# Singlet Carbenes Are Stereoinductive Main Group Ambiphiles

Jan Lorkowski, Patrick Yorkgitis, Fanny Morvan, Jennifer Morvan, Nicolas Vanthuyne, Thierry Roisnel, Milan Gembicky, Guy Bertrand, Marc Mauduit, Rodolphe Jazzar

► To cite this version:

Jan Lorkowski, Patrick Yorkgitis, Fanny Morvan, Jennifer Morvan, Nicolas Vanthuyne, et al., Singlet Carbenes Are Stereoinductive Main Group Ambiphiles. Journal of the American Chemical Society, 2025, 147 (17), pp.14777-14784. 10.1021/jacs.5c03845. hal-05050687

HAL Id: hal-05050687

https://hal.science/hal-05050687v1

Submitted on 18 Jul 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
SINGLET CARBENES ARE STEREOINDUCTIVE MAIN GROUP
AMBIPHILES

Jan Lorkowski<sup>a,b§</sup>, Patrick Yorkgitis<sup>a§</sup>, Fanny Morvan<sup>b</sup>, Jennifer Morvan<sup>b</sup>, Nicolas Vanthuyne<sup>c</sup>, Thierry Roisnel<sup>b</sup>,
Milan Gembicky<sup>a</sup>, Guy Bertrand<sup>a,*</sup> Marc Mauduit<sup>b,*</sup> Rodolphe Jazzar<sup>a,*</sup>

§ J.L. and P. Y. contributed equally to this work

KEYWORDS. Carbene, Enantioselective, Main Group, DFT

**ABSTRACT:** Stereogenic units are a critical source of molecular complexity, but their stereoselective formation via main group ambiphiles—
which are suitable for derivatizing a wide scope of functionalities—is largely unexplored. Herein, using chiral cyclic (alkyl)(amino)carbenes
(<sup>Ch</sup>CAACs), we study stereoinduction during the oxidative addition of E–H σ-bonds (E = C, N, O, Si, P). Through computational modeling,
the relationship between stereochemical outcome and mechanism is elucidated, providing insight into when and why <sup>Ch</sup>CAACs exhibit excel-
lent stereoselectivities. Altogether, these results demonstrate the potential for chiral main group ambiphiles to generate stereogenic units in a
highly controlled manner opening avenues for applying “metal-like” reactivity in metal-free asymmetric syntheses.

INTRODUCTION

Stereogenic units are crucial sources of molecular complexity, play-
ing a pivotal role in a wide range of chemical processes and biological
mechanisms. Harnessing their formation with precision has fueled
relentless advancements in asymmetric synthesis, a field that contin-
ues to drive innovation at the forefront of modern chemis-
try. 1,2 Among these, chiral singlet carbenes have gained considerable
recognition as powerful tools for asymmetric catalysis.3,4 Thanks to
their unique stereoelectronic properties and high modularity, these
species have proven effective not only as chiral ligands in transition-
metal (TM) catalysis, 5 but also as chiral organocatalysts.6 Recently,
their applications have expanded beyond traditional strategies, find-
ing new roles as TM-surrogates. Akin to electron-rich TMs, their dis-
tinct stereoelectronic properties can be leveraged to promote oxida-
tive σ-bond insertions at carbon,7 as well as the reverse reaction—
reductive σ-bond eliminations.8 Individually, these fundamental
steps represent significant milestones for main group ambiphiles,9
which also include constrained phosphines,10 silylenes,11 and other
heavier analogues.12 Collectively, they unlock unexplored avenues in
catalysis.8,10d,13 To the best of our knowledge the stereoselective reac-
tivity of main group ambiphiles, which holds potential for the broad
synthesis of stereogenic units is hitherto largely uncharted. Building
on our recent report on CPL-active molecular propellers,14 we
sought to explore the intermolecular formation of stereogenic units
using cyclic(alkyl)(amino)carbene ambiphiles. A key step in the
synthesis of these propellers (i.e., an intramolecular oxidative addi-
tion at carbon) proceeds with limited stereocontrol, yielding a mix-
ture of diastereomers (Scheme 1).15 We envisaged that extending
this reactivity to an intermolecular oxidative addition would provide

a broader context for systematic investigations of stereochemical
factors governing activations at chiral main group ambiphiles.
Herein, using a combined synthetic and theoretical approach we re-
port the stereoselective oxidative addition of E–H σ-bonds (E = C,
N, O, Si, P) at carbon. To achieve this task, we have devised a meth-
odology to access persistent, configurationally stable and enanti-
opure cyclic(alkyl)(amino)carbenes (<sup>Ch</sup>CAACs) in multigram
quantities. Notably, our results demonstrate that chiral carbenes are
powerful stereoinductive ambiphiles exhibiting excellent thermody-
namic and kinetic control.

