Toxic Furanosesquiterpenoids from Mold-Damaged Sweet Potatoes

18 Toxic Furanosesquiterpenoids from Mold-Damaged Sweet Potatoes Downloaded by KTH ROYAL INST OF TECHNOLOGY on September 3, 2015 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch018

(Ipomoea batatas) LEO T. BURKA and BENJAMIN J. WILSON Center in Environmental Toxicology, Vanderbilt University, Nashville, Tenn. 37232 Sweet potatoes (Ipomoea batatas) when infected with fungus or under certain other stress conditions produce several 3-substituted furans; some of these have now been isolated and identified. Of these the hepatotoxic sesquiterpene ipomeamarone is perhaps the best known and has been investigated for many years. As a result of outbreaks of pulmonary disease in cattle which consumed mold-damaged sweet potatoes, recent investigations have concentrated on the causative agents of this disease which has been described as atypical interstitial pneumonia. In addition to ipomeamarone and other hepatotoxins, a series of 1-(3-furyl)-l,4dioxygenated pentanes has been isolated from sweet potatoes infected with Fusarium solani. These compounds, especially 1-(3-furyl)-4-hydroxy-1-pentanone (4-ipomeanol), show marked pulmonary toxicity in laboratory animals. It seems likely that these compounds are also the toxic factors in the bovine disease. The isolation, identification, synthesis, and toxicity of several of these furans are discussed. In response to stress conditions the sweet potato produces several metabolites which normally are absent or present in only minute amounts. These stress metabolites are formed under a variety of conditions includ ing fungus infection, treatment with heavy metal salts and other com pounds (1), and mechanical injury from slicing (2) or weevil infestation (3). The known stress metabolites fall into two general classes: hydroxycinnamic acid derivatives (including coumarins) and furanosesquiterpenes. Although several of the cinnamic acid derivatives seem important to the defense mechanism of the plant (4), the emphasis of this review focuses 387

In Mycotoxins and Other Fungal Related Food Problems; Rodricks, J.; Advances in Chemistry; American Chemical Society: Washington, DC, 1976.

388

MYCOTOXINS

o n t h e f u r a n m e t a b o l i t e s since s o m e of these are a p p a r e n t l y c a u s a t i v e agents i n t h e enzootics of l i v e s t o c k p o i s o n i n g t h a t r e s u l t f r o m i n g e s t i o n of m o l d - d a m a g e d sweet potatoes ( 5 , 6 ) .

T h e furans thus f a r i d e n t i f i e d f a l l

i n t o t w o categories: those c o n t a i n i n g a n o r m a l u n r e a r r a n g e d sesquiter p e n e skeleton, a n d those c o n t a i n i n g less t h a n fifteen c a r b o n atoms b u t r e t a i n i n g the sesquiterpene skeleton. T h e latter c o m p o u n d s

are p r o b a b l y

the result of m e t a b o l i c d e g r a d a t i o n of the sesquiterpenes. Downloaded by KTH ROYAL INST OF TECHNOLOGY on September 3, 2015 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch018

A m o n g the stress m e t a b o l i t e s p r o d u c e d b y the sweet p o t a t o i m pomeamarone

( 1 ) is p e r h a p s t h e best k n o w n . T h e c o m p o u n d w a s

i s o l a t e d b y H i u r a ( 7 ) , a n d e a r l y s t r u c t u r a l studies w e r e p e r f o r m e d

first by

1

s e v e r a l Japanese groups

( 8 , 9, 10).

F i n a l structure determination was

accomplished b y K u b o t a a n d co-workers

(11).

S t r u c t u r a l d e t e r m i n a t i o n w a s b a s e d p r i m a r i l y o n i d e n t i f i c a t i o n of the p r o d u c t s of o x i d a t i v e d e g r a d a t i o n . O z o n o l y s i s of 1 g a v e t w o p r o d u c t s : ipomeanic acid (2)

a n d i p o m i c lactone ( 3 )

(II).

T h e latter was con

v e r t e d to m e t h y l a n h y d r o i p o m a t e ( 4 ) b y saponification, d e h y d r a t i o n , a n d reesterfication. T h e s e m i c a r b a z o n e of 4 w a s o z o n i z e d ; m e t h y l l e v u l i n a t e

Ό'

H0 C 2

C H 2 C C H 2 C H (CH3) 2

2

Ο

O'

Ό'

C H 2 C C H 2 C H (CH3) 2

3

Ο Ο

CH

3

CH OCCH CH C=CHCCH CH(CH3)2 3

2

2

II

2

ο


4

18.

