Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge.


Introduction
Carbohydrates, in the form of oligosaccharides, polysaccharides, and glycoconjugates, are ubiquitous in nature and play crucial roles in a wide range of intercellular recognition events, including adhesion, signaling, trafficking, immune response, metastasis, inflammation, as well as bacterial and viral infections [1][2][3]. Due to these important biological functions, the development of sugar-based drugs could be of great pharmaceutical interest [4,5]. However, the sensitivity of the native glycosidic bond to chemical and enzymatic degradation hinders the therapeutic application of carbohydrates [6].
Next, thiol-ene reactions of enopyranosides bearing an exomethylene moiety at the C2 position were studied (Schemes 2-4). The properly protected methyl α-d-glucopyranoside derivative 14 [39] was converted into the C2-exomethylene derivative 16 in two steps, including oxidation with Dess-Martin periodinane [40] and olefination of the resulting 2-ulose 15 by a Wittig reaction (Scheme 2). The addition of 1-thioglucose tetra-O-acetate 2a onto 2-exomethylene 16 at room temperature readily occurred to result in an inseparable 1:1 mixture of the d-gluco and d-manno configured thiodisaccharides (17a,b) with 91% yield. After the acidic removal of the butane-2,3-diacetal (BDA) group, the partially protected diastereoisomeric glycomimetics 18 and 19 were successfully separated and characterized.  The methyl α-D-galactopyranoside derivative 22 with a C2 exocyclic double bond was also synthesized, starting from compound 20, in order to study the effect of the enose configuration on the stereochemical outcome of the hydrothiolation reaction [41] (Scheme 3). Swern-oxidation [42] of 20, followed by Wittig-olefination of the resulting 2-ulose 21 furnished 22 with good overall yield. Addition of β-1-thiosugar 2a onto the galactose-derived enoside 22 at rt occurred with lower efficacy than in the gluco-case and led again to the formation of an inseparable diastereoisomeric mixture of the corresponding axially and equatorially coupled C-S-bonded disaccharides 23a and 23b. In this For studying the impact of the anomeric configuration on the stereochemical outcome of the thiol-ene reaction, compound 29, the β-analogue of 22, was prepared from methyl β-D-galactoside 27 [43] via oxidation and Wittig-olefination (Scheme 4). Surprisingly, the addition of 2a and 2e onto 29 at rt proceeded with low efficacy resulting in the C-S bridged products 30 and 31 in low yields. On the other hand, an opposite and increased stereoselectivity was observed with both thiols when compared to the α-configured enoside 22. Using 2a as the thiol, a 4:1 mixture was formed at rt in favour of the galacto-configured product with 22% yield, while complete galacto selectivity was observed with thiol 2e, albeit the yield was only moderate at rt. Running the reaction at −80 °C significantly increased the yields and exclusive formation of the D-galacto configured products was observed with both thiols.
The methyl α-D-galactopyranoside derivative 22 with a C2 exocyclic double bond was also synthesized, starting from compound 20, in order to study the effect of the enose configuration on the stereochemical outcome of the hydrothiolation reaction [41] (Scheme 3). Swern-oxidation [42] of 20, followed by Wittig-olefination of the resulting 2-ulose 21 furnished 22 with good overall yield. Addition of β-1-thiosugar 2a onto the galactose-derived enoside 22 at rt occurred with lower efficacy than in the gluco-case and led again to the formation of an inseparable diastereoisomeric mixture of the corresponding axially and equatorially coupled C-S-bonded disaccharides 23a and 23b. In this case a moderate selectivity was observed in favour of the d-talo-configured product. Recently, we have found that cooling was advantageous to the thiol-ene reactions of enosides to increase the yields [29], and, in the case of enofuranosides and pentopyranosyl endoglycals, to raise the stereoselectivity significantly [18,31]. Indeed, conducting the reaction between 22 and 2a at −80 • C the yield of 23a,b reached 88%. However, surprisingly, a complete lack of stereoselectivity was observed at this temperature.
Reacting 22 with α-1-thiomannose derivative 2e at rt occurred with a higher d-talo selectivity, which resulted in a 4:1 mixture of the C-S-bonded glycomimetics 24a and 24b. The cooling was again beneficial to the efficacy and detrimental to the diastereoselectivity of the reaction affording the d-talo and d-galacto configured products in a 1:1 ratio in 96% yield. The partial deprotection of 24a,b with TFA gave a mixture of 25 and 26, from which the d-talo configured 25 could be isolated in the pure form.
