A Method For Synthesis Of 6-Deoxy-L-Hexoses From L-Rhamnose

FIELD OF THE INVENTION

The present invention relates to a process for synthesis of 6-deoxy-L-Hexoses of formulae 3 from L-rhamnose 1. The invention particularly relates to a process for synthesis of 6-deoxy-L- fucoside, 6-deoxy-L-quinovoside, 6-deoxy-L-taloside, 6-deoxy-L-iodoside, 6-deoxy-L-altroside, L-vallaroside, 6-deoxy-L-guloside, 6-deoxy-L-alloside. BACKGROUND OF THE INVENTION

The rare 6-deoxy-L-hexoses form key components of several biologically important glycopeptides, antibiotics, oligosaccharides and terpene glycosides. Some representative structures are shown in Figure 1. For example, 6-deoxy-L-talose containing repeating disaccharide is found in serotype c of the Gram-negative bacterium Actinobacillus actinomycetemcomitans, which is associated with periodontitis and endocarditis. 6-Deoxy-L- talose is also present in talopeptin, and in the glycopeptidolipid antigens of Mycobacterium avium serovar 20, as well as 045, 045-related and 066 antigens of Escherichia coli. The 6- deoxy-L-glucose (L-quinovose) is present in the O-polysaccharides of Gram-negative bacteria Yersinia pseudotuberculosis and Providencia stuartii 044:H4 (strain 3768/51). L-Quinovose is also present in the naturally occurring glycomacrolide Apoptolidin A, which is a potent antitumor agent known to induce apoptosis in cancer cell lines. Zorbamycin, a member of the bleomycin family of glycopeptide-derived antitumor antibiotics, is comprised of a 6-deoxy-L- gulose unit. Likewise, a potent anticancer agent Datiscoside C isolated from the plant Datisca glomerata consists of a 6-deoxy-L-allose. 6-Deoxy-L-idose occurs in the diterpene glycoside isolated from Aster spathulifolius Maxim. Interestingly, the trisaccharide repeating unit of the pathogen Yersinia enterocolitica serovars 0:1.2a,3 and 0:2a,2b,3 contains 6-deoxy-L-altrose as the sole component. Finally, L-fucose (6-deoxy-L-galactose) is a constituent of many important glycans including Sialyl lewis X (SLex) blood group antigen, whereas L-rhamnose (6-deoxy-L- mannose) is ubiquitous in various bacterial glycans.

The 6-deoxy-L-sugars are commercially not available except for L-rhamnose and L-fucose. Numerous methods have been explored for the synthesis of rare 6-deoxy-L-sugars using de novo approaches or from readily available sugar starting materials. An attractive de novo method was developed by O'Doherty and co-workers starting from acyl furan via Noyori's reduction and Achmatowicz rearrangement as key steps to access 6-deoxy-L-sugars. Recently, Bols and coworkers reported the synthesis of all eight stereoisomers of 6-deoxy-L-hexoses as their thioglycoside donors starting from the commercially available L-rhamnose or L-fucose employing stereoselective reductions or Mitsunobu inversions. Although this approach is a marked improvement over the earlier carbohydrate approaches, the development of more convenient routes to synthesize all isomers of 6-deoxy-L-hexoses is still in great demand.

Therefore, it is the need of the hour to provide a simple and straightforward method to transform easily available L-rhamnose into of all the 6-deoxy-L-sugars as stable thioglycoside building blocks. DESCRIPTION OF THE INVENTION:

The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

One aspect of the present invention provides a method for preparing 6-deoxy L-hexose derivatives of formulae 3 from cheaply available L-rhamnose of formula 1 via regioselective protection of individual hydroxyls of monosaccharide units followed by regio- and stereoselective nucleophilic displacement of triflates. The process entails regioselective protections, one-pot double displacements of triflates and/or cascade inversions.

