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A cyclic hydrazide catalyst bearing a pendant anthracene catalyzes the polyene cyclization of 1,5-hexadiene-2-carboxaldehydes. Bicyclic closure proceeds in substrates with non-activated terminating groups that fail to react with simple hydrazide catalysts. Computational analysis shows that stabilization through cation–π interactions throughout the reaction sequence leads to the enhanced reactivity of the catalyst.

Reported herein a concise and enantioselective total synthesis of Schizozygine alkaloids (–)-strempeliopine. This synthetic strategy features a palladium-catalyzed decarboxylative asymmetric allylic alkylation of N-benzoyl lactam to set up the absolute configuration at the C20 position, a highly diastereoselective one-pot Bischler-Napieralski/lactamization and iminium reduction sequence for the construction of the pentacyclic core structure, and a late-stage dearomative addition of indole leading to the challenging hexacyclic indoline framework with complete control of correct four neighbouring stereocenters.

Billions of years of evolution have led to the biosynthesis of complex molecules that dictate and control life from simple precursors. Synthetic chemists have continued to pursue discoveries that mimic the capability of enzymatic biosynthesis. In following this pursuit, we have focused on developing new methods that enable site selective oxidations and improve upon current methodology of iminium organocatalysis. Heteroaromatic N-oxides are an important class of molecules as bioactive compounds, drug metabolites, and synthetic precursors. The oxidation of nitrogen heterocycles in the presence of aliphatic amines is a transformation that typically requires exhaustive oxidation followed by selective reduction to achieve. We have developed a method using a strong Brønsted acid that protonates and deactivates the more electron rich aliphatic amine, enabling selective oxidation of less electron-rich heterocyclic nitrogen by an iminium catalyst. The N-oxide products can be subjected to a large selection of known transformations. This method can be used as a platform to synthesize enzymatic metabolites or as means for late-stage functionalization of nitrogen heterocycles. Direct oxidation of unactivated C–H bonds is a field of increasing importance in modern synthetic chemistry. A longstanding problem in the is the lack of a general method to achieve chemoselective C–H oxidations when in the presence of other oxidizable groups. Our lab has previously developed two methods utilizing the same iminium catalyst for selective C–H hydroxylation and amination. We have streamlined and improved the synthesis of this iminium catalyst and have developed a library of new iminium salts to pursue a second-generation catalyst improving on our hydroxylation and amination methodology. Additionally, we have introduced new conditions and iminoiodinane reagents to improve our iminium catalyst’s amination capabilities. These new iminoiodinane reagents can be used in intramolecular and intermolecular aminations and provide enhanced reactivity over traditional iminoiodinane reagents.

International audience; The synthesis and characterization of cyclic (alkyl)(amino)carbene, bicyclic (alkyl)(amino)carbene and cyclic (amino)(barrelene)carbene copper (I) complexes is reported. These complexes are obtained via a scalable, versatile, green, and cost/user-friendly strategy.

Indoloquinazolines functionalized at C-12, which are structural analogs of the natural alkaloid cephalanthrin B, are readily constructed via Ph3P/I2-mediated one-pot reactions of isatins with aromatic alcohols. In the presence of excess phenols, the C-12 aryloxy ester products are obtained in moderate to good yields under mild conditions. Moreover, fused bicyclic hydroxyaryl derivatives such as 8-hydroxyquinoline give rise to novel C-12 spiro-γ-lactone derivatives. A reactive iminium cation species derived from dehydration of the C-12 hydroxy ester precursor is proposed as the transient intermediate responsible for these transformations.

Asymmetric organocatalysis is emerging as an elegant tool for accelerating chemical reactions and creating specific types of molecules. Chiral Brønsted acid catalysis is an important area of organocatalysis. We recently described an intramolecular iminium-ion cyclization reaction of 2-alkenylbenzaldimines catalyzed by a chiral Brønsted acid (a BINOL-derived N-triflylphosphoramide) for the synthesis of chiral 1-aminoindenes and tetracyclic 1-aminoindanes in good yields and high enantioselectivities. One of the resulting 1-aminoindenes is a useful intermediate for the synthesis of (S)-rasagiline, an effective drug for the symptomatic treatment of Parkinson’s disease. Moreover, some tetracyclic 1-aminoindanes are present in the skeletons of homoisoflavanoid natural products such as brazilin.

