Alkaloid Synthesis: (-)-Aurantioclavine (Stoltz), (-)-Esermethole (Nakao/Hiyama/ Ogoshi), (-)-Kainic Acid (Tomooka), Dasycarpidone (Bennasar), (-)-Cephalotaxine (Ishibashi) and Lysergic Acid (Fujii/Ohno)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Kainic Acid ◽  
Absolute Configuration ◽  
Lysergic Acid ◽  
Ni Catalyst ◽  
Cascade Cyclization ◽  
Alkaloid Synthesis ◽  
Radical Cascade ◽  
The Absolute ◽  
The University ◽  
Stereogenic Center

Intriguing strategies have been developed for the stereocontrolled assembly of complex alkaloid structures. Brian M. Stoltz of Caltech prepared (J. Am. Chem. Soc. 2008, 130, 13745) the enantiomerically-pure alcohol precursor to the secondary amine 1 by enantioselective oxidation of the racemic alcohol. Intramolecular Mitsunobu coupling of 1 then led to (-)-Aurantioclavine 3. Yoshiaki Nakao and Tamejiro Hiyama of Kyoto University and Sensuke Ogoshi of Osaka University developed (J. Am. Chem. Soc. 2008, 130, 12874) an enantioselective Ni catalyst for the cyclization of 4 to 5. Oxidation and cyclization then delivered (-)-Esermethole 6. Although the sulfonamide 7 appears to be prochiral, in fact its two most stable conformations are bent, and enantiomers of each other, with a significant barrier for interconversion. Katsuhiko Tomooka of Kyushu University separated (Tetrahedron Lett. 2008, 49, 6327) the enantiomers of 7, then carried the enantiomercially-pure 7 on, by Pd-catalyzed Cope rearrangement, to 8 and so to (-)-Kainic Acid 9. M.-Lluïsa Bennasar of the University of Barcelona prepared (J. Org. Chem. 2008, 73, 9033) the acyl selenide 11 from the indole 10. While the radical derived from 11 might have been expected to undergo 5-exo cyclization, in the event the 6-endo mode dominated, to give Dasycarpidone 12 and its diastereomer. Hiroyuki Ishibashi of Kanazawa University showed (Organic Lett. 2008, 10, 4129) that the radical cascade cyclization of the enamine 13, derived from diethyl tartrate, proceeded with remarkable diastereocontrol, to give 14. The amide 14 was converted to (-)-Cephalotaxine 15. Nobutaka Fujii and Hiroaki Ohno, also of Kyoto University, used (Organic Lett. 2008, 10, 5239) a Pd catalyst to mediate the cascade cyclization of 16 to 17. Although 16 has two stereogenic centers, including the allene, it is the aminated stereogenic center of 17 that sets the absolute configuration of the product Lysergic Acid 18. One intermediate in the conversion of 16 to the tetracyclic 17 is the tricyclic π-allyl Pd complex. If all the material could be channeled through that pathway, there is a good chance that the chiral Trost catalyst could effectively control the absolute configuration of the aminated stereogenic center as it is formed, leading to the enantiomerically enriched product 18.

Alkaloid Synthesis: (−)-α-Kainic Acid (Ohshima), Serpentine (Scheidt), (−)-Galanthamine ( Jia), (+)-Trigolutes B (Gong), Sarain A (Yokoshima/Fukuyama), DZ-2384 (Harran)

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Kainic Acid ◽  
Absolute Configuration ◽  
Diazonamide A ◽  
Antimitotic Activity ◽  
Alkaloid Synthesis ◽  
Northwestern University ◽  
Peking University ◽  
The Absolute ◽  
Sarain A ◽  
The University

