Chiral pyrrolidine thioethers and 2-azanorbornane derivatives bearing additional nitrogen functions. Enantiopure ligands for palladium-catalyzed Tsuji-Trost reaction

An efficient procedure for the synthesis of new enantiopure pyrrolidine-based sulfides bearing additional nitrogen donors and secondary amines based on a bicyclic 2-azanorbornane skeleton was developed. Their application as ligands in palladium-catalyzed Tsuji-Trost reactions led to high yields and up to 82% ee


Introduction
The pyrrolidine ring can be found in various biologically important compounds, including the amino acids proline 1 and hydroxyproline 2, and numerous alkaloids (nicotine 3, hygrine 4, cuscohygrine 5, and others, Figure 1).Pyrrolidine derivatives (e.g.procyclidine, bepridil, pramanicin, rolipram, piracetam, epolactaene, and kainic acid), in many cases chiral, are used as drugs or have been tested as drug candidates, to fight numerous disorders such as cancer, Alzheimer's disease, epilepsy, and cardiovascular diseases.The appropriately substituted five-membered nitrogen-containing ring has also served as a skeleton of useful chiral building blocks for asymmetric synthesis.The resulting structures, often available in both enantiomeric forms, have found wide application as catalysts or ligands in various stereoselective transformations as well as chiral resolving agents. 2 In our laboratory, we have prepared a number of pyrrolidine derivatives which were found to be effective as bidendate ligands for asymmetric catalysis. 3,4The trans-diol 6 was used as a convenient starting material, which was subjected to nucleophilic substitution (Hata reaction 5 ), leading to the corresponding bis-sulfides 7 (Scheme 1) with complete inversion of configuration.Similarly, the N-substituted 3-hydroxypyrrolidine 8 was converted into the corresponding monosulfides 9. We tested the obtained chiral ligands containing a sulfur donor in the palladium-catalyzed Tsuji-Trost reaction (asymmetric allylic alkylation, AAA). 6The best results (with enantiomeric excesses up to 90% accompanied with an 80% yield) were noted for derivatives 9, acting as N,S-donor ligands. 7heme 1. Synthesis of chiral S-donating pyrrolidine derivatives.
2-Azanorbornane (2-azabicyclo[2.2.1]heptane) 10 can be regarded as an intrinsically chiral bridged pyrrolidine derivative (Figure 2).This bicyclic system is easily available in a highly stereoselective aza-Diels-Alder reaction and can be used as a convenient platform for the synthesis of ligands and catalysts with wide application in asymmetric synthesis. 82-Azanorbornane-derived ligands were also assessed in a palladiumcatalyzed Tsuji-Trost reaction.The oxazolidine derivative prepared by Okayama et al. showed a poorer performance than its pyrrolidine analog. 9In our studies, we converted aldehyde 11 into Schiff bases 12a, 12b and thioacetals 12c, 12d; using these derivatives, we obtained the product of the AAA reaction in 86-95% yield and 48-95% ee.These results prompted us to explore further the use of pyrrolidine and 2-azanorbornane skeletons as a convenient platform for the synthesis of enantiopure derivatives bearing additional sulfur and nitrogen functions for their possible use in Tsuji-Trost and other metal-catalyzed or organocatalytic asymmetric transformations.

Results and Discussion
Our earlier investigations proved the utility of Hata reactions for the stereoselective preparation of mono-and bis-sulfides based on a five-membered pyrrolidine and cyclopentane ring. 3,4We decided to test the protocol using disulfides bearing additional nitrogen donors in their structure.The substitution of hydroxyl groups in the trans-diol (3S,4S)-6a proceeded according to a S N 2 mechanism with a complete inversion of configuration of both stereocenters in 76% (13a) and 28% yield (13b, Scheme 3).The difficulties in the synthesis of bistetrazole derivative can be explained by a steric hindrance introduced by the phenyl-substituted heterocyclic rings.Both 1 H NMR and 13 C NMR spectra revealed the presence of a single diastereomer of 13a and 13b.In the latter case, however, the hindered rotation of tetrazole substituents creates two non-equivalent sides in the molecule, which results in the increased number of signals in the NMR spectra.
Substitution of the hydroxyl group in the pyrrolidine-derived alcohol (3S)-8 was also performed, leading to monosulfides 14a-14c in 71-90% yields.A complete inversion of configuration resulted in (R)-products in agreement with the S N 2 mechanism (Scheme 3).This observation was further confirmed by a small-scale synthesis in which alcohol (3R)-8 was used: enantiomers of compounds 14a-14c were obtained with the opposite values of specific rotation.The presence of an amine group in derivative 14c opens the possibility of modification of this arylthiopyrrolidine.To verify this, we converted this compound into the Schiff base derivative 15 (32% yield; Scheme 4).For comparison, we synthesized another imine with a nitrogen donor directly attached to the pyrrolidine fragment.1][12] Imine 17 was formed as a single stereoisomer in 89% yield (Scheme 5).This way, an enantiopure ligand was obtained combining two structural motifs -pyrrolidine and 2-azanorbornane.This compound can be regarded as an analogue of the previously described bicyclic derivative 12a bearing an additional nitrogen donor.

