A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from d-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-N(a)-methylvellosimine (5). The approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5, by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common intermediate 27 was then converted via a straightforward sequence of reactions into the alpha-amino nitrile 39. The derived silyl enol ether 40 underwent ionization upon exposure to BF(3).OEt(2) to give the intermediate iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver (+)-N(a)-methylvellosimine (5). This transformation provides experimental support for the involvement of such a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.
[formula: see text] A concise asymmetric synthesis of the indole alkaloid (+)-geissoschizine (1) has been completed. The synthesis features the highly diastereoselective vinylogous Mannich reaction of 3 with 4 to give 5, which is elaborated into the key tetracyclic intermediate 7 in two steps. Following the stereoselective introduction of the ethylidene moiety to give 9, reduction of the lactam and radical decarboxylation via an acyl selenide gave 12, which was converted into (+)-geissoschizine by formylation. The synthesis requires only 11 chemical operations and proceeds in an overall yield of 17%.
The sequential application of singlet oxygenation and peroxyl radical rearrangement provides an asymmetric entry to 4-peroxy-2-enols and 4-peroxy-2-enones. Enantiomerically enriched 2-hydroperoxy-3-alkenols, obtained via hydroxyl-directed addition of (1)O(2) to Z-allylic alcohols, undergo stereospecific radical rearrangement to form 4-hydroperoxy-2-alkenols. The yields of the rearrangement are improved in the presence of excess tert-butyl hydroperoxide, which limits dimerization of the substrate peroxyl radicals. However, the rearrangement equilibrium is unaffected by the presence of polar co-solvents or by the incorporation of a group able to selectively hydrogen bond to the product hydroperoxide. Photoisomerization of the (E)-4-hydroperoxy-2-enone rearrangement products results in irreversible ring closure to furnish diastereomeric mixtures of enantiomerically enriched dioxinols. The strategy is applied to the total synthesis of the alkoxydioxine natural products chondrillin and plakorin. Comparison of the optical rotation of the synthetic material against literature reports indicates that the natural products are either enantiomerically pure or highly enriched in one enantiomer. In addition, our results conclusively demonstrate that the reported configuration of chondrillin is in error.
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