Rh₂(S-PTTL)₃TPA—A Mixed Ligand Dirhodium(II) Catalyst for Enantioselective Reactions of α-Alkyl-α-Diazoesters

Abstract

Herein we report the synthesis of the mixed ligand paddlewheel complex dirhodium(II) tris[N-phthaloyl-(S)-tert-leucinate] triphenylacetate, Rh₂(S-PTTL)₃TPA, the structure of which bears similarity to the chiral crown complex Rh₂(S-PTTL)₄. Rh₂(S-PTTL)₃TPA engages substrate classes (aliphatic alkynes, silylacetylenes, α-olefins) that are especially challenging in intermolecular reactions of α-alkyl-α-diazoesters, and catalyzes enantioselective cyclopropanation, cyclopropenation, and indole C-H functionalization with yields and enantioselectivities that are comparable or superior to Rh₂(S-PTTL)₄. Mixing ligands on paddlewheel complexes offers a versatile handle for diversifying catalyst structure and reactivity. The results described herein illustrate how mixed ligand catalysts can create new opportunities for the optimization of catalytic asymmetric processes.

Rh(II)-carboxylate catalysts supported by N-phthaloyl- and N-naphthaloyl amino acid ligands are robust tools for asymmetric synthesis.¹ These catalysts were pioneered by Hashimoto,² and in recent years have opened new modes of reactivity including highly enantioselective cyclopropanation³, cyclopropenation⁴, and C-H functionalization⁵ of α-alkyl-α-diazoesters; cyclopropanation and C-H functionalization of α-aryl- and α-vinyl- α-diazoesters⁶; cyclopropanation of PMP-α-diazoketones,⁷ and cycloadditions of β-keto-α-diazoesters⁸.

We recently reported that dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh₂(S-PTTL)₄ (Fig. 1), gives high enantioselectivity in the cyclopropanation reactions of α-alkyl-α-diazoesters.³ The model for enantioselectivity was explained by a “chiral crown” structure, in which all four N-phthalimide groups are presented on the same face of the catalyst in an α, α, α, α conformation.⁹ Charette also proposed that the α, α, α, α conformation is important for Rh-catalysts supported by N-phthaloyl amino acid ligands in cyclopropanation reactions of α-4-methoxyphenyl-α-diazoketones.⁷ Crystallographic support for the chiral crown structure in bimetallic paddlewheel complexes has been established in subsequent study¹⁰, which includes work on Rh₂(S-NTTL)₄ catalyzed cyclopropanation by Ghanem,¹¹ Rh₂(S-TBPTTL)₄ catalyzed cyclopropenation⁴ by Hashimoto, and Rh₂(S-NTTL)₄ catalyzed C-H functionalization of indoles by our group.⁵

Fig. 1.

(a) Top view and (b) side view of crystal structure of Rh₂(S-PTTL) ₃TPA. Axial ethanol ligands are not displayed. (c) Lowest energy conformation of Rh₂(S-PTTL) ₃TPA from DFT calculation.

(1)

The chiral crown structure offers a unique platform for catalyst design. Inspection of transition state models involving chiral crown catalysts implies that non-covalent ligand-substrate interactions contribute to the induction of asymmetry.^3,5,7 We hypothesized that the chiral pocket would still be maintained in structures where one of the chiral carboxylate ligands of Rh₂(S-PTTL)₄ was replaced by an achiral ligand. We further reasoned that introducing a ligand with a large aromatic surface area could have a beneficial influence on the yield and enantioselectivity in intermolecular reactions. Herein, we report the mixed ligand catalyst dirhodium(II) tris [N-phthaloyl-(S)-tert-leucinate] triphenylacetate, Rh₂(S-PTTL)₃TPA (Eq 1). Computational and crystallographic studies show that Rh₂(S-PTTL)₃TPA adopts a structure in which the N-phthaloyl groups are presented on the same face of the catalyst. For a number of recalcitrant substrates, Rh₂(S-PTTL)₃TPA is shown to give results in enantioselective cyclopropanation, cyclopropenation, and indole C-H functionalization that are superior to the parent catalyst, Rh₂(S-PTTL)₄.

