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Reports: UR153693-UR1: Intramolecular Cycloaddition Reactions of Electron-Rich Alkynes: New Methods for the Synthesis of Optically Active Building Blocks for Organic Synthesis

Thomas G. Minehan, California State University (Northridge)

Our investigation of the chemistry of electron-rich alkynes (including ynamines and ynol ethers) has led to the discovery of an important and useful synthesis of alpha-methylene, alpha-alkylidene, and alpha-benzylidene lactones. The alpha-alkylidene lactone moiety is found in numerous synthetically challenging and biologically important natural products, many of which possess anticancer, antimalarial, antibacterial, antifungal, antiviral, and/or anti-inflammatory activities. Of particular significance are the numerous members of the alpha-methylene-gamma-butyrolactone family of sesquiterpenes, to which belong the germacranolides, (pseudo)guaianolides, eudesmanolides, and the cembranolides. Recently, synthetic attention has also been directed toward the alpha-benzylidene-gamma-butyrolactones megacerotonic acid and shimobashiric acid, due to their heightened biological profile. We have found that treatment of alcohol-tethered ynol ethers (1) with aldehydes and ketones at -78oC in the presence of TMSOTf leads to the formation of five- and six-membered alpha-alkylidene and alpha-benzylidene lactones (5) in good to excellent yields (Figure 1). The lactone products formed are of predominantly Z-configuration.

Figure 1.

The process likely proceeds by intermolecular electrophilic reaction of the ynol ether functional group with the carbonyl compound to form an acyclic unsaturated hydroxy-ester intermediate, followed by subsequent acid-promoted lactonization and E-to-Z alkene isomerization. Indeed, when substrates lacking quaternary centers are used as substrates, mixtures of the acyclic unsaturated ester and unsaturated lactone are formed. (Figure 2). Treatment of the unsaturated hydroxyester intermediate with TFA yields the Z-configured lactone in good yields.

Figure 2.

Similarly, treatment of ynol ethers 1 with Eschenmoser salt at room temperature in CH2Cl2 affords alpha-methylene-gamma-butyrolactones and alpha-methylene-gamma-valerolactones after lactonization under acidic conditions (Scheme 1).

Scheme 1.

To form lactones from substrates lacking quaternary centers, a protocol involving temporary alcohol silylation, reaction with the aldehyde or ketone under TMSOTf promotion, and TFA-promoted desilylation/lactonization provided good to excellent yields of alpha-alkylidene and alpha-benzylidene lactone products (Scheme 2).

Scheme 2.

As an extension of these processes, we are currently exploring the synthesis of nitrogen heterocycles from azide-tethered ynol ethers. Treatment of azides with Bronsted acids is known to induce nitrene formation, which upon cycloaddition with the electron-rich ynol ether is expected to provide substituted pyrrolidines of the type 7. Ynol-imines can also be prepared from ynol azides by Staudinger-type reaction with PPh3 followed by treatment with an aldehyde or ketone. To promote a 6-endo-trig cyclization, a variety of Bronsted (TFA) and Lewis (TMSOTf, Sc(OTf)3, BF3­) acids will be screened, and the diasteroselectivity of the cyclization reaction will be studied as a function of both Lewis acid catalyst and temperature (Scheme 3).

Scheme 3.

Another area of current investigation involves the exploration of radical reactions of ynol ethers. Halo-ynol ethers can be easily prepared from the corresponding alcohols and subjected to free-radical conditions. 5-Exo or 6-exo dig cyclizations are expected to yield a captodative radical which upon reduction and hydrolysis would provide an aldehyde product containing a new carbon-carbon bond and a ring. The process can be further extended to allow preparation of enals and fused ring systems by tandem radical cyclizations (Scheme 4).

Scheme 4.