All-Heteroatom-Substituted Carbon Spiro Stereocenters: Synthesis, Resolution, Enantiomeric Stability, and Absolute Configuration

Abstract

Chiral tetra-heterosubstituted methanes (i.e., tetraoxa and azatrioxa carbon spiro stereocenters) are synthesized under CpRu catalysis, using cyclic carbonates and carbamates as substrates and α-diazo-β-ketoesters as reagents. Single enantiomers, isolated by chiral stationary phase chromatography, display chiroptical properties, from g_abs ∼10^-5 to ∼10^-4, which, together with TD-DFT calculations, provide robust absolute configuration assignments. Crystalline spiro diastereomers were also obtained, confirming further the structural and configurational assignments. Using enantioselective dynamic chromatography, remarkable enantiomerization barriers were determined for the ortho-carbonates and ortho-carbamates, with values of up to 27.6 and 34.6 kcal/mol (half-lives 227 days and >84,000 years at 25 °C, respectively). DFT further elucidates the origin of this large difference pointing toward preferred C-O or C-N bond cleavages in the rate-determining step of the S_N1-like mechanism.

1

Carbon stereocenters. (A) Type Cabcd (priority a > b > c > d, S and R enantiomers) and key examples 3–7. (B) Spiro C­(ab)­(a′b′) (a > a′ > b > b′) and unique configurationally labile diazadithia 8. (C) All-heteroatom-substituted spiro stereocenters: tetraoxa 9 and azatrioxa 10.

2

Ortho-carbonates. (A) Synthetic procedure (methods a and b) and substrate scope: 9a to 9d. Isolated yields (NMR yields in parentheses). (B) CSP-HPLC analysis of 9a (racemic and enantiomers) and ECD spectra of (−)-9a (blue) and (+)-9a (red) with absorption spectra (underlying filled curve) in the UV range. Right panel: comparison between experimental and calculated ECD spectra. (C) Enantioselective DGC (140–180 °C) and Eyring analysis of the temperature-dependent kinetics. The orange band represents the confidence interval of the linear regression with a confidence level of 95%. (D) Activation parameters for the enantiomerization of rac-9a (Figure S12).

3

Ortho-carbamates. (A) Synthetic procedure (methods a and b, see Figure for details) and reactivity scope: 10a to 10h. Isolated yields (NMR yields in parentheses). (B) ECD spectra of (−)-10a (blue) and (+)-10a (red) with absorption spectra (underlying filled curve) in the UV range. Comparison between experimental and calculated ECD spectra and configuration assignment. (C) Enantioselective DGC of 10b (105–125 °C) and Eyring analysis of the temperature-dependent kinetics. The orange band represents the confidence interval of the linear regression with a level of confidence of 95%.

4

(A) Zwitterionic intermediates I to IV obtained by the dissociation of the four possible C–O or C–N bonds in 9a and 10a. (B) Energy scans following the dissociation of the four bonds. (C, D) Suggested enantiomerization mechanisms exemplified for 9a and 10a, with calculated ΔG (black) or ΔH (blue; H atoms of Boc are removed for clarity).

5

(A) Synthesis of 9e as a 1.2:1 mixture of diastereomers. Chromatographic separation into (2S,3a′R,4′R,6′R,7a′S)-9e′ (first eluted, CCDC 2406355) and (2R,3a′R,4′R,6′R,7a′S)-9e′′ (second eluted, CCDC 2406356). (B) Synthesis of 10i and 10j as 1.4:1 and 1.8:1 mixtures of diastereomers. Preparative TLC separation into (5S,8S)-10i′ (CCDC 2440356)/10i′′ and 10j′/10j′′ (first/second eluted). (C) ECD spectra of 9e′ (blue) and 9e′′ (red) with absorption spectra (underlying filled curve) in the UV range. (D) ECD spectra of 10i′ (blue) and 10i′′ (red) with absorption spectra (underlying filled curve) in the UV range.