Rauwolfia alkaloid synthesis approach employing the zwitterionic amino-Claisen rearrangement. Improvements in the efficiency for yohimbane ring construction and unambiguous de-ring-fusion stereochemical assignments

1984 ◽  
Vol 49 (15) ◽  
pp. 2708-2711 ◽  
Author(s):  
Schouchung Chao ◽  
Fen Ann Kunng ◽  
Jia Ming Gu ◽  
Herman L. Ammon ◽  
Patrick S. Mariano
Keyword(s):  
Claisen Rearrangement ◽  
Ring Fusion ◽  
Alkaloid Synthesis ◽  
Synthesis Approach ◽  
Rauwolfia Alkaloid

Alkaloid Synthesis: (−)-L-Batzellaside A (Toyooka), Limazepine A (Zemribo), (+)-Febrifugine (Pansare), Amathaspiramide F (Tambar), Allomatrine (Brown), Lyconadine C (Waters), Tabersonine (Andrade)

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Absolute Configuration ◽  
Claisen Rearrangement ◽  
Medical Center ◽  
University Of Texas ◽  
Temple University ◽  
Lycopodium Alkaloid ◽  
Alkaloid Synthesis ◽  
The University ◽  
Acyl Azide ◽  
Stereogenic Center

Naoki Toyooka of the University of Toyama prepared (Eur. J. Org. Chem. 2013, 2841) the lactam 1 from commercial tri-O-benzyl-D-glucal. Reduction with Dibal followed by coupling of the intermediate with allyltrimethylsilane delivered the piper­idine 2, that was carried on to (−)-L-batzellaside A 3. Ronalds Zemribo of the Latvian Institute of Organic Synthesis effected (Org. Lett. 2013, 15, 4406) Ireland–Claisen rearrangement of the lactone 4 to give the pyrroli­dine 5 with high geometric control. This was readily converted to limazepine E 6. Sunil V. Pansare of Memorial University used (Synthesis 2013, 45, 1863) an organo­catalyst to set the relative and absolute configuration in the addition of 7 to 8 to give 9. The acyclic stereogenic center of 9 was inverted twice en route to (+)-febrifugine 10. Uttam K. Tambar of the University of Texas Southwestern Medical Center combined (Org. Lett. 2013, 15, 5138) 11 with 12 under Pd catalysis to set the rel­ative configuration of 13. Late-stage bromination completed the synthesis of amathaspiramide F 14. Richard C. D. Brown of the University of Southampton used (Org. Lett. 2013, 15, 4596) the sulfinylimine of 15 to direct the stereochemical sense of the addition of 16. The product 17 was carried over several steps to the tetracyclic alkaloid allomatrine 18. Stephen P. Waters of the University of Vermont devised (Org. Lett. 2013, 15, 4226) what appears to be a general route to pyridones. On warming, the acyl azide derived from the acid 19 rearranged to the isocyanate, that cyclized to the pyridone 20. Deprotection led to the Lycopodium alkaloid lyconadin C 21. Among the several creative routes to indole alkaloids that have been put forward in recent months, the synthesis of tabersonine 25 (J. Am. Chem. Soc. 2013, 135, 13334) by Rodrigo B. Andrade of Temple University stands out. Deprotonation of 22 led to an anion that was condensed with 23 to give 24, with the relative and absolute configuration directed by the pendant sulfinylimine. In addition to tabersonine, the intermediate 24 was carried on to vincadifformine and to aspidospermidine.

The Carreira Synthesis of (–)-Dendrobine

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Magnesium Bromide ◽  
Gel Chromatography ◽  
Ring Fusion ◽  
Enantiomerically Pure ◽  
Schwartz Reagent ◽  
Radical Reduction ◽  
Silica Gel Chromatography ◽  
Stereogenic Center

