Synthesis and absolute configuration of the insecticidal sesquilignan ( + )-haedoxan a in honour of professor G. H. Neil towers 75th birthday

Article abstract of DOI:10.1016/S0031-9422(98)00270-2

The insecticidal neolignan, ( + )-haedoxan A, was synthesized from (S)-( + )-vinyl-y-butyrolactone and (2R,3R)-(+)-6-formyl-7-methoxy-3-methoxymethyl-2-(3,4-methylenedioxyphenyl)-1,4- benzodioxane, and its absolute configuration was unequivocally establis

Full text of DOI:10.1016/S0031-9422(98)00270-2

Phytochemistry\ Vol[ 38\ No[ 1\ pp[ 502Ð511\ 0887
Þ 0887 Elsevier Science Ltd[ All rights reserved
Printed in Great Britain
Pergamon
\
9920Ð8311:87:,Ðsee front matter
PII] S9920Ð8311"87#799169Ð1
SYNTHESIS AND ABSOLUTE CONFIGURATION OF THE
INSECTICIDAL SESQUILIGNAN "¦#!HAEDOXAN A
IN HONOUR OF PROFESSOR G[ H[ NEIL TOWERS 64TH BIRTHDAY
FUMITO ISHIBASHIꢀ and EIJI TANIGUCHI$
ꢀFaculty of Fisheries\ Nagasaki University\ 0!03 Bunkyo!Machi\ Nagasaki\ 741\ Japan^ $Department of Agricultural
Chemistry\ Faculty of Agriculture\ Kyushu University\ Hakozaki 5!09!0\ Higashiku\ Fukuoka\ 701\ Japan
"Received 4 November 0886^ received in revised form 8 March 0887#
Key Word Index*Phryma leptostachya L[^ Phrymaceae^ insecticidal sesquilignan^ synthesis^
absolute con_guration^ "¦#!haedoxan A
Abstract*The insecticidal neolignan\ "¦#!haedoxan A\ was synthesized from "S#!"¦#!b!vinyl!g!butyrolactone
and
"1R\2R#!"¦#!5!formyl!6!methoxy!2!methoxymethyl!1!"2\3!methylenedioxyphenyl#!0\3!benzodioxane\
and its absolute con_guration was unequivocally established as 0S\1R\4R\5S\1ýR\2ýR[ Þ 0887 Elsevier Science
Ltd[ All rights reserved
INTRODUCTION
The herbaceous perennial plant Phryma leptostachya
L[ has been traditionally used as a natural insecticide
in Japan[ From the root extract of this plant\ various
lignans of the 2\6!dioxabicycloð2[2[9Łoctane "furo!
furan# type have been isolated ð0Ð3Ł[ Haedoxan A "0a#
is a representative member of the lignans of this plant
and is shown to exhibit signi_cant insecticidal activity
against various insect species ð4Ł[ The basic chemical
structure of 0a involving 0Sꢀ\1Rꢀ\4Rꢀ\5Sꢀ!relative
con_guration of the 2\6!dioxabicycloð2[2[9Łoctane
moiety and 1ý\2ý!trans relationship of the benzo!
dioxane moiety had been elucidated on the basis of
spectroscopic data and partial synthesis ð5Ł[ However\
its complete stereochemistry including absolute con!
_guration has not been established[ Herein\ we
describe the unambiguous synthesis of "¦#!0a from
chiral synthons of de_nite stereochemisty\ which
enable us to determine the absolute con_guration of
the natural product[
RESULTS AND DISCUSSION
Synthetic strate`y
The strategy for the synthesis of "¦#!0a is basically
the same as that for our previous synthesis of racemic
0a ð6Ł except for using optically active starting
materials and the method for introduction of the ary!
loxy group at C!1[ In the synthesis of the racemate\
ꢀ Author to whom correspondence should be addressed[
the 5a!aryl!0a!hydroxy!2\6!dioxabicycloð2[2[9Łoctane
502

503
F[ ISHIBASHI and E[ TANIGUCHI
Scheme 0
Scheme 1[ "a# "S#!"!#!naphthylethylamine\ 1!hydroxypyridine^ "b# KOH\ ethylene glycol^ "c# p!TsOH\ benzene^ "d# H1\ Pd:C\
EtOH^ "e# LiAIH3\ ether[
framework "4# was stereoselectively constructed from catalytic amount of 1!hydroxypyridine ð00Ł to give an
b!vinyl!g!butyrolactone "2# and the aromatic aldehyde oily mixture of the hydroxy amides "7a and 7b# in
3 "Scheme 0#[ However\ the _nal tin"II# chloride!silver 59) combined yield[ After separation of the mixture
perchlorate promoted acetalization ð7Ł of the ~uoride by medium!pressure liquid chromatography "MPLC#
5 with the phenol 13 gave an equimolar mixture of 1a! on silica gel\ each diastereomer was subjected to alka!
0a and its 1b!epimer 0b\ as well as their stereoisomers line hydrolysis "KOH\ ethyleneglycol\ 069># followed
formed by epimerization at C!5[ In the present by lactonization "p!TsOH\ benzene# to give the respec!
synthesis\ a PPTS catalyzed 1a!selective acetalization\ tive enantiomer of 2 with an enantiomeric excess "ee#
developed for the synthesis of "¦#!sesamolin ð8Ł\ was over 84) whose absolute con_gurations was deter!
successfully applied for the _nal acetalization of the mined by converting to the known diol 8 ð02Ł by sub!
lactol 6[
sequent reductions ð01Ł[
Another building block\ "1R\2R#! or "1S\2S#!6!for!
myl ! 5 ! methoxy ! 1 ! methoxymethyl ! 2 ! "2\3 !methyl!
enedioxyphenyl#!0\3!benzodioxane "3# was pre!
Preparation of the chiral synthons
Each enantiomer of b!vinyl!g!butyrolactone "2#\ pared through optical resolution of "2#!1!hyd!
was prepared from its racemate ð09Ł by optical res! roxymethyl!5!methoxy!2!"2\3!methylenedioxyphenyl#!
olution "Scheme 1#[ The racemate was reacted "049># 0\3!benzodioxane "09# "Scheme 2#[ The racemic
with "S#!"−#!naphthylethylamine in the presence of a alcohol ð03Ł was reacted with "S#!"−#!a!methylbenzyl

Synthesis and absolute con_guration of the insecticidal sesquilignan "¦#!haedoxan A
504
Scheme 2 "a# "S#!"!#!a!methylbenzyl isocyanate\ cat[ DMAP\ toluene\ 44>^ "b# Cl2SiH\ Et2N\ CH1Cl[1[
Scheme 3[
isocyanate ð04Ł "DMAP\ toluene\ 44># to quan! dominantly proceeded via a chelated intermediate "16#
titatively give a mixture of the carbamates "00a and to a}ord preferentially the threo!isomer 03a as an anti!
00b#[ Each diastereomer was separated by MPLC on Cram adduct\ whereas in a polar solvent such as Et1O!
silica gel followed by recrystallization[ Decar! THF the reaction favoured the Cram product\ ery!
bamoylation "Cl2SiH\ Et2N\ CH1Cl1# ð05Ł of 00a fur! thro!03b[ The threo!acetonide 03a quantitatively gave
nished "−#!09 in 65) yield\ whereas another dias! "0R\1R#!"−#!01 by methanolysis[
tereomer 00b gave "¦#!09 in 76) yield[
On ozonolysis "CH1Cl1\ −04>\ 0[4 h\ Et2N workup#
The absolute con_gurations of "¦#! and "−#!09 followed by alkaline hydrolysis "NaOH\ aq[ EtOH#\
were determined by converting them to the optically "−#!09 produced a levorotatory triol "−#!01 in 3)
active triols 01 and comparing their optical rotations yield with 83) recovery of "−#!09[ A similar ozon!
