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Gram-scale carbasugar synthesis via intramolecular seleno-Michael/aldol reaction

Carbasugars represent an important category of natural products possessing a broad spectrum of biological activities. Lots of effort has been done to develop gram scale synthesis. We are presenting a new approach to gram scale synthesis of the carbasugar skeleton via intramolecular seleno-Michael/aldol reaction. The proposed strategy gave gram amounts of 6-hydroxy shikimic ester in a tandem process in 36% overall yield starting from d-lyxose. We have attempted to demonstrate the synthetic utility of 6-hydroxyshikimic acid derivatives by covering the important synthetic modifications and related applications, namely synthesis of protected (−)-gabosine E, (−)-MK7606, (−)-valienamine and finally unprotected methyl (−)-shikimate.


Introduction
Carbasugars are analogues of sugars that have attracted the interest of medicinal chemists due to their potential application as active pharmaceutical ingredients. These compounds are structurally related to carbohydrates where the ring oxygen is replaced with a methylene group. 1,2 Carbasugar fragments have been found in various natural products. 3,4 The structural similarity of carbasugar fragments to conventional monosaccharides suggests that they are likely to bind and inhibit the same protein targets. The advantage of carbasugar containing compounds is the lack of a glycosidic linkage resulting in the increased stability toward enzymatic degradation. 5,6 For example, synthetic nucleotide analogues containing thiosugar or carbasugars have been reported to be glycosyltransferase inhibitors. [7][8][9] The mechanism of glycosidase inhibition has been studied and several carba-analogues, such as Sergliozin-A 10 or SL0101, 11 have been introduced (Fig. 1). Growing interest of carbasugar use is limited due to their low availability from natural sources.
General strategies to obtain carbapyranoses can be broadly classied into two groups: (i) synthetic methods that employ non-carbohydrates as starting materials and (ii) protocols that utilize carbohydrates as precursors. Multi gram synthesis of carbasugar fragments is still challenging and extremely important.
Carbohydrates, especially monosaccharides, are excellent starting material for total synthesis of various natural and valuable synthetic compounds. Their availability is usually very high, prices are low and chemistry of carbohydrates is well known. An application of monosaccharides to carbohydrate mimetic synthesis seems to be a natural choice. 12 General synthesis of carbasugars moieties is employing Grubbs cross metathesis reaction, [13][14][15][16] aldol-type cyclization, 17,18 Corey-Fuchs reaction 19 and others. 3 Total synthesis of gabosines has been recently reviewed by Mac and co-workers. 20 Our proposal of shikimic-type esters synthesis and their reduced analogues is based on modication of 6-hydroxyshikimic ester 21,22 obtained via intramolecular seleno-Michael/ aldol reaction from D-lyxose (Scheme 1).

Results and discussion
First, we prepared oxo-a,b-unsaturated ester (8) according to the literature method in multi-gram scale. 23 Mixture of 2,3,4-tri-Obenzyl-D-lyxopyranoses (6) have been reuxed with excess of ylide over 12 h yielding mixture of E/Z isomers of 7. Alcohol 7 has been oxidized to corresponding aldehyde 8 using Swern oxidation in 78% yield. Compound 8 has been subjected to intramolecular seleno-Michael/aldol reaction with consecutive oxidation-elimination process to afford a mixture of 6-hydroxyshikimic esters (5) in 56% yield for 7 h (Scheme 2). 24 Aer short optimization, multistep tandem reaction gave the carbocyclic products (6S)-5 and (6R)-5 in 76% yield over 3 steps as an 1 : 0.33 mixture of axial and equatorial alcohol ( Table 1). The 6S/R-isomers of 5 have been separated easily by column chromatography (Experimental section). Having established the optimized conditions for the cyclic core synthesis, further functionalization has been achieved.
Synthesis of methyl (À)-shikimate (À)-Shikimic acid is an important metabolite in plants and microorganisms. This compound can be isolated from the Japanese star anise or synthetized starting from chiral and achiral substrates. Recently, Candeias et al., 25 summarized Scheme 2 Synthesis of key intermediate. known methods of (À)-shikimic acid synthesis. Starting from diastereomeric mixture of alcohols 5 several deoxygenation methods have been tested (Table 2). Finally, alcohol 5 was converted to mesylate 16. Unfortunately, all of our attempts to displace the mesylate group with hydride reagents resulted only in the 1,4-displacement. We decided to change mesylate group to iodide (17) and we found that halogenated compound (17) is unstable in the presence of light. In the end, reduction of iodide crude mixture carried out in the dark gave ethyl (À)-tri-O-benzylshikimate (18) in 2 h in 73% yield over 3 steps. Ethyl ester has been removed under basic conditions to give (À)-3,4,5tri-O-benzylshikimic acid in quantitative yield. Exposure of 19 to BCl 3 gave methyl (À)-shikimate (20) in 67% yield (Scheme 6).

