Antiviral activity of arylnaphthalene and aryldihydronaphthalene lignans

Article abstract of DOI:10.1139/v00-059

A practical method for large scale synthesis of 1- arylnaphthalene and 1-aryl-1,2-dihydronaphthalene lignans is described. The method makes use of the classic Stobbe condensation followed by regioselective reactions that provide access to both the common

Full text of DOI:10.1139/v00-059

553
Antiviral activity of arylnaphthalene and
aryldihydronaphthalene lignans
Christopher Cow, Carmen Leung, and James L. Charlton
Abstract: A practical method for large scale synthesis of 1-arylnaphthalene and 1-aryl-1,2-dihydronaphthalene lignans
is described. The method makes use of the classic Stobbe condensation followed by regioselective reactions that pro-
vide access to both the common and retrolactone lignans, e.g., 2 and 3. A total of 25 compounds, many of which are
known natural products, were prepared and their antiviral activity against human cytomegalovirus measured.
Key words: lignan, Stobbe, arylnaphthalene, antiviral.
Résumé : On décrit une méthode pratique de réaliser des synthèses à grande échelle de 1-arylnaphtalène et de
1-aryl-1,2-dihydronaphtalène lignanes. La méthode fait appel à la condensation classique de Stobbe suivie de réactions
régiosélectives qui conduisent aussi bien aux lignanes normales que rétrolactoniques, par exemple 2 et 3. On a ainsi
préparé vingt-cinq composés, dont plusieurs sont des produits naturels connus, et on a mesuré leur activité antivirale
vis-à-vis le cytomégalovirus humain.
Mots clés : lignane, Stobbe, arylnaphtalène, antiviral.
[Traduit par la Rédaction] Cow et al. 561
Introduction
aryl-1,2-dihydroanthracenes 7 has not previously been inves-
tigated. DDQ oxidation of 7 led to the arylnaphthalene
diesters 8 that could be regioselectively hydrolysed and re-
duced to form the lactones 2 or 3. The dihydrodiesters 7 and
8, and the lactones 2 and 3, were tested for antiviral activity
against human cytomegalovirus using a standard plaque re-
duction assay.
Lignans are natural products that are well known for their
broad spectrum of medicinal properties (1–4). They are
found in many plant species and are believed to be derived
from the dimerization of two phenyl propanoid units at the
central carbons of their side chains (see Scheme 1) (4).
Further cyclization of lignans can lead to cyclolignans,
such as 1-arylnaphthalenes, 1, (as well as reduced 1-arylna-
phthalenes and dibenzocyclooctadienes). Natural 1-arylna-
phthalene lignans often feature a γ-lactone ring at the 2,3-
position most commonly oriented as in structure 2, but also
found as in 3 (retrolactone) (see Scheme 1) (4).
A recent review of the antiviral activity of lignans (5)
prompted us to carry out a more extensive study of the anti-
viral activity of several 1-arylnapthalene and 1-aryl-1,2-
dihydronaphthalene lignans, and their analogs. Although
several excellent methods for the synthesis of arylnaphtha-
lene lignans have been published (1–4, 6, 7), we sought a
simple method that would yield both 1-arylnaphthalene and
1-aryl-1,2-dihydronaphthalene compounds. The general
method that we have used is shown in Scheme 2.
Results and discussion
The classic Stobbe condensation of diethyl succinate with
piperonal (3,4-methylenedioxybenzaldehyde) (a), veratralde-
hyde (3,4-dimethoxybenzaldehyde) (b) and 3,4,5-trimethoxy-
benzaldehyde (c) was used to prepare the corresponding
mono-acids 4a–c (8, 9) The crude mono-acids were esterified
to the diethyl esters 5a–c (9) followed by short path distilla-
tion under vacuum. Each of the diesters was treated with
strong base (LDA) and condensed with each of the three aro-
matic aldehydes (except for the reaction of 5c with
veratraldehyde) to provide a library of eight alcohols, 6aa–
6ca, and 6cc. It was necessary to quench the condensations
with acetic acid at low temperature to prevent lactonization
and elimination reactions from occurring. The alcohols were
not purified or characterized but were immediately dissolved
in trifluoroacetic acid and stirred at room temperature for
one hour to form the eight 1-aryl-1,2-dihydronaphthalenes
7aa–7ca and 7cc. Although there are many methods for the
preparation of 1-aryltetralin and 1-aryldihydronaphthalene
lignans in the literature, we could find no precedent for this
direct and relatively straightforward preparation of 1-aryl-
1,2-dihydronaphthalenes from the Stobbe diesters 5.
The method is short, convergent, and the purification of
intermediates is relatively straightforward. Although the
classic Stobbe condensation (first step) is well known (8), it
appears that the route from the Stobbe diester 5 to the 1-
Received October 20, 1999. Published on the NRC Research
Press website on May 8, 2000.
C. Cow, C. Leung, and J.L. Charlton.1 Department of
Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2,
Canada.
Aromatization of the dihydronaphthalenes 7 was accom-
plished using dicyanodichloro-p-benzoquinone (DDQ) in
refluxing toluene. This worked well for compounds 7aa–7bc
but did not work for the more hindered derivatives 7ca and
1Author to whom correspondence may be addressed.
Telephone: (204) 474-9267. Fax: (204) 474-7608.
e-mail: charltn@cc.umanitoba.ca
Can. J. Chem. 78: 553–561 (2000)
© 2000 NRC Canada

554
Can. J. Chem. Vol. 78, 2000
Scheme 1.
sured using a tetrazolium salt MTT (10). Seven compounds
had EC50s in the low micromolar range (EC50/TC50: 7aa 25/
>37 µM; 7ac 1.4/ >25 µM; 7bc 22/ >33 µM; 2aa 1.2/
>19 µM; 2ac 1.4/ >2.0 µM; 3ab 63/50 µM; 3ba 7.2/
>65 µM). Most of the remaining compounds did not show
substantial antiviral activity at their solubility limit (ca.
50 µM).
Conclusions
A simple, convergent procedure has been developed for
the synthesis of 1-arylnaphthalene and 1-aryl-1,2-dihydron-
aphthalene lignans and lignan analogs. The compounds prepared
were screened for activity against human cytomegalovirus
using a standard plaque reduction assay. While antiviral ac-
tivity was found, the activity did not extend into the nano-
molar range and was often paired with high cytotoxicity.
Only 2aa (Taiwanin C) and 3ba (Retrojusticidin B) had a
clear antiviral window.
7cc, presumably due to steric crowding. The naphthalenes
8aa–8bc could all be recrystallized from the crude reaction
mixtures using CHCl3–hexanes as solvent.
Experimental
General methods
The general experimental procedures and instrumentation
have been described in a previous publication (12).
The selective hydrolysis of 1-arylnaphthalene diesters
similar to 8 has been described in the literature (6). We
found that hydrolysis using KOH in methanol–water gave
the six mono-acids 9aa–9bc in good yield. Formation of the
lactones 2 was accomplished by reducing 9 using borane–
dimethylsulfide in THF followed by lactonization in acid. In
this way, lactones 2aa (Taiwanin C), 2ab (Chinensin), 2ac
(dehydroanhydropodophyllotoxin), 2ba (Justicidin B), 2bb,
and 2bc (7-deoxydiphyllin) were prepared. Formation of the
retrolactones 3 was accomplished by reducing the ester
group using sodium borohydride – lithium chloride in diglyme
at 120°C followed by lactonization in acid. The lactones 3aa
(Justicidin E), 3ab (Retrochinensin), 3ac (5′-methoxyretro-
cinensin), 3ba (Retrojusticidin B), 3bb, and 3bc were pre-
pared.
Stobbe condensation – general procedure
tert-Butyl alcohol was charged to a 500 mL flask, and
then potassium metal (1.2 equiv., ca. 0.5 M) was cut into
pieces and added to the flask. The mixture was heated at re-
flux until the potassium metal had disappeared (ca. 1 h), and
then was cooled to room temperature. Diethyl succinate (2.0
equiv.) and the substituted benzaldehyde (1.0 equiv.) were
dissolved in tert-butyl alcohol (30 mL), and this mixture
added, with stirring, via a dropping funnel over 20 min. The
dropping funnel was rinsed with tert-butyl alcohol, and the
reaction mixture stirred at room temperature for 3 h, during
which time a yellow precipitate formed.
Most of the compounds represented by structures 2, 3, 7,
and 8 were tested for their ability to inhibit human
cytomegalovirus virus using a standard plaque reduction as-
say. The cytotoxicities of the compounds were also mea-
The mixture was poured into 10% HCl (100 mL) in a
separatory funnel and extracted with EtOAc (3 × 100 mL).
The organic layers were combined and washed with satu-
Scheme 2.
© 2000 NRC Canada

Cow et al.
555
rated aqueous NaHCO3 (3 × 100 mL). The basic extracts
were combined, acidified with concentrated HCl, and ex-
tracted into fresh EtOAc (3 × 50 mL). This second organic
extract was washed with water (10 mL), dried over anhy-
drous magnesium sulfate, filtered, and evaporated to give
crude product, which was reacted in the next step without
further purification.
