From ferrocene to decasubstituted enantiopure ferrocene-1,1'-disulfoxide derivatives.

The functionalization of (R,R)-S,S'-di-tert-butylferrocene-1,1'-disulfoxide by deprotolithiation-electrophilic trapping sequences was studied towards polysubstituted, enantiopure derivatives for which the properties were determined. While the 2,2'-disubstituted ferrocene derivatives were obtained as expected, subsequent functionalization of the 2,2'-di(phenylthio) and 2,2'-bis(trimethylsilyl) derivatives occurred primarily at the 4- or 4,4'-positions. This unusual regioselectivity was discussed in detail in light of pKa values and structural data. The less sterically hindered 2,2'-difluorinated derivative yielded the expected 1,1',2,2',3,3'-hexasubstituted ferrocenes by the deprotometallation-trapping sequence. Further functionalization proved possible, leading to early examples of 1,1',2,2',3,3',4,4'-octa, nona and even decasubstituted ferrocenes. Some of the newly prepared ferrocene-1,1'-disulfoxides were tested as ligands for enantioselective catalysis and their electrochemical properties were investigated.

Alkylation of N,N-Dibenzylaminoacetonitrile: From Five- to Seven-Membered Nitrogen-Containing Heterocyclic Systems.

The syntheses of several alkaloids and nitrogen-containing compounds including N-Boc-coniine (14b), pyrrolizidine (1), δ-coniceine (2), and pyrrolo[1,2a]azepine (3) are described. New C-C bonds in the α position relative to the nitrogen atom were formed by the alkylation of metalated α-aminonitriles 4 and 6a-c with alkyl iodides possessing the requisite size and functionality. In all of the reported cases, the pyrrolidine ring was formed in the aqueous medium through a favorable 5-exo-tet process involving a primary or a secondary amino group and a terminal δ-leaving group. Conversely, the azepane ring was efficiently formed in N,N-dimethylformamide (DMF), as the preferred aprotic solvent, through an unreported 7-exo-tet cyclization process involving a more nucleophilic sodium amide and a terminal mesylate borne by a saturated six carbon chain unit. In this way, we successfully synthesized pyrrolo[1,2a]azepane 3 and 2-propyl-azepane 14c in good yields from inexpensive and readily available materials without tedious separation methods.

From ferrocene to 1,2,3,4,5-pentafluoroferrocene: halogen effect on the properties of metallocene.

The sequentially fluorinated ferrocenes (1-, 1,2-di, 1,2,3-tri, 1,2,3,4-tetra and 1,2,3,4,5-pentafluoroferrocene) have been synthesized from ferrocene. Rather than a 'perfluoro' effect, experimental and computational analysis of the complete series robustly demonstrates a linear additive effect of fluorine on the electrochemical and spectroscopic properties of ferrocene.

Isolation and Structure Identification of Novel Brominated Diketopiperazines from Nocardia ignorata-A Lichen-Associated Actinobacterium.

Actinobacteria are well known for their potential in biotechnology and their production of metabolites of interest. Lichens are a promising source of new bacterial strains, especially Actinobacteria, which afford a broad chemical diversity. In this context, the culture medium of the actinobacterium Nocardia ignorata, isolated from the terrestrial lichen Collema auriforme, was studied. The strain was cultivated in a BioFlo 115 bioreactor, and the culture medium was extracted using an XAD7HP resin. Five known diketopiperazines: cyclo (l-Pro-l-OMet) (1), cyclo (l-Pro-l-Tyr) (2), cyclo (d-Pro-l-Tyr) (3), cyclo (l-Pro-l-Val) (4), cyclo (l-Pro-l-Leu) (5), and one auxin derivative: indole-carboxaldehyde (8) were isolated, along with two new brominated diketopiperazines: cyclo (d-Pro-l-Br-Tyr) (6) and cyclo (l-Pro-l-Br-Tyr) (7). Structure elucidation was performed using HRMS and 1D and 2D NMR analysis, and the synthesis of compounds 6 and 7 was carried out in order to confirm their structure.

Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds through the Alkylation of Anodically Prepared α-Amino Nitriles.

α-Amino nitrile 2a was conveniently prepared in two individual steps from chiral hexafluorophosphate salt isoquinolinium (-)-8b including anodic cyanation as an efficient means to activate the sp(3) C1-H bond of the THIQ nucleus. The lithiation of 2a was carried out in THF at -80 °C in the presence of LDA to produce a stable α-amino carbanion which was condensed on a large variety of alkyl halides. The resulting quaternary α-amino nitriles were subjected to a stereoselective reductive decyanation in ethanol in the presence of NaBH4 as the hydride donor to yield N-Boc-1-alkyl-THIQs (+)-10a-g in up to 97:3 er's after removal of the chiral auxiliary group. Examination of the ORTEP view of THIQ (+)-1f revealed that the newly created stereogenic center had an absolute S configuration. Likewise, (-)-xylopinine was synthesized in four workup steps in an overall 63% yield from α-amino nitrile (+)-2b. In this process, crystallization of an enantioenriched mixture (90:10) of (-)-norlaudanosine with 1 equiv of (-)-N-acetyl-l-leucine afforded the leucinate salt (+)-13 (99:1 dr). Similarly, (+)-salsolidine was displaced from its (-)-DBTA salt (-)-12 in 99:1 er, which was determined by proton and carbon NMR spectroscopy in the presence of thiophosphinic acid (+)-14 as the chiral solvating agent.

