A new benzannulation reaction and its application in the multiple parallel synthesis of arylnaphthalene lignans

Article abstract of DOI:10.1016/S0040-4020(02)00616-6

A new aromatic annulation reaction based on sequential Horner-Emmons and Claisen condensation reactions is described. The method is high yielding and provides a rapid entry to arylnaphthalenes. The lignan natural products justicidin B 1, retrojusticidin B 2, taiwanin C 3, justicidin E 4, chinensin 5 and retrochinensin 6 have all been synthesised in good overall yield using this protocol, demonstrating its potential in multiple parallel synthesis. The selective oxidation of diols 34-36 to the corresponding retrolactones with barium manganate(VI) is also noteworthy.

Full text of DOI:10.1016/S0040-4020(02)00616-6

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5989±6001
A new benzannulation reaction and its application in the multiple
parallel synthesis of arylnaphthalene lignans
Stuart R. Flanagan, David C. Harrowvenp and Mark Bradley
Department of Chemistry, The University of Southampton, Southampton S017 1BJ, UK
Received 27 March 2002; revised 21 May 2002; accepted 13 June 2002
AbstractÐA new aromatic annulation reaction based on sequential Horner±Emmons and Claisen condensation reactions is described.
The method is high yielding and provides a rapid entry to arylnaphthalenes. The lignan natural products justicidin B 1, retrojusticidin B 2,
taiwanin C 3, justicidin E 4, chinensin 5 and retrochinensin 6 have all been synthesised in good overall yield using this protocol, demon-
strating its potential in multiple parallel synthesis. The selective oxidation of diols 34±36 to the corresponding retrolactones with barium
manganate(VI) isalso noteworthy. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
1.1. Background
Arylnaphthalene lignansoccur widely in nature and have
frequently been identi®ed asconstituentsof tree barksand
1,2
plantswith folkloric medicinal uasge.
Numerousbio-
logical assays have been conducted on lignans in this sub-
group.3 For example, the lactonesjusticidin B 1, taiwanin C
3 and chinensin 5 have recently been shown to inhibit
calcium release from a fetal long-bone culture,4 while justi-
cidin B 1 hasbeen reported to have isgni®cant antiviral
activity.5 The corresponding retrolactones, 2, 4 and 6 are
less common in nature and have been less well studied.6
Nonetheless, antimicrobial and anti-platelet activating
factor activity have been reported in thisseriesand retro-
justicidin B 2 has been shown to inhibit HIV-1 reverse
transcriptase.7±9
Most of the aforementioned studies have been conducted on
individual natural products or on small groups isolated from
the same plant source.3±9 Asa consequence, it isdif®cult
to draw meaningful structural activity relationships from
the data presently available. A synthetic entry to the aryl-
naphthalenes that is amenable to multiple parallel synthesis
would therefore be desirable in order to probe biological
function in a systematic way. Though several ingenious
10±12
routesto arylnaphthaleneshave been reported,
wished to approach the problem from a new direction.
we
1.2. Our retrosynthetic analysis
The route we envisioned targeted diesters akin to 9 asthese
could be readily transformed into lactones 7 and retro-
lactones 8 using known procedures.11,12 An opportunity
to construct the central arene ring through sequential
Keywords: annulation; Claisen condensation; combinatorial chemistry;
Horner±Emmons; lignans; natural products.
Corresponding author. Tel.: 144-23-8059-3302; fax: 144-23-8059-
3781; e-mail: dch2@soton.ac.uk
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00616-6

5990
S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
tions.13,14 The approach was blessed with limited success.
While it was possible to synthesise arylnaphthalene 17
through base promoted union of ketoaldehyde 14 and
diethyl succinate 16, the reaction led to a complex product
mixture. One complication wasthe formation of both diester
17 and itshalf acid 18 which, though useful, had to be
isolated and puri®ed separately. More importantly, an
intramolecular Cannizzaro reaction leading to lactone 21
was a signi®cant side reaction.15 Many parameterswere
examined in an attempt to biasthe reaction in favour of
the desired cyclisation pathway, but to little avail. Indeed,
the best conditions we were able to establish employed
potassium tert-butoxide in THF and gave rise to a separable
mixture of diester 17 (15%), half acid 18 (26%) and
g-lactone 21 (16%).
When the same conditions were applied to ketoaldehyde 15,
a similar product mixture resulted. The desired diester 19
wasagain produced in low yield (9%), with the half acid 20
(34%) and g-lactone 22 (15%) accounting for much of the
outstanding mass balance (Scheme 2). As it was clear that
the reaction'sinef®ciency stemmed in part from an inability
to enhance the rate of the initial Stobbe condensation
relative to the Cannizzaro reaction, we decided to explore
alternative methodsof effecting the union of an ester enolate
and an aldehyde.
Scheme 1.
condensation reactions between a ketoaldehyde 10 and a
succinate derivative then presented itself (Scheme 1); the
requisite ketoaldehydes 10 being easily synthesised in four
steps as outlined in Section 4 (Scheme 5).
2.2. Arene annulation by sequential Horner±Emmons
and Claisen condensation reactions
Following unsuccessful attempts to effect a tandem
Knovenagel condensation between diacid 12 (R0ˆMe)16
and ketoaldehyde 23 (a reaction giving g-lactone 33 in
51% yield), we decided to see if the desired aromatic
2. Results and discussion
annulation could be accomplished by means of
a
2.1. Sequential Stobbe/Claisen condensations
tandem Horner±Emmons±Claisen condensation sequence.
Pleasingly, simply stirring a solution of ketoaldehyde 14
and phosphonosuccinate 25 with sodium ethoxide at 08C
in ethanolic THF provided the corresponding arylnaphtha-
lene 17 in 68% yield and half acid 18 in 5% yield.17
Initially, we sought to construct the central aromatic ring
using sequential Stobbe and Claisen condensation reac-
The annulation wasthen extended to ketoaldehydes 15 and
23 and phosphonosuccinate 24.18 In each case, the desired
aromatic annulation proceded in good yield, with the
respective half acids and g-lactonesbeing given asminor
byproducts in most cases. These were easily separated from
the diester as they remained in the aqueous phase whilst it
wasbasic. Later, we found that the reaction could also be
mediated by a combination of DBU and LiCl in acetonitrile,
though yields were compromised in some cases (Scheme 3).
2.3. Completing the total syntheses
Completing the total syntheses from this juncture was
straightforward.11,12 Taking advantage of a procedure
developed by Padwa et al. the diesters 17, 19 and 26 were
each saponi®ed with potassium trimethylsilanoate to the
corresponding half acids 18, 20 and 30.11 Each wasthen
reduced with borane±dimethyl sul®de to give lactones
justicidin B 1, taiwanin C 3 and chinensin 5, respectively
after acidi®cation.12 Likewise, it was possible to access the
corresponding retrolactones by sequential deprotonation of
the half acids( 18, 20 and 30) with sodium hydride, ester
Scheme 2.

S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
5991
Scheme 3.
reduction with lithium borohydride and acid mediated
lactonisation.11 In this way synthetic samples of retro-
justicidin B 2, justicidin E 4 and retrochinensin 6 were
generated (Scheme 4).
A complimentary end game for the synthesis of these retro-
lactones has also been developed. First, the diesters 27±29
were reduced with lithium aluminium hydride to the
corresponding diols 34±36. Oxidation of these materials
Scheme 4.

5992
S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
4. Experimental
4.1. General remarks
Melting pointswere recorded on a Grif®n melting point
apparatusand are uncorrected. UV spectra were recorded
on either a Pye Unicam SP8-400 or a Shimadzu UV-240
Graphicord spectrophotometer as solutions in dichloro-
methane or methanol. IR spectra were recorded using a
Bio-Rad FTS 135 Fourier transform infrared spectrometer
equipped with a Golden Gate Single Re¯ection Diamond
ATR or a Nicolet Impact 400 spectrometer equipped with a
SpectraTech Thunderdome attachment (n.b. IR data was
attained directly from solid samples). NMR spectra were
recorded on a Bruker AC300 operating at 300 MHz for
1H, 75 MHz for 13C and 121.5 MHz for 31P. Chemical shifts
are reported asvaluesin partsper million relative to tetra-
methylsilane (dH 0.00, dC 0.00), CDCl3 (dC 77.2) or residual
CHCl3 (dH 7.27). Mass spectra were attained using chemical
ionisation (CI) or electron ionisation (EI) on a Thermoquest
Trace GCMS spectrometer whilst electrospray (ES) experi-
mentswere performed on a MicromassPlatform (MP)
spectrometer. High resolution mass spectra (HRMS) were
recorded on a VG Analytical 70-250-SE normal geometry
double focusing mass spectrometer using 70 eV ionisation
energy and a 2008C source temperature.
All reactionswere magnetically tsirred under nitrogen,
unless stated otherwise. Reactions were monitored by thin
layer chromatography using Macherey±Nagel Alugram Sil
G/UV254 precoated aluminium foil platesof layer thickness
0.25 mm. Compounds were visualised ®rst by UV irradia-
tion then heating plates exposed to solutions of phosphomo-
lybdic acid in ethanol or basi®ed aqueous potassium
permanganate. Column chromatography wasperformed on
Sorbsil 60 silica (230±400 mesh), slurry packed and run
under slight positive pressure.
Scheme 5.
Tetrahydrofuran was dried by distillation over sodium and
benzophenone. Dichloromethane wasdried by ditsillation
over calcium hydride. Ether refersto diethyl ether and petrol
refersto the fraction of petroleum ether in the boiling point
range 40±608C.
to retrolactones 2, 4 and 6 wasthen achieved uisng
either manganese(IV) oxide or barium manganate(VI).
Product yieldswere alwayshigher with BaMnO
,
4
though these were sometimes compromised by the forma-
tion of the regioisomeric lactones in signi®cant quantity
(Scheme 4).
4.2. Preparation of the precursors (Scheme 5)
6-Bromopiperonal (38a) [white crystalline solid, mp 129±
1308C (ethanol/H2O), lit.20 127±128.58C] and 6-bromo-
veratraldehyde (38b) [white needles, mp 151±1528C (aq.
ethanol), lit.20 149±1518C] were prepared following the
procedure of Orr et al.20 (6-Bromo-benzo[1,3]dioxol-5-yl)-
methanol (39a) [white needles, mp 87±898C (ether/petrol),
lit.21 908C (petrol)] wasprepared following the procedure of
Mann et al.21 (2-Bromo-4,5-dimethoxyphenyl)-methanol
(39b) [white solid, mp 95±968C (Et2O/petrol), lit. 97±
988C] wasprepared following the procedure of Crombie
and Josephs.22 2,3-Bis-methoxycarbonyl-succinic acid (12)
[white solid, mp 204±2058C, lit.16 not reported] was
prepared following the procedure of Walker and Apple-
3. Conclusion
In conclusion, we have developed a new aromatic annu-
lation reaction based on sequential Horner±Emmons and
Claisen condensation reactions. The method has been
exploited in ef®cient and robust syntheses of six aryl-
naphthalene lignans: the natural products justicidin B 1,
retrojusticidin B 2, taiwanin C 3, justicidin E 4,
chinensin 5 and retrochinensin 6. The selective oxidation
of diols 34±36 to the corresponding retrolactones 2, 4
and 6 with barium manganate(VI) isalos notable asit
providesa meansof converting the more common `lactone'
natural productsinto retrolactonesvia the correpsonding
diol.19
yard.16
Dimethyl 2-(dimethoxyphosphoryl)-succinate
(24) [viscous colourless oil] was prepared following
the procedure of Trost and Melvin.18 Diethyl

