Pseudolaric acid

The TMM [4-1-3] cycloaddition to pyrone has been employed in a synthetic study of a novel biologically active diterpene pseudolaric acid B (106), in which the formation of the bridged adduct (107) from the 2-pyrone (108) is the key step in the sequence (Scheme 2.29). A mixture of the other isomer (109) and the methylenecyclopentane (110) was also isolated from the reaction. It is important to point out that the presence of a tin co-catalyst is critical in effecting the reaction. This is the first example a "tin-effect observed in a [4-1-3] cycloaddition [40]. 

Scheme 2.29 TMM [4+3 cydoadditions in the synthetic study of pseudolaric acid B (106)...

M.17 Tu-jin-pi is a root bark used in traditional Chinese medicines for the treatment of athlete s foot. One of the active ingredients in tu-jin-pi is pseudolaric acid A, which is known to contain carbon, hydrogen, and oxygen. A chemist... 

Copper hydride species, notably Stryker s reagent [Ph3PCuH]6, are capable of promoting the conjugate reduction of a,( >-unsalurated carbonyl compounds [42], Taking advantage of this trustworthy method, Chiu et al. demonstrated in 1998 an intramolecular reductive aldol reaction in the synthesis of novel terpenoid pseudolaric acids isolated from Chinese folk medicine (Scheme 28) [43]. Two equivalents of [Ph3PCuH]6 enabled cycli-zation of keto-enone 104 to provide the bicyclic diastereomers 105 (66%) and 106 (16%). The reaction also was applied to the transformation of 107... 

Chiu s group [193] used this domino process for an entry to pseudolaric acid 6/2-27, starting from 6/2-28, to yield 6/2-29 and 6/2-30 as an almost l l-mixture of di-astereomers (Scheme 6/2.5). Attempts to improve the stereoselectivity by using chiral rhodium complexes did not change the picture very much. The pseudolaric acids A, B and C are diterpenoids, which were isolated from the root bark of Pseudo-larix kaempferi Gordon (Pinaceae), and are components of the traditional Chinese medicine called tujinpi. They reveal antifungal activity and cytotoxicities at submicromolar levels [194]. 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

In a very recent example, Chiu and co-workers (84-86) used the tandem ylide-cycloaddition methodology to prepare advanced intermediates directed toward the synthesis of the pseudolaric acids. Pseudolaric acids are a family of diterpenes isolated from the root bark of Pseudolarix kaempferi. These novel compounds have shown antimicrobial activity comparable to that of amphotericin B and have demonstrated cyctotoxicity against several cancer cell lines (Fig. 4.5). 

Chiu s retrosynthetic analysis of the pseudolaric acids proposed a simple intermediate incorporating a bridging ether, similar to that used by Dauben and McMills. Cleavage of the ether bridge further reduced the problem to a tandem ylide formation-cycloaddition through a simple acyclic ot-diazoketone with a tethered olefin (Scheme 4.45). 

The synthetic applications of 1,3-dipolar cycloaddition of carbonyl ylids generated from diazo ketones have been reviewed with particular focus on pseudolaric acids.12... 

It is worthy of note that this reaction is still the subject of solid and productive interest, as shown by the following recent examples. Chiu has exploited a rhodium carbene-promoted intramolecular formation of a carbonyl ylid - cycloaddition cascade as the key reaction in the synthesis of the nucleus of the cytotoxic diterpenoids pseudolaric acids A and B [54]. Although the diastereoselectivity was preferential for the undesired isomer 64, use of Hashimoto s chiral rhodium catalyst Rh2(SBPTV)4 reversed the selectivity in favor of 65 (64 65, 1 1.4) [55] (Scheme 29). 

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