A. Reversible E–H bond activation in main group ambiphiles (unselective)

<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

J. Am. Chem. Soc.
2014, 17634

<figure><img src="image_4.png" /></figure>

Angew. Chem. Int. Ed.
2015, 11559

<figure><img src="image_5.png" /></figure>

Angew. Chem. Int. Ed.
2015, 14355

<figure><img src="image_6.png" /></figure>

J. Am. Chem. Soc.
2019, 9823

B. Intramolecular C(sp³)-H bond activation (diastereoselective)

<figure><img src="image_7.png" /></figure>

C. Intermolecular E–H bond activation (enantioselective)

<figure><img src="image_8.png" /><figcaption>**Scheme 1.** Stereoselective E–H insertion reactions with carbene–CAACs.</figcaption></figure>

<footnote>a UCSD-CNRS Joint Research Laboratory (IRL 3555), Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States</footnote>

<footnote>b Univ Rennes, École Nationale Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France</footnote>

<footnote>c Aix Marseille Univ, CNRS, Centrale Med, FSCM, Marseille, France</footnote>

<footnote>* Email: gbertrand@ucsd.edu, marc.mauduit@ensc-rennes.fr, rodolphe.jazzar@cnrs.fr</footnote>
## RESULTS AND DISCUSSION

To begin this study, we first considered the reaction of a terminal alkyne (i.e., phenyl-acetylene) with the bulky and enantiopure (L)-menthyl cyclic(alkyl)(amino)carbene (<sup>Menth</sup>CAAC) derived from the chiral pool.<sup>16</sup> However, in this case the carbene insertion into the C(sp)-H bond resulted in a 50:50 mixture of diastereomers (See ESI for details). We attributed this result to the conformational flexibility of the menthyl group which is known to interfere with stereoinduction.<sup>17</sup> To circumvent this problem we devised a general route to conformationally rigid enantiopure CAACs.<sup>18</sup> Racemic chiral CAAC iminium salts (<b>rac</b>-1) are readily available on a multigram scale.<sup>19</sup> Selective reduction with LiAlH<sub>4</sub> afforded the CAAC-H<sub>2</sub> racemate (<b>rac</b>-2) in nearly quantitative yield.<sup>20a</sup> Using preparative chiral

HPLC, both enantiomers (<b>R</b>-2 and (<i>S</i>-2 were separated and isolated in excellent yield and high enantiopurity (>98.5% ee; First eluted (<b>R</b>-2; second eluted (<i>S</i>-2). Electronic circular dichroism (ECD) confirmed the mirror-image spectra of both enantiomers, (<b>R</b>-2 and (<i>S</i>-2, and their absolute configuration was established by X-ray diffraction (see ESI for details). Subsequent reoxidation with bromine followed by anion exchange with ammonium tetrafluoroborate yielded (<b>R</b>-1 and (<i>S</i>-1 in excellent yield (>70% over 3 steps) without loss of enantiopurity (Scheme 2).<sup>20b</sup> We evaluated the generality of this method, which also allowed for the preparation of both R and S salts 3-6 with excellent enantioselectivities. The absolute configuration of iminium salts was assigned by single crystal X-ray diffraction (see SI for details).

<figure><img src="image_9.png" /><figcaption>**Scheme 2. Preparation and characterization of chiral CAAC precursors**</figcaption></figure>

**C-H, N-H and O-H bond activation.** With these configurationally rigid chiral CAACs (<sup>Ch</sup>CAAC) in hand, we looked at their reactivity with phenyl acetylene. In marked contrast with <sup>Menth</sup>CAAC, reaction of free <sup>Ch</sup>CAAC (<b>R</b>-7 (obtained by deprotonation of (<b>R</b>-1 with KHMDS) led to the selective formation of adduct (<b>R</b>,<b>R</b>-8 (>95:5 dr) resulting from the diastereoselective oxidative addition of the carbene into the alkyne C(sp)-H bond (Scheme 3). X-ray diffraction analysis established the absolute configuration of 8 and revealed the *anti*-orientation of the alkyne fragment relative to the *α*-carbon phenyl substituent. This result underscores the importance of controlling the chiral pocket around the carbene center. We also considered C(sp<sup>2</sup>)-H bonds using pentafluorobenzene (<b>R</b>,<b>S</b>-9,

<figure><img src="image_10.png" /><figcaption>**Scheme 3. Enantioselective oxidative addition of <sup>Ch</sup>CAAC (<b>R</b>-7 into the C(sp)-H bond of phenylacetylene.**</figcaption></figure>

C(sp<sup>3</sup>)-H bonds using chloroform **10** and acetonitrile **11**, N-H bonds with isopropyl amine **12** and O-H bonds with *tert*-butanol **13** (Scheme 4). In all cases, excellent diastereoselectivities (>95:5 dr) in favor of the *anti*-oxidative addition product were observed (established by NOESY experiments and confirmed by DFT; See ESI for details).

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /><figcaption>**Scheme 4. Enantioselective oxidative addition of <sup>Ch</sup>CAAC (<b>R</b>-7 into E-H bonds (E=C, N, O).**</figcaption></figure>
Encouraged by this efficient creation of stereochemical complexity, we envisaged that this process might permit simultaneous control over the configuration of multiple stereocenters, such as with prochiral E-H bonds. To test this hypothesis, $^{Chi}$CAAC (*R*)-7 was reacted with 4-methylbenzyl cyanide (Scheme 5). Gratifyingly, we observed the clean formation of β-amino nitrile (*R*,*R*,*R*)-14 which was obtained in good yield (87%) and high diastereoselectivity (>95.5 dr). We confirmed the absolute configuration by X-ray diffraction analysis. This result showcases the extensive control that the $^{Chi}$CAAC scaffold can exert over stereochemical outcomes at positions remote to the stereogenic α-carbon. It is worth mentioning that chiral β-amino nitriles are important intermediates in the synthesis of biologically active compounds.²¹ In that regard, this approach, which involves the direct diastereoselective C(sp³)-H insertion of an amnocarbene into prochiral alkyl nitriles, represents a new methodology for their preparation.²²

