Ace to Genin as Natural Es

7/22/2019 Ace to Genin as Natural Es

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~ PergamonPl h S0031-9422(97)00917-5

Phyto~hemisto,,Vol . 48 , No . 7 . pp . 1087 1117 . 1998i 1 9 9 8 E l s e v i e r S c i e n c e L t d . A l l r i g h t s r e s e r v e dP r i n t e d i n G r e a t B r i t a i n0 0 3 1 9 4 2 2 / 9 8 $ 1 9 . 0 0 + 1 ) . 0 0

REVIEWARTICLENUMBER131N A T U R A L A C E T O G E N I N S F R O M A N N O N A C E A E , S Y N T H E S I S A N D

M E C H A N I S M S O F A C T I O NIN HONOUR OF THE RETIREMENT OF PROFESSOR ANDRI~ CAVIl

M. CARMEN ZAFRA-POLO, BRUNO FIGADI~RE, TERESAGALLARDO, JOSI~ R. TORMO and DIEGO CORTES*Departamento de Farmacologia, Farmacognosia y Farmacodinamia, Facultad de Farmacia, Universidad de Valencia,46100 Burjassot, Valencia, Spain; t Laboratoire de Pharmacognosie, associd au CNRS (BIOCIS), Universit~Paris-Sud, Facult6 de Pharmacie, 92296 Chfitenay-Malabry, France

(Received4 August 1997)Key Word Inde x--A nnon ace ae; linear, epoxy, mono- and bis-tetrahydrofura nic acetogenins;miscellaneous acetogenins; total synthesis; biological activity; mechanism of action.

Abst ract --The search concern ing Anno nace ous acetogenins has increased in the last two years. The goal ofthe present review is to summarize the knowledge about new isolated acetogenins as well as the advances insynthesis, biological activity and mecha nism of action. 1998 Elsevier Science Ltd. All rights reserved

INTRODUCTIONSince our last review was pub lished [1], research in thefield of Annonaceous acetogenins dealing with theisolation, structural elucidation, hemisynthesis ortotal synthesis, and mechanism of the cytotoxicaction, has evidenced a rapid increase. In fact, to the128 compounds then reviewed, a total of 113 newacetogenins enlarged the list of isolated compounds.

Thus, the primary aim of this review is to bringup-to-date, in graphical form, those data with thecompounds described during the period from June1995-June1997, together with their origin and litera-ture references. The classification is made followingthe same criteria and based on the structural charac-teristics shown in Fig. 1. Three new subgroups ofacetogenins are presented, characterized by a differenttype of side chain: (T-G.I) (T-G.2) and (T-H). Inaddition, a new type of y-lactone moiety (L-D) char-acterized by a 7-hydroxy-y-methyl unsatu rated-; ,-lactone ring is included.

As in our previous reviews [1-5] we discuss, byconsidering the spectral data, several uncertainaspects on compo unds described as new acetogenins.

* Author to whom correspondence should be addressed.E-mail: [email protected] of the authors (B.F. and D.C.) want to express theirgratitude to Prof. Andr6 Cav6 for transmitting his knowledgeand passion in the world of Natural Products.

Within the tables, compounds are presented accordingto the chronological order of discovery. For a com-plete revision, both new and previously published dataare reported. To improve the comprehension of thetables, only identical compound s with different names,but isolated at the same time (linked by 'or'), aremaintained, for the acetogenins referred therein [1].The great number of compounds to be added madenecessary the inclusion of new subgroups but theirnumber listed in the previous review are maintainedwith only one exception. Because of the s ubdivision ofadjacent b is -TH F acetogenins, i n c~,c(-dihydroxylated(Table 6) and c~-monohydroxylated (Table 7), num-bers of compounds included as panalicin type havebeen changed (type 15 in [1] and here considered astype 14b). The additional new compounds are givenunderlined. The reliable numb er of acetogenins mustbe considered as 241 so far, 15 of them being linear,14 epoxy, 113 mono-THF, 94 bis-THF, and 5 otheracetogenins that we include in a miscellaneous group(see Tables 1-10).

Table 11 summarizes the botanical sources fromwhich new acetogenins have been isolated inde-pendently their further isolation from other Annon-aceous species. Three new genera, Polyalthia, Porceliaan d Disepalum, were found to con tain acetogenins. InTable 12 the acetogenins cited in this review are listedin alphabetical order. A survey on the last two yearsadvances in the total synthesis, and the biologicalactivities of acetogenins, is included.

1087


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1088 M.C. ZAFRA-POLO t al.* T y p e s o f T H F a n d T H P 0 t - h y d r o x y l a t e d s y s t e m s :

H O O H O H H O O H

T - A T - B T - C

T - D

OH

T - E

OH

T - F T - G . 1

O H O O HH 0 O H

T - G . 2Fig. 1. Tetrahydrofuran (THF), tetrahydropyran (THP), ~,-lactoneand epoxy systems in Annonaceous acetogenins.

LINEAR ACETOGENINS

The isolated natural linear acetogenins, claimed asthe biogenetic precursors of epoxy- and THF-ace-togenins, differ in the degree of unsaturation andhydroxylation of their alkyl chain. We can considerhere three subgroups [1, 6-13] (Table l).

(i) Vicinal dihydroxylated and olefinic acetogenins(la: giganin type) are the most abundant subgroup,which include eight compounds. They are char-acterized by the presence of a vicinal diol and, withthe only exception of t onkineli n (1.6), by one or twodouble bonds. In all of these acetogenins a c i s -geometry for the double bond and a t h r e o relativeconfiguration at the vicinal diol has been estab-lished.

Cohibins-A (1.8) and B (1.9) were obtained as amixture and their structures established by MS/MSspectrometry [10]. Venezinone (1.10), with a 2-ace-tonyl s aturat ed 7-1actone moiety (L-B), was describedas a classical mixture of two 2 , 4 - c i s and 2 , 4 - t r a n sisomers. This can be rationalized by trans-lactonization of acetogenins possessing an OH at C-4[14, 15], giving the pair o f compo unds currently name d'iso'-acetogenins , as me ntioned below in the chaptersof mono- and bis-THF actogenins.

(ii) Hydroxylated (or ketonic) linear acetogenins(lb: reticulatamol type) in which the saturated hy dro-carbo n chain is substituted by one or more non-vi cinalhydroxyl groups (or ketone group).

(iii) Olefinic and acetylenic acetogenins (le: mur-idienin-I type) without hydroxyl groups on the alkylchain. Two non classical linear acetogenins, isolatedfrom the Brazilian Annonaceae P o r c e l ia m a c r o c a r p a ,have been described here. Their structures are char-acterized by a short alkyl chain with a triple bond,bearing a terminal saturated /~-hydroxy ?-methyl 7-lactone (L-C) [13]. It is the first report on ace togeninswith an acetylenic side chain and without a C35/C3vbut a C25 skeleton. A biogenetic pattern involvingClaisen condensation of a C2z fatty acid with pyruvicacid is proposed for 1.14 and 1.15 [13].

EPOXY ACETOGENINS

In the group of epoxy-acetogenins (Table 2), onlyepomusen ins-A and B (2.4 and 2.5) [16], two mon o-epoxy and olefinic compo unds obta ined as a mixture,are added. As we have described above, epoxy-acetogenins, originating by oxidation of linear and


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N a t u r a l a c e t o g e n i n s f r o m A n n o n a c e a e , s y n t h , a n d m e c h . o f a c t i o n 1 08 9* T y p e s o f e p o x y r i n gs :

O O

E -AO O O

E -C

0

E -B

* T y p e s o f ~ ,- l a c to n e r i n g s :

35/37H 3 C ~

L -A(R= H or OH)

t o35137X ) , . > .H3C v


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1090 M .C . ZAFRAopOLO t al .Table 1 . Ace togen ins wi thou t te t rah ydro fu ran r ings : l inea r ace togen ins

Ole fin ic Hydroxy l Re la t ive Mo lecu la r Ann onacea e spec ies**pos i t ion pos i t ions conf igura t ion* fo rmu la M [Ref. ]1 . L i n e a r a e e t o g e n i n s

l a . V i c i n a l d i h y d r o x y l a t e d a n d o l e f i n i c l in e a r a c e t o g e n i n s , ' g i g a n i n t y p e ':L - A O H

. o .R = H o r O H o r = O

3 2 / 3 4( C H z ) n C H 3

3 5 / 3 71.1 giganin CI3~ CI4 4,10,17,18 c- th C35H6406 580 G . 9 i g a n t e u s [1, 6]1 .2 v e n e z e n i n C 2 L z C 2 2 4 ,1 7 ,1 8 ( C O ,1 0 ) th-c C 3 7 H 6 6 06 60 6 X . a r o m a t i c a [1]1 .5 co r iad ien in C~ 3~- C1 4; 4 ,10 ,21 ,22 c-c- th C 3 7 H 6 6 06 60 6 A . c or i ac e a [7]C ] ~ C ~ 81.6 ton kine lin 17,18 th C 3 7 H 7 0 04 57 8 U . t onk i ne s i s [8]1.7 mo nt ec ris tin C~7~-----CI8; 13,14 th-c -c C 3 7 H 6 6 04 57 4 A . m ur i c a t a [9]

C2]=C221 .8 coh ib in -A C 1~C20 15,16 th-c C 3 5 H 6 4 04 548 A . m ur i c a t a [10]1.9 coh ibin -B C~7-----C,8 13,14 t h - c C35H6404 548 A . m u r i c a t a [ 1 0 ]L -B

03 7 ~ 1 ~ 2 ~ 4 . ~ 7 ~ 3 4~ ' ~ h A A A 1 ~H , ,C - - ( C H 2 ) , o C H s

H O H 21 221 .10 venez inone C21~---------C22 1 0 , 1 7 , 1 8 th-c C 3 7 H 6 8 06 60 8 X . a r o m a t i c a [11]lb . H ydroxy la ted (o r ke ton ic ) l inea r ace togen ins , ' r e t icu la tamol type ' :

R 'L - A 2

R R = H o r O HH s C 1 O R ' = H o r O H o r = O

53 4 A . r e t i c u l a t a [1]53 2 A . r e t i c u l a t a [1]56 6 A s . l ong i f o l i a [6]

3234~ (CH=) ,aCH3

51 454 2

A . m ur i c a t a [12]A . m u r i c a t a

3 51.3 reticula tamo l - - 15 - - C35H66031.4 reticu latam one (CO , 15) - - C35H64031.1 1 longa nin 4,10,18 - - C3sH660 5le. Olefinic and acetylenic l inear acetogenins (non hydroxylated), 'muridienin-1 type ' :

- I , : A ,

H 3 C "O " 1 " O35/371.12 muridienin-1 C]3zC~4; c- c C 3 5 H 6 2 021.13 mu ridienin-2 C~5 ~C~ 6; c-c C37H6602C,~-----C20

L - C 1 3 1 4

2 51.14 butyrola ctone-1 C21~C22 C25H42Os 390 P . m a c r o c a r p a1 .15 bu ty ro lac tone-2 - - - - C25H4403 392 P . m a c r o c a r p a

* th: thr eo; c: cis.** G : G on i o t h a l am us ; X : X y l op i a ; A : A nno na; U : U v ar ia ; A s : A s i m i na; P : P orc e l i a .


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Natu ra l ace togen ins f rom Annon aceae , syn th , and m ech . o f ac t ionTab le 2 . Ace togen ins wi thou t te t rahydro fu ran r ings : epoxy-ace togen ins

1091

Olefin ic Epoxy Mo lecu la r Ann onaceae species*pos i t ion pos i t ions fo rmula M + [Ref. ]

I1 . E p o x y - a e e t o g e n i n s2 . Mo no-epo xy o le f in ic, ' epoxymur in -A type ' :

E - A0 ~ 3 2 / 3 4l . - ,t / \' ' ' ~ L - A . ~ ( e l l2 ) . CHa

3 5 / 3 7H3 C" " 0 / "(32 .1 epoxymur in -A

o r e p o m u r i c e n in - A2 .2 epoxymur in -B2 .3 epomur icen in -B2.4 e p_omusenin-A2 .5 e pomusen in -B3. Bis-epoxy, ' d ie p o m u r i c a n i n -A t y p e ':

C ~ 2 0 1 5 , 1 6 C3sH620~ 53 0C I 5 ~ - - - - ~ 1 6 19,20 C35H6203 530C~7~-Cts 13,14 C35H6203 53 0C2~----C22 17,18 C37H660 3 55 8C L ~ 2 0 1 5 , 1 6 C37H6603 55 8

A. muricata [1]A. muricata [1]A. muricata [1]A. muricata [1]R. mucosa [16]R. mucosa [16]

R O

3 5 / 3 C ~ ~ ' # ~ O ( R =~ - - " ~ " H o r =0)H3 O = =

o 3 2 / 3 4/ / - - - ~ (C H 2 ). e lls

3 .1 d iepom ur ican in -A - - 15 ,16 ,19 ,20 C35H6204 54 6 A. muricata [1]3.2 core pox ylon e (C- -O ,10) 15,16,19,20 C35H6oO5 560 A. muricata [1]3.3 dieporeticanin-1 -- 17,18,21,22 C37H6604 57 4 A. reticulata [1]3.4 diepore ticanin-2 - - 19,20,23,24 C37H6604 57 4 A. reticulata [1]3 .5 d iepore t icen in C2 3zC 24 15 ,16 ,19 ,20 C37H6404 572 A. reticulata [1]3.6 diepo xym ontin - - 11,12,13,14 C35H6204 54 6 A. montana [1]3.7 diepo mu ricanin -B - - 17,18,21,22 C35H620 4 54 6 R. membranacea [1]3.8 diepox yrollin - - 15,16,19,20 C37H6604 57 4 R. membranacea [1]4. Tri-epoxy, ' t r i p o x y r o i l i n type ' :

E - c

4.1

/ ~ N O 3 4

37X L4H,C- "O" -(3t ri p o xy r o ll i n - - 1 5 , 1 6 , 1 9 , 2 0 , 2 3 , 2 4 C37H640 5 58 8 R. membranacea [I ]

* A.: Annona; R: Rollinia.

( 7. 22 ) a n d r o l l i n e c i n s - A + B ( 7 .2 3 ) a re c l a i m e d a s 1 2a n d 1 4 - e p i m e r s , r e s p e c t i v e l y , b a s e d o n l y i n a n i n v a l u -a b l e d if f e re n c e in t h e i r ~ H - N M R s p e c t ra l d a t a . T h ed i f fe r e n c e b e tw e e n a r i a n a c i n a n d j a v o r i c i n w a s e s t a b -l i sh e d b y t h e p r o t o n r e s o n a n c e o f th e m e t h i n e a t C -1 2 , 3 3 .6 3 a n d 6 3 .6 0 , r e s p e c t i v e l y [ 2 9] . F o r r o l l i n e c i n s -A a n d B th e m e t h i n e r e s o n a n c e s a t C - 1 4 w e r e 63 . 6 3 /3 . 6 2 a n d 6 7 1 . 7 2 / 71 . 9 0 i n t h e I H - N M R a n d ~ 3C -

N M R [ 30 ]. A s i m i l a r d i f f e r e n c e w a s d e s c r i b e d f o rg i g a n t r a n s e n i n s - A + B (7 .3 4 ), r e p o r t e d a s 2 3 - ep i m e r sb e c a u s e o f a d i f f e r e n c e o f 0 .0 2 p p m w a s o b s e r v e db e t w e e n b o t h H - 2 3 [ 3 6 ] . I n o u r o p i n i o n , t h e s e v e r ym i n o r d i f f e r e n c e s i n s p e c t r a l s h i f t s a r e i n s u f f i c i e n t, s of a r, t o c o n s i d e r t h o s e c o m p o u n d s a s d i ff e r e n t a c e t o -g e n i n s .

