Synthesis and Some Practical Aspects of Brassinosteroids - American

Chapter 5 Synthesis and Some Practical Aspects of Brassinosteroids V. A. Khripach, V. N. Zhabinskii, and R. P. Litvinovskaya

Downloaded by UNIV OF ARIZONA on January 9, 2013 | http://pubs.acs.org Publication Date: November 4, 1991 | doi: 10.1021/bk-1991-0474.ch005

Institute of Bioorganic Chemistry, Byelorussian SSR Academy of Sciences, 220045, Minsk, Zhodinskaya, 5/2 Union of Soviet Socialist Republics

This b r i e f review covers the p e r i o d of the l a s t ten years in the development of b r a s s i n o s t e r o i d chemistry i n our l a b o r a t o r y . Our i n t e r e s t has been focused on the s y n t h e s i s of n a t u r a l b r a s s i n o s t e r o i d s ( b r a s s i n o l i d e , homobrassinolide, epibrassinolide, norbrassinolide, etc.), t h e i r analogues and intermediates s t a r t i n g from s t i g m a s t e r o l , e r g o s t e r o l , or pregnenolone. Some aspects of b i o l o g i c a l activity are discussed.

The i s o l a t i o n and s t r u c t u r a l e l u c i d a t i o n of b r a s s i n o l i d e (1), a novel p o l y h y d r o x y s t e r o i d a l lactone with strong p l a n t growth-promoting a c t i v i t y , was the beginning of i n t e n s i v e study of a new c l a s s of phytohormones, termed b r a s s i n o s t e r o i d s (BS). Since then, a number of r e l a t e d compounds have been i d e n t i f i e d and i s o l a t e d from v a r i o u s p l a n t s (2,3). The a b i l i t y of BS t o a c t i v a t e at very low concentrations the metabolic and growth processes was e s t a b l i s h e d and consequently t o i n c r e a s e total plant productivity. These properties, along with specific s t r u c t u r a l f e a t u r e s and extremely low content of BS i n natural sources, made their synthesis especially i n t e r e s t i n g . The e f f o r t s of s c i e n t i f i c groups i n d i f f e rent c o u n t r i e s (USA, Japan, I t a l y , and some others) l e d to the e l a b o r a t i o n of many schemes f o r BS s y n t h e s i s (2,3, and Lakhvich,F., Khripach,V., Zhabinskii,V. Uspekhi Khim., i n p r e s s . ) . In extending our s t u d i e s i n n a t u r a l and transformed s t e r o i d s , BS s y n t h e s i s was the subject i n our l a b o r a t o r y f o r a number of years. During t h i s p e r i o d , d i f f e r e n t s y n t h e t i c approaches s t a r t i n g with a c c e s s i b l e natural s t e r o i d s have been developed, and a l o t of n a t u r a l BS and t h e i r analogues have been synthesized and b i o l o g i c a l l y t e s t e d i n laboratory and f i e l d c o n d i t i o n s .

0097-6156/91/0474-0043$06.00/0 © 1991 American Chemical Society In Brassinosteroids; Cutler, H., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

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BRASSINOSTEROIDS: CHEMISTRY, BIOACTIVITY, AND APPLICATIONS

Synthesis of BS from s t i g m a s t e r o l . For our purpose commercially a v a i l a b l e s t i g m a s t e r o l 1 was a t t r a c t i v e as a s t a r t i n g m a t e r i a l because i t s 3P-hydroxy-5-ene f u n c t i o n a lity permitted the necessary transformations of the c y c l i c part and the s i d e chain. The conversion of 1 i n t o n a t u r a l BS was achieved using two d i f f e r e n t s t r a t e g i e s : a) with the r e t e n t i o n of the carbon s k e l e t o n f o r the s y n t h e s i s of C d e r i v a t i v e s ; and b) v i a the C-22 2 9

aldehyde f o r the construction especially f o r BS of the C


2 7

of

new sidec hains, and C series.The 2 8

transformation of 1 i n t o 22S,23S-homobrassinosteroids without replacement of the n a t i v e s i d e chain i s shown i n F i g u r e 1. The t o s y l a t e of 1 was s o l v o l y s e d to the corresponding 3,5-cyclo-6-alcohol which upon o x i d a t i o n gave cycloketone 2 (4), the key intermediate i n BS synthesis from s t i g m a s t e r o l . The cycloketone 2 was t r e a t e d at room temperature with hydrobromic a c i d to regioselectively give the bromoketone 3. Its dehydrobromination i n b o i l i n g DMF i n the presence of lithium carbonate followed by hydroxylation of the r e s u l t a n t dienoketone with osmium t e t r o x i d e gave (5) the tetrahydroxyketone 4, the 22S,23S isomer of the n a t u r a l hormone e t h y l b r a s s i n o n e . F i n a l l y , 22S,23S-homobrassinol i d e 5 was s y n t h e s i z e d from 4 v i a s u c c e s s i v e steps by protecting the hydroxyl groups, Baeyer-Villiger o x i d a t i o n , s a p o n i f i c a t i o n and r e l a c t o n i z a t i o n . Another s y n t h e s i s of 5 was a l s o accomplished (Figure 2) (6-9). I t e l i m i n a t e d the n e c e s s i t y of p r o t e c t i n g and d e p r o t e c t i n g the hydroxyl groups and gave a r e l a t i v e l y good y i e l d of

