.
In the case of the 3Ј,5Ј-dimethoxyphenyldioxolanes 4 and 5,
the aromatic ring is sufficiently activated towards electrophilic
substitution that camphorsulfonic acid in refluxing methylene
dichloride is sufficient to promote isochromane lactone form-
ation. Low acid concentrations favour the all-cis isomer 26 as
the kinetic product. Higher acid concentrations cause epimeris-
ation of the C-5 position through protonation of O-4 and
reversible opening of the activated benzylic C(5)–O(4) bond,
affording the thermodynamically favoured isochromane
lactone 29 in which the C-5 methyl group is now trans to the
fused lactone ring (Scheme 4). With titanium tetrachloride, the
Oxidative demethylation of the all-cis isochromane lactone
28 with cerium() ammonium nitrate11 afforded the corres-
ponding quinone 40 in 69% yield. The homoallylic coupling
constant of 1.8 Hz between 5-H and 9b-H in this product was
expected from their pseudoaxial and pseudoequatorial orien-
tations.12,13 A Diels–Alder reaction with 1-acetoxybuta-1,3-
diene, followed by enolisation and oxidation in the presence of
sodium carbonate, then gave in 66% yield the known14,15 5-epi-
7-deoxykalafungin 41.
MeO
MeO
H
O
4O
OH
29
26
MeO
MeO
O
O
O
Scheme 4
Discussion
These conversions of methyl 4,5-trans-4-aryl-1,3-dioxolan-5-
ylacetates 1 into methyl isochroman-3-ylacetates 2 and iso-
chromane γ-lactones 3 extend the previously reported isomeris-
ations of 2,5-dimethyl-4-phenyl-1,3-dioxolanes, and probably
proceed through similar mechanisms.3,4
Initial protonation (X = H) or coordination of titanium
tetrachloride (X = TiCl4Ϫ) at O-3 leads to ring opening of the
dioxolanylacetates 1 at the C(2)–O(3) bond to afford the corre-
sponding intermediate oxocarbenium ions 35 (Scheme 3).
all-cis isochromane ester 36 is formed initially, but undergoes
secondary rearrangement in the presence of the Lewis acid at
higher temperatures to form the dihydroisobenzofuran ester 37.
Cleavage of the activated benzylic C(1)–O(2) bond is here
caused by coordination of the Lewis acid to O-2, ring closure
by the available free benzylic hydroxy group then ensuing to
give the dihydroisobenzofuran ester.3
The less reactive 2Ј-chloro-5Ј-methoxyphenyldioxolanes 6
and 7 and 2Ј,5Ј-dimethoxyphenyldioxolanes 8 and 9 are
unaffected by treatment with camphorsulfonic acid. The former
pair with titanium tetrachloride gives the expected all-cis iso-
chromane ester 38 corresponding to 36, but which lacks the
additional activating influence of a 6-methoxy group and con-
sequently does not epimerise or rearrange to a dihydroiso-
benzofuran. The 2Ј,5Ј-dimethoxyphenyldioxolane pair 8 and 9
with titanium tetrachloride yields severe mixtures. This add-
itional reactivity in the presence of the Lewis acid compared to
their regioisomeric pair 4 and 5 results from alternative benzylic
cleavages promoted by the 2Ј-methoxy substituent, as has been
observed previously.4 Treatment with phosphoric acid, however,
results in efficient rearrangement to the epimeric isochromane
lactones 28 and 31. The factors controlling diastereoselectivity
in this reaction have not been studied. The fact that similar acid
treatment of the hydroxy lactone 22 in the presence of acetalde-
hyde gives the isochromane lactone 28 as the sole product
implies that these alternative routes to the isochromane lactone
28 do not share common intermediates, and that the isochro-
mane lactone 28 once formed does not epimerise.
MeO
MeO
X
O
O
R
R
OX
CO2Me
O
CO2 Me
34
MeO
O
26, 28, 31
R
OX
CO2Me
35
The diastereoselectivity of the process for the configuration
of the isochromane methyl group is thus dependent upon the
aryl substitution, the reagent and the reaction conditions. The
kinetic preference noted in related rearrangements4 for the
induction of cis stereochemistry of the benzylic methyl sub-
36, 38
Scheme 3
3952
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956

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stituent relative to the benzylic hydroxy substituent in the iso-
chromane products was observed again in this study in the
formation of the isochromanes 26, 27, 28, 36 and 38.
mixture was allowed to warm to room temperature and stirred
for 2 h before heating under reflux for 12 h and then removal of
the solvent under reduced pressure. The residue was stirred for
2 h with methanol (20 ml) which was removed under reduced
pressure to afford the crude ester (1.7 g). Chromatography in
15% ethyl acetate–hexane as eluent gave the ester 13 as a yellow
oil (1.50 g, 83%) (Found: C, 66.2; H, 6.9. C13H16O4 requires C,
66.1; H 6.8%); δH 6.53 (2H, d, J 2.2, 2Ј- and 6Ј-H), 6.43 (1H, dt,
J 15.9 and 1.5, 4-H), 6.38 (1H, t, J 2.2, 4Ј-H), 6.27 (1H, dt,
J 15.9 and 7.2, 3-H), 3.80 (6H, s, 2 × OCH3), 3.72 (3H, s,
COOCH3), 3.25 (2H, dd, J 7.2 and 1.5, 2-CH2); δC 171.8 (C-1),
160 (C-3Ј and C-5Ј), 138.7 (C-1Ј), 134.4 (C-4), 122 (C-3), 104
(C-2Ј and C-6Ј), 99.8 (C-4Ј), 55.2 (2 × OCH3), 51.8 (COOCH3),
38.0 (C-2); m/z 236 (Mϩ, 49%), 177 (100), 176 (54), 161 (21), 146
(23), 91 (36), 77 (26), 65 (24), 59 (25).
