A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

A straightforward, two-step asymmetric synthesis of octahydroindoles has been developed on the basis of two complementary strategies: (i) an organocatalyzed Michael reaction followed by a tandem Robinson–aza-Michael double cyclization catalyzed by PS-BEMP, and (ii) a diastereoselective cyclization, which formally constitutes a remote 1,6 asymmetric induction mediated by PS-BEMP. This allowed the construction of complex octahydroindoles with up to four stereocenters, excellent enantioselectivities (up to 95% ee), and complete diastereoselective control in a single-pot operation. DFT calculations were performed to understand the origin of this effect.

A revised structure for the Lycopodium alkaloid huperzine N is proposed and confirmed by synthesis. The key synthetic steps involve an epimerization of a cis-5-oxodecahydroquinoline to the corresponding trans isomer and a coupling, followed by a diastereoselective hydrogenation using Wilkinson’s catalyst to incorporate the pyridylmethyl moiety. This route allowed the alkaloid serralongamine A to be synthesized for the first time, and two additional steps led to the revised structure of huperzine N, both products bearing an unusual decahydroquinoline stereostructure.

Synthesis of the tetracyclic cores of madangamines D–F was achieved, featuring a reductive radical process from an ethoxycarbonyldichloroacetamide to build the morphan nucleus, a Mitsunobu-type aminocyclization toward the common diazatricyclic intermediate, and ring-closing metathesis reactions for the macrocyclization step leading to the 13- to 15-membered rings.

An unexpected C–C bond cleavage was observed in trichloroacetamide-tethered ketones under amine treatment and exploited to develop a new synthesis of normophans from 4-amidocyclohexanones. The reaction involves an unprecedented intramolecular haloform-type reaction of trichloroacetamides promoted by enamines (generated in situ from ketones) as counter-reagents. The methodology was applied to the synthesis of compounds embodying the 6-azabicyclo[3.2.1]octane framework.

The ABC-ring system of calyciphylline A-type alkaloids has been synthesized. The key steps of the synthetic approach are an atom transfer radical cyclization of a trichloroacetamide upon an enol acetate to generate the B ring, and a sulfone-based conjugated addition upon a β-methyl-α,β-unsaturated ketone to give the target azatricyclic ketone. Selecting the cation (K+ or Cs+) of the carbonate in the C ring-forming intramolecular Michael addition gives stereodivergent access to both epimers of the cyclized product.

•The first synthesis of (+)-4a,5,8a-trimethyloctahydronaphthalen-2-one is accomplished.•An olefin reduction by hydroboration and a radical-mediated protonolysis is used.•A new enantiopure building-block for terpene synthesis is made available.The synthesis of an enantiopure building-block with a contiguous all-cis-trimethyldecalin motif embedded in unusual terpenes is described. Starting from the Wieland–Miescher ketone, the key step is a one-pot hydroboration of an exocyclic methylene double bond promoted by disiamylborane and radical-mediated protonolysis of the corresponding alkylborane using 4-tert-butylcatechol.

Intramolecular Kharasch-type additions of trichloroacetamides on anisole and enol acetates catalyzed by Grubbs’ ruthenium carbenes are described. This protocol provides access to highly functionalized 2-azaspiro[4.5]decanes, morphan compounds, and the azatricyclic core of FR901483.

A general effective organocatalyzed synthesis of enantioenriched morphans with up to 92% ee was developed. The morphan scaffold was constructed in a one-pot tandem asymmetric organocatalyzed Michael addition followed by a domino Robinson annulation/aza-Michael intramolecular reaction sequence from easily available starting materials.

A concise synthesis of the Lycopodium alkaloid lycoposerramine Z is reported. Key to the strategy is a one-pot organocatalyzed Michael reaction followed by a domino Robinson annulation/intramolecular aza-Michael reaction promoted by LiOH, leading to enantiopure cis-decahydroquinolines.

An atom transfer radical dearomatizing spirocyclization from N-benzyltrichloroacetamides using CuCl regioselectively leads to 2-azaspiro[4.5]decadienes, in which the labile allylic chlorine atom is easily replaced by a hydroxyl group in aqueous medium or by quenching with methanol or allylamine. After oxidation of the target compound, the N-tert-butyl group can be removed from the resulting spirocyclohexanedienone.

A novel synthetic entry to 2-azabicyclo[3.3.1]nonanes based on a copper(I)-catalyzed intramolecular coupling of amino-tethered trichloroacetamides and unsaturated nitriles, esters and alkenes, as well as enol acetates, is described. A study of the reaction conditions and the scope of the process is reported.

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.

The six-membered nitrogen-containing ring of the morphan scaffold, ubiquitous in natural products, is formed by an intramolecular aldol process of an aza-tethered dicarbonyl compound, leading to the first asymmetric synthesis of a morphan derivative using organocatalysis.

A highly congested decalin embodying an α-methylene ketone is synthesized in 11 steps from the Wieland–Miescher ketone and efficiently converted to the polycyclic frameworks of anominine and tubingensin A, which constitutes the first approach to the skeleton of these indole diterpenoids.

