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Hypervalent iodine oxidation products of papaverine and its microbial metabolites
Tetrahedron Letters, Vol. 36, No. 7, pp. 1001-1002, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(94)02426-X
Hypervalent Iodine Oxidation Products of Papaverine and Its Microbial Metabolites G. Chandrasekara Reddy .I Department of Medicinal Chemistry and Department of Pharmacology College of Pharmacy, The University of Texas, Austin, Tx 78712, U.S.A.
Abstract: (Diacetoxyiodo)benzene (DAIB) o x i d i z e s p a p a v e r i n e t o p a p a v e r a l d i n e (2) a n d to l - h y d r o x y m e t h y l - 6 , 7 - d i m e t h o x y i s o q u i n o l i n e (3), whereas 3 ' - d e s m e t h y l p a p a v e r i n e and 6-desmethylpapaverine are c o n v e r t e d into n o v e l p r o d u c t s (4) a n d (5), r e s p e c t i v e l y .
P a p a v e r i n e ( 1 ) is a s m o o t h m u s c l e r e l a x a n t k n o w n to c a u s e h e p a t o t o x i c i t y in man, b y an u n k n o w n m e c h a n i s m 2 e v e n t h o u g h the m a j o r r o u t e s of its m e t a b o l i s m are known. 3 The major mammalian metabolites are 6- a n d 4 ' - d e s m e t h y l p a p a v e r i n e s (3'- a n d 7d e s m e t h y l c o m p o u n d s are minor) a n d one f e a s i b l e m e c h a n i s m for the h e p a t o t o x i c i t y in the c a s e of 4 ' - d e s m e t h y l p a p a v e r i n e m i g h t be its o x i d a t i o n to the c o r r e s p o n d i n g ~ - q u i n o n e m e t h i d e , w h i c h w o u l d serve as an e l e c t r o p h i l e (via M i c h a e l a d d i t i o n b y a biological nucleophile) s i m i l a r to a c e t a m i n o p h e n . 4 W h i l e a t t e m p t i n g to g e n e r a t e quinone methide intermediates a n d r e l a t e d compounds, we t r i e d D A I B r e a g e n t on p a p a v e r i n e a n d its m i c r o b i a l m e t a b o l i t e s , s It is k n o w n that e x c e s s of D A I B r e a g e n t 6 o x i d i z e s m o n o h y d r i c p h e n o l s to ~-quinone ketals. 4'-Desmethylpapaverine with DAIB reagent yielded intractable products. However, 3'-desmethylpapaverine w h e n t r e a t e d w i t h two e q u i v a l e n t s of D A I B in m e t h a n o l at r o o m t e m p e r a t u r e y i e l d e d an u n u s u a l p r o d u c t 4 in 16% yield. 7 The m e c h a n i s m of this r e a c t i o n is p r o p o s e d in S c h e m e I. However, p a p a v e r i n e w i t h D A I B in m e t h a n o l at r o o m t e m p e r a t u r e g a v e p a p a v e r a l d i n e ( 2 ) in 26% yield, but at r e f l u x t e m p e r a t u r e b e n z y l i c c l e a v a g e o c c u r r e d w i t h the f o r m a t i o n 8 of l - h y d r o x y m e t h y l - 6 , 7 dimethoxyisoquinoline (3) in 12% yield. It is k n o w n that p a p a v e r i n o l (6) w h e n t r e a t e d w i t h 90% H2SO 4 y i e l d e d 6 , 7 - d i m e t h o x y i s o q u i n o l i n e l-carboxaldehyde. ~ In a n a l o g y w i t h this, the f o r m a t i o n of 3 is b e i n g p u r s u e d . Scheme
