P-Lactones synthesis

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Both ketones and aldehydes, as well as acylsilanes can be employed as carbonyl substrates in the new p-lactone synthesis (Table). Reactions involving ketones are most conveniently carried out by adding the neat carbonyl compound to the thiol ester enolate solution. Under these conditions aliphatic aldehydes react to form substantial quantities of 2 1 adducts however, formation of these side products can be suppressed simply by slowly adding the aldehyde component as a precooled (-78°C) solution to the reaction mixture. Wide variation is also possible in the thiol ester component, although a few limitations of the method have been noted. For example, a,p-unsaturated ketones such as methyl vinyl ketone and cyclohexenone fail to yield p-lactones, and attempts to generate p-lactones with severe steric crowding have also met with limited success.3... 

Nucleophilic addition of ketene to aldehyde for p-Lactone synthesis... 

The ester of quinine (5) is an excellent catalyst for p-lactone synthesis from ketene and certain aldehydes. ... 

The BINOL-Ti-catalyzed aldol reaction of chiral P-benzyloxy aldehyde and silyl enol ether provides a facile route to the stereoselective synthesis of both syn and anti-diastereomers of p,S-dihydroxy thioesters, which can be used as the key intermediates for P-lactone synthesis [111] (Scheme 14.39). The high diastereoselectivity of this reaction was found to be dictated by the chirality of the BINOL-Ti catalyst rather than that of the chiral aldehyde substrate. A catalytic enantioselective resolution of secondary alcohol containing silylenol ether moiety has been realized by an aldol reaction catalyzed by BINOL-Ti Lewis acid [112]. 

Lactones General Synthesis Synthesis of P-Lactones Synthesis of Butyrolactones Synthesis of Butenolides Synthesis of Phthalides Synthesis of Tetronic Acids Synthesis of a-Methylenebutyrolactones Synthesis of Valerolactones... 

As [2 + 2]cycloaddition, carbo[2 + 2] cycloaddition of a, P-unsaturated carbonyls with vinyl ethers and P-lactone synthesis through [2 + 2]cycloaddition of ketenes with aldehydes were examined. As shown in Scheme 6.99, since under nonpho-tochemical conditions the concerted mechanism for both reactions are disallowed by Woodward-Hoffmann rules, ground-state catalytic reactions must proceed through a stepwise mechanism. 

FIGURE 3.5 Two plausible mechanistic rationales for phosphine-catalyzed p-lactone synthesis. 

Lactones whose rings are three or four membered (a lactones and p lactones) are very reactive making their isolation difficult Special methods are normally required for the laboratory synthesis of small ring lactones as well as those that contain rings larger than SIX membered... 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

The first synthesis of sorbic acid was from crotonaldehyde [4170-30-3] and malonic acid [141-82-2] in pyridine in 32% yield (2,17,18)- The yield can be improved with the use of malonic acid salts (19). One of the first commercial methods involved the reaction of ketene and crotonaldehyde in the presence of boron trifluoride in ether at 0°C (20,21). A P-lactone (4) forms and then reacts with acid, giving a 70% yield. 

An unexpected, one-step synthesis of a-chloro-P-lactones in 40-83% yield resulted when phenyl esters of a-chlorocarboxylic acids were treated under the conditions of the Darzens reaction with strong base in the presence of ketones or aldehydes <95AG(E)2028>. Previously, phenyl esters do not appear to have been used in this reaction. 

Wilson JE, Fu GC (2004) Asymmetric synthesis of highly substituted P-lactones by nucleophile-catalyzed [2 -t 2] cycloadditions of disubstituted ketenes with aldehydes. Angew Chem Int Ed 43 6358-6360... 

The existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities... 

Scheme 13.34. Prelog-Djerassi Lactone Synthesis P. A. Grieco and Co-Workersa...

Scheme 13.44. Prelog-Djerassi Lactone Synthesis R. E. Ireland and J. P. Daub3...

SYNTHESIS OF p-LACTONES BY ALDOLIZATION OF KETONES WITH PHENYL ESTER ENOLATES ... 

Fig. 38 Synthesis of enantiopure P-lactones from achiral precursors...

Another way to deal with the problem of the toxicity of the metal is the enantiopure synthesis of p-BL from racemic PO. The extremely low activity and enantiomeric excess of this process prohibits its application on industrial scale. In addition, there is still a lack of catalysts that convert enantiopure p-lactones to isotactic polymers with good polymerization control and whilst retaining high activities. 

Barbaud C, Fay F, Abdillah F, Randriamahefa S, Guerin P (2004) Synthesis of new homopolyester and copolyesters by anionic ring-opening polymerization of a, a , P-trisubstituted P-lactones. Macromol Chem Phys 205 199-207... 

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