S u r p r i s i n g l y , a m e t h i n e r e s o n a n c e a t b 8 6 . 2 ( C - 1 6 )


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1092 M .C . ZAFRA-POLO t a l .Tab le 3. M on o- TH F ~,c(-dihydroxylated 7-1actone acetoge nins

Hydrox y l TH F- re la t ive Mo lecu la r Ann onaceae species*pos i t ions conf igura t ion* fo rmula M + [Ref. ]

1 1 I. M o n o - T H F ~ t ,~ t '- d ih y d r ox y la t ed a e e t o g e n i n s

R R H 0 T - A O H

3 5 / 3 7 , ~ 1 ~ _ n k .. .. .. _/H a C O ( R = H o r O i l o r = O )

5 . Dihydroxy la ted , ' u v a r i a m i c i n - 1 t y p e ' :5.1 uvariam icin-I 15,20 t h / t / t h C 7H68Os 5925.2 uvariamicin-I1 17,22 t h / t / t h C~7H6805 592

or re t icu la tac in5 .3 uvar iam ic in - I l l 19 ,24 t h / t / t h C~7H6~O~ 5925.4 solam in 15,20 t h / t / t h C35H6405 5645.5 uvariam icin-IV 13,18 t h / t / t h C~7H6805 5925.6 bullatencin (C23~------------~24) 15,20 t h / t / t h CwH6605 5905.7 reticulatain-1 17,22 t h / t / e r C ~ 7 H 6 8 O s 59 25.8 reticulatain-2 19,24 t h / t / e r C3vH6805 5925 .9 anno tem oyin - I 17 ,22 t h / I / t h C35H6405 5645 .10 anno temo yin -2 17 ,22 t h / t / e r C 3 5 H 6 4 05 56 4

3234( C H 2 ) . C H a

U . n a r u m [1]U . n a r u m [1]A . r e t i c u l a t a [1]U . n a r u m [1]A . m u r i c a t a [1]A . b u l l a t a [1]A . b u l l a t a [1]A . r e t i c u l a t a [1]A . r e t i c u l a t a [1]A . a t e m o y a [20]A . a t e m v a [20]

6. Trihydroxylated and dihydroxylated ketonic, 'murisolin t y p e ' :6.1 mu risolin 4,15,20 t h / t / t h C 3 5 H 6 4 066.2 corosso lin 10,15,20 t h / t / t h C 3 5 H 6 4 066 .3 co rosso lone (C= O,1 0) 15 ,20 t h / t / t h C ~ s H 6 2 0 66.4 gig an en in (C,~---CI~) 13,18,21 t h / t / t h C37H~00~6.5 asirninenin-A (C23=C2~) 4,15,20 t h / c / t h C ~ 7 H 6 6 066.6 asiminenin-B (C23~C24) 4,15,20 th/t,,'th C37H66066.7 cis-murisolin 4,15,20 th/c,,'th C~5H640~,6.8 mu risolin -A 4,15,20 t h / t / e r C 3 5 H 6 4 066.9 uvarig ranin 15,OAc-17,22 e r / t / t h C~9H70076.10 tonkine cin 5,17,22 t h / t / t h C37H680~,6.11 longifolicin 10,13,18 t h : ' t / t h C35H64066.12 longicoric in 10,15,20 t h / t / t h C37H68066 .13 4 -deoxyann omo ntac in 10 ,17 ,22 t h / t / t h C 7 H 6 8 0 6

58 0 A . m u r i c a t a [I ]58 0 A . m u r i c a t a [1]57 8 A . m u r i c a t a [1]60 6 G . g i g a n t e u s [1]60 6 A s . t r i l o b a [21]60 6 As . t r i loba 2[~]58 0 A s . t r i l o b a [22]58 0 A s . t r i l o b a [22]65 0 U . g r a n d ! f l o r a [23]60 8 U . t o n k i n e s i s [24]58 0 As. longifol ia 2[~_]60 8 As. longi/bl ia 2[~_]60 8 G . , q i q a n t e u s [26]

7 . Te t rahydroxy la ted and t r ihydroxy la ted ke tonic :7 a - w i t h O H i n 4 'a n n o n a e i n t y p e' :7.1 ann onac in 4,10,15,20 t h / t / t h C 3 5 H 6 4 0 77.2 gonio thalam icin 4,10,13,18 t h / t / t h C 3 5 H 6 4 0 77.3 an no na ci no ne (C~-----O, 0) 4,15,20 t h / t / t h C 3 5 H 6 2 0 77.4 anno nacin -A 4,10,15,20 t h / t / e r C35H64077.5 anno mo ntac in 4,10,17,22 t h / t / t h C37H68077.6 anno reticu in 4,9,15,20 t h / t / t h C35H64077 .7 annore t icu inone (C =O ,9) 4 ,15 ,20 t h / t / t h C35H62077.8 xylop ianin 4,8,15,20 t h / t / t h C35H64077.9 xylopiacin 4 , 8 , 1 5 , 2 0 t h / t / t h C37H68077.10 xylom aticin 4,10,15,20 t h / t / t h C 3 7 H 6 8 077 .11 re t icu lac inone (C ~O , I 1 4 ,15 ,20 t h / t / t h C35H62077 .12 squamo sten-A (C23--C 24) 4 ,12 ,15 ,20 t h / t / t h C37H66077 .13 gon ionen in (C21~C22) 4,10,13,18 t h / t / t h C37H66077.14 xylopien (C2~------------~24) 4,8,15,20 t h / t / t h C 3 7 H 6 6 0 77 . 1 5 x y l om a t e n in ( C 2 3 ~ C 2 4 ) 4 ,10 ,15 ,20 t h / t / t h C-~7H660o r a n n o g a l e n e7.16 annose negalin 4,10,15,20 t h / t / e r C37H68077.1 7 longicin 4,10,13,18 t h / t / e r C35H64077 .18 annom utac in 4 ,10 ,17 ,22 t h / t / e r C 3 7 H 6 8 077.19 cis-ann onacin 4,10,15,20 t h / c / t h C 3 5 H 6 4 077.2 0 cis- ann ona cin one (C~------O,10) 4,15,20 t h / c / t h C 3 5 H 6 2 0 7

59 6 A . d e n s i c o m a [1]59 6 G . g i g a n t e u s [1]59 4 A . d e n s i e o m a [1]59 6 A . s q u a m o s a [1]62 4 A . m o n t a n a [1]59 6 A . r e t i c u l a t a [1]59 4 A . r e t i c u l a t a [1]59 6 X . a r o m a t i c a [1]62 4 X . a r o m a t i c a [1]62 4 X . a r o m a t i c a [1]59 4 A . r e t i c u l a t a [1]62 2 A . s q u a m o s a [1]62 2 G . g i g a n t e u s [1]62 2 X . a r o m a t i c a [1]62 2 X . a r o m a t i c a [l ]

A . s e n e g a l e n s i s [1]62 4 A . s e n e g a l e n s i s [1]59 6 As. longi .fol ia 2[~_]62 4 A . m u r i c a t a [ 2 8]59 6 A . m u r i c a t a [ 2 9 ]59 4 A . m u r i c a t a [29]


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Natura l ace togen ins from A nnonaceae , syn th , and m ech. o f ac t ionTable 3. (continued)

1093

Hydroxy l TH F- re la tive Molecu la r Anno naceae spec ies*pos i t ions conf igura tion* fo rmula M + [Ref . ]7.21 c i s - g o n i o t h a l a m i c i n7 .2 ~ a r i a n a ci n + j a v o r i c i n ?7 .23 ro l l inec ins -A+ B 'I"7 .24 4 -ace ty lannonac in7~25 4_-acetylx~lomatici7 .26 d i sepa l in7 .2 7 m o s i n- B ( C = O ,9 )7 . 2 8 m o s in - C { C : O , 9 )

4,1 O, 13,18 th/ c/th C~H~40~ 596 A . mur ic a ta [29]4,12,15,20 th / t / th C3~H640~ 596 A . mur ic a ta [29]4,14,17,22 th / t / e r C~vH~O~ 624 R . muc os a [30]OAc-4,10,15,20 th / t / th C37H**O,~ 638 As. long(folia [31]OAc-4, I 0,15,20 th / t / th C~,,H~O~ 666 As. Iony(J~dja [31]4,10,15,OAc-20 th / t / th C~H~00~ 666 D . a n o m a l u m [32]4,15.20 th / t / e r C~H~,_,O~ 594 A . s quamos a [33.]4.15,20 th /c , lh C~H~,_~O~ 594 A . s quamos a [33]

7 b - w i t h o u t O H i n 4 ' p l a g io n i c i n - A t y p e ':7b.1 plagio_nicin-A 5,10,15,207b.2 tonk inin- A (C--O ,5) 15,17,227b.3 tonk inin- B (C- -O, 5) 15,17,227b .4 tonk in in -C (C= O,5 ) 15 ,OAc-17 ,227b.5 tonkin esin-A 5,15.17,227b.6 tonkin esin-B 5,15,17,227b.7 tonkin esin-C 5,15,OAc-17,227b=8 ~g!~antransenins-A+ B t 1 0 ,1 3 ,1 8 ,2 3

(C_~,=C2~)7b .9 g igan t ransen in -C (C : := C: 0 10 ,13 ,18 ,21

th / t / thth / t / e rth / t / thlh / t / e rth / t / e rth / t : thth / t / e rth / t / thth / t / th

8. Polihydroxylated and tetrahy droxylated ketonic, ' a n n o m o n i c i n type ' :8 .1 ann om oni cin 4,8,13,15,20 th / t / th8.2 mo nta nac in 4,8,13,19,24 th / t / th8.3 8-hy drox yann onac in 4,8,10,15,20 th / t / th8 .4 annom ur ic in -A 4 ,10 ,11 , l 5 ,2 0 th - th / t / e r8.5 anno mu ricin-B 4,10,11,15,20 e r - th / t / e r8 .6 m u r i c a ti n - C ( C ~ O ,1 0 ) 4 ,1 5 ,2 0 ,2 5 t h / t t h8.7 mu ricatocin -A 4,10,12,15,20 p s e r - t h / t / t h8.8 murica tocin-B 4,10,12,15,20 ps e r - th / t / e r8.9 muric atocin-C 4,10,12,15,20 ps th - th / t / e r8 .10 annom ur ic in -C 4 ,10 ,11 ,15 ,20 th - th / t / th8 .1 1 a n n o h e x o c i n 4 .8 ,10 ,12 ,15 ,20 th / t / e r8.1 2 murica tal icin 4,7,13,15,20 th / t / th8. 13 corihej?tocin-A 4,7,12,14,16,19,20 er , , t / th-an-th

4 ,7 ,12 ,14 ,16 ,19 ,20 th / t / th -an- th:.!4 corihe~tocin-B

C~,H6~O~ 596 ~ l a g i o n e u r a [34]Cs:H6607 622 U. tonk ines is [35]C~H6607 622 U. tonk ines is [35]C~H~sOs 664 U. tonk ines is [35]CsvH6sO7 624 U. tonk ines is [.3_5_]C~TH~sO~ 624 U. tonk ines is [_35_]C~H~0Os 666 U. tonk ines is [35]C~H~O~ 622 G . . q i g g n t f u s [36]C~TH~Ov 622 G. ,qiganteus [3_6j

CasH~,40~ 612 A . m o n t a n a [1]C~:H


8/31

1094 M. C. ZAFRA-POLOe t a l .Table 4. Mono-THF c~-monohydroxylated~,-lactoneacetogenins

Hydroxyl THF and diols Molecular Annonaceae species**positions relat, config.* formula M + [Ref.]I V . M o n o - T H F ~ - m o n o h y d r o x y l a t e d a c e t o g e n i n s

R T - B O H R

3 5 / 3 7 ~H s C 0 (R = H o r O H )

9. THF c~-monohydroxylated:9a-with OH in 4 ' g i g a n t e t r o e i n - A t y p e ':9.1 gigantetrocin-A 4,14,17,18 t / t h - t h C35H640 7 5969.3 densicomacin-1 4,14,17,18 t / e r - t h C35H640 7 5969.4 gigantetronenin (C2~Cz2) 4,14,17,18 t / t h - t h C 3 7 H 6 6 0 7 6229.6 gigantetrocin-Bt 4,14,17,18 t / t h - t h C35H640 7 5969.7 muricatetrocins-A + B:~ 4,16,19,20 t / e r or t h - l h C 3 5 H 6 4 0 7 5969.8 senegalene C2 ~3 0) 4,12,13,21 t h - t / t h C 3 7 H 6 6 0 7 6229.9 muricatin-A 4,14,17,18,23 t / t h - t h C35H640 8 6129.10 muricatin-B 4,14,17,18,19 t / t h - t h / e r C35H6408 6129.11 coriacin (C~-~C~8) 4,14,21,22 t / t h - t h C37H660 7 6229.12 murihexocins-A+ B~ 4,7, 8,16 ,19, 20 t h - t / t h - t h C35H640 9 6289.13 muricatalin 4,14,15,17,18 t / e r / e r - t h C35H6408 6129.14 annopentocins-A + B+ 4,10 ,16,19,20 t / t h - t h C35H~O8 6129.15 annopentocin-C 4,10,16,19,20 t / t h - e r C35H6408 6129.16 4-acetylgigantetrocin-A 4-OAc, 14,17,18 t / t h - t h C37H660 8 6389.17 muricatetrocin-C 4,16,19,20 t / t h - e r C 3 5 H 6 4 0 7 5969.18 glaucafilin 4,16,19,20 t / t h - e r C35H~O 7 5969.19 glabranin (C23~-~-C24) 4,16,19,20 t / t h - t h C37H6607 6229b-without OH in 4 'g igantr ioc in type' :9.2 gigantriocin 14,17,18 t / t h - t h C35H6~O 6 5809.5 gigantrionenin (C21~C2z) 14,17,18 t / t h - t h C37H6606 6069.20 4-deoxycoriacin(C~C~8) 14,21,22 t / t h - t h C 3 7 H 6 6 0 6 6069.21 cis-gigantrionenin (C21~---------C22) 14,17,18 c / t h - t h C37H6606 606

