Lactone, intramolecular cyclization

When the platinum-catalyzed hydrothiolation was performed for acetylenic alcohols, intramolecular cyclization took place to afford a-methylene lactone 25 in up to 67% yield (Eq. 7.19) [30]. 

Intramolecular lactonization can also be carried out with DCCI and DMAP. As with most other macrolactonizations, the reactions must be carried out in rather dilute solution to promote the intramolecular cyclization in competition with inter-molecular reaction, which leads to dimers or higher oligomers. A study with 15-hydroxypentadecanoic acid demonstrated that a proton source is beneficial under these conditions and found the hydrochloride of DMAP to be convenient.130... 

The phthalide 25, obtainable by condensation of 4,4 -bisdimethyl-aminobenzophenone-2-carboxylic acid with 3-dimethylaminoacetanilide and subsequent hydrolysis, was diazotized in sulfuric acid and the resultant diazonium salt treated with copper powder to yield 26. However, better yields are reportedly obtained by carrying out ring closure of the diazonium salt in phosphoric acid.103 A further synthetic route has also been described in which phthalides undergo intramolecular cyclization in the presence of aluminum chloride and urea.104,105 Thus, Crystal Violet lactone (2) has been directly converted into phthalide 26.106... 

Oxandrolone Oxandrolone, 17j3-hydroxy-17a-methyl-2-oxa-5-androstan-3-one (29.3.10), is made by oxidation of the C1-C2 double bond of 17j3-hydroxy-17a-methyl-l-androsten-3-one by a mixture of lead tetraacetate and osmium tetroxide with an opening of the A ring of the steroid system, which forms an aldehyde acid (29.3.9). Upon reducing the aldehyde group with sodium borohydride, intramolecular cyclization takes place, directly forming a lactone (29.3.10), which is the desired oxandrolone [31,32]. 

Ring opening of a 4-(hydroxyalkyl)-substituted oxazolone using dimethylamine gives an amide 245 that can be used as an intermediate in a subsequent intramolecular cyclization to prepare lactones 247 (Scheme 1.19) ... 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

S. Velazquez, S. Huss, and M.-J. Camarasa, Stereoselective synthesis of [3.3.0] fused lactones (y-butyrolactones) of sugars and nucleosides by free radical intramolecular cyclization, J. Chem. Soc. Chem. Commun. p. 1263 (1991). 

Few examples of intramolecular enol silyl ether or silyl ketene acetal cyclizations to oc,3-enones have been reported. Notable, as exemplified in Scheme 34, is the iodotrimethylsilane-mediated intramolecular cyclization of 5-(iodoacetoxy)-a,3-enones (211) to 5-lactones (214). These cyclizations proceed with in situ generated silyl ketene acetals (212) arising from iodotrimethylsilane reduction of the iodoacetoxy moiety.87... 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Lithium enolates of phenyl esters (28) react with aldehydes or ketones to give O-lithiated phenyl 3-hydroxyalkanoates (29) which undergo spontaneous intramolecular cyclization to P-lactones (30) (95JOC758), Also, lithium enolates are used in the synthesis of 3-[l-(dialkylamino)alkyl]()-lactoncs (94JOC7994), which are precursors for a-oxo-P-lactones. 

Intramolecular cyclization is a useful method for the preparation of lactones and cyclic ethers.39 The most common examples are iodolactonization and iodoetherification, the difference being that... 

Several indium-mediated intramolecular carbonyl allylation reactions have been investigated, and it has been found that these reactions provide an easy access to a variety of cyclic compounds. The intramolecular cyclization of 49a-c mediated by indium in aqueous media proceeds smoothly to afford carbocyclic systems containing y-hydroxy-Q -methylene esters 50a-c, which either spontaneously or readily cyclize to give fused o -methylene-y-butyrolactones 51a-c (Scheme 52). The same cyclization of 49d is too slow to compete with the side-reaction, in which the bromide is substituted by a hydroxy group. The ring junction stereochemistry of fused lactones 51 has been found to be cis in all cases. Of the two possible transition states, the one leading to the m-fused compounds is preferred, because the chair-chair conformation is favored over the chair-boat conformation.209... 

To finish our discussion of bromonium ions, you need to know about one more important class of reactions, those in which the nucleophile is located within the same molecule as the bromonium ion. Here is an example the nucleophile is a carboxylate, and the product is a lactone (a cyclic ester). This type of reaction—the cyclization of an unsaturated acid—is known as a bromolactonization. Intermolecular attack on the bromonium ion by bromide ion does not compete with the intramolecular cyclization step. 

The redox-sensitive linker 1.34 (91), obtained in several steps from Merrifield resin and a lactone precursor, was charged with a N-protected aminoacid, treated with NBS to debenzylate and oxidize the linker to quinone, and submitted to SPS. The quinone linker was reductively activated to dihydroquinone with NaBH4 in THF/MeOH for 30 min at rt, then cleaved by treatment with anhydrous TBAF in THF for 20 h at rt to provide the free acidic peptide via intramolecular cyclization of the linker moiety. 

Formation of p-Lactams, Peptides and Oligonucleotides. The intramolecular cyclization technology to form /8-lactams using DCC in the condensation reaction was used by Sheehan and Henery-Logan in the total synthesis of penicilline in 1957. They also found that N-trityl penicilloates are cyclized with diisopropylcarbodiimides. Other p-lactames, such as cephalothin lactone and (—)-thienamicin are similarly constructed. The latter synthesis proceeds in a stereospecific manner and DCC is used in combination with triethylamine to give a 93 % yield of the /3-lactam 661. 

Hydroxyls have often been observed to participate in intramolecular cyclization reactions to form lactones from carboxylic acids, esters, and thioesters, especially if lactone is a five- or six-membered ring [21]. 

Phosphonoacetate cycHzation. Intramolecular cyclization of keto phosphonates can be used for construction of macrocyclic a, -unsaturated lactones. Stork s laboratory found that use of lithium isopropoxide or lithium hexamethyidisilazide in THF containing 1% HMPT minimized formation of cyclic dilactones. Use of sodium or potassium counterions was much less satisfactory. An example is shown in equation (I). 

A useful extension of the alkoxycarbonylation reaction has been devised in order to obtain 3,4-dihydro-4-hydroxy-l//-2-benzopyran-3-acetic acid lactones from 5-alkene-l,4-diols. The intramolecular cyclization of 7, carried out with palladium(II) acetate and copper(II) chloride under a carbon monoxide atmosphere, affords the m-lactone 8 in 68% yield. The configuration is assigned on the basis of H-NMR double resonance methods86. 

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