Conclusions
Lewis acid catalysed diastereoselective rearrangement of
methyl 4,5-trans-4-aryldioxolan-5-ylacetates 1 provides a con-
venient route to substituted isochromane-γ-lactones 3. The
choice of Lewis acid depends on the substitution pattern of the
aromatic ring. For the 3Ј,5Ј-dimethoxyphenyldioxolanes 4 and
5, camphorsulfonic acid was highly effective, and its concen-
tration controlled the preferred stereochemistry of the C-5
methyl group of the resulting isochromane lactone 26 or 29. In
the case of the 2Ј-chloro-5Ј-methoxyphenyldioxolanes 6 and 7,
titanium tetrachloride stereoselectively afforded the all-cis
hydroxyisochromane ester 38 which could be cyclised with
camphorsulfonic acid to the corresponding isochromane-γ-
lactone 27 without loss of stereochemistry. For the 2Ј,5Ј-
dimethoxyphenyldioxolanes 8 and 9, phosphoric acid was effi-
cient but gave a mixture of the C-5 epimeric isochromane
lactones 28 and 31.
Reaction of the hydroxy lactone 22 with acetaldehyde in the
presence of phosphoric acid yielded the all-cis isochromane-γ-
lactone 28 with complete diastereoselectivity. Its oxidative
demethylation led to quinone 40, which on annulation was
readily converted into the corresponding benzoisochromane-
quinone 5-epi-7-deoxykalafungin 41 closely related to a number
of natural products.
rel-(4R,5R)-2,3,4,5-Tetrahydro-4-hydroxy-5-(3Ј,5Ј-dimethoxy-
phenyl)furan-2-one 14
The ester 13 (1.50 g, 6.3 mmol) in acetone (20 ml) was added to
a solution of osmium tetroxide (5 mg) and N-methylmorpho-
line N-oxide6 (0.85 g, 7.3 mmol) in water at 0 ЊC. The mixture
was allowed to warm to room temperature and was stirred for
18 h. Acetone was removed under reduced pressure and the
aqueous solution acidified with dilute hydrochloric acid (2 M,
20 ml). The organic materials were extracted into ethyl acetate
(5 × 50 ml), and the combined extracts washed with water
(3 × 100 ml), dried, filtered, and the solvent removed under
reduced pressure to give a light brown oil (1.4 g). Chromatog-
raphy using 40% ethyl acetate–hexane as eluent afforded the
lactone 14 as a colourless oil (1.32 g, 87%) (Found: C, 60.5; H,
6.1. C12H14O5 requires C, 60.5; H, 5.9%); νmax/cmϪ1 (neat) 3467
Experimental
(OH), 1776 (C᎐O), 1599 (C᎐C aromatic); δH 6.50 (2H, d, J 2.2,
᎐
᎐
General
2Ј- and 6Ј-H), 6.43 (1H, t, J 2.2, 4Ј-H), 5.42 (1H, d, J 3.8, 5-H),
4.58 (1H, dd, J 3.8 and 5.4, 4-H), 3.78 (6H, s, 2 × OCH3), 2.85
(1H, dd, J 17.5 and 5.4, 3-H), 2.70 (1H, d, J 17.5, 3-H); δC 175.2
(C-2), 161.2 (C-3Ј and C-5Ј), 135.1 (C-1Ј), 103.8 (C-2Ј and
C-6Ј), 100.8 (C-4Ј), 85.1 (C-5), 70.1 (C-4), 55.5 (2 × OCH3),
38.5 (C-3); m/z 238 (Mϩ, 24%), 167 (43), 166 (100), 139 (36), 135
(14), 109 (33), 77 (20).
Instrumentation and general procedures were as described
previously.4
(E)-4-(3Ј,5Ј-Dimethoxyphenyl)but-3-enoic acid 12
3,5-Dimethoxybenzaldehyde 11 (5.2 g, 30 mmol) in dry tetra-
hydrofuran (100 ml) was added in portions to a stirred solu-
tion of (2-carboxyethyl)triphenylphosphonium chloride17
(12.5 g, 30 mmol) in dry dimethyl sulfoxide (100 ml) at room
temperature. The mixture was cooled to 0 ЊC, sodium hydride
(1.0 g, 60% dispersion in oil) was added in portions, and the
mixture was then allowed to warm to room temperature and
stirred for 14 h. Aqueous sodium hydroxide (10%) was added,
and the resulting solution was washed with toluene (5 × 100 ml)
then with diethyl ether (2 × 100 ml). The aqueous phase was
acidified with concentrated hydrochloric acid and extracted
with methylene dichloride (3 × 150 ml). The combined extracts
were washed with dilute hydrochloric acid, dried and evapor-
ated to give a brown oil. Chromatography using 25% ethyl
acetate–hexane as eluent gave unreacted aldehyde 11 (1.5 g,
29%) followed by the acid 12 as a yellow oil (3.50 g, 50%),
crystallised from methylene dichloride, mp 53–54 ЊC (Found: C,
64.9; H, 6.5. C12H14O4 requires C, 64.9; H, 6.4%); λmax/nm
(MeOH) 250 (log ε 4.3), 300 (log ε 3.4); νmax/cmϪ1 (neat) 1710
rel-(2S,4R,5R) and rel-(2R,4R,5R)-5-Methoxycarbonylmethyl-
4-(3Ј,5Ј-dimethoxyphenyl)-2-methyl-1,3-dioxolanes 4 and 5
The lactone 14 (500 mg, 2.1 mmol), 1,1-dimethoxyethane (400
mg, 4.1 mmol) and ( )-camphorsulfonic acid1 (10 mg, 0.043
mmol) in dry methylene dichloride (100 ml) were heated under
reflux for 72 h. The reaction was quenched with saturated
aqueous sodium hydrogen carbonate (5 ml), poured into
cold water and extracted with methylene dichloride (3 × 100
ml). The combined extracts were dried, filtered and the sol-
vent removed under reduced pressure to give a colourless oil.