The tetracyclic alkaloid (–)-dendrobine 3 has at its core a cyclohexane that is substituted at each of its six positions, including one quaternary center. Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2012, 51, 3436) to assemble this ring by the Ireland-Claisen rearrangement of the lactone 1. The absolute configuration of the final product stemmed from the commercial enantiomerically pure acetonide 4, which was selectively converted to the Z-ester 5. Following the precedent of Costa, TBAF-mediated conjugate addition of 2-nitropropane to 5 proceeded with high diastereocontrol, to give, after free radical reduction, the ester 6, which was carried on the aldehyde 7. Exposure of the alkyne 9 to an in situ-generated Schwartz reagent followed by iodination gave 10 with 10:1 regioselectivity. It was possible to separate 10 from its regioisomer by careful silica gel chromatography. Metalation followed by the addition to 7 gave an intermediate that was conveniently debenzoylated with excess ethyl magnesium bromide to deliver the diol 11. Selective oxidation led to the lactone 1. Exposure of 1 to LDA and TMS-Cl induced rearrangement to the cyclohexene acid, which was esterified to give 2. Deprotection and oxidation then gave the enone 12. Cyclohexene construction by tethered Claisen rearrangement is a powerful transformation that has been little used in target-directed synthesis. Selective addition of pyrrolidine to the aldehyde of 12 generated an enamine, leading to an intramolecular Michael addition to the enone. This selectively gave the cis ring fusion, as expected, but the product was a mixture of epimers at the other newly formed stereogenic center. This difficulty was overcome by forming the enamine from N-methylbenzylamine. After cyclization, hydrogenation set the additional center with the expected clean stereocontrol, and also effected debenzylation to give 14. To close the last ring, the ketone 14 was brominated with the reagent 15, which was developed (Can. J. Chem. 1969, 47, 706) for the kinetic bromination of ketones. Exposure of the crude α-bromo ketone to 4-dimethylaminopyridine then effected cyclization to 16. Following the literature precedent, reduction of the ketone of 16 with NaBH4 followed by gentle warming led to (–)-dendrobine 3.

Indole alkaloid synthesis via Claisen rearrangement. Total synthesis of secodine

1981 ◽  
Vol 103 (9) ◽  
pp. 2419-2421 ◽  
Author(s):  
Stanley Raucher ◽  
James E. Macdonald ◽  
Ross F. Lawrence
Keyword(s):  
Total Synthesis ◽  
Claisen Rearrangement ◽  
Indole Alkaloid ◽  
Alkaloid Synthesis

Alkaloid Synthesis: Paliurine F, Lepadiformine, and 7-Deoxypancratistatin

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Amino Acid ◽  
Grignard Reagent ◽  
Imperial College ◽  
K Channel ◽  
Amino Acid Derivatives ◽  
Ring Fusion ◽  
Alkaloid Synthesis ◽  
Phenyl Sulfone ◽  
Emory University ◽  
Epoxide Opening

The sedative alkaloid paliurine F 7 is a pentapeptide bridged by an arene. Gwilherm Evano of the Université de Versailles took advantage of this in his synthesis (Angew. Chem. Int. Ed. 2007, 46, 572) of 7, although it was necessary to prepare, from serine, one of the amino acid derivatives, the protected 3-hydroxyprolinol 2. The key step in the synthesis was the Cu-catalyzed intramolecular coupling of 5 to give the macrolactam 6. Deprotection and acylation then gave paliurine F 7. Lepadiformine 14, isolated from the tunicate Clavelina lepadiformis, shows moderate cytotoxicity, and is also a K+ channel blocker. The synthesis of 14 (Angew. Chem. Int. Ed. 2007, 46, 2631) by Donald Craig of Imperial College started with the aziridine 8, prepared from the corresponding epoxide. Opening of the protected aziridine with the anion of methyl phenyl sulfone set the stage for condensation of the dianion derived from 9 with the aldehyde 10, to give, with high diastereocontrol, the amine 11. Deprotection followed by cyclization then led to the activated ether 12. While the opening of 12 with an alkyl Grignard reagent proceeded with undesired inversion at the reacting center, opening with the alkynyl Grignard delivered mainly the desired 13. Reduction followed by oxidation, epimerization and reduction then gave lepadiformine 14. The Amaryllidaceae alkaloid 7-deoxypancratistatin 21 has potent antiviral activity. A challenge in the assembly of 21 is that the ring fusion is trans, less stable than the corresponding cis diastereomer. The synthesis of 21 (J. Org. Chem. 2007, 72, 2570) by Albert Padwa of Emory University started with 17, the preparation of which by the combination 15 and 16 he had previously reported in the course of his synthesis of lycoricidine (OHL December 11, 2006). Ester 17 had the desired trans ring fusion, but with an angular ester substituent that had to be removed. While it would be expected from the mechanism that Rh-mediated decarbonylation of an aldehyde would proceed with retention of absolute configuration, and this had been confirmed experimentally, this reaction had not been applied to such a challenging substrate. In the event, the transformation proceeded smoothly, to give the desired trans 19. Dehydration and dihydroxylation of 19 led to the cyclic sulfate 20, selective SN2 opening of which delivered 7-deoxypancratistatin 21.

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