Gold(I)-catalyzed asymmetric [3 + 2]-cycloadditions of γ-1-ethoxyethoxy-propiolates and aldehydes

Abstract

A gold-catalyzed asymmetric intermolecular [3 + 2]-cycloaddition of γ-1-ethoxyethoxy-propiolate and aldehydes by the use of the chiral phosphoramidite (S,R,R)-5a is developed, which provides facile access to highly substituted 2,5-dihydrofurans in up to 84% yield with up to 97% ee. Control experiments support the result that this transformation indeed proceeds via an all-carbon gold 1,3-dipole with an open carbocation rather than a S_N2 type reaction.

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The development of homogeneous gold catalyzed cycloadditions has been remarkably rapid in the past few years,¹ due to their good tolerance to air and moisture and high capability to activate C–C π-bonds. The inherent linear binding mode keeps the chiral ligand of the gold complex away from the generated stereogenic center, resulting in the development of enantioselective gold catalysis,² which still poses considerable difficulty, especially for the intermolecular cases,³ although some strategies have been developed to address this challenging issue.

Substituted 2,5-dihydrofurans represent a class of important structural scaffolds, which are not only frequently found in natural products and biologically active molecules but also found to be useful building blocks.⁴ In 2008, The group of L. Zhang developed an elegant method for the synthesis of substituted 2,5-dihydrofurans from readily available γ-1-ethoxyethoxy-propiolates and aldehydes or ketones via a gold-catalyzed intermolecular [3 + 2]-cycloaddition.⁵ However, the enantioselective variant of this intermolecular cycloaddition and the mechanism (1,3-dipolar cycloaddition vs. tandem S_N2/cyclization) of this reaction have not been well addressed so far. Due to the continual interest in developing asymmetric gold-catalysis,⁶ we have developed herein an enantioselective gold(I)-catalyzed intermolecular [3 + 2]-cycloaddition by the application of chiral Binol-derived phosphoramidite as the ligand. The control experiments support the result that the reaction pathway of this reaction is through a 1,3-dipole rather than tandem S_N2/cyclization.⁷

γ-1-Ethoxyethoxy-propiolate 1a and 4-methoxybenzaldehyde 2a were chosen as model substrates to test a series of chiral ligands. Given the success of chiral bisphosphines in gold-catalyzed enantioselective reactions, our initial efforts focused on the use of chiral bisphosphines such as chiral Bipheps as ligands (see ESI†), only the privileged ligand (R)-MeO-dtbm-biphep 6 was found to be the most efficient in enantioinduction to give 65% ee. We next turned to examine chiral phosphoramidites as ligands (Fig. 1), which can easily undergo substitution at many positions.⁸ We were pleased to find that a moderate degree of enantioinduction (68% ee) could be obtained with the Binol-derived phosphoramidite (R,R,R)-4a as the ligand (Table 1, entry 1). With this encouraging result, other modified chiral phosphoramidites by introduction of various substituents at 3 and 3′-positions of the BINOL moieties were then prepared and investigated (Table 1, entries 3–6). 85% ee was observed by the use of (R,R,R)-4c with a 3,3′-phenyl group as the ligand albeit with only 33% yield (Table 1, entry 4), while the corresponding (S)-BINOL derived (S,R,R)-4c induced a slightly lower enantioselectivity (77% ee, Table 1, entry 7). Attempts to improve the enantioselectivity failed by introducing other substituents such as methyl (4b), bulky Ph₃Si (4d) and 3,5-bis-(trifluoro-methyl)phenyl (4e) at 3 and 3′-positions of the chiral ligand. The spirobiindane derived phosphoramidite (S)-SIPHOS-PE could not give high ee either (73% ee, Table 1, entry 8) and even its diastereomer (R)-SIPHOS-PE gives lower ee (43% ee, Table 1, entry 9), which indicates that not only the chirality of the axial backbone but also the stereogenic center affects the enantioselectivity. The knowledge gained from our previous work^6a that the bite angle also plays a crucial role in gold-catalyzed asymmetrical reaction encouraged us to test the octahydrobinol-derived phosphoramidites 5a and 5b with different bite angles (Table 1, entries 10–12). After some attempts, the methyl substituted (R,R,R)-5b resulted in a substantially higher enantioselectivity than the corresponding 4b (82% ee vs. 59% ee, Table 1, entries 11 vs. 3). To our delight, (S,R,R)-5a delivered excellent enantioselectivity (90% ee, Table 1, entry 12). Notably, (S,R,R)-5a and (R,R,R)-5a derived gold complexes result in different enantiomers of 2,5-dihydrofurans, indicating that the axial chirality dictates the absolute stereochemistry of the [3 + 2] cycloadduct. With the use of (S,R,R)-5a as a chiral ligand, a series of silver salts such as AgOTf, AgSbF₆, AgBF₄, AgO₂C₄F₇ and NaBAr₄ (Ar = 3,5-CF₃C₆H₃) were then examined, among which AgNTf₂ afforded the best result. There is a slight improvement in the enantioselectivity when the reaction is run at 0 °C. The addition of 3 Å MS led to a remarkable improvement in the yield. When 4 equiv. of anisaldehyde 2a were used, the desired product 3aa was isolated in 78% yield with 92% ee (entry 18). These results clearly validated the strategy and suggested that further improvement might be feasible not only by introducing substituents at 3 and 3′-positions but also through the modification of the bite angle. Other γ-1-ethoxyethoxy-propiolate esters such as methyl (1b), ethyl (1c) and tert-butyl (1d) are applicable to the reaction conditions except for the benzyl ester (1e), leading to a similar level of enantioselectivity (Table 1, entries 19–22).

