Diastereo- and Enantioselective Ruthenium-Catalyzed C-C Coupling of 1-Arylpropynes and Alcohols: Alkynes as Chiral Allylmetal Precursors in Carbonyl anti-(α-Aryl)allylation

Abstract

Highly tractable 1-aryl-1-propynes, which are readily accessible via Sonogashira coupling, serve as chiral allylmetal pronucleophiles in ruthenium-JOSIPHOS-catalyzed anti-diastereo- and enantioselective aldehyde (α-aryl)allylations with primary aliphatic or benzylic alcohol proelectrophiles. This method enables convergent construction of homoallylic sec-phenethyl alcohols bearing tertiary benzylic stereocenters. Both steric and electronic features of aryl sulfonic acid additives were shown to contribute to the efficiency with which a more selective and productive iodide-bound ruthenium catalyst is formed. As corroborated by isotopic labelling studies, a dual catalytic process is operative in which alkyne-to-allene isomerization is followed by allene-carbonyl reductive coupling via hydrogen auto-transfer. Crossover of ruthenium hydrides emanating from these two discrete catalytic events is observed. The utility of this method is illustrated by conversion of selected reaction products to the corresponding phenethylamines and the first total syntheses of the neolignan natural products (−)-crataegusanoids A-D.

Graphical Abstract

Introduction

Carbonyl addition is the Proteus of metal-mediated C-C couplings.¹ Recent analysis of >9 million patents from pharmaceutical industry shows that carbonyl addition (alongside the Suzuki coupling) persists as one of the most widely utilized methods for C-C bond formation in process R&D.² Despite its importance, the majority of methods for carbonyl addition require preformed carbanions, which can be hazardous and are often generated using multiple sacrificial reagents, for example through halogenation-metalation-transmetalation sequences. Metal-catalyzed carbonyl reductive coupling of unsaturated pronucleophiles has emerged as an alternative to stoichiometric carbanions, but many reductants used in such processes are not ideal for chemical manufacture on scale (e.g. Mn, Zn, Et₃B, Et₂Zn, SiR₃).^3,4 We have advanced a broad, new family of metal-catalyzed carbonyl reductive couplings that exploit feedstock pronucleophiles in combination with feedstock reductants (H₂, 2-PrOH, HCO₂H), as well as related hydrogen autotransfer processes wherein alcohols serve dually as reductants and carbonyl proelectrophiles.⁴ These efforts include processes that exploit alkynes as allylmetal pronucleophiles.^5,6,7

Given the tractability of 1-aryl-1-propynes and their wide availability via Sonogashira coupling (eq. 1), we sought to

(eq. 1)

develop catalytic enantioselective carbonyl (α-aryl)allylations via transfer hydrogenative couplings of 1-aryl-1-propynes with primary alcohols (Figure 1). Despite decades of work on asymmetric carbonyl allylation,⁷ enantioselective carbonyl (α-aryl)allylations are largely limited to isolated examples that embody moderate levels of asymmetric induction and deliver simple aryl fragments. These methods fall into two categories: (a) those involving chiral auxiliaries⁸ and (b) catalytic enantioselective protocols.^9,10 In the former category, one systematic study involving allylbenzene pronucleophiles was reported by Gong,^8g but this method is restricted to aryl aldehydes (Figure 1). In the latter category, systematic studies are limited to activated aldehydes (glyoxamides^9e formaldehyde,^10a fluoral and difluoroacetaldehyde^10b) and a Nozaki-Hiyama-Kishi (α-aryl)allylation to form quaternary benzylic stereocenters.⁹ⁱ Catalytic enantioselective carbonyl (α-aryl)allylations applicable to both aliphatic and aromatic aldehydes are unknown, and would enable convergent construction of tertiary benzylic stereocenters and stereogenic C-O bonds, which are ubiquitous among natural products and FDA approved drugs. Here, using a ruthenium catalyst modified by the JOSIPHOS ligand SL-J009-1, we report that diverse 1-aryl-1-propynes engage in C-C coupling with primary aliphatic or benzylic alcohols to furnish products of (α-aryl)allylation bearing relatively complex aryl moieties in good yield with complete anti-diastereoselectivity and high levels of enantioselectivity.

Figure 1.

Convergent construction of sec-phenethyl alcohols bearing tertiary benzylic stereocenters via enantioselective carbonyl anti-(α-aryl)allylation of unactivated aldehydes.

