Chiral-at-Ruthenium-SEGPHOS Catalysts Display Diastereomer-Dependent Regioselectivity: Enantioselective Isoprene-Mediated Carbonyl tert-Prenylation via Halide Counterion Effects

Abstract

The first correlation between metal-centered stereogenicity and regioselectivity in a catalytic process is described. Alternate pseudo-diastereomeric chiral-at-ruthenium complexes of the type RuX(CO)[η³-prenyl][(S)-SEGPHOS] form in a halide-dependent manner, and display divergent regioselectivity in catalytic C-C couplings of isoprene to alcohol proelectrophiles via hydrogen auto-transfer. Whereas the chloride-bound ruthenium-SEGPHOS complex prefers a trans-relationship between the halide and carbonyl ligands and delivers products of carbonyl sec-prenylation, the iodide-bound ruthenium-SEGPHOS complex prefers a cis-relationship between the halide and carbonyl ligands and delivers products of carbonyl tert-prenylation. The chloride- and iodide-bound ruthenium-SEGPHOS complexes were characterized in solution and the solid phase by ³¹P NMR and X-ray diffraction. DFT calculations of the iodide-bound catalyst implicate a Curtin-Hammett-type scenario in which the transition states for aldehyde coordination from an equilibrating mixture of sec- and tert-prenylruthenium complexes is rate- and product-determining. Control of metal-centered diastereoselectivity has unlocked the first catalytic enantioselective isoprene-mediated carbonyl tert-prenylations.

Graphical Abstract

Introduction

Halide counterions can profoundly influence metal-catalyzed reactions, yet the precise nature of their effect is seldom understood.¹ In recent work,² experimental and computational analyses of the halide-bound ruthenium-JOSIPHOS complexes, RuX(CO)(η³-C₃H₅)(JOSIPHOS), where X = Cl, Br, I, revealed that the enhanced enantioselectivities of iodide-containing catalysts emanate from iodide’s capacity to promote selective formation of a chiral-at-ruthenium octahedral stereocenter,^2,3 and engage in formyl CH···I hydrogen bonding in the transition state for carbonyl addition.⁴ By exploiting iodide counterions in combination with C₁-symmetric JOSIPHOS ligands, the intervention of predominantly one of 10 possible diastereomeric transition structures⁵ could be achieved, enabling highly enantioselective ruthenium-catalyzed 1-aryl-1-propyne-mediated carbonyl (α-aryl)allylations,² 2-butyne-mediated carbonyl vinylations,⁶ and butadiene/methylallene-mediated crotylations (Figure 1).⁷

Figure 1.

Halide-directed regio- and enantioselectivity unlocks isoprene-mediated carbonyl tert-prenylation.

These data impelled a survey of halide counterions in ruthenium-SEGPHOS-catalyzed reactions of isoprene (>10⁵ tons/yr)⁸ with primary alcohol proelectrophiles via hydrogen auto-transfer. Not only was a halide-dependent partitioning of diastereomeric chiral-at-ruthenium-SEGPHOS complexes observed, but it was also found that the diastereomeric complexes display regiodivergent reactivity:⁹ chloride- and bromide-bound ruthenium-SEGPHOS catalysts preferentially promote carbonyl sec-prenylation, whereas the diastereomeric iodide-bound ruthenium-SEGPHOS catalyst delivers products of carbonyl tert-prenylation. These data represent the first correlation between metal-centered stereogenicity and regioselectivity in metal catalysis, which, in turn, has enabled a method for catalytic enantioselective isoprene-mediated carbonyl tert-prenylation beyond premetalated reagents.^10–15

