A Mukaiyama–Claisen Approach to 3,5-Diketo Esters

Dedicated to ‘uncle Peter’, in deep admiration for his marvelius contributions to chemical synthesis, including Synlett.

Abstract

A thermally promoted synthesis of 3,5-diketo esters via a Mukaiyama–Claisen reaction of 4H-1,3-dioxin-4-one derivatives with silyl enolates has been developed. The desired oligocarbonyl compounds were obtained with moderate to good yields.

Key words

3,5-diketo esters - Mukaiyama–Claisen reaction - thermal reaction - silylated nucleophiles

Oligocarbonyl compounds, especially 3,5-diketo ester derivatives, are important building blocks for the synthesis of polyketides and polyols, such as erythromycin A, rosuvastatin, tetracycline and wailupemycin F (Figure [1]).[1] [2] [3]

Figure 1 Representative examples of polyketides and polyols

Therefore, approaches towards their synthesis are of interest. Several methodologies have previously been developed to synthesize oligocarbonyl compounds.[4] Among them, Claisen condensation approaches have proven efficient in building up the carbon backbone. The Langer group recently reported the reaction of silylated nucleophiles with acyl chloride to give 3,5-diketo esters.[4a] [b] [c] [d] Tanabe and co-workers utilized a similar strategy to access analogous 1,3-dicarbonyl compounds.[4e,f] However, to our knowledge, esters themselves have not been used as electrophiles in Mukaiyama-type Claisen condensations. Notably, 4H-1,3-dioxin-4-one derivatives are useful synthetic equivalents for 1,3-dicarbonyls. In the context of a different study, we have recently described a single example in which a 3,5-diketo ester was accessed by reacting an enol silane with a 4H-1,3-dioxin-4-one derivative.[5] [6] Herein, we explore the generality of this unique transformation and report an improved thermal approach for the synthesis of 3,5-diketo esters via a Mukaiyama–Claisen reaction of 4H-1,3-dioxin-4-one derivatives with silyl ketene acetals.

Under optimized conditions both aliphatic and α,β-unsaturated 4H-1,3-dioxin-4-one derivatives could be employed in the thermally promoted Mukaiyama–Claisen reaction. Simply treating compounds 1 with an excess of silyl ketene acetals 2a or 2b, gave the corresponding 3,5-diketo esters in good yields after desilylation (Table [1]). Using an N-Boc carbamate containing substrate, the corresponding tricarbonyl products 3a and 3b were obtained in 85% and 78% yield, respectively. With an O-TBS protected substrate, the reactions proceeded smoothly, giving 3c and 3d in 85% and 84% yield, respectively. Reactions involving a conjugated alkenyl substrate required higher temperature (110 °C), and the corresponding products 3e and 3f were obtained in 61% and 73% yield, respectively. Using the simple, methyl-substituted substrate, the desired tricarbonyl compounds 3g and 3h were obtained in 73% and 75% yield, respectively.

Table 1 Substrate Scope of the Mukaiyama–Claisen Reaction

Entrya	Product		Yield (%)
1	3a		85
2	3b		78
3	3c		85
4	3d		84
5b	3e		61
6b	3f		73
7	3g		73
8	3h		75

^a Reactions were carried out with 1 (0.1 mmol) and 2 (0.4 mmol) in toluene (1 mL) for 4–5 h at 90 °C.

^b Reactions were carried out at 110 °C.

Interestingly, when a silyl enol ether (2c) was explored as the nucleophile, an intramolecular cyclization was observed and 2-methyl-6-phenyl-4H-pyran-4-one (4) was isolated in 59% yield (Scheme [1]). Presumably, under these conditions, a triketone is initially formed and subsequently undergoes cyclization to heterocycle 4.[7]

Scheme 1 Intramolecular cyclization observed using silyl enol ether 2c as nucleophile

In summary, a thermally promoted synthesis of 3,5-diketo esters via a Mukaiyama–Claisen reaction of 4H-1,3-dioxin-4-one derivatives with silylated enolate nucleophiles has been developed.[8] The desired oligocarbonyl compounds were obtained in good yields. This methodology may find applications in the synthesis of bioactive polyketides or polyols.

Scheme 2

Acknowledgment

Generous support by the Max-Planck-Society and the European ­Research Council (Advanced Grant ‘High Performance Lewis Acid ­Organocatalysis, HIPOCAT’) is gratefully acknowledged.

• References and Notes

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• 6 An acyl ketene intermediate has recently been proposed in thermal reactions of 4H-1,3-dioxin-4-ones (Scheme 2):
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• 8 A cooling-finger-capped Schleck tube with a stirring bar was charged with the corresponding 4H-1,3-dioxin-4-one derivative 1 (0.1 mmol), silylated nucleophile 2 (0.4 mmol), and anhydrous toluene (1 mL). The resulting mixture was heated to 90 °C or 110 °C for 4–5 h until full consumption of the starting material was observed (monitored by TLC). The solvent was removed under reduced pressure, MeOH (1 mL) and KHF₂ (10 equiv) were added, and the reaction mixture was stirred at r.t. for 10 min. After filtering through a thin layer of Celite, the residue was purified by column chromatography (isohexanes–EtOAc, 5:1 to 1:1).