Scheme 5. Preparation of Schiff base 17
1][12] In our laboratory, it was utilized in the preparation of ligands bearing additional donor atoms (N, S, P, O) and polyamine derivatives exhibiting interesting antiproliferative activity. 10,13,14In particular, amine 18 based on a 2-azanorbornyl skeleton was obtained from 11 via its conversion into an oxime followed by reduction. 14In the present work, we decided to extend the family of N,N-donating ligands containing four stereogenic centers by reacting amine 18 with aryl aldehydes leading to the series of imines 19a-19e (Scheme 6).Since these imines were too unstable to be isolated, they were reduced in situ to the corresponding secondary amines with various aryl substituents 20a-20e (85-90% overall yields).All new compounds were characterized by HRMS, IR, 1 H and 13 C NMR spectroscopy, and their structures were further confirmed by 2D NMR spectra.This allowed a full assignment of NMR resonances which is given in Table S1 (Supplementary Material).
We tested the newly obtained chiral derivatives as ligands in a palladium-catalyzed Tsuji-Trost (AAA) reaction between dimethyl malonate and a racemic 1,3-diphenyl-2-propenyl acetate.The results are collected in Table 1.The reaction was conducted over 3 days at room temperature with 10% of chiral ligand L*. b The reaction was performed at 5 °C.
On the basis of our previous experiments with sulfides 9, 7 we could expect a good performance of compounds 14a-14c.However, a racemic product was obtained (in ca.30% yield) when sulfide 14b was applied as a source of chirality, and the use of 14a resulted in a similar yield and a modest enantiomeric excess (68%).Still, this result is encouraging when compared with the lack of asymmetric induction observed for alcohol 8 in this reaction.
In the series of bicyclic ligands, the (S) enantiomer of the product was preferentially formed in all cases, except for 20e.Molecular models of the transition state indicate that formation of η 3 -1,3-diphenylallyl Mshaped complex should be restricted due to the spatial proximity of the substituent of the coordinating N(2) atom of the norbornyl system and one of the phenyl groups of substrate (Figure 3).Predominant formation of a W-shaped complex, together with the preference of the nucleophile for trans attack with respect to the secondary nitrogen donor is responsible for the observed stereochemical outcome of catalytic reaction with 17, 18, and 20a-20d.An interesting reversal of stereochemical preference observed for the 2-pyridyl derivative 20e can be accounted for by the presence of an additional donor in the molecule, which apparently is engaged in palladium coordination.As a consequence, a different transition state structure can be expected, leading to the preferred formation of the (R) product (albeit with rather low ee).
An example with ligand 20b shows the influence of temperature on the outcome of the catalytic reaction.When the AAA process was conducted at 5 °C, the stereoselectivity remained practically unchanged, while the yield was significantly lower as compared to the original conditions.Imine 17 (90% yield, 68% ee) performed better than its analogue 12a described previously (86% yield, 50% ee), 10 but the results were significantly inferior to those obtained for 12b (epimer of 12a; 95% yield, 90% ee).

Conclusions
A series of new heterocyclic chiral pyrrolidine derivatives was obtained by the Hata reaction, and 2azanorbornane-based imines and secondary amines were prepared from the respective amine and aldehyde precursors.The new enantiopure ligands were applied in the asymmetric induction in AAA (Tsuji-Trost) reaction between dimethyl malonate and a racemic 1,3-diphenyl-2-propenyl acetate, and they led to generally high yields and up to 82% ee.Our studies extended the family of N,N-and N,S-donating heterocyclic and bicyclic compounds which may find further application in asymmetric synthesis.

Experimental Section
General.IR spectra were recorded on a Perkin Elmer 1600 FTIR spectrophotometer. 1 H NMR and 13 C NMR spectra were measured on a Bruker CPX ( 1 H, 300 MHz) or a Bruker Avance ( 1 H, 500 MHz or 1 H, 600 MHz) spectrometers using solvent residual peak as an internal standard.Optical rotations were measured using an Optical Activity Ltd.Model AA-5 automatic polarimeter.High resolution mass spectra were recorded using a microTOF-Q and WATERS LCT Premier XE instruments utilizing electrospray ionization mode.Separations of products by chromatography were performed on silica gel 60 (230-400 mesh) purchased from Merck.Thin layer chromatography was carried out using silica gel 60 precoated plates (Merck).HPLC analyses were performed on Chiracel OD-H or Chiralpak AD-H chiral columns (flow rate of 1.0 mL/min).
4][5] Tributylphosphine (4.0 mmol, 0.84 g, 0.98 mL) was added by syringe to a solution of (S)-1-benzylpyrrolidin-3-ol 8 (1.0 mmol, 0.18 g) and diaryldisulfide (3.0 mmol) in dry toluene (3 mL).The mixture was transferred to an ampoule, filled with argon and sealed.This reaction mixture was kept in an oil bath at 80 °C for three days.Diethyl ether (10 mL) was added to the cooled solution, the organic layer was washed with 10% aqueous NaOH, water and brine, and dried over anhydrous Na 2 SO 4 .
The solvent was evaporated and the obtained product was purified by column chromatography using hexaneethyl acetate (9:1 v/v) as eluent.
For the preparation of bissulfides 13a, 13b from diol 6a, the amounts of diaryldisulfide and tributylphosphine were doubled (6.0 and 8.0 equivalents, respectively).