Gold-Catalyzed Synthesis of Chiral Cyclopentadienyl Esters via Chirality Transfer

Abstract

Efficient access to chiral cyclopentadienyl esters from readily accessible chiral enynyl ester substrates is developed. Typically high levels of chirality transfer realized in this homogeneous gold catalysis are attributed to the intermediacy of a chiral bent allene gold complex. Cyclopentadienyl esters can be prepared in good yields and with excellent enantiomeric excesses. The synthetic utilities of the chiral cyclopentadienyl esters are demonstrated by the Diels–Alder reactions, fluorination, alkylation, and epoxidation without any notable erosion of enantiopurity.

Graphical Abstract

Cyclopentadienes are important synthetic intermediates widely used as reactive dienes in the Diels–Alder reaction¹ and as ligand precursors in organometallic chemistry, and the enantiomerically enriched ones are highly valued in complex molecular synthesis.² Aside from modification from chiral five-membered ring precursors,^2a–d,3 which can be of limited scope, asymmetric synthesis of this class of chiral cyclic dienes from acyclic substrates offers a potentially more efficient and flexible synthetic alternative, but there have been only a few reported studies of limited scope and/or moderate enantiopurity.⁴ Moreover, few reports have documented such an approach to cyclopentadienes with heterofunctionalization at the ring. In this work, we report a study of this nature based on gold-catalyzed efficient chirality transfer,^4b,5 which permits the synthesis of cyclopentadienyl esters with generally excellent enantiomeric access from readily accessible chiral substrates.

In 2006, one of us reported the gold-catalyzed cycloisomerization of enynyl esters into cyclopentenones.^6,7 An example is shown in Scheme 1A. The proposed reaction mechanism entails a gold-catalyzed 3,3-sigmatropic rearrangement to deliver enallenyl acetate 3, its subsequent gold-catalyzed Nazorov-type cyclization, and hydrolysis. The intermediacy of cyclopentadienyl acetate 2 was confirmed by its detection when the reaction was performed in dry DCM instead of wet DCM. Pentadienyl cation A was invoked as the reactive intermediate in the conversion of 3 to 1. However, the subsequent studies by Gandon, Fensterbank, and Malacria⁸ that trap the gold carbene intermediate of type B by a tethered alkene revealed that gold-coordinated bent allene structures C and C′ are the alternative intermediates that account for the observed efficient chirality transfer (Scheme 1B). These works explored only a few substrates. We reasoned that this chirality transfer would similarly permit efficient access to chiral cyclopentadienyl esters from chiral enynyl esters (Scheme 1C), and expanded exploration of the substrate scope would shed more light on chirality transfer. During our study, Carreira reported a related efficient chirality transfer process, in which an intramolecular aldol reaction serves to terminate the tandem gold-catalyzed 3,3-sigmatropic rearrangement and the Nazarov reaction (Scheme 1D).⁹

Scheme 1.

Previous Work on the Gold-Catalyzed Cycloisomerizations of Enynyl Esters and This Chemistry

At the outset, we employed (S)-1-(cyclohex-1-en-1-yl)oct-1-yn-3-yl ester 4a as the substrate. It is readily prepared from the corresponding enynone via Noyori’s asymmetric transfer hydrogenation¹⁰ and subsequent esterification. Anticipating the nature of the acyl group in 4a might influence the desired chirality transfer, and to simplify chiral HPLC analysis, we opted to first optimize the chirality transfer by examining the hydrolyzed bicyclic cyclopentenone product 6a′, which could be directly obtained with wet methylene chloride as the reaction solvent. In the presence of catalytic Ph₃PAuCl (5 mol %) and AgSbF₆ (10 mol %), the acetate version of 4a indeed underwent smooth cycloisomerization and hydrolysis to afford 6a′ in 70% yield (entry 1). Moreover, the enantiomeric excess of the product was 67%, confirming a significant level of chirality transfer from the chiral enyne substrate. The configuration of 6a′ is assigned on the basis of mechanistic consideration and supported by the prior report.⁹ Switching the acyl group of 4a to a pivaloyl led to slight improvements in the reaction yield and the product ee (entry 2). The product ee was improved to 74% by using the sterically hindered JohnPhos as the metal ligand^8b,9 (entry 3) and further to 77% by using the even bulkier ^tBuBrettPhos (entry 4). Much to our delight, when the benzoate of 4a was employed as the substrate, the yield was improved to 84% and the ee to 94% (entry 5). Modifications on the benzoate benzene ring did not further improve the reaction yield or the efficacy of chirality transfer (entries 6–8) or in the case of 4-NO₂ led to little reaction (entry 9). With the optimal substrate and catalyst in hand, we then turned our attention to avoiding the hydrolysis of 6a to 6a′ during the gold catalysis. To this end, anhydrous toluene was used as the reaction solvent. To our delight, the desired cyclopentadienyl benzoate 6a was formed with 93% ee, albeit accompanied by a substantial amount of hydrolyzed product 6a′. Decreasing the amount of AgSbF₆ to 5 mol % (entry 11) or switching it to 5 mol % AgNTf₂ (entry 12) did not prevent the formation of a substantial amount of 6a′. Remarkably, when NaBARF (5 mol %) was used as the chloride abstractor, the undesired hydrolysis was completely shut down, and 6a was formed in 91% yield while maintaining the excellent ee value (entry 13). Similar phenomena were detected with PhCF₃ or DCM as the solvent, albeit the yields were slightly lower (entry 14 or 15, respectively).