1
M~ OH
OH
"OMe M
M
MeO" "~ ~
~
OH
"
I
OMe
MMeO II 0
6-Desmethylpapaverine on t r e a t m e n t w i t h e x c e s s of D A I B in m e t h a n o l at r o o m temperature g a v e a c o m p o u n d in 10% y i e l d (apart f r o m o t h e r m i n o r u n i d e n t i f i e d c o m p o u n d s ) w i t h n e i t h e r a m e t h o x y n o r an a c e t o x y g r o u p I° in the p o s i t i o n p a r a to the o x i d i z e d p h e n o l b u t r a t h e r an i o d o p h e n y l group(5) . T h i s is q u i t e c o n c e i v a b l e as i o d o b e n z e n e s e r v e s as a n u c l e o p h i l e , a n d e v i d e n c e that the p o s i t i o n o r t h o to the
I001
1002
iodo group participated in n u c l e o p h i l i c attack comes f r o m the IH-NMR (COSY s p e c t r u m ) , xl In c o m p o u n d 5, a one p r o t o n b r o a d d o u b l e t at 66.81 for the 3" p r o t o n is s t r o n g l y c o u p l e d to the 4"- a n d 5 " - p r o t o n s at 67.30 w h i c h in t u r n are c o u p l e d to the 6 " - p r o t o n at 67.04. T h e 5 ' - p r o t o n at 66.83 is c o u p l e d to the 6 ' - p r o t o n at 66.91. A s h a r p p e a k at 1648 cm -I in the i n f r a r e d s p e c t r u m of 5 s u p p o r t e d the p r e s e n c e of a c a r b o n y l g r o u p . The f r a g m e n t at m / z 151 in the EI m a s s s p e c t r u m i n d i c a t e d an intact dimethoxy benzyl moiety.
5
MeO
MeO
4
MeOCC~N 2 H (3)
R~
3'Me "OMe
Me;) (1) R1-R2-CH3
; R3-H2
(2) ~-R2-CHa
; R3-O
M~
( 4 ) P. - H ; R2" CH3 ; R3 - (OCHa) 2 ( 6 ) R 1 - R 2 - C H 3 ; R 3 - H , OH Acknowledgement The
author
discussions REFERENCES
i. 2. 3. 4. 5.
6.
7.
8.
9.
I0. ii.
- This project
wishes and AND
to
thank
(5) m/z 151
was
Drs.
supported P.
J.
in p a r t b y P H S / N I H g r a n t
Davis
and
D.
Acosta
for
ROI-ES0420.
their
helpful
encouragement. NOTES
Present address: Department of Medicinal Chemistry, College of Pharmacy, Univ. of Florida, Box J-i00485, J.H.M.H.C., Gainesville, F1 32610-0485. Driemen, P . M . J . Am. Geriatr. Soc., 1973, 21, 202. Hifnawy, M. S.; Muhtadi, F. J. Analytical Profiles of Drug substances, Vol. 17, ed. by Klaus Florey, Academic Press, Inc., Harcourt Brace Javonovich Publishers, 1988, p. 388. Reddy, C. S. G.; Acosta, D.; Davis, P. J. Xenobiotica, 1990, 20, 1281. The mammalian metabolites of