Enantio‐ and Diastereoselective Suzuki–Miyaura Coupling with Racemic Bicycles

Abstract Herein, we describe a rhodium‐catalyzed enantio‐ and diastereoselective Suzuki–Miyaura cross‐coupling between racemic fused bicyclic allylic chlorides and boronic acids. The highly stereoselective transformation allows for the coupling of aryl, heteroaryl, and alkenyl boronic acids and gives access to functionalized bicyclic cyclopentenes, which can be converted into other five‐membered‐ring scaffolds with up to five contiguous stereocenters. Preliminary mechanistic studies suggest that these reactions occur with overall retention of the relative stereochemistry and are enantioconvergent for pseudo‐symmetric allylic chloride starting materials. In addition, a bicyclic allylic chloride starting material without pseudo‐symmetry undergoes a highly enantioselective regiodivergent reaction.

Conventional cross-coupling procedures are powerful tools for the construction of C(sp 2 )ÀC(sp 2 )b onds. [1] Asymmetric transition-metal-catalyzed cross-coupling reactions that form C(sp 3 )-hybridized stereocenters are significantly less developed, [2] despite being highly desired for drug development. [3] In this context, complex bicyclica nd polycyclics tructures with multiple C(sp 3 )c hiral centers are attractive molecular targets.B aran and co-workers have recently reported on am odular cycloaddition/desymmetrization/cross-coupling approach towards bridged bicyclics tructures (Figure 1), [4] and Lautens and co-workers have developed ar hodiumcatalyzed hydroarylation of strained bicyclic alkenes ( Figure 1). [5] Both methods desymmetrize prochiral meso starting materials and produce multiple stereogenic centers in asingle reaction step.
Asymmetric methods that generate highly enantioenriched chiral molecules from racemic substrates are inherently attractive as there are theoretically more chiral than prochiral molecules. [6,7] While kinetic resolutions (KRs) are well explored, these procedures suffer from the intrinsic drawback of yields lower than 50 %. [7] Dynamic asymmetric processes that convert racemic mixtures of starting materials into highly enantioenriched products-theoretically quantitatively-are significantly less developed. [8] Several powerful enantioconvergent asymmetric allylic substitution reactions that use stabilized nucleophiles (pK a < 25) have been developed with different transition metals. [9] Using non-stabilized nucleophiles (pK a > 25) in enantioconvergent asymmetric allylic alkylation was found to be much more challenging and has only recently been reported. [10][11][12] Building on this work, we reported highly enantioselective rhodium-catalyzed Suzuki-Miyaura-type couplings between racemic cyclic allylic halides with sp 2 -hybridized boronic acid derivatives. [13] These procedures allow the coupling of functionalized and heterocyclic coupling partners,apowerful strategy for drug development, [14] and are practical as they share many of the same features that make standard Suzuki-Miyaura reactions popular;t hey use experimentally convenient and often commercially available boronic acid derivatives. [15] In order to help address the longstanding need for crosscoupling products with increased three-dimensional shape in the pharmaceutical industry, [14] we wanted to examine bicyclic allylic halides as substrates for rhodium-catalyzed asymmetric arylation. Thedevelopment of such aprocedure would allow am odular cross-coupling between two components and absolute control over multiple stereogenic centers in as ingle reaction step.C hallenges in developing the method include how to achieve high enantio-and diastereoselectivity from addition to two different chiral species,and the inherent steric congestion of 1,2,3-trisubstitued cyclopentenes,w hich makes this transformation challenging. [16] Comparable transformations of bicyclics tarting materials have only been reported using heteroatom nucleophiles in combination with palladium catalysis. [17] Herein, we present an enantio-and diastereoselective rhodium-catalyzed Suzuki-Miyaura-type coupling with racemic bicyclic allylic chlorides and discuss mechanistic aspects of this reaction.
Using bicyclicallylic chloride (AE)-1 as amodel compound, we examined conditions similar to those reported for the coupling of 1-chlorocyclohex-2-ene and aryl boronic acids. [13] (S)-L1 and (S)-L2 in combination with [Rh(cod)OH] 2 and Cs 2 CO 3 in THF at 65 8 8Ca fforded the product 3aa with moderate enantioselectivity and incomplete conversion (see Table 1, entries 1a nd 2). Thep roducts were obtained with relative trans stereochemistry.Changing the base to aqueous CsOH (50 wt %) improved the conversion significantly (entries 2a nd 3). Different bidentate phosphine ligands were tested (entries 3-11), and excellent enantioselectivities and yields were only obtained with SEGPHOS-type ligands. (S)-L8 and (S)-L9 gave comparable results whereas more sterically demanding (S)-L10 gave low conversion and lower enantioselectivity.L igand (S)-L8 was chosen for further experiments.T he reaction is highly diastereoselective,a nd we were only able to observe trace amounts of the minor diastereomer (dr > 20:1) in crude reaction mixtures.
With optimized conditions in hand, we investigated the boronic acid scope (Scheme 1). Abroad range of substituted aryl boronic acids gave good to excellent yields and excellent enantioselectivities.B oth electron-rich and -poor boronic acids as well as halogenated aryl boronic acids gave good to excellent results (Scheme 1a,p roducts 3aa-3aj)b ut the present conditions are not suitable for boronic acids bearing ortho substituents.M ore challenging boronic acids bearing functional groups such as acetyl, olefin, and cyano groups as well as difluoroarenes were compatible with our reaction conditions (3ak-3an). In many cases,w eobserved protodeborylation [18] and homocoupling of the boronic acid, and unreacted allylic halide was recovered. Extended reaction times generally do not improve the yields of the coupling products.
