Samarium diiodide-induced reductive coupling of chiral nitrones prepared from D -isoascorbic acid with methyl acrylate

Chiral nitrones 13 - 15 prepared from D -isoascorbic acid were found to effectively undergo an SmI 2 -mediated radical addition to methyl acrylate affording γ - N -hydroxylamino esters 19 - 22 with high diastereomeric control. The unsubstituted nitrone 14 afforded in the SmI 2 -induced coupling with methyl acrylate the γ - N -hydroxylamino ester 21 as minor product. The pyrrolidinones 23 - 25 were prepared in a single step from 19 and 22 involving N-O bond cleavage with Zn/AcOH or SmI 2 and subsequent spontaneous cyclization.


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 3 equivalents SmI 2 in THF at -78 °C with the formation of γ-N-hydroxylamino esters 2 in fairly good yields, with a 85:15 diastereomeric ratio (Scheme 1).When chiral nitrones were used as substrates, significant diastereoselectivities were observed in this reactions. 4

Scheme 1
Moreover, Skrydstrup et al. have found that alkyl nitrones possessing N-substituted sugars as chiral auxiliaries effectively undergo an SmI 2 -mediated radical addition to n-butyl acrylate affording γ-amino acid derivatives with high diastereomeric control. 5This 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. 2,3n our first two papers we have found that the reaction course of samarium diiodide-induced reductive coupling of chiral sugar derived nitrones with methyl acrylate is dependant on the structure of the starting chiral nitrone. 8The nitrones 3 and 5 possessing C−2/C−3 threo configuration were found to effectively undergo an SmI 2 induced reductive coupling to methyl acrylate affording γ-N-hydroxylamino esters 4 and 6 with high diastereomeric control (Scheme 2).On the other hand, the coupling of the nitrones 7 and 10 possessing C−2/C−3 erythro configuration with methyl acrylate proceeded slower, the expected γ-N-hydroxylamino esters 8 and 11 were obtained as minor products along with products resulting from unusual reductive deoxygenation 9 and dimethyl adipate (12), the product of the radical dimerisation/addition step involving the acrylate (Scheme 3).In this communication we wish to describe the SmI 2 -induced coupling of Nbenzylsubstituted D-erythro nitrones 13-15 prepared from D-isoascorbic acid with methyl acrylate with the subsequent conversion of the formed γ-N-hydroxylamino esters into γ-lactams.The TBDMS substituted nitrone 13 has been employed in [3+3] cyclizations with lithiated alkoxyallenes and a subsequent rearrangement of the resulting 1,2-oxazine derivatives to novel carbohydrates mimetics. 9

Results and Discussion
Initial experiments were performed with the TBDMS-substituted D-erythro-nitrone 13.Whereas the synthesis of D-erythrose derived nitrone 13 starting from D-isoascorbic acid has been reported in the literature, 10 the preparation of the new nitrones 14 and 15 is described here.The Derythrose derived nitrone 14 possessing a free hydroxy group was synthesized by condensation of O-isopropenylidene-D-erythrose 17 with N-benzylhydroxylamine according to the method of Dondoni and Merino. 10The required aldehyde O-isopropenylidene-D-erythrose 17 was prepared from known 11 aldehyde 16 by desilylation with TBAF in THF and was used directly without any isolation in the condensation with N-benzylhydroxylamine (Scheme 4).The synthesis of Obenzylated O-isopropenylidene-D-erythrose 18 starting from D-isoascorbic acid has been reported in the literature. 12

