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Lignans, Neolignans, and Related Compounds

R . S. Ward
Chemistry Department, University of Swansea, Singleton Park, Swansea SA2 8PP

Reviewing the literature published between January 1989 and December 1991
(Continuing the coverage of literature in Natural Product Reports, 1990, Vol. 7 , p. 349)

1Introduction to separate lignan glucosides isolated from stinging nettle roots,

1.1Analysis and Identification Urtica dioica, after appropriate deri~atization.~ With the aid of
1.2Biological Activity mass spectrometry and NMR spectroscopy, eleven lignan
1.3Biosynthesis glucosides have been identified, five of which were previously
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

2 Lignans unknown. The mass spectra of the trimethylsilylated glucosides

2.1 Dibenzylbutanes and Dibenzylbutanediols show typical fragment ions which establish whether the glucose
2.2 Dibenzylbutyrolactones residue is attached to an alcoholic or a phenolic hydroxyl group
2.3 Substituted Tetrahydrofurans of the aglycone.
.O]octanes
2.4 2,6-Diaryl-3,7-dioxabicyclo[3.3 Pyrolysis-GC has been used for the first time for the analysis
2.5 Arylnaphthalene Derivatives of l i g n a n ~ .Compounds
~ belonging to the 2,6-diaryl-3,7-
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2.6 Dibenzocyclooctadiene Derivatives dioxabicyclo[3.3.0]octane series have been examined. The

2.7 Miscellaneous Lignans
3 Neolignans
4 Oligomeric Lignans and Neolignans
5 Hybrid Lignans
6 Norlignans
7 References
1 introduction
The period under review has been marked by the publication of
what is, in fact, only the second monograph wholly devoted to
the chemistry of lignans and related compounds.l Not
surprisingly, it is both more up-to-date and more comprehensive
than its predecessor. A review of the asymmetric synthesis of
lignans has also been published.*
It is intended that the classification and organization of this
report should largely follow on the same lines as those
established in the preceding reports in this series, including the
use of the same abbreviations for some of the most commonly
encountered aryl groups (Figure 1). Short introductory sections
have, however, been added, dealing with significant advances in
analysis and identification, biological activity, and the bio-
synthesis of lignans and related compounds.
1.1 Analysis and Identification
Capillary GC using short glass capillary columns has been used
pyrolysis products were analysed by capillary GC using an ion
trap detector and were identified on the basis of their mass
spectra. The major pyrolysis products were found to be
mononuclear aromatic derivatives having a 1, 2, or 3 carbon
side chain. In some cases highly specific cleavage processes were
detected giving intense fragment peaks which are highly
characteristic of the compound concerned. The effect of varying
the time and temperature of pyrolysis was also investigated.
High speed countercurrent chromatography linked with
thermospray mass spectrometry has been shown to provide a
versatile method for the analysis of naturally occurring l i g n a n ~ . ~
The resolution achieved and the speed of separation are
claimed to be comparable with HPLC. The technique has been
used to separate and identify the lignans from Schisandra
rubzflora, a traditional Chinese herbal medicine used for the
treatment of hepatitis. Thermospray-CCC/MS identified the
main active ingredients as schisanhenol, pregomisin, meso-
dihydroguaiaretic acid, and schisanhenol acetate.
1.2 Biological Activity
Of increasing significance is the suggestion that lignans in foods
are converted by intestinal microflora into hormone-like
substances which act as cancer-protective agents.6 This could
explain the low mortality from hormone-dependent cancer in
Japanese men and women consuming a traditional Japanese
diet. A study of the urinary excretion of compounds such as
enterolactone and enterodiol by residents of a rural Japanese

OH
/

OMe

Ar6 = 4 ; M e Ar7= -@OH

OMe OMe OMe OMe OMe

OMe OMe OMe OMe

/ /

-
Ar" = a O C H 2 P h =a O S i R 3 ArI3 = *OM. Ar14 = e O G l " Ar15 = QOMe

OMe Me0
Figure 1
1

1-2

2 NATURAL PRODUCT REPORTS. 1993
village using isotope dilution GC-MS has shown that excretion
of lignans could be correlated with soybean product intake.
The low mortality due to breast and prostate cancer in women
and men respectively could be due to a high intake of soybean
products.
Mammalian lignans such as enterolactone and enterodiol
have also been suggested as playing a role in the cancer-
protective effect of vegetarian diets.’ The amounts produced
from 68 different plant foods using in vitro fermentation with
human fecal microbiota have been determined. The results
show a wide range in the amount of lignans produced, with
oilseeds producing the highest amounts followed by dried
seaweeds, whole legumes, cereal brans, legume hulls, whole
grain cereals, vegetables, and fruit. Vegetables produced the
second highest concentration when data were expressed on a
moisture-free basis. Flaxseed flour was the highest single
producer of lignans.
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001
The effect of short-term flaxseed consumption on lignan and
hormone levels in man has been studied.8 Urinary levels of
enterolactone and enterodiol were significantly higher following
1, 2, 4, and 6 week wholewheat flaxseed bread feeding.
However, although dietary lignans may influence hormone
dependent cancer incidence by modulating hormone levels, an
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increase in short-term flaxseed consumption did not lead to
significant differences in hormone levels.
It has been shown that two lignans isolated from the tropical
climbing shrub Ipomoea cairica, (-)-arctigenin and (-)-
trachelogenin, strongly inhibit the replication of the human
immunodeficiency virus (HIV-1) in ~ i t r o It . ~ is thought that
these compounds may prevent the increase of topoisomerase I1
activity involved in virus replication after infection of cells with
HIV- 1. Other lignans displayed no anti-HIV activity.
The effect of various podophyllotoxin derivatives on DNA
topoisomerase I1 activity, tubulin polymerization, and VP- 16
resistant tumour cells has been examined.’O This study has
shown that introduction of a substituent with the P-configur-
ation at C-4 resulted in compounds with greater inhibitory
activity against DNA topoisomerase I1 and lower inhibitory
activity against tubulin polymerization than those with the 01-
configuration. These active analogues exhibited the same
mechanism of DNA topoisomerase I1 inhibition as the
epipodophyllotoxin derivative VP- 16, which causes protein-
linked DNA breaks in vitro and in vivo. Compounds with a
OCH,CH,NH, or NHCH,CH,OH group in place of the
glycosidic moiety of VP-16 had a different spectrum of
antitumour activity from VP-16 itself and therefore may be
useful when VP- 16 resistance occurs.
Several podophyllotoxin derivatives have also been shown to
possess significant antifungal activity. l1 Structure-activity
studies show that this action is sensitive to changes at the 4 and
4’ positions of the podophyllotoxin skeleton in a manner
analogous to the structure-activity profiles seen in the inhibition
of mammalian topoisomerase 11. Particularly important is the
observation that 4’-demethyldeoxypodophyllotoxin, 4’-de-
methylpodophyllotoxin, and 3’,4‘-didemethyldeoxypodophyl-
lotoxin, which display the greatest antifungal activity, are the
most potent topoisomerase I1 inhibitors. However, etoposide
(VP-l6), generally regarded as an inhibitor of mammalian
topoisomerase 11, showed no activity in this assay.
It has been shown that kadsurenone and related lignans are
antagonists of the platelet activating factor receptor.12 They
inhibit PAF-induced platelet aggregation by blocking the
receptor with which the agonist interacts to produce its
biological activity. Several 2,6-diaryl-3,7-dioxabicyclo[3.3.0]-
octanes and dibenzylbutyrolactones also show high PAF
antagonist activity. 3,4-Dibenzyltetrahydrofuranssynthesized
by catalytic reduction of the corresponding 2,3-dibenzyl-
butyrolactones have also been shown to have PAF antagonist
activity .l 4
There is evidence that episesamin and/or sesamin function as
a regulator of cholesterol and linoleate metabolism in rats.”
View Online
kTco2
H202
Ar ~~2~
(Ar = Ar2 or Ar? - Ar
C02H
Scheme 1
Plants synthesize a large number of chemicals that are toxic to
insects. Some plants also produce compounds which inhibit the
polysubstrate mono-oxygenases (PSMOs) employed by insects
to detoxify such compounds.16The most numerous, active, and
economically important PSMO inhibitors, often used as
insecticide synergists, contain a methylenedioxyphenyl group
which appears to preferentially bind to the heme of the PSMO
forming relatively stable adducts. Thus, it has been shown that
diasesartemin, sesamolin, and to a lesser extent cubebin, all of
which contain a methylenedioxy substituted phenyl group, are
inhibitors of PSMO activity in the European corn borer
Ostrinia nubilalis, an important crop pest. Epiyangambin on
the other hand, which does not contain a methylenedioxy
group, had little effect.
1.3 Biosynthesis
The purification from the leaves of Bupfeurum saficifblium of a
new peroxidase capable of catalysing the dimerization of either
caffeic or ferulic acid with the formation of a P,8-linkage has
been reported (Scheme 1). The purified peroxidase does not
exhibit activity on other phenyl propanoids and has no
detectable phenol oxidase or NADPH oxidase activity.”
Lewis et af. have shown that (+)-pinoresin01 in Forsythia
suspensa and ( - )-secoisolariciresinol in Forsythia intermedia
are formed via direct stereoselective coupling of the two
coniferyl alcohol units, whereas ( -)-matairesinol is formed by
dehydrogenation of ( -)-secoisolariciresinol. l 9 In the case of
pinoresinol formation, they have shown that horseradish
peroxidase or a crude cell free enzyme preparation from F.
suspensa, and even shoots of F. suspensa, convert coniferyl
alcohol to racemic pinoresinol. Only when phenylalanine is
administered to the shoots is (+)-pinoresin01 obtained,
suggesting that phenylalanine and its subsequent metabolites
(presumably including coniferyl alcohol) are compart-
mentalized prior to oxidative coupling and not exposed to the
non-specific peroxidases which give the racemic product. In the
case of secoisolariciresinol formation, only the ( - )-enantiomer
is obtained, both in vivo and in vitro, and only the (-)-
enantiomer is subsequently converted into matairesinol.
Dewick et al. have shown that phenylalanine and ferulic acid
are good precursors of the dibenzylbutyrolactones arctigenin
and matairesinol and the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]-
octanes phillygenin and epipinoresinol in Forsythia intermedia.
They also provide evidence that the lignans are formed by
direct oxidative coupling of two coniferyl alcohol units rather
than by coupling of two ferulic acid or aldehyde units.*O They
have established callus and cell suspension culture from F.
intermedia tissues which give either dibenzylbutyrolactones or
2,6-diaryl-3,7-dioxabicyclo[3.3.0]octanesas the predominant
metabolites, thus substan tiating the proposed biosyn the tic
relationship between the two classes.
The same group have shown that (-)-matairesinol is
efficiently incorporated into the aryltetralin lactone lignans
podophyllotoxin, 4’-demethylpodophyllotoxin,P-peltatin, ct-
peltatin, and 4’-demethyldeoxypodophyllotoxin in Podo-
phyllum hexandrum roots, P. Peltatum leaves and Diphylleia
cymosa leaves.,l This demonstrates that matairesinol is a
common precursor of both the 3,4,5-trimethoxy and 4-hydroxy-
3,5-dimethoxyphenyl groups of Podophyllum lignans, and may
be the branch point leading to the two series (Scheme 2).
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NATURAL PRODUCT REPORTS, 1993-R. S. WARD 3

