Academic literature on the topic 'Piperidine alkaloid synthesis'

The pentacyclic alkaloid ( + )-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. The pentacyclic alkaloid (+)-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. The pentacyclic skeleton of 3 was constructed around a central organizing piperidine ring 9. This was prepared from the known (and commercial) enantiomerically-pure lactone 4. The akylated stereogenic center of 9 was assembled by diastereoselective hydroxy methylation of the acyl oxazolidinone 5 with s-trioxane, followed by protection. Reduction of the imide to the alcohol led to the mesylate 7, which on reduction of the azide spontaneously cyclized to give, after protection, the piperidine 8. Selective desilylation of the primary alcohol then enabled the preparation of 9. The plan was to assemble the first carbocyclic ring of 3 by intramolecular aldol condensation of the keto aldehyde 15. The enantiomerically-pure secondary methyl substituent of 15 derived from the commercial monoester 10. Activation as the acid fluoride followed by selective reduction led to the volatile lactone 11. Opening of the lactone with H3CONHCH3HCl gave, after protection, the Weinreb amide 12. Alkylation of the derived hydrazone 13, selectively on the methyl group, led, after deprotection, to 15. The intramolecular aldol condensation of 15 did deliver the unstable cyclohexenone 1. Under the acidic conditions of the aldol condensation, the enol derived from the piperidone added in a Michael sense, from the axial direction on the newly-formed ring, to give the trans-fused bicyclic diketone 2.

Palakodety Radha Krishna of the Indian Institute of Chemical Technology observed (Synlett 2012, 2814) high stereocontrol in the addition of allyltrimethylsilane to the cyclic imine derived from 1. The product piperidine 2 was carried onto (+)-deoxoprosopinine 3. Glenn C. Micalizio of Scripps Florida condensed (J. Am. Chem. Soc. 2012, 134, 15237) the amine 4 with 5. The ensuing intramolecular dipolar cycloaddition led to 6, which was carried onto the Dendrobates alkaloid (–)-205B 7. Pei-Qiang Huang of Xiamen University showed (Org. Lett. 2012, 14, 4834) that the quaternary center of 9 could be established with high diastereoselectivity by activation of the lactam 8, then sequential addition of two different Grignard reagents. Subsequent stereoselective intramolecular aldol condensation led to FR901843 10. More recently, Professor Huang, with Hong-Kui Zhang, also of Xiamen University, published (J. Org. Chem. 2013, 78, 455) a full account of this work. In an elegant application of the power of phosphine-catalyzed intermolecular allene cycloaddition, Ohyun Kwon of UCLA added (Chem. Sci. 2012, 3, 2510) 12 to the imine 11 to give 13. The cyclization elegantly set two of the four stereogenic centers of (+)-ibophyllidine 14. Tohru Fukuyama of the University of Tokyo initiated (Angew. Chem. Int. Ed. 2012, 51, 11824) a cascade cyclization between the enone 15 and the chiral auxiliary 16. The product lactam 17 was carried onto (–)-lycoposerramine-S 18. Mark Lautens explored (J. Am. Chem. Soc. 2012, 134, 15572) the utility of the intramolecular aryne ene reaction, as illustrated by the cyclization of 19 to 20. Oxidation cleavage of the vinyl group of 20 followed by an intramolecular carbonyl ene reaction led to (±)-crinine 21.

Günter Helmchen of the Ruprecht-Karls-Universität Heidelberg set (Organic Lett. 2010, 12, 1108) the absolute configuration of 3 by Ir*-mediated coupling of 1 with 2. Diastereoselective Pauson-Khand cyclization then led to (-)-α-kainic acid 5. Till Opatz, now at the Johannes Gutenberg-Universität Mainz, showed (Organic Lett. 2010, 12, 2140) that the product from the Dibal reduction of 6 could be condensed with the amine 7 without epimerization. Kim cyclization then directly delivered the pentacyclic alkaloid (+)-tylophorine 9. The interesting dimeric alkaloid lycoperine A 13 was recently isolated from the Japanese club moss Lycopodium hamiltonii. Scott D. Rychnovsky of the University of California, Irvine, prepared (Organic Lett. 2010, 12, 72) 12 by double alkylation of the bis-nitrile 11 with the enantiomerically pure allylic bromide 10. Although the projected reductive decyanation of 12 failed, hydrolysis followed by diastereoselective reductive amination successfully gave 13. Retrosynthetic analysis of fluvirucinine A2 16 could lead to an acyclic amino acid, which could be cyclized to the macrolactam. Young-Ger Suh of Seoul National University took (Organic Lett. 2010, 12, 2040) a different approach, building up the 14-membered ring system by two four-carbon ring expansions, beginning with an enantiomerically pure piperidine precursor. The second of these enolate-based aza-Claisen ring expansions is illustrated in the conversion of 14 to 15. Richmond Sarpong of the University of California, Berkeley, faced (J. Am. Chem. Soc. 2010, 132, 5926) a different sort of challenge in the synthesis of the dimeric Lycopodium alkaloid complanadine A 19. Even with established access to monomers such as 17 and its precursors, it was not clear how the 5-position of the pyridine ring could be selectively activated for bond formation. The solution to this dilemma was found in the work of Hartwig. Following that precedent, Ir-catalyzed activation of 17 converted it cleanly into the borinate 18, which could then be coupled with a pyridone triflate to complete the synthesis of 19.

In addition to the monomeric coccinellid alkaloids produced by the ladybug, some dimeric alkaloids, exemplified by psylloborine A 3, have been isolated. Scott A. Snyder of Scripps/Florida initially attempted a direct dimerization strategy for the assembly of 3, but when that failed, he devised (J. Am. Chem. Soc. 2014, 136, 9743) a route to the tethered dimer 1, that could indeed be cyclized to 2, the immediate precursor to 3. The starting material for both 9, the lower half of 1, and 13, the upper half of 1, was the commercial, enantiomerically-pure piperidine 4. Metalation followed by allylation gave the desired trans diastereomer 5. Oxidative cleavage followed by con­densation with 6 gave the ester 7, that was hydrogenated, then converted with 8 to the desired phosphonate 9. To prepare 13, 4 was metalated and alkylated with methallyl bromide. The prod­uct 10 was carried on to the enone 12 by oxidative cleavage followed by the addition of 11, oxidative cleavage, and dehydration. Reduction to the desired diastereomer was achieved by conjugate addition of hydride in the presence of the sterically very demanding Yamamoto Lewis acid ATPH. Deprotection followed by oxidation then gave 13, that was condensed with 9 and deprotected to give 14. Selective deprotection followed by oxidation and condensation with 15 then led to 1. A key element in the design of this synthesis was the ability to easily tune the sul­fone activating group, to direct the proper order of bond formation. The vision was that regeneration of the enone and deprotection, with tetramethylguanidine, would lead to 16. The free amine would add to the saturated ketone to give an enamine, that would in turn add in a conjugate sense to the enone to give 17. Further deprotec­tion of 17 under acid conditions would again generate an enamine that, it was hoped, would, after further cyclization, add to the unsaturated sulfone to give 2. As illustrated, the 3,5-bis(trifluoromethyl)phenyl sulfone gave the best results. Desulfurization of 2 completed the synthesis of the complex dimeric alkaloid psylloborine A 3.