Based on the stereoelectronic considerations, β-L-thiorhamnoside 1 was selected as a suitable precursor. The present invention relates to a process for synthesis of 6-deoxy-L-Hexoses of formulae 3 from L-Rhamnose of formula 1 comprising the steps of

a) Optional regioselective protection of C3-, C4- and/or C2-OH of the L-Rhamnose of formula 1 to obtain compounds of formulae 2; and b) subjecting compounds of formulae 2 to triflation followed by nitrite anion or water mediated inversion to obtain 6-deoxy-L-Hexoses of formulae 3

wherein

R ₁ is selected from H, Tert-Butyldimethylsilyl (TBS), Benzyl (Bn), Benzoyl (Bz) and/or 2,2,2- Trichlorethoxycarbonyl (Troc);

R ₂ is selected from H, Benzoyl (Bz), Acetate (Ac), and/or Tosyl (Ts);

R3 is selected from H, and/or, Benzoyl (Bz);

R ₄ is selected from H, Tert-Butyldimethylsilyl (TBS), Benzyl (Bn), Benzoyl (Bz), Acetyl (Ac) and/or 2,2,2-Trichlorethoxycarbonyl (Troc);

R5 is selected from H, Benzoyl (Bz), Acetyl (Ac), and/or methyl (Me); and R ₆ is selected from H, Acetyl (OAc) and/or, Benzoyl (Bz); and

The specific compounds prepared include

The triflation is carried out using triflic anhydride and pyridine followed by nitrite anion or water mediated inversion using tetrabutylammonium nitrite (or potassium nitrite) in acetonitrile.

The selective protection is carried out using commonly available groups selected from, but not limited to, Tert-Butyldimethylsilyl, Tert-Butyldiphenylsilyl, Trimethylsilyl (TMS), Benzyl, p- Methoxybenzyl (PMB), 2-Naphthylmethyl (Nap), Benzyl, Benzoyl, Acetyl, Levulinoyl, Pivaloyl, Methyl, Tosyl, Mesyl, Fmoc and 2,2,2-Trichlorethoxycarbonyl.

The 3-O-benzoylation reaction is carried out optionally in presence of a catalyst selected from Dimethyltin dichloride, 2-(trifluoromethyl)pheyl boronic acid, 3,5-Bis(trifluoromethyl)phenyl boronic, Iron(III) chloride or Copper triflate.

The process thus provides for process to transform cheaply available L-rhamnose into L-fucose, 6-deoxy-L-talose, L-vallarose, L-quinovose, 6-deoxy-L-gulose, 6-deoxy-L-altrose, 6-deoxy-L- allose and 6-deoxy-L-idose thioglycosides.

The stable thioglycoside building blocks of the rare sugars can be further utilized in stereoselective glycosylations for the synthesis of biologically important complex glycoconjugates and natural products.

Thus, all the isomeric 6-deoxy-L-sugars are synthesized from a common starting material L- rhamnoside 1. Depending on the stereorelationship, a regio selective protection of the triol was carried out (Benzoylation, acteylation and silylation) to mask remaining hydroxyl groups, leaving behind the hydroxyl groups free to be subjected to triflation and inversion. All the sugars were synthesized by using S _N 2 nucleophilic displacement of triflates using Tetrabutyl Ammonium Nitrate as a common reagent or via intramolecular S _N 2 displacement of triflates via neighboring acyl (Ac or Bz) group. Examples

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

First, 3-O-benzoylation of β-L-thiorhamnoside 1 was carried out by using 5.0 mol% of various catalysts in N,N-Diisopropylethylamine (DIPEA), benzoyl chloride and THF to obtain 2a (Table 1). The 03-benzoylation of 1 is known to be achieved by using 5 mol% of dimethyl tin dichloride to afford 2a within 10 min at rt in 95% yield (Table 1, Entry 1). However, it is known that tin based catalysts are toxic and hence we carried out the reaction using various nontoxic transition metal and metalloid catalysts to achieve this transformation under the same reaction conditions. As shown in Table 1 below, organoboron species were evaluated as catalyst for selective benzoylation. 2-(Trifluoromethyl)phenylboronic acid and 3,5- bis(trifluoromethyl)phenylboronic acid provided 2a in 78% and 58% yields, respectively, after stirring for 30 h (entries 2 and 3). Anhydrous Iron(III) Chloride (entry 4) as a catalyst under same set of reaction conditions provided 2a in 20% yield. Finally, copper triflate (Cu(OTf)2) was found to the best readily available, environmentally benign catalyst for this transformation affording 2a in 5h in 90% yield (entry 5).

