ABSTRACT

The Herzon Synthesis of (-)-AcutumineThe alkaloid (-)-Acutumine (3), isolated from the roots of the chinese moonseed Sinomenium acutum, improves object and social recognition in the Wistar rat model. With four rings and three adjacent fully-substituted stereogenic centers, 3 presents a significant synthetic challenge. Seth B. Herzon of Yale University assembled (Angew. Chem. Int. Ed. 2013, 52, 3642. DOI: 10.1002/anie.201210076) 3 by the intramolecular Sakurai cyclization of 1 to 2.

The convergent preparation of 1 required the alkyne 10. The literature construction (Org. Lett. 2005, 7, 5075. DOI: 10.1021/ol052106a) by A. B. Smith III of the enone 7 from ribose 4 began with protection to 5. Conversion of the primary alcohol to the iodide followed by reduction delivered the aldehyde. Addition of vinyl magnesium bromide followed by exposure to the first generation Grubbs catalyst gave the cyclopentenol, that was oxidized to 7. Conjugate silyation led to the triflate 8, that was carried on to 10.

In earlier work, Professor Herzon had shown (Angew. Chem. Int. Ed. 2011, 50, 8863. DOI: 10.1002/anie.201102226) that the prochiral quinone from oxidation of 11 could be added to the diene 12 under enantioselective catalysis, to give 13 in high ee. Reduction of the azide gave the imine, that was quaternized with methyl triflate. Addition of the Li salt of 10 to that sensitive intermediate proceeded with high facial selectivity. With aromatization blocked, the product from the addition of 10 could be thermolyzed to yield 14. The stannylation of the alkyne proceeded with high regio- and stereoselectivity, to give the alkene 1. Exposure of the allylic silane to tetrabutylammonium fluoride drove the desired cyclization to give 2. Chlorination followed by acetonide removal then completed the preparation of the diol 15.

The completion of the synthesis required extensive experimentation. Eventually, a protocol was established to oxidize 15 over several steps to the dienone 16. Selective reduction of the ketone (the other carbonyls are vinylogous esters) proceeded with the desired facial selectivity, to give 17. Selective hydrogenation using a Rh catalyst then delivered (-)-Acutumine (3)

ABSTRACTThe Tanino Synthesis of (-)-Glycinoeclepin A(-)-Glycinoeclepin A (3) is effective at picogram/mL concentrations as a hatch-stimulating agent for the soybean cyst nematode. Approaching the synthesis of 3, Keiji Tanino of Hokkaido University envisioned (Chem. Lett. 2010, 39, 835. DOI: 10.1246/cl.2010.835) the convergent coupling of the allylic tosylate 2 with the bridgehead anion 1. The assembly of the fragment 2 was particularly challenging, as the synthesis would require the establishment not just of the two adjacent cyclic quaternary centers, but also control of the relative configuration on the side chain.

The preparation of 1 began with the prochiral diketone 3. Enantioselective reduction of the mono enol ether 4 set the absolute configuration of 5. Iodination followed by cyclization then completed the assembly of 1.

The construction of the bicyclic tosylate 2 began with m-methyl anisole (7). Following the Rubottom procedure, Birch reduction followed by mild hydrolysis gave the ketone 8. Epoxidation followed by -elimination delivered the racemic 9, which was exposed to lipase to give, after seven days, the residual alcohol in 40% yield and high ee.

The side chain nitrile was prepared from the diol 12. Homologation gave the nitrile 14, that was equilibrated to the more stable enol ether 15. The two cyclic quaternary centers of 3 were set in a single step, by the conjugate addition of the anion of 16 to the crystalline enone 11. Mild hydrolysis of 17 gave the keto aldehyde, that underwent aldol condensation to give the enone 18.

The hydroboration of 19 followed by coupling of the intermediate organoborane with 20 delivered 21 with 94:6 relative diastereocontrol. Formylation of the enone 22 followed by triflation and reduction then led to 2.