(−)-α-Kainic acid 3 is widely used in neuropharmacological studies. En route to 3, Takashi Ohshima of Kyushu University found (Chem. Eur. J. 2015, 21, 3937) that the intramolecular ene cyclization of 1 delivered 2 with high diastereocontrol. Karl A. Scheidt of Northwestern University set (Angew. Chem. Int. Ed. 2015, 54, 6900) the absolute configuration of 5 and so of serpentine 6 by the organocatalyzed cyclization of 4. This is the first total synthesis of that alkaloid. Yanxing Jia of Peking University prepared (Angew. Chem. Int. Ed. 2015, 54, 6255) the benzofuran 8 by the Pd-mediated cyclization of the alkyne 7. An organo­catalyzed intermolecular Michael addition set the absolute configuration of (−)-galanthamine 9. Liu-Zhu Gong of the University of Science and Technology of China assem­bled (Chem. Eur. J. 2015, 21, 8389) (+)-trigolutes B 13 by the organocatalyzed addition of 10 to 11 to give 12. Barry M. Trost of Stanford University employed (Chem. Sci. 2015, 6, 349) a similar strategy in a synthesis of (−)-perophoramidine (not illustrated). Satoshi Yokoshima and Tohru Fukuyama of Nagoya University showed (Angew. Chem. Int. Ed. 2015, 54, 7367) that on deprotection, 14 was converted to an eight-membered cyclic nitrone, that further cyclized to 15. This set the stage for the synthesis of sarain A 16. Patrick G. Harran of UCLA has extensively studied the complex alkaloid (−)-diazonamide A (not illustrated). Structural simplification and optimization of antimitotic activity led to the macrolactam DZ-2384 18. It is exciting that 18 could be prepared (Angew. Chem. Int. Ed. 2015, 54, 4818) on a multigram scale by selective electrochemical oxidation of the much simpler precursor 17.

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.

Stereocontrolled Construction of C-N Rings: The Vanderwal Synthesis of Norfluorocurarine

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Absolute Configuration ◽  
Enantiomeric Excess ◽  
Silver Catalyst ◽  
West Virginia University ◽  
Science And Engineering ◽  
Enantiomerically Pure ◽  
The Absolute ◽  
Asymmetric Transformation ◽  
The University ◽  
Stereogenic Center

Forrest E. Michael of the University of Washington described (Organic Lett. 2009, 11, 1147) the Pd-catalyzed aminative cyclization of 1 to the differentially-protected diamine 3. Peter Somfai of KTH Chemical Science and Engineering observed (Organic Lett. 2009, 11, 919) that [1,2]-rearrangement of 4 proceeded to deliver 5 with near-perfect maintenance of enantiomeric excess. Tushar Kanti Chakraborty of the Central Drug Research Institute, Lucknow applied (Tetrahedron Lett. 2009, 50, 3306) the Ti(III) reduction of epoxides to the Sharpless-derived ether 6, leading to the pyrrolidine 7. Chun-Jiang Wang of Wuhan University devised (Chem. Commun. 2009, 2905) a silver catalyst that directed the absolute sense of the dipolar addition of 9 to 8 to give 10. Homoallyic azides such as 11 are readily prepared in high enantiomeric excess from the corresponding alcohol. Bernhard Breit of Albert-Ludwigs-Universität, Freiburg and André Mann of the Faculté de Pharmacie, Illkirch showed (Organic Lett. 2009, 11, 261) that Rh-mediated hydroformylation could be effected in the presence of the azide. Subsequent reduction delivered the piperidine 12. Jan-E. Bäckvall of Stockholm University applied (J. Org. Chem. 2009, 74, 1988) the protocol for dynamic kinetic asymmetric transformation (DYKAT) that he had developed to the cyanodiol 13. Remarkably, a single enantiomerically- pure diasteromer emerged, which he carried on to 14. Xiaodong Shi of West Virginia University found (Organic Lett. 2009, 11, 2333) that the stereogenic center of 17, even though it ended up outside the ring, directed the absolute configuration of the other centers of 18 as they formed. Jan Vesely of Charles University and Albert Moyano and Ramon Rios of the Universitat de Barcelona established (Tetrahedron Lett. 2009, 50, 1943) that an organocatayst directed the absolute configuration in the addition of 19 to 20 to give 21. Osamu Tamura of Showa Pharmaceutical University effected (Organic Lett. 2009, 11, 1179) cyclization of the malic acid-derived amide 22 to give 23 with high diastereocontrol.

