This work has been digitalized and published in 2013 by Verlag Zeitschrift für Naturforschung in cooperation with the Max Planck Society for the Advancement of Science under a Creative Commons Attribution 4.0 International License. Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschung in Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht: Creative Commons Namensnennung 4.0 Lizenz. Synthesis of Isoponcimarin P. Rodighiero, A. Guiotto*, P. Manzini, and G. Pastorini Istituto di Chimica Farmaceutica dell'Universita di Padova, Centro di Studio della Chimica del Farmaco e dei Prodotti Biologicamente attivi del CNR, Via Marzolo 5, 1-35100 Padova, Italy Z. Naturforsch. 34b, 1010-1014 (1979); received February 19, 1979 Isoponcimarin, Isomeranzin, Dihydrooroselone, Synthesis Synthesis of isoponcimarin, 7-(3'-methyl-2',3'-epoxy-butiloxy)-8-(3"-methyl-2"-oxo- butyl) coumarin, a natural coumarin isolated from Poncirus trifoliata L., was obtained starting from acetyl osthenol. From the intermediate 7-acetoxy-8-(3'-methyl-2'-oxobutyl) coumarin, the coumarin derivatives isomeranzin and dihydrooroselone were also prepared. In a previous paper [1] we reported the isolation and identification from unripe fruits of Poncirus trifoliata L. (fam. Rutaceae; subfam. Aurantioideae) of a new coumarin, which was named isoponcimarin. This compound is a neutral coumarinic derivative, optically active [a]»j 5 — 6,94° (CHCls), m.p. 85 °C (from w-hexane), violet-blue fluorescent to UV light (365 nm) and has molecular formula C18H22O5. On the basis of the chemical and spectroscopical evi- dences to isoponcimarin was assigned the structure 7-(3 / -methyl-2',3'-epoxy-butyloxy)-8-(3''-methyl- 2"-oxo-buthyl) coumarin (6) [1, 2]; therefore iso- poncimarin is a structural isomer of poncimarin, 7-(3'-methyl-2',3'-epoxy-butyloxy)-8-(3"-methyl- 2",3"-epoxy-buthyl) coumarin (10), isolated from the same natural source [3] and confirmed by total synthesis [4], A number of natural coumarins were known, in which isopentenyl and geranyl side chains are present at various oxidation level [5]. The oxi- genated function may be an epoxide group, a diol, a ketonic or an aldehydic group. It has been suggested a biogenetic pathway (not tested up to now) which from the epoxide derivative, via the diol derivative, give rise to the formation of the keto- or formyl-derivative by a pinacol-type re- arrangement [6]. In this way poncimarin (10) will be hydrolized to a diol derivative, which so far failed to be identified from extracts of Poncirus trifoliata. On the other hand a direct rearrangement of the epoxide group may also be assumed: in this hypothesis poncimarin (10) may be considered the direct precursor of the isoponcimarin (6). * Reprint requests to Dr.Prof.ManfredMutter. 0340-5087/79/0700-1010/5 01.00/0 In this paper we describe the synthesis of iso- poncimarin obtaining a definite confirmation of the proposed structure 6 of this substance; in addition, we describe the synthesis of two other chemically correlated compounds. The preparation (see Fig. 1) started from osthenol, 7-hydroxy-8-(3'-methyl-but-2-enyl) coumarin, in which an isopentenylic residue branched from the 8-position of the coumarin nucleus is already present; osthenol was prepared in good yield by Claisen rearrangement of 7-(l,l-dimethyl-prop-2- enyloxy) coumarin [7] in boiling diethylaniline [4, 8]. Osthenol was acetylated and then epoxidated by treatment with perbenzoic acid in chloroformic solution. The phenolic group ortho to the isopenteny- lic moiety must be protected before the epoxida- tion, because it was proved [9] that the direct epoxidation of osthenol affords to products of an oxidative cyclisation, i.e. the dihydrofuranocouma- rin, (±)-columbianetin, when the treatment with peracid was conducted under neutral conditions and the dihydropyranocoumarin, (±)-lomatin. by treat- ment in acidic medium. The rearrangement with boron trifluoride in ethereal solution of the 7-acetoxy-8-(3'-methyl- 2',3'-epoxy-butyl) coumarin (3) gave the desired ketoderivative, 7-acetoxy-(3'-methyl-2'-oxo-butyl)- coumarin (4), as the major product other than a minor amount of the formyl isomer, 7-acetoxy- (2'-formyl-2'-methyl-propyl) coumarin (7). It is well known [10] that the course of the rearrangement process of the epoxide ring is governed by two main factors: the direction of ring opening and the rela- tive migratory aptitude of the different substituent groups; other factors how r ever, i.e. the steric effects or the solvent, must be important, as we have observed in the present case. It was reported [11] in
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Synthesis of Isoponcimarinzfn.mpdl.mpg.de/data/Reihe_B/34/ZNB-1979-34b-1010.pdf · mide in acetonic solution and in the presence of K2CO3 to the 7-isoprenyloxy-analogue, which by
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This work has been digitalized and published in 2013 by Verlag Zeitschrift für Naturforschung in cooperation with the Max Planck Society for the Advancement of Science under a Creative Commons Attribution4.0 International License.
Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschungin Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung derWissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht:Creative Commons Namensnennung 4.0 Lizenz.