S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
5993
2-(diethoxyphosphoryl)-succinate (25) [viscous pale yellow
oil] wasprepared following the procedure of Harvey.
nm) lmax (1max) 290 (6900), 242 (10,400); 1H NMR
(300 MHz, CDCl3) dH 6.82 (1H, d, Jˆ8.1 Hz, ArH), 6.81
(1H, s, ArH), 6.80 (1H, s, ArH), 6.79 (1H, dd, Jˆ8.1,
1.1 Hz, ArH), 6.77 (1H, d, Jˆ1.1 Hz, ArH), 6.01 (2H, s,
OCH2O), 5.86 (1H, s, CHOH), 4.55 (1H, br d, Jˆ12.1 Hz,
CHHOH), 4.41 (1H, br d, Jˆ12.1 Hz, CHHOH), 3.85 (3H,
s , OCH3), 3.79 (3H, s, OCH3), 3.07 (1H, br s, OH), 1.86 (1H,
br s, OH); 13C NMR (75 MHz, CDCl3) dC 148.5 (C), 148.3
(C), 147.8 (C), 146.9 (C), 137.1 (C), 134.9 (C), 130.9 (C)
119.8 (CH), 113.4 (CH), 111.9 (CH), 108.2 (CH), 107.3
(CH), 101.2 (CH2), 73.4 (CH), 63.4 (CH2), 56.2 (CH3),
56.1 (CH3); LRMS (CI) 301 ([MH2H2O]1, 100%);
HRMS (EI) m/z Found: M1, 318.1101, C17H18O6 requires
318.1103.
17
4.2.1. Benzo[1,3]dioxol-5-yl-(6-hydroxymethyl-benzo-
[1,3]dioxol-5-yl)-methanol (40a). To a stirred solution of
39a (10.00 g, 43.3 mmol) in THF (100 mL) at 2788C was
added n-butyllithium (2.26 M in hexanes, 40.2 mL,
90.9 mmol) via cannula over 30 min at a rate suf®cient to
maintain the reaction temperature below 2708C. After
30 min, a solution of piperonal (6.823 g, 45.4 mmol) in
THF (30 mL) wasadded via cannula over 10 min. After a
further 30 min, saturated ammonium chloride solution
(40 mL) wasadded and the reaction mixture waswarmed
to room temperature and partitioned between ether
(140 mL) and water (100 mL). The aqueousphaes was
washed with ether (2£100 mL) and the combined ether
phases were dried (MgSO4) and concentrated in vacuo to
a pale orange oil. Puri®cation by column chromatography
(gradient elutionÐ60% Et2O in petrol to neat Et2O)
afforded ®rst piperonyl alcohol as a colourless solid
(1.25 g, 8.22 mmol, 19%) then diol 40a asa pale yellow
oil (10.61 g, 35.1 mmol, 81%); IR (neat, cm21) nmax 3428
br w, 1501 w, 1476 s, 1444 w, 1341 w, 1280 m, 1243 s, 1035
vs, 933 m, 805 w, 787 w; UV (CH2Cl2, nm) lmax (1max) 292
(5900); 1H NMR (300 MHz, CDCl3) dH 6.81 (1H, d,
Jˆ1.8 Hz, ArH), 6.80 (1H, dd, Jˆ8.0, 1.8 Hz, ArH), 6.79
(1H, s, ArH), 6.78 (1H, d, Jˆ8.0 Hz, ArH), 6.71 (1H, s,
ArH), 5.92±5.98 (4H, m, OCH2O), 5.88 (1H, br s,
CHOH), 4.60 (1H, br d, Jˆ12.3 Hz, CHHOH), 4.40 (1H,
br d, Jˆ12.3 Hz, CHHOH), 3.70 (1H, br s, OH), 2.97 (1H,
br s, OH); 13C NMR (75 MHz, CDCl3) dC 147.9 (C), 147.5
(C), 147.0 (2£C), 136.8 (C), 136.6 (C), 132.4 (C), 119.9
(CH), 110.4 (CH), 109.1 (CH), 108.2 (CH), 107.3 (CH),
101.4 (CH2), 101.2 (CH2), 73.1 (CH), 63.5 (CH2); LRMS
(CI) 285 ([MH2H2O]1, 100%), 149 ([M2C8H9O3]1, 47%);
HRMS (EI) m/z Found: M1, 302.0801, C16H14O6 requires
302.0790.
4.2.3. (3,4-Dimethoxyphenyl)-(6-hydroxymethylbenzo-
[1,3]dioxol-5-yl)-methanol (41). To a stirred solution of
39a (10.00 g, 43.3 mmol) in THF (100 mL) at 2788C was
added n-butyllithium (2.25 M in hexanes, 40.4 mL,
90.9 mmol) via cannula over 30 min at a rate suf®cient to
maintain the reaction temperature below 2608C. After
30 min, a solution of veratraldehyde (7.55 g, 45.4 mmol)
in THF (30 mL) wasadded via cannula over 10 min. After
a further 30 min, saturated ammonium chloride solution
(50 mL) wasadded and the reaction mixture waswarmed
to room temperature and partitioned between ether
(100 mL) and water (100 mL). The aqueousphaes was
washed with ether (2£100 mL) and the combined ether
phases were dried (MgSO4) and concentrated in vacuo to
a viscous orange oil. Puri®cation by column chroma-
tography (gradient elutionÐ50% Et2O in petrol to Et2O
with 5% MeOH) afforded ®rst piperonyl alcohol as a
colourless solid (1.98 g, 13.0 mmol, 30%) then diol 41 as
a white solid (9.49 g, 29.8 mmol, 69%): mp 41±438C; IR
(neat, cm21) nmax 2943 w, 2834 w, 1514 m, 1475 m, 1340 w,
1279 m, 1259 s, 1234 m, 1159 w, 1138 s, 1028 vs, 938 w,
844 w, 806 m; UV (CH2Cl2, nm) lmax (1max) 285 (6500),
236 (11,400); 1H NMR (300 MHz, CDCl3) dH 6.92 (1H, br
s , AHr ), 6.85 (1H, dd, Jˆ8.0, 2.0 Hz, ArH), 6.85 (1H, d,
Jˆ8.0 Hz, ArH), 6.80 (1H, s, ArH), 6.67 (1H, s, ArH), 5.96
(1H, s, CHOH), 5.91±5.95 (2H, m, OCH2O), 4.65 (1H, br
d, Jˆ11.8 Hz, CHHOH), 4.42 (1H, br d, Jˆ11.8 Hz,
CHHOH), 3.88 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.71
(1H, br s, OH), 2.98 (1H, br s, OH); 13C NMR (75 MHz,
CDCl3) dC 149.1 (C), 148.5 (C), 147.5 (C), 147.0 (C), 136.7
(C), 135.3 (C), 132.6 (C), 118.8 (CH), 111.1 (CH), 110.4
(CH), 109.9 (CH), 109.2 (CH), 101.5 (CH2), 73.0 (CH),
63.4 (CH2), 55.9 (CH3), 55.8 (CH3); LRMS (CI) 301
([MH2H2O]1, 100%); HRMS (EI) m/z Found: M1,
318.1111, C17H18O6 requires318.1103.
4.2.2.
Benzo[1,3]dioxol-5-yl-(2-hydroxymethyl-4,5-di-
methoxyphenyl)-methanol (40b). To a stirred suspension
of petrol washed sodium hydride (1.77 g of a 60% dis-
persion in mineral oil, 26.6 mmol) in THF (25 mL) at 08C
wasadded a oslution of 6-bromo-3,4-dimethoxybenzyl
alcohol 39b (5.47 g, 22.1 mmol) in THF (50 mL) via
cannula over 10 min. Further THF (75 mL) wasadded and
the reaction mixture wasallowed to warm to room tempera-
ture and stirred until effervescence ceased (30 min). The
resulting white suspension was then cooled to 2788C and
n-butyllithium (1.40 M in hexanes, 16.6 mL, 23.3 mmol)
was added dropwise via syringe over 10 min. After
30 min, a solution of piperonal (3.491 g, 23.3 mmol) in
THF (30 mL) wasadded via cannula over 10 min. After a
further 30 min, saturated ammonium chloride solution
(50 mL) and ether (100 mL) were added, the mixture was
warmed to room temperature and the two phases separated.
The aqueousphaes wasextracted with ether (2 £100 mL)
and the combined ether phases were dried (MgSO4) and
concentrated in vacuo to yield a yellow oil. Puri®cation
by column chromatography (gradient elutionÐ90% Et2O
in petrol to Et2O with 5% MeOH) afforded 40b asa clear
viscous oil (5.48 g, 17.2 mmol, 78%); IR (neat, cm21) nmax
3374 br w, 2915 br w, 1608 w, 1504 m, 1487 m, 1441 m,
1337 w, 1241 s, 1099 s, 1036 s, 929 m, 871 w; UV (CH2Cl2,
4.2.4. Benzo[1,3]dioxol-5-yl-(6-formyl-3,4-dimethoxy-
benzyl)-methanone (14). Diol 40b (5.48 g, 17.2 mmol) in
dichloromethane (50 mL) wasadded via ysringe to a
suspension of PCC (12.4 g, 40.5 mmol) on alumina (45 g)
in dichloromethane (400 mL) at room temperature. After
30 min, the reaction mixture was®ltered through ¯oriisl
and the solids were washed with dichloromethane
(400 mL). The combined organic phases were concentrated
in vacuo to a brown solid. Puri®cation by column chromato-
graphy (gradient elutionÐ80% chloroform in petrol
to neat chloroform) gave ketoaldehyde 14 (4.057 g,
12.9 mmol, 75%) asa pale yellow oslid: mp 157±160 8C

