Oxidative rearrangements natural product synthesis

Enzymatic Baeyer-Villiger oxidations have been studied for a long time some very useful applications in natural product synthesis date back more than two decades. For example, prochiral (3A, 5,S )-4-hydroxy-3,5-dimethylcyclohexanone was successfully oxidized using a CHMO from Acinetobacter sp. NCIMB 9871. In this case the seven-membered ring formed rearranges spontaneously into the thermodynamically more stable y-lactone. The rearranged lactone has been used in the synthesis of natural products such as tirandamycin or calyculin A (Fig. 25) [157-159],... 

This rearrangement-cyclization cascade was applied to natural products synthesis. For example, DDQ oxidation of the appropriate dihydro-3 (27T)-furanone enol acetates (Table 3.5, entries 1 and 7) afforded bullatenone and the antitumor agent geiparvarin in a very rapid route (Fig. 3.1).69 70... 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

A simple two-step protocol for the generation of a terminal diene is to add allyl magnesium bromide to an aldehyde or a ketone and subsequent acid or base catalysed dehydration (equation 34)72. Cheng and coworkers used this sequence for the synthesis of some indole natural products (equation 35)72a. Regiospecific dienones can be prepared by 1,2-addition of vinyllithium to a,/l-unsaturated carbonyl compounds and oxidative rearrangement of the resulting dienols with pyridinium dichromate (equation 36)73. 

We can illustrate the synthesis of allylic alcohols from allylic sulfoxides with this synthesis of the natural product nuciferal. We mentioned this route on p. 1257 because it makes use of a heterocyclic allyl sulfide to introduce an alkyl substituent regioselectively. The allyl sulfide is oxidized to the sulfoxide, which is converted to the rearranged allylic alcohol with diethylamine as the thiophile. Nuciferal is obtained by oxidizing the allylic alcohol to an aldehyde with manganese dioxide. 

The allylic oxidation of alkenes by O2 involves an ene reaction, and proceeds with rearrangement s as in Scheme 4. The intermediate allylic hydroperoxide (5) can be reduced to yield an allylic alcohol (6), or be treated with base to give an unsaturated carbonyl conqiound (7). The reaction works best on tri- or tetra-substituted alkenes, and the relative preference for attack is Me - CH2 CH. The O2 allylic oxidation has been used in the synthesis of a large number of natural products, including some naturally occurring allylic hydroperoxides. It is possible that O2 reactions of this type are involved in biosynAetic processes. 

The first asymmetric total synthesis of the macrocyclic lactone metabolite (+)-pyrenolide D was accomplished in the laboratory of D.Y. Gin. The natural product has a densely functionalized polycyclic structure and its absolute configuration had to be established. The key step of the synthesis was a stereoselective oxidative ring-contraction of a 6-deoxy-D-gulal, which was prepared from anomeric allylic sulfoxide via the Mislow-Evans rearrangement. 

The Moffatt oxidation was utilized in the endgame of the total synthesis of (+)-paspalicine by A.B. Smith et al. The advanced intermediate hexacyclic homoallylic alcohol was subjected to the Moffatt oxidation conditions using pyridinium trifluoroacetate as the acid catalyst. Under these conditions, the desired p,y-unsaturated ketone and the rearranged a,p-unsaturated ketone (paspalicine) were formed in a 5 1 ratio. The final step was the Rh-catalyzed isomerization of the p,y-unsaturated ketone to the natural product. 

The defined geometry of these steps has permitted the synthesis of some cycloheptane acids related to terpenoid natural products. The key reaction was the rearrangement of a suitably substituted bicy-clo[4.2.0]octane. Thus the photoaddition of ethylene to 3-methylcyclohexenone gave the ketone (42), which was converted to the alcohol (43). On treatment with HgO and HBF4 this gave the unstable hydroxy aldehyde (44), which was readily oxidized to the dicarboxylic acid (45 Scheme 17).- Ring expansion methodology was also used in an approach to the synthesis of the trichothecenes (see Scheme 18).32... 

The reaction between the acid chloride of chromone-2-carboxylic acid and ethyl ethoxymagnesioacetoacetate probably leads to the expected fi-diketone which enolizes and cyclizes spontaneously to spirofuranone(52).127 A different approach was made by Hungarian workers in their synthesis of tachrosin (53), an unusual kind of flavone isolated from Tephrosia poly-stachyoides and one of the earliest natural furanones to be isolated. They subjected an unsaturated ketone (Scheme 32) to oxidative rearrangement by thallium(III) salts, a reaction well known in chalcone chemistry, and eliminated methanol from the product to obtain the necessary starting material.128... 

The aza-annulation methods developed for conversion of 88 to 94 were extended to the synthesis of the antileukemic and antitumor natural product ( )-camptothecin (125, Scheme 11 ).47 Aza-annulation of 109 with 121 in the presence of NaBH4 resulted in heterocycle formation to give 122 without subsequent elimination of the malonate species. A dye sensitized photo-oxidation promoted the rearrangement of the indolo[a]quinolizinone ring to the indolizino[l,2-h]quinolone ring 123. Compound 123 was converted to 124, which constituted a formal total synthesis of camptothecin (125). 

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