Role of the Nozaki–Hiyama–Takai–Kishi Reaction in the Synthesis of Natural Products

Abstract

The Nozaki-Hiyama-Takai-Kishi (NHTK) reaction was discovered in the late 1970s and, since then, its main application has been its use in total synthesis. In this comprehensive review, the efficiency of the NHKT reaction in the synthesis of a great number of different scaffolds present in complex natural products is analyzed. The preparation of enol and allylic and propargylic alcohol motifs is discussed, highlighting factors such as yield, chemoselectivity, stereoselectivity, or the importance of protecting groups. The review is divided into two main sections: intermolecular and intramolecular NHTK reactions. A final discussion about the current "state-of-art" and future perspectives for the use of this transformation in total synthesis is also included.

Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide‐2a

“…Vinyl iodide 6 was to be prepared from bis-tetrahydrofuran 9 by performing a syn-specific hydrometalation of an alkynet o install the vinyl iodide moiety of 6.W ee nvisaged the synthesis of 9 from epoxide 10 throughs equentials tereospecific cycloetherifications for constructing two tetrahydrofuran rings. Meanwhile, olefin 7 should be available from alcohol 11 by an asymmetrica llylation, and the latter was further traced back to enol triflate 12 by considering aN ozaki-Hiyama-Kishi coupling [17,18] with propanal.…”

Nickel Catalyzed Intermolecular Carbonyl Addition of Aryl Halide

“…The Nozaki–Hiyama–Kishi (NHK) reaction is a viable alternative for such stoichiometric organometallic transformations and has been applied in several total syntheses of naturally occurring products , . In this context, Cheng et al developed a nickel‐catalyzed reaction that couples aldehydes with aryl halides under reductive conditions to produce secondary alcohols in 2000 .…”

“…The Nozaki-Hiyama-Kishi (NHK) reaction is a viable alternative for such stoichiometric organometallic transformations and has been applied in several total syntheses of naturally occurring products. [8,9] In this context, Cheng et al developed a nickel-catalyzed reaction that couples aldehydes with aryl halides under reductive conditions to produce secondary alcohols in 2000. [10] In the reductive coupling chemistry field, there have been a few reports of a surprising process for the intermolecular addition of aryl halides to aldehydes via transition-metal catalysis.…”

Total Syntheses of (+)‐Aquatolide and Related Humulanolides

“…[26] Oxidation of 14 with the Dess-Martin reagent provided the aldehyde 15,w hich was subjected to Takai-Utimoto olefination [27,28] to afford the alkenyl iodide 16 with high E selectivity. [23,24] Considering the highly strained structure of the 11-membered ring, the high yield of 10 was remarkable. In this reaction, the iodoalkene moiety remained intact.…”