5994
S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
[lit. 162±1638C];23 IR (solid, cm21) nmax 1751 m, 1681 m,
1591 m, 1521 m, 1500 m, 1490 m, 1445 s, 1352 m, 1285 vs,
1270 vs, 1218 s, 1141 m, 1116 s, 1071 w, 1034 vs, 923 m,
869 w; UV (CH2Cl2, nm) lmax (1max) 318 (10,400), 270
NMR (75 MHz, CDCl3) dC 193.0 (C), 188.7 (CH), 154.2
(C), 151.8 (C), 149.8 (C), 149.5 (C), 139.4 (C), 131.4 (C),
130.6 (C) 126.5 (CH), 111.1 (CH), 110.1 (CH), 109.0 (CH),
107.6 (CH), 102.8 (CH2), 56.4 (CH3), 56.3 (CH3); LRMS
(CI) 315 (MH1, 62%), 301 (65%), 299 ([M2CH3]1, 100%).
Anal. found: C, 64.68; H, 4.48; C17H14O6 requiresC, 64.97;
H, 4.49.
1
(11,500), 240 (20,100); H NMR (300 MHz, CDCl3) dH
9.88 (1H, s, CHO), 7.54 (1H, s, ArH), 7.41 (1H, d, Jˆ
1.8 Hz, ArH), 7.30 (1H, dd, Jˆ8.1, 1.8 Hz, ArH), 6.97
(1H, s, ArH), 6.84 (1H, d, Jˆ8.1 Hz, ArH), 6.10 (2H, s,
OCH2O), 4.02 (3H, s, OCH3), 3.96 (3H, s, OCH3); 13C
NMR (75 MHz, CDCl3) dC 194.0 (C), 189.2 (CH), 153.1
(C), 152.7 (C), 150.7 (C), 148.6 (C), 137.0 (C), 132.8 (C),
129.1 (C) 127.7 (CH), 111.2 (CH), 109.8 (CH), 109.2 (CH),
108.1 (CH), 102.3 (CH2), 56.6 (CH3), 56.4 (CH3); LRMS
(CI) 315 (MH1, 88%), 301 (100%), 299 ([M2CH3]1, 46%).
Anal. found: C, 64.59; H, 4.49; C17H14O6 requiresC, 64.97;
H, 4.49.
4.3. Cyclisation reactions
4.3.1. Diethyl 6,7-dimethoxy-1-(benzo[1,3]dioxol-5-yl)-
naphthalene-2,3-dicarboxylate (17), 6,7-dimethoxy-1-
(benzo[1,3]dioxol-5-yl)-naphthalene-2,3-dicarboxylic acid
2-ethyl ester (18) and 3-benzo[1,3]dioxol-5-yl-5,6-di-
methoxy-3H-isobenzofuran-1-one (21). To a stirred solu-
tion of potassium tert-butoxide (225 mg, 2.00 mmol) in
THF (20 mL) at room temperature wasadded a oslution
of ketoaldehyde 14 (300 mg, 0.96 mmol) and diethyl suc-
cinate 16 (0.17 mL, 1.00 mmol) in THF (20 mL), dropwise
over 20 min. After 30 min, the dark brown reaction mixture
wasdiluted with water (20 mL) and extracted with ether
(3£50 mL). The combined ether phases were dried
(MgSO4) and concentrated in vacuo to an orange semi-
solid. Puri®cation by column chromatography (50±60%
Et2O in petrol) yielded diester 17 asan off-white oslid
(64 mg, 0.14 mmol, 15%): mp 192±1948C [lit. 195±
1978C].12 The aqueousphase wasacidi®ed with 6 M HCl
(10 mL) and extracted with chloroform (3£50 mL). The
combined chloroform phases were dried (MgSO4), concen-
trated in vacuo and puri®ed by column chromatography
(40±50% EtOAc in petrol with 0.5% acetic acid) to yield
g-lactone 21 asan off-white solid (49 mg, 0.16 mmol, 16%):
mp 156±1588C [lit. 157.5±1588C],25 then mono-ester 18 as
a cream solid (106 mg, 0.25 mmol, 26%): mp 200±2028C
[lit. not reported];12 IR (solid, cm21) nmax 2961 w, 2918 w,
2844 w, 1723 m, 1678 m, 1504 m, 1475 m, 1431 s, 1236 vs,
1207 s, 1163 m, 1111 m, 1097 m, 1037 s, 1008 m; UV
(CH2Cl2, nm) lmax (1max) 290 (14,000), 259 (47,500), 216
4.2.5. Benzo[1,3]dioxol-5-yl-(6-formylbenzo[1,3]dioxol-
5-yl)-methanone (15). Diol 40a (1.00 g, 3.31 mmol) in
dichloromethane (50 mL) wasadded via ysringe to a
suspension of PCC (2.85 g, 13.24 mmol) on alumina
(11.5 g) in dichloromethane (100 mL) at room temperature.
After 2 h, the reaction mixture was®ltered through ¯orisil
and the solids were washed with dichloromethane (300 mL).
The combined organic phases were concentrated in vacuo to
a viscous brown oil. Puri®cation by column chroma-
tography (gradient elutionÐ60% Et2O in petrol to neat
Et2O) gave ketoaldehyde 15 asa cream oslid (0.606 g,
2.03 mmol, 61%): mp 126±1308C [lit. 133±1348C];24 IR
(solid, cm21) nmax 1680 m, 1601 m, 1504 m, 1493 m,
1367 m, 1286 m, 1267 vs, 1098 m, 1035 s, 764 m; UV
1
(MeOH, nm) lmax (1max) 317 (10,900), 294 (8800); H
NMR (300 MHz, CDCl3) dH 9.82 (1H, s, CHO), 7.48 (1H,
s , ArH), 7.39 (1H, d, Jˆ1.7 Hz, ArH), 7.30 (1H, dd, Jˆ8.2,
1.7 Hz, ArH), 6.92 (1H, s, ArH), 6.84 (1H, d, Jˆ8.2 Hz,
ArH), 6.15 (2H, s, OCH2O), 6.09 (2H, s, OCH2O); 13C
NMR (75 MHz, CDCl3) dC 193.5 (C), 188.7 (CH), 152.8
(C), 151.8 (C), 149.8 (C), 148.6 (C), 139.2 (C), 132.2 (C),
131.2 (C), 127.8 (CH), 109.2 (CH), 108.9 (CH), 108.1 (CH),
107.8 (CH), 102.8 (CH2), 102.3 (CH2); LRMS (ES1) 317
([M1NH4]1, 85%), 299 (MH1, 100%); HRMS (ES1)
m/z Found: [M1Na]1, 321.0365, C16H10O6Na requires
321.0369.
1
(25,000); H NMR (300 MHz, CDCl3) dH 9.50 (1H, br s,
COOH), 8.54 (1H, s, ArH), 7.25 (1H, s, ArH), 6.91 (1H, d,
Jˆ7.9 Hz, ArH), 6.88 (1H, s, ArH), 6.86 (1H, d, Jˆ1.0 Hz,
ArH), 6.82 (1H, dd, Jˆ7.9, 1.0 Hz, ArH), 6.07 (1H, s,
OCHHO), 6.03 (1H, s, OCHHO), 4.14 (2H, q, Jˆ7.2 Hz,
OCH2CH3), 4.02 (3H, s, OCH3), 3.80 (3H, s, OCH3), 1.15
(3H, t, Jˆ7.2 Hz, OCH2CH3); 13C NMR (75 MHz, CDCl3)
dC 171.5 (C), 169.1 (C), 152.2 (C), 150.7 (C), 147.5 (C),
147.5 (C), 136.6 (C), 131.3 (C), 130.8 (C), 130.7 (CH),
130.5 (C), 128.5 (C), 124.0 (CH), 121.8 (C), 111.0 (CH),
108.3 (CH), 107.6 (CH), 105.5 (CH), 101.4 (CH2), 61.4
(CH2), 56.2 (CH3), 56.0 (CH3), 14.0 (CH3); LRMS (ES2)
537 ([M1CF3CO2]2, 97%), 356 (100%); HRMS (ES1) m/z
Found: [M1Na]1, 447.1056, C23H20O8Na requires
447.1050.
4.2.6. 3,4-Dimethoxybenzyl-(6-formylbenzo[1,3]dioxol-
5-yl)-methanone (23). Diol 41 (5.15 g, 16.2 mmol) in
dichloromethane (50 mL) wasadded via ysringe to a
suspension of PCC (8.73 g, 40.5 mmol) on alumina (35 g)
in dichloromethane (200 mL) at room temperature. After
30 min, the reaction mixture was®ltered through ¯oriisl
and the solids were washed with dichloromethane
(500 mL). The combined organic phases were concentrated
in vacuo to a brown solid. Puri®cation by column chroma-
tography (chloroform) gave ketoaldehyde 23 (3.33 g,
10.6 mmol, 65%) asa pale yellow oslid: mp 171±173 8C
(MeOH); IR (solid, cm21) nmax 1680 w, 1649 w, 1586 w,
1488 w, 1361 w, 1267 vs, 1228 w, 1126 m, 1037 s, 1022 s,
928 w; UV (CH2Cl2, nm) lmax (1max) 314 (10,200), 280
Alternatively, sodium (75 mg, 3.26 g atom) was added
portionwise at room temperature to vigorously stirred
anhydrousethanol (5 mL). On conusmption of the metal
the solution was cooled to 08C and ketoaldehyde 14
(250 mg, 0.80 mmol) and phosphonate 25 (493 mg,
1.60 mmol) in THF (20 mL) and ethanol (7 mL) were
added via a dropping funnel over 20 min. After 5 h, the
reaction mixture waswarmed to room temperature, concen-
trated in vacuo and partitioned between water (50 mL) and
1
(10,000), 262 (11,300), 233 (20,400); H NMR (300 MHz,
CDCl3) dH 9.83 (1H, s, CHO), 7.57 (1H, d, Jˆ2.0 Hz, ArH),
7.50 (1H, s, ArH), 7.23 (1H, dd, Jˆ8.4, 2.0 Hz, ArH), 6.95
(1H, s, ArH), 6.85 (1H, d, Jˆ8.4 Hz, ArH), 6.16 (2H, s,
OCH2O), 3.97 (3H, s, OCH3), 3.96 (3H, s, OCH3); 13C

