Merrilactone

Meisenheimer rearrangement 52f. 1,2-mercapto alcohol 236 f. merrilactone A 241 (-) -mesembrine 306 metal etiolates... 

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... 

The intramolecular Paterno-Buchi reaction is capable of installing new oxetane units with significant regio- and stereoselectivity, as is evident in the construction of a tetracycle related to merrilactone (Equation (26) see also Section 2.06.12.2) <2005OL3969>. The chirality of an atropoisomer recrystallized from an interconverting (4/z = 468 s at — 20 °C) mixture of enantiomers was preserved by photocycloaddition (Equation 27) the atropoiso-meric oxetane products do not interconvert unless heated <2003JOC942>. 

The stereospecific isomerization of 3,4-epoxyalcohols under acidic or basic conditions <2002T6199, 1998TL8259> has been the method of choice for the final step in syntheses of merrilactone (Equation 48) <2006AGE4843>. An analogous acid-promoted closure of benzyl ethers of epoxy alcohols has also been observed <2000H(52)171>. An unusual 4-/ro/o-isomerization of a hydroxy epoxide apparently reflects the inability of a primary alcohol to cyclize via 4-exo- or 5-endo-modes transesterification liberates the secondary alcohol, which undergoes a 4-< //6>-cyclization (Equation 49). An X-ray structure of the product has been reported <2003JOC4422>. Section... 

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... 

A six-step synthetic approach to the tetracyclic skeleton of neurotrophic sesquiterpene merrilactone A, using intramolecular photocycloaddition to form the oxetane ring, was reported.902 Irradiation of a degassed acetonitrile solution of 262 gave the product 263 (Scheme 6.108) in a very high yield (93%). This reaction creates three stereocentres in two new rings, forming an oxa[3.3.3]propellane framework. 

On the other hand, merrilactone C (86 and 87) was obtained as an inseparable mixture with a ratio of 5 1 due to a lactol ring. In fact, this mixture was treated with trimethylsilyl diazomethane in methanol to give a sole methylated product 86a. Fortunately, 86a gave single crystals suitable for X-ray analysis. The ORTEP drawing of 86a as shown in Fig. (15) reflects that the methoxyl group attaches downward at the C-14 position, making up the same convex-shaped structure as 84. 

Merrilactones A (85) and B (88) are presumably derived from anislactone B (83) by cross-esterification between the C-l and C-4 hydroxyl groups. Thus intramolecular transesterification was attempted to preliminarily obtain 88 from 83. At first, 83 was subjected to acidic conditions at room temperature, but no reaction occurred. Next, heating a solution of 83 in methanol-water (1 1) in the presence of sodium hydroxide, followed by acidification, afforded a mixture of anislactone A (82) and two diastereomers (89 and 90) of 88 in 26%, 12%, and 14%, respectively (Scheme 4). Contrary to our expectations, none of 85 and 88 was found in the products. The structural assignments for 89 and 90 were unambiguously done by extensive analyses of their 2D NMR data, indicating the plane structures of 89 and 90 being the same as 88. 

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