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. 2017 Sep 13;139(36):12374-12377.
doi: 10.1021/jacs.7b06286. Epub 2017 Sep 1.

Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems

Matthew J Kier  1 , Robert M Leon  1 , Natasha F O'Rourke  1 , Arnold L Rheingold  2 , Glenn C Micalizio  1
Affiliations

Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems

Matthew J Kier et al. J Am Chem Soc. .

Abstract

Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring-formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with β- or γ-dicarbonyl systems. These processes embrace a variant of metallacycle-mediated annulation chemistry where initial alkyne-carbonyl coupling is followed by a second, now intramolecular, stereoselective C-C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Introduction.
Figure 2
Figure 2
Intermolecular alkyne–dicarbonyl coupling reactions.
Figure 3
Figure 3
Annulation reactions involving diketones. Reaction conditions: (a) Ti(Oi-Pr)4, i-PrMgCl, THF, −78 to −20 °C, then aq NaHCO3; (b) Ti(Oi-Pr)4, i-PrMgCl, THF, −78 to −20 °C (or rt), then t-BuOOH, then aq NaHCO3.
Figure 4
Figure 4
Exploring synthesis design with the alkyne–dicarbonyl annulation reaction–control of relative stereochemistry in the ring-forming process, and application to the synthesis of fused tricyclic carbocycles containing a fully substituted cyclopentene or cyclopentane, and including up to six contiguous stereocenters. Reaction conditions: (a) Ti(Oi-Pr)4, i-PrMgCl, THF, −78 to −20 °C, then aq NaHCO3; (b) Ti(Oi-Pr)4, i-PrMgCl, THF, −78 to −20 °C, then t-BuOOH, then aq NaHCO3.
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