Dual Ruthenium-Catalyzed Alkene Isomerization–Hydrogen Auto-Transfer Unlocks Skipped Dienes as Pronucleophiles for Enantioselective Alcohol C–H Allylation

Abstract

The first use of 1,4-pentadiene and 1,5-hexadiene as allylmetal pronucleophiles in regio-, anti-diastereo- and enantioselective carbonyl addition from alcohol proelectrophiles is described. As corroborated by deuterium labelling experiments, primary alcohol dehydrogenation delivers a ruthenium hydride that affects alkene isomerization to furnish a conjugated diene followed by transfer hydrogenative carbonyl addition. Hydrometalation appears to be assisted by formation of a fluxional olefin-chelated homoallylic alkylruthenium complex II, which exists in equilibrium with its pentacoordinate η¹ form to enable β-hydride elimination. This effect confers remarkable chemoselectivity: while 1,4-pentadiene and 1,5-hexadiene are competent pronucleophiles, higher 1,n-dienes are not, and olefinic functional groups of the products remain intact under conditions in which the 1,4- and 1,5-dienes isomerize. A survey of halide counterions reveals iodide-bound ruthenium-JOSIPHOS catalysts are uniquely effective in these processes. This method was used to prepare a previously reported C1-C7 substructure of (−)-pironetin in 4 vs 12 steps.

Graphical Abstract

INTRODUCTION

In the course of advancing catalytic methods for hydrogen transfer-mediated carbonyl additions,¹ we recently developed novel “chain-walking processes”² in which carbonyl vinylation or allylation mediated by vinyl halides^3a,b and butadiene,^3c respectively, is followed by redox isomerization to form saturated ketones (Figure 1).^3,4 These rhodium-catalyzed processes rely on the reversible dissociation of monodentate phosphine ligands to facilitate generation of coordinatively unsaturated metal centers that engage in β-hydride elimination from the transient allylic or homoallylic rhodium alkoxides.³ In related ruthenium-catalyzed couplings of primary alcohols and butadiene,⁵ the homoallylic alcohol products resist redox isomerization due to “double chelation” of the metal by the product and the bis(phosphine) ligand, which leads to full occupancy of all coordination sites and suppression of β-hydride elimination (eq. 1, left). Indeed, if the chelating bis(phosphine) is replaced by a monodentate phosphine ligand, β-hydride elimination is restored (eq. 1, right).⁶

Figure 1.

Selected examples of merged metal-catalyzed carbonyl C-C coupling-redox isomerization.

(eq. 1)

The development of enantioselective metal-catalyzed carbonyl addition processes that merge alkene redox-isomerization and carbonyl addition appeared unlikely, as the majority of asymmetric carbonyl reductive couplings to form alcohol products require chiral bis(phosphine) ligands that tend to suppress β-hydride elimination. Reported ruthenium-catalyzed diene isomerizations suggested the feasibility of utilizing “skipped” dienes⁷ as precursors to conjugated diene pronucleophiles.⁸ In elegant work by Yin (Figure 1),^9a 1,4-pentadienes were used as pronucleophiles for asymmetric ketone (Z)-dienylation, but the diene is activated via deprotonation of the allylic C-H bond. It was unclear whether isomerization via hydrometalation-β-hydride elimination would be possible, as 1,n-dienes such as 1,5-cyclooctadiene (COD) and norbornadiene (NBD) are potent chelators and can suppress catalysis.¹⁰ Despite this potential obstacle, we herewith report that iodide-bound ruthenium-JOSIPHOS catalysts recently developed in our laboratory^5d,11 promote highly diastereo- and enantioselective redox-neutral C-C couplings of 1,4- or 1,5-diene pronucleophiles with primary alcohol proelectrophiles via hydrogen auto-transfer to form branched products of carbonyl addition as single regioisomers.¹²

RESULTS AND DISCUSSION

Conditions for merged enantioselective ruthenium-catalyzed redox-isomerization-carbonyl addition were inspired by those utilized for the coupling of 1-sec-alkyl-1-propynes^13a or 1-aryl-1-propynes^11,13b with primary alcohols, which occur through a dual catalytic process wherein alkyne-to-allene isomerization is followed by allene-carbonyl reductive coupling via hydrogen auto-transfer. In these processes, the dihydride precatalyst RuH₂(CO)(PPh₃)₃ undergoes acid-base reaction¹⁴ with an arylsulfonic acid in the presence of Bu₄NI and a JOSIPHOS ligand to affect generation of the active iodide-bound ruthenium-JOSIPHOS catalyst (eq. 2). As this catalyst was effective for alkyne-to-allene isomerization, it was posited that it might also promote the coupling of 1,4- pentadiene 1a with 1,3-propanediol tert-butyldiphenylsilyl ether 2a via isomerization of 1a to the conjugated diene. Indeed, after a brief survey of JOSIPHOS ligands,¹⁵ arylsulfonic acids and solvents, the catalyst generated from RuH₂(CO)(PPh₃)₃ (5 mol%), SL-J502–2 (5 mol%), 2-NO₂PhSO₃H (5 mol%) and Bu₄NI (10 mol%) in anisole¹⁶ (0.5 M) at 80 °C was found to promote formation of the targeted product of C-C coupling 3a in 99% yield as a single regioisomer with excellent control of diastereo- and enantioselectivity (Table 1, entry 1). The use of alternate chiral chelating phosphine ligands did not avail further improvement (Table 1, entries 2–6). Consistent with our prior observations,¹¹ the iodide-bound catalyst performs better than the corresponding chloride or bromide complexes (Table 1, entries 1, 7–9).¹⁷ Notably, conditions developed for related couplings of 1,3-butadiene that exploit the precatalyst RuI(CO)(η³-C₃H₅) gave low yields (<10%),^5d demonstrating the unique efficacy of the present catalytic system vis-á-vis olefin isomerization (see Figure S1).

