Diterpenes syntheses

The selective bromination of a ketone in the presence of another susceptible functional group was achieved in a diterpene synthesis 240). A competing bromination of an anisole ring could be avoided here through the use of a pyrrolidine enamine derivative for activation of the methylene group adjacent to the carbonyl function. 

It is of considerable Interest to find that t-butyl esters may be reduced satisfactorily, in contrast to aliphatic t-butyl esters, which are cleaved to acids under Birch conditions. Also noteworthy is the regio-selective reduction of the ester (136 Scheme 24), in marked contrast to the reduction of the corresponding acid. Hydronaphthoate esters (137), (138) and (139) have been prepared (Scheme 25) and are envisaged as useful intermediates for diterpene synthesis. 

However, domino cyclization reactions had not been reported for diterpene synthesis. 

Benchikh le-Hocine, M., Do Khac, D., Fetizon, M. Model studies in taxane diterpene synthesis. Part III. Synth. Commun. 1992, 22, 245-255. 

The synthesis of tricyclic compounds based on the cyclisation of methyl geranyl-geranoate was described eighteen years ago. However, the discovery of expoxy-squalene as an intermediate in steroid biosynthesis, and the corresponding in vitro cyclisation experiments, have re-awoken interest in this area of diterpene synthesis. The structural and stereochemical course of the in vitro cyclisation of the epoxy-trans-olefin (138) has been studied. Two A/B-trans-fused tricyclic compounds (139) and (140) have been isolated. The levantenolides (142) and (143) have been obtained by two closely related routes. In the first, the butenolide (141), derived from monocyclofamesyl bromide, afforded the a- and P levantenolides (142) and (143) on cyclisation with stannic chloride. In the second, the corresponding acyclic butenolide derived from famesyl bromide was cyclised. 

The wide diversity of diterpenes has spnrred organic chemists to develop new reactions and innovative tactics. Among them, the pericyclic reactions stood as one the most efficient transformations to generate a wide array of structural diversity. Although the biosyntheses of several diterpenes are not fully elucidated, one can propose that some pericyclic reactions, notably the Diels-Alder reaction, could be involved in these processes. The selected examples in this chapter demonstrate the importance of these transformations in the context of complex diterpene synthesis. Although pericyclic reactions were discovered almost 100 years ago, their use in synthesis is still in its infancy. 

The Gassman method has proven to be adaptable to complex structures, such as the intermediate 7.20B used in the synthesis of the indole diterpenes paspalicine and pasalinine[5]. Table 7.5 gives some other examples. 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Provided that the silanolate elimination proceeds with anti selectivity, it must be concluded, that the intermediate homoallylic alcohol has an anti configuration, and thus the reagent has an ( -configuration. Acidic hydrolysis of the enol ether leads to enones the overall sequence consists of a nucleophilic acroylation. This has also been applied in the total synthesis of the marine diterpene ( )-aplysin-2067. 

Double stereodifferentialing Hiyarna reactions are the key steps in the total synthesis of ( + )- and (-)-nephromopsinic acid12 and (-)- and ( + )-dihydrocanadensolide33. The enantiomcrically pure diterpene cycloaraneosene is assembled by two chromium(II) chloride mediated coupling reactions from (3S,87 )-9-benzyloxy-7-chloroirid-1-ene (3) and (3[Pg.444]

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxy-neodolabelline (70) was accomplished by D. R. Williams et al. [58]. The trans-disubstituted dihydropyran moiety in key intermediate 69 was efficiently prepared from mixed acetal 66 by RCM with second-generation catalyst C and subsequent Lewis acid-catalyzed allylation of ethyl glycosides 67 with allylsi-lane 68 (Scheme 12) [59]. 

Guanacastepene A (444) is a novel tricyclic diterpene with fused five-, seven-, and six-membered rings. The possibility of constructing polycyclic compounds via tandem RCM of dienynes was used in Hanna s synthesis of a highly functionalized tricyclic system 443 related to 444. Under the conditions outlined in Scheme 87, trienyne 440 provided the desired tricycle 442 in a single step, as a result of sequential enyne RCM followed by RCM of intermediate 441. Compound 442 was then further functionalized to 443 [182]. 

An example of stereocontrol by high pressure is given by the regio- and diastereoselective synthesis of hydrophenanthrenones [18] which are useful intermediates for synthesizing diterpenes and steroids, by EtAlCli-catalyzed cycloadditions of heteroannular bicyclic dienone 50 with (E)-piperylene (24) and 2,3-dimethyl-1,3-butadiene (51) (Scheme 5.4). 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

Hiersemann M, Helmboldt H (2005) Recent Progress in the Total Synthesis of Dolabellane and Dolastane Diterpenes. 243 73-136... 

Entries 10 to 14 show reactions involving acetals. Interestingly, Entry 10 shows much-reduced stereoselectivity compared to the corresponding reaction of the aldehyde (The BF3-catalyzed reaction of the aldehyde is reported to be 24 1 in favor of the anti product ref. 80, p. 91). There are no stereochemical issues in Entries 11 or 12. Entry 13, involving two cyclic reactants, gave a 2 1 mixture of stereoisomers. Entry Mis a step in a synthesis directed toward the taxane group of diterpenes. Four stereoisomeric products were produced, including the Z E isomers at the new enone double bond. 

The tricyclic substance 18A and 18B are both potential synthetic intermediates for synthesis of the biologically active diterpene forskolin. These intermediates can be prepared from the monocyclic precursors shown. Indicate the nature of the reactions involved in these transformations. 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

This reaction can be used in synthesis of medium-sized rings by cleavage of specific bonds. An example of this reaction pattern can be seen in a fragmentation used to construct the ring structure found in the taxane group of diterpenes. 

NATURAL DITERPENE AND TRITERPENE QUINONE METHIDES STRUCTURES, SYNTHESIS, AND BIOLOGICAL POTENTIALS... 

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