# Organocatalytic enantioselective allylic alkylation of α-aryl γ-lactones: an approach to densely functionalized quaternary stereocentres

Morgane Mando, Fabienne Grellepois, Emmanuel Riguet

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Morgane Mando, Fabienne Grellepois, Emmanuel Riguet. Organocatalytic enantioselective allylic alkylation of α-aryl γ-lactones: an approach to densely functionalized quaternary stereocentres. Chemical Communications, 2020, 56 (49), pp.6640-6643. 10.1039/D0CC02058C. hal-02882087

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# Organocatalytic Enantioselective Allylic Alkylation of α-Aryl γ-Lactones: An Approach to Densely Functionalized Quaternary Stereocentres

Morgane Mando,ª Fabienne Grellepoisª and Emmanuel Riguetª*

Université de Reims Champagne Ardenne, CNRS, Institut de Chimie Moléculaire de Reims UMR 7312, 51097 Reims, France.

The Asymmetric Allylic Alkylation (AAA) of α-aryl γ-lactones involving the activation of Morita-Baylis-Hillman (MBH) carbonates by an original chiral Lewis base is reported. A wide range of γ-lactones bearing a quaternary stereocentre was thus obtained in both high yields and high enantiomeric ratios. The direct alkylation by MBH alcohol using *in situ* activation has been also established. Additionally synthetically useful functional transformations of groups surrounding the quaternary stereocentre have been performed.

Among strategies used to improve the success in the discovery of biologically active small molecules, the exploration of the chemical space by increasing the number of sp³ carbons and the selective incorporation of carbon stereocentres are currently under scrutiny, especially in order to address the promiscuity issue.¹ Additionally to their ubiquity in many natural and biologically active products, carbon stereocentres bearing four carbon substituents, so called quaternary stereocentres, are archetypal structural elements that potentially exhibit both three-dimensionality and functional diversity. Despite the challenging nature of their constructions, useful asymmetric catalytic methodologies have recently emerged.² Among them Asymmetric Allylic Alkylation (AAA) of trisubstituted prochiral enolates catalysed by transition metals has appeared as a powerful approach.³ Nevertheless some important classes of these kind of nucleophiles including the ones from α-substituted lactones are underexplored.⁴ In this context, the generation and the asymmetric alkylation of enolates from lactones α-substituted with non-stabilizing groups are especially demanding.⁴b-e To the best of our knowledge there are only two reports dealing with the synthesis of chiral quaternary α-allyl-α-aryl-disubstituted γ-lactones by AAA (Scheme 1).⁴c, ⁴d Both of them highlighted the indirect Decarboxylative Asymmetric Allylic Alkylation (DAAA) pathway to generate mildly the reactive enolate. In spite of their merits, such as the good to excellent levels of enantioselectivities, these strategies inherently imply the multi-steps synthesis of starting materials and hence limit the structural diversity of the reachable products. Moreover, transition metal catalysis *de facto* excludes the use of lactones bearing halogenated phenyl ring regardless of their great synthetic usefulness.

We became interested in overcoming these limitations by developing a direct organocatalytic Asymmetric Allylic Alkylation of α-aryl substituted γ-lactones (scheme 1). We were especially concerned to develop a methodology providing an access to highly functionalized quaternary stereocentres accommodating both various α-aryl substituents and functionalized allyl group. We anticipated that the activation of an allyl carbonate entailing the formation of naked *tert*-butanolate could avoid the use of an additional stoichiometric strong base. Organocatalytic activation of carbonates has found great applications through the use of Morita-Baylis-Hillman (MBH) derivatives.⁵
<figure><img src="image_2.png" /><figcaption>Scheme 1 AAA of α-aryl γ-lactones: State of the art and project</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>Table 1: Organocatalytic AAA of γ-lactone **1a** with MBH carbonates **2a-b**</figcaption></figure>

The reactions were carried out with 0.25 mmol of **1a**, 0.55 mmol of **2a-b** and 0.0125 mmol of catalyst in CHCl₃ (1 mL). <sup>a</sup> Determined by chiral HPLC analysis. <sup>b</sup> Absolute configuration was assigned by analogy with compound **28**, see Scheme 5. <sup>c</sup> In brackets, reaction carried out on 1 mmol scale.

