Enantioselective Ruthenium-BINAP-Catalyzed Carbonyl Reductive Coupling of Alkoxyallenes: Convergent Construction of syn-sec,tert-Diols via (Z)-σ-Allylmetal Intermediates

Abstract

The first catalytic enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles is described. Using an iodide-modified ruthenium-BINAP-catalyst and O-benzhydryl alkoxyallene 1a, carbonyl (α-alkoxy)allylation occurs from the alcohol or aldehyde oxidation level to form enantiomerically enriched syn-sec,tert-diols. Internal chelation directs intervention of (Z)-σ-alkoxyallylruthenium isomers, which engage in stereospecific carbonyl addition.

Graphical Abstract

INTRODUCTION

Convergent construction of enantiomerically enriched acylic stereodiads bearing fully substituted carbon stereocenters remains a persistent challenge in chemical synthesis.¹ Among such motifs, syn-sec,tert-diols appear ubiquitously as substructures across diverse secondary metabolites, especially type I polyketides. One approach to their preparation involves stereospecific aldehyde addition of geometrically defined γ,γ-disubstituted chiral allylboron reagents through closed chair-like transition structures (Figure 1).^2,3 Corresponding catalytic enantioselective processes that generate syn-sec,tert-diols from tractable alkoxyallene pronucleophiles represents an alternate approach that is hitherto undescribed.^3,4 In connection with our studies of carbonyl reductive coupling via hydrogenation, transfer hydrogenation and hydrogen auto-transfer,⁵ which includes the use of allene pronucleophiles,^6,7 an iridium-catalyzed reductive coupling of 1,1-disubstituted allenes with fluoral to form acyclic stereodiads bearing quaternary carbon centers was developed.⁷ We posited that the enhanced oxaphilicity of ruthenium⁸ might enable asymmetric couplings to unactivated aldehydes. In the case of alkoxyallenes, such oxaphilicity might also result in internal chelation to form (Z)-σ-allylmetal nucleophiles (Scheme 1).^9,10 Hence, to accommodate aldehyde binding, such chelation must be reversible and, to preserve syn-diastereoselectivity, carbonyl addition must be fast relative to (Z)-to-(E)-isomerization of the fluxional allylruthenium intermediates.¹¹ Furthermore, as described by Marek,¹² for γ,γ-disubstituted allylmetal nucleophiles gauche interactions associated with the developing C-C bond can reverse the equatorial vs axial preference of the aldehyde substituent to erode or invert diastereoselectivity. Despite these challenges, we herewith report ruthenium-BINAP-catalyzed syn-diastereo- and enantioselective carbonyl reductive couplings of O-benzhydryl 3-alkoxy-1,2-butadiene to form syn-sec,tert-diols from primary alcohol reactants (via hydrogen auto-transfer) or aldehyde reactants (via 2-propanol-mediated reductive coupling).^13,14 These processes represent the first catalytic enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles.^4,6,7,15,16

Figure 1.

Stoichiometric vs catalytic synthesis of enantiomerically enriched syn-sec,tert-diols, a pervasive substructure among type I polyketide natural products.

Scheme 1.

Potential multiplicity of chair-like transition structures in ruthenium-catalyzed carbonyl (α-alkoxy)allylation to form syn-sec,tert-diols.

RESULTS AND DISCUSSION

Recently, we found that ruthenium catalysts bearing iodide counterions¹⁷ display enhanced selectivity and productivity in anti-diastereo- and enantioselective couplings of primary alcohol proelectrophiles with arylpropynes to form products of aldehyde (α-aryl)allylation.¹⁸ This observation suggested the feasibility of utilizing chiral ruthenium iodide complexes to catalyze alcohol-mediated carbonyl reductive couplings of O-benzhydryl 3-alkoxy-1,2-butadiene 1a. Branch-selective couplings of this type would generate fully substituted carbon stereocenters in the form of monoprotected syn-sec,tert-diols. With these thoughts in mind, a series of experiments were conducted to assess the influence of counterion in reactions of alkoxy allene 1a with p-bromo benzyl alcohol 2a using the catalyst assembled from H₂Ru(CO)(PPh₃)₃ (5 mol%) and (R)-BINAP (5 mol%) in cyclopentyl methyl ether (CPME) solvent at 70 °C. In the absence of added halide ion, the anticipated product of (α-alkoxy)crotylation 4a was formed in 18% yield with an enantiomeric enrichment of 73% (Table 1, entry 1). Notably, a 4:1 mixture of diastereomers in favor of the syn-isomer was observed. Under these conditions, the introduction of the halide additives LiX = Cl, Br, I (10 mol%) led to progressively higher yields and stereoselectivities (Table 1, entries 2-4), with the iodide-bound catalyst providing 4a in 80% yield, 8.5:1 diastereomeric ratio and 86% ee (Table 1, entry 4). The selectivities obtained using HClRu(CO)(PPh₃)₃ as precatalyst (for which chloride is preinstalled) are in excellent alignment with the outcome observed using H₂Ru(CO)(PPh₃)₃ and LiCl (Table 1, entry 2 vs 5). The stereoselectivities obtained upon addition of LiI to either H₂Ru(CO)(PPh₃)₃ or HClRu(CO)(PPh₃)₃ are also strikingly similar (Table 1, entry 4 vs 6), corroborating efficient formation of the halide-modified catalyst. As slightly better performance was observed using H₂Ru(CO)(PPh₃)₃, subsequent optimization focused on this precatalyst. Conducting the reaction in THF (Table 1, entry 7), increasing temperature (Table 1, entry 8) and slightly decreasing concentration were all beneficial, enabling formation of 4a in 78% yield with excellent control of syn-diastereo- and enantioselectivity (Table 1, entry 9). The catalyst derived from HClRu(CO)(PPh₃)₃ and LiI gave 4a in similar, but slightly lower, yields and selectivities (Table 1, entry 10).

