The 5-Endo-trig Cyclization of d-Glucose Derived γ-Alkenylamines with Mercury (II) Salts: Synthesis of 1-Deoxy-castanospermine and its 8a-epi-Analogue

The intramolecular aminomercuration of γ-alkenylamines 1a, 1b and 4 was shown to afford the 5-endo-trig cyclized product exclusively in good yield. The utility of pyrrolidine derivatives thus obtained from D-glucose derived γ-alkenylamines 1a and 1b was demonstrated in the synthesis of 1-deoxycastanospermine (3a) and 1-deoxy-8a-epi-castanospermine (3b).


Figure 1
This class of compounds, in particular the polyhydroxylated indolizidine alkaloid castanospermine (2), has attracted considerable attention because of their promising glycosidase inhibitory activity. In the pursuit of structure-activity relationships a number of natural and unnatural derivatives of castanospermine [5] have been synthesized and evaluated for glycosidase inhibition in the treatment of various diseases such as diabetes [6], cancer [7], and viral infections, including AIDS [8]. As a part of our continuing interest in the synthesis of azasugars [9], we thought of utilizing the intramolecular aminomercuration strategy, in a 5-endo-trig fashion, with the D-glucose derived γ-alkenylamine 1 for the construction of a pyrrolidine ring skeleton that could be elaborated to 1-deoxy castanospermine (3a) and its 8a-epi analogue 3b (Figure 1) [10]. Our results with the successful mercury (II) mediated 5-endo-trig cyclization of γ-alkenylamines towards the pyrrolidine ring skeleton are discussed.

Results and Discussion
In order to know whether the differentially substituted γ-alkenylamines obey the usual Baldwin's ring closure rule or not [10], we have investigated the model reaction with α-phenyl-substituted-γalkenylamine 4. The required compound 4 was obtained by 1,3-addition of allylmagnesium bromide to the benzaldehyde-derived nitrone 5 [11], followed by reductive cleavage of the N−O bond with zincacetic acid (Scheme 1) [4]. The reaction of γ-alkenylamine 4 with mercury (II) acetate in (1:1) THFwater at 25 °C for 18 h, followed by reductive demercuration with sodium borohydride afforded the 5endo-trig product 6 exclusively in 81% yield. With the success in 5-endo-trig aminomercuration of γ-alkenylamine 4 in hand, we have exploited the same strategy with the D-glucose derived γ-alkenylamine 1. As reported earlier, the reaction of Dglucose nitrone 7 with allylmagnesium bromide in the presence of TMSOTf (1 equiv) at -78 °C in dry THF, afforded a diastereomeric mixture of D-gluco-and L-ido-configurated N-benzylhydroxylamines 8a and 8b in the ratio of 86:14 (Scheme 2). The treatment of 8a and 8b, individually, with zinc-acetic acid afforded the D-gluco-γ-alkenylamine 1a and L-ido-γ-alkenylamine 1b in good yield [4]. In the next step, the aminomercuration of 1a with mercury (II) acetate in THF-water (1:1) at room temperature for 18 h, followed by reductive demercuration with sodium borohydride afforded exclusively the 5-endo-trig cyclized product 9a in 78% yield. Similarly, the aminomercuration of 1b afforded the pyrrolidine derivative 9b in 76% yield. The spectroscopic and analytical data obtained for 9a and 9b were in agreement with the assigned structures.

Conclusions
We have demonstrated that the intramolecular aminomercuration of γ-alkenylamines, derived from aromatic as well as from sugar substrates, results in exclusive 5-endo-trig cyclisation leading to pyrrolidine ring skeletons. The utility of 5-endo-trig cyclized pyrrolidine derivatives 9a and 9b was demonstrated in the synthesis of 1-deoxy-castanospermine analogues 3a and 3b, respectively.

Acknowledgements
We are thankful to CSIR, New Delhi for the SRF to SMJ. We are grateful to UGC, New Delhi for the financial support to procure the high field NMR (300 MHz) facility.

General
Melting points were recorded with a Thomas-Hoover melting point apparatus and are uncorrected. IR spectra were recorded with a FTIR-8400, Shimadzu spectrophotometer as a thin film or in nujol mulls and are expressed in cm −1 . 1 H-NMR (300 MHz) and 13 C-NMR (75 MHz) Mercury YH 300, Varian, spectra were recorded in CDCl 3 as a solvent unless otherwise noted. NMR Chemical shifts are reported in δ ppm) downfield from TMS. Elemental analyses were carried out with Hosli elemental analyzer. Optical rotations were measured with JASCO DIP 181 polarimeter using sodium light (D line 589.3 nm) at 25 °C. TLC was performed on pre-coated plates (0.25 mm, silica gel 60 F 254 ). Column chromatography was carried out with 100-200-mesh silica gel. The reactions were carried out in oven-dried glassware under dry N 2 . Allylmagnesium bromide was prepared prior to use from Mg and allyl bromide in dry ether. N-Benzylhydroxylamine hydrochloride, Cbz-Cl, and mercury acetate was purchased from Aldrich and/or Fluka. Methanol (MeOH), diethyl ether (Et 2 O), dichloromethane (CH 2 Cl 2 ) and THF were purified and dried before use. Petroleum ether (PE) refers to a distillation fraction collected between 40-60 °C. After work up, organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

Preparation of N-benzyl-N-(1-phenylbut-3-enyl)amine (4).
Allylmagnesium bromide (1M in Et 2 O, 1.4 mL, 6.52 mmol) was added dropwise to a stirred solution of nitrone 5 (0.725 g, 3.43 mmol) in THF at 0 °C. The mixture was stirred at 0 °C for 2h, then quenched with a saturated solution of NH 4 Cl (5 mL) and filtered. The filtrate was concentrated and the residue was dissolved in Et 2 O (30 mL). The ethereal layer was washed with brine, dried with sodium sulphate and evaporated to give oil, which was used directly in the next step. Zinc dust (0.257 g, 4.50 mmol) was added to a solution of copper (II) acetate (0.015 g) in glacial acetic acid (1 mL) under nitrogen and the mixture was stirred at room temperature for 15 min until the color disappeared. The crude oil (0.30 g, 0.75 mmol) in glacial acetic acid (0.7 mL) and water (0.3 mL) was added, the reaction mixture was heated at 70 °C for 1h and then cooled to room temperature. The sodium salt of EDTA (0.1 g) was added and the mixture was stirred for 10 min and then made alkaline to pH 10 by addition of 3N NaOH. The resulting solution was extracted with CHCl 3 (10 mL x 3) the combined organic layer was washed with brine dried over Na 2 SO 4 and evaporated to give oil. Purification by column chromatography gave 4 (0.21 g, 70%) as a thick liquid; R f = 0.51 (EtOAc/hexane = 3:7); IR ν max (neat) = 3475, 1634 cm −1 ; 1 H-NMR: δ 1. Preparation of N-benzyl-2-phenyl pyrrolidine (6).