H
4'-demethylpodophyllotoxin
a-peltatin

"'3; A?
Ar7 0

podophyllotoxin
P-peltatin
0
Ars 0
Scheme 2
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

Ar
57 A + Y Ar?( A@TCH2OR

--. "CH~OR
AT Ar5 Ar7 Ar"'
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(1) Ar=Ara (3) (4) Ar = Ar' (6) R = H

A
p
r(2) Ar=Ar4

..CH20Me A

HO
f l F A
(5) Ar =Ar3

P TCH20H
(7) R = AC

Ar7>cHz0H

CH20Me .*CH,OH CH2OH

AP AP Ar4 Ar7

(8) Ar =Ar6 (10) (11)

(9) Ar = A ?

Ar"'
CO,& i NaOMe C02Me
i LiAIH4
A~~~~~~~ ~ ii EK)Ac/H+ ii CH2N2
C0,Me
0 AP AF
(1 4) (13)
Scheme 3

2 Lignans second involving a Stobbe condensation.29 Dihydro-

2.1 Dibenzylbutanes and Dibenzylbutanediols
A number of new dibenzylbutanes and related compounds
have been reported [(I)-(12)]. For example, three new
compounds named saururin (l), saururenin (2), and saur-
urinone (3) have been isolated from Suururus cernuus.22
Isopregomisin (4) and guayacasin ( 5 ) have been isolated
together with meso-dihydroguaiaretic acid from Porfieriu
chilensis, and their antioxidant activity 24 Four more
dibenzylbutane derivatives (6)-(9) have been isolated from
Phyffunthus niruri, bringing to eight the total number of such
compounds now isolated from this plant.25Two new dibenzyl-
butane derivatives (10) and (1 1) have been isolated from the
fruits of Virolu elongutu. 26 A new bis-0-rhamnoside of
secoisolariciresinol has been isolated from the stems and leaves
of Pursonsiu f~eviguta,~'and ssioriside, a xyloside of the
aglycone (12) has been isolated from the bark of Prunus ssiori
and P. padus.28
Prasanthaline (1 3), a lignan isolated from Jutropha
gossypifofiu, has been synthesized by two routes (Scheme 3), the
first starting from naturally occurring suchilactone (14), the
prasanthaline has also been identified as a co-occurring natural
product, although it has not yet been isolated in pure form.
Depending upon the stereochemistry (which is not defined) it
may turn out to be identical with the diacetate of 2,3-
desmethoxy-secoisolintetralin (7).
The isolation of ( - )-dihydroguaiaretic acid ( 15) from
Saururus cernuus has been reported, along with its synthesis
from ( -)-austrobailignan-5 (16) by regioselective cleavage of
the methylenedioxyphenyl groups (Scheme 4).30
When dihydrocubebin (17) is treated with DDQ in acetic
acid the tetrahydrofuran (18) is ~ b t a i n e d . ~However,
' when
DDQ in trifluoroacetic acid is used the dibenzocyclooctadiene
(19) is produced. This provides a valuable new method for the
oxidative non-phenolic coupling of dibenzylbutane derivatives
to give the dibenzocyclooctadiene system (Scheme 5 ) .
2-2 DibenzYlbutYrolactones
Six new lignans of the dibenzylbutyrolactone type have been
isolated from Bupfeurum suficifofium and their structures