Table 1.

Selected optimization experiments in the enantioselective ruthenium-catalyzed C-C coupling of alkoxyallene 1a with alcohol 2a.^a

	Entry	Solvent [M]	Additive	T°C	3a (Yield)	dr	ee
	1	CPME [0.4]	---	70	18%	4:1	73%
	2	CPME [0.4]	LiCl	70	50%	6:1	59%
	3	CPME [0.4]	LiBr	70	76%	7:1	79%
	4	CPME [0.4]	Lil	70	80%	8.5:1	86%
	5c	CPME [0.4]	---	70	56%	6:1	58%
	6c	CPME [0.4]	Lil	70	65%	8:1	87%
	7	THF [0.4]	Lil	70	73%	9.5:1	87%
	8	THF [0.4]	Lil	75	75%	9:1	89%
→	9	THF [0.3]	Lil	75	78%	9:1 (10:1)b	90%
	10c	THF [0.3]	Lil	75	72%	7.5:1	88%

^aYields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR of crude reaction mixtures. Enantioselectivities were determined by chiral stationary phase HPLC analysis.

^bDiastereoselectivity was determined after chromatographic purification.

^cHClRu(CO)(PPh₃)₃ (5 mol%). See Supporting Information for experimental details.

Optimal conditions identified for the formation of 4a were applied to structurally diverse benzylic and hetero-benzylic alcohols 2b-2p (Table 2). As illustrated by the formation of adducts 4a-4g, diverse substitution patterns of the benzene ring, including ortho-substituents, are tolerated. Additionally, as demonstrated by the formation of adduct 4b, the reaction conditions are sufficiently mild that pinacol boronates are tolerated. Adducts 4h-4p derived from hetero-benzylic alcohols incorporating furan, thiophene, benzothiazole, pyrrole, pyrazole, pyridine and pyrimidine rings also were formed in an efficient and selective manner. The conversion of alcohols 2a-2p to adducts 4a-4p represent redox-neutral hydrogen auto-transfer processes. The corresponding aldehydes 3a-3p also can be transformed to adducts 4a-4p via 2-propanol-mediated reductive coupling under otherwise identical reaction conditions. Notably, reactions conducted from the aldehyde oxidation level generally displayed slightly higher yields and stereoselectivities, which is attributed to more efficient capture of the transient allylruthenium nucleophiles.

Table 2.

Diastereo- and enantioselective ruthenium-catalyzed C-C coupling of alkoxyallene 1a with benzylic alcohols 2a-2p and aryl aldehydes 3a-3p to form mono-protected syn-sec,tert-diols 4a-4p.^a

^aYields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR of purified materials. Enantioselectivities were determined by chiral stationary phase HPLC. Standard conditions: 0.2 mmol scale. See Supporting Information for experimental details.

^b10% catalyst.

^c48h.

Aliphatic alcohols did not react efficiently under the optimal conditions for the formation of 4a. To facilitate the carbonyl addition process, the reaction was conducted from the aldehyde oxidation level at slightly higher catalyst loadings in a less Lewis basic solvent, DIPE (diisopropyl ether), to promote association of the aldehyde with the allylruthenium intermediate (see Supporting Information for selected optimization experiments). Under these conditions, aliphatic aldehydes 3q-3ee engage in efficient 2-propanol-mediated reductive coupling with allene 1a to furnish adducts 4q-4ee (Table 3). syn-Diastereoselectivities ranging from 8:1 to 15:1 were accompanied by excellent levels of enantioselectivity (87-99% ee). Additionally, a series of chiral β-stereogenic aldehydes 3ff, 3gg, 3hh, 3ii and 3jj were subjected to reductive coupling with allene 1a using catalysts modified by (R)- and (S)-BINAP. In each case, excellent levels of catalyst-directed asymmetric induction were observed. The utility of this method is highlighted by conversion of adduct 4r to (−)-citreodiol, a secondary metabolite of the ascomycetous fungi Penicillium citreoviride B (Scheme 2).^19,20

Table 3.

