Diastereo-, Enantio-, and anti-Selective Formation of Secondary Alcohol and Quaternary Carbon Stereocenters by Cu-catalyzed Additions of B-Substituted Allyl Nucleophiles to Carbonyls

Abstract

A general method for the synthesis of secondary homoallylic alcohols containing α-quaternary carbon stereogenic centers in high diastereo- and enantioselectivity (up to >20:1 dr and >99:1 er) is disclosed. Transformations employ readily accessible aldehydes, allylic diboronates, a chiral copper catalyst, and proceed by γ-addition of in situ generated enantioenriched boron-stabilized allylic copper nucleophiles. The catalytic protocol is general for a wide variety of aldehydes as well as a variety of 1,1-allylic diboronic esters. Hammett studies disclose that diastereoselectivity of the reaction is correlated to the electronic nature of the aldehyde, with dr increasing as aldehydes become more electron poor.

Graphical Abstract

Numerous biologically important compounds contain quaternary carbon stereogenic centers, and catalytic enantio- and diastereoselective reactions that deliver them are highly desirable.¹ Homoallylic alcohols comprising a vicinal carbon stereocenter can be prepared by catalytic additions of substituted allyl fragments to aldehydes,^2,3,4 however, related transformations that deliver quaternary carbon stereogenic centers enantio- and diastereoselectively, is difficult. While there are many examples for the construction of quaternary stereocenters via aldehyde allylation,⁵ few enantioselective methods exist. Prior disclosures include the enantiospecific intermolecular addition reactions of allylzincs derived from enantioenriched alkynylsulfoxides,⁶ as well as transformations with enantioenriched allylsilanes⁷ and allylboronic esters.⁸ In contrast, catalytic enantioselective versions are scarce.⁹ One study shows the catalytic enantioselective reactions of γ,γ-disubstituted allyl trichlorosilanes with aldehydes are efficiently promoted by chiral bisphosphoramide (Scheme 1A).¹⁰ Another disclosure includes a Cr-catalyzed allylation utilizing γ,γ-disubstituted allylchlorides (Scheme 1B); however, the use of four transition metals, two in stoichiometric amounts, detracts from the method.¹¹ Elegant studies by Krische describe Ir-catalyzed reductive couplings of vinyl epoxides, dienes, and allenes with in situ generated aldehydes (Scheme 1C).¹² A more recent approach involves a dual isomerization/enantioselective allylation sequence with allylic alcohols and homoallylic boronic esters, catalyzed by an Ir/chiral phosphoric acid protocol.¹³ In the case of quaternary stereogenic centers, however, a wide range of dr and er were observed.

Scheme 1.

Catalytic Enantioselective Additions to Aldehydes with γ,γ-Disubstituted Allyl Reagents

While significant advances in quaternary stereocenter synthesis by aldehyde allylation have been made, addition to alkyl aldehydes remains a significant challenge, and variation at the quaternary carbon center is largely absent. Furthermore, very few catalytic, enantioselective methods exist that afford products in high diastereo- and enantioselectivities. Our objective was the development of a general protocol for setting quaternary centers in homoallylic alcohols by employing γ,γ-disubstituted allylic 1,1-diboronate esters. Allylic 1,1-diboronic esters have been employed in the crotylation and prenylation of aldehydes,^14,15 however, extension of these methods for enantio- and diastereoselective allyl addition beyond prenylation to set quaternary stereocenters has not been achieved.

Encouraged by our previous studies regarding the enantio- and diastereoselective reactions of γ,γ-disubstituted allylic 1,1-bis(boronates) with aldimines¹⁶ and ketones,¹⁷ we envisioned the stereoselective reaction in Scheme 1E. The enantio- and diastereoselective preparation of complex secondary homoallyl alcohols with vicinal quaternary carbon stereocenters bearing a functional E-alkenylboron can be achieved by catalytic reactions between an array of aldehydes (1) and readily accessible stereodefined 2.

