Phosphine-catalyzed asymmetric [3 + 2] annulation of chalcones with allenoates for enantioselective synthesis of functionalized cyclopentenes

Abstract

Chiral phosphine-catalyzed asymmetric [3 + 2] annulation reaction of various Boc-amino-substituted chalcones with allenoates has been developed, leading to efficient formation of 1,4,5-trisubstituted cyclopentenes with high yields, excellent diastereoselectivities and enantioselectivities (up to 99% ee and up to 98% yield).

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Nucleophilic phosphine-catalyzed cycloaddition reactions have been established as a reliable and powerful tool for the synthesis of carbo- and heterocycles from simple starting materials.¹ In particular, phosphine-catalyzed [3 + 2] annulations of allenoates with electron-deficient olefins for cyclopentenes are one of most studied reactions, and considerable progress has been made since the pioneering contribution from Lu.² In the presence of phosphines, a variety of activated olefins, including α,β-unsaturated enones,³ α,β-unsaturated esters,⁴ α,β-unsaturated cyanoethylenes⁵ and α,β-unsaturated acrylamides,⁶ could undergo [3 + 2] annulation with allenoates to afford medicinally important compounds.⁷ By employing a handful of chiral phosphine catalysts, asymmetric [3 + 2] annulation reactions have also been achieved.¹ Among various electron-deficient alkenes, α,β-unsaturated enones are one of the most important substrates and has attracted much attention. In 2006, using a chiral phosphepine catalyst based on a binaphthyl skeleton, Fu developed the first asymmetric [3 + 2] annulation of ethyl allenoate and various α,β-unsaturated enones, affording highly functionalized cyclopentenes possessing two contiguous stereocenters in 54–76% yields and 75–90% ee.^3a Subsequently, using a stoichiometric amount of a α-amino acid-based phosphine, Miller achieved enantioselective [3 + 2] annulation of allenoates with enones to give highly substituted cyclopentenes as single regio- and diastereomers in excellent yields with 87–93% ee.^3b Although a catalytic amount of phosphine (20 mol%) still afforded 93% ee, but only 38% yield. Compared with the above two catalytic systems, using planar chiral 2-phospha[3]ferroceneophanes as the catalyst, Marinetti obtained better enantioselectivities (89–95% ee), but the yields ranged between 60 and 80% in most cases.^3d Although the above successful examples have been reported, the yields were below 80% or ee's were below 90% in the [3 + 2] annulation reactions of many chalcones.^3a,3b,3d Obviously, developing phosphine-catalyzed highly efficient and enantioselective [3 + 2] annulation of allenoates with chalcones still is a challenged issue.

Recently, in the area of asymmetric nucleophilic phosphine organocatalysis, the multifunctional chiral phosphines bearing nucleophilic phosphine and a key activation moiety on a molecular chiral backbone provided an effective strategy for achieving high catalytic activity and high enantioselectivity.^1i,1m In several multifunctional chiral phosphines,^3b,8 Boc-amino has been used as a requisite moiety to help achieve high yield and enantioselectivity. Inspired by this strategy, we envisioned that installing a Boc-amino moiety onto enones, thus leading to excellent yields and enantioselectivities for [3 + 2] annulation reaction, might be feasible (Scheme 1). Herein, using Boc-amino-substituted chalcones as substrates, we report chiral phosphine-catalyzed highly enantioselective [3 + 2] annulation of allenoates for synthesis of biologically important highly functionalized cyclopentenes⁹ (Scheme 1).

Scheme 1 Phosphine-catalyzed enantioselective [3 + 2] annulation of Boc-amino-substituted chalcones with allenoates.

Initially, we chose the reaction of 2-Boc-aminochalcone (1a) and ethyl allenoate (2a) as model reaction and examined several multifunctional chiral phosphines (P1–P4) in THF at room temperature (Table 1, entries 1–4). In the presence of 20 mol% of chiral phosphine, in these cases, the annulation reactions proceeded smoothly in THF at room temperature to afford the [3 + 2] cycloadduct 3aa as a single regioisomer and diastereomer in good yields, but with poor enantioselectivities (Table 1, entries 1–4). Subsequently, we turned our attention to a commercially available chiral phosphine (R)-SITCP (P5).¹⁰ To our delight, in the presence of 20 mol% of P5, the reaction worked efficiently to provide the product 3aa in 90% yield with 87% ee (entry 5). Next concise solvent screening revealed that dichloromethane (DCM) is the optimal solvent, resulting in the product 3aa in 92% yield with 94% ee (entries 6–7). We next investigated the influence of the variation of the ester moiety in allenoate structure. Changing the ester moiety of allenoate 2a to methyl led to a decrease of both yield and ee (entry 8). In contrast, using cyclohexyl allenoate 2c as the substrate, both yield and ee were increased to 93% and 96%, respectively (entry 9). Lowering the reaction temperature to 0 °C slightly increased yield and ee to 95% and 98%, respectively (entry 10). But further lowering the temperature to −20 °C, did not bring improvement (entry 11). The absolute configuration was identified by X-ray crystallographic analysis of the product 3ab.¹¹ On the basis of the above screening of reaction conditions. The optimal reaction conditions were identified as follows: in the presence of 20 mol% chiral phosphine P5 using the allenoate 2c as the substrate in CH₂Cl₂ at 0 °C.

