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. 2014 May 14;136(19):7092-100.
doi: 10.1021/ja502280w. Epub 2014 Apr 29.

Congested C-C bonds by Pd-catalyzed enantioselective allyl-allyl cross-coupling, a mechanism-guided solution

Michael J Ardolino  1 , James P Morken
Affiliations

Congested C-C bonds by Pd-catalyzed enantioselective allyl-allyl cross-coupling, a mechanism-guided solution

Michael J Ardolino et al. J Am Chem Soc. .

Abstract

Under the influence of a chiral bidentate diphosphine ligand, the Pd-catalyzed asymmetric cross-coupling of allylboron reagents and allylic electrophiles establishes 1,5-dienes with adjacent stereocenters in high regio- and stereoselectivity. A mechanistic study of the coupling utilizing reaction calorimetry and density functional theory analysis suggests that the reaction operates through an inner-sphere 3,3'-reductive elimination pathway, which is both rate-defining and stereodefining. Coupled with optimized reaction conditions, this mechanistic detail is used to expand the scope of allyl-allyl couplings to allow the generation of 1,5-dienes with tertiary centers adjacent to quaternary centers as well as a unique set of cyclic structures.

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Figures

Figure 1
Figure 1
Reaction rates with 0.1% (R)-4 (blue line), 5% Pd2(dba)3 + 10% (R)-L1 (red line), and 0.1% (R)-4 + 15% dba (green line) under standard conditions as described in Table 1.
Figure 2
Figure 2
Reaction progress kinetic analysis of the Pd-catalyzed coupling of allylB(pin) and allyl carbonate 1a with (R)-4 as described in Table 1. (A) Reaction rate versus [1a] for 0.1% (R)-4 (blue line) and 0.05% (R)-4 (red line). (B) Heat flow versus time for the standard amount (0.5 M, blue line) versus excess (1.0 M, red line) of 1a. (C) Heat flow versus time for the standard amount (0.6 M, blue line) versus excess (1.2 M, red line) of allylB(pin). (D) Reaction rate versus [1a] for the standard (0.5 M 1a, 0.6 M allylB(pin), ‘excess’ allylB(pin)= 0.1 M, blue line) versus modified initial concentrations (0.3 M 1a, 0.4 M allylB(pin), ‘excess’ allylB(pin)= 0.1 M, red line).
Figure 3
Figure 3
DFT computed potential energy surface to distinguish between the inner- and outer sphere pathways as well as the preferred mode of reductive elimination to give experimentally observed (S)-3a, (Si-pathway, blue), (R)-3a, (Re-pathway, red), or linear product (green). All calculations performed at the B3LYP-PCM(THF)/LANL2DZ-6-31G** level of theory, some hydrogen atoms were removed from the displayed structures for clarity. Energies relative to GS1 + T.
Figure 4
Figure 4
(A) Optimized structure and coordinates for TS3,3’ Si A (B) Activation energies relative to GS2 for other possible allyl conformations during 3,3’-reductive elimination. B3LYP-PCM(THF)/LANL2DZ-6-31G** (333.15 K).
Figure 5
Figure 5
Calculated activation free energy for transmetallation of fluoride-activated 9 (W, left) and 19 (X, right) to GS1. B3LYP-PCM(THF)/LANL2DZ-6-31G** (298.15K).
Scheme 1
Scheme 1. Pd-Catalyzed Allyl-Allyl Couplings
Scheme 2
Scheme 2. Proposed Catalytic Cycle
Scheme 3
Scheme 3. Labeling Studies of Reaction Stereochemistry
Scheme 4
Scheme 4. Stereochemical Model for 3,3'-Reductive Elimination
Scheme 5
Scheme 5. Initial Results for Congested Bond Formations
Scheme 6
Scheme 6. Increased Reactivity with α,α-Disubstituted Allylboron Nucleophiles
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