Chiral (Acyclic Diaminocarbene)Gold(I)-Catalyzed Dynamic Kinetic Asymmetric Transformation of Propargyl Esters

Abstract

A highly enantioselective transformation catalyzed by chiral (acyclic diaminocarbene)gold(I) complexes is reported. The enantioselective synthesis of 2-substituted chromenyl pivalates from racemic phenol-substituted propargyl pivalates was developed. Rearrangement of the substrates in the presence of cationic gold gave allene intermediates, whose cyclization resulted in formation of enantioenriched product through a dynamic kinetic asymmetric transformation.

Gold(I)-catalyzed nucleophilic addition to allenes has been studied intensively in recent years as an atom-economical approach to the synthesis of heterocyclic compounds.¹ While several examples of enantioselective reactions catalyzed by cationic gold(I) complexes bearing phosphorus ligands are now known,^2–4 these complexes are not universally applicable in gold-catalyzed transformations. Notably, gold(I)–carbene complexes can catalyze reactions with reactivity and selectivity dramatically different from those observed when the phosphine-ligated complexes are employed as catalysts.^5,6 However, transformations using chiral cationic gold(I)–carbene complexes as catalysts have generally proceeded with low to moderate levels of enantioselectivity.⁷ Herein, we report a highly enantioselective synthesis of substituted chromenyl pivalates catalyzed by a gold(I)–carbene complex.

(1)

The gold-catalyzed rearrangement of propargylic esters to allenes through formal [3,3] sigmatropic rearrangement is well-known.⁸ We envisioned a scenario in which the intermediate gold(I) allene complex formed in such a rearrangement could be trapped by a pendant phenol nucleophile to give a 6-endo-trig cyclization intermediate (eq 1). In previously reported gold-catalyzed transformations involving allenes, both chirality transfer and loss of chirality have been observed, depending on both the substitution pattern of the allene and the nature of the gold catalyst.⁹ In the case of propargylic esters, the donating oxygen substituent of the product allene greatly stabilizes the planar allyl cation-like form B, resulting in relatively shallow barriers to loss of configuration.^9b We hypothesized that chiral ligands for gold that provided access to this achiral intermediate could be employed in a dynamic kinetic asymmetric transformation.¹⁰

To test our hypotheses, we surveyed gold(I)–phosphine complexes that were previously used successfully in asymmetric allene additions. Encouragingly, when propargyl ester 1a was treated with (R)-DTBM-Segphos(AuCl)₂ or (R)-DTBM-MeO-Biphep(AuCl)₂ in the presence of sodium tetrakis[3,5-bis-(trifluoromethyl)phenyl]borate (NaBARF), the desired adduct 2a was formed with moderate enantioselectivity (Table 1, entries 1 and 2).

Table 1.

Au(I) Catalyst Screen

entrya	precatalyste	R	% eef (% yieldh)
1	L1 · (AuCl)2	–	52
2	L2 · (AuCl)2	–	60
3b	L3 · (AuCl)	–	0
4b	L4 · (AuCl)	–	7
5	A1 · (AuCl)2	H	22
6	A2 · (AuCl)2	Ph	56
7	A3 · (AuCl)2	3,5-(MeO)2C6H3	7
8	A4 · (AuCl)2	2,6-(MeO)2C6H3	– g
9	A5 · (AuCl)2	2-Naph	50
10	A6 · (AuCl)2	4-tBuC6H4	63
11	A7 · (AuCl)2	4-MeOC6H4	68
12	A8 · (AuCl)2	4-CF3C6H4	73 (56)
13c	A8 · (AuCl)2	4-CF3C6H4	85 (78)
14d	A8 · (AuCl)2	4-CF3C6H4	91

^aConditions: CH₂Cl₂ (0.05 M), 5 mol % precatalyst, 10 mol % NaBARF for 16 h at room temperature.

^bWith 5 mol % NaBARF used.

^cWith 10 mol % AgOTf used in place of NaBARF.

^dWith 10 mol % AgOTf used in place of NaBARF, in CDCl₃ (0.1 M) at 0 °C in 85% isolated yield.

^eL1 is (R)-DTBM-Segphos, and L2 is (R)-DTBM-MeO-Biphep.

^fDetermined by chiral HPLC.

^gLow yield of 2a; enantioselectivity not determined.

^hDetermined by ¹H NMR with m-dinitrobenzene as the internal standard.

We posited that the modest enantioselectivity in these transformations might be the result of a slow gold-promoted equilibration of the allene enantiomers through B whose rate could be enhanced by electron-rich ligands for gold. In accord with this hypothesis, phosphoramidite catalyst L3 · (AuCl),^3c which we have successfully applied in gold-catalyzed reactions of allenes, catalyzed the formation of 2a with poor enantioselectivity. Therefore, we hypothesized that electron-donating carbene ligands would be ideal for this transformation; however, chiral NHC complex L4 · (AuCl)^7b afforded product 2a with poor enantioselectivity (entry 4).