4 NATURAL PRODUCT REPORTS. I993
(R = CHZSTol)
Scheme 4
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AP Ar
(20) R = H (22) Ar = Ar4 (23) Ar=Ar3
(21) R = A c (29) Ar = Ar5 (24) Ar = Ar2
(30) X = OH, Y = H
(31) X = H, Y = O h
determined.32--34They are quayadequiol (20) and its acetate
(2 l), quayadequiene (22), buplerol (23), quayarol (24), and
isokaerophyllin (25) [(20)-(36)]. Three new lignans (26)-(28)
have also been isolated from Calocedrus formosana,35 and 2,3-
di(3,4-methylenedioxybenzyl)butenolide (29) has been isolated
from Hyptis ~ a p i t a t a Epipodorhizol
.~~ (30) has been isolated
for the first time from Juniperus t h ~ j f e r u , ~and
‘ podorhizol
acetate (31) and 3’4-demethyl yatein (32) have been isolated
from J . ~abina.~’Three new dibenzylbutyrolactones (33)-(35)
have been isolated from Vivola elongutu.26
With an increasing number of unsaturated lactones being
reported it is appropriate that the structure of one such
compound, savinin (36), has been studied in some detail both
in solution, using a variety of NMR techniques, and in the solid
state by X-ray crystallography.3gThe NMR data indicate that
in solution the two aromatic rings overlap. In contrast, the
conformation in the solid state is quite different, emphasizing
the need for caution in extrapolating from the solid state to
solution shapes of biological molecules.
Savinin (36) and its stereoisomer gadain (37) have been
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OR
(25) (27) A r = A r ”
(28) Ar = Ar’
Ar
(33) Ar = Ar’ (35) Ar = Ar4
(34) Ar=Ar’’ (36) Ar = Ar5
synthesized from the a-stann ylmeth y lene-y -bu tyrolactone
(38).40 Treatment of gadain (37) with tributyltin hydride and
azobisisobutyronitrile converts it into savinin (36) (Scheme 6).
Deoxypodorhizone (39) has been synthesized by tributyltin
hydride induced cyclization of the a-bromoester (40).41
Trachelogenin (41) has been synthesized by hydroxylation of
the enolate derived from the parent dibenzylbutyrolactone (42)
(Scheme 7)42(cf. Scheme 9 below).
Brown et al. have published full details of their work on the
asymmetric synthesis of a large number of lignans based on the
resolution of monobenzyl succinate derivative (43) obtained via
the Stobbe c ~ n d e n s a t i o n . ~ ” The
~ ~ epimeric 5-hydroxy-
dibenzylbutyrolactones (44) and (45) serve as precursors for the
synthesis of aryltetralin lactones (46) (Scheme 8).
Hydroxylation of the enolates derived from the homochiral
dibenzylbutyrolactones adds a further dimension to this
approach, giving the a-hydroxy-dibenzylbutyrolactones (48)
and (49) (Scheme 9).44
An alternative method for the synthesis of the homochiral
monobenzylbutyrolactones (47) involves a stereospecific ad-
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NATURAL PRODUCT REPORTS, 1993-R. S. WARD 5

AIBN

0
Bu3SnH
AIBN

Scheme 6 (37)
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

AB AS
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(82:18)
Scheme 7

ArCHO -
C02Me

A r T C 0 2 H
(Ar = A?,Ar4,Ar5,Ar6)
“2
pd-c
m- A
T
r
C0,Me

W2H
-i resolve

ArHg-Q
0
+ kT 0
(43)
(SH47) (R)-(47)

(46) (Ar = Ars,Ar7,Ar3)

Scheme 8

(48) (1:l) (49)

Scheme 9
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6 NATURAL PRODUCT REPORTS, 1993

n-

(2)-(50) (1.711) (€)-(50)

Cl&=C=O
- Ar5
- i ZdHOAc

AlBN
i LDA
Ar'COCI

(R)-(47)
94% e.e.
Scheme 10
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

Me0

Omenthyl mthvl Me0 A /

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L#

i Ar4C(SPh),
ii ArkH2Br

(52) (53)X = S P h
(55)X = H
U

Omenthyl

i Ar4c(SPh)2
Me
ii ArCHO *
0

(54) X = S P h
(56)X = H H-uH
k.**
(0y-
Ar

(Ar = Ar4)
Scheme 11

NHBoc NHBoc
6 steps ArEHSPh 7 steps
L-glutamic acid -
0
(57)
(4-(58)
Scheme 12

ditive Pummerer rearrangement of the alkenyl sulfoxides (50)
with di~hloroketene.~' Acylation of the resulting monobenzyl
compounds gives (+) and (-)-podorhizone (51) (Scheme 10).
An entirely different approach to the asymmetric synthesis of
dibenzylbutyrolactones, and hence to a wide range of other
lignans, involves tandem conjugate addition of a carbanion to
a chiral b ~ t e n o l i d e . ~Two
* * ~ ~groups have made use of this
approach using the menthyloxy- butenolide (52) and have
shown that it undergoes diastereoselective addition to afford
the initial adducts (53) and (54). These then undergo
desulfurization using Raney nickel or nickel boride to give (55)
and (56). The former serve as precursors for the synthesis of
dibenzocyclooctadiene lignans while the latter lead directly to
the aryltetralins and furofurans (Scheme 11).
In contrast, conjugate addition to a six-membered un-
saturated lactone (57) is involved in a reported synthesis of
(-)-hinokinin (58) (Scheme 12).j0The unsaturated lactone (57)
was prepared in six steps from L-glutamic acid.
The approach adopted by Rehnberg and Magnusson also
involves a conjugate addition reaction, in this case to the
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NATURAL PRODUCT REPORTS, 1993-R. S. WARD 7

0 0

I
(-)-(60) (Ar = Ar')
steps
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

(-)-trichostin Ar = Ar8 (-)-(58) (Ar = Ar5)

(-)-cubebin Ar = Ar5
Scheme 13
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"p HO '
(67) Ar = Ar4 (70) Ar = Ar3, R = p-D-gtu (73) (75a) Ar = Ar6 (7%) Ar = Ar'
(68) Ar = Ar3 (71) Ar = A?, R = P-D-att (75b) Ar = Ar' (75d) Ar = A?
(69) Ar =Arlo (72) Ar = Ar7, R = PD-glu

Arl &Arl k-.. '-Ar

(76a) Ar = Ar' (77) (79a) Ar = Ar6

(76b) A r = A ? (79b) Ar=Ar'
(76c) Ar = Ar4

homochira benzoyl-dihydrofuran derivatives (59) (Scheme from Berchemia r a c e m ~ s a2-hydroxyolivil

13).51These compounds in turn are prepared in 8 steps from D-
or L-arabinose. Desulfurization and reduction yield either 3,4-
dibenzyltetrahydrofurans such as burseran (60) or, after further
modification, 2,3-dibenzylbutyrolactones such as hinokinin
(58).
2.3 Substituted Tetrahydrofurans
New tetrahydrofuran derivatives are (61)-(79). Shonanin (61)
is a 3,4-dibenzyltetrahydrofuranisolated from the leaves of
Calocedrus formosana. 5 2 Jusglaucinol (62) from Justicia
g l a ~ c afargesol(63)
,~~ from Magnolia f ~ r g e s i iberchemol(64)
,~~
,~~ (65) from Carduus
~ s s o i ,actifolin
~~ (66) from Actinodaphne l o n g i f o l i ~ ,and
~~
compounds (67)-(69) from Virola elongata26are new 2-aryl-4-
benzyltetrahydrofurans. Three new glycosides (70)-(72) named
as tanegosides A-C have been isolated from Trachelospermum
liukiuense. 27 Icariol A, (73) from Epimedium s ~ g i t t a t u m , ~ ~
eupobennettin (74) from Eupomatia be~nettii,~' de-0-
methylgrandisin (75a) and dide-0-methylgrandisin (75b) from
Licaria aurea'" and Virola pavonis,61(75c), (75d), (76a), (76b),
(77), and (78) from Larrea tridentata,62 ganschisandrine (76c)
from Schisandra ~ p h e n a n t h e r a ,and
~ ~ (79a) and (79b) from
Aristolochia birostriP and Krameria interioP5 respectively are
new 2,5-diaryl-tetrahydrofurans.
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8 NATURAL PRODUCT REPORTS, 1993

- DDQ/TFA

'A
(90

AP
H

(80)
Scheme 14
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cis (85) (84) = (18)

