Batzelladines

The pyrimidine skeleton has also been found in several marine natural products with interesting biological activities [103]. Among the most notable of these are the crambescidin (9-125) [104] and the batzelladine (9-126) [105] alkaloids which show pronounced bioactivity (Scheme 9.26). Thus, batzelladine A and B are new leads for... 

Six-membered cyclic guanidine 197 was transformed into the corresponding bicyclic guanidine hemiaminal after deprotection of the Cbz and contemporary cyclization on the masked aldehyde function (Equation 4). This product, 198, was then employed in a Biginelli reaction to form a precursor of alkaloid batzelladine F <1999JOC1512>. 

The validity of the oxauracil strategy for a stereoselective construction of the azabicyclic core has been proven for the syntheses of biologically important polyguanidinium alkaloids, namely, batzelladine A and D [58]. Reaction (7.48) shows that treatment of 41 under the standard free-radical conditions furnished the desired azabicycle in a 77 % yield, in a high diastereoisomeric ratio. Here it can be seen the effect of H donation from the more accessible face of the molecule. 

Several natural products and pharmaceuticals have been made in which a TRAP-catalysed oxidation of a primary alcohol to aldehyde step occnrs, and these are listed in 2.1.3 abscisic acid, altohyrtin A, (+)-arisngacin A, 14-[2H]-arteether (Fig. 2.4), astrogorgin, avermectin-Bla (Fig. 2.6), (H-)-batzelladine A (Fig. 1.13), brevetoxin B, (+)-catharanthin, ( )-epibatidine, 2-epibotcinolide, (-)-7-epicylin-drospermopsin, ( )-epimaritidine, epothilone C, irisqninone (Fig. 2.3), gambieric... 

There is a primary alcohol-to-aldehyde step in the synthesis of (+)-batzelladine A, and it was suggested that the oxidation of the primary alcohol (1) with TRAP/ NMO/PMS/CH Cl proceeds through an iminium-Ru alkoxide complex (2), rearranging as in (3)-(4) to give the aldehyde (5) (Fig. 1.13) [101] (a similar mechanism was proposed for the Ru-catalysed oxidative cyanation of tertiary amines [403] cf. 5.1.3.4, Fig. 5.3). 

Other procedures using TPAP/NMO/PMS/CH Cl include steps in the synthesis of (+)-altholactone (lactol to lactone) [78] antheliolide A [168] the AChE inhibitor (+)-arisugacin A and B (primary alcohol to aldehyde step also) [83] the marine macrolide amphidinolide T1 [169] the alkaloid (+)-batzelladine D cf. mech. 

In an effort to extend the scope of various synthetic studies towards 2-amino derivatives of 1,4-dihydropyridine, Kappe and co-workers performed a microwave-mediated regioselective construction ofnovelpyrimido[l,2-a]pyrimidines (Scheme 3.51)81. This ring system can be found in marine-derived natural products such as Crambescidin and Batzelladine alkaloids. 

Nitrosonium terafluoroborate initiates the cation radical-mediated imino-Diels-Alder reaction of IV-arylimines with IV-vinylpyrrolidinones to give cw-4-(2-oxopyr- (g) rolidin-l-yl)tetrahydroquinolines.175 Also, 2,4,6-triphenylpyrylium tetrafluoroborate catalyses the Diels-Alder addition of IV-arylimines with IV-vinylpyrrolidinone and IV-vinylcarbazole to yield the corresponding 2-oxopyrrolidin-l-yl- and carbazole-9-yl-tetrahydroquinolines.176 The tricyclic core (151) of the batzelladine alkaloids has been prepared by a diastereoselective 4 + 2-annelation of the vinylcarbodiimide (150)... 

On scanning numerous natural sources only the extracts from the Caribbean sponge Batzella sp. proved to be active [9], This led to the isolation of the batzelladines A (12) and B as the first low-molecular-weight compounds able to inhibit this interaction. Subsequently, batzelladines F (13) and G (14) were shown to induce dissociation of thyrosin kinase p56 and CD4 cells highly specific in an immunosuppressivity-based assay [lOJ. 

The isolation of the batzelladines attracted the attention of several groups, and some work has appeared in recent years concerned with partial syntheses, mainly in the racemic series 17, 18, 19]. The efforts of Snider culminated in a nine-step synthesis of racemic batzelladine E, following the biomimetic strategy [ 18bj. The only enan-tioselective synthesis reported to date established the absolute. stereochemistry of batzelladine B (Scheme 10) [20a], Diol 39 (obtained by /(-keto ester chemistry) was transformed into guanidine 41 via the diazide. An improved Biginelli type condensation with methyl acetoacetate in tri-... 

Scheme 10. Partial synthesis of batzelladine B and improved Biginelli condensation.

The [2+4] diastereoselective annulation of vinyl carbodiimides 48 to cyclic N-alkylimines 49 affords the S,S-diastereomer of the bicyclic dihydropyrimidine 50. This reaction is used in the synthesis of batzelladin alkaloids. 

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