We report the first catalytic enantioselective conjugate addition of allyl groups to α,β-unsaturated aldehydes. The chemistry exploits the visible-light-excitation of chiral iminium ions to activate allyl silanes towards the formation of allylic radicals, which are then intercepted stereoselectively. The underlying radical mechanism of this process overcomes the poor regio- and chemoselectivity that traditionally affects the conjugate allylation of enals proceeding via polar pathways. We also demonstrate how this organocatalytic strategy could selectively install a valuable prenyl fragment at the β-carbon of enals.

Class I aldolases catalyze asymmetric aldol addition reactions and have found extensive application in the biocatalytic synthesis of chiral β-hydroxy-carbonyl compounds. However, the usefulness of these powerful enzymes for application in other C-C bond-forming reactions remains thus far unexplored. The redesign of class I aldolases to expand their catalytic repertoire to include non-native carboligation reactions therefore continues to be a major challenge. Here, we report the successful redesign of 2-deoxy-d-ribose-5-phosphate aldolase (DERA) from Escherichia coli, an archetypical class I aldolase, to proficiently catalyze enantioselective Michael additions of nitromethane to α,β-unsaturated aldehydes to yield various pharmaceutically relevant chiral synthons. After 11 rounds of directed evolution, the redesigned DERA enzyme (DERA-MA) carried 12 amino-acid substitutions and had an impressive 190-fold enhancement in catalytic activity compared to the wildtype enzyme. The high catalytic efficiency of DERA-MA for this abiological reaction makes it a proficient "Michaelase" with potential for biocatalytic application. Crystallographic analysis provides a structural context for the evolved activity. Whereas an aldolase acts naturally by activating the enzyme-bound substrate as a nucleophile (enamine-based mechanism), DERA-MA instead acts by activating the enzyme-bound substrate as an electrophile (iminium-based mechanism). This work demonstrates the power of directed evolution to expand the reaction scope of natural aldolases to include asymmetric Michael addition reactions and presents opportunities to explore iminium catalysis with DERA-derived catalysts inspired by developments in the organocatalysis field.

A variety of 4-trifluoromethylquinolines bearing an aryl (or cyclopropyl, tert-butyl, trimethylsilyl) group at C-2 and a nitro group at ring position 6, 7 or 8 have been prepared in good to high yields from 3-substituted 1-(trifluoromethyl)prop-2-yne 1-iminium triflate salts and o-, m- or p-nitroaniline. These reactions include an aza-Michael reaction at room temperature followed by an intramolecular electrophilic aromatic substitution step, which requires additional thermal activation in most cases. In contrast, the conjugate addition of 2,4-dinitroanilines at the acetylenic iminium ions proceeds much more slowly and some of the adducts can be converted thermally into 2-(2,4-dinitrophenyl)-5-trifluoromethylpyrroles. Analogously, 2-(4-pyridyl)-5-trifluoromethylpyrroles were obtained from 3-aryl-1-(trifluoromethyl)propyn­iminium salts and 4-aminopyridinium triflate. A novel variation of the Truce–Smiles rearrangement is probably involved in the formation of these pyrroles.

Cyclopropane rings are an important structural motif frequently found in many natural products and pharmaceuticals. Commonly, biocatalytic methodologies for the asymmetric synthesis of cyclopropanes rely on repurposed or artificial heme enzymes. Here, we engineered an unusual cofactor‐independent cyclopropanation enzyme based on a promiscuous tautomerase for the enantioselective synthesis of various cyclopropanes via the nucleophilic addition of diethyl 2‐chloromalonate to α,β‐unsaturated aldehydes. The engineered enzyme promotes formation of the two new carbon‐carbon bonds with excellent stereocontrol over both stereocenters, affording the desired cyclopropanes with high diastereo‐ and enantiopurity (d.r. up to 25:1; e.r. up to 99:1). Our results highlight the usefulness of promiscuous enzymes for expanding the biocatalytic repertoire for non‐natural reactions., Engineering of a promiscuous 4‐oxalocrotonate tautomerase (4‐OT) resulted in an unusual cofactor‐independent cyclopropanation enzyme that promotes the stereoselective addition of diethyl 2‐chloromalonate to substituted cinnamaldehydes to afford various cyclopropanes with high diastereo‐ and enantiopurity.