With the optimized reaction conditions in hand, we first probed the reaction scope by varying the n-pentyl group of 4a. As shown in Table 2, the sterically more demanding cyclohexyl (entry 1), a methyl (entry 2), a benzyl (entry 3), and an oxygenated alkyl group (entry 4) are all readily accommodated, and the cyclopentadienyl esters were isolated in good to excellent yields and with ≥92% ee. Incorporation of a heteroatom such as O (entry 5) and N (entry 6) in the cyclohexene ring led to lower yields, but the chirality transfer remained efficient. When 4h contained a dihydronaphthalene ring as the substrate, the reaction was quite slow under standard conditions (entry 7). It was accelerated at 60 °C. Due to the contamination of side products, the cyclopentadienyl ester product was subsequently hydrolyzed under acidic conditions, affording cyclopentenone 6h′ in a much improved 61% yield and with a slightly lower ee (87%). For cycloheptene substrate 4i, cyclopentadienyl ester 6i was unstable. As such, the hydrolytic conditions in entry 5 of Table 1 were employed to afford 5,7-fused enone 6i′ in 84% yield (entry 8). However, the ee value is moderate, which may be due to a relatively slow cyclization of the bent allene intermediate of type C and hence its increased level of racemization^8a or conversion to achiral pentadienyl cations of type A.

Table 2.

Scope of with Substrates Featuring Cyclic Alkenes^a

Entry	Propargylic ester 4	Cyclopentadienyl Ester 6	Yield	ee
1			80%	96%b
2			92%	93%
3			77%	92%
4			90%	95%
5			48%	96%
6			62%	94%
7			23%c	93%
			61%d	86%
8			84%e,f	63%

^aReaction conditions: 5 mol % ^tBuBrettPhosAuCl, 5 mol % NaBARF, 0.2 mmol of 4 (0.05 M in toluene), rt, 3 h.

^bee was determined after hydrolysis.

^cThe standard condition was applied and followed by hydrolysis.

^dThe standard condition but at 60 °C for 4 h was applied and followed by hydrolysis.

^eWith 5% ^tBuBrettPhosAuCl, 10% AgSbF₆, and wet DCM applied.

^fcis:trans ratio of 14:1.

Table 1.

Initial Trial and Condition Optimization

entry	catalyst (5 mol %/5 mol %)	solvent	R	yield (%) of 6a/6a′	ee (%)c
1	PPh3AuCl/AgSbF6a	wet DCM	CH3	0/70	67
2	PPh3AuCl/AgSbF6a	wet DCM	tBu	0/76	70
3	JohnPhosAuCl/AgSbF6a	wet DCM	tBu	0/75	74
4	L1AuCl/AgSbF6a,b	wet DCM	tBu	0/74	77
5	L1AuCl/AgSbF6a,b	wet DCM	Ph	0/84	94
6	L1AuCl/AgSbF6a,b	wet DCM	mesityl	0/70	92
7	L1AuCl/AgSbF6a,b	wet DCM	4-MeOPh	0/84	93
8	L1AuCl/AgSbF6a,b	wet DCM	4-BrPh	0/78	94
9	L1AuCl/AgSbF6a,b	wet DCM	4-NO2Ph	0/trace	–
10	L1AuCl/AgSbF6a,b	toluene	Ph	49/29	93
11	L1AuCl/AgSbF6b	toluene	Ph	52/33	93
12	L1AuCl/AgNTf2b	toluene	Ph	48/44	91
13	L1AuCl/NaBARFb	toluene	Ph	91/0	95
14	L1AuCl/NaBARFb	PhCF3	Ph	87/0	95
15	L1AuCl/NaBARFb	DCM	Ph	82/0	96

^aWith 10 mol % AgSbF₆.