Table 1 Investigation of reaction conditions of asymmetric [3 + 2] annulation of 2-Boc-aminochalcones (1a) with allenoates (2)^a

Entry	Px	R	Solvent	t (h)	3	Yield^b (%)	ee^c (%)
a Reactions of 1a (0.1 mmol), 2 (0.15 mmol) and phosphine (0.02 mmol) were carried out in the solvent.b Isolated yields.c The ee values were determined by HPLC analysis using a chiral stationary phase. The regioisomer ratios are >20 : 1, determined by ^1H NMR analysis of the crude products.d The reaction was carried out at 0 °C.e The reaction was carried out at −20 °C.
1	P1	Et (2a)	THF	3	3aa	76	12
2	P2	Et (2a)	THF	3	3aa	76	20
3	P3	Et (2a)	THF	3	3aa	75	5
4	P4	Et (2a)	THF	3	3aa	85	33
5	P5	Et (2a)	THF	3	3aa	90	87
6	P5	Et (2a)	DCM	3	3aa	92	94
7	P5	Et (2a)	DCE	3	3aa	91	88
8	P5	Me (2b)	DCM	3	3ab	75	92
9	P5	Cy (2c)	DCM	3	3ac	93	96
10^d	P5	Cy (2c)	DCM	7	3ac	95	98
11^e	P5	Cy (2c)	DCM	12	3ac	95	98

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With the optimal reaction conditions in hand, we investigated the scope of Boc-amino-substituted chalcones. As summarized in Table 2, various Boc-amino-substituted chalcone derivatives bearing different substituent patterns on the benzene rings were all very well tolerated in this reaction, giving the 1,4,5-trisubstituted cyclopentenes as a single diastereomer in good to excellent yields with excellent regioselectivities (>20 : 1) and enantioselectivities (entries 1–23). Regardless of the electron-donating or -withdrawing substituents at different position on the benzene rings in 2-Boc-aminochalcones 1, all the reactions were extremely efficient, affording the functionalized cyclopentenes in 69–98% yield with 94–98% ee (entries 1–22). In particular, alkyl enone 1w is also a compatible substrate, undergoing the reaction to give the corresponding product in 96% yield with 97% ee (entry 23).

Table 2 Substrate scope of phosphine-catalyzed asymmetric [3 + 2] annulation of 2-Boc-aminochalcones (1) with allenoates (2c)^a

Entry	R^1/R^2 in 1	3	Yield^b (%)	ee^c (%)
a Unless otherwise noted, reactions of 1a (0.1 mmol), 2 (0.15 mmol) and chiral phosphine P5 (0.02 mmol) were carried out in CH2Cl2 at 0 °C for 12 h.b Isolated yields.c The ee values were determined by HPLC analysis using a chiral stationary phase. The regioisomer ratios are >20 : 1, determined by ^1H NMR analysis of the crude products.d The reaction completed within 7 h.
1^d	H/Ph (1a)	3ac	95	98
2	H/4-OMeC6H4 (1b)	3bc	97	95
3	H/4-PhC6H4 (1c)	3cc	98	97
4	H/3-BrC6H4 (1d)	3dc	93	96
5	H/4-BrC6H4 (1e)	3ec	96	95
6	H/4-CF3C6H4 (1f)	3fc	92	97
7	3-Me/Ph (1g)	3gc	96	97
8	3-Me/4-OMeC6H4 (1h)	3hc	94	97
9	3-Me/4-BrC6H4 (1i)	3ic	94	94
10	5-Me/4-PhC6H4 (1j)	3jc	85	96
11	5-Me/4-BrC6H4 (1k)	3kc	92	98
12	5-Me/4-CF3C6H4 (1l)	3lc	80	96
13	5 F/Ph (1m)	3mc	93	96
14	5 F/4-OMeC6H4 (1n)	3nc	98	97
15	5 F/4-PhC6H4 (1o)	3oc	69	98
16	4-Cl/Ph (1p)	3pc	81	97
17	5-Cl/Ph (1q)	3qc	92	97
18	5-Cl/4-BrC6H4 (1r)	3rc	87	98
19	5-Br/Ph (1s)	3sc	90	96
20	5-Br/4-OMeC6H4 (1t)	3tc	89	97
21	5-Br/4-BrC6H4 (1u)	3uc	80	96
22	6-Br/Ph (1v)	3vc	97	97
23	H/Me (1w)	3wc	96	97

