Halolactonization reaction

Terashima et al. 231) reported an asymmetric halolactonization reaction. This highly stereoselective reaction permits the synthesis of intermediates for the preparation of chiral a,a-disubstituted a-hydroxycarboxylic acids (227)231c), a-hydroxyketones (228) 231c), functionalized epoxides (229) 231d,e) and natural products 231h,j). Only amino acids have so far been used as a source of the chiral information in the asymmetric halolactonization reaction. Again, the best results have been obtained by using cyclic imino acid enantiomers, namely proline. 

In the total synthesis of an anthracycline antibiotic, the key step was an asymmetric halolactonization reaction. The corresponding bromolactones were formed with high stereoselectivity (d.s. > 90%). (S)-Proline was used as chiral auxiliary. 

Formation of 3-lactones by 4-endo cyclization has been observed in very few cases. Examples of such halolactonization reactions proceeding by stereospecific anti addition have been discussed in previous reviews. P 2b... 

The asymmetric halolactonization reactions of unsaturated L-proline amides, developed by Terashima and coworkers,184 has been extended to a-alkyl acrylic acid derivatives (equation 75 and Table 21).185 This allows for the synthesis of either enantiomer of an a-methyl-a-hydroxy acid using L-proline as the auxiliary. Less successful approaches to asymmetric induction with a chiral auxiliary include iodolac-... 

Saponification of the ester provided 39 as a cyclohexylamine salt. The functionalization at C4 and C5 to install the necessary vicinal aminoalcohol begins with a selective halolactonization reaction of 39 to give lactone 40, bearing the incorrect alcohol stereochemistry at C4, and a rather challenging stereochemistry at C5, which would require the amino group be installed with retention at the C5-Br bond. Both issues are remedied by treatment of 40 with lithium hydroxide to generate an intermediate epoxide with inversion at C5, which, upon acidification, opens with inversion at C4 to give the y-lactone 41.37... 

The effect of a 2-nitrogen substituent on the halolactonization reaction of 4-pentenoic acid derivatives has been examined40. A relatively high 1,3-cm selectivity is observed, in contrast to the selectivities observed with a nonpolar substituent (e.g., R = CH3, C6H5). 

The halolactonization reaction is a useful tool for synthesizing (5-lactones starting from easily accessible 5-unsaturated acids. The reaction can be carried out under kinetic or thermodynamic control. Under the latter conditions, good 1.2- and 1,3-asymmetric induction has been obtained. In fact, a predominant 1,2-trans and 1,3-m relationship of the substituents is observed in the formation of six-membered rings, owing to the preferential chairlike conformation assumed in the transition state, with the substituents in the equatorial position. 

The halolactonization reaction can be utilized to synthesize enantiomerically pure ot-hydroxy acids. In fact, cyclization of the (S)-/V-(a,/ii-unsaturated acyl)proline 1, prepared by the condensation of ( S )-pi oline and ( )-2-methyl-2-butenoyl chloride in 86 % yield, proceeds stereoselec-tively. The halolactonization, carried out by stirring the unsaturated amide with an equivalent of jY-bromosuccinimide in dimethylformamide for 20 hours, provides the bromolactone 2 in 84% yield and a diastereomeric ratio of 94.5 5.5. Debromination with tributyltin hydride in benzene affords the crude lactone 3 which is hydrolyzed with 36% hydrochloric acid at reflux to give (R)-2-hydroxy-2-methylbutanoic acid (4)1,2,4b. 

By analogy to the halolactonization reaction, the synthesis of cyclic iodocarbonates has been studied with the aim of functionalizing a double bond under regio- and stereocontrol, starting from allylic or homoallylic alcohols. These heterocyclic intermediates are employed for the synthesis of epoxy alcohols, diols and triols. 

The first asymmetric halolactonization reactions were performed with a,(3-unsaturated amides of (5>pioline 1.64 (R = COOH) [261], Reactions of amides with NBS g)ve functionalized bromolactones 7.127. After Bu3SnH treatment and hydrolysis, chiral a-hydroxyacids are obtained with a high enantiomeric excess. The methyl substituent on the a-position of the double bond is reqinred for high selectivity (Figure 7.80). 

Bicyclo[2.2.1]hept-5-ene-2-e rfo-carboxylic acid is especially well suited to the iodolactonization reaction, which has been used for the determination of the optical purity of stereoselective steps leading to the bicyclic system166. This application demonstrates the confidence in the stereoselectivity of the halolactonization reaction. 

The vinylgold intermediate 3 (Scheme 4.1) then typically reacts with an electrophile (E) in most of the literature this is a proton. Only a few cases of the use of halogen electrophiles have been reported [25]. This use of halogen electrophiles is problematic because, similar to halolactonization reactions, the electrophilic halide can possibly induce the cyclization without the gold. 