(R = TBDMS)
Scheme 15

(E = C0,Me)
EeEC
___)
Ar13 Vk13
(major isomer) 38%
Scheme 16

Treatment of the 3,4-dibenzyltetrahydrofuran (80) derived
from dihydrocubebin (17) with DDQ in acetic acid causes
dehydrogenation to the aryltetralin (8 l), presumably via the
acetoxy compound (82) which is obtained as a second product
from the reaction. However, the same reaction carried out in
trifluoroacetic acid affords the dibenzocyclooctadiene (83)31
(Scheme 14). (cf. Scheme 5 above).
A number of compounds belonging to the 2-aryl-4-benzyl
tetrahydrofuran series, including dihydrosesamin (84), have
been synthesized by reduction of the corresponding 3-arylidene
lactones.66The starting materials are the cis and trans paraconic
acid derivatives (85) (Scheme 15). The stereochemistry at C-5 in
(86) and (87) determines the outcome of the hydrogenation step
leading to (84) or (88) respectively.
A novel approach to the synthesis of 2,5-diaryltetrahydro-
furans involves the 1,3-dipolar cycloaddition of a carbonyl ylid
to an acetylenic or fumarate ester (Scheme 16).67Unfortunately,
the reaction does not proceed stereoselectively and gives a
mixture of isomeric products.
2.4 2,6-Diaryl-3,7-dioxabicyclo[3.3.O]octanes
Three new lignans of this type have been reported [(89)-(91)].
Compound (89) has been isolated from the aerial parts of
Mikania saltensis,68 while 5'-methoxysesamin and 5'3''-
dimethoxysesamin have been isolated from the roots of
Podolepsis r ~ g a t a . ~In
' addition, salicifoliol (90), a new 2-aryl-
3,7-dioxabicyclo[3.3.O]octanone,has been isolated from the
aerial parts of Bupleurum s a l i ~ i f o l i u mand
, ~ ~4-keto-pinoresinol,
previously isolated from Aegilops ovata, has now also been
isolated from Coix lachryma-jobi
A number of new glycosides have also been reported. These
include a 4-O-P-~-apiosyl-( 1 -+2)-P-~-glucosideof pinoresinol
from Parsonsia laevigata leaves,27 icariside E, (9 1) from the
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NATURAL PRODUCT REPORTS, 1993-R. S. WARD 9
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

, t
;,,---;
H 4.12 d(9.5)
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H 3.32 m
H, 3.84
0
H 4.85 d(5.3)
3.84 m H H------ ------ -.*'

2.91 A 3.32 m
Figure 2

Scheme 17

Ar4
Me0

(95)
(97)
Scheme 18

aerial parts of Epimedium s a g i t t a t ~ r nthree

, ~ ~ new syringaresinol
di-, tri-, and tetra-glycosides from the bark of Albizzia
julibrissin," and a new glucoside of medioresinol, named
isoeucommin A, from the leaves of Osmanthus asiati~us.~'
The mono- and di-glucosides of syringaresinol and the
monoglucoside of pinoresinol have been synthesized by the
reaction of a-acetobromoglucose with either syringaresinol or
pinoresinol in aqueous alkali.73
X-ray crystal structures of pinoresinol dimethyl ether
( e ~ d e s m i n )and
~ ~ methyl pluviatilol ( f a r g e ~ i n )have
~ ~ been
reported. The latter, as an example of a compound having
differently substituted aryl groups and one of its aryl groups in
an axial orientation is particularly interesting in view of the
problems involved in assigning structures to such compounds
and the continued efforts to unequivocally assign the signals in
their lH NMR spectra. Thus, a revision of the chemical shift
assignments of the axial and equatorial methylene protons of
epipinoresinol has been p r o p o ~ e d , 'based
~ on NOE difference
spectra. The new assignments are shown in Figure 2.
The absolute configuration of (+)-phrymarolin I (92) has
been revised on the basis of its NOESY spectrum and by
comparison with the spectrum of its epimer, (-)-iso-
phrymarolin I (93) (Scheme 17).77The latter compound has
been synthesized in racemic form by reaction of the 1,2-
thiocarbonate (94) with 2-methoxy-4,5-methylenedioxyphenol,
followed by acetylation.
The reaction of gmelinol (95) with triethylsilane and boron
trifluoride-etherate gives two products, the major one (96)
being an isomer of cycloolivil dimethyl ether (Scheme 18).78It
is formed by reductive rearrangement of the 2,6-diaryl-3,7-
dioxabicyclo[3.3.0]octane skeleton. The minor product (97) is a
2-aryl-4-benzyltetrahydrofuran in which a methoxy group has
been removed from one of the aromatic groups.
(&)-Paulownin (98, Ar = Ar5) has been synthesized using a
 View Online
10 NATURAL PRODUCT REPORTS. 1993

-
OCH2A6

Ar'CHO MgCl ,hv_ H--Q:Z

iii PTSA
AP --- ii ArSCH2X
AP *-- I
.
*

iv PCC

(99) (98) (Ar = Ar5)

Scheme 19
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

(E= C02Me)

e:fH
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AP
23 :eo2cr
(102)
ii MeOH
i LDA
TMSCl
iii CH2N2
Ar5..-
ii LiA'H4-
Os04

NdO4 A$--'
H--- steps*

AS-"
H--Q:HAr

(100) (Ar = A?)

Scheme 21

novel photocyclization reaction (Scheme 19).'' The starting OMe r\

material (99) was prepared in six steps from piperonal. This is HO CONH(CH2),Ar1
the first generally applicable synthesis of the 1-hydroxy-2,6-
diary1 series of compounds and can presumably be applied to
the synthesis of other members of this series, such as isogmelinol HO CONH(CH2)2Ar1 0
(98, Ar = Ar4).
(+)-Sesamin (100) has been synthesized by two routes, the
first involving the conversion of a 2,6-diaryl-bicyclo-
[3.3.O]octane-3,7-dione ( 101) into the 3,7-dioxabicyclo[3.3.O]-
octane by a sequence of reactions involving a Baeyer-Villiger
0
oxidation followed by photolysis of a hypoiodite intermediate
(Scheme 20).80
The second approach to (*)-sesamin involves a Claisen
rearrangement of the silyl enol ether derived from the lactone HOQ
$o RO
(102) (Scheme 21).81This approach has the advantage that it
can also be applied to the synthesis of unsymmetrically Ar
substituted compounds such as methyl piperitol (100, Ar = (106) R = H , A r = A r 5
Ar4).
(107) R = Me, Ar = Ar5
(109) R = H , A r = A r 3
2.5 Arylnaphthalene Derivatives
Seven new arylnaphthalenes and two new dihydro-derivatives
have been reported [( 103)--(11 l)]. Cannabisin A (103) is a new
arylnaphthalene bis-amide isolated from the fruits of Cannabis
sutivu.82Two new lignans, named simply J, and J, (104) and
(105), have been isolated from the leaves of Justiciu hyssopi-
f 0 1 i a . ~Two
~ new arylnaphthalenes (106) and (107) and a 3,4-
dihydro-derivative (108) have been isolated from the bark of
Virolu c ~ l o p h y l l aDehydroguaiaretic
.~~ acid (109) and its 1,2-
dihydro-derivative (1 10) have been isolated from the bark of OH
Kremu f u r f u r ~ c e u .Junaphtoic
~~ acid (1 11) has been isolated
from the leaves of Juniperus sub in^.^^
In addition, a new glycoside of diphyllin, isomeric with
Cleistanthin C, has been isolated from the heartwood of
Flucourtiu rumontchi,86 and a number of new arylnaphthalene
and aryltetralin glycosides have been isolated from Huplo-
phyllum buxbuumii.
 View Online

NATURAL PRODUCT REPORTS, 1993-R. S. WARD 11

R1 ~2 R3 ACO O M e OH

\
0
8
HO
I

Ars O
(112) R' = R2 = R3 = H (1 16)
(1 13) R' = O M e , R2 = R3 = H
(114) R' = OMe, R2 =OH, R3 = H
(1 15) R' = O M e , R2 = H, R3 = OH R
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

(121) R=H,H
(122) R = O
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Me0 Me0-T

/
Me0 Me0 AcO
H

(124) R' = M e ,
(125) R' =OH,
R2 = OH
R2 = M e
OJ
Q- OAc
OMe

(126) R = H
(127) R =OH

NC OSiR3

refl.
Me0
0 Ar5 AP 0
iii A?CHO (70%)
TFACH2Cldl:l)

