Diastereoselective, Catalytic Access to Cross‐Aldol Products Directly from Esters and Lactones

Abstract High oxidation‐state carbonyl coupling partners including esters and lactones were reacted with enones to give aldol‐type products directly using two‐fold organoborane catalysis. This new retrosynthetic disconnection to aldol‐type products is compatible with enolisable coupling partners, without self‐condensation, and couples the high reactivity of secondary dialkylboranes with the stability of pinacolboronic esters. Excellent chemoselectivity, substrate scope (including those containing reducible functionalities and free alcohols) and diastereocontrol were achieved to access both the syn‐ and anti‐aldol‐type products. Mechanistic studies confirmed the two‐fold catalytic role of the single secondary borane catalyst for boron enolate formation and formation of an aldehyde surrogate from the ester or lactone coupling partner.

Synthetic chemistry has continually been inspired by and sought to mimic Nature. [1]Cell membrane formation, which relies upon the synthesis of β-hydroxy-carbonyl compounds by type I and type II fatty acid synthases, is one of the most essential biological functions (Figure 1a). [2]Biologically, this is a two-step process: carbon-carbon bond formation (coupling) with a high oxidation-state carbonyl functionality to give a 1,3-dicarbonyl and subsequent chemoselective reduction to a β-hydroxy-carbonyl.The synthetic equivalent requires a Claisen condensation [3] to give the 1,3-dicarbonyl followed by chemoselective reduction to a β-hydroxycarbonyl.One-step access to β-hydroxy-carbonyls is possible chemically but requires the use of, low oxidation-state, aldehyde coupling partners (Figure 1b). [4]Chemical aldol reactions have been elegantly used to recreate the reactivity of polyketide synthases (PKS I and II) and offer synthetic alternatives to biological reactivity. [5]The high reactivity of aldehydes has necessitated the development and use of control strategies to direct cross-aldol reactivity over selfcondensation, e.g. the use of silyl enol ethers. [6]One-step access to β-hydroxy ketones using higher oxidation-state coupling partners is unknown and such a coupling would provide a unique retrosynthetic disconnection without chemical or biological precedence.
The control of enolate chemistry is key to aldol methodologies.Enolates are conventionally generated by deprotonation of a carbonyl compound using base, [7] however, rhodium-, [8] copper-, [9] and boron [10] hydrides can react with α,β-unsaturated carbonyls to give enolates (Figure 1b), including catalytic variants. [8,9,11] I all cases the formation of a β-hydroxy carbonyl product requires an aldehyde or ketone coupling partner.Dialkylboranes (HBR 2 ) have been used for the stoichiometric reduction of enones to boron enolates [10a-d] and the stoichiometric reduction of esters and lactones to alcohols. [12,13] lthough never isolated or inter- cepted at this stage, the reduction of an ester to an alcohol by a borane proceeds through an aldehyde intermediate.Thus, the potential for the catalytic generation of both the nucleophilic (boron enolate) and electrophilic (aldehyde) coupling partners of an aldol-type reaction using a single borane catalyst was postulated, and for the first time the reaction of high oxidation-state carbonyl reagents could be used to give aldol-type products (Figure 1c).Crucially, aldehyde self-condensation would be avoided by the lack of base-mediated enolate formation, and the use of lactone coupling partners would give access to substrates unamenable to conventional aldol strategies without protecting groups.
Transborylation has enabled the stoichiometric reactions of common organoboranes to be rendered catalytic, [14] however, this turnover strategy has not been applied to CÀ C bond formation or diastereoselective coupling reactions.It was hypothesised that the rates of both enone reduction to the boron enolate and ester reduction to the aldehyde surrogate could be controlled using transborylation as both require a borane catalyst and a dioxaborolane as the terminal reductant.Therefore, control of transborylation (boron-boron exchange) would control the overall reaction kinetics and enable a chemically unknown, catalytic, aldoltype reaction using high oxidation-state carbonyl coupling partners using a single catalyst (Figure 1c).Significantly, this application of transborylation would be outwith established stoichiometric and catalytic coupling, including organoboron, chemistries. [15]sing chalcone 1 a and ethyl acetate 2 a, the two-fold catalytic coupling was optimised across secondary boranes (catalyst) and dioxaborolanes (terminal reductant) (See Supporting Information section 2 for details).9-Borabicyclo-[3.3.1]nonane,[H-B-9-BBN] 2 , (15 mol%) and pinacol borane (HBpin) (5 equiv) were found to be the optimal catalytic system giving the β-hydroxy ketone 3 a with high syn-selectivity, presumably through generation and coupling of a (Z)-boron enolate.No aldehyde self-condensation product was observed.Other dialkylboranes including dicyclohexylborane and diisocamphenylborane were found to be unreactive for the ester reduction.Control reactions in the absence of the secondary borane (H-B-9-BBN) catalyst showed no coupling reaction or reduction of the ketone or enone using HBpin alone.Ethyl esters gave the best yields and diastereoselectivity.The use of phenyl and tert-butyl esters resulted in reduced yields and increased side reactions, including reduction of the enone to a saturated ketone.Replacing ethyl acetate with acetic anhydride or acetic acid also gave the β-hydroxy ketone 3 a, albeit in reduced yield (40 % and 12 %, respectively).
The use of lactones as coupling partners was next explored as this would highlight a significant advantage over traditional aldol strategies for the use of substrates bearing free alcohol groups (Scheme 1a).Generally, an aldol reaction with a hydroxyaldehyde as the coupling partner would require protection of the alcohol to prevent deactivation by the substrate oligimerisation. [18]Lactones are widely commercially available, inexpensive, and offer greater stability than aldehydes.Due to the greater reactivity with respect to esters, only 5 equivalents of lactone were required.A dialkylborane catalyst was still required for the reduction of the lactone.Chalcone 1 a was reacted with five-membered lactone, γ-butyrolactone, to give the aldol-type product with a free pendant alcohol 4 a in 77 % isolated yield and 90 : 10 d.r.The seven-member lactone, ɛ-caprolactone, was also reacted to give dihydroxy ketone 4 b in 70 % yield and 86 : 14 d.r.Scale-up of this reaction to 1 gram scale gave the product 4 b in 66 % yield which recrystallised on standing to give the syn-diastereoisomer only (23 %).The presence of substituents about the lactone did not hinder reactivity with (�)-γ-nonanoic lactone and it was successfully coupled to the syn-aldol-type product 4 c (69 %, 90 : 10 syn:anti), as a mixture of alcohol epimers reflective of the use of racemic lactone.Lactone coupling could be further applied to alkylenones, 4-hexen-2-one 4 d (52 %, isolated as single diastereomer) and 4-octen-2-one 4 e (56 %, isolated as single diastereomer).
The diastereoselectivity of the aldol reaction has been widely studied with the nature of the enolate having a direct influence on the diastereoselectivity of the β-hydroxy carbonyl product. [5]Two organoboron species are present in the reaction, H-B-9-BBN and HBpin, and both could form the reacting enolate, O-B-9-BBN enolate 5 a and O-Bpin enolate 5 b, respectively (Scheme 1c).To investigate which enolate was active, and the inherent stereoselectivity of this enolate, both enolates were independently prepared and reacted with an aldehyde under reaction conditions.In the reaction with acetaldehyde, the O-B-9-BBN enolate gave the β-hydroxy ketone in higher diastereoselectivity (> 95 : 5 d.r.) than the O-Bpin enolate (90 : 10 d.r.).The latter diastereoselectivity matched that of the catalytic reaction, thus it was proposed that enone-ester coupling proceeds through an O-Bpin enolate 5 b.Using 3,3-dimethylbutyraldehyde, the O-B-9-BBN enolate, 5 a, gave excellent diastereoselectivity (> 95 : 5 d.r.), however, the O-Bpin enolate, 5 b gave a lower diastereoselectivity (77 : 23 d.r.) than that of the catalytic reaction (84 : 16 d.r.), indicating a role for both boron enolates in some cases.
To investigate whether both enolates were contributing to the catalytic reaction, the reaction of chalcone 1 a with ethyl acetate 2 a was tracked over time (see Supporting Information Figure S11).The 1 H and 11 B NMR spectra studies revealed that the enone was fully converted to the

