Lactones spiro, synthesis

In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to epoxides are not widely used in the synthesis of complex molecules. Following the seminal work of Danishefsky [64], who introduced the use of Et2AlCl as an efficient catalyst for the reaction, Taylor obtained valuable spiro lactones through the addition reaction of the lithium eno-late of tert-butyl acetate to spiro-epoxides, upon treatment of the corresponding y-... 

The availability of cyclopentenones from butanolides allows the lactone annulation to facilitate the synthesis of cyclopentyl natural and unnatural products. An example that highlights the latter is dodecahedrane (178) for which 179 constitutes a critical synthetic intermediate 136,137). Lateral fusion of cyclopentenones as present in 179 can arise by acid induced reorganization and dehydration of 180. While a variety of routes can be envisioned to convert a ketone such as 182 into 180, none worked satisfactorily137 On the other hand, the cyclobutanone spiro-annulation approach via 181 proceeds in 64 % overall yield. Thus, the total carbon cource of dodecahedrane derives from two building blocks — cyclopentadiene and the cyclopropyl sulfonium ylide. 

The stereocontrolled synthesis of a chiral, polyhydroxy 1,7-dioxa-spiro[5.5]undecene from 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone... 

Nair and co-workers reported the diastereoselective synthesis of spiro y-butyro-lactones from 1,2-dicarbonyls [125]. The authors studied the reaction with 1,2-cyclohexane dione 230 which produces the desired lactone 232 in good yields Eq. 22a. Isatins 233 are more reactive, but the products 235 are obtained as a 1 1 separable mixture of diastereomers Eq. 22b. The Nair research group extended this methodology to include homoenolate addition to tropanone 236 to form bicyclic 5-lactones 238 Eq. 22c [126]. 

As part of our efforts to develop new efficient one-pot methodologies to access novel heterocyclic structures, we also reported an efficient synthesis of spiro[4,61-lactones and lactames by sequential multicomponent reaction/metal-catalyzed carbo-cyclizations from simple five-membered cyclic (3-ketoesters and (3-ketoamides,... 

The most recent method for /3-lactone synthesis involves a very novel approach. Phenyl-ethynolate anion (which may be in equilibrium with phenylketene anion) can be generated by the reaction of n-butyllithium or f-butyllithium in THF at -78 °C. This highly nucleophilic species reacts with cyclohexanone to give the spiro-/3-lactone (54), probably through intermediacy of the lithium alkoxide of the /8-hydroxyketene (53). The /3-lactone (54) was isolated in about 50% yield (79LA219,82JA321). 

Spirofuran-2(5H),2 (3 H)furo[2,3-6]furan synthesis, 4, 659 Spirofuranones synthesis, 3, 734 Spiro[3.3]heptane physical properties, 1, 590 Spiroindazoles irradiation, 5, 252 Spiroisoarsindolinium salts, 1, 544 Spiroisoxazolines synthesis, 6, 108 Spirolactones synthesis, 3, 846-847 Spiro-/3-lactones synthesis, 7, 395 Spiro nomenclature, 1, 26 Spirooxadiazoles synthesis, 4, 822 Spirooxaziridines photorearrangement, 7, 541 (8-scission, 7, 211 Spirooxetanes synthesis, 7, 393 Spirooxiranes cleavage... 

Scheme 59 Selective synthesis of a spiro lactone derivative 201 achieved using continuous flow methodology.

Table 30 Summary of the results obtained for the continuous flow synthesis of a spiro lactone 201...

Hydroxyalkanoic acids are easily dehydrated to either spiro or fused /3-lactones. Sulfonyl chlorides have been the traditional reagents employed for this transformation <1996S586, 2001CC753>. However, as illustrated in Equation (38) for a cyclization used as part of a synthesis of lactacystin/omuralide (see also Section 2.06.12.4), bis(oxazolidi-none) phosphinyl chloride (BOP-C1) has proven an effective agent for application in sensitive structures note also the selectivity for introduction of the fused (vs. spiro) lactone <2006JOC1220>. 

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]. 

The preparation of a number of medium ring benzoic acid lactones was achieved by treatment of compounds such as VIII/176 with an excess of meta-chloroperoxybenzoic acid in dichloromethane, Scheme VIII/33 [103]. However, this oxidation reaction is not general for the synthesis of aromatic lactones. If the same reaction conditions are used as in the conversion of VIII/176 to VIII/177, the methoxy derivative VIII/178 is not transformed into the corresponding lactone. Instead the cyclic carbonate VIII/183 was isolated in a yield of 50 %. The proposed mechanism of this abnormal reaction is shown in Scheme VIII/33. From model compounds, the methoxyl group in the para-position to the center of oxidation seems to be important for the formation of VIII/183 [103]. The carbonate VIII/183 is unstable in aqueous alkaline medium and decomposes to the spiro compound, VIII/185, Scheme VIII/33 [103]. For an analogous reaction, see ref. [104]. 

Pyrolysis of lactone tosylhydrazoue salts. Agosta et ai have developed a process that is formally a reversal of the Baeyer-Villigcr oxidation, that is, a method for conversion of lactones into cyclic ketones. An example is the synthesis of the spiro[3.4]-ociane-l-one (5). I he starting material is the lactone (1) this is converted into the... 

Ethyl a-(bromomethyl)acrylate has proved to be an excellent reagent for conversion of aldehydes and ketones, both acyclic and cyclic, into the corresponding a-methylene-y-butyrolactone derivatives " in a Re-formatsky type reaction. The yield was excellent in the case of several spiro a-methylene-y-butyrolactones. Synthetic a-methylene-y-butyro-lactone derivatives have been shown to possess antitumor activity. " Ethyl a-(bromomethyl)acrylate has also proven of value in the synthesis of alkylated products of enol ethers of cyclohexane-1,3-dione. ... 

The difficulties associated with the synthesis of spiro y-lactones include the generation of a quaternary carbon center and the introduction of functionalities used for lactonization. Much work has been done in an effort to develop useful synthetic routes [13], However, most methods require the use of complex reagents and multiple synthetic steps to accomplish the overall process. 

Scheme 4 Synthesis of a spiro y-lactone from the magnesium complex of 1,2-dimethylenecyclo-hexane, acetone, and CO-.

Scheme 5 Synthesis of spiro y-lactones from (2,3-dimethyl-2-butene-1.4-diyl)magnesium. cyclic ketones, and CO-,...

The overall procedure of the spiro y-lactone and 7-lactone synthesis can be considered as a molecular-assembling process in which three simple independent species (i.e., a conjugated diene, a ketone, and carbon dioxide) are used to build a complex organic molecule in a well-controlled fashion. 

Table 4 Synthesis of Spiro y-Lactones from Conjugated Dienes, Ketones, and COj...

The synthesis of spiro y-lactones has been extended to the synthesis of spiro -lactones. This one-pot transformation of 1,3-dienes reacted with epoxides, mediated by Rieke magnesium to spiro -lactones in good isolated yields, was recently reported [15]. Much work has been done to elucidate novel synthetic routes for these types of molecules [16]. In particular, -substituted 5-lactones have recently attracted considerable attention, mainly because molecules of this class include many natural products that exhibit substantial biological activity [17]. However, most methods for the synthesis of these molecules require... 

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