J = 7.1 Hz, CHϭC-CO2-CH2CH3), 4.14 (q, 2H, J = 7.2 Hz,
CO2-CH2CH3), 3.85 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
3.53 (s, 2H, CH2), 1.29 (t, 3H, J = 7.1 Hz, CO2CH2CH3),
1.22 (t, 3H, J = 7.2 Hz, CO2CH2CH3); 13C NMR (CDCl3,
75 MHz) δ 171.1 (CϭO), 167.3 (CϭO), 149.5, 148.6, 141.4,
127.5, 124.2, 122.4, 112.0, 110.9, 60.8, 60.7, 55.7, 55.6,
33.7, 14.1, 14.0; EIMS m/z = 322 [M+] (base), 276, 249,
175; HRMS calcd. for C17H22O6: 322.1416, found:
322.1436. The preparation of this compound has been previ-
ously reported (8).
Stobbe acid – 4a
Piperonal (3,4-methylenedioxybenzaldehyde, 15 g, 100 mmol),
potassium metal (4.7 g, 120 mmol), tert-butyl alcohol
(250 mL), and diethyl succinate (33 mL, 200 mmol), follow-
ing the general procedure gave a crude product as a light
yellow oil (14.0 g, 50% yield).
Stobbe diester – 5c
Crude acid 4c (27.2 g, 83.8 mmol), concentrated H2SO4
(4.0 mL), and ethanol (100 mL) gave 5c as a clear pale yel-
low distillate (15.7 g, 53% yield). 1H NMR (300 MHz, CDCl3)
δ 7.78 (s,1H, Ar-CHϭC), 6.59 (s, 2H, Ar-H), 4.24 (q, 2H,
J = 7.13 Hz, CO2-CH2-CH3), 4.14 (q, 2H, J = 7.13 Hz, CO2-
CH2-CH3), 3.83 (s, 3H, p-O-CH3), 3.81 (s, 6H, m-O-CH3),
3.52 (s, 2H, CH2-CO2), 1.30 (t, 3H, J = 7.12 Hz, O-CH2CH3),
1.22 (t, 3H, J = 7.13 Hz, O-CH2CH3); 13C NMR (CDCl3,
75 MHz) δ171.0 (CϭO), 167.1 (CϭO), 153.0, 141.6, 138.5,
130.3, 125.5, 106.2, 60.9, 60.8, 60.6, 55.9, 33.8, 14.03,
14.01; EIMS m/z = 352 [M+] (base), 278, 263, 205; HRMS
calcd. for C18H24O7: 352.1522, found: 352.1509. The prepa-
ration of this compound has been previously reported (8).
Stobbe acid – 4b
Veratraldehyde (3,4-dimethoxybenzaldehyde, 20 g,
120 mmol), potassium metal (5.6 g, 144 mmol), tert-butyl
alcohol (250 mL), and diethyl succinate (42 mL, 240 mmol),
following the general procedure gave a crude product as a
light yellow oil (29.7 g, 77% yield).
Stobbe acid – 4c
3,4,5-Trimethoxybenzaldehyde (20 g, 102 mmol), potas-
sium metal (4.8 g, 123 mmol), tert-butyl alcohol (250 mL),
and diethyl succinate (34 mL, 204 mmol), following the
general procedure gave crude product as a yellow oil
(27.2 g, 82% yield).
Dihydronaphthalene diesters – general method
Lithium diisopropylamide (1.2 equiv.) was prepared by
addition of n-BuLi (1.2 equiv., 2.5 M in hexanes) to diiso-
propylamine (1.3 equiv.) in freshly distilled THF at –70°C.
The solution was warmed briefly to 0°C, then recooled to
–70°C. A solution of the diester 5 (1 equiv.) in THF was
added dropwise through a plug (ca. 1 g) of activated alu-
mina, which was then rinsed with THF. On addition of the
diester, the solution turns orange to deep red; this colour
persists until the reaction is quenched. The mixture was
stirred for 10 min, then a solution of the aldehyde (a, b, or c)
in THF was added, and stirring was continued for 1 h. The
reaction was quenched with glacial acetic acid at –70°C,
then warmed to room temperature.
The mixture was extracted with EtOAc (3 × 20 mL),
washed with water (20 mL), dried over anhydrous magne-
sium sulfate, filtered, and evaporated on the rotary evapora-
tor at 30–40°C. The residue was subjected to high vacuum
for 1/2 h to remove solvent, then excess trifluoroacetic acid
(TFA) (3–4 mL) was added and the solution stirred at room
temperature for 1 h. The reaction was poured into saturated
aqueous NaHCO3 and extracted into EtOAc (3 × 20 mL).
The organic extracts were washed with saturated aqueous
NaHCO3 (3 × 10 mL) and water (10 mL), dried over anhy-
drous magnesium sulfate, filtered and evaporated. The prod-
ucts were isolated by flash column chromatography on silica
gel using 20–30% (depending on the polarity of the final
product) EtOAc–hexane as the eluant. The product appears
as a fluorescent spot on thin layer chromatography (silica)
under UV light.
Esterification reaction – general procedure
The crude acid-ester 4 was dissolved in anhydrous EtOH
(100 mL, ca. 0.4 M), concentrated H2SO4 was added (cata-
lytic amount) and the mixture was heated at reflux for 16 h.
The majority of the ethanol was removed on a rotary evapo-
rator, the mixture poured into saturated aqueous NaCl
(150 mL) and extracted with EtOAc (3 × 50 mL). The or-
ganic extracts were combined and washed with saturated
aqueous NaHCO3 (3 × 50 mL) and water (50 mL). The mix-
ture was dried over anhydrous magnesium sulfate, filtered,
and evaporated to give a yellow oil. This crude oil was puri-
fied by short path, high vacuum (0.01 mm Hg) distillation to
give the product.
Stobbe diester – 5a
Crude acid 4a (14.0 g, 50.3 mmol), concentrated H2SO4
(2.5 mL), and ethanol (100 mL) gave 5a as a clear pale yel-
low distillate (10.7 g, 70% yield). 1H NMR (300 MHz, CDCl3)
δ 7.78 (s, 1H, Ar-CHϭC), 6.8–6.9 (m, 3H, Ar-H), 5.99 (s,
2H, O-CH2-O), 4.26 (q, 2H, J = 7.1 Hz, CHϭC-CO2-
CH2CH3), 4.19 (q, 2H, J = 7.1 Hz, CO2-CH2CH3), 3.53 (s,
2H, CH2-CO2Et), 1.32 (t, 3H, J = 7.1 Hz, CO2CH2CH3),
1.26 (t, 3H, J = 7.1 Hz, CO2CH2CH3); 13C NMR (CDCl3,
75 MHz) δ 171.1 (CϭO), 167.4 (CϭO), 148.2, 147.9, 141.4,
128.9, 124.9, 123.9, 109.1, 108.5, 101.4, 61.0, 60.9, 33.8,
14.3, 14.2; EIMS m/z = 306 [M+] (base), 261, 232, 203, 175,
159; HRMS calcd. for C16H18O6: 306.1103, found: 306.1084.
Stobbe diester – 5b
Crude acid 4b (19.0 g, 64.5 mmol), concentrated H2SO4
(2.5 mL), and ethanol (100 mL) gave 5b as a clear yellow
distillate (16.0 g, 77% yield). H NMR (300 MHz, CDCl3) δ
7.78 (s, 1H, Ar-CHϭC), 6.7–7.0 (m, 3H, Ar-H), 4.22 (q, 2H,
Dihydronaphthalene diester – 7aa
Diester 5a (1.00 g, 3.28 mmol), diisopropylamine
(597 µL, 4.26 mmol), n-BuLi (1.79 mL of 2.2 M,
3.94 mmol), piperonal (516 mg, 3.44 mmol), and TFA
1
© 2000 NRC Canada

556
Can. J. Chem. Vol. 78, 2000
(3 mL) were used in the general method above. Flash col-
umn chromatography on silica gel using 20% EtOAc–hex-
anes gave diester 7aa (684 mg, 48% yield) as a yellow oil,
166.5 (CϭO), 153.1, 149.3, 146.8, 137.8, 136.9, 136.8,
131.9, 125.4, 123.6, 109.7, 108.7, 104.9, 101.5, 61.1, 60.7
(both ethyl CH2 carbons), 56.1, 47.2, 46.5, 14.3, 14.0;
EIMS m/z = 484 [M+], 410 (base), 365, 338; HRMS calcd.
for C26H28O9: 484.1733, found: 484.1718.
1
which foamed under vacuum. H NMR (300 MHz, CDCl3) δ
7.58 (s, 1H, Ar-CHϭC), 6.81 (s, 2H, Ar-H), 6.67 (d, 1H, J =
7.5 Hz, Ar-H), 6.60 (s, 1H, Ar-H), 6.53 (dd, 1H, J = 1.9,
7.5 Hz, Ar-H), 6.52 (s, 1H, Ar-H), 5.95 (s, 2H, O-CH2-O),
5.88 (m (AB), 2H, O-CH2-O), 4.56 (d, 1H, J = 3.0 Hz, CH-
CO2Et), 4.21 (m (2 overlapping doublets of quartets), 2H, J
= 7.1 Hz, CHϭC-CO2CH2CH3), 4.08 (m (2 overlapping
doublets of quartets), 2H, J = 7.2 Hz, CH-CO2CH2CH3),
3.93 (d, 2H, J = 3.1 Hz, CH-Ar), 1.29 (t, 3H, J = 7.1 Hz,
CH2CH3), 1.16 (t, 3H, J = 7.1 Hz, CH2CH3); 13C NMR
(75 MHz, CDCl3) δ 172.2 (CϭO), 166.6 (CϭO), 149.4,
147.7, 147.1, 146.4, 137.1, 136.3, 132.0, 125.5, 123.2,
120.8, 109.7, 108.9, 108.2, 108.1, 101.5, 101.0, 61.2, 60.8,
47.4, 46.2, 14.3, 14.1; EIMS m/z = 438 [M+], 410, 364
(base), 319, 292; HRMS calcd. for C24H22O8: 438.1315,
found: 438.1311.