with that of "0R\1R#!"−#!01 which was unequivocally olysis "MeOH\ −04>\ 0[4 h\ Me1S workup\ then
prepared from D!mannitol[ The reference sample of NaOH\ aq[ EtOH# of diacetate of "¦#!09 gave a
the triol was prepared as shown in Scheme 3[ Addition dextrorotatory triol "¦#!01 in 5) yield "Scheme 4#[
of 0!lithio!2\3!methylenedioxybenzene "0!bromo!2\3! Consequently\ the absolute con_gurations of "¦#! and
methylenedioxybenzene\ t!BuLi\ −64>\ Et1O# to iso! "−#!09 were determined as 1S\2S and 1R\2R\ respec!
propylidene!D!glyceraldehyde "02# prepared from D! tively[
mannitol ð06Ł gave a mixture of the threo and erythro
The chiral building blocks\ "1R\2R#!3 or "1S\2S#!3
adducts in the ratio of 51:27 "based on HPLC# in were obtained by sequential methylation "MeI\ NaH\
22) combined yield[ In accord with the description THF!DMF# and formylation "Du} reaction# of
of Mulzer and Angermann ð07Ł\ this reaction pre! "1R\2R#!"−#!09 and "1S\2S#!"¦#!09\ respectively[

505
F[ ISHIBASHI and E[ TANIGUCHI
Scheme 4[ "a# O2\ CH1Cl1\ 04> then Et2N^ "b# NaOH\ aq[ EtOH^ "c# NaH\ Mel\ DMF^ "d# hexamethylenetetramine\ AcOH\
re~ux[
Scheme 5[ "a# LDA\ THF\ −64>^ "b# t!Bu"Me1#SiOTf\ 1\5!lutidine\ CH1Cl1\ −04>^ "c# LiAIH3\ THF\ −09>^ "d# OsO3\
NMO\ acetone!t!BuOH!H1O^ "e# NalO3\ MeOH\ 9>^ "f # Ag1CO2!Celite\ benzene\ re~ux^ "g# MsCl\ Et2N\ CH1Cl1 then DBU^
"h# TBAF\ THF\ 9>^ "i# cat[CSA\ CH1Cl1^ "j# i!Bu1AlH\ CH1Cl1\ −64>^ "k# cat[ PPTS\ benzene\ re~ux[
Synthesis of "¦#!haedoxan A
marolin I and would be also enantiotopically con!
structed from "S#!"¦#!2[ However\ it was not obvious
We have established the "0S\1R\4R\5S#!con_gura! which enantiomer of the aldehydes 3 would a}ord
tion of "¦#!phrymarolin I ð0Ł\ which is a lignan iso! "¦#!0a by combination with "S#!2 since the relative
lated from the same source as 0a\ on the basis of stereochemistry between the benzodioxane and diox!
synthesis of the natural "¦#!enantiomer from "S#! abicycloð2[2[9Łoctane moieties of 0a was unknown[
"¦#!2
ð01Ł[
This
suggested
that
the Thus\ a small quantity of each enantiomer of 3 was
dioxabicycloð2[2[9Łoctane moiety of "¦#!0a would preliminary condensed with "S#!"¦#!2[ As the result\
have the same absolute con_guration as that of phry! the silyl ethers of the aldol products of "S#!"¦#!2 and

Synthesis and absolute con_guration of the insecticidal sesquilignan "¦#!haedoxan A
506
"1R\2R#!"−#!3\ 06a and 06b\ were found to be the good agreement with those of the natural "¦#!0a
enantiomers of two of the four diastereomers derived "ðaŁD¦007[3>#[ In addition\ "¦#!haedoxan D "1a#\
from "2#!2 and "2#!3 which gave rise to racemic 0a[ similarly synthesized by the acetalization of 6 with 1!
Consequently\ it was suggested that combination of methoxy!3\4!methylenedioxyphenol\ exhibited insec!
"S#!"¦#!2 and "1R\2R#!"¦#!3 would be suitable for ticidal activity as high as natural "¦#!haedoxan D\
obtaining "¦#!0a[
whereas enantiomeric "−#!1a synthesized from "R#!
Thus\ the synthesis of "¦#!0a was commenced with 2 and "1S\2S#!3 was totally inactive "Table 0#[ The
the condensation between "S#!"¦#!2 and "1R\2R#! absolute con_guration of the natural "¦#!haedoxan
"−#!3 "LDA\ THF\ −64>#\ in which a\b!trans dis! A was thus established as 0S\1R\4R\5S\1ýR\2ýR on
ubstituted
butyrolactones
05a
and
05b the basis of the absolute con_guration of starting "¦#!
"05a:05bꢁ69:29\ based on NMR# were selectively 2 and "¦#!3\ and the a\b!trans stereoselectivity of the
produced due to steric hindrance of the b!vinyl group condensation between them[
of "S#!"¦#!2[ Their stereochemical features were read!
EXPERIMENTAL
ily assigned from the coupling constants according to
the criteria of Jthreo "5Ð8 Hz#×Jerythro "1Ð3 Hz# ð08Ł^ the
erythro isomer 05a displayed two double doublets at
d 4[37 "Ha\ Jabꢁ2\ Jadꢁ4 Hz# and d 2[94 "Hb\ Jabꢁ2\
Jbcꢁ09 Hz#\ whereas the threo isomer 04b showed a
doublet and a double doublet at d 4[00 "Ha\ Jabꢁ6 Hz#
and d 1[37 "Hb\ Jabꢁ6\ Jbcꢁ09 Hz#\ respectively[ The
mixture of the aldol adducts was silylated ðt!Bu"Me#1
SiOTf\ 1\5!lutidine ð19Ł\ CH1Cl1\ −04>\ 79)Ł and the
diastereomers were separated by chromatography on
silica gel[ The separation was not always necessary for
the synthesis since both diastereomers furnished the
same intermediate "4# at a succeeding synthetic step[
On reduction "LiAlH3\ Et1O!THF\ −09># followed by
aqueous workup\ the erythro isomer 06a gave the diol
07 in 80) yield[ The vinyl group of 07 was then
oxidized to carbonyl functionality by successive treat!
ment with OsO3 and N!methylmorpholine N!oxide
"NMO# "Me1CO!t!BuOH!H1O# ð10Ł\ followed by
NaIO3 "aq[ MeOH#\ and _nally Ag1CO2!Celite "ben!
zene\ re~ux# ð11Ł to give the hydroxy!lactone 19 in
73) overall yield for the three steps[ The alcohol
19 was dehydrated by sequential mesylation "MsCl\
Et2N\ benzene# and desulfonation "DBU#\ giving the
methylene lactone 10 in 77) yield[ Stereoselective
glycolization "OsO3!NMO\ Me1CO!t!BuOH!H1O#
from the less hindered a!face of 10 gave the "2S\3R#!
glycol 11 in quantitative yield[ Desilylation of 11 "n!
Bu3NF ð12Ł\ THF\ 9>\ 71)# and subsequent dehy!
drative cyclization of the resulting triol 12 ðcat[ 09!
camphorsulfonic acid "CSA#\ CH1Cl1Ł furnished "¦#!
"0S\4R\5S\1?R\2?R#!perhydrofurofuranone 4 in 65)
yield as a sole product[ This key intermediary lactone
was also obtained from the threo!isomer 06b by the
same procedure as from erythro!06a[ Reduction of 4
"i!Bu1AlH\ CH1Cl1\ −64># produced the lactol 6 in
78) yield[ Finally\ the lactol 6 was reacted with the
phenol 13 in the presence of a catalytic amount of
pyridinium p!toluenesulfonate "PPTS# ð8Ł in re~uxing
benzene under an azeotropic removal of the water to
selectively produce 1a!isomer 0a in 27) yield along
with the dimeric compound 14[ In the acetalization
reaction\ epimerization at the C!5 and C!2? position
was totally exclusive[
0
Mps are uncorr[ Unless stated otherwise H NMR
spectra were measured in CDCl2 at 099 MHz[ J values
are in Hz[ Gravity CC and medium!pressure liquid
chromatography "MPLC# used Merck silica gel 59
"69Ð129 mesh ASTM# and Merck Lichroprep Si 59
"39Ð52 mm#\ respectively[ Prep[ TLC was performed
on precoated silica gel plates 59 F143\ 9[4 mm thickness
supplied by E[ Merck[
Optical resolution of b!vinyl!g!butyrolactone "2#[
A mixture of "2#!2 "4[49 g\ 33[5 mmol#\ "S#!"−#!
naphthylethylamine "6[49 g\ 32[7 mmol# and 1!hyd!
roxypyridine "9[51 g\ 5[5 mmol# was heated at 049> for
09 hr[ The mixture was then cooled to room temp\
diluted with EtOAc\ washed with water\ dried
"Na1SO3#\ and concd[ MPLC ðEtOAc!n!hexane!i!
