Stereoselective synthesis of 1-deoxynojirimycin, D -glucono-δ-lactam and D -altrono-δ-lactam from a common chiral intermediate derived from D -mannitol

A stereoselective synthesis of 1-deoxynojirimycin, D -glucono-δ-lactam and D -altrono-δ-lactam were accomplished from a common chiral intermediate derived from D -mannitol. The key transformations in the synthesis include Miyashita C-2 selective endo-mode azide opening of epoxy alcohol and Sharpless asymmetric dihydroxylation


Introduction
Polyhydroxylated piperidines and their derivatives commonly known as azasugars or iminosugars are of great interest in synthetic organic chemistry, bio-chemistry, and pharmacology due to their extraordinary biological properties. 1 A large number of azasugars have been extracted from natural sources, mainly from plants, microorganisms and more recently from insects and sea sponges. 2 Among the azasugars, naturally occurring 1-deoxy-azasugars and their analogues such as deoxynojirimycin 1 (DNJ), deoxymannojirimycin 2 (DMJ), adenophorine 3, fagomine 4 and D-glucono-δ-lactam 5 (Figure 1) are the structural analogues of pyranose carbohydrates in which the ring oxygen atom is replaced by a nitrogen atom have been found to act as potent glycosidase and glycosyl transferase inhibitors. 3Moreover these 1-deoxy-azasugars are used as therapeutic agents for the treatment of various conditions such as cancer, HIV infection, hepatitis C virus infection, diabetes, influenza viral infection, and other carbohydrate related metabolic disorders. 4Synthetic 1-deoxynojirimycin derivatives such as N-hydroxyethyl-DNJ 7 (Miglitol or Glyset) and N-butyl-DNJ 8 (Zavesca) have been already approved for the treatment of non-insulin-dependent diabetes and Gaucher's disease respectively. 5At present there are about 35 natural azasugars that act as glycosidase inhibitors; however, their isolation in the pure form from natural sources is a laborious and expensive exercise.Although a number of synthetic routes to azasugars are published to date, development of new synthetic strategy for the synthesis of natural as well as unnatural azasugars from easily available starting materials with high level of stereocontrol is always in demand in organic chemistry. 6In continuation of our research on the synthesis of N-heterocyclic compounds 7 and natural products, 8 herein we describe an efficient synthetic approach to the stereoselective synthesis of 1-deoxynojirimycin (1), as well as its analogues D-glucono-δ-lactam (5) and D-altrono-δ-lactam (6) in good yield from a common chiral intermediate derived from the inexpensive starting material D-mannitol.

Results and Discussion
A retrosynthetic analysis for the synthesis of targeted azasugars is shown in Scheme 1.The target molecules 1, 5 and 6 were envisioned to be obtained from the common chiral intermediate 10 that could be derived from 9 through regioselective epoxide opening with azide nucleophile and Wittig olefination as key steps.The epoxy alcohol 9 could be obtained from D-mannitol via cyclohexylidene D-glyceraldehyde.Scheme 1. Retrosynthetic plan for the synthesis of the title compounds 1, 5 and 6.
Reagents and conditions: (a)  Accordingly, the starting material (E)-allylic alcohol 11 was synthesized according to the reported procedure from D-mannitol. 9 Thus synthesized E-allyl alcohol 11 was subjected to Sharpless catalytic asymmetric epoxidation 10 by using diethyl L-tartrate, Ti(O i Pr)4 and cumene hydroperoxide to afford epoxy alcohol 9 in 93% yield with 94% de, determined by GC-MS analysis (see Experimental part).Our next task was to introduce an azido group at C-2 position of 2,3-epoxy alcohol 9 in a highly regioselective manner.Towards that objective, the highly C-2 regioselective azido epoxide opening of 9 was accomplished by using NaN3-(CH3O)3B system developed by Miyashita et al. 11 Under Miyashita conditions, in our substance the azide nucleophile selectively attacks at the favorable C-2 position rather than at C-3 which is blocked by the hydrogens of the C-5 methylene group 12 as well as the cyclohexylidene group, affording the single compound 12 in 95% yield.
The hydroxyl groups of the obtained azido-diol compound 12 were protected as benzyl ethers using benzyl bromide, followed by selective deprotection of cyclohexylidene group with 1N HCl in CH3CN, afforded the 4-azido-1,2-diol 14 in good yield.The obtained azido-diol compound 14 was subjected to oxidative cleavage with NaIO4 to achieve the corresponding aldehyde.This obtained aldehyde was almost pure and without column purification it was subjected to HWE olefination with triethyl phosphonoacetate under Masamune-Roush conditions 13 to afford the desired, highly E-selective α,β-unsaturated ethyl ester 10 in 93% yield (E:Z, 98:2 based on 1 H NMR analysis).
With compound 10 in hand, the next step was its selective dihydroxylation (Scheme 3).For our study we required both the dihydroxylated compounds, and towards that objective we investigated the stereoselective dihydroxylation of the α,β-unsaturated ethyl ester 10 under various reaction conditions; the results are summarized in Table 1.