BURKA

Toxic

A N D WILSON

389

Furanosesquiterpenoids

a n d the b i s s e m i c a r b a z o n e of i s o b u t y l g l y o x a l w e r e i s o l a t e d . B a r b i e r - W i e l a n d d e c o m p o s i t i o n a l l o w e d t h e c o n v e r s i o n of 2 to 3. C o m p o u n d 3 w a s s u b s e q u e n t l y s y n t h e s i z e d . A l d e r - R i c k e r t d e g r a d a t i o n of 1 gave f u r a n - 3 , 4 -

ι

0

» I « BrCH COEt + CH CCH CH COEt ./I^CH^COEt 2

3

2

2

— —

Zn —

Downloaded by KTH ROYAL INST OF TECHNOLOGY on September 3, 2015 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch018

(1) O H ,CH

3

S0C1

(2)

o

2

(3) C d ( C H C H ( C H ) ) 2

OEt

3

2

2

d i c a r b o x y l i c a c i d i n d i c a t i n g t h a t the f u r a n r i n g i n S t r u c t u r e 1 m u s t b e ^ - s u b s t i t u t e d . T h i s i n f o r m a t i o n , c o u p l e d w i t h i d e n t i f i c a t i o n of t h e o z o nolysis p r o d u c t s e s t a b l i s h e d S t r u c t u r e 1 as i p o m e a m a r o n e except f o r t h e s t e r e o c h e m i s t r y a b o u t the t e t r a h y d r o f u r a n r i n g . C o n t e m p o r y w i t h K u b o t a ' s w o r k , groups f r o m A u s t r a l i a w e r e i n v e s t i g a t i n g n g a i o n e , a t o x i c p r i n c i p l e of the N g a i o b u s h (Myoporum

laetum)

a n d r e l a t e d p l a n t s , w h i c h was first d e s c r i b e d b y M c D o w a l l ( 1 2 , 1 3 , T h e s i m i l a r i t y b e t w e e n n g a i o n e a n d i p o m e a m a r o n e w a s n o t e d (15), after some i n i t i a l c o n f u s i o n (16) ( 1 1 , 17).

14). and

t h e y w e r e e s t a b l i s h e d as e n a n t i o m o r p h s

T h u s the u n u s u a l s i t u a t i o n exists i n w h i c h a m a j o r p h y t o a l e x i n

of the sweet potato is the e n a n t i o m e r of a n o r m a l constituent of s e v e r a l species of Myoporum

and

Eremorphila.

A synthesis of r a c e m i c i p o m e a m a r o n e w a s d e s c r i b e d b y K u b o t a ( I I , 17).

T h e last step i n this r e a c t i o n sequence, t r e a t m e n t of t h e a c i d c h l o

ride

6 w i t h d i i s o b u t y l c a d m i u m , gave the t r i c y c l i c ketone

7 as

the

m a j o r p r o d u c t a n d a m i n o r p r o d u c t ( 8 ) w h i c h was s i m i l a r to 1 b u t d i f -

0 CCH COEt 2

il

0

Ο

Tvj

II

+

B r C H JC = C H C O E t CH

a

Benzene

2

3

Ο Il

Ο II

.CÇHCH O=CHC0Et 2

Λ

Il l /

O

}

Ç=0 OEt

CH

3

(1)H* (2)CH N 2

2


390

MYCOTOXINS

,CCH CH C=CHCOMe 2

2


CH

Al(OCH(CH ) )

3

OH I ,CHCH2CH2

3

2

3

Ο II =CHCOMe (1) O H -

CHo

(2) (C0C1)

S

Cd(CH CH(CH )2)2 2

,CH Ό'

3

3

^CHsCCHgCHiCHsia O 8

ferent i n s p e c t r a l characteristics. It w a s a r g u e d t h a t since most of the cis a c i d c h l o r i d e c y c l i z e d to g i v e 7, 8 m u s t h a v e a trans c o n f i g u r a t i o n a b o u t the tetrahydrofuran ring. corresponding

Ipomeamarone,

cis c o m p o u n d .

b e e n i s o l a t e d f r o m Myoporum

Compound sp

i t is p o s t u l a t e d , m u s t b e the 8, s o - c a l l e d e p i n g a i o n e ,

has

(18).

