# Merging Enantioselective Lewis Base Organocatalysis and Gold(I) Catalysis: A One-Pot Access to Chiral-Fused Polycyclic Compounds

Rémi Pereira, Pierre Locquet, Aurélien Blanc, Fabienne E Grellepois, Emmanuel Riguet

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Rémi Pereira, Pierre Locquet, Aurélien Blanc, Fabienne E Grellepois, Emmanuel Riguet. Merging Enantioselective Lewis Base Organocatalysis and Gold(I) Catalysis: A One-Pot Access to Chiral-Fused Polycyclic Compounds. Journal of Organic Chemistry, 2025, 90 (9), pp.3475-3479. 10.1021/acs.joc.5c00051 . hal-05059677

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# Merging Enantioselective Lewis Base Organocatalysis and Gold(I) Catalysis: A One-Pot Access to Chiral Fused Polycyclic Compounds.

Rémi Pereira,ª Pierre Locquet,ᵇ Aurélien Blanc*,ᵇ Fabienne Grellepois,*,ᵃ and Emmanuel Riguet*,ᵃ

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

**ABSTRACT:** Reported herein is a route to functionalized chiral heteroaromatic polycyclic compounds leveraging two un-
friendly catalytic cycles in a one-pot sequential process. α-Heteroaromatic-γ-butyrolactones were engaged in a highly regio-
, diastereo- and enantioselective Lewis base Asymmetric Allylic Alkylation (AAA) with alkyne functionalized Morita-Baylis-
Hillman (MBH) carbonates. Gratefully to the low Lewis base catalyst loading, subsequent gold catalyzed Friedel-Crafts type
cyclization, entailing the formation of fused polycyclic compounds, proceeded efficiently affording structurally complex
highly enantioenriched products.

INTRODUCTION

Due to their widespread presence in numerous natural products, biologically active compounds and drugs, heteroaromatic
rings are unquestionably privileged structures in the field of drug discovery.¹ Furthermore, it has also been established that
scaffolds embedding three dimensional features and chiral centers are more likely to succeed the transition from compound
discovery to drugs.² Thus development of strategies enabling straightforward access to polycyclic chiral compounds from
simple heteroaromatic molecules is of great interest. To reach this goal, enantioselective organocatalysis is an attractive tool
due to its ability to accommodate polyfunctional reactants. We recently established that asymmetric allylic alkylation (AAA)
can be performed using Morita-Baylis-Hillman (MBH)³ carbonate and chiral Lewis Base (LB) catalyst affording chiral lac-
tones containing a quaternary⁴ or two adjacent quaternary and tertiary stereocenters⁵ (Scheme 1, A). We became interested
in evaluating the versatility of this methodology by using more functionalized MBH carbonates to assess their association
with another catalytic cycle.

<footnote>ªUniversité de Reims Champagne-Ardenne, CNRS, Institut de Chimie Moléculaire de Reims, UMR 7312, 51097 Reims, France</footnote>

<footnote>ᵇUniversité de Strasbourg, CNRS, Institut de Chimie, UMR 7177, 4 rue Blaise Pascal, CS 90032, 67081 Strasbourg, France</footnote>
<figure><img src="image_3.png" /><figcaption>**Scheme 1.** Enantioselective Functionalization of α-Heteroaromatic-γ-butyrolactones</figcaption></figure>

**Main challenges:**

* Use of alkyne functionalized MBH carbonates in asymmetric organocatalysis.

* Merging Lewis Base enantioselective organocatalysis and Gold(I) catalysis.