<figure><img src="image_13.png" /><figcaption>**Scheme 5.** Enantioselective reaction of $^{Chi}$CAAC (*R*)-7 with prochiral 4-methylbenzyl cyanide.</figcaption></figure>

To obtain further insight into the stereoselectivity of this reaction, we modeled the free energy profile of the proposed mechanism using density functional theory (DFT) at the ωB97X-V/def2-mTZVPP/SMD(Benzene)//r2SCAN-3c/CPCM (Benzene) level of theory (Figure 1).²³ Note, for simplicity, benzyl cyanide was modeled in place of 4-methylbenzyl cyanide. The reaction proceeds with the formation of **INT2**, a transient contact ion-pair between an iminium cation and an α-cyano carbanion, through **TS1**. Subsequent nucleophilic addition via **TS2** (ΔG‡ = +15.7 kcal/mol) leads to the observed diastereomer (**R**,**R**,**R**)-14 (ΔG = -20.1 kcal/mol). Curious as to when stereoinduction arises along the reaction coordinate, we modelled the other diastereoisomers of **INT1**, **INT2**, and **TS2**. Interestingly, there is no indication of significant stereoinduction before C-C bond formation begins in TS2 (see ESI for details). However,

<figure><img src="image_14.png" /><figcaption>**Figure 1:** DFT free energy profile of the reaction between $^{Chi}$CAAC (*R*)-7 and benzyl cyanide.</figcaption></figure>

the formation of (*R*,*R*,*R*)-14 is strongly favored both kinetically (ΔΔG‡ ≤ -3.9 kcal/mol) and thermodynamically (ΔΔG ≤ -4.3 kcal/mol), in agreement with the excellent experimentally observed diastereoselectivity. Importantly, this suggests that the stereochemical outcome of oxidative addition at carbon may be acutely sensitive to the nature of the stereocenter-forming transition state, which may change with the identity of the E-H bond (vide infra).

**Si-H bond activation.** Organosilanes are valuable substances in organic synthesis and medicinal chemistry but also in materials science where carbenes have been used to modulate the properties of silicon surfaces.²⁴,²⁵ From the perspective of asymmetric synthesis, silanes have several similarities with C(sp³) carbon atoms (i.e., tetrahedral geometry), but also present some key differences (i.e., electronegativity, covalent radius and potential hypervalency) which can impart significant challenges in enantioselective transformations.²⁶ To probe the diastereoselective oxidative addition of carbenes to silanes, $^{Chi}$CAAC (*R*)-7 was reacted with diphenylsilane in THF solution (Scheme 6). In this case, we obtained the corresponding adduct (*R*,*S*)-15 in excellent yield and selectivity (>95:5 dr). Confirming its absolute configuration by X-ray diffraction revealed the syn-orientation of the silane fragment with respect to the α-carbon phenyl substituent which contrasted with our results so far. To rationalize this divergent outcome, we modeled the free energy profile for the formation of (*R*,*S*)-15. As shown in Figure 2 and in agreement with existing literature,²⁷ we propose that the reaction proceeds via the formation of pentacoordinate carbene-silane complex **INT4** through **TS3**, which rearranges via 1,2-hydride shift through transition states **TS4** anti or syn to yield (*R*,*S*)-15 or (*R*,*R*)-15, respectively. Interestingly (*R*,*S*)-15 is kinetically favored (ΔΔG‡ = -2.0 kcal/mol) but thermodynamically disfavored (ΔΔG = +3.3 kcal/mol). This can be rationalized by the mechanism for Si-H insertion, wherein the smaller half of the E-H bond, hydrogen, is the nucleophile in the stereocenter-forming transition state, **TS4**. Evidently, the $^{Chi}$CAAC scaffold directs the nucleophile, whether E or H, towards the less hindered side of the carbene center, anti to the

<figure><img src="image_15.png" /><figcaption>**Scheme 6.** Enantioselective oxidative addition of (*R*)-7 into diphenylsilane.</figcaption></figure>

<figure><img src="image_16.png" /><figcaption>**Figure 2:** DFT free energy profile of the reaction between $^{Chi}$CAAC (*R*)-7 and benzyl cyanide.</figcaption></figure>
phenyl. Thus, for Si-H bonds, in which the electrons are polarized
towards hydrogen, the silane substituent ultimately ends up syn to
the phenyl, contrasting with the outcomes for C-H, N-H, O-H, and
P-H (vide infra) addition. Finally, although (R,S)-15 is the kinetic
product, the high barrier to regenerating the silicate (ΔG‡ = 41.5
kcal/mol) prevents equilibration to the thermodynamic product. Si-
stereogenic silanes have been prepared via TM-catalyzed carbene in-
sertion reactions, but uncatalyzed variants using free carbenes re-
main unexplored so far. Inspired by our results with prochiral C-H
bonds, we extended this study to prochiral Si-H bonds. Reaction of
<sup>Chl</sup>CAAC (R)-7 with methylphenylsilane produced adduct 16 as a
mixture of (R<sub>s</sub>,S<sub>s</sub>) and (R<sub>s</sub>,S<sub>R</sub>) diastereomers in a 76:24 ratio
(Scheme 7). Although not fully diastereoselective, the good dia-
stereoselectivity observed with diphenylsilane and the prochiral 4-
methylbenzyl cyanide suggest that, in the appropriate steric environ-
ment, prochiral silanes could undergo fully diastereoselective bond
insertion with main group ambiphiles.