papaverine are generated by microorganisms using the concept of microbial models of mammalian metabolism. Rosazza, J. P.; Kammer, M.; Youel, L.; Smith, R. V.; Erhardt, P. W.; Truong, D. H.; Leslie, S. W. Xenobiotica, 1977, 7, 133; 6-desmethylpapaverine using Aspergillus alliaceus 315, 4'desmethylpapaverine using Cunninghamella echinulata ATCC 9244, whereas 3'desmethylpapaverine, a minor metabolite from C. echinulata, was obtained by fractional crystallization (using MeOH/CHCI3/EtOAc) of the mixture from the liquid HBr hydrolysis of papaverine, Brossl, A.; Teitel, S. J. Org. Chem., 1970, 35, 1684. Pelter, A.; Elgandy, S. Tetrahedron Let~., 1988, 29, 677. 500Yd4z IH-NMR(COSY spectrum) of 4 (CDCI 3) 6: 3.2(S,2xOCH3), 3.81(s,OCH3), 3.84(s,OCH3), 3.98(s,OCH3), 6.75(d,J=8.4Hz,5'-H), 6.98(s,8-H), 7.12(dd, J=8.4 and 2.1Hz, 6'-H), 7.18 (d,J=2.1HZ,2'-H), 7.41(d,J=5Hz,4-H), 7.89(s, 5-H) and 8.48(d,J=5Hz,3-H). 5'-H at 6.75 was spin coupled with 6'-H at 7.12. High resolution EI-MS accounted for the formula C21HnNO6 (Found: 385.152981; Calculated: 385.152538). In compound 3 the PMR signal for -CH20H appeared at 65.14 which is relatively downfield compared to the benzylic protons at 64.50 in papaverine. High resolution EI-MS (Found: 219.089504; Calculated: 219.089543) indicated it to be C12HnN% with a major fragment at m/z 189 corresponding to the loss of -CH20). Ruchirawat, S.; Tongpenyai, N.; Prastipan, N.; Prempree, P. Heterocycles, 1976, 4, 1893. Siegel, A.; Antony, F. Monatsh. Chem., 1955, 86, 292. 500MZ4z IH-NMR (COSY spectrum) of 5 (CD3COCD 3) 6: 3.72(s, OCH3), 3.73(s, OCH3), 3.85(s, OCH~) , 4.65 (s, -CH2-) , 6.81(br d, J=SHz, 3"-H) , 6.83 (m, 2' -H and 5' -H) , 6.91(dd, J=8 and 2Hz, 6'-H), 7.04(m, 5-H and 6"-H), 7.30(dd, J=SHz, 4"-H and 5"-H), 7.81(d, J=5.2Hz,4-H), 7.86(s, 8-H) and 8.51(d,J=5.2Hz,3-H). High resolution EI-MS (Found: 527.058905; Calculated: 527.059360) accounted for the formula C2sH22INO4 .
(Received in USA 29 June 1994; revised 7 December 1994; accepted 9 December 1994)
Pergamon 0040-4039(94)02426-X
Hypervalent Iodine Oxidation Products of Papaverine and Its Microbial Metabolites G. Chandrasekara Reddy .I Department of Medicinal Chemistry and Department of Pharmacology College of Pharmacy, The University of Texas, Austin, Tx 78712, U.S.A.
Abstract: (Diacetoxyiodo)benzene (DAIB) o x i d i z e s p a p a v e r i n e t o p a p a v e r a l d i n e (2) a n d to l - h y d r o x y m e t h y l - 6 , 7 - d i m e t h o x y i s o q u i n o l i n e (3), whereas 3 ' - d e s m e t h y l p a p a v e r i n e and 6-desmethylpapaverine are c o n v e r t e d into n o v e l p r o d u c t s (4) a n d (5), r e s p e c t i v e l y .
