Phytochernistry,

Vol. 33, No. 3, pp. 523-530, 1993 003 l-9422/93 $6.00 + 0.00
Printedin Great Britain. Q 1993 Fergamon F’ress Ltd

REVIEW ARTICLE NUMBER 77

LIGNANS AND NEOLIGNANS FROM PIPERACEAE

WREN JENSEN, JESPER HANSEN and PER M. BOLL

Department of Chemistry, Odense University, DK-5230 Odense M, Denmark

(Received 1 October 1992)

Key Word Index-Piper; Macropiper; Piperaceae; lignans; neolignans; secolignans.

Abstract-During the past decade many new lignans and neolignans have been isolated from the Piperaceae. Lignans
and neolignans are known to possess biological activity. This review summarizes the structures of lignans and
neolignans presently known in the Piperaceae.

INTRODUCTION some cases only the relative configuration is known; this

is indicated by an asterisk (*) at the number of the
Since the isolation of piperine from Piper niggrum [l],
compound in Scheme 2. Some compounds occur as
scientists have been searching for new physiologically
racemates or are mesoforms; these are cited without
active compounds in plants from the family Piperaceae
asterisks. Moreover some compounds are not cited with
[2, 31. The interest has focused primarily on amides. A
sign of [a-JD,since it has not been given explicitly in the
recent review on the biological activity of lignans [4]
reference. In Scheme 3 the structure of each compound is
prompted us to gather information on lignans and neo-
presented.
lignans presently known from Piperaceae. Compounds
isolated from Indian Piper species [S] and from Piper
species in general L-6,7J have been reviewed previously,
but since the latest review at least 28 new species have
been investigated. Ar
x A
Ar
Ar

30 07

DJWINITIONS *
Ho OH Af
The terms lignan and neolignan have been defined F
elsewhere [S, 91. These references also give a good Al x As
general treatment on the subject of lignans. We have
B 9
divided the compounds into nine groups (A-I) dependent ,A./y9
upon common structural features. These nine groups are
7
presented in Scheme 1 together with the numbering Ar
m
0
system used for each group in this review. Although a
numbering system for lignans and neolignans has been
described [8, 93, we have, whenever there has been
consistency in the literature concerning the numbering of C

a group of compounds, adopted it. The numbering of 0

group A and B should be obvious. The numbering of C
3
and D are according to Chemical Abstracts as used by 01
4
most authors. The members of group E have been c

reviewed recently [ ZO]and numbering is according to this

D
review. For group F the numbering accepted in the

ki
literature is as indicated in Scheme 1. Group G is named 4 3
the benzofuran group and group H as 1,2-diarylpropanes.
In Scheme 2 each compound is represented by a Ar’s 0 2 Ar

number (referring to Scheme 3), its sign of optical rotation E

(if stated in reference), trivial name, molecular mass, plant
sources from which it has been isolated and references. In Scheme 1.