<figure><img src="image_17.png" /><figcaption>**Scheme 7.** Enantioselective oxidative addition of (R)-2 into prochiral Si–H bonds.</figcaption></figure>

**P–H bond activation.** Phosphines are another important class of
molecules which shine as ligands in transition metal catalysis or as
organocatalysts in enantioselective transformations. 28 We per-
formed the reaction of <sup>Chl</sup>CAAC (R)-7 with diphenylphosphine in
THF at room temperature and obtained adduct 17 as a mixture of
(R<sub>s</sub>R) and (R<sub>s</sub>S) diastereomers in a 60:40 ratio (confirmed by <sup>31</sup>P
and <sup>1</sup>H NMR spectroscopy; Scheme 8)²⁹. Provided a suitable steric
environment, the oxidative addition of CAACs to phosphines is
thermally reversible. 8 In that respect, <sup>Chl</sup>CAAC (R)-7 can be seen as
a midpoint between the very bulky adamantyl CAAC and the very
small dimethyl CAAC. 19 We thus hypothesized that the steric profile
of (R)-7 could facilitate a reversible reductive elimination/oxidative
addition equilibrium to favor the thermodynamic isomer. Gratify-
ingly, heating the reaction mixture at 80°C for 18 hours led to the
diastereoselective formation of adduct (R<sub>s</sub>R)-17 (>95:5 dr) which
was confirmed by XRD analysis and 2D-NMR spectroscopy (See
ESI for details). DFT calculations support a mechanism analogous
to that found in our earlier studies on reductive elimination at carbon
(Figure 3). 8b After formation of the iminium phosphide INT5
through TS5, both stereoisomers are accessible through transition
states TS6syn and TS6anti relatively close in energy (ΔΔC‡ = 1.5
kcal/mol). In line with the observed kinetic product distribution, the
kinetically favored (R<sub>s</sub>R)-17 dominates, albeit slightly. However,
unlike in Si–H insertion, regeneration of the preceding intermediate
from (R<sub>s</sub>S)-17 is thermally accessible, allowing equilibration of the
mixture towards enantiopure (R<sub>s</sub>R)-17. This outcome is somewhat
surprising, since P–H insertion of diphenylphosphine is significantly
less kinetically selective than the analogous Si–H insertion for di-
phenylsilane. However, analysis of the transition state geometries
provides some insights. In Si–H bond insertion, the nucleophile is
positioned much closer to the carbene carbon (δ<sub>avg</sub>(C---H) = 1.95
Å, (δ<sub>avg</sub>(C---P) = 3.25 Å) than in the P–H bond insertion. The more
compact nature of the product-determining transition state—which

cannot be fully attributed to the smaller covalent radius of hydrogen (0.31 Å) compared to phosphorus (1.07 Å)—likely explains the superior kinetic selectivity observed in Si–H insertion. A similar phenomenon is at play with the mechanistically analogous second-row E–H insertion reactions, which generally feature less hindered substrates than diphenylphosphine, yet exhibit superior kinetic selectivity. Inspection of the transition states for C–H insertion of benzyl cyanide reveals a δ<sub>avg</sub>(C---C) of 2.87 Å, a reflection of the smaller covalent radius of carbon (0.76 Å) relative to phosphorus.

<figure><img src="image_18.png" /><figcaption>Scheme 8. Enantioselective oxidative addition of <sup>Chl</sup>CAAC (R)-7 into P–H bonds.</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>**Figure 3:** DFT free energy profile of the reaction between <sup>Chl</sup>CAAC (R)-7 and diphenylphosphine.</figcaption></figure>

Despite the growing notoriety of chiral carbenes,³,⁵ chiral phos-
phines remain a cornerstone of asymmetric catalysis, enabling a wide
range of sophisticated enantioselective transformations.²⁸ Among
them, P-stereogenic phosphorus ligands stand out for their ability to
promote highly enantioselective transformations.³⁰ Building on our
experimental and computational results with diphenylphosphine,
we reasoned that <sup>Chl</sup>CAACs could provide a platform for accessing P-
stereogenic phosphines. In this scenario, we envisioned that asym-
metric equilibration of the diastereomeric mixture, facilitated by re-
versible C–P bond formation, could lead to an enantioenriched
phosphine, due to the thermodynamically favored diastereomer act-
ing as a “sink.”³¹ This strategy, if successful, would represents an ex-
citing uncatalyzed strategy to prepare P-stereogenic phosphines.³²
Following that reasoning we explored the reaction of <sup>Chl</sup>CAAC (R)-
7 with (rac)-P(mesityl)(phosphine) in THF at room temperature
(Scheme 9). Under these conditions rapid formation of adduct 18
as a mixture of two diastereoisomers was observed by NMR spec-
troscopy. We tentatively assigned the absolute configuration of the
minor stereoisomer as (R,S,R) based on 2D NMR measurements and DFT-based NMR chemical shift calculations (See ESI). Grati-fyingly, heating this mixture at 80°C for 2 hours enabled a clean equi-libration to diastereomerically pure, P-stereogenic (R,R,S)-18 (>95:5 dr), the absolute configuration of which was confirmed by ¹H-¹H NOESY NMR.