According to this strategy, the AAA occurs through an SN2'/SN2' mechanism.<sup>6</sup> Despite its successful application to the formation of quaternary stereocentre, to the best of our knowledge, only well stabilized enolates were engaged as prochiral partners.<sup>7</sup>

In order to establish the opportunity to develop a direct organocatalytic AAA of α-aryl lactones we initiated our study using lactone **1a**,<sup>4e</sup>,<sup>8</sup> as model of enolate precursor, and MBH carbonate **2** (Table 1). We first established that the reaction proceed very efficiently in CHCl₃ using DMAP (5 mol%) as Lewis base catalyst. Indeed the racemic α-quaternary γ-lactones **3a** was obtained in excellent yield (97%) in a short reaction time (2h) (Table 1, entry 1). We first attempted to turn the process enantioselective using cinchona alkaloids, the privileged catalysts for the
activation of MBH carbonates by an SN2'/SN2' pathway.⁶ Albeit that the lactone **3a** was obtained in good to excellent yield (up to 95 %) only moderate enantioselectivities were observed (up to 69:31 er)(see SI for details). We turned our attention on known chiral DMAP analogues.⁹ The use of both Fu chiral planar DMAP **C**₁¹⁰ and Connon catalyst **C**₂¹¹ led to the expected lactone **3a** in excellent yields (93 % and 97% respectively) but with low enantiomeric ratios (70:30) (Table 1, entries 2 and 3). Although these results were disappointing, we planned that efficient catalyst could be obtained based on the Connon's design of catalyst **C**₂ by increasing the shielding effect and the hydrogen bond ability of the substituents, both could be beneficial to rise the enantioselectivity. Thus we synthesised and evaluated the catalytic activity of catalyst **C**₃·₇ bearing a DMAP core substituted by a prolineamide-β-aminoalcohol moiety (Table 1, entries 4-8). Catalyst **C**₃ which contains a single stereocentre gave rise to the lactone **3a** in 98 % yield and short reaction time (1h30) but still with low enantioselectivity (60:40) (Table 1, entry 4). A first significant improvement of the enantioselectivity occurred using catalyst **C**₄, bearing a β-aminoalcohol moiety derived from L-tert-leucine, as lactone **3a** was isolated in high yield (96%) and a 88:12 enantiomeric ratio (Table 1, entry 5). The catalyst **C**₅ whose *t*-butyl group was replaced by a benzyl gave rise to the lactone **3a** in excellent yield (98%) only after a prolonged reaction time (24h) and in a lower enantioselectivity (82:18 er) (Table 1, entry 6). Finally, we found that the best catalyst was **C**₆ containing an *i*-butyl side chain giving the lactone **3a** in 96% and good enantiomeric ratio of 90:10 in a short reaction time (3h30)(Table 1, entry 7). It is noteworthy that the enantioselectivity dramatically decreased (from 90:10 to 60:40) using the epimeric catalyst **C**₇ (Table 1, entry 8). Eventually the use of tert-butyl ester analogue **2b** with the best catalyst **C**₆ entails a slight increase of the enantiomeric ratio (92:8) without notorious deleterious effect on the reaction time (5h) and yield (93%)(Table 1, entry 9). Several variations of the reaction conditions didn't significantly improve the outcome of the process (see SI for details).