Synthesis of Isoponcimarin
P . R o d i g h i e r o , A . G u i o t t o * , P . M a n z i n i , a n d G . P a s t o r i n i
Ist ituto di Chimica Farmaceutica dell 'Universita di Padova , Centro di Studio della Chimica del Farmaco e dei Prodott i Bio logicamente attivi del C N R , V ia Marzolo 5, 1-35100 Padova , I taly
Z. Naturforsch. 34b , 1010-1014 (1979); received February 19, 1979
Synthesis o f isoponcimarin, 7 - (3 ' -methy l -2 ' , 3 ' - epoxy -but i l oxy ) -8 - (3 " -methy l -2 " -oxo -butyl ) coumarin, a natural coumarin isolated f rom Poncirus trifoliata L., was obtained starting f r o m acetyl osthenol. F r o m the intermediate 7 -acetoxy-8 - (3 ' -methyl -2 ' -oxobuty l ) coumarin, the coumarin derivatives isomeranzin and dihydrooroselone were also prepared.
I n a p r e v i o u s p a p e r [1] w e r e p o r t e d t h e i s o l a t i o n
a n d i d e n t i f i c a t i o n f r o m u n r i p e f r u i t s o f Poncirus trifoliata L. ( f a m . R u t a c e a e ; s u b f a m . A u r a n t i o i d e a e )
o f a n e w c o u m a r i n , w h i c h w a s n a m e d i s o p o n c i m a r i n .
T h i s c o m p o u n d is a n e u t r a l c o u m a r i n i c d e r i v a t i v e ,
o p t i c a l l y a c t i v e [a]»j5 — 6 ,94° ( C H C l s ) , m . p . 85 °C
( f r o m w - h e x a n e ) , v i o l e t - b l u e f l u o r e s c e n t t o U V l i g h t
(365 n m ) a n d h a s m o l e c u l a r f o r m u l a C18H22O5. O n
t h e b a s i s o f t h e c h e m i c a l a n d s p e c t r o s c o p i c a l e v i -
d e n c e s t o i s o p o n c i m a r i n w a s a s s i g n e d t h e s t r u c t u r e
7 - ( 3 / - m e t h y l - 2 ' , 3 ' - e p o x y - b u t y l o x y ) - 8 - ( 3 ' ' - m e t h y l -
2 " - o x o - b u t h y l ) c o u m a r i n (6) [1 , 2 ] ; t h e r e f o r e iso-
p o n c i m a r i n is a s t r u c t u r a l i s o m e r o f p o n c i m a r i n ,
7 - ( 3 ' - m e t h y l - 2 ' , 3 ' - e p o x y - b u t y l o x y ) - 8 - ( 3 " - m e t h y l -
2 " , 3 " - e p o x y - b u t h y l ) c o u m a r i n (10), i s o l a t e d f r o m
t h e s a m e n a t u r a l s o u r c e [3] a n d c o n f i r m e d b y t o t a l
s y n t h e s i s [4],
A n u m b e r o f n a t u r a l c o u m a r i n s w e r e k n o w n , i n
w h i c h i s o p e n t e n y l a n d g e r a n y l s ide c h a i n s a r e
p r e s e n t a t v a r i o u s o x i d a t i o n l e v e l [5]. T h e o x i -
g e n a t e d f u n c t i o n m a y b e a n e p o x i d e g r o u p , a d i o l ,
a k e t o n i c o r a n a l d e h y d i c g r o u p . I t h a s b e e n
s u g g e s t e d a b i o g e n e t i c p a t h w a y ( n o t t e s t e d u p t o
n o w ) w h i c h f r o m t h e e p o x i d e d e r i v a t i v e , via t h e
d i o l d e r i v a t i v e , g i v e r i s e t o t h e f o r m a t i o n o f t h e
k e t o - or f o r m y l - d e r i v a t i v e b y a p i n a c o l - t y p e re-
a r r a n g e m e n t [6].
I n t h i s w a y p o n c i m a r i n (10) w i l l b e h y d r o l i z e d t o
a d i o l d e r i v a t i v e , w h i c h so f a r f a i l e d t o b e i d e n t i f i e d
f r o m e x t r a c t s o f Poncirus trifoliata. O n t h e o t h e r
h a n d a d i r e c t r e a r r a n g e m e n t o f t h e e p o x i d e g r o u p
m a y a l s o b e a s s u m e d : i n t h i s h y p o t h e s i s p o n c i m a r i n
(10) m a y b e c o n s i d e r e d t h e d i r e c t p r e c u r s o r o f t h e
i s o p o n c i m a r i n (6).
* Reprint requests to Dr . Prof. Manfred M u t t e r . 0340-5087/79/0700-1010/5 01.00/0
I n t h i s p a p e r w e d e s c r i b e t h e s y n t h e s i s o f iso-
p o n c i m a r i n o b t a i n i n g a d e f i n i t e c o n f i r m a t i o n o f t h e
p r o p o s e d s t r u c t u r e 6 o f t h i s s u b s t a n c e ; i n a d d i t i o n ,
w e d e s c r i b e t h e s y n t h e s i s o f t w o o t h e r c h e m i c a l l y
c o r r e l a t e d c o m p o u n d s .
T h e p r e p a r a t i o n (see F i g . 1) s t a r t e d f r o m o s t h e n o l ,
7 - h y d r o x y - 8 - ( 3 ' - m e t h y l - b u t - 2 - e n y l ) c o u m a r i n , i n
w h i c h a n i s o p e n t e n y l i c r e s i d u e b r a n c h e d f r o m t h e
8 - p o s i t i o n o f t h e c o u m a r i n n u c l e u s is a l r e a d y
p r e s e n t ; o s t h e n o l w a s p r e p a r e d i n g o o d y i e l d b y
C l a i s e n r e a r r a n g e m e n t o f 7 - ( l , l - d i m e t h y l - p r o p - 2 -
e n y l o x y ) c o u m a r i n [7] i n b o i l i n g d i e t h y l a n i l i n e
[4, 8].
