The Chemistry of Cyclic Peroxides - American Chemical Society

6 The Chemistry of Cyclic Peroxides: The Formation and Decomposition of Prostaglandin Endoperoxide Analogs NED A. PORTER, JOHN R. NIXON, and DENNIS W. GILMORE

Downloaded by CORNELL UNIV on May 23, 2017 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0069.ch006

Paul M. Gross Chemical Laboratory, Duke University, Durham, N C 27706

I n t e r e s t i n the chemistry and biochemistry of peroxides has been r e c e n t l y stimulated by the f a c t that the important c l a s s o f n a t u r a l products, the p r o s t a g l a n d i n s , has two members (PGG and PGH) that contain the peroxide l i n k a g e . F u r t h e r , the proposed mechanism f o r the b i o s y n t h e s i s of these peroxides i n v o l v e s a novel peroxy r a d i c a l b i c y c l i z a t i o n . Thus, one mechanism f o r biosynthe s i s o f PGG, proposed i n 1967 (1, 2), i n v o l v e s an a u t o x i d a t i v e -type conversion of f a t t y a c i d t o endoperoxide via a peroxy r a d i c a l mechanism (Figure 1). For the past three years, our research has focused on aspects of peroxide and f r e e r a d i c a l chemistry r e l a t e d to the formation and decomposition of monocyclic and bicyclic peroxides analogous to these p r o s t a g l a n d i n intermediates, and we present here our r e s u l t s concerning the formation and decomposi t i o n of these compounds. Monocyclic

Peroxides

Formation. Although a peroxy r a d i c a l c y c l i z a t i o n mechanism was proposed (1, 2) f o r p r o s t a g l a n d i n b i o s y n t h e s i s , t h i s mode of r e a c t i o n had r e c e i v e d little chemical a t t e n t i o n . E a r l y r e p o r t s suggested that peroxy r a d i c a l c y c l i z a t i o n was an important v a r i a n t i n the a u t o x i d a t i o n of polyunsaturated m a t e r i a l s such as squalene (3) and cyclododecatriene (4). Products were not fully c h a r a c t e r i z e d i n these s t u d i e s , however, due t o the difficulties of perox ide i s o l a t i o n and p u r i f i c a t i o n . Perhaps the best documented case of peroxy r a d i c a l c y c l i z a t i o n was the r e p o r t (5) that α-farnesene undergoes r a d i c a l a u t o x i d a t i o n to y i e l d the completely c h a r a c t e r i z e d monocyclic peroxide, 1. A u t o x i d a t i v e peroxy r a d i c a l c y c l i z a t i o n has precedent, then, but t h i s a u t o x i d a t i o n format i s cumbersome f o r a systematic study.

©

0-8412-0421.7/78/47-069-089$05.00/0

Pryor; Organic Free Radicals ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

ORGANIC F R E E RADICALS


90

PGG Figure 1.

Proposed mechanism for prostaglandin biosynthesis (1,2)


6.

PORTER E T A L .

Cyclic Peroxides

o

91

2

Ιη·


1 We developed a method f o r the study o f peroxy r a d i c a l c y c l i z a t i o n based on the generation of peroxy r a d i c a l s from unsaturated hydroperoxides (6, 7 ) . Thus, treatment o f the hydroperoxide with f r e e r a d i c a l i n i t i a t o r s such as DBPO (8) l e d to the formation of monocyclic peroxides that could be i s o l a t e d by l i q u i d chromato graphy and c h a r a c t e r i z e d by standard techniques.

OOH

Η

2

3

Systematic i n v e s t i g a t i o n has shown that the ease of c y c l i z a t i o n i s [ i n the terminology proposed by Baldwin (9)] 5 or 6 e x o c y c l i c > 6 or 7 e n d o c y c l i c c y c l i z a t i o n . The mechanism f o r c y c l i c peroxide formation presumably i n v o l v e s formation o f β-peroxy a l k y l r a d i c a l s l i k e 3 which can r e a c t with oxygen to y i e l d u l t i m a t e l y c y c l i c peroxide products. An a l t e r n a t e pathway a v a i l a b l e to ^, however, i s i n t r a m o l e c u l a r r a d i c a l a t t a c k on the peroxide linkage (10,11) y i e l d i n g ultimately the epoxy-alcohol product. We wished to i n v e s t i g a t e t h i s S n i pathway s y s t e m a t i c a l l y and sought other, more c o n t r o l l e d methods f o r the p r e p a r a t i o n of r a d i c a l s l i k e ^.



92

P o t e n t i a l methods f o r generation of r a d i c a l s l i k e 3 i n v o l v e the use of β-mercurated c y c l i c peroxides. Alkyl-mercurie com pounds r e a c t with borohydride to y i e l d the corresponding a l k y l r a d i c a l U2, 13). The mechanism of r a d i c a l production has been thoroughly i n v e s t i g a t e d (14) and i n v o l v e s an intermediate a l k y l hydrido mercury compound, R-Hg-H. Chain propagation occurs as shown below by r a d i c a l a t t a c k on R-Hg-H.