For studying the impact of the anomeric configuration on the stereochemical outcome of the thiol-ene reaction, compound 29, the β-analogue of 22, was prepared from methyl β-d-galactoside 27 [43] via oxidation and Wittig-olefination (Scheme 4). Surprisingly, the addition of 2a and 2e onto 29 at rt proceeded with low efficacy resulting in the C-S bridged products 30 and 31 in low yields. On the other hand, an opposite and increased stereoselectivity was observed with both thiols when compared to the α-configured enoside 22. Using 2a as the thiol, a 4:1 mixture was formed at rt in favour of the galacto-configured product with 22% yield, while complete galacto selectivity was observed with thiol 2e, albeit the yield was only moderate at rt. Running the reaction at −80 • C significantly increased the yields and exclusive formation of the d-galacto configured products was observed with both thiols.
Next, we turned our attention to hydrothiolation of pyranoses containing a C4 exocyclic double bond (Schemes 6 and 7). The oxidation of the methyl α-D-glucopyranoside derivative 36 [39] at position 4, followed by Wittig-olefination resulted in the unsaturated sugar 37 bearing 6-O-silyl and 2,3-O-butane diacetal protecting groups (Scheme 6). The hydrothiolation of 37 with 1-thioglucose peracetate 2a went to completion within 15 min. to result in an inseparable mixture of two compounds. On the basis of NMR and MS data, the components of the obtained mixture were Scheme 5. Thiol-ene reactions of enoside with a C3-exomethylene moiety.
Next, we turned our attention to hydrothiolation of pyranoses containing a C4 exocyclic double bond (Schemes 6 and 7). The oxidation of the methyl α-d-glucopyranoside derivative 36 [39] at position 4, followed by Wittig-olefination resulted in the unsaturated sugar 37 bearing 6-O-silyl and 2,3-O-butane diacetal protecting groups (Scheme 6). The hydrothiolation of 37 with 1-thioglucose peracetate 2a went to completion within 15 min. to result in an inseparable mixture of two compounds. On the basis of NMR and MS data, the components of the obtained mixture were tentatively identified as the expected disaccharide mimetic 38a and its sulfoxide derivative 38b, although at this stage of the study the configuration of the C4 stereocenter of the methyl glucopyranoside residue was uncertain. The attempted separation of compounds 39a and 39b obtained by TBAF-mediated desilylation failed. Fortunately, after deacetalation while using TFA, the major product was isolated in pure form and, after acetylation, undoubtedly identified as the the equatorially 4-C-S-bonded disaccharide mimetic. Interestingely, the acetylation of compound 40 led again to an inseparable mixture of the corresponding fully protected thiodisaccharide 41a and its sulfoxide derivative 41b. glucopyranoside residue was uncertain. The attempted separation of compounds 39a and 39b obtained by TBAF-mediated desilylation failed. Fortunately, after deacetalation while using TFA, the major product was isolated in pure form and, after acetylation, undoubtedly identified as the the equatorially 4-C-S-bonded disaccharide mimetic. Interestingely, the acetylation of compound 40 led again to an inseparable mixture of the corresponding fully protected thiodisaccharide 41a and its sulfoxide derivative 41b. We were curious as to whether the susceptibility to oxidation of 38 was due to the C4 position of the C-S bond or the substitution pattern of the enoside reactant. Therefore, C4-exomethylene 44, a 2,3-di-O-methylated analogue of 37, was prepared from 42 [46] via the oxidation-Wittig-olefination reaction sequence (Scheme 7).  glucopyranoside residue was uncertain. The attempted separation of compounds 39a and 39b obtained by TBAF-mediated desilylation failed. Fortunately, after deacetalation while using TFA, the major product was isolated in pure form and, after acetylation, undoubtedly identified as the the equatorially 4-C-S-bonded disaccharide mimetic. Interestingely, the acetylation of compound 40 led again to an inseparable mixture of the corresponding fully protected thiodisaccharide 41a and its sulfoxide derivative 41b. We were curious as to whether the susceptibility to oxidation of 38 was due to the C4 position of the C-S bond or the substitution pattern of the enoside reactant. Therefore, C4-exomethylene 44, a 2,3-di-O-methylated analogue of 37, was prepared from 42 [46] via the oxidation-Wittig-olefination reaction sequence (Scheme 7).  We were curious as to whether the susceptibility to oxidation of 38 was due to the C4 position of the C-S bond or the substitution pattern of the enoside reactant. Therefore, C4-exomethylene 44, a 2,3-di-O-methylated analogue of 37, was prepared from 42 [46] via the oxidation-Wittig-olefination reaction sequence (Scheme 7).
