Synthesis and evaluation of isourea-type glycomimetics related to the indolizidine and trehazolin glycosidase inhibitor families

A practical synthesis of reducing isourea-derived azasugar glycomimetics related to the indolizidine and trehazolin glycosidase inhibitor families with different pK(a) values is disclosed. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves the preparation of a 5-deoxy-5-carbodiimido adduct by triphenylphosphine-mediated tandem Staudinger--aza-Wittig-type coupling of azide and isothiocyanate precursors, intramolecular cyclization of a transient vic-hydroxycarbodiimide derivative, and nucleophilic addition of the endocyclic nitrogen atom of the generated 2-amino-2-oxazoline intermediate, with a pseudo-C-nucleoside structure, to the masked aldehyde group of the monosaccharide. The last step is pH-dependent so that the final compounds can pivot between the furanose and the 2-oxaindolizidine forms. Nevertheless, the indolizidine tautomer having the R configuration at the aminoacetalic center, fitting the anomeric effect, was the only species detected in solution at neutral or slightly acidic pH when starting from solutions at basic pH. Glycosidase inhibition tests (K(i) values down to 1.9 microM) showed a marked dependence of the selectivity and potency toward alpha- and beta-glucosidases upon the nature of the substituent at the exocyclic isourea nitrogen, shifting from alpha- to beta-selectivity when going from hydrophilic to hydrophobic substituents. Enzyme inhibition is also pH dependent, supporting a dominant role for the uncharged form of the polyhydroxyiminoindolizidine system in the inhibition of beta-glucosidases.     

Solid-phase synthesis of indolizidine and quinolizidine derivatives

An efficient method for the construction of simple indolizidine and quinolizidine derivatives on solid support has been developed. An intramolecular tandem Michael reaction initiated by the nucleophilic attack of a suitably placed amino group on the tethered Wittig condensation products between 4- or 5-aminoaldehydes attached to a trityl chloride resin and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-b utanon e is the key step.     

A new synthetic method for an indolizidine skeleton by C-N bond formation via a pi-allylpalladium complex

Pd(0)-catalyzed intramolecular cyclic reaction via a pi-allylpalladium complex provided an indolizidine skeleton in satisfactory high and reproducible yields by using allylic compound having an acetoxyl group as a leaving group. These results must be available for syntheses of various functional indolizidine alkaloids.     

Diversity-oriented syntheses of 7-substituted lentiginosines

Diversity-oriented synthesis of derivatives of the potent glycosidase inhibitor lentiginosine can be achieved in an efficient and versatile way by two modular approaches on key intermediates. After assembling the indolizidine ring system through 1,3-dipolar cycloaddition of a dihydroxylated pyrroline N-oxide with 4-butenol followed by elaboration of the isoxazolidine moiety, the 7-amino and 7-azido derivatives synthesized can be conjugated with functionalised chains by coupling, respectively, with an amino acid, or an alkyne in copper-catalyzed Huisgen cycloadditions.     

Stereoselective synthesis of polyhydroxylated quinolizidines from C-glycosides by one-pot double-conjugate addition

An effective one-pot synthesis of polyhydroxylated quinolizidines from 1-C-(2'-oxo-4'-pentenyl)-5-azido-C-glycofuranosides was developed. Reduction of the 5-azido group using triphenylphosphine followed by base treatment produced quinolizidines in good yield. The base-mediated ring-opening beta-elimination produced an acyclic alpha,beta-conjugated ketone as a Michael acceptor, which was followed by an intramolecular nitrogen conjugate addition to form an aza-C-glycopyranoside intermediate. Meanwhile, the beta,gamma-double bond of the aglycon migrated under the basic conditions to form another alpha,beta-conjugated ketone. The subsequent intramolecular conjugate addition by the azasugar nitrogen led to the formation of the quinolizidines in a highly stereoselective manner. The stereoselectivity of the first conjugate addition giving azasugar is affected by the stereochemistry of the monosaccharide substrate, whereas the stereoselectivity in the second conjugate addition was likely directed entirely by steric repulsion from the azasugar.     

