Rhodium-Catalyzed Enantioselective Intermolecular Hydroacylation Reactions*

Pure Appl. Chem., Vol. 83, No. 3, pp. 577–585, 2011. doi:10.1351/PAC-CON-10-09-23 © 2011 IUPAC, Publication date (Web): 31 January 2011 Rhodium-catalyzed enantioselective intermolecular hydroacylation reactions*

Carlos González-Rodríguez and Michael C. Willis‡

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK

Abstract: Rhodium-catalyzed enantioselective hydroacylation reactions allow rapid access to chiral substituted ketones. However, due to the low reactivity of disubstituted alkenes in intermolecular versions of this process, only a small number of asymmetric intermolecular reactions have been described. Strategies employed to avoid reactivity issues include the use of norbornadienes, linear dienes, acrylamides, and allenes as the alkene components. In addition, our laboratory has recently reported the rhodium-catalyzed enantioselective intermolecular alkyne hydroacylation reaction, leading to the formation of enone products via a kinetic resolution procedure.

Keywords: aldehydes; alkynes; enantioselective catalysis; phosphines; rhodium.

INTRODUCTION The development of new enantioselective reactions remains a considerable challenge in modern organic chemistry. Transition-metal catalysis has been responsible for a number of important contributions in this area [1]. The intermolecular hydroacylation reaction between aldehydes and alkenes or alkynes is a highly atom-economic method for the preparation of unsymmetrical ketones or α,β-unsaturated enones [2]. A limitation of the method is the formation of products resulting from decarbonylation of the key acyl metal hydride intermediate (I, Scheme 1). One successful approach to limit decarbonylation has been to stabilize the acyl metal species by chelation [3,4].

Scheme 1 An alkene hydroacylation reaction and the undesired decarbonylation process.

Paper based on a presentation made at the 18th International Conference on Organic Synthesis (ICOS-18), Bergen, Norway, 1–6 August 2010. Other presentations are published in this issue, pp. 411–731. ‡Corresponding author

577 578 C. GONZÁLEZ-RODRÍGUEZ AND M. C. WILLIS

Over the last several years, our laboratory has developed the use of β-S-chelating aldehydes as substrates for rhodium-catalyzed alkene and alkyne hydroacylation reactions (Scheme 2) [5]. The use of a β-sulfide group leads to the formation of a stabilized five-membered intermediate II, allowing hydroacylation reactions to proceed without decarbonylation under mild conditions and in high yields. The methodology has also been extended to include thioacetal-substituted aldehydes [6].

Scheme 2 Intermolecular Rh-catalyzed hydroacylation reactions using β-S-chelating aldehydes.

ENANTIOSELECTIVE INTERMOLECULAR HYDROACYLATION REACTIONS Although a number of achiral intermolecular hydroacylation reactions have now been described, reports of asymmetric reactions are still limited. This is in contrast to the intramolecular variant of the reaction, for which a number of highly efficient and selective reactions have been developed [7]. The first examples of these highly enantioselective cyclizations were described by both Sakai and Bosnich for the con- version of 4-pentenals (1) to give cyclopentanone products (2), catalyzed by chiral cationic rhodium complexes (Scheme 3) [8].

Scheme 3 Asymmetric intramolecular alkene and alkyne hydroacylation reactions.

The first example of a hydroacylative alkynal cycloisomerization was described by the Fu group, and employed racemic 4-alkynal substrates (3) in a kinetic resolution process (Scheme 3) [9]. Desymmetrizing and parallel kinetic resolution variants of this process have also been described [10]. Although intramolecular enantioselective hydroacylation reactions have been well documented, there are fewer examples of the corresponding intermolecular transformations. Challenges to be addressed in developing these asymmetric intermolecular reactions include stabilization of the key acyl metal intermediates, identification of selective chiral catalysts, and identifying suitably reactive aldehyde and alkene combinations. This last factor is particularly challenging as di- and tri-substituted alkenes often display low reactivity in hydroacylation reactions [11]. The first example of an enantioselective intermolecular hydroacylation reaction was described by the Bolm group and was based on the combination of salicylaldehydes and norbornadiene-type alkenes (Scheme 4) [12]. They found that it was possible to modulate the diastereoselectivity of the reaction using bidentate or monodentate ligands. For example, when bidentate phosphine ligands such as fer- rocene-based 4 were employed, the exo-isomers were obtained with good enantioselectivity (up to 82 % ee). When monodentate phosphate or phosphoramidite ligands such as 5 were used, the endo-isomers were obtained as the major products, albeit with only moderate enantioselectivity. The exo-selectivity obtained with bidentate phosphines was explained by the absence of a vacant site in the metal sphere for the coordination of the second alkene group of the norbornadiene.