Dihydronaphthalene diester – 7ba
Diester 5b (1.70 g, 5.31 mmol), diisopropylamine
(1.04 mL, 7.4 mmol), n-BuLi (2.98 mL of 2.5 M,
6.86 mmol), piperonal (911 mg, 6.07 mmol), and TFA
(4 mL) were used in the general method above. Flash col-
umn chromatography on silica gel using 20% EtOAc–hex-
anes gave diester 7ba (1.08 g, 42% yield) as a yellow oil,
1
which foamed under vacuum. H NMR (300 MHz, CDCl3) δ
7.65 (s, 1H, Ar-CHϭC), 6.86 (s, 1H, Ar-H), 6.66 (d, 1H, J =
8.0 Hz, Ar-H), 6.62 (s, 1H, Ar-H), 6.50 (dd, 1H, J = 1.7,
8.0 Hz, Ar-H), 6.48 (d, 1H, J = 1.7 Hz, Ar-H), 5.88 (m
(AB), 2H, O-CH2-O), 4.60 (d, 1H, J = 2.7 Hz, CH-CO2Et),
4.21 (q, 2H, J = 7.0 Hz, CHϭC-CO2CH2CH3), 4.10 (m (2
overlapping doublets of quartets), 2H, J = 7.0 Hz, CH-
CO2CH2CH3), 3.94 (d, 2H, J = 2.7 Hz, CH-Ar), 3.90 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3) 1.30 (t, 3H, J = 7.0 Hz,
CH2CH3), 1.16 (t, 3H, J = 7.0 Hz, CH2CH3); 13C NMR
(75 MHz, CDCl3) δ 172.3 (CϭO), 166.6 (CϭO), 150.8,
148.2, 147.7, 146.4, 137.1, 136.7, 130.1, 124.3, 122.9,
120.8, 112.0, 111.8, 108.2, 108.16 101.0, 61.2, 60.7, 56.1,
56.0, 47.6, 45.8, 14.3, 14.1; EIMS m/z = 454 [M+], 380
(base), 335, 308); HRMS calcd. for C25H28O8: 454.1627,
found: 454.1624
Dihydronaphthalene diester – 7ab
Diester 5a (1.26 g, 4.1 mmol), diisopropylamine (692 µL,
4.9 mmol), n-BuLi (1.8 mL of 2.5 M, 4.5 mmol), 3,4-
dimethoxybenzaldehyde (814 mg, 4.9 mmol), and TFA
(4 mL) were used in the general method above. Flash col-
umn chromatography on silica gel using 30% EtOAc–hex-
anes gave diester 7ab (1.01 g, 54% yield) as a yellow oil,
1
which foamed under vacuum. H NMR (300 MHz, CDCl3) δ
7.58 (s, 1H, Ar-CHϭC), 6.82 (s, 2H, Ar-H), 6.70 (d, 1H, J =
8.4 Hz, Ar-H), 6.66 (d, 1H, J = 2.0 Hz, Ar-H), 6.61 (s, 1H,
Ar-H), 6.50 (dd, 1H, J = 2.0, 8.1 Hz, Ar-H), 5.96 (s, 2H, O-
CH2-O), 4.58 (d, 1H, J = 3.4 Hz, CH-CO2Et), 4.21 (m (2
overlapping doublets of quartets), 2H, J = 7.0 Hz, CHϭC-
CO2CH2CH3), 4.08 (m (2 overlapping doublets of quartets),
2H, J = 7.7 Hz, CH-CO2CH2CH3), 3.98 (d, 1H, J = 3.4 Hz,
CH-Ar), 3.82 (s, 3H, O-CH3), 3.80 (s, 3H, O-CH3), 1.29 (s,
3H, J = 7.0 Hz, CH2CH3), 1.15 (s, 3H, J = 7.0 Hz,
CH2CH3); 13C NMR (75 MHz, CDCl3) δ 172.3 (CϭO),
166.5 (CϭO), 149.3, 148.9, 147.9, 146.9, 136.9, 134.7,
132.2, 125.5, 123.5, 119.8, 111.1, 110.9, 109.7, 108.7,
101.4, 61.1, 60.7, 55.9, 55.8, 47.3, 46.1, 14.3, 14.1;
EIMS m/z = 454 [M+], 380 (base), 335, 308; HRMS calcd.
for C25H26O8: 454.1628, found: 454.1647.
Dihydronaphthalene diester – 7bb
Diester 5b (1.00 g, 3.11 mmol), diisopropylamine
(611 µL, 4.36 mmol), n-BuLi (1.8 mL of 2.5 M,
4.03 mmol), 3,4-dimethoxybenzaldehyde (574 mg,
3.45 mmol), and TFA (4 mL) were used in the general
method above. Flash column chromatography on silica gel
using 30% EtOAc–hexanes gave diester 7bb (694 mg, 46%
yield) as a yellow oil, which foamed under vacuum. 1H
NMR (300 MHz, CDCl3) δ 7.64 (s, 1H, Ar-CHϭC), 6.87 (s,
1H, Ar-H), 6.69 (d, 1H, J = 8.4 Hz, Ar-H), 6.64 (s, 2H, Ar-
H), 6.47 (dd, 1H, J = 2.0, 8.1 Hz, Ar-H), 4.62 (d, 1H, J =
3.0 Hz, CH-CO2Et), 4.18 (m (2 overlapping doublets of
quartets), 2H, J = 7.0 Hz, CHϭC-CO2CH2CH3), 4.06 (m (2
overlapping doublets of quartets), 2H, J = 7.0 Hz, CH-
CO2CH2CH3), 3.96 (d, 2H, J = 3.0 Hz, CH-Ar), 3.90 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.78 (s,
3H, OCH3), 1.29 (t, 3H, J = 7.1 Hz, CH2CH3), 1.15 (t, 3H, J
= 7.2 Hz, CH2CH3); 13C NMR (CDCl3, 75 MHz) δ 172.5
(CϭO), 166.6 (CϭO), 150.7, 148.9, 148.1, 147.9, 137.0,
135.1, 130.4, 124.4, 123.2, 119.8, 111.7, 111.3, 110.6,
110.3, 61.2, 60.8, 56.1, 56.0, 55.9, 55.88, 47.5, 45.8, 14.3,
14.1; EIMS m/z = 470 [M+], 396 (base), 351, 324; HRMS
calcd. for C26H30O8: 470.1941, found: 470.1965.
Dihydronaphthalene diester – 7ac
Diester 5a (751 mg, 2.4 mmol), diisopropylamine
(446 µL, 3.2 mmol), n-BuLi (1.3 mL of 2.5 M, 2.9 mmol),
3,4,5-trimethoxybenzaldehyde (483 mg, 2.5 mmol), and
TFA (4 mL) were used in the general method above. Flash
column chromatography on silica gel using 30% EtOAc–
hexanes gave diester 7ac (495 mg, 42% yield) as a yellow
oil, which foamed under vacuum. 1H NMR (300 MHz,
CDCl3) δ 7.57 (s, 1H, Ar-CH-C), 6.81 (s, 1H, Ar-H), 6.61 (s,
1H, Ar-H), 6.26 (s, 2H, Ar-H), 5.96 (m (AB), 2H, O-CH2-
O), 4.55 (d, 1H, J = 4.0 Hz, CH-CO2Et), 4.21 (m (2 overlap-
ping doublets of quartets), 2H, J = 7.0 Hz, CHϭC-
CO2CH2CH3), 4.08 (m (2 overlapping doublets of quartets),
2H, J = 7.4 Hz, CH-CO2CH2CH3), 3.98 (d, 2H, J = 3.7 Hz,
CH-Ar), 3.78 (s, 3H, p-OCH3), 3.75 (s, 6H, 2 × m-OCH3)
1.29 (t, 3H, J = 7.1 Hz, CH2CH3), 1.14 (t, 3H, J = 7.1 Hz,
CH2CH3); 13C NMR (75 MHz, CDCl3) δ 172.3 (CϭO),
Dihydronaphthalene diester – 7bc
Diester 5b (1.10 g, 3.11 mmol), diisopropylamine
(672 µL, 4.79 mmol), n-BuLi (2.0 mL of 2.2 M, 4.43 mmol),
3,4,5-trimethoxybenzaldehyde (724 mg, 3.69 mmol), and
TFA (5 mL) were used in the general method above. Flash
column chromatography on silica gel using 30% EtOAc–
hexanes gave diester 7bc (804 mg, 44% yield) as a yellow
© 2000 NRC Canada

Cow et al.