Table 1:

Table 1. Regioselective monobenzoylation of -L-thiorhamnosicle 1 using various catalysts (5.0 mol %)

a. Other isomers were not observed and unreacted starting material was recovered Next, the 2,4-diol 2a was treated with triflic anhydride (Tf ₂ O) and pyridine to obtain the corresponding 2,4-bistriflate which underwent a facile double inversion with 4 equiv of tetrabutyl ammonium nitrite (TBANO ₂ ) in acetonitrile (Lattrel-Dax reaction) to furnish L-fucose derivative 3a in 50% yield over 2 steps (Scheme 1). The 2-OH of 2,4-diol 3a was regio selectively acetylated using catalytic amount of Me ₂ SnCl ₂ to obtain selectively protected L- fucoside 4 in 82% yield. Scheme 1. Direct transformation of L-rhamnose into regioselectively protected L-fucose derivative 3a and 4

L-Quinovose is a C2 epimer of L-rhamnose (Scheme 2a). For the C2 epimerization, a regio selective silyl protection of L-rhamnosyl diol 2a at 04 position was carried out by treatment with TBSC1 and imidazole in DMF to afford 4-O-TBS derivative 2b as a major product (66%) along with minor 2-O-TBS product (-10%). Subsequent triflation of 2b followed by displacement of the so formed C2-0-triflate with TBANO ₂ afforded L-quinovoside 3b in 71% yield over 2 steps.

Scheme 2. Synthesis of L-quinovosides 3b and 3c via C2 epimerization.

Similarly, selective 3-O-benzoylation of the easily accessible L-rhamnosyl 2,3-diol 2c under tin mediated conditions provided alcohol 2d in 91% yield (Scheme 2b). Subsequent triflation of the 2-OH of 2d, followed by S 2 displacement of the formed C2-OTf by nitrite anion furnished L- quinovoside 3c in 81% yield over 2 steps.

6-Deoxy-L-talose is a C4 epimer of L-rhamnose. Regio selective 2,3-O-benzoylation of L- rhamnoside 1 using 2.1 equiv of benzoyl chloride and pyridine in CH2CI2 at -30°C afforded 2,3- di-OBz derivative 2e in 71% yield (Scheme 3). Compound 2e was treated with Tf ₂ 0 and pyridine to form the corresponding C4-OTf derivative in 10 min, which was subsequently subjected to a water mediated intramolecular S 2 displacement of the C4-OTf by C3-OBz group from the bottom face, to obtain 2-OH L-taloside 3d (67%) via an orthoester intermediate. In this reaction, a double migration of the benzoyl group occurred from C3 to C4 (with inversion of stereochemistry) and concomitant migration from C2 to C3 to give 3d. Scheme 3. Synthesis of 6-deoxy-L-taloside 3d via C4 inversion.