<figure><img src="image_20.png" /></figure>

<caption>**Scheme 9.** Reaction of <sup>Ch</sup>CAAC (R)-7 with (rac)-P(Ph)(Mes)-H allows for the preparation of enantiopure P-stereogenic phos-phine.</caption>

CONCLUSION

Herein, by leveraging a new route to readily accessible enantiopure cyclic (alkyl)(amino)carbenes (<sup>Ch</sup>CAACs), we investigated factors governing stereoinduction in the oxidative addition of E–H σ-bonds (E = C, N, O, Si, P) to chiral carbon ambiphiles. Our results reveal that these carbenes serve as powerful synths for constructing ste-reochemical complexity, exemplified by their ability to precisely control the formation of two stereocenters with prochiral reagents. Notably, their capacity to direct stereochemistry at silicon and phos-phorus centers underscores their broader potential in asymmetric synthesis. DFT calculations confirm the intimate connection be-tween the structure of the product-determining transition states and reaction thermodynamics with the observed stereoselectivities un-der either kinetic or thermodynamic control. This relationship is particularly evident in the stereoselectivity observed in Si–H and P–H bond activation pathways. Altogether, this work positions chiral ambiphilic carbenes as a new paradigm in asymmetric synthesis, with far-reaching implications for organic chemistry, catalysis, and mate-rials science. We believe these findings extend to other main group ambiphiles, an area still largely unexplored in enantioselective trans-formations.

ASSOCIATED CONTENT

**Supporting Information**

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/xxxx. Experimental procedures, analytical data (¹H, ¹³C, ³¹P, ¹⁹F NMR, HRMS), computational details and DFT-optimized structures (PDF) CIF/PLATON report (PDF)

**Accession Codes**

CCDC 2385234-2385239, 2385854-2385856, 2401279-2401282 and 2428557-2428558 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_re-request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallo-graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

**Data Availability**

All computational data underlying this study are openly available for download, free of charge, from the UC San Diego Library Digital Collections at DOI: 10.6075/J0154HDK.

**Author Contributions**

G. B., M. M. and R. J. conceived, designed and directed the project. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. These authors contributed equally.

**Funding Sources**

We are grateful to the French Centre National de la Recherche Scientifique (CNRS), the Ecole Nationale Supérieure de Chimie de Rennes and the University of California San Diego. This work was supported by the "Prematuration Program" of CNRS (MM), the Agence Nationale de la Recherche (ANR) under award #ANR-19-CE07-0017-ChiCAAC (MM, RJ) and #ANR-20-CE07-0030-cResolu (MM, RJ). This work was supported by the NSF (CHE-2246948) (GB).

ACKNOWLEDGMENTS

This research was supported in part by the W. M. Keck Foundation through computing resources at the W. M. Keck Laboratory for Integrated Biology.

REFERENCES

1 a) Wright, B. A.; Sarpong, R. Molecular Complexity as a Driving Force for the Advancement of Organic Synthesis. *Nat. Rev. Chem.* **2024**, *8*, 776–792. b) Leigh, D.A., Pérez, E.M. Dynamic Chirality: Molecular Shuttles and Motors. In: Crego-Calama, M., Reinhoudt, D.N. (eds) Supramolecular Chirality. Topics in Current Chemistry, vol 265. Springer, Berlin, Heidelberg.

2 Selected recent examples: a) Tae Han, J.; Tsuji, N.; Zhou, H.; Leutzsch, M.; List, B. Organocatalytic asymmetric synthesis of Si-stereogenic silycycles. *Nat. Commun.* **2024**, *15*, 5846. b) Jin, L.; Li, Y.; Mao, Y.; He, X.-B.; Lu, Z.; Zhang, Q.; Shi, B.-F. Chiral dinitrogen ligand enabled asymmetric Pd/norbornene cooperative catalysis toward the assembly of C–N axially chiral scaffolds. *Nat. Commun.* **2024**, *15*, 4908. c) Cheng, P.-M.; Jia, T.; Li, C.-Y.; Qi, M.-Q.; Du, M.-H.; Su, H.-F.; Sun, Q.-F.; Long, L.-S.; Zheng, L.-S.; Kong, X.-J. Bottom-up construction of chiral

metal-peptide assemblies from metal cluster motifs. *Nat. Commun.* **2024**, *15*, 9034. d) Kim, H.; Choi, W.; Kim, Y. J.; Kim, J.; Ahn, J.; Song, I.; Kwak, M.; Kim, J.; Park, J.; Yoo, D.; Park, J.; Kwak, S. K.; Oh, J. H. Giant Chiral Amplification of Chiral 2D Perovskites via Dynamic Crystal Reconstruction. *Sci. Adv.* **2024**, *10*, eado5942.

3 a) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. An Overview of N-Heterocyclic Carbenes. *Nature* **2014**, *510*, 485–496. b) Bel-lotti, P.; Koy, M.; Hopkinson, M. N.; Glorius, F. Recent advances in the chemistry and applications of N-heterocyclic carbenes. *Nat. Rev. Chem.* **2021**, *5*, 711–725.

4 Janssen-Müller, D.; Schlepphorst, C.; Glorius, F. Privileged Chiral N-Heterocyclic Carbene Ligands for Asymmetric Transition-Metal Catalysis. *Chem. Soc. Rev.* **2017**, *46*, 4845–4854.

<footnote>(*) absolute configuration confirmed by NOESY NMR experiments</footnote>
5 César, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chiral N-Heterocyclic Carbenes as Stereodirecting Ligands in Asymmetric Catalysis. *Chem. Soc. Rev.* **2004**, *3*, 619–636.

6 a) Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-Heterocyclic Carbenes. *Chem. Rev.* **2007**, *107*, 5606–5655. b) Yao, W.; Bazan-Bergamino, E. A.; Ngai, M.-Y. Asymmetric Photocatalysis Enabled by Chiral Organocatalysts. *ChemCatChem* **2022**, *14*, e202011292.

