Catalytic Enantioselective Synthesis of 1,4-Keto-Alkenylboronate Esters and 1,4-Dicarbonyls.

Abstract

A catalytic enantioselective method for the synthesis of 1,4-ketoalkenylboronate esters via a rhodium-catalyzed conjugate addition pathway is disclosed. A variety of novel, bench-stable alkenyl gem-diboronate esters are synthesized. These easily accessible reagents react smoothly with a collection of cyclic α,β-unsaturated ketones, generate a new C–C bond and stereocenter. Products are isolated in up to 99% yield, >20:1 E/Z, and >99:1 er. Mechanistic studies show the site-selectivity of transmetalation and reactivity is ligand dependent. The utility of the approach is highlighted by gram-scale synthesis of enantioenriched cyclic 1,4-diketones, and stereoselective transformations entailing hydrogenation, allylation, and isomerization.

Graphical Abstract

An enantioselective method for the synthesis of 1,4-keto-alkenylboronate esters via a Rh-catalyzed 1,4-addition is disclosed. A variety of alkenyl gem-diboronate esters react smoothly with a range of cyclic enones to afford products bearing an E-alkenylboron, which are isolated in up to 99% yield, >20:1 E/Z, and >99:1 er. Mechanistic studies show the site-selectivity of transmetalation and reactivity is ligand dependent.

1,4-Dicarbonyl compounds are common motifs in natural products and serve as versatile intermediates to the synthesis of pharmaceutical scaffolds.^[1] These compounds are difficult to access as constructing their 1,4-relationship usually requires polarity inversion methods^[2] or oxidative coupling processes and chiral, pre-functionalized starting materials. The stereoselective synthesis of 1,4-dicarbonyls is highly sought after and even though recent advances have been reported, notable deficiencies still remain in this area. Most current methods for enantioselective synthesis of 1,4-dicarbonyl moieties rely on the use of stoichiometric chiral auxiliaries as demonstrated by the pioneering work of Baran,^[3] Thomson,^[4] and Maulide^[5] (Scheme 1 A). These methods employ pre-functionalized starting materials and are applicable only to generating acyclic 1,4-dicarbonyl motifs. Catalytic enantioselective methods for the synthesis of 1,4-carbonyls have largely centered around the enantioselective Stetter reaction,⁶ and the acyl anion reactivity enabled by chiral NHCs.^[7] In addition, related catalytic enantioselective umpolung reactions have been developed that employ acyl silanes,^[8] acyl radicals,^[9] and enamine radical cations,^[10] which afford good enantioselectivities, however, reactions are limited to acyclic substrates, excluding access to cyclic scaffolds.

Scheme 1.

Enantioselective Synthesis of 1,4-Dicarbonyl Compounds.

Previously, our group and others have developed catalytic enantioselective C–C bond forming methods that employ alkyl gem-diborons; for example, additions to carbonyls,^[11] imines,^[12] and allyl^[13] electrophiles, and cross coupling.^[14] In wherein the alkyl boron products serve as versatile groups for accessing a wide array of chemical functionality, including boron oxidation transformations that overall correspond to net umpolung reactivity. To address some of the deficiencies in the stereoselective preparation of cyclic 1,4-dicarbonyls, and other cyclic 1,4-functionality, we set out to examine the application of α-boryl–C(sp²)–metal nucleophiles (e.g., 2) in enantioselective conjugate addition;^[15],[16] such a process concurrently generates a C–C bond and installs an alkenyl C(sp²)-boronate ester as masked acyl synthon (3),^[17] or a functional handle for other downstream transformations (Scheme 1C). To access the requisite α-boryl–C(sp²) nucleophiles (e.g., 2) we planned to take advantage of the reactivity of 1,1-diborylalkenyl reagents (1),^[18] which have recently generated great interest in the synthetic community;^[19] however, to-date their applications have been limited to non-enantioselective bond formations such as cross coupling.^[20] Furthermore, 1,1-diborylalkenes are readily accessible bench stable reagents. Potential challenges that arise in the reaction of 1 are (i) site-specific transmetalation, (ii) the control of alkenyl boron geometry, and (iii) avoiding proto-deboration of starting material 1 or product 4. Herein, we report on the first general method for the catalytic enantioselective synthesis of cyclic 1,4-keto-alkenylboronate esters with facile access to the corresponding 1,4-diketones.

