Lactonization, kinetic control

The 1,3-dipolar cycloadditions of nitrones (551), (595), (614), (615) and their enantiomers (595 ent), (614 ent), (615 ent) (Fig. 2.40) to a.p-unsaturated y-lactones, such as achiral D7 g and D-glycero D7 h, provide an interesting example of double asymmetric inductions. The reactions are kinetically controlled. However, on heating and at longer reaction times, the reversibility of the cycloaddition (595 + D7 h) was observed, and the presence of a more stable thermodynamic product (620) was detected. Moreover, in the case of lactone D7 h, a... 

A toluene solution of the benzocyclobutene (327) was thermolyzed by heating in a sealed-tube at 180-200 °C for 48 hours to yield the lactone (328), via an intriguing epimerization pathway113), in which the initially formed kinetically controlled trans product was isomerized to the charged intermediate and then recyclized to furnish the thermodynamic m-isomer (328) u3). 

The conformational kinetic control of the chiral centres present in a molecule may be exemplified by the rran -diaxial opening of an epoxide i rf a polycyclic system [7]. In this case, the less stable conformation is also "frozen" by forming an auxiliary lactone bridge, which reverses temporarily the conformations of the rings and the substituents. 

The opening of the epoxide in the cij-decalin 24 by acetic acid leads exclusively to the hydroxyacetate 25 (through a kinetically controlled rrani-diaxial opening) rather than to the wanted diastereomer 26 (c/ the stereochemistry of the "southern" part of reserpine). To obtain the correct diastereomer the epoxy-lactone 22 is first formed (Scheme 8.6). Thus the conformation of the cij-decalin system, and therefore that of the substituents, is reversed. The kinetic tran -diaxial opening of the epoxide occurs in a regio- and stereoselective manner to afford compound 28 in which the substituents have the correct position and configuration (a-OH, P-OAc),... 

Successive addition of monomers to the end of macromolecular initiator is the usual technique for the synthesis of tailored blockcopolymers. Anionic polymerization of pivalolactone, a-pyrrolidone— and the NCA of T-methyl-D-glutamate -2 was started from the end group of a prepolymer consisting carboxylate group or acyl lactam group or amino group. Living polymer of C-capro-lactone was expected to be formed by the initiated polymerization from polymer carbanion under kinetic controlled condition. 

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-... 

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. 

Examples of 1,3-asymmetric induction in cyclizations to 8-lactones have been observed. Iodolactonization of 3-methyl-5-hexenoic acid to a 8-lactone under equilibrating conditions showed reasonable stereoselectivity (6 1 cis trans).l20b Recent studies have examined the formation of 8-lactones from cyclization of 5-hexenoic acids with a homoallylic oxygen substituent at C-3.135 Selenolactonization of 3-hydroxy-5-hexenoic acid under conditions of kinetic control provided the trans lactone in modest yield (40%) and high stereoselectivity.13515 Equilibrating conditions led to a slight preponderance of the cis... 

An interesting experimental result was observed in the study of the mild acid hydrolysis of the cis and the trans bicyclic orthoesters 87 and 88 (60). The cis orthoester 87 gave under kinetically controlled conditions the dihydroxy methyl ester 89 whereas the trans orthoester 88 produced directly the hydroxy-lactone 90 under the same experimental conditions. These results can be explained on the basis of the principle of stereoelectronic control. 

Barnett and Sohn (12, 13, see also 14) have discovered that the iodolactoni-zation of b,r-unsaturated carboxylic acid salts 37 yield, under kinetically controlled conditions, the Y-iodo-B-lactones 39 in preference to the more stable B-iodo-Y-lactones l. Similar results were obtained in the course of the bromolactonization reaction. Thus, here again, the formation of a four-membered ring is more facile than that of a five-membered ring. This can be rationalized on the basis of Stork s analysis, i.e. the internal opening by the carboxylate anion of the three-membered ring iodonium ion (or bromonium) 38 39 is preferred over the other mode of opening 40 41 for stereoelectronic reason. 

The rate constants for oxidation of a series of cycloalkenes with ozone have been determined using a relative rate method. The effect of methyl substitution on the oxidation of cycloalkenes and formation of secondary organic aerosols has been analysed.155 Butadiene, styrene, cyclohexene, allyl acetate, methyl methacrylate, and allyl alcohol were epoxidized in a gas-phase reaction with ozone in the absence of a catalyst. With the exception of allyl alcohol, the yield of the corresponding epoxide ranged from 88 to 97%.156 Kinetic control of distereoselection in ozonolytic lactonization has been (g) reported in the reaction of prochiral alkenes.157... 