Chromatography in 20% ethyl acetate–hexane as eluent
afforded a 1.3:1 mixture of the epimeric dioxolanes 4 and 5 as a
colourless oil (436 mg, 70%) (Found: C, 61.0; H, 6.9. C15H20O6
requires C, 60.8; H, 6.8%); δH 6.53 and 6.49 (each d, J 2.2,
2Ј- and 6Ј-H of each isomer), 6.41 (m, 4Ј-H of both isomers),
5.46 and 5.35 (each q, J 4.9, 2-H of each isomer), 4.59 and 4.57
(each d, J 6.9, 4-H of each isomer), 4.26 and 4.12 (each dt, J 4.9
and 6.9, 5-H of each isomer), 3.79 (s, OCH3 of both isomers),
3.67 (s, COOCH3 of both isomers), 2.75–2.58 (m, CH2 of both
isomers), 1.51 and 1.46 (each d, J 4.9, 2-CH3 of each isomer);
m/z 296 (Mϩ, 8%), 193 (22), 179 (43), 165 (18), 151 (32), 87 (30),
77 (24), 59 (100). Further elution gave the isochromane lactone
26, a white powder (34 mg, 7%), with 1H NMR and mass spec-
tral data given below. Further chromatography of the mixture
of dioxolanes 4 and 5 (100 mg) using 15% ethyl acetate–hexane
afforded the single dioxolane 4 (20 mg), δH 6.53 (2H, d, J 2.2, 2Ј
and 6Ј-H), 6.41 (1H, t, J 2.2, 4Ј-H), 5.35 (1H, q, J 4.9, 2-H), 4.59
(1H, d, J 6.9, 4-H), 4.26 (1H, dt, J 4.9 and 6.9, 5-H), 3.79 (6H, s,
2 × OCH3), 3.67 (3H, s, COOCH3), 2.68 (1H, dd, J 15.0 and
(CO H), 1653 (C᎐C), 1596 (C᎐C aromatic); δ 6.53 (2H, d,
᎐
᎐
2
H
J 2.2, 2Ј- and 6Ј-H), 6.45 (1H, dt, J 15.9 and 1.5, 4-H), 6.38 (1H,
t, J 2.2, 4Ј-H), 6.27 (1H, dt, J 15.9 and 7.2, 3-H), 3.80 (6H, s,
2 × OCH3), 3.30 (2H, dd, J 7.2 and 1.5, 2-CH2); δC 177.6 (C-1),
160.8 (C-3Ј and C-5Ј), 138.6 (C-1Ј), 133.9 (C-4), 121.4 (C-3),
104.4 (C-2Ј and C-6Ј), 100.0 (C-4Ј), 55.3 (2 × CH3O), 37.9
(C-2); m/z 222 (Mϩ, 82%), 182 (31), 177 (100), 168 (46), 161
(22), 147 (22), 146 (24), 139 (28), 109 (26), 103 (21), 91 (43), 79
(21), 77 (49), 69 (29).
Methyl (E)-4-(3Ј,5Ј-dimethoxyphenyl)but-3-enoate 13
The acid 12 (1.70 g, 7 mmol) in dry methylene dichloride (15
ml) was treated with oxalyl chloride (1.0 g, 8 mmol) at 0 ЊC. The
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956
3953

View Article Online
6.9, CH2), 2.63 (1H, dd, J 15.0 and 4.9, CH2), 1.51 (3H, d, J 4.9,
2-CH3). The 1H NMR spectrum of the fraction containing
the dioxolane 5 showed about 25% contamination with the
epimer 4.
the epimeric dioxolanes 6 and 7 as a colourless oil (550 mg,
81%) (Found: Mϩ Ϫ C2H4O, 256.0502. C12H1335ClO4 requires
Mϩ Ϫ C2H4O, 256.0502); δH 7.23 (2H, d, J 9.1, 3Ј-H of both
isomers), 7.14 and 7.05 (each 1H, d, J 3.1, 6Ј-H of each isomer),
6.78 (2H, dd, J 9.1 and 3.1, 4Ј-H of both isomers), 5.53 and 5.38
(each 1H, q, J 4.9, 2-H of each isomer), 5.13 and 5.11 (each 1H,
d, J 6.9, 4-H of both isomers), 4.31 (2H, m, 5-H of both
isomers), 3.80 (6H, s, OCH3 of both isomers), 3.60 (6H, s,
COOCH3 of both isomers), 2.95–2.75 (4H, m, CH2 of both
isomers), 1.56 and 1.48 (each 3H, d, J 4.9, 2-CH3 of each
isomer); m/z 302 [Mϩ(37Cl), 2%], 300 [Mϩ(35Cl), 6], 265 (8),
258 (15), 256 (47), 226 (25), 197 (18), 183 (22), 169 (45), 167
(57), 155 (36), 119 (28), 91 (25), 77 (23), 59 (100).
(E)-4-(2Ј-Chloro-5Ј-methoxyphenyl)but-3-enoic acid 16
2-Chloro-5-methoxybenzaldehyde 15 (3.0 g, 17.6 mmol) in dry
tetrahydrofuran (100 ml) was added to a stirred solution of
(2-carboxyethyl)triphenylphosphonium chloride (7.5 g, 18.0
mmol) in dry dimethyl sulfoxide (100 ml). The procedure
described above for the synthesis of acid 12 was followed to
afford the aldehyde 15 (1.0 g, 33%) and the acid 16 as a yellow
oil (1.7 g, 50%), which was crystallised from methylene dichlor-
ide, mp 92–94 ЊC (Found: C, 58.2; H, 4.8; Cl, 15.7. C11H11ClO3
requires C, 58.3; H, 4.9; Cl, 15.6%); νmax/cmϪ1 (neat) 1710
(E)-4-(2Ј,5Ј-Dimethoxyphenyl)but-3-enoic acid 20
(COOH), 1653 (C᎐C), 1596 (C᎐C aromatic); δ 7.23 (1H, d,
2,5-Dimethoxybenzaldehyde 19 (2.0 g, 12.05 mmol) in tetra-
hydrofuran (200 ml) was added in portions to (2-carboxyethyl)-
triphenylphosphonium chloride (5.0 g, 12.05 mmol) in dry
dimethyl sulfoxide (100 ml) at room temperature. The pro-
cedure described for the synthesis of acid 12 afforded unreacted
aldehyde 19 (0.3 g, 15%) followed by the acid 20 as a yellow oil
(1.8 g, 67%) (Found: C, 65.0; H, 6.4. C12H14O4 requires C, 64.85;
᎐
᎐
H
J 8.8, 3Ј-H), 7.06 (1H, d, J 3.0, 6Ј-H), 6.88 (1H, dt, J 15.8 and
1.5, 4-H), 6.76 (1H, dd, J 8.8 and 3.0, 4Ј-H), 6.29 (1H, dt, J 15.8
and 7.2, 3-H), 3.81 (3H, s, OCH3), 3.37 (2H, dd, J 7.2 and 1.5,
CH2); δC 177.8 (C-1), 158.3 (C-5Ј), 135.3 (C-2Ј), 130.2 (C-1Ј),
124.5 and 123.7 (C-3, C-4), 114.9 (C-4Ј and C-6Ј), 111.6 (C-3Ј),
55.5 (OCH3), 38.0 (C-2); m/z 228 [Mϩ (37Cl), 21%], 226 [Mϩ
(35Cl), 65], 186 (29), 181 (45), 146 (100), 145 (47), 131 (30), 115
(45), 103 (49), 102 (24), 77 (51), 63 (49).
