Synthesis of - -Lasubine II

Following the studies on the synthesis of halosatine, Blechert and Zaja presented the synthesis of (—)-lasubine II [48]. Cyclopentenone 107 was chosen as the metathesis substrate in order to avoid the failure of the CM step observed in 98 with the incorporation of the bulky TBS group. Rearrangement of 107 in the presence 

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The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

The second synthesis of lasubine II (6) by Narasaka et al. utilizes stereoselective reduction of a /3-hydroxy ketone O-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-/3-amino alcohol (Scheme 5) 17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehyde was converted to 46 in 64% yield via alkylation with 2-bromo-l,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with O-benzylhydroxylamine hy-... 

The third synthesis of lasubine II (6) involves stereoselective intramolecular nitrone cycloaddition as a key step (Scheme 6 (19). The hydroxylamine 54 was obtained from 3,4-dimethoxybenzaldoxime (52) by reflux in carbon tetrachloride with ethylene glycol boronate 53 in 68% yield. Condensation of 54 with methyl 5-oxopentanoate (55) afforded the nitrone 56, which was directly subjected to cycloaddition in refluxing toluene to give a l-aza-7-oxanorbomane (57) in 50%... 

The dihydropyridines resulting from analogous reactions of /V-acyl- or N-alkoxycarbonylpyridinium salts may be isolated and characterized moreover, they are valuable intermediates in elegant syntheses of alkaloids. What is more, the /V-alkoxycarbonylpyridinium salts may be generated in situ by the reaction of the pyridine with a chloroformate even in the presence of a Grignard reagent [9], An example is a four-step synthesis of ( )-lasubine II (Scheme 5.2), and a procedure is given for the key step [10]. 

The same two ketones featured again in a synthesis of ( )-lasubine II (910) by Pilli et al. (Scheme 119) (368,369). In this case, reaction of A -Boc-2-ethoxypiperidine (925) with enone 926 in the presence of trimethylsilyl triflate sparked off a remarkably efficient (90%) one-pot synthesis involving condensation (via an A -acyliminium ion to give the intermediate 927), deprotection, and intramolecular conjugate addition. The familiar products 921 and 922 were obtained as a 3 2 mixture. Base-induced epimerization of the mixture enriched the latter component, which was converted into ( )-910 by reduction with LS-Selectride (lithium trisiamylborohydride) according to the procedure developed by Comins (vide infra). 

Synthesis of (—)-Lasubine II. A reductive desulfonylation with lithium in ammonia is employed in the total synthesis of quinolizidine alkaloid (—)-lasubine II.264 A conjugate addition of methyl (.S )-(2-pipcridyl)acetate to an acetylenic sulfone, followed by lithium diisopropylamide (LDA)-promoted intramolecular acylation is the key step in the preparation of the quinolizine structure of (—)-lasubine II (Eq. 154). 

Yu, R. T., Rovis, T. (2006). Enantioselective rhodium-catalyzed [2-I-2-I-2] cycloaddition of alkenyl isocyanates and terminal alkynes application to the total synthesis of (+)-lasubine II. Journal of the American Chemical Society, 128,12370-12371. 

Routes Employing Late-Stage Bond Formation to C-1 A one-pot N-alkylation/intramolecular conjugate addition/cyclization sequence of reactions between methyl 7-iodohept-2-ynoate (1348) and the chiral amine 1349 was the starting point in the synthesis of (—)-lasubine II (1342) by Ma and Zhu (Scheme 168). The reaction, carried out in... 

The tetra-O-pivaloyl derivative of P-D-galactopyranosylamine was employed as a chiral auxiliary in the synthesis of (—)-lasubine II (1342) by... 

Carretero s chiral 2,6-a5-disubstituted piperidin-4-one intermediate (+)-1423," "" used in the previously described synthesis of (+)-lasubine II (e i-1342) (cf Scheme 180), also made an appearance in a synthesis of (+)-lasubine I (e i-1341) (Scheme 187). In this variant, detosylation of 1423 to (—)-1466 was followed by N-alkylation with l-chloro-4-iodobu-tane and halogen exchange of the alkylated product with sodium iodide under Finkelstein conditions to give the iodo product (—)-1467. The free-radical species generated by treating 1467 with tributyltin hydride in the presence of AIBN underwent fairly efficient (69%) diastereoselective cychzation to the ketone (+)-e i-1377, but also produced a small quantity (16%) of the dehalogenated product (—)-1468. The ketone was reduced in... 

In contrast to all of the previous routes, the formal synthesis of (—)-lasubine II (1342) by Aube and coworkers not only used rearrangement for building the quinolizidine ring but also incorporated the 3,4-dimethoxyphenyl substituent only at the end of the sequence (Scheme 189). Their route began with the precursor (S)-(—)-1471, a familiar building block for prostaglandin... 

Use of the phosphoramidite ligand (-)-199 proved to be crucial for the enantioselective rhodium-catalyzed crossed [2 + 2 + 2] cycloaddition of alkenyl isocyanate 197 with phenylacetylene 198, which provided the vinylogous amide 200 in 62% yield (98% ee). Thereafter, cycloaddition product 200 underwent a diastereoselective hydrogenation followed by a Mitsunobu reaction to complete the total synthesis of (+)-lasubine II (201). 

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