S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
5995
1:1 THF/ether (100 mL). The aqueouslayer waswahsed
with 1:1 THF/ether (2£50 mL), then the combined organic
phases were washed with saturated sodium bicarbonate
solution (2£30 mL), dried (MgSO4) and concentrated in
vacuo to a yellow solid. Puri®cation by column chroma-
tography (50% Et2O in petrol) yielded diester 17 (246 mg,
0.54 mmol, 68%) asa white solid. The combined aqueous
phases were acidi®ed with 6 M HCl (25 mL) and extracted
with chloroform (3£50 mL). The combined chloroform
phases were then dried (MgSO4) and concentrated in
vacuo to an oily yellow solid. Puri®cation by column
chromatography (40% ethyl acetate in petrol10.5% acetic
acid) yielded half-acid 18 (16 mg, 0.038 mmol, 5%) asa
pale yellow solid. Data as stated above.
2.68 mmol) in THF (32 mL) and ethanol (10 mL) were
added via a dropping funnel over 20 min. After 3 h the
reaction mixture waswarmed to room temperature and
partitioned between water (50 mL) and 1:1 THF/ether
(100 mL). The aqueouslayer waswahsed with 1:1 THF/
ether (2£100 mL), then the combined organic phases were
dried (MgSO4) and concentrated in vacuo to a viscous oil.
Puri®cation by column chromatography (40±50% Et2O in
petrol) yielded diester 19 (394 mg, 0.90 mmol, 67%) asan
off-white solid. The aqueous phase was acidi®ed with 6 M
HCl (50 mL) and extracted with chloroform (3£50 mL).
The combined chloroform phases were then dried
(MgSO4) and concentrated in vacuo to a brown solid.
Puri®cation by column chromatography (40% ethyl acetate
in petrol10.5% acetic acid) yielded ®rst g-lactone 22
(18 mg, 0.06 mmol, 5%) then mono-ester 20 (14 mg,
34 mmol, 3%). Data asstated above.
4.3.2. Diethyl 5-benzo[1,3]dioxol-5-yl-naphtho[2,3-d]-
[1,3]dioxole-6,7-dicarboxylate (19), 5-benzo[1,3]dioxol-
5-yl-naphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid-7-
ethyl ester (20) and 7-benzo[1,3]dioxol-5-yl-7H-furo-
[30,40:4,5]benzo[1,2-d][1,3]dioxol-5-one (22). To a stirred
solution of potassium tert-butoxide (236 mg, 2.10 mmol) in
THF (20 mL) at room temperature wasadded a solution of
ketoaldehyde 15 (300 mg, 1.00 mmol) and diethyl succinate
16 (0.175 mL, 1.05 mmol) in THF (20 mL), dropwise over
20 min. After 30 min the dark brown reaction mixture
wasdiluted with water (25 mL) and extracted with ether
(3£50 mL). The combined ether phases were dried
(MgSO4) and concentrated in vacuo to a dark orange oil.
Puri®cation by column chromatography (40±50% Et2O in
petrol) yielded diester 19 asan off-white oslid (39 mg,
0.089 mmol, 9%): mp 169±1728C, [lit. 171±1728C].12 The
aqueousphaes wasacidi®ed with 6 M HCl (15 mL) and
extracted with chloroform (3£50 mL). The combined
chloroform phases were dried (MgSO4), concentrated in
vacuo and puri®ed by column chromatography (40±50%
EtOAc in petrol with 0.5% acetic acid) to yield g-lactone
22 asan off-white solid (46 mg, 0.15 mmol, 15%): mp 139±
1428C (benzene/petrol) [lit. 146±1478C];26 then mono-ester
20 asa cream solid (140 mg, 0.34 mmol, 34%): mp 223±
2268C [lit. not reported];12 IR (solid, cm21) nmax 1689 w,
1487 w, 1457 s, 1238 s, 1106 w, 1039 s, 941 w, 753 w; UV
(CH2Cl2, nm) lmax (1max) 292 (12,200); 1H NMR (300 MHz,
CDCl3) dH 8.34 (1H, s, ArH), 7.15 (1H, s, ArH), 6.81 (1H, d,
Jˆ7.9 Hz, ArH), 6.79 (1H, s, ArH), 6.73 (1H, d, Jˆ1.5 Hz,
ArH), 6.70 (1H, dd, Jˆ7.9, 1.5 Hz, ArH), 5.994 (1H, d,
Jˆ1.0 Hz, OCHHO), 5.988 (1H, d, Jˆ1.0 Hz, OCHHO),
5.97 (1H, d, Jˆ1.5 Hz, OCHHO), 5.95 (1H, d, Jˆ1.5 Hz,
OCHHO), 4.03 (2H, q, Jˆ7.2 Hz, OCH2), 1.03 (3H, t,
Jˆ7.2 Hz, CH3); 13C NMR (75 MHz, D6-DMSO) dC
168.0 (C), 167.0 (C), 150.2 (C), 148.6 (C), 147.1 (C),
147.0 (C), 136.2 (C), 131.3 (C), 130.4 (C), 130.2 (C),
129.6 (C), 129.6 (CH), 124.0 (C), 123.5 (CH), 110.6
(CH), 108.1 (CH), 105.0 (CH), 102.2 (CH2), 102.1 (CH),
101.3 (CH2), 60.4 (CH2), 13.7 (CH3); LRMS (ES2) 521
([M1CF3COO]2, 9%), 407 ([M2H]2, 10%); HRMS
(ES1) m/z Found: [M1Na]1, 431.0746, C22H16O8Na
requires431.0737.
4.3.3. Diethyl 6,7-methylenedioxy-1-(3,4-dimethoxyphenyl)-
naphthalene-2,3-dicarboxylate (26), 6,7-methylenedioxy-
1-(3,4-dimethoxyphenyl)-naphthalene-2,3-dicarboxylic
acid 2-ethyl ester (30) and 7-(3,4-dimethoxyphenyl)-7H-
furo[30,40:4,5]benzo[1,2-d][1,3]dioxol-5-one (33). Sodium
(150 mg, 6.52 g atom) wasadded portionwies at room
temperature to vigorously stirred anhydrous ethanol
(10 mL). On consumption of the metal, the solution was
cooled to 08C and ketoaldehyde 23 (500 mg, 1.59 mmol)
and phosphonate 25 (987 mg, 3.18 mmol) in THF (50 mL)
and ethanol (12 mL) were added via a dropping funnel over
20 min. After 2 h, the reaction mixture waswarmed to room
temperature, concentrated in vacuo and partitioned between
water (50 mL) and 1:1 THF/ether (200 mL). The aqueous
layer waswashed with 1:1 THF/ether (2 £100 mL), then the
combined organic phases were washed with saturated
sodium bicarbonate solution (2£50 mL), dried (MgSO4)
and concentrated in vacuo to an orange oil. Puri®cation by
column chromatography (50% Et2O in petrol) yielded
diester 26 (332 mg, 0.73 mmol, 46%) asa pale yellow
solid: mp 159±1628C [lit. not reported];12 IR (solid, cm21
)
max 1727 m, 1710 m, 1460 s, 1256 s, 1235 vs, 1207 s, 1157
n
m, 1144 m, 1030 s, 811 m; UV (CH2Cl2, nm) lmax (1max
)
300 (14,800), 258 (59,600); 1H NMR (300 MHz, CDCl3) dH
8.39 (1H, s, ArH), 7.23 (1H, s, ArH), 6.95 (1H, d, Jˆ8.2 Hz,
ArH), 6.88 (1H, dd, Jˆ8.2, 2.0 Hz, ArH), 6.87 (1H, s, ArH),
6.85 (1H, d, Jˆ2.0 Hz, ArH), 6.05 (2H, s, OCH2O), 4.39
(2H, q, Jˆ7.2 Hz, OCH2), 4.08 (2H, m, OCH2), 3.95 (3H, s,
OCH3), 3.85 (3H, s, OCH3), 1.40 (3H, t, Jˆ7.2 Hz, CH3),
1.04 (3H, t, Jˆ7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3) dC
169.3 (C), 166.1 (C), 150.3 (C), 148.8 (2£C), 148.6 (C),
137.3 (C), 132.5 (C), 130.7 (C), 130.0 (CH), 130.0 (C),
129.6 (C), 123.4 (C), 122.9 (CH), 113.7 (CH), 110.8
(CH), 105.0 (CH), 103.5 (CH), 101.9 (CH2), 61.6 (CH2),
61.2 (CH2), 56.1 (2£CH3), 14.4 (CH3), 14.0 (CH3); LRMS
(CI) 452 (M1, 100%), 407 ([MH2EtOH]1, 84%), 379
([M2CO2Et]1, 31%); HRMS (ES1) m/z Found:
[2M1Na]1, 927.2828, C50H48O16Na requires927.2835.
The combined aqueousphaesswere acidi®ed with 6 M
HCl (50 mL) and extracted with chloroform (3£100 mL).
The combined chloroform phases were then dried (MgSO4)
and concentrated in vacuo to a yellow oil. Puri®cation by
column chromatography (40% ethyl acetate in petrol10.5%
acetic acid) yielded g-lactone 33 (45 mg, 0.14 mmol, 9%) as
a white solid: mp 173±1748C; IR (solid, cm21) nmax 1733 s,
Alternatively, sodium (126 mg, 5.5 g atom) was added
portionwise at room temperature to vigorously stirred
anhydrousethanol (8 mL). On conusmption of the metal,
the solution was cooled to 08C and ketoaldehyde 15
(400 mg, 1.34 mmol) and phosphonate 25 (832 mg,

