Asymmetric syntheses of 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine

Asymmetric syntheses of both 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine, polyhydroxylated indolizidine alkaloids that act as selective glycosidase inhibitors, have been accomplished in seven steps. The key feature of our unique syntheses includes the stereoselective introduction of the C-3 and C-4 hydroxyl groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-controlled stereoselective transannulation of the resulting azoninone intermediate.     

Allylated monosaccharides as precursors in triple reductive amination strategies: synthesis of castanospermine and swainsonine

The feasibility of the triple-reductive amination reaction for the synthesis of complex indolizidine frameworks is illustrated by application to the potent glycosidase inhibitors castanospermine and swainsonine. The target compounds were obtained from known carbohydrate precursors in yields of 23 and 14%, over nine and 13 steps, respectively. The iodoetherification reaction of allylated monosaccharides was shown to be a practical reaction for the synthesis of the tricarbonyl precursors for the key triple reductive amination reactions.     

Stereocontrolled synthesis of substituted chiral piperidines via one-pot asymmetric 6π-azaelectrocyclization: asymmetric syntheses of (-)-dendroprimine, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine

The asymmetric one-pot 6π-azaelectrocyclization of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and (-)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0) catalyst stereoselectively produced the tetracyclic aminoacetal compounds, resulting from the four-bond formation accompanying by controlling the stereochemistry at the two asymmetric centers. The produced cyclic aminoacetals can be regarded as synthetic precursors of substituted chiral piperidines, and the syntheses of 2,4- and 2,4,6-substituted piperidines were realized from the obtained aminoacetals by the stereoselective hydrogenation of the double bond conjugated with the C-4 ester group and alkylation at the aminoacetal moiety. In addition, the stereoselective synthesis of an indolizidine alkaloid, (-)-dendroprimine, and its three stereoisomers, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine, were achieved.     

Titanium-Mediated Cyclization of omega-Vinyl Imides in Alkaloid Synthesis: Isoretronecanol, Trachelanthamidine, 5-Epitashiromine, and Tashiromine

A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means of titanium-mediated cyclization of omega-vinyl imides is described. The general procedure involves treatment of readily available omega-vinyl imides 9 and 10 with 2.5 equiv of cyclopentylmagnesium chloride in the presence of ClTi(O-i-Pr)(3) (1.1 equiv) and subsequent stereoselective reduction of the N-acylaminal group. The cis and trans ring junction stereoisomers can be stereoselectively prepared by catalytic hydrogenation (H(2), PtO(2), EtOAc) and NaCNBH(3) reduction (TFA, MeOH), respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target alkaloids 1-8 in good yields.     

Stereoselective synthesis of novel glyco-pyrano pyrrolidines/pyrrolizidines/indolizidines through intramolecular [3+2] cycloaddition approach

An efficient and stereoselective synthesis of novel furo-pyrano pyrrolidine/pyrrolizidine/indolizidine derivatives has been achieved by intramolecular [3+2] cycloaddition reaction of azomethine ylide generated in situ from O-allyl sugar-derived aldehyde and different secondary amino acids.     

Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-α-methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expansion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine intermediate that was transformed into (+)-lentiginosine.     

Stereoselective synthesis by double reductive amination ring closure of novel aza-heteroannulated sugars

We present here the stereoselective synthesis of a series of 2/3-N-pyrrolidine derivatives of glycosides produced by diastereoselective double reductive amination ring closure of 1,4-dicarbonyl compounds. These precursors were produced by tandem ozonolysis-reduction or Wacker oxidation of known alkenes. The potential of these new compounds as glycosidase inhibitors is illustrated for compound 16, showing selective inhibition of β-d-galactosidase.     