Chiral α-amino-β2,2-amino acid is an ubiquitous fragment that presents in natural products, pharmaceuticals, and bioactive molecules. However, the catalytic enantioselective synthesis of α-amino-β2,2-amino acids with structural complexity and diversity remains a significant challenge. Herein, a highly enantioselective formal C–N bond insertion of aminals with metal carbene species that was generated in situ from diazo compound has been developed by employing a cooperative catalysis of achiral dirhodium complex with chiral phosphonic acid, providing a practical and efficient protocol for expeditious access to optically pure α-amino-β2,2-amino acid derivatives bearing an α-tetra-substituted stereo center with broad substrate scope. The reaction was proposed to proceed through an enantioselective reassembly of enolate intermediate generated in situ from rhodium carbene with methylene iminium ion via chiral ionic pair interaction. Further synthetic applications of these generated poly-functionalized products furnish different types of key intermediates for the formal synthesis of many bioactive molecules. In addition, these amino acid derivatives could also serve as novel potential tail chains of resorcinol dibenzyl ether type PD-1/PD-L1 small molecule inhibitors.

1,3-Bis(trifluoromethyl)prop-2-ene 1-iminium triflate salts were prepared for the first time and some synthetic applications as 1,3-biselectrophilic building blocks were established. They were found to react with dimethoxybenzenes or methylene-1,2-dioxybenzenes to furnish vinylogous trifluoroacetylation products (4-aryl-1,1,1,5,5,5-hexafluoropent-3-en-2-ones) and 1-dialkylamino-1,3-bis(trifluoromethyl)-1H-indenes. With aniline and ring-substituted anilines, 2,4-bis(trifluoromethyl)quinolines were formed. An unusual 4H-pyran, formally a condensation product of the N,N-dimethyl-1,3-bis(trifluoromethyl)prop-2-en-1-iminium ion and its enaminone precursor, is also reported.

Nitrogen-containing scaffolds are ubiquitous in nature and constitute an important class of building blocks in organic synthesis. The asymmetric aza-Michael reaction (aza-MR) alone or in tandem with other organic reaction(s) is an important synthetic tool to form new C–N bond(s) leading to developing new libraries of diverse types of bioactive nitrogen compounds. The synthesis and application of a variety of organocatalysts for accomplishing highly useful organic syntheses without causing environmental pollution in compliance with ‘Green Chemistry” has been a landmark development in the recent past. Application of many of these organocatalysts has been extended to asymmetric aza-MR during the last two decades. The present article overviews the literature published during the last 10 years concerning the asymmetric aza-MR of amines and amides catalysed by organocatalysts. Both types of the organocatalysts, i.e., those acting through non-covalent interactions and those working through covalent bond formation have been applied for the asymmetric aza-MR. Thus, the review includes the examples wherein cinchona alkaloids, squaramides, chiral amines, phase-transfer catalysts and chiral bifunctional thioureas have been used, which activate the substrates through hydrogen bond formation. Most of these reactions are accompanied by high yields and enantiomeric excesses. On the other hand, N-heterocyclic carbenes and chiral pyrrolidine derivatives acting through covalent bond formation such as the iminium ions with the substrates have also been included. Wherever possible, a comparison has been made between the efficacies of various organocatalysts in asymmetric aza-MR.

Organic radicals are open-shell species and have been extensively applied to functional materials due to their unique physicochemical properties with unpaired electrons; however, most of them are highly reactive and short-lived. Herein, a series of stable radicals were readily accessed in two steps from a bis(imino)acenaphthene-supported N-heterocyclic carbene (IPr(BIAN)) through enhancing the delocalization of spin density. The IPr(BIAN)-based radicals 3a-c, obtained by reduction of the corresponding iminium salts 2a-c with KC8, have been spectroscopically and crystallographically (3a,c) characterized. DFT calculations indicate that increasing the electron-withdrawing properties of the para substituent on the carbene carbon atom results in the spin density evolving from the acenaphthene ring to the phenyl ring. The IPr(BIAN)-based radicals 3a-c show excellent stability: they have half-lives of 1 week in well-aerated solutions and feature a high thermal decomposition temperature up to 200 °C.

