Lactones Reformatsky synthesis

A furanose-fused c/.,(3-unsaturated 8-lactone was also prepared from ester 11 as a key chiral intermediate for the synthesis of the enantiomer of (+ )altholactone, a natural product with cytotoxic and antitumor activities.18 A Reformatsky reaction with ethylbromoacetate or a Wittig... 

The synthesis started with the homo-Reformatsky reaction between the alkoxytitanium homoenolate Eq. (30) and aldehyde 27, which afforded the product 28 with Cram orientation with >6 1 selectivity. An inversion at the sterically hindered C22 position was readily achieved by mesylation, followed by KOH treatment in hot aqueous MeOH to give lactone 30 after add-catalyzed lactonization. 

White et al. developed a stereospecific synthesis of Z-olefins, including isotretinoin [84]. Thus, isotretinoin was obtained by a Reformatsky reaction of p-cyclocitral with the C5 bromoester, followed by DIBAL-H lactone reduction, lactol ring opening, selective olefin bond formation with ethyl 4-diethoxyphosphoryl-3-methyl-2-butenoate and further saponification, Fig. (46). 

A three-carbon unit can be introduced on ketosugars under Reformatsky conditions, as recently demonstrated by several groups [33,34], The analogous Dreiding-Schmidt procedure has also been applied in this case with successful double stereodifferentiation [35]. This is exemplified on ketone 18 which yields lactone 20 as a single isomer (see Scheme 10). The condensation on ketosugars of trimethylsilylacetate [36] or acrylate [33], in the presence of fluoride ion, has also been used with success for the synthesis of P-hydroxy acids or ra-methylene-y-lactones, respectively. 

R. Csuk, A. Fiirstner, H. Sterk, and H. Weidmann, Synthesis of carbohydrate derived ot-methylene-y-lactones by diastereoselective, low temperature Reformatsky-type reactions, J Carbohydr. Chem. 5 459 (1986). 

Inanaga and coworkers [109] used a modified intramolecular Reformatsky reaction in the synthesis of the beetle aggregate phermone ferrulactone I (187). As shown in Scheme 61, precursor 185 was cyclized with Smij followed by acylation of the resulting unstable P-hydroxydecadienolide to afford the 11-membered lactone benzoate 186 in 47% yield. There are more applications of the Reformatsky reaction for macrocyclization [110]. 

Similar condensations can be accomplished with other types of stabilized carbanions, e.g. sulfonyl anions, as illustrated by equation (81). The resulting sulfonyl lactone (228) eliminates sulfinic acid on treatment with p-TsOH to furnish the a,3-unsaturated system (229).Spirolactonization is the result of the Reformatsky reaction of ester (231) with cyclic ketones. In equation (82), this reaction is applied to the synthesis of the lysergic acid precursor (232), which is formed stereoselectively from (230). ... 

Nitriles and esters are also unreactive in Smh-promoted Barbier reactions. A very useful procedure for lactone synthesis has been developed making use of this fact. Treatment of 7-bromobutyrates or 8-bro-movalerates with Smh in THF/HMPA in the presence of aldehydes or ketones results in generation of lactones through a Barbier-type process (equations 25 and 26). This nicely complements the -metaUo ester or homoenolate chemistry of organosamarium(III) reagents described above (Section 1.9.2.1), and also the Reformatsky-type chemistry promoted by Sml2 (Section 1.9.2.3.2). Further, it provides perhaps the most convenient route to 7- and 8-carbanionic ester equivalents yet devised. 

The total synthesis of pederin, a potent insect toxin was achieved by T. Takemura and co-workers. One of the key steps of the synthesis was an intramolecular samarium diiodide induced Reformatsky reaction to construct the lactone subunit of the molecule. The transformation was carried out in tetrahydrofuran at 0 °C without the use of additives or catalysts. 

The Reformatsky reaction of 4-bromocrotonate esters with conjugated enones can conceivably give four regioisomers, as shown in equation (27). Several workers have applied such reactions to the synthesis of vitamin A and related compounds. In most cases, 8-lactones derived from 1,2-7-adducts were obtained, as exemplified by results with -cyclocitral (equation 28). ... 

Synthesis of a marine sterol, depresosterol (25), illustrates the utility of the homoenolate as a multifunctional, three-carbon building block. Homo-Reformatsky reaction between an alkoxytitanium homoenolate (11 Section 1.14.5.1) and an aldehyde (19) afforded the undesired Cram product (20) in a ratio of >6 1 (Scheme 29). Inversion of the stereochemistry at the sterically hindered C-22 position was achieved through internal solvolysis by taking advantage of the terminal ester function. Stereoselective hydroxymethylation of the lactone (22) followed by introduction of the C-26 and C-27 methyl groups to (23) afforded depresosterol (25). 

The synthesis of 6-substituted-4-hydroxy-5,6-dihydro-2f/-pyran-2-ones is accomplished through a double Reformatsky reaction of aldehydes with ethyl bromozincacetate, followed by lactonization (Scheme 52). This synthetic protocol is applied to the synthesis of naturally occurring... 

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