O s t h e n o l w a s a c e t y l a t e d a n d t h e n e p o x i d a t e d b y
t r e a t m e n t w i t h p e r b e n z o i c a c i d i n c h l o r o f o r m i c
s o l u t i o n . T h e p h e n o l i c g r o u p ortho t o t h e i s o p e n t e n y -
l ic m o i e t y m u s t b e p r o t e c t e d b e f o r e t h e e p o x i d a -
t i o n , b e c a u s e i t w a s p r o v e d [9] t h a t t h e d i r e c t
e p o x i d a t i o n o f o s t h e n o l a f f o r d s t o p r o d u c t s o f a n
o x i d a t i v e c y c l i s a t i o n , i.e. t h e d i h y d r o f u r a n o c o u m a -
r i n , ( ± ) - c o l u m b i a n e t i n , w h e n t h e t r e a t m e n t w i t h
p e r a c i d w a s c o n d u c t e d u n d e r n e u t r a l c o n d i t i o n s a n d
t h e d i h y d r o p y r a n o c o u m a r i n , ( ± ) - l o m a t i n . b y t r e a t -
m e n t i n a c i d i c medium.
T h e r e a r r a n g e m e n t w i t h b o r o n t r i f l u o r i d e i n
e t h e r e a l s o l u t i o n o f t h e 7 - a c e t o x y - 8 - ( 3 ' - m e t h y l -
2 ' , 3 ' - e p o x y - b u t y l ) c o u m a r i n (3) g a v e t h e d e s i r e d
k e t o d e r i v a t i v e , 7 - a c e t o x y - ( 3 ' - m e t h y l - 2 ' - o x o - b u t y l ) -
c o u m a r i n (4), a s t h e m a j o r p r o d u c t o t h e r t h a n a
m i n o r a m o u n t o f t h e f o r m y l i s o m e r , 7 - a c e t o x y -
( 2 ' - f o r m y l - 2 ' - m e t h y l - p r o p y l ) c o u m a r i n (7). I t is w e l l
k n o w n [10] t h a t t h e c o u r s e o f t h e r e a r r a n g e m e n t
p r o c e s s o f t h e e p o x i d e r i n g is g o v e r n e d b y t w o m a i n
f a c t o r s : t h e d i r e c t i o n o f r i n g o p e n i n g a n d t h e r e l a -
t i v e m i g r a t o r y a p t i t u d e o f t h e d i f f e r e n t s u b s t i t u e n t
g r o u p s ; o t h e r f a c t o r s h o w r e v e r , i.e. t h e s t e r i c e f f e c t s
or t h e s o l v e n t , m u s t b e i m p o r t a n t , a s w e h a v e
o b s e r v e d i n t h e p r e s e n t c a s e . I t w a s r e p o r t e d [ 1 1 ] i n
P. Rodighiero et al. • Synthesis of Isoponcimarin 1011
CH3 CH3
f a c t t h a t t h e r e a r r a n g e m e n t o f t h e e p o x i d a t e osthol ,
7 - m e t h o x y - 8 - ( 3 ' - m e t h y l - 2 ' , 3 ' - e p o x y - b u t y l ) c o u m a -
rin, w i t h b o r o n t r i f l u o r i d e e t h e r a t e i n d i o x a n solu-
t ion , i n s t e a d o f e t h e r e a l s o l u t i o n a s u s e d b y us,
a f f o r d e d as a m a j o r p r o d u c t t h e f o r m y l d e r i v a t i v e ,
7 - m e t h o x y - 8 - ( 2 ' - f o r m y l - 2 ' - m e t h y l - p r o p y l ) c o u m a -
r in, o t h e r t h a n a s m a l l a m o u n t o f t h e k e t o d e r i v a t i v e ,
7 - m e t h o x y - 8 - ( 3 ' - m e t h y l - 2 ' - o x o - b u t h y l ) c o u m a r i n
( i someranzin) .
T h e 7 - a c e t o x y - 8 - ( 3 ' - m e t h y l - 2 ' - o x o - b u t y l ) c o u m a -
r in w a s d i r e c t l y i s o p r e n y l a t e d w i t h i s o p r e n y l bro-
m i d e in a c e t o n i c s o l u t i o n a n d i n t h e presence of
K2CO3 t o t h e 7 - i s o p r e n y l o x y - a n a l o g u e , w h i c h b y
e p o x i d a t i o n w i t h p e r b e n z o i c a c i d in c h l o r o f o r m i c
s o l u t i o n g a v e t h e ( ± ) - i s o p o n c i m a r i n . S y n t h e t i c
i s o p o n c i m a r i n is n e c e s s a r i l y a r a c e m a t e , t h e m . p .
o f w h i c h (90 °C; f r o m w - h e x a n e ) is s l i g h t l y d i f f e r e n t
f r o m t h a t o f t h e n a t u r a l o p t i c a l l y a c t i v e c o m p o u n d
(85 °C; f r o m w - h e x a n e ) : S p e c t r o s c o p i c a l d a t a ( U V ,
I R , 1 H N M R ) o f b o t h s y n t h e t i c a n d n a t u r a l iso-
p o n c i m a r i n are s u p e r i m p o s a b l e .