Incorporation of the fluoromethyl group can profoundly influence the physicochemical properties of organic molecules, offering a promising strategy for the discovery of novel pharmaceutical agents. Direct fluoromethylation of unfunctionalized C(sp2) centres can be achieved using fluoromethyl radicals, but current methods for their generation usually rely on the activation of non-commercial or expensive radical precursors via inefficient single electron transfer pathways, which limits their synthetic application. Here we report the development of a fluoromethylation strategy based on the generation of fluoromethyl radicals from commercially available fluoroiodomethane via halogen atom transfer. This mode of activation is orchestrated by visible light and tris(trimethylsilyl)silane, which serves as both a hydrogen- and halogen atom transfer reagent to facilitate the formation of C(sp3)–CH2F bonds via a radical chain process. The utility of this metal- and photocatalyst-free transformation is demonstrated through the multicomponent synthesis of complex α-fluoromethyl amines and amino acid derivatives via radical addition to in situ-formed iminium ions, and the construction of β-fluoromethyl esters and amides from electron-deficient alkene acceptors. These complex fluoromethylated products, many of which are inaccessible via previously reported methods, may serve as useful building blocks or fragments in synthetic and medicinal chemistry both in academia and industry., Generation of fluoromethyl radicals via visible light-mediated halogen atom transfer activation of fluoroiodomethane facilitates both the multicomponent synthesis of α-fluoromethyl amines and the hydrofluoromethylation of electron-deficient alkenes.

A catalytic asymmetric total synthesis of (+)-vincamine is presented. Key features of the synthesis include a Pd-catalyzed enantioselective decarboxylative allylation to form the C20 quaternary stereogenic center and a stereoselective iminium reduction to install the critical cis-C20/C21 relative stereochemisty.

Cross-couplings involving organozinc reagents usually require a Pd-catalyst (Negishi cross-coupling), however, uncatalyzed cross-couplings of zinc organometallics proceed well in the absence of transition-metal catalysts with reactive electrophiles such as benzal 1,1-diacetates, benzhydryl acetates, and iminium trifluoroacetates. Organozinc compounds also undergo C–N bond formation with O-benzoylhydroxylamines or organic azides in the presence of cobalt- or iron-catalysts. Highly diastereoselective and enantioselective cross-couplings can be readily performed with room-temperature configurationally stable alkylzinc species, producing diastereoselectively and enantiomerically enriched products. Finally, highly regioselective magnesiations of functionalized arenes and heteroarenes undergo Negishi (after transmetalation with ZnCl2) or Cu-catalyzed cross-couplings.1 Introduction2 Uncatalyzed Cross-Couplings of Organozinc Reagents with Highly Electrophilic Partners3 Iron- and Cobalt-Catalyzed Aminations using Organozinc Reagents4 Stereo- and Regioselective Cross-Couplings of Organozinc Reagents5 Conclusion

Roussi's landmark work on the generation of 1,3-dipoles from tertiary amine N-oxides has not reached its full potential since its underlying mechanism is neither well explored nor understood. Two competing mechanisms were previously proposed to explain the transformation involving either an iminium ion or a diradical intermediate. Our investigation has revealed an alternative mechanistic pathway that explains experimental results and provides significant insights to guide the creation of new N-oxide reagents beyond tertiary alkylamines for direct synthetic transformations. Truhlar's M06-2x functional and Moller-Plesset second-order perturbation theory with Dunning's [jul,aug]-cc-pv[D,T]z basis sets and discrete-continuum solvation models were employed to determine activation enthalpies and structures. During these mechanistic explorations, we discovered a unique multi-ion bridged pathway resulting from the rate-determining step, which was energetically more favorable than other alternate mechanisms. This newly proposed mechanism contains no electrophilic intermediates, strengthening the reaction potential by broadening the reagent scope and limiting the possible side reactions. This thoroughly defined general mechanism supports a more direct route for improving the use of N-oxides in generating azomethine ylide-dilithium oxide complexes with expanded functional group tolerance and breadth of chemistry.

An efficient aminocatalytic enantioselective double-activation strategy has been developed that combines several different aminocatalytic modes in a cascade process, such as iminium ion, vinylogous iminium ion, trienamine, and dienamine activations. By using this strategy, 2-hydroxycinnamaldehydes worked well with various dienals via [4 + 2] cycloaddition and the oxa-Michael reaction-initiated cascade, respectively, leading to chiral polycyclic tetrahydrocarbazole and chromane derivatives with excellent diastereo- and enantioselectivities.

