Chiral Aminoalcohol-Derived δ-Lactams Provide Easy Access to Piperidines and Acyclic Five-Carbon Building Blocks Bearing a Tertiary and a Quaternary Stereocenter.

A procedure for the synthesis of enantiopure piperidines and acyclic building blocks (5-aminopentanols, O-protected 5-hydroxypentanenitriles) containing a tertiary and a quaternary stereocenter has been developed. Starting from a phenylglycinol- or aminoindanol-derived δ-lactam bearing an alkyl substituent at the α-position of the N,O-acetal carbon, easily accessible by a cyclocondensation reaction, the stereoselective dialkylation at the carbonyl α-position generates the quaternary stereocenter and the subsequent two-step reductive removal of the chiral inductor provides enantiopure 3,3,5-trisubstituted piperidines. Alternatively, the simultaneous reductive opening of the oxazolidine and piperidone rings of the dialkylated lactams followed by reductive or oxidative cleavage of the chiral inductor opens access to chiral 2,2,4-trisubstituted 5-amino-1-pentanols or 2,4,4-trisubstituted 5-hydroxypentanenitriles.

Total Synthesis of (-)-Cylindricine H.

Starting from (R)-phenylglycinol-derived tricyclic lactam 1, the enantioselective synthesis of (-)-cylindricine H is reported. From the stereochemical standpoint, the key steps are the stereoselective generation of the quaternary C10 stereocenter, the stereoselective introduction of the C4 acetoxy and C2 butyl substituents taking advantage of the lactam carbonyl functionality, and the assembly of the pyrrolidine ring with the required functionalized one-carbon chain at C13 by intramolecular opening of an epoxide.

A Novel Series of Indole Alkaloid Derivatives Inhibit Dengue and Zika Virus Infection by Interference with the Viral Replication Complex.

Here, we identified a novel class of compounds which demonstrated good antiviral activity against dengue and Zika virus infection. These derivatives constitute intermediates in the synthesis of indole (ervatamine-silicine) alkaloids and share a tetracyclic structure, with an indole and a piperidine fused to a seven-membered carbocyclic ring. Structure-activity relationship studies indicated the importance of substituent at position C-6 and especially the presence of a benzyl ester for the activity and cytotoxicity of the molecules. In addition, the stereochemistry at C-7 and C-8, as well as the presence of an oxazolidine ring, influenced the potency of the compounds. Mechanism of action studies with two analogues of this family (compounds 22 and trans-14) showed that this class of molecules can suppress viral infection during the later stages of the replication cycle (RNA replication/assembly). Moreover, a cell-dependent antiviral profile of the compounds against several Zika strains was observed, possibly implying the involvement of a cellular factor(s) in the activity of the molecules. Sequencing of compound-resistant Zika mutants revealed a single nonsynonymous amino acid mutation (aspartic acid to histidine) at the beginning of the predicted transmembrane domain 1 of NS4B protein, which plays a vital role in the formation of the viral replication complex. To conclude, our study provides detailed information on a new class of NS4B-associated inhibitors and strengthens the importance of identifying host-virus interactions in order to tackle flavivirus infections.

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3'-oxindole] Alkaloids.

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3'-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.

Enantioselective formal synthesis of the marine macrolide (-)-callyspongiolide.

A short enantioselective synthesis of the macrocyclic core 19 of callyspongiolide, involving a homocrotylboration of aldehyde 4, a Still-Genari olefination, an esterification with alcohol 17, and a ring-closing metathesis, is reported.

Access to Enantiopure Advanced Intermediates en Route to Madangamines.

The synthesis of enantiopure ABCE and ABCD tetracyclic advanced intermediates en route to madangamine alkaloids and studies for the construction of the triunsaturated 15-membered D ring of madangamine B and the saturated 13-membered D ring of madangamine E are reported.

Enantioselective formal synthesis of (+)-madangamine A.

An enantioselective formal synthesis of the marine alkaloid madangamine A using phenylglycinol-derived lactam 1 as the starting enantiomeric scaffold is reported. The synthesis involves the construction of the C-9 substituted diazatricyclic ABC core and the final closure of D and E rings from the polyunsaturated skipped intermediate 19.

Enantioselective Synthesis of the Ethyl Analog of the Marine Alkaloid Haliclorensin C.

The enantioselective synthesis (3.7% overall yield in nine steps from 2) and biological screening of the ethyl analog of the macrocyclic marine alkaloid haliclorensin C (compound 5) are reported. Amino alcohol 3, generated by a LiNH2BH3-promoted reductive ring-opening/debenzylation sequence from phenylglycinol-derived lactam 2, was used as the starting chiral linear building block. Incorporation of the undecene chain via the nosyl derivative 12, methylenation of the pentanol moiety, and a ring-closing metathesis are the key steps of the synthesis.

A Straightforward Synthesis of Functionalized cis-Perhydroisoquinolin-1-ones.

Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type reagents are reported. The effect of the solvent polarity and the concentration of the reagents is studied. The process involves two successive Michael additions and stereoselectively provides functionalized cis-perhydroisoquinolin-1-ones.

Studies on the Synthesis of Phlegmarine-Type Lycopodium Alkaloids: Enantioselective Synthesis of (-)-Cermizine B, (+)-Serratezomine E, and (+)-Luciduline.

The synthesis of the Lycopodium alkaloids, (-)-cermizine B, (+)-serratezomine E, and (+)-luciduline using phenylglycinol-derived tricyclic lactams as chiral scaffolds, is reported. The requisite lactams are prepared by a cyclocondensation reaction between ( R)- or ( S)-phenylglycinol and the substituted δ-keto ester 11, easily accessible from ( R)-pulegone. The factors governing the stereoselectivity of these cyclocondensation reactions are discussed. Key steps of the synthesis from the stereochemical standpoint are the stereoselective elaboration of the allyl substituent to the ( S)-2-(piperidyl)methyl moiety and the stereoselective removal of the chiral inductor to give a cis-decahydroquinoline.