(129) (100%)
Scheme 22

Deoxypicropodophyllin (1 12) has been isolated from Justicia trangueb~riensis.~~Four new aryltetralones
Juniperus th~jiferu.~' P-Peltatin methyl ether (1 13), 5-methoxy- (124)--(127) have been isolated from the fruits of Virolu
epipicropodophyllin (1 14), 5-methoxypicropodophyllin (1 1 9 , eZongutu.26A new triacetoxy aryltetralin (128) has been isolated
epipodophyllotoxin acetate (1 16) and epipicropodophyllin from the heartwood of the armand pine, Pinus ~ r m a n d i i . ~ ~
acetate (117) have all been isolated from J . ~ u b i n u ~ ~ A new two-step synthesis of 1-arylnaphthalene lignans has
[(112)-( 128)]. 5'-Demethoxy-5-methoxypodophyllotoxin (1 18) been reported,93invoIving a tandem conjugate addition reaction
has been isolated from cell cultures of Linum F l u ~ u m . ~ ~ followed by acid-catalysed cyclization (Scheme 22). By con-
A new aryltetralin diol, named lingueresinol (1 19); has been trolling the conditions required to bring about the cyclization
isolated from the bark of Persea Z i n g ~ e .Otobanone
~~ (120), step it is reported to be possible to isolate the aryltetralin (129)
cagayanin ( I 2 l), and cagayanone (122) are new lignans isolated as a mixture of two diastereoisomers. The full potential of this
from the nutmeg of Myristica c a g ~ y a n e s i s .8-Methoxyiso-
~~ highly functionalized product has not so far been realized.
lariciresinol (123) has been isolated from the aerial parts of An alternative elegant route to arylnaphthalene lactones
 View Online
12 NATURAL PRODUCT REPORTS. 1993

i Bu"Li
ii Ar'CHO
iii MnOP
-
v i LHDS

0
?H 11 H
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

(130)
Scheme 23
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(0 O q ;

-
Ar5
( 132)
A?C=CCH,OH LYxylene
4 p4-vp Ar'CrCCOCI p4-pv D- Ar5C=CC02CH2CaCAr5
0 (131)(92%)
A9
(87%) 0
h5
(133)
Scheme 24

Ap&CH,OH
ArCSCOCI P4-VP ArC=CCO2CH2-
\ YMF-
Me0 Me0
Ar = Ar4 (134)
Ar = Ar5 Ar Me0 Ar
(major) (1 35) (minor) (136)
Scheme 25

involves a bimolecular conjugate addition/cyclization sequence
(Scheme 23).94The beauty of this approach is that the tandem
conjugate addition yields the cyclized product directly. Once
again a highly functionalized intermediate (130) is necessarily
involved in the overall scheme so that an attractive route to
aryltetralin lactones is offered.
Stevenson et al. have shown that the solid-phase copolymer
of 4-vinylpyridine is an excellent reagent for the direct
conversion of arylpropiolic acids to 1-arylnaphthalene
anhydrides, and for the synthesis of acetylenic esters such as
(131) (Scheme 24).95.96 The latter compound can be cyclized on
heating to give a 1 : 1 mixture of the isomeric arylnaphthalene
lactones (132) and (133), along with minor amounts of the
corresponding 7,8-disubstituted compounds.
Polymer mediated esterification of arylpropiolic acid
chlorides with cinnamyl alcohols also proceeds in high yield to
give esters (134) which cyclize regioselectively to give the 3,4-
dihydronaphthalane lactones (135) and ( 1 36) in over 90 % yield
(Scheme 25).
Direct catalytic hydrogenation of 3,4-dihydronaphthalene
lactones prepared in this way is known to yield only the all-cis
aryltetralin (137) (Scheme 26). However, hydrolysis of the
unsaturated lactone prior to hydrogenation gives a mixture of
the two saturated hydroxy-acids which can then be cyclized to
the corresponding saturated lactones (137) and ( 138).97398
The propargyl-cinnamyl ether (139) undergoes cyclization on
treatment with base to afford the cyclic ether (140) (Scheme
27).99In this case the mechanism of the reaction is thought to
involve the formation of an allenyl ether (141) followed by
cycloaddi tion.
A simple route to symmetrically substituted aryltetralins
involves non-oxidative Lewis acid catalysed dimerization of
cinnamate esters (Scheme 28).lo0 Somewhat surprisingly, two
stereoisomeric products are obtained, (142) and (143), and
indeed the 2,3& compound (142) predominates.
A new synthesis of podophyllotoxin has been reported
starting from the o-quinonoid pyrone (144) (Scheme 29).Io1
Reaction with dimethyl maleate gives an adduct (not shown)
which undergoes decarboxylation and a 1,5-sigrnatropic shift
on heating to give the unsaturated diester (145). Selective
reduction of the @-unsaturated ester group followed by
bromohydrin formation and debromination gives (146) which
on oxidation and epimerization gives (147). Reduction of the
ketone and lactonization gives podophyllotoxin (148).
 View Online
NATURAL PRODUCT REPORTS, 1993-R. S. WARD 13

?$&Q - (PP i HdPd-C

( 137)

P
m
KOH - +
0 C0,H
H20H iiiii H+
DCCI
R
I H
AS AF
(R = H or Me) 0

As O
(1 38)
Scheme 26
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001
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t -

Scheme 27

Ar &CO,Me ff3.Et20, R0q..0c02Me + R0wc02Me

/
RO “‘CO,Me RO ‘“C0,Me
Ar = Ar4 (R = Me) Ar Ar
Ar = Ar5 (R + R = CH2) (142) (3:l) (1 43)
Scheme 28

LiBHEt3 ~ <mcH , ’”C0,Me

Scheme 29
 View Online
14 NATURAL PRODUCT REPORTS, 1993

H2
Pd-C ( o ~ * o * c o 2 M e

0 ‘“C0,Me

As
HdRa-Ni

J
i LiBHEt3
ii -0Me
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

I
OH OH
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As

epipodophyllotoxin isopodophyllotoxin
Scheme 30

AS
(150)
Scheme 31

OMe
(152)
Ar*= G O C H 2 P h

OMe Scheme 32

This is just one of a number of syntheses of the podophyllo-
toxin series which exploit the ability of the Diels-Alder reaction
to control the configuration at up to four contiguous chiral
centres. Rodrigo et al. have used the isobenzofuran adduct
(149) as the key intermediate (Scheme 3O).lo2Stereoselective
reduction of the carbon+arbon double bond followed by
direct hydrogenolysis affords access to the isopodophyllotoxin
series, whereas C-3 epimerization followed by hydrogenolysis
gives epipodophyllotoxin.
The same general route has also been used to synthesize
dimethyl conidendrin and dimethyl retrodendrin.lo3
The y-keto ester (150) is a key intermediate in several
syntheses of the podophyllotoxin series. An improved synthesis
of this compound has now been reported involving a manganese
(111)acetate mediated addition to the cinnamate ester (151)
followed by acylation and Lewis acid catalysed rearrangement
(Scheme 31).lo4
Kutney has used the tandem conjugate addition approach to
synthesize the dibenzylbutyrolactone (1 52) and combined this
with the use of a cell-free enzyme preparation from
Catharanthus roseus to bring about the oxidative coupling to
give 4’-demethylepipodophyllotoxin( I 53) (Scheme 32).lo5The
route demonstrates the elegance of utilizing an efficient chemical
approach to the dibenzylbutyrolactone system with the stereo-
selectivity of the enzyme-catalysed cyclization.
A radical cyclization of the unsaturated lactone (155)
prepared by dehydration of the hydroxy-dibenzylbutyrolactone
(1 54) gives deoxyisopicropodophyllin ( I 37), while an intra-
 NATURAL PRODUCT REPORTS, 1993-R.