7 a) Frey, G. D.; Lavallo, V.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Facile Splitting of Hydrogen and Ammonia by Nucleophilic Activation at a Single Carbon Center. *Science* **2007**, *316*, 439–441. b) Frey, G. D.; Masuda, J. D.; Donnadieu, B.; Bertrand, G. Activation of Si-H, B-H, and P-H Bonds at a Single Nonmetal Center. *Angew. Chem. Int. Ed.* **2010**, *49*, 9444–9447. c) Vermersch, F.; Wang, V.; Abdellaoui, M.; Jazzar, R.; Bertrand, G. Ambiphilicity of Ring-Expanded N-Heterocyclic Carbenes. *Chem. Sci.*, **2024**, *15*, 3707–3710.

8 a) Teator, A. J.; Tian, Y.; Chen, M.; Lee, J. K.; Bielawski, C. W. An Isolable, Photoswitchable N-Heterocyclic Carbene: On-Demand Versatile Ammonia Activation. *Angew. Chem., Int. Ed.* **2015**, *54*, 11559–11563. b) Tolentino, D. R.; Neale, S. E.; Isaac, C. J.; Macgregor, S. A.; Whittlesey, M. K.; Jazzar, R.; Bertrand, G. Reductive Elimination at Carbon under Steric Control. *J. Am. Chem. Soc.* **2019**, *141*, 9823–9826.

9 a) Power, P. P. Main-group elements as transition metals. *Nature* **2010**, *463*, 171–177. b) Martin, D.; Soleilhavoup, M.; Bertrand, G. Stable singlet carbenes as mimics for transition metal centers. *Chem. Sci.* **2011**, *2*, 389–399. c) Chu, T.; Nikonov, G. I. Oxidative Addition and Reductive Elimination at Main-Group Element Centers. *Chem. Rev.* **2018**, *118*, 3608–3680. d) Dewhurst, R. D.; Légaré, M.-A.; Braunschweig, H. Towards the catalytic activation of inert small molecules by main-group ambiphiles. *Commun. Chem.* **2020**, *3*, 131.

10 a) McCarthy, S. M.; Lin, Y.-C.; Devarajan, D.; Chang, J. W.; Yennawar, H. P.; Rioux, R. M.; Ess, D. H.; Radosevich, A. T. Intermolecular N–H Oxidative Addition of Ammonia, Alkylamines, and Arylamines to a Planar σ3-Phosphorus Compound via an Entropy-Controlled Electrophilic Mechanism. *J. Am. Chem. Soc.* **2014**, *136*, 4640–4650. b) Abbenseth, J.; Goicoechea, J. M. Recent developments in the chemistry of non-trigonal pnictogen pincer compounds: from bonding to catalysis. *Chem. Sci.* **2020**, *11*, 9728–9740. c) Lipshultz, J. M.; Li, G.; Radosevich, A. T. Main Group Redox Catalysis of Organopnictogens: Vertical Periodic Trends and Emerging Opportunities in Group 15. *J. Am. Chem. Soc.* **2021**, *143*, 1699–1721. d) Bawari, D.; Toami, D.; Jaiswal, K.; Dobrovetsky, R. Hydrogen splitting at a single phosphorus centre and its use for hydrogenation. *Nat. Chem.* **2024**, *16*, 1261–1266.

11 a) Rodriguez, R.; Contie, Y.; Mao, Y.; Saffon-Merceron, N.; Baceiredo, A.; Branchadell, V.; Kato, T. Reversible Dimerization of Phosphine-Stabilized Silylenes by Silylene Insertion into Si¹⁻–H and Si¹⁻–Cl σ-Bonds at Room Temperature. *Angew. Chem., Int. Ed.* **2015**, *54*, 15276–15279. b) Rodriguez, R.; Contie, Y.; Nougué, R.; Baceiredo, A.; Saffon-Merceron, N.; Sotiropoulos, J.-M.; Kato, T. Reversible Silylene Insertion Reactions into Si–H and P–H σ-Bonds at Room Temperature. *Angew. Chem., Int. Ed.* **2016**, *55*, 14355–14358. c) Rodriguez, R.; Gau, D.; Contie, Y.; Kato, T.; Saffon-Merceron, N.; Baceiredo, A. Synthesis of a Phosphine-Stabilized Silicon(II) Hydride and Its Addition to Olefins: A Catalyst-Free Hydrosilylation Reaction. *Angew. Chem., Int. Ed.* **2011**, *50*, 11492–11495.