H, 6.35%); νmax/cmϪ1 (neat) 1710 (COOH ), 1653 (C᎐C), 1596
᎐
(C᎐C aromatic); δ 7.02 (1H, d, J 2.3, 6Ј-H), 6.83 (1H, dt, J 15.9
᎐
H
and 1.5, 4-H), 6.80 (2H, m, 3Ј and 4Ј-H), 6.31 (1H, dt, J 15.9
and 7.2, 3-H), 3.82 and 3.80 (each 3H, s, OCH3), 3.34 (2H, dd,
J 7.2 and 1.5, 2-CH2); δC 177.6 (C-1), 153.8 and 151.1 (C-2Ј and
C-5Ј), 128 (C-4), 126.5 (C-1Ј), 121.7 (C-3), 113.8, 112.2 and
112.1 (C-3Ј, C-4Ј, C-6Ј), 56.2 (OCH3), 55.7 (OCH3), 38.3 (C-2);
m/z 222 (Mϩ, 100%), 177 (45), 161 (77), 147 (15), 146 (15), 91
(27), 77 (21), 65 (25), 55 (19).
Methyl (E)-4-(2Ј-chloro-5Ј-methoxyphenyl)but-3-enoate 17
Phenylbutenoic acid 16 (1.7 g, 7.50 mmol) in dry methylene
dichloride (15 ml) was treated with oxalyl chloride (1.0 g, 8.0
mmol) at 0 ЊC. The procedure described above for the synthesis
of ester 13 was followed to afford the ester 17 as a yellow oil (1.5
g, 83%) (Found: C, 59.5; H, 5.7; Cl, 14.9. C12H13ClO3 requires
C, 59.8; H, 5.4; Cl, 14.7%); δH 7.25 (1H, d, J 8.8, 3Ј-H), 7.06
(1H, d, J 3.0, 6Ј-H), 6.83 (1H, dd, J 15.8 and 1.5, 4-H), 6.73
(1H, dd, J 8.8 and 3.0, 4Ј-H), 6.29 (1H, dt, J 15.8 and 7.1, 3-H),
3.80 (3H, s, OCH3), 3.73 (3H, s, COOCH3), 3.31 (2H, dd, J 7.1
and 1.5, CH2); δC 171.1 (C-1), 158.2 (C-5Ј), 135.5 (C-2Ј), 130.2
and 129.4 (C-4, C-3), 124.5 (C-1Ј), 114.8 (C-4Ј and C-6Ј), 111.5
(C-3Ј), 55.5 (OCH3), 51.9 (COOCH3), 38.0 (C-2); m/z 242
[Mϩ(37Cl), 21%], 240 [Mϩ(35Cl), 63], 183 (21), 181 (68), 146
(100), 145 (39), 131 (28), 115 (33), 103 (47), 102 (23), 77 (34),
51 (30).
Methyl (E)-4-(2Ј,5Ј-dimethoxyphenyl)but-3-enoate 21
Phenylbutenoic acid 20 (1.7 g, 7.0 mmol) in methylene dichlor-
ide (15 ml) was treated with oxalyl chloride (1.0 g, 8 mmol) as
for the preparation of ester 13 to afford the ester 21 as a yellow
oil (1.5 g, 83%) (Found: C, 66.25; H, 7.15. C13H16O4 requires C,
66.1; H, 6.8%); νmax/cmϪ1 (neat) 1750 (COOCH ), 1653 (C᎐C);
᎐
3
δH 7.01 (1H, d, J 2.3, 6Ј-H), 6.82 (1H, dt, J 15.9 and 1.4, 4-H),
6.78 (2H, m, 3Ј and 4Ј-H), 6.30 (1H, dt, J 15.9 and 5.6, 3-H),
3.80, 3.78 and 3.72 (each 3H, s, 2 × OCH3 and COOCH3), 3.28
(2H, dd, J 5.6 and 1.4, CH2); δC 172.1 (C-1), 153.6 and 150.9
(C-2Ј, C-5Ј), 128.0 and 126.6 (C-1Ј, C-4), 122.4 (C-3), 113.6,
112.1 and 111.9 (C-3Ј, C-4Ј, C-6Ј), 56.1 (OCH3), 55.6 (OCH3),
51.8 (COOCH3), 31.5 (C-2); m/z 236 (Mϩ, 95%), 181 (11), 177
(100), 162 (23), 161 (84), 147 (20), 146 (24), 121 (17), 103 (12),
91 (32), 77 (19), 65 (29).