UV-light initiated addition of thiol 2a onto 44 occured with complete diastereoselectivity to provide the corresponding equatorially coupled disaccharide mimetic 45 with 81% yield. The addition between 2a and 44 was also elicited by using triethylborane in combination with catechol, which was recently reported by Renaud and co-workers as an efficient reagent system for radical hydrothiolation of allylic double bonds [47]. The reaction took place with similar efficacy to the one that was observed in the case of photoinitiation and the formation of sulfoxide was not observed in either case.
To push the scope of the reaction further, we extended our study to disaccharide 47 bearing exocyclic double bonds at positions C5 and C5 (Scheme 8). The 6,6 -diiodo trehalose derivative 46 [48] was treated with AgF [49] in pyridine to afford the 5,5 -dienoside 47 with 54% yield. The hydrothiolation of 47 with 1-thiomannose derivative 2e at rt while using the usual thiol:alkene ratio (1.5 equiv thiol/double bond) resulted in the thiotrisaccharide 48 as the major product (27%) and the expected dithiotetrasaccharide 49 could not be isolated in pure form. The reaction was carried out in a mixture of DMF and toluene due to the low solubility of 47 in toluene. Conducting the reaction at −80 • C increased the yield and provided 33% of 48 and 18% of 49. Raising the thiol excess to 4.5 equivalents (2.25 equiv. thiol/double bond) and running the addition reaction at −80 • C afforded 49 (60%) as the major product, along with 4% of 48. Changing the solvent to CH 2 Cl 2 , a more clean and efficient reaction was observed, providing 49 with 74% yield. As the trisaccharide enoside 48 can be subjected to further hydrothiolation reaction with different thiosugars, the hydrothiolation of a dienoside offers the possibility for homo-and heterodisubstitution, depending on the thiol excess applied. UV-light initiated addition of thiol 2a onto 44 occured with complete diastereoselectivity to provide the corresponding equatorially coupled disaccharide mimetic 45 with 81% yield. The addition between 2a and 44 was also elicited by using triethylborane in combination with catechol, which was recently reported by Renaud and co-workers as an efficient reagent system for radical hydrothiolation of allylic double bonds [47]. The reaction took place with similar efficacy to the one that was observed in the case of photoinitiation and the formation of sulfoxide was not observed in either case.
To push the scope of the reaction further, we extended our study to disaccharide 47 bearing exocyclic double bonds at positions C5 and C5′ (Scheme 8). The 6,6′-diiodo trehalose derivative 46 [48] was treated with AgF [49] in pyridine to afford the 5,5′-dienoside 47 with 54% yield. The hydrothiolation of 47 with 1-thiomannose derivative 2e at rt while using the usual thiol:alkene ratio (1.5 equiv thiol/double bond) resulted in the thiotrisaccharide 48 as the major product (27%) and the expected dithiotetrasaccharide 49 could not be isolated in pure form. The reaction was carried out in a mixture of DMF and toluene due to the low solubility of 47 in toluene. Conducting the reaction at −80 °C increased the yield and provided 33% of 48 and 18% of 49. Raising the thiol excess to 4.5 equivalents (2.25 equiv. thiol/double bond) and running the addition reaction at −80 °C afforded 49 (60%) as the major product, along with 4% of 48. Changing the solvent to CH2Cl2, a more clean and efficient reaction was observed, providing 49 with 74% yield. As the trisaccharide enoside 48 can be subjected to further hydrothiolation reaction with different thiosugars, the hydrothiolation of a dienoside offers the possibility for homo-and heterodisubstitution, depending on the thiol excess applied. Finally, the thiol-ene reaction was utilized for the synthesis of a C-S-bridged analogue of the biorelevant N-acetyl-neuraminic-acid-α(2,6)-d-galactose disaccharide sequence [50][51][52]. The galacto-configured 6,7-enopyranose 50 [53][54][55] was reacted with 2-thio-neuraminic acid derivative 2f to achieve this goal (Scheme 9). The reaction afforded the expected sialyl galactoside mimetic 51 with 62% yield at rt and a slightly increased 69% yield at −80 • C. Finally, the thiol-ene reaction was utilized for the synthesis of a C-S-bridged analogue of the biorelevant N-acetyl-neuraminic-acid-α(2,6)-D-galactose disaccharide sequence [50][51][52]. The galactoconfigured 6,7-enopyranose 50 [53][54][55] was reacted with 2-thio-neuraminic acid derivative 2f to achieve this goal (Scheme 9). The reaction afforded the expected sialyl galactoside mimetic 51 with 62% yield at rt and a slightly increased 69% yield at −80 °C. Scheme 9. Rapid, thio-click route to the biorelevant sialyl galactoside mimetic 51.

