Tricyclic 6-lactones

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

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). 

Thus, reaction of 6/4-25a gave 6/4-26a as a single product by applying a CO pressure of 50 psi under a nitrogen atmosphere, the isomer 6/4-27 is the main product The procedure can also be used for the synthesis of O- and N-tricyclic lactones as 6/4-26b and 6/4-26c with the epoxides 6/4-25b and 6/4-25c as substrates. 

The aza-tricyclic lactone 320 is an intermediate in the synthesis of the indolizidine 321, which is the indolizine analogue of the pyrrolizidine alkaloid platynecine <1995TL5109> (Scheme 84). 

As exemplified below, an interesting rearrangement of fused 2,5-dihydrofurans to tricyclic lactones under strongly acidic conditions was observed <06JOC9544>. 

Olefins containing at least one allylic hydrogen atom react with 02 to form an allylic hydroperoxide. The analogous formal reaction of such alkenes with ethylene is known as ene-reaction. The tricyclic lactone peroxypartheno-lide has been prepared by such a reaction (6.13)619). 

Pentanenitrile oxide, BuCNO, formed in situ from 1-nitropentane, PhNCO and Et3N in benzene, added stereo- and regioselectively to 8-.vv7/-(dimethoxymethyl)-3-oxo-2-oxabicyclo[3.2. l]oct-6-ene to give 75% of the tricyclic lactone 111 (276). Introduction of a methoxycarbonyl group into the plane asymmetrical double bond of 2,3-dioxa- and 2,3-oxazabicyclo[2.2.2]oct-5-enes, brought about a clear-cut increase in syn selectivity of their reactions with 1,3-dipoles (277). 

A benzene ring can act as the diene in the intramolecular [4 + 2]-cycloaddition with an activated allene. Thus, aryl allene carboxylates 147 gave tricyclic lactones 148 (Table 12.10) [124],... 

Tricyclic lactone systems were synthesized by the analogous intramolecular [4+ 2]-reaction followed by hydration and oxidation of the resulting dihydropyran ring. This isomerization-cycloaddition sequence was successfully applied to the synthesis of (+)-platyphyllide [134]. 

Recently, Sugimoto et al. presented a strategy toward the synthesis of tricyclic lactones containing a 2-azabicyclo[3.3.1]nonane skeleton via tandem intra-... 

Treatment of the bicyclic dibromo-y-lactone 1 with DBU in acetonitrile at 0-20 °C gave the tricyclic lactone 2 with formation of the cyclopropane ring in 90% yield66. 

LDA was used in the cyclization of tosylate 9, an intermediate in the synthesis of the pyrrolizidine alkaloid (+)-retronecine, which was prepared from (+ )-(7 )-malic acid in nine steps. The tricyclic lactone 10 was isolated in 53% yield70. 

This reduction was useful in a synthesis of a thromboxane B intermediate (9) from 6, prepared in a few steps from a readily available carbohydrate levoglucosan. Hydride reduction of 6 to 7 is regiospecific because of the a-allyl group. RuOz-NalOA oxidation (2, 358-359) gives the tricyclic lactone 8, which is cleaved by Amberlyst 15 in methanol to 9 and 10. The a-isomer 9 has been converted to thromboxane B2 (II) in two laboratories.3... 

Ketone 5 was converted to acetal 27 with ethylene glycol (Scheme 9), and 27 was reduced with LiAlH The diol 28 was then boiled in concentrated aqueous HC1 to provide the tricyclic lactone 29 in ca. 60% yield. The selectivity of the LiAltLi for the esters over the CN group was noteworthy. Another nice feature of this step was the lactonization, which served to differentiate the two CH2OH groups in 28. 

Encouraged by this calculation, the racemic ester 46 was prepared readily in 5 steps from a-ionone in 65% overall yield via a known sequence used in the synthesis of forskolin [Scheme 9].14 The subsequent intramolecular Diels-Alder reaction of 13 in refluxing n-decane gave the tricyclic lactone 47 in 65% yield.52... 