5996
S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
1518 w, 1475 w, 1460 w, 1323 m, 1256 m, 1234 w, 1142 w,
1102 m, 1023 vs, 954 w, 935 m, 878 w; UV (CH2Cl2, nm)
l
saturated sodium bicarbonate solution (2£50 mL), dried
(MgSO4) and concentrated in vacuo to an orange oil.
Puri®cation by column chromatography (40% Et2O in
petrol) yielded diester 27 (376 mg, 0.89 mmol, 56%) asa
white solid, mp 169±1718C [lit. 169±1708C].27 The
combined aqueousphaesswere acidi®ed with 6 M HCl
(50 mL) and extracted with chloroform (3£100 mL). The
combined chloroform phases were dried (MgSO4) and
concentrated in vacuo to a yellow oil. Puri®cation by
column chromatography (gradient elutionÐ30 to 50%
ethyl acetate in petrol10.5% acetic acid) yielded ®rst
g-lactone 21 (53 mg, 0.17 mmol, 11%) asa white oslid:
mp 156±1588C [lit. 157.5±1588C];25 then mono-ester 31
(98 mg, 0.24 mmol, 15%) asa white solid: mp 251±253 8C
[lit. 255±2568C];27 IR (solid, cm21) nmax 1730 m, 1679 m,
1474 m, 1436 m, 1239 s, 1209 m, 1047 m, 850 m; UV
(CH2Cl2, nm) lmax (1max) 288 (13,000), 258 (51,300), 214
(23,600); 1H NMR (300 MHz, CDCl3) dH 8.42 (1H, s, ArH),
7.18 (1H, s, ArH), 6.85 (1H, d, Jˆ8.0 Hz, ArH), 6.81 (1H, s,
ArH), 6.79 (1H, d, Jˆ1.0 Hz, ArH), 6.76 (1H, dd, Jˆ8.0,
1.0 Hz, ArH), 6.02 (1H, s, OCHHO), 5.98 (1H, s, OCHHO),
3.97 (3H, s, COOCH3), 3.74 (3H, s, OCH3), 3.60 (3H, s,
OCH3); 13C NMR (75 MHz, CDCl3) dC 174.7 (C), 172.7
(C), 156.4 (C), 155.2 (C), 152.2 (C), 152.0 (C), 141.0 (C),
135.4 (C), 135.3 (C), 135.1 (C), 134.7 (CH), 133.3 (C),
128.5 (CH), 128.4 (C), 115.5 (CH), 112.9 (CH), 112.1
(CH), 110.1 (CH), 106.0 (CH2), 60.8 (CH3), 60.6 (CH3),
57.0 (CH3); LRMS (ES2) 523 ([M1CF3COO]2, 100%);
HRMS (ES1) m/z Found: [M1Na]1, 433.0896,
C22H18O8Na requires433.0894.
max (1max) 300 (4500), 285 (4700), 229 (10,600); 1H NMR
(300 MHz, CDCl3) dH 7.25 (1H, s, ArH), 6.87 (1H, d, Jˆ
1.0 Hz, ArH), 6.86 (1H, s, ArH), 6.68±6.64 (2H, m, ArH),
6.21 (1H, s, OCH), 6.12 (1H, d, Jˆ1.2 Hz, OCHHO), 6.11
(1H, d, Jˆ1.2 Hz, OCHHO), 3.89 (3H, s, OCH3), 3.82 (3H,
s , OCH3); 13C NMR (75 MHz, CDCl3) dC 170.2 (C), 154.0
(C), 150.1 (C), 149.6 (C), 149.6 (C), 146.6 (C), 128.8 (C),
120.2 (CH), 119.6 (C), 111.2 (CH), 109.8 (CH), 104.2 (CH),
102.9 (CH2), 102.7 (CH), 82.4 (CH), 56.1 (CH3), 56.1
(CH3); LRMS (CI) 332 ([M1NH4]1, 13%), 315 (MH1,
100%); HRMS (EI1) m/z Found: [2M1Na]1, 651.1473,
C34H28O12Na requires651.1493; then mono-etesr
(125 mg, 0.30 mmol, 19%) asa white oslid: mp 200±
30
2038C [lit. not reported];12 IR (solid, cm21) nmax 1743 m,
1687 m, 1460 s, 1236 vs, 1037 m; UV (CH2Cl2, nm) lmax
(1max) 304 (17,600), 254 (73,400); H NMR (300 MHz,
1
CDCl3) dH 8.24 (1H, s, ArH), 7.05 (1H, s, ArH), 6.79
(1H, d, Jˆ8.0 Hz, ArH), 6.70 (1H, dd, Jˆ8.0, 1.7 Hz,
ArH), 6.69 (1H, s, ArH), 6.68 (1H, d, Jˆ1.7 Hz, ArH),
5.89 (2H, s, OCH2O), 3.90 (2H, m, OCH2), 3.78 (3H, s,
OCH3), 3.67 (3H, s, OCH3), 0.90 (3H, t, Jˆ7.2 Hz,
CH2CH3); 13C NMR (75 MHz, CDCl3) dC 174.0 (C),
172.4 (C), 154.9 (C), 153.4 (2£C), 153.2 (C), 141.7 (C),
137.0 (C), 135.6 (C), 134.9 (CH), 134.6 (C), 134.4 (C),
128.7 (C), 127.6 (CH), 118.4 (CH), 115.6 (CH), 109.6
(CH), 108.0 (CH), 106.6 (CH2), 65.8 (CH2), 60.7
(2£CH3), 18.7 (CH3); LRMS (CI) 537 ([M1CF3COO]2,
100%); HRMS (ES1) m/z Found: [M1Na]1, 447.1048,
C23H20O8Na requires447.1050.
4.3.6. Dimethyl 6,7-dimethoxy-1-(benzo[1,3]dioxol-5-yl)-
naphthalene-2,3-dicarboxylate (27). To a stirred suspen-
sion of lithium chloride (166 mg, 3.92 mmol) in acetonitrile
(30 mL) wasadded ketoaldehyde 14 (300 mg, 0.96 mmol).
A solution of phosphonate 24 (486 mg, 1.91 mmol) in
acetonitrile (10 mL) wasthen added via cannula imme-
diately followed by DBU (0.60 mL, 3.92 mmol) in one
portion via syringe. After 16 h at room temperature the
reaction mixture wasdiluted with water (20 mL) and
extracted with ether (2£50 mL) and 1:1 THF/ether
(50 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo to an orange oil. Puri-
®cation by column chromatography (50±60% Et2O in
petrol) gave 27 asa white oslid (284 mg, 0.67 mmol,
70%). Data asstated above.
4.3.4. 7-(3,4-Dimethoxyphenyl)-7H-furo[30,40:4,5]benzo-
[1,2-d][1,3]dioxol-5-one (33). To a solution of keto-
aldehyde 23 (200 mg, 0.64 mmol) and diacid 12 (297 mg,
1.27 mmol) in pyridine (5 mL) wasadded via ysringe
piperidine (0.130 mL, 1.31 mmol). The reaction washeated
at 1008C for 48 h then cooled to room temperature and
added carefully to conc. hydrochloric acid (10 mL) on ice
(20 g) resulting in a yellow suspension. After extraction
with ether (3£50 mL), the combined organic phases were
washed with brine (50 mL), dried (MgSO4) and concen-
trated in vacuo to a viscous brown oil. Puri®cation by
column chromatography (gradient elutionÐ60 to 80%
ether in petrol) gave 33 asa white oslid (101 mg,
0.32 mmol, 51%). Data asstated above.
4.3.5. Dimethyl 6,7-dimethoxy-1-(benzo[1,3]dioxol-5-yl)-
naphthalene-2,3-dicarboxylate (27) 6,7-dimethoxy-1-
(benzo[1,3]dioxol-5-yl)-naphthalene-2,3-dicarboxylic
acid 2-methyl ester (31) and 3-benzo[1,3]dioxol-5-yl-5,6-
4.3.7. Dimethyl 5-benzo[1,3]dioxol-5-yl-naphtho[2,3-d]-
[1,3]dioxole-6,7-dicarboxylate (28), 5-benzo[1,3]dioxol-
5-yl-naphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid-7-
methyl ester (32) and 7-benzo[1,3]dioxol-5-yl-7H-furo-
[30,40:4,5]benzo[1,2-d][1,3]dioxol-5-one (22). Sodium
(126 mg, 5.5 g atom) wasadded portionweis at room
temperature to vigorously stirred anhydrous methanol
(8 mL). On consumption of the metal the solution was
cooled to 08C and ketoaldehyde 15 (400 mg, 1.34 mmol)
and phosphonate 24 (680 mg, 2.68 mmol) in THF (32 mL)
and methanol (10 mL) were added via a dropping funnel
over 20 min. After 3 h the reaction mixture waswarmed
to room temperature and partitioned between water
(50 mL) and 1:1 THF/ether (100 mL). The aqueous
layer waswahsed with 1:1 THF/ether (2 £100 mL), then
the combined organic phases were dried (MgSO4) and
dimethoxy-3H-isobenzofuran-1-one
(21).
Sodium
(150 mg, 6.52 g atom) wasadded portionwies at room
temperature to vigorously stirred anhydrous methanol
(10 mL). On consumption of the metal, the solution was
cooled to 08C and ketoaldehyde 14 (500 mg, 1.59 mmol)
and phosphonate 24 (810 mg, 3.18 mmol) in THF (50 mL)
and methanol (12 mL) were added via a dropping funnel
over 20 min. After 3 h, the reaction mixture waswarmed
to room temperature, concentrated in vacuo and partitioned
between water (50 mL) and 1:1 THF/ether (200 mL). The
aqueouslayer waswashed with 1:1 THF/ether (2 £100 mL),
then the combined organic phases were washed with

