Samarium diiodide-induced reductive coupling of chiral nitrones with methyl acrylate

D-Lyxose derived nitrone 7 was found to effectively undergo an SmI 2 -mediated radical addition to methyl acrylate affording γ - N -hydroxylamino ester 8 with high diastereomeric control. The pyrrolidinone 9 was prepared in a single step from 8 involving N-O bond cleavage with Zn/AcOH and subsequent spontaneous cyclization. D-Xylose derived nitrone 10 afforded in the SmI 2 -induced coupling with methyl acrylate the γ - N -hydroxylamino ester 11 as minor product. The major product the nitrone 12 is formed by unusual reductive deoxygenation of the starting nitrone.


Introduction
Nitrogen-containing heterocycles and their derivatives have broad application in synthetic materials, and biological chemistry, and as a result their synthesis and reactivity is subject of considerable interest.Over the years, nitrones have become important building blocks in organic synthesis. 1During the last years we have learned know-how about the preparation of optically active nitrone templates for the asymmetric 1,3-dipolar cycloadditions. 2,3Py, Vallée and coworkers 4a,b have recently described the first samarium diiodide-induced umpolung of nitrones, which were able to undergo reductive coupling with α,β-unsaturated esters.D-Glyceraldehyde derived nitrone 1 reacted with methyl acrylate in presence of 2 equivalents SmI 2 in THF at -78 °C with the formation of γ-N-hydroxylamino esters 3 in fairly good yields, with a 90: 10 diastereomeric ratio (Scheme 1).When chiral nitrones were used as substrates, significant diastereoselectivities were observed in this reactions. 4oreover, Skrydstrup et al. have found that alkyl nitrones 4 possessing N-substituted sugars as chiral auxiliaries effectively undergo an SmI 2 -mediated radical addition to n-butyl acrylate affording γ-amino acid derivatives 6 with high diastereomeric control (Scheme 1). 5 This methodology opens a direct route to γ-N-hydroxylamino esters. 4,5The derivatives of γ-amino buryric acid (GABA) could be potential, selective and irreversible inhibitors of GABA amino transferase, the enzyme involved in the catabolism of GABA. 6,7As in principle γ-lactams should be easily obtained from the corresponding γ-N-hydroxylamino esters we have paid our attention to the synthesis of biologically important γ-amino acids from the sugar-derived nitrones previously used by us in the chiral cycloadditions.

N
In this communication we wish to describe the SmI 2 -induced coupling of N-benzylsubstituted D-xylose and D-lyxose derived nitrones with methyl acrylate under the formation of chiral 4substituted γ-N-hydroxylamino esters.
Initial experiments were performed with the D-lyxose derived nitrone 7 that was easily prepared from the corresponding aldehyde following the described procedure.2i,8 When treated with samarium diiodide 9 (3 equiv.) at -78 °C, nitrone 7 was reduced to an α-amino radical species, that was trapped in situ with methyl acrylate (2, 1.4 equiv.).In our attempt to optimize the reaction conditions, we found that the yield of product 8 could be increased to 83% when more SmI 2 (3 equiv.instead of 2 equiv., 62%) was used.The reaction was performed in the presence of water since it has been demonstrated that the addition of water to SmI 2 has a rate accelerating effect on the radical addition to α,β-unsaturated esters.4b A new C-C bond was thus formed to afford γ-N-hydroxylamino ester 8 in good yield (83%) and high diastereoselectivity (90: 10).The relative configuration at the new stereogenic center in 8 could not be assigned at this stage; however it was deduced from the structure of a cyclized derivative 9 (Scheme 2).Considering the well-known propensity of N-hydroxylamines to be reduced to amines, we have prepared pyrrolidinone 9 in a single step from 8 involving N-O bond cleavage with Zn/AcOH and subsequent spontaneous cyclization.The newly created stereogenic center in 8 was assigned the (R)-configuration on the basis of a single crystal X-ray structure of the pyrrolidinone 9 (Fig. 1).The formation of major anti isomer 8 is consistent with a β-chelated transition state suggested by previously work.When D-xylose derived nitrone 10 2a was treated with 3 equivalents of samarium diiodide in THF at low temperature with methyl acrylate was less rewarding in its coupling reaction, the expected γ-N-hydroxylamino ester 11 was obtained as a minor product in low yield (19%, Scheme 3).On the other hand the reaction is completely diastereoselective within the limits of 1 H NMR analysis of the crude product.This observation is in good agreement with the studies realized by Py and Skrydstrup. 4,5e O SmI 2 , THF, -78 o C +