12 a) Spikes, G. H.; Fettinger, J. C.; Power, P. P. Facile Activation of Dihydrogen by an Unsaturated Heavier Main Group Compound. *J. Am. Chem. Soc.* **2005**, *127*, 12232–12233. b) Peng, Y.; Ellis, B. D.; Wang, X.; Power, P. P. Diarylstannylene Activation of Hydrogen or Ammonia with Arene Elimination. *J. Am. Chem. Soc.* **2008**, *130*, 12268–12269. c) Protchenko, A. V.; Birjkumar, K. H.; Dange, D.; Schwarz, A. D.; Vidovic, D.; Jones, C.; Kaltsoyannis, N.; Mountford, P.; Aldridge, S. A Stable Two-Coordinate Acyclic Silylene. *J. Am. Chem. Soc.* **2012**, *134*, 6500–6503. d) Dahcheh, F.; Martin, D.; Stephan, D. W.; Bertrand, G. Synthesis and Reactivity of a CAAC–Aminoborylene Adduct: A Hetero-Allene or an Organoboron Isoelectronic with Singlet Carbenes. *Angew. Chem. Int. Ed.* **2014**, *53*, 13159–13163. e) Soleilhavoup, M. Bertrand, G. Borylenes: An Emerging Class of Compounds. *Angew. Chem., Int. Ed.* **2017**, *56*, 10282–10292. f) Légaré, M.-A.; Bélanger-Chabot, G.; Dewhurst, R. D.; Welz, E.; Krummenacher, I.; Engels, B.; Braunschweig, H. Nitrogen fixation and reduction at boron. *Science* **2018**, *359*, 896–900. g) Hicks, J.; Vasko, P.; Goicoechea, J. M.; Aldridge, S. Synthesis, structure and reaction chemistry of a nucleophilic aluminyl anion. *Nature* **2018**, *557*, 92–95. h) Hicks, J.; Vasko, P.; Goicoechea, J. M.; Aldridge, S. The Aluminy! Anion: A New Generation of Aluminium Nucleophile. *Angew. Chem., Int. Ed.* **2021**, *60*, 1702–1713.

13 a) Peltier, J. L.; Tomás-Mendivil, E.; Tolentino, D. R.; Hansmann, M. M.; Jazzar, R.; Bertrand, G. Realizing Metal-Free Carbene-Catalyzed Carbonylation Reactions with CO. *J. Am. Chem. Soc.* **2020**, *142*, 18336–18340. b) Gautam, N.; Logdi, R.; Sreejyothi, P.; Roy, A.; Tiwari, A. K.; Mandal, S. K. Bicyclic (alkyl)(amino)carbene (BICAAC) in a dual role: activation of primary amides and CO2 towards catalytic N-methylation. *Chem. Sci.* **2023**, *14*, 5079–5086.

14 Lorkowski, J.; Bouetard, D.; Yorkgitis, P.; Gembicky, M.; Roisnel, T.; Vanthuyne, N.; Munz, D.; Favereau, L.; Bertrand, G.; Mauduit, M.; Jazzar, R. *Angew. Chem., Int. Ed.* **2023**, *62*, e202305404.

15 Pichon-Barré, D.; Zhang, Z.; Cador, A.; Vives, T.; Roisnel, T.; Baslé, O.; Jarrige, L.; Cavallo, L.; Falivene, L.; Mauduit, M. Chiral Oxazolidines Acting as Transient Hydroxyalkyl-Functionalized N-Heterocyclic Carbenes: An Efficient Route to Air Stable Copper and Gold Complexes for Asymmetric Catalysis. *Chem. Sci.* **2022**, *13*, 8773–8780.

16 Lavallo, V.; Canac, Y.; Präsang, C.; Donnadieu, B.; Bertrand, G. Stable Cyclic (Alkyl)(Amino)Carbenes as Rigid or Flexible, Bulky, Electron-Rich Ligands for Transition-Metal Catalysts: A Quaternary Carbon Atom Makes the Difference. *Angew. Chem., Int. Ed.* **2005**, *44*, 5705–5709.

17 Pichon, D.; Soleilhavoup, M.; Morvan, J.; P. Junor, G.; Vives, T.; Crévisy, C.; Lavallo, V.; Campagne, J.-M.; Mauduit, M.; Jazzar, R.; Bertrand, G. The Debut of Chiral Cyclic (Alkyl)(Amino)Carbenes (CAACs) in Enantioselective Catalysis. *Chem. Sci.* **2019**, *10*, 7807–7811.

18 The preparation of N-chiral CAACs have recently been disclosed: a) Madron du Vigné, A.; Cramer, N. Chiral Cyclic Alkyl Amino Carbene (CAAC) Transition-Metal Complexes: Synthesis, Structural Analysis, and Evaluation in Asymmetric Catalysis. *Organometallics* **2022**, *41*, 2731–2741. b) Madron du Vigné, A.; Cramer, N. Streamlined synthetic assembly of α-chiral CAAC ligands and catalytic performance of their copper and ruthenium complexes. *Chem. Sci.* **2024**, *15*, 13864–13871.

19 Vermersch, F.; Oliveira, L.; Hunter, J.; Soleilhavoup, M.; Jazzar, R.; Bertrand, G. Cyclic (Alkyl)(amino)carbenes: Synthesis of Iminium Precursors and Structural Properties. *J. Org. Chem.* **2022**, *87*, 3511–3518.

20 a) Shvydenko, T.; Nazarenko, K.; Shvydenko, K.; Boron, S.; Gutov, O.; Tolmachev, A.; Kostyuk, A. Reduction of imidazolium salts – An approach to diazocines and diazocanes. Tetrahedron, **2017**, *73*, 6942–6953. b) Fournier, P.-A.; Collins, S. K.; A Highly Active Chiral Rutheinum-Based Catalyst for Enantioselective Olefin Metathesis. *Organometallics* **2007**, *26*, 2945–2949.

21 a) Zhao, J.; Liu, X.; Luo, W.; Xie, M.; Lin, L.; Feng, X. Asymmetric Synthesis of β-Amino Nitriles through a Sc³⁻-Catalyzed Three-Component Mannich Reaction of Silyl Ketene Imines. *Angew. Chem., Int. Ed.* **2013**, *52*, 3473–3477. b) Zhang, G.; Liang, Y.; Qin, T.; Xiong, T.; Liu, S.; Guan, W.; Zhang, Q. Copper-Catalyzed Asymmetric Hydroamination: A Unified Strategy for the Synthesis of Chiral β-Amino Acid and Its Derivatives. *CCS Chem.* **2021**, *3*, 1737–1745.