Results and Discussion

In 2008, our laboratory disclosed the first use of dienes as allylmetal pronucleophiles in late transition metal-catalyzed carbonyl addition.^16a This study encompassed racemic examples of isoprene-mediated sec-prenylation and involved the use of a chloride-bound ruthenium catalyst. Subsequent efforts to develop asymmetric variants of this process focused on butadiene,^16b-d as reactions of isoprene often led to regioisomeric mixtures of sec-prenylation and tert-prenylation products. Our recent finding that halide counterions can guide formation of pseudo-diastereomeric chiral-at-metal ruthenium complexes led us to probe the question of whether regioisomerism observed in couplings of isoprene occurred in response to metal-centered diastereogenicity. Toward this end, alcohol 2a (100 mol%) and isoprene 1a (400 mol%) were exposed to RuH₂(CO)(PPh₃)₃ (5 mol%) and (S)-SEGPHOS (5 mol%) in THF (0.5 M) and trifluoroethanol (TFE) (300 mol%) at 115 °C in the absence and presence of the halide additives LiX, where X = Cl, Br and I (Table 1, entries 1–4). Whereas the chloride-modified catalyst exclusively promoted formation of the sec-prenylated product sec-3a, an increasing proportion of the tert-prenylated adduct tert-3a was observed using the catalysts modified by bromide and iodide. Remarkably, in the case of the iodide-modified catalyst, a 12:1 regioisomeric mixture favoring tert-3a was formed in 65% yield and 91% enantiomeric excess (Table 1, entry 4), thus representing a halide-dependent inversion in regioselectivity. This trend persisted in reactions conducted using the precatalysts RuHCl(CO)(PPh₃)₃ and RuHBr(CO)(PPh₃)₃ in the absence of added lithium halides (Table 1, entries 5 & 6), and in reactions using RuHCl(CO)(PPh₃)₃ with added LiBr and LiI (Table 1, entries 7 & 8). Higher yields and regioselectivities in the formation of the tert-3a could be achieved using KI instead of LiI, perhaps due to the increased solubility of KI in ethereal solvent (Table 1, entry 9). Further variation of ligand (Table 1, entries 10–14) did not improve conversion or selectivity. Reactions conducted with the precatalyst Ru(CF₃CO₂)₂(CO)(PPh₃)₂ favored formation of sec-3a (35% yield, 12:1 rr, 3:1 dr, 21% ee), as did the arylsulfonate-modified catalyst generated from the acid-base reaction^16c of RuH₂(CO)(PPh₃)₃ with p-toluenesulfonic acid (42% yield, 3:1 rr, 5:1 dr, 18% ee).

Table 1.

Halide-dependent tert- and sec-prenylation in ruthenium-catalyzed C-C couplings of isoprene 1a with alcohol 2a via hydrogen auto-transfer.^a

Entry	X	Additive	Ligand	Yield	tert-3a (ee)	3a (tert:sec)
1	H	—	(S)-SEGPHOS	54%	-	1:3
2b	H	LiCI	(S)-SEGPHOS	42%	-	>1:20
3	H	LiBr	(S)-SEGPHOS	40%	-	1:6
4	H	Lil	(S)-SEGPHOS	65%	91%	12:1
5c	Cl	—	(S)-SEGPHOS	74%	-	1:16
6	Br	—	(S)-SEGPHOS	72%	-	1:5
7	Cl	LiBr	(S)-SEGPHOS	64%	-	1:4
8	Cl	Lil	(S)-SEGPHOS	66%	91%	12:1
→ 9	Cl	Kl	(S)-SEGPHOS	75%	91%	17:1
10	Cl	Kl	(S)-DM-SEGPHOS	59%	89%	12:1
11	Cl	Kl	(S)-BINAP	83%	65%	15:1
12	Cl	Kl	(S)-tol-BINAP	74%	72%	13:1
13	Cl	Kl	(S)-CI.MeO-BIPHEP	45%	58%	9:1
14	Cl	Kl	(S,S)-DIOP	73%	85%	12:1

^aYields of material isolated by silica gel chromatography as isomeric mixtures. Enantioselectivities were determined by HPLC analysis.

^bsec-3a (3:1 dr, 11% ee).

^csec-3a (3:1 dr, 11% ee). See Supporting Information for further details on reaction optimization.

To assess whether the observed halide-dependent inversion in regioselectivity was due to intervention of pseudo-diastereomeric chiral-at-ruthenium-SEGPHOS complexes, crystals of the indicated chloride- and iodide-bound π-allylruthenium complexes were subjected to X-ray diffraction analysis (Figure 2). A trans-relationship between the carbonyl and chloride ligands, which reside in apical coordination sites, was observed for the π-allylruthenium chloride complex. In contrast, the π-allylruthenium iodide complex exhibited a cis-relationship between the carbonyl and iodide ligands in apical and equatorial coordination sites, respectively. The diastereomeric preference observed in the solid state may reflect crystal packing forces. Hence, it was essential to determine whether this preference persisted in solution. A comparison of the solid and solution phase ³¹P NMR spectra¹⁷ of the chloride and iodide complexes suggested this to be the case. The respective solid and solution phase spectra matched and a single (but distinct) diastereomer was observed for both the chloride and iodide complexes. Notably, for the chloride complex, two signals with very similar chemical shifts were observed in solution (δ = 33.3, 31.7), which is consistent with two phosphorus atoms in similar chemical environments. In contrast, the phosphorus atoms of the iodide complex appeared at very different chemical shifts (δ = 32.7, 48.7) with a low-field doublet consistent with that of a phosphine atom that is trans to a halide.¹⁸ As the haptomeric equilibria of π-allylruthenium complexes is dynamic,¹⁹ enabling interconversion of diastereomeric chiral-at-ruthenium-SEGPHOS complexes via Berry pseudorotation via pentacoordinate σ-allyl complexes,²⁰ the collective data suggest the diastereomeric preferences of the chloride- and iodide-bound complexes reflect a thermodynamic bias.

