Asteltoxin synthesis

A more complex example with stereochemistry comes from Schreiber s asteltoxin synthesis.16 Hydroboration of the bicyclic acetal 96 with borane itself occurs on the underside of the folded bicyclic molecule to give 97. But this is not the end of the story. The product of the hydroboration is the THF 98. 

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

In a synthesis of (-i-)-asteltoxin, Cha applied the Suzuki-Tsuchihashi rearrangement to silyloxy epoxide 184 for the enantioselective construction of the unusual... 

Efficient synthesis of the mycotoxin asteltoxin 189 was accomplished beginning with the cycloaddition between 3,4-dimethylfuran and 3-benzyloxypropanal, which furnished pho-toaldol 183 in 63% yield (Scheme 42)84. Epoxidation from the convex face of this adduct, with subsequent epoxide opening, afforded 184, which was then elaborated through a series of steps to 185. The side chain was introduced via lithiosulfoxide 186 to furnish, after double sigmatropic rearrangement, 187. Hydrolysis of this afforded 188, which was oxidized and elaborated to 189 in two steps. 

The UV irradiation of allyloxy-ketones and -aldehydes has led, by 5-hydrogen abstraction, to a useful high-yield synthesis of the 2-alkenyl-3-hydroxytetrahydrofurans (80CC657). This substitution pattern occurs in the natural mycotoxins citreoviridin and asteltoxin (Scheme 56). 

The exo-selective formation of bicyclic oxetanes of furan derivatives is reported as being successful when applied to the synthesis of natural products (Scheme 7.19) [15e,37]. For example, the total synthesis of asteltoxin and avenaciolide was achieved from 3,4-dimethylfuran and furan, with the PB reaction being used as an initial step of the synthesis. 

The facial diastereoselectivity derived from-the ratio (3 + 4)/(5 + 6) was 50%, while the exo/endo selectivity derived from the product ratio (3 + 5)/(4 4- 6) was 40%. Oxetanes 9a,b were obtained with a low diastereoselectivity from the reaction of (R)-isopropylideneglyceraldehyde 7 with 3,4-dimethylfuran 8 [6]. Oxetanes 9a,b have been used for the synthesis of asteltoxin. Enantiopure acyl cyanides were used in the same way as chiral carbonyl reaction partners [7] and camphor for the addition with electron-poor alkenes like dicyanoethylene [8]. In the latter case the reaction occurs in the S i state of the carbonyl compound. 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

One of the key steps used in a new synthesis of the bis(tetrahydrofuran) moiety of Asteltoxin (94) is the photoaddition of the propanal (95) to 3,4-dimethylfuran, yielding the adduct (96). This cycloaddition is a common outcome of the irradiation of aldehydes or ketones with furans. An analogous adduct (97) results from the photoreaction of butyl glyoxalate with 2-methylfuran. Two other products [(98) and (99)] are also formed, the first of which is presumably the result of ring opening of the isomeric oxetane (100), while (99) is produced by a hydrogen abstraction radical coupling pathway. 

The convergent total synthesis of the mytotoxic (+)-asteltoxin was accomplished by J.K. Cha et al. The coupling of the two main fragments was achieved by the HWE olefinatlon of a jb/s(tetrahydrofuran) aldehyde with an a-pyrone phosphonate. The b/s(tetrahydrofuran) aldehyde was prepared by the Swern oxidation of the corresponding b/s(tetrahydrofuran) primary alcohol. Interestingly, under the oxidation conditions there was no epimerization of the a-stereocenter, but during the HWE olefinatlon a small amount of C8 epimer was formed. 

Various other functionalization procedures have been developed and all have been summarized in detail in a recent review10. Some representative examples should be mentioned synthesis of the antifungal metabolite ( )-avenaciolide (6)74, the mycotoxin asteltoxin (7)75,76 and the antileukemic cembranolide isolobophytolide (8)77. 

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