Lactone intermediate

The enzyme-mediated Baeyer-Villiger oxidation to chiral lactone intermediates has received considerable attention in recent years as it offers several advantages in chemo-, regio-, and stereoselectivity compared to other catalytic strategies... 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

A recent synthesis of P-D lactone (Scheme 13.51) used an enantioselective catalytic approach. A conjugate addition of a silyl ketene acetal derived from an unsaturated ester gave an unsaturated lactone intermediate. The catalyst is CuF-(S )-tol-BINAP.30 The catalytic cycle for the reaction is shown below. 

Another enantioselective synthesis, shown in Scheme 13.17, is based on enantiose-lective reduction of bicyclo[2.2.2]octane-2,6-dione by baker s yeast.129 The enantiomeri-cally pure intermediate is then converted to the lactone intermediate by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group is then introduced stereoselec-tively from the exo face of the bicyclic lactone in step C-l. A final crucial step in this synthesis is a [2,3] sigmatropic rearrangement to complete sequence D. 

Sugar-derived a,(3-unsaturated lactones are relevant motifs considering their ability to act as functionalized substrates for a variety of transformations. Some of them are bioactive [218-222]. An early synthesis of the enantiomer of (+)-altholactone, a natural product with cytotoxic and antitumor activities (for a review on the bioactivity of styryUactones see [223, 224]), involves the preparation of a furanose-fused a,p-unsaturated 8-lactone intermediate 189 [225]. Starting from a a-D-xy/o-pentodialdofuranose derivative 187, aReformatsky reaction with ethyl bromoacetate introduces the carboxyhc side chain necessary for intramolecular lactonization (Scheme 46). 

Lactone intermediates, 94,127, 228 Lateral overlap, orbitals, 9 Lead alkyls, 301 anti-knock, 305 thermolysis, 301, 304, 324 Leaving groups, 98, 99, 127,139, 237 ability of, 98, 251... 

The lactone intermediate is prepared in another industrial process by cyclization of homofarnesic acid in the presence of SnCU as a catalyst [184]. Pure diastereomers are obtained by acid cyclization of trans- and cw-4-methyl-6-(2,6,6-trimethyl-cyclohex-l(2)enyl)-3-hexen-l-ol, prepared from 2-methyl-4-(2,6,6-trimethylcyclo-hex-l(2)-enyl)-2-butenal [185]. 

DeCamp et al.t19l synthesized the lactone intermediate of the 1-hydroxyethylene isostere with high yields and stereoselectivity. As summarized in Scheme 10 (Section 10.6.2), the titanium homoenolate is prepared from ethyl 3-iodopropionate. The iodide is metalated with zinc/copper couple to give the iodozinc homoenolate species. The alkyltitanium homoenolate is then generated by transmetalation of the iodozinc precursor with one of the several chlorotitanium isopropoxide species. The resulting titanium homoenolate reacts with a N-protected a-amino aldehyde, leading to a mixture of 45-diastereomers. In the last step, the product is lactonized. 

Most stereoselective alkylations to the lactone intermediates are accomplished using the method reported by Kleinman and co-workers.1201 The dianion form is prepared by treating the lactone with lithium or sodium hexamethyldisilanazide. Then, the reaction between the dianion and an alkyl halide produces the 2-alkylated lactone (Scheme 11, Section 10.6.2). Kleinman and co-workers reported that the ratio of the trans- and ds-lactone is 47 3. When a doubly protected a-amino aldehyde [e.g., dibenzylamino aldehyde, (/ert-butoxycarbonyl)-benzylamino aldehyde] is used, the c/.v-lactone is not obtained. As an example, the alkylation of (55,1 5)-5-[l -[/V-(/< rt-butoxycarbonyl)benzylamino]-2 -phenylethyl]dihydrofuran-2(3/7)-one to produce (3/ ,55,l 5)-3-benzyl-5-[1 -[/V-(/ert-butoxycarbonyl)benzylamino]-2 -phenyl-ethyl]dihydrofuran-2(3//)-one is described in this section. 

Ab initio calculations have been carried out on the decomposition of mandelic acid (70) at the MP2/6-31G level.62 Three competitive pathways have been characterized. Two are stepwise processes with die formation of an a-lactone intermediate and ring... 

The text-book Walden-style cycle which interconverts the stereochemical configurations of chlorosuccinate (3) and malate (5) involves a /3-lactone intermediate (2) in preference to an a-lactone intermediate (4) (Scheme 2) because the OnUc-C-Cl angle in the transition structure for the former (174°) is more favourable than that for the latter (139°), as determined by PCM(e = 78.4)/B3LYP/6-31+G calculations the smaller ring-strain energy of the /3-lactone contributes little to the reactivity difference.2 (V,A-Dimethylethanolamine esterified hexanoic acid about 10-fold faster than did hexanol as a consequence of intermolecular hydrogen bonding a seven-membered transition state (6) was proposed.3... 

Behr A, Henze G (2011) Use of carbon dioxide in chemical syntheses via a lactone intermediate. Green Chem 13 25-39... 

There have been extensive studies on the reaction of dioxetanes and dioxetanones with nucleophiles (C, N, P, and S) and the reader is directed to CHEC-II(1996) for an exhaustive list up to 1996. The most common reactions of dioxetanes have been with phosphorus nucleophiles. The phosphines and phosphites first insert into the 0-0 bond. The phosphorane intermediate then collapses to afford phosphine oxide or the trialkylphosphate and the corresponding epoxide (Scheme 6). The same is true for the treatment of a-peroxy lactones with phosphines and phosphites except that the so-formed a-lactone intermediate undergoes decarboxylation and ultimately furnishes a ketone <1997JOC1623>. 

The a,a-difluoro Reformatsky reagent has been applied extensively to the preparation of compounds containing the -CF2C(0)- group and its derivatives,2 since this functionality often confers enhanced biological activity. Typical examples include the preparation of selectively fluorinated thromboxane A2 analogues24 and the preparation of a difluoro-y-lactone intermediate which was subsequently converted to l-(2-deoxy-2,2-difluororibofuranosyl) pyrimidine nucleosides (Equation 4.10).25... 

The reaction of CH2 with C02 was first postulated by Kistiakowsky and Sauer (13) as taking place via an a-lactone intermediate. The occurrence of this reaction was subsequently demonstrated by Milligan and Jacox (14) in low temperature matrices. These low temperature matrix isolation experiments, however, could not determine definitely the structure of the CH2 C02 intermediate. The result of our laser absorption experiment shows that the CO is vibrationally excited up to v — 4 with a distribution close to the one predicted by a statistical model assuming the existence of a long-lived CH2 C02 complex. This calculation, however, is insensitive to the structure of the complex assumed. Since the ground state triplet CH2 is known to be less reactive and kinetically behaves like CHj (15,16), which does not react readily with C02, the singlet A CH2 is assumed to be involved in the reaction. 

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