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Published in final edited form as: Tetrahedron Lett. 2021 Sep 8;82:153392. doi: 10.1016/j.tetlet.2021.153392

Sequential iodine-mediated diallylsilane rearrangement/asymmetric dihydroxylation: Synthesis and reactions of enantioenriched oxasilacycles

Christopher R Myers a, Paul Spaltenstein a, Lauren K Baker a, Cody L Schwans a, Timothy B Clark b, Gregory W O’Neil a,*
PMCID: PMC8714181  NIHMSID: NIHMS1742612  PMID: 34970013

Abstract

Products from an iodine-mediated diallylsilane rearrangement were taken into an asymmetric dihydroxylation (AD) reaction resulting in the formation of diastereomeric 6-membered oxasilacycles. Removal of the epimeric stereocenter among this mixture of diastereomers by elimination of iodine produced a single enantioenriched cyclic allyl silyl ether. The resulting allyl silane was then successfully engaged in several further transformations, providing an alternative means to prepare useful intermediates for enantioselective synthesis.

Keywords: Diallylsilane, Rearrangement, Asymmetric Dihydroxylation, Oxasilacycle, Allylsilane

Our group recently reported the discovery of an iodine-mediated rearrangement of diallylsilanes.1 The reaction results in the formation of a new carbon-carbon bond (red, Scheme 1) and a new stereocenter (*, racemic), proceeding presumably through a cationic intermediate 1. Intramolecular allylation of the cation then ultimately leads to the formation of iodosilane 2. Compound 2 is not isolated, rather addition of an amine base (e.g. triethylamine or Hünig’s base) and an alcohol to the reaction flask gives stable silyl ether products 3 in good yields. Compared to other similar diallylsilane rearrangements,2–4 this iodine mediated process is attractive in generating synthetic intermediates containing multiple functional group handles (e.g. alkyl iodide, alkene) allowing for further functionalizations. For instance, 3 can be alkylated with methyl malonate, substituted by nitrogen nucleophiles, or engaged in olefin metathesis.1

Scheme 1.

Scheme 1.

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Iodine-mediated diallylsilane rearrangement and further transformations.

In an attempt to extend this methodology to asymmetric synthesis, we envisioned performing a reaction that would enantioselectively incorporate a new stereocenter on the rearranged products, thereby producing enantiopure diastereomers that might be separable. Herein we report results from the asymmetric dihydroxylation (AD) of iodine-mediated diallylsilane rearrangement products 3. The reaction generates diastereomeric and enantioenriched 6-membered cyclic silylethers that proved to be partially separable by flash chromatography on silica. Moreover, a method was developed for the efficient elimination of iodine post AD, resulting in cyclic allyl silanes that could be engaged in a number of further transformations.

Our studies focused on reactions of diphenylsilyl rearranged product 5, since we found diallyldiphenyl silane (4) to be best for our iodine-mediated rearrangement (Scheme 2).1 Compound 5 has been obtained consistently in high yields on multi-gram scale by treatment of 4 with iodine in DCM at room temperature for 3 h followed by the addition of triethylamine and isopropanol. Among the possible alcohols that could be used to trap the intermediate iodosilane initially formed (ref. Scheme 1), isopropanol is preferred because it provides sufficient stability to the product (e.g. stable to hydrolysis) as well as being low-boiling allowing for easy removal of any excess alcohol under vacuum. Dihydroxylation of 5 with AD-mix-β5,6 occurred with concomitant cyclization and loss of isopropanol, giving cyclic silyl ether 7 as an expected 1:1 mixture of 4R,6R- and 4S,6R-diastereomers. Using flash chromatography on silica, samples of each pure diastereomer could be isolated.7 NMR analysis then allowed us to differentiate between the cis-substituted R,R-7 and the trans-substituted S,R-7 compounds we had obtained. For instance, the (4R,6R)-stereoisomer displayed a characteristic crosspeak in its NOESY spectrum between protons at positions 4 and 6 indicative of a cis arrangement whereas this signal was absent in the NOESY spectrum for the (4S,6R)-stereoisomer (Scheme 2).8 In some cases small amounts of the non-ring closed diol 6 were also isolated after chromatography. Placement of this compound under vacuum (designed to promote cyclization by removal of isopropanol as it is formed) produced 7 enriched in the 4S,6R-trans-stereoisomer. This presumably reflects the higher energy of this compound relative to cis-7 (i.e. one group axial and one equatorial compared to both being equatorial), making it slower to form and providing further support for our NMR assignments.