F i g u r e 1. Synthesis of 22S,23S-homobrassinolide

In Brassinosteroids; Cutler, H., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


5. KHRIPACH ET AL.

Synthesis and Some Practical Aspects

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Figure 2 . A l t e r n a t i v e s y n t h e s i s of 22S,23S-homobrassinolide the d e s i r e d product. The key step to t h i s approach was the r e g i o s e l e c t i v e a d d i t i o n of bromine and hydrogen bromide to the double bond and cyclopropane of 2, r e s p e c t i v e l y . Subsequent B a e y e r - V i l l i g e r o x i d a t i o n of the tribromoketone 6 and debromination with simultaneous dehydrobromination of 7 under the a c t i o n of l i t h i u m carbonate i n b o i l i n g DMF l e d to the dienolactone 8. The o x i d a t i o n of the l a t t e r with osmium t e t r o x i d e a f f o r d e d the tetrahydroxylactone 5. Unfortunately, the d i r e c t h y d r o x y l a t i o n of 22-ene precursors leads, p r e f e r e n t i a l l y , to the 22S,23S c o n f i g u r a t i o n of hydroxyl f u n c t i o n s . That i s why f o r the s y n t h e s i s of BS, possessing natural c o n f i g u r a t i o n s of s u b s t i t u e n t s i n the s i d e chain, we used an approach (10,11) based on the transformation of 22R,23R-epoxides which are the major isomers i n the epoxidation of 2 2 - o l e f i n e s with MCPBA. As shown i n F i g u r e 3, the epoxidation of 3 and f u r t h e r dehydrobromination gave the unsaturated epoxide 9. Trans-opening of the epoxide r i n g with HBr and a c e t y l a t i o n followed by n u c l e o p h i l i c s u b s t i t u t i o n of bromine i n the bromoacetate intermediate gave the diacetate 10. It was further transformed i n t o homocastasterone 11 and homobrassinolide 12 i n the usual way. The same method has been a l s o employed for the synthesis of 22S,23S-homob r a s s i n o s t e r o i d s (9,12).



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F i g u r e 3. Synthesis of homobrassinolide


5. KHRIPACH ET AL.

Synthesis and Some Practical Aspects


Some BS-analogues with a d d i t i o n a l double bond i n the A - c y c l e were synthesized using the a - c i s - h y d r o x y l a t i o n method developed by us e a r l i e r (13-16). As shown i n F i g u r e 4, the o x i d a t i o n of 2 with osmium t e t r o x i d e followed by bromination and dehydrobromination l e d to dienoketone 13 which was subjected to h y d r o x y l a t i o n under the a c t i o n of i o d i n e and s i l v e r acetate i n aqueous a c e t i c a c i d t o give the unsaturated BS analogue 14. Synthesis of BS v i a 22-aldehydes. A large number of BS possessing both natural and unnatural side chains (brassinolide, norbrassinolide, homobrassinolide and their isomers) have been synthesized employing the r e a c t i o n of s u l f o n e d e r i v a t i v e s 16 with the s t e r o i d a l 22-aldehyde 15, as shown i n Figure 5 (18-20). Sulfones 16 were obtained from i s o v a l e r i c a c i d by s u c c e s s i v e steps of cc-alkylation, LAH-reduction, t o s y l a t i o n of resulting alcohols, n u c l e o p h i l i c s u b s t i t u t i o n of t o s y l a t e s by s u l f i d e anion and MCPBA-oxidation of the corresponding s u l f i d e s . Reaction of the aldehyde 15, obtained from s t i g m a s t e r o l , by o z o n o l y s i s of the 22-double bond, with the carbanion d e r i v e d from 16 and f u r t h e r a c e t y l a t i o n gave β-acetoxy s u l f o n e 17. I t s r e d u c t i o n with Na-amalgam

F i g u r e 5. Synthesis of b r a s s i n o s t e r o i d s v i a sulfones


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followed by d e p r o t e c t i o n gave an o l e f i n i c product 18 with a complete carbon s k e l e t o n . The c o n s t r u c t i o n of the 22,23-dihydroxy functionality starting from 18 and subsequent transformation of the d i o l s i n t o aim products were achieved as d i s c u s s e d above f o r homobrassinolide. I t should be pointed out that t h i s method i n the case of b r a s s i n o l i d e s y n t h e s i s gives with 7.8% a higher t o t a l y i e l d than the approach proposed e a r l i e r by K.Mori et a l . (21) with 1.3% s t a r t i n g from s t i g m a s t e r o l . Along with the products of the normal 20£-series some 20«-methyl analogues of BS have been s y n t h e s i z e d i n a s i m i l a r manner. A number of methods f o r the s i d e chain c o n s t r u c t i o n i n BS s y n t h e s i s u t i l i z e s a r e a c t i o n of s t e r o i d a l 22-aldehydes with v a r i o u s v i n y l carbanions. The main shortcomings of these approaches are the formation of 22P-alcohols along with d e s i r e d 22

Synthesis and Some Practical Aspects of Brassinosteroids - American

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