Results and Discussion

In prior work from our laboratory,^6c it was found that protonation of H₂Ru(CO)(PPh₃)₃ by the aryl sulfonic acid 2,4,6-(ⁱPr)₃PhSO₃H delivers a cationic ruthenium(II) complex that exists in equilibrium with a ruthenium(0) complex. This ruthenium(0) species promotes two discrete catalytic events: (a) alkyne-to-allene isomerization, and (b) transfer hydrogenative allene-carbonyl reductive coupling by way of a transient oxaruthenacycle. This process converts alkyl-substituted alkynes and primary alcohols to linear secondary (Z)-homoallylic alcohols (Scheme 1, eq. 2).^6c Remarkably, in the presence of iodide and a chelating phosphine ligand, an alternate dual catalytic process becomes operative in which alkyne-to-allene isomerization is followed by hydrometalation of the transient allene to form an allylruthenium(II) species. This process converts alkyl-substituted alkynes and primary alcohols to branched secondary homoallylic alcohols with excellent control of regio-, diastereo- and enantioselectivity (Scheme 1, eq. 3).^6e As corroborated by deuterium labelling studies, both processes involve alkyne-to-allene isomerization. The fate of the resulting allene largely depends on the intervention of cationic vs neutral ruthenium complexes, which partition entry into catalytic cycles involving either allene-carbonyl oxidative coupling or allene hydrometalation, respectively.^6c,e,11

Scheme 1.

Alkynes as latent allenes in alcohol-mediated hydrohydroxyalkylation to form linear or branched homoallylic alcohols (Ar = 2,4,6-triisopropylphenyl).

Both catalytic processes are largely restricted to α-branched alkyl-substituted propynes, such as 4-methyl-2-pentyne. We speculate that α-branched alkyl groups at the acetylenic position may facilitate alkyne-to-allene isomerization by favorably influencing the regioselectivity of alkyne hydrometalation. Initial attempts to exploit 1-aryl-1-propynes as pronucleophiles for asymmetric carbonyl (α-aryl)allylation were inefficient, and especially low isolated yields were observed for 1-aryl-1-propynes bearing electron deficient aromatic rings. To overcome this limitation, efforts to optimize the carbonyl (α-aryl)allylation of 1-(4-CF₃-phenyl)-1-propyne 1a and primary aliphatic alcohol 2a were undertaken (Scheme 2). Under conditions effective for couplings of 4-methyl-2-pentyne (but without 2-PrOH, which is used to reduce uncoupled aldehyde so it can reenter the catalytic cycle),^6d the product of carbonyl (α-aryl)allylation 3a was obtained in 17% yield with only modest levels of enantiomeric enrichment (Scheme 1, entry 1). When catalyst loading was doubled, a proportionate increase in the yield of 3a was observed (Scheme 1, entry 2). Replacing 2,4,6-(ⁱPr)₃PhSO₃H with 4-MePhSO₃H and 4-NO₂PhSO₃H led to successive improvements (Scheme 1, entries 3 and 4, respectively). These data are significant, as they reveal both steric and electronic features of the catalyst impact efficiency and enantioselectivity. Using 2,4,6-(ⁱPr)₃PhSO₃H in DME, slightly higher enantioselectivity was observed (Scheme 1, entries 2 vs 5), but lower temperatures limited conversion (Scheme 1, entry 6). The iodide-bound catalyst is generated through the acid-base reaction of the ruthenium dihydride with the arylsulfonic acid followed by substitution by iodide (eq. 4).¹² Notably, the more

(eq. 4)

acidic, less hindered arylsulfonic acid 4-NO₂PhSO₃H appears to enhance the efficiency of this process, allowing temperature to be reduced, augmenting enantioselectivity without diminishing conversion (Scheme 1, entry 7). Under these conditions, moving from THF to DME solvent, 3a could be obtained in 85% yield with >20:1 anti-diastereoselectivity and high enantioselectivity (88% ee) (Scheme 1, entry 8). Omission of Bu₄NI led to a significant decrease in yield and selectivity that could not be fully restored through use of Bu₄NCl or Bu₄NBr (Scheme 1, entries 9-11). Racemic product was obtained using the achiral ligand DIPPF in combination with (+)-camphor sulfonic acid (Scheme 1, entry 12). The collective data suggest both conversion and enantioselectivity depends on the efficiency with which the iodide-bound catalyst is formed.¹³

Scheme 2.

Influence of arylsulfonic acid in the reaction of 1-(4-CF₃-phenyl)-1-propyne 1a and alcohol 2a to form the product of carbonyl (α-aryl)allylation 3a.^a

^aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. Diastereoselectivities were determined via ¹H NMR analysis of crude reaction mixtures. ^bConditions described in Scheme 1, eq. 3 were applied using H₂Ru(CO)(PPh₃)₃ (5 mol%), SL-J009-1 (5 mol%), Bu₄NI (10 mol%). ^cDIPPF (10 mol%) was used as ligand.

