Lactonization, from amides

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

Although some examples of C-substitutions of silylated Schiff bases and iminium salts, in particular the formation of / -lactams, have already been mentioned in Sections 5.1.3 and 5.1.5 (cf. also C-substitutions of lactones and amides in Section 4.8) in this section several additional and typical C-substitutions of 0,0- and 0,N-acetals and of iminium salts derived from carbonyl groups are discussed. 

TV-Acyl indoles derived from amides have been employed for the conversion of lactones into protected hydroxyacids. Thus, (chloromethyl)alumi-num 2-(2-propenyl)anilide reacts (120) with 1,4- and 1,5-lactones, as for example per-O-terZ-butyldimethylsilyl-D-ribono-1,4-lactone (104), to afford hydroxyamides. After protection of the free hydroxyl group, these amides were converted by ozonolysis into TV-acyl indoles, 105, which were readily saponified to the acid 106. 

In heterodetic peptides, the ring system is formed from amides and other heteroatom linkages, for example, a disulfide bridge, a thioether or a lactone linkage. The most common nonamide links in heterodetic peptides are the disulfide bonds (found in posterior pituitary hormones such as oxytocin and vasopressin) and the ester (lactone) fnnction. " ... 

In general, dehydration means loss of water molecules from chemical substances, irrespective of their structure. Even if all cases where water is bonded in hydrate form are excluded, a number of reactions remain which also include formation of nitriles from amides, lactones from hydroxy acids etc. However, the present treatment will concentrate on the heterogeneous catalytic decomposition of alcohols in the vapour phase, which can be either olefin-forming or ether-forming reactions, and on the related dehydration of ethers to olefins. 

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

Since the discovery of the synthesis of 1,3,5-triazine-2,4-diamines from biguanide and its derivatives,328-329 a large variety of carboxylic acid derivatives, e.g. acid chlorides,332 342,346 lactones,333 amides,334,335 imides,336,337 ortho esters,338 amidines,338 esters334, 339- 343 and acid anhydrides,332,344,345 have been used as starting materials in the preparation of these triazines (Table 8).330,331 The preferred procedure is the reaction of biguanides 1 with esters 2 in alcoholic solution, sometimes in the presence of a basic catalyst. The reaction mechanism is thought to be as indicated.341... 

A carbonyl group is a carbon double-bonded to an oxygen an acyl group is a carbonyl group attached to an alkyl or aryl group. Acyl halides, acid anhydrides, esters, and amides are called carboxylic acid derivatives because they differ from a carboxylic acid only in the nature of the group that has replaced the OH group of the carboxylic acid. Cyclic esters are called lactones cyclic amides are lactams. There are symmetrical anhydrides and mixed anhydrides. 

Tuberonic acid (5) was isolated as a lactone from J. grandiflorum L. [19], An acetyl tuberonic acid amide with phenylalanine was isolated from Praxelis dematidea [20] and the glucoside was isolated from Solanum tuberosum L. as a potato tuber-inducing substance [21,22], The methylester of the glucoside was isolated from Helianthus... 

The (S)-lactone acid 1, obtained from L-glutamic acid by nitrous acid deamination, was converted to the acid chloride, then treated with excess diazomethane followed by hydrogen iodide to yield the keto-lactone 2. Amidation occurred quantitatively to give the partially racemized amide 3, which was purified by repeated recrystallizations. The vicinal diol resulting from reaction with excess methylmagnesium iodide was protected as the acetonide 4. An isomeric mixture of olefins (Z , 26 74) was obtained from the subsequent Wittig reaction. Reduction followed by separation on silver nitrate coated silica gel gave the (Z)-and ( )-alcohols in 20% (6) and 61% (5) yield, respectively. Conversion of the (S)-( )-alcohol (5) to the chloride then afforded the thioether (7) on reaction with sodium phenylsulfide. The thio ether anion was formed by treatment with n-butyllithium. Alkylation with the allylic chloride" (8), followed by removal of sulfur, then yielded the diene 9, which was converted in several steps to (/ ) (-t-)-10,11 -epoxy famesol. 

