Synthesis of a sucrose-based macrocycle with unsymmetrical monosaccharides "arms"

An efficient methodology for the selective substitution of both terminal positions (C6 and C6’) in 1’,2,3,3’,4,4’-hexa-O-benzylsucrose with different unsaturated monosaccharide units is presented. Such a highly functionalized intermediate was cyclized under RCM conditions to afford a macrocyclic derivative containing a 31-membered ring in 26% yield.

Sucrose was also used by other groups as a precursor for the preparation of biodegradable polymers [22][23][24] and polymeric nanoparticles [25].On the other hand, sucrose derivatives demonstrate antimicrobial and antitumor activities [26,27].
We have decided, therefore, to elaborate another method leading to functionalized sucrose amines of type 9 (Figure 2) which will be obtained by a selective introduction of different fragments 8 (obtained from, e.g., glucose, mannose, etc.).
At this stage we were focused on the elaboration of a methodology allowing to introduce different fragments at the sucrose terminals.We chose, therefore, derivatives of methylated hexitols which are easy to prepare and are more convenient than benzyls in the interpretation of the NMR spectra.
We faced, however, a serious problem in the synthesis of amines of type 8. Treatment of aldehyde 11 -generated in situ from iodide 10 according to Vasellas' procedure [31,32] -with benzylamine under the reductive amination conditions afforded an inseparable mixture of two products differing in the configuration at the C2 center (12a and 12b; Scheme 2); such a phenomenon -epimerization under these conditions -is known [33].
The alternative way to the desired amine 12a, based on the S N 2 reaction of the activated alcohol 13 [34,35] with benzylamine, also failed (Scheme 2).The Mitsunobu approach to convert the hydroxy group into an amine function was also unsuccessful.Although 13 reacted with phthalimide gave the desired product 13a, the deprotection of the amine function with hydrazine caused also reduction of the C5-C6 double bond; two peaks at 189 and 191 Da were observed in the MS spectrum of crude post-reaction mixture (for 13b and 13c, respectively).
Aldehyde 20 [37] -obtained by Swern oxidation [38] of alcohol 19 -was reacted with amine 17 to afford the desired amine isolated as acetate 21 in 85% total yield.Removal of the TBDPS protecting group from the C6'-position gave alcohol 22 in 97% yield.Under the same "Swern oxidation-reductive amination-acetylation" conditions, alcohol 22 was converted into aldehyde 23, which reacted further with amine 18, furnishing diolefin 24 in 64% total yield.Cyclization of precursor 24 induced by the Hoveyda-Grubbs catalyst (II gen.) afforded the target macrocycle 25 in 26% yield (Scheme 4).The E-configuration of the newly created C=C-bond in the final product was proven by 1 H NMR analysis (J 15-15' = 15.9Hz).

Conclusion
In summary, we proposed an efficient method of the synthesis of a 31-membered macrocycle with sucrose scaffold.The proposed methodology allows for the regioselective introduction of various polyhydroxylated unsaturated fragments (derived from different sugars) at either terminal position of sucrose which undergo an efficient cyclization under the RCM conditions.Although, for practical reasons, the method was elaborated for the methylated derivatives of hextitol pendants it might be, eventually, applied also for synthons with other protecting groups.

Experimental General
The NMR spectra were recorded with a Varian VNMRS 600 MHz spectrometer for solutions in CDCl 3 at 25 °C.The 13 C NMR data for compound 25 were recorded with a Varian VNMRS 500 MHz spectrometer.The structures were assigned, whenever necessary, with the help of 2D correlation experiments (COSY, HSQC, HMBC).Chemical shifts were reported with reference to TMS.Optical rotations were measured with a Jasco P 1020 polarimeter (sodium light) in chloroform at room temperature.Mass spectra were recorded with a Synapt G2-S HDMS (Waters Inc) mass spectrometer equipped with an electrospray ion source and a q-TOF type mass analyzer.The instrument was controlled and recorded data were processed using the MassLynx V4.1 software package (Waters Inc).Thinlayer chromatography (TLC) was performed on silica gel plates coated with fluorescent indicator.Column chromatography was performed on silica gel (Merck, 230-400 mesh).Organic solutions were dried over anhydrous MgSO 4 .

Synthesis of amino compounds 17 and 18
To a solution of nitro compound 14 or 16 (232 mg, 0.74 mmol) in aq ethanol (14 mL, 1:1 v/v), K 2 CO 3 (304 mg, 2.22 mmol) and Na 2 S 2 O 4 (322 mg, 1.85 mmol) were added, and the mixture was stirred for 30 min at rt. Ethyl acetate (15 mL) was added, the layers were separated, and the aqueous one extracted with ethyl acetate (3 × 8 mL).The combined organic solutions were dried, concentrated, and the crude product 17 or 18 was used in the next step without further purification.

Figure 2 :
Figure 2: Possible route to dienes of type 9.