T h e a v a i l a b i l i t y o f s y n t h e t i c i s o p o n c i m a r i n al-
l o w e d us t o r e c o n f i r m t h e u n e x p e c t e d res is tence t o
t h e a c i d h y d r o l y s i s , conc . H2SO4 in A c O H s o l u t i o n ,
o f t h e e t h e r e a l l i n k a g e b e t w e e n t h e e p o x i d a t e iso-
p e n t e n y l m o i e t y a n d t h e 7 - p o s i t i o n o f t h e c o u m a r i n
n u c l e u s [2].
U n d e r these c o n d i t i o n s t h e e p o x i d e g r o u p u n d e r -
w e n t r e a r r a n g e m e n t g i v i n g t h e d i k e t o d e r i v a t i v e
7 - ( 3 , - m e t h y l - 2 ' - o x o - b u t y l o x y ) - 8 - ( 3 " - m e t h y l - 2 " - o x o -
b u t y l ) c o u m a r i n a n d a c e t o l y s i s g i v i n g t h e m o n o -
a c e t a t e 7 - (2 ' - a c e t o x y - 3 ' - h y d r o x y - 3 ' - m e t h y l b u t y l -
o x y ) - 8 - ( 2 " - o x o - 3 " - m e t h y l - b u t y l ) c o u m a r i n a n d t h e
d e h y d r a t i o n p r o d u c t o f t h e l a s t c o m p o u n d , 7-(2'-
a c e t o x y - 3 / - m e t h y l - b u t - 3 ' - e n y l o x y ) - 8 - ( 2 " - o x o - 3 " -
m e t h y l - b u t y l ) c o u m a r i n .
T h e r e a c t i o n o f 4 w i t h m e t h y l i o d i d e in a c e t o n i c
so lut ion a n d in t h e presence o f K2CC>3 e a s i l y g a v e
i s o m e r a n z i n ( i s o a u r a p t e n e ) , 7 - m e t h o x y - 8 - ( 2 ' - o x o -
3 ' - m e t h y l - b u t y l ) c o u m a r i n (8). -.'J
I s o m e r a n z i n is a n a t u r a l c o u m a r i n [12] a n d w a s
p r e v i o u s l y p r e p a r e d b o t h b y t r e a t m e n t o f a u r a p t e n e
1012 P. Rodighiero et al. • Synthesis of Isoponcimarin 1012
( m e r a n z i n ) , 7 - m e t h o x y - 8 - ( 2 ' , 3 ' - e p o x y - 3 ' - m e t h y l -
b u t y l ) c o u m a r i n , w i t h 2 0 % s u l f u r i c a c i d [13] a n d b y
t r e a t m e n t o f a u r a p t e n o l , 7 - m e t h o x y - 8 - ( 2 ' - h y d r o x y -
3 ' - m e t h y l - b u t - 3 ' - e n y l ) c o u m a r i n , i n t h e s a m e condi-
t i o n s [14] , a s w e l l a s b y t o t a l s y n t h e s i s [ 1 1 ] . C o m -
p o u n d 4 r e f l u x e d w i t h h y d r o c h l o r i c a c i d in a c e t i c
a c i d s o l u t i o n u n d e r w e n t c y c l i s a t i o n g i v i n g d i h y d r o -
o r o s e l o n e , 8 - ( m e t h y l - e t h y l ) - 2 H - f u r o [ 2 , 3 - h ] - [ l ] - b e n -
z o p y r a n - 2 - o n e (9). T h i s c o m p o u n d is n o t a n a t u r a l l y
o c c u r i n g c o u m a r i n a n d w a s p r e v i o u s l y o b t a i n e d b y
o t h e r w a y s , t h a t is b y t r e a t m e n t w i t h h y d r o b r o m i c
a c i d o f t h e e p o x i d a t e d o s t h o l [15] a n d b y a c i d
c a t a l y z e d d e h y d r a t i o n o f l o m a t i n [16], 9 , 1 0 - d i h y d r o -
9 - h y d r o x y - 8 , 8 - d i m e t h y l - 2 H , 8 H - b e n z o [ l ,2 -b : 3,4-b']-
d i p y r a n - 2 - o n e , a n d o f c o l u m b i a n e t i n [17] , 8 - ( l -
h y d r o x y - m e t h y l - e t h y l ) - 8 , 9 - d i h y d r o - 2 H - f u r o [ 2 , 3 - h ] -
[ l ] - b e n z o p y r a n - 2 - o n e .
Experimental M p s , d e t e r m i n e d i n o p e n c a p i l l a r y , a r e u n c o r -
r e c t e d . S i l i c a g e l p l a t e s 60 F - 2 5 4 ( M e r c k c a t . 5 7 1 5 ) w e r e u s e d f o r T L C , u s i n g a s d e v e l o p i n g s o l v e n t a E t O A c - c y c l o h e x a n e ( 3 5 : 6 5 ) m i x t u r e .
A l l t h e s u b s t a n c e s s y n t h e s i z e d w e r e a n a l y z e d f o r C , H a n d r e s u l t s w e r e w i t h i n ± 0 . 3 % o f t h e o r e t i c a l v a l u e s .
X H N M R s p e c t r a w e r e r e c o r d e d a t 60 M H z o n H i t a c h i - P e r k i n E l m e r R - 2 4 A or B r u k e r W P - 6 0 s p e c t r o m e t e r a n d a r e g i v e n i n <5 r e l a t i v e t o T M S a s i n t e r n a l s t a n d a r d , c o u p l i n g c o n s t a n t s a r e g i v e n in H z ; a l l a s s i g n e m e n t s a r e i n a g r e e m e n t w i t h r e l a t i v e p e a k a r e a s a n d w e r e a p p l i c a b l e w i t h d e c o u p l i n g e x p e r i m e n t s .