S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
5997
concentrated in vacuo to a viscous yellow oil. Puri®cation
by column chromatography (40±60% Et2O in petrol)
yielded diester 28 (462 mg, 1.13 mmol, 84%) asa white
solid: mp 217±2198C, [lit. 218±2198C].11 The aqueous
phase was acidi®ed with 6 M HCl (50 mL) and extracted
with chloroform (3£50 mL). The combined chloroform
phases were then dried (MgSO4) and concentrated in
vacuo to a yellow solid. Puri®cation by column chroma-
tography (40% ethyl acetate in petrol10.5% acetic acid)
yielded ®rst g-lactone 22 (14 mg, 0.05 mmol, 4%),26 then
mono-ester 32 (26 mg, 0.07 mmol, 5%): mp 234±2378C [lit.
243±2448C].11
6 M HCl (50 mL) and extracted with chloroform
(3£100 mL). The combined chloroform phases were dried
(MgSO4) and concentrated in vacuo to a yellow solid.
Column chromatography (30% ethyl acetate in petrol1
0.5% acetic acid) yielded a further quantity of diester 29
(355 mg, 0.79 mmol, 53%). Data asstated above.
4.4. Completion of the total syntheses
4.4.1. 6,7-Dimethoxy-1-(benzo[1,3]dioxol-5-yl)-naphtha-
lene-2,3-dicarboxylic acid 2-ethyl ester (18). The pro-
cedure of Padwa et al.11b is followed. To a stirred solution
of diester 17 (246 mg, 0.54 mmol) in THF (30 mL) at room
temperature was added potassium trimethylsilanolate
(308 mg, 2.40 mmol). After 5 h, the solution was acidi®ed
with 5% HCl (50 mL) and extracted with chloroform
(3£50 mL). The combined chloroform extractswere
washed with brine (50 mL), dried (MgSO4) and concen-
trated in vacuo to yield the half-acid 18 asan off-white
solid (215 mg, 0.51 mmol, 93%). Data as stated above.
4.3.8. Dimethyl 6,7-methylenedioxy-1-(3,4-dimethoxy-
phenyl)-naphthalene-2,3-dicarboxylate (29). To a stirred
suspension of lithium chloride (166 mg, 3.92 mmol) in
acetonitrile (30 mL) wasadded ketoaldehyde 23 (300 mg,
0.96 mmol). A solution of phosphonate 24 (486 mg, 1.91
mmol) in acetonitrile (10 mL) wasthen added via cannula,
followed immediately by DBU (0.60 mL, 3.92 mmol) in
one portion via syringe. After 16 h at room temperature
the reaction mixture wasdiluted with water (50 mL) and
extracted with 1:1 THF/ether (50 mL) and dichloromethane
(2£50 mL). The combined organic phases were washed
with brine (50 mL), dried (MgSO4) and concentrated in
vacuo to a dark orange oil. Puri®cation by column chroma-
tography (gradient elutionÐ60±80% Et2O in petrol) gave
29 asan off-white oslid (199 mg, 0.47 mmol, 49%): mp
252±2548C, [lit. 248±2508C (CHCl3/hexane)];28 IR (solid,
cm21) nmax 1731 w, 1716 m, 1457 s, 1256 m, 1235 s, 1212
m, 1130 m, 1024 s, 929 m, 849 m, 835 s; UV (CH2Cl2, nm)
4.4.2. 5-Benzo[1,3]dioxol-5-yl-naphtho[2,3-d][1,3]dioxole-
6,7-dicarboxylic acid 7-ethyl ester (20). The procedure of
Padwa et al.11b is followed. To a stirred solution of diester 19
(200 mg, 0.46 mmol) in THF (20 mL) at room temperature
was added potassium trimethylsilanolate (260 mg, 2.00
mmol). After 4 h, the solution was acidi®ed with 5% HCl
(35 mL) and extracted with chloroform (3£50 mL). The
combined chloroform extractswere dried (MgSO 4) and
reduced in vacuo to yield a pale green solid. Column
chromatography (40% EtOAc in petrol with 0.5% acetic
acid) gave 20 asa light cream solid (185 mg, 0.45 mmol,
98%). Data asstated above.
l
max (1max) 300 (10,700), 254 (50,400); 1H NMR (300 MHz,
CDCl3) dH 8.39 (1H, s, ArH), 7.22 (1H, s, ArH), 6.96 (1H, d,
Jˆ7.9 Hz, ArH), 6.88 (1H, s, ArH), 6.87 (1H, dd, Jˆ7.9,
1.0 Hz, ArH), 6.85 (1H, d, Jˆ1.0 Hz, ArH), 6.06 (2H, s,
OCH2O), 3.95 (3H, s, COOCH3), 3.93 (3H, s, COOCH3),
3.85 (3H, s, OCH3), 3.63 (3H, s, OCH3); 13C NMR
(75 MHz, CDCl3) dC 169.8 (C), 166.5 (C), 150.4 (C),
148.9 (C), 148.8 (C), 148.6 (C), 137.4 (C), 132.5 (C),
130.5 (C), 130.0 (CH), 129.4 (C), 125.7 (C), 122.9 (C),
122.8 (CH), 113.5 (CH), 110.8 (CH), 105.0 (CH),
103.5 (CH), 101.9 (CH2), 56.1 (CH3), 56.0 (CH3), 52.6
(CH3), 52.4 (CH3); LRMS (CI) 424 (M1, 100%), 393
([MH2MeOH]1, 91%); HRMS (ES1) m/z Found:
[2M1Na]1, 871.2249, C46H40O16Na requires871.2209.
4.4.3.
6,7-Methylenedioxy-1-(3,4-dimethoxyphenyl)-
naphthalene-2,3-dicarboxylic acid 2-ethyl ester (30).
The procedure of Padwa et al.11b isfollowed. To a stirred
solution of diester 26 (205 mg, 0.45 mmol) in THF (20 mL)
at room temperature was added potassium trimethylsilano-
late (260 mg, 2.00 mmol). After 5 h the solution was acidi-
®ed with 5% HCl (50 mL) and extracted with chloroform
(3£50 mL). The combined chloroform extractswere dried
(MgSO4) and concentrated in vacuo to a pale green solid.
Puri®cation by column chromatography (40% ethyl acetate
in petrol10.5% acetic acid) gave 30 asa white oslid
(227 mg, 0.55 mmol, 94%). Data asstated above.
Alternatively, sodium (150 mg, 6.52 g atom) was added
portionwise at room temperature to vigorously stirred
anhydrousmethanol (12 mL). On conusmption of the
metal the solution was cooled to 08C and ketoaldehyde 23
(500 mg, 1.59 mmol) and phosphonate 24 (810 mg,
3.18 mmol) in THF (50 mL) and methanol (12 mL) were
added via a dropping funnel over 20 min. After 3 h the
reaction mixture waswarmed to room temperature, concen-
trated in vacuo and partitioned between water (50 mL) and
1:1 THF/ether (200 mL). The aqueouslayer waswahsed
with 1:1 THF/ether (2£100 mL), then the combined organic
phases were washed with saturated sodium bicarbonate
solution (2£50 mL), dried (MgSO4) and concentrated in
vacuo to an orange semi-solid. Puri®cation by column
chromatography (50% Et2O in petrol) yielded diester 29
(84 mg, 0.20 mmol, 12%) as a sparingly soluble pale yellow
solid. The combined aqueous phases were acidi®ed with
4.4.4.
6,7-Dimethoxy-1-(3,4-methylenedioxyphenyl)-
naphthalene-2,3-dimethanol (34). To a stirred solution of
diester 27 (275 mg, 0.65 mmol) in THF (20 mL) at 2788C
wasadded lithium aluminium hydride (100 mg, 2.66 mmol)
in one portion. The reaction mixture wasallowed to warm to
08C over 1 h then water (1 mL) wasadded dropwies via
syringe. Once effervescence had ceased, 15% NaOH
(1 mL) and water (1 mL) were added. After stirring
vigorously at room temperature for 16 h, anhydrous
MgSO4 (10 g) wasadded. After tsirring for 150 min the
reaction mixture was®ltered, concentrated in vacuo and
puri®ed by column chromatography (gradient elutionÐ
90% Et2O in petrol to 5% MeOH in Et2O) to give diol 34
(180 mg, 0.49 mmol, 75%) asa white solid: mp 191±193 8C
(benzene/petrol), [lit. 1918C];10r IR (solid, cm21) nmax 3320
br w, 2768 w, 1509 m, 1434 m, 1233 s, 1155 m, 1037 m,

