Unsaturated lactones Synthesis

Enantiomerically pure epoxide 58 was available from o-norvaline via the same route to epoxides as in our viriditoxin synthesis. Reaction of epoxide 58 with the lithium anion of OBO-sulfone 57 produced lactone in 60% overall yield after hydrolysis, lactonization, and elimination. We were pleased to discover that this reaction allowed for use of 1.3 equivalents of 57, whereas three equivalents of Ghosez s reagent were often used in related transformations. Although we have not examined the reactions of the viriditoxin or pig-mentosin A epoxides with this reagent, we hypothesize that our modified reagent 57 would allow for a unified a,(3-unsaturated lactone synthesis and thus access to a variety of derivatives of binaphthopyranones. 

The reaction can be applied to the synthesis of q, /3-unsaturated esters and lactones by treatment of the ketene silyl acetal 551 with an allyl carbonate in boiling MeCN[356]. The preparation of the q,, 3-unsaturated lactone 552 by this method has been used in the total synthesis of lauthisan[357]. 

Unsaturated -lactone 34 adopts a well-defined conformation and provides a suitable platform for the introduction of the stereogenic center at C-24 (monensin numbering). Catalytic hydrogenation of the carbon-carbon double bond in 34 takes place preferentially from the less hindered side of the molecule and provides an 8 1 mixture of stereoisomers in favor of 35 (100% yield). Cleavage of -lactone 35 with concentrated hydriodic acid at 130°C, followed by treatment of the resultant iodide 36 with triphenylphosphine, completes the synthesis of intermediate 19. 

Lactams 618 <5-Lactols 627 Lactones 617 reactions of 636 synthesis of 632, 737, 815 a,fl-unsaturated - see a,/J-Unsaturated lactones... 

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. 

A. P. Rauter, J. A. Figueiredo, I. Ismael, T. Canda, J. Font, and M. Figueiredo, Efficient synthesis of a,/ -unsaturated /-lactones linked to sugars, Tetrahedron Asym., 12(2001) 1131-1146. 

Intramolecular cycloadditions of a,p-unsaturated lactones to alkenes have been used as key step in the synthesis of a precursor of the terpene reserpine 480) (4.68) and of fused cyclooctanes (4.69) 481 ... 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

One of the earliest and most important discoveries in metal-catalyzed asymmetric synthesis is Sharpless s Ti-catalyzed epoxidation of allylic alcohols. A mere mention of all the total syntheses that have used this technology would require a separate review article Here, we select Trost s masterful total synthesis of solamin (100, Scheme 14), for its beautiful and multiple use of Sharpless s asymmetric epoxidation.1161 Optically pure epoxy alcohol 95 is converted to both epoxy iodide 96 and diol 97 The latter two intermediates are then united to give 98, which is oxidized and converted to dihydrofuran 99 by a Ramberg-Backlund transformation. The Re catalyzed butenolide annulation that is used to afford the requisite unsaturated lactone only adds to the efficiency of this beautiful total synthesis. 

A similar approach had been described for the synthesis of the mycotoxin patulin (2,3-pyranose-fused unsaturated lactone) from a 2-arabinopyranos-2-uloside derivative,16 and more recently, for the synthesis of a potent germination stimulant and some analogous compounds from D-xylose or commercially available D-glucuronic acid y-lactone.17... 

Rauter s group exploited the synthesis of sugar derived bicyclic butenolides ( e.g. 140, Fig. 44),60 which possess cytotoxic and antitumor activities. The key structural feature of such compounds consists of the presence of the a,(3-unsaturated lactone, which allows them to act as Michael acceptors for the addition of enzymes nucleophiles. 

D-Ribonolactone is a convenient source of chiral cyclopentenones, acyclic structures, and oxacyclic systems, useful intermediates for the synthesis of biologically important molecules. Cyclopentenones derived from ribono-lactone have been employed for the synthesis of prostanoids and carbocyclic nucleosides. The cyclopentenone 280 was synthesized (265) from 2,3-0-cyclohexylidene-D-ribono-1,4-lactone (16b) by a threestep synthesis that involves successive periodate oxidation, glycosylation of the lactol with 2-propanol to give 279, and treatment of 279 with lithium dimethyl methyl-phosphonate. The enantiomer of 280 was prepared from D-mannose by converting it to the corresponding lactone, which was selectively protected at HO-2, HO-3 by acetalization. Likewise, the isopropylidene derivative 282 was obtained (266) via the intermediate unsaturated lactone 281, prepared from 16a. Reduction of 281 with di-tert-butoxy lithium aluminum hydride, followed by mesylation, gave 282. 

Unsaturated lactones can be obtained from alkynols and according to the substrate and/or the catalyst as well as to the reaction conditions, the double bond can be endo- or exocyclic. Thus, we will distinguish the two modes of synthesis. 

A synthesis of 149, cucujolide VIII, proceeded via the tert-butyldimethylsi-lyl-(TBS)-ether of methyl (E)-12-hydroxydodec-4-enoate B [293] (Fig. 7). Deprotonation in a-position and reaction with di(4-methoxyphenyl)diselenide furnished C. This was transformed to the macrolide E after saponification of the ester moiety, deprotection of the hydroxy group, and Mitsunobu lactonization. Alternatively, the unsaturated lactone F was synthesized from B following a sequence similar to that from C to D. Oxidative elimination of the arylseleno group... 

Pentzer EB, Gadzikwa T, Nguyen ST (2008) Substrate encapsulation an efficient strategy for the RCM synthesis of unsaturated -lactones. Org Lett 10 5613-5615... 

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). 

Fukuyama and Yang (49) developed a highly efficient synthesis of the tetracyclic intermediate 241, used in a total synthesis of mitomycin A (Scheme 9.49). The required azide 240 was produced from 239 in several steps. Upon heating in refluxing toluene, the azide 240 underwent smooth intramolecular cycloaddition with the unsaturated lactone followed by extrusion of nitrogen to give aziridine 241 in 85% yield. 

Dihydroxy esters of the type 5a can easily be lactonized with concomitant elimination of water to give the corresponding a, 3-unsaturated lactones. Therefore, hydroxy keto ester (R)-2c, obtained by recLBADH-catalyzed reduction of Ic, was reduced with NaBH4 prior to acid-catalyzed lactonization for the synthesis of labdanum fragrance compound (R)-16 (Scheme 2.2.7.8) [12]. 

Reduction of unsaturated -/-lactones (e.g. 91) has been applied to the synthesis of furanophanes lactonization of (92) followed by reduction with DIBAL gives (93) (70TLli). 

Stereoselective preparation of functionalized unsaturated lactones and esters via functionalized magnesium carbenoids. Synthesis 2003, 1797-1802. 

The inexpensive, commercially available D-g/ycero-D-gw/o-heptono-1,4-lactone ( glucoheptonolactone since it is prepared from D-glucose) is the precursor for the 2,7-dibromo-2,7-dideoxy-D-g/ycm -D-/afo-heptono-1,4-lactone (1) (Scheme 13) which, via the unsaturated lactone 2a and radical induced carbocyclisation, could be transformed into the crystalline dihydroxy cyclopentane lactone 4a in high yield (Scheme 14). This short and efficient synthesis of the cis-fused cyclopentane lactone provides easy access to a chiral synthon which might be modified stereospecifically for many purposes. Such... 

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