Enantioselective γ-Alkylation of α,β-Unsaturated Malonates and Ketoesters by a Sequential Ir-Catalyzed Asymmetric Allylic Alkylation/Cope Rearrangement

Abstract

A catalytic, enantioselective γ -alkylation of α,β-unsaturated malonates and ketoesters is reported. This strategy entails a highly regio- and enantioselective iridium-catalyzed α-alkylation of an extended enolate, and a subsequent translocation of chirality to the γ-position via a Cope rearrangement.

Graphical abstract

Enantioenriched unsaturated carbonyl compounds are valuable synthetic intermediates owing to their multiple reactive sites poised for further manipulation to synthesize complex molecules with contiguous stereocenters.¹ Direct asymmetric functionalization at the γ -position of α,β-unsaturated carbonyl derivatives would be a straightforward way to access such motifs. However, this transformation has proven challenging, likely due to the absence of proximal functionality to interact with a catalyst in order to induce facial selectivity. Furthermore, issues arise with regard to regioselectivity (α- versus γ -functionalization) and chemoselectivity (C vs O-alkylation). To date, this transformation has only been achieved in a handful of examples.^2,3 In particular, work from the Tunge group demonstrated the ability of α,β-unsaturated carbonyls to undergo palladium-catalyzed decarboxylative allylation/Cope rearrangement, but only one asymmetric example with alkylidene malononitriles was provided with poor enantiocontrol.^2b Recently, the Jørgensen group reported an asymmetric γ -allylation of α,β-unsaturated aldehydes via organocatalysis combined with either iridium or palladium catalysis, providing branched or linear products respectively.^3g Alternatively, a Birch–Cope sequence has been developed by the Malachowski group as an efficient method to access γ -alkylated α,β-unsaturated ketoesters, although stoichiometric alkali metals and chiral auxiliaries were required.⁴ Despite these reports, a general strategy to selectively produce γ -functionalized unsaturated carbonyl derivatives has remained elusive.

Since the initial report in 1997, iridium-catalyzed allylic alkylation has emerged as a successful strategy for the assembly of chiral chemical architectures. ^{5, 6} Numerous studies have been performed in this field elucidating a wide range of suitable nucleophiles.^5,7 However, the use of α,β-unsaturated carbonyls as nucleophiles has seen little attention. We hypothesized that α-alkylation of an extended enolate derived from such compounds could provide chiral 1,5-dienes poised to undergo a [3,3]-sigmatropic rearrangement, producing γ -alkylation products (Scheme 1).⁸ A similar approach was utilized by Arseniyadis and Cossy to produce γ -substituted 2(5H)-furanones.⁹

Scheme 1. Sequential Asymmetic Allylic Alkylation/Cope Rearrangement.

We began our studies with the seven-membered cyclic alkylidene malonate 1a and cinnamyl carbonate 2a as the model substrates (Table 1). A variety of conditions including different bases, solvents, and substrate ratios were examined with iridacycle catalysts¹⁰ generated in situ by the treatment of [Ir(cod)Cl]₂ and phosphoramidites (Figure 1) with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).^{11, 12} Using N-aryl phosphoramidite ligand L1, developed by the You group,^{12, 13} α-alkylation product 3aa is furnished in perfect enantioselectivity and moderate regioselectivity (entry 1). The investigation of solvents revealed that THF affords optimal reactivity and selectivity (See SI for details). The use of Feringa-type ligands¹⁴ L2 and L3 resulted in either a lack of reactivity or formation of a complex mixture of side products (entries 2 and 3). Moreover, ligands L4 and L5 led to diminished regio-and enantioselectivity, respectively (entries 4 and 5). The use of the more sterically congested 3,3′-diphenyl-substituted phosphoramidite L6¹⁵ resulted in a dramatic improvement in regioselectivity, and a modest improvement in yield (entry 6). After a careful analysis of the crude reaction mixture, we found that the moderate yield is due to hydrolysis of the carbonate under the reaction conditions. Thus, by increasing the quantity of the carbonate (1.5–2 equiv) and switching the base (LiOt-Bu), we were able to obtain the desired product 3aa in 93% yield, >99% ee, and >20:1 regioselectivity (entries 8 and 9). The absolute configuration of α-alkylated product (R)-3aa was determined by X-ray crystallography.¹⁶

