Preparation and reactivity of imino glycals: stereocontrolled,divergent approach to imino sugars

The synthesis of 3,4,6-tri-O-acetyl imino D-glucal 2 from D-glucal is reported. This imino glycal participates in a variety of Lewis acid mediated carbon-carbon bond forming reactions by allylic displacement of the C-3 acetate group by added nucleophiles. Allyl silanes, trimethylsilyl enol ethers, alkenes and dialkyl zinc reagents serve as suitable reaction partners. In all the cases studied, the beta-anomer is predominant. Using imino glycal 8, epimeric at C-5, it is established that the configuration at C-5 of the piperidine ring plays a major role in controlling the stereochemical outcome. These results are rationalised by invoking the intermediacy of a conjugated N-acyliminium ion. A short stereocontrolled synthesis of (+)-deoxoprosophylline is achieved using this chemistry. Additionally, imino glucal 2 is transformed into bromo piperidine 16, whose X-ray crystal structure is determined. Bromide 16 participates in palladium catalysed Stille and Suzuki cross-couplings allowing access to C-2 substituted imino sugars 17 and 18. In other studies, imino sugar C-glycosides 21 and 22 are made by combining the Lewis acid mediated carbon-carbon bond forming reactions with stereospecific dihydroxylations.     

Diastereoselective nitrenium ion-mediated cyclofunctionalization: total synthesis of (+)-castanospermine

The asymmetric total synthesis of the α-glucosidase inhibitor (+)-castanospermine is reported. The central theme in our approach to this polyhydroxylated alkaloid is the simultaneous generation of the piperidine ring and the C-1/8a erythro stereodiad through the diastereoselective, oxamidation of an unsaturated O-alkyl hydroxamate. This process is believed to proceed sequentially via singlet acylnitrenium and aziridinium ion intermediates.     

Asymmetric synthesis of (+)-tetrahydropseudodistomin

An efficient asymmetric synthesis of (+)-tetrahydropseudodistomin is described. The important synthetic features include a Maruoka asymmetric allylation and a Sharpless asymmetric dihydroxylation as key steps for the generation of chirality at C-2, -4, and -5 of the trisubstituted piperidine ring.     

Asymmetric synthesis of (2S,3R)-(−)-epi-CP-99,994 using sulfinimine-derived anti-2,3-diamino esters

A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(−)-epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dibenzylamino group.     

First asymmetric synthesis of trans-3,4-dimethyl-4-arylpiperidines

The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was established via CBS reduction and stereoselective anti-SN2' cuprate displacement of the derived allylic phosphonate. The resultant vinyl bromide was then elaborated to the target compound by Suzuki coupling and trans-selective 4-methylation. Extension of this methodology should allow general enantioselective access to highly substituted piperidine ring systems.     

Development of a one-pot asymmetric azaelectrocyclization protocol: synthesis of chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines

[reaction: see text] A one-pot procedure for tetracyclic chiral aminoacetals, the useful precursors for substituted piperidine synthesis, has been established via Stille-Migita coupling, 6pi-azaelectrocyclization, and aminoacetal formation from readily prepared vinylstannanes, vinyliodides, and cis-aminoindanol derivatives. Based on the method, chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines, bearing a variety of aromatic substituents at the C-2 position, have been prepared.     

Synthesis of a New C-15 Phosphorus Ylide Used for the Preparation of Some β-End-Group Retinoid Derivatives

A synthesis of a new C-15 phosphorus ylide from a C-14 enaminone is reported. This reagent, which undergoes selective 1,2- or 1,4-additions with saturated and unsaturated aldehydes, may find some synthetic use for the preparation of β-end-group retinoid derivatives.     

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases

A simple protocol for the synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid, with a secondary cyclic amine (morpholine or piperidine) at the 4α position, has been set-up, starting from peracetylated N-acetylneuraminic acid methyl ester that undergoes, sequentially to its direct N-transacylation followed by a C-4 amination, a β-elimination, and a selective hydrolysis of the ester functions, without affecting the sensitive perfluorinated amide.     

Chemoenzymatic synthesis of isogalactofagomine

A new chemoenzymatic synthesis of optically pure isogalactofagomine 2 starting from achiral starting materials is presented. Dimethyl 4-hydroxypyridine-3,5-dicarboxylate (7) was synthesized and converted to the corresponding saturated piperidine 8. Then the key step of the synthesis was carried out: Lipase M catalyzed hydrolysis of the prochiral diester 8 to cause formation of an asymmetric monoacid with at least 98% enantiomeric excess. Reduction of the acid, saponification of the remaining ester, and radical iododecarboxylation gave an iodide that after substitution with silver trifluoroacetate and hydrolysis gave 2.     

Gold-catalyzed synthesis of oxygen- and nitrogen-containing heterocycles from alkynyl ethers: application to the total synthesis of andrachcinidine

In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones. Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration, alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran and piperidine formation are very good to excellent. This method has been applied to an efficient total synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the scope of products that can be accessed through this protocol.     

Enantioselective synthesis of trans-4-methylpipecolic acid

An asymmetric synthesis for the preparation of both enantiomers of trans-methylpipecolic acids is described. It is based on Sharpless epoxidation as a chirality source, regioselective ring opening with allylamine, and ring-closing metathesis to construct the piperidine ring. The stereogenic center at C-4 is set by stereoselective hydrogenation that is directed by the alcohol functionality of an intermediate and proceeds with good diastereomeric control (trans/cis 16/1). Crystallization of the Boc-protected amino acid afforded the target products with excellent chemical (98% de) and enantiomeric purity (99% ee).     