We began our studies with the reaction of benzaldehyde (1a) and allyl diboronic ester 2a (Table 1). Initial control reaction between 1a and 2a in THF at −60 °C followed by an aqueous (entry 1) and NaBH₄ (entry 2) workup, revealed significant background addition of unreacted 2a occurs upon workup (38% conv, >20:1 dr vs <2% conv). This outcome highlighted the need for a reductive quench during catalyst optimization. In the presence of 5 mol % CuOtBu, 10 mol % ligand, and 1.05 equiv MeOH in THF at −60 °C, several classes of chiral ligands were examined. Bidentate phosphines L1–3 proved ineffective; <2–8% conversion to 3a (entries 3–5). Switching to phosphoramidite L4 delivered 3a in 89% yield (>98:2 γ-allylation) in 2.7:1 dr and >99:1 er (entry 6). Notably, <2% conversion to 3a is observed in the absence of methanol (entry 7). Investigation of phosphoramidite 3,3’-aryl substitution (entries 8–10) identified 3,5-i-Pr-4-OMe substitution (L7) as optimal (>99:1 er, 4:1 dr) (entry 10). In an effort to further improve the dr, the reaction with L7 was run at −78 °C, however, this resulted in no improvement in selectivity. To test if a reductive workup was necessary given the high conversion with L7 in 16 h, the equivalent reaction with aqueous workup was found to afford a near identical result (98% NMR yield, 4:1 dr, 98.5:1.5 er). Consequently, provided catalytic reactions proceed to >98% consumption of aldehyde, a reductive work up is not required.¹⁸

Table 1.

Reaction Optimization^a

entry	ligand	alcohol	NMR yield (%)b	drb	erc
1d	-	-	38	>20:1	-
2	-	-	<2	-	-
3	L1	MeOH	<2	-	-
4	L2	MeOH	<2	-	-
5	L3	MeOH	8	nd	nd
6	L4	MeOH	89	2.7:1	>99:1
7	L4		<2	-	-
8	L5	MeOH	70	1.5:1	>99:1
9	L6	MeOH	>98	1:1	99:1
10	L7	MeOH	98	4:1	>99:1
11e	L7	MeOH	94	4:1	>99:1
12f	L7	MeOH	98	4:1	98.5:1.5

^aReactions performed under N₂ atmosphere.

^bNMR yield and diastereomeric ratios (dr) determined by analysis of ¹H NMR spectra of crude reactions with hexamethyldisiloxane as internal standard.

^cEnantiomeric ratios (er) determined by SFC analysis.

^dNo CuOtBu, ligand, or NaBH₄ quench.

^eReaction at −78 °C.

^fNo NaBH₄ quench. See the SI for details.

The robustness of the reaction conditions was surveyed, and it was found to be broad. As shown in Scheme 2A, a wide variety of aromatic substrates are tolerated, including those containing electron-donating groups (3b), halogens (3c–d), as well as electron-withdrawing ester (3e), nitrile (3f), nitro groups (3g–h) and trifluoromethyl (3i), to deliver products in excellent yields and er. Notably, meta and ortho substituted arenes undergo efficient and selective reaction (3h-k). Furthermore, a range of heteroarene products including pyridine (3k), furan (3l), and thiophene (3m) moieties are accessible in excellent yield and er albeit in 3:1–4:1 dr. In reaction with aldehydes containing extended π-systems, such as indole (3n), benzofuran (3o), and benzothiophene (3p), products are generated in higher diastereoselectivity in excellent yields and enantioselectivities. Moreover, synthesis of indole 3n on a 1.0 mmol scale demonstrated robustness of the protocol.

Scheme 2.

Aldehyde Scope^a

^aReactions performed under N2 atmosphere. Yields of purified products after SiO2 Chromatography. Experiments were run in duplicate. Diastereomeric ratios (dr) determined by analysis of ¹H NMR spectra of purified products. Enantiomeric ratios (er) determined by HPLC or SFC analysis. See the SI for details. ^b1.0 mmol scale.