The first applications in total syntheses started from amide 188. The rearrangement, under standard conditions, led diastereoselectively to amide 189 in 77% yield no traces of other diastereomers were found. Amide 189 was converted into (-)-isoiridomyrmecm 190 via diastereoselective hydroboration. Oxidative work-up and a final lactonization in the presence of a pTsOH (41.4% yield over three steps) (28f. Alternatively, LLAlHj-reduction of 189 resulted in amine 191 (80%), a final five step sequence enabled one to synthesize (-r)- -skytanthine 192 with 60% yield (Scheme 10.42) [28g],... 

Lead tetraacetate iodine/irradiation y-Lactones from carboxylic acid amides... 

Lactones from carboxylic acid amides via — s. 19, 738 of terf-aminomethyl compounds s. 19, 738 ferrocene derivatives s. Am. Soc. 87, 1241 (1965)... 

Stiller and associatesin the Merck laboratories a little less than a year after the collaboration began isolated the lactone from concentrates, and determined its structure by classical methods to be -hydroxy-/5,/ -dimethyl-y-butyrolactone. This was synthesized and resolved into its optical isomers. The levo-rotatory lactone when condensed with /3-alanine by various pro-ceduresi >22>2 yields dextro-rotatory pantothenic acid with full biological activity. The antipode was found to be inactive. The biologically active form has, according to Hudson s amide rule, the D-configuration24.2s. 

The aldonic acids are the initial oxidation products produced from aldoses by most oxidants and are usually isolated as the metallic salts or the lactones. As a result of the ease with which the crystalline lactones, salts, amides, hydrazides, and other derivatives can be formed, aldonic acids are... 

When the amide (4) was treated under Mitsunobu conditions, cyclization occurred through oxygen to give the L-xylono-1,4-lactone derivative (5). A convenient large-scale synthesis of D-ribono-1,4-lactone from D-ribose has been described, and 5-0-glucopyranosylarabinonic acid can be obtained selectively by oxidative removal of C-1 from isomaltulose. Rate constants for the hydrolysis of D-glucono-1,5-lactone, and for the reverse reaction, have been determined. ... 

A mixture of phenylacetic acid, benzyl alcohol, and tri-n-butylamine in methylene chloride added under argon to a mixture of l-methyl-2-bromopyridinium iodide and methylene chloride, and refluxed 3 hrs. benzyl phenylacetate. Y 97%. F. e., also with l-methyl-2-chloropyridinium iodide, s. T. Mukaiyama et al., Chem. Lett. 1975, 1045 Bull. Chem. Soc. Japan 50, 1863 (1977) carboxylic acid amides from amines (cf. Synth. Meth. 26, 367) s. ibid. 1975, 1163 3,4-dihydro-2H-pyrido-[1,2-a]pyrimid-2-one as acid scavenger cf. ibid. 1976, 13, 57 lactones from hydroxycarboxylic acids (cf. Synth. Meth. 17, 320) with 2-chloropyridine methio-dide and triethylamine s. ibid. 1976, 49 esters with 2 halogeno-3-ethylbenzothia-zolium salts of ibid. 1976, 267 2-chloro-N-methylbenzothiazolium triflate as condensing agent s. F. Souto-Bachiller, G. S. Bates, and S. Masamune, Chem. Com-mun. 1976, 719. 

Lactams are intramolecular amides of amino acids (especially y-, -e-amino acids) formed similarly to lactones from hydroxy acids. After hydrolysis the acid formed is identified. 

A general approach for the synthesis of 8-lactones from 8-hydroxy esters and amides has been described by Yamaguchi et al. [41]. The strategy involves addition of lithium enolates generated from the esters or amides to oxetanes 30 to afford the corresponding 8-hydroxyesters or 8-hydroxyamides 31 (Scheme 5). Hydrolysis of these intermediates and subsequent lactonization was achieved under either acidic or basic conditions to furnish 8-lactone 32. 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

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