Scheme 2.

Scheme 2.

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Iodine rearrangement/asymmetric dihydroxylation synthesis of enantioenriched and diastereomeric cyclic silyl ethers 7 that were partially separable by chromatography on silica.

Despite being partially separable by chromatography on silica, significant amounts (typically >50% of the total mass after one round of chromatography) of mixed fractions containing both diastereomers of compound 7 were also obtained. While repeated chromatography can increase the yield of isolated R,R-7 and S,R-7 which might be attractive if both stereoisomers are desired, we also envisioned that this mixture could be converted to a single enantioenriched compound by removal of the epimeric stereocenter via elimination of iodine. Unfortunately, standard E2-elimination conditions using potassium tert-butoxide (KOtBu)9 or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)10 failed with or without protecting the primary alcohol (e.g. TBS-7). Elimination with in situ prepared Ni(0)11 was partially successful, however resulted in the formation of significant unidentified byproducts. Ultimately, it was found that a two-step procedure involving conversion to the corresponding selenoether 8 followed by selenoxide elimination12 gave the desired product 9 (or TBS-9) in 78% yield from 7 (Scheme 3).

Scheme 3.

Scheme 3.

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Convergence of diastereomeric compounds 7 to cyclic allylsilane 9 by iodine elimination.

We anticipated that allylsilane 9 could be engaged in a number of subsequent nucleophilic addition reactions.13,14 As an initial demonstration, we were able to convert 9 (or TBS-9) into products 10, 11, and 12 through formation of a new C-H bond, C-C bond, and C-O bond respectively (Scheme 4). More specifically, treatment of 9 with TBAF in MeCN resulted in protodesilylation and formation of diol 10 in 90% yield. A titanium-mediated allylation between TBS-9 and benzaldehyde dimethyl acetal gave 11 in 60% yield, albeit as a ~2:1 mixture of diastereomers.15 Standard Tamao-oxidation conditions (e.g. KF, H2O2 or KHF2, mCPBA)16,17 failed to reliably produce 12, instead resulting in significant decomposition. The use of mCPBA by itself, however, worked nicely, giving 12 in 70% yield. This reaction presumably occurs by acidic opening of the intermediate epoxide 13 rather than nucleophilic attack at silicon associated with the Tamao-oxidation.18 Compounds 1219 and 1020 are known and proven to be useful synthetic intermediates. Our method provides an alternative and flexible (i.e. the S-enantiomer could be obtained by using AD-mix-α)5,6 approach that also avoids the use of pyrophoric reagents to access these important compounds.

Scheme 4.

Scheme 4.

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Further transformations of allylsilane 9 via C-H, C-C, and C-O bond formation.

In sum, the combination of iodine-mediated diallylsilane rearrangement followed by asymmetric dihydroxylation can be used to generate diastereomeric and enantioenriched 6-membered oxasilacycles that were partially separable by chromatography on silica. Rather than separating, this mixture could be converted to a single compound by elimination of iodine and formation of an enantioenriched allyl silyl ether. This cyclic allyl silyl ether was then further transformed via the formation of new C-H, C-C, or C-O bonds. Altogether, the sequence represents an approachable and high yielding method for the enantioselective preparation of polyhydroxylated intermediates. Efforts are currently aimed at optimizing and showcasing this strategy in the synthesis of important complex target molecules.

Supplementary Material

1

Highlights for: Sequential iodine-mediated diallylsilane rearrangement/asymmetric dihydroxylation: synthesis and reactions of enantioenriched oxasilacycles.

  • A new sequence for enantioenriched oxasilacycle synthesis is reported.

  • Iodine-promoted diallylsilane rearrangement provides suitable substrates for AD.

  • Elimination of iodine produces enantioenriched cyclic allyl silanes.

  • These allyl silanes can be further transformed by reactions with electrophiles.

Acknowledgments

Financial support from the National Institutes of Health (R15 GM119034) and the American Chemical Society Petroleum Research Fund (62228-UR1) is gratefully acknowledged.

Footnotes

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Supplementary Material

Analytical data and experimental procedures for compounds 5, 7–12.

graphic file with name nihms-1742612-f0002.jpg

References and notes

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Supplementary Materials

1
NIHMS1742612-supplement-1.pdf (1MB, pdf)

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