523
Group A (f,4-diaryl-2,3dimethylcyclobutane)
No. Trivial name CW Isolated from Ref.
1* Magnosalin 416 Piper cubeba Cl13
2 Heterotropan 416 Piper cubeba Cl11
3* Andamanicin 416 Piper sumatrunum Cass. DC. cm
Group B (2,3dibenzylbutan-1,4diol)
No. Trivial name WI+ Isolated from Ref.
4 ( - )-Dihydrocubebin 358 Piper cubeba Cl31
Piper trichostachyon Cl41
Piper clwsii Cass. DC Cl51
Piper guineense WI
5* ( - )-Dihydrotrichostin 388 Piper trichostachyon Cl41
6 434 Piper clusii Cl71
7 (- )-Dihydroclusin 404 Piper cubeba Cl31
8 Hemiareinsin Piper cubeba Cl11
Group C (3,4-dibenzyl-y-butyrolactol)
NO. Trival name WI’ Isolated from Ref.
9 ( - )-Clusin 402 Piper clusii Cass. DC CW
Piper cubeba Cl31
10 (-)-Cubebin 356 Piper trichostachyon DC Cl43
Piper cubeba Cl31
Piper nigrm Linn. Cl81
Piper ribesoides Wall. Cl91
Piper lacuvwsum WI
Piper ciwiii Cass. DC Cl51
11* ( - )-Trichostin 386 Piper trichosthacyon DC Cl41
12 (-)-Clusinethylether 430 Piper clusii c171
13 ( - )-Cubebinin 448 Piper cubebu Cl33
14 a-O-Ethylcubebin 384 Piper cubeba Cl11
15 B-O-Ethylcubebin 384 Piper cubeba Clll
16 372 Piper nigrum Linn. L-211
17 372 Piper nigrum Linn. c211
Group D (y-butyrolactones)
No. Trivial name WI+ Isolated from Ref.
18 (-)-Hinokinin 354 Piper clusii Cass. DC WI
Piper cubeba Cl31
19 (-)-Yatein 400 Piper clusii Cass. DC cwl
Piper cubeba cm
20 (- )-Cubebininolide 446 Piper cubeba L-221
Piper clusii Cl71
21 370 Piper cubeba WI
22 ( - )-Cubebinone 430 Piper cubeba C221
23 (- )-Isoyatein 400 Piper cubeba I221
24 416 Piper cubeba I?21
25 ( - )-5”-Methoxyhinokinin 384 Piper cubeba Cl11
*Piper trichostachyon DC Cl43
26 ( -t )-Peperomin A 414 Peperomea japonica Makino c233
27 (+ )-Peperomin B 430 Peperomea japonica Makino c231
28 (+ )-Peperomin C Peperomea japonica Makino P31
Group E (2,5-bisaryl-3+dimethyl tetrahydrofurans)
No, Trivial name WI’ Isolated from Ref.
29 (+ )-Calopiptin 356 Piper schmidtii Hook C241
30 (- )-Zuionin-A 340 Piper schmidtii Hook c243
31* (- )-Machilin-G 356 Piper schmidtii Hook C241
32* (- )-Galbelgin 372 Piper thomsonii 0.D. Tyagi, per-
sonal communi-
cation
Piper attenuatum c251
33 Galgravin 372 Piper schmidtii Hook WI
Piper wailichii Hand.-Mazz c271
Piper hancei Maxim. c271
34* ( + )-Grandisin 432 Piper polysyporum C. DC CW
Scheme 2. Continued on facing page.
Group F (2,6-biaaryl-3,7dioxa[3,3,O]bicyclooctane)
No. Trivial name WI’ Isolated from Ref.
35 ( + )-Sesamine 354 Piper brachystachyum Wall. PI
Piper retrofiuctum Vahl. CM1
Piper. peepuloides C311
Piper lowong ~321
Piper sylvaticum c331
Piper guineense Pl
Piper clusii c351
Piper longpun 1361
36* (+ )-Yangambin 446 Piper guineense t371
Macropiper excelsum C381
37 Ascbantin Piper guinea c351
Piper clusii C35aI
38* ( + )-Excelsin 414 Macropiper excelsum c391
39* ( + )-Dimetboxyexcelsin 384 Macropiper excelsum c391
40’ ( + )-Asarinine 354 Piper brachystackyum c401
Piper sumatranum Cass. DC cm
41* ( + )-Epiexcelsin 414 Macropiper excelsum c391
Piper aborescens C4ll
42* ( + )-Sylvateslnin 372 Piper sylvaticum Roxb. r.421
43* Fargesin 370 Piper braehystaehyum Wall. ~291
44* Pluviatilol 356 Piper brachystachyum Wall. ~291
45* (+)Diaeudesmin 386 Piper peepuloides c431
Piper longum L-441
46* (+ )-Diayangambin 446 Macropiper excelsum c391
Piper aborescens c411
Group G (benzofurans)
No. Trivial name WI’ Isolated from Ref.
49+ Fb-53A 356 Piper clarkii c451
w ( + )Xadsurenon 356 Piperfitokudzura Sieb & Zucc r.461
Piper w&i&i Hand-Mazz c271
Piper hancei Maxim. ~271
51* (- )-Kadsurin A 372 Piperfutokadzura Sieb & Zucc C&l
Piper schmidtii Hook ~241
!32* (-)Xadsurin J3 374 Piper futokadsura Sieb & Zucc C&l
53 (-)-Fiperenone 388 Piper futokadzura Sieb & Zucc c47l
!!4* *(- )-Scbmiditin 374 Piper schmidtii Hook VI
55* 340 Piper capense c431
56; 338 Piper capense t481
!!7+ Han&on 340 Piper huncei Maxim. c491
ss Denudatin B 356 Piper hancei Maxim. C491
Piper wallichii Hand-Map. ~271
59 ( + )-Burcbellin . 340 Piper hancei Maxim. w1
60 Eupomantene 322 Piper interuptum Opiz Cal
Group H ( l&diarylpropanes)
No. Trivial name WI’ Isolated from Ref.
61* 340 Piper capense C5ll
62 (- )-Isodihydrofutoquinol A 356 Piperfitokadzura Sieb & Zucc c521
Piper schmidtii Hook P41
63 ( + )&odihydrofutoquinoI B 356 Piper futokadzura Sieb & ZUIX ~521
Piper schidtii Hook ~241
64. 342 Piper capense c511
65* (Two epimers) 340 Piper capense C5ll
66 (+ )-Lancifolin D 372 Piper polysyphorum C. DC cw
67 Futoquinol (bancinon D) 354 Piperfitokadzura Sieb & Zucc c531
Piper schmidtii Hook ~241
Piper hancei Maxim. ~271
Piper polysyphorum C. DC IPI
6% Han&on B 356 Piper hancei Maxim. PI
69 Hancinon C 400 Piper hancei Maxim. t541
Piper wallichii Hand-Mazz cvl
70 Wallicbinine 370 Piper wullichii Hand-b&z ~271
Piper polysyphorum C. DC Bl
71 Isofutoquinol B 354 Piper futokadzura Sieb & ZUGC ~521