Scheme 4 Bolm’s enantioselective salicylaldehyde-based alkene hydroacylation reactions.

The Suemune group has also developed enantioselective intermolecular hydroacylation reactions based on salicylaldehyde substrates. In this second system, 1,5-hexadiene substrates were employed to provide branched-selective hydroacylation products via a double-chelation model in which both the aldehyde and the diene act as chelating components (Scheme 5) [13]. Good enantioselectivities (up to

Scheme 5 Suemune’s diene-based enantioselective hydroacylation chemistry.

78 % ee) were obtained for reactions employing (S)-BINAP (6) as the chiral ligand; however, the reactions were not completely regioselective, and linear, achiral products were also isolated. The Tanaka group has reported a highly enantioselective Rh-catalyzed intermolecular hydroacylation process using unfunctionalized aldehydes (7) and 1,1-substituted acrylamides (8) as the reaction components (Scheme 6) [14]. In this system, instead of relying on chelating aldehydes to stabilize the key reaction intermediates, stabilization was achieved by bidentate coordination of the acrylamide substrates to the metal center [15]. In addition, this coordination was also invoked to account for the high enantioselectivity observed (up to 98 % ee). The reactions employ the P-chiral bisphosphine lig- and QuinoxP* (9).

Scheme 6 Tanaka’s acrylamide-based enantioselective hydroacylation.

ENANTIOSELECTIVE INTERMOLECULAR HYDROACYLATION REACTIONS EMPLOYING ␤-S-CHELATING ALDEHYDES In 2008 our group reported an enantioselective intermolecular hydroacylation reaction employing β-S-substituted aldehydes in combination with 1,3-disubstituted allenes [16]. Excellent enantio - selectivities and yields were obtained using a Me-Duphos-derived cationic rhodium catalyst [17]. By employing 1,3-disubstituted allenes 11 as more reactive equivalents of disubstituted alkenes, it was possible to obtain chiral β,γ-enones 12 via a dynamic kinetic asymmetric transformation involving in situ racemization of the allenes (Scheme 7). The process was more selective when the rigid aromatic aldehyde 10 was employed, allowing ees as high as 96 % to be obtained. Both electron-withdrawing or -donating groups could be tolerated on the allene substrates. Extension of the chemistry to tri-substituted allene substrates resulted in products with high ee, but unfortunately in only low yields.

Scheme 7 The Willis group’s enantioselective allene hydroacylation chemistry.

The examples described so far illustrate how specific substrate combinations are required to achieve an efficient intermolecular hydroacylation process. The main reason for this is the low reactivity of disubstituted alkenes in the reaction; only in the Bolm chemistry were 1,2-disubstituted alkenes employed, and in these cases reactive norbornadienes were used (Scheme 4). In the other examples, linear dienes, acrylamides, or allenes were used as the alkene components (Schemes 5, 6, and 7). A limitation of these methods is therefore the lack of variation possible in the choice of substrates. We proposed that a more general enantioselective hydroacylation reaction could be achieved using alkyne substrates. Employing substituted-β-S-aldehyde substrates, the methodology would allow access to more complex enantioenriched enone products. To achieve this goal we have developed the enantioselective synthesis of α- and β-substituted enones using rhodium-catalyzed kinetic resolutions (Scheme 8) [18].

Scheme 8 Enantioselective alkyne hydroacylation using kinetic resolution.