PrOH "04]4]0#Ł gave 2[47 g of 7a "01[4 mmol# and
2[82 g of 7b "02[8 mmol# in 59) combined yield[ 7a]
mp 007Ð019>^ ðaŁ1D9−76[2> "CHCl2^ c 0[9#[ 7b] mp 005Ð
007>^ ðaŁ1D9−38[9> "CHCl2^ c 0[9#[ An analytically pure
sample was obtained by recrystallization from i!Pr1O!
benzene[ Anal[ Calcd for C07H10NO1] C\ 65[29^ H\
6[36^ N\ 3[83[ Found] C\ 65[15^ H\ 6[33^ N\ 3[75)[
A soln of 7a "2[47 g\ 01[4 mmol# and KOH "0[01 g\
19[9 mmol# in ethylene glycol "19 ml# was heated at
054> for 09 hr[ The mixture was then cooled to room
temp\ acidi_ed with 1 M HCl "19 ml#\ diluted with
brine\ extracted 2 times with EtOAc\ dried "Na1SO3#\
and concd[ The crude product was dissolved in ben!
zene "49 ml# containing a catalytic amount "ca 09 mg#
of p!TsOH[ The resulting soln was heated under re~ux
with azeotropic removal of water for 09 min[ The mix!
ture was then cooled to room temp and concd[ Silica
gel CC ðn!hexane!ether "0]0#Ł gave crude "¦#!2\ which
upon distillation with micro!Kugelrohr gave 9[70 g of
"S#!"¦#!2 "6[1 mmol\ 47)# as a colorless oil] bp 059>
"oven temp#:19 mmHg^ ðaŁ0D8¦5[9> "EtOH^ c 0[57#[
In the same manner as above\ the amide 7b gave
"R#!"−#!2 in 53) yield] ðaŁ0D8−4[5> "EtOH^ c 0[59#[
Optical resolution of "2#!1!hydroxymethyl!5!
methoxy!2!"2?\3?!methylenedioxyphenyl#!1\2!dihydro!
0\3!benzodioxine "09#
Both the 0H NMR spectral data\ as well as the sign
and magnitude of the optical rotation of synthetic
A soln of alcohol 09 "4[81 g\ 05[6 mmol#\ "S#!"−#!
"0S\1R\4R\5S\1ýR\2ýR#!0a "ðaŁD¦003[9># were in a!methylbenzyl isocyanate "2[99 g\ 19[3 mmol# and

507
F[ ISHIBASHI and E[ TANIGUCHI
Table 0[ Insecticidal activity of "¦#!\ "2#!\ and "−#!haedoxan D against
Musca domestica ðmortality ")#Ł[ꢀ
dose "ng:~y#
LD49
09
6[4
4
1[4
"ng:~y#
"¦#!1a
"2#!1a
"−#!1a
89
89
9
Ð
39
9
49
19
9
19
Ð
Ð
3[5
6[1
ꢀEach compound was topically applied to adult female house~ies as a
solution of acetone with piperonyl butoxide "4 mg:~y#[ The insecticidal
activity was evaluated as the mortality after 13 hr at 16>[
DMAP "099 mg# in dry toluene "49 ml# was heated mixture was then diluted with EtOAc\ washed with
at 44>C for 06 hr[ After cooling to room temp\ the 4) aq[ NaHCO2\ dried "Na1SO3#\ and concd[ Silica
crystalline amides were collected by _ltration[ The gel CC ðn!hexane!EtOAc "0]0#Ł gave ca 099 mg of
_ltrate was concd and the residue was chro! crude oxidized products with 83) recovery of "−#!
matographed ðbenzene!EtOAc "84]4#Ł to give a second 09[ The products showed one major "Rf 9[06# and
crop of the carbamates[ The two diastereomers\ 00a three minor spots "Rf 9[11\ 9[03 and 9[98# on TLC ðn!
and 00b\ were separated by MPLC ðbenzene!EtOAc hexane!EtOAc "0]0#Ł\ and the former was char!
"84]4#Ł[ 00a] yield 2[81 g\ 7[36 mmol\ 40)\ mp 054Ð acterized as diester 15] 0H NMR] d 0[06Ð0[07 "0H\ br\
055>^ ðaŁ2D1−37[0> "CHCl2^ c 0[93#[ 00b] yield 2[53 g\ OH#\ 2[26Ð2[89 "1H\ m\ CH1OH#\ 2[54 "2H\ s\ OCH2#\
6[75 mmol\ 36)\ mp 053Ð054>C^ ðaŁ2D1−0[6> "c 0[10\ 4[96 "0H\ m\ ÐCHOC1O#\ 4[13 "0H\ s\ MeOÐ
CHCl2
max
CHCl2#^ IRn
cm−0] 0937\ 0044\ 0089Ð0144 "br#\ C1CHÐCO1#\ 4[85 "1H\ s\ OCH1O#\ 5[95 "0H\ d\
0334\ 0449 "br#\ 0591\ 0639\ 2349 "br#^ MS] m:z 352 Jꢁ09\ ArÐCH#\ 5[06 "0H\ d\ Jꢁ01\ CH1CHÐCO1#\
"M¦#\ 205\ 067\ 059\ 049\ 036\ 024\ 021 "base#\ 011\ 5[25 "0H\ d\ Jꢁ01\ ÐCH1CHÐCO1#\ 6[58Ð6[87 "2H\
094\ 66[ Anal[ Calcd for C15H14O6N] C\ 56[27^ H\ 4[33^ m\ ArÐH|s#[
N\ 2[91[ Found] C\ 56[91^ H\ 4[39^ N\ 1[84[
A soln of the crude products in a mixture of EtOH
A soln of 00a "2[81 g\ 7[36 mmol#\ Cl2SiH "0[00 ml\ "4 ml# and 0 M NaOH "0[7 ml\ 0[7 mmol# was stirred
00[90 mmol# and Et2N "0[66 ml\ 01[60 mmol# in dry at room temp for 2 hr[ The soln was then concd and
CH1Cl1 "79 ml# was stirred at room temp for 2 hr[ The the residue was extracted with EtOAc\ washed with
mixture was then poured into 09) aq[ NH3Cl and brine\ dried "Na1SO3#\ and concd[ Puri_cation by
_ltered through a pad of Celite with the aid of CH1Cl1[ prep[ TLC "EtOAc# gave 06 mg of "0R\1R#!"−#!01
The CH1Cl1 layer was separated and the aq[ layer was "9[97 mmol# in 3) overall yield from "−#!09]
extracted with CH1Cl1[ The combined CH1Cl1 extracts ðaŁ1D4−20[9> "CHCl^ c 0[9#[ Triacetate of "−#!01]
0
were dried "Na1SO3# and concd[ Recrystallization ðaŁ1D4−28[9> "CHCl2^ c 0[9#^ H NMR] d 1[95 "5H\ s\
"benzene# gave 0[49 g of "−#!09] mp 88Ð099>^ Ac|s#\ 1[96 "2H\ s\ Ac#\ 2[65 "0H\ dd\ Jꢁ5\ 01\ H!2#\
ðaŁ2D9−18[2> "CHCl2^ c 9[64#[ Silica gel CC of the con! 3[12 "0H\ dd\ Jꢁ3\ 1\ H!2#\ 4[23 "0H\ m\ H!1#\ 4[72
centrate of the mother liquor ðbenzene!EtOAc "84]4#Ł "0H\ d\ Jꢁ7\ H!0#\ 4[82 "1H\ s\ OCH1O#\ 5[53Ð5[77
gave a second crop of "−#!09 "9[42 g#[
"2H\ m\ ArÐH|s#[
In the same manner as above\ 00b a}orded "¦#!09
In a similar manner as above\ "¦#!09!acetate
in 76) yield] mp 099Ð090>^ ðaŁ2D9¦25[3> "CHCl2^ c "9[35 g\ 0[17 mmol# a}orded 06 mg of "0S\1S#!01
9[77#[
"9[97 mmol# in 5) overall yield] ðaŁ1D4¦23[9> "CHCl2^
c 0[9#[
De`radation of "¦#:"−#!5!methoxy!1!methoxy
methyl!2!"2?\3?!methylenedioxyphenyl#!1\2!dihydro!