<figure><img src="image_4.png" /><figcaption>**Scheme 2.** Overview of Reactions Optimization for Both Catalytic Steps and their Combination.</figcaption></figure>

**Step 1: AAA Optimization Conditions**

<figure><img src="image_5.png" /><figcaption>**Catalystª**
LB 10 mol%, 2-MeTHF</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>LB2 80 min 93%
dr 34:66
er 44:56 / 88:12</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>LB1 30 min 87%
dr 43:57
er 37:63 / 82:18</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>LB3 40 min 93%
dr 17:83
er 32:68 / 96:4</figcaption></figure>

<caption>**Solventª**
LB3 10 mol%</caption>

THF

20 min 98%
dr 25:75
er 35:65 / 94:6

Et₂O

20 min 96%
dr 16:84
er 35:65 / 97:3

CH₂Cl₂

60 min 93%
dr 23:77
er 35:65 / 96:4

toluene

30 min 92%
dr 13:87
er 44:56 / 96:4

3a (R=CH₃) 3b (R=tBu)

**Step 2: Gold Catalysts Screening**

LAuCl + AgX
side reactions entailing
low yields
X= SbF₆, NTf₂, BF₄, OTf

preactivated catalysts LAuX
yield up to 90%
X= SbF₆, NTf₂

**Best Catalyst:**
JohnPhosAu(MeCN)SbF₆

**Two-step Process vs One-pot Reaction Sequence**

<figure><img src="image_9.png" /></figure>

1.06 mmol

<figure><img src="image_10.png" /></figure>

2b 0.9 mmol

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

**Two-step process**

1. LB3 2 mol%
toluene (2 mL), 8 h

3b dr 3:97, 233 mg (85%), er 98:2

2. JohnPhosAu(MeCN)SbF₆ 5 mol%

CH₂Cl₂ (2 mL), 24 h

4 150 mg (66%), er 98:2
56% overall yield

**One-pot sequence**

LB3 2 mol%
toluene (2 mL), 8 h (dr 3:97)

then
JohnPhosAu(MeCN)SbF₆ 5 mol%
CH₂Cl₂ (2 mL), 24 h

4 186 mg (68%), er 98:2

<table><caption>**Catalyst loadingª**
LB3 in toluene</caption><tr><td>10 mol%</td><td>2 mol%</td></tr><tr><td>30 min</td><td>120 min</td></tr></table>

yield, dr & er unaffected

**Best Conditions:** LB3 2 mol% in toluene

<figure><img src="image_12.png" /></figure>

<footnote>ªWith MBH adduct 2a. JohnPhos = (2-Biphenyl)di-tert-butylphosphine.</footnote>
MBH carbonates β-substituted by an alkyne were recently used for the synthesis of polyfunctional molecules,⁶ nevertheless to the best of our knowledge their use in an enantioselective process has not been explored to date. Use of multi-catalysis where more than one catalyst work in relay emerged as a powerful tool to master the reactivity of polyfunctional molecules.⁷ Strategies involving Gold complexes including sequential, relay or cooperative catalysis, has proven very valuable over the last decade.⁸ We anticipated that MBH carbonates β-substituted by an alkyne would be useful to construct chiral polycyclic compounds through combining organocatalysis and gold(I) catalysis⁹ (Scheme 1, B). The cornerstone of these catalytic approaches is the ability of chiral organocatalyst to induce highly stereoselective transformations of polyfunctional compounds coupled to the strong carbophilicity of gold(I) complexes, enable to activate π-bonds. However, these processes involve a restricted number of families of organocatalysts, and often required the use of high catalysts loading and/or the use of scavengers.⁹,¹⁰ Indeed, due to the anticipated mutual deactivation of both catalysts, the combination of a Lewis base and a gold(I) catalyst remains underexplored.¹⁰

