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General Intermediates for the Synthesis of 6-C-Alkylated DMDP-Related Natural Products

Protected L-homoDMDP en-8 and its C-6 epimer en-7 were prepared through two different pathways starting from the vinylpyrrolidine en-9. Based on the NMR and X-ray analysis, the stereochemistry of homoDMDP at C-6 was confirmed to be consistent with reported data. Compounds en-7 and en-8 are general intermediates for the synthesis of a series of 6-C-alkylated DMDP-related natural products, such as broussonetine G, homoDMDP-7-O-apioside, homoDMDP-7-O-β-D-xyloside and so on.

Although Wong et al. had indicated the absolute configuration of homoDMDP to be (2R,3R,4R,5R,6S) based on their enantiospecific synthesis of a series of five-membered iminosugars [22], no direct experimental proof was available until our group reported the synthesis of L-homoDMDP [19]. There, we disclosed the stereochemistry of L-homoDMDP determined by analyzing the 2D-NMR of an oxazinone intermediate, a conformation-locked L-homoDMDP. In this article, we report a further confirmation of L-homoDMDP's stereochemistry based on X-ray and 2D-NMR analysis of its oxazolidinone derivatives. In addition, both epimers of protected L-homoDMDP at C-6 were obtained readily, which are common intermediates for enantiomers of 6-C-alkyl-DMDP natural products such as homoDMDP-7-O-apioside and homoDMDP-7-O-β-D-xyloside.

Results and Discussion
6-C-Alkyl-DMDP iminosugars have attracted lots of attention, and several syntheses are available in the literature [7,22]. However, these syntheses are either tedious or the method was only suitable for a specific compound. In order to solve the material supply problem and speed up the study of glycosidase inhibition, a practical synthesis of this family of natural products is in great demand. In this regard, the collective synthesis strategy [12] relying on an advanced common intermediate provides a good opportunity. In addition, a full assignment of the stereochemistry of 6-C-alkyl-DMDP iminosugars requires both epimers.
Taking homo-DMDP-7-O-apioside and homo-DMDP-7-O-β-D-xylopyranoside as examples, we envisioned that it is necessary to obtain both C-6 epimers 7 and 8, which could be reached from the same intermediate 9 (Scheme 1). Furthermore, conformation-locked molecules 7 and 8 are very good intermediates for stereochemistry assignment based on 2D-NMR analysis, and all the isomers or intermediates represent interesting medicinal chemistry targets. From a retrosynthesis point of view, homoDMDP-related natural products 5 and 6 could be synthesized via glycosylation of alcohol 7 or 8, which could be accessed from all-trans substituted pyrrolidine 9 by alkene oxidation. Based on the well-developed chemistry of highly stereoselective addition of organometallic reagents to cyclic nitrones [23][24][25], pyrrolidine 9 could be prepared on a large scale with extreme purity.  With grams of vinyl-containing pyrrolidine en-9 [19] in hand, the synthesis of en-7 and en-8 was attempted (Scheme 1). The terminal alkene en-9 was treated with iodine in acetonitrile, and the oxazolidinone 11 was obtained in 57% yield, with structure supported by its IR data (ν max 1,762 cm −1 ) and 13 C-NMR spectrum (δ 159.98 ppm). Its relative configuration was studied by its NOESY spectrum based on the full assignment of all protons through 1 H-NMR and 2D-NMR (COSY, HMBC). The strong correlations observed between H-3/H-1 as well as H-5/H-1 revealed that H-1,H-3 and H-5 were on the underside of the pyrrolidine ring ( Figure 2), while the strong correlations between H-2/H-4 showed they were on the same side. i.e., the pyrrolidine was all-trans substituted, which was consistent with the previous results reported by our group. The correlations between H-5/H-1 as well as H-5/H-7 showed the C(7)H 2 I was on the upper side of the oxazolidinone ring. Furthermore, the above determination of relative as well as absolute configuration of the oxazolidinone 11 was unambiguously confirmed to be (2S,3S,4S,5R,6S) by X-ray diffraction [26]. The treatment of iodide 11 by silver nitrate followed by reductive hydrolysis [27] furnished the alcohol en-7 in a total yield of 77% over two steps. Since during these two steps the stereocenters have not been touched, the streochemistry of en-7 was determined to be (2S,3S,4S,5S,6S). In the course of the synthesis of L-homoDMDP, we were delighted to find that the major product 13 (Scheme 2) obtained from dihydroxylation on terminal alkene en-9 was the right diastereomer for L-homoDMDP, which was prepared by the hydrogenation on diol 13 to remove the protecting groups. The stereochemistry of L-homoDMDP was confirmed to be (2S,3S,4S,5S,6R) based on a conformationlocked oxazinone intermediate [19]. In order to provide more evidence for the stereochemistry confirmation of homoDMDP, as well as common intermediates in the collective synthesis of homoDMDP-related pyrrolidine natural products, we decided to make the correseponding oxazolidinone derivatives. The diol 13 was selectively protected as trityl ether 14, the secondary alcohol 14 was then treated with alkaline solution, and the oxazolidinone 15 was obtained in 69% yield over two steps. After treatment of trityl ether 15 with mineral acid, the alcohol en-8 was obtained in 85% yield (Scheme 2). Conformation of the oxazolidinone structure was supported by its IR data (ν max 1,758 cm −1 ) and 13 C-NMR spectrum (δ 160.03 ppm). Similarly, the relative configuration of alcohol en-8 was assigned unambiguously through NOESY spectrum ( Figure 3). The strong correlations observed between H-3/H-1, H-5/H-1, as well as H-5/H-3 revealed H-1, H-3 and H-5 were on the upper side of the pyrrolidine ring, i.e., the pyrrolidine was all-trans-substituted. The correlations between H-7/H-4 showed the C(7)H 2 OH was on the underside of the oxazolidinone ring. Based on the above analysis as well as comparison with en-7, the stereochemistry of en-8 was deduced to be (2S,3S,4S,5S,6R), and the configuration of homoDMDP was determined as (2R,3R,4R,5R,6S), which was consistent with reported data [19]. With both C-6 epimers en-7 and en-8 in hand, the syntheses of the enantiomers of homo-DMDP-7-O-apioside and homo-DMDP-7-O-β-D-xylopyranoside by glycosylation of en-7 and en-8 were on the right course. In addition, iodide 11 represents an ideal intermediate for the total synthesis of enantiomers of 6-C-alkyl-DMDP natural products such as L-6-C-butyl-DMDP and (+)-broussonetine G. For the total synthesis of the natural 6-C-alkyl-DMDP pyrrolidines, we are currently working on the synthesis of cyclic nitrone 10. The relevant results will be reported in due course.