"1R\2R#!0\1\2!Trihydroxy!2!"2?\3?!methyl!
0\3!benzodioxine to "¦#:"−#!0\1\2!trihydroxy!0!"2?\3?! enedioxyphenyl#butane 0\1!O!isopropylideneketal
methylenedioxyphenyl#propane ð"¦#:"−#!09 to "¦#: "03a#
"−#!01Ł
A 0[37 M n!pentane soln of t!BuLi "5[75 ml\
A CH1Cl1 "19 ml# soln of "−#!09 "9[51 g\ 0[85 mmol# 09[05 mmol# was dropwise added via a syringe to a
was subjected to ozonolysis by bubbling O2 "ca[ soln of 3!bromo!0\1!methylenedioxybenzene "0[07 g\
4[7 mmol#:O1 for 01 min at −04>[ After the remaining 4[74 mmol# in dry ether "19 ml# with keeping the temp
O2 had been removed by air bubbling\ Et2N "9[44 ml\ between −59 and −69> under Ar[ The resulting soln
2[81 mmol# was added and the reaction mixture was was stirred at −64> for 19 min and treated dropwise
gradually warmed up to room temp over 0[4 hr[ The with a soln of isopropylidene!D!glyceraldehyde ð03Ł

Synthesis and absolute con_guration of the insecticidal sesquilignan "¦#!haedoxan A
508
"02\ 9[29 g\ 1[43 mmol# in dry ether "04 ml#[ After "1S\2S# and "1R\2R#!5!Formyl!6!methoxy!2!methoxy!
29 min at −64>\ the reaction was quenched by methyl!1!"2?\3?!methylenedioxyphenyl#!1\2!dihydro!
addition of 09) aq[ NH3Cl "29 ml# and the mixture 0\3!benzodioxines "3#
was allowed to warm up to room temp[ The organic
A soln of "1R\2R#!"−#!04 "9[69 g\ 1[01 mmol# and
layer was separated\ washed with 4) aq[ NaHCO2\
hexamethylenetetramine "9[34 g\ 2[07 mmol# in AcOH
dried "Na1SO3#\ and concd[ Silica gel CC ðn!hexane!
"04 ml# was heated under re~ux for 09 hr[ The mixture
EtOAc "2]0#Ł gave 9[10 g of a diastereomeric mixture
was then cooled to room temp\ poured into water\ and
of 03a and 03b "9[72 mmol\ 22)#\ which were sep!
concd[ The residue was taken up in EtOAc\ washed
arated by MPLC ðn!hexane!EtOAc "1]0#Ł[ The ratio of
successively with water and 4) NaHCO2\ dried
03a]03b was determined to be 51]27 by HPLC analysis
"Na1SO3#\ and concd[ Silica gel CC ðn!hexane!EtOAc
ðZorbax!SIL column "14 cm×3[5 mm#^ pressure\
"2]0#Ł gave 9[34 g of "1R\2R#!3 "0[15 mmol\ 48)# as a
79 kg:cm1^ ~ow rate\ 0 ml:min^ detection 175 nm^
0
viscous oil] ðaŁ1D9¦17[2> "CHCl2^ c 9[81#^ H NMR] d
solvent\ n!hexane!EtOAc "1]0#Ł[ "1R\2R#!03a]
2[17 "0H\ dd\ Jꢁ00\ 4\ H!0#\ 2[22 "2H\ s\ OCH2#\ 2[59
0
ðaŁ1D4−01[4> "EtOH^ c 0[57#^ H NMR] d 0[24 "2H\ s\
"0H\ dd\ Jꢁ00\ 2\ H!0#\ 2[70 "2H\ s\ ArOCH2#\ 2[85
CH2#\ 0[34 "2H\ s\ CH2#\ 1[97Ð1[59 "0H\ br\ OH#\ 2[68
"0H\ m\ H!1#\ 4[95 "0H\ d\ Jꢁ7\ H!2#\ 4[87 "1H\ s\
"0H\ dd\ Jꢁ6\ 8\ H!0#\ 2[83 "0H\ t\ Jꢁ8\ H!0#\ 3[96Ð
OCH1O#\ 5[40 "0H\ s\ H!4#\ 5[74 "2H\ s\ ArÐH|s#\ 6[34
3[20 "0H\ m\ H!1#\ 3[62 "0H\ d\ Jꢁ4\ H!2#\ 4[80 "1H\
CHCl2
"0H\ s\ H!7#\ 09[11 "0H\ s\ CHO#^ IRn
cm−0]0919\
max
s\ OCH1O#\ 5[52Ð5[77 "2H\ m\ ArÐH|s#[ "1R\2S#!03b]
0017\ 0134\ 0297\ 0384\ 0489\ 0519\ 0564[ "1S\2S#!3]
mp 049Ð040>^ ðaŁ1D9−20[8> "CHCl2^ c 0[02#[ Anal[
Found] C\ 52[21^ H\ 4[00[ Calcd for C08H07O6] C\
52[57^ H\ 4[95)[
0
ðaŁ1D4−4[2> "EtOH^ c 0[40#^ H NMR] d 0[27 "2H\ s\
CH2#\ 0[37 "2H\ s\ CH2#\ 1[13Ð1[79 "0H\ br\ OH#\ 2[42Ð
2[78 "1H\ m\ H!0#\ 3[99Ð3[17 "0H\ m\ H!1#\ 3[33 "0H\
d\ Jꢁ7\ H!2#\ 4[81 "1H\ s\ OCH1O#\ 5[52Ð5[82 "2H\
m\ ArÐH|s#[
"2R\3S\0?R:S\1ýR\2?R#!3!Ethenyl!2!ð0?!hydroxy!0?!
ð6ý!methoxy!2ý!methoxymethyl!1ý!"21\31!
methylenedioxyphenyl#!1ý\2ý!dihydro!0ý\3ý!
benzodioxin!5ý!ylŁmethylŁdihydro!1"2H#!furanones
"05a and 05b#
"0R\1R#!0\1\2!Trihydroxy!0!"2?\3?!
methylenedioxyphenyl#propane "01#
"1R\2R#!03a was treated with a catalytic amount of
p!TsOH in MeOH at room temp to give "0R\1R#!01
after puri_cation by prep[ TLC "EtOAc#[ "0R\1R#!01]
colorless oil^ ðaŁ1D4−17[9> "CHCl2^ c 0[9#[ Triacetate of
"0R\1R#!01] colorless oil^ ðaŁ1D4−26[2> "CHCl2^ c 9[72#[
To a cooled "−67># soln of LDA ðprepared from n!
BuLi "04 wt) in n!hexane\ 0[24 ml\ 1[07 mmol# and
diisopropylamine "9[20 ml\ 1[07 mmol# at −09> for
04 min in dry THF "01 ml#Ł was added dropwise a soln
of "S#!"¦#!2 "9[13 g\ 1[07 mmol# in dry THF "2 ml#
under Ar[ The resulting orange soln was stirred at
−64> for 29 min\ at which time a soln of "1R\2R#!"¦#!
3 "9[41 g\ 0[34 mmol# in dry THF "4 ml# was dropwise
added[ The soln was stirred at −64> for 2 hr before
being quenched with 09) aq[ NH3Cl "19 ml#[ After
being warmed to room temp\ the mixture was
extracted twice with a 0]0 mixture of ether and EtOAc
"29 ml#[ The combined organic layers were washed
with 4) aq[ NaHCO2\ dried "Na1SO3#\ and concd[
Silica gel CC ðbenzene!EtOAc "8]0#Ł gave 9[14 g of a
diastereomeric mixture of aldols\ 05a and 05b\
"1S\2S# and "1R\2R#!5!Methoxy!1!methoxymethyl!2!