7-Acetoxy-8-(3'-methyl-but-2'-enyl) coumarin (2) 7 - H y d r o x y - 8 - ( 3 ' - m e t h y l - b u t - 2 - e n y l ) c o u m a r i n
( o s t h e n o l ) (2.5 g ; 10.8 m m o l e s ) w a s d i s s o l v e d in a c e t i c a n h y d r i d e (20 m l ) a n d p y r i d i n e ( f e w d r o p s ) w a s a d d e d . T h e m i x t u r e w a s r e f l u x e d f o r 2 h a n d p o u r e d i n t o i c e - c o l d w a t e r s t i r r i n g v i g o r o u s l y . T h e so l id w a s c o l l e c t e d b y filtration, w a s h e d w i t h w a t e r a n d c r y s t a l l i z e d f r o m M e O H : 7 - a c e t o x y - 8 - ( 3 ' -m e t h y l - b u t - 2 ' - e n y l ) c o u m a r i n , w h i t e n e e d l e s , (2.4 g ; y i e l d 8 1 % ) ; m . p . 94 ° C ; ^H N M R ( C D C 1 3 ) : <5 7.68 ( l H ; d ; J = 9 .5 H z ; H - 4 ) ; <5 7 .36 ( 1 H ; J = 8.5 H z ; H - 5 ) ; <5 7.01 ( 1 H ; d ; J = 8.5 H z ; H - 6 ) ; <5 6.40 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; <5 5 .20 ( 1 H ; t , b r o a d e n i n g ; J = 7 H z ; H - 2 ' ) ; <5 3 . 5 3 ( 2 H ; d , b r o a d e n i n g ; J = 7 H z ; 2 H - 1 ' ) ; «5 2 .32 ( 3 H ; s ; a c e t y l g r o u p ) ; <5 1 .82 a n d <5 1 .67 ( e a c h 3 H ; s s ; t w o Me) .
7 - A c e t o x y - 8 - ( 3 ' - m e t h y l - b u t - 2 ' - e n y l ) c o u m a r i n (1 .0 g ; 3.7 m m o l e s ) w a s d i s s o l v e d i n a n h y d r o u s C H C I 3 (40 m l ) a n d a v o l u m e o f c h l o r o f o r m i c s o l u t i o n
c o n t a i n i n g t h e s t o i c h i o m e t r i c q u a n t i t y o f per-b e n z o i c a c i d w a s a d d e d . T h e m i x t u r e w a s a l l o w e d t o s t a n d a t r o o m t e m p e r a t u r e f o r 2 h , w h e n t h e m i x -t u r e , m o n i t o r e d b y T L C , a p p e a r e d t o b e d e v o i d o f t h e s t a r t i n g m a t e r i a l . T h e c h l o r o f o r m i c s o l u t i o n w a s d i l u t e d w i t h f r e s h c h l o r o f o r m t o 1 5 0 m l a n d w a s h e d t h r e e t i m e s w i t h 50 m l p o r t i o n s o f s a t u r a t e d N a H C 0 3 s o l u t i o n . T h e o r g a n i c l a y e r w a s d r i e d ( N a 2 S 0 4 ) a n d t h e s o l v e n t e l i m i n a t e d u n d e r v a c u u m . T h e r e s i d u e w a s d i s s o l v e d i n E t O A c a n d p e t r . e t h e r (30-50 °C) w a s a d d e d t o t h i c k e n i n g ; b y l o n g s t a n d i n g a c r o p of c r y s t a l s w a s f o r m e d o f 7 - a c e t o x y -8 - ( 3 ' - m e t h y l - 2 ' , 3 ' - e p o x y - b u t y l ) c o u m a r i n (0.850 g ; 7 8 . 5 % ) ; m . p . 101 ° C ; * H N M R ( C D C 1 3 ) : <5 7 .70 ( 1 H ; d ; J = 9 .5 H z ; H - 4 ) ; <5 7 . 4 1 ( 1 H ; d ; J = 8.5 H z ; H - 5 ) ; <5 7 .05 ( 1 H ; d ; J = 8.5 H z ; H - 6 ) ; <5 6.39 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; f r o m <5 3.50 t o 2 .70 ( 3 H ; m u l t i -
/ 0 \ p l e t ; C H 2 - C H - C ) ; <5 2 .33 ( 3 H ; s ; a c e t y l g r o u p ) ; <51.45 a n d <5 1 .30 ( e a c h 3 H ; s s ; t w o M e ) .
Rearrangement of the 7-acetoxy-8-(3'-methyl-2',3'-epoxy-butyl) coumarin
I n t o a d r y e t h e r s o l u t i o n o f 7 - a c e t o x y - 8 -( 3 ' - m e t h y l - 2 ' , 3 ' - e p o x y - b u t y l ) c o u m a r i n (0.350 g ; 1 .2 m m o l e s ) a s t r e a m o f B F 3 w a s b u b b l e d as l o n g a s t h e s o l u t i o n b e c a m e p a l e - y e l l o w p e r s i s t e n t i n c o l o u r , w h i l e h e a t w a s d e v e l o p e d .
