The Telescoped Intramolecular Michael/Olefination (TIMO) Approach to α‐Alkylidene‐γ‐butyrolactones: Synthesis of (+)‐Paeonilactone B

Abstract

a-Alkylidene-g-butyrolactones are widespread in nature and have diverse and potentially useful biological properties. [1] Representative examples range from the relatively simple paeonilactone B, [2] to more complex compounds such as helenalin isobutyrate [3a] and the recently isolated montahibisciolide. [3b] Numerous procedures are available to prepare a-alkylidene-g-butyrolactones; in particular, the initial construction of the lactone with subsequent methylenation is popular, but the majority of the routes are lengthy and low yielding. [1][2][3] As part of our growing interest in tandem or telescoped processes, [4] we designed a one-pot approach to a-alkylidene-g-butyrolactones (Scheme 1). The key was the use of diethyl phosphonoacetate 1, which, after deprotonation, was expected to undergo an intramolecular Michael addition [5,6] to give enolate 2. We anticipated subsequent proton transfer to generate the more stable phosphonate anion 3 and then addition of an aldehyde to initiate an intermolecular HornerWadsworth-Emmons (HWE) olefination [7] to yield cyclic dicarbonyl compound 4. In addition, we anticipated that the sequence would be cis selective in the formation of tetrahydrobenzofuran-2,5-dione 4 (n = 1).Ketophosphonate 5 was used to assess the viability of the approach shown in Scheme 1. Compound 5 was prepared from readily available 4-hydroxy-2-cyclohexenone [8] and commercially available diethyl phosphonoacetic acid by using 2-propanephosphonic acid anhydride (T3P) as the coupling agent. When ketophosphonate 5 was treated with KOtBu in THF, the expected Michael adduct 6 was obtained in 50 % yield (Scheme 2). Phosphonate 6 was used to optimize the key HWE methylenation in terms of base, solvent, stoichiometry, and formaldehyde source. KOtBu in THF proved to be the best base/solvent combination and paraformaldehyde was the optimal formaldehyde source. The amethylene lactone product 7 a was highly base-sensitive, and the use of a substoichiometric quantity of base (0.95 equiv) gave product 7 a in 83 % yield.A more efficient transformation was achieved by performing a sequential one-pot process. Thus, treatment of ketophosphonate 5 with KOtBu (0.95 equiv) in THF, and the addition of paraformaldehyde after 60 minutes, produced the expected a-methylene lactone 7 a in 77 % overall yield. This result emphasizes the advantages of a sequential one-pot process-it avoids a complicated intermediate workup process and the overall yield is improved (77 %, compared to 43 % over two steps). This variant was termed a telescoped intramolecular Michael addition/HWE olefination (TIMO) process. Lactone 7 a is novel although the corresponding trans isomer is known.[9] The cis arrangement of 7 a was confirmed by obtaining an X-ray crystallographic structure.[10] Scheme 1. Proposed TIMO approach to a-alkylidene-g-butyrolactones.

Halocarbocyclization Entry into the Oxabicyclo[4.3.1]decyl Exomethylene-δ-Lactone Cores of Linearifolin and Zaluzanin A: Exploiting Combinatorial Catalysis

“…4 Against this medicinal chemistry backdrop there has been vigorous synthetic activity in the exomethylene SQL area, 5 including approaches that permit core synthesis 6 and chain extension. 7 While a number of routes focus on end game methylenation, 8 we favored a convergent strategy in which a formal halometalation/carbocyclization would at once close the lactone, control ring fusion geometry, and set in place the reactive, conjugated exomethylene moiety.…”

Synthesis of (±)-oleocanthal via a tandem intramolecular Michael cyclization–HWE olefination

“…We envisioned the dialdehyde moiety of 3 arising from the reduction and oxidation of lactone 5 whose carbon framework could be assembled through a key tandem Michael cyclization and Horner-Wadsworth-Emmons (HWE) olefination9 of phosphonoacetic ester 6 . This allows for the simultaneous assembly of the desired lactone core, the addition of the two-carbon olefin sidechain, and the introduction of a stereogenic center.…”

The Preparation of α‐Alkylidene‐γ‐Butyrolactones Using a Telescoped Intramolecular Michael/Olefination (TIMO) Sequence: Synthesis of (+)‐Paeonilactone B

“…The success of this approach has been reported in a preliminary communication 11. Herein, we give a full account of the development and optimisation of this telescoped intramolecular Michael/olefination (TIMO) sequence and discuss investigations to establish its scope, limitations and applications.…”