Palladium-Catalyzed Asymmetric Allylic Alkylation of Electron-Deficient Pyrroles with Meso Electrophiles

Abstract

Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in 7 steps to demonstrate the synthetic utility of this transformation.

The assembly of organic molecules in an enantioselective fashion remains an important synthetic challenge. The Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) is a powerful method for the construction of several different bond types, including C–C, C–N, C–O, and C–S bonds.¹ Typically, the Pd-AAA requires the use of soft, stabilized nucleophiles, such as malonates or imides. Recently, less stabilized nucleophiles have been successfully employed in the Pd-AAA.²

The importance of nitrogen-contaning compounds makes the stereoselective construction of C–N bonds an important synthetic endeavor. Pyrrole-substituted nucleoside analogues have been shown to act as universal nucleosides in PCR amplification of DNA.³ This activity has been attributed to the the electronic distribution of the pyrrole nucleus, which interacts equally well with all four natural nucleoside bases. Further, due to the broad-spectrum anti-viral activity observed in the drug ribavirin, pyrrole-containing nucleoside analogues have been studied as isosteres for their potential antiviral properties and other useful biological activities (Figure 1).³ Likewise, these nucleoside analogues have been used to study the mechanism of action of ribavirin.⁴

Figure 1.

Representative Compounds

While nucleoside analogues have a wealth of applications, traditional syntheses of these compounds are limited by their reliance on chiral pool strategies. These strategies only provide access to the natural enantiomer of ribose. Recently, some L-nucleoside analogues have been shown to have higher potency and lower toxicity when compared to their D-enantiomer.⁵ As a result, processes that provide access to both enantiomers are desirable. Inspired by the wealth of biological activity present in pyrrole-substituted nucleoside analogues, we sought to develop a general method to utilize these nitrogen heterocycles as nucleophiles in the Pd-AAA. While pyrroles have been shown to act as competent nucleophiles in the Pd-AAA with vinyl aziridines,⁶ and in the context of a total synthesis,⁷ the generality of utilizing meso electrophiles with pyrroles has not been studied. By employing a meso starting material, both D- and L-enantiomers of ribose can be accessed simply by switching the chiral ligand used in the enantiodetermining Pd-AAA.

Our initial studies examined the reaction between 2-nitro-1H-pyrrole (1a) and meso-cyclopentene dicarbonate 2 in the presence of 2 mol % Pd₂(dba)₃•CHCl₃ and 6 mol % chiral ligand (Table 1). Employing (R,R)-L1 as the ligand facilitated the desired alkylation reaction in a promising 53% yield and 83% enantiomeric excess (entry 1). Switching to (R,R)-L2, which contains a bulkier naphthyl phosphine, improved the reaction yield to 80% and the enantiomeric excess to 98% (entry 2). Employing (R,R)-L3, provided the alkylated pyrrole 3a in 78% yield and 90% enantiomeric excess (entry 3). Finally, using (R,R)-L4 as the chiral ligand delivered the product in 62% yield and an 82% enantiomeric excess (entry 4). With an optimal ligand in hand, the effects of various additives were studied to further improve reactivity (entries 5–8). Addition of acetic acid had a detrimental effect on the reaction and none of the desired product could be observed. In general, adding base to the reaction medium had a positive effect on the reactivity. Triethylamine (entry 6) showed comparable results to no additives, however, potassium carbonate improved the reaction to afford the product 3a in 94% with >98% enantiomeric excess (entry 7). Changing to the softer cesium counterion delivered the product 3b in 90% yield as a single observable enantiomer by chiral HPLC (entry 8).

Table 1.

Selected Optimization Studies^a

entry	ligand	additive	% yieldb	% eec
1	(R,R)-L1	none	55	83
2	(R,R)-L2	none	80	98
3	(R,R)-L3	none	78	90
4	(R,R)-L4	none	62	82
5	(R,R)-L2	HOAc	-	-
6	(R,R)-L2	NEt3	75	97
7	(R,R)-L2	K2CO3	94	98
8	(R,R)-L2	Cs2CO3	90	>99

^aAll reactions were performed with 1.0 equiv of 1a, 1.1 equiv of 2, and 1.1 equiv of the indicated additive at ambient temperature, 0.25 M in DCE for 24 h.

^bIsolated yield.

^c% ee determined by chiral HPLC.

With the optimized conditions in hand, the scope of the desymmetrization was explored by varying the pyrrole nucleophile (Scheme 1). A number of functional groups were tolerated at either the 2 or 3 positions of the pyrrole nucleus, including nitro groups (3a and 3c), nitriles (3b), aldehydes (3d), ketones (3e), esters (3f), and halides (3f). The reaction also proceeded smoothly using a six-membered cyclohexyl dicarbonate, providing the desired cyclohexyl-substituted pyrrole 3g in quantitative yield as a single observed enantiomer. The presence of an electron-withdrawing group was necessary to facilitate the transformation, and only starting materials were observed after 24 h when electron rich or electron neutral pyrroles were used (3h and 3i). Employment of a weaker electron-withdrawing group, like an aldehyde or ester, led to diminished yields while retaining high levels of enantioselectivity. The presence of an electron-withdrawing group was likely needed to increase the acidity of the pyrrole N-H as well as to make the anionic nucleophile softer and more compatible with the soft π-allyl Pd electrophile. In all cases examined, the desymmetrized product was observed as a single regio- and diastereomer, and only unreacted starting materials were isolated in cases where lower yields were observed.

