Application of a process friendly morpholine synthesis to (S,S)-Reboxetine

We report our results on the construction of a morpholine ring system from the corresponding epoxide and amino alcohol. From this study, we were able to convert a previous four-step synthesis into a more efficient two-step process.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

Enantioselective synthesis of (8S,13S,14R)-7-oxa-estra-4,9-diene-3,17-dione

The first enantioselective synthesis of (8S,13S,14R)-7-oxa-estra-4,9-diene-3,17-dione with the trans-C/D ring junction is described. Key features of the synthesis include Ag₂O-mediated C-O bond formation, thermodynamically controlled axial-equatorial inversion, one-pot of halogen exchange and Co/Cr-mediated C-C bond formation, and intramolecular aldol condensations.     

A chemoenzymatic asymmetric synthesis of (9S,12S,13S)- and (9S,12RS,13S)-pinellic acids

A brief and facile synthesis of the title compounds has been developed by using an efficient lipase-catalyzed acylation and a chiral template-directed diastereoselective alkylation for incorporating the stereogenic centres. A cross-metathesis was employed to get the required E-olefin geometry.     

Synthesis of (+)-(1R,2S,9S,9aR)-octahydro-1H-pyrrolo[1,2-a]azepine-1,2,9-triol: a potential glycosidase inhibitor

The title compound was prepared as a potential glycosidase inhibitor. Key steps in the synthesis are vinyl epoxide aminolysis, ring-closing metathesis, cis-dihydroxylation and then ring closure.     

Easy access to 4-nitrothiochroman S,S-dioxides via ring-enlargement from 3-nitrobenzo[b]thiophene

The (E)-2-aryl-1-[2-(methylthio)phenyl]-1-nitroethylenes 5 can easily be oxidized to the relevant sulfones 6 and effectively subjected to cyclization via an intramolecular Michael addition after metallation with lithium bis(trimethylsilyl)amide in THF. After quenching with ammonium chloride the 3-aryl-4-nitrothiochroman S,S-dioxides 2 are obtained as diastereomeric mixtures in good to excellent yields. Both yields and stereochemistry of the ring-closure step appear to be influenced by steric effects of the 3-aryl moiety. As sulfides 5 derive from an initial ring opening of 3-nitrobenzo[b]thiophene (1), the overall 1 to 2 process can be considered as an effective 5 to 6 ring enlargement of the sulfur heterocycle. A conformational ¹H NMR and molecular-mechanics investigation on the isolated diastereomeric 2 has also been accomplished.     

Ring expansion approach for the synthesis of the (3S,4S)-hexahydroazepine core of balanol and ophiocordin

A new and efficient formal total synthesis of (3S,4S)-balanol, a potent protein kinase C inhibitor, was accomplished from tri-O-acetyl-d-glucal. Balanol and ophiocordin consists of a chiral hexahydro azepine-containing fragment and a benzophenone fragment. The azepine core was prepared in chiral form through intramolecular aza Wittig reaction. A triphenylphosphine mediated ring expansion process was employed to form the seven-membered nitrogen heterocycle. The aldehyde equivalent key intermediate was treated with triphenylphosphine to give the azepine core. To demonstrate the applicability of the new route, a synthesis of the balanol is described.     

Amino-zinc-ene-enolate cyclisation: a short access to (2S,3R)- and (2S,3S)-3-benzylprolines (3-benzylpyrrolidine-2-carboxylic acids)

The synthesis of 3-benzylprolines can be easily achieved in a diastereoselective and enantioselective way via amino-zinc-ene-enolate cyclisation. Transmetalation of the cyclic zinc intermediate with Pd₂(dba)₃/P(o-Tolyl)₃ allowed functionalisation with an aromatic ring. One-pot hydrogenolysis and Boc-protection led to the cis-isomer readily usable for peptide synthesis. The trans-isomer was obtained by epimerisation of the α-centre in a sealed tube at 200 °C.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-acetals

Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene compounds. The priority of the formation of the thiophene or pyrrole ring is investigated.     