Under these conditions, the ruthenium-catalyzed coupling of diverse 1-aryl-1-propynes 1a-1ff with primary alcohols 2a-2ff to form enantiomerically enriched phenethyl alcohols 3a-3ff was explored (Table 1). As illustrated by the formation of phenethyl alcohols 3c, 3x and iso-3x, ortho-substituted aryl propynes are competent partners for C-C coupling. Heteroaryl-substituted propynes are converted to adducts 3d-3h, 3p and 3s, establishing compatibility with Lewis basic sulfur (3d) and nitrogen (3e-3h, 3p, 3s) functional groups. Additionally, as demonstrated by the formation of adducts 3g-3o, primary alcohols bearing a tethered N-Boc amine (3g) or pyrazole (3h), 2- aminopyridine (3i), oxazole (3j), furan (3k), thiophene (3l), and indole (3m-3o) moieties are competent partners for arylpropyne-mediated asymmetric (α-aryl)allylation. Notably, adducts 3j and 3n derive from the FDA approved therapeutic agents oxaprozin and indomethacin, respectively, highlighting the potential applicability of this method to drug discovery. Adducts derived from primary alcohols that incorporate strained saturated ring systems, including cyclopropanes (3t), difluorocyclobutanes (3u), azetidines (3r, 3v) and oxetanes (3w) were well tolerated. Whereas low conversion was associated with the use of acyclic α-stereogenic primary alcohols, the corresponding β-stereogenic primary alcohols were converted to products of (α-aryl)allylation (3x, iso-3x, 3y, iso-3y) with high levels of catalyst-directed diastereoselectivity. Finally, primary benzylic alcohols undergo (α-aryl)allylation as shown by the formation of adducts 3aa-3ff. Here, compatibility of pinacolboronate functional groups, as demonstrated by formation of 3bb and 3ff, is significant. In certain cases, minor decreases or increases in reaction temperature were made to improve enantioselectivity or increase conversion, respectively. The assignment of absolute stereochemistry for adducts 3a-3ff is made in analogy to that determined for compound 3r by single crystal X-ray diffraction analysis. Attempted coupling of the more highly substituted aryl alkyne, 1-phenyl-1-butyne, results in internal redox-isomerization to form the terminal π-allyl, delivering products of carbonyl anti-(α-benzyl)allylation in low yield.

Table 1.

Ruthenium-catalyzed coupling of 1-aryl-1-propynes 1a-1ff with primary alcohols 2a-2ff to form enantiomerically enriched phenethyl alcohols 3a-3ff.^a

^aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. Diastereoselectivities were determined via ¹H NMR analysis of crude reaction mixtures. For standard conditions see Scheme 2, entry 7, 0.2 mmol scale, 48 h. See Supporting Information for further experimental details.

^b75 °C.

^c90 °C.

^dSL-J009-2.

^e65 °C.

Phenethylamines represent a broad class of psychoactive substances.¹⁴ To further illustrate the potential utility of this method to discovery efforts in pharmaceutical research, representative adducts 3d, 3j and 3r were transformed to the corresponding N-Boc-protected phenethylamines (Scheme 3). The phenethyl alcohols 3d, 3j and 3r were exposed to diphenylphosphoryl azide in the presence of diisopropyl azodicarboxylate and triphenylphosphine to furnish the azides 4d, 4j and 4r with complete inversion of stereochemistry and only trace quantities of competing elimination to form the conjugated dienes.¹⁵ One-pot Staudinger reduction¹⁶ of 4d, 4j and 4r followed by treatment with di-tert-butyl dicarbonate provided phenethylamines 5d, 5j and 5r, respectively, in good yield.

Scheme 3.

Conversion of phenethyl alcohols 3d, 3j and 3r to phenethylamines 5d, 5j and 5r.^a

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

(−)-Crataegusanoids A-D¹⁷ were recently isolated from the fruit of the Chinese mountain hawthorn tree, Crataegus pinnatifida, which are used to make “haw flakes,” a traditional candy from northern China. In an in vitro evaluation against two human hepatocellular carcinoma cell lines, HepG2 and Hep3B, (−)-crataegusanoids A and B displayed moderate cytotoxicity. To further illustrate the utility of the present method for asymmetric alkyne-mediated carbonyl (α-aryl)allylation, total syntheses of neolignan natural products (−)-crataegusanoids A-D were undertaken (Scheme 4). To this end, phenethyl alcohol ent-3aa was subjected to ozonolysis followed by treatment with NaBH₄ to provide a 1,3-diol. Acetal or ketal formation followed by concomitant cleavage of the TIPS silyl ether and phenolic tosylate moieties delivered (−)-crataegusanoids A-D.