Reductive transformations of unsaturated azabicyclic nitrolactams

Using different reducing methods unsaturated indolizidine and quinolizidine lactams substituted with a nitro group were transformed into various alkaloid-like derivatives. Hydrogen transfer and palladium catalyzed hydrogenation gave compounds of ketolactam or lactam type meanwhile the nitro group was eliminated. On the other hand, in presence of Raney-nickel catalyst the nitro compounds were reduced to diastereomeric amino derivatives whose stereochemistry was elucidated by NMR spectroscopy. Using sodium bis-dimethoxy-ethoxy-aluminum-hydride (Red-Al) as reducing agent an unexpected tricyclic azetidine was isolated and characterized.     

Variable and stereoselective synthesis of azasugar analogues by a ruthenium-catalyzed ring rearrangement

A novel ruthenium-catalyzed ring opening/ring closing tandem metathesis reaction with a catalytic transfer of stereocenters from a ring to an olefinic chain is described. This ring rearrangement serves as the key step in the stereoselective synthesis of the new azasugar analogues 1 and 2.     

Stereoselective synthesis of partially protected azasugar derivatives

Five-membered azasugar derivatives with partially protected hydroxyl groups, and their fluorinated derivatives were synthesized via the key intermediates of norbornyl-like bicyclic acetals using d-xylose and d-glucose as starting materials. The glycosylation of the azasugar intermediate and 1-methylenesugar was also explored. Translated from Chemical Journal of Chinese Universities, 2006, 27 (4) (in Chinese)     

A concise sequential photochemical-metathesis approach for the synthesis of (+)-castanospermine and possible uniflorine-A stereoisomers

A recently developed strategy for polyhydroxylated indolizidine ring construction has been applied to the synthesis of (+)-castanospermine and possible isomers of uniflorine-A. The routes to these targets rely on the use of the earlier discovered photocyclization reaction of pyridinium perchlorate in a concise route for preparation of a key N-allylacetamidocyclopentendiol intermediate. Ring rearrangement metathesis of this substance gives an allyl-tetrahydropyridine, which is then transformed to the targets by execution of regio- and stereo-controlled hydroxylation processes followed by indolizidine ring construction.     

Radical-mediated hydroalkylation of 2-vinylpyrrolidine derivatives: a versatile entry into indolizidine alkaloids

A concise route for the preparation of two simple optically pure indolizidin-5-ones has been developed. The key chain elongation process was achieved using a triethylborane/catechol mediated hydroalkylation of Boc-protected 2-vinylpyrrolidines. By using complementary strategies, these two bicyclic lactams can be alkylated with complete control of the stereochemistry at C(5) and their conversion to a variety of indolizidine alkaloids such as coniceine, indolizidine 209 D and 167 B, 5-epi-indolizidine 249A and monomorine has been reported in the literature.     

Tuning the acceptors in catalyzed cyclizations initiated by allenes. Silylstannylation/cyclization of allene-aldehydes for synthesis of polyalkylated indolizidines including 223A congeners

Starting from succinamide and 1,2-heptadiene-4-ol, a racemic allene-aldehyde substrate, 20, suitable for R(3)SiSnR'(3)-mediated cyclization was synthesized in six steps and in 21% yield. Stereoselective cyclization (relative cis configuration at the new stereogenic centers of the homoallyl alcohol generated) proceeded smoothly, giving a mixture of indolizidinols bearing five contiguous stereocenters in a combined yield of 80%. Relative configurations of each of the products were unequivocally established by a combination of 2D NMR experiments and single-crystal X-ray analysis. The major indolizidinol obtained in 32% yield was elaborated into indolizidine 5,8-epi-indolizidine 223A via a five-step reaction sequence in 32% overall yield. The second major component (24%) of the key cyclization yielded, in four steps, indolizidine 6,8-epi-223 in 14% yield. Even though revision of the initially postulated structure foiled our original synthetic plans for the natural product, indolizidine 223A, the new stereoselective cyclization strategy and several selective transformations of the indolizidine derivatives reported here may find further applications for the synthesis of highly alkylated indolizidine and other related alkaloids.     

Amidyls in radical cascades. The total synthesis of (±)-aspidospermidine and (±)-13-deoxyserratine

Concise routes to aspidospermidine and 13-deoxyserratine are described, hinging on a cascade starting from an amidyl radical and allowing the construction of the key indolizidine cores in one step.     