T h e m i x t u r e w a s a l l o w e d t o s t a n d a t r o o m t e m -p e r a t u r e 2 h . A f t e r t h i s t i m e t h e s t a r t i n g m a t e r i a l a p p e a r e d t o b e a b s e n t f r o m t h e m i x t u r e b y T L C , w h i l e a m a i n p r o d u c t w a s f o r m e d o t h e r t h a n a m i n o r d e r i v a t i v e w i t h h i g h e r Rf v a l u e ; b o t h s p o t s r e a c t e d w h e n s p r a y e d w i t h t h e d i - N 0 2 - p h e n y l - h y d r a z i n e r e a g e n t .
a) 7-Acetoxy-8-(3'-methyl-2'-oxo-butyl) coumarin (4): T h e m i x t u r e w a s d i l u t e d t o 200 m l w i t h m o i s t e t h e r a n d e x t r a c t e d t w o t i m e s w i t h w a t e r . T h e o r g a n i c p h a s e w a s d r i e d ( N a 2 S 0 4 ) a n d t h e s o l v e n t e l i m i n a t e d . T h e r e s i d u e w a s d i s s o l v e d i n t o a s m a l l v o l u m e o f e t h e r , p e t r . e t h e r w a s a d d e d a n d b y s t a n d i n g a n d c o o l i n g a c r y s t a l l i n e s o l i d w a s o b t a i n e d (0.198 g ; 5 7 . 5 % ) . T h e s o l i d w a s r e c r y s t a l -l i z e d f r o m a E t O A c - n - h e x a n (20/80) m i x t u r e g i v i n g w h i t e c r y s t a l s o f 7 - a c e t o x y - 8 - ( 3 ' - m e t h v l - 2 ' - o x o -b u t v l ) c o u m a r i n , m . p . 1 1 4 - 1 1 5 ° C ; * H N M R ( C D C 1 3 ) : <5 7.67 ( 1 H ; d ; J = 9 . 5 H z ; H - 4 ) ; <5 7 . 4 1 ( 1 H ; d ; J = 8.5 H z ; H - 5 ) ; <5 7.06 ( 1 H ; d ; J = 8.5 H z ; H - 6 ) ; <5 6.32 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; <5 3 .96 ( 2 H ; s ; P h - C H 2 - C O ) ; <5 2.82 ( 1 H ; s e p t e t ; J = 7 H z : - C H M e 2 ) ; <5 2.28 ( 3 H ; s ; A c e t y l g r o u p ) ; <5 1 .20 ( 6 H ; d ; J = 7 H z ; - C H M e 2 ) .
b) 7-Acetoxy-8- (2'-formyl-2'-methyl-propyl) cou-m a r i n (7): T h e m o t h e r l i q u o r s o f c r y s t a l l i z a t i o n o f t h e k e t o d e r i v a t i v e s (4) w e r e d e p r i v e d o f t h e s o l v e n t a n d c h r o m a t o g r a p h e d i n a s i l i ca g e l c o l u m n b y e l u t i n g w i t h CHCI3. T h e first f r a c t i o n s c o n t a i n i n g o n l y t h e c o m p o n e n t w i t h h i g h e r Rf w e r e p u t t o g e t h e r a n d b y e l i m i n a t i o n o f t h e s o l v e n t a n o i l y
P. Rodighiero et al. • Synthesis of Isoponcimarin 1013
r e s i d u e o f 7 - a c e t o x y - 8 - ( 2 ' - f o r m y l - 2 ' - m e t h y l - p r o p y l ) c o u m a r i n (0.0035 g ; 1 0 % ) w a s o b t a i n e d , w h i c h f a i l e d t o c r y s t a l l i z e f r o m s e v e r a l s o l v e n t s ; X H N M R ; <5 9.56 ( 1 H ; s ; - C H O ) ; 6 7 .62 ( 1 H ; d ; J = 9 . 5 H z ; H - 4 ) ; 6 7 .39 ( 1 H ; d ; J = 8.5 H z ; H - 5 ) ; <5 7.00 ( 1 H ; d ; J = 8.5 H z ; H - 6 ) ; 6 6.26 ( 1 H ; d ; J = 9 . 5 H z ; H - 3 ) ; <5 2.98 ( 2 H ; s ; P h - C H 2 - C ) ; 6 2 .32 ( 3 H ; s ; A c O - ) ; 6 1 .08 ( 6 H ; s ; M e s ) .
A n u m b e r o f f r a c t i o n s c o n t a i n i n g b o t h t h e k e t o a n d t h e f o r m y l d e r i v a t i v e w e r e t h e n e l u t e d . I n t h e n e x t f r a c t i o n s a f u r t h e r c r o p o f p u r e 7 - a c e t o x y - 8 -( 3 ' - m e t h y l - 2 ' - o x o - b u t y l ) c o u m a r i n , k e t o d e r i v a t i v e (4) w a s o b t a i n e d .