(154)
S. WARD

(1 55) (major)
AIBN
BusSnH- <e0 A r 6 O
(137) (R = H) (29%)
View Online
15

J Pd(OAc)2/PPh3

Ar' =

Br

(156) (28%)
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

Scheme 33
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0
i HBr or TMSI t (q
0
X
i H

j\y7 0
(X=OR,SR,OCOR,
OH, NH2, NHR)

Ar Ar
Ar = Ar6 or Ar'
Scheme 34

(R = p-D-4,6-Qethylidene glucose)

Ar7 0 Ar 0

etherate.lo7The tetralone (158) in which the familiar benzo-

HO
Ar
molecular Heck reaction gives y-apopicropodophyllin (1 56)
(Scheme 33).lo6However, in both cases the yield of the cyclized
product is low.
Podophyllotoxin can be converted directly into P-apopicro-
podophyllin (1 57) by treatment with boron trifluoride-
dioxole unit is replaced by a benzodioxan has also been
synthesized by a modification of the Gensler route (Scheme
34).lo7 A number of groups continue to concentrate on
preparing new derivatives (e.g. 159) of podophyllotoxin with a
view to enhancing its antitumour activity.lo8-ll2 A number of
other interesting analogues have been reported (Scheme 34),113
and some spin-labelled derivatives of podophyllotoxin have
also been prepared.114*115
Simple analogues of etoposide have also been prepared (e.g.
160 and 161),116-118 and three syntheses of 2-azapodophyllo-
toxins (1 62) and (1 63) have been reported [( 160)-( 164)].'l9-I2'
These syntheses all involve the preparation of an appropriate
dihydro- or tetrahydro-isoquinoline derivative followed by
further manipulation. A number of other aza analogues ( e . g .
164) have also been prepared.122

2 N P R 10

16
KOH/NaBH4
- 4
(84%) (81'Yo)
0
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001
Downloaded by University of Sussex on 04 October 2012
(169) (170)
R = (S)-CHMeC02Me
Scheme 36
A tandem conjugate addition is involved in the asymmetric
synthesis of (-)-epipodophyllotoxin (165) reported by
Vandewalle et al. (Scheme 35).123In this case the outcome of
the cyclization has been controlled by the use of a silylene ether
group. This group plays a crucial role during the cyclization by
holding the reacting centres (C-1 and C-8a) in the required
alignment. However, this control is only achieved by adding
many steps to the overall synthesis. The required absolute
configuration is induced by using the homochiral butenolide
(52).
C h ~ y and
' ~ ~ Charlton et al.1253126 have used asymmetric
Diels-Alder reactions to synthesize podophyllotoxin deriva-
tives. Choy used the benzocyclobutene (166) as the diene
precursor and the homochiral butenolide (167) as the dienophile
in his synthesis of ( -)-epiisopodophyllotoxin (168). Charlton
et al., on the other hand, used the aldehyde (169) as the diene
precursor and the homochiral fumarate ester (170) as the
dienophile in their synthesis of the podophyllotoxin series
(Scheme 36).
Achiwa et aI.l2' have prepared the homochiral unsaturated
lactone (171) as shown in Scheme 37. Acylation of the
monobenzyl lactone (R)-(47) affords the P-keto-lactone (172)
which cyclizes with acid to give (171). Reduction of the
corresponding hydroxy-acid (see Scheme 34) gave ( - )-deoxy-
podophyllotoxin (138) as the major product.
Brown et a1.128have carried out asymmetric syntheses of
View Online
NATURAL PRODUCT REPORTS, 1993
n
:To
i LDA
ii Ti(NEt&CI
iii Ar'CHO
0 (86%)
Iaq. HgC12
CaC03
(83%)
(-)-a-conidendrin and an analogue as shown in Scheme 38.
Thus, bromination at the benzylic position of the appropriate
monobenzyl lactone, followed by introduction of a benzyloxy
group and alkylation afforded the dibenzyl-butyrolactone
(173). Cyclization of this compound using a Lewis acid gave
the corresponding retro-lactone (1 74).
2.6 Dibenzocyclooctadiene Derivatives
Kadsulignans A and B (175) and (176) have been isolated from
~ ~ kadsulignans C and D
the seeds of Kadsura c ~ c c i n e a 'while
(177) and (178) have been isolated from the root bark of K.
longiped~nculata'~~ [(175)-( I 88)l. Acetyl, propionyl, iso-
valeroyl, and benzoyl derivatives of oxokadsurane (179) and
isovaleroyl oxokadsuranol (180) have been isolated from the
stems of K. c ~ c c i n e a . 'The
~ ~ oxokadsurane derivative could be
converted into oxokadsuranol derivatives (e.g. 180) by addition
of NaOMe followed by stirring at room temperature for 5 days.
Isobutyroyl, isovaleroyl, and benzoyl esters of binankadsurin
A (181) have been isolated from the stems of K. longi-
pedunculata.132 Interiorin A-D isolated from K. interior are
esters of the spirodienone (182).133Gomisin A (183) and
gomisin N (1 84) have been isolated from Korean red ginseng,134
while benzoylgomisin Q (185), benzoylgomisin P (186), benzoyl-
gomisin U (187), and tigloylgomisin 0 (188) have been isolated
from the fruits of Schisandra ~phenanthera.'~~. 136 The structure
 View Online
NATURAL PRODUCT REPORTS, 1993-R. S. WARD 17

i LDA see scheme 26

* (-)-(138)(R = H)
0
0
(W(47) (172) = (+)-(51) (171)= (156)
Scheme 37
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

X = Br
(173)X = OCH2Ph (174)R' = Me, R2 = H, Ar = Ar3
X = OCH2Ph
R',R2 = CH2, Ar = Ar5
Ar = A?
Ar = A?
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Scheme 38

Me0
'@
ro ]CH,
0 0
0 0 %H3 ''-CH3
Me0 \
Me0 Me0 Me0
(175)R = H (177) R' = COPh, R2 = AC (179) R' = R 2 = H (181) R = H
(176)R=OAc (180) R' = C2H&H(CH3)CO, R2 = OH
(178) R' = R2 = $

r Me0
\

Me0
Me0%...CH3

OR
Me0 Me0 Me0
(182) R = H (183)R = O H (185)R = COPh (186) R=COPh
(184)R = H

HO

Me0
0 r h , . . C H 3
Me0
Me0

I Me0
Me0
co
(187) R=COPh (188) R = )=\

18
Me0
-
Meow
Me0 I
H+
Scheme 39
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001
Me0
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Me0
Me0
(194)
Scheme 40
Me0
AP
2
Ar
- lTFA
BF3.Et f l
(197)
Scheme 41
of isoschizandrin has also been revised to (189).136,145
Eupodienones-8 and -9, isolated from the flowers of Eupomatia
laurina, have been assigned structures (190) and (191) re-
~pective1y.l~~ They rearrange on exposure to HCl/dioxan to
(192) and (193) respectively, the former involving aryl group
migration, the latter alkyl group migration (Scheme 39).
Reaction of schizandrin (194) and related compounds under
Ritter reaction conditions gives the tetracyclic dienone (195)
(Scheme 40).138.139
As mentioned earlier (Schemes 5 and 14) DDQ in TFA can
be used to bring about non-phenolic oxidative coupling of
diarylbutanes to dibenzocyclooctadienes. This reagent has been
used by several groups140-142and, along with Mn(OAc),,
thallium (111) trifluoroacetate, ruthenium (IV) tetrakis (tri-
fluoroacetate), and vanadium (v) oxyhalides, provides a wide
choice of reagents for bringing about this transformation. Of
particular note is the synthesis of (+)-neoisostegane (197),
from (196), by this route (Scheme 41).Ig3Highest yields can be
obtained using the ruthenium reagent system (RuO, .2H,O in
TFA-TFAA/BF,-Et,O) although this fails when methyl-
enedioxy groups or benzyloxy groups are Since
many biologically active lignans contain the methylenedioxy
group this is a serious limitation and highlights the advantage
View Online
<q
NATURAL PRODUCT REPORTS, 1993
---Me
(192) R’ = H, R2 = Me
(193) R’ = Me, R2 = H
H+
0
OMe
0
Me0
BF3.Et20
Me0
of having a range of alternative reagents available. The RuO,
system gives good yields (80-85 %) in some cases when phenolic
OH groups are present and can be adapted in all cases to give
shorter reaction times by using triflic acid and its anhydride in
place of TFA/TFAA or by using ultrasound. Somewhat
surprisingly, oxidative coupling of the cis lactone (198) gave the
‘normal’ biaryl atropisomer (199) rather than the ‘iso’ series
usually obtained. This product has been converted into (+)-
deoxyschizandrin.
Meyers et al. have used their oxazoline-mediated coupling
approach to carry out an asymmetric synthesis of (-)-
schizandrin ( - )-(189) and ( -)-isoschizandrin ( - )-(194)
(Scheme 42).145
A detailed comparison of the cytotoxic activities of a whole
range of steganacin congeners and analogues has been
~ 0 n d u c t e d . lIt~ ~has been shown that the correct absolute
configuration around the biaryl bond and the orientation of the
lactone carbonyl are critical for expression of the antitumour
activity. The configuration of the acetoxy group is also
important.
The VOF, nonphenolic oxidative coupling procedure men-
tioned earlier has been used to synthesize an aza analogue of
isopicrostegane (Scheme 43).147
 View Online
NATURAL PRODUCT REPORTS, 1993-R. S. WARD 19