32/34( C H = ) . C H 3

G . g i g a n t e u s [1]A . d e n s i c o m a [1]G . g i g a n t e u s [1]A . m u r i c a t a [1]A . m u r i c a t a [1]A . s e n e g a l e n s i s [ 1A . m u r i c a t a [1]A . m u r i c a t a [1]A . c o r i a c e a 4 [~ ]A . m u r i c a t a [ ~A . m u r i c a t a 4 ~ ]A. mu r ica ta 4[~_]A . m u r i c a t a [ 4 6 ]G. ,q(qa nteu s 4147]R . m u c o s a 4 ~A . g l a u c aA. ,q labra

G . # i g a n t e u s [1]G . # i g a n t e u s [1]A . c o r ia c e a 4141414141414141414~JG. ,q iqan teus [47]

* th : threo; er : ery thro; t : t rans ; c : c i s .* * G . : G o n i o t h a l a m u s ; A . : A n n o n a ; R . : R o l l i n i a .t gigantetrocin-B (9.6): 17,18-diepimer rom gigantetrocin-A (9.1), for the authors [1].(9.7): 15-epimer for the authors [1]; (9.12): 19,20-diepimerfor the authors [44]; (9.14): 19,20-diepimer for the authors[46].

these compounds described as a 2 , 4 - c i s and 2 , 4 - t r a n smixture are characterized by the presence of a 2-ace-tonyl satura ted 7-1actone moiety (L-B). Since 1994 itis well known, and further largely referred, that the'ketolactones' or 'iso'-acetogenins, obtained as mix-ture of 2-epimers, are spont aneousl y formed by trans-lactonization from classical 4-hydroxylated aceto-genins during extraction procedures, by a simple lightbasic medium (for example by the presence of alka-loids), or after light heating in MeOH [1-5, 14]. So,these compounds must not be considered as naturalproducts but as artifacts. In fact, with the exceptionof anno muri cino ne-D (10.9), isomurisolen in (10.12)and mosin one-A (10.13), the equiv alent 4-hydroxyl-ated acetogenins are known for all of the 'iso'-ace-togenins. These exceptions as well as a different yield

of the two isomers ( 2 , 4 - c i s and 2 , 4 - t r a n s ) led theauthors to c onsider 'iso'-acetogenins as natura l prod-ucts. In our opin ion, unsubs tanti al reasons are givenbecause a total lactonization might occur and thenthe natural aceogenins are not isolated. On the otherhand, it is well known that 2-substituted 7-1actonesmay easily epimerize, leading to the rmodyn amic mix-tures whose proportions strongly depend on the nat-ure of the substituents.

The difference in C-10 stereochemistry betweenannonacin-A-one 10.5) isolated from A s i m i n a t r i l o b a[51] and the comp ound isolated from A n n o n ar n u r i c a t a , 10-R-ann onacin- A-one [28], is based ondifferences in some of the physical data a nd the mul-tiplicity of the H-10 signals: 63.59, pseudoq uartet for10R and 63. 60, multiplet for lOS!!. Thus the absolute


9/31

N a t u r a l a c e t o g e n i n s f r o m A n n o n a c e a e , s y n t h , a n d m e c h . o f a c t i o n 1095T a b l e 5 . M o n o - T H F a c e t o g e n i n s w i t h a L - B , L - C o r L - D l a c t o n e m o i e t y

H y d r o x y l T H F - r e l a t i v e M o l e c u l a r A n n o n a c e a e s p ec ie s* *pos i t i on s conf igur a t ion* f o r m ula M + [ Ref. ]

L - B R :O 1

3 5 / 3 7 ~ , ~ 2 ~ e ~ ~ 4H aC~ v ~ v " RHR :

1 0. " Is o ' m o n o - T H F , ' isoannonacin t ype ' :10 . 1 i s oann onac in 10 ,15 ,20 t h / t / t h10 . 2 i s oann onac inon e ( CO, 10) 15 ,20 t h / t / t h1 0 . 3 s q u a m o n e ( C O , 9 ) 1 5 ,2 0 t h / t / t h10 . 4 i s oanno r e t i cu in 9 , 15 , 20 t h / t / t h1 0 . 5 a n n o n a c i n o n e - A t 1 0 ,1 5 ,2 0 t h / t / e r

V. l so -ace togen ins , mo no-TH F[ 1 0 . 1 - 1 0 . 5 ; 1 0 . 7 - 1 0 . 9 ]Fir O H O H [10.11-10.13]

~ (CH=)n CHa T - A( R ' = H o r O H o r = O )

OH OH

10 . 6 g igan te t r oc ino ne 14 ,17 ,18 t / t h - t h10 . 7 gon io tha l am ic inon e 10 ,13 ,18 t h / t / t h10 . 8 mu r i s o l inone 15 ,20 t h / t / t h1 0 . 9 a n n o m u r i c i n o n e - D 1 0 ,1 1 ,1 5 ,2 0 e r - t h / t / t h10.1 0 gi ga nt et ro ne ni no ne (C2~-----------C22) 4,17 ,18 t / t h - t h10 . 11 ann om ontac inon e 10 ,17 ,22 t h / t / t h10 . 12 i s omu r i s o l en in ( CH =C , 2) 15 ,20 t h / t / t h10 .13 m o si n o n e- A (C23~--------C24) 15 ,20 t h / t / t h

[ 1 0 . 6 ; 1 0 . 1 0 ]T - B

C35H6407 596 A . d e n s i c o m a [1]C35H6207 594 A . d e n s i c o m a [1]C 3 5 H 6 2 0 7 59 4 A . s q u a m o s a [1]C35H~O 7 596 A . r e t i c u l a t a [I ]C35H6407 596 A s . t r i l o b a [51]A . m u r i c a t a ~ 8 _ ]C35He407 596 A s . t r i l o b a [1]C 3 5 H 6 4 0 7 59 6 A s . I o n g i f o l i a [27]C ~ s H ( , 4 0 6 58 0 A s . t r i l o b a [52]C35H6408 612 A . m u r i c a t a [46]C 3 7 H 6 6 0 7 62 2 A s . l o n g i f o l i a [25]CwH~,807 624 G. g iq an te u s 21212~]C~sHe20~ 578 A . r e t i c u l a t a [53]C 3 7 H 6 4 0 7 62 0 A . s q u a m o s a [33]

V i a . / I - H y d r o x y - a c e t o g e n i n s , m o n o - T H FT - A

L - C OH OHH 3 2

HsC 1 035

1 a . f l - Hydr oxy- 7- methy l - ) , - l ac tones : jetein t ype ' :I1.1 jete in 10,15,20,33 t h / t / ' er C~H6607 598 A . c h e r i m o l i a [1]

L - DH O ~ ~ ~ H R

HsC "O" 1 O OH35

R :

VI b . 34-H ydr oxy ac e toge n insI~ O H O H [ 11 .2 ; 11.4; 11.51

~ ( C H = ) . C H 3 T - A( R ' = H o r O H )

OH OH []1.31R : ~ ~ ~ ~ ~ " (C H z). CH3 T-B,.. OH

1 b . 3 4 - H y d r o x y a c e t o g e n i n s: 'donnaienin-A type ':11 . 2 donna ie n in - A + 34 ep i 4 , 15, 20 ,3411 . 3 donna ien in - B + 34 ep i 4 , 14, 17 ,18 ,341 1 . 4 g o n i o d o n i n + 3 4 e p i 4 ,1 0 ,1 5 ,2 0 ,3 41 1 . 5 c i s - g o n i o d o n i n + 3 4 e p i 4,10,15,20,34

t h / t / t h C35H6407 596 G. don na ien sis 5154_t / t h - t h C35H640~ 612 G . d o n n a i e n s i s [54]t h / t / t h C 3 5 H 6 4 0 ~ 612 G. do nn aie nsi s 5[~_]t h / c / t h C~H6408 612 G . d o n n a i e n s i s [_5_5]

* th : threo; er : ery thro ; t : t rans .* * A . : A n n o n a ; A s . : A s i m i n a ; G . : 9 o n i o t h a l a m u s .t (10.5) : 10-epimers for the authors [28] .


10/31

1096 M .C . ZAFrtA-POLo t a l .Table 6 . Ad jacen t b is -THF ~S-d ihydroxy la ted , ? - lac tone ace togen ins

Hydroxy l TH F-re la t iv e Mo lecu la r Ann onaceae spec ies**pos i t ions conf igura t ion* fo rmula M + [Ref. ]VII. Adjacent bis-T HF ~,~'-dihydroxylated aeetogenins

R R O H T - C H O R

3 5 / 3 7 ~ 1 ~ , ~ I'1 ~H ~ C O ( R = H o r O H o r = O )12. Dihydroxylated, 'uvaricin type':12.1 uvaricin 15 (OA c-24) t h / t / t h / t / e r C39H6807 6481 2 . 2 d e s a ce t y lu v a r ic i n 1 5 , 2 4 t h / t / t h / t / e r C37H6606 6061 2 ,3 n e o a nn o n in 1 3 , 2 2 t h / t / t h / t / e r C35H6206 57812,4 isodesacetyluvaricin 1 5 ,2 4 t h / t / t h / t / t h C37H6606 6061 2 .5 m e m b r a n ac i n 1 5 , 2 4 t h / c / t h / c / e r C~7H6606 6061 2 . 6 s q u a m o c i n - I 1 3 , 2 2 e r / t / t h / t / t h C , 5 H 6 2 0 6 5 7 81 2 .7 s q u a m o ci n - K 1 3 , 2 2 t h / t / t h / t / t h C35H6206 5781 2 .8 s q u am o c i n -N 1 5 , 2 4 t h / c / t h / c / t h C37H6(,O6 6061 2 .9 m e m b r a ro l li n 1 3 , 2 2 t h / c / t h / c / e r C35H6206 578

3 2 / 3 4(CH2)n CH3

U . a c u m i n a t a [1]U . a c u m i n a t a [1]A . s q u a m o s a [1]U . n a r u m [ I ]R . m e m b r a n a c e a [1]A . s q u a m o s a [1]A . s q u a m o s a [1]A . s q u a m o s a [ 1 ]R . m e m b r a n a c e a [56]

13. T r ihydroxy la ted and te t rahyd roxy la ted (wi th OH in 4 ), "asimic in type' :13.1 asimicin 4,15,2413.2 roll iniasta tin-I 4 ,15,241 3 . 3 roll iniastatin-2 4,15,24

or bu l la tac in13 .4 molv iza r in 4 ,13 ,2213.5 tr i lobacin 4,15,2413.6 r ioclarin 4,15,24,2813.7 purpure acin-2 4,12,15,24(= 12-OH-bu l la tac ins -A + B)- tlY8 parviflorin 4,13,22o r s q u a m o c i n - E

( = a temo yac in -A)13.9 anno glauc in 4,10,15,2413.10 glaucanisin 4,13,22

( = squam otac in )13.11 30-O H-b ullatacin ? 4,15,24,3013.12 3 l-O H- bulla tacin 4,15,24,3113.13 32-O H-b ullatacin 4,15,24,3213.14 araticulin 4,12,15,2413.15 annon isin 4,8,13,2213.16 10-OH -asimicin 4,10,15,2413.17 10-O H-triloba cin 4,10,15,2413.18 longim icin-A 4,11,2013.19 longimicin-B 4,11,2013.20 longim icin-C 4,9,1813.21 roll im em brin 4,13,22

t h / ' t / t h : t / t h C~71"16607 622 A s ' . t r i l o b a [1]d l / c / t h / c / e r C37H6607 622 R . m u c o s a [1]t h / t / t h / t / e r C 371- I 6607 62 2 R . m u c o s a [1]

A . b u l l a t a [1]t h / t / t h / t / e r C35H620 7 59 4 A . c h e r i m o l i a [1]t h / t / e r / c / ' t h C , 7 H 6 6 0 7 6 2 2 A s . t r i l o b a [1] [57]t h / t / t h / t / e r C ~ 7 H 6 6 0 8 63 8 R . m e m b r a n a c e a [1]t h / t / t h , ' t / e r C 3 7 H ~ , 6 0 ~ 63 8 A . p u r p u r e a [1]

R . m u c o s a [58]t h / t / t h / t / t h C35H6207 594 A s . p a r r ( f l o r a [1]A . s q u a m o s a [1]

A . a t e m o v a [59]t h / t / t h / t / e r C37H~oO~ 638 A . . q l a u c a [1]t h / t / t h , , ' t / e r C 3 7 H e , 6 0 62 2 A . . q l a u c a [1]

A . s q u a m o s a [60]t l / t / t h / t / e r C371-1660 638 A . b u l l a t a [61]t h / t / t h / t , ' e r C37H6608 638 A . b u l l a t a [ 6 ~ ]t h / t / t h / t , ' e r C~7171660 63 8 A . b u l l a t a [ 6 ~ Jt h / t / t h / t / t h C37H660 x 63 8 A . c r a s s ( f l o r a [62]t h , ' t / t h / t / t h C35H620~ 610 A . a t e m o v a [63]t h / t / t h / t / t h C 3 7 H 6 6 0 6 3 8 A s . t r i l o b a [64]

A . r e t i c u l a t a [65]t h / t / e r / c / t h C 3 7 H 6 6 0 ~ ; 63 8 A s . t r i l o b a [64]t h / t / t h / t / t h C 3 7 1 - 1 6 6 0 7 62 2 A s . l o n q ( / b l i a [66]t h / t / t h / t / t h C~5H6207 594 A s . l o n q i J o l ia [66]t h / t / t h / t / t h C35H6eO7 594 A s . l o n g ( ] o l i a [66]t h / c / t h / c / e r C35H6207 59 4 R . m e m b r a n a c e a [67]

14. T r ihydroxy la ted , d ihydroxy la ted ke ton ic and te t rahydroxy la ted (w i thou t OH in 4) :14a- w i t h ou t O H i n 4 'sq u am oc i n t yp e ':14 .1 squamo cin 15 ,24 ,28 t h / t / t h / t / e r C 3 7 H 6 6 0 714 .2 i so ro l l in ic in+ 1 5 , 2 4 , 2 8 t h / t / t h / t / e r C371-I66071 4 . 3 s q u a m o c i n o n e ( C O ,2 8 ) 1 5 , 2 4 t h / t / t h / t / e r C37H~40714 .4 motr i l in 15 ,24 ,29 t h / t / t h / t / e r C 3 7 H 6 6 0 7or annon in - I I11 4 . 5 s q u a m o c i n -B 1 3 , 2 2 , 2 6 t h / t / t h / t / e r C35H~2071 4 . 6 s q u a m o c i n - D 1 5 , 2 4 , 2 8 t h / t / t h / t / t h C 3 7 H 6 0 0 7or as iminac in1 4 . 7 s q u a m o c i n - F 1 2 , 1 5 , 2 4 t h / t / t h / t / t h C 3 7 H 6 6 0 714 .8 as imin 10 ,15 ,24 t h / t / t h / t / t h C37H660714 .9 as iminec in 15 ,24 ,29 t h / t / t h / t / t h C37H6607

62 2 A . s q u a m o s a [1]62 2 R . p a p i l o n e l la [l ]62 0 U . n a r u m [1]62 2 A . c h e r i m o l i a [1]

A . s q u a m o s a [ 159 4 A . s q u a m o s a [1]62 2 A . s q u a m o s a [I ]A s . t r i l o b a [l ]

62 2 A . s q u a m o s a [1]62 2 A s . t r i l o b a [1]62 2 A s . t r i l o b a [1]


11/31

N a t u r a l a c e t o g e n i n s f r o m A n n o n a c e a e , s y n t h , a n d m e c h . o f a c t io nTa ble 6 . ( c ont inue d)

1 0 9 7

Hydroxy l TH F- re la t iv e Mo le c ula r An non a c e a e spec ie s**pos i t ions c onf igura t ion* form u la M + [Ref .]

