Retro lactones

The tandem additions proceeded as usual to give 42, and methylation of the mixture of stereoisomers gave the unsaturated retro-lactone, 43, an excellent precursor for retro-lactones at a variety of oxidation levels. Gentle acid treatment yielded the normal lactones, shown to be stereoisomers at C-4, by desulphurisation to trans-dihydrocollinusin, 45. 

Accordingly the series of reactions shown in Scheme 29 was carried out. Reaction of the usual tandem addition products with perchloric acid yielded the desired isomer 5 in 47% yield and the retro-lactone 54 in 43%... 

The reaction of o-iodophenol, norbornadiene and CO proceeds via alkene and CO insertions to afford the lactone 562, which is converted into coumarin (563) by the retro-Diels-Alder reaction. In this coumarin synthesis, norbona-diene behaves as a masked acetylene[4)3],... 

The same paper reports another route to 11-membered acetylenic lactones via an intramolecular retro-Dieckmann reaction (equation I). Thus treatment of 3 with... 

The norbornene derivative 16, obtained exclusively as the exo adduct via a Diels-Alder reaction of itaconic anhydride with cyclopentadiene followed by hydrolysis and esterification [7], was found to be a suitable precursor for an enolate of type 14 (Scheme 2). Due to the quaternary center at C-3 eno-lization with base proceeded unambiguously, giving rise to a diastereomeric mixture of lactones 17/18 after reaction with hexanal. Retro-Diels-Alder reaction led to the monocyclic lactones 19/20 (2 1), elegantly unmasking the cxo-methylene group found in so many paraconic acids [8]. Hydrolysis of this mixture in refluxing butanone with 6 N HCl [9] effected epimerization... 

Diols were converted to lactols by TPAP/NMO/PMS/CHjCN [352] or TPAP/NMO/ PMS/CH Clj-CHjCN [353] oxidation of a keto hemi-ketal by TPAP/NMO/PMS/ CH Cl in an avermectin synthesis yielded a lactol, via an intermediate retro-aldol [354], The 1,4-diols in Fig. 2.19 (R=C3H, Ph) produced lactones with TPAP/ NMO/PMS/CHjClj as did the 1,5-diol HO(CH3) C(OH)C5H, [46]. 

CPO has been used occasionally in complex syntheses. An important application of CPO as an enantioselective epoxidation catalyst is the efficient synthesis of (R)-2-mevalonolactone (Scheme 2.26a) [270]. A survey of the literature revealed that the previous methods required many steps to produce the lactone, in low overall yield, with moderate ee, in addition to expensive starting materials. Meanwhile, a retro-synthetic analysis starting with an appropriately functionalized epoxide provided confidence that CPO could rescue the situation if used in the key stereogenic step. Another completed synthesis is depicted in Scheme 2.26b. Again, the epoxide is generated in high yield with conversion to (R)-dimethyl-2-methylaziridine-l,2-dicarboxylate, which may serve as a synthon for P-methylamino acids [283],... 

Hetero-Diels-Alder reaction of 44 with enol ether 13 as the dienophile gives cycloadduct 45, which is not isolable but reacts with the water formed in the condensation step with loss of acetone and C02 to lactone 15. A suggested mechanism for the formation of lactone 15 is a retro Diels-Alder reaction which leads to the ketene intermediate 46. Ketene 46 adds to the water formed in the previous condensation step, yielding /3-keto-carboxylic acid 47, which then undergoes decarboxylation to 48. 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

The deMayo-type photochemistry of 1,3-dioxin-4-ones has been beautifully applied by Winkler et al. to the synthesis of complex natural products. Substrate 133 gave under sensitized irradiation (with acetone as cosolvent) product 134 as single diastereoisomer (Scheme 6.47). The diastereoselectivity results from cyclic stereocontrol exerted by the two stereogenic centers in the spiro-bis-lactone part of the starting material. After installation of the furan, saponification and bond scission in a retro-aldol fashion generated a keto carboxylic add, which produced the natural product ( )-saudin (135) by simultaneous formation of two acetal groups [128]. 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

Hesse s excellent general introduction to alkaloid chemistry naturally contains numerous references to indole alkaloids, and in particular contains a detailed discussion of the structure elucidation of villalstonine, by way of illustration of modern experimental methods used in alkaloid chemistry.1 Indole alkaloids also receive mention in a brief review of hypotensive principles from plants,20 in a review of synthesis via photocyclization of enamides,2 and in another on the use of lactones in alkaloid synthesis.21 Kametani has also reviewed (unfortunately, in Japanese) the synthesis, by his group, of alkaloids by retro mass spectral synthesis .2d The proceedings of the 1979 meeting of the Phytochemical Society of Europe, which were entirely devoted to indole alkaloids, are now available.3... 

---