Intramolecular cyclization of unsaturated carboxylic acid derivatives using strong electrophiles is one of the most effective and common approaches to y-lactones. Not to mention, reactions of the unsaturated carboxylic acids with halonium sources such as X2 and NXS, the so-called halolactonization, produce the synthetically useful halolactones [4], N-Halosuccinimide (NXS) reaction is also commonly utilized for the construction of y-lactone structures. These days, development of effective catalysts, especially for enantioselective cyclization of unsaturated carboxylic acids including halolactonization reaction, is a hot topic in synthetic organic chemistry. 

Although the field of organocatalysis has flourished over the past decade, there are still some areas that remain virtually untouched, such as the asymmetric a-halogenation of olefins. Several enanhoselective halolactonization reactions of exocyclic carboxylic acids have been reported since 2010 [41]. Borhan and coworkers reported the first highly enanhoselective chlorolactonization of alkenoic acids... 

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

There is also a category of intramolecular reactions/transforms which involves total mechanistic stereocontrol with conformationally restricted structures, for example the halolactonization transform 149 150 and the internal cycloaddition 151 152. These... 

Examples of halolactonization and related halocyclizations can be found in Scheme 4.4. The first entry, which involves NBS as the electrophile, demonstrates the anti stereospecificity of the reaction, as well as the preference for five-membered rings. 

The same models as for intermolccular processes are applied for intramolecular diastereoface differentiating double-bond additions. However, there are some advantages in the intramolecular version. Firstly, the entropy factor lowers the barrier of activation and allows reactions to proceed at lower temperatures, which increases the selectivity. Secondly, the cyclic transition states introduce the elements of ring strain and transannular interactions, which lead to enhanced differences between two diastereomorphous geometries. Both of these factors cooperate to increase the selectivity of the intramolecular reaction. For example, halolactonization, by definition, is an intramolecular process. 

Enol lactones with a halogen at the vinylic position have been synthesized as potential mechanism-based inactivators of serine hydrolyases <81JA5459). 5-Hexynoic acids (181) can be cyclized with mercury(II) ion catalysis to y-methylenebutyrolactones (182) (Scheme 41). Cyclization of the 6-bromo and 6-chloro analogues leads stereospecifically to the (Z)-haloenol lactones (trans addition) but is quite slow. Cyclization of unsubstituted or 6-methyl or 6-trimethylsilyl substituted 5-hexynoic acids is more rapid but alkene isomerization occurs during the reaction. Direct halolactonization of the 5-hexynoic acids with bromine or iodine in a two-phase system with phase transfer catalysis was successful in the preparation of various 5-halomethylene- or 5-haloethylidene-2-phenylbutyrolactones and 6-bromo-and iodo-methylenevalerolactones (Scheme 42). 

Several recent reviews have included specific types of electrophilic cyclofunctionalization reactions.1 Important areas covered in these reviews are halolactonization u cyclofunctionalization of unsaturated hydroxy compounds to form tetrahydrofurans and tetrahydropyrans lb cyclofunctionalization of unsaturated amino compounds lc cyclofunctionalization of unsaturated sulfur and phosphorus compounds ld lf electrophilic heterocyclization of unconjugated dienes 1 synthesis of y-butyrolactones 1 h synthesis of functionalized dihydro- and tetrahydro-furans lj cyclofunctionalization using selenium reagents lk lm stereocontrol in synthesis of acyclic systems 1" stereoselectivity in cyclofunctionalizations lP and cyclofunctionalizations in the synthesis of a-methylenelactones.lq Previous reference works have also addressed this topic.2... 

Cyclizations of (3,7-un saturated acids form -lactones (4-exo cyclization) when the reactions are conducted under conditions of kinetic control.1 - The most common procedure for (3-lactone formation, developed by Barnett, involves halolactonization in a two-phase system using an aqueous solution of the carboxylate salt of the substrate with the halogen (Br2 or I2) added in an organic solvent.18 Cyclization with bis(, ym-collidine)iodine(I) perchlorate provides a higher yield than the Barnett procedure in cases where cyclization is not favored by geminal a-substitution (Table 2, entries 1 and 2).14 Iodo- and bromo-... 

The conversion of an alkene to a halohydrin can also be considered as an epoxidation because this can be achieved by a simple ring closure.184 Although no reagent is yet available to perform an asymmetric conversion of an isolated alkene to a halohydrin, the reaction can be controlled through diastereoselection. One such case is the halolactonization of y,8-unsaturated carboxylic acids, N,N-dialkylamides.185189... 

Instead of H20, COOH or OH groups of the substrate located at a suitable distance can also open the halonium ion intermediate through a nucleophilic backside reaction. In this way, cyclic halohydrin derivatives are produced (Figure 3.47). They are referred to as halolactones or haloethers. 

Similar addition mechanisms explain the so-called halolactonization and the related haloetherification (Figure 3.47). With the help of these reactions one can produce halogenated five- and six-membered ring lactones or ethers stereoselectively. Dehalogenation afterward is possible (Figure 1.38). 

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