Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with β,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters

(Ph3C)[BPh(F)4]-catalyzed Hosomi-Sakurai allylation of allylsilanes with β,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.


Introduction
α-Ketoesters are important synthons [1-3] and can be transformed into a variety of building blocks, which have found wide utility in natural products synthesis. As shown in Scheme 1, a Bi(OTf) 3 -catalzyzed intermolecular cascade annulation of α-ketoesters with alkynols has been developed to construct γ-spiroketal-γ-lactones [4], a core structure in massarinoline A [5]. α-Ketoesters can also react with α-ketoacids to form isotetronic acids [6], a core structure in aspernolide A [7], by an asymmetric aldol/lactonization/enolization reaction. In this regard, development of new methods enabling an efficient synthesis of structurally diverse α-ketoesters is highly desirable.

Introduction
α-Ketoesters are important synthons [1-3] and can be transformed into a variety of building blocks, which have found wide utility in natural products synthesis. As shown in Scheme 1, a Bi(OTf)3-catalzyzed intermolecular cascade annulation of α-ketoesters with alkynols has been developed to construct γ-spiroketal-γ-lactones [4], a core structure in massarinoline A [5]. α-Ketoesters can also react with α-ketoacids to form isotetronic acids [6], a core structure in aspernolide A [7], by an asymmetric aldol/lactonization/enolization reaction. In this regard, development of new methods enabling an efficient synthesis of structurally diverse α-ketoesters is highly desirable. Scheme 1. Synthetic utility of α-ketoesters in the synthesis of natural products. "cat*" refers to chiral catalysts.
The trimethylsilyl enol ethers that initially formed in the reactions shown in Tables 2  and 3 were difficult to isolate because of their instability. Switching the silyl moiety from Me3Si to a bulkier Et3Si group in allylsilane 2h-2j led to formation of the stable silyl enol ethers 5a-5c in good to high yields (Scheme 4). The Z-silyl enol ether was favored either as a single isomer (5a and 5c) or the major isomer (5b).
Trimethylallylsilanes 2b-2e bearing alkyl or aryl substituents at the 2-position reacted well with 1a, giving 3q-3t in 85-96% yields ( Table 2, entries 1-4). The high catalytic ability of (Ph 3 C)[BPh( F ) 4 ] also allowed facile anti-SE' allylation of the bulky 3,3-dimethyl-1trimethylallylsilanes 2f with 1a (entry 5). However, this catalyst did not efficiently control the diastereoselectivity of allylation: the reaction of Z-crotyltrimethylsilane 2g-Z afforded 3v in 96% yield but as a 3:2 [54] mixture of antiand syn-diastereomers (entry 6). A similar ratio of 3:1 was obtained using E-crotyltrimethylsilane 2g-E (entry 7).   The trimethylsilyl enol ethers that initially formed in the reactions shown in Scheme 3 and Table 2 were difficult to isolate because of their instability. Switching the silyl moiety from Me 3 Si to a bulkier Et 3 Si group in allylsilane 2h-2j led to formation of the stable silyl enol ethers 5a-5c in good to high yields (Scheme 4). The Z-silyl enol ether was favored either as a single isomer (5a and 5c) or the major isomer (5b).

Mechanistic Investigations
Some mechanistic investigations have been performed for trityl different groups, but the results appear to be contradictory, particular actions involving allylsilanes or silyl enol ethers. For example, three ca been suggested for Mukaiyama aldol reactions. Denmark [14] an 13,17,19] proposed the catalytic species to be a trityl cation. In this p transfer of the silyl group releases the product and regenerates the tr Bosnich [18] and Chen [16] proposed the catalytic species to be a sily  Scheme 3. Scope of β,γ-Unsaturated α-Ketoesters a . a Reaction conditions: 0.11 mmol of 1, 0.13 mmol of 2a, 1.0 mol % of (Ph3C)[BPh( F )4] in 2.0 mL of CH2Cl2 at 25 °C. b Isolated yields. c Ratios were determined by 1 H NMR spectroscopy of the crude products.

Mechanistic Investigations
Some mechanistic investigations have been performed for trityl cation catalysis by different groups, but the results appear to be contradictory, particularly in the case of reactions involving allylsilanes or silyl enol ethers. For example, three catalytic species have been suggested for Mukaiyama aldol reactions. Denmark [14] and Mukaiyama [9][10][11][12][13]17,19] proposed the catalytic species to be a trityl cation. In this path, intramolecular transfer of the silyl group releases the product and regenerates the trityl cation catalyst. Bosnich [18] and Chen [16] proposed the catalytic species to be a silyl cation, which is a stronger Lewis acid than trityl cation. In another case, Kagan [20][21][22] proposed the catalytic species to be a Brønsted acid, potentially generated by decomposition of the trityl cation. The accessibility of silyl enol ethers allowed us to perform detailed mechanistic investigations for our reaction (Scheme 5). Allylsilanes 2a, 2i, 2h and 2b were reacted separately with β,γ-unsaturated α-ketoester 1a. In the merged 1 H NMR spectra of the resulting crude silyl enol ethers 5d, 5b, 5a and 5e, we were able to clearly distinguish the H a signals of the different products (Scheme 5(b1)). Therefore, we reacted a mixture of 2a (1.2 equiv.) and 2i (1.2 equiv.) with 1a (2.0 equiv.) in one pot (Scheme 5a). A mixture of 5d, 5b, 5a and 5e was generated in a ratio of 93(5d + 5b):7(5a + 5e) (Scheme 5(b2)). We attribute the formation of 5a and 5e to crossed silyl cation catalysis. This result implies that 7% of 5d and 5b may form via silyl cation catalysis, meaning that the ratio of trityl to silyl cation catalysis should be approximately (93−7):(7+7) or 86:14. Next we reacted a mixture of 2h (1.2 equiv.) and 2b (1.2 equiv.) with 1a (2.0 equiv.) in one pot. A mixture of 5d, 5b, 5a and 5e was generated in a ratio of 6(5d + 5b):94(5a + 5e) (Scheme 5(b3)). The ratio of trityl to silyl cation catalysis in this reaction should be (94−6):(6+6) or 88:12. The results from these two control reactions suggest that silyl cation catalysis occurs but makes a minor contribution to our results.
Molecules 2022, 27, x FOR PEER REVIEW 6 of 9 5 as the major product ( Scheme 5(b2,b3)). This also regenerates the trityl cation and catalyzes the next cycle.
Brønsted acid catalysis is another competing catalytic pathway, which we cannot rule out currently. This pathway seems unlikely to make a major contribution based on our

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Samples of the compounds 3a-3v are available from the authors.