557
oil, which foamed under vacuum. 1H NMR (300 MHz,
CDCl3) δ 7.64 (s, 1H, Ar-CHϭC), 6.88 (s, 1H, Ar-H), 6.66
(s, 1H, Ar-H), 6.24 (s, 2H, Ar-H), 4.62 (d, 1H, J = 3.4 Hz,
CH-CO2Et), 4.23 (m (2 overlapping doublets of quartets),
2H, J = 6.8 Hz, CHϭC-CO2CH2CH3), 4.09 (m (2 overlap-
Aromatization – formation of arylnapthalene diesters –
general procedure
The dihydronaphthalene diesters 7 were dissolved in tolu-
ene (ca. 0.015 M), then dicyanodichloroquinone (DDQ, 1.2
equiv.) was added, and the mixture was heated at reflux for
2–5 h. The reaction mixture was cooled to room tempera-
ture, and quenched by addition of 100 mL 0.1 M KOH. The
product was extracted into 60 mL EtOAc (60 mL) and
washed with aqueous KOH (0.1 M, 2 × 50 mL). The aque-
ous layer was extracted with additional EtOAc (2 × 50 mL),
the organic layers combined and washed with water (20 mL)
and saturated aqueous NaCl (20 mL). The solution was dried
over anhydrous magnesium sulfate, filtered, and evaporated.
The resulting red-brown residue was dissolved in the mini-
mum amount of dichloromethane, then passed through a fil-
ter column of silica gel using 30% EtOAc–hexanes as the
eluant and evaporated. Further purification, to get better than
95% purity by HPLC, required recrystallization from
CHCl3–hexanes.
ping doublets of quartets), 2H,
J = 7.4 Hz, CH-
CO2CH2CH3), 4.00 (d, 2H, J = 3.0 Hz, CH-Ar), 3.92 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.73 (s,
6H, 2 × m-OCH3), 1.30 (t, 3H, J = 7.1 Hz, CH2CH3), 1.16 (t,
3H, J = 7.2 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ
172.4 (CϭO), 166.6 (CϭO), 153.1, 150.7, 148.3, 138.2,
136.9, 130.0, 124.4, 123.4, 112.1, 111.6, 104.9, 61.2, 60.8,
60.7, 56.1, 56.06 (2 × OCH3), 47.5, 46.3, 14.3, 14.1 (one
quaternary carbon not observed, may be obscured by peak at
136.9); EIMS m/z = 500 [M+], 426 (base), 381, 354; HRMS
calcd. for C27H32O9: 500.2046, found: 500.2049.
Dihydronaphthalene diester – 7ca
Diester 5c (1.01 g, 2.87 mmol), diisopropylamine
(523 µL, 3.73 mmol), n-BuLi (1.9 mL of 1.76 M,
3.44 mmol), piperonal (443 mg, 2.95 mmol), and TFA
(4 mL) were used in the general method above. Flash col-
umn chromatography on silica gel using 30% EtOAc–hex-
anes gave diester 7ca (498 mg, 36% yield) as a yellow oil,
Arylnaphthalene diester – 8aa
Diester 7aa (656 mg, 1.5 mmol), DDQ (409 mg,
1.8 mmol) was heated at reflux in toluene (20 mL) for 5 h,
and worked up as in the general method above to give 8aa
(571 mg, 87% yield) as off-white crystals; mp = 171–172°C;
1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H, CHϭC-CO2Et),
7.23 (s, 1H, Ar-H), 6.8–6.9 (m, 4H, Ar-H), 6.06 (s, 2H, O-
CH2-O), 6.03 (m (AB), 2H, O-CH2-O), 4.39 (q, 2H, J =
7.1 Hz, CO2-CH2CH3), 4.12 (q, 2H, J = 7.1 Hz, CO2-
CH2CH3), 1.40 (t, 3H, J = 7.1 Hz, CO2-CH2CH3), 1.11 (t,
3H, J = 7.1 Hz, CO2-CH2CH3); 13C NMR (75 MHz, CDCl3)
δ 168.9 (CϭO), 166.0 (CϭO), 150.3, 148.7, 147.3, 136.9,
132.3, 130.64, 130.59, 129.9, 129.86, 123.9, 123.4, 111.0,
108.1, 104.9, 103.3, 101.7, 101.2, 61.5, 61.1, 14.3, 13.9 (one
quaternary carbon not detected; perhaps under 147.3);
EIMS m/z = 436 [M+] (base), 391, 363; HRMS calcd. for
C24H20O8: 436.1158, found: 436.1140.
1
which foamed under vacuum. H NMR (300 MHz, CDCl3)
δ; 7.62 (s, 1H, Ar-CHϭC), 6.70 (s, 1H, Ar-H), 6.49–6.62
(m, 3H), 5.85 (m (AB), 2H, O-CH2-O), 4.93 (bs, 1H, CH-
CO2Et), 4.19 (q, 2H, J = 7.0 Hz, CHϭC-CO2CH2CH3), 4.09
(m (2 overlapping doublets of quartets), 2H, J = 7.1 Hz, CH-
CO2CH2CH3), 3.94 (d, 2H, J = 1.0 Hz, CH-Ar), 3.90 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 1.28 (t, 3H,
J = 7.0 Hz, CH2CH3), 1.18 (t, 3H, J = 7.0 Hz, CH2CH3); 13
C
NMR (75 MHz, CDCl3) δ 171.8 (CϭO), 166.5 (CϭO),
152.7, 151.3, 147.5, 146.2, 144.3, 137.0, 136.9, 127.1,
124.5, 123.3, 120.5, 108.4, 108.1, 108.0, 100.9, 61.2, 60.9,
60.8, 56.1, 56.0, 46.9, 39.3, 14.3, 14.1; EIMS m/z = 484
[M+], 410, 352 (base), 278, 263, 205; HRMS calcd. for
C26H28O9: 484.1733, found: 484.1753.
Arylnaphthalene diester – 8ab
Dihydronaphthalene diester – 7cc
Diester 7ab (838 mg, 1.85 mmol), DDQ (503 mg,
2.21 mmol) was heated at reflux in toluene (10 mL) for 3 h,
and worked up as in the general method above to give 8ab
(826 mg, 99% yield) as off-white crystals. 1H NMR
(300 MHz, CDCl3) δ 8.37 (s, 1H, CHϭC-CO2Et), 7.21 (s,
1H, Ar-H), 6.94 (d, 1H, J = 8.0 Hz, Ar-H), 6.87 (dd, 1H, J =
2.0, 8.0 Hz, Ar-H), 6.86 (s, 1H, Ar-H), 6.85 (s, 1H, Ar-H),
6.04 (s, 2H, O-CH2-O), 4.38 (q, 2H, J = 7.0 Hz, CO2-
CH2CH3), 4.07 (2s, 2H, J = 7.0 Hz, CO2-CH2CH3), 3.94 (s,
3H, OCH3), 3.84 (s, 3H, O-CH3), 1.39 (t, 3H, J = 7.1 Hz,
CO2-CH2CH3), 1.03 (t, 3H, J = 7.1 Hz, CO2-CH2CH3); 13C
NMR (75 MHz, CDCl3) δ 169.0 (CϭO), 165.9 (CϭO),
150.1, 148.6, 148.59, 148.4, 137.1, 132.3, 130.5, 129.8,
129.4, 123.3, 122.7, 113.6, 110.7, 104.8, 103.3, 101.6, 61.4,
61.0, 55.9 (2 × OCH3), 14.2, 13.8 (one quaternary carbon
not detected); EIMS m/z = 452 [M+] (base), 407, 379, 363,
335; HRMS calcd. for C25H24O8: 452.1471, found:
452.1470.
Diester 5c (3.01 g, 8.50 mmol), diisopropylamine (1.55 mL,
11.05 mmol), n-BuLi (6.0 mL of 1.76 M, 10.2 mmol), 3,4,5-
trimethoxybenzaldehyde (1.68 g, 8.56 mmol), and TFA (5 mL)
were subjected to the general method above. Flash column
chromatography on silica gel using 30% EtOAc–hexanes
gave diester 7cc (704 mg, 16% yield) as a yellow oil, which
1
foamed under vacuum. H NMR (300 MHz, CDCl3) δ 7.62
(s, 1H, CHϭC-CO2Et), 6.71 (s, 1H, Ar-H), 6.28 (s, 2H, 2 ×
Ar-H), 5.00 (d, 1H, J = 1.2 Hz, CH-CO2Et), 4.23 (2 overlap-
ping quartets, 2H, J = 7.1 Hz, CO2-CH2CH3), 4.12 (2 over-
lapping quartets, 2H, J = 7.2 Hz, CO2-CH2CH3), 4.06 (d,
1H, J = 1.2 Hz, CH-Ar), 3.89 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 3.72 (s, 6H, 2 × m-OCH3), 3.67
(s, 3H, OCH3), 1.31 (t, 3H, J = 7.1 Hz, CH2CH3), 1.19 (t,
3H, J = 7.2 Hz, CH2CH3); 13C NMR (CDCl3, 75 MHz) δ
171.7 (CϭO), 166.5 (CϭO), 152.9, 152.7, 151.4, 144.2,
138.4, 136.7, 127.1, 124.9, 123.2, 108.2, 104.6, 61.2, 60.84,
60.77, 60.71, 56.0 (4 × OCH3), 46.2, 39.4, 14.3, 14.1 (one
quaternary carbon not observed); EIMS m/z = 530 [M+], 456
(base), 411, 384, 196; HRMS calcd. for C28H34O10:
530.2152, found: 530.2129.