## RESULTS AND DISCUSSION

We first studied the Asymmetric Allylic Alkylation with benzofuran substituted lactone 1 and methyl ester MBH carbonate substituted with an alkyne function 2a, using various chiral LB in previously established reaction conditions with aromatic substituted MBH adducts (10 mol% of organocatalyst in 2-methyl-THF at room temperature)⁵ (Scheme 2, Step 1). With Lewis base LB1 and LB2, embedding a prolineamide-β-aminoalcohol moiety, the transformation into lactone 3a occurred with total regioselectivity (no linear product was detected in the ¹H NMR spectra of the crude reaction mixture), albeit with poor stereoselectivities. Indeed, the diastereoselectivities are low (dr 43:57 and 34:66), and more disappointingly, very poor enantiomeric ratios (er 37:63 and 44:56) were observed for the less abundant diastereomer and only moderate ones (er 82:18 and 88:12) were observed for the major diastereomer (Scheme 2). We further established that the use of LB3,¹¹ bearing a prolinol moiety, still enabled to form the expected product 3a without traces of the linear product, in an improved diastereomeric ratio of 17:83 and a significantly better enantiomeric ratio for the major diastereomer (er 96:4). Encouraged by these results, we carried out additional modifications to the catalyst structure, which unfortunately failed to improve the stereoselectivities (see Table S1 & S2 in SI for details). We next noticed that the reaction proceeded at a high rate in a wide range of solvents affording the expected product 3a in high yields but with a decrease of diastereomeric ratio in most cases (see Table S3 in SI). Even so, when the reaction was carried out with LB3 in toluene, lactone 3a was isolated in a high yield (92%) as diastereomeric mixture (dr 13:87) with a very good enantiomeric ratio for the major diastereomer (er 96:4). Noteworthy, the reaction can be performed with only 2 mol% of catalyst LB3 without affecting the stereoselectivity and entailing only a slight increase of reaction time (see Table S4 in SI for details). Ultimately, we were pleased to find that the reaction conducted with tert-butyl ester MBH carbonate 2b led to the lactone 3b with a significant increase of the diastereoselectivity (dr 4:96) together with a further slight improvement of enantiomeric ratio (er 98:2) (See Table S5 in SI).

After the optimization for the Asymmetric Allylic Alkylation, we next studied the capacity of gold(I) to catalyze an intramolecular Friedel-Crafts type cyclization using lactone 3b as starting material (Scheme 2, Step 2). When this latter was mixed in dichloromethane in the presence of 10 mol% of triphenylphosphine gold(I) chloride and silver(I) salts ($SbF_6$, $NTf_2$, $BF_4^-$ and $OTf$), we failed to isolate the desired compound 4 due to the formation of a significant amount of side products arising from the hydrolysis of the tert-butyl ester moiety under these reaction conditions (see Table S6 in SI). Using various preactivated gold(I) catalysts embedding soft counter-anions, we were pleased to discover that the cyclization occurred smoothly and delivered the polycyclic compound 4 in high yield. Ultimately, we identified $JohnPhosAu(MeCN)SbF_6$ as the best catalyst and 5 mol% as the best loading for this transformation (see Table S6).

To evaluate the entire process, i.e. the Asymmetric Allylic Alkylation followed by the gold-catalyzed cyclization, the AAA reaction was carried out on 0.6 mmol scale of lactone 1 in the presence of 1.5 equiv of MBH carbonate 2b in the presence of LB3. The reaction proceeded in excellent diastereoselectivity (dr 97:3) in 8 h affording the compound 3b as a diastereomeric mixture in very good yield (85%) and excellent enantiomeric ratio (98:2) (Scheme 2, two-step process). The entire amount of 3b so obtained in this first step was subjected to gold(I) catalysis. The use of 5 mol% of $JohnPhosAu(MeCN)SbF_6$ results in a full conversion to polycyclic compound 4 in 24 h. The major diastereomer of 4 could be isolated in pure form in 66% yield and with an excellent enantiomeric ratio of 98:2, indicating that the stereochemical integrity of the stereocenters formed in the first step had been entirely preserved. The overall yield of this two-step process is therefore 56%.
<figure><img src="image_13.png" /><figcaption>**Scheme 3.** Scope of the One-pot Reaction Sequence.ᵃ</figcaption></figure>

A: Benzothiophene

<figure><img src="image_14.png" /></figure>

B: Benzofuran

<figure><img src="image_15.png" /></figure>

C: Indole

<figure><img src="image_16.png" /></figure>

D: Thiophene

<figure><img src="image_17.png" /></figure>

We next examine the opportunity to carried out the reaction sequence in a one pot process, 5 mol% of JohnPhosAu(MeCN)SbF₆ in CH₂Cl₂ was thus directly added to the rection mixture after full conversion of the starting lactone **1** into the AAA product **3b** (Scheme 2, one-pot sequence). Despite the risk to jeopardize the gold catalyst process due to the presence of the excess MBH carbonate and **LB3**, we were pleased to see that the cyclization proceeded smoothly leading to the full conversion of lactone **3b** into polycyclic lactone **4** after 24h. The pure major diastereomer of **4** arising from this one pot reaction sequence was obtained with excellent enantioselectivity (er 98:2) and isolated in 68% yield.