Figure 2.

Single crystal X-ray diffraction data for chloride-vs iodide-bound ruthenium-SEGPHOS complexes and their solution and solid phase ³¹P NMR spectra.^a

^aDisplacement ellipsoids are scaled to the 50% probability level. Hydrogen atoms have been omitted for clarity. See Supporting Information for complete crystallographic and ³¹P NMR data.

To assess reaction scope, optimal conditions identified for the isoprene-mediated tert-prenylation of alcohol 2a were applied to primary alcohols 2b–2m (Table 2). The homoallylic alcohols 3b–3m and epi-3m were formed in good to excellent yields, regioselectivities and enantioselectivities. Diverse N-heterocycles were tolerated, including piperidines (3d), pyridines (3e, 3l), pyrazoles (3f), unprotected indoles (3h), thiophenes (3i), thiazoles (3j), and pyrimidines (3k). The chiral δ-stereogenic alcohol 2m underwent tert-prenylation with good levels of catalyst-directed diastereoselectivity. Attempted reactions of primary benzylic and allylic alcohols led to low yields of sec-prenylated adduct. The reaction of myrcene 1b with alcohol 2a provides the product tert-geranylation 4a, thus forming an acyclic quaternary carbon stereocenter (eq. 1).²¹ Finally, using 2-propanol as reductant, isoprene-mediated tert-prenylation of aldehydes dehydro-2a and dehydro-2b occurred with good regio- and stereocontrol (Scheme 1). The absolute stereochemical assignments of adducts 3a-3m and 4a were made in analogy to 3e, which was established via single crystal X-ray diffraction.

Table 2.

Regio- and enantioselective isoprene-mediated tert-prenylation of alcohol proelectrophiles 2a–2m via ruthenium-SEGPHOS-catalyzed hydrogen auto-transfer.^a

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

^b120 °C.

^c110 °C.

^dDME (0.5M).

^eRu-ligand (7.5 mol%), KI (20 mol%).

^fRuH₂(CO)(PPh₃)₃ (5 mol%), LiI (10 mol%). See Supporting Information for further details.

Scheme 1.

Regio- and enantioselective isoprene-mediated tert-prenylation of aldehydes dehydro-2a and dehydro-2b.^a

^aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary-phase HPLC analysis. See Supporting Information for further details.

(eq.1)

To gain insight into the reaction mechanism, deuterium la-beling experiments were performed (Scheme 2). Exposure of the alcohol deuterio-2a to isoprene 1a under standard conditions for tert-prenylation using the iodide-bound catalyst led to formation of deuterio-3a, which incorporates deuterium at the primary and secondary vinylic positions (H_c = 12% ²H, H_d/e = 15% ²H) and the methyl groups (H_b = 15% ²H). A substantial loss of deuterium is observed at the carbinol position (H_a = 54% ²H). Omitting potassium iodide, but under otherwise identical conditions, deuterio-2a and isoprene 1a are converted to the sec-prenylation product deuterio-sec-3a, which retains significantly more deuterium at the carbinol position (H_a = 89% ²H). Notably, deuterium is not transferred to the vinylic positions of deuterio-sec-3a (H_d/e = 0% ²H). Reexposure of deuterio-3a or deuterio-sec-3a to the reaction conditions does not alter deuterium content at the carbinol position. These data corroborate reversible hydrogen transfer between alcohol deuterio-2a and isoprene 1a prior to carbonyl addition. For the iodide-bound catalyst, formation of a more highly substituted 3°-4° C-C bond, lowers the rate of carbonyl addition, which increases H/D-exchange between deuterio-2a and isoprene 1a and results in greater deuterium loss at the carbinol position. Hydroruthenation of the less substituted olefin of isoprene 1a is kinetically preferred.^22b,c Hydroruthenation of the more substituted olefin of isoprene 1a, only occurs when the rate of carbonyl addition is retarded via formation of the more highly substituted 3°-4° C-C bond. Incomplete deuterium transfer is attributed to H/D-exchange with isoprene, as well H/D-exchange between the ruthenium deuteride and the hydroxyl hydrogens of the alcohol reactant or TFE.²³ Thus, a catalytic cycle is envisioned wherein reversible alcohol dehydrogenation via ruthenium alkoxide I delivers aldehyde and ruthenium hydride II. Hydroruthenation of isoprene²² favors formation of the n-prenylruthenium species IIIa (and haptomers), which engages the aldehyde in carbonyl addition to form the homoallylic alkoxide IV. TFE-assisted exchange of the homoallylic ruthenium alkoxide IV² with alcohol reactant releases the product of tert-prenylation and reforms ruthenium alkoxide I to close the cycle (Scheme 3).