Heteroaryl and alkenyl boronic acids are known to be challenging coupling partners in Suzuki-Miyaura couplings because of rapid protodeborylation. [18] Under our conditions, heteroaryl boronic acids,i ncluding 2-chloropyridine,3 -thiophene,and an azaindole,were well tolerated, with good yields and excellent enantioselectivities (Scheme 1b). Fora lkenyl boronic acids including (E)-styrene and (E)-alkenyl boronic acids ligand L2 was used in order to achieve higher levels of stereoselectivity (Scheme 1c). [19] We subsequently prepared additional coupling partners that are pseudo-symmetric about the allyl chloride unit  . These substrates required only minimal alterations from the above reaction conditions to achieve excellent results.F or each substrate (Scheme 2), we examined several coupling partners and found that these allowed for absolute control over multiple stereogenic centers in as ingle reaction step.A llylic chloride (AE)-1b showed competing hydrolysis under the reaction conditions but still allowed for highly stereoselective coupling reactions in moderate to good yields. [20] Then itrogen-containing allylic chlorides (AE)-1c and (AE)-1d required slightly increased temperature (heating to 80 8 8Ci nasealed flask) to achieve full conversion with phenylboronic acid and consistently gave excellent enantioselectivities. [21] Our protocol is very robust and is easily scalable with almost identical results obtained on a6 .0 mmol scale (Scheme 3a)t og ive 1.2 go fc oupled product. Thed ownstream reactivity of the obtained products was also investigated (Scheme 3b). Thec yclic acetal group of 3aa and the sulfamide of 3cacan be cleaved to give cyclopentenes bearing vicinal diols (4)and amines (5)with three defined stereogenic centers in high yields.T his illustrates the utility of af used bicyclicp rotecting group in as ynthetic sequence.F urthermore, 3aawas dihydroxylated to give cyclopentene 6 with five contiguous stereocenters.
In order to gain ab etter understanding of the observed process of enantioconvergence, we monitored the enantiomeric excess of allylic chloride 1a and product 3aa over time at 40 8 8C( Scheme 4a). [22] While the ee of 3aa was constant, ak inetic resolution of the racemic allylic chloride occurred, with enantiomerically pure starting material being observed at about 75 %c onversion. However,t here is no apparent change in the rate of product formation with the observed resolution at about 50 %c onversion, and so the step that resolves the allyl chloride is unlikely to be the rate-determining step.
We propose the following mechanism in order to explain the enantioconvergence,r esolution of starting material, and retention of the relative stereochemistry in the reaction (Scheme 4b). Following transmetalation of the aryl boronic acid to aRh I -hydroxide complex, [23] oxidative addition of the allylic chloride occurs via insertion into the C À Cl bond or a syn S N 2'-type mechanism. As reductive elimination also occurs syn,a no verall retentive process is observed, maintaining the relative trans stereochemistry between the fused ring and the chloride in the starting material and the arene substituent in the product. This mechanism is different to those proposed in previous studies on Rh-catalyzed arylations of cyclic allylic halides where anti oxidative addition was believed to occur. [13] We propose that both enantiomers of the allylic chloride give the same pseudo-meso Rh-p-allyl complex.
Based on this mechanistic proposal, we expected that only ap seudo-symmetric bicyclica llylic halide (structures with acorresponding meso carbocation) could converge to asingle isomer of desired product. To test this hypothesis,w e subjected (AE)-1e as as ingle regioisomer to our standard reaction conditions (Scheme 4c). Twor egioisomers were Scheme 2. Rhodium-catalyzed asymmetric cross-couplingofdifferent allylic chlorides. All experiments were performed on 0.4 mmol scale. All compounds were isolated as single diastereomers (dr > 20:1). Enantiomeric ratios were determined by SFC analysis on achiral nonracemic stationary phase. †Ligand (S)-L2 used instead. formed in a1 :1 ratio with excellent enantiocontrol (98 and 99 %e e) but with decreased diastereoselectivity (trans isomers favored over cis by a4:1 and 5:1ratio). This process is an enantioselective regiodivergent reaction of ar acemic mixture where as ingle catalyst is used to convert each enantiomer of the starting material into ad ifferent product with high ee. [24] Regiodivergent reactions of racemic mixtures differ from parallel kinetic resolutions (PKRs), where two different chiral agents or catalysts react with the two different enantiomers. Here,t he complete absence of any matched/mismatched effects,w hich would lower the ee of one of the formed regioisomers,i sr emarkable. [25] Such an asymmetric regiodivergent reaction could potentially be au seful strategy in the synthesis of compound libraries and gives easy access to enantiopure compounds.Inaddition, this experiment suggests that sterically demanding groups about the allylic chloride are required to achieve the excellent levels of trans/cis diastereoselectivity observed with substrates 1a-1d.
In summary,w eh ave developed ah ighly enantio-and diastereoselective Suzuki-Miyaura cross-coupling reaction between bicyclic allylic chlorides and boronic acids.T he method gives access to ab road range of valuable,h ighly functionalized, and novel aryl-, heteroaryl-, and alkenylsubstituted fused-bicyclic cyclopentenes.P reliminary mechanistic experiments suggest that syn-selective oxidative addition to form apseudo-meso endocyclic allylic rhodium species occurs,f ollowed by rate-and enantiodetermining reductive elimination, to give as ingle enantiomer of product from racemic starting materials with overall retention of the relative configuration. This approach provides access to complex chiral structures in am odular way,a nd we envision its ready application in target synthesis and drug development.