Presented herein is a novel and efficient α-C(sp3)-H alkenylation of cyclic amines with maleimides. Mechanistically, this C(sp3)-H/C(sp2)-H cross dehydrogenative coupling (CDC) reaction involves a cascade procedure including oxidative α-amino radical formation from the cyclic amine substrate and nucleophilic addition of the in situ formed α-amino radical onto the electron-deficient carbon-carbon double bond of maleimide followed by oxidation and β-elimination. Notably, this direct α-functionalization provides an effective alternative to the conventional ionic reaction mode, in which an imine or iminium intermediate is formed to react with electron-rich coupling partners other than electron-deficient ones. In general, this method features readily available and structurally diverse substrates, a green and economical catalyst, a unique reaction pathway, mild reaction conditions, high efficiency, and excellent atom economy. This new reaction enriches the application of Fe(III)-catalyzed C(sp3)-H activation and functionalization.

A new and practical two-step transition metal-free methodology for the C(sp3)-C(sp3) functionalisation of saturated N-heterocyclic systems is disclosed. First, aminal derivatives are generated through the anodic oxidation of readily accessible carboxylic acids. Then, in the presence of BF3·OEt2, iminium ions are unmasked and rapidly alkylated by organozinc reagents under flow conditions. Secondary, tertiary and quaternary carbon centers have been successfully assembled using this new methodology. Such an approach is especially relevant to drug discovery since it increases C(sp3)-functionalities rapidly within a molecular framework. As proof of concept, our new methodology was applied to derivatization of peptides and an API.

The first heterogeneously catalyzed process for the reductive coupling of imines and iminium ions is reported using precious metal catalysts in combination with hydrogen gas as the terminal reductant. The optimized method in terms of catalyst composition and reaction conditions allowed to produce aromatic vicinal diamines without the use of stoichiometric amounts of zero or low valent metals, which is currently the preferred method. The most important mechanistic features of the reaction were unraveled by a combined experimental and computational approach. The developed methodology is very efficient for the coupling of aromatic iminium ions with yields up to 88% while imines give only low to moderate yields.

A set of fentanyl molecules when subjected to vacuum UV atmospheric pressure photoionization (VUV-APPI) in the presence of dopants (ammonia and anisole) shows two major bands in the ion mobility-mass spectrometry (IMS-MS) spectrum corresponding to (a) the protonated fentanyl, [M+H]+ and (b) a unique [M-74]+ ion. For the parent fentanyl, the [M-74]+ ion is at m/z 262 but, in the absence of ammonia, the product ion is shifted to m/z 245, corresponding to a difference of NH3. Collision-induced dissociations (CID) of the [M-74]+ ions for all the different fentanyls examined here show the same pattern of neutral losses, namely NH3 and HN=CH2, and the dominant product ion is at m/z 84 (shifted to m/z 98 for 3-methylfentanyl and m/z 142 and 231 for carfentanyl). Dissociation of the [M-74-NH3]+ ion derived from the fentanyls yields the same product ions as found in the electron impact (EI) ionization spectra of the fentanyls. The dissociation products of the [M-74-HN=CH2]+ ion are different, include the ion at m/z 84, and correspond to the fragmentation products of protonated norfentanyls. Theoretical modeling supports the opening of new fragmentation channels as a result of the reaction of the initially formed iminium cation with ammonia at atmospheric pressure.

3-(Trifluoromethyl)prop-2-yne 1-iminium triflate salts were generated from 3-trifloxy-3-(trifluoromethyl)prop-2-ene 1-iminium salts by triethylamine-assisted elimination of triflic acid and trapped in situ in various cycloaddition reactions. 3-(Trifluoromethyl)prop-2-yne 1-iminium triflate salts were generated from 3-trifloxy-3-(trifluoromethyl)prop-2-ene 1-iminium salts by triethylamine-assisted elimination of triflic acid and trapped in situ in various cycloaddition reactions. These included Diels-Alder reactions with 1,3-dienes, [2+2] cycloaddition with 1,4-diphenylbuta-1,3-diene, and [3+2] cycloaddition with organoazides. All these reactions revealed the excellent dienophilic and dipolarophilic reactivity of the electrophilic C,C triple bond of the novel 3-CF3-propyniminium salts., publishedVersion