We initiated our studies with the reaction of cyclohexenone 6 with 1,1-diborylalkenylhexene 7a (Table 1). A key objective of the optimization centered on the ability to efficiently and selectively form the desired C–C bond in high enantioselectivity, and E/Z ratio while maintaining mild conditions to avoid protodeborative side reactions. When cyclohexenone 6 (1.0 equiv) and 1,1-diborylalkene 7a (1.05 equiv) are subjected to aqueous basic conditions in the presence of 2.5 mol % [Rh(coe)₂Cl]₂ and L1 at 22 °C in dioxane/H₂O for 18 h, 57% conversion to 1,4-ketoalkenylboronate ester 8 is observed as a 1:2 mixture of E/Z isomers, in >99:1 er (E) and 50:50 er (Z), respectively). Of particular note, is disparity in er corresponding to each alkene isomer, while the E-isomer is formed in high er, the Z-isomer is formed as the racemate. Phosphine ligands L2 and L3 failed to significantly improve conversion and E/Z selectivity, and Josiphos ligand L4 proved ineffective resulting in <2% conversion to 8. With phosphine ligand L5, we found that 8 was generated in 17% as a single E-olefin isomer and in 99:1 er. Improved conversion was obtained with MTBE as solvent (entry 7), and through further optimization it was found that K₂CO₃ furnished 8 in the greatest efficiency (83% conv) (entry 9). These optimal conditions met our dual requirements for high selectivity and mild reaction conditions.

Table 1.

Optimization of Rh(I)–Catalyzed α-Borylalkenyl 1,4-Addition^[a]

Entry	Ligand	Base	Solvent	Conv (%)[b]	E:Z ratio[b]	er[c]
1[d]	-	-	dioxane	100	1:3	-
2	L1	KOH	dioxane	57	1:2	>99:1(E);50:50(Z)
3	L2	KOH	dioxane	8	1:2	>99:1(E);50:50(Z)
4	L3	KOH	dioxane	20	1:3	>99:1(E);50:50(Z)
5	L4	KOH	dioxane	<2	-	-
6	L5	KOH	dioxane	17	>20:1	>99:1
7	L5	KOH	MTBE	64	>20:1	>99:1
8	L5	Na2Co3	MTBE	67	>20:1	>99:1
9	L5	K2Co3	MTBE	83	>20:1	>99:1

^[a]Reactions performed under N₂ atmosphere.

^[b]Yields and E:Z ratios determined by analysis of 400, 500, or 600 MHz ¹H NMR spectra of crude reactions with DMF as internal standard.

^[c]Enantiomeric ratios (er) determined by HPLC analysis; see the SI for details.

^[d]With [Rh(cod)OMe]₂.

With the optimized conditions in hand, we set out to investigate the scope of the 1,1-diborylalkene component in 1,4-addition (Scheme 2). We found that a wide variety of functionality was tolerated and afforded products in excellent yields and enantiomeric ratios. Furthermore, all products were furnished as single E alkene isomers where applicable. An array of trisubstituted 1,1-diborylalkenes participate in the reaction including alkyl groups 8a–c of varying steric bulk. In addition, the reaction is amenable to scalability as exemplified by the 1 gram synthesis of 8a with 1.0 mol % Rh catalyst loading. Reactions with 1,1-diborylalkenes bearing TBS ether 8d and 3-propylphenyl 8e moieties proceeded efficiently as well. Heterocycles such as indole and furan 8f and 8g participated as does 8h, derived from (R)-(+)-citronellal, offering opportunities to introduce complexity from chiral pool molecules. Unsubstituted parent ethylene 1,1-diboron was also found to be well tolerated, and upon oxidation 8i furnishes a formal acetyl conjugate addition product. Unsaturated diene products are also accessible through this method; 8j is formed in 95% yield and 98:2 er. Notable exceptions to the optimal reaction conditions are styrenyl and tetrasubstituted 1,1-diboron reagents. Such reagents undergo rapid metal-catalyzed protodeboration to the corresponding alkenyl-monoboron, which then undergo rapid alkenyl conjugate addition. To overcome this limitation and supress protodeboration a KIE effect was employed. By using D₂O in place of H₂O, reactivity could be restored albeit at the cost of incorporating a deuterium atom α to the carbonyl. Nonetheless, through the modified protocol products 8k–m could be accessed in high yield and er. Tetrasubstituted 1,1-diboron 7n proved resilient to the modified conditions (>98% protodeboration); considering the complete loss in er for Z-isomer products (Table 1, entries 2–4) it is unclear if 8n could be formed enantioselectively.