Table 1.

Selected experiments deviating from optimal conditions for the ruthenium-catalyzed coupling of 1,4-pentadiene 1a with alcohol 2a to form homoallylic alcohol 3a.^a

^aYield of material isolated by silica gel chromatography. See Supporting Information for experimental details.

(eq. 2)

To assess reaction scope, optimal conditions identified for the conversion of 1,4-pentadiene 1a and alcohol 2a to provide homoallylic alcohol 3a were applied to primary alcohols 2b-2r (Table 2). The resulting branched homoallylic alcohols 3b-3r were formed as single regioisomers in good to excellent yields, anti-diastereo- and enantioselectivities. Notably, diverse nitrogen heterocycles were tolerated, including indoles (3b), oxazoles (3c), pyrroles (3d), pyrazoles (3e), pyridines (3f, 3l) phthalimides (3g) and azetidines (3i). Both primary aliphatic alcohols and benzylic alcohols are competent proelectrophiles, as demonstrated by the formation of 3a-3j, 3n-3r and 3k-3m, respectively. Finally, β-stereogenic primary alcohols 2n-2r were exposed to standard reaction conditions using the enantiomeric ruthenium-JOSIPHOS catalysts modified by SL-J502–2 and SL-J502–1. The resulting branched homoallylic alcohols 3n-3r and epi-3n-epi-3r were formed with moderate to good levels of catalyst-directed diastereoselectivity. Most remarkably, while 1,4-pentadiene participates in isomerization, olefinic functional groups of the reactants remain intact, as do the terminal homoallylic olefins of the reaction products. Such chemoselectivity suggests hydrometalation of the skipped diene pronucleophile is chelation-assisted.

Table 2.

Ruthenium-catalyzed coupling of 1,4-pentadiene 1a with alcohols 2a-2r to form homoallylic alcohols 2a-2r.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by HPLC analysis. Diastereoselectivities were determined by ¹H NMR analysis of crude reaction mixtures. ^b7.5 mol% catalyst. ^cPhOMe (1.0 M). ^d10 mol% catalyst. ^e1,4-pentadiene (1000 mol%). ^f70 °C. ^g100 °C. ^h60 °C. See Supporting Information for experimental details.

To further explore the scope of this process and probe the influence of chelation on the efficiency of tandem isomerization-hydrogen auto-transfer carbonyl addition, reactions of higher skipped dienes were attempted. 1,5-Hexadiene 1b was found to react with alcohols 2a-2c, 2e, 2q to form the homologous homoallylic alcohols homo-3a-3c, 3e, 3q, epi-3q, although more forcing conditions were required (Table 3). For 1,5-hexadienes, it was also necessary to change the iodide source from Bu₄NI to LiI to maintain optimal yields of product. Corresponding reactions of 1,6-heptadiene failed to deliver preparatively useful quantities of the targeted coupling products, and skipped cyclic dienes did not participate in C-C coupling. As illustrated in equation 3, 1,4-hexadiene forms the same product as 1,5-hexadiene, but in significantly lower yield (37% vs 88% yield, respectively). These data again underscore the importance of chelation-initiated isomerization, as 1,5-hexadiene incorporates less substituted olefin moieties, and the stability of late transition metal-olefin π-complex decreases with increasing degree of olefin substitution.¹⁸ Finally, 3-methyl-1,4-pentadiene 1c reacts with benzylic alcohol 2k to form Me-3k in good yield (eq. 4). Although absolute stereocontrol was somewhat modest, diastereo- and enantioselective formation of an acyclic quaternary carbon stereocenter bearing methyl, ethyl and vinyl moieties is notable.¹⁹

Table 3.

Ruthenium-catalyzed coupling of 1,5-hexadiene 1b with alcohols 2a-2c, 2e, 2q to form the homologous homoallylic alcohols homo-3a-3c, 3e, 3q, epi-3q.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by HPLC analysis. Diastereoselectivities were determined by ¹H NMR analysis of crude reaction mixtures. ^b1,5-hexadiene (1000 mol%). ^cPhOMe (0.25 M). See Supporting Information for experimental details.