P a p a v e r i n e ( 1 ) is a s m o o t h m u s c l e r e l a x a n t k n o w n to c a u s e h e p a t o t o x i c i t y in man, b y an u n k n o w n m e c h a n i s m 2 e v e n t h o u g h the m a j o r r o u t e s of its m e t a b o l i s m are known. 3 The major mammalian metabolites are 6- a n d 4 ' - d e s m e t h y l p a p a v e r i n e s (3'- a n d 7d e s m e t h y l c o m p o u n d s are minor) a n d one f e a s i b l e m e c h a n i s m for the h e p a t o t o x i c i t y in the c a s e of 4 ' - d e s m e t h y l p a p a v e r i n e m i g h t be its o x i d a t i o n to the c o r r e s p o n d i n g ~ - q u i n o n e m e t h i d e , w h i c h w o u l d serve as an e l e c t r o p h i l e (via M i c h a e l a d d i t i o n b y a biological nucleophile) s i m i l a r to a c e t a m i n o p h e n . 4 W h i l e a t t e m p t i n g to g e n e r a t e quinone methide intermediates a n d r e l a t e d compounds, we t r i e d D A I B r e a g e n t on p a p a v e r i n e a n d its m i c r o b i a l m e t a b o l i t e s , s It is k n o w n that e x c e s s of D A I B r e a g e n t 6 o x i d i z e s m o n o h y d r i c p h e n o l s to ~-quinone ketals. 4'-Desmethylpapaverine with DAIB reagent yielded intractable products. However, 3'-desmethylpapaverine w h e n t r e a t e d w i t h two e q u i v a l e n t s of D A I B in m e t h a n o l at r o o m t e m p e r a t u r e y i e l d e d an u n u s u a l p r o d u c t 4 in 16% yield. 7 The m e c h a n i s m of this r e a c t i o n is p r o p o s e d in S c h e m e I. However, p a p a v e r i n e w i t h D A I B in m e t h a n o l at r o o m t e m p e r a t u r e g a v e p a p a v e r a l d i n e ( 2 ) in 26% yield, but at r e f l u x t e m p e r a t u r e b e n z y l i c c l e a v a g e o c c u r r e d w i t h the f o r m a t i o n 8 of l - h y d r o x y m e t h y l - 6 , 7 dimethoxyisoquinoline (3) in 12% yield. It is k n o w n that p a p a v e r i n o l (6) w h e n t r e a t e d w i t h 90% H2SO 4 y i e l d e d 6 , 7 - d i m e t h o x y i s o q u i n o l i n e l-carboxaldehyde. ~ In a n a l o g y w i t h this, the f o r m a t i o n of 3 is b e i n g p u r s u e d . Scheme
1
M~ OH
OH
"OMe M
M
MeO" "~ ~
~
OH
"
I
OMe
MMeO II 0
6-Desmethylpapaverine on t r e a t m e n t w i t h e x c e s s of D A I B in m e t h a n o l at r o o m temperature g a v e a c o m p o u n d in 10% y i e l d (apart f r o m o t h e r m i n o r u n i d e n t i f i e d c o m p o u n d s ) w i t h n e i t h e r a m e t h o x y n o r an a c e t o x y g r o u p I° in the p o s i t i o n p a r a to the o x i d i z e d p h e n o l b u t r a t h e r an i o d o p h e n y l group(5) . T h i s is q u i t e c o n c e i v a b l e as i o d o b e n z e n e s e r v e s as a n u c l e o p h i l e , a n d e v i d e n c e that the p o s i t i o n o r t h o to the
I001
1002
iodo group participated in n u c l e o p h i l i c attack comes f r o m the IH-NMR (COSY s p e c t r u m ) , xl In c o m p o u n d 5, a one p r o t o n b r o a d d o u b l e t at 66.81 for the 3" p r o t o n is s t r o n g l y c o u p l e d to the 4"- a n d 5 " - p r o t o n s at 67.30 w h i c h in t u r n are c o u p l e d to the 6 " - p r o t o n at 67.04. T h e 5 ' - p r o t o n at 66.83 is c o u p l e d to the 6 ' - p r o t o n at 66.91. A s h a r p p e a k at 1648 cm -I in the i n f r a r e d s p e c t r u m of 5 s u p p o r t e d the p r e s e n c e of a c a r b o n y l g r o u p . The f r a g m e n t at m / z 151 in the EI m a s s s p e c t r u m i n d i c a t e d an intact dimethoxy benzyl moiety.
5
MeO
MeO
4
MeOCC~N 2 H (3)
R~
3'Me "OMe
Me;) (1) R1-R2-CH3
; R3-H2
(2) ~-R2-CHa
; R3-O
M~
( 4 ) P. - H ; R2" CH3 ; R3 - (OCHa) 2 ( 6 ) R 1 - R 2 - C H 3 ; R 3 - H , OH Acknowledgement The
author
discussions REFERENCES
i. 2. 3. 4. 5.
6.
