Enantioselective Lactonization of 3 , 3 , 6-Trimethyl-4 ( E )-heptenoic Acid Esters

Studies on the use of lactonization in the asymmetric synthesis of 6,6-dimethyl-4-isopropyl-3-oxabicyclo[3.1.0]hexan-2-one were described. An asymmetrically induced lactonization reaction was performed on 3,3,6-trimethyl-4(E)-heptenoic acid esters (1) and enantiomerically pure alcohols such as (−)-menthol (a), (+)-menthol (b), (−)-borneol (c), (+)-isomenthol (d), (−)-isopinocampheol (e), and (S)-(−)-1-(2-bornylphenyl)-1-ethanol (f ). *e enantiomerically pure alcohols that were used as ancillary chiral substances were characterized by markedly different values of induction power; menthol (a, b), borneol (c), and phenetyl alcohol (f ) performed better in asymmetric δ-lactonization, whereas isomenthol (d) and isopinocampheol (e) tended to favor asymmetric c-lactonization.

e structure of the resulting esters was confirmed by IR and 1 H NMR spectra.High values of the chemical shifts of carbinol protons, being in the range from δ � 4.62 ppm for 2a to δ � 6.13 ppm for 2f, are typical of esters of secondary alcohols, in which such proton is unshielded by the carboester group orbital π and, in the case of 2f, additionally, by the adjacent aromatic ring.Interestingly enough, despite the chirality of the carbinol proton in the ester molecule, anisotropy of the methyl groups located on C-3 on the side of the carboxylic acid residue was not observed, with the exception of one compound.e signals from such groups are usually six-proton singlets, except for 2f, where their signals in the form of two tri-proton singlets are chemically shifted from each other by 0.01 ppm.A more frequently observed phenomenon is diastereotopicity of the hydrogen atoms located on C-2 on the carboxyl side, caused by the chiral alcohol residue.Type AB signal of the protons in the form of two doublets is observed in all menthol esters (2a, 2b, δ � 2.18 and 2.23 ppm, J � 13.3 Hz) as well as 1-(2-bornylphenyl)-ethanol ester (2f, δ � 2.27 and 2.33 ppm, J � 13.4 Hz).Absolute optical rotation in chloroform was measured for each ester.
e main objective of the present work was to investigate the usefulness of halolactonization of enantiomerically pure alcohol esters 2a-f for enantioselective synthesis of lactones.N-halosuccinimides were used as the lactonizing substances.When used in the electrophilic cyclization of c, δ-unsaturated esters having a dimethyl substitute in the C-3 position, the compounds tend to give, as dominant products in a kinetic process, thermodynamically less stable c-haloδ-lactones 3, 5, 7, which are easily transformed into a bicyclic lactone 9 (Scheme 2).e product is a useful substrate in the synthesis of chrysanthemic acid.Moreover, NXS-type reactants are more convenient in laboratory conditions, enabling single-phase reactions to be performed.In order to provide a homogeneous reaction mixture, ester lactonization with NXS is carried out with the use of organic solvents that are miscible with water as one of the substrates.In this work, THF containing water in the ratio 20 : 1 was used as a solvent.A typical lactonization procedure consisted in preparing the solution of a suitable ester 2a-f in a THF/H 2 O mixture, cooling it down to a suitable temperature, and then adding dropwise the solution of a suitable N-halosuccinimide in THF or, in the case of low reactivity, N-chlorosuccinimide (NCS), gradually adding the solid.After the complete conversion of the ester 2a-f, a small amount of 10% HCl was added to the reaction mixture and the solution was heated at 40 °C until the complete decomposition of intermediate compounds.Any excess of haloimide was removed by means of sodium thiosulfate.Isomeric halolactones were purified by column chromatography over silica gel, performed twice.
Halolactonization is an electrophilic anti-addition to a C�C double bond; therefore, it is a highly stereoselective reaction.e halolactones 3-8 being formed in the process have, at all times, the trans-orientation of the substituents introduced and, for a fixed configuration of the C�C double bond, halolactones are formed in a diastereoselective manner.Obviously, when performed on non-chiral and enantiomerically impure (optically inactive) esters, the reaction provides racemic mixtures of the respective stereoisomers.As shown in Scheme 2, 1,3-eliminationcyclization of δ-lactones 3, 5, 7 yielding a bicyclic compound 9 is also a diastereoselective synthesis.In addition, the mutual orientation of the isopropyl substituents and the cyclopropane ring in the bicyclic lactone 9 being formed depend stereospecifically on the mutual orientation of the substituents X and R in the tetrahydropyranyl ring.If the C�C double bond in the ester has an E configuration, then the bicyclic product (9) of dehydrohalogenation of c-haloδ-lactones 3, 5, 7 acquires a trans-configuration.Possible mechanisms of halolactonization of analogous c, δ-unsaturated substrates were proposed by Denmark and Burk [51], which were carried out via irreversible cyclization and one in which the nucleophile is deprotonated after cyclization.
e resulting esters of 3,3,6-trimethyl-4(E)-heptenoic acid and enantiomerically pure alcohols 2a-f were subjected initially to bromolactonization under the effect of N-bromosuccinimide.In order to establish optimum reaction conditions providing high product yields in addition to high enantioselectivity, lactonization was carried out at different temperatures.e reactions for (−)-menthol ester (2a) were carried out at +20 °C, 0 °C, −20 °C, and −40 °C.It was observed that enantioselectivity for the formation of c-bromo-δ-lactone 3 was low at +20 °C, while at −40 °C the reaction rate was low and the product yield was reduced.Moreover, the ratio between lactones δ (3) and c (4) in the postreaction mixture was observed to decrease with temperature.
