A unified approach for divergent synthesis of contiguous stereodiads employing a small boronyl group

Abstract

Acyclic contiguous stereocenters are frequently seen in biologically active natural and synthetic molecules. Although various synthetic methods have been reported, predictable and unified approaches to all possible stereoisomers are rare, particularly for those containing non-reactive hydrocarbon substituents. Herein, a β-boronyl group is employed as a readily accessible handle for predictable α-functionalization of enolates with either syn or anti selectivity depending on reaction conditions. Contiguous tertiary-tertiary and tertiaryquaternary stereocenters are thus accessed in generally good yields and diastereoselectivity. Based on experimental and computational studies, mechanism for syn selective alkylation is proposed, and Bpin (pinacolatoboronyl) behaves as a smaller group than most carboncentered groups. The synthetic utility of this methodology is demonstrated by preparation of several key intermediates for bioactive molecules.

How Big is the Pinacol Boronic Ester as a Substituent?

“…Interestingly, like the A-values, the ligand cone angle appears to capture the planar oxygenboron-oxygen motif, but not the ligand backbone. [9] The percent buried volume (%V Bur ) steric parameter describes the percentage of a sphere (r = 3.5 ) around the metal centre that is occupied by a given ligand and we postulated that it might better incorporate the effect of the diol backbone. [25] The percent buried volume values, using fully optimized C-R distances to capture differences in bond lengths as noted above (see Table S3 in ESI), are provided in Figure 2 and show the same trend as the experimental Diels-Alder Figure 2.…”

Stereoselective Installation of Five Contiguous Stereogenic Centers in a Double Aldol–Tishchenko Cascade and Evaluation of the Key Transition State through DFT Calculation

“…To further test the synthetic utility of this methodology, we applied our reaction conditions to more challenging acyclic substrates using the 2-butanone derived sulfinimine ( 1c ) (Scheme ). This substrate clearly possesses two possible sites for deprotonation: at the kinetically favored methyl carbon and the thermodynamically favored methylene.…”

How Big is the Pinacol Boronic Ester as a Substituent?

“…Measurements of the ligand cone angle θ (at a normalized M‐L bond length of 2.28 Å, using the Solid‐G [26] and Exact Cone Angle [27] implementations, Figure 2 and Table S3 in ESI) predict that Bpin and methyl groups have comparable sizes, again, in contrast to the experimental observations in the Diels–Alder reaction. Interestingly, like the A‐values, the ligand cone angle appears to capture the planar oxygen‐boron‐oxygen motif, but not the ligand backbone [9] . The percent buried volume (%V Bur ) steric parameter describes the percentage of a sphere ( r =3.5 Å) around the metal centre that is occupied by a given ligand and we postulated that it might better incorporate the effect of the diol backbone [25] .…”

“…ethylene glycol) give much higher E selectivity (>95:5) as a result of the reduced gauche interactions in TS B [7] . However, two diastereoselective reactions have recently been reported, whose stereochemical outcomes are attributed to the Bpin group being in turn larger [8] and smaller [9] than a phenyl group (Scheme 1 B). We became interested in the question of Bpin's size during a recent study which engaged the dienyl tertiary pinacol boronic ester 1 with 4‐phenyl‐3 H ‐1,2,4‐triazole‐3,5(4 H )‐dione in a Diels–Alder cycloaddition reaction (Scheme 1 C).…”

“…Interestingly, like the A-values, the ligand cone angle appears to capture the planar oxygenboron-oxygen motif, but not the ligand backbone. [9] The percent buried volume (%V Bur ) steric parameter describes the percentage of a sphere (r = 3.5 ) around the metal centre that is occupied by a given ligand and we postulated that it might better incorporate the effect of the diol backbone. [25] The percent buried volume values, using fully optimized C-R distances to capture differences in bond lengths as noted above (see Table S3 in ESI), are provided in Figure 2 and show the same trend as the experimental Diels-Alder A-values, [12] calculated cone angle [26] and percent buried volume [25] for different substituents.…”