The construction and engineering of artificial enzymes consisting of abiological catalytic moieties incorporated into protein scaffolds is a promising strategy to realize non-natural mechanisms in biocatalysis. Here, we show that incorporation of the noncanonical amino acid para-aminophenylalanine (pAF) into the nonenzymatic protein scaffold LmrR creates a proficient and stereoselective artificial enzyme (LmrR_pAF) for the vinylogous Friedel-Crafts alkylation between α,β-unsaturated aldehydes and indoles. pAF acts as a catalytic residue, activating enal substrates toward conjugate addition via the formation of intermediate iminium ion species, while the protein scaffold provides rate acceleration and stereoinduction. Improved LmrR_pAF variants were identified by low-throughput directed evolution advised by alanine-scanning to obtain a triple mutant that provided higher yields and enantioselectivities for a range of aliphatic enals and substituted indoles. Analysis of Michaelis-Menten kinetics of LmrR_pAF and evolved mutants reveals that different activities emerge via evolutionary pathways that diverge from one another and specialize catalytic reactivity. Translating this iminium-based catalytic mechanism into an enzymatic context will enable many more biocatalytic transformations inspired by organocatalysis.

Deprotonation of an N-arylated iminium salt affords a new, but unstable, acyclic amino carbene (AAC), which can be efficiently trapped at low temperatures with selected s-, p-, and d-block elements...

The chemistry occurring in the interstellar medium (ISM) is an active area of contemporary research. New aspects of interstellar chemistry are getting unraveled regularly. In this context, the role of metal-ions in the chemistry occurring in the ISM is not well-studied so far. Herein, we highlight the role of metal-ions in interstellar chemistry. For this purpose, we choose the problem of gas-phase formamide formation in interstellar molecular clouds. Formamide is a key biomonomer and contains the simplest peptide [-(C═O)-NH-] linkage. With its two electronegative atoms ("O" and "N"), it provides an excellent platform to probe the role of the metal-ions. The metal-ions chosen are Na+, K+, Al+, Mg+, and Mg2+-all of them present in the ISM. The metal-ions are studied in three different forms as bare positively charged ions, as hydrated metal-ions co-ordinated with a molecule of water, and when the metal-ions are part of a neutral covalent molecule. With the aid of electronic structure calculations [CCSD(T) and DFT methods], we study different gas-phase pathways which result in the generation of interstellar formamide. Throughout our study, we find that metal-ions lower the barriers (with Mg+, Mg++, and Al+ offering maximal stabilization of the transition states) and facilitate the reactions. The chemical factors influencing the reactions, how we consider the putative conditions in the ISM, the astrochemical implications of this study, and its connection with terrestrial prebiotic chemistry and refractory astrochemistry are subsequently presented. Based on our results, we also recommend the detection of two new closed-shell molecules, NH2CH2OH (aminomethanol) and CH2NH2+ (iminium ion), and two open-shell molecules, CONH2 (carbamyl radical) and HCONH (an isomer of carbamyl radical), in the ISM.

The borane-catalyzed synthesis of dihydroquinoline-4-ones is developed. The amino-substituted chalcones undergo a 1,7-hydride shift upon Lewis acid activation to form a zwitterionic iminium enolate...

We have developed an unprecedented approach for the synthesis of transient 1-phosphafulvenes through three component reactions of phospholes. The generation of 1-phosphafulvenes was demonstrated by in situ [6 + 4] cycloaddition with 2H-phospholes and [6 + 6] self-dimerization. The [6 + 4] and [6 + 6] reaction pathway could be modulated by the starting ketones and aldehydes. The construction of 1-phosphafulvenes is illustrated by a proposed mechanism combining nucleophilic addition of phospholide to the iminium or isomerized azomethine ylide and a [1,5]-shift of phosphole.

A catalytic asymmetric dehydrogenative cross-coupling reaction between enones and tertiary amines enabled by synergistic photoredox and chiral primary amine catalysis is reported. The reaction was proposed to proceed via the interception of iminium ion intermediate, in situ generated from photoredox oxidation, by dienamine at α-position, followed by isomerization, leading to aza-Morita–Baylis–Hillman-type products with good diastereo- and enantioselectivity.

The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported., Enantiomerically enriched azabicyclic compounds found in several important families of alkaloids can be prepared by a remarkably stereospecific and stereoselective intramolecular Schmidt reaction. The initial asymmetric alcohol center controls the whole process, leading to the formation of one out of up to four possible diastereoisomers with inversion of the configuration at the original asymmetric center.