While studies on chiral bimetallic rhodium (II) complexes have been extensive,¹² there has been relatively little study on bimetallic Rh(II) complexes bearing different ligand types. Corey reported that Rh₂(DPTI)₃(OAc), which is capable of achieving high enantioselectivity in cyclopropenation and cyclopropanation reactions of ethyl diazoacetate.¹³ Doyle has reported immobilized Rh(II) mixed ligand carboxamidates as useful catalysts for intramolecular cyclopropanation and C-H insertion reactions,¹³ and Hashimoto has reported a polymer-supported analogue of Rh₂(S-PTTL)₄ as a useful recyclable catalyst for C-H insertion reactions.¹³ Concurrent with the work being reported here, Charette and coworkers have developed chiral Rh-catalysts bearing mixed N-phthaloyl amino acid ligands that give excellent enantioselectivity in the cyclopropanation reaction of α-nitro-α-diazo-p-methoxyacetophenone with styrene.¹⁴

As shown in Eq. 1, the unsymmetrical complex Rh₂(S-PTTL)₃TPA can be synthesized in 40% yield by simply combining N-phthaloyl-(S)-tert-leucinate (3 equiv), triphenylacetic acid (1 equiv) and Rh₂(OAc)₄ (1 equiv). Also formed in the reaction are Rh₂(S-PTTL)₄ (40%) and isomers of Rh₂(S-PTTL)₂TPA₂ (20%).

We began work on Rh₂(S-PTTL)₃TPA with computational and crystallographic studies. Crystals of Rh₂(S-PTTL)₃TPA were grown from ethanol. Rh₂(S-PTTL)₃TPA adopts a conformation in the solid state in which all of the phthaloyl groups are displayed on the α-face (Fig 1a–b). When DFT calculations (B3LYP/LAN2DZ) were used to computationally optimize the crystallographic coordinates, the lowest energy structure displayed in Fig 1c was found. An energetically and structurally similar structure to the one displayed in Fig 1c was also found as the result of a conformational search.¹⁵ Starting from several different conformations, Rh₂(S-PTTL)₃TPA was subjected to molecular dynamics-based conformational (LowModeMD¹⁶), and the lowest energy structures were optimized using DFT calculations (B3LYP/LAN2DZ).

The largest difference between the computed and solid state structures of Rh₂(S-PTTL)₃TPA is the ψ-angle for one the PTTL ligands, which is −11.1° in the x-ray structure (Fig 1b), but 44.0° in the calculated structure (Fig 1a). This clockwise ψ-angle twist¹⁷ in the crystal structure may be a result of attractive intramolecular (2.456 Å) and intermolecular (2.512 Å) interactions between the phthalimide carbonyl and a nearby aromatic hydrogen from the TPA ligand. However, there is an overall good agreement between the predicted and crystallized structure of Rh₂(S-PTTL)₃TPA.

As shown in table 1, the reaction to produce Rh₂(S-PTTL)₃TPA also produced isomers of Rh₂(S-PTTL)₂TPA₂ (20%). The cis-isomer crystallized from a solution of CD₃CN. In the x-ray structure of cis-Rh₂(S-PTTL)₂TPA₂, both phthalimido groups are projected on the same face of the catalyst.

Table 1.

Catalyst screening for enantioselective cyclopropanation of styrene with ethyl α-diazobutanonate: Rh₂(S-BPTTL)₄= dirhodium(II) tetrakis[N-2,3-naphthaloyl-(S)-tert-leucinate]; Rh₂(S-NTTL)₄= dirhodium(II) tetrakis[N-1,8-naphthaloyl-(S)-tert-leucinate]; Rh₂(S-TBPTTL)₄= dirhodium(II) tetrakis[N-tetrabromophthaloyl-(S)-tert-leucinate];

;
Rh(II) Catalyst	Solvent	%yda	drb	%eec
Rh2(S-PTTL)4	Hexanes	95	92:8	79
Rh2(S-BPTTL)4	Toluene	80	88:12	73
Rh2(S-NTTL)4	Toluene	61	75:25	45
Rh2(S-TBPTTL)4	CH2Cl2	6	97:3	11
Rh2(S-TBPTTL)4	Toluene	10	88:12	16
Rh2(S-TBPTTL)4	Hexanes	23d	84:16	16
Rh2(TPA)(S-PTTL)3	Toluene	66	95:5	81
Rh2(TPA)(S-PTTL)3	Hexanes	91	96:4	88

^aIsolated yields.