With these optimized one-pot sequential reaction conditions in hand, we next explored the scope of this process with respect to both MBH carbonate and α-(hetero)aromatic-γ-butyrolactones (Scheme 3). MBH carbonates substituted with electron donating and electron withdrawing groups on phenyl were first evaluated on α-benzothiophene lactone. All reactions proceeded in high diastereoselectivity (dr within the range 95:5 and 97:3) and the major diastereomer of polycyclic products **5-11**, isolated in pure form in most cases, was formed with an excellent enantiomeric ratio (er 97:3 to 99:1). Reactions of MBH carbonates with α-benzofuran lactone led to a mixture of diastereomers with a very good, albeit slightly lower, diastereomeric ratio (dr ranging from 90:10 to 92:8). In addition, it should be noted that it was necessary to use 10 mol% of gold(I) catalyst with halogen-substituted benzofurans to reach full conversion for the cyclization. The major diastereomer of

<footnote>ᵃUnless specified, yields refer to the major diastereomer in diastereomerically pure form (no traces of the minor diastereomer detected by ¹H NMR). ᵇLactones isolated as a mixture of diastereomers: 5 dr 97:3, 13 dr 98:2, 14 dr 97:3, 15 dr 94:6, 21 dr 94:6, 24 dr 98:2. ᶜAnother fraction containing a mixture of diastereomers was also isolated: 7 41% dr 98:2, 13 41% dr 80:20, 20 21% dr 89:11. ᵈ2x5 mol% of Au(I) catalyst were used to complete the reaction.</footnote>
polycyclic products **12-16**, which was sometimes difficult to isolate in pure form, was nevertheless obtained with an excel-
lent enantiomeric ratio (er 97:3 or 98:2). Applying these reaction conditions on unprotected α-indole lactones, the
diastereoselectivity of the AAA was within the same range of values (dr ranging from 90:10 to 93:7) and we noticed a signif-
icant increase of the gold catalyzed cyclization rate (only 30 min to complete the reaction). However, the instability of the
polycyclic products on silica and alumina prevented their purification. To solve this problem, a supplementary step was per-
formed *in-situ* to protect the indole with a Boc group and to enable the purification of the desired products **17-19** which
were obtained with an excellent enantioselectivity (er ranging from 95:5 to 97:3). These reaction conditions were also ap-
plied to α-thiophene lactone to access to polycyclic products **20-23** (dr ranging from 90:10 to 93:7, er 98:2). As previously
observed in some cases 10 mol % of gold(I) catalyst was required to complete the Friedel-Crafts reaction step. The absolute
configurations of the created stereocenters were unambiguously determined by single crystal X-ray analysis of compound
**20**. This reaction sequence could be also successfully run with aromatic lactones, such as *m*-methoxyphenyl substituted
lactone. Despite the slightly lower diastereoselectivity of the AAA step (dr 90:10), the polycyclic compound **24** was obtained
with an excellent enantiomeric ratio (er 97:3). With MBH carbonate containing an alkyne substituted by a butyl moiety
rather than an aromatic ring, the AAA step proceeded uneventfully; nevertheless, we didn't succeed to isolate the expected
product mainly due to low conversion of the gold catalyzed step