Arylnaphthalene diester – 8ac
Diester 7ac (464 mg, 0.96 mmol), DDQ (260 mg,
1.15 mmol) was heated at reflux in toluene (10 mL) for 3 h,
© 2000 NRC Canada

558
Can. J. Chem. Vol. 78, 2000
and worked up as in the general method above to give 8ac
(414 mg, 90% yield) as off-white crystals; mp = 178–182°C;
1H (300 MHz, CDCl3) δ 8.39 (s, 1H, CHϭC-CO2Et), 7.24
(s, 1H, Ar-H), 6.91 (s, 1H, Ar-H), 6.55 (s, 2H, Ar-H), 6.07
(s, 2H, O-CH2-O), 4.39 (q, 2H, J = 7.1 Hz, CO2-CH2CH3),
4.10 (q, 2H, J = 7.2 Hz, CO2-CH2CH3), 3.92 (s, 3H, p-
OCH3), 3.83 (s, 6H, 2 × m-OCH3), 1.40 (t, 3H, J = 7.2 Hz,
CO2-CH2CH3), 1.03 (t, 3H, J = 7.1 Hz, CO2-CH2CH3); 13C
NMR (75 MHz, CDCl3) δ 169.0 (CϭO), 165.9 (CϭO),
152.9, 150.2, 148.8, 137.6, 137.3, 132.5, 132.0, 130.3,
130.0, 129.9, 123.4, 107.7, 104.9, 103.3, 101.8, 61.5, 61.1,
61.0, 56.2, 14.3, 13.9; EIMS m/z = 482 [M+] (base), 410,
393, 365; HRMS calcd. for C26H26O9: 482.1576, found:
482.1566.
OCH3), 3.84 (s, 6H, 2 × m-OCH3), 3.79 (s, 3H, O-CH3),
1.40 (t, 3H, J = 7.1 Hz, CO2-CH2CH3), 1.04 (t, 3H, J =
7.1 Hz, CO2-CH2CH3); 13C NMR (75 MHz, CDCl3) δ 169.2
(CϭO), 166.0 (CϭO), 152.9, 151.8, 150.6, 137.6, 136.7,
132.6, 130.2, 130.0, 129.5, 128.5, 123.2, 107.6, 107.3,
105.4, 61.4, 61.1, 61.0, 56.2, 56.1, 56.0, 14.3, 13.9;
EIMS m/z = 498 [M+], 425, 409, 322, 196 (base); HRMS
calcd. for C27H30O9: 498.1890, found: 498.1899.
Formation of arylnapthalene mono-acids – general
procedure
The arylnaphthalene diesters 8 were dissolved in MeOH
(20 mL, ca. 0.05 M), aqueous KOH (0.4 M, 1.2 equiv.) was
added, and the mixture was heated at reflux for 3 h. The
mixture was cooled, quenched by addition of 10% HCl until
precipitation occurred (pH of <2), then the mixture extracted
into EtOAc (3 × 20 mL). The organic layers were combined
and extracted with 3 × 20 mL (sat.) NaHCO3. This basic ex-
tract was washed with EtOAc (20 mL), then acidified and
extracted with ethyl acetate (3 × 10 mL), backwashing with
10 mL of water. The mixture was dried over anhydrous mag-
nesium sulfate, filtered, and evaporated to give a powdery
white solid.
Arylnaphthalene diester – 8ba
Diester 7ba (914 mg, 2.01 mmol), DDQ (548 mg,
2.4 mmol) was heated at reflux in toluene (10 mL) for 5 h,
and worked up as in the general method above to give 20
(878 mg, 97% yield) as off-white crystals; mp = 195–197°C;
1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H, CHϭC-CO2Et),
7.24 (s, 1H, Ar-H), 6.79–6.92 (m, 4H, Ar-H), 6.02, 6.07 (2s,
2H, O-CH2-O, hindered rotation), 4.39 (q, 2H, J = 7.1 Hz,
CO2-CH2CH3), 4.13 (q, 2H, J = 7.1 Hz, CO2-CH2CH3), 4.03
(s, 3H, OCH3), 3.79 (s, 3H, O-CH3), 1.40 (t, 3H, J = 7.1 Hz,
CO2-CH2CH3), 1.10 (t, 3H, J = 7.1 Hz, CO2-CH2CH3); 13C
NMR (75 MHz, CDCl3) δ 169.1 (CϭO), 166.1 (CϭO),
151.7, 150.5, 147.4, 147.3, 136.4, 130.7, 130.6, 130.4,
129.5, 128.5, 123.9, 123.2, 110.9, 108.1, 107.3, 105.3,
101.2, 61.4, 61.1, 56.1, 55.9, 14.3, 13.9; EIMS m/z = 452
[M+] (base), 407, 379; HRMS calcd. for C25H24O8:
452.1471, found: 452.1525.
Acid – 9aa
Arylnaphthalene diester 8aa (356 mg, 0.82 mmol) and
KOH (6 mL, 0.4 M, 2.4 mmol) were subjected to the general
procedure described above, producing 9aa (291 mg, 87%
1
yield) as a fine white powder. H NMR (300 MHz, acetone-
d6) δ 11.40 (br. s, 1H, CO2H), 8.49 (s, 1H, CHϭC-CO2H),
8.00 (s, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 6.97 (d, 1H, J =
7.7 Hz, Ar-H), 6.83 (s, 1H, Ar-H), 6.80 (d, 1H, J = 1.3 Hz,
Ar-H), 6.76 (dd, 1H, J = 1.7, 7.7 Hz, Ar-H), 6.18 (2s, 2H,
O-CH2-O, hindered rotation), 6.09 (m (AB), 2H, O-CH2-O),
4.02 (q, 2H, J = 7.1 Hz, CO2-CH2CH3), 1.05 (t, 3H, J =
7.1 Hz, CO2-CH2CH3); 13C NMR (75 MHz, acetone-d6) δ
168.5 (CϭO), 166.9 (CϭO), 151.2, 149.6, 148.2, 137.4,
132.7, 131.9, 131.4, 130.62, 130.55, 124.5, 124.3, 111.5,
108.5, 105.4, 103.1, 102.9, 102.1, 60.9, 14.0 (one quaternary
carbon not observed); EIMS m/z = 408 [M+], 362 (base),
290, 260, 232, 174; HRMS calcd. for C22H16O8: 408.0845,
found: 408.0823.
Arylnaphthalene diester – 8bb
Diester 7bb (594 mg, 1.33 mmol), DDQ (363 mg,
1.59 mmol) was heated at reflux in toluene (10 mL) for 3 h,
and worked up as in the general method above to give 8bb
(586 mg, 99% yield) as off-white crystals; mp = 127–128°C;
1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H, CHϭC-CO2Et),
7.24 (s, 1H, Ar-H), 6.85–7.00 (m, 4H, Ar-H), 4.39 (q, 2H, J
= 7.1 Hz, CO2-CH2CH3), 4.09 (dq, 2H, J = 2.4, 7.1 Hz,
CO2-CH2CH3), 4.03 (s, 3H, OCH3), 3.95 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 3.76 (s, 3H, O-CH3), 1.40 (t, 3H, J =
7.1 Hz, CO2-CH2CH3), 1.05 (t, 3H, J = 7.1 Hz, CO2-
CH2CH3); 13C NMR (75 MHz, CDCl3) δ 169.3 (CϭO),
166.1 (CϭO), 151.7, 150.5, 148.6, 148.5, 136.6, 130.6, 129.6,
129.4, 128.5, 123.2, 122.7, 113.6, 110.8, 107.3, 105.4, 61.4,
61.1, 56.1, 56.0, 55.94, 55.87, 14.3, 13.9 (one quaternary car-
bon not observed; perhaps under 129.4); EIMS m/z = 468
[M+] (base), 423, 395; HRMS calcd. for C26H28O8:
468.1784, found: 468.1794.
Acid – 9ab
Arylnaphthalene diester 8ab (602 mg, 1.33 mmol) and
KOH (4 mL, 0.4 M, 1.6 mmol) were subjected to the general
procedure described above, producing 9ab (491 mg, 87%
1
yield) as a fine white powder. H NMR (300 MHz, CDCl3)
8.49 (s, 1H, CHϭC-CO2H), 7.25 (d, 1H, J = 2.8, Ar-H),
6.8–7.0 (m, 5H, Ar-H), 6.07 (s, 2H, O-CH2-O), 4.09 (2 over-
lapping quartets, 2H, J = 7.1 Hz, CO2-CH2CH3), 3.95 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 1.09 (t, 3H, J = 7.1 Hz, CO2-
CH2CH3); 13C NMR (75 MHz, CDCl3) δ 170.7 (CϭO),
169.1 (CϭO), 150.9, 149.10 149.09, 148.8, 137.7, 131.3,
131.2, 130.1, 129.6, 123.1, 122.1, 113.9, 111.1, 105.4,
103.8, 101.8, 61.6, 56.3 (2 × OCH3), 14.2 (one quaternary
carbon not observed); EIMS m/z = 424 [M+], 378 (base),
335, 291, 248; HRMS calcd. for C23H20O8: 424.1158, found:
424.1152.