Although the ketone 1 could be deprotonated with LDA, the only product observed, even at -78C, was the derived aldol dimer. The metalated dimethylhydrazone 25, in contrast, coupled smoothly with 2 to give, after hydrolyis, the desired adduct 26. Pd-mediated carboxylation of the enol triflate followed by selective oxidative cleavage and hydrolysis then completed the synthesis of (-)-Glycinoecleptin A (3).

ABSTRACTThe Boger Synthesis of (-)-VindolineThe periwinkle-derived alkaloids vinblastine (2a) and vincristine (2b) are still mainstays of cancer chemotherapy. The more complex half of these dimeric alkaloids, vindoline (1), presents a formidable challenge for total synthesis. Building on his previous work (Org. Lett. 2005, 7, 4539. DOI: 10.1021/ol051975x), Dale L. Boger of Scripps, La Jolla devised (J. Am. Chem. Soc. 2010, 132, 3685. DOI: 10.1021/ja910695e) a strikingly simple solution to this problem, based on sequential cycloaddition.

The starting point for the synthesis was the ester 3, derived from D-asparagine. This was extended to 4, condensation of which with 5 gave the enol ether 6. On heating, 7 cyclized to 8, which lost N2 to give the zwitterion 9. Addition of the intermediate 9 to the indole then gave 10. In one reaction, the entire ring system of vindoline, appropriately oxygenated, was assembled, with the original stereogenic center from D-asparagine directing the relative and absolute configuration of the final product.

To complete the synthesis, the pendant carbon on 11 had to be incorporated into the pentacyclic skeleton. After adjusting the relative configuration of the secondary alcohol, the N was rendered nucleophilic by reduction of the amide to the amine. Oxidation delivered 14, that on activation as the tosylate smoothly rearranged to the ketone 15. Reduction and regioselective dehydration then completed the synthesis of vindoline (1).

ABSTRACTThe Li/Yang Synthesis of ()-Maoecrystal VMaoecrystal V (3), isolated from the Chinese medicinal herb Isodon eriocalyx, shows selective inhibition of HeLa cells at low nanomolar concentration (IC50 = 60 nm). Chuang-Chuang Li of Shenzen Graduate School of Peking University and Zhen Yang of Peking University, Beijing designed (J. Am. Chem. Soc. 2010, 132, 16745. DOI: 10.1021/ja108907x) the first total synthesis of 3, based on the intramolecular Diels-Alder cyclization of 1 to 2.

The preparation of 1 began with the ketone 4. Methoxycarbonylation of 4 followed by coupling with 6 delivered 7. As would be expected, hydride reduction of the cyclic -keto ester proceeded with high diastereocontrol to give the undesired trans diastereomer. Fortunately, the bulky tetrabutylammonium borohydride delivered the cis diastereomer, that could then be reduced to the diol 8. Rh-catalyzed carbene insertion into the O-H bond followed by condensation with formaldehyde then completed the preparation of the precursor 10.

Deprotection of 10 followed by oxidation presumably gave 1. There are two faces to the diene of 1, and then the acetoxylated stereogenic center, so four products are possible. In the event, three of the four were observed, of which 2 was the major.

To complete the synthesis of 3, the secondary alcohol of 11 was introduced by allylic bromination followed by radical reduction and trapping with TEMPO. The acetoxy group was reduced off, then the more reactive alkene was removed by selective hydrogenation. Oxidation and base treatment then delivered the equilibrium mixture of ()-Maoecrystal V (3) and its methyl epimer.

The synthesis of 3 as reported led to the racemate of the natural product. The starting cyclohexene 1 can be prepared (Tetrahedron Lett. 2000, 41, 3871. DOI: 10.1016/S0040-4039(00)00542-6) from 2,2-dimethylcyclohexane-1,3-dione (12). Yeast reduction of the prochiral 12 is known to proceed with high (S)-induction. It may be that a route could be devised from the reduction product 13 to enantiomerically-pure 7.