Finally, this one pot two-step reaction sequence was performed on 2 mmol scale of benzothiophene lactone **1**. A 97:3 mix-
ture of diastereomers was formed and the major diastereomer **4** was isolated in 95% yield, better than that obtained on 0.6
mmol scale, and with an excellent enantiomeric ratio (er 98:2) (Schemes 2 vs 4, A). To provide a first overview of the poten-
tial structural diversification of these fused polyfunctional chiral building blocks, we exploited the reactivity of α,β-
unsaturated ester group in selective transformations (Scheme 4, B). Deprotection of the ester function of **4** followed by
reaction with L-leucine methyl ester hydrochloride under classical amide bond formation conditions led to the amide **25** in
63 %. Interestingly, reaction with L-cysteine methyl ester hydrochloride under the same conditions led to the
diastereomerically pure amide derivative **26** (61 % yield), containing an additional 7-membered ring cycle resulting from
the conjugate addition of the thiol group of the side chain. Finally, 1,3-Dipolar cycloaddition of **4** with the *in-situ* generated
nitrile oxide gave the diastereomerically pure derivative **27**, isolated in 52% yield, illustrating the opportunity to quickly
achieve the synthesis of conjugated molecules containing an additional oxazoline ring.

<figure><img src="image_18.png" /><figcaption>**Scheme 4.** Two Millimoles Scale Synthesis of Lactone **4** and Valuable Synthetic Transformations.</figcaption></figure>

CONCLUSION
In summary, we have developed a one-pot sequential process involving two independent catalytic cycles, an organocatalyzed Asymmetric Allylic Alkylation reaction followed by a gold catalyzed cyclization. The overall sequence usually involved low (2 mol% of organocatalyst) and moderate (5 mol% of gold catalyst) catalysts loading. Original fused polycyclic derivatives containing two vicinal quaternary tertiary stereocenters, were obtained in very good to excellent diastereoselectivity (dr from 90:10 to 97:3) and excellent enantioselectivity (er ranging from 95:5 to 99:1). Thanks to the polyfunctional nature of these chiral building blocks their structural diversity can be further increased by selective transformations involving α,β-unsaturated ester moiety.¹² The exploration of reactivity entrenched in the heteroaromatic scaffold will be studied and reported in due course.

# EXPERIMENTAL SECTION

Experimental details, synthetic procedures, and characterization data are included in the Supporting Information.

# ASSOCIATED CONTENT

## Data Availability Statement

The data underlying this study are available in the published article, in its Supporting Information, and NMR primary files openly available in Research Data Gouv at https://doi.org/10.57745/DKYK7T.

## Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

Experimental procedures, characterization data, copies of NMR spectra of all new compounds, HPLC chromatograms for **3-24**. (PDF)

## Accession Codes

CCDC 2404672 contains the supplementary crystallographic

data for this paper. This data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033AUTHOR INFORMATION

## Corresponding Authors

Emmanuel Riguet - orcid.org/0000-0002-8926-113X; Université de Reims Champagne-Ardenne, CNRS, Institut de Chimie Moléculaire de Reims, UMR 7312, 51097 Reims, France
emmanuel.riguet@univ-reims.fr

Fabienne Grellepois - orcid.org/0000-0002-0992-722X; Université de Reims Champagne-Ardenne, CNRS, Institut de Chimie Moléculaire de Reims, UMR 7312, 51097 Reims, France
fabienne.grellepois@univ-reims.fr

Aurélien Blanc - orcid.org/0000-0003-4240-3281; Université de Strasbourg, CNRS, Institut de Chimie, UMR 7177, 4 rue Blaise Pascal, CS 90032, 67081 Strasbourg, France
ablanc@unistra.fr

# ACKNOWLEDGMENTS

We thank the French Agency of Research (ANR-22-CE07-0021, ArCopeRebirth), the CNRS, the universities of Strasbourg and Reims Champagne-Ardenne, the Communauté Urbaine du Grand Reims, and the French Ministry of Higher Education, Research, and Innovation for financial support. We gratefully acknowledge Dr Christelle Kowandy for X-ray crystallographic structure determination of compound **20**, Alexis Vallée for Chiral HPLC analysis and Dr Anthony Abou Dib for HRMS analysis (Université de Reims Champagne Ardenne).

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(12) A version of this work was previously published as preprint: Pereira R, Iocquet P, Blanc A, Grellepois F, Riguet emmanuel. Merging Enantioselective Lewis Base Organocatalysis and Gold(I) Catalysis: A One-Pot Access to Chiral Fused Polycyclic Compounds. *ChemRxiv*. **2024**; doi:10.26434/chemrxiv-2024-nrz6q.