rel-(4R,5R)-2,3,4,5-Tetrahydro-4-hydroxy-5-(2Ј-chloro-5Ј-
methoxyphenyl)furan-2-one 18
The ester 17 (600 mg, 2.49 mmol) in acetone (10 ml) was added
to a solution of osmium tetroxide (5 mg) and N-methyl-
morpholine N-oxide (540 mg, 4.60 mmol) in water (30 ml) at
0 ЊC. The procedure described for the synthesis of lactone 14
afforded the lactone 18 as a colourless oil (450 mg, 75%)
(Found: C, 54.6; H, 4.8; Cl, 14.7. C11H11ClO3 requires C, 54.45;
rel-(4R,5R)-2,3,4,5-Tetrahydro-4-hydroxy-5-(2Ј,5Ј-dimethoxy-
phenyl)furan-2-one 22
H, 4.6; Cl, 14.6%); νmax/cmϪ1 (KBr) 3525 (OH), 1770 (C᎐O),
The ester 21 (400 mg, 1.69 mmol) in acetone (10 ml) was added
to osmium tetroxide (5 mg) and N-methylmorpholine N-oxide
(226 mg, 1.94 mmol) in water (30 ml) at 0 ЊC. The procedure
described for the synthesis of hydroxy lactone 14 afforded the
lactone 22 as a colourless oil (370 mg, 92%) (Found: C, 60.25;
H, 6.1; C12H14O5 requires C, 60.5; H, 5.9%); νmax/cmϪ1 (neat)
3420 (OH), 1772 (C᎐O), 1612 cmϪ1 (C᎐C); δ 7.06 (1H, d, J 2.2,
᎐
1596 (C᎐C); δ 7.29 (1H, d, J 8.8, 3Ј-H), 7.10 (1H, d, J 3.1,
᎐
H
6Ј-H), 6.86 (1H, dd, J 8.8 and 3.1, 4Ј-H), 5.76 (1H, d, J 3.4,
5-H), 4.93 (1H, dd, J 3.4 and 5.4, 4-H), 3.80 (3H, s, OCH3), 2.96
(1H, dd, J 17.6 and 5.4, 3-H), 2.72 (1H, d, J 17.6, 3-H); δC 174.9
(C-1), 158.7 (C-5Ј), 131.9 (C-2Ј), 130.3 (C-3Ј), 121.9 (C-1Ј),
116.4 and 113.2 (C-4Ј, C-6Ј), 82.6 (C-5), 68.3 (C-4), 55.7
(OCH3), 38.3 (C-2); m/z 244 [Mϩ(37Cl), 10%], 242 [Mϩ(35Cl),
32], 173 (23), 172 (40), 171 (87), 170 (100), 169 (44), 143 (22), 77
(23), 63 (27).
᎐
᎐
H
6Ј-H), 6.84 (2H, m, 3Ј-H and 4Ј-H), 5.72 (1H, d, J 3.5, 5-H),
4.78 (1H, dd, J 3.5 and 5.3, 4-H), 3.80 and 3.76 (each 3H, s,
OCH3), 2.87 (1H, dd, J 17.5 and 5.3, 3-H), 2.66 (1H, d, J 17.5,
3-H); δC 175.4 (C-2), 153.8 and 149.6 (C-2Ј, C-5Ј), 122.1 (C-1Ј),
114.8 (C-6Ј), 112.9 and 111.3 (C-3Ј, C-4Ј), 81.8 (C-5), 68.7
(C-4), 55.8 (2 × OCH3), 38.2 (C-3); m/z 238 (Mϩ, 100%), 167
(97), 166 (96), 151 (35), 139 (38), 137 (35), 120 (22).
rel-(2S,4R,5R) and rel-(2R,4R,5R)-5-Methoxycarbonylmethyl-
4-(2Ј-chloro-5Ј-methoxyphenyl)-2-methyl-1,3-dioxolanes 6 and 7
The lactone 18 (600 mg, 2.48 mmol) in dry methylene dichloride
(100 ml) was treated with 1,1-dimethoxyethane (400 mg, 4.1
mmol) and ( )-camphorsulfonic acid (10 mg, 0.043 mmol) as
for the synthesis of dioxolanes 4 and 5 above, to afford the
hydroxy lactone 18 (40 mg, 10%) followed by a 1:1 mixture of
rel-(2S,4R,5R) and rel-(2R,4R,5R)-5-Methoxycarbonylmethyl-
4-(2Ј,5Ј-dimethoxyphenyl)-2-methyl-1,3-dioxolanes 8 and 9
The lactone 22 (320 mg, 1.34 mmol) in dichloromethane (100
3954
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956

View Article Online
ml) was treated with 1,1-dimethoxyethane (400 mg, 4.1 mmol)
and ( )-camphorsulfonic acid (10 mg, 0.043 mmol) as for the
synthesis of dioxolanes 4 and 5 to afford, first, recovered lac-
tone 22 (100 mg, 31%), followed by the isochromane lactone 28
(17 mg, 5%) and finally the dioxolanes 8 and 9 in a 1:1 ratio as a
colourless oil (190 mg, 60%) (Found: C, 60.8; H, 6.9. C15H20O6
aqueous sodium hydrogen carbonate (2 ml) before pouring into
water. The organic layer was separated, the aqueous layer
extracted with methylene dichloride (3 × 10 ml), and the
organic extracts dried and evaporated to give a colourless oil.
Analysis by GC, GC-MS and 1H NMR spectroscopy indicated
a mixture of three compounds: dioxolanes 4 and 5 (55%);
isochromane ester 36 (20%), GC-MS m/z 296 (Mϩ, 13%), 281
(100), 221 (6), 207 (7), 203 (14), 193 (8), 179 (11), 175 (6); and
dihydroisobenzofuran 37 (25%). Repetition of the reaction at
room temperature for 2 h gave a crude product (40 mg), GC,
GC-MS and 1H NMR spectroscopy of which indicated the
dihydroisobenzofuran ester 37, δH 6.43 (1H, d, J 2.5, 7Ј-H), 6.36
(1H, d, J 2.5, 5Ј-H), 5.40 (1H, dq, J 3.0 and 6.2, 3Ј-H), 5.26 (1H,
t, J 3.0, 1Ј-H), 4.31 (1H, ddd, J 8.8, 3.0 and 4.0, 3-H), 3.82
and 3.81 (each 3H, s, OCH3), 3.72 (3H, s, COOCH3), 2.62 (1H,
dd, J 16.0 and 4.0, 2-H), 2.53 (1H, dd, J 16.0 and 8.8, 2-H),
1.47 (3H, d, J 6.2, 3Ј-CH3); m/z 296 (Mϩ, 4%), 278 (21), 193
(100), 151 (7). Attempted chromatography of the dihydroiso-
benzofuran 37 on silica gel or neutral alumina resulted in
decomposition.