Scheme 4
The TBDMS-substituted D-erythro-nitrone 13 reacted smoothly with methyl acrylate in THF in the presence of three equivalents of samarium diiodide 13,14 and eight equivalents of H 2 O at -78° C over two hours to give γ-N-hydroxylamino ester 19 in 90% yield along with ester 20 (5%) (Scheme 5).The formation of conjugated imine 20 can be rationalized by dehydratation of the primary formed ester 19.The analogous formation of the imine derivative by SmI 2 -mediated radical addition of nitrones to methyl acrylate was also observed by Py and Greene.4h The addition proceeded with excellent (>95:5) diastereoselectivity, with only the anti-diastereomer 19 being detected.The O-benzylsubstituted D-erythro-nitrone 15 reacted with methyl acrylate in THF in the presence of three equivalents of samarium diiodide and eight equivalents of H 2 O at -78° C over two hours fully analogously to afford exclusively (>95:5) anti-γ-N-hydroxylamino ester 22 in 93% yield (Scheme 5).
In contrast, when D-erythrose derived nitrone 14 possessing a free hydroxyl group was treated with three equivalents of SmI 2 and eight equivalents of H 2 O in THF at -78° C over two hours with methyl acrylate, the expected γ-N-hydroxylamino ester 21 was obtained in low 5% yield along with dimethyl adipate (70%) and substantial amounts of unreacted nitrone 14 (44%, Scheme 6).On the other hand the reaction is completely diastereoselective (>95:5) within the limits of NMR analysis of the crude product.The TBDMS substituted γ-N-hydroxylamino ester 19 was deprotected with TBAF in THF to afford after separation the γ-N-hydroxylamino ester 21 in 50% yield.All structures described were determined by 1 H and 13 C MNR measurements.The relative stereochemistry, previously determined through single-crystal X-ray structure analysis, 8 has been assigned in the other adducts by analogy.The formation of anti isomers 19-22 is consistent with a β-chelated transition state suggested by Py and Skrydstrup
In conclusion, the reductive cross-coupling of chiral sugar derived D-erythro-nitrones 13-15 prepared from D-isoascorbic acid with alkyl acrylates allows the stereoselective synthesis of 4substituted γ-N-hydroxylamino esters and their reduction provides entry to the optically active pyrrolidinones possessing structural similarities to the glycosidase inhibitors. 15This method opens a novel, short, and general route for the synthesis of biologically important trihydroxysubstituted 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 and Varian INOVA-600 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.TLC analysis was carried out using Merck TLC silica gel 60 F254 aluminium sheets and visualized by UV light or oxidize in KMnO 4 solution (NaOH/KMnO 4 /K 2 CO 3 /H 2 O 1:8:80:1200).The O-isopropenylidene-D-erythrose derived nitrone 13, 10 O-isopropenylidene-D-erythrose 16 11 and O-benzylated O-isopropenylidene-D-erythrose 18 12 were prepared by literature procedure.

General procedure for preparation of 23, 25 and 26
Method A. The γ-hydroxylamino ester was dissolved in mixture (AcOH/THF/H 2 O, 2:1:1, 10 mL).Zinc dust was added and reaction mixture was stirred at 60 °C for 1h.Reaction was controlled with TLC.Water (100 mL) was added after reaction and obtained mixture was treated with Na 2 CO 3 to basic reaction (pH > 10).The solution was extracted with EtOAc (4 x 50 mL), and the combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtred, and concentrated in rotatory evaporator.The residue was purified by silica gel column chromatography using AcOEt:hexanes (1:1).Method B. The γ-hydroxylamino ester was dissolved in dry THF and this mixture was treated with solution of SmI 2 (0.1 M in THF) and stirred at room temperature under nitrogen atmosphere.The reaction was confirmed to be complete by TLC, whereupon a solution of Na 2 S 2 O 3 (50 mL, 1 M in water) was added.The mixture was extracted with EtOAc (4 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtred, and concentrated in rotatory evaporator.The crude product was dissolved in mixture (MeOH/H 2 O/ethyl ether, 1:1:1, 60 mL) and K 2 CO 3 (0.3 g) was added.The obtained mixture was stirred at room temperature for 20 min.After this period reaction mixture was extracted with EtOAc (4 x 40 mL) and the combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtred, and concentrated in rotatory evaporator.The residue was purified by silica gel column chromatography using AcOEt:hexanes (1:1).The TBAF (0.127 g, 0.403) and water (0.2 mL) were put to solution of pyrrolidinone 23 (0.169 g, 0.403 mmol) in THF (10 mL) and mixture was stirred at room temperature for 2.5 h.The reaction was controlled by TLC.At the end of the reaction THF was removed on rotatory evaporator.The pyrrolidinone 24 was obtained after purification by column chromatography (silica gel, EtOAc) as a colorless crystals (0.117 g, 95%), mp: 159-162°C; R f : 0.  The hydroxypyrrolidinone 24 (0.046 g, 0.15 mmol) was dissolved in THF (5 mL) and NaH (0.040 g, 1.66 mmol) was added.The mixture was stirred at room temperature for 1 h.After then benzylbromide (0.035, 0.30 mmol) was added and reaction mixture was stirred at room temperature for 3 h.The reaction mixture was controlled by TLC.The water and toluene were added at the end of the reaction and solvents were removed by reduced pressure.The

8
Scheme 3 8,5as well as with our previous results.8 To stirred solution of crude aldehyde 18 (1.78g, 7.18 mmol) in dichloromethane (35 mL) anhydrous of magnesium sulfate (8.61 g, 71.8 mmol) and Nbenzylhydroxylamine (0.88 g, 7.18 mmol) were added.The reaction mixtures was stirred at room temperature for 18 h.The progress of the reaction was monitored by TLC.After end of the reaction magnesium sulfate was removed and the solvent was removed under reduced pressure.