Diels–Alder Cycloaddition: Sarcandralactone A (Snyder), Pseudopterosin (−)-G-J Aglycone (Paddon-Row/Sherburn), IBIR-22 (Westwood), Muironolide A (Zakarian), Platencin (Banwell), Chatancin (Maimone)

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Absolute Configuration ◽  
Alder Reaction ◽  
Diels Alder ◽  
University Of California ◽  
Enantiomerically Pure ◽  
Protein Protein Interaction ◽  
South Wales ◽  
National University ◽  
The Absolute ◽  
The University

En route to sarcandralactone A 3, Scott A. Snyder of Scripps Florida effected (Angew. Chem. Int. Ed. 2015, 54, 7842) Diels–Alder cycloaddition of the activated enone 1 to the Danishefsky diene. On exposure to trifluoroacetic acid, the adduct was unraveled to the ene dione 2. Michael N. Paddon-Row of the University of New South Wales and Michael S. Sherburn of the Australian National University prepared (Nature Chem. 2015, 7, 82) the allene 4 in enantiomerically-pure form. Sequential cycloaddition with 5 followed by 6 gave an adduct that was decarbonylated to 7. Further cycloaddition with nitro­ethylene 8 led to the pseudopterosin (−)-G-J aglycone 9. The protein–protein interaction inhibitor JBIR-22 12 contains a quaternary α-amino acid pendant to a bicyclic core. Nicholas J. Westwood of the University of St. Andrews set (Angew. Chem. Int. Ed. 2015, 54, 4046) the absolute configuration of the core 11 by using an organocatalyst to activate the cyclization of 10. Metal catalysts can also be used to set the absolute configuration of a Diels–Alder cycloaddition. In the course of establishing the structure of the marine natural prod­uct muironolide A 15, Armen Zakarian of the University of California, Santa Barbara cyclized (J. Am. Chem. Soc. 2015, 137, 5907) the enol form of 13 preferentially to the diastereomer 14. Unactivated intramolecular Diels–Alder cycloadditions have been carried out with more and more challenging substrates. A key step in the synthesis (Chem. Asian. J. 2015, 10, 427) of (−)-platencin 18 by Martin G. Banwell, also of the Australian National University, was the cyclization of 16 to 17. In another illustration of the power of the unactivated intramolecular Diels–Alder reaction, Thomas J. Maimone of the University of California, Berkeley cyclized (Angew. Chem. Int. Ed. 2015, 54, 1223) the tetraene 19 to the tricycle 20. Allylic chlo­rination followed by reductive cyclization converted 20 to chatancin 21.

The Reisman Synthesis of (+)-Salvileucalin B

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Absolute Configuration ◽  
Claisen Rearrangement ◽  
Primary Alcohol ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Diazo Ketone ◽  
The Absolute ◽  
Institute Of Technology ◽  
Highly Strained ◽  
Stereogenic Center

Salvileucalin B 3 exhibits modest cytotoxicity against A549 (human lung adenocarcinoma) and HT-29 (human colon adenocarcinoma) cell lines. The compelling interest of 3 is its complex, highly functionalized heptacyclic skeleton. Sarah E. Reisman of the California Institute of Technology envisioned (J. Am. Chem. Soc. 2011, 133, 774) that the intramolecular cyclization of the diazo ketone 1 could offer an efficient entry to 2 and thus to 3. The key intermediate for the preparation of 1 was the acid 11. It was not possible to achieve communication between the two stereogenic centers of 11, so the decision was taken to establish these independently. This led to a strategy centered on the construction of the 1,2,3,4-tetrasubstituted aromatic ring. The absolute configuration of the stereogenic center of 8 was set by enantioselective addition of 5 to the commercial aldehyde 4. The absolute configuration of the second center was set using the Myers protocol. Although 10 could not be hydrolyzed without epimerization, cyclization followed by hydrolysis was effective, delivering 11 as a 10:1 mixture of diastereomers. From the algebra of mutual resolution, the major diastereomer, separated at a later stage, was of high enantiomeric purity. The acid 11 was homologated, first by the Arndt-Eistert procedure, then by condensation of the methyl ester so prepared with the anion of acetonitrile. Exposure of the derived diazo nitrile 1 to Cu catalysis under brief microwave irradiation led to smooth cyclization to the hexacyclic ketone 2. Although the skeleton of 2 was readily assembled, it is highly strained. This was made clear on Dibal reduction of the derived enol triflate. The product was clearly not the desired aldehyde 2, but rather 12, the product of Claisen rearrangement. Reasoning that the Claisen rearrangement is thermally reversible, and that the ether 12 would be stable to hydride, they carried forward with Dibal reduction—and were rewarded by the appearance of the desired primary alcohol from the reduction of 2. Pd-mediated cyclocarbonylation delivered 13, which was selectively oxidized to (+)-salvileucalin B 3.