Arylnaphthalene diester – 8bc
Diester 7bc (538 mg, 1.08 mmol), DDQ (293 mg,
1.29 mmol) was heated at reflux in toluene (20 mL) for 2 h,
and worked up as in the general method above to give 8bc
(535 mg, 100% yield) as off-white crystals; mp = 148–
1
149°C; H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H, CHϭC-
CO2Et), 7.24 (s, 1H, Ar-H), 6.93 (s, 1H, Ar-H), 6.61 (s, 2H,
Ar-H), 4.39 (q, 2H, J = 7.1 Hz, CO2-CH2CH3), 4.12 (q, 2H,
J = 7.1 Hz, CO2-CH2CH3), 4.03 (s, 3H, OCH3), 3.92 (s, 3H,
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559
Acid – 9ac
(75 MHz, acetone-d6) δ 168.9, 167.1, 153.9, 152.9, 151.8,
138.7, 137.3, 133.3, 130.6, 130.0, 129.3, 124.1, 108.7,
108.3, 106.0, 61.0, 60.6, 56.4, 56.0, 55.7, 14.0 (one quater-
nary carbon not observed); EIMS m/z = 470 [M+], 424 (base),
409, 381, 363; HRMS calcd. for C25H26O9: 470.1577, found:
470.1568.
Arylnaphthalene diester 8ac (840 mg, 1.74 mmol) and
KOH (6 mL, 0.4 M, 2.4 mmol) were subjected to the general
procedure described above, producing 9ac (644 mg, 82%
1
yield) as a fine white powder. H NMR (300 MHz, CDCl3) δ
8.48 (s, 1H, CHϭC-CO2H), 6.92 (s, 1H, Ar-H), 6.56 (s, 2H,
Ar-H), 6.08 (s, 2H, O-CH2-O), 4.10 (2 overlapping quartets,
2H, J = 7.1 Hz, CO2-CH2CH3), 3.93 (s, 3H, p-OCH3), 3.83
(s, 6H, 2 × m-OCH3), 1.07 (t, 3H, J = 7.1 Hz, CO2-
CH2CH3); 13C NMR (75 MHz, CDCl3) δ 169.9 (CϭO),
168.7 (CϭO), 150.6, 152.9, 148.8, 137.7, 137.5, 132.6,
132.2, 131.0, 130.5, 129.7, 107.7, 105.0, 103.4, 101.8, 61.3,
61.0, 56.2, 13.8 (one quaternary carbon not detected);
EIMS m/z = 454 [M+], 408 (base), 393, 380, 365; HRMS
calcd. for C24H22O9: 454.1264, found: 454.1285.
Formation of arylnaphthalene lactones – general
procedure
The arylnaphthalene mono-acids 9 were dissolved in dry
THF (ca. 0.05 M) under nitrogen, a borane-dimethylsulfide
solution (2.0 M in ether, 10 equiv.) added, and the mixture
stirred at room temperature for 2 h. The reaction was
quenched with 3% HCl–EtOH (prepared by addition of
0.5 mL acetyl chloride to 9.5 mL of anhydrous ethanol),
then the solvent removed on a rotary evaporator. Anhydrous
ethanol (20 mL) was added and evaporated, the solid residue
dissolved in chloroform and washed with saturated aqueous
NaHCO3 (3 × 10 mL) to remove any remaining acid. The or-
ganic extract was washed with water (10 mL), dried over an-
hydrous magnesium sulfate, filtered, and evaporated to give
a white powder. Further purification, to get better than 95%
purity by HPLC, involved recrystallization from CHCl3–hex-
anes.
Acid – 9ba
Arylnaphthalene diester 8ba (877 mg, 1.94 mmol) and
KOH (6 mL, 0.4 M, 2.4 mmol) were subjected to the general
procedure described above, producing 9ba (613 mg, 74%
1
yield) as a fine white powder. H NMR (300 MHz, CDCl3) δ
8.52 (s, 1H, CHϭC-CO2H), 6.92 (d, 1H, J = 8.0 Hz, Ar-H),
6.88 (s, 1H, Ar-H), 6.86 (d, 1H, J = 1.0 Hz, Ar-H), 6.83 (dd,
1H, J = 1.3, 8.0 Hz, Ar-H), 6.04 (m (AB), 2H, O-CH2-O,
hindered rotation), 4.14 (q, 2H, J = 7.1 Hz, CO2-CH2CH3),
4.03 (s, 3H, O-CH3), 3.80 (s, 3H, O-CH3), 1.15 (t, 3H, J =
7.1 Hz, CO2-CH2CH3); 13C NMR (75 MHz, CDCl3) δ 170.9
(CϭO), 168.8 (CϭO), 152.1, 150.5, 147.4, 147.3, 136.5,
131.2, 130.6, 130.5, 130.4, 128.4, 123.8, 121.6, 110.9,
108.1, 107.5, 105.4, 101.2, 61.2, 56.1, 55.9, 13.9; EIMS m/z
= 424 [M+], 378 (base), 306, 291, 276; HRMS calcd. for
C23H20O8: 424.1158, found: 424.1159.
Taiwanin C – 2aa
Arylnaphthalene acid 9aa (99 mg, 0.24 mmol) and BH3–
DMS (1.2 mL, 2.4 mmol) were subjected to the above con-
ditions to give taiwanin C (2aa) (70 mg, 82% yield) as a
1
white powder. H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H,
CHϭC-CH2O), 7.19 (s, 1H, Ar-H), 7.11 (s, 1H, Ar-H), 6.95
(d, 1H, J = 7.7 Hz, Ar-H), 6.80 (s, 1H, Ar-H), 6.77 (d, 1H, J
= 1.3, 7.7 Hz, Ar-H), 6.08 (s, 2H, O-CH2-O), 6.06 (2 s, 2H,
O-CH2-O, hindered rotation), 5.37 (s, 2H, CH2-O-CϭO);
13C NMR (75 MHz, CDCl3) δ 169.7 (CϭO), 149.9, 148.6,
147.6, 147.5, 140.1, 139.8, 134.6, 130.5, 123.5, 128.3,
119.0, 118.9, 110.5, 108.2, 103.7 (broad, 2 carbons), 101.8,
101.2, 68.0; EIMS m/z = 348 [M+] (base), 319, 289, 261;
Acid – 9bb
Arylnaphthalene diester 8bb (906 mg, 1.94 mmol) and
KOH (6 mL, 0.4 M, 2.4 mmol) were subjected to the general
procedure described above, producing 9bb (763 mg, 90%
1
yield) as a fine white powder. H NMR (300 MHz, acetone-
1
d6) δ 11.32 (br. s, 1H, CO2H), 8.51 (s, 1H, CHϭC-CO2H),
7.55 (s, 1H, Ar-H), 7.06 (d, 1H, J = 8.0 Hz, Ar-H), 6.96 (s,
1H, Ar-H), 6.93 (d, 1H, J = 2.0 Hz, Ar-H), 6.88 (dd, 1H, J =
2.0, 8.0 Hz, Ar-H), 4.01 (q, 2H, J = 7.1 Hz, CO2-CH2CH3),
4.00 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 3.72 (s, 3H, OCH3), 1.02 (t, 3H, J = 7.2 Hz, CO2-
CH2CH3); 13C NMR (75 MHz, CDCl3) δ 171.3 (CϭO),
169.0 (CϭO), 152.0, 150.5, 148.6, 148.4, 136.7, 131.2,
130.5, 130.4, 129.3, 128.3, 122.7, 121.6, 113.5, 110.7,
107.4, 105.4, 61.2, 56.0, 55.9, 55.7 (2 × OCH3), 13.8;
EIMS m/z = 440 [M+], 394 (base), 307; HRMS calcd. for
C24H24O8: 440.1471, found: 440.1469.
HRMS calcd. for C20H12O6: 348.0634, found: 348.0629. H
NMR data identical to that published previously (12, 13).
Chinensin – 2ab
Arylnaphthalene acid 9ab (198 mg, 0.47 mmol) and BH3–
DMS (2.3 mL, 4.7 mmol) were subjected to the above con-
ditions to give Chinensin (2ab) (166 mg, 97% yield) as a
1
white powder. H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H,
CHϭC-CH2O), 7.20 (s, 1H, Ar-H), 7.12 (s, 1H, Ar-H), 7.02
(d, 1H, J = 8.0 Hz, Ar-H), 6.88 (dd, 1H, J = 1.7, 8.4 Hz, Ar-
H), 6.86 (d, 1H, J = 1.7 Hz, Ar-H), 6.07 (s, 2H, O-CH2-O),
5.37 (2s, 2H, CH2-O-CϭO), 3.97 (s, 3H, O-CH3), 3.87 (s,
3H, O-CH3); 13C NMR (75 MHz, CDCl3) δ 169.7 (CϭO),
149.9, 148.9, 148.6, 148.5, 140.5, 139.8, 134.6, 130.5,
127.2, 122.5, 118.9, 118.8, 113.4, 110.8, 103.7, 103.6,
101.8, 67.9, 55.9, 55.8; EIMS m/z = 364 [M+] (base); HRMS
Acid – 9bc
Arylnaphthalene diester 8bc (621 mg, 1.25 mmol) and
KOH (6 mL, 0.4 M, 2.4 mmol) were subjected to the general
procedure described above, producing 9bc (516 mg, 88%
1
calcd. for C21H16O6: 364.0947, found: 364.0958. H NMR
1
data identical to that published previously (12).