"2?\3?!methylenedioxyphenyl#!1\2!dihydro!0\3!
benzodioxines "04#
To a stirred slurry of NaH "9[13 g\ 5[99 mmol 59)
in oil#\ washed free of oil with dry petrol\ in dry DMF
"09 ml# was added dropwise a soln of "1S\2S#!"¦#!09
"0[48 g\ 4[92 mmol# in dry THF "09 ml# at −09> and
the soln was stirred at room temp for 29 min[ To this
MeI "9[51 ml\ 09[9 mmol# was dropwise added and
stirred for another 1 hr[ The reaction was then quen!
ched by addition of 09) aq[ NH3Cl\ extracted with
EtOAc\ dried "Na1SO3#\ and concd[ Silica gel CC ðn!
hexane!EtOAc "2]0#Ł gave 0[47 g of "1S\2S#!04
"3[68 mmol\ 84)# as white crystals] mp 040Ð042>^
"0[00 mmol\ 66)# as
a pale yellow powder]
CHCl2
IRn
cm−0] 2249\ 0659\ 0590\ 0499\ 0334\ 0059\
max
0954\ 0919^ MS] m:z 369 "M¦#\ 248\ 247\ 216\ 215\
081\ 050\ 059 "base#\ 020\ 092\ 43[ Anal[ Calcd for
C14H15O2] C\ 52[72^ H\ 4[42[ Found] C\ 52[66^ H\
4[45)[
0
ðaŁ1D0¦17[5> "CHCl2^ c 9[52#^ H NMR] d 2[16 "0H\
dd\ Jꢁ09\ 4\ H!0#\ 2[21 "2H\ s\ OCH2#\ 2[44 "0H\ dd\
Jꢁ09\ 2\ H!0#\ 2[60 "2H\ s\ ArOCH2#\ 2[85 "0H\ m\
H!1#\ 3[84 "0H\ d\ Jꢁ7\ H!2#\ 4[85 "1H\ s\ OCH1O#\
5[29Ð5[42 "1H\ m\ ArÐH|s#\ 5[69Ð6[99 "3H\ m\ ArÐ
H|s#^ IRnKmaBxrcm−0] 0494\ 0389\ 0164\ 0149\ 0134\ 0014\
0929^ MS] m:z 229 "M¦\ base#\ 188\ 147\ 082\ 050\
021\ 092[ "1R\2R#!04] ðaŁ1D0−14[5> "CHCl2^ c 9[32#[
Anal[ Found] C\ 54[22^ H\ 4[40[ Calcd for C07H07O5]
C\ 54[34^ H\ 4[34)[
"2R\3S\0?S:R\1ýR\2ýR#!2!ð0?!ð"t!
Butyldimethylsilyl#oxyŁ!0?!ð6ý!methoxy!2ý!
methoxymethyl!1ý!"21\31!methylenedioxyphenyl#!
1ý\2ý!dihydro!0ý\3ý!benzodioxin!5ý!ylŁmethylŁ!3!
ethenyldihydro!1"2H#!furanones "06a and 06b#
To a cooled "−04># soln of the mixture of 05a
and 05b "9[55 g\ 0[39 mmol# and 1\5!lutidine "9[25 ml\

519
F[ ISHIBASHI and E[ TANIGUCHI
2[97 mmol# in dry CH1Cl1 "04 ml# was added dropwise 1ý#\ 4[61Ð5[02 "0H\ m\ CH1CH1#\ 5[90 "1H\ s\
t!BuMe1SiOTf "9[49 ml\ 1[07 mmol# in CH1Cl1 "2 ml# OCH1O#\ 5[49 "0H\ s\ H!7ý#\ 5[73Ð5[86 "2H\ m\ ArÐ
under Ar[ The resulting soln was stirred at −04> for H|s#\ 6[99 "0H\ s\ H!4ý#[ Anal[ Calcd for C20H33O8Si]
0 hr\ at which time the reaction was quenched by C\ 52[13^ H\ 6[42[ Found] C\ 51[70^ H\ 6[46)[
addition of 4) aq[ NaHCO2[ The mixture was then
extracted with ether "49 ml#\ subsequently washed
"1R\2R\0?S\1ýR\2ýR#!3!0?!ð"t!Butyldimethylsilyl#oxyŁ!
with 19) aq[ Cu"NO2#1 "04 ml×1# and 4) aq[
0?!ð6ý!methoxy!2ý!methoxymethyl!1ý!"21\31!
NaHCO2 "19 ml#\ dried "Na1SO3#\ and concd[ MPLC
methylenedioxyphenyl#!1ý\2ý!dihydro!0ý\3ý!
ðbenzene!EtOAc "84]4#Ł _rst a}orded 9[34 g of 06a
benzodioxin!5ý!ylŁmethylŁ!2!hydroxymethyldihydro!
"9[66 mmol\ 44)#\ followed by 9[23 g of 06b
1"2H#!furanone "19#
"9[23 mmol\ 13)# in order of elution[ Erythro!06a]
0
mp 038Ð049>^ H NMR] d −9[97 "2H\ s\ SiÐCH2#\
A soln of 07 "9[44 g\ 9[83 mmol#\ N!methyl!
9[96 "2H\ s\ SiÐCH2#\ 9[89 "8H\ s\ SiC"CH2#2#\ 1[73 morpholine N!oxide monohydrate "NMO# "9[04 g\
"0H\ dd\ Jꢁ6\ 2\ H!2#\ 2[96Ð2[26 "1H\ m\ H!3 and 9[83 mmol# and 1) aq[ OsO3 "9[4 ml# in a mixture of
CHOMe#\ 2[29 "2H\ s\ OCH2#\ 2[50 "0H\ dd\ Jꢁ00\ 2\ acetone "7 ml#\ t!BuOH "1 ml# and water "1 ml# was
CHOMe#\ 2[58 "2H\ s\ ArOCH2#\ 2[71Ð3[92 "1H\ m\ stirred at room temp for 04 hr under Ar\ at which
H!4 and H!2ý#\ 3[26 "0H\ t\ Jꢁ7\ H!4#\ 3[41Ð3[70 "1H\ time the reaction was quenched by additions of Celite
m\ CH1CH1#\ 3[85 "0H\ d\ Jꢁ7\ H!1ý#\ 4[04Ð4[36 "9[4 g# followed by 09) aq[ NaHSO2 "0 ml#[ The
"0H\ m\ ÐCH1CH1#\ 4[42 "0H\ d\ Jꢁ1\ H!0?#\ 4[85 resulting mixture was _ltered with the aid of acetone
"1H\ s\ OCH1O#\ 5[30 "0H\ s\ H!7ý#\ 5[68Ð5[78 "2H\ m\ and the _ltrate was concd under reduced pressure[
CHCl2
max
ArÐH|s#\ 6[96 "0H\ s\ H!4ý#^ IRn
cm−0] 2249\ 0659\ The oily residue was taken up in EtOAc "29 ml#\
0590\ 0499\ 0334\ 0059\ 0954\ 0910[ Anal[ Calcd for washed with brine "19 ml#\ dried "Na1SO3#\ and evap!