14.10 bul la t in 10,15,24 t h / t / t h / t , e r C 3 7 H 6 6 0 7 6 2 2 A s . t r i l o b a [1]14.11 bulla nin~ 15,24,30 t h / t / t h / t e r C~H6607 622 A s . t r i l o b a [1][68]14.12 bulla c in 6,13,22 t h ' t / t h , t t h C ~ s H 6 , O ~ 5 9 4 A . b u l l a t a [1]14.13 tr i lob in 10,15,24 t h , t / e r / c ' t h C' ,H, ,O , 622 A s . t r i l o b a [57]14.14 as i tr ib in 15,24,28 t h , ' / / e r : c ' t h C vH~,~O, 622 A s . t r i l o b a [21]14.15 ule irol l in 12,15,24 t h / t / t h , ' t , e r C 7H~,~,O7 62 2 R . u l e i [ 5 ]14.16 a s im inoc in 15 ,24 ,30 t h , t / t h , t t h ( - ' , 7 H ~ O 7 6 2 2 A s . t r i l o b a [68]14.17 bull a te tro cin 15,24,31,32 t h , ' t / t h / t e r - e r C~TH6~Os 638 A s . l r i l o b a [64]14 .18 Iongim ic in-D 10 ,13 ,22 t h / t / t h , t l h C~7H6~,O7 622 A s . l o n y ( [ b l i a [66]14 .19 m uc ox in 8 ,14 ,17 / h / t , t h ; c ) / / t h C~7H~,~,O7 622 R . m u c o s a [69]14.20 rol l i tac in 1 5 , 2 4 , 2 8 , 2 9 t l / t / t h / t ' e r - e r C~7H,~Os 638 R . m u c o s a [70]14 .21 gua n a c on e (CO,10) 15 ,24 t / / t / t h , ' t ' e r C~ 7H, ,407 620 A:a f f . s T o ' a g u e i [71]1 4 b w i t h o u t O H i n 4, b u t w i th O H i n 5 ' p a n a l i c i n t y p e ' :14b.1 pa na l i c in 5 , 1 5 , 2 4 , 2 8 t h / t / / h / t / e r C~ THI ,60 638 U . n a r u m [1]14b.2 naru mic in-I 5,15,24 t h / t / t h / t / t h C ~ 7 H 6 6 0 7 6 2 2 U . n a r u m [1]14b.3 na ru m ic in - l l 5 , 15 ,24 t h / / / t h / t ' e r C 3 7 H ~ O 7 6 2 2 U . n a r u m [1]14b.4 espelic in 5, t5,24,29 t h / t / t h / t / e r C ~ , H 6 6 O s 6 3 8 U . p a u c i - o t , u l a t a [_72]14b.5 uva riasolin -I 5,6,15,24 t h - t h / t / l h / t / t h C37H~,~O~ 638 U . p a u c i - o t , u l a t a [72]14b.6 uva riasolin -II 5,6,15,24 t h - t h / t / t h / t / e r C~ 7H660 638 U . p a u c i - o v u l a t a [_72]

* t h : t h r e o ; e r : e r y t h r o ; t : t r a n s ; c : c i s .* * U . : U r a r i a ; A . : A n n o n a ; R . : R o l l i n i a : G . : G o n i o t h a l a m u s : A s . : A s i r n i n a .? (13.73: 12-OH -bul la ta c ins -A +B , 12 e p im e r f rom purpure a c in-2 , for the a u th or s [58] ; (13 .113:30 e pim e r for the a u thor s

[61]: (14.11 ) : 3(1 epim ers fo r th e aut ho rs [1, 68].++sorol l in ic in (14 .2) : would ha ve to be a C-23 or C -24 e pim e r f rom squa m oc in (14.13 [1].

Ta ble 7 . Adja c e nt b i s -THF ~ -m onohydroxyla te d 7-1a c tone a c e toge ninsHydro xyl THF - re la t ive Mo le c ula r An non a c e a e spec ie s**pos i t ions c onf igura t ion* form ula M ~ [Ref .]

V I I I . A d j a ce n t b i s - T H F ~ - m o n o h y d r o x y l a t e d a c e t o g e n i n sT -E O H R

L - A 4 ~ , ~ I J

3 5 3 7 ~ 1 \ F t * RH 3 C O ( R = H o r O H )

3 2 1 3 4( C H 2 ) n C H 3

1 5. A d j a c e n t b i s - T H F 2 - m o n o h y d r o x y l a t e d a c e t o g e n in s , " u v a r i c in t y p e ' :1 5 .1 g o n io d en in (C2,~---------C22) 4,1 8 t / t h / t , ' t h - c C~vH~40~, 60415.2 a s im i lobin 4 ,18 t , ' t h / t / t h C3~H6,O6 57815.3 a nno s i l in-A 20 ,23 ,24 t / t h / t / t h - t h C 3 7 H 6 6 0 7 6 2 215.4 rol l idecin -A 4,20,23,24 t / t h / c / t h - t h C37H~ 6Os 63815 .5 rol l idecin -B 4,20,23,24 t / t h / c / / h - e r C~vHc,~O 63815.6 ro l l ina c in 4 ,10 ,20 t / t h / t / / h t C~sH~zO7 594

G . , q ( q a n t e u s [73JG . , q i y a n t e u s [73]A s . t r i l o b a [51]A . s q u a m o s a [74]R . m ucos_ aa[48]R . m u c o s a [48]R . m u c o s a [70]

* l h : t h r e o : e r : e r y t h r o ; t : t r a n s ; c : c i s .* * G .: G o n i o t h a l a m u s ; As.: A s i m i n a ; A . : A n n o n a ; R . : R o l l in i a .+ (15.63 it s r e la tive c onf igu ra t ion h a s n ot be e n c on f i rm e d.

c o n f i g u r a t io n i n d i c a t e d f o r 1 0 - R - a n n o n a c i n - A - o n ew a s g i v e n w i t h o u t s o l i d p r o o f .A n e w s u b c l a s s o f a c e t o g e n i n s w i t h a C 3~ s k e l e t o na n d a n u n u s u a l 3 4 - O H - u n s a t u r a t e d l a c to n e m o i e ty

( L - D ) w a s f o u n d o n l y i n G o n i o t h a l a m u s d o n n a i e n s i s .O n e o f th e s e a c e t o g e n i n s , d o n n a i e n i n - B ( 1 1 . 3) ,s h o w e d a m o n o - T H F - ~ - m o n o h y d r o x y l a t e d s y st ema n d t h e t h r e e o t h e r o n e s a m o n o - T H F - ~ S - d i h y -


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1098 M . C . ZAFRA-POLO t a l .Table 8. Non-adjacent bis-t etrah ydr ofur an 7-1actone acetogenins

Hydroxyl TH F-relative Molecular Annonaceae species**positions configuration* formula M [Re f.]I X . N o n - A d j a c e n t b i s - T H F a c e t o g e n i n s

T-D

3537 ~ x 1 ) , ~ R L _ _ _ / H O O HH s C 0

3 2 1 3 4(CHa)n CHs

16. Nonad jacent bis-TH F (with OH in 4), 'sylvaticin type':16.1 sylvaticin 4,16 ,19,24 t / t h - t h / c / e r C37H660 8 638 R . s y l v a t i c a [1]R . m u c o s a [ 7 5 J16.2 gigantecin 4,14,17,22 t / t h - t h / t / t h C37H6608 638 G . 9 i g a n t e u s [1]16.3 cherimolin-1 4,16 ,19,24 t / t h - t h / t / e r C37H660 8 638 A . c h e r i m o l i a [1]

or bullatalic in A . b u l l a t a [1]16.4 cherimolin-2 4,16,19,24 t / t h - t h / t / t h C37H6608 638 A . c h e r i m o l i a [1]or bullatanocin A . b u l l a t a [1]16.5 parvifloracin 4,14,17,22 t / t h - t h / t / t h C35H6208 610 A s . p a r v i f l o r a [1]16.6 1 2 , 1 5 - c i s - b u l l a t a l i c i n 4,16,19,24 c / t h - t h / t / e r C37H6608 638 A . b u l l a t a [1]16.7 1 2 , 1 5 - c i s - b u l l a t a n o c i n 4 , 1 6 , 1 9 , 2 4 c / t h - t h / t / t h C37H660 8 638 A . b u l l a t a [1]16.8 1 2 , 1 5 - c i s - s y l v a t i c i n 4,16,19,24 c / t h - t h / c / e r C37H660 8 638 R . mu c o s a 7171717[~16.9 trilobalicin 4,14 ,17,22 t / t h - t h / t / e r C35H6208 610 A s . t r i l o b a [76]17. Nonadjacent bis- TH F (without OH in 4), ' s q u a m o s t a t i n - A o r a l m u n e q u i n type ' :17.1 squam ostatin-A 16,19,24,28 t / t h - t h / t / e r C37H6608 638 A . s q u a m o s a [1]or almunequin A . c h e r i m o l i a [1]17.2 4-deoxygigantecin 14, 17, 22 t / t h - t h / t / t h C37H6607 622 G . g i g a n t e u s [1]17 .3 squamos ta t in -D 16 ,19 ,24 t / t h - t h / t / e r C37H66Ov 622 A . s q u a m o s a [1]17.4 squamostatin-E 16,19 ,24 t / t h - t h / t / t h C37H6607 622 A . s q u a m o s a [1]

* th : threo; er : ery th ro; t : trans ; c : c i s .* * R . : R o l l i n i a ; G . : G o n i o t h a l a m u s ; A . : A n n o n a ; A s . : A s i m i n a .

d r o x y l a t e d o n e . A l l o f t h e m ( 1 1 .1 - 1 1 .4 ) w e r e i s o l a t e da s m ix tu re s o f 3 4 -e p im e rs [54 , 5 5] .

B I S -T H F A C E T O G E N I N SA l t h o u g h a g r e a t n u m b e r o f n ew c o m p o u n d s h a v e

b e e n in c lu d e d in th i s g ro u p , a n id e n t i c a l c l a s s i f i c a t io ni s m a d e in th i s r e v ie w : a d ja c e n t a c e to g e n in s [1, 5 , 2 1 ,4 8 , 5 1 , 5 6 -7 4 ] (T a b le s 6 -7 ) , n o n -a d ja c e n t a c e to g e n in s[1, 75 , 76 ] (T a b le 8 ) a n d s a tu r a t e d l a c to n e a c e to g e n in s[1, 61, 76, 77] (Table 9).

A d j a c e n t b is - T H F a c e t o # e n i n sA l l o f t he a d j a c e n t b i s - T H F a c e t o g e n i n s p r e v i o u s l y

d e s c r i b e d p o ss e s s a b i s - T H F s y s t em f l a n k e d i n ~ a n d~ ' b y tw o h y d ro x y l g ro u p s (T -C ) . R e c e n t ly , s ix a c e -t o g en i n s w i th a n ~ - m o n o h y d r o x y l a t e d b i s - T H F r i n g(T -E ) w e re i s o l a t e d . T h i s s y s t e m o n ly h a s b e e n p re -v i o u s l y r e p o r t e d f o r b u l l a d e c i n o n e ( 1 8. 5) , a b i s - T H F' i s o ' - a c e to g e n in [7 8 ].

T h e r e l a t i v e c o n f i g u r a t i o n o f t h e k n o w n c o m p o u n d

t r i lo b a c in (1 3 . 5 ) h a s b e e n r e v i s e d a n d e s t a b l i s h e d a st h r e o / t r a n s / e r y t h r o / c i s / t h r e o o n t h e b a s i s o f C O S Y ,N O E S Y a n d M o s h e r e x p e ri m e n t s o f i ts d i a ce t a ted e r i v a t i v e [5 7 ]. M o r e o v e r , t h i s c o n f i g u r a t i o n w a s c o n -f i rm e d b y s y n th e s i s [79 ].

S u r p r i s i n g ly , i n a R a p i d C o m m u n i c a t i o n p u b l i s h e di n F e b r u a r y 1 99 6, s q u a m o t a c i n i s c l a i m e d b y H o p p[60 ] a s a n e w c o m p o u n d w i th s e l e c t iv i ty o n h u m a np r o s t a t e t u m o r c e l l l i n e s ( P C - 3 ) . T h e s t r u c t u r e p r o -p o s e d f o r s u ch c o m p o u n d i s t h a t o f g l a u c as i n i n(1 3 .1 0 ) , a n a c e to g e n in a l r e a d y p u b l i s h e d in 1 99 5 a n din c lu d e d in o u r l a s t r e v ie w [1 ]. In th e s a m e l in e , 1 2 -O H - b u l l a t a c i n s - A + B w e r e d e s c r i b e d a s n e w c o m -p o u n d s w i th d i f f e re n t s t e re o c h e m is t ry a t C -1 2 [5 8 ] .T h e m i n o r d i f f e re n c e s i n t h e ~ H N M R a n d ~3C N M Ra t C -1 2 a re in s u f f i c i e n t a n d l e d u s to c o n s id e r t h e s ec o m p o u n d s i d e n t i c al t o p u r p u r e a c i n - 2 ( 1 3. 7) , i s o l a t e df r o m A n n o n a p u r p u re a [80].

I s o l a t i o n o f t h r e e n e w h y d r o x y l a t e d d e r i v a t i v e s o fb u l l a t a c in , a t 3 0 , 3 1 o r 3 2 p o s i t i o n ( c o m p o u n d s 1 3 . 1 1 -1 3 . 1 3 ) f ro m b a rk o f A n n o n a b u l l a t a [6 1 ] s u p p o r t s o u rh y p o t h e s i s t h a t ' i s o ' - a c e t o g e n i n s a r e a r t i f a c t s. I n f a c t,


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Natural acetogenins from Annonaceae, synth. and mech. of actionTable 9. Saturated lactone bis-THF acetogenins

1099

Hydroxylpositions

THF-relative Molecular Annonaceae species**configuration* formula M+ [Ref.]