T o c o m p l e t e the synthesis of 1 K u b o t a r e l i e d o n a r e a c t i o n f r o m the e a r l y w o r k o n n g a i o n e , i.e., t r e a t m e n t w i t h p o t a s s i u m acetate i n acetic a n h y d r i d e to g i v e the r i n g - o p e n e d acetate 9 (12, 13, 14).

T h e hydrolysis

of 9 h a d b e e n r e p o r t e d to g i v e r a c e m i c 1, i m p l y i n g t h a t c y c l i z a t i o n oc c u r r e d t o g i v e the cis c o n f i g u r a t i o n at t h e t e t r a h y d r o f u r a n r i n g


(16).

18.

BURKA

Toxic

AND WILSON

391


OAc

Ο

I

II

C H C H C H C = C H C C H C H (CH ) 2

2

2

CH

KOAc

3

2

3


AcoO

T h u s w h e n s y n t h e t i c 8 was t r e a t e d w i t h p o t a s s i u m acetate a n d acetic a n h y d r i d e , t h e n saponified, the c y c l i z e d m a t e r i a l w a s i d e n t i c a l to t h a t o b t a i n e d b y t r e a t i n g n a t u r a l 1 i n the same w a y ( I I , 1 7 ) . A s a result of t h e n e e d for a source of 1 t o f u r t h e r investigate t h e t o x i c i t y of i p o m e a m a r o n e , B u r k a et a l . d e s c r i b e d a s e c o n d synthesis of 1 (19).

It was f o u n d that 9 c o u l d be synthesized i n good y i e l d f r o m

ipomeanyl

acetate

(vide

(10)

OAc

infra)

and

phosphonate

2

?ν

2

+

(CH 0) PCHCCH CH(CH ) θ 3

2

10

2

3

2

11

H y d r o l y s i s of 9 r e s u l t e d i n f o r m a t i o n of

11.

1-

Wittig

Ο

CHCH CH CCH3

reagent

the

1:1

m i x t u r e of

e p i m e r s 1 a n d 8 w h i c h c o u l d b e s e p a r a t e d b y h i g h pressure l i q u i d c h r o m atography.

T h e saponification was further investigated b y scanning re

p e a t e d l y t h e N M R s p e c t r u m of a s o l u t i o n of 9 i n m e t h a n o l i c s o d i u m hydroxide.

It was d e t e r m i n e d t h a t 1 a n d 8 w e r e f o r m e d at a b o u t the

same rate a n d t h a t t h e i r r e l a t i v e concentrations

d i d not change

with

e q u i l i b r a t i o n . A p p a r e n t l y the r i n g c l o s u r e is n o t stereospecific. T w o sesquiterpenes, w h i c h are s i m i l a r s t r u c t u r a l l y to 1 h a v e b e e n i s o l a t e d f r o m m o l d - d a m a g e d sweet potatoes. m a r o n o l (12) (20)

T h e first of these, i p o m e a -

w a s s i m u l t a n e o u s l y i s o l a t e d a n d i d e n t i f i e d b y Y a n g et a l .

a n d b y K a t o et al. ( 2 1 , 22).

T h e structure elucidation was deter

m i n e d m a i n l y f r o m s p e c t r a l d a t a . O g u n i et al. r e c e n t l y r e p o r t e d the i s o l a t i o n of d e h y d r o i p o m e a m a r o n e potatoes ( 2 3 , 24, 1 5 ) . Anihenasia

(13)

f r o m C.

sp b y B o h l m a n n a n d R a o ( 2 6 )

H a m i l t o n et a l . ( 1 8 ) .

fimbriata

infected

sweet

C o m p o u n d 13 h a d p r e v i o u s l y b e e n i s o l a t e d f r o m a n d f r o m Myoporum

N o synthesis of 12 or 13 has b e e n r e p o r t e d .


sp b y


392

MYCOTOXINS

A n a d d i t i o n a l sesquiterpene,

7 - h y d r o x y m y o p o r o n e (14),

has b e e n

i s o l a t e d w h i c h does not c o n t a i n the t e t r a h y d r o f u r a n r i n g f o u n d i n 1, a n d 13 ( 2 7 ) .

Compound

12,

14 w a s i d e n t i f i e d b y s p e c t r a l means a n d b y

o x i d a t i v e d e g r a d a t i o n to t h e a c i d 15 w h i c h i n t u r n w a s s y n t h e s i z e d .