erefore, other bromolactonization reactions were investigated at temperatures 0 °C and −20 °C.Any enantiomeric excess of the resulting lactones was determined by chiral gas chromatography with a capillary column, 2 Journal of Chemistry packed with enantiomerically pure c-cyclodextrin.When determining the enantiomeric composition of the resulting compounds, it was observed that δ-halo-c-lactones 4, 6, 8 were divided satisfactorily into enantiomeric fractions at retention times up to 30 minutes.Unfortunately, isomeric c-halo-δ-lactones 3, 5, 7, the typical principal products of the reaction, were not divided chromatographically into enantiomers, even at retention times of more than 60 minutes.erefore, the resulting c-halo-δ-lactones 3, 5, 7 were subjected to dehydrohalogenation with the use of DBU which, via 1,3-elimination, underwent cyclization to form bicyclic lactone 9, which was further effectively divided into enantiomers under the effect of c-cyclodextrin.In the analysis of the enantiomers of the bicyclic lactone 9, the retention times recorded were 22.50′ and 24.24′, which means the difference between them is more than 1.7′.e configuration of chiral centers in the obtained stereoisomers of c-halo-δ-lactones 3, 5, 7 was determined indirectly, taking advantage of the fact that the product of their 1,3-elimination-cyclization 9 is a known compound, obtained in the form of enantiomers, and having an established stereochemical structure.e configurations of the obtained stereoisomers were correlated by measuring the sign of optical rotation and comparison with literature data [28].Knowing that 1,3-dehydrohalogenation-cyclization is a diastereoselective process, the stereochemical structure of the eliminated, enantiomerically pure halolactones 3, 5, 7 was established from the configuration of chiral centers of the resulting bicyclic lactone 9, according to the mechanism presented in Scheme 2. e enantiomeric composition of the resulting δ-halo-c-lactones 4, 6, 8 was expressed as the ratio between the enantiomers, stated in the increasing order of retention times, recorded in the course of the analysis on chiral GC.
In all the electrophilic cyclizations of esters conducted by the present authors, the resulting c-bromo-δ-lactone 3 e highest enantioselectivity during δ-lactonization was observed in the case of menthol ester 2a (enantiomeric excess (ee) 36%) and borneol 2c ester (24% ee).For benzyl alcohol ester 2f and isomenthol 2d, enantiomeric excess was 13%ee and 11%ee, respectively.Isopinocampheol (e) proved to be inductively inactive.e highest ratios between the enantiomers of bromolactone 4 obtained in asymmetric c-lactonization reactions were recorded for the isomenthol 2d (21%ee) and the lowest for the benzyl alcohol 2f (2%ee).Reduction of the temperature of the reaction mixture tended to lead to increased enantioselectivity of e only exception was the synthesis of δ-bromo-c-lactone 4 from menthol ester 2a and 2b, during which the relationship was inversed: the value of ee increased with temperature from 0%ee at −40 °C to 14%ee at +20 °C.As mentioned before, reduction of temperature to less than −20 °C resulted in much longer duration of the process and markedly lower reaction yields.
e recorded value of enantioselectivity of bromolactonization of (+)-menthol ester 2b (37%ee), although somewhat higher than that for (−)-menthol (a), was within the limits of measurement error for the GC apparatus and may be attributable to the higher optical purity of (+)-menthol (b) used in the reaction.
e promising results of asymmetric bromolactonization have encouraged the present authors to investigate chiral esters in iodo-and chlorolactonization reactions with the use of N-iodo-and N-chlorosuccinimide (NIS and NCS).
e reactions were carried out in a similar manner as the bromolactonization before.In comparison with NBS, both reactions proceeded at a lower rate; therefore, chlorolactonization was affected at a room temperature.Menthol esters 2a and borneol esters 2c, both showing the highest abilities to symmetrize δ-lactonization, were tested in the reactions.Moreover, in the reaction with NIS, the authors tested isomenthol ester 2d, which was characterized by the strongest asymmetric induction in the course of c-lactonization.e highest enantiomeric excess of product (30%ee) was observed for c-iodo-δ-lactone 5, obtained, as before, from menthol ester, at a temperature of −40 °C.e highest enantioselectivity of δ-iodo-c-lactonization (18%ee) was also recorded for menthol ester 2a.Whereas, for δ-lactones, a decrease in temperature leads to an increase in the values of enantiomeric excess, and in the case of δ-iodo-c-lactone 6, a decrease in temperature leads to a decrease in the process enantioselectivity in every iodolactonization test.It is worth noting that iodolactonization under the effect of NIS is definitely more regioselective, compared with bromolactonization under the effect of NBS and the content of c-iodoδ-lactone in the lactone mixture was typically higher than 80%, and the highest (85%) for borneol ester 2c.As in bromolactonization, a decrease in the temperature of iodolactonization resulted in lower regioselectivity of the synthesis of c-iodo-δ-lactone 5 and for menthol ester 2a, its percentage dropped from 83% at 0 °C to 75% at −40 °C.Chlorolactonization reactions were characterized by very low enantioselectivity for the formation of c-chloro-δ-lactone 7 (8%ee for menthol ester 2a) or its lack for δ-chloroc-lactone 8 (er.50 : 50).Moreover, the authors observed a considerable decrease in regioselectivity and, in the case of menthol ester 2a, δ-chloro-c-lactone 8 was simply the principal product (57%).
e optical rotations determined for the products were as follows:

