Inversion of Enantioselectivity in Allene Gas versus Allyl Acetate Reductive Aldehyde Allylation Guided by Metal-Centered Stereogenicity: An Experimental and Computational Study

Abstract

The use of gaseous allene as an allyl pronucleophile in enantioselective aldehyde reductive coupling is described. Notably, using the same antipode of chiral ligand, (S)-tol-BINAP, an inversion of enantioselectivity is observed for allene vs allyl acetate pronucleophiles. Experimental and computational studies corroborate intervention of diastereomeric π-allyliridium-C,O-benzoate complexes, which arise via allene hydrometalation (from a pentacoordinate iridium hydride) vs allyl acetate ionization (from a square planar iridium species).

Graphical Abstract

In connection with longstanding efforts to use abundant chemical feedstocks as pronucleophiles in metal-catalyzed carbonyl reductive coupling,^1f a diverse suite of enantioselective C-C couplings was developed in our laboratory.^1,2 A distinguishing feature of these processes resides in the use of inexpensive terminal reductants (e.g. H₂, 2-PrOH) or, more ideally, dual use of alcohols as carbonyl proelectrophiles and reductants in carbonyl addition via hydrogen auto-transfer.¹ Given the high occurrence of allenes as constituents in the C3, C4 and C5 petroleum cracking fractions (Figure 1), these patterns of reactivity were applied to the first (2007) allene-carbonyl reductive couplings to furnish homoallylic alcohols (Figure 2).³ Using allene, methylallene and dimethylallene as pronucleophiles, products of carbonyl allylation, crotylation and tert-prenylation were obtained in reactions conducted from either the alcohol or aldehyde oxidation level.³ Shortly thereafter (2009), we reported the first enantioselective reactions of this type using dimethyl allene.^4a Following this and other catalytic enantioselective allene-carbonyl additions developed in our laboratory,^4,5 Buchwald reported an allene-ketone reductive coupling mediated by (MeO)₂MeSiH.⁶

Figure 1.

Allene feedstocks formed in petroleum cracking.

Figure 2.

Milestones in metal-catalyzed allene-carbonyl reductive coupling and related hydrogen auto-transfer processes.

In this account, we report the first enantioselective allene-aldehyde reductive couplings.⁷ Additionally, we demonstrate that using the same antipode of chiral ligand, (S)-tol-BINAP, an inversion of enantioselectivity is observed for carbonyl allylations that employ gaseous allene vs allyl acetate as pronucleophile solely in response to stereogenicity at iridium.^8,9 Experimental and computational studies corroborate intervention of diastereomeric π-allyliridium-C,O-benzoate complexes, which arise via allene hydrometalation (from a pentacoordinate iridium hydride) vs ionization of allyl acetate (from a square planar iridium species).

An initial series of experiments were conducted in which a sealed reaction vessel back-filled with gaseous allene 1a and charged with aldehyde 2a (100 mol%), 2-propanol (200 mol%), THF (0.4 M) and an iridium catalyst (5 mol%) were heated to 60 °C (Table 1) for 24 hours. It was determined that the (S)-tol-BINAP-modified iridium catalyst, Ir-V, delivered the desired product 3a with the highest levels of enantioselectivity as the (R)-enantiomer, which is the opposite enantiomer observed in corresponding carbonyl allylations mediated by allyl acetate 1b.¹⁰ This surprising result compelled us to evaluate the diastereomeric composition of the iridium catalyst Ir-V, which is easily accomplished via LCMS due to the chromatographic stability of π-allyliridium-C,O-benzoates (Figure 3). The catalyst prepared from allyl acetate is enriched in diastereomer D, which, as indicated by experiment and computation, is the thermodynamically most stable isomer. In contrast, the catalyst recovered from the reaction mixture using allene or prepared from allene itself is enriched in diastereomer C. It was posited that use of Ir-V derived from allene would improve enantioselectivity in the allene-mediated allylation of aldehyde 2a. Indeed, an increase from 86% to 92% ee in the formation of homoallylic alcohol 3a was observed (Table 1).

Table 1.

Selected optimization experiments in the enantioselective reductive coupling of allene 1 with aldehyde 2a and divergent enantioselectivity observed upon use of allyl acetate vs allene pronucleophiles.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis.

^bPhMe (0.4 M).

^cPhMe (0.1 M).

^d(S)-Ir-V derived from allene. See Supporting Information for experimental details.

Figure 3.

Diastereomeric composition of the (S)-Ir-V and calculated thermodynamic stabilities.

Using catalyst (S)-Ir-V derived from allene, the scope of the allene-mediated reductive aldehyde allylation mediated by 2-propanol was explored (Table 2). Diverse aryl aldehydes 2a-2i and heteroaryl aldehydes 2j-2p were converted to the corresponding homoallylic alcohols 3a-3p in good yield with uniformly high levels of enantioselectivity. As illustrated by the formation of adduct 3d, due to the mild reaction conditions, sensitive functional groups such as pinacol boronates are tolerated. The formation of 3l, which incorporates an unprotected indole nitrogen, also is notable. The α,β-unsaturated aldehyde 2q, as well as linear and branched aliphatic aldehydes 2r and 2s also participate in highly enantioselective allylation. Allene-mediated allylation of 2a mediated by d₈-2-propanol delivers deuterio-3a (eq. 1).¹¹ The pattern of deuterium incorporation corroborates reversible allene hydrometalation with incomplete regiocontrol. The relatively low levels of deuterium incorporation are attributed to reversibility of the hydrometalation event and H/D-exchange with adventitious water.¹²

Table 2.

