Synthesis of brassinolide

Baeyer-Villiger oxidation of the 5a-6-keto steroid 1 with trifluoroperacedc acid is 1000 times faster than oxidation with m-chloroperbenzoic acid and also is more regioselective. This oxidation was used in the last step in a synthesis of brassinolide (2), a natural steroid that promotes plant growth.2... 

Schmittberger, T. Uguen, D. A formal synthesis of brassinolide. Tetrahedron Lett. 1997, 38, 2837-2840. 

Fraser-Reid and co-workers have examined serial radical cyclization of pyranose-derivatives [95AJC333] in the stereocontrolled synthesis of Woodward s reserpine precursor [95JOC3859]. Treatment of the bromosilane 188 under reductive conditions resulted in a 5-exo followed by a 6-exo cyclization. The intermediate radical eliminates phenylsulfinyl radical to provide the alkene 189 as the product. The intermediate has been converted to the reserpine precursor 190. The temporary silicon method has been utilized for the synthesis of brassinolide side chain [95SL850]. 

Before discussing our synthetic studies, mention should be made of different approaches employed in the synthesis of brassinolide by other investigators. The most practical method would be to start with a readily available steroid having the same carbon skeleton as brassinolide, and then introduce the required functional groups in rings A and B and the sidechain. In the case of 28-homobrassinolide (5), tiie ideal starting compound would be the abundant sterol stigmasterol (4). 

The required starting compound for the synthesis of brassinolide by hydroxylation of a A22 double bond is 22-dehydrocampesterol, which is not readily available (7). It can be isolated as a mixture with the C-24 epimer, brassicasterol, from oysters (Crassostrea virginica), but the mixture is difficult to separate. It is more readily prepared by synthesis (6). For the synthesis of 24-epibrassinolide, brassicasterol, which can be obtained from rapeseed oil, is an obvious starting compound (15). Ergosterol, which is readily available, has also been employed (16). 

Our first synthesis of brassinolide started from stigmasterol which was converted to (20S)-6p-methoxy-3a,5-cyclo-5a-pregnane-20-carboxaldehyde (2). This pathway involved formation of the mesylate with methanesulfonyl chloride in pyridine and tetrahydrofuran, treatment of the mesylate with potassium acetate in methanol, and ozonolysis of die i-sterol with reductive work-up. 

Subsequent to our use of butenolide anions in aldol reactions to construct sidechains of steroids, two groups have reported a similar method for synthesis of brassinolide or its analogs. Kametani and co-workers employed the dianion of 3-isopropyltetronic acid which was reacted with a 20-keto steroid. The aldol product was dehydrated and the product hydrogenated to furnish the brassinolide sidechain (28,29). Zhou and Tian have used the reaction of a C-22 aldehyde derived from... 

The first chemical synthesis of brassinolide was achieved by us in 1980 (5), but its multi-step synthesis process indicated costly preparation for agricultural use. The situation did not change, even after the discovery of many different synthetic routes were discovered. Thus, only a few brassinosteroids candidates have been tested in the field during the past several years. 

The discovery of brassinolide by scientists at USDA led to the development of a new group of plant growth substances, termed brassinosteroids, which have the potential for increasing crop yields and biomass. The chapter summarizes the USDA s contributions to brassinosteroids, which include isolation and identification of brassinolide, synthesis of brassinolide and its analogs, and limited biological and field studies on brassinosteroids. An overview of the current data requirements for the registration of brassinosteroids as biochemical pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act is presented. 

Inspection of the brassinolide structure revealed that the molecule is unique, because it contains 13 asymmetric centers, not found in any other steroid. With these many asymmetric centers, theoretically 213 (= 8192) stereoisomers can be derived when one undertakes the total synthesis of brassinolide, but nature produces only one isomer. Chemists in recent years, however, have designed synthetic schemes in such a way that the desired isomer can be obtained very selectively or specifically. Because... 

The first synthesis of brassinolide (30) was achieved by Fung and Siddall in 1980,62 and also by Ikekawa and coworkers in the same year.63 Since then, many plant-growth promoters related to 30 with steroidal structures have been isolated from plants (Figure 2.21). They are called brassinosteroids. The early phase of our synthetic works on brassinosteroids has been reviewed.64... 

Synthesis of brassinolide and castasterone. Reprinted with permission of Shokabo Publishing... 

Many total syntheses take advantage of the temporary introduction of a sulfide or a sulfone group. As illustrated in Scheme 5, an allenyl sulfone is a key intermediate in the synthesis of brassinolide reported by Back [31a]. It is obtained through sequential addition of TsSePh, base-promoted migration of the double bond, and oxidative elimination of the phenyl selenide. The addition of EtSH to the... 

In several studies concerning the synthesis of brassinolides such as compound 343 described by Takatsuto [77, 78], the Claisen-Johnson rearrangement afforded stereoselectively functionalized side chains. As previously, formation of the center in of ester group was stereoselective. A mixture of epimers at the a-stereocenter was formed during the process, but since this carbon atom was no longer stereo-genic in compound 343, this lack of stereoselectivity was of no consequence (Scheme 6.56). 

The exceptionally high stereoselectivity found in proline-catalyzed aldol reactions involving hydroxyacetone has recently been used in a total synthesis of brassinolide (156), a steroidal plant-growth regulator [128]. Readily available aldehyde 151 underwent proline-catalyzed aldolization with hy-... 

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