We first established that aromatic and heteroaromatic S-substituted thioaldehydes (13) could be combined with a range of alkynes using a Me-DuPhos-derived catalyst (Scheme 9). Variations in the structure of the alkyne were also possible, and the enantioenriched products were obtained for aromatic, alkyl, or silylated acetylenes, with selectivity factors (s) ranging from 20 to 45 [19].

Scheme 9 Synthesis of β-substituted enones via kinetic resolution.

When the aldehyde β-substituent was changed to an alkyl group, such as methyl (15), the enantioselectivity of the reaction decreased, and in order to achieve higher selectivity it was necessary to employ the diphosphine ligand Duanphos 16 (a ligand previously employed in ketone hydroacylation) [20]. Under these new conditions, and by changing the solvent to the more coordinating acetone, it was possible to obtain good selectivities (s = 12–17), but at a level lower than for the aromatic substituted aldehydes (Scheme 10). An interesting result was observed when 3-(phenylthio)butanal 17 was used as a substrate, as only unreacted starting materials were recovered from the reaction. The bulkier substi- tution on the sulfur group presumably results in either difficulty in forming a stable chelated-intermediate, or in a formed chelated-intermediate being unable to react with the alkyne due to increased steric hindrance.

Scheme 10 Reactions of methyl-substituted aldehyde 15 and SPh-aldehyde 17.

In addition to the high yields and enantioselectivities obtained for the β-substituted aldehyde substrates, we were able to show that by using similar conditions it was also possible to achieve enantioselective reactions for α-substituted aldehydes 18 (Scheme 11). Again, higher selectivities were observed for the aromatic substituted examples, such as phenyl or p-tolyl, with lower selectivities obtained with alkyl-substituted substrates. A range of alkynes could again be employed.

Scheme 11 Synthesis of α-substituted enones via kinetic resolution.

Several of the more selective hydroacylation reactions allowed the unreacted aldehyde starting material to be isolated in enantioenriched form. This has allowed us to achieve two sequential hydroacylation reactions in a one-pot process, to obtain two different enantioenriched ketones, 14 and 20, with opposite absolute stereochemistry (Scheme 12). The first ketone product results from the standard kinetic resolution reaction, and the second originates from the combination of the second alkyne substrate (hexyne in this example) with the unreacted, but enantioenriched, starting aldehyde.

Scheme 12 One-pot sequential alkyne hydroacylation reactions.

To demonstrate the utility of the enantioenriched α- and β-substituted ketone products obtained from the kinetic resolution chemistry, we have explored their use in some simple carbonyl reduction α processes (Scheme 13). Using the -substituted enone 19, direct reduction in presence of LiAlH4 at low temperature produced the corresponding syn-configured allylic alcohol 21 in good yield and with excellent diastereoselectivity. The configuration of the product is consistent with hydride addition to the less hindered position predicted using the Felkin model [21]. Chelation-controlled reduction [22] of β-substituted enone 14 with Zn(BH4)2 provided syn-allylic alcohol 22 in excellent yield and diastereo - selectivity. The configuration obtained can be rationalized by considering hydride addition to the less hindered axial position in a six-membered chelated-intermediate.

Scheme 13 Stereoselective reduction of α- and β-substituted ketones.

In conclusion, we have developed an efficient kinetic resolution-based method for the rhodium- catalyzed enantioselective hydroacylation of alkynes. Both α- and β-substituted aldehydes can be employed to deliver substituted enone products with good selectivities. This contribution expands the scope of products that are accessible using enantioselective intermolecular hydroacylation reactions, the majority of which are based on the use of alkene substrates. Despite the important advances in the field of enantioselective intermolecular hydroacylation that have taken place over the last few years [23], sig- nificant limitations still remain. In particular, reactions which are general with regard to both aldehyde and alkene (or alkyne) structure, are yet to be realized. These present ideal challenges for the future.

ACKNOWLEDGMENTS We thank the EPSRC (Advanced Research Fellowship to MCW), Xunta de Galicia PGIDIT-INCITE and FSE (Angeles Alvariño contract and Estadías grants: 2008/178, 2009/188, and 2010/163 to CGR) for support of this work.

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