Inspired by the success with 3,3′-modified BINOL-derived phosphoramidite ligands in gold catalysis,³ we considered acyclic carbene ligands¹¹ based on 3,3′-functionalization of BINAM. Although initial experiments with the reported^7a acyclic carbene A1 · (AuCl)₂ as a catalyst resulted in disappointing enantioselectivities, we found that complex A2 · (AuCl)₂ with phenyl substituents at the 3,3′-positions of the BINAM scaffold gave improved enantioselectivities (entry 6). We investigated the effect of 3,3′-substitution on reactivity and enantioselectivity in more detail. Of the substitution patterns surveyed, only 4-substitution of the 3,3′-aryl group resulted in improved enantioselectivities, while the electronics of the substituents appeared to be unimportant (entries 10–12). Further optimization of 4-tri-fluoromethylphenyl-substituted catalyst A8 (Figure 1) with respect to the counterion revealed that using AgOTf in place of NaBARF resulted in further improvements in yield and enantioselectivity (entry 13).¹² Finally, lowering the reaction temperature to 0 °C afforded 2a in 85% yield and 91% enantiomeric excess (entry 14).

Figure 1.

X-ray structure of A8.

Under these conditions, we examined the scope of the gold-catalyzed kinetic dynamic asymmetric transformation (Table 2). Steric bulk at the ortho and para positions of the propargyl aryl ring was tolerated (entries 3–5). Moreover, electron-withdrawing substituents on the aryl moiety also furnished the desired adducts with good yields and enantioselectivities (entries 2 and 6). Good yields and enantioselectivities were also obtained from the gold-catalyzed rearrangement of substrates with further substitution on the phenol (entries 7 and 8).¹³

Table 2.

Enantioselective Synthesis of Chromenyl Pivalate from Phenols

entrya,b	1	R	Ar	% yieldc	% eed
1	1a	H	Ph	85	91
2	1b	H	p-BrC6H4	86	86
3	1c	H	2-Naph	68	84
4	1d	H	o-MeC6H4	77	84
5	1e	H	p-iPrC6H4	73	89
6	1f	H	p-CF3C6H4	76	88
7	1g	Me	Ph	85	90
8	1h	Br	Ph	83	83

^aConditions: CDCl₃ (0.1 M), 5 mol % A8 · (AuCl)₂, 10 mol % AgOTf for 4 h at 0 °C.

^bAbsolute stereochemistry assigned by analogy to 4e (Table 3).

^cIsolated yield of product after column chromatography.

^dDetermined by chiral HPLC.

We next looked at alkylated phenols, to explore the possibility of generating 3-substituted chromenes. Carbodemetalation of the vinylgold intermediate by a stabilized carbocation lost from the oxonium moiety would result in formal 1,3-migration of an electron-rich alkyl group and formation of a carbon–carbon bond. Gratifyingly, p-methoxybenzylether 3a reacted smoothly under the standard conditions to afford 3-substituted product 4a in excellent yield and enantioselectivity (entry 1). A variety of other electron-rich arylmethyl phenyl ethers, including those derived from N-, O-, and S-heterocycles, similarly underwent cyclization and O-to-C transfer to provide the products in excellent enantioselectivity and yield (Table 3).^14,15

Table 3.

Enantioselective Synthesis of Chromenyl Pivalate from Phenol Ethers

entrya,b	3	R	R'	% yieldb	% eed
1	3a	H		92	>99
2	3b	Me		75	>99
3c	3c	Me		62	99
4	3d	H		91	>99
5	3e	H		59	99
6c	3f	H		75	>99
7	3g	H		75	97
8	3h	H		73	99
9c	3i	H		73	96
10	3j	H		94	95

^aConditions: CDCl₃ (0.1 M), 5 mol % A8 · (AuCl)₂, 10 mol % AgOTf for 4 h at 0 °C.

^bIsolated yield of product after column chromatography.

^cAt room temperature.

^dDetermined by chiral HPLC.

To gain a better mechanistic understanding of the reaction, the gold-catalyzed rearrangement of enantioenriched 1a (60% ee) was examined. When the reaction was halted at 70% conversion, starting material was reisolated in a diminished 17% ee and product 2a in 88% ee (eq 2). This observation suggests either racemization of starting material via B (eq 1) or selective reactivity of the enantiomers of 1a, resulting in kinetically resolved starting material. To distinguish between these possibilities, the A8 · (AuCl)₂-catalyzed reaction of racemic 1a was conducted until 60% conversion had been reached (eq 2). Under these conditions, the recovered starting material 1a was isolated in 47% ee (enriched in the opposite enantiomer) and the product 2a in 90% ee. These results imply a kinetic resolution of the starting material and a relatively slow equilibration between the starting material and the intermediate gold-coordinated allene. Enantiodetermining cyclization onto the rapidly interconverting isomers of A and/or B then accounts for the observed dynamic kinetic resolution.

(2)

(3)

In summary, we report the application of modular 3,3′-substituted BINAM-derived acyclic diaminocarbene ligands to a highly enantioselective gold(I)-catalyzed reaction. The chiral acyclic carbenegold(I) catalyzed dynamic kinetic asymmetric transformation allows for the enantioselective synthesis of chromenyl pivalates from racemic propargyl pivalates. These adducts serve as useful precursors to enantioenriched chromanones. For example, treatment of 4d with LiAlH₄ at 0 °C provided chromanone 5d as a single diastereomer in >99% ee (eq 3).^16,17 The chiral carbene catalysts offer better enantioselectivity and reactivity than phosphine– and phosphoramidite–gold(I) catalysts that have previously been developed for enantioselective gold catalysis. Finally, we demonstrate that the generation of configurationally labile intermediates from propargyl esters is a promising strategy for asymmetric gold catalysis.