C20H39O8Si] C\ 52[57^ H\ 5[81[ Found] C\ 52[60^ H\ orated to give 9[52 g of crude tetraol as an oil[
5[81)[ Threo!06b] a white powder^ 0H NMR] d −9[95
The crude tetraol was dissolved in MeOH "7 ml#
"2H\ s\ SiÐCH2#\ 9[01 "2H\ s\ SiÐCH2#\ 9[82 "8H\ s\ and cooled to 9>[ To this was added dropwise a soln
SiC"CH2#2#\ 1[69 "0H\ dd\ Jꢁ3\ 7\ H!2#\ 2[99 "0H\ of NaIO3 "9[19 g\ 9[83 mmol# in water "1 ml# and the
deformed t\ Jꢁ6\ H!3#\ 2[15 "0H\ dd\ Jꢁ3\ 00\ resulting soln was stirred at 9> for 19 min\ at which
CHOMe#\ 2[21 "2H\ s\ OCH2#\ 2[52 "0H\ dd\ Jꢁ2\ 00\ time the reaction was quenched with 4) aq[ Na1SO2
CHOMe#\ 2[56 "2H\ s\ ArOCH2#\ 2[57Ð3[03 "2H\ m\ "09 ml#[ After almost of the MeOH had been removed
H!4 and H!2ý#\ 3[86 "0H\ d\ Jꢁ7\ H!1ý#\ 3[73Ð4[13 under reduced pressure\ the residue was extracted
"1H\ m\ CH1CH1#\ 4[18 "0H\ d\ Jꢁ2\ H!0?#\ 4[49Ð twice with EtOAc "19 ml#\ washed with brine "04 ml#\
4[81 "0H\ m\ ÐCH1CH1#\ 4[85 "1H\ s\ OCH1O#\ 5[30 dried "Na1SO3#\ and concd[ Silica gel CC "EtOAc#
"0H\ s\ H!7ý#\ 5[61Ð5[85 "2H\ m\ ArÐH|s#\ 6[08 "0H\ s\ gave 9[44 g of crude lactol 08 as an oil[
H!4ý#[
A mixture of the crude lactol 08 and Ag1CO2 on
Celite "0[49 g\ containing ca 0[49 mmol of Ag1CO2# in
benzene "19 ml# was heated under re~ux for 29 min[
The mixture was then cooled to room temp and
_ltered[ The residue was washed well with benzene
and the _ltrate was concd[ Silica gel CC ðn!hexane!
"1R\2R\0?S\1ýR\2ýR#!1!ð0?!ð"t!
Butyldimethylsilyl#oxyŁ!0?!ð6ý!methoxy!2ý!
methoxymethyl!1ý!"21\31!methylenedioxyphenyl#!
1ý\2ý!dihydro!0ý\3ý!benzodioxin!5ý!ylŁmethylŁ!2!
ethenyl!0\3!butanediol "07#
EtOAc "1]0#Ł gave 9[35 g of 19 "9[67 mmol\ 73)# as a
CHCl2
white powder] IRn
cm−0] 724\ 0956\ 0149\ 0209\
max
To a stirred slurry of LiAlH3 "9[94 g\ 0[21 mmol# in 0499\ 0591\ 0691\ 2099Ð2599^ 0H NMR] d −9[15 "2H\
dry ether "04 ml# was added dropwise a soln of 06a s\ SiÐCH2#\ 9[97 "2H\ s\ SiÐCH2#\ 9[78 "8H\ s\ SiÐ
"9[51 g\ 0[95 mmol# in dry THF "4 ml# at −09> under C"CH2#2#\ 1[59Ð2[01 "2H\ m\ H!2\ H!3\ OH#\ 2[12 "0H\
Ar[ The resulting soln was stirred at −09> for 34 min dd\ Jꢁ00\ 3\ CHOMe#\ 2[22 "2H\ s\ OCH2#\ 2[51 "0H\
and the excess reagent was decomposed by careful dd\ Jꢁ00\ 2\ CHOMe#\ 2[61 "2H\ s\ ArOCH2#\ 2[67Ð
addition of EtOAc "09 ml# followed by 09) aq[ citric 3[15 "4H\ m\ H!4|s\ CH1OH\ H!2ý#\ 3[87 "0H\ d\ Jꢁ7\
acid "49 ml#[ The organic layer was separated and H!0?#\ 4[10 "0H\ d\ Jꢁ6\ H!1ý#\ 4[87 "1H\ s\ OCH1O#\
the aq[ layer was extracted with ether "49 ml#[ The 5[34 "0H\ s\ H!7ý#\ 5[63Ð5[89 "2H\ m\ ArÐH|s#\ 5[88
combined organic extracts were washed with 4) aq[ "0H\ s\ H!4ý#[ Anal[ Calcd for C29H39O09Si] C\ 50[10^
NaHCO2 "19 ml#\ dried "Na1SO3#\ and concd[ Silica H\ 5[74[ Found] C\ 50[93^ H\ 5[67)[
gel CC ðn!hexane!EtOAc "0]0#Ł gave 9[46 g of 07
CHCl2
max
"9[86 mmol\ 80)# as a viscous oil] IRn
cm−0
]
"3R\0?S\1ýR\2ýR#!3!0?!ð"t!Butyldimethylsilyl#oxyŁ!0?!
ð6ý!methoxy!2ý!methoxymethyl!1ý!"21\31!
methylenedioxyphenyl#!1ý\2ý!dihydro!0ý\3ý!
benzodioxin!5ý!ylŁmethylŁ!2!methylenedihydro!1"2H#!
furanone "10#
2899\ 1849\ 0591\ 0491\ 0334\ 0144\ 0086\ 0044\ 0957\
0932^ 0H NMR "acetone!d5#] d −9[07 "2H\ s\ SiÐCH2#\
9[00 "2H\ s\ SiÐCH2#\ 9[81 "8H\ s\ SiÐC"CH2#2#\ 1[37Ð
1[64 "1H\ m\ OH|s#\ 2[14 "2H\ s\ OCH2#\ 2[15 "0H\ dd\
Jꢁ01\ 3\ CHOMe#\ 2[39Ð2[87 "6H\ m\ CH1OH×1\
H!1\ H!2\ CHOMe#\ 2[87Ð3[06 "0H\ m\ H!2ý#\ 3[71Ð
Methanesulfonyl chloride "9[974 ml\ 0[09 mmol#
4[09 "2H\ m\ CH1CH1\ H!0?#\ 4[24 "0H\ d\ Jꢁ5\ H! was added to a cooled "9># soln of 19 "9[32 g\

Synthesis and absolute con_guration of the insecticidal sesquilignan "¦#!haedoxan A
510
9[62 mmol# and Et2N "9[19 ml\ 0[32 mmol# in dry ben! stirred at 9> for 1 hr\ at which time the reaction was
zene "5 ml#[ The resulting soln was stirred at room quenched by addition of 09) aq[ NH3Cl "19 ml#[ The
temp for 1[4 hr\ at which time DBU "9[08 g\ mixture was extracted twice with EtOAc "29 ml#\ dried
0[14 mmol# was added[ The mixture was stirred at "Na1SO3#\ and concd[ Silica gel CC ðEtOAc!THF
room temp for 29 min\ diluted with ether "29 ml#\ "1]0#Ł gave 9[57 g of triol 12 "0[28 mmol\ 71)# as a
washed successively with 09) aq[ NH3Cl and 4) aq[ white powder[
NaHCO2\ dried "Na1SO3#\ and concd[ Silica gel CC
The triol was dissolved in dry CH1Cl1 "29 ml# con!
