Y-Hydroxy esters

A demonstration of the utility of the electroreductive cyclization reaction is provided by the formal total synthesis of the antitumor agent quadrone (16, Scheme 4) [17]. The first stage of the synthesis involved a controlled potential reduction of (9) in the presence of dimethyl malonate as the proton donor. An efficient cyclization ensued, leading to the formation of the y-hydroxy ester (10)... 

In practice, reduction of 35 (—2.43 V vs SCE) in the presence of 3,5-dimethylphenol as a proton donor, tetra- -butylammonium hexafluorophos-phate as the supporting electrolyte, and DMF as the solvent, led to the y-hydroxy ester 40 and lactone 41 [22]. No sign of any material resulting from cyclization onto the alkene was detected. It was concluded that radical cyclization does not occur in this instance, and that the homogeneous electron transfer rate exceeds that of a 5-exo-trig radical cyclization, thereby implying the operation of either a radical anion or carbanion cyclization pathway. 

Controlled potential reduction of 60 in the presence of dimethyl malonate as a proton donor afforded a mixture of two products, the y-hydroxy ester 65 and lactone 66, in a combined yield of 89% each was converted to a common intermediate, 67. 

Another example of a case where acid-base chemistry competes with cyclization is found in efforts to construct an analog of the Corey lactone [45], The enantiomerically pure unsaturated ester 91 was assembled and subjected to the conditions indicated in Eq. (26). In this instance, dimethyl methylmalonate was used as the proton donor to avoid 1,4-addition of the conjugate base to 91. Cyclization afforded a combined 77% isolated yield of the y-hydroxy ester 92 and the lactone 93 the former could be converted to the lactone in the... 

Lithium borohydride, 92 y-Hydroxy esters and lactones Zinc chloride, 349... 

Ketones do not react with 2. Surprisingly, 2 is inert to benzoyl chloride and to the more reactive complex with AlCl,. Aliphatic aldehydes react with 2 to form y-hydroxy esters in high yield. 

P-HYDROXY ESTERS Aceto(cprbonyl)cyclo-pentadienyl(triphenylphosphine)iron. (S)-(—)-Menthyl p-toluenesulfinate. y-HYDROXY esters Titaniurh(IV) chloride. (x-HYDROXY- P-keto ESTERS Lithium diiso-propylamide. 

Addition of lithium enolates derived from esters and ketones to epoxides has been the object of some consideration, because it offers a direct route for the synthesis of y -hydroxy esters and y-hydroxy ketones, very useful for difunctionahzed organic compounds" . In fact, more complex molecules can be synthesized by using these compounds as synthons... 

S-methylmalate (92%). The keto group may also be in the gamma position to the ester group, which may be in the form of acetoxy, CH,COO—, or carbethoxy, —COjCjH, y-hydroxy esters being formed by hydrogenation over nickel Catalysts. ... 

Cyclization afforded a combined 77% isolated yield of the lactone 137 and the y-hydroxy ester 138 the hydroxy ester could be converted to the lactone in a straightforward manner, thus allowing it to be used to throughput additional material to the target structure. Unfortunately, these materials were accompanied by the formation of the conjugated diene 136, a substance that undoubtedly arises via the intervention of acid-base chemistry, leading to -elimination of the silyloxy unit from 135. 

This zinc-promoted reaction has been used with a variety of carbonyl compounds. Thus, the Luche conditions were applied in a synthesis of (-1-)-muscarine using an aldehyde derived from ethyl lactate [109]. Allyl halide condensation onto a-ketoamides of proline benzyl ester gave good diastereoselec-tivity when performed in the presence of zinc dust and pyridinium p-toluene-sulfonate in a water/THF mixture. In this way, a-hydroxy ketones were obtained with good enantioselectivity after removal of the chiral auxiliary [110]. Reactions of allyl bromide under the Luche conditions with y-aldo esters afforded y-hydroxy esters, which were converted in a one-pot reaction to y-allyl-y-butyro-lactones (Scheme 22) [111]. 

Protection of acids and phenols. Carboxylic acids can be protected as the p-bromophenacyl esters, prepared by the reaction of the carboxylate anion with p-bromophenacyl bromide in water or DMF. The protecting group is removed at room temperature by zinc in glacial or aqueous acetic acid. The new method is comparable to Woodward s protection of carboxylic acids as /3-trichloroethyl esters, which are also cleaved by zinc (see Trichloroethanol, this volume), y-Lactones are converted into y-hydroxy esters. 

Acid-promoted lactonization of y-hydroxy esters is an important way to construct lactones. For example, Scolastico and co-workers first reported the lactonization of MBH adducts 213 using 0.7 m HCl in ACOH-H2O, obtaining cx-methylene-p-hydroxy-5-butyrolactones 215a,b in moderate yields (Scheme 4.65). Trifluoroacetic acid, CSA and sulfuric acid were also used in such lactonizations. In an alternative method, ot-methylene-p-hydroxy-8-butyrolactone 215c was synthesized by the intramolecular MBH reaction in 62% yield (Scheme 4.66). A series of a-alkylidene-8-butyrolactones and multi-substituted a-methylene-8-butyrolactones have been synthesized from MBH adducts (Figure 4.2). 

The 1,3-dipolar cycloadditions of azomethine ylides with aldehydes readily produced high yields of oxazolidines, which hydrolysed to anti a-amino-y -hydroxy esters." Non-stabilized azomethine ylides with isotonic anhydrides produced oxa-zolidine intermediates, which were converted into l,3-benzodiazepin-5-ones via ringopening-decarboxylation-ring-closing reaction cascades." ... 

The reaction of the siloxycyclopropane with titanium(IV) chloride produces the titanium homoenolate (3-titaniopropionate) in good yield this, however, is relatively unreactive (eq 2). Addition of one equivalent of Ti(OR )4 generates a more reactive RTiChOR species, which smoothly reacts with carbonyl compounds below room temperature. The y-hydroxy ester adducts are useful synthetic intermediates and serve as precursors to y-lactones and cyclopropanecarboxylates. A useful variation involves the use of the cyclopropanecarboxylate ester as a functionalized homoenolate precursor to obtain levulinic acid derivatives (eq 3). ... 

Homoenolate Reactivity. Since the previous e-EROS report, a number of examples have been described using the cyclopropanone acetals. Thus, the zinc homoenolate, known to undergo a highly regioselective and stereoselective Sn2 allylation reaction (eq 6), is used in the synthesis of moenomycin analogues. The activated titanium homoenolate reacts with aldehydes or ketones to give y-hydroxy esters that serve as precursors to y-lactones. ... 

The reductions of y-keto esters and 5-keto esters are also facile using (-)-DIP-Cl. The reductions provide high % ee for the reduction of aryl ketones, while low % ee are observed in the case of aliphatic ketones (Scheme 23.56). The products obtained, y-hydroxy esters and 8-hydroxy esters, are valuable intermediates they can be readily converted to the corresponding lactones by treatment with a catalytic amount of trifluoroacetic acid. 

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