OMe

Ph
---CH20Me ArMgBr- oxS i R 3
k z F C H 2 0

Me0 Me0 (6.2:l)

Me0 Me0
\
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

Me0 Me0 MeLi

(-)-(189) + (-)-(194) (8~1)
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Me0 Me0
(1:l)
Scheme 42

R
(206) X,Y = O (208) R = H, Ar = Ar13
(207) X = H, Y =OH (209) R = OMe, A r = Ar13
(215) R=OMe, A r = A r 3
I (216) R=OMe, Ar=Ar5
Me0
Scheme 43
- + - A r ,

R Ar
A+j
(210) R=OMe, Ar=Ar4
R
'jf A F k
Me".
0
Me"*
(211)
(212)
(213)
R = OMe,
R = H, Ar
R = H, Ar
Ar = Ar13
= Ar'
= Ar13
(214) R = H, Ar = Ar13
(217) R=OMe, Ar=Ar3
Arl " ~ ~ 1 5 0 0
(202)
2.7 Miscellaneous Lignans
A new member of a small group of cyclobutane lignans (200)

A+3ko
has been isolated from the stem and leaves of Piper sumatranurn
[(200)-(2 1S)]. 148 Three novel seco-lignans, peperomins A-C
(20 1)-(203), have been isolated from Peperomia japonica. An
X-ray structure of peperomin B (102) has been obtained and all
4 : : - - three
Stobbe compounds
condensation.
have149-151
been synthesized by routes involving a
Me"*
0 OMe

(203) (204) 3 Neolignans

H0CH2* 6 CHZOH

--- \ /
OMe
OCH(CH2OH)Z
Two new dihydrobenzofurans (204) and (205) have been
isolated from the latex of Croton erythro~hilus'~~
of Prunus j u r n ~ s a k u r a lrespectively
~~

of Krarneria l a n ~ e o l a t a ,and
and the bark
[(200)-(2 1S)]. Two new
benzofurans (206) and (207) have been isolated from the roots
~ ~ ~four such compounds, eupo-
matenoids 15-1 8 (208)-(211) have been isolated from the
tubers and aerial parts of Eupomatia bet~nettii.~'Compound
(208) has also been isolated from Krameria k i n a where it
OMe
occurs along with (212)-(214).155 Three potential antifungal
(205) neolignans (2 15)+2 17) have been isolated from the fruits of
 View Online

dH
20 NATURAL PRODUCT REPORTS, 1993

\ / \ /
Ar5

Me0
OHC
r--"
(218)

..CH20H
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

OHC'
(221 1 (222) R' = OH, R2 = R3 = H
(223) R' = R3 = OH, R2 = H
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(224) R' = R3 = H, R2 = OH
(225) R' = H, R 2 = OH, R3=OMe

ArSQOMe
*** &kl
X Y +Arl3

Me0
OH
' OMe ' OMe ' OMe
(228) X,Y = 0 (231) Ar=Ar'
(229) X = H , Y =OH (232) Ar = Ar13

g'uoF
OH
Me0
' OR

Ar

' OMe ArT4

. Ar = Ar', R = OMe
(233)
. (235) R = H while icariol A, (249) is obtained along with icariside E, (250)
R=H
(234) Ar =
(236) R = am,^
0 oglu from Epimediurn s ~ g i t t a t u r n[(238)-(25O)l.
~~
Two other neolignans which do not readily fit into any
prescribed categories are megacerotonic acid (25 1) and antho-
cerotonic acid (252) which have been isolated from Megaceros
, ~ ~ ~schmiditin (218) is a new hexahydro-
Virola k o s ~ h n y iwhile J-lagellaris and Anthoceros punctatus respectively.164
benzofuran isolated from Piper schrnidtii.15' Two naturally occurring dihydrobenzofurans (253) and (254)
A number of new biphenyl derivatives have also been have been synthesized by oxidative coupling of methyl ferulate
reported. Thus (219) has been isolated from the bark of using silver (Scheme 44). Dihydrobenzofurans have
Magnolia h e n r ~ i 'and
~ ~ (200)-(226) have been isolated from also been prepared by oxidation of phenols with iodobenzene
the bark of M . oficinalis [(219)-(226)].159 bis(trifluor0acetate) in the presence of electron rich styrene
A new bicyclo[3.2.lloctane neolignan (227) has been isolated derivatives (Scheme 45).16,316'
from the trunk wood of Ocotea costulatum [(227)-(237)]. 160 The chemistry of the quinone-methide (255), which is thought
Seven other PC-aryl bonded neolignans (228)-(234) have been to be a key intermediate in the biosynthesis of several classes of
isolated from the roots of Krarneria lanceolata and K. neolignans, has been investigated. 168 The quinone-methide was
~ ~Two
i ~ i n a . '155 , yC-aryl bonded neolignan glycosides, named generated from the epi-burchellin derivative (256) which was
tangshenoside I11 and IV, (235) and (236) have been isolated synthesized as shown in Scheme 46. Treatment of (256) with
from the roots of Codonopsis tangshen.161A new biphenyl ether fluoride ion gave high yields of the bicyclo[3.2.lloctane
(237) has been isolated from the bark of Magnolia henryi.15' derivative (257). The quinone-methide (255) is a presumed
Four new benzodioxanes (238)-(241) and two new P- intermediate in this transformation. Treatment of (256) with
aryloxyarylpropanes (242) and (243) have been isolated from TiCl, gave a quantitative yield of the spiro[5.5]undecane
Licaria chrysophylla.162 A number of other P- derivative (258). In this case the intermediate is thought to be
aryloxyarylpropanes (244)-(248) have been isolated from L. the benzyl cation (259). Finally, treatment of the silyl ether of
aurea,60Aristolochia b i r ~ s t r i sand
, ~ ~ Nardostachys jatamansi, 163 (257) with TiCl, gave a quantitative yield of (258) indicating
 View Online
NATURAL PRODUCT REPORTS, 1993-R. S. WARD 21

Ar
(238) Ar = Ar8, R = CH2CH=CH2 \ (242) Ar = Ar6, R = CH=CHCH20H \
(239) Ar = Ar7, R = CH2CH=CH2 (2411 (247)
(243) Ar = Ar6, R = CH=CHCHO
(240) Ar = A?, R = CH=CHCH20H (244) Ar = Ar6, R = CH=CHCH3
(245) Ar = Ar6, R = CH2CH=CH2
(246) Ar = Ar5, R = CH2CH=CH2
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

(249) X,Y = 0, R = H
(2511
(250) X = H , Y =OH, R=Rham
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OMe bMe