7.
8.
9.
I0. ii.
- This project
wishes and AND
to
thank
(5) m/z 151
was
Drs.
supported P.
J.
in p a r t b y P H S / N I H g r a n t
Davis
and
D.
Acosta
for
ROI-ES0420.
their
helpful
encouragement. NOTES
Present address: Department of Medicinal Chemistry, College of Pharmacy, Univ. of Florida, Box J-i00485, J.H.M.H.C., Gainesville, F1 32610-0485. Driemen, P . M . J . Am. Geriatr. Soc., 1973, 21, 202. Hifnawy, M. S.; Muhtadi, F. J. Analytical Profiles of Drug substances, Vol. 17, ed. by Klaus Florey, Academic Press, Inc., Harcourt Brace Javonovich Publishers, 1988, p. 388. Reddy, C. S. G.; Acosta, D.; Davis, P. J. Xenobiotica, 1990, 20, 1281. The mammalian metabolites of papaverine are generated by microorganisms using the concept of microbial models of mammalian metabolism. Rosazza, J. P.; Kammer, M.; Youel, L.; Smith, R. V.; Erhardt, P. W.; Truong, D. H.; Leslie, S. W. Xenobiotica, 1977, 7, 133; 6-desmethylpapaverine using Aspergillus alliaceus 315, 4'desmethylpapaverine using Cunninghamella echinulata ATCC 9244, whereas 3'desmethylpapaverine, a minor metabolite from C. echinulata, was obtained by fractional crystallization (using MeOH/CHCI3/EtOAc) of the mixture from the liquid HBr hydrolysis of papaverine, Brossl, A.; Teitel, S. J. Org. Chem., 1970, 35, 1684. Pelter, A.; Elgandy, S. Tetrahedron Let~., 1988, 29, 677. 500Yd4z IH-NMR(COSY spectrum) of 4 (CDCI 3) 6: 3.2(S,2xOCH3), 3.81(s,OCH3), 3.84(s,OCH3), 3.98(s,OCH3), 6.75(d,J=8.4Hz,5'-H), 6.98(s,8-H), 7.12(dd, J=8.4 and 2.1Hz, 6'-H), 7.18 (d,J=2.1HZ,2'-H), 7.41(d,J=5Hz,4-H), 7.89(s, 5-H) and 8.48(d,J=5Hz,3-H). 5'-H at 6.75 was spin coupled with 6'-H at 7.12. High resolution EI-MS accounted for the formula C21HnNO6 (Found: 385.152981; Calculated: 385.152538). In compound 3 the PMR signal for -CH20H appeared at 65.14 which is relatively downfield compared to the benzylic protons at 64.50 in papaverine. High resolution EI-MS (Found: 219.089504; Calculated: 219.089543) indicated it to be C12HnN% with a major fragment at m/z 189 corresponding to the loss of -CH20). Ruchirawat, S.; Tongpenyai, N.; Prastipan, N.; Prempree, P. Heterocycles, 1976, 4, 1893. Siegel, A.; Antony, F. Monatsh. Chem., 1955, 86, 292. 500MZ4z IH-NMR (COSY spectrum) of 5 (CD3COCD 3) 6: 3.72(s, OCH3), 3.73(s, OCH3), 3.85(s, OCH~) , 4.65 (s, -CH2-) , 6.81(br d, J=SHz, 3"-H) , 6.83 (m, 2' -H and 5' -H) , 6.91(dd, J=8 and 2Hz, 6'-H), 7.04(m, 5-H and 6"-H), 7.30(dd, J=SHz, 4"-H and 5"-H), 7.81(d, J=5.2Hz,4-H), 7.86(s, 8-H) and 8.51(d,J=5.2Hz,3-H). High resolution EI-MS (Found: 527.058905; Calculated: 527.059360) accounted for the formula C2sH22INO4 .
(Received in USA 29 June 1994; revised 7 December 1994; accepted 9 December 1994)