yield) as a fine white powder. H NMR (300 MHz, acetone-
d6) δ 11.25 (br. s, 1H, CO2H), 8.54 (s, 1H, CHϭC-CO2H),
7.56 (s, 1H, Ar-H), 7.03 (s, 1H, Ar-H), 6.64 (s, 2H, Ar-H),
4.03 (q, 2H, J = 7.0 Hz, CO2-CH2CH3), 4.01 (s, 3H, OCH3),
3.84 (s, 6H, 2 × m-OCH3), 3.81 (s, 3H, OCH3), 3.75 (s, 3H,
OCH3), 1.03 (t, 3H, J = 7.0 Hz, CO2-CH2CH3); 13C NMR
Dehydroanhydropodophyllotoxin – 2ac
Arylnaphthalene acid 9ac (201 mg, 0.44 mmol) and BH3–
DMS (2.2 mL, 4.4 mmol) were subjected to the above con-
ditions to give dehydroanhydropodophyllotoxin (2ac)
© 2000 NRC Canada

560
Can. J. Chem. Vol. 78, 2000
(122 mg, 70% yield) as a white powder. 1H NMR
(300 MHz, CDCl3) δ 7.70 (s, 1H, CHϭC-CH2O), 7.20 (s,
1H, Ar-H), 7.12 (s, 1H, Ar-H), 6.55 (s, 2H, Ar-H), 6.09 (s,
2H, O-CH2-O), 5.38 (2s, 2H, CH2-O-CϭO), 3.97 (s, 3H, p-
OCH3), 3.84 (s, 6H, 2 × m-OCH3); 13C NMR (75 MHz,
CDCl3) δ 169.6 (CϭO), 152.9, 150.0, 148.6, 140.4, 139.8,
137.8, 134.6, 130.3 (broad, 2 carbons), 119.1, 118.7, 107.3,
103.7, 103.6, 101.8, 68.0, 60.9, 56.1; EIMS m/z = 394 [M+]
(base), 379; HRMS calcd. for C22H18O7: 394.1052, found:
Formation of arylnaphthalene retrolactones – general
procedure
The arylnaphthalene mono-acids, 9, sodium borohydride
(10–15 equiv.), and lithium chloride (10–15 equiv.) were
charged to a 25 mL flask as powders, then diglyme (10 mL)
was added and the resulting mixture was heated at ~120°C
for 3–16 h. The mixture was cooled and quenched with 10%
HCl (10 mL), which was stirred for 1.5 h. The product was
extracted into EtOAc (3 × 20 mL) and washed with saturated
aqueous NaHCO3 (3 × 10 mL) to remove any remaining
acid. The organic extract was washed with water (10 mL),
dried over anhydrous magnesium sulfate, filtered, and evapo-
rated to give a white powder. Recrystallization from CHCl3–
hexanes provided a white powder, which was a mixture of
the desired lactone and the corresponding diol as a side
product from over-reduction. The lactone was purified by
recrystallization from hot EtOH (95%), providing crystals
that were >90% pure by HPLC.
1
394.1041. H NMR data identical to that published previ-
ously (14).
Justicidin B – 2ba
Arylnaphthalene acid 9ba (273 mg, 0.65 mmol) and BH3–
DMS (3.2 mL, 6.5 mmol) were subjected to the above con-
ditions to give justicidin B (2ba) (223 mg, 95% yield) as a
1
white powder. H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H,
CHϭC-CH2O), 7.18 (s, 1H, Ar-H), 7.10 (s, 1H, Ar-H), 6.96
(d, 1H, J = 7.7 Hz, Ar-H), 6.84 (d, 1H, J = 2.0 Hz, Ar-H),
6.83 (dd, 1H, J = 2.0, 7.7 Hz, Ar-H), 6.08, 6.03 (2s, 2H, O-
CH2-O, hindered rotation), 5.37 (2s, 2H, CH2-O-CϭO), 4.04
(s, 3H, OCH3), 3.80 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3) δ 169.9 (CϭO), 151.7, 150.0, 147.49, 147.46, 139.55,
139.46, 133.1, 128.8, 128.3, 123.4, 118.4, 118.2, 110.5,
108.1, 106.0, 105.8, 101.2, 68.0, 56.0, 55.8; EIMS m/z = 364
[M+] (base); HRMS calcd. for C21H16O6: 364.0947, found:
Justicidin E – 3aa
Arylnaphthalene acid 9aa (125 mg, 0.31 mmol), NaBH4
(174 mg, 4.6 mmol), LiCl (194 mg, 4.6 mmol) were used in
the general procedure above (16 h reflux time) to give
justicidin E (3aa) (20.5 mg, 19.2% yield) as colourless crys-
1
tals. H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H, CHϭC-
CO2), 7.30 (s, 1H, Ar-H), 7.09 (s, 1H, Ar-H), 6.97 (d, 1H, J
= 8.4 Hz, Ar-H), 6.80 (s, 1H, Ar-H), 6.79 (dd, 1H, J = 1.6,
8.4 Hz, Ar-H), 6.09 (s, 2H, O-CH2-O), 6.08 (2s, 2H, O-CH2-
O, hindered rotation), 5.20 (AB doublet, 2H, ∆δ = 17.6 Hz, J
= 15.0 Hz, C-CH2-O); 13C NMR (75 MHz, CDCl3) δ 171.4
(CϭO), 150.5, 148.4, 148.2, 147.7, 138.4, 133.4, 132.7,
131.3, 129.6, 124.7, 122.7, 121.6, 109.6, 109.0, 105.2,
102.0, 101.8, 101.4, 69.4; EIMS m/z = 348 [M+] (base), 319,
233; HRMS calcd. for C20H12O6: 348.0634, found:
1
364.0958. H NMR data identical to that published previ-
ously (15).
Lactone – 2bb
Arylnaphthalene acid 9bb (304 mg, 0.69 mmol) and BH3–
DMS (3.4 mL, 6.9 mmol) were subjected to the above con-
ditions to give lactone 2bb (250 mg, 95% yield) as a white
1
1
powder. H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H, CHϭC-
348.0604. H NMR spectral properties identical with those
CH2O), 7.19 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 7.04 (d, 1H,
J = 8.4 Hz, Ar-H), 6.96 (dd, 1H, J = 2.0, 8.2 Hz, Ar-H), 6.93
(dd, 1H, J = 2.0 Hz, Ar-H), 5.38 (2s, 2H, CH2-O-CϭO),
4.05 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ
169.9 (CϭO), 151.8, 150.0, 148.9, 148.5, 139.9, 139.6,
133.1, 128.8, 127.1, 122.6, 118.3, 118.1, 113.4, 110.8, 106.0
previously reported (6,12).
Retrochinensin – 3ab
Arylnaphthalene acid 9ab (311 mg, 0.73 mmol), NaBH4
(277 mg, 7.3 mmol), LiCl (309 mg, 7.3 mmol) were used in
the general procedure above (5 h reflux time) to give
retrochinensin (3ab) (165.7 mg, 62.3%; 86.2 mg, 32.4%
yield after recrystallization from 95% EtOH) as colourless
(broad,
2 carbons), 68.0, 56.05, 55.96, 55.80, 55.77;
EIMS m/z = 380 [M+] (base), 365; HRMS calcd. for
1
crystals. H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H, CHϭC-
1
C22H20O6: 380.1260, found: 380.1256. H NMR data identi-
CO2), 7.28 (s, 1H, Ar-H), 7.09 (s, 1H, Ar-H), 7.03 (d, 1H, J
= 8.2 Hz, Ar-H), 6.89 (dd, 1H, J = 1.9, 8.1 Hz, Ar-H), 6.84
(d, 1H, J = 1.9 Hz, Ar-H), 6.08 (s, 2H, O-CH2-O), 5.19 (AB
doublet, 2H, ∆δ = 17.8 Hz, J = 14.8 Hz, C-CH2-O), 3.97 (s,
3H, O-CH3), 3.88 (s, 3H, O-CH3); 13C NMR (75 MHz,
CDCl3) δ 171.4 (CϭO), 150.4, 149.3, 148.9, 148.3, 138.3,
133.4, 132.9, 131.2, 128.5, 124.5, 121.6, 112.2, 111.7,
105.2, 102.0, 101.8, 69.5, 56.04, 55.99 (one quaternary car-
bon not observed); EIMS m/z = 364 [M+] (base), 350, 335,
319; HRMS calcd. for C21H16O6: 364.0947, found:
cal to that published previously (13).
7-Deoxydiphyllin – 2bc
Arylnaphthalene acid 9bc (191 mg, 0.41 mmol) and BH3–
DMS (2.0 mL, 4.1 mmol) were subjected to the above con-
ditions to give lactone 2bc (233 mg, 80% yield) as a white
1
powder. H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H, CHϭC-
CH2O), 7.20 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 6.62 (s, 2H,
2 × Ar-H), 5.40 (2s, 2H, CH2-O-CϭO), 4.06 (s, 3H, OCH3),
3.98 (s, 3H, OCH3), 3.85 (s, 6H, 2 × m-OCH3), 3.80 (s, 3H,
OCH3); 13C NMR (75 MHz, CDCl3) δ 169.7 (CϭO), 152.9,
151.9, 150.1, 139.9, 139.5, 137.8, 133.2, 130.2, 128.6,
118.3, 118.2, 107.4 (broad, 2 carbons), 106.0, 68.0, 61.0,
56.2, 56.1, 55.9; EIMS m/z = 410 [M+] (base), 395; HRMS
1
364.0927. H NMR spectral properties identical with those
previously reported (17).