Scheme 1.

Scope of Pd-AAA of Pyrroles with Cyclopentene Dicarbonate 2a

^a All reactions were performed with 1.0 equiv of pyrrole nucleophile (1), 1.1 equiv of meso electrophile 2, and 1.1 equiv Cs₂CO₃ at ambient temperature, 0.25 M in DCE for 24 h. Yield refers to isolated yield. % ee determined by chiral HPLC. ^b (R,R)-L1 was used.

To expand the scope of this transformation, meso dihydrofuran 4 was utilized as an electrophile in the transformation (Scheme 2). Dihydrofuran 4 is a more challenging system due to its high propensity to undergo elimination/aromatization under basic conditions leading to the undesired, achiral furan product. To our delight, dihydrofuran 4 could serve as an electrophile to afford the alkylated product without any observed aromatization of the product to the undesired furan. Electron deficient pyrroles substituted at either the 2– or 3– positions served as nucleophiles to provide chiral dihydrofurans 5a–d in good yield and with excellent levels of enantioselectivity. These products were observed exclusively with recovered starting materials accounting for the remainder of the mass balance.

Scheme 2.

Scope of Pd-AAA of Pyrroles with Dihydrofuran 4a

^a All reactions were performed with 1.0 equiv of pyrrole nucleophile (1), 1.1 equiv of 4, and 1.1 equiv Cs₂CO₃ at ambient temperature, 0.25 M in DCE for 24 h. Yield refers to isolated yield. % ee determined by chiral HPLC.

To demonstrate the synthetic utility of this process, dihydrofuran 5c was elaborated into a pyrrole-substituted nucleoside analogue 11 (Scheme 3). Previously, nitropyrrole-substituted nucleoside analogues were reported to act as universal bases in DNA transcription.³ Unfortunately, prior syntheses of these compounds started from carbohydrate precursors, which are available only as the natural D-enantiomer, and require extensive use of protecting groups.

Scheme 3.

Synthesis of Pyrrole-substituted Ribonucleoside Analogue 11

To introduce the hydroxymethylene functionality, benzoate 5c was substituted with acetoxy Meldrum’s acid, (6) using a Pd-catalyzed diastereoselective substitution, which afforded dihydrofuran 7 in 95% yield as a single diastereomer.⁸ Being substrate controlled, this reaction was conducted using (Rac.)-L1, which is far more cost-effective than the chiral variant of the same ligand. Previous work has demonstrated that using (Rac.)-L1 in place of an achiral ligand can improve the outcome of a diastereoselective allylic substitution.^7c Os-catalyzed dihydroxylation of dihydrofuran 7 provided diol 8 as a >20:1 mixture of diastereomers in 72% yield. Conversion of the free diol to the subsequent acetonide 9 proceeded in 84% yield. Without isolation or purification, acetonide 9 was converted to primary alcohol 10. First, acetonide 9 was treated with LiOH in THF/H₂O, which chemoselectivly hydrolyzed the Meldrum’s acid acetonide in the presence of the diol acetonide and furnished a dicarboxylic acid intermediate. This dicarboxylic acid was treated with lead(IV) acetate in acetone to effect the oxidative double decarboxylation and unmask the monocarboxylic acid. This monocarboxylic acid was then reduced using BH₃•DMS providing the primary alcohol 10 in 67%. Finally, removal of the acetonide in methanolic HCl afforded the desired nucleoside analogue (11) in >99% yield without the need for purification. Characterization data for 11 was in agreement with previous reports.^3d,9

To rationalize the observed absolute configuration of the products obtained from the Pd-AAA of pyrrole with meso electrophiles, we propose the following explanation based on the wall-and-flap model we have previously disclosed (Scheme 4).^1d,10 Matched ionization from one of the prochiral faces of the meso electrophile 12 proceeds as the enantiodetermining step with inversion such that the leaving group (OR) departs from underneath the “flap” of the (R,R)-Pd-ligand complex 13. Nucleophilic attack proceeds in a matched manner under the flap of the (R,R)-Pd-ligand complex 14 with another inversion, on the same face that ionization occurred delivering product 15. The absolute configuration of 11 as well as other systems are in agreement with this model.

Scheme 4.

Mechanistic Rationale for Observed Stereochemistry

In conclusion, we have demonstrated that pyrroles can act as nucleophiles in the Pd-AAA with meso electrophiles. Both cyclopentene dicarbonates and dihydrofuran dibenzoates were used as electrophiles in the transformation. The reaction proceeded with high chemoselectivity and tolerated a variety of functional groups on the pyrrole nucleus. The products of this transformation were obtained in high yield and enantiomeric excess, as single regio- and diastereomers. To demonstrate the synthetic utility, a pyrrole-containing ribonuceloside analogue was synthesized in 8 steps and 30% overall yield using minimal protecting groups. Unlike other strategies, both natural and unnatural enantiomers of the nucleoside analogues could be readily accessed.