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Using chiral phosphine P5 as the catalyst, we also tested the scope of other chalcones without Boc-amino group. With this kind of chalcones as the substrates, we found that allenoate 2a delivered better results than allenoate 2c did under the standard reaction conditions. As shown in Table 3, several chalcones with electron-donating or electron-withdrawing group could undergo asymmetric [3 + 2] annulation with allenoate 2a to give the desired cyclopentene derivatives as a single diastereomer in excellent regioselectivities and enantioselectivities. However, in comparison with those chalcones with Boc-amino group, some substrates displayed weak activities, leading to the products in moderate yields (entries 2, 4–6). In particular, using the amino substituted chalcone as the substrate instead of Boc-amino substituted chalcone, the reaction did not work (entry 7). It indicated that the bulky Boc-amino group is extremely important for achieving this asymmetric reaction and exerted dual influences on activity and stereoselectivity. The cyclopentene products are biologically important compounds⁹ and could also be further transformed into other useful functionalized cyclopentene derivatives. For example, treatment of the cyclopentene product (7) with MCPBA (m-chloroperoxybenzoic acid) in 1,2-dichloroethane (DCE) at room temperature for 12 h gave the epoxide (8) in 89% yield with excellent diastereoselectivity (>20 : 1) and 96% ee (its absolute configuration has not been assigned) (Scheme 2). Unfortunately, 2D-NOESY spectra were not conclusive regarding the relative stereochemistry of the epoxide.

Table 3 Substrate scope of phosphine-catalyzed asymmetric [3 + 2] annulation of chalcones (4) with allenoates (2a)^a

Entry	R^1/R^2	5	Yield^b (%)	5 : 6^c	ee^c (%)
a Reactions of 4 (0.1 mmol), 2a (0.15 mmol) and chiral phosphine P5 (0.02 mmol) were carried out in CH2Cl2 at 0 °C for 12 h.b Isolated yields.c The ee values were determined by HPLC analysis using a chiral stationary phase. The regioisomer ratios were determined by ^1H NMR analysis of the crude products.
1	Ph/Ph (4a)	5aa	90	90 : 10	91
2	2-MeC6H4/Ph (4b)	5ba	68	90 : 10	95
3	4-MeC6H4/Ph (4c)	5ca	85	99 : 1	93
4	4-MeOC6H4/Ph (4d)	5da	40	97 : 3	90
5	Ph/4-MeC6H4 (4e)	5ea	30	95 : 5	89
6	4-ClC6H4/4-MeC6H4 (4f)	5fa	45	94 : 6	92
7	2-NH2C6H4/Ph (4g)	—	0	—	—

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Scheme 2 Further transformation of the product.

Experimental

General procedure for chiral phosphine-catalyzed asymmetric [3 + 2] annulation of chalcones with allenoates: under a nitrogen atmosphere, to a stirred solution of 2-tert-butoxycarbonyl aminochalcone 1 (0.05 mmol, 1.0 equiv.) in CH₂Cl₂ (1 mL) was sequentially added 2,3-butadienoate 2 (0.075 mmol, 1.5 equiv.) and the catalyst P5 (0.01 mmol, 20 mol%) via syringes. Then the resulting solution was vigorously stirred at 0 °C, and monitored by TLC. After the reaction was complete, the mixture was directly purified by column chromatography on silica gel (11% EtOAc/petroleum ether as the eluent) to furnish the corresponding product 3.

Conclusions

In summary, we have developed chiral phosphine-catalyzed asymmetric [3 + 2] annulation of chalcones with allenoates to give multi-substituted cyclopentenes in good to excellent yields with excellent regioselectivities, diastereoselectivities and enantioselectivities. Compared with previous works on chiral phosphine-catalyzed [3 + 2] annulation reactions of chalcones with allenoates, the yields and enantioselectivities have remarkably been improved when 2-Boc-amino-substituted chalcones were used as the substrates.

Acknowledgements

We are grateful for the financial support from NSFC (21172253 and 21372256) and the National S&T Pillar Program of China (2015BAK45B01).

Notes and references

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11. Crystallographic data for 3ab has been deposited with the Cambridge Crystallographic Data Centre as deposition number CCDC 1416080.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectral data and crystallographic data. CCDC 1416080. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra20603k

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