requires C, 60.8; H, 6.8%); νmax/cmϪ1 (KBr disc) 1685 (C᎐O),
᎐
1654 (C᎐C); δ 7.12 and 7.02 (each 1H, d, J 2.2, 6Ј-H of each
᎐
H
isomer), 6.78 (4H, m, 3Ј-H and 4Ј-H of both isomers), 5.41 and
5.34 (each 1H, q, J 4.8, 2-H of each isomer), 5.04 and 4.98 (each
1H, d, J 6.0, 4-H of each isomer), 4.28 (2H, m, 5-H of both
isomers), 3.78, 3.76 and 3.68 (each 6H, s, 2 × OCH3 and
COOCH3 of both isomers), 2.85 (4H, m, CH2 of both isomers),
1.51 and 1.47 (each 3H, d, J 4.8, 1-CH3 of each isomer); m/z 296
(Mϩ, 42%), 252 (37), 194 (30), 193 (59), 179 (29), 165 (52), 161
(26), 153 (48), 151 (54), 87 (35), 59 (100).
rel-(3aR,5S,9bR)- and rel-(3aR,5R,9bR)-3,3a,5,9b-Tetrahydro-
6,8-dimethoxy-5-methyl-2H-furo[3,2-c][2]benzopyran-2-ones 26
and 29
(a) The phenyldioxolane mixture 4 and 5 (1.3:1, 100 mg, 0.34
mmol) and ( )-camphorsulfonic acid (20 mg, 0.086 mmol)
in dry methylene dichloride (15 ml) were heated under reflux for
18 h. The reaction was quenched with saturated aqueous
sodium hydrogen carbonate (1 ml) and extracted with methyl-
ene dichloride. The organic extracts were dried, filtered and
concentrated to give a residue (90 mg), which was chromato-
graphed in 40% ethyl acetate–hexane to afford a mixture of
the isochromane lactones 26 and 29, in 6.8:1 ratio from
GC-MS and 1H NMR analysis, as a colourless oil (80 mg,
86%).
Methyl [rel-(1S,3R,4R)-5-chloro-4-hydroxy-8-methoxy-1-
methylisochroman-3-yl]acetate 38
To the dioxolanes 6 and 7 (1:1, 250 mg, 1.03 mmol) in methy-
lene dichloride (40 ml) stirred at 0 ЊC in an atmosphere of argon
was added titanium tetrachloride (0.23 ml, 2.06 mmol). After
stirring at room temperature for 5 h, the reaction was quenched
with saturated aqueous sodium hydrogen carbonate (2 ml)
and poured into water. The organic layer was separated, the
aqueous layer extracted with methylene dichloride (3 × 10 ml),
and the organic extracts dried and evaporated to give a colour-
less oil. Analysis by GC and GC-MS indicated a mixture of two
compounds. Chromatography using 40% ethyl acetate–hexane
as eluent first afforded the isochromane ester 38 as a colourless
oil (160 mg, 64%) (Found: C, 55.9; H, 5.9; Cl, 11.9. C14H17ClO5
requires C, 55.9; H, 5.7; Cl, 11.8); δH 7.26 (1H, d, J 8.8, 6-H),
6.78 (1H, d, J 8.8, 7-H), 4.94 (1H, q, J 6.2, 1-H), 4.69 (1H, d,
J 1.3, 4-H), 4.02 (1H, dt, J 1.3 and 7.1, 3-H), 3.80 (3H, s,
OCH3), 3.72 (3H, s, COOCH3), 2.84 (2H, m, CH2), 1.54 (3H, d,
J 6.2, 1-CH3); m/z 302 [Mϩ(37Cl), 2%], 300 [Mϩ(35Cl) 6], 287 (5),
285 (15), 253 (10), 225 (12), 209 (18), 200 (32), 198 (100), 183
(27), 169 (36). This was followed by the diol ester 39 as a colour-
less oil (30 mg, 12%), δH 7.24 (1H, d, J 8.8, 3Ј-H), 7.10 (1H, d,
J 3.0, 6Ј-H), 6.79 (1H, dd, J 8.8 and 3.0, 4Ј-H), 5.02 (1H, d,
J 5.7, 4-H), 4.15 (1H, m, 3-H), 3.80 (3H, s, OCH3), 3.70 (3H, s,
COOCH3), 2.68 (1H, dd, J 17.0 and 7.5, 2-H), 2.48 (1H, dd,
J 17.0 and 3. 2, 2-H); m/z 274 [Mϩ(35Cl), 1%], 256 (12), 183 (12),
174 (30), 172 (100).
(b) The reaction was repeated using ( )-camphorsulfonic
acid (300 mg, 1.29 mmol), affording a 1:3.6 mixture of iso-
chromane lactones 26 and 29 as a colourless oil (82 mg, 89%).
This mixture was separated by HPLC using 20% tetrahydro-
furan–hexane as eluent to afford, first, the isochromane lactone
26 (15 mg, 18%), which was crystallised from methylene
dichloride–hexane, mp 138–140 ЊC (Found: C, 63.3; H, 6.1.