We then investigated the AAA of more challenging substrates i.e α-phenyl-γ-lactones employing these optimized reaction conditions (Scheme 2).
<figure><img src="image_4.png" /><figcaption>Scheme 2: Organocatalytic AAA of α-phenyl γ-lactones with MBH carbonates. The reactions were carried out with 0.25 mmol of lactone, 0.55 mmol of **2a-b**, 0.025 mmol of **C₆** in CHCl₃ (1 ml). <sup>a</sup> Reaction carried out on 0.5 mmol scale. <sup>b</sup> Reaction carried out on 1 mmol scale. <sup>c</sup> After recrystallization.</figcaption></figure>

When γ-lactone bearing an unsubstituted phenyl ring was used, we observed a lowering of the reaction rate that required the use of the more reactive carbonate **2a** and 10 mol% of catalyst **C₆**. The lactone **4** was isolated in moderate yield (58%) after a prolonged reaction time (48h). Pleasingly, a good level of enantioselectivity was observed (89:11). The para-electron donating group on the phenyl ring has a deleterious effect both on the kinetic of the reaction and its enantioselectivity, as highlighted by the moderate yields (41% and 18%) and lower enantiomeric ratios (76:24 and 86:14 er) obtained for lactones **5** and **6** respectively. These results could arise from a destabilisation of the lactone enolate formed during the course of the reaction. The para substitution of the phenyl ring by a lower electron donating group (i. e. -SCH₃) led to a total conversion in lactone **7** which was isolated in high yield (92%) and very good enantiomeric excess (94:6 er). More significantly para-substitution of the phenyl ring by an halogen atom (F, Cl and Br) induces both good conversions in a shorter reaction time and higher enantioselectivities. Indeed lactones **8**, **9** and **10** were obtained in high yields ranging from 80% to 98% and good to very good enantioselectivities (from 87:13 to 93:7). It is noteworthy that excellent enantiomeric ratios could be obtained after recrystallisation of solid compounds as illustrated for lactone **10** (74%, 99:1 er). We also demonstrated that when the AAA was applied to lactone bearing an α-biphenyl group, the corresponding lactone **11** was isolated in good yield (73%) and very good enantioselectivity (94:6). We then investigated the effect of a meta substituent on the phenyl ring. The lactones **12** and **13** bearing a meta methyl or methoxy group respectively were obtained in higher yields (70% and 43%) and good enantioselectivities (86:14 and 95:5 er) compared with para substituted lactones **5** and **6**. More importantly lactones **14**, **15** and **16** bearing meta-halogenated phenyl rings were obtained in both high yields ranging from 80% to 98% and high enantioselectivities (92:8-96:4 er).
<figure><img src="image_5.png" /><figcaption>Scheme 3: Organocatalytic AAA of other γ-lactones with MBH carbonate **2b** The reactions were carried out with 0.25 mmol of lactone, 0.55 mmol of **2b** and 0.025 mmol of **C**<sub>6</sub> in CHCl<sub>3</sub> (1 ml). <sup>a</sup> After recrystallization.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Scheme 4: AAA of γ-lactones through *in situ* activation of MBH alcohol. The reactions were carried out with 0.25 mmol of lactone, 0.55 mmol of **2** and 0.025 mmol of **C**<sub>6</sub> in CHCl<sub>3</sub> (1 ml). <sup>a</sup> Reaction carried out on 1 mmol scale.</figcaption></figure>

Disappointingly, no conversions were observed for most of the ortho-substituted-α-phenyl-γ-lactones (e. g. -CH<sub>3</sub>, -OCH<sub>3</sub>, Cl and Br). These results could be explained by the inhibition of coplanarity and the resulting destabilization of the expected enolate. Nevertheless lactone **17** with an ortho-fluoro substituted phenyl ring could be isolated in a moderate yield (65%) and enantioselectivity (78:22 er). The negative ortho-effect is also comforted by the sluggish reaction leading to the isolation of lactone **18** in a very low yield (12%) and enantioselectivity (73:27 er). Finally we were able to obtain quaternary naphthyl lactones **19** and **20** in very good yields (96% and 98%) and enantioselectivities (93:7 er).