Scheme 4.

Total syntheses of neolignan natural products (−)-crataegusanoids A-D.^a

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

A series of experiments were performed to probe the reaction mechanism (Scheme 5). Under standard reaction conditions, allene iso-1r is converted to the product of carbonyl (α-aryl)allylation 3r in 45% yield (eq. 5). This experiment demonstrates that allenes are competent partners for carbonyl (α-aryl)allylation, corroborating their role as reactive intermediates. Notably, the yield of 3r obtained from allene iso-1r is significantly lower than the yield of 3r obtained from the corresponding 1-aryl-1-propyne 1r (eq. 5). These data highlight the value of utilizing tractable 1-aryl-1-propynes as reservoirs for less stable and less abundant aryl-substituted allenes. Exposure of deuterio-1ee to furfuryl alcohol 2ee under standard conditions delivers deuterio-3ee-I (eq. 6). Deuterium is transferred to the internal vinylic position (50% ²H at H_c) and allylic positions (20% ²H at H_d). These data corroborate alkyne isomerization through successive, reversible alkyne hydrometalation-β-hydride elimination, and that the ruthenium hydrides initiating hydrometalation and arising via β-hydride elimination can emanate from either the alkyne or the alcohol. Additionally, small but significant loss of deuterium is observed at the olefinic terminus (93.5% ²H at H_a,b), indicating allene hydrometalation occurs with reversibly incomplete regioselectivity. In alignment with this interpretation, the reaction of alkyne 1ee with the deuterated furfuryl alcohol deuterio-2ee (eq. 7) also results in transfer of deuterium to the internal vinylic position (50% ²H at H_c), and hydrogen-deuterium exchange occurs at the carbinol position of the primary alcohol in both reactions (7% ²H at H_e, eq. 6; 90% ²H at H_e, eq. 7) likely via reversible alcohol dehydrogenation. In equation 6, deuterium content is not completely conserved, which may be due to exchange with adventitious water.

Scheme 5.

Experiments corroborating intervention of allenes as reactive intermediates.^a

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

The collective data are consistent with the indicated catalytic cycle (Scheme 6). Ruthenium-catalyzed alkyne-to-allene isomerization is followed by allene hydrometalation to form fluxional σ-allyl- and π-allylruthenium complexes I.¹⁹ Aldehyde coordination followed by stereospecific carbonyl addition by way of the (E)-σ-allyliridium through the chair-like transition structure II delivers a homoallylic ruthenium alkoxide III, which upon exchange with the primary alcohol releases the product of carbonyl (α-aryl)allylation and forms the ruthenium alkoxide IV. β-Hydride elimination from ruthenium alkoxide IV delivers the ruthenium hydride V along with aldehyde to close the catalytic cycle. The π-bound alkene in III prevents β-hydride elimination at this stage by occupying the adjacent coordination site. Notably, two discrete catalytic events are operative: (a) alkyne-to-allene isomerization and (b) transfer hydrogenative carbonyl addition. Yet, as demonstrated by deuterium labelling studies (eq. 5 and 6), crossover of ruthenium hydrides that arise in these two catalytic processes is observed.

Scheme 6.

Proposed catalytic cycle for ruthenium-catalyzed C-C coupling of 1-arylpropynes with primary alcohols to form products of carbonyl (α-aryl)allylation.

Conclusions

In summary, we report that abundant, tractable 1-aryl-1-propynes serve as chiral allylmetal pronucleophiles in reactions with primary alcohol proelectrophiles to form products of carbonyl (α-aryl)allylation. These hydrogen auto-transfer processes enable access to homoallylic phenethyl alcohols with excellent control of diastereo- and enantioselectivity. This method was successfully applied to the synthesis of psychoactive phenethyl amines, as well as the neolignan natural products (−)-crataegusanoids A-D. Both steric and electronic features of the aryl sulfonic acid additive were shown contribute to the efficiency with which a more productive and selective iodide-bound ruthenium catalyst is formed. As established by deuterium labelling studies, the present processes contribute to a growing class of enantioselective metal-catalyzed C-C and C-X coupling reactions in which alkynes serve as reservoirs for less abundant and less stable allenes.^5,6 Future work will focus on the development of related catalytic C-C couplings of π-unsaturated feedstocks that occur in the absence of stoichiometric organometallic reagents.^4f,20,21