General
All reagents were used as received from commercial sources without further purification or prepared as described in the literature. Tetrahydrofuran was distilled from sodium and benzophenone immediately before use. Reaction mixtures were stirred using Teflon-coated magnetic stir bars. Analytical TLC was performed with 0.20 mm silica gel 60F plates with 254 nm fluorescent indicator. Plates were visualized by ultraviolet light and treatment with Pancaldi reagent [(NH 4 ) 6 MoO 4 , Ce(SO 4 ) 2 , H 2 SO 4 , H 2 O] or 0.5% ninhydrin in acetone stain, followed by gentle heating. Chromatographic purification of products was carried out by flash chromatography on silica gel (230-400 mesh) as well as on the 001 × 7 (732 # ) strong acid styrene cation exchange resin (Tianjin Kermel Chemical Reagent Development Center, Tianjin, China). Melting points were determined using an Electrothermal melting point apparatus. Both melting points and boiling points are uncorrected. Infrared spectra were recorded on a JASCO FT/IR-480 plus Fourier transform spectrometer. NMR spectra were measured in CDCl 3 (with TMS as internal standard) or D 2 O on a Bruker AV300 and AV600 magnetic resonance spectrometers. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in Hz. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High-resolution mass spectra (HRMS) were recorded on an APEXII FT-ICR (SIMS) mass spectrometer. Polarimetry was carried out using an Optical Activity AA-10R polarimeter and the measurements were made at the sodium D-line with a 0.5 dm pathlength cell. Concentrations (c) are given in gram per 100 mL. Single-crystal X-ray diffraction was collected on a Rigaku RAPID-AUTO diffractometer. (11). To a solution of alkene en-9 (0.22 g, 0.39 mmol) in acetonitrile (3 mL), iodine (0.36 g, 1.4 mmol) was slowly added, and the resulting purple mixture was stirred at r.t. for 3.5 h. The reaction was then quenched by adding sat. aqueous Na 2 S 2 O 3 , and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na 2 SO 4 , concentrated, the residue was purified by FCC (silica gel, eluted with 10%-20% EtOAc in petroleum ether) to give the title oxazolidinone 11 as a colorless crystalline product (0.13 g, yield 57%). IR(KBr, cm  137.84, 137.36, 137.30, 128.64, 128.51, 128.45, 128.21, 127.96, 127.91, 127.78, 127. 1S,5S,6S,7S,7aR)-6,7-bis(Benzyloxy)-5-((benzyloxy)methyl)-tetrahydro-1-(O-nitroate-methyl)pyrrolo [1,2-c] oxazol-3(1H)-one (12). To a solution of iodide 11 (0.21 g, 0.35 mmol) in acetonitrile (6 mL) silver nitrate (0.18 g, 1.0 mmol) was added, the resulting reaction mixture was heated to reflux for 40 h. The resulting solid was filtered off, the filtrates was concentrated, the residue was purified by FCC (silica gel, eluted with 10-30% EtOAc in petroleum ether) to give the nitrate 12 (0. 16 13

Conclusions
In summary, the access to both C-6 epimers of protected L-homoDMDP was achieved with high efficiency. The (6S)-epimer en-7 was prepared in 44% overall yield from vinylpyrrolidine en-9 using the iodolactonization as a key step. The (6R)-epimer en-8 was synthesized in 59% overall yield from the known diol 13 through a 3-step-sequence-regioselective tritylation of diol 13, lactonization to give oxazolidinone and acidic hydrolysis of the trityl ether. The stereochemistry confirmation of L-homoDMDP was achieved through 2D-NMR and X-ray data based on the bicyclic oxazolidinone intermediate en- 8. This work will lead to the collective synthesis of homoDMDP-related natural products and their analogues, and potentially to the unambigous disclosure of their stereochemistry.

Supplementary Materials
1 H and 13 C-NMR spectra of compounds en-7 and en-8 were available free of charge.