Merrilactone synthesis

In a recent total synthesis of the novel neurotrophic agent merrilactone A (22, Scheme 4) by Inoue and Hirama [24], key intermediate 21 with the cis-bicyclo[3.3.0] octane framework embedded within the caged pentacycle 22 was elaborated from cyclobutane 18 by a sequence of RCM and immediate cleavage of the resulting bicyclic vicinal diol 19 to raeso-diketone 20. Cyclooctenedione 20 then underwent regioselective transannular aldol reaction at low temperature (LHMDS, THF, -100 °C) to produce a 3 1 mixture of isomers in 85% combined yield. The major isomer 21 with the required stereochemistry was then converted into the racemic natural compound ( )-22 in 19 steps. 

Scheme 4 A sequence of RCM-glycol cleavage-transannular aldol reaction in Inoue s total synthesis of merrilactone A (22) [24]...

An elegant application of this protocol has recently been reported, which relied on the desymmetrization of a meso-epoxide to produce a key intermediate for the synthesis of merrilactone A (Equation (76)).275... 

Merrilactone A, via ring-closing diene metathesis, 11, 210 Mesitylato complex, with Pd, 8, 347 Mesitylbismuth dibromide, synthesis, 3, 916 Mesitylbismuth dichloride, synthesis, 3, 916 Mesitylcopper complex, characteristics, 2, 157... 

After these pioneering works, several reviews cover the enormous number of papers published in this field [3-7]. The synthesis of oxetanes can have a great importance in the development of compounds with relevant biological properties oxetane ring is present in the skeleton of taxol (1), an important drug used in the treatment of ovarian cancer [8] in merrilactone A (2), a new sesquiterpene dilactone with neurotrophic activity [9] and in several antiviral oxetanes, such as 3, 4, and 5, which have been described in literature (Scheme 3.2) [10-12],... 

Substituted maleic anhydrides have been directly exdted, but sensitization may also be used. In some cases the first method is better, and in some cases the second. In an approach to merrilactone A, which is closely related to the earlier-mentioned synthesis (Scheme 6.30), 2,3-dimethylmaleic anhydride was employed as a starting material in a sensitized [2 + 2]-photocydoaddition to 1,2-dichlorethene [114]. The reaction of tetrahydrophthalic anhydride (120) with alkenols and alkynols was conducted by direct irradiation in a Pyrex vessel. As an example, the reaction with allyl alcohol is depicted. The exo-product 121 was the preferred product with the endo-product cydizing spontaneously to lactone 122 (Scheme 6.43) [115]. Other alkenols reacted similarly. 

Mehta, G. and Singh, S.R. (2006) Total synthesis of ( )-merrilactone A. Angewandte Chemie, International Edition, 45, 953-955. 

Inoue, M., Lee, N., Kasuya, S., Sato, T., Hirama, M., Moriyama, M., and Fukuyama, Y. (2007) Total synthesis and bioactivity of an unnatural enantiomer of merrilactone a development of an enantioselective desymmetrization strategy. Journal of Organic Chemistry, 72, 3065-3075. 

In 2005, Greaney and coworkers applied the PB reaction to the synthesis of merrilactone A (Scheme 7.30) [48]. Very recently, Hammaecher and Portella developed a clean formation of the intramolecular PB reaction of acylsilanes (Scheme 7.31) [49]. 

Scheme 7.30 Synthesis of merrilactone A using the intramolecular PB reaction.

Iriondo, J., Peras-Buceta, J.E., and Greaney, M.F. (2005) A Paterno-Biichi approach to the synthesis of merrilactone A. Organic Letters, 7, 3969-3971. 

During the total synthesis of the pentacyclic sesquiterpene dilactone (+)-merrilactone A by S.J. Danishefsky et al., a two-carbon unit was introduced at C9 by a Johnson-Claisen rearrangement. This high yielding transformation was carried out in the presence of catalytic 2,2-dimethyl propanoic acid at 135 °C using mesitylene as the solvent. A mixture of diastereomeric esters were formed, which were later hydrolyzed and subjected to iodolactonization to form the second lactone ring present in merrilactone A. The natural product was synthesized in 20 steps with an overall yield of 10.7%. 

S.J. Danishefsky and co-workers reported the total synthesis of pentacyclic sesquiterpene dilactone, merrilactone A. ° In their approach, they utilized Keck s radical allylation method to achieve the required chain extension. This sidechain was later used to construct one of the cyclopentane rings of the natural product. 

The total synthesis of (+)-merrilactone A was accomplished by S.J. Danishefsky and co-workers. The last step of the sequence was an acid-induced homo-Payne rearrangement. The tetracyclic homoallylic alcohol precursor was first epoxidized using mCPBA. The epoxidation was expected to occur from the same face as the C7 hydroxyl group, but due to the congested nature of the C1-C2 double bond at its 3-face, the epoxide was formed predominantly on the a-face. The epoxide substrate then was exposed to p-toluenesulfonic acid at room temperature to afford the desired oxetane ring of the natural product. 

Case Study 6.18 Synthesis of cage compounds - merrilactone A analogue... 

Long-range stereocontrol and asymmetric desymmetrization in total synthesis of merrilactone A 07Y419. 

As already mentioned above, the Mizoroki-Heck reaction tolerates almost any functional group and was, therefore, elegantly applied in numerous complex molecule syntheses (Chapter 16). Fukuyama and coworkers [34] recently disclosed a short synthesis of the AB ring motif towards the synthesis of merrilactone A (54), employing the intramolecular Mizoroki-Heck cyclization of 52 as the key step (52 53, Scheme 5.10). The B ring,... 

Scheme 14.29 Greaney s formal synthesis of merrilactone A (197) via domino conjugate addition/aldol cyclization.

A detailed investigation was later reported by Frontier in which a conrotatory electrocyclization of silyloxyfurans 79 was catalyzed by the same Ir(III) complex (76) to produce lactones 80 in good yield. This work culminated in the total synthesis of racemic merrilactone A (83) (Scheme 3.18) [21]. Generally, only one diastereoisomer was isolated from the Nazarov reaction. These cyclizations also demonstrated complete transfer of the trialkylsilyl group from the silyloxyfuran to the ketone oxygen. It had been previously demonstrated that trialkylsilyl species can catalyze the Nazarov reaction further experiments showed that although... 

Scheme 3.18 Iridium catalyzed Nazarov cydization in the synthesis of (+/-)-merrilactone A.

Inoue M, Lee N, Kasuya S, Sato T, Hirama M, Moriyama M, Fukuyama Y. Total synthesis and bioactivity of an uimatural enantiomer of merrilactone A development of an enantioselective desymmetrization strategy. J. Org. Chem. 2007 72 3065-3075. 

Additional investigations of chiral salen metal complexes revealed that the corresponding Co-salen complex 142 promotes intramolecular epoxide openings with alcohols in an enantioselective fashion [126]. This approach was elegantly utilized by Danishefsky in an asymmetric total synthesis of the neurotrophic growth factor merrilactone A (144 Scheme 9.17) [127]. 

---