Lactones halolactonization

Hydrolysis of the amide, followed by reductive ozonolysis furnished 44 (99.5 0.5 mixture of 44a and 44b), which can be alkenylated to 45 via the aldehyde 44b. Halolactonization could be achieved to the frans-disubstituted lactone 46 via the iodonium ion 51 (Fig. 2), being preferred to 52 because of lesser allylic 1,3-strain [24]. Methylation of 46 gave rise to a 3 1 1 mixture of 47-49, which can be easily separated by chromatography. Deprotection followed by oxidation furnished (-)-roccellaric acid (1) [25], (-)-dihydropro-tolichesterinic acid (4) and the dimethylated acid 50 in pure form. 

If the alkylation products 3 contain appropriately placed double bonds, they can subsequently be subjected to halolactonization with high diastereoselectivity to furnish mixtures of chiral diastereomeric lactones, e.g., 4, along with the chiral auxiliary. 

Oxetanones can be generally prepared by displacement processes on various /3-substituted carboxylic acids or by halolactonization of /3,y-unsaturated acids. A very general and reliable method consists of treatment of a /8-hydroxy acid with benzenesulfonyl chloride and pyridine at 0°C (equation 91). The yields of /3-lactones are usually in excess of 80% (79JOC356, 74JOC1322). An alternative method involves cyclization of the benzenethiol ester of a /3-hydroxy carboxylic acid by means of mercury(II) methanesulfonate in acetonitrile (equation 92). The yields were excellent in the two cases reported (76JA7874). 

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). 

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-... 

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... 

As mentioned earlier in the discussion of cyclizations leading to (3-lactones, the (3-lactones formed from halolactonization of 1,4-dihydrobenzoic acids readily rearrange to produce bridged ring y-lac-tones.19 In some cases, the substitution pattern favors formation of the y-lactone even under conditions of kinetic control (equation 23).20 Synthesis of a variety of y-lactones by iodolactonization of dihydroben-zoic acid derivatives has been reported recently by Hart (equation 24).91 Attempted iodolactonization of the acid in the case where R = H resulted primarily in an oxidative decarboxylation however, iodolactonization was effected using the amide derivative. 

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). 

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... 

Iodolactonization of yfi-unsaturated amides. Halolactonization (I2 or NBS) of a-substituted "y,8-unsaturated amides in DME/H,0 at room temperature gives predominantly fra/w-2,4-disubstituted y-butyrolactones (equation I). This 1,3-stereoselectivity is in sharp contrast to the moderate 1,3-cw-selectivity observed with a-substituted y,8-unsaturated acids (8,257 9,248). Both diastereomers of a, 3-disubstituted y.S-unsaturated amides are converted into 2.4-rram-2,3,4-trisub tituted lactones (equation II). 

Moreover, a study on the halolactonization of y,i5-unsaturated acid 9 showed that bromolac-tonization gives a greater percentage of y-lactone than iodolactonization17. 

The electrophile-promoted cyclization in cyclic systems is a highly regio- and stereoselective reaction that can be carried out under various conditions and with a range of electrophiles. The bicyclic lactone products have the cfs-ring fusion, indicating that the electrophile approaches from the face of the molecule anti to the carboxyalkyl side chain. Such halolactonizations constitute a useful approach to bicyclic and polycyclic compounds. 

High cis selectivity has been observed in the halolactonization of 2-amino-5-substituted (Z)- and ( )-4-pentenoie acids. Treatment of (S)-(Z)-2-/m-butoxycarbonylamino-6-hydroxy-4-hexenoic acid [(S)-(Z)-8] with A -bromosuccinitrude in tetrahydrofuran at 0 °C for 5 minutes gives a 90 10 mixture of the cisjtrans-y-lactone 9 in 95% yield41. The major n.s-isomer can be purified by crystallization from chloroform/hexane. 

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. 

Low asymmetric induction is observed when (R)-3-benzyloxycarbonylamino-5-hexenoic acid (1, R = H) is iodolactonized under kinetic conditions (iodine/potassium iodide/sodium hydrogen carbonate). A mixture of the cis- and trww-iodo-5-lactones (60 40) in 94% yield is obtained. Better stereoselectivity can be obtained when the. V-benzyl derivative 1 (R = Bn) is cyclized under the same conditions. In fact, an 86 14 cisjtram) ratio is observed, showing that halolactonization is kinetically favored over halocarbamation, with the bulky substituent at nitrogen inducing high selectivity7. n n... 

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. 

Auxiliary cleavage with concomitant carbon-carbon bond formation is a particularly attractive option, which has been demonstrated in a bimolecular sense using the dianion of methyl sulfone (giving a methyl ketone), and in an intramolecular sense using a Claisen-type condensation of a p-acetoxy enolate (giving a 5-lactone). An interesting halolactonization procedure has... 

Lactones, cyclic esters such as compound A, are prepared by halolactonization, an addition reaction to an alkene. For... 

Cycloalkenes tethered with a y,5- or 5,8-unsaturated acid side chains react with Brj or I2 to furnish the corresponding halolactones. lodolactonization is more commonly used than bromolactonization since iodine is easier to handle (solid) and is more chemoselective (less reactive) than bromine. Halolactonization with aqueous base is kinetically controlled and proceeds via addition of a Br or B atom to the double bond to form a transient halonium ion. In the absence of strong directing steric effects, formation of the halonium ion may occur at either diastereoface of the double bond. However, only the halonium ion intermediate which allows trans-diaxial Sj. 2 opening by the neighboring carboxylate nucleophile leads, if the intramolecular reaction is sterically favorable, to the lactone. 

In the example shown above, halolactonization controls the relative stereochemistries of three contiguous stereocenters ( ) the two newly created stereocenters (C-0 and C-I) are trans to each other and the lactone is by necessity part of a cis-fused ring system. 

Reductive removal of the halogen atom with either Raney-Ni or with tributyltin hydride in the presence of AIBN (azobisisobutyronitrile) as a free-radical initiator furnishes the halide-free lactone. Halolactonization followed by base-induced anti- im-ination of H-I with DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) produces the unsaturated lactone. 

Halolactonizations have been used extensively for achieving high degrees of functionalization in a regio- and stereo-controlled manner. The conversion of (284) into (285 equation 101) is a key step in Corey s prostaglandin synthesis to prepare the central intermediate (286). For p,7-unsaturated acids like (287) the P-lactone (288) is formed under kinetic control, which then equilibrates to the 7-lactone isomer (2 9 equation 102). ... 

Asymmetric halolactonization is a much used procedure for the stereoselective formation of C — Br and C —I bonds (see also Sections D.4.6. and D.7.2.). This intramolecular reaction is used to transfer chiral information in the molecule over three or four bonds, sometimes with high stereoselectivity. Formation of a halonium complex with the olefin is the first step of the reaction followed by intramolecular lactonization. Induction of asymmetry is achieved in different ways. 

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