CD-Spectroscopic Investigations for the Determination of the Absolute Configuration of α-Alkylated 1,4-CycIohexanedione Derivatives

2000 ◽  
Vol 55 (11) ◽  
pp. 1011-1014 ◽  
Author(s):  
Jörg Fleischhauer ◽  
Sven Gabriel ◽  
Dieter Ender ◽  
Anja Nühring ◽  
Axel Wollmer
Keyword(s):  
Absolute Configuration ◽  
Membered Ring ◽  
Cd Spectra ◽  
Pure Material ◽  
Enantiomerically Pure ◽  
System 2 ◽  
The Absolute ◽  
Stereogenic Center ◽  
Rotational Strengths

The absolute configuration of the conformationally flexible six membered ring system 2-methyl- and 2,6-dimethyl-l,4-cyclohexanedione monoethylene acetal was determined by comparison of measured and calculated CD spectra. The rotational strengths were calculated by means of the CNDO/S-method assuming R at the stereogenic center. The results were compared with the predictions made by the octant rule. The enantiomerically pure material was synthesized via the corresponding SAMP- and RAMP-hydrazones.

(R)-1-(2-Hydroxy-5-methylphenyl)-N-[(S)-1-(2-methoxy-5-methylphenyl)-2-phenylethyl]butan-1-aminium chloride

2007 ◽  
Vol 63 (11) ◽  
pp. o4368-o4369
Author(s):  
Guang-You Zhang ◽  
Ming Li ◽  
Wan-Hui Wang ◽  
Xun-Gang Gu
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Absolute Configuration ◽  
Title Compound ◽  
Compound C ◽  
The Absolute ◽  
Stereogenic Center

2-{(R)-1-[(S)-1-(2-Methoxy-5-methylphenyl)-2-phenylethylamino]butyl}-4-methylphenol has been synthesized and its absolute configuration determined from the crystal structure of its hydrochloride, the title compound, C27H34NO2 +·Cl−. The absolute configuration of the stereogenic center that carries the 2-methoxy-5-methylphenyl substituent was found to be R. Intermolecular N—H...Cl and O—H...Cl and intramolecular N—H...O hydrogen bonds stabilize the structure.

CD-Spectroscopic Confirmation of the Absolute Configuration of a Conformationally Flexible Aldehyde Ester Containing a Quarternary Stereogenic Center

1998 ◽  
Vol 53 (10-11) ◽  
pp. 891-895 ◽  
Author(s):  
Jörg Fleischhauer ◽  
Axel Koslowski ◽  
Jan Schiffer ◽  
Axel Wollmer ◽  
Dieter Enders ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Structure Determination ◽  
Matrix Method ◽  
Aldehyde Ester ◽  
Cd Spectra ◽  
Perfect Agreement ◽  
X Ray ◽  
The Absolute ◽  
Stereogenic Center

Abstract The absolute configuration of the conformationally flexible aldehyde ester methyl-2-formyl-2-(phe-nylsulfanyl)-3-(3,4,5-trimethoxyphenyl)-propanoate was determined by comparison of measured and calculated CD spectra.The spectra were calculated by means of the so-called matrix method assuming R configuration at the stereogenic center. Calculated and observed signs of the first three most intense CD bands agree. Therefore, it was concluded that the absolute configuration of the compound was also R, which is in perfect agreement with the results of an X-ray structure determination.

Alkaloid Synthesis: (–)-α-Kainic Acid (Cohen), Hyacinthacine A2 (Fox), (–)-Agelastatin A (Hamada), (+)-Luciduline (Barbe), (+)-Lunarine (Fan), (–)-Runanine (Herzon)

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Kainic Acid ◽  
Aldol Condensation ◽  
Catalyst System ◽  
Diels Alder ◽  
Yale University ◽  
University Of Pittsburgh ◽  
Agelastatin A ◽  
Alkaloid Synthesis ◽  
Carbocyclic Rings ◽  
The University