;&&4R

H

X. Iso-acetogenins, bis-THFrR: ,,H2jnH~lcH2j;;;; 18.2; 8.6-s

[18.3;18.4]

R: (CH,), (CH2),CHs T-D

18. Iso bis-THF, bullatacinone type:18.1 bullatacinone 15,24

(= isoannonareticin)18.2 rollinone l&2418.3 bullatalicinone 16,19,24

or isocherimolin-118.4 bullatanocinone 16,19,2418.5 bulladecinone 20,23,2418.6 32-OH-bullatacinone l&24,3218.7 31-OH-bullatacinone 15,24,3118.8 30-OH-bullatacinone l&24,3018.9 isomolvizarin-1 13,2218. IO isomolvizarin-2 13,2218.11 IO-OH-bullatacinone 10,15,2418. I2 12-OH-bullatacinone 12,15,2418. I3 29-OH-bullatacinone 15,24,2918.14 28-OH-bullatacinone 15,24,2818.15 trilobacinone 15,24

-

thltjthlt:erth/c/th/c/erth-thltlerth-thjtjtht/th/t/th-erthjtjthjtierthlt/thlt,erthlt/thlt/erth/t/th/t/erth/t/th/t!thth/t/th/t/erth/t/th/t/erth/t/th/t/erth/tjth/t/erth/t,lerlclth

-

CdW, 622G&O, 622GH,,O, 638GH,,O, 638G,H,,O, 638G,H,,O, 638GH,,O, 638CI-IH,,O, 638G,H,,O, 594GsHuO, 594G&608 638C,,H,,O, 638G&,0, 638%H,,O, 638GH,,O, 622-

A. bullata [l]A. reticulata [7J]R. papilionella [l]A. bullata [l]A. cherimolia [l]A. bullata [I]A. bullata [l]A. bullata [l]A. bullata [l]A. bullata [l]A. cherimolia [I]A. cherimolia [I]A. bullata [I]A. bullata [l]A. bullata [l]A. bullata [61]As. &

Xl. j?-Hydroxy-acetogenins, bis-THF[19.1;19.2]

I?: (cH~):~(CH~).CHS T-C[19.3]

HO RIL

(CHACH, T-D

19. /I-Hydroxy methyl y-lactones, laberradurin type:19. I laherradurin 15,24,35 th/t/th/tler19.2 itrabin 13,22,33 th/tlth/tler19.3 otivarin 16,19,24,35 tith-thltier

W-W, 624 A. cherimolia [l]G&O, 596 A. cherimolia [l]G&Q 640 A. cherimoliu [l]

+ th: three; er: erythro; t: tram; c: cis.**A.: Annona; R.: Rollinia; As.: Asimina.

compounds 18.618.8 (Table 9) previously isolated 30s and 30R isomers based on the doubtful doublefrom the same plant material [l, 811 should be their carbon signal observed in their %NMR spectrumrespective iso-acetogenins. Moreover, compounds [61, 681.13.11 and 14.11 have been considered as a mixture of Finally, mucoxin (14.19) is the first unusual


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1100 M. C. ZAFRA-POLO t al .Tab le 10. Miscellaneous acetogenins

Hydroxyl Relative Molecular Annonaceae species*positions configuration* formu la M + [Re f.]X Ih Tr i - THF ac e t oge n i u s

20. Tri-T HF acetogenins, 'gonioc in type ' :T - F O HL - A 344 0

3 7 cHa20 .1 gon ioc in 4 ,2 2 t / t h , , t / t h / t / t h C37H6407 620 G . g i g a n t e u s [ 1 ]

X I I I . T H F - T H P a c et o ge n in s21. Nonadjacent TH F-T HP acetogenins, 'mncocin type' :

T - G . 1H O ~ , ~ O H

o . o

21.1 mucocin 4,16,19,23 t / t h - t h / c C 3 7 H 6 6 08 638 R . m u c o s a [83]22. Adjacent TH F-T HP acetogenins, " m u c on i n type':

T - G . 2H O OHL-A 4 ~ 4

37 ~ (CH2)4HsC22 .1 muconin 4 ,1 2 ,2 2 t h / c / t h / t / t h C37H6607 622 R . m u c o s a [69]

X IV . 4 - 7 / 16 - 19 N on ad j ac en t b i s - TH F ac e toge n in s23.4-7./1 (~19 Nonadjacent bis-TH F acetogenins, 'aromin type' :

L-A ~ 0 H 0 OH

H3 c23.1 arom in 15,20 t - g h / t / t h C35H600 7 59223. 2 aromicin 15,20 t - t h / t / t h C37H6407 620

(CH=) . CHs

X . a r o m a t i c a [84]X . a r o m a t i c a [84]

* th: threo; t: trans; c: cis.** G . : G on i o t ha l am u s ; R . : R o l l i n ia ; X . : X y l op i a .

r e p o r t e d a c e t o g e n i n w i t h a h y d r o x y l g r o u p a t o n e o ft h e m e t h y l e n e c a r b o n s o f t h e T H F r i n g [6 9] .

N o n - a d j a c e n t b & - T H F a c e t o g e n i n s

O n l y t w o c o m p o u n d s a r e a d d e d i n t h e g r o u p o fn o n - a d j a c e n t b i s - T H F a c e t o g e n i n s : 1 2 , 1 5 - c i s - s y l -v a t i c in (1 6 . 8 ) i s o l a t e d f ro m R o l l i n i a m u c o s a [7 5 ] a n d

t r i l o b a l i c in (1 6 .9 ) fo u n d in A s i m i n a t r i l o b a [76] . Ther e l a ti v e c o n f i g u r a t i o n c i s / t h r e o - t h r e o / c i s / e r y t h r o fo r(1 6 .8 ) w a s e s t a b l i s h e d . In th e s a m e w o rk , t h e i s o l a t io no f th e k n o w n s y lv a t i c in (1 6 .1 ) i s r e p o r t e d a n d i t s r e l a -t i v e c o n f i g u r a t i o n r e v i s e d a n d n o w e s t a b l is h e d a st r a n s / t h r e o - t h r e o / c i s / e r y t h r o . A s i n m o n o - T H F - ~ , ~ ' -d ih y d ro x y la t e d a c e to g e n in s , o n ly d i f f e re n c e s in th eI H - N M R c h e m i c a l s h i ft s f o r t h e m e t h y l e n e p r o t o n s a t


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N a t u r a l a c e t o g en i n s f r o m A n n o n a c e a e , s y n t h, a n d m e c h . o f a c t i o n I 10 1T a b l e 1 1 S p e c ie s o f t h e A n n o n a c e a e w i t h n e w a c e t o g e n in s

S p e c ie s O r g a n C o m p o u n d s R e f .Annona atemoya s e e d 5 . 9 a n n o t e m o y i n - 1_ [2 0 ]( A. cherimolia A. squamosa) 5 . 1 0 a n n o t e m o y i n -2 _ [2 0 ]

1 3 . 1 5 a n n o n i s i n [ 63 ]Anmma hullata b a r k 5 . 5 u v a r i a m i c i n - l V [ 1]

5 . 6 b u l l a t e n i c i n [1]1 3 .3 b u l l a t a c i n ( o r r o l l i n i a s t a ti n - 2 ) [ I ]1 3 .1 1 3 0 - O H - b u l l a t a c i n [ 6 []1 3 .1 2 3 1 - O H - b u l l a t a c i n [ 61 ]1 3 .1 3 3 2 - O H - b u l l a t a c i n [ 61 ]1 4 . 12 b u l l a c i n [1]1 6 .3 b u l l a t a l ic i n ( o r c h e r i m o l i n - 1 ) [ I ]1 6 .4 b u l l a t a n o c i n ( o r c h e r i m o l i n - 2 ) [ 1]1 6 . 6 1 2 , 1 5 -c i s -b u l l a t a l i c in [1]16.7 12,15-cis-bullatanocin [I ]1 8 . 1 b u l l a t a ci n o n e [ I]1 8 .3 b u U a t a l i c i n o n e ( o r i s o c h e r i m o l i n - l ) [ I ]1 8 .4 b u l l a t a n o c i n o n e [ 1]1 8 . 5 b u l l a d e c i n o n e [1]1 8 .6 3 2 - O H - b u l l a t a c i n o n e [ 1]1 8 .7 3 I - O H - b u l l a t a c i n o n e [ 1]1 8 .8 3 0 - O H - b u l l a t a c i n o n e [ I]1 8 .1 1 1 0 - O H - b u l l a t a c i n o n e [ I ]1 8 .1 2 1 2 - O H - b u l l a t a c i n o n e [ I ]1 8 . 1 3 2 9 - O H - b u l l a t a c i n o n e [ 1]1 8 .1 4 2 8 - O H - b u l l a t a c i n o n e [ 61 ]

Annona cherimolia s e e d 11.1 je te in [1]1 3 . 4 m o l v i z a r i n [1]1 4 .4 m o t r i l i n ( o r a n n o n i n - l l l ) [ 1]1 6 . 3 c h e r i m o l i n -1 (o r b u l l a t a l i c i n ) [1]1 6 .4 c h e r i m o l i n - 2 ( o r b u l l a t a n o c i n ) [ I ]1 7 . 1 a l m u n e q u i n ( o r s q u a m o s t a t i n - A ) [1 ]1 9 . 1 l a h e r r ad u r i n [ I]19.2 i t rab in [1]1 9 . 3 o t i v a r i n [1]

r o o t 1 8 .3 i s o c h e r i m o l i n - I ( o r b u l l a t a l i c i n o n e ) [ 1]1 8 . 9 i s o m o l v i z a r i n -1 [1]1 8 .1 0 i s o m o l v i z a r i n - 2 [ 1]

Annona coriacea r o o t 1 . 5 c o r i a d i e n i n [Z]8 . 1 3 c o r i h e p t o c i n - A [ 41 ]8 . 1 4 c o r i h e p t o c i n - ~ [ 41 ]9 . 11 c o r i a c i n [4 3 ]9 . 2 0 4 - d e o x y c o r i a c i n [ 4 3 ]

Annona C r t l s s i [ l o r a s e e d 1 3 . 1 4 a r a t i c u l i n [6 2]Annona densicoma s e e d 7 . 1 a n n o n a c i n [1 ]

7 . 3 a n n o n a c i n o n e [ 1]b a r k 8 .3 8 - h y d r o x y a n n o n a c i n [ I]

9 . 3 d e n s i c o m a c i n - 1 [ l ]1 0 .1 i s o a n n o n a c i n [ 1]1 0 .2 i s o a n n o n a c i n o n e [ 1]

Annona 91abra s e e d 9 . 1 9 g l a b ra n i n [5 0]

,4 nnona ,qlauca r o o t 1 3 .9 a n n o g l a u c i n [ 1]s e e d 9 . 1 8 g l a u c a f i l i n [4 9]1 3 . 10 g l a u c a n i s i n [1]


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1 1 0 2 M . C . Z A F R A -P O L Oe t al .T a b l e I 1 . ( c o n t i n u e d )

S p e c ie s O r g a n C o m p o u n d s R e f .A n n o n a m o n t a n a s e ed 7 . 5 a n n o m o n t a c i n [ 1]

8 .1 a n n o m o n i c i n [ 1]8 . 2 m o n t a n a c i n [ 1]

f r u i t 3 . 6 d i e p o x y m o n t i n [ 1]A n n o n a m u r i c a ta s e ed 2 .1 e p o m u r i c e n i n - A ( o r e p o x y m u r i n - A ) [ 1]

2 . 3 e p o m u r i c e n i n - B [ 1]3 .1 d i e p o m u r i c a n i n - A [ 1]3 . 2 c o r e p o x y l o n e [ 1]5 . 4 s o l a m i n [ 16 . 1 m u r i s o l i n [1 ]6 . 2 c o r o s s o l i n [ 1]6 . 3 c o r o s s o l o n e [ 1]7 . 1 9 c i s -annonac in7 . 2 0 c i s -annonac inone [ 297.21 c i s -gon io tha lamic in [29]7 . 2 2 a r i a n a c i n + j a v o r i c i n 212[~]8 . 1 2 m u r i c a t a l i c i n [ 40 ]9 . 6 g i g a n t e t r o c i n - B [ 19 . 7 m u r i c a t e t r o c i n - A + B [ 1]9 . 1 3 m u r i c a t a l i n [ 45 ]

A n n o n a m u r i c a ta b a r k 2 .1 e p o x y m u r i n - A ( o r e p o m u r i c e n i n - A ) [ 1]2 . 2 e p o x y m u r i n - B [ 1]8 . 6 m u r i c a t i n - C [ 1]9 . 9 m u r i c a t i n - A [ 1]9 . 1 0 m u r i c a t i n - B [ 1]

l e a f 7 . 1 8 a n n o m u t a c i n8 . 4 a n n o m u r i c i n - A [ 1 ]8 . 5 a n n o m u r i c i n - B [ 1]8 . 7 m u r i c a t o c i n - A 3[~_]8 . 8 m u r i c a t o c i n - B [ 3 7]8 . 9 m u r i c a t o c i n - C8 . 1 0 a n n o m u r i c i n - C8 . I 1 a n n o h e x o c i n 3 ~ ]9 . 12 m u r i h e x o c i n - A + B 4 ~ ]9.1 4 an no pe n to ci n- A + B 41414[~]9 . 15 a n n o p e n t o c i n - C [ 46 ]1 0 . 9 a n n o m u r i c i n o n e -D 4146_]

r o o t 1 . 7 m o n t e c r i s t i n [_9]1 . 8 c o h i b i n - A1 . 9 c o h i b i n - B 1 [[~ ]1 . 1 2 m u r i d i e n i n - I 1 [[~]1 .1 3 m u r i d i e n i n - 2 1 [~ ]

A n n o n a p u r p u r ea,4nnona re ticulata

l e a fb a r k

1 3 .7 p u r p u r e a c i n - 2 [ 1]5 . 2 r e t i c u l a t a c i n ( o r u v a r i a m i c i n - I I ) [ 1]7 . 1 1 r e t i c u l a c i n o n e [1 ]

l e a f 7 . 6 a n n o r e t i c u i n [ 1]7 . 7 a n n o r e t i c u i n o n e [ 1]1 0 .4 i s o a n n o r e t i c u i n [ 1]

s e e d 1 .3 r e t i c u l a t a m o l [ I ]1 . 4 r e t i c u l a t a m o n e [ 1]3 . 3 d i e p o r e t i c a n i n - 1 [ I ]3 . 4 d i e p o r e t i c a n i n - 2 [ 1]3 . 5 d i e p o r e t i c e n i n [ 1J5 . 7 r e t i c u l a t a i n -1 [I ]5 . 8 r e t i c u l a t a i n - 2 [ 11 0 .1 2 i s o r o u r i s o l e n i n 5 ~ ]


17/31

N a t u r a l a c e t o g e n in s f r o m A n n o n a c e a e , s y n t h , a n d m e c h . o f a c t i o n 1 10 3T a b l e 1 1 . ( c o n t i n u e d )

S p ec ie s O r g a n C o m p o u n d s R e f .Annona senegalensis s e e d 7 . 1 5 a n n o g a l e n e ( o r x y l o m a t e n i n ) [ 1]

7 . 1 6 a n n o s e n e g a l i n [ 1]9 . 8 s e n e g a l e n e [ 1

A n n o n a a f t . spra,auei s e e d 1 4 . 21 g u a n a c o n e [7 1]A n n o n a s q u a m o s a s e e d 7 . 4 a n n o n a c i n - A [ I ]