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corresponding Bpin enolate 5 b before any significant amount of aldol-type product 3 could be observed to form, and that the rate of enone reduction greatly exceeded that of ester reduction (See Supporting Information section 10).Moreover, at each time point the d.r.matched that of the stoichiometric reaction of the O-Bpin enolate (see Supporting Information Figure S4).
13b] However, a catalytic variant is unknown and the semi-reduction of esters or lactones has not been harnessed to enable aldehyde-type reactivity.The mechanism of this catalytic, semi-reduction was therefore investigated.Stoichiometric reaction of γ-butyrolactone with HBpin (2 equiv) gave no reduction to the lactol, 2-hydroxytetrahydrofuran, or alcohol, 1,4-butanediol, as observed by 1 H and 11 B NMR spectroscopy (See Supporting Information section 8).Upon addition of [H-B-9-BBN] 2 (15 mol%) complete reduction to the alcohol was observed (Scheme 2a).The hemiacetal derived from γ-butyrolactone, 2hydroxytetrahydrofuran, was independently reacted with stoichiometric H-B-9-BBN (2 equiv) and HBpin (2 equiv).In both cases the formation of the corresponding aldehyde, 4-hydroxybutyraldehyde, was observed.Control experi- A mechanism for the boron-catalysed reductive enoneester coupling was proposed where the catalyst, (H-B-9-BBN) , reacts with the enone to give an O-B-9-BBN enolate, I.This enolate react with HBpin to give an O-Bpin enolate, II, and regenerate the catalyst, H-B-9-BBN.Concurrently the catalytic system acts to reduce the ester to a hemiacetal intermediate, III, which can be converted into the aldehyde and reacts with the, previously generated, O-Bpin enolate to give the product β-hydroxy ketone 3, with the O-Bpin bond hydrolysed on work-up (Figure 2).In cases where highly reactive aldehyde or lactol substrates were used, aldol-type reaction proceeded through the O-B-9-BBN enolate I, i.e. the rate of CÀ C bond formation was equal or faster than transborylation of the enolate.
In summary, two-fold boron catalysis has been developed to enable the preparation of aldol-type products using a novel retrosynthetic disconnection.β-Hydroxy ketones were prepared directly from high oxidation-state carbonyl reagents with both syn-and anti-selectivity and proceeded without the observation of any self-condensation products.This application of organoborane catalysis to enone-ester and enone-lactone coupling reactions provides the first example of BÀ O transborylation in two-fold catalysis and for diastereoselective CÀ C bond formation.H-B-9-BBN and HBpin were used as the catalyst and turnover reagent for the reaction which was applied to a broad substrate scope showing tolerance to reducible functionalities and biological derivatives.Mechanistic studies identified a boron enolate and aldehyde surrogate as potential on cycle species, both of which were generated by boron catalysis enabled by BÀ O transborylation.