5998
S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
1005 m, 984 m, 851 vs; UV (CH2Cl2, nm) lmax (1max) 331
(6100), 289 (14,600), 246 (78,500); H NMR (300 MHz,
UV (CH2Cl2, nm) lmax (1max) 314 (2000), 274 (12,800), 238
(60,400); 1H NMR (300 MHz, CDCl3) dH 7.68 (1H, s, ArH),
7.13 (1H, s, ArH), 7.00 (1H, d, Jˆ7.7 Hz, ArH), 6.85 (1H,
dd, Jˆ7.7, 2.0 Hz, ArH), 6.84 (1H, d, Jˆ2.0 Hz, ArH), 6.76
(1H, s, ArH), 6.01 (2H, s, OCH2O), 4.91 (2H, s, CH2OH),
4.62 (2H, s, CH2OH), 3.98 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 2.64 (2H, br s, 2£CH2OH); 13C NMR (75 MHz,
CDCl3) dC 148.8 (C), 148.3 (C), 148.0 (C), 147.8 (C),
139.8 (C), 135.8 (C), 133.5 (C), 131.3 (C), 128.0 (C),
128.0 (CH), 122.3 (C), 122.3 (CH), 113.3 (CH), 111.1
(CH), 103.8 (CH), 103.7 (CH), 101.2 (CH2), 65.5 (CH2),
61.0 (CH2), 56.1 (CH3), 56.1 (CH3); LRMS (CI) 368 (M1,
4%), 351 ([MH2H2O]1, 62%), 350 ([M2H2O]1, 100%);
HRMS (ES1) m/z Found: [2M1Na]1, 759.2427,
C42H40O12Na requires759.2412.
1
CDCl3) dH 7.64 (1H, s, ArH), 7.09 (1H, s, ArH), 6.93
(1H, d, Jˆ7.7 Hz, ArH), 6.80 (1H, d, Jˆ1.7 Hz, ArH),
6.75 (1H, dd, Jˆ7.7, 1.7 Hz, ArH), 6.72 (1H, s, ArH),
6.08 (1H, d, Jˆ1.5 Hz, OCHHO), 6.03 (1H, d, Jˆ1.5 Hz,
OCHHO), 4.83 (2H, s, CH2OH), 4.57 (2H, s, CH2OH), 3.98
(3H, s, OCH3), 3.73 (3H, s, OCH3); 13C NMR (75 MHz,
CDCl3) dC 150.2 (C), 150.0 (C), 148.1 (C), 147.3 (C),
139.2 (C), 136.1 (C), 133.6 (C), 132.9 (C), 129.2 (C),
129.0 (C), 127.7 (CH), 123.9 (CH), 111.2 (CH), 108.7
(CH), 106.7 (CH), 106.4 (CH), 101.6 (CH2), 65.6 (CH2),
61.1 (CH2), 56.4 (CH3), 56.3 (CH3); LRMS (CI) ([MH2
H2O]1, 100%), 350 ([M2H2O]1, 79%); HRMS (ES1) m/z
Found: [2M1Na]1, 759.2444, C42H40O12Na requires
759.2412.
4.4.7. Justicidin B (1) and retrojusticidin B (2). Method
IÐusing a borane reduction. The procedure of Cow et al.12
is followed. To a stirred solution of half-acid 18 (30 mg,
0.17 mmol) in THF (1.5 mL) at room temperature was
added borane±dimethyl sul®de complex (10.0 M solution
in dimethylsul®de, 0.080 mL, 0.80 mmol) dropwise via
syringe. After 3 h, 3% HCl in ethanol (5 mL) was added.
Once effervescence had ceased, the solvent was removed in
vacuo. The residue was dissolved in anhydrous ethanol
(3 mL), concentrated in vacuo to a yellow solid and
dissolved in chloroform (25 mL). Washing with saturated
sodium bicarbonate solution (3£25 mL) and water (25 mL),
drying (MgSO4) and concentrating in vacuo, gave a white
solid. Puri®cation by column chromatography (10% ethyl
acetate in toluene) gave justicidin B 1 (25 mg, 0.069 mmol,
97%) asa white solid, mp 237±239 8C [lit. 235±2388C];1g IR
(solid, cm21) nmax 1759 s, 1506 s, 1481 m, 1439 m, 1387 w,
1343 w, 1262 s, 1239 s, 1217 s, 1198 s, 1158 m, 1044 s,
1021 m, 1002 m, 932 w, 876 m; UV (CH2Cl2, nm) lmax
4.4.5. 6,7-Methylenedioxy-1-(3,4-methylenedioxy)naph-
thalene-2,3-dimethanol (35). To a stirred solution of
diester 28 (250 mg, 0.61 mmol) in THF (50 mL) at 2788C
wasadded lithium aluminium hydride (95 mg, 2.51 mmol)
in one portion. The reaction mixture wasthen warmed to
08C over 1 h then water (1 mL) wasadded dropwies via
syringe. Once effervescence had ceased, 15% NaOH
(1 mL) and water (1 mL) were added. After stirring
vigorously at room temperature for 16 h, anhydrous
MgSO4 (10 g) wasadded. After tsirring for 150 min the
reaction mixture was®ltered, concentrated in vacuo and
puri®ed by column chromatography (gradient elutionÐ
90% Et2O in petrol to 5% MeOH in Et2O) to yield 35
(179 mg, 0.51 mmol, 83%) asa white oslid: mp 176±
1798C [lit. 181±1838C];29 IR (solid, cm21) nmax 3349 br
w, 1504 w, 1486 m, 1459 s, 1234 s, 1038 s, 1013 m, 939
m, 885 w; UV (CH2Cl2, nm) lmax (1max) 332 (3300), 294
(12,400); 1H NMR (300 MHz, CDCl3) dH 7.65 (1H, s, ArH),
7.10 (1H, s, ArH), 6.93 (1H, d, Jˆ8.1 Hz, ArH), 6.70±6.85
(3H, m, ArH), 5.89±6.13 (4H, m, OCH2O), 4.87 (2H, s,
CH2OH), 4.61 (2H, s, CH2OH); 13C NMR (75 MHz,
CDCl3) dC 148.2 (C), 147.9 (C), 147.8 (C), 147.1 (C),
139.6 (C), 135.9 (C), 133.6 (C), 132.6 (C), 130.2 (2£C),
128.2 (CH), 123.6 (CH), 110.9 (CH), 108.5 (CH), 103.9
(CH), 103.8 (CH), 101.3 (2£CH2), 65.4 (CH2), 60.8
(CH2); LRMS (CI) 321 ([MH2MeOH]1, 100%); HRMS
(ES1) m/z Found: [2M1Na]1, 727.1798, C40H32O12Na
requires727.1786.
1
(1max) 340 (3100), 286 (8300), 252 (38,000); H NMR
(300 MHz, CDCl3) dH 7.71 (1H, s, ArH), 7.19 (1H, s,
ArH), 7.12 (1H, s, ArH), 6.98 (1H, d, Jˆ7.7 Hz, ArH),
6.86 (1H, d, Jˆ1.2 Hz, ArH), 6.84 (1H, dd, Jˆ7.7, 1.2 Hz,
ArH), 6.10 (1H, d, Jˆ1.0 Hz, OCHHO), 6.05 (1H, d, Jˆ
1.0 Hz, OCHHO), 5.39 (2H, s, CH2OCO), 4.06 (3H, s,
OCH3), 3.82 (3H, s, OCH3); 13C NMR (75 MHz, CDCl3)
dC 169.9 (C), 151.9 (C), 150.2 (C), 147.7 (2£C), 139.7
(2£C), 133.3 (C), 129.0 (C), 128.5 (C), 123.6 (CH), 118.6
(C), 118.5 (CH), 110.7 (CH), 108.4 (CH), 106.1 (CH), 105.9
(CH), 101.4 (CH2), 68.2 (CH2), 56.2 (CH3), 56.0 (CH3);
LRMS (CI) 365 (MH1, 100%); HRMS (ES1) m/z Found:
[M1Na]1, 387.0842, C21H16O6Na requires387.0839.
4.4.6.
6,7-Methylenedioxy-1-(3,4-dimethoxyphenyl)-
naphthalene-2,3-dimethanol (36). To a stirred solution of
diester 29 (100 mg, 0.24 mmol) in THF (50 mL) at 2788C
under argon wasadded lithium aluminium hydride (37 mg,
0.97 mmol) in one portion. After 30 min, the reaction
mixture waswarmed to 0 8C, stirred for a further 1 h then
water (0.4 mL) was added. Once effervescence had ceased,
15% NaOH (0.4 mL) and water (0.4 mL) were added, the
reaction waswarmed to room temperature and vigorously
stirred for 16 h. Anhydrous MgSO4 (5 g) wasthen added
and after 150 min the resulting suspension was ®ltered
and concentrated in vacuo to a pale yellow solid. Puri®-
cation by column chromatography (gradient elutionÐ90%
Et2O in petrol to 5% MeOH in Et2O) yielded 36 asa white
solid (64 mg, 0.17 mmol, 74%): mp 179±1828C [lit.
1838C];10r IR (solid, cm21) nmax 3430 br w, 2943 w, 1515
w, 1462 s, 1248 s, 1229 m, 1139 m, 1025 s, 941 m, 763 m;
Method IIÐusing a lithium borohydride reduction. The
procedure of Padwa et al.11b isfollowed. To a cooled
(08C) solution of half-acid 18 (140 mg, 0.33 mmol) and
sodium hydride (105 mg of a 60% dispersion in mineral
oil and washed with petrol, 2.62 mmol) in 1,4-dioxane
(6.25 mL) wasadded lithium borohydride (2.0 M solution
in THF, 0.94 mL, 1.88 mmol) dropwise via syringe. Once
effervescence had ceased, the reaction mixture was heated
to re¯ux for 28 h then cooled to 08C and acidi®ed with 5%
HCl (15 mL). The resulting biphasic mixture was extracted
with dichloromethane (4£20 mL) and the combined organic
phases were dried (MgSO4) and concentrated in vacuo to
a white solid. Puri®cation by column chromatography
(gradient elutionÐ5 to 15% ethyl acetate in toluene)

