Abstract
Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-catalyzed addition of sulfinamide nucleophiles to alkenes.
2,5-Disubstituted pyrrolidines are an important class of heterocycles featured in numerous natural products, pharmaceuticals, ligands for transition metals, and organocatalysts.1 PdII-catalyzed aerobic oxidative cyclization reactions provide efficient routes to pyrrolidines (eq 1);2,3 however, few of these methods enable
 |
(1) |
stereoselective C–N bond formation. The first examples of enantioselective oxidative cyclization have been reported only recently.4–6 Here, we show that chiral γ-aminoalkene substrates bearing a tBu-sulfinyl auxiliary undergo efficient PdII-catalyzed aerobic oxidative cyclization to afford enantiopure 2,5-disubstituted pyrrolidines.7 tBu-Sulfinamides have been used extensively for the stereoselective synthesis of amines, as summarized in an extensive recent review by Ellman;8 however, the present reactions are the first use of sulfinamides in metal-catalyzed nucleophilic functionalization of alkenes.9
Our strategy to prepare 2,5-disubstituted pyrrolidines is illustrated in Scheme 1 and begins with readily available cis-4-hexen-1-ols.10 Aerobic oxidation of the alcohol11 and condensation of the resulting aldehyde with tBu-sulfinamide8,12 furnishes the sulfinyl imine derivative 1. Methods for stereoselective addition of nucleophiles to chiral sulfinyl imines provide access to a variety of enantiopure α-substituted sulfinamides 2.8 PdII-catalyzed aerobic oxidative cyclization of 2 affords the desired 2,5-disubstituted pyrrolidines.
Scheme 1.
Stereoselective Synthesis of 2,5-Disubstituted Pyrrolidines
The enantiopure α-Me-substituted sulfinamide 3 was used as the substrate in the development of a suitable heterocyclization catalyst (Table 1).13 Testing of catalyst systems that have been shown previously to promote aerobic oxidative cyclization of γ-aminoalkene derivatives led to mixed results (Table 1, entries 1–4).3,14 Good product yields were obtained with PdII catalysts in which DMSO was used as a solvent and/or ligand (entries 1 and 4),3a,14 while PdII/pyridine-based catalyst systems (entries 2 and 3)3b,c afforded low yields. Further screening of anionic base additives, the PdII source, and solvents (Table 1, entries 5–11; Table S1) revealed that optimal results were obtained with Pd(TFA)2 (TFA = trifluoroactate) as the PdII source, one equivalent of LiOAc, and DMSO as the solvent. All conditions tested led to formation of a single diastereomeric product (>20:1 dr), affording the cis disubstituted pyrrolidine 4. The sulfinamide group is readily removed upon treatment of 4 with 4 M HCl,15 affording the HCl salt of the unprotected pyrrolidine in 95 % yield.16
Table 1.
Optimization of a Catalyst System for Diastereoselective Oxidative Cyclizationa
 | |||
|---|---|---|---|
| entry | [PdII]/additives | solvent | yieldc |
| 1 | Pd(OAc)2/2 equiv NaOAc, no 3 Å MS | DMSO | 87 |
| 2 | Pd(OAc)2/20 mol % pyridine | toluene | 38 |
| 3 | Pd(TFA)2/40 mol % pyridine, 2 equiv Na2CO3, no 3 Å MS | toluene | 8 |
| 4 | Pd(TFA)2/20 mol % DMSO, 1 equiv LiOAc | THF | 83 |
| 5 | Pd(TFA)2/no base | DMSO | 6 |
| 6 | Pd(TFA)2/1 equiv NaOAc | DMSO | 81 |
| 7 | Pd(TFA)2/1 equiv NaOBz | DMSO | 79 |
| 8 | Pd(TFA)2/1 equiv LiOAc | DMSO | 92 |
| 9 | Pd(TFA)2/1 equiv Na2CO3 | DMSO | 14 |
| 10 | PdCl2/1 equiv LiOAc | DMSO | 81 |
| 11 | Pd(OPiv)2/1 equiv LiOAc | DMSO | 13 |
Conditions: substrate (0.08 mmol), PdII (0.008 mmol), 3 Å MS (40 mg), O2 (1 atm), solvent (0.8 mL), 50 °C, 14 h.
Diastereomeric ratio determined by 1H NMR spectroscopy.
Yield determined by 1H NMR spectroscopy, int. std. = PhSiMe3.