(2S,5R/2R,5S)-Aminoethylpipecolyl aepip-aegPNA chimera: synthesis and duplex/triplex stability

This article reports the design and facile synthesis of novel chiral six-membered PNA analogues (2S,5R/2R,5S)-1-(N-Boc-aminoethyl)-5-(thymin-1-yl)pipecolic acid, aepipPNA IV that upon incorporation into standard aegPNA sequences effected stabilization of complexes with complementary target DNA. Substitution of aegPNA unit by the designed monomer at the C-terminus was more effective than substitution at N-terminus. The stabilizing behaviour improved with degree of substitution and was found to be dependent on their relative positions in the sequence. The six-membered piperidine ring in the design may freeze the rigid chair conformations and the relative stereochemistry of the substituents may in effect direct the complex formation with DNA/RNA by sequence-specific nucleobase recognition. In the present aepipPNA analogues, the l-trans stereochemical disposition of the substituents seems to lead to the favorable pre-organization of the PNA oligomers for complex formation with DNA. The results reported here further expand the repertoire of cyclic PNA analogues.     

Synthesis of (+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids

(+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids have been prepared in >97% ee and in 33% and 20% overall yields starting from a single, chiral, bicyclic compound perceived as a chiral uracil equivalent. Construction of the cyclobutane ring is achieved via a [2+2] photocycloaddition reaction of this chiral precursor with ethylene.     

Synthesis of (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratrane. Amplification of enantiomeric purity in the reacti

The synthesis is described of the two enantiomerically pure isomers (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratr The structures were determined by ¹H- and ¹³C-NMR spectroscopy. A method for increasing the enantiomeric purity by trimerization reactions of partially-resolved (S) propylene oxide is proposed. The reaction was studied from the kinetic viewpoint and interpreted according to a binomial probability scheme. The experimental findings point to a rapid growth in enantiomeric purity for the (SSS) trimer compared with the starting material, whilst no increase was found for the (SSR) trimer.     

Total synthesis of (3S,4S,2′S)- and (3R,4R,2′S)-viridiofungin A triester

The total synthesis of an alkylcitrate secondary metabolite from the fungi Trichoderma viride is described. An ester dienolate [2,3]-Wittig rearrangement and a S. Julia-Kocienski olefination served as key C/C-connecting transformations. The highly convergent synthesis consists of a longest linear sequence of 17 steps.     

Transformation of esters into allyl halides via substituted cyclopropanols. Application in the synthesis of (2S,3R,7R/S)-3,7-dimethyltridec-2-yl acetate and propionate, sex attractants of pine sawfly Diprion pini

A convenient new approach to the synthesis of the acetate and the propionate of (2S,3R,7R/S)-3,7-dimethyltridecan-2-ol, sex attractants of Diprion pini L., using the cyclopropanation of the ethoxycarbonyl group in O-THP protected ethyl (S)-lactate with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide followed by C-2-C-3 cyclopropane ring opening as the key steps has been performed.     

Total synthesis of (9S,12R,13S)-pinellic acid

The total synthesis of (9S,12R,13S)-pinellic acid, a novel and potentially useful oral adjuvant, isolated from Pinelliae tuber has been accomplished.     

An asymmetric synthesis of (2S,3S)-safingol

Two efficient asymmetric syntheses of (2S,3S)-safingol have been developed starting from easily available (R)-cyclohexylideneglyceraldehyde. The key steps in the syntheses were a diastereoselective addition of a suitable alkylmagnesium or lithium reagent, and simple organic transformations. Compared to earlier syntheses, the route involving alkyllithium addition is more viable practically due to its excellent diastereoselectivity, use of inexpensive materials/reagents and operational simplicity.     

Stereoselective synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

A stereoselective synthesis of the pentaketide lactone (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone has been achieved.     

An expeditious synthesis of a (3S,4S,5R)-trihydroxyazepane

A practical approach for the synthesis of the (2S,3S,4R)-trihydroxyazepane 1d has been reported. Starting from α-d-xylo-pentodialdose, readily available from d-glucose, the sequence involves Wittig olefination and reductive amination as key steps.     

Synthesis of (15S,16S,21R)-4-deoxyrollicosin analog

Synthesis of 4-deoxy rollicosin analog 2 was completed in nine steps, which was based on palladium-catalyzed coupling of two building blocks 3 and 4. Lactone 3 was synthesized from 5-hexyn-1-ol, and vinyl iodide 4 was accessed from l-glutamate and 1-hexyne.