0

0

0

II

, C C H C H C H C H C C H C H (CH ) I Ho OH IO42

2

A:

2

3

2

Ο

A

CCH CH CHCH COH 2

2

2

CH

3

15

14

O g a w a a n d H i r o s e r e p o r t e d t h e p r e s e n c e of d e n d r o l a s i n (16)

and

t h e k e t o n e 17 i n f u s e l o i l r e s u l t i n g f r o m f e r m e n t a t i o n of s w e e t potatoes ( 2 8 ) , b u t A k a z a w a c o u l d n o t e s t a b l i s h t h e p r e s e n c e of 16 a n d 17 i n C . fimbriata

i n f e c t e d sweet potatoes

(29).


18.

BURKA AND WILSON

Toxic H i

H I

C H C H C = C C H C H C = C (CH ) 2

2

2

CH


393


2

3

2

C H C H C H C H C H C C H C H (CH ) 2

2

2

2

CH

16

S

2

3

2

17 3

S e a w r i g h t a n d M a t t o c k s f o u n d t h a t n g a i o n e ( t h e e n a n t i o m e r of e p i n g a i o n e , a n d i p o m e a m a r o n e ( 1 ) are a l l h e p a t o t o x i c ; L D t h e c o m p o u n d s center a b o u t 2 0 0 m g / k g ( 3 0 ) .

5 0

1),

values f o r

S e a w r i g h t a n d OTDonahoo

m a d e a d e t a i l e d s t u d y o f t h e p a t h o l o g y of n g a i o n e t o x i c i t y i n t h e m o u s e l i v e r (31).

I n v o l v e m e n t of o r g a n s o t h e r t h a n t h e l i v e r w a s n o t m e n t i o n e d .

T h e toxicities of c o m p o u n d s 12, 13, a n d 14 h a v e n o t b e e n s t u d i e d i n d e tail, but apparently the compounds p o t e n t as 1

are h e p a t o t o x i c a n d are about as

(18,20,27).

S e v e r a l c o m p o u n d s t h a t h a v e b e e n i s o l a t e d f r o m m o l d - d a m a g e d sweet potatoes c o n t a i n f e w e r t h a n fifteen carbons a n d seem to b e f o r m e d as a r e s u l t of s e s q u i t e r p e n e c a t a b o l i s m . T w o of these a r e 3 - f u r o i c a c i d and

b a t a t i c a c i d (19)

18

(II).

T h e s t r u c t u r e of

19 w a s

confirmed

(18) by

19

K u b o t a f r o m i s o l a t i n g α - m e t h y l g l u t a r i c a c i d after o z o n o l y s i s a n d f r o m synthesis of 19

(11).

O f greater i n t e r e s t is a series o f c o m p o u n d s c o n t a i n i n g n i n e c a r b o n atoms w h i c h h a v e b e e n r e s e a r c h e d b y W i l s o n a n d c o - w o r k e r s for s e v e r a l years.

W h e n this r e s e a r c h b e g a n , i p o m e a m a r o n e w a s t h e o n l y sweet

potato phytoalexin whose toxicity h a d been studied. T h e primary tar get o r g a n i n c a t t l e p o i s o n e d b y m o l d - d a m a g e d s w e e t potatoes w a s t h e l u n g ( 5 , 6).

T h i s observation suggested that the hepatotoxic i p o m e a

m a r o n e m i g h t n o t b e t h e c a u s a t i v e agent. R e a l i z a t i o n of this i n c o n s i s t e n c y


394

MYCOTOXINS

p r o m p t e d a s e a r c h b y W i l s o n f o r a s o - c a l l e d l u n g e d e m a factor i n sweet potatoes i n f e c t e d w i t h Fusarium

sohni.

A s a result o f this s e a r c h a c o m

p o u n d causing l u n g edema i n mice was isolated b y using a combination of c o l u m n c h r o m a t o g r a p h y a n d gas c h r o m a t o g r a p h y . T h e s t r u c t u r e o f t h e c o m p o u n d , 4 - i p o m e a n o l ( 20 ) , w a s e s t a b l i s h e d b y s p e c t r a l means ( 3 2 , 3 3 ) .


S u b s e q u e n t l y t w o s i m i l a r l u n g e d e m a g e n i c c o m p o u n d s , 1-ipomeanol (21 )

3

20

CHCH2CH2CHCH3

c i

21

CCH2CH2CCH3

cS 0

Toxic Furanosesquiterpenoids from Mold-Damaged Sweet Potatoes

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