The total synthesis of the marine alkaloid halichlorine is described, based on an approach that involves constructing the fully substituted asymmetric center at an early stage. The five-membered ring is formed by 5-exo-trig radical cyclization and the unsaturated six-membered ring by a process that formally represents a sequential combination of conjugate addition and S(N)2' displacement-a method that is general for making bicyclic compounds with nitrogen at a ring fusion position. A formal synthesis of (+)-halichlorine is also reported, based on the development of a general method for preparing optically pure piperidines. The key step of this method, which was used to make one of our intermediates, is the Claisen rearrangement of a 4-vinyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester. Such O-vinyl compounds are easily generated in situ from the corresponding alcohols, which are themselves readily assembled from serine and terminal acetylenes.

The variety of alpha-diazo beta-keto esters (3a-f, 8a-f) with varying substituents (ED/EW) on the phenyl ring of the O-benzyl group were prepared. The rhodium(II) acetate catalyzed decomposition of diazo compounds in benzene reflux conditions. The ratio of 1,4 versus 1,2 migration product was determined. It was found that an increase in electron density on the benzylic carbon of the migrating group prefers 1,4 migration products (4, 9) while a decrease in electron density leads to a preponderance of 1,2 migration products (5, 10). The results obtained were correlated to the mechanistic aspect of the product selectivity. The intermediacy of the intramolecular oxonium ylide formation was demonstrated by crossover experiments. The preference for the formation of 2,3 sigmatropic rearrangement product over 1,2 and 1,4 was demonstrated by performing the reaction with alpha-diazo beta-keto esters (13a, 13b) with O-allyl and O-propargyl at C3. The effect of solvent, temperature, and mole percentage of rhodium(II) acetate was also studied.

The intramolecular aminomercuration of γ-alkenylamines 1a, 1b and 4 was shown to afford the 5-endo-trig cyclized product exclusively in good yield. The utility of pyrrolidine derivatives thus obtained from D-glucose derived γ-alkenylamines 1a and 1b was demonstrated in the synthesis of 1-deoxycastanospermine (3a) and 1-deoxy-8a-epi-castanospermine (3b).

The sequential C-and N-allylation of D-glucose-derived nitrone 2 provides the required diene functionality with nitrogen linker that was used in ring-closing metathesis pathway in the synthesis of quinolizidine alkaloids 1a and 1b.The ring-closing metathesis (RCM) of diene-substrate containing nitrogen functionality has found wide applicability in the synthesis of nitrogen heterocycles, alkaloids, peptides and peptidomimetics. 1 The utility of this approach with sugar substrates wherein the presence of a hydroxylated carbon framework and feasibility to manipulate the functional groups into the required dienefunctionality, containing a nitrogen atom, give an easy access towards the synthesis of a variety of aza-sugars. 2 This class of compounds, especially the polyhydroxylated indolizidine and quinolizidine alkaloids are promising glycosidase inhibitors with potential antibacterial, antiviral, antimetastatic, and antidiabetes activity. 3 Most naturally occurring quinolizidine alkaloids 4 are devoid of polyhydroxylated functionalities and in the search for structureactivity relationship, the hydroxylated unnatural analogues are interesting targets for obtaining the better understanding of mechanisms of action and in design of even more potent inhibitors. As a part of our continuing efforts in the synthesis of aza-sugars, 5 we have developed a new methodology for the synthesis of trihydroxy quinolizidine alkaloids 1a and 1b using ring closing metathesis of D-glucose derived dienes with nitrogen linkage as a key step. A few reports are available for the synthesis of polyhydroxylated quinolizidine alkaloids. 2e,h,o,6 However, only a single report describes the synthesis of 1b while the synthesis of 1a has been reported so far. 2e Recently, we have described the preparation and reaction of D-glucose nitrone 2 in the synthesis of 6-deoxynojirimycin. 5a Similarly, the reaction of nitrone 2 with allylmagnesium bromide in the presence of TMSOTf (1 equiv) at -78°C in dry THF afforded a mixture of D-gluco-and L-ido-diastereomers 3a and 3b in the ratio of 86:14 (Scheme 1). The absolute configuration at the newly generated C5 in 3a and 3b was established by comparing the 1 H NMR data. 7 The appreciable difference in R f values allowed us to separate 3a and 3b by flash chromatography. Subsequently, the N-benzylhydroxylamine (3a) was treated with zinc in acetic acid-water and N-O bond reductive cleavage afforded the N-benzylamino sugar 4a in good yield. The reaction of 4a with allyl bromide, in the presence of potassium carbonate in dry DMF, afforded N-allylated product 5a.