5′-Methoxyretrochinensin – 3ac
Arylnaphthalene acid 9ab (407 mg, 0.89 mmol), NaBH4
(334 mg, 8.9 mmol), LiCl (378 mg, 8.9 mmol) were used in
the general procedure above (5 h reflux time) to give 5′-
1
calcd. for C23H22O7: 410.1365, found: 410.1376. H NMR
data identical to that published previously (16).
© 2000 NRC Canada

Cow et al.
561
methoxyretrochinensin (3ac) (250.7 mg, 71.5%; 163 mg,
(s, 3H, O-CH3), 3.86 (s, 6H, 2 × O-CH3), 3.84 (s, 3H, O-
CH3); 13C NMR (75 MHz, CDCl3) δ 171.4, 153.7, 152.0,
150.1, 137.8, 137.6, 132.2, 131.6, 131.3, 129.8, 124.1,
121.3, 107.6, 106.2, 104.1, 69.5, 60.9, 56.3, 56.0, 55.9;
EIMS m/z = 410 [M+] (base), 395, 379; HRMS calcd. for
C23H22O7: 410.1365, found: 410.1382. 1H NMR spectral
properties identical with those previously reported (13).
46.5% yield after recrystallization from 95% EtOH) as
1
colourless crystals. H NMR (300 MHz, CDCl3) δ 8.26 (s,
1H, CHϭC-CO2), 7.30 (s, 1H, Ar-H), 7.10 (s, 1H, Ar-H),
6.54 (s, 2H, Ar-H), 6.10 (s, 2H, O-CH2-O), 5.22 (s, 2H,
CH2-O-CϭO), 3.96 (s, 3H, p-OCH3), 3.86 (s, 6H, 2 ×
m-OCH3); 13C NMR (75 MHz, CDCl3) δ 171.3 (CϭO),
153.7, 150.5, 148.4, 138.1, 137.9, 133.2, 133.0, 131.6,
131.2, 124.7, 121.6, 106.2, 105.2, 102.0, 101.9, 69.4, 61.0,
56.3; EIMS m/z = 394 [M+] (base), 379, 363; HRMS calcd.
Acknowledgements
1
for C22H18O7: 394.1052, found: 394.1060. H NMR spectral
We are grateful to the Natural Sciences and Engineering
Research Council of Canada, Boehringer Ingelheim (Can-
ada) Ltd., Bio-Méga Research Division, and the University
of Manitoba for financial support of this project. We also
thank Nathalie Dansereau for assaying the compounds in
cell culture.
properties identical with those previously reported (18).
Retrojusticidin B – 3ba
Arylnaphthalene acid 9ba (152 mg, 0.36 mmol), NaBH4
(203 mg, 5.4 mmol), LiCl (226 mg, 5.4 mmol) were used in
the general procedure above (16 h reflux time) to give
retrojusticidin B (3ba) (139.9 mg, 83%; 52.8 mg, 40.3%
yield after recrystallization from 95% EtOH) as colourless
References
1
crystals. H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H, CHϭC-
1. R.S. Ward. Nat. Prod. Rep. 14, 43 (1997).
2. R.S. Ward. Nat. Prod. Rep. 12, 183 (1995).
3. R.S. Ward. Nat. Prod. Rep. 10, 1 (1993).
4. D.C. Ayres and J.D. Loike. In Lignans: chemical, biological
and clinical properties. Cambridge University Press, Cam-
bridge. 1990.
5. J.L. Charlton. J. Nat. Prod. 61, 1447 (1998).
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7. T. Ogiku, S. Yoshida, H. Ohmizu, and T. Iwasaki. J. Org.
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cle).
CO2), 7.28 (s, 1H, Ar-H), 7.09 (s, 1H, Ar-H), 6.98 (d, 1H, J
= 8.2 Hz, Ar-H), 6.84 (s, 1H, Ar-H), 6.83 (d, 1H, J = 8.2 Hz,
Ar-H), 6.10, 6.07 (2s, 2H, O-CH2-O, hindered rotation), 5.22
(s, 2H, CH2O-CϭO), 4.04 (s, 3H, O-CH3), 3.86 (s, 3H,
O-CH3); 13C NMR (75 MHz, CDCl3) δ 171.5 (CϭO), 151.9,
150.0, 148.2, 147.6, 137.9, 131.8, 131.5, 129.8, 129.7,
124.1, 122.7, 121.3, 109.4, 109.0, 107.6, 104.0, 101.4, 69.4,
56.0, 55.9; EIMS m/z = 364 [M+] (base), 335; HRMS calcd.
1
for C21H16O6: 364.0947, found: 364.0943. H NMR spectral
properties identical with those previously reported (19).
8. W.S. Johnson and G.H. Daub. In Organic reactions. Vol VI,
John Wiley and Sons, Inc., New York. pp. 1–73.
9. D.C. Ayres, B.G. Carpenter, and R.C. Denney. J. Chem. Soc.
3578 (1965).
10. C. Lawetz and M. Liuzzi. Antiviral Res. 39, 35 (1998).
11. J.L. Charlton, G.L. Plourde, K. Koh, and A.S. Secco. Can. J.
Chem. 68, 2022 (1990).
Retrolactone – 3bb
Arylnaphthalene acid 9bb (187 mg, 0.54 mmol), NaBH4
(203 mg, 5.4 mmol), LiCl (227 mg, 5.4 mmol) were used in
the general procedure above (16 h reflux time) to give
retrolactone 3bb (105.2 mg, 51%; 60.1 mg, 29.3% yield af-
ter recrystallization from 95% EtOH) as colourless crystals.
1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H, CHϭC-CO2),
7.29 (s, 1H, Ar-H), 7.12 (s, 1H, Ar-H), 7.06 (d, 1H, J =
8.1 Hz, Ar-H), 6.95 (d, 1H, J = 8.2 Hz, Ar-H), 6.91 (s, 1H,
Ar-H), 5.22 (d, 2H, J = 6.2 Hz, CH2O-CϭO), 4.05 (s, 3H,
O-CH3), 4.00 (s, 3H, O-CH3), 3.89 (s, 3H, O-CH3), 3.83 (s,
3H, O-CH3); 13C NMR (75 MHz, CDCl3) δ 171.5 (CϭO),
151.9, 150.0, 149.3, 148.9, 137.8, 132.1, 131.6, 129.8,
128.6, 124.0, 121.5, 121.3, 112.2, 111.6, 107.6, 104.1, 69.5,
56.0 (2 carbons, OCH3), 55.9, 55.8; EIMS m/z = 380 [M+]
(base), 351; HRMS calcd. for C22H20O6: 380.1260, found:
12. T. Hattori, H. Tanaka, Y. Okaishi, and S. Miyano. J. Chem.
Soc. Perkin Trans. 1, 235 (1995).
13. R. Stevenson and J.V. Weber. J. Nat. Prod. 52, 367 (1989).
14. A. San Feliciano, M. Medarde, R.P. Lamamie de Clairac, J.L.
López, P. Puebla, D. García Gravalos, P. Ruiz Lázaro, and T.
García de Quesada. Arch. Pharm. (Weinheim, Ger.), 326, 421
(1993).
15. M. Okigawa, T. Maeda, and N. Kawano. Tetrahedron, 4301
(1970).
16. T. Ukita, Y. Nakamura, A. Kubo, Y. Yamamoto, M. Takahashi,
1
1
380.1267. H NMR spectral properties identical with those
J. Kotera, and T. Ikeo. J. Med. Chem. 42, 1293 (1999). The H
previously reported (13).
NMR of 2bc given in two other references is incorrect.
17. T. Ogiku, S. Yoshida, H. Ohmizu, and T. Iwasaki. J. Org.
Chem. 60, 4585 (1995) and T. Iwasaki, K. Kondo, T. Kuroda,
Y. Moritani, S. Yamagata, M. Sugiura, H. Kikkawa, O.
Kaminuma, and K. Ikezawa. J. Med. Chem. 39, 2696 (1996).
18. S. Ghosal and S. Banerjee. J. Chem. Soc. Chem. Commun.
165 (1979).
19. S. Takano, S. Otaki, and K. Ogasawara. Tetrahedron Lett. 26,
1659 (1985).
20. A. Pelter, R.S. Ward, P. Satyanarayana, and P. Collins. Tetrahe-
dron Lett. 23, 571 (1982).
Retrolactone – 3bc
Arylnaphthalene acid 9bc (310 mg, 0.66 mmol), NaBH4
(250 mg, 6.6 mmol), and LiCl (280 mg, 6.6 mmol) were
used in the general procedure above (3 h reflux time) to give
retrolactone 3bc (230.5 mg, 85.1%; 143.6 mg, 53.0% yield
after recrystallization from 95% EtOH) as colourless crys-
1
tals. H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H, CHϭC-
CO2), 7.27 (s, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 6.60 (s, 2H,
Ar-H), 5.24 (s, 1H, CH2O-CϭO), 4.04 (s, 3H, O-CH3), 3.96
© 2000 NRC Canada