Fischer indolization of enantiopure 2-methoxycarbonyl-cis-octahydroindol-6-ones using AcOH as a catalyst induces racemization of the octahydropyrrolocarbazoles obtained. Conversely, when using TsOH, the α-amino ester moiety preserves its configuration, although the other stereogenic centers show a partial or total stereolability according to the constitutional framework.(2S,3aS,10aR)-1-Benzyl-2-methoxycarbonyl-1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazoleC23H24N2O2[α]D22=-102 (c 1.25, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (2S,3aS,10aR)(2S,3aR,10aR)-1-Benzyl-2-methoxycarbonyl-1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazoleC23H24N2O2[α]D22=-129 (c 2.14, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (2S,3aR,10aR)(2S,3aS,10aS)-1-Benzyl-2-methoxycarbonyl-1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazoleC23H24N2O2[α]D22=3 (c 0.5, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (2S,3aS,10aS)(2S,3aS,10cR)-1-Benzyl-2-methoxycarbonyl-1,2,3,3a,4,5,6,10c-octahydropyrrolo[3,2-c]carbazoleC23H24N2O2[α]D22=-13 (c 1.4, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (2S,3aS,10cR)

An enantioselective synthesis of protected 1-azaspiro[4.5]dec-6-en-8-one derivatives was achieved using an alkylidene carbene 1,5-CH insertion reaction as the key step.1-tert-Butyl 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylateC11H18N4O4[α]D23=-40.3(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S1-tert-Butyl 2-methyl (2S,4S)-4-(N-methoxycarbonyl)aminopyrrolidine-1,2-dicarboxylateC13H22N2O6[α]D23=-23.7(c0.85,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4Stert-Butyl 2-methyl (2S,4S)-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1,2-dicarboxylateC14H24N2O6[α]D23=-44.7(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4Stert-Butyl (2S,4S)-2-(hydroxymethyl)-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC13H24N2O5[α]D23=-43.7(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4Stert-Butyl (2S,4S)-2-formyl-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC13H22N2O5[α]D23=-70.7(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4Stert-Butyl (2S,4S)-2-[(1E)-3-oxobut-1-enyl]-4-[(N- methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC16H26N2O5[α]D23=-31.8(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4Stert-Butyl (2S)-2-[(1E)-3-oxobut-1-enyl]pyrrolidine-1-carboxylateC13H21NO3[α]D23=-86.9(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 2Stert-Butyl (2R,4S)-2-(3-oxobutyl)-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC16H28N2O5[α]D23=-47.3(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2R,4Stert-Butyl (2S)-2-(3-oxobutyl)pyrrolidine-1-carboxylateC13H23NO3[α]D23=-51.8(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 2Stert-Butyl (3S,5R)-4-[(N-methoxycarbonyl)-N-methylamino]-7-methyl-1-azaspiro[4.4]non-6-ene-1-carboxylateC17H28N2O4[α]D23=-78.3(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 3S,5Rtert-Butyl (5R)-7-methyl-1-azaspiro[4.4]non-6-ene-1-carboxylateC14H23NO2[α]D23=-104.8(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 5Rtert-Butyl (3S,5R,6R,7S)-6,7-dihydroxy-4-[(N-methoxycarbonyl)-N-methylamino]-7-methyl-1-azaspiro[4.4]nonane-1-carboxylateC17H30N2O6[α]D23=+11.8(c1.05,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 3S,5R,6R,7Stert-Butyl (5S,6R,7S)-6,7-dihydroxy-7-methyl-1-azaspiro[4.4]nonane-1-carboxylateC14H25NO4[α]D23=+40.5(c1.05,CHCl3)Source of chirality: l-prolineAbsolute configuration: 5S,6R,7Stert-Butyl (2R,4S)-2-formyl-4-[(N-methoxycarbonyl)-N-methylamino]-2-(3-oxobutyl)pyrrolidine-1-carboxylateC17H28N2O6[α]D23=+12.5(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2R,4Stert-Butyl (2S)-2-formyl-2-(3-oxobutyl)pyrrolidine-1-carboxylateC14H23NO4[α]D23=+11.9(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 2Stert-Butyl (3S,5R)-4-[(N-methoxycarbonyl)-N-methylamino]-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylateC17H26N2O5[α]D23=-18.3(c1.05,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration:3S,5Rtert-Butyl (5S)-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylateC14H21NO3Ee ⩾90% by HPLC on Chiralpak® AD column[α]D23=-111.5(c0.95,CHCl3)Source of chirality: l-prolineAbsolute configuration: 5S

The first total synthesis of anominine has been achieved, and the absolute configuration of the product has been determined. The key features include the development of a new, highly efficient organocatalyzed method for the asymmetric synthesis of Wieland−Miescher ketone building blocks, an unusual selenoxide [2,3]-sigmatropic rearrangement, and a ZrCl4-catalyzed indole coupling as well as several chemoselective transformations controlled by the structurally congested nature of the bicyclic core.

A unified strategy for the synthesis of the cis-phlegmarine group of alkaloids is presented, leading to the first synthesis of serratezomine E (1) as well as the putative structure of huperzine N (2). A contrasteric hydrogenation method was developed based on the use of Wilkinson’s catalyst, which allowed the facial selectivity of standard hydrogenation to be completely overturned. Calculations were performed to determine the mechanism, and structures for huperzines M and N are reassigned.

A novel synthetic entry to 2-azabicyclo[3.3.1]nonanes based on a copper(I)-catalyzed intramolecular coupling of amino-tethered trichloroacetamides and unsaturated nitriles, esters and alkenes, as well as enol acetates, is described. A study of the reaction conditions and the scope of the process is reported.

A highly congested decalin embodying an α-methylene ketone is synthesized in 11 steps from the Wieland–Miescher ketone and efficiently converted to the polycyclic frameworks of anominine and tubingensin A, which constitutes the first approach to the skeleton of these indole diterpenoids.

The six-membered nitrogen-containing ring of the morphan scaffold, ubiquitous in natural products, is formed by an intramolecular aldol process of an aza-tethered dicarbonyl compound, leading to the first asymmetric synthesis of a morphan derivative using organocatalysis.

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.