Scheme 3
The major product was surprisingly not the ester 11 but the nitrone 12.The stereochemical arrangement and absolute configuration of this unexpected product was subsequently confirmed by X-ray-crystallographic analysis (Figure 2 and experimental section).Its origin can be explained by very unusual and as yet not described deoxygenation of the starting α-alkoxysubstituted nitrone 10 by SmI 2 -induced reduction.The analogous deoxygenation was described in the reduction of α-alkoxy ketones at -78 °C on addition of the substrate in THF/MeOH to a solution of SmI 2 in THF. 10 For example; benzoin methyl ether is converted to deoxybenzoin quantitatively.It was also found that small-membered ring ethers can be cleaved with SmI 2 . 11A relevant precedent exists also in the SmI 2 -promoted deoxygenation of carbohydrate-derived to α,β-unsaturated esters.In conclusion, the reductive cross-coupling of chiral sugar derived nitrones with alkyl acrylates allows the stereoselective synthesis of 4-substituted γ-N-hydroxylamino esters and their reduction provides entry to the optically active pyrrolidinones possessing structural similarities to the HIV inhibitors.This method opens a novel, short, and general route for the synthesis of biologically important trihydroxy-and tetrahydroxysubstituted γ-amino acids and pyrrolidinones.We are currently extending the scope of this synthetically useful reaction to various chiral sugar derived nitrones.

Experimental Section
General Procedures.Melting points were determined using a Kofler hot-stage apparatus and are uncorrected. 1H NMR and 13 C NMR spectra were recorded on a Varian VRX-300 in CDCl 3 solution using TMS as internal standard.Chemical shifts are reported in ppm.IR spectra were recorded on FTIR NICOLET MAGNA 750 instrument.Specific rotations [α] were measured on an IBZ Messtechnik Polar-LµP polarimeter at the sodium D line (589 nm) using a 1 dm cell.Elemental analyses were conducted using the Fisons EA 1108 Analysator.Nitrones 7 2i and 10 2a were prepared from the corresponding aldehyde by the reaction with N-benzylhydroxylamine according to the procedure already described. 8TLC analysis was carried out using Merck TLC silica gel 60 F254 aluminium sheets and visualized by UV light or oxidized in KMnO4 solution (NaOH/KMnO 4 /K 2 CO 3 /H 2 O 1:8:80:1200).

General procedure for preparation of 8, 11 and 12
A stirred and carefully deoxygenated solution of the corresponding nitrone (0.5 mmol) in dry THF (5 mL) was cooled to -78 °C under argon.Methyl acrylic ester (2) and water were degassed by boiling under a stream of argon for 20 min.Methyl acrylic ester (0.7 mmol), water (4 mmol) and solution of SmI 2 (15 mL of 0.1 M in THF, 1.5 mmol) were then added.The temperature was kept at -78 °C until the reaction was judged to be complete by TLC (1.5 h for 7 and 2 h for 10), whereupon a saturated aqueous solution of Na 2 S 2 O 3 (40 mL) was added.The mixture was extracted with EtOAc (4 x 30 mL) and the combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated in rotatory evaporator.The residue was purified by silica gel column chromatography using AcOEt/hexanes (1:2).

Figure 2 .
Figure 2. Structure Determination of compound 12 by X-ray diffraction with crystallographic numbering and 30% ellipsoids.
Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre.The corresponding deposition numbers are CCDC 663043 and CCDC 663044.Copies of the data can be obtained free of charge on request to The ARKAT USA, Inc.

Table 1 .
Crystal and experimental data for compound 9