ðbenzene!EtOAc "8]0#Ł gave 9[251 g of 10 "9[53 mmol\ taining CSA "29 mg# and allowed to stand at room
0
77)# as white crystals] mp 043Ð046>^ H NMR] d temp for 07 hr[ The reaction was quenched by addition
−9[07 "2H\ s\ SiÐCH2#\ 9[92 "2H\ s\ SiÐCH2#\ 9[77 of one drop of Et2N and the mixture was concd[ Silica
"8H\ s\ SiÐC"CH2#2#\ 2[97Ð2[25 "1H\ m\ CHOMe\ H! gel CC ðn!hexane!EtOAc "0]1#Ł gave 9[49 g of lactone
3#\ 2[22 "2H\ s\ OCH2#\ 2[51 "0H\ dd\ Jꢁ2\ 01\ 4 "0[95 mmol\ 65)# as white crystals] mp 068Ð079>^
CHOMe#\ 2[62 "2H\ s\ ArOCH2#\ 2[76Ð3[21 "2H\ m\ ðaŁ0D5¦18[5> "CHCl2^ c 9[70#^ 0H NMR] d 1[87 "0H\ s\
H!4 and H!2ý#\ 4[99 "0H\ d\ Jꢁ6\ H!1ý#\ 4[95 "0H\ d\ OH#\ 2[01 "0H\ m\ H!4#\ 2[16 "0H\ dd\ Jꢁ4\ 00\
Jꢁ5\ H!0?#\ 4[24 "0H\ br s\ C1CH1 endo#\ 4[87 "1H\ CHOMe#\ 2[22 "2H\ s\ OCH2#\ 2[47 "0H\ dd\ Jꢁ2\ 00\
s\ OCH1O#\ 5[12 "0H\ br s\ C1CH1 exo#\ 5[34 "0H\ s\ CHOMe#\ 2[62 "2H\ s\ ArOCH2#\ 2[86 "0H\ m\ H!2?#\
H!7ý#\ 5[65Ð5[81 "2H\ m\ ArÐH#\ 5[86 "0H\ s\ H!4ý#^ 3[07 "1H\ s\ H!7|s#\ 3[23 "0H\ dd\ Jꢁ5\ 00\ H!3b#\ 3[54
CHCl2
max
IRn
cm−0] 1849\ 0644\ 0599\ 0493\ 0382\ 0354\ "0H\ dd\ Jꢁ8\ 09\ H!3a#\ 3[86 "0H\ d\ Jꢁ7\ H!1?#\
0337\ 0298\ 0142\ 0084\ 0052\ 0010\ 0984\ 0956\ 0928\ 4[09 "0H\ d\ Jꢁ4\ H!5#\ 4[86 "1H\ s\ OCH1O#\ 5[38
746\ 726[ Anal[ Calcd for C29H27O8Si] C\ 52[03^ H\ "0H\ s\ H!7?#\ 5[61Ð5[81 "2H\ m\ ArÐH|s#\ 6[03 "0H\ s\
CHCl2
max
5[60[ Found] C\ 51[71^ H\ 5[69)[
H!4?#^ IRn
cm−0] 2399\ 0666\ 0590\ 0491\ 0384\
0358\ 0349\ 0224\ 0144\ 0199\ 0069\ 0014\ 0962\ 0931\
0194^ MS] m:z 361 "M¦#\ 081 "base#\ 051\ 050\ 059\
024\ 020\ 092[ Anal[ Calcd for C13H13O09] C\ 50[91^ H\
4[97[ Found] C\ 59[88^ H\ 4[06)[
"2S\3R\0?S\1ýR\2ýR#!3!0?!ð"t!Butyldimethylsilyl#oxyŁ!
0?!ð6ý!methoxy!2ý!methoxymethyl!1ý!"21\31!
methylenedioxyphenyl#!1ý\2ý!dihydro!0ý\3ý!
benzodioxin!5ý!ylŁmethylŁ!2!hydroxy!2!
"hydroxymethyl#dihydro!1"2H#!furanone "11#
"0S\1S\4R\5S\1?R\2?R#!0\1!Dihydroxy!5!ð6?!methoxy!
2?!methoxymethyl!1?!"2ý\3ý!methylenedioxyphenyl#!
1?\2?!dihydro!0?\3?!benzodioxin!5?!ylŁ!2\6!
dioxabicycloð2[2[9Łoctane "6#
A soln of 10 "9[87 g\ 0[61 mmol#\ NMO "9[14 g\
0[74 mmol# and 1) aq[ OsO3 "9[7 ml# in a mixture of
acetone "29 ml#\ t!BuOH "4 ml# and water "4 ml# was
stirred at room temp in the dark for 19 hr under Ar[
To a cooled "−64># and stirred soln of lactone 4
The reaction was then quenched by addition of Celite "27 mg\ 9[970 mmol# in dry CH1Cl1 "2 ml# was drop!
"0 g# followed by 09) aq[ NaHSO2 "1 ml#[ The result! wise added a 0 M soln of i!Bu1AlH in n!hexane
ing mixture was _ltered and the residue was washed "199 mL\ 9[19 mmol# via a syringe[ The resulting soln
well with acetone[ The _ltrate was concd\ taken up was stirred at −64> for 0 hr\ at which time the reaction
in EtOAc "49 ml#\ washed with brine "09 ml#\ dried was quenched by addition of 9[4 M aq[ HCl "2 ml#[
"Na1SO3#\ and concd[ Silica gel CC ðn!hexane!EtOAc The mixture was extracted with EtOAc "4 ml×1#\
"0]0#Ł gave 0[92 g of 11 "0[60 mmol\ 88)# as a viscous washed with brine "4 ml#\ dried "Na1SO3#\ and concd[
0
oil] H NMR] d −9[15 "2H\ s\ SiÐCH2#\ 9[09 "2H\ s\ Silica gel CC "EtOAc# gave 23 mg of lactol 6
0
SiÐCH2#\ 9[80 "8H\ s\ SiÐC"CH2#2#\ 1[41Ð 1[65 "0H\ br\ "9[961 mmol\ 78)# as a white powder] H NMR] d
OH#\ 1[81Ð2[05 "1H\ m\ OH\ H!3#\ 2[16 "0H\ dd\ Jꢁ2\ 1[39Ð1[53 "0H\ m\ H!4#\ 2[18 "0H\ dd\ Jꢁ00\ 3\
00\ CHOMe#\ 2[22 "2H\ s\ OCH2#\ 2[52 "0H\ dd\ Jꢁ2\ CHOMe#\ 2[23 "2H\ s\ OCH2#\ 2[28Ð2[38 "0H\ br\
00\ CHOMe#\ 2[62 "2H\ s\ ArOCH2#\ 2[73Ð3[13 "4H\ OH#\ 2[48 "0H\ dd\ Jꢁ00\ 2\ CHOMe#\ 2[61 "2H\ s\
m\ H!4\ CH1OH and H!2ý#\ 4[99 "0H\ d\ Jꢁ7\ H!1ý#\ ArOCH2#\ 2[62 "0H\ d\ Jꢁ09\ H!7b#\ 2[73Ð3[98 "2H\
4[17 "0H\ d\ Jꢁ7\ H!0?#\ 4[87 "1H\ s\ OCH1O#\ 5[36 m\ H!3b\ H!2?\ OH#\ 3[14 "0H\ d\ Jꢁ09\ H!7a#\ 3[21
"0H\ s\ H!7ý#\ 5[79Ð5[85 "2H\ m\ ArÐH|s#\ 6[99 "0H\ s\ "0H\ dd\ Jꢁ09\ 6\ H!3a#\ 3[75 "0H\ d\ Jꢁ6\ H!5#\ 3[85
CHCl2
H!4ý#^ IRn
cm−0] 727\ 0907\ 0939\ 0149\ 0204\ "0H\ d\ Jꢁ6\ H!1?#\ 4[08 "0H\ br s\ H!1#\ 4[88 "1H\ s\
max
0384\ 0591\ 0666\ 2199Ð2549[ Anal[ Calcd for OCH1O#\ 5[38 "0H\ s\ H!7?#\ 5[71Ð5[81 "2H\ m\ ArÐ
CHCl2
max
C29H39O00Si] C\ 48[48^ H\ 5[56[ Found] C\ 48[31^ H\ H|s#\ 6[13 "0H\ s\ H!4?#^ IRn
cm−0] 0919\ 0954\
5[60)[
0084\ 0134\ 0381\ 0492\ 2019Ð2549[ Anal[ Calcd for
C13H15O09] C\ 59[65^ H\ 4[41[ Found] C\ 59[47^ H\
4[40)[
"0S\4R\5S\1?R\2?R#!0!Hydroxy!5!ð6?!methoxy!2?!
methoxymethyl!1?!"2ý\3ý!methylenedioxyphenyl#!1?\2?!
dihydro!0?\3?!benzodioxin!5?!ylŁ!2\6!
"0R\1S\4S\5R\1Rý\2Rý#!"¦#!Haedoxan A "0a#
dioxabicycloð2[2[9Łoctan!1!one "4#
A soln of lactol 6 "83[8 mg\ 9[199 mmol#\ 1\5!di!