7 .1 2 s q u a m o s t e n - A [1 ]7 . 2 7 m o s i n - B [ 33 ]7 . 2 8 m o s i n - C [ 33 ]1 0 .1 3 m o s i n o n e - A [ 33 ]1 2 .3 n e o a n n o n i n [ 1]1 2 .6 s q u a m o c i n - I [ 1]1 2 .7 s q u a m o c i n - K [ 1]1 2 .8 s q u a m o c i n - N [ 1]1 3 .8 s q u a m o c i n - E ( o r p a r v i f l o r i n ) [ 1]1 4 .1 s q u a m o c i n [ 1]1 4 .4 a n n o n i n - I l I ( o r m o t r i l i n ) [ 1]1 4 .5 s q u a m o c i n - B [ 1]1 4 .6 s q u a m o c i n - D ( o r a s i m i n a c i n ) [ I]1 4 .7 s q u a m o c i n - F [ I]1 5 . 3 a n n o s i l i n -A [7 4]1 7 . 1 s q u a m o s t a t i n - A ( o r a l m u n e q u i n ) [1 ]1 7 .3 s q u a m o s t a t i n - D [ l ]1 7 .4 s q u a m o s t a t i n - E [ 1]

b a r k 1 0 .3 s q u a m o n e [ I ]Asimina long([blia l e a v e s a n d

t w i g s1 . 1 1 l o n g a n i n [ 6]6 . 11 l o n g i fo l i c i n [2 5]6 . 1 2 l o n g i c o r i c i n [2 5]7 .17 Ion gic in 2[~_]7 . 2 4 4 -a c e t y l a n n o n a c i n _ [3 1]7 . 2 5 4 - a c e t y l x y l o m a t i c i n [ 31 ]1 0 .7 g o n i o t h a l a m i c i n o n e [ 27 ]1 0 .1 0 g i g a n t e t r o n e n i n o n e 2 [~ ]1 3 .1 8 l o n g i m i c i n - A [ 66 ]1 3 . 19 l o n g i m i c i n -B [6 6 ]1 3 .2 0 l o n g i m i c i n - C [ 66 ]1 4 .1 8 l o n g i m i c i n - D [ 66 ]

Asimina parv~[tora s t e m 1 3 .8 p a r v i f l o r i n ( o r s q u a m o c i n - E ) [ 1]1 6 .5 p a rv i f l o ra c i n [ 1 ]

A s imina t r i loba r o o t a n ds e e d sb a r k

1 3 .1 a s i m i c i n [1 ]1 0 . 5 a n n o n a c i n o n e - A1 0 . 6 g i g a n t e t r o c i n o n e1 3 . 5 t r i l o b a c i n1 3 . 1 6 1 0 - O H - a s i m i c i n1 3 . 1 7 1 0 - O H - t r i l o b a c i n1 4.6 a s i m i n a c in ( o r s q u a m o c i n - D )1 4 . 8 a s i m i n1 4 . 9 a s i m i n e c i n1 4 . 1 0 b u l l a t i n1 4 . 1 1 b u l l a n i n1 4 . 1 6 a s i m i n o c i n1 4 . 1 7 b u l l a t e t r o c i n1 6 . 9 t r i l o b a l i c i n1 8 . 1 5 t r i l o b a c i n o n e

[ 2 8 ] , [ 5 1 1[1 1[ 1 1 [ 5 7 1[ 6 4 1 , [ 6 5 _ 1[ 6 _ 4 1[1 1[1 1[1 1[ 1 ][ 1 1 [ 6 8 ][ 6 8 1[ 6 4 1[ 7 6 ][ 7 6 ]


18/31

1 1 0 4 M . C . ZA F R A - PO LOe t al .T a b l e 1 1 . ( c o n t i n u e d )

S p e ci e s O r g a n C o m p o u n d s R e f .A s imina t r i loba s e e d 6 . 5 a s i m i n e n i n - A [ 21 ]

6 . 6 a s i m i n e n i n - B [ 21 ]6 . 7 c i s - m u r i s o l i n [ 22 ]6 . 8 m u r i s o l i n - A [ 22 ]1 0 .8 m u r i s o l i n o n e [ 52 ]1 4 . 13 t r i l o b in [ 5 7]1 4 .1 4 a s i t r ib in [ 2 1]1 5 .2 a s im i lo b in [ 5 2]

Dis e pa lum anomalum b a r k 7 . 2 6 d i s e p a l i n [ 32 ]Gonio tha lamus amuy on s e e d k n o w n a c e t o g e n i n s ( 6 .2 , 7 .1 a n d 9 . 1 ) [ 12 3 ]Goniothalamus donnaiensis r o o t 1 1 .2 d o n n a i e n i n - A + 3 4 e p i [ 54 ]

11 .3 d o n n a i e n i n - B + 3 4 e p i [ 54 ]1 1 .4 K o n i o d o n i n + 3 4 e p i [ 55 ]1 1 .5 c i s - g o n i o d o n i n + 3 4 e p i [ 55 ]

Gonio tha lamus g iy an te us b a r k 1.1 g ig an in [1] , [6]6 . 4 g i g a n e n i n [ 16 . 13 4 - d e o x y a n n o m o n t a c i n [ 26 ]7 . 2 g o n i o t h a l a m i c i n [ 1]7 . 1 3 g o n i o n e n i n [ 1]7 b . 8 g ! g 2 a n t r a n s e n i n - A + B [36]7b.9 ig~%antransenin-C [36]9 .1 g i g a n t e t r o c i n - A [1 ]9 . 2 g i g a n t r i o c i n [1 ]9 . 4 g i g a n t e t r o n e n i n [ 1]9 . 5 g i g a n t r i o n e n i n [ 1]

Gonio tha lamus g igan te us b a r k 9 . 1 6 4 - a c e t y l g i g a n t e t r o c i n - A [ 47 ]9 .2 1 c i s - g i g a n t r o n e n i n [ 47 ]1 0.1 1 a n n o m o n t a c i n o n e [ 26 ]1 5 .1 g o n i o d e n i n [ 73 ]1 5 .2 a s im i lo b in [ 7 3]1 6 .2 g ig a n tec in [ 1]1 7 .2 4 - d e o x y g i g a n t e c i n [ 1]2 0 . 1 g o n io c in [ I]

Goniothalamus sesquipedalis b a r k - - k n o w n a c e t o g e n i n ( 9. 1) [ 12 4 ]P oly a l th ia p lay ione ur a s eed 7 b . 1 p lag io n i c in - A [ 3 4]P or c e l ia mac r oc ar pa s eed 1 . 14 b u t y r o lac to n e - 1 [ 1 ~]1 .1 5 b u t y r o l a c t o n e - 2 [ 13 ]R ol l in ia me mbr anac e a s eed 3 . 7 d i e p o m u r i c a n i n - B [ 13 . 8 d i e p o x y r o l l i n [1 ]

4 . I t r ip o x y r o l l in [ 1]1 2.5 m e m b r a n a c i n [1 ]1 2 .9 m e m b r a r o l l i n [ 56 ]1 3 .6 r io c la r in [ 1]1 3 .2 1 r o l l i m e m b r i n [ 67 ]

R ol l in ia muc os a s eed 1 3 . 2 r o l l in i a s t a t in - 1 [ 1]1 3 .3 r o l l i n i a s t a t i n - 2 ( o r b u l l a t a c i n ) [ 1]7 . 2 3 r o l l i n e c i n s - A + B [ 30 ]9 . 1 7 m u r i c a t e t r o c i n - C [ 48 ]1 4 , 1 9 m u c o x i n [ 69 ]1 4 ,2 0 r o l l i t a c in [ 7 0]

l e a f


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N a t u r a l a c e t o g e n in s f r o m A n n o n a c e a e , s y n t h , a n d m e c h . o f a ct i o n 1105T a b l e 1 1. ( c o n t i n u e d )

S p e c ie s O r g a n C o m p o u n d s R e f .R o l l in i a m u c o s a 1 5 . 4 ro l l i d e c i n -A [4 8 ]

1 5 . 5 ro l l i d e c i n -B [4 8 ]1 5 . 6 ro l l i n a c i n [7 0 ]1 6 . 8 1 2 , 1 5 -c i s - s y l v a t i c i n [7 5 ]2 1 .1 m u c o c i n [ 83 ]2 2 .1 m u c o n i n [ 6 9]

f r u i t 2 . 4 e p o m u s e n i n - A [16_]2.5 ep om us en in- B [_1_6]

R ol l i n i a pap i l i one l l a ro o t 1 4 . 2 i s o ro l l i n i c i n [1 ]1 8 . 2 ro l l i n o n e [ I ]

R ol l i n i a s e r i c e a b a r k k n o w n a c e t o g e n in s [ 12 5](1 3 . 2 a n d 1 4 . 1 )

R ol l i n i a s y h , a t i c a f r u i t 1 6 . 1 s y l v a t i c i n [ I , 7 5 ]R ol l i n i a u l e i l e a f 1 4 . 15 u l e i ro l l i n [5 ]U v a r i a a c u m i n a t a ro o t 1 2 . 1

12.2u v a r i c i nd e s a c e t y l u v a r i c i n i l lI l l

U v ar i a gram t ! f l o ra r o o t 6 . 9 u v a r i g r a n i n [ 23 ]U v ar i a glIrllHl r oo t 5 .1 u v a r i a m i c i n - I [ 1]

5 . 2 u v a r i a m i c i n - l l ( o r r e t i c u l a t a c in ) [ 1]5 . 3 u v a r i a m i c i n - l l l [ 1]1 2 .4 i s o d e s a c e t y l u v a r i c i n [ t ]1 4 .3 s q u a m o c i n o n e [ 1]1 4 b .1 p a n a l i c i n [1 ]1 4 b .2 n a r u m i c i n - I [1 ]1 4 b .3 n a r u m i c i n - l I [ 1]

U v a r i a p a u c i - o v u l a t a r o o t 1 4 b .4 e s p e l i c i n [7 2 ]1 4 b .5 u v a r i a s o l i n -1 [7 2 ]1 4 b . 6 u v a r i a s o l i n - l l [ 7 2]1 . 6 t o n k i n e l i n [_8]6 . 1 0 t o n k i n e c i n [ 2 4]7 b . 2 t o n k i n i n - A [ 3 5]7 b . 3 t o n k i n i n - B [ 35 ]7 b . 4 t o n k i n i n - C [ 35 ]7 b . 5 t o n k i n e s i n - A [ 35 ]7 b . 6 t o n k i n e s i n - B [ 35 ]7 b . 7 t o n k i n e s i n - C [ 35 ]

U v a r i a t o n k i n e s i s r o o t

X y l o p i a a r o m a t i c a b a r k 1 . 2 v e n e z e n i n [1 11 .1 0 v e n e z i n o n e [ H ]7 . 8 x y l o p i a n i n [ 1]7 . 9 x y l o p i a c i n [ I ]7 . 1 0 x y l o m a t i c i n [ 1]7 . 1 4 x y l o p i e n [ I ]7 . 1 5 x y l o m a t e n i n ( o r a n n o g a l e n e ) [ 1]2 3 . 1 a ro m i n [8 4 ]2 3 . 2 a r o m i c i n [ 8 4]


20/31

1 1 06 M . C . Z A F R A -P O L o t a l .T a b l e 1 2. N a m e s o f a c e t o g e n i n s f r o m A n n o n a c e a e c i t ed i nt h i s r e v ie w ( a l p h a b e t i c o r d e r )

A c e t o g e n i n R e f .7 .2 4 4 - A c e t y l a n n o n a c i n [ 31 ]9 .1 6 4-A cety lgiga ntetr ocin -A_ 414[~]7 .2 5 4 - A c e t y l x y l o m a t i c i n [ 31 ]17 .1 A l m u n e q u i n ( o r s q u a m o s t a t i n A ) [1 ]7 .1 5 A n n o g a l e n e ( o r x y l o m a t e n i n ) [ 1]1 3 .9 A n n o g l a u c i n [ 1]8 .1 1 A n n o h e x o c i n [ 39 ]8 .1 A n n o m o n i c i n [ 17 .5 A n n o m o n t a c i n [1 ]1 0 .1 1 A n n o m o n tac in o n e 212[~]8 . 4 A n n o m u r i c i n - A [1 ]8 .5 A n n o m u r i c i n - B [1 ]8 .1 0 A n n o m u r i c i n - C [3 8]1 0 .9 A nn o m ur ic in o n e- D 4141414[~]7 .1 8 A n n o m u t a c i n [ 28 ]7 .1 A n n o n a c i n [1 ]7 .1 9 c i s - A n n o n a c i n [ 29 ]7 .4 A n n o n a c i n - A [1 ]7 .3 A n n o n a c i n o n e [1 ]7 .2 0 c i s - A n n o n a c i n o n e 2 [~ ]1 0 . 5 A n n o n a c i n o n e -A [ ~ [5 1]1 4 .4 A n n o n i n - I I I ( o r m o t r i l i n ) [ 1]13.15 A nn o n is in 61616~]1 5 . 3 A n n o n s i l i n - A [ 7 4 ]9 .1 4 A n n o p e n t o c i n s - A + B [4 6]9 . 1 5 A n n o p e n t o c i n - C [46_]7 .6 A n n o r e t i c u i n [1 ]7 .7 A n n o r e t i c u i n o n e [1 ]7 .1 6 A n n o s e n e g a l i n [1 ]5 . 9 A n n o t e m o y i n - 1 [ 20 ]5 . 1 0 A n n o tem o y in - 2 212[~]1 3 . 14 A r a t i cu l in 6 [ ~]7 .2 2 A r i a n a c i n [ 29 ]2 3 . 2 A r o m i c i n [ 84 ]2 3 .1 A r o m i n [ 84 ]1 3 . 1 A s i m i c i n [1 ]15.2 A s im ilo bi n [51] 717[~]1 4 . 8 A s i m in [ 1]1 4 .6 A s i m i n a c i n ( o r s q u a m o c i n - D ) [1 ]1 4 .9 A s i m i n e c i n [ 1]6 . 5 A s i m i n e n i n - A [2 1]6 . 6 A s i m i n e n i n - B 2 [~ ]14.16 A s im ino ci n 616[~]1 4 . 14 A s i t r ib in [ 2 1]1 4 . 12 B u l l ac in [ 1]1 8 .5 B u l l a d e c i n o n e [ 1]1 4 . 1 1 B u l l a n i n [ 1] [ 68 ]1 3 . 3 B u l l a t a c i n ( o r r o l l i n i a s t a t i n - 2 ) [ 1]1 8 . 1 B u l l a t a c i n o n e [1 ]1 6 .3 B u l l a t a l i c i n ( o r c h e r i m o l i n - l ) [ 1]1 6 . 6 1 2 , 1 5 - c i s - B u l l a t a l i c i n [ 11 8 . 3 B u l l a t a l ic i n o n e ( o r i s o c h e ri m o l i n - 1 ) [1 ]1 6 .4 B u l l a t a n o c i n ( o r c h e r i m o l i n - 2 ) [ 1]16.7 12, 1 5 - c i s - B u l l a t a n o c i n [1 ]1 8 .4 B u l l a t a n o c i n o n e [1 ]5 . 6 B u l l a t e n c i n [ 114.17 Bu llat etro cin 6[64]1 4 . 10 B u l l a t in [ 1]1 .1 4 B u t h y r o l a c t o n e - 1 [ 13 ]1 . 1 5 B u t h y r o l a c t o n e - 2 U1 6 . 3 C h e r i m o l i n - I ( o r b u l l a t a l ic i n ) [1 ]

16.41. 81. 93 .29.111. 58.138.146 .26 .39. 36.139.2017.212.23. 13 .73. 33 .43. 53 .63 .87.2611.211.32. 12 .32 .42 .52. 12 .21 4 b . 46 .41.116.29. 19 .610.69 .410.107 b . 87 b . 99 .29 .59.219 . 1 99.1813.1020.115.111.411.57.137 .27.2110.714.218. 313.1613.1113.1213.13

T a b l e 1 2 . ( c o n t i n u e d )A c e t o g e n i n R e f .