Conclusions
In summary, we have developed simple methods that provide a rapid entry into the synthesis of a series of shikimate ester and shikimate analogues, including (À)-gabosine E and (À)-MK7606. Our synthesis of 6-hydroxy shikimates from D-lyxose has been efficiently achieved in six steps with a 35% overall yield. The strategies described take place through short, highyield reaction sequences. Partial protection of D-lyxose derivative enable access to selective modication of hydroxyl groups. Deoxygenation of 6-hydroxyshikimic ester gave methyl (À)-shikimate in 49% yield total.

General experimental procedures
All starting materials and reagents were purchased from commercial sources and used without purication. Reactions were controlled using TLC on silica [alu-plates (0.2 mm)]. Plates were visualized with UV light (254 nm) and by treatment with: aqueous cerium(IV) sulfate solution with molybdic and sulfuric acid followed by heating. All organic solutions were dried over anhydrous magnesium sulfate. Reaction products were puried by column chromatography using silica gel 60 (240-400 mesh). Optical rotations were measured at room temperature with a digital polarimeter. CDCl 3 , D 2 O, CD 3 OD were used as NMR solvents. 1 H spectra were recorded with 600 and 300 MHz, and referenced relative to: CDCl 3solvent residual peak (d ¼ 7.26 ppm); D 2 Osolvent residual peak (d ¼ 4.79 ppm); CD 3 ODsolvent residual peak (d ¼ 3.31 ppm). Data are reported as follows: chemical shi in parts per million (ppm), multiplicity (s , coupling constants (in hertz) and integration. 13 C NMR spectra were measured at 150 and 75 MHz with complete proton decoupling. Chemical shis were reported in ppm from the residual solvent as an internal standard: CDCl 3 (d ¼ 77.16 ppm); CD 3 OD (d ¼ 49.00 ppm). High-resolution mass spectra were acquired using ESI-TOF method.