ABSTRACTThe Tanino/Miyashita Synthesis of Solanoeclepin ABuilding on the Tanino synthesis of Glycinoeclepin ( 2011, January 3), the hatch-stimulating substance for the soybean cyst nematode, Keiji Tanino of Hokkaido University and Masaaki Miyashita, now at Kogakuin University, described (Nature Chem. 2011, 3, 484. DOI: 10.1038/nchem.1044) a convergent synthesis of Solanoeclepin A (3), the hatch-stimulating substance for the potato cyst nematode. A key step in the synthesis was the diastereoselective Diels-Alder cyclization of 1 to 2.

The starting point for the synthesis was the conjugate addition of 5 to 3-methyl cyclohexenone (4), followed by aldol condensation. The secondary acetate corresponding to 6 was readily resolved by lipase hydrolysis. The next challenge was the installation of the angular vinyl group. Enone transposition gave 7, to which vinyl Grignard added with high diastereocontrol, leading to the diol 8. TMSOTf-mediated epoxide rearrangement with concomitant 1,2 vinyl shift then delivered 9. Epoxidation followed by Stork cyclization completed the construction of the cyclobutane 10.

The allylic alcohol 12 was enantiomerically pure, so the relative configuration of the sidechain cyclopropane could be set by the Charette protocol. Grieco dehydration of 14 then gave 16, a latent form of the cyclobutanone of 3. Condensation of the ketone 17 with 18 delivered the expected keto enamine, that rearranged nicely on exposure to Tf2O to the aldehyde 19. Diastereoselective addition of the furyl lithium 20 followed by Pd-catalyzed coupling with 21 then completed the assembly of the Diels-Alder substrate 1.

The Me2AlCl-mediated intramolecular Diels-Alder cyclization of 1 led to 2 with remarkable diastereocontrol. Oxidation gave 22, that was further oxidized to the protected enol 23. Reduction, alkene cleavage and protecting group manipulation then set the stage for the final oxidation of 24 to Solanoeclepin A (3).

ABSTRACTThe Qin Synthesis of (+)-Gelsemine(+)-Gelsemine (3) has no particular biological activity, but its intricate architecture continues to inspire the ingenuity of organic synthesis chemists. Yong Qin of Sichuan University devised (Angew. Chem. Int. Ed. 2012, 51, 4909. DOI: 10.1002/anie.201201736) an enantiospecific synthesis of 3, a key step of which was the cyclization of 1 to 2.

The starting material for the synthesis was the inexpensive diethyl tartrate 4, which was converted over six steps into the N-sulfonyl aziridine 5. The addition of 6 was highly regioselective, leading, after N-methylation, to the alkyne 7. After alcohol protection, the sulfonyl group was smoothly removed by sonication with Mg powder in methanol. Addition to acryonitrile then gave 8.

Semi-hydrogenation of 8 set the stage for construction of the lactone 1. The anion of 1, generated by exposure to LDA, cyclized to 2 with significant diastereoselectivity.The lactone of 2 was selectively reduced with Dibal, to give an aldehyde that was protected as the acetal. The exposed primary alcohol was then oxidized to the aldehyde 9. Condensation of 9 with the enolate of 10 followed by dehydration delivered the alkene 11, with the stage set for a second intramolecular nitrile anion addition.

In the event, the cyclization of 11 delivered 12, the wrong diastereomer. This was corrected by selenation and oxidation to give an alkene, that was hydrogenated to 13. Exposure to acid deprotected both the MOM group of 13 and the acetal, then promoted cyclization to 14. Reduction of the nitrile to the aldehyde followed by methylenation completed the synthesis of (+)-Gelsemine (3). It should be noted that the hydrogenation to form 13 had to be carried out carefully, to avoid premature removal of N-methoxy group. That group was critical for the successful conversion of 13 to 14.