The presence of two stereocenters in 3, one associated with the sulfinyl group and the other α to the nitrogen atom, raises fundamental questions concerning the origin of stereocontrol in these reactions. The optimized catalyst system was used to probe these issues (Table 2). Substrate 5, which lacks a stereocenter adjacent to nitrogen, underwent cyclization with 7:1 dr (68% yield, entry 1), demonstrating that the tBu-sulfinyl group could be used as an auxiliary to achieve stereocontrol when no other stereocenters are present in the substrate. The influence of the α-Me group on diastereoselectivity was evaluated by performing the cyclization of 6, in which the tBu-sulfinyl group was replaced with an achiral toluenesulfonyl (Ts) group. This reaction afforded the cis-pyrrolidine product with moderate diastereoselectivity (6:1 dr, entry 2). The cooperative effect of the two stereocenters is evident from the improved yield and diastereoselectivity in the cyclization of the parent substrate 3 (98% yield, >20:1 dr; entry 3). The pairwise influence of the sulfur- and carbon-based stereocenters was analyzed further by testing the reaction of epi-3, in which the stereochemical configuration α to nitrogen is inverted (entry 4). This substrate afforded the corresponding cis-pyrrolidine16 as a single diastereomer, but with moderately reduced yield relative to the reaction of 3. This observation suggests that rotation about the N–S bond enables the sulfinamide to act cooperatively with either epimeric form of the substrate to enforce highly diastereoselective C–N bond formation. Finally, analysis of the alkene stereochemistry revealed that significantly lower yield and diastereoselectivity was observed with substrate 7, bearing a trans-alkene (cf. entries 3 and 5).17
Table 2.
Substrate Effects on the Diastereoselectivity of PdII-Catalyzed Oxidative Cyclizationa
Conditions: substrate (0.07 mmol), Pd(TFA)2 (0.007 mmol), 3 Å MS (35 mg), O2 (1 atm), DMSO-d6 (0.7 mL), 50 °C, 24 h.
Yield determined by 1H NMR spectroscopy, int. std. = PhSiMe3.
Diastereomeric ratio determined by 1H NMR spectroscopy of crude reaction mixture.
With these results in hand, we investigated the reactivity of a number of different substrates (Table 3). A benzyl-substituted alkene underwent cyclization in 85% yield to provide the stryenyl product (entry 1). Each of the other substrates, bearing diverse functional groups in the α position, was readily obtained by stereoselective addition of the appropriate nucleophile to the sulfinylimine precursor (cf. Scheme 1).8,16 Oxidative cyclization of these substrates proceeded with excellent diastereoselectivity, in most cases affording a single detectable diastereomer (Table 3). All of the reactions proved to be operationally straightforward, with substrates and reagents weighed and combined in a flask open to the air and stirred under a balloon of O2. Substrates with relatively large α substituents, including isopropyl and aryl groups, proceeded effectively, albeit with a somewhat lower yield relative to the α-Me derivative 3 (61–74% yield, entries 2–4). Subtrates featuring an aryl chloride (entry 4), phosphonate (entry 5), carboxylic ester (entry 6), or acetal (entry 7) also underwent successful cyclization. The latter functional groups are appealing because they are readily amenable to further functional-group manipulations to prepare more complex molecules.
Table 3.
Stereoselective Oxidative Cyclization of Alkenes Bearing Tethered α-Substituted tBu-Sulfinamide Nucleophilesa
 | ||||
|---|---|---|---|---|
| entry | substrates | product | yieldc | drb |
| 1 |
|
|
85% | >20:1 |
| 2 |
|
|
64% | >20:1 |
| 3 |
|
|
68% | >20:1 |
| 4 |
|
|
71% | >20:1 |
| 5 |
|
|
54% | >20:1 |
| 6 |
|
|
80% | >20:1 |
| 7 |
|
|
67% | >20:1 |
| 8 |
 8 |
 9 |
70%d | 15:1 |
Conditions: substrate (0.5 mmol), Pd(TFA)2 (0.05 mmol), 3 Å MS (250 mg), O2 balloon, DMSO (5 mL), 50 °C, 24 h.
Isolated yield.
Diastereomeric ratio determined by 1H NMR spectroscopy of crude reaction mixture.
Performed at 70 °C, 3 atm O2.
Substrate 8, which contains an α-propenyl substituent, cyclized in good yield with increased temperature and O2 pressure (Table 3, entry 8). Alkene metathesis of the diene product 9 using the Grubbs II catalyst yielded the azabicyclic tropene 10 in 82% yield (Scheme 2).16 Tropane alkaloids have received substantial attention in recent years due to the effect of these molecules on the central nervous system,18 and tropene derivatives directly analogous to 10 have been converted by straightforward methods to various alkaloid products.18d
Scheme 2.
Synthesis of a Common Precursor for the Synthesis of Tropane Alkaloids
In summary, we have developed catalytic conditions that enable Wacker-type aerobic oxidative cyclization of alkenes bearing tethered tBu-sulfinamide nucleophiles. These reactions benefit from efficient access to the enantiopure substrates and highly diastereoselective cyclization, and they enable modular, stereocontrolled synthesis of a diverse collection of cis-2,5-disubstituted pyrrolidines. These results highlight the prospective utility of tBu-sulfinamides as chiral nitrogen nucleophiles in metal-catalyzed additions to alkenes and related electrophiles.
Supplementary Material
Acknowledgments
We thank the NIH (R01 GM67163) and Abbott Laboratories (graduate fellowship for R.I.M) for financial support. Spectroscopic instrumentation was partially funded by the NSF (CHE-9208463, CHE-0342998, CHE-9629688, CHE-9974839), and high-pressure instrumentation was funded by the NSF (CHE-0946901).
Footnotes
Supporting Information Available Experimental proceedures, 1H and 13C NMR spectra, and methods for determination of configuration. This material is available free of charge via the Internet at http://pubs.acs.org.
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