2,3,4-Tri-O-benzyl-D-lyxopyranose (6)
To methanolic solution of 1% HCl (50 mL) (prepared by dissolving 1 mL SOCl 2 in anhydrous methanol) D-lyxose (5.0 g, 33.3 mmol) was added in one portion and resulting mixture was reuxed for 5 h under argon (reaction was monitored by TLC CH 2 Cl 2 /MeOH 2 : 1). The reaction mixture was allowed to cool to room temperature, neutralized by addition of solid NaHCO 3 and concentrated under reduced pressure. The residue was dissolved in EtOH (40 mL) and concentrated to the half of the original volume, toluene (25 mL) was added and the mixture was concentrated to dryness. The residue crude mixture oil was used without further purication in the next step. The viscous oil from the previous step was dissolved in anhydrous DMF (50 mL) and anhydrous THF (50 mL) and in 5 portion was added to 60% NaH suspension in mineral oil (6.8 g, 170 mmol) cooled to 0 C. Aer hydrogen evolution was complete the mixture was treated with BnBr (14.8 mL, 122 mmol) and stirred for 30 min in 0 C and then 12 h in room temperature. The reaction mixture was carefully quenched with cold, 10% aqueous solution of NH 4 Cl (30 mL) followed by addition of water (75 mL). The aqueous layer was extracted with EtOAc (3 Â 50 mL) and combined organic layers were washed with water (2 Â 60 mL) and brine (50 mL), then dried over anhydrous MgSO 4 and concentrated under reduced pressure. Crude mixture of D- lyxosides from previous step was heated under reux for 15 h with 1 M H 2 SO 4 (42 mL), AcOH (48 mL) and 1,4-dioxane (44 mL). Mixture was cooled to rt and extracted with EtOAc (2 Â 100 mL). Organic phase was washed twice with water (2 Â 50 mL) and brine (50 mL) and dried over anhydrous MgSO 4 . Aer solvent evaporation residue was puried by column chromatography (Hex/EtOAc 2 : 1 to 3 : 2) to afford mixture of anomers of 2,3,4tri-O-benzyl-D-lyxopyranose as a colorless oil (10.97 g, 26.1 mmol, yield ¼ 78%). 1 H and 13 C spectra were compared with lit. 23 Ethyl (4R,5R,6R)-4,5,6-tri-O-benzyl-7-hydroxyhept-2-enoate (7) To a solution of 6 (10.0 g, 23 (5) A suspension of elemental selenium (1.09 g, 13.75 mmol) in anhydrous THF (250 mL) was cooled in an ice bath and n-BuLi (1.6 M in hexanes, 8.6 mL, 13.75 mmol) was added dropwise (a clear solution was produced) and the mixture was stirred for 15 min in 0 C. Aer that reaction mixture was cooled to À78 C, solution of 8 (5.60 g, 11.46 mmol in 100 mL of anhydrous THF) was added dropwise and stirring was continued through the next 30 min and then cryo-bath was removed and mixture was allowed to warm to room temperature and stirring was continued for the next 1 h. Aer that time, reaction was cooled to 0 C and hydrogen peroxide (35% v/v, 10.1 mL, 114.6 mmol) and pyridine (4.6 mL, 57.3 mmol) were added. Ice bath was removed and mixture was heated to 50 C for 1 h (solution became clear and colorless). Aer solvent evaporation under reduced pressure oily residue was dissolved in ethyl acetate (200 mL), washed twice with water (2 Â 80 mL) and brine (100 mL) and dried over anhydrous MgSO 4 . Solvent was evaporated under reduced pressure and crude product was puried by column chromatography (Hex/EtOAc 4 : 1 to 3 : 1) to give title product as colorless syrup (4.

3,4,5-Tri-O-benzyl-(À)-MK7607 ((6R)-9)
A solution of compound (6R)-5 (0.10 g, 0.2 mmol) in anhydrous methylene chloride (5 mL) was cooled to À30 C and solution of DIBAL-H (1 M in methylene chloride, 1.2 mL, 1.2 mmol) was added dropwise. When the addition was complete, the mixture was stirred at À10 C for 3 h. Aer that time, methanol (1 mL) was added to quench the reaction, and mixture was stirred at À10 C for 30 min. Aer water addition (5 mL) and few drops of 1 M aqueous HCl, water phase was extracted with methylene chloride (3 Â 5 mL) and combined organic phases were washed with water (2 Â 5 mL) and brine (10 mL) and dried over anhydrous MgSO 4 . Solvent was evaporated under reduced pressure. Crude oil was puried by column chromatography (Hex/EtOAc 2 : 1 to 1 : 1) to give title compound as a colorless syrup (0.03 g, 0.067 mmol, 33%

3,4,5-Tri-O-benzyl-(À)-gabosine E (15)
A solution of compound 14 (0.038 g, 0.056 mmol) in anhydrous THF (1 mL) was cooled to 0 C and excess of HF$Py (0.05 mL) complex was added dropwise and ice bath was removed and stirring was continued for next 12 h in room temperature. Aer that time reaction was quenched with water (2 mL) and product was extracted with EtOAc (3 Â 5 mL). Combined organic layers were washed with water (5 mL), brine (10 mL) and dried over anhydrous MgSO 4 . Solvent was evaporated under reduced pressure. Crude product was puried by column chromatography (Hex/EtOAc 4 : 1 to 1 : 1) to afford title compound as a clear syrup (0.022 g, 0.05 mmol, 89%).