(eq. 3)

(eq. 4)

The stereodiads formed via ruthenium-catalyzed coupling of 1,4-pentadiene 1a represent polyketide “butyrate” substructures.²⁰ This motif is evident in (−)-pironetin,^20b,21,22 a microtubule destabilizing agent that arrests cell cycle progression at the G2/M phase.^22,23 Many FDA approved anticancer drugs perturb microtubule dynamics,²⁴ however, pironetin is unique as it is the only microtubule destabilizing agent that binds α-tubulin.^22,25 Consequently, pironetin has attracted the attention of synthetic chemists, resulting in over a dozen total syntheses,²⁶ as well as the synthesis and evaluation of simplified analogues.²² To illustrate the utility of the present ruthenium-catalyzed coupling of 1,4-pentadiene 1a, a known C1-C7 substructure of pironetin was prepared using this method (Scheme 1).^26j Thus, propane diol mono-TBS ether 2s was subjected to standard conditions for C-C coupling to form the homoallylic alcohol 3s (not shown), which was exposed to crotonic acid under Mitsunobu conditions²⁷ to furnish the α,β-unsaturated ester 4 with good control of relative and absolute stereochemistry. Ring-closing metathesis²⁷ followed by removal of the TBS ether²⁸ provides the C1-C7 substructure 5 in 4 steps; a compound that previously required a 12-step preparation.^26j

Scheme 1.

Synthesis of C1-C7 of pironetin.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by HPLC analysis. Diastereoselectivities were determined by ¹H NMR analysis of crude reaction mixtures. See Supporting Information for experimental details.

A catalytic cycle has been proposed and corroborated by a deuterium labelling experiment (Scheme 2). Hydroruthenation of 1,4-pentadiene 1a by the ruthenium hydride I provides the chelated homoallylic alkylruthenium complex II. Hydrometalation appears to be assisted by formation of the indicated chelate, as 1,4-pentadiene and 1,5-hexadiene are competent pronucleophiles while higher 1,n-dienes are not. This assertion is consistent with a study revealing that 1,4- and 1,5-dienes form chelated ruthenium carbonyl complexes while 1,6-dienes do not.^7a Just as a COD or NBD ligand can dissociate from a metal precatalyst, olefin binding in the chelated homoallylic alkylruthenium complex II is fluxional, thus providing an open coordination site for β-hydride elimination of the allylic C-H to form the hydride-containing conjugated η²-diene-ruthenium complex III. Diene hydroruthenation forms the π-allylruthenium complex IV.²⁹ Carbonyl addition from the primary σ-allylruthenium haptomer (not shown) provides the homoallylic ruthenium alkoxide V. Finally, alkoxide exchange with the reactant alcohol 2 releases the product of C-C coupling 3 and forms the primary ruthenium alkoxide VI. β-Hydride elimination from the alkoxide concomitantly forms the aldehyde dehydro-2 and the ruthenium hydride I to close the catalytic cycle. To corroborate this interpretation of the mechanism, the isotopically labeled primary alcohol deuterio-2a was treated with 1,4-pentadiene 1a under standard reaction conditions. The reaction product deuterio-3a incorporated deuterium at every diene-derived carbon atom. Additionally, significant loss of deuterium was observed at the carbinol position. These data demonstrate highly reversible diene hydrometalation-β-hydride elimination and highly reversible hydrogen transfer from the alcohol reactant 2 to 1,4-pentadiene 1a. Re-exposure of the reaction product deuterio-3a to the reaction conditions did not alter the extent of deuterium incorporation at the carbinol position, suggesting chelation of the homoallylic olefin suppresses β-hydride elimination from the homoallylic alkoxide V.

Scheme 2.

Proposed catalytic cycle for successive alkene isomerization-hydrogen auto-transfer carbonyl allylation as corroborated by deuterium labelling experiments.^a

^aDeuterated materials were characterized by ¹H NMR, ²H NMR and HRMS. See Supporting Information for further experimental details.

CONCLUSION

In summary, we report the first use of nonconjugated dienes as allylmetal pronucleophiles in regio-, anti-diastereo- and enantioselective carbonyl additions from alcohol proelectrophiles. As demonstrated by the formation of the C1-C7 substructure of pironetin (4 vs 12 steps), these processes streamline access to butyrate substructures evident in type I polyketide natural products. The collective data, including deuterium labeling studies, corroborate a catalytic mechanism in which hydrometalation of the non-conjugated diene appears to be assisted by formation of the fluxional olefin-chelated homoallylic alkylruthenium complex II, which exists in equilibrium with its pentacoordinate η¹ form to enable β-hydride elimination. This effect results in remarkable chemoselectivity: while 1,4-pentadiene and 1,5-hexadiene are competent pronucleophiles higher 1,n-dienes are not, and olefinic functional groups of the products remain intact under conditions in which the 1,4- and 1,5-skipped dienes isomerize.