Table 1. Optimization of Ir-Catalyzed Allylic Alkylation Reactions^a.

entry	ligand	base	conv (%)b,c	3aa:4aab	ee of 3aa(%)d
1	L1	KOt-Bu	>95 (57)	3:1	>99
2	L2	KOt-Bu	<10e	–	–
3	L3	KOt-Bu	>95e	>20:1	>99
4	(±)-L4	KOt-Bu	>95	1:1	–
5	L5	KOt-Bu	52	2:1	40
6	L6	KOt-Bu	>95 (69)	>20:1	>99
7f	L6	KOt-Bu	89 (84)	>20:1	>99
8f	L6	LiOt-Bug	92 (90)	>20:1	>99
9h	L6	LiOt-Bug	>95 (93)	>20:1	>99

^aReactions performed with 0.1 mmol of 2a, 0.2 mmol of 1a, 0.1 mmol of base in 1 mL of THF at 20 °C for 12–24 h.

^bRegioselectivity determined by ¹H NMR analysis of the crude reaction mixture.

^cYields of isolated product 3aa given in parentheses.

^dDetermined by SFC.

^eComplex mixture.

^fWith 0.1 mmol of 1a and 0.15 mmol of 2a.

^g1.2 equiv.

^hWith 0.1 mmol of 1a and 0.2 mmol of 2a.

Figure 1.

Representative phosphoramidite ligands.

With optimized conditions for the α-alkylation procedure established, we next examined the possibility of intramolecular chirality transfer by a Cope rearrangement. To our delight, 1,5-diene 3aa was converted to the rearranged γ-alkylated product 5aa¹⁷ in 98% yield and 95% ee after heating in toluene (Scheme 2). The high degree of chirality transfer (96%)¹⁸ can be rationalized by the preferential rearrangement of the diene 3aa through a chair-like transition state (TS1), over the corresponding boat-like transition state (TS2). A one-pot procedure for the allylic alkylation/Cope rearrangement is also possible, providing the product 5aa in 91% overall yield and 96% ee (Scheme 3).

Scheme 2. Cope Rearrangement of 3aa.^a.

^aReaction conditions: 0.1 mmol of 3aa in toluene at 100 °C for 5 h.

Scheme 3. Substrate Scope of Sequential (One-Pot) Ir-Catalyzed Allylic Alkylation/Cope Rearrangement.^a,b,c.

^aReactions performed on a 0.2 mmol scale in 2 mL of THF at 20 °C for 12–16 h, followed by stirring in toluene at 100 °C for 5 h, see SI for details. ^b Regioselectivity of the allylic alkylation determined by ¹H NMR analysis of the crude mixture (>20:1 b:l for all cases), and ee determined by SFC. ^c Yields of isolated product. ^d One-pot procedure employed. ^e Inseparable mixture with carbonate 2g, NMR yield.

We next explored the impact of functional groups and ring size on this sequential protocol (Scheme 3).¹⁹ A variety of cinnamyl carbonates containing either electron-rich or electron-deficient substituents are well tolerated and the corresponding γ-alkylation products (5ab–5af) were obtained in high yield and excellent enantioselectivity. Moreover, a thienyl-substituted allylic carbonate is also compatible in this reaction, delivering product 5ag in good yield and enantioselectivity. Five-and six-membered unsaturated malonates provide the desired products (5ca and 5ba), albeit in slightly decreased yield (75% and 83%) and enantioselectivity (90% ee and 91% ee), respectively. Notably, oxygen, sulfur, and nitrogen containing heterocycles were compatible, providing the corresponding products (5da–5fa) in excellent ee and yield, except for 5ea which was obtained in moderate yield.