Enantioselective Total Synthesis of (+)-Gephyrotoxin 287C.

A synthesis of (+)-gephyrotoxin 287C using (S)-phenylglycinol-derived tricyclic lactam 7 as the starting enantiomeric scaffold is reported. From the stereochemical standpoint, the key steps are the generation of the DHQ C-5 stereocenter by hydrogenation of the C-C double bond, removal of the chiral inductor to give a cis-DHQ, introduction of the DHQ C-2 substituent, completion of the (Z)-enyne moiety, and generation of the C-1 stereocenter during closure of the pyrrolidine ring.

Enantioselective Synthesis of Spiro[indolizidine-1,3'-oxindoles].

A three-step procedure for the enantioselective synthesis of spiro[indolizidine-1,3'-oxindoles], consisting of a stereoselective cyclocondensation reaction between (S)-tryptophanol and a prochiral or racemic δ-oxoester, bromination of the resulting oxazolopiperidone lactam, and a final stereoselective spirocyclization, is reported.

Access to Enantiopure 5-, 7-, and 5,7-Substituted cis-Decahydroquinolines: Enantioselective Synthesis of (-)-Cermizine B.

Stereoconvergent cyclocondensation reactions of (R)- or (S)-phenylglycinol with appropriately substituted cyclohexanone-based δ-keto esters are the key steps of short synthetic routes to enantiopure 5-, 7-, and 5,7-substituted cis-decahydroquinolines. The factors governing the stereoselectivity of the cyclocondensation are discussed. The potential of the methodology is illustrated by a protecting-group-free synthesis of the phlegmarine-type Lycopodium alkaloid (-)-cermizine B.

Stereocontrolled Access to Enantiopure 7-Substituted cis- and trans-Octahydroindoles.

Cyclocondensation of (R)-phenylglycinol with stereoisomeric mixtures (racemates, cis/trans) of 3-substituted 2-oxocyclohexaneacetates stereoselectively afforded tricyclic oxazoloindolone lactams, from which straightforward procedures for the stereocontrolled formation of enantiopure 7-substituted octahydroindoles with a variety of stereochemical patterns have been developed. The methodology has been successfully applied to the synthesis of (+)-α-lycorane.

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists.

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

Enantioselective Total Synthesis of Fluvirucinin B1.

A convergent synthesis of fluvirucinin B1 from acid ent-6a and nitrile ent-9, involving an organocopper coupling, a stereoselective allylation, a ring-closing metathesis reaction, and a stereoselective hydrogenation as the key steps, is reported. The starting building blocks have been prepared in a straightforward manner from a common phenylglycinol-derived lactam 1. An unprecedented regioselective oxidation of phenylglycinol-derived secondary amines 5 to carboxylic acids 6 has been developed.

Stereocontrolled Annulations of Indolo[2,3-a]quinolizidine-Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine-Type Derivatives.

The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 has been studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind -unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert-butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov-derived adducts is demonstrated by their conversion into allo and epiallo yohimbine-type targets.

Enantioselective synthesis of lepadins A-D from a phenylglycinol-derived hydroquinolone lactam.

The marine alkaloids (-)-lepadins A-C and (+)-lepadin D, belonging to two diastereoisomeric series, were synthesized from an (R)-phenylglycinol-derived tricyclic lactam via a common cis-decahydroquinoline intermediate. Crucial aspects of the synthesis are the stereochemical control in the assembly of the cis-decahydroquinoline platform, in the introduction of the C2 methyl and C3 hydroxy substituents, and in the generation of the C5 stereocenter.

The alkaloids of the madangamine group.

This chapter is focused on madangamines, a small group of complex diamine alkaloids isolated from marine sponges of the order Haplosclerida, and covers their isolation, characterization, biogenesis, biological activity, and synthesis. Structurally, madangamines are pentacyclic alkaloids with an unprecedented skeletal type, characterized by a common diazatricyclic core and two peripheral macrocyclic rings. The isolation of these alkaloids from Xestospongia ingens (madangamines A-E) and Pachychalina alcaloidifera (madangamine F) is described in detail. Physical and complete spectroscopic 1H and 13C NMR data are included. The proposed biogenesis of madangamines from ammonia, a functionalized three-carbon unit, and saturated or unsaturated linear long-chain dialdehydes, via partially reduced bis-alkylpyridine macrocycles, is discussed. The synthesis of alkaloids of the madangamine group has been little explored, with only one total synthesis reported so far, that of (+)-madangamine D. This review also describes several model synthetic approaches to the diazatricyclic ABC core of these alkaloids, as well as model studies on the construction of the (Z,Z)-unsaturated 11-membered E macrocycle common to madangamines A-E, the 13- and 14-membered D rings of madangamines C-E, and the all-cis-triunsaturated 15-membered D ring of madangamine A. Some members of this group have shown significant in vitro cytotoxicity against a number of cancer cell lines.

Stereoselective total synthesis of the putative structure of nitraraine.

After the structure originally proposed for nitraraine was shown to be incorrect by total synthesis, the alternative structure 5 was recently suggested for the alkaloid on biosynthetic grounds and by comparison with the (1)H NMR data of tangutorine. The unambiguous synthesis of 5 is reported from tryptophanol and ketodiester 6, via oxazoloquinolone lactam 7. However, the melting point and (1)H NMR data of 5 did not match those reported for the natural product.