Enantioselective synthesis of 2-[(3-ethyl-4-piperidyl)methyl]indoles from a phenylglycinol-derived lactam: formal synthesis of Strychnos alkaloids

A diastereodivergent synthesis of enantiopure cis- and trans-2-[(3-ethyl-4-piperidyl)methyl]indole (cis-1b and trans-1b) from a common phenylglycinol-derived oxazolopiperidone lactam 3 is reported. The key step is a stereocontrolled conjugate addition, either under kinetic or thermodynamic control, of the dilithium salt of 2-(2-indolyl)-1,3-dithiane to unsaturated lactam 3.     

The Pauson-Khand reaction as a new entry to the synthesis of bridged bicyclic heterocycles: application to the enantioselective total synthesis of (−)-alstonerine

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. Moreover, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the macroline alkaloid (−)-alstonerine.     

Synthesis of 3,5-diazabicyclo [5.1.0] octenes. A new platform to mimic glycosidase transition states

All-cis 1-hydroxymethyl 2,3 bis-aminomethyl cyclopropane was used to construct the first 3,5-diazabicyclo [5.1.0]-3-octenes. This system has the interesting ability to exist in a conformation that resembles a snapshot of a glycoside hydrolysis reaction with respect to charge and geometric analogy to an oxocarbenium ion, and the positioning of the departing aglycon. The cis-configured cyclopropane core was synthesized by Cu-catalyzed intramolecular cyclopropanation of benzyl protected cis-2-butene-1,4-diol diazoacetate ester. Serial functionalization to bis-aminomethyl cyclopropanes and subsequent cyclization to amidines lead to the target bicyclic compounds in good overall yields. Several glycosidases were surveyed for the inhibitory potential of these transition state analogs, and amongst them, selective competitive inhibitors with micromolar K_i values were identified.     

A new asymmetric synthesis of (+)-12b-epidevinylantirhine

We report a new asymmetric synthesis of the indole alkaloid derivative (+)-12b-epidevinylantirhine through stereoselective cyclization of a tethered indole nucleus onto an N-acyliminium ion intermediate, generated from a readily available non-racemic bicyclic lactam building block, and subsequent template modification through a highly diastereoselective conjugate addition protocol. In addition, we present the first X-ray crystal structure of this indole target.     

Stereoselective synthesis of bicyclic tetrahydrofuran-fused β-lactams and their conversion into methyl cis-3-aminotetrahydrofuran-2-carboxylates

cis-3-Benzyloxy-4-(2-mesyloxyethyl)azetidin-2-ones were shown to be useful starting products for the synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones in high overall yields and purity upon hydrogenolysis of the benzyl ether substituent followed by intramolecular nucleophilic substitution using sodium hydride in THF. These unconventionally C-fused bicyclic β-lactams were easily converted into the corresponding methyl cis-3-aminotetrahydrofuran-2-carboxylates via acidic methanolysis. This methodology constitutes a convenient alternative for the known preparation of cis-4,4-dimethyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones and methyl cis-3-amino-4,4-dimethyltetrahydrofuran-2-carboxylates, as their 4,4-nor-dimethyl variants are usually considered to be more promising compounds within the field of drug design.     

Expeditious synthesis of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo-[3,2h]isoquinoline/[2,3-f]quinoline via azomethine ylide-alkene [3+2] cycloaddition

Expeditious syntheses of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo-[3,2h]isoquinoline/[2,3-f]quinoline have been developed. The syntheses started with commercially available materials and afforded excellent overall yields in straightforward steps. Intramolecular azomethine ylide-alkene [3+2] cycloaddition is the key step in the construction of these pyrroloisoquinoline and pyrroloquinoline scaffolds. This route is much more atom-economic than those reported in the literature and is appropriate for scale-up synthesis.     

Synthesis of enantiopure (R,R)- and (S,S)-cis-2,3-propanoprolines

A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopenta[b]pyrrole-6a(1H)-carboxylic acid (‘2,3-propanoproline’), has been developed. The method relied on tandem Strecker-nucleophilic cyclization reaction of 2-(2-bromoethyl)cyclopentanone. The overall synthetic scheme included six steps and resulted in 18% overall yield of both enantiomers of the title amino acid.     

