A New and Efficient Total Synthesis of (±)-Laurencenone C

Abstract

A novel total synthesis of laurencenone C, a chamigrene sesquitepenoid natural product, has been accomplished in 11 steps. In the synthetic sequence, the B-ring of the spirocyclic core was constructed by a one-pot operation involving a Knoevenagel condensation between ethyl cyanoacetate and paraformaldehyde combined with a Diels-Alder reaction of the resulting ethyl 2-cyanoacrylate with isoprene. Moreover, a lithium naphthalenide-induced reductive alkylation of the Diels-Alder adduct was employed to create the C-6 quaternary center and to set the stage for assembling the A-ring.Laurencenone C (1) belongs to an abundant family of sesquitepenoids known as the chamigrenes, which includes more than one hundred members 1 and is characterized by a spiro[5.5]undecane core bearing two vicinal quaternary carbon centers at C-5 and C-6 positions. It was first isolated from the alga of the genus Laurencia obtuse, 1 along with three other structurally related chamigrenes, namely laurencenones A, B, and D (Figure 1). 2 These natural products contain the same A-ring bearing an enone moiety, and differ from each other by the functionalities on the B-ring. Like many other chamigrenes, 3 laurencenone C has attracted attention from the synthetic community with five total syntheses so far having been documented in the literature. 4-8 The first total synthesis was reported by Takeshita and co-workers. 4 In their synthetic sequence, a photo-cycloaddition of terpinolene with methyl 2,4-dioxopentanoate followed by a base-promoted retro-benzilic acid rearrangement of the resulting hydroxy spiro-[3.5]nonene ester was employed to prepare the key precursor for assembling the spiro framework. Following this, Chen's group described the synthesis of 1 by utilizing a crucial intramolecular radical cyclization of an a-allenic ketone to access the spiro ring fusion. 5 However, both syntheses provided 1 in relatively low overall yields (2.9 and 6.4%, respectively) due to the formation of other regio-and stereoisomers as side products in the key synthetic steps. In similar approaches, Srikrishna and co-workers twice described the total synthesis of 1 through the use of an Ireland ester Claisen rearrangement combined with a RCM reaction 6 or an intramolecular type II carbonyl ene reaction 7 as the key operations. Besides these approaches, the RCM strategy was also employed in an enantioselective synthesis of 1 recently reported by Stoltz and Grubbs et al. 8 As can be seen, the syntheses of 1, as well as other chamigrenes, 3 are critically dependent on the efficient creation of the quaternary spirocenter with the necessary functionalities for building the spiro[5.5]undecane core.

ipso-Cyclization of unactivated biaryl ynones leading to thio-functionalized spirocyclic enones

“…1). 3 Accordingly, dearomative ipso -annulation of aromatic compounds with an alkene/alkyne has been shown to be an effective approach to access spirocyclic skeletons. 4–7 Recently, biaryl ynones have emerged as promising substrates for radical reactions providing spiro[5,5]trienones via 6- exo -trig cyclization or dibenzocycloheptanones through 7- endo -trig cyclization (Scheme 1).…”

Visible Light Promoted Brominative Dearomatization of Biaryl Ynones to Spirocycles

“…Dearomatization and installation of chemical functionalities in a complex molecular backbone with high degree of precision are still highly challenging and one of the most promising intrigues to solve molecular complexity at higher levels . In this aspect, dearomative cascade spiro-annulation of biaryl ynones deliver spiro[5.5]­trienone skeleton, ubiquitous in many biologically active natural products and also prevalent as a template in diverse functionalization in organic synthesis and medicinal chemistry . For instance, the natural product laurencenone B, pulchelstyrene D, as well as a potent inhibitor platencin with spiro[5.5]­trienone skeleton manifest antibiotic and antiviral activities .…”

Electrochemical Arene Radical Cation Promoted Spirocyclization of Biaryl Ynones: Access to Alkoxylated Spiro[5,5]trienones

“…Spiro­[5,5]­enones are a privileged class of highly rigid three-dimensional structural motifs that widely occur in many natural products and synthetic biologically active molecules . In particular, spiro­[5,5]­enone scaffolds have already well rendered their applications with success in antitumor, antiinflammatory, and antidiabetic activities (Figure ).…”