2. Continued overleaf.
526 S. JE~xsEN et al.

Group I (miscellaneous)
No. Trivial name WI+ Isoiated from Ref.
72* (+)-Han&o1 358 Piper hancei Maxim. WI
73* Clarkinol 342 Piper clarkii c451
74 Isofutoquinol A 354 Piper futokadzura Sieb & Zucc ~521
75 Futoenon 340 Piper,futokad.zuru Sieb & Zucc t54al
76* 358 Piper capense L-481
77* Polysyphorin 418 Piper polysyphorum C. DC r21
78* (+ )-Virolongin A 402 Piper polysyphorum C. DC cw
79* (+)-Sylvone 432 Piper sylvaticum Roxb. c551
Scheme 2. Lignans isolated from Piperaceae.

2 3

NoArM No Al Ar’
9 h Ar6 18 Ar6 &i
10 Ar6 Ar6 19 Arl Are
x1* Ar, Ar6 20 Ar, Aq
13 Ar, Ar, 21 h6 h2
16 he Ara 22 Aq Arl
17 Arz Are 23 k6 kl
24 Aq Ar2
25 Ar, Are

No. Ar AI’
12 hl Ab
14 k6 Ar6,/3H-2
15 k6 ArGaH-2

Scheme 3. Continued on facing page.

 Lignans and neolignans from Piperaceae 527

2 -
55 -!b
‘0 / /
-0
-0

‘0 / /
-0 -
0

$ d

:: -
.3-5 ‘0
.$
’ /
0

$
528 S. JENSENet al.

