Reformatsky reaction intramolecular

Asymmetric intramolecular Reformatsky reactions/ The bromoacetates (1) of (3-hydroxy ketones undergo a Reformatsky-type reaction when treated with Sml2 to give (3-hydroxy-8-valerolactones (2). These products are useful in their own... 

The first three retrosynthetic cleavages are formation of the C7-C8 aldol by intramolecular chromium-Reformatsky reaction of linear precursor 51, esterification between northern and southern half building blocks and Wit-tig reaction of phosphonium salt 52 known from Mulzer s work [85] and northern half precursor 53. The final disconnections were placed at the C2-C3 aldol in 51 (again to be formed by chromium-Reformatsky reaction, here between bromoacetimide 56 and aldehyde 57) and the C14-C15 bond by alkylation of acetoacetate 54 with neryl bromide 55. 

Even more interesting turned out to be the Sml2 -promoted intramolecular Reformatsky reaction. It opens a route to medium and large ring systems, as shown by the examples reported in Table l79a e. 

Following a similar strategy, the synthesis of tetracyclic models of aziridinomitosenes, bioactive degradation products of mitomycins, was based on the Reformatsky reaction of thiolactam 100, as shown in equation 59. The synthetic plan and reagent design were directed to the use of an intramolecular Heck reaction of 101 to complete the target skeleton146. 

Reformatsky reaction. Fiirstner4 has reviewed literature (1887-1988) on this reaction, both inter- and intramolecular. A comparison of different forms of zinc for the reaction suggests that metal prepared by reduction of ZnCl2 with silver-graphite (13, 348) is the most satisfactory. 

Scheme 14.2 An intramolecular Reformatsky reaction/alkylation sequence.17...

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

It is in the intramolecular sense that the Sml2-mediated Reformatsky reaction has been used to greatest effect. Rather surprisingly, there are several examples of intramolecular Sml2 Reformatsky reactions that employ protic cosolvents. In some cases, the alcohol cosolvent is essential for efficient Reformatsky cyclisation. 

The Reformatsky reactions of methyl or ethyl bromoacetate with 4-acetoxy-,2,24 4-benzyloxy-,2 4-tetrahydropyranyloxy-,2 4-chloro-,8 and 4,4-dimethoxy-2-butanone1418 have been carried out. The adducts were converted to mevalonolactone by hydrolysis and, in the case of the acetal reactant, by appropriate reduction and oxidation procedures. The same Reformatsky-type syntheses of mevalonolactone have also been performed using the lithium and magnesium carbanions of acetate esters5,19 25 26 and the dianion of acetic acid28,27 instead of the usual zinc reagent. The intramolecular Reformatsky reaction of 4-(bromoacetoxy)-2-butanone gives mevalonolactone directly.28 A related route to mevalonolactone involves boron trifluoride-catalyzed cycloaddition of ketene to 4-acetoxy-2-butanone followed by hydrolysis.183... 

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]. 

Reductive cyclizadons of 3-bromoacetoxy aldehydes and ketones promoted by Sml2 afford 3-hydroxyvalerolactones with unprecedented degrees of 1,3-asymmetric induction (equation 57). Numerous attempts at utilizing zinc-mediated intramolecular Reformatsky reactions to access these lactones have failed. The successful development of the Smh-based methodology therefore provides perhaps the most convenient entry to this important class of molecules. ... 

Yields in the Sml2-promoted intramolecular Reformatsky reaction are typically higher for ketones than for aldehyde substrates, but in both series diastereoselectivity is virtually complete. It has been suggested that reaction of Smh with the 3-bromoacetoxy initially generates a Sm ester enolate, with cyclization taking place through a rigid cyclic transition structure enforced by chelation (Scheme 4). ... 

Seven-membered ring lactones can be accessed in excellent yields by the Smia-mediated intramolecular Reformatsky reaction as well. Although several substitution patterns provide exceptional relative asymmetric induction in this process (equation 62), it is clear that high diastereoselectivity cannot be achieved for all substitution patterns in the formation of seven-membered ring lactones. ... 

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. 

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