Aldehyde esters, from hydroxy-ketones

The synthesis began with Prins qrchzation of the symmetric vinylo-gous ester 273, prepared from heptadienol 272, followed by hydrolysis of the resulting trifluoroacetate and benzylation, to afford the desired 2,6-cis-tetrahydropyran 274 with 92 8 diastereoselection at C5 [113], By this novel desymmetrization, 2,4,6-all-ci5 trisubstituted pyran was efficiently provided. Boron-enolate aldol reaction, as Carreira did, of the methyl ketone 274 with aldehyde 275 gave hydroxy ketone 271 as a single isomer. In contrast to Car-reira s result, samarium-catalyzed intramolecular Tishchenko reduction [114]... 

As a kind of nucleophilic addition reaction similar to the Grignard reaction, the Reformatsky reaction can afford useful ft-hydroxy esters from alkyl haloacetate, zinc, and aldehydes or ketones. Indeed, this reaction may complement the aldol reaction for asymmetric synthesis of //-hydroxy esters. 

Some of the problems associated with the synthesis of a-dicarbonyl starting materials have been alleviated by the use of propane-1,3-dithiol, which reacts with aldehydes to give cyclic thioacetals. With butyllithium the resulting stable dithiane anions (134) can be transformed into a-diketones or a-hydroxy ketones (Scheme 73). A further approach to such compounds is found in the reaction of a-ketonitrate esters with sodium acetate (Scheme 73), while aryl a-diketones are also available from a-ketoanils (prepared from the cyanide-ion-catalyzed transformation of aromatic aldimines) (70AHC(12)103). 

The aldol condensation involves the reaction between a car-banion from an aldehyde or ketone and a second carbonyl component and leads to a P-hydroxy ketone. The Claisen condensation between two molecules of an ester leads to a P-keto ester. 

A simultaneous reduction-oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (8) [33], This is an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, because of its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules, including natural and unnatural products. Thus, treatment of hydroxy aldehyde 18 with 8 (5 mol%) in CH2CI2 at 21 °C for 12 h resulted in formation of hydroxy ketone 19 in 78 % yield. As expected, the use of 25 mol% 8 enhanced the rate and the chemical yield was increased to 92 %. A similar tendency was observed with the cyclohexanone derivative. It should be noted that the present reduction-oxidation sequence is highly chemoselective, and can be utilized in the presence of other functionalities such as esters, amides, rert-alco-hols, nitriles and nitro compounds, as depicted in Sch. 10. 

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]. 

Preparation of the chiral oxazolidine-aldehyde 64 from D-serine 59 required various steps, including conversion into the silyl ether 60, reaction with ketone 61 to provide oxazolidine silyl ether 62 and subsequent desilylation of the tert-butyldiphenylsiloxy group. Oxidation of the hydroxy functionality and hydrogeno-lytic cleavage of the benzyl ester then gave the corresponding aldehyde 63. The acid functionality of 63 was then coupled to aminomethylated Merrifield resin (Scheme 12.26). 

Aldol reactions. Aldol products are obtained in good yields from reaction of ketones with glyoxylic acid monohydrate with assistance of ultrasound irradiation. Substrate-control (by 1,3- + 1,5-asynmietric induction) of the aldol reaction involving y-amino-a-ketoesters under solvent-free conditions is very effective.- With lithium dicyclohexylamide and InCl, the reaction of esters with aldehydes furnishes P-hydroxy esters, and that of a-bromo esters affords a,p-epoxy esters." These are typical Reformatsky and Darzens reaction products, respectively. 

---