Enantioselective iridium-catalyzed reductive coupling of gaseous allene 1a with aldehydes 2a-2s mediated by 2-propanol.^a

^aYields are of material isolated by silica gel chromatography. The catalyst (S)-Ir-V prepared from allene was used. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for experimental details.

(eq. 1)

The experimental data suggest that the observed divergence in enantioselectivity in reactions of allene vs allyl acetate is due to intervention of diastereomeric π-allyliridium-C,O-benzoate complexes C and D, which arise via allene hydrometalation (from an pentacoordinate iridium hydride) vs ionization of allyl acetate (from a square planar iridium species), respectively (Figure 4).^13,14 To challenge the veracity of our hypothesis, we then turned our efforts to density functional theory (DFT) calculations.¹⁵ The reaction pathways to form the π-allyliridium complexes under the different experimental conditions were first computed. When allyl acetate pronucleophile is used, the π-allyliridium is formed via coordination of allyl acetate to the C,O-benzoate complex 4 followed by ionization (TS1, Figure 5A). Although the common intermediate 4 can potentially lead to all four diastereomeric π-allyl complexes, formation of D is kinetically and thermodynamically favored (see Figure S2 for less favorable pathways to A and B). The relatively low barrier of TS1D suggests a reversible ionization process. The thermodynamically more stable complex D is operative in the subsequent aldehyde addition step (vide infra). On the other hand, π-allyliridium complexes derived from allene are formed via hydrometalation from a square pyramidal iridium hydride (6C or 6D, Figure 5B). DFT calculations suggest 6C is thermodynamically more stable than 6D, and subsequent allene coordination to form 7C and hydrometalation via TS3C are both very facile. Therefore, π-allyl complex C is formed preferentially from allene hydrometalation.

Figure 4.

Hypothesis for enantiodivergence in aldehyde allylations mediated by gaseous allene vs allyl acetate.

Figure 5.

Computed energy profiles of the kinetic pathways leading to diastereomers D and C and, therefrom, (S)-and (R)-product enantiomers, respectively.

The calculated transition states for allylation of aldehyde 2a by the diastereomeric complexes C and D provide further insight into the origins of enantiodivergence. Complexes C and D are supported by the same antipode of the (S)-tol-BINAP ligand, but their stereogenicity at iridium is opposite. Therefore, examination of the transition states for carbonyl addition will reveal whether enantioselectivity is influenced more by the chirality of the metal center¹⁶ or the bisphosphine ligand. The aldehyde addition with C and D occurs by way of Zimmerman-Traxler-type transition states that place the Ar group of the aldehyde in a pseudo-equatorial position (Figure 6).¹⁷ In the reaction with D, addition to the (Si)-face of the aldehyde (TS2D-S) to form (S)-3a is 2.2 kcal/mol more favorable than the (Re)-face addition (TS2D-R) to form (R)-3a. TS2D-R is destabilized by the 1,3-diaxial interactions between the aldehyde hydrogen and the benzene ring of the benzoate, which is co-planar with the aldehyde. In TS2D-S, the axial aldehyde hydrogen and the benzoate are on opposite faces of the chair, which relieves steric repulsion. In the allylation transition states with complex C (Figure 6B), because the stereogenicity at iridium is inverted, the (S)-selective transition state (TS2C-S) is now destabilized by the 1,3-diaxial interactions between the aldehyde hydrogen and the benzoate. As such, the most favorable transition state from C is TS2C-R, which eventually leads to the (R)-enantiomer of the homoallylic alcohol product 3a.

Figure 6.

Enantioselectivity-determining aldehyde allylation transition states with π-allyliridium complexes D and C. Activation free energies are with respect to D and C, respectively. The (S)-tol-BINAP ligands are omitted for clarity

In summary, we report the first catalytic enantioselective aldehyde allylations mediated by gaseous allene. These processes exploit a feedstock pronucleophile (allene) in combination with a feedstock reductant (2-propanol) under non-cryogenic conditions with acetone as the sole stoichiometric byproduct. Remarkably, use of allene vs allyl acetate as pronucleophile results in an inversion of enantioselectivity using the same antipode of chiral ligand, (S)-tol-BINAP. The collective experimental and computational data corroborate intervention of diastereomeric π-allyliridium-C,O-benzoate complexes, which arise via allene hydrometalation (from a pentacoordinate iridium hydride) vs allyl acetate ionization (from a square planar iridium species). These data should facilitate the design of related chiral-at-metal complexes for enantioselective catalysis by providing insight into the structural and interactions features of the catalyst that influence enantioselectivity. More broadly, these studies and other work from our laboratory demonstrate how reactions that traditionally have employed organometallic reagents may now be conducted catalytically in the absence of premetalated reagents using abundant feedstocks.^1f,18