Decarboxylative lactone formation

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

Since we have already made compounds like 2 in chapter 25 from P-keto-esters, it makes sense to use the same strategy here. Addition of ethylene oxide 3 to the enolate of 5 gives the lactone 6 directly and treatment with HBr accomplishes decarboxylation and formation of the bromide 7 in one pot.1 Vogel2 uses the chloroketone to make 1 R=H in 82% yield by this method with NaOH for the base. 

MSAS from P. patulum was separated from the FAS via sucrose gradient centrifugation [121,122] and thus shown to constitute a distinct multifunctional enzymatic system. It was purified to homogeneity and found to be a 190 kDa multifunctional enzyme [22,120]. The enzyme was more stable in the presence of its substrates and at mildly basic pH values. The pH optimum of the enzyme was 7.6 and apparent K values for its substrates were 10 pM (acetyl-CoA), 7 pM (malonyl CoA), and 12 pM (NADPH) [115,120,123]. The rate for triacetate lactone formation in the absence of NADPH was determined to be ten-fold lower than for 6-MSA formation (Fig. 5) [120]. Analogous to FASs and peptide synthetases, 4 -phosphopantetheine is a covalently bound cofactor of 6-MSAS [124]. Likewise, iodoacetamide and N-ethylmaleimide were found to inactivate the enzyme, suggesting the presence of catalytic sulfhydryl residues in 6-MSAS [124]. Furthermore, in the presence of malonyl CoA and NADPH, low concentrations of iodoacetamide convert 6-MSAS into a malonyl CoA decarboxylase. Without external addition of acetyl-CoA, 6-MSAS decarboxylates the malonyl group and the derived acetyl moiety is used as a starter unit for the formation of 6-MSA [125]. 

One alternative approach to lactone synthesis with CO in the absence of C—X and C—M bonds involves the decarboxylation of cyclic carbonates where lactone formation occurs with concomitant loss of CO2 (Scheme 2.22) [48-50]. Since CO2 is the sole byproduct, this process is considerably more green than carbonylation of C—X and C—M bonds. 

Nair and coworkers showed in 2006 that Michael acceptors (112) can also act as electrophiles for achiral imidazolium-derived homoenolates, although the expected cyclopentanone products were not obtained [96]. Instead, dx-substituted cyclopentenes 114 resulting from a proton transfer, aldol, P-lactone formation, and decarboxylation sequence were isolated (Scheme 18.20). 

Mukaiyama s conditions have also been used in other aerobic oxidation reactions of substrates including thiols (Table 5.2, entries 1—4, 10 and 11), alkanes (entries 8, 12 and 14) and alcohols (entries 9 and 13), as well as reactions involving lactone formation via a Baeyer-ViUiger oxidation (entries 5-7) and oxidative decarboxylation (entry 16) [15-17]. While nickel, iron and cobalt aU selectively oxidize thiols to sulfoxides, Co(II) is the most active (entries 1—4) [15 b]. Of particular synthetic interest, the chemoselective and diastereoselective aerobic oxidation of the complex sulfide, exomethylenecepham (entries 10 and 11), was observed with no overoxidation to the suUbne or oxidation of the olefin [16 a]. The diverse substrate scope in entries 1-9 suggest iron and nickel species tend to have similar reactivity with substrates, but cobalt behaves differently. For example, both iron and nickel displayed similar reactivity in Baeyer-Villiger oxidations, with cobalt being much less active (entries 5-7), yet the opposite trend was observed for sulfide oxidation (entries 1—4) [15]. Lastly, illustrating the broad potential scope of Mukaiyama-type oxidations, alcohol oxidation (entries 9 and 13) and oxidative decarbonylation (entry 15) reactions, which are oxidase systems, have also been reported [16b, 17b]. 

As the mechanism, a radical and a cationic pathway are conceivable (Eq. 31). The stereochemical results with rac- or mcjo-1,2-diphenyl succinic acid, both yield only trans-stilbene [321], and the formation of a tricyclic lactone 51 in the decarboxylation of norbornene dicarboxylic acid 50 (Eq. 32) [309] support a cation (path b, Eq. 31) rather than a biradical as intermediate (path a). 

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. 

A systematic study of the impact of geminal a-fluorine substitution upon the rate of decarboxylation of /1-lactones has included investigation of die thermolysis of a,a-difluoro /1-lactones, to give CO2 and 1,1-difluoroalkenes, in die gas phase and in solution.48 The gas-phase results have been interpreted, with reference to ab initio calculations on the fluoro- and non-fluormated /1-lactone systems, in terms of a probable concerted, asynchronous, non-polar mechanism. However, a polar mechanism which probably involves formation of an intermediate zwirterion has been invoked to explain the solvent dependence observed. 

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