Lasubine, synthesis

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

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

Another example of this useful domino process is the enantioselective synthesis of the quinozilidine alkaloid (-)-lasubine II [234]. Condensed tricyclic compounds as 6/3-28 can also be prepared from norbomene derivatives 6/3-27 in excellent yield, as shown by Funel and coworkers (Scheme 6/3.6) [235]. 

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... 

Natural Product Synthesis Using Grubb Metathesis Lasubine II, Ingenol, and Ophirin ... 

Practitioners of total synthesis have been pushing the limits of Grubbs metathesis. Siegfried Blechert of the Technisches Universitat, Berlin, envisioned (Tetrahedron 2004,60,9629) that Grubbs metathesis of 1 could open the cyclopentene, to give a new Ru alkylidenc that could condense with a styrene such as 2. In practice, this transformation worked well, yielding 3. Deprotection, intramolecular Michael addition and reduction then gave (-)-lasubine II4. 

Natural Product Synthesis using Grubbs Metathesis Lasubine II, 134... 

Cross metathesis (CM) reactions can also be used as the key step in a piperidine synthesis (Scheme 40) <2004TL1167> or in sequence with ring-rearrangement metathesis, for example, in the synthesis of (—)-lasubine (Scheme 41) <2004T9629>. 

Conjugate addition.s The key step in a stereocontrolled synthesis of the Lyth-raceae alkaloid lasubine II (4) is the conjugate addition of an alkylcopper complexed with BF3 to the N-acyl-2,3-dihydro-4-pyridone 1 to give the d.v-product 2 in 56% yield and >96% stereoselectivity. Hydrogenation in the presence of Li2C03 effects cyclization and deprotection of nitrogen to give the ketone 3, which is reduced stereoselectively by lithium trisiamylborohydride to the desired alcohol 4. 

The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine 1 (2) utilizes the intramolecular tt cyclization of an /V-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions... 

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 acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic /3 lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (-)-lasubine (I). Tin tetrachloride mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be aUylated with high diastereoselectivity to give optically active homoaUyhc amines (Scheme 87). 

The same chiral auxiliary has also been used for the stereoselective synthesis of arene-chromium complexes treatment of an aromatic aminal with chromium hexacarbonyl gives the corresponding complex with high diastereomeric excess. This protocol was recently applied in a total synthesis of (—)-lasubine (eq 4). A successful application of 1,2-diaminocyclohexane (as its IR,2R enantiomer) as a chiral auxiliary is illustrated by the di-astereoselective alkylation of the potassium enolate of bis-amide (3) with electrophiles such as benzyl bromide to give bis-alkylated products with excellent diastereoselectivity (eq 5). Lower levels... 

Lythraceous alkaloids include several 4-arylquinolizidin-2-ols and their esters, as well as a variety of piperidine- and quinolizidine-based maciocyclic variants (macrolides, cyclophanes) possessing biaryl linkages. Only the former groiq> is relevant to this review. No new simple quinolizidine metabolites have been reported for over two decades, and recent publications have dealt almost exclusively with the synthesis of fom alkaloids, lasubine I (909), lasubine II (910), and their 3,4-dimethoxyciimamate esters subcosine I (911) and subcosine II (912) (Fig. 17). The naturally occurring enantiomers are represented in the diagrams. 

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). 

Reactions of A -3-alkenyl nitrones are less stereoselective, and different stereoisomers of the same regioisomeric product are obtained101 102. In a synthesis of the alkaloid lasubine II, the thermal cycloaddition of the nitrone 1 gave an 83 10 7 mixture of bridged l-aza-7-oxabi-cyclo[2.2.1]heptanes, the major isomer possessing the correct stereochemistry for conversion into the natural product101. 

Sequential RRM and cross metathesis (CM) reactions were used in a carefully-designed step in a synthesis of (-)-lasubine 125. The cyclopentenone 126 undergoes RRM to provide the intermediate 127, which reacts with 128 in a CM to provide the intermediate 129 <04T9629>. 

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