The scope of the reaction was then explored by applying the methodology to α-heteroaryl-γ-lactones (Scheme 3). The 3-functionalized benzofuran derived lactone was successfully alkylated by carbonate **2b** leading to the quaternary lactone **21** in high yield (88%) and very good enantiomeric ratio (94:6 er). Lactones **22** and **23** bearing α-benzothiophen and α-thiophen rings were also obtained in high yield (98 and 96%) and enantiomeric ratios (95:5 and 96:4). Regarding the relevance of the indole ring in biologically active compounds, we are pleased to highlight that lactones bearing unprotected indole ring can be regioselectivity alkylated to form the corresponding lactones **24** and **25** in excellent yields (90 and 98%), although the enantioselectivities were significantly lower (78:22 er). Finally the lactones **26** and **27** were obtained in good yields (84% and 86% respectively) but with low enantioselectivities (70:30 and 76:24 er) (see also SI for related lactones).

We next explored the direct AAA of lactones by MBH alcohols through *in situ* activation by (Boc)<sub>2</sub>O as this strategy seemed unexplored, to date, in spite of its attractiveness (Scheme 4). This could be explained by the anticipation
that the formed lactone enolate might be trapped as the corresponding tert-butylenolcarbonate. The reaction of lactone **1a** MBH alcohol **2c** (2.2 equiv) and (Boc)₂O (2.2 equiv) led uneventfully to the desired functionalized lactone **3b** in both high yield (92%) and enantiomeric ratio (93:7) identical to those obtained using carbonate **2b** (Scheme 4 and Table 1, entry 9). As we anticipated, no conversion of the starting materials was observed in absence of (Boc)₂O. The obtention of lactone **16** in same high enantiomeric ratio (94:6 er) and yield (86%) than the ones obtained via preactivation of the electrophile as carbonate confirmed the attractiveness of the method (Schemes 2 and 4).

<figure><img src="image_7.png" /><figcaption>Scheme 5 Synthetically useful transformations of α-quaternary γ-lactones</figcaption></figure>

In the last part of this study we wished to provide a first overview on the synthetic utility of the functional diversity surrounding the quaternary stereocentre created by this new methodology (Scheme 5). Acyclic quaternary stereocentre can be easily obtained by selective reduction of the lactone ring providing the diol **28** in good yield (82%). The absolute stereochemistry of the quaternary stereocentre of compound **28** was determined by X-Ray crystallographic analysis. The usefulness of α-halogenated phenyl γ-lactones was illustrated by the easy access to polyaromatic quaternary lactone **29** in 82% yield through Suzuki cross coupling reaction. Finally, starting from lactone **21**, highly functionalized spirocyclic quaternary lactone **30** can be reached in good yield (81%) by ring closing metathesis.

In summary, we have developed a direct organocatalytic enantioselective allylic alkylation for the synthesis of α-quaternary γ-lactones. The proposed approach afforded chiral lactones in very good yields (up to 98%) and enantiomeric ratios (up to 96:4). The main features of the reaction enabled to construct a great structural diversity surrounding the quaternary stereocentre including halogenated substituted phenyl and heteroaromatic rings. As a first highlight of the synthetic utility of this methodology, straightforward accesses to highly functionalized chiral building blocks were established. Further studies to apply this reaction to a wider scope of lactones and to rationalize its stereochemical outcome are currently in progress in our laboratory.
We gratefully thank the Université de Reims Champagne-Ardenne for financial support (MM), CNRS, the "Conseil Régional de Champagne-Ardenne", and the EU-program FEDER for the facilities of the Analytical Platform (PIAneT CPER project). We thank M. Fares for helpful synthesis of some starting materials, A. Martínez for her help with NMR analyses, A. Vallée and C. Machado for their assistance with HPLC and HRMS and Dr C. Kowandy for X-ray crystallographic structure determination of compound 28.

Conflicts of interest

There are no conflicts to declare.

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