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. 2020 Aug 7;85(15):9464-9474.
doi: 10.1021/acs.joc.0c01132. Epub 2020 Jul 22.

Utilization of the Thorpe-Ingold Effect in the Synthesis of Cyclooctanoid Ring Systems via Anionic 6- exo- dig Cyclization/Claisen Rearrangement Sequence

Weston C DeLomba  1 , Elizabeth A Stone  1 , Kimberly A Alley  1 , Victoria Iannarone  1 , Emily Tarsis  1 , Sami Ovaska  1 , Timo V Ovaska  1
Affiliations

Utilization of the Thorpe-Ingold Effect in the Synthesis of Cyclooctanoid Ring Systems via Anionic 6- exo- dig Cyclization/Claisen Rearrangement Sequence

Weston C DeLomba et al. J Org Chem. .

Abstract

We demonstrate a facile approach for the synthesis of gem-disubstituted cyclooctanoids, a motif found in several biologically active compounds. Appropriately substituted 1-alkenyl-5-pentyn-1-ols bearing gem-dialkyl substituents at either the C2, C3, or C4 position serve as useful precursors to a number of cyclooct-4-enone derivatives via a tandem, microwave-assisted oxyanionic 6-exo-dig cyclization/Claisen rearrangement reaction. gem-Dialkyl activation is necessary for these reactions to occur, as unactivated 1-alkenyl-5-pentyn-1-ols fail to undergo 6-exo-dig cyclization under the conditions employed. Further application of the methodology to the corresponding gem-dialkoxy system was also explored to facilitate access to more complex carbocycles.

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Figures

Figure 1.
Figure 1.
Representative examples of cyclooctanoid natural products highlighting the prevalence of gem-dimethyl groups (blue).
Scheme 1.
Scheme 1.. Synthetic Strategies for the Construction of 7- and 8-Membered Ring Systems via Tandem exo-dig Cyclization/Claisen Rearrangement Reactions
Scheme 2.
Scheme 2.. Synthesis of Cyclooctenones 5 and 22*
* Reagents and conditions: (a) (COCl)2, DMSO, then TEA, DCM, −78 °C; (b) cyclohexenyllithium, then NH4Cl, −78 °C, Et2O; (c) TBAF, THF; (d) 10 mol % LHMDS, μwave heating, 210 °C, PhOEt, 1 h; (e) n-BuLi, then TMSCl, then aq HCl, THF, −78 °C; (f) (COCl)2, DMSO, then TEA, DCM, −78 °C; (g) cyclopentenyllithium, then NH4Cl, −78 °C, Et2O; (h) TBAF, THF; (i) 10 mol % LHMDS, μwave heating, 210 °C, PhOEt, 1 h.
Scheme 3.
Scheme 3.. Preparation of Cyclooctenone 38.A
AReagents and conditions: (a) (COCl)2, DMF, DCM, rt; (b) tris(trimethylsilyloxy)ethylene, TEA, THF, 0 °C, then μwave heating, 100 °C, 10 min; (c) BzCl, TEA, cat. DMAP, DCM, 0 °C; (d)trimethyl orthoformate, cat. TsOH, MeOH, rt; (e) LHMDS, then TMSCl, THF, −78 C; (f) MeLi, Et2O, −78 C; (g) (COCl)2, DMSO, then TEA, DCM, −78 °C; (h) cyclopentenyllithium, then H2O, −78 °C, Et2O; (i) TBAF, THF; (j) 20 mol % LHMDS, 10 mol % TEA, μwave heating, 210 °C, PhOEt, 2.5 h.
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