The intramolecular ene cyclization is still little used in organic synthesis. Theodore Cohen of the University of Pittsburgh trapped (J. Org. Chem. 2011, 76, 7912) the cyclization product from 1 with iodine to give 2, setting the stage for an enantiospecific total synthesis of (–)-α-kainic acid 3. Intramolecular alkene hydroamination has been effected with transition metal catalysts. Joseph M. Fox of the University of Delaware isomerized (Chem. Sci. 2011, 2, 2162) 4 to the trans cyclooctene 5 with high diastereocontrol. Deprotection of the amine led to spontaneous cyclization, again with high diastereocontrol to hyacinthacine A2 6. Yasumasa Hamada of Chiba University devised (Org. Lett. 2011, 13, 5744) a catalyst system for the enantioselective aziridination of cyclopentenone 7. The product 8 was carried on to the tricyclic alkaloid (–)-agelastatin A 9. Guillaume Barbe, now at Novartis in Cambridge, MA, effected (J. Org. Chem. 2011, 76, 5354) the enantioselective Diels-Alder cycloaddition of acrolein 11 to the dihydropyridine 10. Ring-opening ring-closing metathesis later formed one of the carbocyclic rings of (+)-luciduline 13, and set the stage for an intramolecular aldol condensation to form the other. Chun-An Fan of Lanzhou University employed (Angew. Chem. Int. Ed. 2011, 50, 8161) a Cinchona-derived catalyst for the enantioselective Michael addition to prepare 14. Although 14 and 15 were only prepared in 77% ee, crystallization to remove the racemic component of a later intermediate led to (+)-lunarine 16 in high ee. Seth B. Herzon of Yale University used (Angew. Chem. Int. Ed. 2011, 50, 8863) the enantioselective Diels-Alder addition with 18 to block one face of the quinone 17. Reduction of 19 followed by methylation delivered an iminium salt, only one face of which was open for the addition of an aryl acetylide. Thermolysis to remove the cyclopentadiene gave an intermediate that was carried on to (+)-runanine 20.

Adventures in Alkaloid Synthesis: ( + )-α-Kainic Acid (Jung), 223AB (Ma), Pumiliotoxin 251F (Jamison), Spirotryprostatin B (Trost), (-)-Drupacine (Stoltz)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Kainic Acid ◽  
Enantiomeric Excess ◽  
Oxidative Cyclization ◽  
Substantial Contribution ◽  
University Of Southern California ◽  
Alkaloid Synthesis ◽  
Stereogenic Centers ◽  
Cu Catalyst ◽  
Natural Amino Acids ◽  
The University

Enantiomerically-pure natural amino acids can serve as starting materials for alkaloid synthesis. In his synthesis (J. Org. Chem. 2007, 72, 10114) of (-)-α-kainic acid 3, Kyung Woon Jung of the University of Southern California prepared the diazo sulfone 1 from (L)-glutamic acid. Rh-mediated intramolecular C-H insertion proceeded with the predicted high diastereoselectivity, to give the lactam 2, containing seven of the ten carbon atoms and two of the three stereogenic centers of (-)-α-kainic acid 3. The absolute configuration of the nitrogen ring system(s) can also be established by chiral catalysis. Dawei Ma of the Shanghai Institute of Organic Chemistry has developed (J. Am. Chem. Soc. 2007, 129, 9300) a chiral Cu catalyst that mediated the addition of alkynyl esters and ketones to the prochiral acylated pyridine 4 in high enantiomeric excess. The dihydro-pyridines (e.g. 5) so produced will be versatile starting materials both for alkaloid synthesis, as illustrated by the preparation of the Dendrobatid alkaloid 223AB 6, and for the production of pharmaceuticals. In his synthesis of the Dentrobatid alkaloid pumiliotoxin 251D 9, Timothy F. Jamison took (J. Org. Chem. 2007, 72, 7451) as his starting material another amino acid, proline. Ni-mediated cyclization of the epoxide 8 proceeded with high geometric and regiocontrol, to give 9. The chemistry to convert 7 into 8 with high diastereocontrol and without racemization is a substantial contribution that will have many other applications. In his synthesis (Organic Lett. 2007, 9, 2763) of spirotryprostatin B 12, Barry M. Trost of Stanford University also started with proline, which was readily elaborated to the oxindole 10. The question was, could the Pd-catalyzed decarboxylation of 10 be induced to provide specifically 11? Counting geometric isomers of the trisubstituted alkene, and allylic regioisomers, as well as diastereomers, there were sixteen possible products from this prenylation. Using chiral Pd control, the rearrangement proceeded with 14:1 regiocontrol, and 16:1 diasterocontrol. Oxidative cyclization of 11 then delivered spirotryprostatin B 12. The Cephalotaxus alkaloid (-)-drupacine 19 has five stereogenic centers, including four of the five positions on the cyclopentane ring.

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