Electrochemical access to 8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-7-carbonitrile. Application to the asymmetric syntheses of (+)-myrtine and alkaloid (+)-241D.

The total syntheses of both enantiomers of trans-quinolizidine (+)-myrtine and cis-2,4,6-trisubstituted piperidine alkaloid (+)-241D are reported here. Our approach was based on the N-Boc-directed metalation of enantiopure 4-piperidone (-)-11, which was prepared in four steps from α-amino nitrile 6 through a stereoselective alkylation-reduction decyanation process. α-Amino nitrile 6 was prepared at the anode through electrochemical oxidation of 4-piperidone (+)-5. In our study, α-phenylethylamine (α-PEA) allowed an efficient 1-3 stereoinduction, and an orthogonal cleavage of the N-Boc protecting group in piperidone derivatives was carried out by stirring them in a suspension of SnCl4·(Et2O)2 complex in diethyl ether. When appropriate, the er's were determined by proton and carbon NMR spectroscopy utilizing (+)-tert-butylphenylphosphinothioic acid and (+)-DBTA as chiral solvating agents.

Electrochemical synthesis and chemistry of chiral 1-cyanotetrahydroisoquinolines. An approach to the asymmetric syntheses of the alkaloid (-)-crispine a and its natural (+)-antipode.

The stereoselective convergent total syntheses of both enantiomers of the tetrahydroisoquinoline (THIQ) alkaloid crispine A are described. The THIQ precursors (-)-6 (90:10 dr) and (-)-11 (85:15 dr) were prepared from the alkylation-reduction sequence of a common α-amino nitrile (+)-4 derivative that has been conveniently prepared by anodic cyanation. Elaboration of the pyrrolidine ring of the title compound was cleanly achieved by two efficient ring closures methods involving (a) the displacement of a halogen atom and (b) the formation of a cyclic iminium cation to afford (-)-crispine A in 90% and 85% yields, respectively. A crystallization of enantioenriched (-)-crispine A (90:10 er) with 1 equiv of (-)-DBTA afforded the tartrate salt (-)-14 (≥98:2 dr) in 81% yield. The absolute S configuration of (-)-crispine A was simply deduced from examination of the X-ray data of tartrate salt (-)-14. Likewise, the natural (+)-crispine A was prepared in seven workup steps in an overall 30% yield, and reciprocal crystallization with (+)-DBTA afforded the enantiomeric tartrate salt (+)-14 in a ≥98:2 dr. Both enantiomers of crispine A were liberated from their respective DBTA salts in ≥98:2 er's which were determined by proton and carbon NMR spectroscopy, utilizing (R)-(+)-tert-butylphenylphosphinothioic acid (+)-15 as chiral solvating agent.

Synthesis of tetrahydroisoquinoline alkaloids via anodic cyanation as the key step.

We report a new route to tetrahydroisoquinoline (THIQ) alkaloids involving the alkylation of alpha-aminonitrile 2 as a key step. The latter compound was prepared by anodic cyanation of the corresponding tertiary amine 1. Reductive decyanation of alpha-aminonitriles 6a-c proceeded diastereoselectively (up to 95% de) to deliver the C1-substituted alkaloids precursors 9a-c. The syntheses of (+/-)-carnegine, (+/-)-norlaudanosine, and (+/-)-O,O-dimethylcoclaurine have been achieved.

Metal-free Brønsted acid catalyzed formal [3 + 3] annulation. straightforward synthesis of dihydro-2H-chromenones, pyranones, and tetrahydroquinolinones.

Brønsted acids catalyze the addition of enolizable beta-diketones, beta-ketoesters, and vinylogous amides to alpha,beta-unsaturated aldehydes to lead to substituted chromenones, pyranones, and tetrahydroquinolinones in good yields under mild reaction conditions via a formal [3 + 3] cycloaddition.

Diastereoselective preparation of 2,4,6-trisubstituted-2'-cyanopiperidines: application to the construction of the carbon framework of perhydrohistrionicotoxin.

The anodic cyanation of methanolic solutions of the 2-alkyl-N-phenylpiperidines 6b-d was performed in a flow cell equipped with a graphite felt anode. The reaction led to the formation of the 2-cyano-6-alkyl-N-phenylpiperidines 2b-d and proceeded with a high degree of regioselectivity. The 1H NMR spectra of the aminonitriles 2b-d showed an epimeric mixture at C-6. The major isomer has a trans configuration in which the cyano group is axial and the alkyl substituent is equatorial. Conversely, electrochemical oxidation of the 4-methyl-6-pentyl-N-phenylpiperidine 6e afforded the trisubstituted aminonitrile 2e as a single diastereomer (> 98% de). The 4-cyanobutyl side chain was incorporated in a two-step procedure to yield dinitrile 4e. This latter compound was directly converted into spiropiperidine 5e by using the Thorpe-Ziegler annulation procedure. The overall sequence (4 steps, 43%) allows the construction of the basic carbon framework of perhydrohistrionicotoxin.