C h e r i m o l i n - 2 ( o r b u l l a t a n o c i n ) [1 ]C o h i b i n - A [ 1 0 ]C o h i b i n - B [ 1 0 ]C o r e p o x y l o n e [ 1 ]C o r i a c i n [ 4 3 ]C o r i a d i e n i n [ 7 ]C o r i h e p t o c i n - A [ 4 ~ ]C o r ih ep to c in - B [ 4 1 _ ]C o r o s s o l i n [ 1 ]C o r o s s o l o n e [ 1 ]D e n s i c o m a c i n - 1 [ 1 ]4 - D e o x y a n n o m o n t a c i n [ 2 6 ]4 - D e o x y c o r i a c i n [ 4 3 ]4 - D e o x y g i g a n t e c i n [ 1 ]D e s a c e t y l u v a r i c i n [ 1 ]D i e p o m u r i c a n i n - A [ 1 ]D i e p o m u r i c a n i n - B [ 1 ]D i e p o r e t i c a n i n - 1 [ 1]D i e p o r e t i c a n i n - 2 [ 1 ]D i p o r e t i c e n i n [ 1 ]D i e p o x y m o n t i n [ 1 ]D i e p o x y r o l l i n [ I ]Disepalin 313[~]D o n n a i e n i n - A + 3 4 e p i [ 54 ]D o n n a i e n i n - B + 3 4 e p i [ 54 ]E p o m u r i c e n i n - A o r e p o x y m u r i n - A [1 ]E p o m u r i c e n i n - B [ 1 ]E p o m u s e n i n - A [ 1 6 ]E p o m u s e n i n - B [ 1 6 ]E p o x y m u r i n - A ( o r e p o m u r i c e n i n - A ) [ 1]E p o x y m u r i n - B [ 1 ]Es p e l i c in [ 7 2 ]G i g a n e n i n [ I ]G i g a n i n [ 1] [ 6]G i g a n t e c i n [ 1 ]G i g a n t e t r o c i n - A [ 1 ]G i g a n t e t r o c i n - B [ I ]G i g a n t e t r o c i n o n e [ 1 ]G i g a n t e t r o n e n i n [ 1 ]G ig a n te tr o n e n in o n e 2121212[~]G i g a n t r a n s e n i n s - A + B [ 36 ]G i g a n t r a n s e n i n - C [ 3 6 ]G i g a n t r i o c i n [ 1 ]G i g a n t r i o n e n i n [ 1 ]c i s - G i g a n t r i o n e n i n [47]G l a b r a n i n [ 5 0 ]G l a u c a f i l i n [ 4 9 ]G l a u c a n i s i n [ 1 ]G o n i o c i n [ 1 ]G o n i o d e n i n 7 [ 7 3 ]G on io d o n in + 34- epi 51515[~]c i s - G o n i o d o n i n + 3 4 - e p i [ 55 ]G o n i o n e n i n [ 1 ]G o n i o t h a l a m i c i n [ 1 ]c i s - G o n i o t h a l a m i c i n [ 2 9 ]G o n i o t h a l a m i c i n o n e [ 2 7 ]G u a n a c o n e [ 7 1 ]8 - H y d r o x y - a n n o n a c i n [ 1 ]10 - H y d r o x y - a s i m i c i n [64], 6161616161616161616~3 0 - H y d r o x y - b u l l a t a c i n [ 6 1 ]3 1 - H y d r o x y - b u l l a t a c i n [ 61 ]3 2 - H y d r o x y - b u U a t a c i n [ 6 1 ]


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18.1118.1218.1418.1318.818.718.613.1710.110.210.418.312.410.1218.918.1014.219.27.2211.119.11.117.176 . 1 26.1113.1813.1913.2014.18i 2 . 512.913.48 .21. 77.277.2810.1314.421.1.22.114.198.129.139 .79.179 .99 . 1 08 .68. 78 .88. 91.121.139.126. 16 .76. 810.814b.214b.312.319.3

N a t u r a l a c e t o g e n in s f r o m A n n o n a c e a e , s y n t h , a n d m e c h . o f a c t i o nT a b l e 1 2 . ( c o n t i n u e d )A c e t o g e n i n R e f .

T a b l e 1 2 . ( c o n t i n u e d )A c e t o g e n i n R e f .

1 0 - H y d r o x y - b u l l a t a c i n o n e1 2 - H y d r o x y - b u l l a t a c i n o n e2 8 - H y d r o x y - b u l l a t a c i n o n e2 9 - H y d r o x y - b u l l a t a c i n o n e3 0 - H y d r o x y - b u l l a t a c i n o n e3 1 - H y d r o x y - b u l l a t a c i n o n e3 2 - H y d r o x y - b u l l a ta c i n o n e1 0 - H y d r o x y - t r i l o b a c i nI s o a n n o n a c i nI s o a n n o n a c i n o n el s o a n n o r e t i c u i nl s o c h e r i m o l i n - 1 ( o r b u l l a t a l i c i n o n e )I s o d e s a c e t y l u v a r i c i nl s o m u r i s o l e n i nl s o m o l v i z a r i n - 1l s o m o l v i z a r i n - 2I s o r o l l i n i c i nl t r a b i nJ a v o r i c i nJ e t e i nL a h e r r a d u r i nL o n g a n i nL o n g i c i nL o n g i c o r i c i nL o n g i f o l i c i nLo n g i m i _ c i n -AL o n g i m i c i n - BL o n g i m i c i n - CL o n g i m i c i n - DM e m b r a n a c i nM e m b r a r o l l i nM o l v i z a r i nM o n t a n a c i nM o n t e c r i s t i nM o s i n - BM o s i n - CM o s i n o n e - AM o t r i l i n ( o r a n n o n i n - l l I )M u c o c i nM u c o n i nM u c o x i nM u r i c a t a l ic i nM u r i c a t a l i nM u r i c a te t r o c i n s - A + BM u r i c a t e t r o c i n - CM u r i c a t i n - AM u r i c a t i n - BM u r i c a t i n - CM u r i c a t o c i n - AM u r i c a t o c i n - BM u r i c a t o c i n - CM u r i d i e n i n - 1M u r i d i e n i n - 2M u r i h e x o c i n s - A + BM u r i s o l i nH s - M u r i s o l i nM u r i s o l i n - AM u r i s o l i n o n eN a r u m i c i n - IN a r u m i c i n - l IN e o a n n o n i nO t i v a r i n

[1 ][11[ 6 1 1[ 1 ][11[11[11[143][11[1 ][11[11[1 ][531[1 ][1 ][1 ][11[29][ 1 ][ ! ][ 6 ][2_.7_][ 2 5 ][251[66][ 6 6 ][ 6 6 1[66][1 1[561[1 ][1 ][9 ][33_][33][331[1 ][_83][691[691[_40_1[4~1[11[481[1 ][1 ][1 ][371[ 3 7 1[ 3 8 1[121[ 1 2 1[ 1 0 8 ][1 1[ 2 2 ][221[521I l l[11[I ][I ]

14b.116.513.87 b . l13.77.115 .25 .75 .81. 31. 413.615.415.513.2115.67.2313.213,318,21 4 2 09 .85 .414.114.514.613.814.712.612.712.814.310.317.117.317.47.1216.116.86 . 1 01. 67 b . 57 b . 67 b . 77 b . 27 b . 37 b . 413.518.1516.914.134. 114.155. 15 .25 .35 .514b.514b.612.16, 91, 2

P a n a l i c i n [ 1 ]P a r v i f l o r a c i n [ 1 ]P a r v i f lo r i n ( o r s q u a m o c i n - E ) [ 1]Plagionicin-A__ [34]P u r p u r e a c i n - 2 [ 1 ]R e t i c u l a c i n o n e [ 1 1R e t i c u l a t a c i n ( o r u v a r i a m i c i n - l I ) [ 1]R e t i c u l a t a i n - 1 [ 1 ]R e t i c u l a t a i n - 2 [ 1 ]R e t i c u l a t a m o l [ 1 ]R e t i c u l a t a m o n e [ I ]R i o c l a r i n [ 1 ]R o l l i d e c i n - A [ 4 8 ]R o l l i d e c i n - B [ 4 8 ]R o l l i m e m b r i n [ 6 7 ]Rollinacin [_7_0]R o l l i n e c i n s - A + B [ 30 ]R o l l i n i a s t a t i n - 1 [1 ]R o l l i n i a s t a t i n - 2 ( b u l l a t a c i n ) [ I ]R o l l i n o n e [ 1 ]R o l l i t a c i n [ 7 0 ]S e n e g a l e n e [ 1 ]S o l a m i n [ 1 ]S q u a m o c i n [ I ]S q u a m o c i n - B [ 1 ]S q u a m o c i n - D ( o r a s i m i n a ci n ) [ 1]S q u a m o c i n - E ( o r p a r v i f lo r i n ) [1 ]S q u a m o c i n - F [ 1 ]S q u a m o c i n - I [ 1 ]S q u a m o c i n - K [ 1 ]S q u a m o c i n - N [ 1 ]S q u a m o c i n o n e [ 1 ]S q u a m o n e [ 1 ]S q u a m o s t a t i n - A ( o r a l m u n e q u i n ) [ 1]S q u a m o s t a t i n - D [ 1 ]S q u a m o s t a t i n - E [ 1 ]S q u a m o s t e n - A [ 1 ]Sy lva tic in [1] [7_5_]12,15-c i s -Sylva t ic in [7_5]T o n k i n e c i n [ 2 4 ]To n k i n e l i n [8 _ ]To n k i n e s i n -A [3 _ 5 ]To n k i n e s i n -B [3 _ 5 ]Tonkinesin-C 31313~]T o n k i n i n - A [ 3 5 ]T o n k i n i n - B [ 3 5 ]T o n k i n i n - C [ ~ 5 ]Tr i l o b a c i n [1] [5 7 ]Tr i l o b a c i n o n e [7 _ 6 ]Tr i l o b a l i c i n [_ 7 6 ]T r i l o b i n [ 5 7 ]T r i p o x y r o l l i n [ 1 ]Ul e i ro l l i n [5 ]U v a r i a m i c i n - I [ 1 ]U v a r i a m i c i n - I I ( o r r e t i c u l a t a c in ) [ 1]U v a r i a m i c i n - I I l [ 1 ]U v a r i a m i c i n - I V [ 1 ]U v a r i a s o l i n - I [ 7 2 ]U v a r i a s o l i n - I I [ 7 2 ]U v a r i c i n [ 1 ]U v a r i g r a n i n [ 2 3 ]V e n e z e n i n [ 1 ]

1107


22/31

1108 M .C . ZAFRA-POLO t al.Table 12. (continued)Acetogenin Ref.

1. 10 Venezinone 1[[~1]7 .1 5 Xylomatenin (or annogalene) [1]7 .1 0 Xylomaticin [1]7.9 Xylo piacin [1]7.8 Xy lopia nin [1]7 . 14 Xylopien [1]

t h e T H F s y s t em a r e a r g u e d t o c o n f i r m t h e c is o r t r a n sT H F c o n f ig u r a ti o n .

S a t u r a t e d l a c t o n e bLY-T H F a c e to g e ni n sT w o b i s - T H F ' i s o ' - a c e t o g e n i n s h a v e b e e n r e p o r t e d

i n t h i s p e r i o d : 2 8 - h y d r o x y - b u l l a t a c i n o n e ( 18 .1 4 ) ( m u s tb e d e r iv e d f ro m r io c la r in , 1 3 . 6 ) a n d t r i l o b a c in o n e(1 8 .1 5 ) (m u s t b e d e r iv e d f ro m t r i l o b a c in , 1 3 .5 ).

I n t h e g r o u p o f f l - h y d r o x y - a c e t o g e n i n s ( 1 9: l a h -e r r a d u r i n t y p e ) n o c o m p o u n d i s a d d e d . S o f a r , t h e sec o m p o u n d s h a v e b e e n c o n s i d e r e d a s e x c l us i v e t oA n n o n a c h e r i m o l i a [8 2 ], b u t r e c e n t ly , c o m p o u n d s 1 9 .1a n d 1 9 .2 h a v e b e e n i s o l a t e d , b y o u r g ro u p , f ro m s e e d so f A n n o n a 9 1 a b r a [50].

MISCELLANEOUSACETOGENINSI n T a b l e l 0 w e i n c l u d e d a m i s c e ll a n e o u s g r o u p o f

a c e t o g e n in s c h a r a c t e r i z e d b y a n a t y p i c a l s u b s t i t u te da lk y l c h a in [1 , 69 , 8 3, 8 4 ]. A c e to g e n in s w i th a T H Fr i n g a n d a n o n - a d j a c e n t ( t y p e 2 1 ) o r a d j a c e n t ( t y p e2 2 ) t e t r a h y d r o p y r a n ( T H P ) r i n g , w e r e i s o l a t e d f r o m

R o l l i n i a m u c o s a [69 , 83] . Mucoc in (21 .1 ) is the f i rs ta c e t o g e n i n w i t h a n u n u s u a l h y d r o x y l a t e d T H P r i n ga n d a r e l a t iv e c o n f ig u ra t io n t r a n s / t h r e o - t h r e o / c i s .F i n a l l y , n o n - a d j a c e n t b i s - T H F a c e t o g e n i n s (2 3: a r o -ra in ty p e ) p o s s e ss in g a T H F s y s t e m b e tw e e n th e 4 /7a n d 1 6/19 p o s i t i o n s w e re fo u n d in X y l o p i a a r o m a t i c a[841.

TOTAL SYNTHESI S

Since our la s t rev iews [85 , 86] , numerous newa p p r o a c h e s t o A n n o n a c e o u s a c e t o g e n i n s h a v ea p p e a r e d i n t h e l i t e r a t u r e. W e w i l l n o t d e s c r i b e h e re i nt h e p r e p a r a t i o n o f k e y i n t e r m e d i a t e s ; i n s t e a d w e w i l lf o c u s o n s e v e r a l s y n t h e ti c p a t h w a y s w h i c h l e d t o t h et o t a l s y n t h e si s o f n a t u r a l a n d e n a n t i o m e r i c a c e t o -g e n in s .