A New Asymmetric α-Amido-hydroxyalkylation Mediated by SmI_2

Polyhydroxylated indolizidine alkaloids, such as castanospermine (I) and swainsonine (II) are of longstanding interest due to their powerful glycosidase inhibitory activity. Asymmetric hydroxyalkylation via α-amido carbanions to form C-C bands would provide a convenient approach to these compounds. HO HO H OH H OH HO OH N N HO I II In continuation of our efforts in developing asymmetric α-amido-hydroxyalkylation method,1 we report a new SmI2 mediated flexible…     

Polyhydroxy alkaloids: chromatographic analysis

Polyhydroxy alkaloids are a burgeoning category of natural products that encompass several structural types and generally exhibit potent activity as inhibitors of glycosidases. As presently defined the group consists of monocyclic or bicyclic aLkaloids of the pyrrolidine, piperidine, pyrrolizidine, indolizidine and tropane classes, bearing two or more hydroxyl groups. These structural features render the compounds highly water soluble and frequently quite insoluble in non-hydroxylic solvents, so that their isolation and analysis by chromatographic means are consequently difficult. This problem is further confounded by the lack of a chromophore which would permit their detection by UV absorption. This review presents chromatographic techniques that have been successfully applied to the problem of isolating, purifying, detecting and analyzing polyhydroxy alkaloids.     

Hybrid sugars as glycosidase inhibitors en route to 2-deoxy-2-amino C-glycosyl amino acids

Sugar-azasugar hybrid molecules made up of d-galactose with nojirimycin-δ-lactam and pyrrolidine analogues are synthesized using intramolecular cyclization as a key step from 2-nitro galactal and found to be glycosidase inhibitors. Further, some of the intermediate compounds are converted into 2-deoxy-2-amino C-glycosyl glycines and C-glycosyl alanines.     

Intramolecular 5-endo-trig aminomercuration of beta-hydroxy-gamma-alkenylamines: efficient route to a pyrrolidine ring and its application for the synthesis of (+)-castanospermine and analogues

The intramolecular aminomercuration reaction of sugar-derived beta-hydroxy-gamma-alkenylamines 8a-c undergoes 5-endo-trig cyclization in high yield. The sugar-substituted pyrrolidines thus obtained were elaborated to the synthesis of polyhydroxylated indolizidine alkaloids, namely, castanospermine 1a, 1-epi-castanospermine 1b, and 8a-epi-castanospermine 1c, having promising glycosidase inhibitory activities.     

A New Route to Pyrrolidines: One-Step Cyclization of 1,4-Azido Alcohol Synthesis of 1,4-Dideoxy-1,4-Imino-L-Lyxitol

Several optically active 3,4-dihydroxy-2-hydroxymethyl pyrrolidines are potent α-glycosidase inhibitors; for example, 1,4-dideoxy-1,4-imino-D-lyxitol (1) is a powerful inhibitor of α-galactosidase.¹ Furthermore, pyrrolidine 1 can be easily converted into the indolizidine alkaloid swainsonine to which it is structurally related.² (-) Swainsonine exhibits α-D-mannosidase inhibitory activity and immunoregulatory activity. Certain swainsonine stereoisomers have glycosidase inhibitory activity as well, and therefore have attracted considerable interest.³ 1,4-Dideoxy-1,4-imino-L-lyxitol (2) (enantiomer of 1) could be of biological interest. This communication describes the first synthesis of 2, starting from D-ribonolactone.     

Asymmetric acylation of carboxamides having -2,5-bis(methoxymethoxymethyl)pyrrolidine moiety as a chiral auxiliary and stereoselective reduction of the resulting 2-alkyl-3-oxoamides

-2,5-Bis(methoxymethoxymethyl)pyrrolidine proved to be an excellent chiral auxiliary for the asymmetric acylation of the corresponding carboxamide enolates and the stereoselective Zn(BH₄)₂ reduction of the resulting 2-alkyl-3-oxo amides provided a useful alternative to asymmetric aldol reaction.     