Discussion
We prepared nine enopyranosyl derivatives with an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions and studied their UV-initiated hydrothiolation reactions while using various sugar thiols. The reactions, except for the C2-exomethylene cases, took place with complete regioand stereoselectiviy providing the corresponding equatorial C-S-bonded di-and oligosaccharide mimetics with high yields.
The thiol-ene reaction proceeds through a reversible thiyl addition (propagation) step, followed by an irreversible hydrogen abstraction (chain transfer) step by the carbon centered radical intermediate formed (Scheme 10A) [56][57][58]. While the addition of thiyl radicals to unsymmetrically substituted linear alkenes generally exhibits poor stereoselectivity, in the case of substituted cyclic olefins with an endocyclic double bond, the addition is known to preferentially occur in a transdiaxial manner as the result of a kinetically favored axial attack of the thiyl radical onto the cyclic alkene in its half-chair conformation together with a stereoselective hydrogen abstraction from the thiol into an axial position [27][28][29][30][31]59,60]. We assume that, in the case of exo-glycal 10 and C3-, C4-, and C-5 exomethylenes 33, 37, 44, and 47, respectively, the thiol-ene reactions exclusively occur through the stable 4 C1 chair conformer of the corresponding carbon-centered radical (Scheme 10B). Axial H-abstraction by these radicals from a thiol leads to the formation of the equatorial C-S interglycosidic linkages. Other possible carbon-centered radical intermediates of higher energy rather decompose in an intramolecular reaction, instead of forming the final product intermolecularly, due to the rapidly reversible nature of the thiyl addition step [58].

Discussion
We prepared nine enopyranosyl derivatives with an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions and studied their UV-initiated hydrothiolation reactions while using various sugar thiols. The reactions, except for the C2-exomethylene cases, took place with complete regio-and stereoselectiviy providing the corresponding equatorial C-S-bonded di-and oligosaccharide mimetics with high yields.
The thiol-ene reaction proceeds through a reversible thiyl addition (propagation) step, followed by an irreversible hydrogen abstraction (chain transfer) step by the carbon centered radical intermediate formed (Scheme 10A) [56][57][58]. While the addition of thiyl radicals to unsymmetrically substituted linear alkenes generally exhibits poor stereoselectivity, in the case of substituted cyclic olefins with an endocyclic double bond, the addition is known to preferentially occur in a trans-diaxial manner as the result of a kinetically favored axial attack of the thiyl radical onto the cyclic alkene in its half-chair conformation together with a stereoselective hydrogen abstraction from the thiol into an axial position [27][28][29][30][31]59,60]. We assume that, in the case of exo-glycal 10 and C3-, C4-, and C-5 exomethylenes 33, 37, 44, and 47, respectively, the thiol-ene reactions exclusively occur through the stable 4 C 1 chair conformer of the corresponding carbon-centered radical (Scheme 10B). Axial H-abstraction by these radicals from a thiol leads to the formation of the equatorial C-S interglycosidic linkages. Other possible carbon-centered radical intermediates of higher energy rather decompose in an intramolecular reaction, instead of forming the final product intermolecularly, due to the rapidly reversible nature of the thiyl addition step [58].