C a s s a d y [ 8 7 ] p r e p a r e d ( + ) - 1 3 , 1 4 - t h r e o - d e n s i c o -m a c i n u s i n g a c o n v e r g e n t s t r a t eg y w h i c h r e q u i r e d t op r e p a r e e n a n t i o s e l e c ti v e l y t h e T H F p a r t a n d t h e l a c -t o n e m o i e t y , p r i o r t o c o u p l e b o t h s y n t h o n s t h r o u g ht h e S o n o g a s h i r a - L i n s t r u m e l l e - A l a m i r e a c t i o n ( S c h -e m e 1 ). T h e T H F p a r t o f th e m o l e c u l e w a s p r e p a r e df r o m t h e ( E , E , E ) t r i e n e w h i c h w a s o b t a i n e d t h r o u g ha n 11 s t e p p ro c e d u re f ro m 1 , 5 -h e x a d iy n e . T h e n a f t e ra s y m m e t r i c e p o x i d a t i o n o f t h e a l l y li c a l c o h o l , a d o u -b l e a s y m m e t r i c d i h y d r o x y l a t i o n a f fo r d e d t h e t e t r a o l ,w h i c h u p o n b a s i s t r e a t m e n t g a v e t h e T H F p a t t e r n .A f t e r h y d r o x y l p r o t e c t i o n , t h e t e r m i n a l e p o x i d e w a sc o n v e r t e d t o t h e d e s i r e d a l k y n e b y o p e n i n g w i t h t r i -m e t h y l s i l y l l i t h i u m a c e t y l i d e . C o n c e r n i n g t h e l a c t o n ef r a g m e n t , t h e s t r a t e g y w a s in s p i r e d b y F r a n c k ' s w o r k[88 ]. In d e e d L -g lu ta m ic a c id w a s c o n v e r t e d in to th ec o r r e s p o n d in g e p o x id e [8 9] in fiv e s t e p s . T h e n a d d i t io no f t r i m e t h y l s i l y l l i t h i u m a c e t y li d e , f o l lo w e d b y

~ Iz ==~ ~ O H a ,b C14H21 . . . . . . , . . . . . . ~ ~~ c,d im~ C , , ~ H ~ O T$OH OH OH

C14H = ~ C ) H ~ OTs e. f = ~ g, h, i, jC14H~'~

t, U - ~ 014H~cI4H~ fL - g lu t a m ic c i d / I v Xol ref. x 0 ~ 0 (+)-13,14-threo~ensicomacin0[~ OMe BT M S ~ - T H P ~ IOTHP

Scheme 1.


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Natural acetogenins from Annonaceae, synth, and mech. of act ioni o .a , b , c _-- ~ O H d , e .

H2)l lO 'h MOMO" "(OH2) l lQq3M O b l O ~j , a , h ~L, ,,~ i

HO~

MOMO (31-13 SPh

O

~ d fO ~ ' ~ h i d E E O ~ ~

MOMO- - ( C H ~

H2)11Scheme 2.

1109

h y d r o x y l p r o t e c t i o n g a v e t h e b r o m o p r o p a r g y l t e t r a -hyd r opy r a n de r i va ti ve . A dd i t i on o f t r i m - bu t y l t inh y d r i d e i n t h e p r e se n c e o f A I B N g a v e t h e c o r -r e s p o n d i n g v i n y l t in c o m p o u n d . I n t r o d u c t i o n o f th el a c t one w a s pe r f o r m e d by e no l i z a t i on , f o l l ow e d bya d d i t io n o f O - M O M ( S ) -l a c ta l d e hy d e , d e p r o t e c t io na n d l a c to n i z a ti o n . T h e t i n - c a r b o n b o n d w a s t h e n c le a -ve d by b r om i ne t o a f f o r d t he c o r r e s pond i ng v i ny l b r o -m i n e. D e h y d r a t i o n o f t h e m e s y la t e o b t a in e d f r o m t h ec o r r e s pond i ng a l c oho l a f f o r de d t he de s i r e d s yn t hon .The c oup l i ng r e a c t i on w a s pe r f o r m e d i n t he p r e s e nc eo f pa l l a d i um t r i phe ny l pho s ph i ne t e tr a k i s , c opp e r i od -i de a nd d i e t hy l a m i ne , l e a d i ng t o t he e nyne , w h i c h w a ss e le c ti ve ly hyd r oge na t e d i n t he p r e s e nc e o f Wi l k i ns onc a t a l y s t [ 90 ]. D e p r o t e c t i on o f t he hyd r o xy l s a f f o r de dt he t a r ge t m o l e c u l e.

Tanaka [19, 91] (Scheme 2) descr ibed the synthes i so f (15S,16R,20R,34S)-diepomuricanin, t he na t u r a lb i s - e pox ide p r e c u r s o r o f s o l a m i n ( 5 .4 ), a nd t hus w a sa b l e t o de t e r m i ne t he a bs o l u t e c on f i gu r a t i ons o f t hes t e r e oge n i c c e n t e r s o f t he na t u r a l p r oduc t . S i nc ea bs o l u t e c o n f i gu r a t i ons o f s o l a m i n ( 5 .4 ) a r e a l s okno w n a f t e r c om pl e t i on o f i ts t o t a l s yn t he s i s, i t is nowpos s i b le t o p r opo s e t ha t t he ox i r a ne ope n i ng f o l low e db y T H F f o r m a t i o n i s u n d e r e n z y m a t i c c o n t r o l a n dt ha t t he f i r s t w a t e r a t t a c k oc c u r s a t C - 15 w i t h i nve r -s i on o f c on f i gu r a t i on , f o l l ow e d by t he c a s c a de r e a c t i onl e a d i ng t o t he 2 ,5 - d i s ubs t i t u t e d TH F ( t he r e ve r s er e a r r a nge m e n t w ou l d ha ve l e d t o t he oppos i t e c on -f i gu r a t i on a c r os s t he TH f pa t t e r n ) . The s yn t he s i s o ft he b i s - e pox i de s t a r t e d w i t h t he know n m ur i c a t a c i n[ 5] w h i c h a f t e r hyd r oxy l p r o t e c t i on , D I B A L r e duc t i on

a nd Wi t t i g r e a c t i on ga ve t he ~o - hydr oxy- ~ , f i - uns a t u -r a t e d es te r. H yd r oxy l p r o t e c t i on a nd a s ym m e t r i cd i hyd r oxy l a t i on a f f o r de d t he t e t r a o l . The n s e ve r a lt r a ns f o r m a t i ons l e d t o t he de s i r e d a l kyne . The l a c t onef r a gm e n t w a s p r e pa r e d a s a l re a dy de s c r i be d a s a v i ny li od i de de r i va t ive [ 92 ] . C r os s c o up l i ng r e a c t i on w a sp e r f o r m e d b e t w e e n t h e t w o s y n t h o n s u n d e r p a l l a d i u mc a t a l y s i s t h r ough t he Sonoga s h i r a - L i ns t r um e l l e -A l a m i r e a c ti o n . T h e n h y d r o g e n a t i o n o f th e e n y n e s oob t a i ne d w a s pe r f o r m e d i n the p r e s e nc e o f Wi l k i ns onc a t a l y s t . F i na l l y Wi l l i a m s on r e a c t i on a nd ox i da t i vee l i m i na t i on a f f o r de d t he de s i r ed m o l e c u l e . I t i s w o r t hno t i ng t ha t t he s a m e a u t ho r s s uc c e e de d i n t he t o t a ls yn t he s is o f t he p r opos e d a nd e r r one o us s t r uc t u r e f o re poxy r o l l i n - A a nd e po xyr o l l i n - B [1 ].

Sc h a r f [ 93 ] p r e pa r e d t he 15-epi-annonin 1 ( Sc he m e3), a n unn a t u r a l i s om e r o f t he na t u r a l s qua m o c i n( 14 .1 ) , a l s o na m e d a nnon i n I . The ke y s t a r t i ngm a t e r i a l w a s a bu i l d i ng b l oc k p r e pa r e d a s i n R e f .[94] , which af ter l eading to an epoxide gave the a ly l ica l c o h o l t h r o u g h t h e p r o p a r g y l a l c o h o l . T h e n S h a r -p l e s s e pox i da t i on , f o l l ow e d by t o s y l a t i on a nd r i ngr e a r r a nge m e n t , a f f o r de d t he b i s - TH F pa t t e r n . O pe n-i ng o f the e pox i de by t r e a t m e n t w i t h t he l i t h ia t e dh o m o c h i r a l a l k y n e , f o l l o w e d b y h y d r o g e n a t i o n a n dh y d r o x y l p r o t e c t i o n s , g a v e t h e e x p e c t e d c o m p o u n d .The l a t t e r a f f o r de d t he de s i r e d t e r m i na l e pox i de w h i c hupo n t r e a t m e n t w i t h t he l a c tone f r a gm e n t [ 95 ] ga vet h e c o u p l e d p r o d u c t w h i c h a f t e r d e p r o t e c t i o n a f f o r d e dt he t a r ge t m o l e c u l e .Keinan [79, 96] prepared as imic in (13.1) , buyl -la tac in or ro l l in i s ta t in-2 (13.3) ( two natura l epimers a t


24/31

I110 M. C. ZAFRA-POLO t a l .OHT s O v ' l ' ~ ~ 0 a- 'o . " - ' 3o ~

oOH

O ~ Cell13OTBS o'rBs

OH" OHO

" OTBS ,,

f ,,, ~ ~ ~ ~ ~ ~ Cell13/ ]g,h

1 3 , 1 4- t h re o p i - a n n o m n IScheme 3.

a I H O . . . . .

c o ~a ~ I ~ s BP ~ = = oo ,o ~ o . ~ ~ h ~ , o .> < .o

X [ o ,, , ,

-o- - -o- -o-

asimicinor bullatacin r ~ ' i l o b a c i nScheme 4.

C-24) and trilobacin (13.5) through a similar strategy(Scheme 4): asymmetric dihydroxylation of a tris-unsatu rated ester, Ke nned y's oxidative-cyclization ofa bis-homoallylic alcohol with rhe nium oxide for theprepara tion of the TH F s ynthons for bullata cin (13.3)and asimicin (13.1). For parviflorin (13.8), Wittigcoupling reaction between a chiral aldehyde with achiral phosphoru s ylide gave the desired alkene whichafter di-hydroxylation and Williamson reactionafforded the TH F pattern. The lactone fragment pos-

sessing at one terminus an aldehyde was preparedwithout any details. Then a Wittig reaction was per-formed for the coupling reaction between both frag-ments. Again, selective hydrogen ation of the isolateddouble bond in the presence of Wilkinson catalyst,followed by deprotection o f the hydroxyls led to thetarget molecules.

Hoye [97] prepared (+)-p arvi flori n (13.8) from asymmetrical (E,E,E)-triene through a double asym-metric epoxidation of allylic diol, followed by an


25/31

Natural acetogenins from Annonaceae, synth, and mech. of act ionH O S B T O

O T B S

a ,b , c , d e , f g ,h i , j

% +%+(31-t OTBS

H

7H15

omsC~-o

(+)-parviflorin ., y , Z OrBS O

C~lsScheme 5.

1 1 1 1

a s y m m e t r i c d i h y d r o x y l a t i o n o f t h e r e s u lt a n t d o u b l ebond ( Sc he m e 5 ) . O x i r a ne s ope n i ng i n a c i d i c c on -d i t i ons le d t o t he b i s - TH F pa t t e r n pos s e s s i ng t w o 1 ,2 -d i o l s w h i c h w e r e e a s i l y c onve r t e d i n t o t he c o r -r e s pond i ng e pox i de s . The n s ucc e ss ive a dd i t i ons o f t ri -methyls i ly l l i th ium acetyl ide , fo l lowed by l i th ia tednonyn e , l e d t o t he bu i l d i ng b l oc k pos s e s s i ng a t e r m i na lt r ip l e bon d . S i nc e the c oup l i ng r e a c t i on w i t h t he l a c -t o n e f r a g m e n t w a s b a s e d o n t h e S o n o g a s h i r a -L i ns t r um e l l e - A l a m i r e a c t i on , v i ny l i od i de w a s p r e -p a r e d t h r o u g h a n o r i g i n a l a p p r o a c h . N a m e l y , t h e 4 -h y d r o x y b u t e n o l i d e w a s p r e p a r e d f r o m 6 - i o d o - h e x en ea f t e r b is - a l ky l a t ion o f hyd r oqu i non e f o l l ow e d bya s ym m e t r i c d i hyd r oxy l a t i on , a nd s uc c e s s i ve f o r -m a t i on o f t he e pox i de s f r om t he 1 ,2 -d io ls ob t a i ne d .O pe n i ng o f the e pox i de s w i t h l i t h i a te d op t i c a l ly pu r e3 - bu t yn - 2 - o l de r i va t ive , a nd s el ec ti ve de p r o t e c t i on o ft he p r opa r gy l hyd r oxy l s l e d t o t he de s i r e d de r i va t i vew h i c h w a s r e a dy f o r a R e da l r e duc t i on f o l l ow e d byi od i ne t r e a t m e n t a nd S t i l l e c a r bony l a t i on t o g i ve t hebu t e no l i de . O x i da t i ve r e l e a s e , Sw e r n ox i da t i on a ndr e a c t i o n w i t h c h r o m i u m ( I I ) c h l o r i d e a n d i o d o f o r mga ve t he r e qu i r e d v i ny l i od i de w i t h a h i gh op t i c a lpu r i t y . The f i na l c oup l i ng r e a c t i on unde r pa l l a d i umc a t a l y s i s ( Sonoga s h i r a - L i ns t r um e l l e - A l a m i r e a c t i on ) ,f o l l ow e d by t he s e l e c t i ve hyd r oge na t i ons a ndhydr ox y l s de p r o t e c t i ons l e d t o ( + ) - pa r v i f l o r i n ( 13 .8 ).

F i ga d6r e [ 98 ] ( Sc he m e 6 ) p r e pa r e d t he C ~ C34 skel-e t on o f ( - ) - de ox ya s i m i c i n t h r o ugh a r e pe t i ti ve s t e re o -s el ec ti ve C - g l yc o s y l a t i on o f a nom e r i c a c e t a t e s w i t ht r i m e t hy l s il y l oxy f u r a n . The s t a r t i ng m a t e r i a l w a s p r e -pa r e d f r om L- g l u t a m i c a c i d a s r e po r t e d [ 99 ] . The n aWi t t i g r e a c t i on f o l l ow e d by hyd r oge na t i on ga ve t heCI-C34 r a g m e n t o f( - ) - 4 - d e o x y a s i m i c i n . K n o w n p r o -c e du r e s f o r i n t r oduc t i on o f the C35-C37 a c t one r i ng[100] wo uld lead to ent-asimicin.

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