Experimental
Chemicals were purchased from Fluka and Sigma-Aldrich (Poznań, Poland).e progress of reactions and purity of compounds synthesized were checked by TLC on silica gelcoated aluminum or plastic plates using a solvent system hexane : ethyl acetate in various ratios.e same eluents and methylene chloride were used in the course of preparative column chromatography on silica gel (Kieselgel 60, 230-400 mesh).GC analyses were performed on a Varian CP3380 instrument, using capillary columns: HP-5 (cross-linked 5% phenyl methyl siloxane), 30 m × 0.53 mm × 0.88 μm and HP-1 (cross-linked methyl siloxane), 25 m × 0.32 mm × 0.52 μm or on a Hewlett Packard HP5890 Series II instrument using a CP-cyclodextrin, 25 m × 0.25 mm × 0.25 μm chiral column. 1 H NMR spectra were recorded on a Bruker Avance DRX 300 MHz spectrometer for CDCl 3 solutions, with tetramethylsilane (TMS) as an internal standard.e IR spectra were taken for liquid films or KBr pellets on a FTIR ermo-Mattson IR spectrometer.Melting points (uncorrected) were measured on a Boetius apparatus.

Synthesis of Esters of Enantiomerically Pure Alcohols:
General Procedure.To a solution of 0.004 mole of carboxylic acid 1 in 10 ml of dry benzene, 0.58 ml (0.952 g, 0.008 mol) of thionyl chloride was added, and the mixture was heated under a reflux condenser in the absence of moisture for 2 hours.e postreaction solution was sent to a rotary evaporator to evaporate the benzene and any excess of thionyl chloride.After the complete evaporation of the solvent and thionyl chloride, the residue was dissolved in 20 ml of anhydrous diethyl ether and the resulting solution was added dropwise to the solution of 0.004 mole of enantiomerically pure alcohol in 20 ml of diethyl ether with addition of 1.68 ml (1.22 g; 0.012 mol) of triethylamine and catalytic amounts of DMAP (0.1 g, 4-N,N-dimethylaminopyridine), after cooling the solution to 0 °C.Stirring was continued at a room temperature for 12 hours, and the progress of the reaction was controlled by means of TLC.

Halolactonization: General
Procedure.An enantiomerically pure alcohol ester (0.002 mole) and 0.5 ml of water were dissolved in 10 ml of THF. e solution was cooled down to a suitable temperature and doses of 0.003 mole of N-bromosuccinimide or N-iodosuccinimide solution in 5 ml of THF or 0.003 mole of N-chlorosuccinimide in solid state were added.