We have found that the hydrothiolation of the C2-exomethylene derivatives 16, 22, and 29 led to diastereoisomeric mixtures of disaccharide mimetics linked through axial and equatorial methylenesulfide bonds. We assume that, in these cases, the reaction can proceed through both the 4 C 1 chair and 4 H 5 half-chair conformers of the C2-centered radical bearing an equatorial or a quasi equatorial C2 substituent (Scheme 11). The equatorially C-S-linked products can be formed either through the 4 C 1 or the 4 H 5 conformation of the C2 radicals via axial H-abstraction from the upper face. At the same time, axial H-abstraction by the 4 H 5 conformer from the bottom face might lead to the formation of the epimeric disaccharides with an axial interglycosidic connection at position C2. The ratio of products showed great variation, depending on the configuration of enosides and thiols, as well as the temperature. The different stereoselectivity that was observed with the different thiosugars can be explained by the different fitting of the C2 radicals to thiols of different configurations. This phenomenon, which is known as double stereodifferentiation, is well-documented in the field of chemical glycosylation [61,62]. In the case of the β-configured 29, the addition reactions occurred with remarkable or complete d-galacto-selectivity, which was probably due to the 1,3-diaxial repulsion between the aglycon and the C4-substituent in the 4 H 5 conformation, which increases the energy, thereby decreasing the lifetime of this conformer.
olefins with an endocyclic double bond, the addition is known to preferentially occur in a transdiaxial manner as the result of a kinetically favored axial attack of the thiyl radical onto the cyclic alkene in its half-chair conformation together with a stereoselective hydrogen abstraction from the thiol into an axial position [27][28][29][30][31]59,60]. We assume that, in the case of exo-glycal 10 and C3-, C4-, and C-5 exomethylenes 33, 37, 44, and 47, respectively, the thiol-ene reactions exclusively occur through the stable 4 C1 chair conformer of the corresponding carbon-centered radical (Scheme 10B). Axial H-abstraction by these radicals from a thiol leads to the formation of the equatorial C-S interglycosidic linkages. Other possible carbon-centered radical intermediates of higher energy rather decompose in an intramolecular reaction, instead of forming the final product intermolecularly, due to the rapidly reversible nature of the thiyl addition step [58]. We have found that the hydrothiolation of the C2-exomethylene derivatives 16, 22, and 29 led to diastereoisomeric mixtures of disaccharide mimetics linked through axial and equatorial methylenesulfide bonds. We assume that, in these cases, the reaction can proceed through both the 4 C1 chair and 4 H5 half-chair conformers of the C2-centered radical bearing an equatorial or a quasi equatorial C2 substituent (Scheme 11). The equatorially C-S-linked products can be formed either through the 4 C1 or the 4 H5 conformation of the C2 radicals via axial H-abstraction from the upper face. At the same time, axial H-abstraction by the 4 H5 conformer from the bottom face might lead to the formation of the epimeric disaccharides with an axial interglycosidic connection at position C2. The ratio of products showed great variation, depending on the configuration of enosides and thiols, as well as the temperature. The different stereoselectivity that was observed with the different thiosugars can be explained by the different fitting of the C2 radicals to thiols of different configurations. This phenomenon, which is known as double stereodifferentiation, is welldocumented in the field of chemical glycosylation [61,62]. In the case of the β-configured 29, the addition reactions occurred with remarkable or complete D-galacto-selectivity, which was probably due to the 1,3-diaxial repulsion between the aglycon and the C4-substituent in the 4 H5 conformation, which increases the energy, thereby decreasing the lifetime of this conformer.
According to our previous results [27][28][29][30][31], cooling was beneficial to the efficacy of the additions, which can be explained by the rapid reversibility of the thiyl addition step. At higher temperatures, the dissociation of the carbon-centered radical is entropically favored, which shifts the equilibrium toward reactants before the carbon-centered radical can be trapped through hydrogen abstraction fom a thiol, thus reducing the overall conversion. Conducting the reaction at −80 °C increases the lifetime of the intermediate radical, allowing it to react with a thiol in the irreversible hydrogen abstraction step and, thus, increasing the overall conversion.
Conducting the reactions at low temperature also modified the stereoselecivity of the reactions by shifting the product ratio toward the stereoisomer, the formation of which required lower transition state energy. Scheme 11. Assumed conformations of the C2-centered radicals and the configuration of the possible products formed from these radicals upon axial H-abstraction.
We demonstrated that the thiol-ene coupling reaction can successfully be extended to disaccharide dienoside 47, which opens the way for a rapid synthesis of higher thio-oligosaccharides under mild conditions. The practical utility of the presented method was also demonstrated by the Scheme 11. Assumed conformations of the C2-centered radicals and the configuration of the possible products formed from these radicals upon axial H-abstraction.