C14H16O5 requires C, 63.6; H, 6.1%); νmax/cmϪ1 (KBr) 1781
(C᎐O), 1600 (C᎐C); δ 6.58 (1H, d, J 2.3, 9-H), 6.48 (1H, d,
᎐
᎐
H
J 2.3, 7-H), 5.07 (1H, d, J 2.5, 9b-H), 4.79 (1H, q, J 6.5, 5-H),
4.35 (1H, dd, J 2.5 and 4.6, 3a-H), 3.82 and 3.80 (each 3-H, s,
OCH3), 2.88 (1H, dd, J 17.5 and 4.6, 3-H), 2.74 (1H, d, J 17.5,
3-H), 1.56 (3H, d, J 6.5, 5-CH 3); δC 175.3 (C-2), 159.4 and 157.1
(C-6, C-8), 129.1 and 121.8 (C-5a, C-9a), 105.6 (C-9), 100.4
(C-7), 76.9, 70.9 and 69.8 (C-3a, C-5, C-9b), 55.5 (OCH3), 55.3
(OCH3), 38.3 (C-3), 21.3 (CH3). This was followed by the iso-
chromane lactone 29 (47 mg, 57%), which was crystallised from
methylene dichloride–hexane, mp 127–128 ЊC (Found: C, 63.7;
H, 6.3. C14H16O5 requires C, 63.6; H, 6.1%); νmax/cmϪ1 (KBr)
rel-(3aR,5S,9bR)-9-Chloro-3,3a,5,9b-tetrahydro-6-methoxy-5-
methyl-2H-furo[3,2-c][2]benzopyran-2-one 27
1780 (C᎐O), 1612 (C᎐C); δH 6.58 (1H, d, J 2.1, 9-H), 6.46 (1H,
᎐
᎐
d, 2.1, 7-H), 5.10 (1H, q, J 6.6, 5-H), 5.01 (1H, d, J 3.0, 9b-H),
4.77 (1H, dd, J 5.4 and 3.0, 3a-H), 3.82 and 3.81 (each 3H, s,
OCH3), 2.99 (1H, dd, J 17.8 and 5.4, 3-H), 2.69 (1H, d, J 17.8,
3-H), 1.46 (3H, d, J 6.6, 5-CH3); δC 174.8 (C-2), 159.6 and 155.9
(C-6, C-8), 128.2 and 121.6 (C-5a, C-9a), 104.9 (C-9), 99.7
(C-7), 75.5, 67.3 and 65.8 (C-3a, C-5, C-9b), 55.4 (2 × OCH3),
37.7 (C-3), 18.5 (CH3); m/z 264 (Mϩ, 10%), 249 (100), 221 (2),
193 (3), 177 (7), 162 (10).
The isochromane 38 (150 mg, 0.62 mmol) and ( )-camphor-
sulfonic acid (100 mg, 0.43 mmol) in methylene dichloride
(10 ml) were heated under reflux for 3 h. The reaction was
quenched with saturated aqueous sodium hydrogen carbonate
(2 ml), and the organic layer was separated, washed with water,
dried and evaporated. Chromatography using 25% ethyl
acetate–hexane as eluent afforded the isochromane lactone 27
as a colourless oil (112 mg, 83%) (Found: C, 57.8; H, 4.9; Cl,
13.5. C13H13ClO4 requires C, 58.1; H, 4.9; Cl, 13.2%); νmax/cmϪ1
Methyl rel-(1S,3R,4R)-4-hydroxy-6,8-dimethoxy-1-methyliso-
chroman-3-ylacetate 36 and methyl rel-(1ЈR,3R,3ЈS)-3-hydroxy-
3-(1Ј,3Ј-dihydro-4Ј,6Ј-dimethoxy-3Ј-methylisobenzofuran-1Ј-yl)-
propanoate 37
(neat) 1780 (C᎐O), 1590 (C᎐C); δ 7.34 (1H, d, J 8.8, 8-H), 6.88
᎐
᎐
H
(1H, d, J 8.8, 7-H), 5.30 (1H, d, J 2.2, 9b-H), 4.86 (1H, q, J 6.3,
5-H), 4.34 (1H, dd, J 2.2 and 4.4, 3a-H), 3.83 (3H, s, OCH3),
2.90 (1H, dd, J 17.2 and 4.4, 3-H), 2.73 (1H, d, J 17.2, 3-H),
1.57 (3H, d, J 6.3, 5-CH3); δC 175.4 (C-2), 154.6 (C-6), 131.5,
128.3 and 126.7 (C-5a, C-9, C-9a), 112.6 and 112.0 (C-7, C-8),
74.1, 71.1 and 69.7 (C-3a, C-5, C-9b), 55.5 (OCH3), 38.1 (C-3),
21.1 (CH3); m/z 270 [Mϩ(37Cl), 5%], 268 [Mϩ(35Cl), 15%], 255
(35), 253 (100), 225 (14), 197 (11), 169 (12).
To a stirred solution of a 1.3:1 mixture of dioxolanes 4 and 5
(50 mg, 0.17 mmol) in dry methylene dichloride (25 ml) at
Ϫ78 ЊC was added titanium tetrachloride (0.05 ml, 0.34 mmol).
The reaction mixture was warmed to Ϫ30 ЊC, stirred for 30
minutes, then quenched with methanol (0.1 ml) and saturated
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956
3955

View Article Online
rel-(3aR,5S,9bR)-3,3a,5,9b-Tetrahydro-6,9-dimethoxy-5-
methyl-2H-furo[3,2-c][2]benzopyran-2-one 28
(each 1H, d, J 8.3, 7-H and 8-H), 5.10 (1H, dd, J 2.5 and 1.8,
9b-H), 4.64 (1H, dq, J 1.8 and 6.5, 5-H), 4.32 (1H, dd, J 2.5 and
4.7, 3a-H), 2.87 (1H, dd, J 17.5 and 4.7, 3-H), 2.69 (1H, d,
J 17.5, 3-H), 1.57 (3H, d, J 6.5, 5-CH3); m/z 234 (Mϩ, 28%), 219
(22), 191 (24), 179 (39), 91 (24), 77 (33), 55 (100).