Scheme 2.

Alkenyl 1,1-Diboron Scope. Reactions performed under N₂ atm on 0.05 mmol scale with 1.0 equiv of 6, 1.05 equiv. of 7a-n, in 0.165 ml of MTBE/H₂O (10:1). Yields and enantiomeric ratios of the isolated products 8a–n are indicated below each entry (average of two runs per substrate). [a] Conversion to 8i; value determined by analysis of 600 MHz ¹H NMR spectra of crude mixtures with DMF as internal standard. [b] Product isolated and characterized as the 1,4-diketone upon oxidation. [c] Reaction with D₂O instead of H₂O.

A broad range of cyclic enones participate in the reaction with high efficiency (Scheme 3). Varying the enone ring size (5→8) 11–13, and gem-dimethyl substitution on the ring 14 were allowed. Spirocyclic enone 15, formed in 94% yield and 99:1 er, is a solid and permitted an X-ray structure to be obtained and the absolute stereochemistry to be determined as R.^[21] Cyclic enones containing an oxygen atom at the 4-position are also effective substrates, as demonstrated by the formation of 16 in 91% yield and in 94:6 er. Remarkably, 6-Me substituted enone 17, formed from racemic starting material, participates in a dynamic kinetic resolution to provide product in 95% yield, >20:1 dr, and 99:1 er. Racemic prostaglandin related 3-TBSO-cyclopentenone can also participate in the reaction through a kinetic resolution to provide 18 in 47% NMR yield, >20:1 dr, and 86:14 er. At present, unfortunately, this current method does not appear to be compatible with acyclic enones, which do not participate in C–C bond formation.^[22]

Scheme 3.

Enone Scope. Reactions performed under N₂ atm on 0.05 mmol scale with 1.0 equiv of 9, 1.05 equiv. of 7, in 0.165 ml of MTBE/H₂O (10:1). Yields and enantiomeric ratios of the isolated products 11–18 are indicated below each entry (average of two runs per substrate). [a] Conversion to 17 and 18; values determined by analysis of 400 or 600 MHz ¹H NMR spectra of crude mixtures with DMF as internal standard. [b] Product isolated and characterized as the 1,4-diketone upon oxidation.

The synthetic applicability of this method towards the gram scale synthesis of enantioenriched 1,4-diketones with lower catalyst loading, is highlighted in the efficient preparation of diketone 20 through a telescoped process. Treatment of cycloheptenone 19 with 1.0 g of indole-derived diboron 7f in the presence of 1.0 mol % Rh catalyst, followed by oxidation of the crude product with NaBO₃•4H₂O affords 1,4-diketone 20 in 87% yield and 97:3 er.