DCC/DMAP mediated esterification of 2-butynoic acid using (+)-(/ )-89 followed by intramolecular Diels-Alder cycloaddition of the resulting ester in refluxing n-decane [cone. 0.07 M] provided the tricyclic lactone (+)-47 in 60% overall yield [Scheme 21]. Epoxidation of (+)-47 using m-CPBA led to P-epoxy lactone (+)-48 in 64% yield. The P-epoxy lactone (+)-48 is highly crystalline, unlike the racemic form. 

Related studies on meso tricyclic anhydrides were published in 1988 and 1990 by Aitken et al. [7, 8]. Their best result was achieved in the methanolysis of the tetracyclic anhydride 6 with (—)-quinine (2) as catalyst (Scheme 13.2 57% yield of the lactone ester 7 with 76% ee). The enantiomeric purity of the tricyclic lactone-ester 7 could be increased significantly (> 99% ee) by subsequent recrystallization in the presence of (—)-quinine (2). 

In another synthesis of this alkaloid the tricyclic lactone 30 was prepared by a series of reactions in which most of the steps gave satisfactory yields. Hydrolysis with aqueous oxalic acid and condensation with anthraniladehyde generated compound 31 which had already been converted into camptothecine (21). It should be added that the early promise of this alkaloid as a therapeutic agent in cancer therapy has not been confirmed in clinical trials (22). 

Alternatively, enantioselective intramolecular photocycloisomerizations result from the use of hydroxy acids as chiral tethers, as illustrated in the conversion of 3-oxocyclohexenylcarboxylate 51 to the tricyclic lactone 52 which proceeds with 94% ee [67]. The chiral tether can be recycled by saponification to 53 and this hydroxyacid again converted to lactone 54 without loss of optical purity. 

Although most of the work with Rh-mediated intramolecular C-H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(OAc>4, diazoketone 2 was cyclized to the tricyclic lactone 3 [2. This product had previously been transformed by Paquette into pentalenolactone E (4) [3]. 

Use of this cyclization in combination with an intramolecular Diels-AIder reaction is illustrated by a synthesis of the tricyclic lactone 4. 

This cyclization has been used for a synthesis of enterobactin (5), a natural iron carrier (previous synthesis, 8, 215-216) by cyclization of a linear trimer of serine. Thus the lactone 3, derived from L-serine, cyclizes in the presence of 1 to the tricyclic lactone 4 in 23% yield. This product was converted into 5 by detritylation and acylation.3... 

Palladium-catalyzed cycloisomerization of lactone 276 produced the tricyclic lactone 277 (Scheme 31). The lactone was saponified and the generated acid was decarboxylated to the bicyclic sulfone 278. Oxidation of the primary alcohol to the acid with Jones reagent was followed by esterification yielding 279. Now, the... 

When the exomethylene ketones rac-1 a, b were treated with sodium hydroxide followed by oxidation with Collins reagent, the tricyclic lactones rac-2a, b were isolated in good yield as single stereoisomers44. Presumably, the aldehyde moiety is initially hydrated, cyclizes and then the resulting lactol is oxidized to the lactone. In line with this argument, treatment of rac-1 a with sodium methoxide in methanol resulted in the formation of the tricyclic acetal rac-3. 

An intramolecular version of this reaction was especially efficient with ji-dicarbonyl derivatives such as 420- 22. In fact, the transformations of these substrates into the tricyclic lactones 423-425 occurred under mild conditions and gave the target compounds in good yields and with complete control over the regio- and stereochemistry of the ring junctions. It is also to be noted that the starting substrates were prepared by routine methods from readily available precursors. 

Homoconjngate addition to cyclopropanes. Corey and Fuchs have investigated the reaction of cyclopropanes with organocopper reagents as a possible synthetic route to prostanoids. For example, the tricyclic lactone ester (1) reacts with divinylcopper-lithiura (2.0 eq.) in ether at -12° (19 hr.) to give the vinylcyclopentane lactone ester (2). Tliis product was treated directly with lithium iodide (5 eq.) in pyridine (1,615-616) at reflux for 3 hr. to give the lactone (3) in about 37% yield. 

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