To a stirred solution of lactone 22 (600 mg, 2.52 mmol) in
freshly distilled acetaldehyde (110 mg, 2.50 mmol) was added
orthophosphoric acid (6 ml). After 22 h at room temperature,
water (100 ml) was added and the aqueous solution was
extracted with methylene dichloride (3 × 50 ml). The organic
extracts were washed with water, dried, and evaporated to give a
brown residue, which was dissolved in toluene (7 ml) to which
hexane (30 ml) was added. The resultant precipitate was filtered
and the filtrate concentrated to afford an orange residue, which
was chromatographed using 33% ethyl acetate–hexane as eluent
to give the isochromane lactone 28 as a yellow oil (532 mg, 76%)
(Found: Mϩ, 264.0998. C14H16O5 requires 264.0998); νmax/cmϪ1
rel-(3aR,5S,11bR)-3,3a,5,6,11,11b-Hexahydro-5-methyl-2H-
furo[3,2-b]naphtho[2,3-d]pyran-2,6,11-trione 41
The quinone 40 (30 mg, 0.13 mmol) and 1-acetoxybuta-1,3-
diene (60 mg, 0.54 mmol) in benzene (5 ml) was heated at 60 ЊC
for 5 h. The solvent was evaporated, the residual oil dissolved
in ethanol (3 ml) to which was added 1% sodium carbonate
solution (0.3 ml), and the mixture stirred at room temperature
for a further 5 h. Dilution with ethyl acetate (10 ml), washing
with water, drying and evaporation gave a crude oil, which
was chromatographed in 25% ethyl acetate–hexane as eluent to
afford 5-epi-7-deoxykalafungin 41 as an orange oil (24 mg,
66%), crystallised from hexane–diethyl ether, mp 191–193 ЊC,
(KBr disc) 1786 (C᎐O), 1602 (C᎐C); δ 6.89 and 6.78 (each 1H,
᎐
᎐
H
d, J 8.9, 7-H and 8-H), 5.32 (1H, d, J 2.3, 9b-H), 4.84 (1H, q,
J 6.5, 5-H), 4.28 (1H, dd, J 2.3 and 4.3, 3a-H), 3.84 and 3.78
(each 3H, s, OCH3), 2.84 (1H, dd, J 17.2 and 4.3, 3-H), 2.69
(1H, d, J 17.2, 3-H), 1.57 (3H, d, J 6.5, 5-CH3); δC (CDCl3)
175.7 (C-2), 152.7 and 149.7 (C-6, C-9), 130.3 (C-5a), 117.7
(C-9a), 112.3 and 108.9 (C-7, C-8), 72.5, 70.9 and 69.6 (C-3a,
C-5, C-9b), 56.1 (OCH3), 55.6 (OCH3), 38.2 (C-3), 21.1
(5-CH3); m/z 264 (Mϩ, 50%), 249 (100), 221 (12), 165 (15), 91
(19), 77 (22).
1
lit.,16 190–193 ЊC (decomp.), with H NMR and MS data in
agreement with literature.16
Acknowledgements
We gratefully acknowledge receipt of an Australian Post-
graduate Research Award (to B. S. S.), expert technical assist-
ance from Mr A. J. Herlt, and the provision of mass spectra by
Ms J. M. Rothschild.
rel-(3aR,5S,9bR)- and rel-(3aR,5R,9bR)-3,3a,5,9b-Tetrahydro-
6,9-dimethoxy-5-methyl-2H-furo[3,2-c][2]benzopyran-2-ones 28
and 31
References
The mixed dioxolanes 8 and 9 (1:1, 150 mg, 0.05 mmol) were
treated with orthophosphoric acid (2 ml) at room temperature
for 18 h. Water (50 ml) was added, the aqueous solution was
extracted with methylene dichloride (3 × 20 ml), and the
organic extracts were washed with water, dried, and evaporated
to give a brown residue. This residue was dissolved in toluene
(7 ml), hexane (20 ml) was added, the resultant precipitate was
filtered and the filtrate concentrated to afford an orange residue.
Chromatography using 33% ethyl acetate–hexane as eluent gave
1 R. G. F. Giles, I. R. Green, L. S. Knight, V. R. Lee Son and S. C.
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10 T. Li and R. H. Ellison, J. Am. Chem. Soc., 1978, 100, 6263.
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13 D. W. Cameron, D. G. I. Kingston, N. Sheppard and Lord Todd,
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1
the isochromane lactones 28 and 31 in 1:1 ratio by H NMR
analysis, as a yellow oil (119 mg, 70%), δH 6.90–6.76 (4H, m,
7-H and 8-H of both isomers), 5.33 (2H, br d, J ~2.9, 9b-H of
both isomers), 5.14 (1H, q, J 6.5, 5-H of 31), 4.85 (1H, q, J 6.5,
5-H of 28), 4.69 (1H, dd, J 2.9 and 5.0, 3a-H of 31), 4.28 (1H,
dd, J 2.3 and 4.3, 3a-H of 28), 3.84 (6H, s, OCH3 of both
isomers), 3.79 and 3.78 (each 3H, s, OCH3 of each isomer), 2.92
(1H, dd, J 17.2 and 5.0, 3-H of 31), 2.84 (1H, dd, J 17.2 and 4.3,
3-H of 28), 2.69 (1H, d, J 17.2, 3-H of 28) and 2.66 (1H, d,
J 17.2, 3-H of 31), 1.57 (3H, d, J 6.5, 5-CH3 of 28), 1.46 (3H, d,
J 6.5, 5-CH3 of 31).
rel-(3aR,5S,9bR)-3,3a,5,6,9,9b-Hexahydro-5-methyl-2H-furo-
[3,2-c][2]benzopyran-2,6,9-trione 40
To a stirred solution of isochromane lactone 28 (200 mg, 0.75
mmol) in acetonitrile (15 ml) and water (20 ml) was added
cerium() ammonium nitrate (870 mg, 1.59 mmol) in water
(1.5 ml) during five minutes at room temperature. The mixture
was stirred for a further 30 minutes then extracted with methyl-
ene dichloride (3 × 10 ml). The extracts were washed with
water, dried and evaporated to afford an orange residue which
was chromatographed using 25% ethyl acetate–hexane as eluent
to give the quinone 40 as an orange oil (120 mg, 69%) (Found:
Mϩ, 234.0529. C12H10O5 requires 234.0528); δH 6.87 and 6.83
14 T. Kometani and E. Yoshii, J. Chem. Soc., Perkin Trans. 1, 1981,
1191.
15 M. A. Brimble and S. J. Stuart, J. Chem. Soc., Perkin Trans. 1, 1990,
881.
16 J. E. Baldwin and M. J. Lusch, Tetrahedron, 1982, 38, 2939.
17 D. B. Denney and L. C. Smith, J. Org. Chem., 1962, 27, 3404.
Paper 8/07005I
3956
J. Chem. Soc., Perkin Trans. 1, 1998, 3949–3956