Diastereo- and enantioselective ruthenium-catalyzed reductive C-C coupling of alkoxyallene 1a with aliphatic aldehydes 3q-3jj to form mono-protected syn-sec,tert-diols 4q-4jj mediated by 2-propanol.^a

^aYields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR of purified materials. Enantioselectivities were determined by chiral stationary phase HPLC. Standard conditions: 0.2 mmol scale. See Supporting Information for experimental details.

^b10% catalyst.

^c48 h.

Scheme 2.

Total synthesis of (−)-citreodiol.

To corroborate the catalytic mechanism, a series of deuterium labelling experiments were performed (Scheme 3). Under standard reaction conditions, d₂-3-furfuryl alcohol deuterio-2h is converted to deuterio-4h-I which completely retains deuterium at the carbinol position. Deuterium is transferred to the internal vinylic position (56% ²H at H_c) and the terminal vinylic position (13% ²H at H_a). These data suggest dehydrogenation of the primary alcohol is irreversible due to rapid allene hydroruthenation at the central allene carbon atom, and that the secondary alcohol product is resistant to dehydrogenation due to internal coordination of the alkene. In a related experiment, 3-furfural 3h is subjected to standard reductive coupling conditions mediated by d₈-2-propanol. Deuterium is transferred to the internal vinylic position (71% ²H at H_c) and the terminal vinylic position (7% ²H at H_a). The absence of deuterium at the carbinol position again suggests the secondary alcohol product is inert with respect to dehydrogenation and that allylruthenium generation occurs via hydroruthenation at the central allene carbon atom. In both experiments, deuterium loss is attributed to H/D-exchange involving adventitious water and, in the former experiment, the hydroxyl functional group of the primary alcohol reactant.²¹ It is notable that deuterium is incorporated at Ha but not Hb in both experiments, suggesting a strong kinetic stereocontrol in the allene hydroruthenation event, possibly due to coordination of ruthenium to the ether oxygen.

Scheme 3.

General catalytic mechanism as corroborated by isotopic labeling studies.

Based on these data, the indicated reaction mechanism is proposed (Scheme 3). Hydroruthenation of alkoxyallene 1a delivers (Z)-σ-allylruthenium species I in which internal coordination of the benzhydryl ether oxygen to ruthenium defines alkene stereochemistry. Aldehyde coordination triggers carbonyl addition by way of a closed six-centered transition structure II, resulting in the formation of the homoallylic ruthenium alkoxide III. Exchange with a primary alcohol reactant releases product and forms the ruthenium alkoxide IV, which upon β-hydride elimination generates the aldehyde and the ruthenium hydride V. That internal chelation defines (Z)-stereochemistry of the transient allylruthenium intermediate is corroborated by reactions of alkoxyallenes 1a vs 1b (eq. 1). Alkoxyallene 1b contains a smaller benzyl ether and, hence, is anticipated to form a more stable chelate than alkoxyallene 1a, which incorporates a larger benzhydryl ether. Indeed, the reaction of the less hindered alkoxyallene 1b proceeds with higher levels of syn-diastereoselectivity but with significantly lower levels of enantioselectivity. A related bis-(1-napthyl)-alkoxyallene was prepared but coupling product was not observed upon exposure to 3a under standard conditions. Preparation of tertiary allenic ethers could not be achieved, as lithiation occurs predominately at the γ-position.²² Attempted synthesis of the ethyl-substituted allene via lithiation of the mono-substituted alkoxyallene followed by reaction with ethyl iodide resulted in incomplete ethylation, possibly due to competing elimination.

(eq. 1)

CONCLUSIONS

In summary, we report the first enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles. This method employs an inexpensive ruthenium-BINAP-catalyst and O-benzhydryl 3-alkoxy-1,2-butadiene 1a, which can be prepared in 2 steps from benzhydryl alcohol on >15 gram scale (see Supporting Information) - attributes that make this method a practical protocol for the generation of enantiomerically enriched syn-sec,tert-diols, which appear ubiquitously among type I polyketide natural products. Two remarkable effects were uncovered: (a) the enhanced selectivity and productivity of ruthenium catalysts bearing iodide counterions,¹⁷ and (b) the oxaphilicity of the ruthenium(II) center is sufficient to direct internal chelation to form (Z)-σ-alkoxyallylruthenium intermediates. The physical basis of the “iodide effect” remains unclear, however, due to its size and stronger binding,^17,23 we speculate that the iodide counterion may accentuate energetic differences between diastereomeric transition structures and suppress catalyst decomposition pathways. Computational studies aimed at establishing the veracity of this interpretation are ongoing. This work contributes to a growing class of catalytic enantioselective carbonyl reductive couplings beyond premetalated reagents.²⁴