^bL1 = ^tBuBrettPhos.

^cOf the major product.

To further explore the reaction scope, we turned our attention to substrates featuring acyclic C=C bonds for the synthesis of chiral cyclopentadienyl esters without ring fusion. As shown in Table 3, under the optimized conditions, these reactions proceeded smoothly, affording the tetrasubstituted cyclopentadienes in good to excellent yields and with excellent enantiomeric excesses (entries 1–7). Electron-withdrawing groups on the substrate phenyl ring (entries 6 and 7) are tolerated, albeit in lower yet serviceable yields. Under the standard conditions, the reaction of 4q resulted in a complicated mixture, which is attributed to 1,5-hydride shifts of the cyclopentadiene moiety. When 4q was subjected to the hydrolytic conditions, to our surprise, the cyclopentenone product 6q′ barely exhibits any ee. This result indicates the steric hindrance offered by the R¹ group is essential for hindering the formation of the corresponding achiral pentadienyl cation and/or the allene racemization.

Table 3.

Scope of Substrates Containing Acyclic Alkenes^a

Entry	4	6	Yield	ee
1			85%	91%
2			89%	95%
3			98%	95%
4			89%	93%
5			89%	94%
6			68%	95%
7			74%	94%
8			76%b	3%

^aReaction conditions: 5 mol % ^tBuBrettPhosAuCl, 5 mol % NaBARF, 0.2 mmol 4 (0.05 M in toluene), rt, 3 h.

^bWith 5% ^tBuBrettPhosAuCl, 10% AgSbF₆, and wet DCM applied.

To demonstrate the synthetic utilities of this chemistry, we carried out a scale-up synthesis of 6a (Scheme 2). Hence, with only 1 mol % catalyst loading, 0.51 g of the product of high enantiomeric purity (94% ee) was isolated, although the reaction required overnight and the yield was slightly decreased due to the much lower catalyst loading. The reactions of 6a were then pursued first with the isolated material. For example, it underwent the Lewis acid-promoted Diels–Alder reaction with methyl acrylate at −40 °C to deliver bridged tricycle 7 in 84% yield while maintaining the ee value, and its epoxidation by DMDO smoothly afforded the cis-fused α′-hydroxycyclopentenone 8 upon hydrolytic workup. The endo nature of the major isomer of 7 is confirmed by two-dimensional NMR studies. One-pot processes without the isolation of 6a were also demonstrated. For example, the Diels–Alder reaction with N-phenylmaleimide smoothly delivered the tetracycle 9 in 86% overall yield and with 93% ee, demonstrating a rapid increase in structural complexity.¹¹ Fluorination at the enone α′-position by Selectfluor afforded selectively cis-fused 10 in a serviceable yield and without erosion of ee, and diastereoselective installation of a methyl group at the same position was achieved with similar results.

Scheme 2.

Synthetic Transformations of Cyclopentadienyl Benzoate 6a

In conclusion, we have developed efficient access to chiral cyclopentadienyl esters from readily accessible chiral enynyl ester substrates. Typically high levels of chirality transfer realized in this homogeneous gold catalysis can be attributed to the intermediacy of chiral bent allene gold complexes. Cyclopentadienyl esters with or without ring fusion can be prepared in good yields and with excellent enantiomeric excess. Benzoates are shown to be more conducive to chirality transfer than aliphatic esters, and a trisubstituted C=C bond in the substrate is found to be essential to minimize the racemization of the bent allene gold complex or the access to pentadienyl cations of type A. The synthetic utilities of the chiral cyclopentadienyl esters are demonstrated by one-pot or sequential Diels–Alder reactions, fluorination, alkylation, and epoxidation without any notable enantiopurity erosion.