\
(0 b
:_o\
0 , p” 3 O\
I 0I-I
0'

72

‘0

O\

79

Scheme3.

though Koul ef al. [14] have observed a negative Cotton

4 relative configuration at C-3 and C-4 by ‘HNMR ana-
In the groups B, C and D, the absolute stereochemistry
has been determined by chemical interconversion,
‘HNMR and ORD comparison with compounds
of known absolute stereochemistry [ll, 13-15, 17,
223 namely (-)-cubebin [56-J, (-)-hinokinin [57] and
( - )-yatein [58 J. In this way all compounds except 5 in the
group B were assigned the absolute configuration 2R, 3R
and all compounds except 11 in group C and 25-28 in
group D were assigned the absolute configuration 3R, 4R.
Compounds 26-28 belong to the secolignans [23]. Al-
effect for compound 25 in a similar manner to Badheka et
al. for the same compound [ll], they have assigned the
absolute configuration 3S, 4s to 25. This assignment as
well as the 2S, 35 and 3S, 4s assignments of 5 and 11,
respectively, should be changed to relative configura-
tions. According to Harmatha et al. the proper way to
determine absolute configuration is first to establish the
lysis and second to find the absolute configuration by
comparing the molar rotation with those of similar
compounds of known absolute stereochemistry [!%I. In
group E the absolute configuration of 29 and 30 has been
established through chemical derivatization and de-
gradation and by NMR techniques [59, 601. To our
knowledge only compounds 35 and 37 from group F have
been examined concerning the absolute stereochemistry
191. It is noteworthy that in group G the absolute
configuration has only been established for (-)-
piperenone (53) [61], denudatin B (58) [62] and (+ )-
burchellin (59) [63]. In group H the absolute configura-
tion of 62, 63 and 66 has been established by ORD
measurement [WJ.
Group H can be divided into two subgroups: com-
pounds which are A7 (67-71) and those which are satura-
ted at C-7 (61-66). None of the compounds which are A7
show optical activity. This has been explained by a
biosynthetic pathway involving radicals [65]. Compound
66 has been shown to be a racemic mixture by X-ray
 Lignans and neolignansfrom Piperaceae
analysis [27], thus indicating the correctness of the above
assumption concerning the biosynthetic pathway.
Han et al. [27, 28, 461 have tested extracts of Piper
hancei, P. wallichii, P. futokadsura and P. polysyphorum
with the platelet activating factor binding assay (PAF).
Compound 50 has shown activity in the PAF binding
assay and a route for HPLC-purification has been de-
rived [66]. Compound 53 has shown some antifeeding
activity against the larvae Spodoptera Zitura[47]. Several
of the lignans isolated from Piperaceae show varied
biological activities [4].
Compound 3 has been synthesized by irradiating asar-
one with sunlight [12]. Several members of the groups B,
C and D have been synthesized by chemical inter-
conversion among the compounds [13-15,17,58]. How-
ever, a total synthesis of the compounds (-)-ct.&bin and
(-)-hinokinin has been achieved [56, 57l. Sarkanen
et al. have achieved synthesis of several members of group
E [67]. Compounds 62,67,71,74 [68] and the racemates
of !!I$75 [69] and !I8 [70] have been synthesized.
From Scheme 2 it should be noted that with two
exceptions the species of the genus Piper so far investig-
ated can be divided into two groups depending on the
types of lignans they have been reported to contain. One
group contains only lignans from the groups B-D and
F. These plants are: P. aborescens, P. brachystachyum, P.
clusii, P. cubeba, P. guineense, P. lacunosum, P. longum, P.
lowong, P. nigrum, P. peepuloides, P. retrofiactum, P.
ribesoides, P. sumatranum, P. sylvuticum and P. trichosta-
chyon. Another group of plants has been found to contain
only neolignans (groups A, G, H) and group E lignans.
These arc: P. attenuatum, P. capense, P. clarkii, P. cubeba,
P.futokadzura, P. hancei, P. interruptum, P. polysyphorum,
P. schmidtii, P. sumatranum, P. thomsonii and P. wallichii.
The exceptions are P. cubeba and P. sumatranum which
are represented in group A (1, 2) and in group F (40),
respectively.
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