^bMeasured by GC.

^cMeasured by chiral HPLC.

^dRun at −60 °C for 2 hours. No reaction occurred at −78 °C.

As reported previously, the Rh₂(S-PTTL)₄ catalyzedcyclopropanation of styrene by ethyl-α-diazobutanoate was not particularly enantioselective, providing 1 in 79% ee. As shown in Table 1, a number of Rh-catalysts were surveyed, including Rh₂(S-NTTL)₄, the most useful catalyst from our prior work on indole C-H functionalization,⁵ and Rh₂(S-TBPTTL)₄, a catalyst recently reported by Hashimoto to be useful in cyclopropenation⁴ and also reported to be useful in the cyclopropanation of α-diazopropionates.¹⁸ Of the catalysts surveyed, Rh₂(S-PTTL)₃TPA gave the best enantioselectivity in hexanes with 88% ee (Table 1).¹⁹

To determine if Rh₂(S-PTTL)₃TPA could also improve the selectivity for other cyclopropanation reactions, we surveyed a range of substrates as shown in Scheme 1. In addition to cyclopropane 1, significant improvements in enantioselectivity were observed in the cases of cyclopropanation products 2–6 when Rh₂(S-PTTL)₃TPA was used instead of Rh₂(S-PTTL)₄. Slight enantioselectivity improvements were also noted for 7 and 8, and results comparable to Rh₂(S-PTTL)₄ were observed in the case of cyclopropanation product 9. In general, yields and diastereoselectivities were comparable for the reactions studied. A notable exception was 3-methoxystyrene, where the diastereoselectivity to form 2 increased from 83:17 with Rh₂(S-PTTL)₄ to 99:1 with Rh₂(S-PTTL)₃TPA.

Scheme 1.

Rh₂(S-PTTL)₃TPA catalyzed cyclopropanation of styrene derivatives with α-alkyl diazoesters

^a The enantioselectivity with Rh₂(S-PTTL)₄ was the same as that observed for Rh₂(S-PTTL)₃TPA. ^b The dr with Rh₂(S-PTTL)₄ was only 83:17

In prior studies on intermolecular cyclopropanation with α-alkyl-α-diazoesters, it was noted that α-olefins are particularly challenging substrates. The reaction between 1-octene and ethyl α-diazobutanoate did not yield cyclopropane products with Rh₂TPA₄, a catalyst that is effective in cyclopropanation reactions of α-alkyl-α-diazoesters with styrenes or vinyl ethers.²⁰ Very recently, Hashimoto reported the cyclopropanation of diazopropionate with 1-hexene.¹⁸ Still unknown, however, is α-olefin cyclopropanation by α-n-alkyl-α-diazocarbonyl compounds, which contain weaker β-C-H bonds. As shown in Scheme 3, the reaction between 1-hexene and isobutyl α-diazobutanoate (5 equiv.) is successful with with Rh₂(S-PTTL)₄, but gives cyclopropane 10 in only 33% yield. With Rh₂(S-PTTL)₃TPA, cyclopropane 10 can be obtained in a more useful 64% yield, albeit with modest dr (72:28) and enantiomeric excess (72% ee and 65% ee for the major and minor diasteroemers, determined by reduction to 10a). This represents the first example of an α-olefin cyclopropanation with an α-n-alkyl-α-diazocarbonyl compound that is selective over β-hydride elimination. We previously reported a method to access cyclopropenation products of α-alkyl-α-diazoesters using low reaction temeperatures and Rh₂Piv₄ as a catalyst.²⁰ Very recently, Hashimoto reported an elegant method for enantioselective cyclopropenation using α-alkyl-α-diazoesters.⁴ Despite these advances, considerable challenges remain. Silylacetylenes had not proven effective substrates for cyclopropenation reactions with α-alkyl-α-diazoesters. Avoiding β-elimination in cyclopropenation of aliphatic alkynes had also been limited to α-methyl-α-diazocarbonyls, which possess strong bonds to β-hydrogens.²² Unknown were cyclopropenation reactions between aliphatic alkynes and diazo compounds with weaker β-C-H bonds. Previously, we reported that the scope of cyclopropenation could be extended to α-n-alkyl-α-diazoesters by using Rh₂Piv₄ at low temperature.²¹ These conditions were successful with aromatic alkynes and enynes. However, cyclopropenation products were not observed with 1-hexyne.