The difference between the structures of L-rhamnose and 6-deoxy-L-idose is the stereochemistry at C3 and C4 positions. Accordingly, a regio selective 3-O-acetylation of triol 1 was carried out using Me ₂ SnCl ₂ , DIPEA and acetyl chloride in THF to afford compound 2f in 98% yield (Scheme 4). Regioslective 2-O-benzoylation of 2,4-diol 2f under basic conditions by using benzoyl chloride in pyridine at -15°C furnished compound 2g in 92% yield. Triflation of the remaining free 4-OH of 2g was carried out using Tf ₂ 0 in pyridine in 10 min. Upon completion of the reaction, water was added and the reaction mixture was further heated at 50°C for 3h to furnish 6-deoxy-L-taloside 3e in 75% yield via intramolecular displacement of triflate by acetate from the bottom face. In this reaction, we obtained 3-OAc L-taloside 3e instead of the expected axial 4-OAc L-taloside derivative. It could be that the first formed C4-OAc would have migrated to C3 position under the reaction conditions. The 4-OH of 3e was protected as Troc ester, followed by removal of the acetyl group using acetyl chloride in methanol to furnish 3 -OH 6- deoxy-L-taloside 2h. Compound 2h upon triflation and subsequent nitrite anion mediation inversion afforded differentially protected 6-deoxy-L-idoside 3f in 54% yield over 2 steps.

Scheme 4. Synthesis of 6-deoxy-L-taloside 3e and 6-deoxy-L-idoside 3f by C4 &C3 inversion of 1

In order to synthesize 6-deoxy-L-altrose, inversion at C3-OH of L-rhamnoside was needed (Scheme 5). Therefore we investigated suitable conditions for regio selective 3-O-triflation. Under the optimized conditions, a highly regioslective 3-OTf formation of L-rhamnoside 1 was carried out in 5 min using 3.5 equiv of Tf ₂ O, 5.0 mol% Me ₂ SnCl ₂ and 6.0 equiv of 2,6-lutidine in CH ₂ C1 ₂ . Since the 3-0 triflate intermediate was unstable, immediate addition of excess acetic anhydride was unstable, immediate addition of excess acetic anhydride in the same pot afforded a relatively stable 3-0-triflyl-2,4-acetyl-rhamnoside derivative, which upon a brief work was treated with TBANO ₂ in acetonitrile at 80°C for 8h to afford 6-deoxy-L-altroside 3g in 45% over 3 steps, after a single chromatographic purification, in essentially one-pot manner.

For a convenient synthesis of L-vallaroside 3h, regio selective 3-O-tosylation of triol 1 was achieved using 5.0 mol% Me ₂ SnCl ₂ , 1.1 equiv of toysl chloride, and DIPEA in THF at rt in 5 min to give a stable tosylate 2i (96%), which upon treatment with sodium methoxide in methanol at 70°C for lOh furnished L-vallaroside 3h (82%).

Scheme 5. Synthesis of 6-deoxy-L-altroside 3g and L-vallaroside 3h by C3 inversion of L- rhamnoside 1

For the synthesis of 6-deoxy-L-guloside 3i, it was needed to carry out inversion at C2, C3 and C4 positions of L-rhamnose. First, L-rhamnosyl-2,4-diol 2f was converted to the 2,4-bis-triflate which upon work up was as treated with 3.0 equiv of TBAN0 ₂ and ethylenediamine (EDA) in toluene to obtain 3,4-epoxy alcohol 2'f (64% over 2 steps). Treatment of 2'f with Sc(OTf) ₂ in AcOH furnished 6-deoxy-L-gulose derivative 3i (82%). In this way, the C2, C3 and C4 stereocentres of L-rhamnoside were inverted via a cascade reaction and subsequent epoxide ring opening.

Scheme 6. Synthesis of 6-deoxy-L-guloside 3i via cascade inversion

Finally, the rare sugar-L-allose required a C2 and C3 epimerization of L-rhamnose. For this, the known 4-OH L-rhamnoside derivative 1' was treated with benzoyl chloride in pyridine followed by acetal hydrolysis to afford 2j (79% over 2 steps). The 2,3-hydroxyl groups in 2j were subjected to triflation and subsequent 2,3-bistriflate inversion with TBAN0 ₂ provided 6-deoxy- L-alloside 3j in 62% over 2 steps. Scheme 7. Synthesis of 6-deoxy-L-alloside 2j via vicinal 2,3-O-triflate inversion of L- rhamnoside