S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
5999
yielded ®rstly retrojusticidin B 2 (80 mg, 0.22 mmol, 67%)
asa white oslid mp 216±220 8C [lit. 218±2208C];10t IR
(solid, cm21) nmax 2948 w, 2919 w, 2849 w, 1750 s, 1505
m, 1483 m, 1457 m, 1435 m, 1263 m, 1240 s, 1230 s, 1154
m, 1037 s, 1006 m, 832 m, 761 m; UV (CH2Cl2, nm) lmax
(1max) 310 (8000), 252 (65,600); 1H NMR (300 MHz,
CDCl3) dH 8.30 (1H, s, ArH), 7.30 (1H, s, ArH), 7.10
(1H, s, ArH), 6.99 (1H, d, Jˆ8.4 Hz, ArH), 6.85 (1H, d,
Jˆ1.7 Hz, ArH), 6.84 (1H, dd, Jˆ8.4, 1.7 Hz, ArH), 6.11
(1H, d, Jˆ1.2 Hz, OCHHO), 6.08 (1H, d, Jˆ1.2 Hz,
OCHHO), 5.21 (2H, s, CH2OCO), 4.05 (3H, s, OCH3),
3.86 (3H, s, OCH3); 13C NMR (75 MHz, CDCl3) dC 171.8
(C), 152.2 (C), 150.3 (C), 148.5 (C), 147.8 (C), 138.1 (C),
132.1 (C), 131.8 (C), 130.0 (C), 129.9 (C), 124.4 (CH),
122.9 (CH), 121.5 (C), 109.7 (CH), 109.2 (CH), 107.8
(CH), 104.1 (CH), 101.6 (CH2), 69.7 (CH2), 56.2 (CH3),
56.1 (CH3); LRMS (CI) 364 (M1, 100%); HRMS (ES1)
m/z Found: [M1Na]1, 387.0842, C21H16O6Na requires
387.0839; then justicidin B 1 (34 mg, 0.09 mmol, 28%) as
a white solid.
UV (CH2Cl2, nm) lmax (1max) 340 (4700), 288 (12,400), 251
(50,300); H NMR (300 MHz, D6-DMSO) dH 7.93 (1H, s,
1
ArH), 7.52 (1H, s, ArH), 7.03 (1H, d, Jˆ7.7 Hz, ArH), 6.88
(1H, s, ArH), 6.87 (1H, d, Jˆ1.5 Hz, ArH), 6.73 (1H, dd,
Jˆ7.7, 1.5 Hz, ArH), 6.18 (1H, d, Jˆ2.6 Hz, OCHHO), 6.17
(1H, d, Jˆ2.6 Hz, OCHHO), 6.13 (1H, d, Jˆ1.1 Hz,
OCHHO), 6.12 (1H, d, Jˆ1.1 Hz, OCHHO), 5.42 (2H, s,
CH2OCO); 13C NMR (75 MHz, D6-DMSO) dC 169.1 (C),
149.5 (C), 148.3 (C), 146.9 (2£C), 140.2 (C), 138.6 (C),
134.2 (C), 129.3 (C), 128.3 (C), 123.2 (CH), 119.5 (CH),
118.4 (C), 110.4 (CH), 107.9 (CH), 103.7 (CH), 102.1 (CH),
102.1 (CH2), 101.1 (CH2), 67.9 (CH2); LRMS (CI) 349
(MH1, 100%); HRMS (ES1) m/z Found: [M1Na]1,
371.0527, C20H12O6Na requires371.0526.
Method IIÐusing a lithium borohydride reduction. The
procedure of Padwa et al.11b isfollowed. To a solution of
half-acid 20 (50 mg, 0.12 mmol) and sodium hydride
(39 mg of a 60% dispersion in mineral oil and washed
with petrol, 0.97 mmol) in 1,4-dioxane (2.3 mL) at room
temperature wasadded lithium borohydride (0.49 mL,
0.97 mmol, 2.0 M solution in THF) dropwise via syringe.
Once effervescence had ceased, the reaction mixture was
heated to re¯ux for 28 h then cooled to 08C and acidi®ed
with 5% HCl (10 mL). The resulting biphasic mixture was
extracted with dichloromethane (3£25 mL) and the
combined organic phases were dried (MgSO4) and concen-
trated in vacuo to a white solid. Puri®cation by column
chromatography (5±10% ethyl acetate in toluene) yielded
justicidin E 4 (24 mg, 0.07 mmol, 57%) asa white solid: mp
264±2688C, [lit. 265±2698C];10w IR (solid, cm21) nmax 2920
w, 1757 s, 1498 w, 1458 vs, 1245 s), 1207 m, 1025 s, 1007
m, 931 m; UV (CH2Cl2, nm) lmax (1max) 300 (9500), 244
Method IIIÐusing a manganese dioxide oxidation. To a
stirred solution of diol 34 (25 mg, 0.068 mmol) in dichloro-
methane (10 mL) at room temperature wasadded activated
manganese dioxide (354 mg, 4.1 mmol) in one portion.
After 24 h the suspension was ®ltered through celite and
the solids were washed with chloroform (150 mL). The
combined solutions were concentrated in vacuo and puri®ed
by column chromatography (5±10% EtOAc in toluene) to
give retrojusticidin B 2 (8.3 mg, 0.023 mmol, 34%) asa
white solid.
Method IVÐusing a barium manganate oxidation. To a
stirred solution of diol 34 (25 mg, 0.068 mmol) in dichloro-
methane (10 mL) at room temperature wasadded barium
manganate (174 mg, 0.68 mmol) in one portion. After
16 h the suspension was ®ltered through celite and the solids
were washed with chloroform (150 mL). The combined
solutions were concentrated in vacuo to a white solid
which waspuri®ed by column chromatography (5±10%
EtOAc in toluene) to give ®rstly retrojusticidin B 2
(21.2 mg, 0.058 mmol, 86%) as a white solid, then justicidin
B 1 (3.0 mg, 0.008 mmol, 12%) asa white solid.
1
(33,800); H NMR (300 MHz, D6-DMSO) dH 8.34 (1H, s,
ArH), 7.62 (1H, s, ArH), 7.08 (1H, d, Jˆ8.1 Hz, ArH), 7.03
(1H, d, Jˆ1.5 Hz, ArH), 6.99 (1H, s, ArH), 6.89 (1H, dd,
Jˆ8.1, 1.5 Hz, ArH), 6.18 (2H, s, OCH2O), 6.12 (2H, s,
OCH2O), 5.32 (1H, d, Jˆ14.7 Hz, OCHH), 5.25 (1H, d,
Jˆ14.7 Hz, OCHH); 13C NMR (75 MHz, CDCl3) dC
170.8 (C), 150.4 (C), 148.0 (C), 147.9 (C), 147.3 (C),
138.7 (C), 132.6 (C), 132.1 (C), 131.0 (C), 129.1 (C),
124.1 (CH), 123.0 (CH), 121.2 (C), 109.7 (CH), 108.9
(CH), 105.2 (CH), 102.3 (CH2), 101.4 (CH2), 100.9 (CH),
69.3 (CH2); LRMS (CI) 349 (MH1, 100%); HRMS (ES1)
m/z Found: [M1Na]1, 371.0525, C20H12O6Na requires
371.0526.
4.4.8. Taiwanin C (3) and justicidin E (4). Method IÐ
using a borane reduction. The procedure of Cow et al.12 is
followed. To a stirred solution of half-acid 20 (50 mg,
0.12 mmol) in THF (4 mL) at room temperature was
added borane±dimethyl sul®de complex (10.0 M solution
in dimethylsul®de, 0.12 mL, 0.80 mmol) dropwise via
syringe. After 2 h, 3% HCl in ethanol (5 mL) was added.
Once effervescence had ceased, the solvent was removed in
vacuo. The residue was dissolved in anhydrous ethanol
(5 mL), concentrated in vacuo to a yellow solid and
dissolved in chloroform (25 mL). Washing with saturated
sodium bicarbonate solution (3£25 mL) and water (25 mL),
drying (MgSO4) and concentrating in vacuo, gave a yellow
solid. Puri®cation by column chromatography (5±10%
ethyl acetate in toluene) gave taiwanin C 3 (37 mg,
0.11 mmol, 87%) asa white oslid: mp 270±272 8C, [lit.
270±2728C];1c,10o IR (solid, cm21) nmax 2919 w, 2850 w,
1763 s, 1612 w, 1489 m, 1469 s, 1457 m, 1257 m, 1234
m, 1203 m, 1152 m, 1033 s, 1012 s, 930 m, 874 m, 797 m;
Method IIIÐusing a manganese dioxide oxidation. To a
stirred solution of diol 35 (175 mg, 0.50 mmol) in dichloro-
methane (25 mL) at room temperature wasadded activated
manganese dioxide (2.59 g, 29.8 mmol) in one portion.
After 16 h the suspension was ®ltered through celite and
the solids were washed with chloroform (250 mL). The
combined solutions were concentrated in vacuo and puri®ed
by column chromatography (5% EtOAc in toluene) to give
justicidin E 4 (102 mg, 0.29 mmol, 59%) asa white solid.
Method IVÐusing a barium manganate oxidation. To a
stirred solution of diol 35 (50 mg, 0.14 mmol) in dichloro-
methane (10 mL) at room temperature wasadded barium
manganate (364 mg, 1.42 mmol) in one portion. After
16 h the suspension was ®ltered through celite and the solids
were washed with chloroform (150 mL). The combined

6000
S. R. Flanagan et al. / Tetrahedron 58 (2002) 5989±6001
solutions were concentrated in vacuo and puri®ed by
column chromatography (5±10% EtOAc in toluene) to
give ®rstly justicidin E 4 (35 mg, 0.10 mmol, 71%) asa
white solid, then taiwanin C 3 (7.0 mg, 0.02 mmol, 14%)
asa white solid.
dC 171.7 (C), 150.6 (C), 149.5 (C), 149.2 (C), 148.5 (C),
138.5 (C), 133.6 (C), 133.1 (C), 131.4 (C), 128.7 (C), 124.7
(CH), 121.8 (CH), 121.8 (C), 112.3 (CH), 111.8 (CH), 105.4
(CH), 102.2 (CH), 102.0 (CH2), 69.7 (CH2), 56.2 (CH3),
56.2 (CH3); LRMS (CI) 365 (MH1, 73%), 364 (M1,
100%); HRMS (ES1) m/z Found: [M1Na]1, 387.0844,
C21H16O6Na requires387.0839.
4.4.9. Chinensin (5) and retrochinensin (6). Method IÐ
using a borane reduction. The procedure of Cow et al.12 is
followed. To a stirred solution of half-acid 30 (60 mg,
0.14 mmol) in THF (3 mL) at room temperature was
added borane±dimethyl sul®de complex (10.0 M solution
in dimethylsul®de, 0.14 mL, 1.40 mmol) dropwise via
syringe. After 3 h, 3% HCl in ethanol (5 mL) was added.
Once effervescence had ceased, the solvent was removed in
vacuo. The residue was dissolved in anhydrous ethanol
(5 mL), concentrated in vacuo to a white solid and dissolved
in chloroform (25 mL). Washing with saturated sodium
bicarbonate solution (3£25 mL) and water (25 mL), drying
(MgSO4) and concentrating in vacuo, gave a white solid.
Puri®cation by column chromatography (10% ethyl acetate
in toluene) gave chinensin 5 (50 mg, 0.134 mmol, 97%) asa
white solid: mp 224±2268C [lit. 224±2258C];10o IR (solid,
cm21) nmax 1762 s, 1738 s, 1462 m, 1366 m, 1245 m, 1229 s,
1217 s, 1202 s, 1032 m, 1018 m; UV (CH2Cl2, nm) lmax
Method IIIÐusing a manganese dioxide oxidation. To a
stirred solution of diol 36 (20 mg, 0.054 mmol) in dichloro-
methane (10 mL) at room temperature wasadded activated
manganese dioxide (284 mg, 3.26 mmol) in one portion.
After 48 h the suspension was ®ltered through celite and
the solids were washed with chloroform (100 mL). The
combined solutions were concentrated in vacuo to yield
retrochinensin 6 (18 mg, 49 mmol, 91%) asa white solid.
Method IVÐusing a barium manganate oxidation. To a
stirred solution of diol 36 (20 mg, 0.054 mmol) in dichloro-
methane (5 mL) at room temperature wasadded barium
manganate (140 mg, 0.54 mmol) in one portion. After
48 h the suspension was ®ltered through celite and the solids
were washed with chloroform (100 mL). The combined
solutions were concentrated in vacuo and puri®ed by
column chromatography (5±10% EtOAc in toluene) to
give ®rstly retrochinensin 6 (15.7 mg, 0.043 mmol, 80%)
as a white solid, then chinensin 5 (3.7 mg, 0.010 mmol,
19%) asa white solid.
1
(1max) 340 (5500), 300 (10,600), 250 (46,600); H NMR
(300 MHz, CDCl3) dH 7.70 (1H, s, ArH), 7.21 (1H, s,
ArH), 7.12 (1H, s, ArH), 7.03 (1H, d, Jˆ8.1 Hz, ArH),
6.91 (1H, dd, Jˆ8.1, 1.8 Hz, ArH), 6.87 (1H, d, Jˆ1.8 Hz,
ArH), 6.08 (2H, s, OCH2O), 5.38 (2H, s, CH2OCO), 3.98
(3H, s, OCH3), 3.87 (3H, s, OCH3); 13C NMR (75 MHz,
CDCl3) dC 170.0 (C), 150.1 (C), 149.0 (C), 148.8 (C),
148.7 (C), 140.6 (C), 140.0 (C), 134.8 (C), 130.6 (C),
127.3 (C), 122.6 (CH), 119.1 (CH), 118.9 (C), 113.5
(CH), 110.9 (CH), 103.9 (CH), 103.8 (CH), 102.0 (CH2),
68.1 (CH2), 56.1 (CH3), 56.0 (CH3); LRMS (CI) 365 (MH1,
65%), 364 (M1, 100%); HRMS (ES1) m/z Found:
[M1Na]1, 387.0843, C21H16O6Na requires387.0839.
Acknowledgements
The authorsthank Merck Sharp and Dohme for their
®nancial support and Dr G. J. Langley and J. Herniman
for HRMS analyses.
References
Method IIÐusing a lithium borohydride reduction. The
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