Fig. 1 Screened chiral ligands.

Table 1 Screening reaction conditions^a

Entry	1 R	Ligand	Solvent	Product
				3 (yield %)	ee%
a Unless otherwise noted, substrate 1 (0.4 mmol), 4-methoxybenzaldehyde 2a (2 equiv.) and LAuNTf2 (5 mol%, LAuCl/AgX = 1 : 1) were used in 8 mL of solvent at 25 °C for 1 h. Isolated yields are shown and the enantiomeric excess is determined by chiral HPLC. b The reaction is performed at 0 °C. c 3 Å MS (150 mg) was added. d 4 equiv. of 2a were used.
1	^i Pr(1a)	(R,R,R)-4a	CH2Cl2	3aa (46)	−66
2	1a	(S,R,R)-4a	CH2Cl2	3aa (48)	68
3	1a	(S,R,R)-4b	CH2Cl2	3aa (30)	59
4	1a	(S,R,R)-4c	CH2Cl2	3aa (33)	85
5	1a	(R,R,R)-4d	CH2Cl2	3aa (35)	−66
6	1a	(R,R,R)-4e	CH2Cl2	3aa (23)	−77
7	1a	(R,R,R)-4c	CH2Cl2	3aa (56)	−77
8	1a	(S)-SIPHOS-PE	CH2Cl2	3aa (54)	73
9	1a	(R)-SIPHOS-PE	CH2Cl2	3aa (55)	−43
10	1a	(R,R,R)-5a	CH2Cl2	3aa (46)	−69
11	1a	(R,R,R)-5b	CH2Cl2	3aa (60)	−82
12	1a	(S,R,R)-5a	CH2Cl2	3aa (51)	90
13	1a	(S,R,R)-5a	DCE	3aa (48)	87
14	1a	(S,R,R)-5a	Toluene	3aa (24)	84
15	1a	(S,R,R)-5a	CHCl3	3aa (45)	90
16^b	1a	(S,R,R)-5a	CH2Cl2	3aa (50)	92
17^b^,^c	1a	(S,R,R)-5a	CH2Cl2	3aa (73)	93
18^b^,^c^,^d	1a	(S,R,R)-5a	CH2Cl2	3aa (78)	92
19	Me (1b)	(S,R,R)-5a	CH2Cl2	3ba (53)	87
20	Et (1c)	(S,R,R)-5a	CH2Cl2	3ca (61)	89
21	^tBu (1d)	(S,R,R)-5a	CH2Cl2	3da (64)	83
22	Bn (1e)	(S,R,R)-5a	CH2Cl2	3ea (47)	77

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With the optimized conditions in hand, we explored the substrate scope of the reaction by variation of two reaction components (Table 2). In general, para-substituted aryl aldehydes gave better ees than ortho-substituted ones. For example, the reaction of para-methoxybenzaldehyde 2a with 1a gave the product 3aa with 93% ee, while only 77% ee of 3ad was obtained from the corresponding ortho-methoxy benzaldehyde 2d. 3ae with 84% ee could be obtained in 78% yield from the corresponding 2,4-bismethoxybenzaldehydes 2e and 1a. The highest selectivity was observed in the case of p-Me₂N–C₆H₄CHO as the substrate, where 3ab and 3fb were isolated in 97% ee. Gratifyingly, cinnamaldehyde is also compatible with this transformation to produce the corresponding products 3ac and 3fc in good yields with reasonable enantioselectivities. Heterocyclic 1-H-pyrrole-2-carbaldehyde also enables the highly enantioselective synthesis of pyrrol-2-yl-substituted dihydrofurans 3af and 3ff. Acyclic 1f and cyclic 1h with a five-membered cyclopentane ring are applicable to this transformation very well. However, substrate 1g with a seven-membered cycle only affords the product 3ga in moderate yield and enantioselectivity, indicating that the ring size also affects the enantioselectivity.

Table 2 Study of the reaction scope by the use of (S,R,R)-5a as the ligand^a

a Standard reaction conditions, PMP = para-methoxyphenyl. b The reaction was conducted at −20 °C.