T h e 7 - A c e t o x y - 8 - ( 3 ' - m e t h y l - 2 / - o x o - b u t y l ) c o u m a -r in (0.200 g ; 0.69 m m o l e s ) w a s d i s s o l v e d i n M e 2 C O (5 m l ) . T o t h e a c e t o n i c s o l u t i o n a n e x c e s s o f finely p o w d e r e d K 2 C 0 3 , a c a t a l y t i c a m o u n t o f K J , f e w d r o p s o f H 2 0 a n d a n e x c e s s o f 3 - m e t h y l - b u t - 2 - e n y l -c h l o r i d e (5 ml) w e r e a d d e d a n d t h e m i x t u r e r e f l u x e d u n d e r e n e r g i c a l s t i r r i n g . M o r e 3 - m e t h y l - b u t - 2 - e n y l -c h l o r i d e w a s a d d e d a f t e r 5 ' m i n . A f t e r 3 0 ' m i n t h e m i x t u r e m o n i t o r e d b y T L C a p p e a r e d t o b e d e v o i d o f t h e s t a r t i n g m a t e r i a l . T h e m i x t u r e w a s c o o l e d a n d K 2 C O 3 w a s e l i m i n a t e d b y f i l t r a t i o n , w a s h i n g i t w i t h f r e s h M e 2 C O . F i l t r a t e a n d w a s h i n g s w e r e e v a p o r a t e d u n d e r v a c u u m a n d t h e o i l y r e s i d u e , w h i c h f a i l e d t o c r y s t a l l i z e f r o m s e v e r a l s o l v e n t s , w a s p u r i f i e d i n a s i l ica g e l c o l u m n b y e l u t i n g w i t h CHCI3. F r a c t i o n s c o n t a i n i n g t h e m a i n c o m p o n e n t w e r e c o l l e c t e d , t h e s o l v e n t e l i m i n a t e d a n d t h e so l id b y c r y s t a l l i z a t i o n f r o m w - h e x a n e g a v e 7 - ( 3 ' - m e t h y l - b u t - 2 ' - e n y l - o x y ) -8 - ( 3 " - m e t h y l - 2 " - o x o - b u t y l ) c o u m a r i n , m . p . 86 °C (0.18 g ; 8 2 % ) , i H N M R (CDCI3): 6 7 . 6 1 ( 1 H ; d ; J = 9 .5 H z ; H - 4 ) ; 6 7 . 3 4 ( 1 H ; d ; J = 8.5 H z ; H - 5 ) ; 6 6 .78 ( 1 H ; d ; J = 8 .5 H z ; H - 6 ) ; 6 6 . 1 4 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; 6 5 .39 ( 1 H ; b r o a d e n i n g t ; J = 7 H z ; H - 2 ' ) ; 6 4 . 5 3 ( 2 H ; b r o a d e n i n g d ; J = 7 H z ; H - l ' ) ; 6 3.98 ( 2 H ; s ; H - l " ) ; 6 2.80 ( 1 H ; s e p t e t ; J = 7 H z ; - C H M e 2 ) ; 6 1 .85 a n d 6 1 .81 ( 3 H e a c h ; ss ; C = C M e 2 ) ; 6 1 . 1 8 ( 6 H ; d ; J = 7 H z ; - C H M e 2 ) .
T o a c h l o r o f o r m i c s o l u t i o n o f 7 - ( 3 ' - m e t h y l - b u t - 2 / -e n y l - o x y ) - 8 - ( 3 " - m e t h y l - 2 " - o x o - b u t y l ) c o u m a r i n (0.25 g ; 0.8 m m o l e s ) t h e s t o i c h i o m e t r i c a m o u n t o f c h l o r o f o r m i c s o l u t i o n o f p e r b e n z o i c a c i d w a s a d d e d . T h e m i x t u r e w a s a l l o w e d t o s t a n d a t r o o m t e m -p e r a t u r e f o r 1 h, w h e n t h e s t a r t i n g m a t e r i a l b y T L C a p p e a r e d t o b e c o m p l e t e l y c o n s u m e d . T h e m i x t u r e
w a s d i l u t e d w i t h f r e s h CHCI3 a n d w a s h e d w i t h t w o p o r t i o n s o f s a t u r a t e d N a H C O s s o l u t i o n . T h e o r g a n i c l a y e r w a s d r i e d a n d t h e s o l v e n t e l i m i n a t e d u n d e r v a c u u m . T h e r e s i d u e w a s p u r i f i e d i n a s i l ica g e l c o l u m n b y e l u t i n g w i t h CHCI3. F r a c t i o n s c o n t a i n i n g ( T L C a n a l y s i s ) a s ing le s p o t w i t h a n Rf v a l u e i d e n t i c a l t o t h a t o f n a t u r a l i s o p o n c i m a r i n w e r e d e p r i v e d o f t h e s o l v e n t a n d t h e r e s i d u e b y c r y s t a l l i -z a t i o n f r o m w - h e x a n e f u r n i s h e d ( ± ) 7 - ( 3 ' - m e t h y l -2 / , 3 ' - e p o x y - b u t y l - o x y ) - 8 - ( 3 " - m e t h y l - 2 " - o x o - b u t y l ) c o u m a r i n (0.167 g ; 6 4 % ) , m . p . 90 °C, X H N M R (CDCI3): 6 7 .63 ( 1 H ; d ; J = 9 .5 H z ; H - 4 ) ; 6 7 .37 ( 1 H ; d ; J = 8.5 H z ; H - 5 ) ; 6 6.86 ( 1 H ; d ; J = 8.5 H z ; H - 6 ) ; 6 6.23 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; 6 4 . 2 4 - 4 . 1 0 ( 2 H ; 4-l ine s i g n a l ; - 0 - C H 2 - ) ; 6 4.04 ( 2 H ; s ; P h - C H 2 - C 0 ) ; 6 3.06 ( 1 H ; t ; e p o x i d e r i n g p r o t o n ) ; 6 2.84 ( 1 H ; s e p t e t ; J = 7 H z ; - C H M e 2 ) ; 6 1 . 3 6 a n d 6 1 .34 ( 3 H e a c h ; s s ; = C = M e 2 ) ; 6 1 . 2 1 (6 H ; d ; J = 7 H z ; - C H M e 2 ) .