A neutral,isolable covalent adduct between piperidine and a troponoidal phosphonium salt: A peculiar acylphosphorane

The phosphonium salt obtained by P-methylation of 2-diphenyl-phosphinotropone with methyl iodide was found to undergo C-7 addition by piperidine, and loss of hydrogen iodide, to give an acylsphosphorane which could be isolated; the regiospecificity of piperidine addition was proven by deuterium labeling at the troponoid ring.     

Ionic hydrogenation-directed stereoselective construction of C-20(H) stereogenic center in steroid side chains: Scope and limitations

Stereoselective synthesis of steroidal C-20 tertiary alcohols with n-butyl, vinyl, furyl, thienyl, thiazolyl, aryl and pyridyl side chains via Grignard reaction or organolithium reagents have been realized starting from readily available 16-dehydropregnenolone acetate. The ionic hydrogenation of steroidal C-20 tertiary alcohols having furyl, methylfuryl, thienyl, phenyl and 4-methoxyphenyl side chains, resulted into the deoxygenated product with C-20 natural configuration in excellent yields. However, the alkyl, thiazolyl and pyridyl incorporated steroidal C-20 tertiary alcohols were failed under the same reaction condition. The scope of ionic hydrogenation is further highlighted through the stereoselective reduction of steroidal C-20,21-ene compounds with furyl, thienyl and 4-methoxyphenyl side chains gave the saturated compounds with C-20 natural configuration.     

Michael addition of nitroalkanes to nonactivated α,β-unsaturated δ-thiolactams: reactivity, diastereoselectivity, and comparison to α,β-unsaturated δ-lactams

Aliphatic nitrocompounds add to nonactivated α,β-unsaturated δ-thiolactams leading to 4-nitroalkyl functionalized δ-thiolactams in good yields. The addition is a stereocontrolled process with respect to substituents at C-6, and takes place producing trans 4,6-disubstituted adducts in most cases. Ease of the addition has been studied in relation to the structure of the δ-thiolactam acceptors, within the FMO-theory. Comparative study with analogous δ-lactams has shown the advantages of α,β-unsaturated δ-thiolactams in Michael addition and indicated high prospects of these compounds in the synthesis of 4-functionalized piperidine derivatives.     

Asymmetric synthesis of 2-substituted piperidines using a multi-component coupling reaction: rapid assembly of (S)-coniine from (S)-1-(1-phenylethyl)-2-methyleneaziridine

(S)-Coniine is made using a reaction which assembles the piperidine ring by the sequential formation of four new chemical bonds and installs the C-2 stereogenic centre with high levels of diastereocontrol (90% de).     

Divergent approach to imino sugar C-glycosides using imino glycals: application to the stereocontrolled synthesis of (+)-deoxoprosophylline

Tri-O-acetyl imino glucal 2 is readily made and shown to undergo a variety of Lewis acid mediated carbon-carbon bond forming reactions at C-1 of the piperidine nucleus. In all the reactions studied, the beta-anomer is predominant.     

Synthetic studies toward (-)-FR901483 using a conjugate allylation to install the C-1 quaternary carbon

Two approaches to the aza-tricyclo dodecane skeleton of (-)-FR901483 are reported. Both routes utilized a Grignard addition to an N-acylpyridinium salt to establish the absolute stereochemistry at C-6 and a highly diastereoselective conjugate allylation reaction to form the quaternary center at C-1 of the natural product in an excellent yield. Although the desired polysubstituted piperidine intermediates were prepared regio- and stereoselectively, the construction of the C-8/C-9 bond connectivity could not be achieved. All attempts at a pinacol cyclization or an intramolecular 6-exo-tet epoxide opening were unsuccessful because of an unfavorable A(1,3) strain inherent in the molecule.     

Enantioselective total synthesis of Wieland-Gumlich aldehyde and (-)-strychnine

A total synthesis of (-)-strychnine in 15 steps from 1,3-cyclohexanedione in 0.15% overall yield is described. The sequence followed in the assembling of rings is: E-->AE [2-(2-nitrophenyl)-1,3-cyclohexanedione]-->ACE (3a-aryloctahydroindol-4-one)-->ACDE (arylazatricyclic core)-->ABCDE (strychnan skeleton)-->ABCDEF (Wieland-Gumlich aldehyde)-->ABCDEFG (strychnine). The key steps of the synthesis are the enantioselective construction of the 3a-(2-nitrophenyl)-octahydroindol-4-one ring system and the closure of the piperidine ring by a reductive Heck cyclization to generate the pivotal intermediate (-)-14. In contrast, a Lewis acid promoted a-alkoxypropargylic silane-enone cyclization did not lead to synthetically useful azatricyclic ACDE intermediates. The introduction of C-17 and the closure of the indoline ring by reductive amination of the alpha-(2-nitrophenyl) ketone moiety complete the strychnan skeleton from which, via the Wieland-Gumlich aldehyde, the synthesis of (-)-strychnine is achieved.     

Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis

GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.     

5-epi-Deoxyrhamnojirimycin is a potent inhibitor of an α-l-rhamnosidase: 5-epi-deoxymannojirimycin is not a potent inhibitor of an α-d-mannosidase

Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition of naringinase (an α-l-rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of unambiguous chemical synthesis of such materials in the evaluation of their biological properties. In contrast, moderately weak inhibition towards an α-d-mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6. Mimics of l-rhamnose which are recognised by enzymes that synthesise or process l-rhamnose may inhibit either the biosynthesis of the sugar or its incorporation into mycobacterial cell walls, providing new strategies for the treatment of diseases such as tuberculosis and leprosy. Molecular modelling studies provide a rationale for the surprisingly potent activity of the C-5 epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine glycosidase inhibitors mimic the ⁴H₃ conformation of the relevant glycopyranosyl cation intermediate.