Many works on the synthesis of cyclic polymers and block copolymers using kinetically controlled ring-expansion polymerizations of cyclic monomers, such as lactones and lactides with various types of cyclic tin initiators, were reviewed by Kricheldorf [147,148]. Kricheldorfs group continued the synthesis of cyclic polymers, and their recent works have focused on the following. Polycondensations of 4,4/-difluorodiphenylsulfone with tris(4-hydroxy phenyl)ethane were performed in DMSO to give multi-cyclic poly(ether sulfone)s derived from tris(4-hydroxyphenyl)ethane [149]. 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

When 2,2-dimethy]-3-butenoic acid (1, R = CH,) is treated under the standard iodolactonization conditions, the corresponding /1-lactone 2 (R = C H3) is immediately formed. This compound is converted in 24 hours into the thermodynamically more stable y-lactone 3 (R = CH3)3. When a short reaction time is employed, in the absence of potassium iodide, the iodo-/ -lactone 2 is obtained, showing that the formation of a four-membered ring (rlmo 1827 cm-1) rather than a five-membered ring (vmax 1780 cm-1) is favored under kinetic control. 

Methyl-5-hexenoic acid (1) cyclized under conditions of kinetic control (iodine in acetonitrile in the presence of sodium hydrogen carbonate) shows the preferential formation of the less stable c /.s-lactone (d.r. 70 30). The cis or trans configuration of the product lactones is assigned on the basis of 13C chemical shifts. 

Low 1,4-asymmetric induction1 is reported for the iodolactonization of 2-methyl-5-hexenoic acid (1) which gives a 64 36 (trans/cis) mixture of the corresponding lactones in 78% yield under kinetic control, On the other hand, when the reaction is carried out under thermodynamic conditions, the diastereomeric ratio is 52 48. 

Diastereoselective protonation under kinetic control is a useful strategy for allowing access to particular diastereoisomeric carbonyl derivatives. For example, deprotonation of y-lactone 116 with excess LiHMDS in THF at —78°C, and quenching the resulting lithium enolate with saturated aqueous solution of sodium sulfate, gave the diastereoiso-mericaUy pure y-lactone 116 (equation 27). The diastereoselective protonation of the intermediate hthium enolate with H2O must occur on its less hindered face, controlled by the y-benzyloxymethyl substituent of the y-lactone residue to give the required 116. ... 

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. 

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). ... 

The reactions of ozone with simple tetrahydropyranyl ethers and conforma-tionally rigid p-glycosides were indeed discovered to give the corresponding hydroxy Z-esters exclusively under kinetically controlled conditions lactone formation was not observed [8-10]. For instance, p-D-glucopyranoside 131 reacted under acetylating conditions to form 132 exclusively, Eq. 33. The reactions of the tetrahydrofuranyl ethers 133, Eq. 34, and 135, Eq. 36, were similar to that of 131 only the esters 134 and 136 were obtained, respectively. 

A similar sequence of reactions was done on L-gulono-1,4-lactone to give 99. Azide displacement of the 2-(9-triflate in 99 under kinetic controlled conditions gave the ido-azide 100, which was treated with fcrr-butyldimethylsilyl tritlate to give the fully protected azido lactone 101 (Scheme 18)." Sequential treatment of 101 with aqueous acetic acid, rerr-butyldimethylsilyl chloride and triflic anhydride in pyridine afforded the C-5 tritlate... 

An example of a condensation reaction with diastereotopic group selectivity (see appendix) is the lactonization of either of the two racemic, C2-symmetrical 5-hydroxy-2,4,6,8-tetramethylnonanedioic acids. This reaction desymmetrizes a compound with two pairs of equivalent stereocenters (C-5 is achiral ) into a product with five different stereocenters. The trilithium salt is generated by reduction of the 2,4,6,8-tetramethyl-5-oxononanedioic acid with lithium in ammonia and then either acidified to pH 3 followed by rapid extraction of the lactones formed (kinetic control) or equilibrated at pH w 1 to the lactone mixture (thermodynamic control). Depending on the steric interactions in the chair-like transition states and in the half-chair lactone products, either kinetic or thermodynamic control leads with high diastereoselectivity to the lactone with trans-configuration at C-5 and C-6 of the tetra-hydro-2/f-pyran-2-one ring (T. R. Hoye, 1984). 

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