Next, we sought to garner information regarding the mechanism of 1,1-diborylalkene transmetalation.^[23],[14a] While the reaction with L5 seemed straightforward the observation of E/Z mixture of products with other L1–L3 suggested otherwise. In this regard, isotopically enriched Z-¹⁰B-7a was regioselectively synthesized (see SI for details) and subjected to a variety of reaction conditions (Scheme 5). Accordingly, if transmetalation is site-selective for the sterically less hindered E-B(pin) group, product 8a will show mass ions related to the increased abundance of ¹⁰B proportional to the transmetalation selectivity. Mass spectral analysis of 8a, formed under standard reaction conditions with Z-¹⁰B-7a (Scheme 5A), shows an isotopic composition consistent with that expected for a reaction where either boronate is transmetalated non-selectively (55:45 E-B(pin):Z-B(pin)). This surprising outcome indicates that transmetalation proceeds equally effectively from either B(pin) group, and the resulting Z-α-boryl–C(sp²)-Rh(I) species isomerizes to the E-isomer, which undergoes faster 1,4-addition. The observed isomerization is consistent with stereomutation observed in other hetero-gem-bismetallic alkenyl species.^[24] As a control reaction to check for alkoxide promoted boron exchange in Z-¹⁰B-7a,^[25] stoichiometric reaction between Z-¹⁰B-7a and one equivalent of 21 in MTBE in the absence of K₂CO₃ or H₂O/MeOH, followed by quench with 6 (2 equiv) was performed (Scheme 5B). The reaction furnished cyclohexanone 8a in 82% NMR yield (1.0:2.6 E/Z), and the isotopic composition of the separate E-8a and Z-8a isomers shows that they arise primarily from a slightly Z-selective transmetalation (34:66 E:Z), which is followed by 1,4-addition with minimal E↔Z alkenyl–Rh isomerization. The corresponding catalytic reaction with 2.5 mol % [Rh(cod)Cl]₂ in MeOH and K₂CO₃ also affords a similar result (Scheme 5C): 95% NMR yield, 1.0:3:3 E/Z, and with isotopic distributions indicating E-8a and Z-8a are formed by 33:67 E:Z TM, with slow interconversion of both alkenyl–Rh intermediates prior to 1,4-addition. The preference for TM of the Z-B(pin) likely occurs due to the sterically smaller (cod)Rh–OR being able to react more readily with the more hindered but strained Z-B(pin). Overall, these data provide a working mechanism, where (L5)-Rh reactions proceed via a non-selective transmetalation of 22 → 23 and 24, followed by alkenyl-Rh isomerization and enantioselective 1,4-addition through E-alkenyl-Rh 23. In comparison, (cod)-Rh and (L1)-Rh undergo Z-selective TM, followed by 1,4-addition from both 23 and 24 with equal facility and minimal alkenyl-Rh stereomutation. Notably, in all cases, L1–L5, only high enantioselectivity is observed in the 1,4-addition of the E-alkenyl-Rh 24.^[26] Such non-observable subtleties related to site-selective TM and isomerization could be relevant to other stereospecific reactions of 1,1-alkenyldiborons.^[20]

Scheme 5.

Mechanistic Insights of 1,1-Diborylalkene Transmetalation. See SI for details.

The 1,4-ketoalkenylboronate esters accessed through the conjugate addition method can be further elaborated through a wide variety of synthetically valuable transformations. For example, compound 8a can be easily oxidized to the corresponding 1,4-diketone 25 with no loss of er, providing a general access to otherwise inaccessible chiral, non-racemic cyclic 1,4-diketones. In addition, 8a can engage in subsequent Pd-catalyzed cross coupling to generate stereodefined trisubstituted alkenes; the synthesis of heterocycle 26 in 91% yield from 3-bromopyridine is representative. Generation of the opposite alkene isomer inaccessible through the 1,4-addition method can be achieved through a stereospecific boron–bromine exchange.^[27] Treatment of boronate ester 8a with Br₂ and NaOMe results in alkene stereoinversion to generate alkenylbromide 27 in 82% yield (>20:1 E:Z). The 1,4-keto-alkenylboronate esters also participate in a variety of diastereoselective transformations (Scheme 6B). For example, compound 15 undergoes hydrogenation in the presence of 2 mol % Crabtree’s catalyst in CH₂Cl₂ to afford the corresponding C(sp³)-boronate ester 28 in 99% yield and >20:1 dr, which can be further elaborated. Remarkably, conversion of ketone 15 to the corresponding enoxysilane, followed by a telescoped homologation and allylation sequence with chloroiodomethane and benzaldehyde, respectively, furnishes silylenolether 29 in 74% yield (2 steps) bearing two additional stereocenters formed in >20:1 dr, and a 1,1-disubstituted olefin.

Scheme 6.

Synthetic Versatility of 1,4-Ketoalkenylboronate Esters. See SI for details.

In summary, we have introduced a catalytic enantioselective conjugate addition of α-boryl–C(sp²) nucleophiles for the synthesis of 1,4-ketoalkenylboronate esters. Reactions employ easily accessible 1,1-diborylalkenes and proceed in excellent yields, dr, and er. Mechanistic data shows that the reactions with (L5)-Rh arise from a non-selective transmetalation followed by isomerization, and 1,4-addition through the E-alkenyl-Rh. The resulting 1,4-ketoalkenylboronate esters are readily transformed into the corresponding 1,4-dicarbonyls, as well as to a range of useful molecular scaffolds. Further studies on the reactivity of 1,1-diborylalkenes are in progress.

Scheme 4.

Gram-Scale Enantioselective Synthesis of 1,4-Dicarbonyl 20 with 1.0 mol % Rh catalyst loading.