Enantiospecific synthesis of an indolizidine alkaloid, (+)-ipalbidine

Enantiospecific total synthesis of an indolizidine alkaloid, ipalbidine, was achieved starting from (−)-pyroglutamic acid by employing an intramolecular McMurry coupling reaction with a low-valent titanium, as a key step.     

De novo asymmetric synthesis of D- and L-swainsonine

[reaction: see text] The enantioselective syntheses of both enantiomers of the indolizidine natural product swainsonine have been achieved in 13 steps from furan. The indolizidine ring system is installed by a one-pot hydrogenolysis of both an azide and an O-Bn group along with an intramolecular reductive amination reaction. The asymmetry of swainsonine was introduced by Noyori reduction of an acylfuran. This route relies upon an Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, Luche reduction, and a dihydroxylation reaction.     

Stereoselective synthesis of azasugar thioglycosides

Bicyclic (2-oxapyrrolizidines) and monocyclic (piperidine) azasugar ethyl thioglycosides, a new type of azasugar derivative, are stereoselectively prepared from suitable glycosylenamines, through anhydroazasugar derivatives.     

Total synthesis of (+)-ent-cyclizidine: absolute configurational confirmation of antibiotic M146791

The first total synthesis of the enantiomer of the indolizidine alkaloid, cyclizidine, was accomplished from readily available d-serine as the starting chiron. The relevant key reactions involve the stereocontrolled construction of the indolizidine ring system with the required functionality and further elaboration to install the cyclopropyl dienyl side chain. With this total synthesis, the absolute configuration of the natural product based on a redetermination of its X-ray structure has been confirmed.     

Epoxide-initiated cationic cyclization of azides: a novel method for the stereoselective construction of 5-hydroxymethyl azabicyclic compounds and application in the stereo- and enantioselective total synthesis of (+)- and (-)-indolizidine 167B and 209D

A novel and general method has been developed for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide-initiated cationic cyclization of azides. The key cyclization reaction was systematically studied with the model compound, 3-(1-oxa-spiro[2.4]hept-4-yl)propyl azide 3a, and EtAlCl(2) was found to be an ideal choice as the catalyst. The generality of this transformation was further tested with different ring sizes, where six- and seven-membered epoxyazides 3b,c underwent smooth cyclization to give 5-hydroxymethyl azepine 4b and 5-hydroxymethyl azocine 4c, respectively, as a single detectable diastereomer. This novel methodology was elegantly applied in the stereoselective total synthesis of indolizidine alkaloids 167B and 209D. Further, the enantioselective total synthesis of natural and unnatural indolizidine alkaloids 167B and 209D was accomplished by using Sharpless asymmetric dihydroxylation as a key step.     

De Novo Asymmetric Syntheses of d-, l- and 8-epi-Swainsonine

A highly enantioselective and stereocontrolled approach to d-, l- and 8-epi-d-swainsonine has been developed from achiral furan and γ-butyrolactone. A one-pot hydrogenolysis of both azide and benzyl ether followed by an intramolecular reductive amination has been employed as key step to establish the indolizidine ring system. The absolute stereochemistry was installed by the Noyori reduction and the relative stereochemistry by the use of several highly diastereoselective palladium-catalyzed glycosylation, Luche reduction, dihydroxylation, and palladium-catalyzed azide allylation reactions. This practical approach provide multigram quantities of indolizidine natural product d-swainsonine in 13 steps and 25% overall yield.     

A concise and convergent route to 5,8-disubstituted indolizidine and 1,4-disubstituted quinolizidine ring cores by diastereoselective aza-Diels-Alder reaction

[reaction: see text] A short and convergent synthesis of 5,8-disubstituted indolizidine and 1,4-quinolizidine scaffolds is described. The key steps of the synthetic pathway are the aza-Diels-Alder reaction of a 2-aminodiene with an N-allyl or N-homoallylaldimine and a ring-closing metathesis. The bicyclic alkaloid analogues are obtained with total diastereoselectivity and through a common pathway.     

Convergent approach to pumiliotoxin alkaloids. Asymmetric total synthesis of (+)-pumiliotoxins A,B, and 225F

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation[bond]cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh(3))(4) catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.