(253) R = C H O
Scheme 44 (254) R = C 0 2 M e

PhI(OCOCF3)Z
Ar- +
---Ar
OH R

Ar = Ar4
Ar = Ar5
r( R=H
R = OMe ri‘
R = allyl
Scheme 45

1 Tic14

(259)
(257)
Scheme 46
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22 NATURAL PRODUCT REPORTS, 1993

i Bu'Li i Bu'Li
- i Bu'Li
ii ArCHO

R = CH2CHzCH2
R = CH=CHCH3

'WAr
ii HOAc

'PAr '0
~ HC02H /
Me

OP(NMe,),
R
+ '0 Ar
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

OMe OMe OMe

(261a) Ar = Ar4, R = CH2CH=CH2 (260) (263)
(261b) Ar = Ar5, R = CH=CHCH3
(261c) Ar = Ar', R = CH=CHCH3
Scheme 47
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OH

OR'
--- \ /

(267) X = R2
(269) X = R3
OH

R1 = &OH
\
OH
R2= Me0

HO
qcH20 oHCH20H R3=

AP
X
MeO
OH
(268) X = R2
(270) X = R3
that this is the thermodynamic product under Lewis acid
catalysed reaction conditions.
Several 2-arylbenzofuran neolignans and the corresponding
2,3-dihydrobenzofurans have been synthesized by directed
lithiation of bis(dimethy1amino)phosphoryl derivatives of
phenols (Scheme 47).1693170Reaction with the ester of an
appropriate aromatic acid gives the deoxybenzoin (260) which
can be cyclized to the benzofuran (261). Alternatively, reaction
with an aromatic aldehyde or reduction of (260) with sodium
borohydride gives the threo diastereoisomer (262) as the major
product which, after removal of the bis(dimethy1amino)-
phosphoryl group, can be cyclized to the trans-
dihydrobenzofuran (263). Carinatin (261a), eupomatenoid-1
(26 1b), and eupomatenoid-13 (26 lc) and their dihydro deriva-
tives (263a+) have been prepared in this way.
4 Oligomeric Lignans and Neolignans
A number of new sesqui-lignans and neolignans have been
reported [(264)-(274)]. Macranthol (264) has been isolated
RIO
' 0 QOMe
\@OM=
OH
OH
from Illicium macranthum,171and dihydrobuddlenol B (265)
has been isolated from Prunus jamasakura.153 The cerbera-
lignans J-N (266)-(270) are sesqui-, di-, and tri-lignans isolated
from Cerbera manghas. 17' Four dilignans (27 1)-(274) have
' ~ ~ isolation of
also been isolated from Magnolia o f i ~ i n a l i s . The
haedoxan A from Phryma leptostachya has been
and haedoxans A and D, (275) and (276), have been
~ y n t h e s i z e d (Scheme
l~~ 48).
Dimers produced by acid-catalysed dimerization of the
neolignans ratanhiaphenol I1 and conocarpan have been
characterized and their structures assigned using NMR
spectroscopy. 175
5 Hybrid Lignans
A series of seven sesquiterpene-neolignans have been isolated
from the bark of Magnolia obovata [(277)--(287)]. Eudes-
magnolol and eudeshonokiols A and B (277)-(279) are formed
by combination of a eudesmane-type sesquiterpene with a
biphenyl-type neolignan. Eudesobovatols A and B (280) and
(28 1) combine a eudesmane-type sesquiterpene with a biaryl
 View Online
NATURAL PRODUCT REPORTS. 1993-R. S. WARD 23

OH
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001
Downloaded by University of Sussex on 04 October 2012

OH
(273) (274)

Me0 Me0

(275) A r = @
o (276) A r =

Me0
Scheme 48

JTR
OR'

OR2 /

(280) R'= H, R 2 = X
(281) R' = X , R 2 = H

(277) R = X (278) R' = X, R2 = H

(279) R' = H, R2 = X
x= -9.
 View Online
24 NATURAL PRODUCT REPORTS, 1993

1
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

R PH \
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r:
A

(284) R' = Y, R2 = H
rl (286) R = Y
(285) R' = R2 = Y

OH 0
(294)

R2 WR3 R1

/
0

?
0 OH

R40'
(289) R' = R3 = OMe, R2 = R4 = H, Ar = A?
(290) R' = R3 = OMe, R2 = H, R4 = Ac, Ar = A?
(291) R' = R3 = OMe, R2 = R4 = H, Ar = Ar7
(292) R' = R3 = OMe, R2 = OH, R4 = H, Ar = Ar7
(293) R' = R2 = OH, R3 = R4 = H, Ar = Ar7

ether, while clovanemagnolol (282) and caryolanemagnolol
(283) once again contain a biaryl nit.^'^-''^ Four mono-
terpenyl lignans (284)--(287) have also been isolated from M .
oficinalis. 159
Aleuritin (288) is a new coumarinolignan from Aleurites
fordii. 180 Five new xanthonolignans (289)-(293) have been
isolated from Psorospermum febrifugum,181 and new
flavonolignans (294) and pseudotsuganol (295) have been
isolated from Onopordon corymbosuml g 2 and Pseudotsuga
menziesiilS3[(288)-(29 5)].
The xanthonolignan kielcorin (296) has been synthesized
starting from the hydroxyxanthone (297) which is reacted with
the ethyl 2-bromo-3-aryl-3-oxopropionate (298) (Scheme 49).184
Removal of the benzyl groups from the alkylation product
followed by reduction and cyclization yields (296). A number of
flavonolignans have also been prepared, either by oxidative
coupling of flavonoids with cinnamyl alcohols, catalysed for
example by horseradish p e r ~ x i d a s eor
, ~by
~ ~methods involving
electrochemical oxidation.ls6 For example, deoxysilydianin
methyl ether (299) and its diastereoisomer (not shown) have
 View Online
NATURAL PRODUCT REPORTS, 1993-R. S. WARD 25

0 OCH2Ph Br '0
OH
(297) (298) CH20H
R = CH2Ph, Ar = Ar" C02Et
R = H, Ar=Ar3 (296)
Scheme 49

%-
OR 0 OR 0 OH 0
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001

RO
-A
r-%
. I RO OR / OMe HO 0 --/ OMe
' OH 0 0
(300) R = MOM, Ar = 3-Me0-4-MOM-C6H3 (299)
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Scheme 50

(301) Ar=Ar'5 (303)Ar = 2-Me0-4-HOC6H3 (304) (305)

(302) Ar = 2,4,6-tri(HO)C6H2

(306) R' =OH, R2 = H

(307) R' = H, R2 = OH

been prepared by anodic oxidation of the phenol (300) (Scheme
5O).ls6
6 Norlignans
Several examples of new norlignans and nor-neolignans have
been reported. These compounds are usually found to co-occur
with lignans or neolignans having similar structures. Thus,
benzofurans (30 1)--(303) have been isolated from Krarneria
interior and K. i ~ i n a . ~ The
~ . ' benzodioxane
~~ (304) has been
isolated from Licaria chrysophylla along with the aryl ether
(305).162The latter compound has also been identified in
Liriodendron tulipifera,ls7 while the biphenyl derivatives (306)
and (307) have been isolated from Magnolia oficinalis
[(30 1 )-( 307)].'59
The nor-sesquilignan larreantin (308) has been synthesized
by reacting the 2-naphthyl-4,4-dimethyloxazoline(309) with 4-
isopropoxy-3-methoxyphenyl magnesium bromide (Scheme
51).lss Lithiation of the product of this reaction followed by
reaction with 4-isopropoxy-3-methoxybenzaldehydegave the
phthalide (3 10) which was transformed in a straightforward
manner into (308).
Finally, a potentially useful route to various classes of
neolignans and nor-neolignans involving the Lewis acid
catalysed reaction of styrenes with 1,4-benzoquinones has been

26
Ar = Ar4 or Ar13
R = Me, Bn, pMeObenzyl
Scheme 52
Published on 01 January 1993 on http://pubs.rsc.org | doi:10.1039/NP9931000001
Downloaded by University of Sussex on 04 October 2012
Scheme 53
reported (Scheme 52).189,lS0Furthermore, by using a chiral Ti'"
complex as the Lewis acid catalyst asymmetric induction can be
readily achieved. lS1 A general route to 2-arylbenzofurans has
also been reported involving acylation of 3(2H)-benzofuranones
with aryllead (1v)triacetates (Scheme 53).lS2
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