Scheme 3.

Diastereoselective Rh₂(S-PTTL)₃TPA catalyzed cyclopropanation of 1-hexene. a) Isolated yield. b) Yield by ¹H NMR

As shown in Scheme 4, Rh₂(S-PTTL)₃TPA successfully catalyzes the reactions of α-n-alkyl-α-diazoesters with trimethylsilylacetylene and 1-hexyne. Compared to other catalysts that were surveyed, Rh₂(S-PTTL)₃TPA was superior both in terms of yield and in terms of enantioselectivity. Products of β-elimination dominated the reactions with Rh₂(S-PTTL)₄, Rh₂(S-NTTL)₄ and Rh₂(S-TCPTTL)₄. With Rh₂(S-PTTL)₃TPA, cyclopropenation product 11 was produced from ethyl α-diazobutanoate and trimethylsilylacetylene in 82% yield and 91% ee. For Rh₂(S-PTTL)₄, the next best catalyst, the yield (22%) and enantioselectivity (racemic) were sharply reduced. Similar trends in yield were noted in the cyclopropenation reactions of 1-hexyne to form 12 and 13, with comparable enantioselectivity to Rh₂(S-PTTL)₄ being noted in Rh₂(S-PTTL)₃TPA-catalyzed formation of 12 and superior enantioselectivity to Rh₂(S-PTTL)₄ being noted in Rh₂(S-PTTL)₃TPA-catalyzed formation of 13.

Scheme 4.

Enantioselective cyclopropenation of aliphatic alkynes 1-hexene and trimethylsilylacetylene. Rh₂(S-TCPTTL)₄= dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate]; a) Isolated yield. b) Yield by ¹H NMR. c) Yield by GC.

We recently described a Rh₂(S-NTTL)₄ catalyzed method for enantioselective C-H functionalization of indoles.⁵ Hashimoto and coworkers described the use of dirhodium(II) tetrakis[N-phthaloyl-(S)-triethylalaninate [Rh₂(S-PTTEA)₄] to be useful in the C-H functionalization of indoles by α-diazopropionates.²³ Despite a good scope of reactivity, a number of substrate types have thus far proven problematic, including 4-substituted indoles, which have a nucleus prevalent in biologically active natural products. To date, only Hashimoto has achieved the enantioselective C-H functionalization of a 4-substituted indole: the Rh₂(S-PTTEA)₄ catalyzed reaction of N-methoxymethyl-4-methylindole with 2,4-dimethyl-3-pentyl-α-diazopropionate in 69% ee.

As shown in Table 2, 4-methyl-N-phenylindole 14 reacts poorly with excess ethyl α-diazobutanoate under Rh₂(S-NTTL)₄ catalyzed conditions, leading to product 15 in only 5% yield and 40% ee (Table 2). With an excess of ethyl α-diazobutanoate, Rh₂(S-PTTL)₃TPA gave 15 in superior yield (79%) and enantioselectivity (81% ee) relative to Rh₂(S-PTTL)₄ and Rh₂(S-NTTL)₄.

Table 2.

C-H functionalization of 4-substituted indoles.

Rh(II) Catalyst	%yda	%eeb
Rh2(S-NTTL)4	5	40
Rh2(S-PTTL)4	43	64
Rh2 (S-PTTL)3(TPA)	80	81

^aIsolated yields.

^bMeasured by chiral HPLC

Conclusions

In summary, we have described a mixed ligand catalyst, Rh₂(S-PTTL)₃TPA, which displays all of the N–phthalimide groups on one face in structural similarity to the chiral crown complex Rh₂(S-PTTL)₄. Rh₂(S-PTTL)₃TPA engages substrate classes (aliphatic alkynes, silylacetylenes, α-olefins) that are especially challenging in intermolecular reactions of α-alkyl-α-diazoesters, and catalyzes enantioselective cyclopropanation, cyclopropenation, and indole C-H functionalization with yields and enantioselectivities that are comparable or superior to Rh₂(S-PTTL)₄. The use of mixed ligand catalysts offers new opportunities for the optimization of catalytic processes that are catalyzed by bimetallic paddlewheel complexes.