22 a) Zhang, N., Zhang, C., Hu, X., Xie, X., Liu, Y. Nickel-Catalyzed C(sp³)–H Functionalization of Benzyl Nitriles: Direct Michael Addition to Terminal Vinyl Ketones. *Org. Lett.* **2021**, *23*, 6004–6009. b) Hyodo, K., Nakamura, S., Tsuji, K., Ogawa, T., Funahashi, Y., Shibata, N. Enantioselective Reaction of Imines and Benzyl Nitriles Using Palladium Pincer Complexes with C₂-Symmetric Chiral Bis(imidazoline)s *Adv. Synth. Catal.* **2011**, *353*, 3385–3390.
23 a) Neese, F. Software update: the ORCA program system, version 5.0. *WIRES Comput. Molec. Sci.*, **2022**, *12*, e1606. b) Grimme, S.; Hansen, A.; Ehlert, S.; Mewes, J. r2SCAN-3c: A 'Swiss army knife' composite electronic-structure method. *J. Chem. Phys.*, **2021**, *154*, 064103. c) Bannwarth, C.; Ehlert, S.; Grimme, S. GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions. *J. Chem. Theory Comput.*, **2019**, *15*, 1652-1671.

24 Roy, M. M. D.; Omaña, A. A., Wilson, A. S. S., Hill, M. S., Aldridge, S., Rivard, E. Molecular Main Group Metal Hydrides. *Chemical Reviews* **2021**, *121*, 12784-12965.

25 Zhukhovitskiy, A. V.; Mavros, M. G.; Queeney, K. T.; Wu, T.; Van Voorhis, T.; Johnson, J. A. Reactions of Persistent Carbenes with Hydrogen-Terminated Silicon Surfaces. *J. Am. Chem. Soc.* **2016**, *138*, 8639-8652.

26 Xu, L.-W.; Li, L.; Lai, G.-Q.; Jiang, J.-X. The recent synthesis and application of silicon-stereogenic silanes: a renewed and significant challenge in asymmetric synthesis. *Chem. Soc. Rev.* **2011**, *40*, 1777-1790.

27 Momeni, M. R.; Rivard, E.; Brown, A. Carbene-Bound Borane and Silane Adducts: A Comprehensive DFT Study on Their Stability and Propensity for Hydride-Mediated Ring expansion. *Organometallics* **2013**, *32*, 6201-6208.

28 a) F. Orton, G. R.; S. Pilgrim, B.; R. Champness, N. The Chemistry of Phosphines in Constrained, Well-Defined Microenvironments. *Chem. Soc. Rev.* **2021**, *50*, 4411-4431. b) Ni, H.; Chan, W.-L.; Lu, Y. Phosphine-Catalyzed Asymmetric Organic Reactions. *Chem. Rev.* **2018**, *118*, 9344-9411. c) Wei, Y.; Shi, M. Multifunctional Chiral Phosphine Organocatalysts in Catalytic Asymmetric Morita-Baylis-Hillman and Related Reactions. *Acc. Chem. Res.* **2010**, *43*, 1005-1018.

29 a) Melaimi, M.; Jazzar, R.; Soleilhavoup, M.; Bertrand, G. Cyclic (Alkyl)(Amino)Carbenes (CAACs): Recent Developments. *Angew. Chem., Int. Ed.* **2017**, *56*, 10046-10068. b) Kumar Kushvaha, S.; Mishra, A.; Roesky, H. W.; Chandra Mondal, K. Recent Advances in the Domain of Cyclic (Alkyl)(Amino) Carbenes. *Chem. - Asian J.* **2022**, *17*, e202101301.

30 a) Ye, X.; Peng, L.; Bao, X.; Tan, C.-H.; Wang, H. Recent Developments in Highly Efficient Construction of P-Stereogenic Centers. *Green Synth. Catal.* **2021**, *2*, 6-18. b) Imamoto, T. Synthesis and Applications of High-Performance P-Chiral Phosphine Ligands. *Proc. Jpn. Acad. Ser. B*

**2021**, *97*, 520-542. b) Imamoto, T. P-Stereogenic Phosphorus Ligands in Asymmetric Catalysis. *Chem. Rev.* **2024**, *124*, 8657-8739.

31 a) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J. Weisenburger, G. A. Dynamic Thermodynamic Resolution: Control of Enantioselectivity through Diastereomeric Equilibration. *Acc. Chem. Res.* **2000**, *33*, 715-727. b) Steinreiber, J.; Faber, K.; Griengl, H. De-racemization of Enantiomers versus De-epimerization of Diastereomers—Classification of Dynamic Kinetic Asymmetric Transformations (DYKAT). *Chem. Eur. J.* **2008**, *14*, 8060-8072.

32 a) Zhao, D.; Wang, R. Recent developments in metal catalyzed asymmetric addition of phosphorus nucleophiles. *Chem. Soc. Rev.* **2012**, *41*, 2095-2108. b) Herrera, R. P. Organocatalytic Hydrophosphonylation Reaction of Carbonyl Groups. *Chem. Rec.* **2017**, *17*, 833-840.

TOC Graphic

<figure><img src="image_21.png" /></figure>

Enantioselective synthesis ✓ Broad scope ✓ Gram scale ✓