Κ· + R-Hg-H

•

R-H + Hg + Κ·

The c r u c i a l β-mercurated c y c l i c peroxide precursors of ^ can be prepared by mercuric n i t r a t e i n i t i a t e d c y c l i z a t i o n of unsatura ted hydroperoxides (15). Y i e l d s are e x c e l l e n t and the compounds (as the bromide d e r i v a t i v e s ) can be p u r i f i e d by high pressure l i q u i d chromatography ( h p l c ) . E x o c y c l i c products are formed i n c y c l i z a t i o n s of ^, and 6 with none of the 6-endo products being detected by nmr or h p l c . 5 leads to a 3:1 r a t i o of 6-exo to 7endo c y c l i z a t i o n products. These isomers can be c l e a n l y separated by h p l c and q u a n t i t i e s of a l l of the β-mercurated c y c l i c peroxides are thus r e a d i l y a v a i l a b l e .

HgX

HO-O 4

HgX

Hg(g)

i

o-o 7 Η

β

χ

,HgX

Hg(l)

o-o

The p r e d i c t i o n s f o r c y c l i z a t i o n developed by Baldwin (9) are rather vague when a p p l i e d to these mercury i n i t i a t e d c y c l i z a t i o n s . The r u l e s , as s t a t e d f o r n u c l e o p h i l i c attack on 3-membered r i n g s , "seem to l i e between those f o r t e t r a h e d r a l and t r i g o n a l systems, g e n e r a l l y p r e f e r r i n g exo modes." From our l i m i t e d observation of peroxide attack on the three-membered r i n g mercurinium


6.

PORTER E T A L .

Cyclic Peroxides

93

intermediate, we conclude that exo modes of c y c l i z a t i o n are favored and that 6-endo c y c l i z a t i o n i s d i s f a v o r e d . Sfli Stereochemistry. Treatment of the β-mercurated c y c l i c peroxides with sodium borohydride leads to mixtures of demercurated c y c l i c peroxides and epoxy-alcohols. Thus, ^ r e a c t s to give the c y c l i c peroxides and the epoxy-alcohol i n a 3:1 r a t i o . As noted e a r l i e r , these are products expected from a β-peroxy r a d i c a l ; the c y c l i c peroxide r e s u l t i n g from H atom a b s t r a c t i o n , the epoxy-alcohol from S i r a d i c a l a t t a c k on the peroxide l i n k a g e .


H

HgX (

V

,

O-O

NaBH

4

Cr^

Cxr^

O-O

OH

Ο

7 The r e l a t i v e amount of peroxide product and epoxy-alcohol i s i n t i m a t e l y dependent on the s t r u c t u r e of the intermediate r a d i c a l . In Table I i s presented the product d i s t r i b u t i o n of peroxide and Sfli product (epoxy-alcohol) f o r a s e r i e s of c y c l i c peroxide a l k y l r a d i c a l s . Note that the e x o c y c l i c five-membered r i n g r a d i c a l s £ and ^ lead predominately to peroxide as does the e n d o c y c l i c sevenmembered r i n g r a d i c a l The e x o c y c l i c six-membered r i n g r a d i c a l , on the other hand, gives p r i m a r i l y Sfli products. The amount of peroxide and epoxy-alcohol produced does vary somewhat depending on how borohydride a d d i t i o n i s c a r r i e d out. The product compositions reported i n Table I could be r e p r o d u c i b l y obtained, however, by q u i c k l y s y r i n g i n g the borohydride reducing agent i n t o a mixed phase CH C1 /H 0 s o l u t i o n of the β-mercurated c y c l i c peroxide at 0°. In a d d i t i o n , by reducing mixtures of the v a r i o u s β-mercurated peroxides, the product r a t i o s presented could be confirmed. We suggest that the S i r e a c t i o n reported here o f f e r s the p o s s i b i l i t y of studying the geometric requirements of SJJ2 a t t a c k on the peroxide l i n k a g e . The data suggest that the c r i t i c a l geometric parameter f o r the Sjji r e a c t i o n i s the d i h e d r a l angle, φ, about the OC bond between the a t t a c k i n g r a d i c a l and the l e a v ing oxygen. We assume that f o r maximum Sni r e a c t i v i t y , t h i s d i h e d r a l angle must be 180°. A view down the 0-C bond of a space f i l l i n g model of a six-membered r i n g peroxide with a -CH » center attached α to the peroxide l i n k a g e i s presented i n Figure 2. The c r i t i c a l d i h e d r a l angle about the 0-C bond i s 180°, or n e a r l y so, for t h i s six-membered r i n g r a d i c a l . For the analogous r a d i c a l derived from a five-membered r i n g , the 0-C d i h e d r a l angle i s s u b s t a n t i a l l y l e s s than 180°, having a maximum of approximately 165° i n the most favorable conformation f o r Sni a t t a c k . Thus, the 2

2

2

H

2



94


Table

I.

Product d i s t r i b u t i o n from borohydride r e d u c t i o n of f$ mercurated c y c l i c peroxides.

( V V

o-o

peroxide

s i

75

25

90

10

10

90

H

8

0

The Chemistry of Cyclic Peroxides - American Chemical Society

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