NMR-Spectroscopic, computational and mass-spectrometric investigations on the cis/trans analogues of 2,3,4-trihydronaphthalene-1-one

NMR-Spectroscopic, computational and mass-spectrometric studies of the cis/trans isomers of N-[8-(acetylamino)-4-(2,2-dimethyl-1,1-diphenyl-silapropoxy)-6-fluoro-5-methyl-1-one-2,3,4-trihydronaphthyl]acetamide (1a and 1b), obtained as intermediates in the synthesis of an important class of alkaloid molecules, are reported. ¹H and ¹³C NMR analyses show an unusual axial preference of the TBDPSi- (tert-butyldiphenylsilyl) group in position 4 in both the isomers. Mass spectrometric evidence demonstrates that trans isomer has a higher affinity for ammonium ions than the cis isomer and that only the ammonium adduct [1b+NH₄]⁺ and the protonated molecule [1b+H]⁺ show the fragmentation in which loss of benzene is observed. Moreover, molecular mechanics and semi-empirical calculations indicate that a group of trans conformers tend to place one of the phenyl rings of the TBDPSiO- group in a offset π-stacked geometry with the compound's aromatic ring. The combination and the detailed analyses of these experimental and theoretical results could support the π-π interaction obtained as a conformational preference in the trans isomer.     

Thermal isomerizations of cis,anti,cis-tricyclo[6.4.0.0]dodec-3-ene to trans- and cis,endo-tricyclo[6.2.2.0]dodec-9-ene: diradical conformations and stereochemical outcomes in [1,3] carbon shifts

The gas-phase thermal isomerizations at 315 °C of cis,anti,cis-tricyclo[6.4.0.0^2,7]dodec-3-ene to trans-tricyclo[6.2.2.0^2,7]dodec-9-ene and to cis,endo-tricyclo[6.2.2.0^2,7]dodec-9-ene favor the former, the more geometrically strained product, by a ratio of 2.4:1. These products correspond to suprafacial inversion (si) and suprafacial retention (sr) stereochemical outcomes. The reaction stereochemistry shown by the 11-carbon homolog, cis,anti,cis-tricyclo[6.3.0.0^2,7]undec-3-ene, is strikingly different: the [1,3] carbon shift takes place to give only the ‘forbidden’ sr product. Two related bicyclic vinylcyclobutanes, 8-deuterio- and 8-exo-methylbicyclo[4.2.0]oct-2-enes, evidence contrasting reaction stereochemical predilections in [1,3] shifts, but the 12-carbon tricyclic system and the 8-exo-methyl bicyclic analog isomerize with the same si:sr ratio! These observations prompt fresh considerations of structural influences on conformational preferences available to the alkyl, allyl diradical reactive intermediates involved.     

Formal synthesis of (+/-)-peduncularine: use of the

[reaction: see text] The formal synthesis of the alkaloid (+/-)-peduncularine (1) was accomplished through the use of a [3 + 2] allylic silane annulation. The annulation of cyclohexadienyl silane 6 with chlorosulfonyl isocyanate followed by an in situ reduction provided bicyclic lactam 7. Conversion of this intermediate to 2 in three steps completed the formal synthesis of (+/-)-peduncularine.     

Asymmetric synthesis of β-lactams by [2+2] cycloaddition using 1,4:3,6-dianhydro-d-glucitol (isosorbide) derived chiral pools

Highly diastereoselective synthesis of cis-β-lactams via [2+2] cycloaddition reactions of imines derived from a chiral bicyclic aldehyde and ketenes is described. The chiral bicyclic aldehyde as well as chiral acids were prepared from commercially available inexpensive isosorbide. The cycloaddition reaction was found to be highly diastereoselective; in some cases giving a single diastereomer of cis-azetidin-2-one in very good yields. A moderate diastereoselectivity was observed with chiral ketenes derived from isosorbide.     

Synthesis of enantiopure cyclitols from (±)-3-bromocyclohexene mediated by intramolecular oxyselenenylation employing (S,S)-hydrobenzoin and (S)-mandelic acid as chiral sources

Reaction of 3-bromocyclohexene with (S,S)-hydrobenzoin and (S)-mandelic acid and subsequent intramolecular oxyselenenylation of the resulting allylic ethers followed by oxidation-elimination afforded the valuable cis-fused bicyclic olefins, (1S,3S,4S,6R)-3,4-diphenylbicyclo[4,4,0]-2,5-dioxa-7-decene and (1S,3S,4R)-3-phenyl-4a,7,8,8a-tetrahydro-benzo[1,4]dioxan-2-one, respectively. Further stereoselective transformation of these cis-fused bicyclic olefins afforded the enantiopure cyclohexitols, muco-quercitol, d-chiro-inocitol and allo-inocitol.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Stereoselective synthesis of protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins

The stereocontrolled synthesis of the protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins A and B with potent anti-inflammatory activity, has been achieved. The key steps include (i) installation of a double bond to bicyclic lactam 4 using N-tert-butyl phenylsulfinimidoyl chloride, (ii) highly exo-selective Michael reaction with lithium dimethylcuprate in the presence of chlorotrimethylsilane, and (iii) Ru-catalyzed oxidative deprotection of N,O-benzylidene acetal to the acid anhydride.     

Stereodivergent reduction of enelactams embedded in hexahydroindoles. Synthesis of trans-3-substituted-cis-3a-methyloctahydroindoles

A stereodivergent synthesis of cis- and trans-octahydroindole derivatives from the ethylene acetal of methyl 1-benzyl-3a-methyl-2,5-dioxo-2,3,3a,5,6-hexahydro-1H-3-indoleacetate is reported. Under ionic reduction conditions the enamide group was reduced to afford a trans-ring fused product, while a hydrogenation process led to the formation of a cis-ring fused lactam, which was transformed into a building block for daphniphyllum alkaloid synthesis after an epimerization at C-3.     

Trans-cis octahedral interconversion pathway in diorganotin compounds

Using structural data from bis(bidentate)diorganotin compounds in the Cambridge Structural Database a potential pathway for trans-cis interconversion is envisaged with nondissociative Sn-donor bonds and retaining metal coordination number 6. C-Sn-C bond angles in the range 180-145° correspond to skewed trapezoid bipyramidal geometry for 6- and 5-membered O,O′ chelates; geometries that resemble the transition state of the trans-cis pathway starts forming at about C-Sn-C 134°. cis-Diorganotins explored in this work have C-Sn-C bond angles in the range 102-110°; it is the statistically favored configuration for diphenyltins. The proposed trans-cis conversion pathway is deduced from a series of geometries associated with decreasing the C-Sn-C bond angle and shows 2 weakly (secondary) bound chelating atoms lengthening their bonds until near the transition state and later strengthening; they end up cis to each other and opposite to the organic groups. Conversely, the other 2 (primary) donors shorten their bonds until the transition state is reached and later lengthen; they end up trans to each other. The entire transformation from trans to cis configuration occurs with relative rotation of 3 bonds.     

Total synthesis of a novel 2-thiabicyclo[3.2.0]heptan-6-one analogue of penicillin N

A route has been developed which allows synthesis of novel cyclobutanone analogues of penicillin. This is illustrated by the synthesis of (1R,4R,5R,5′R,7S)-(1b) and (1S,4S,5S,5′R,7R)-7-[5′-amino-5′-carboxy]pentanamido]-2-thiabicyclo[3.2.0]heptan-6-one-4-carboxylate (1a), an analogue of penicillin N. The key steps in the synthesis were the formation of the bicyclic structure via a [2+2] cycloaddition and the introduction of nitrogen at C7 via an intramolecular nitrene insertion.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

Synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid

A full study on the synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid is described. Three different approaches were investigated in order to achieve an efficient synthesis of this unnatural aminoacid. The optimized synthetic route relies upon three key steps: (i) diazomalonate insertion on 4-phtalimido 1-butene, (ii) intramolecular cyclization and (iii) chemoselective reduction of the resulting lactam. Due to its bicyclic nature and conformational constraints, this aminoacid may be an useful building block in medicinal chemistry.     

Lewis acid catalysed rearrangements of unsaturated bicyclic [2.2.n] endoperoxides in the presence of vinyl silanes; access to novel Fenozan BO-7 analogues

Reactions of a series of unsaturated bicyclic [2.2.n] endoperoxides with allyltrimethylsilane in the presence TMSOTf or SnCl₄ provides the cis-configured endoperoxides 9a-12. It is proposed that this novel reaction proceeds via attack of the allylsilane on the carbocation derived from heterolytic cleavage of the endoperoxide bridge. The reaction proceeds with a high degree of diastereoselectivity and we propose that the bulky -CH₂SiMe₃ substituent adopts an equatorial position in a product-like transition state. In contrast to Fenozan B0-7, these compounds displayed poor antimalarial activity versus chloroquine-resistant parasites in vitro.