The catalytic protocol also extends to alkenyl, alkynyl, and alkyl aldehydes (Scheme 2B). Unsaturated cinnamyl, tiglic, and cyclohexenyl aldehyde substrates are converted to homoallylic alcohol products 5a–c in excellent yield and ≥99:1 er, and 4:1–6:1 dr, respectively. In addition, reaction with enantioenriched (–)-myrtenal delivers 5d in 82% yield and 9:1 dr. Reactions of alkynyl aldehydes also react efficiently, however, a decrease in diastereoselectivity results; for example, propargylic alcohol 5e is formed in 84% yield, 2:1 dr, and 98.5:1.5 er (major) and >99:1 er (minor). High yields, and selectivity are similarly observed with more challenging, less electrophilic aliphatic aldehydes. For example, a variety of alkyl-substituted aldehydes bearing t-Bu (5f), cyclic (5g–i), and β-branching (5j) were found to react smoothly to deliver desired products in 68–99% yield, ≥99:1 er, and >20:1–4:1 dr. Additionally, no adverse effects arising from a pendant alkene moiety in reactions with 4-pentenal and (–)-citronellal to afford 5k and 5l, were observed.

Finally, scope of the quaternary carbon stereocenter was investigated by varying the substituents introduced on theallyldiboron reagent. Notably, diastereomers 6b and 6c could be synthesized stereospecifically by subjecting either E- or Z-allyldiboronates to the reaction conditions, with both obtained in high dr and er. The increased sterics associated with α-branched cyclohexyl and cyclopropyl reagents are tolerated to produce 6d and 6e in excellent yield, and selectivity. Moreover, after a single recrystallization, 6e could be enriched to 20:1 dr, and the X-ray structure obtained to confirm the relative and absolute stereochemistry. Lastly, transformations of allyl diboronate reagents containing homobenzyl and silyl ether moieties generate competent nucleophiles; for example, alkenyl and aliphatic aldehyde derived products 6g–h delivered in 4:1–6:1 dr and ≥96.5:3.5 er, are illustrative.

To assess the importance of the allyl diboronate moiety, a comparison to monoboryl reagent 7 was evaluated (Scheme 4A). Under standard conditions with a NaBH₄ quench, <5% conversion to homoallylic alcohol product 8 is observed; control reaction in the absence of Cu/L7 affords 8 in 66% NMR yield and 9:1 dr. Support for an enantio-determining transmetalation step in the reaction mechanism was provided by Swern oxidation of alcohol 3a to ketone 9 in 53% yield, and 97.5:2.5 er (Scheme 4B). The high er of the product strongly suggests an enantioselective transmetalation to form a stereodefined allylic nucleophile, and diastereoselectivity is the result of facial selectivity with the aldehyde. Further evidence for this is found in the high er of the minor diastereomer of 5e (see SI for details). To gain insight into interesting diastereoselectivity trends observed with aryl aldehydes, a Hammett plot was constructed (Scheme 4C). Satisfactory correlations between dr and the electronic effects of the substituents was observed. Notably, it was also found that substituent constant σ_p– values provided the best correlation for the electron-poor aldehydes (p-CO₂Me, p-CN, p-NO₂).¹⁹ The plot in Scheme 4C shows that electron-withdrawing substituents result in improved diastereoselectivity in the reaction (ρ = 0.96, R²= 0.95), indicating the electrophilicity of the aldehyde (vs C=O Lewis basicity) impacts the diastereoselectivity of the reaction.²⁰ This data is consistent with C–C bond formation being diastereo-determining.²¹ At larger sigma values a change in slope of the Hammett plot of opposite sign is observed (ρ = −0.26, R²= 0.95), indicating a lower sensitivity of the allyl addition reaction to electronic changes. The break in the plot is suggestive of a change in diastereo-determining step likely towards aldehyde coordination influencing stereoselectivity.

Scheme 4.

Mechanism Experiments^a

^aSee the SI for details.