To a cooled "9># soln of 11 "0[91 g\ 0[58 mmol# in methoxy!2\3!methylenedioxyphenol "68[9 mg\ 9[399
dry THF "09 ml# was added a 0 M soln of n!Bu3NF mmol# and PPTS "03[9 mg# in dry benzene "7 ml# was
"1[99 ml\ 1[99 mmol# in THF[ The resulting soln was re~ux for 6 hr with concomitant removal of water "MS

511
F[ ISHIBASHI and E[ TANIGUCHI
3A#[ The mixture was then diluted with EtOAc "4 ml#\
washed with 9[4 M NaOH "4 ml×1#\ and the aq[ layer
was re!extracted with EtOAc[ The combined organic
layers were dried "Na1SO3# and concentrated\ leaving
an oily residue[ The crude product was puri_ed by
prep[ TLC ðEtOAc!benzene "2]6#Ł\ giving 0a "Rf 9[37\
16[1 mg\ 9[9305 mmol\ 10)#\ along with two dia!
stereomeric dimers 14 "Rf 9[21\ 15[3 mg and Rf 9[29\
15[7 mg#[ 0a] white crystals\ mp 045Ð046> "lit[ ð2Ł 047Ð
048>#\ ðaŁ0D6¦006> "EtOHÐCH1Cl1^ c 9[13# ðlit[ ð2Ł
ðaŁ0D7¦014> "EtOHÐCH1Cl1^ c 9[21#Ł^ 0H NMR] d 1[52
"0H\ m\ H!4#\ 2[16 "0H\ dd\ Jꢁ3\ 00\ CHOMe#\ 2[23
"2H\ s\ OMe#\ 2[47 "0H\ dd\ Jꢁ2\ 00\ CHOMe#\ 2[60
"0H\ d\ Jꢁ09\ H!7b#\ 2[61 "2H\ s\ ArOMe#\ 2[66 "2H\
s\ ArOMe#\ 2[77Ð3[02 "2H\ m\ OH\ H!2ý\ H!3b#\ 3[99
"2H\ s\ ArOMe#\ 3[17 "0H\ d\ Jꢁ09\ H!7a#\ 3[44 "0H\
dd\ Jꢁ6\ 8\ H!3a#\ 3[80 "0H\ d\ Jꢁ4\ H!5#\ 3[87 "0H\
d\ Jꢁ7\ H!1ý#\ 4[11 "0H\ s\ H!1#\ 4[74 "1H\ s\ OCH1O#\
4[86 "1H\ s\ OCH1O#\ 5[16 "0H\ s\ ArÐH#\ 5[35 "0H\ s\
ArÐH#\ 5[68Ð5[85 "2H\ m\ ArÐH#\ 6[17 "0H\ s\ ArÐH#[
2[ Taniguchi\ E[ and Oshima\ Y[\ A`ricultural and
Biolo`ical Chemistry\ 0858\ 22\ 355[
3[ Taniguchi\ E[ and Oshima\ Y[\ Tetrahedron
Letters\ 0861\ pp[ 542[
4[ Taniguchi\ E[ and Ishibashi\ F[\ Lignan as phy!
tochemical defence against insect[ Paper pre!
sented at XVIII International Congress of Ento!
mology\ Vancouver\ B[C[\ 2Ð8 July 0877[
5[ Taniguchi\ E[\ Imamura\ K[\ Ishibashi\ F[\
Matsui\ T[ and Nishio\ A[\ A`ricultural and Bio!
lo`ical Chemistry\ 0878\ 42\ 520[
6[ Ishibashi\ F[ and Taniguchi\ E[\ A`ricultural and
Biolo`ical Chemistry\ 0878\ 42\ 0454[
7[ Mukaiyama\ T[\ Hashimoto\ H[ and Shoda\ S[\
Chemistry Letters\ 0872\ pp[ 824[
8[ Takano\ S[\ Ohkawa\ T[\ Tamori\ S[\ Satoh\ S[
and Ogasawara\ K[\ Journal of Chemical Society
Chemical Communications\ 0877\ 078[
09[ Kondo\ K[ and Mori\ F[\ Chemistry Letters\ 0863\
pp[ 630[
00[ Openshow\ H[ T[ and Whittaker\ N[\ Journal of
Chemical Society\ 0858\ "C#\ 78[
"0S\1R\4R\5S\1ýR\2ýR#!"¦#!Haedoxan D "1a#
01[ Ishibashi\ F[ and Taniguchi\ E[\ Bulletin of the
Chemical Society of Japan\ 0877\ 50\ 3250[
02[ Bettoni\ G[\ Cellucci\ C[ and Bernardi\ F[\ Journal
of Heterocyclic Chemistry\ 0879\ 06\ 592[
03[ Ishibashi\ F[ and Taniguchi\ E[\ A`ricultural and
Biolo`ical Chemistry\ 0878\ 42\ 0446[
04[ Pirkle\ W[ H[ and Hoekstra\ M[ S[\ Journal of
Or`anic Chemistry\ 0863\ 28\ 2893[
05[ Pirkle\ W[ H[ and Hauske\ J[ R[\ Journal of
Or`anic Chemistry\ 0866\ 31\ 0728[
06[ Baer\ E[ and Fischer\ H[ O[ L[\ Journal of Bio!
lo`ical Chemistry\ 0828\ 017\ 352^ Dumont\ R[
and Pfander\ H[\ Helvetica Chimica Acta\ 0872\
55\ 703[
07[ Mulzer\ J[ and Angermann\ A[\ Tetrahedron
Letters\ 0872\ 13\ 1732[
08[ House\ H[ O[\ Crumrine\ D[ S[\ Teranishi\ A[ Y[
and Olmstead\ H[\ Journal of the American Chemi!
cal Society\ 0862\ 84\ 2209[
19[ Corey\ E[ J[\ Cho\ H[\ Ruker\ C[ and Hua\ D[ H[\
Tetrahedron Letters\ 0870\ 11\ 2344[
The title compound was synthesized in 23) yield
from 6 and 1!methoxy!3\4!methylenedioxyphenol by
the same procedure as for "¦#!0a] a white powder\
ðaŁ0D8¦003[9> "CH1Cl1^ c 9[56#^ 0H NMR "399 MHz# d
0[49Ð0[64 "0H\ br\ OH#\ 1[51Ð1[57 "0H\ m\ H!4#\ 2[29
"0H\ dd\ Jꢁ2[8\ 00[9\ CHOMe#\ 2[24 "2H\ s\ OCH2#\
2[48 "0H\ dd\ Jꢁ1[3\ 00[9\ CHOMe#\ 2[62 "2H\ s\
ArOCH2#\ 2[65 "0H\ d\ Jꢁ8[7\ H!7b#\ 2[67 "2H\ s\
ArOCH2#\ 2[85Ð3[92 "0H\ m\ H!2?#\ 3[97 "0H\ dd\
Jꢁ1[3\ 8[2\ H!3b#\ 3[21 "0H\ d\ Jꢁ8[7\ H!7a#\ 3[34
"0H\ dd\ Jꢁ6[4\ 8[2\ H!3a#\ 3[84 "0H\ d\ Jꢁ4[8\ H!5#\
3[88 "0H\ d\ Jꢁ6[7\ H!1?#\ 4[08 "0H\ s\ H!1#\ 4[80 "1H\
dd\ Jꢁ0[2\ 2[7\ OCH1O#\ 5[99 "1H\ s\ OCH1O#\ 5[49
"0H\ s\ H!7?#\ 5[45 "0H\ s\ ArÐH#\ 5[79 "0H\ s\ ArÐH#\
5[79Ð5[82 "2H\ m\ ArÐH|s#\ 6[15 "0H\ s\ H!4?#^ MS
"29 eV#] m:z 513 "M¦#\ 345\ 081 "base#\ 057\ 050\ 059\
042[ Anal[ Calcd for C29H21O02]C\ 50[43^ H\ 4[05[
Found] C\ 50[38^ H\ 4[14)[
10[ VanRheenen\ V[\ Kelly\ R[ C[ and Cha\ D[ Y[\
Tetrahedron Letters\ 0865\ 0862[
REFERENCES
0[ Taniguchi\ E[ and Oshima\ Y[\ A`ricultural and
Biolo`ical Chemistry\ 0861\ 25\ 0902[
11[ Balogh\ V[\ Fetizon\ M[ and Gol_e\ M[\ Journal
of Or`anic Chemistry\ 0860\ 25\ 0228[
1[ Taniguchi\ E[ and Oshima\ Y[\ A`ricultural and
Biolo`ical Chemistry\ 0861\ 25\ 0378[
12[ Corey\ E[ J[ and Venkateswarlu\ A[\ Journal of
the American Chemical Society\ 0861\ 83\ 5089[