An expeditious synthesis of an analogue of (−)-steviamine by way of the 1,3-dipolar cycloaddition of a nitrile oxide with a 1-C-allyl iminosugar

In our continuing effort to develop inhibitors of the mycobacterial galactan biosynthesis, we planned to synthesize original iminosugar-based analogues of UDP-galactofuranose by way of the 1,3-dipolar cycloaddition reaction between a 1-C-allyl iminosugar and a nitrile oxide, followed by the reductive cleavage of the resulting isooxazoline. In initial studies, it was found that this last step led in one pot to a new polyhydroxylated indolizidine derivative closely related to the recently isolated (−)-steviamine, in good yield, by way of a sequence involving at least five individual reactions. The activity of this new compound as a glycosidase inhibitor was evaluated against a panel of glycosidases and compared to (−)-steviamine.     

1,3-Dipolar cycloaddition reaction of D-glucose-derived nitrone with allyl alcohol: synthesis of 2-hydroxy-1-deoxycastanospermine analogues

[reaction: see text] The synthesis and evaluation of glycosidase inhibitory activity of polyhydroxylated indolizidine alkaloids namely 2-hydroxy-1-deoxycastanospermine 3a,b and 2-hydroxy-1-deoxy-8a-epi-castanospermine 3c,d is reported. The key step involves the intermolecular 1,3-dipolar cycloaddition of allyl alcohol to d-glucose-derived nitrone 4, followed by tosylation, that afforded four diastereomeric sugar-substituted isoxazolidines 5a-d with the desired regioselectivity. The one-pot conversion of 5a-d to pyrrolidines 8a-d by hydrogenolysis, removal of 1,2-acetonoide functionality, and hydrogenation afforded corresponding target molecules 3a-d.     

Asymmetric synthesis of 3-amino-4-hydroxy-2-(hydroxymethyl)pyrrolidines as potential glycosidase inhibitors

Three diastereoisomers of 3-amino-4-hydroxy-2-(hydroxymethyl)pyrrolidine have been synthesised by a divergent route starting from trans-4-hydroxy-L-proline. Regio- and stereoselective introduction of the 3-amino and 4-hydroxyl functional groups was achieved using either a tethered aminohydroxylation reaction or by employing intra- and intermolecular epoxide-opening strategies. Preliminary biological data indicate that two of these novel amino pyrrolidines are moderate inhibitors of beta-galactosidase.     

Synthesis of enantiomerically pure 4-substituted pyrrolidin-3-ols via asymmetric 1,3-dipolar cycloaddition

Asymmetric 1,3-dipolar cycloadditions of chiral azomethine ylides to 3-benzyloxy-substituted alkenoylcamphorsultams are described. trans-3,4-Disubstituted pyrrolidines containing a protected hydroxyl group at C(4) of the pyrrolidine ring are obtained in high diastereomeric ratios. Such compounds can serve as chiral building blocks for the syntheses of enantiopure bioactive pyrrolidines. This is exemplified by a short synthetic route to a known glycosidase inhibitor, (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol and its enantiomer.     

Asymmetric acylation of carboxamides having trans-2,5-bis(methoxymethoxymethyl)pyrrolidine moiety as a chiral auxiliary and stereoselective reduction of the resulting 2-alkyl-3-oxoamides

$\text{trans}$-2,5-Bis(methoxymethoxymethyl)pyrrolidine proved to be an excellent chiral auxiliary for the asymmetric acylation of the corresponding carboxamide enolates and the stereoselective Zn(BH₄)₂ reduction of the resulting 2-alkyl-3-oxo amides provided a useful alternative to asymmetric aldol reaction.     

New asymmetric strategy for the total synthesis of naturally occurring (+)-alexine and (−)-7-epi-alexine

A novel and highly convenient process is described for the asymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids, (+)-alexine [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine] and (−)-7-epi-alexine [(1R,2R,3R,7R,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], as the potent glycosidase inhibitors by featuring the efficient and stereodefined elaboration of the functionalized pyrrolidine derivatives, which were, in turn, prepared via stereoselective manipulation of the homochiral allyl alcohol precursors derived from l-xylose.     

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.