Lepadin synthesis

Lactacystin synthesis 196 Lasubine synthesis 134 Lepadin synthesis 142... 

Perhydropyrido[l,2-A][l,2]oxazines have been utilized as key intermediates in a stereospecific total syntheses of (—)-pumiliotoxin C and 5-< />z-pumiliotoxin C <1996J(P1)1113>, and the marine alkaloids (—)-lepadins A, B, and C and macrocyclic dilactones, (+)-azimine and (+)carpaine <20000L2955, 2001JOC3338, 2003OL3839>. In the total synthesis of the marine alkaloids ( )-fasicularin and ( )-lepadiformine, perhydro[l,2]oxazino[3,2 /]quinolines were used to control the stereochemistry <2000JA4583, 2000TL1205>. 

Synthesis of Heterocyclic Natural Products (-)-Ephedradine A, (-)-a-Tocopherol, (-)-Lepadin D, and (-)-Phenserine... 

A stereospecific route to enantiopure all-cis-2,3,6-trisubstituted piperidines relies on a cyclization step that is dependent upon temperature, and choice and quantity of base (Scheme 42) <2003TL3963>. Further intramolecular alkylation reactions reported include that of the chiral enaminone to the bicylic structure 35, a key intermediate toward the synthesis of lepadin alkaloids (Equation 80) <2004AGE4222>. 

Here, we achieved the first enantioselective total synthesis of clavepictines A and B, pictamine, and lepadin B starting from the... 

Kibayashi s group also completed the total synthesis of lepadins A, B, and C[20]. 

Ozawa, T., Aoyagi, S., Kibayashi, C. Totai Synthesis of the Marine Aikaioids (-)-Lepadins A, B, and C Based on Stereocontrolled intramoiecuiar Acyinitroso-Dieis-Aider Reaction. J. Org. Chem. 2001, 66, 3338-3347. 

Miscellaneous ring closure reactions involving carbon-carbon bond formation are shown in Scheme 72 and 73. An oxidation-cyclization-oxidation process was effected by PCC to convert alcohols 197 to 4-piperidones 198 <04JOC3226>. Intramolecular alkylation was used to covert chiral enaminone 199 to 200, a key intermediate in the total synthesis of lepadin alkaloids... 

The hetero Diels-Alder reaction <01H1591, 01TL5693> and dipolar cycloadditions continue to constitute important approaches to piperidines. Kibayashi and co-workers used an intramolecular acylnitroso Diels-Alder reaction to synthesize (-)-lepadins A,B, and C from an acyclic precursor <01JOC3338>. An intramolecular nitrone cycloaddition was used by Machetti and co-workers to produce both enantiomers of 4-oxopipecolic acid <01T4995>. Their synthesis proceeds from a nitrone bearing an a-methylbenzylamine chiral auxiliary. Noteworthy in this report is the presence of large-scale experimental procedures the nitrone formation and cycloaddition reactions were performed on 285 mmol and 226 mmol scales, respectively. 

This question arose in a synthesis of lepadin 8.429 in which the natural product was to be built up from the simpler unsaturated bicyclic amine 8.430, using the secondary alcohol to direct reduction of the diene... 

Total Synthesis by Alkene Metathesis Amphidinolide X (Urpi/Vilarrasa), Dactylolide (Jennings), Cytotrienin A (Hayashi), Lepadin B (Charette), Blumiolide C (Altmann)... 

In 2008, Blechert et al. reported the total synthesis of e/jt-lepadin F (89) and G (90) by a tandem ene-yne-ene RCM [74]. Lepadins are members of marine alkaloids with decahydroquinoline framework. As a key step in their synthesis (Fig. 26) they planned to construct the decahydroquinoline core skeleton by a selective tandem ene-yne-ene RCM of the dienyne precursor (91). Craiceivably, two different reaction pathways could be expected (1) initiation of metathesis may occur at the terminal double bond followed by two consecutive RCMs to afford the desired 6/6 bicycle (92) or (2) initiation may occur on the disubstituted alkene followed by tandem RCMs to produce the undesired 5/7 bicycle (93). Considering the preference of initiation on monosubstituted double bond as well as the directing effect of free hydroxyl group, pathway (1) may be more favored. Gratilyingly, treatment of dienyne (91) with 10 mol% Gmbbs I catalyst smoothly provided the desired 6/6 bicycle (92) in 90% yield. 

We commenced our synthesis of (-l-)-lepadin F by submitting vinylogous amide 321 and an a,(3-unsamrated iminium salt 333 to aza-[3+3] cycloaddition conditions affording core dihydropyridine 329 in 70% yield with 96 4 diastereoselectivity (Scheme 12.81). Osmium tetroxide... 

At this stage, we were ready to complete the total synthesis of (+)-lepadin F by installing the side chains. To this end, a two-step sequence of Dess-Martin periodinane oxidation and NaBHq reduction was performed to invert the C3-alcohol to its desired stereochemistry (Scheme 12.83). This resultant alcohol was then silylated to give sUyl ether 338 in 91 % yield over three operations. A DIBAL-H reduction of the ester in... 

Our spectroscopic data for (+)-lepadin F matched those reported by Carroll and coworkers [155] for the natural (+)-lepadin F and Blechert s synthetic sample [162], thereby allowing us to claim a completed total synthesis. Yet we believe there is a high margin of error in determining the C5 stereochemistry, since not only was the C5 stereocenter never defined in the isolation report, but also the C5 stereocenter is acyclic and highly insulated on the side chain. Consequentiy, we synthesized the C5 epimer of (+)-lepadin F commencing with advanced intermediate aldehyde 339 and sulfone (E)-340 in the requisite Kocienski-modified Julia olefination (Scheme 12.84) [166]. Spectroscopic comparisons of both H- and C-NMR data sets of our synthetic (+)-lepadin F and (+)-5 -epi-lepadin F with the natural (+)-lepadin F of Carroll and coworkers enabled us to confirm the correct relative stereochemistry at C5 in (+)-lepadin F as S. 

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