The effect of catalyst versus substrate control with chiral aldehydes was examined with α-stereogenic amino aldehydes (Scheme 4D). Treatment of D-alanine-derived (R)-10 with optimal reaction conditions with Me,Me-diboron 2f results in high conversion to 11 as a 3.2:1 (C1:C2) mixture of diastereomers. In addition, when (R)-10 is subjected to the same conditions with n-Bu,Me diboron 2a, amino alcohol 12 is obtained in very similar diastereoselectivity (3.8:1 dr, (C₁:C₂)), indicating the substituents on the allylcopper do not play a significant role in affecting facial selectivity of the aldehyde. In contrast, reaction with aldehyde (S)-10 clearly indicates a matched-mismatched situation as homoallylic alcohol 13 is obtained in diminished stereoselectivity (86% yield, 1:1 dr, C1:C2).²²

Based on the above findings a catalytic cycle and stereochemical model is proposed in Scheme 5 to rationalize our observations. The reaction likely proceeds via S_E2’ transmetalation of (L)Cu–OMe (A) with diboronate 2.^23,24 Subsequent, rapid 1,3-suprafacial shift to the less sterically encumbered boron-stabilized allyl copper species C must occur faster than C–C bond rotation in B to prevent isomerization of alkene geometry.²⁵ Coordination of aldehyde 1 results in cyclization through D, affording Cu-bound product E. As apparent in the crystal structure of 6e, the large substituent occupies the pseudo-equatorial position in D, resulting in the observed diastereoselectivity. Finally, protonation of intermediate E with MeOH releases product 3 and regenerates catalyst A. The observations in Table 1, that show MeOH is required for product formation and to obtain high er, can be rationalized by slow reaction between E and 2, as well as the requirement of (L7)-Cu–OMe species to facilitate highly enantioselective transmetalation. The enantioselective formation of intermediate C is supported by the enantiomeric ratio of the minor diastereomers, which in most cases is high (see 5e, and SI for details).²⁶

Scheme 5.

Proposed Catalytic Cycle and Stereochemical Model

The utility of the method is showcased by the various chemical transformations depicted in Scheme 6. First, we investigated the reduction of enantio-enriched benzylic alcohol in 3b (3:1 dr) by treatment with CF₃CO₂H and HSiEt₃ in CH₂Cl₂ to afford deoxygenated product 14 in 82% yield (Scheme 6A).²⁷

Scheme 6.

Synthetic Utility^a

^aSee the SI for details.

Oxidation of the alkenyl boronic esters 3f and 3h results in hemiacetal formation (Scheme 6B), which followed by either PCC oxidation or silane reduction delivers substituted lactone 15 and tetrahydrofuran 16 in 95% an 50% overall yield, respectively. The versatility of the alkenyl boronic esters moiety was also demonstrated to be effective in Suzuki cross couplings; for example, Pd-catalyzed reaction of 3n with 3-bromopyridine affords N-heterocycle 17 in 44% yield and 13:1 dr. Lastly, the ability of the method to efficiently construct multiple acyclic quaternary carbon stereocenters was demonstrated by a three-step telescoped sequence (Scheme 6C). Beginning with indole 3n, TBS protection of the alcohol followed by alkenyl boron oxidation results in the crude aldehyde, which was then subjected to Cu-catalyzed allyl addition with E-2b to afford alcohol 18 in 24% overall yield, and 9:1 dr with respect to the new stereogenic centers.

In conclusion, we have developed a versatile, robust Cu-catalyzed protocol for the enantio-, diastereo-, and anti-selective synthesis of vicinal homoallyl alcohol and quaternary carbon stereocenters. The method offers both broad aldehyde and quaternary stereocenter scopes utilizes a simple (phosphoramidite)-Cu catalyst. Mechanism studies provide support for the intermediacy of an enantioenriched allyl copper species, as well as reveal a pronounced electronic effect of substituents on diastereoselectivity. Studies are ongoing to understand the factors that control stereoselectivity, and to further develop stereoselective reactions with allyl diborons.

Scheme 3.

1,1-Allylic Diboron Scope^a

^aSee Scheme 2. See the SI for details.