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When we tried to extend the scope of aldehydes to indole-3-carbaldehydes, it was found that the present reaction conditions using (S,R,R)-5a as the chiral ligand were not applicable any more (eqn (1)). A significant erosion in the enantiomeric excess was observed (70% ee). This result indicated that the enantioselectivity of this reaction is kind of substrate dependent. After further investigation, we were pleased to find that this issue can be well addressed by the use of (R,R,R)-5b as the chiral ligand, resulting in the product 3ag as the opposite enantioisomer in 62% yield with 92% ee. Inspired by this result, the reactions of various indole-3-carbaldehydes with 1a and 1f were then examined under the catalysis of the (R,R,R)-5b/gold complex (Table 3). The reaction of 1a with N-allyl indole-3-carbaldehyde 2h afforded the cycloadduct 3ah in 70% yield with 87% ee. Similarly, the reaction of 1a with 5-methoxy indole-3-carbaldehydes 2i and 2j also worked well to provide products 3ai and 3aj in reasonable yields with 90% and 92% ee, respectively.

Table 3 (R,R,R)-5b/Au(I)-catalyzed [3 + 2] reactions of 1 with various indole-3-carbaldehydes

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This catalyst system could also be well applied to the reactions of acyclic 1f and indole-3-carbaldehydes, delivering the desired products 3fg, 3fj and 3fk in high yields with 88–95% ees. The absolute configuration of the products was confirmed by single-crystal X-ray diffraction analysis of compound 3fk.⁹ The absolute chemistry of other compounds was rationalized from compound 3fk. The X-ray crystal structure of (R,R,R)-5bAuCl was also obtained and is shown in ESI.†

In order to gain insight into the reaction mechanism, racemic and enantioenriched secondary alcohol derived substrates were subjected to the reaction conditions. Notably, the reaction of racemic 1i with 2a gave the desired -2,5-dihydrofuran 3ia with two stereocenters in 44% yield with only 16% ee and 6.0 : 1 dr under the catalysis of the (S,R,R)-5a derived gold(I) complex, however, the diastereo- and enantioselectivity could be dramatically improved when (S)-MeO-dtbm-biphep ((S)-6) was employed as the chiral ligand. The yield would be improved to 64% with 5 equivalents of an aldehyde (Scheme 1).

Scheme 1 Asymmetric cycloaddition of (±)-1i with 2a.

Two control reactions of (+)-1j (>98% ee) and 2a were further carried out under the catalysis of two opposite absolute configuration ligand (S or R) derived gold complexes, affording (−)-3ja and its enantiomer (+)-3ja, respectively, in almost the same yield and selectivity (eqn (2) and (3)). These results support the fact that this transformation proceeds via the all-carbon 1,3-dipole B bearing an open carbocation rather than direct S_N2 attack⁷ on the intermediate A by an aldehyde, otherwise, the match and mismatch of the substrate with the chiral ligand will lead to the same enantiomer with different ee.

Furthermore, this asymmetric gold(I)-catalyzed reaction is scalable up to the gram-scale without any loss of selectivity and efficiency. The catalyst loading could be reduced to only 1 mol% on a 5 mmol scale to furnish 1.156 g of 3fa in 69% yield with 95% ee at 10 °C for 10 h (eqn (4)), indicating that this transformation has a potential practical use in organic synthesis.

A catalytic cycle is proposed as depicted in Scheme 2. The reaction is believed to be initiated by the anti-attack on a gold-activated C–C multiple bond (a π-complex) by the intramolecular oxygen atom of the acetal moiety, furnishing intermediate Int-A. Then a 1,3-dipole intermediate Int-B would be produced through the elimination of one molecule of acetaldehyde. Next, the aryl aldehyde attacks the open carbocation to form the intermediate Int-C. Finally, the product is delivered through cyclization and elimination of the catalytic gold species. The observed absolute stereochemistry can be explained by the proposed induction models shown. The transition state Ts-A is more favorably formed than Ts-B to preferentially give the desired product with observed stereochemistry, because of the steric repulsion between the Ar group and the methyl group of the chiral catalyst.

Scheme 2 Possible mechanistic pathway and an induction model.

Conclusions

In summary, we have described a highly enantioselective gold-catalyzed [3 + 2] cycloaddition of in situ generated all-carbon gold-1,3-dipoles with aldehydes under mild conditions. The method has enabled the enantioselective synthesis of a wide variety of functionalized tri- and tetra-substituted 2,5-dihydrofurans in moderate to high yields with good diastereoselectivities and enantioselectivities. A broad array of substrates is applied to this transformation by careful choice of octahydrobinol-derived phosphoramidite or MeO-dtbm-biphep derived gold(I) complexes as catalysts. The control experiments support that this transformation indeed proceeds via an all-carbon gold 1,3-dipole with an open carbocation rather than a S_N2 type reaction. The easy scale-up character also adds value to this transformation to make it a potential practically useful method. Further studies including synthetic applications and extension of the scope of dipolarophiles are currently underway and will be reported in due course.

Notes and references

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9. CCDC 926425 (3fk) and 926426 ((R,R,R)-5bAuCl).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 926425 and 926426. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qo00261j

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