Concurrent with these studies, we investigated the reactivity of a endocyclic α,β-unsaturated β-ketoesters, a more challenging class of nucleophiles. It is widely appreciated that iridium-catalyzed allylic alkylation of prochiral nucleophiles can be problematic due to a lack of diastereocontrol during the formation of vicinal stereocenters.⁵ Until recently, success has been limited to only a few examples.^13,20,21 Subjecting α,β-unsaturated β-ketoester 6a to a slightly modified version of our optimized conditions, the branched product 7aa was formed exclusively, but as a 1:1 mixture of diastereomers (entry 1, Table 2). When ligand L1 was used, a slight increase in diastereo- and enantioselectivity was obtained (entry 2). Lowering the reaction temperature gave modest improvement in diastereoselectivity, however the reaction required days to reach a satisfactory conversion (entry 3).

Table 2.

Ir-Catalyzed Allylic Alkylation of Cyclic α,β-unsaturated Ketoester 6a^a

entry	ligand	conv (%)b	7aa:8aab	dr of 7aab	ee of 7aa (%)c
1	L6	>95	>20:1	1:1	89 (70)
2	L1	>95 (99)d	>20:1	2:1	95 (88)
3e	L1	>95	>20:1	5:1	98 (89)

^aReactions performed with 0.4 mmol of 6a and 0.2 mmol of 2a in 2 mL of THF.

^bDetermined by ¹H NMR analysis.

^cDetermined by SFC.

^dCombined yields of isolated diastereomers.

^eAt 0 °C for 7 days.

Unfortunately, despite extensive attempts to further enhance the diastereoselectivity, no improved conditions were identified. We therefore decided to move forward with this moderate diastereoselectivity and evaluate the substrate scope of the reaction with regard to both reaction partners (Scheme 4). It is worth noting that in each case, both diastereomers were isolated and characterized (see SI for details). The reaction with an eight-membered unsaturated β-ketoester gave desired product 7ba with high branched selectivity and moderate diastereoselectivity. Six-membered substrate afforded the corresponding alkylation product 7ca²² with an increased diastereo- and regioselectivity, but in only moderate yield due to the decomposition of the β-ketoester during the reaction. Lactam derivative 7da was also accessed, although with diminished enantioselectivities for both diastereomers. Finally, several carbonates bearing various electronically differentiated substituents were found to be well tolerated, and the corresponding products 7ad–7af were furnished in good yield, with high enantioselectivity and moderate diastereoselectivity.

Scheme 4. Substrate Scope of Ir-Catalyzed Allylic Alkylation of Cyclic α,β-unsaturated β-Ketoester.^a,b,c,d.

^a Reactions performed with 0.4 mmol of 6a and 0.2 mmol of 2a in 2 mL of THF. ^b Regioselectivity (b:l) was determined by ¹H NMR analysis of the crude mixture and ee was determined by SFC. ^c Combined yields of isolated diastereomers. ^d ee of the minor diastereomer given in parenthesis.

Having investigated the allylic alkylation, we next turned to the Cope rearrangement (Scheme 5). The major isomer (7aa) undergoes the rearrangement more readily than the minor isomer 7aa'. Again, this is likely due to geometrical differences of a chair-like transition state of the major isomer (TSI) in contrast to a boat-like transition state of the minor isomer (TSII). The rigidity of the transition state plays a key role in enabling the chirality transfer (>99%).^4b It is worth noting that the rearranged γ-alkylation products from the major isomer 7aa and the minor isomer 7aa'; have opposite absolute configurations (Scheme 5a and 5b). Since the diastereomers 7aa and 7aa' have identical tertiary chiral centers, the outcome of the rearrangement is controlled solely by the quaternary center.

Scheme 5. Cope Rearrangement of Diastereomeric 1,5-Dienes 7.

^a Unreacted 7aa' was recovered in 61% yield and 86% ee.

In summary, we have developed a sequential iridium-catalyzed allylic alkylation/Cope rearrangement to synthesize enantioenriched γ-substituted α,β-unsaturated malonates and β-ketoesters. The initial alkylation reaction provides efficient access to chiral 1,5-dienes with high regio- and enantioselectivities, with N-aryl phosphoramidite ligands being crucial. Selective translocation of the newly established chirality to the γ-position was realized by a subsequent thermal Cope rearrangement. Further studies toward the application of this useful method in natural product synthesis are currently ongoing in our laboratory.