Scheme 3. Dihydroxylation of azido ester 10.
Initially, compound 10 was treated with the recommended amount of AD-mix α (1.4 g/ 1mmol) 14 along with methanesulfonamide at 0 o C (entry 1).But we observed that the reaction was very slow and even not completed after 5 days.Furthermore the ratio of the vicinal diols was poor in terms of stereoselectivity.In search of the better conditions, it was found that treatment of compound 10 under modified SAD 15 conditions (entry 2) at 0 o C for 3 days gave the desired diol 15a in 73% yield after purification (dr = 15a:15b, 94:6).After successful synthesis of compound 15a, we then treated the α,β-unsaturated ethyl ester 10 with AD-mix β (1.4 g/ 1mmol), but we did not get a good yield (entry 3).Then we applied the modified SAD conditions on ester 10 (entry 4) and the reaction was completed in 3 days and compound 15b was obtained in good yield with improved diastereoselectivity (dr = 15a:15b, 3:97).However, better results were obtained under Upjohn conditions, on treatment of the compound 10 with 5 mol % of OsO4 and N-methylmorpholine oxide (NMO) 16 as re-oxidant at 0 o C (entry 5).The reaction was completed within 7 h and resulted in the formation of diol 15b in 91% yield with good diastereoselectivity (dr = 15a:15b, 1:99).It was eventually concluded that the slow rate of reaction using the AD-mix reagent (either α or β) is due to steric congestion about the double bond of the ester owing to the OBn group which hinders the approach of the bulky oxidation catalyst to the double bond and also the electron-withdrawing nature of the ester group. 14,17This type of interaction between the catalyst and the bulkiness of the substrate in stereoselective dihydroxylation has been reported earlier.After completion of these dihydroxylation experiments on the ester 10, we turned our attention to the synthesis of 1-deoxynojirimcycin (Scheme 4).Towards that, azido dihydroxy ester 15a was converted into corresponding acetonide azido ester 16 using 2,2-dimethoxy propane and acetone in presence of PTSA followed by selective reduction of ester group of the compound 16 by LiBH4, generated in situ, 19 to afford the corresponding alcohol 17 in 87% yield.In accord with our strategy, a leaving group is required for the construction of the piperidine ring through reductive amino cyclization at the penultimate stage, then the primary hydroxyl group of compound 17 was mesylated with MsCl in presence of triethylamine to afford compound 18 in 93% yield.
The piperidine ring closure was achieved by reductive cleavage of the azido group of compound 18 using Lindlar's catalyst (Pd/CaCO3) under hydrogen, followed by base treatment, in 86% yield.The final target compound 1-deoxynojirimycin (1) was obtained by global deprotection of the benzyl and acetonide groups of 19 with Pd/C under hydrogen atmosphere in MeOH containing 6N HCl, followed by treatment with ion-exchange resin Dowex 50Wx8, in 75% yield (Scheme 4).The spectroscopic and analytical data of 1-deoxynojirimycin 1 were in agreement with literature values. 20fter the successful synthesis of 1-deoxynojirimycin 1, we turned our attention to the synthesis of azasugar lactams using the synthesized azido-dihydroxy esters 15a and 15b.Under hydrogen atmosphere, using Pd/C, we have efficiently converted the azido-dihydroxy esters 15a and 15b independently into the corresponding D-glucono-δ-lactam 5 and D-altrono-δ-lactam 6 in one pot, involving debenzylation and reductive lactamization steps, as shown in Scheme 5.The spectroscopic and analytical data of gluconolactam 5 and altronolactam 6 were in good agreement with the literature values.20a,21 Scheme 5. Synthesis of D-glucono-δ-lactam 5 and D-altrono-δ-lactam 6.

Conclusions
In conclusion, the total synthesis of 1-deoxynojirimycin and the related compounds D-glucono-δlactam and D-altrono-δ-lactam has been achieved in a highly stereoselective manner from a common intermediate derived from D-mannitol.A combination of Miyashita C-2 selective endomode azide opening of epoxy alcohol, and Sharpless asymmetric dihydroxylation were employed to generate chiral centers at the desired positions and to obtain the products in good yields.We believe that the synthetic intermediates described in this paper are useful synthons for other natural products and the work is currently under way in this laboratory.

Experimental Section
General.All reactions were carried out under an inert atmosphere unless mentioned otherwise, and standard syringe-septa techniques were followed.Solvents were freshly dried and purified by conventional methods prior to use.The progress of all the reactions was monitored by TLC, using glass plates precoated with silica gel 60 F254 to a thickness of 0.5 mm (Merck).Column chromatography was performed on silica gel (Acme, 60-120 mesh, India); EtOAc and hexane were used as eluents.Optical rotation values were measured either on a Perkin-Elmer P241 polarimeter or Jasco DIP-360 digital polarimeter at 25 0 C, and IR spectra were recorded on a Perkin-Elmer FT-IR spectrophotometer.NMR spectra were recorded on a Varian Gemini 200 MHz or Bruker Avance 300 MHz or Varian Unity 400 MHz spectrometer upon their availability, using TMS as an internal standard for 1 H NMR and CDCl3 for 13 C NMR (chemical shift values in δ, J in Hz).Mass spectra were recorded on Thermo-Finnigan MAT1020B or Micromass 7070H spectrometer operating at 70 eV using direct inlet system.All high resolution mass spectra (HRMS) were recorded on QSTAR XL hybrid MS/MS system equipped with an ESI source.GC-MS were recorded on Agilent 6890 series GC-MS system, GC (Agilent Technologies, Palo Alto, CA) equipped with a model 5973N mass selective detector and HP-5MS capillary column (5% phenyl, 95% PDMS; 30 m × 0.25 mm i.d × 0.25 µm film thickness) was used.

Table 1 .
Dihydroxylation of olefinic ester 10 under various reaction conditions