Scheme 2.

Deuterium labelling experiments.^a

^aDeuterium incorporation was assessed via ¹H, ²H NMR and HRMS. See Supporting Information for further details.

Scheme 3.

Proposed mechanism for regio- and enantioselective ruthenium-SEGPHOS-catalyzed isoprene-mediated tert-prenylation of primary alcohols as corroborated by deuterium labelling.^a

^aThe extent of deuterium incorporation was corroborated ¹H, ²H NMR and HRMS. See Supporting Information for further details.

To gain deeper insight into how halide counterions bias the regioisomeric C-C coupling pathways in isoprene-mediated carbonyl addition via hydrogen auto-transfer, density functional theory (DFT) calculations were conducted.²⁴ First, the structures of the diastereomeric chloride- and iodide-bound π-allyl- and π-prenylruthenium complexes in which the halide counterions reside cis- or trans- to the carbonyl ligand were computed (Figure 3). The trans-diastereomers were determined to be lower in energy for the chloride-bound complexes. For the iodide complexes, the cis-diastereomers were thermodynamically preferred. These data are consistent with the experimentally observed diastereomeric preferences of the chloride- and iodide-bound π-allylruthenium complexes in the solid state and in solution. For the iodide complexes, steric interactions between the large iodide counterion and the phenyl groups of the SEGPHOS ligand overcome the innate preference for a trans-relationship between the π-donating and π-accepting halide and carbonyl ligands.^2,22c,25

Figure 3.

Calculated stabilities of diastereomeric chloride- and iodide-bound π-allyl- and π-prenylruthenium (S)-SEGPHOS complexes.^a

^aSee supporting information for further details.

Next, the energy profiles for the kinetic pathways leading to the regioisomeric tert- and sec-prenylation products were computed (Figure 4). The reaction pathways diverge from the common intermediate ruthenium-hydride A, which hydrometalates isoprene to form the regioisomeric π-allyl complexes B and F, which interconvert with their respective σ-allyl species C and H. Remarkably, the transition states for subsequent aldehyde coordination (TS1A and TS2A) are rate-determining in both pathways and, hence, represent the regio-determining event. The transition state TS2A, which leads to the sec-prenylation product, is higher in energy than TS1A by 2.1 kcal/mol due to a non-bonded interaction between the iodide and the vinylic methyl of the σ-allyl in TS2A (Figure 5). The transition states for the following C-C bond formations (TS1B and TS2B) are lower in energy than TS1A and TS2A, respectively. TS1B is 0.8 kcal/mol higher in energy than TS2B due to steric interactions between the methyl group of acetaldehyde and the southern methyl substituent of the σ-allyl, which is absent in TS2B. Although not explicitly shown, a non-classical CH···I formyl hydrogen bond between the aldehyde and iodide counterion stabilizes the computed transition states for carbonyl addition.^2,4 Thus, the DFT calculations corroborate a scenario in which regioselectivity is determined in a two-fold manner: first by the cis-diastereomeric preference of the iodide and carbonyl ligands at ruthenium, and then by a Curtin-Hammett-type scenario in which the relative energies of the transition states for aldehyde coordination (TS1A and TS2A) to the regioisomeric prenylruthenium complexes is rate- and product-determining.

Figure 4.

Computed energy profiles of the kinetic pathways leading to the regioisomeric tert- and sec-prenylation products.

Figure 5.

Calculated competing transitions states TS1A and TS2A for rate- and regio-determining aldehyde binding.^a

^aSee supporting information for further details.

In summary, we describe the first correlation of metal-centered stereogenicity to regioselectivity in metal catalysis, as demonstrated by regiodivergent carbonyl sec- vs tert-prenylations of alcohol proelectrophiles mediated by isoprene. Specifically, whereas chloride-bound ruthenium-SEGPHOS complexes prefer a trans-relationship between the halide and carbonyl ligands and deliver products of carbonyl sec-prenylation, iodide-bound ruthenium-SEGPHOS complexes prefer a cis-relationship between the halide and carbonyl ligands and deliver products of carbonyl tert-prenylation. DFT calculations of the iodide-bound catalyst implicate a Curtin-Hammett-type scenario in which the transition states for aldehyde coordination from an equilibrating mixture of sec- and tert-prenylruthenium complexes is rate- and product-determining. These studies, which underscore the profound influence of both halide counterions¹ and metal-centered diastereoselectivity³ vis-à-vis selectivity in metal catalysis, have unlocked a practical method for catalytic enantioselective carbonyl tert-prenylation mediated by the abundant feedstock diene isoprene.