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. 2017 Nov 27;9(6):1473-1480.
doi: 10.1039/c7sc04691j. eCollection 2018 Feb 14.

Stereoselective construction of sterically hindered oxaspirocycles via chiral bidentate directing group-mediated C(sp3)-O bond formation

Yechan Kim  1   2 , Seoung-Tae Kim  1   2 , Dahye Kang  1   2 , Te-Ik Sohn  1   2 , Eunyoung Jang  1   2 , Mu-Hyun Baik  1   2 , Sungwoo Hong  1   2
Affiliations

Stereoselective construction of sterically hindered oxaspirocycles via chiral bidentate directing group-mediated C(sp3)-O bond formation

Yechan Kim et al. Chem Sci. .

Abstract

The systematic investigation of chiral bidentate auxiliaries has resulted in the discovery of a chiral 2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine-derived directing group that enables stereoselective palladium(ii)-catalyzed intramolecular C(sp3)-O bond formation. This new chiral directing group exhibited high reactivity in the activation of methylene C(sp3)-H bonds with excellent levels of stereoselectivity (a diastereomeric ratio of up to 39 : 1), which allowed the construction of a wide range of oxaspirocycles. Mechanistic investigations were also conducted to elucidate the reaction mechanism and understand the origin of the diastereoselectivity. DFT calculations suggest that only modest levels of diastereoselectivity are accomplished at the rate-determining C-H metalation-deprotonation step and the d.r. is further enriched at the reductive elimination step.

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Figures

Scheme 1
Scheme 1. Different disconnections (conjugate addition vs. β-C–H functionalization) for the stereoselective synthesis of oxacycles.
Fig. 1
Fig. 1. Chemical structures of effective and ineffective DGs (3a–3j). The X-ray crystal structure of 2a.
Scheme 2
Scheme 2. Application of the asymmetric synthesis of the DGAT1 inhibitor.
Scheme 3
Scheme 3. The proposed SN2-type reductive elimination mechanism.
Fig. 2
Fig. 2. The proposed catalytic cycle of chiral bidentate directing group-mediated C(sp3)–O bond formation.
Fig. 3
Fig. 3. The energy profile of the proposed mechanism.
Fig. 4
Fig. 4. The DFT-optimized geometry of A3-TS (left) and A3-TS′ (right). Nonessential hydrogen atoms are omitted for clarity.
Fig. 5
Fig. 5. DFT-optimized geometry of A5 (left) and B5 (right). Nonessential hydrogen atoms are omitted for clarity.
Fig. 6
Fig. 6. DFT-optimized geometry of A7/B7 and A7-TS/B7-TS with selected distances in Å. Nonessential hydrogen atoms are omitted for clarity.
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