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