According to our previous results [27][28][29][30][31], cooling was beneficial to the efficacy of the additions, which can be explained by the rapid reversibility of the thiyl addition step. At higher temperatures, the dissociation of the carbon-centered radical is entropically favored, which shifts the equilibrium toward reactants before the carbon-centered radical can be trapped through hydrogen abstraction fom a thiol, thus reducing the overall conversion. Conducting the reaction at −80 • C increases the life-time of the intermediate radical, allowing it to react with a thiol in the irreversible hydrogen abstraction step and, thus, increasing the overall conversion.
Conducting the reactions at low temperature also modified the stereoselecivity of the reactions by shifting the product ratio toward the stereoisomer, the formation of which required lower transition state energy.
We demonstrated that the thiol-ene coupling reaction can successfully be extended to disaccharide dienoside 47, which opens the way for a rapid synthesis of higher thio-oligosaccharides under mild conditions. The practical utility of the presented method was also demonstrated by the efficient synthesis of 51, a novel thio-linked analogue of the sialyl-α(2,6)-galactoside structure that is of high biological importance.

General Method for Photoinduced Addition of Thiols to Exoglycals or Sugar Exomethylene Derivatives
Sugar thiol (1.2-1.5 equiv.) and 2,2-dimethoxy-2-phenylacetophenone (DPAP, 0.10 equiv/alkene) were added to a solution of the starting unsaturated monosaccharide in dry toluene (it is indicated when some other solvent was used) (7-8 mL/1 mmol alkene). The solution was irradiated at room temperature (it is indicated when the reaction was performed at lower temperature) for 15 min. The progress of the reaction was monitored by TLC after this reaction period and irradiation and addition of DPAP were repeated if necessary, once or twice more. In these cases, no additional thiol was added to the reaction mixture. Subsequently, the solution was concentrated and the residue was purified by column chromatography or flash column chromatography.   Compound 14 (1.989 g, 3.638 mmol) was dissolved in abs. CH 2 Cl 2 (20 mL). Dess-Martin periodinane (1.855 g, 4.366 mmol, 1.2 equiv.) was added and the reaction was stirred for one hour. When TLC showed complete disappearance of the starting material, the reaction mixture was diluted with CH 2 Cl 2 , aq NaOH solution (28 mL, 1.3 M) was added and the mixture was vigorously stirred for 10 min. In the next step the organic layer was separated and washed with water, dried over MgSO 4 and concentrated in vacuo to yield 15 (1.965 g, 99%). This compound was used in the next step without further purification. Dry tetrahydrofurane (20 mL) was stirred under argon and methyltriphenylphosphonium bromide (2.062 g, 5.772 mmol, 1.6 equiv.) was added. The suspension was cooled to 0 • C and n-butyllithium in hexane (2.309 mL, 5.772 mmol, c = 2.5 M, 1.6 equiv.) was added dropwise. After stirring the mixture for 30 min., 15 (1.965 g, 3.067 mmol) dissolved in dry tetrahydrofurane (10 mL) was added dropwise. The reaction was monitored by TLC. After three hours, ethyl acetate (200 mL) was added, and the organic layer was washed three times with satd aq NH 4 Cl solution and water, dried over MgSO 4 , and evaporated in vacuo. The crude product was purified by column chromatography to give 16 (1. The mixture of 17a and 17b (295 mg, 0.325 mmol) was dissolved in CH 2 Cl 2 (5 mL) and 2 mL 90 v/v% trifluoroacetic acid (1.8 mL trifluoroacetic acid + 0.2 mL water) was added dropwise. After 15 min. toluene (5 mL) was added and the mixture was evaporated in vacuo. The crude product was purified by flash chromatography to give 18 (
Yield: 31% for three steps, colorless syrup. R f 0.13 (CH 2 Cl 2 /acetone 7/3). 1  Compound 40 (430 mg) was dissolved in CH 2 Cl 2 , acetic anhydride (0.141 mL, 1.487 mmol, 3.6 equiv.) and pyridine (0.100 mL, 1.237 mmol, 3.0 equiv.) was added. The mixture was stirred overnight. When TLC showed the complete disappearance of the starting material, the solvent was evaporated in vacuo, and the crude product was purified by column chromatography to give 41a and 41b (223 mg). 41a and 41b cannot be separated from each other.