7 - A c e t o x y - 8 - ( 3 ' - m e t h y l - 2 ' - o x o - b u t y l ) c o u m a r i n (0.135 g ; 0.5 m m o l e s ) w a s d i s s o l v e d i n M e 2 C O (25 m l ) a n d M e l (0.2 ml) a n d a n e x c e s s o f K 2 C 0 3 w e r e a d d e d . T h e m i x t u r e w a s r e f l u x e d 2 h . A f t e r c o o l i n g K 2 C 0 3 w a s filtered o f f a n d w a s h e d w i t h M e 2 C O . T h e r e s i d u e , o b t a i n e d b y e v a p o r a t i o n o f t h e f i l t e r e d s o l u t i o n p l u s w a s h i n g s , b y c r y s t a l l i z a t i o n f r o m a E t O A c - c y c l o h e x a n e m i x t u r e g a v e 7 - m e t h o x y -8 - ( 3 ' - m e t h y l - 2 , - o x o - b u t y l ) c o u m a r i n ( i s o m e r a n z i n ) ( 0 . 1 1 0 g ; 8 4 % ) . m . p . 65 °C, * H N M R (CDCI3): 6 7 .69 ( 1 H ; d ; J = 9 .5 H z ; H - 4 ) ; 6 7 .38 ( 1 H ; d ; J = 8.5 H z ; H - 5 ) ; 6 6.90 ( 1 H ; d ; J = 8.5 H z ; H - 6 ) ; 6 6 .29 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; 6 4 .05 ( 2 H ; s ; P h - C H 2 - C O ) ; 6 3.92 ( 3 H ; s ; - O C H 3 ) ; 6 2.86 ( 1 H ;
s e p t e t ; J = 7 H z ; C O - C H - M e 2 ) ; 6 1 . 2 0 ( 6 H ; d ; J = 7 H z ; - C H - M e 2 ) .
7 - A c e t o x y - 8 - ( 3 ' - m e t h y l - 2 ' - o x o - b u t y l ) c o u m a r i n (0.05 g ; 0 . 1 7 m m o l e s ) w a s d i s s o l v e d i n A c O H (25 m l ) , c o n c . H C l (0.5 m l ) w a s a d d e d a n d t h e m i x t u r e r e f l u x e d f o r 1 h ; m o r e c o n c . H C l (0.5 m l ) w a s a d d e d a n d r e f l u x i n g c o n t i n u e d f o r 2 h. B y d i l u t i n g w i t h H 2 0 (25 m l ) a n d c o o l i n g a p r e c i p i t a t e w a s o b t a i n e d a n d filtered. T h e p r e c i p i t a t e c r y s t a l -l i z e d f r o m c y c l o h e x a n e g a v e 8 - ( m e t h y l - e t h y l ) - 2 H -f u r o [ 2 , 3 - h ] [ l ] - b e n z o p y r a n - 2 - o n e (9); m . p . 1 3 9 . 5 t o 140 ° C ; i H N M R (CDCI3): 6 7 .81 ( 1 H ; d ; J = 9.5 H z ; H - 4 ) ; 6 7 .33 ( 2 H ; s u p e r i m p o s e d s s ; H - 5 a n d H - 9 ) ; 6 6 .74 ( 1 H ; s ; H - 6 ) ; 6 6 .35 ( 1 H ; d ; J = 9 .5 H z ; H - 3 ) ; 6 3 . 1 5 ( 1 H ; s e p t e t ; J = 7 H z ; - C H M e 2 ) ; 6 1 .36 ( 6 H ; d ; J = 7 H z ; - C H M e 2 ) .
1014 P. Rodighiero et al. • Synthesis of Isoponcimarin 1014
[1] A. Guiotto, P. Rodighiero, U. Quintily, and G. Pastorini, Phytochemistry 15, 348 (1970).
[2] A. Guiotto, P. Rodighiero, G. Pastorini, and E. Celon, Phytochemistry 16, 1257 (1977.
[3] A. Guiotto, P. Rodighiero, and U. Quintily, Z. Naturforsch. 30c, 420 (1975).
[4] P. Rodighiero, A. Guiotto, P. Manzini, and G. Pastorini, Z. Naturforsch. 30b, 987 (1975).
[5] R. D. H. Murray, Naturally occurring plant coumarins, Fortschritte der Chemie organischer Naturstoffe. Springer-Verlag (Wien-New York) 35, 199 (1978).
[6] D. L. Dreyer, Tetrahedron 23, 4613 (1967). [7] R. D. H. Murray, M. M. Ballantyne, and K. P.
Mathai, Tetrahedron 27, 1247 (1971). [8] J. Hlubucek, E. Ritchie, and W. C. Taylor, Chem.
Ind. (London) 1969, 1780.
[9] R. D. H. Murray, M. Sutcliffe, and P. H. McCabe, Tetrahedron 27, 4901 (1971).
[10] R. E. Parker and N. S. Isaacs, Chem. Rev. 59, 737 (1959).
[11] A. Chatterjee, R. N. Rej, A. Banerji, and J. Banerji, Chem. Ind. (London) 1976, 410.
[12] E. Atkinson, D. R. Boyd, and M. F. Grundon, Phytochemistry 13, 853 (1974).
[13] H. Bhöme and G. Pietsch, Ber. Dtsch. Chem. Ges. 72, 773 (1939).
[14] W. L. Stanley, A. C. Waiss (Jr.), R. E. Lundin, and S. H. Vannier, Tetrahedron 21, 89 (1965).
[15] W. Bencze, J. Eisenbeiss, and H. Schmid, Helv. Chim. Acta 39, 923 (1956).
[16] T. O. Soine and F. H. Jawad, J. Pharm. Sei. 53, 990 (1964).
[17] R. E. Willette and T. O. Soine, J. Pharm. Sei. 53, 275 (1964).