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COMMUNICATION
Cite this: Chem. Commun., 2013, 49, 11409 Received 10th September 2013, Accepted 12th October 2013 DOI: 10.1039/c3cc46914j
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Tandem regio- and diastereo-selective synthesis of halogenated C-vinyl glycosides from unactivated arylacetylenes† Madhubabu Tatina,ab Anil Kumar Kusunuru,ab Syed Khalid Yousuf*c and Debaraj Mukherjee*ab
www.rsc.org/chemcomm
A highly regio- and diastereo-selective synthesis of halogenated C-vinyl glycosides has been achieved from glycals and unactivated aryl acetylenes in the presence of halogenated Lewis acids via a tandem glycosylation–halogenation reaction. The Lewis acid used served the dual purpose of activating the allylic acetoxy group of glycals and serving as halogen source for Markovnikov addition across the triple bond, which makes the process atom economic. The synthesized glycosyl vinyl halides have been used as precursors for various Pd catalyzed C–C cross coupling reactions.
Stereoselective formation of C-glycosidic linkages constitutes the fundamental process of synthetic carbohydrate chemistry.1 The introduction of a carbon chain into sugar chiron paves the way to achieve the synthesis of various pyran embedded marine natural products like ciguatoxin, tautomycin etc.,2 enumerating their use as a chiral pool. However, the requirement of only strong nucleophiles with stoichiometric amounts of Lewis acids is the prerequisite of the glycosylation process which restricts the wide utilisation of the reaction. Our recent success on the direct synthesis of alkynylglycosides from glycals and unactivated aryl acetylenes3 prompted us to study further transformations of alkenyl glycosides to alkenyl halides with the anticipation that the latter can participate in halogen–metal exchange reactions4 and would be amenable for conversion to stereodefined trisubstituted alkenes, intermediates for the synthesis of marine natural products having cyclic ethers fused with a pyran ring as their main structural feature.2 We initially considered the possibility of hydrohalogenation of the C–C triple bond which is one of the most fundamental reactions in organic chemistry. However, this reaction usually does not proceed in a preparatively useful manner due to the formation of some regio- and stereoisomers that are difficult to separate. a
Academy of Scientific and Innovative Research, CSIR-IIIM, India. E-mail: [email protected]; Fax: +91-011-256-9111 b Indian Institute of Integrative Medicine, Jammu, 180001, India c Indian Institute of Integrative Medicine Br., Srinagar, 190005, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Detailed experimental procedures and compound characterization data. See DOI: 10.1039/c3cc46914j
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The Royal Society of Chemistry 2013
In fact, attempts to hydrohalogenate sugar acetylene derivatives with different halogenating agents were unsuccessful. There is no literature precedent for the synthesis of trisubstituted vinyl glycosides except the cobalt catalysed cross coupling of acetobromosugar and substituted vinyl magnesium bromides.5 However, the major limitation of the vinyl magnesium bromide coupling method lies in the fact that it is restricted to methyl/ hydrogen substituents only which could not be used for further chain elongation. To overcome this synthetic challenge, we then decided to use metal halogen containing reagents capable of acting as both Lewis acids and nucleophilic halide sources.6 We proposed that the Lewis acid may facilitate the removal of the allylic acetoxy group of the glycals affording a glycosyl oxocarbenium ion intermediate under Ferrier conditions. Anti-addition of the glycosyl cation and a halide ion (released by the Lewis acid itself) across the alkyne with concomitant generation of the C(sp2)–X bond may then follow, constituting a new entry to stereodefined trisubstituted halo-vinyl glycosides. This would then be a new example of cascade reactions,7 wherein more than one useful transformation can be carried out in one vessel under the same reaction conditions without adding additional reagents and catalysts, making the process atom economic. In continuance of our recent interest towards the development of one-pot reaction strategies in carbohydrate chemistry,8 herein we report a halogenated Lewis acid promoted tandem glycosylation– halogenation of aryl acetylenes with glycals to form stereo defined a,E-trisubstituted halo vinyl glycosides and their subsequent application in Pd-catalyzed cross-coupling reactions. To test our hypothesis tri-O-acetyl-D-glucal (1) and phenylacetylene (2) were chosen as the model substrates. FeBr3 was selected as a metal halogen reagent due to its advantages such as low cost, nontoxicity, good stability, and easy handling.9 After initial experimentation, we noticed that the addition of 0.35 equiv. of FeBr3 to an equimolar mixture of 1 and 2 in dichloroethane at room temperature yielded 87% of 3 (Table 1, entry 4) within 18 minutes. Careful spectroscopic analysis revealed that the product is an inseparable mixture of four different diastereomers, namely Ea : Eb : Za : Zb (ESI,† Fig. S1A) with the general structure 3 making the process inapplicable for synthetic purposes. In order to Chem. Commun., 2013, 49, 11409--11411
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Table 1 reaction
ChemComm
Optimization of the one-pot tandem glycosylation–halogenation
Entry
Solventa
t (1C)
1 2 3 4 5 6 7 8 9 10
CH3CN DCM DCE DCE DCE DCE DCE THF DCE DCE
rt rt rt 0 25 80 25 rt 25 25
Time (h)
Yieldb (%)
MX3 (mmol)
Ea : Eb : Za : Zbc
1 5 0.3 0.3 1 24 1 12 1 1
0 52 87 87 85 72 26 Trace 34 30
0.35 0.35 0.35 0.35 0.35 0.35 0.1 0.35 0.35d 0.35e
ND 6.6 : 1.6 : 1 : 1.5 6.6 : 1.6 : 1 : 1.5 6.6 : 1.6 : 1 : 1.5 11 : 1 : 0 : 0 6.6 : 1.6 : 1 : 1.5 11 : 1 : 0 : 0 ND 11 : 1 : 0 : 0 7:1:0:0
a In all the cases tri-O-acetyl-D-glucal (1 mmol), phenyl acetylene (1.05 mmol), and iron(III) halide (0.35 mmol) were used with 10 mL solvent. b Isolated yields after column chromatography. c Determined from 1H NMR. ND = not determined. d InCl3 used as a halide source. e SnCl4 used as a halide source.
overcome this demerit, the effect of various components was studied (Table 1). Gratifyingly, lowering the temperature of the reaction to 25 1C led to the formation of the kinetically controlled product 3a (Ea) as the major isomer (ESI,† Fig. S1B) with excellent yield (85%) and stereoselectivity (Table 1, entry 5), whereas decrease in the amount of FeBr3 to 0.1 equiv. lowered the yield substantially (Table 1, entry 7). Use of more polar solvents such as THF or CH3CN failed to effect the transformation (Table 1, entries 1 and 8). The use of other Lewis acids such as InCl3 or SnCl4 in DCE at 25 1C decreased the yield of product 3a (Table 1, entries 9 and 10). The basic skeleton of product 3a was confirmed by an upfield shift of the anomeric proton signal from d 6.6 to 4.6, indicating the formation of a C-glycosidic linkage. The occurrence of peaks at d 6.36 (d, J = 9.5, 1H) and d 5.83 (m, 2H) assignable to the exocyclic vinylic proton and H-2, H-3 of the pseudo glucal double bond, respectively, proved the formation of the bromovinyl glycoside 3a. Finally, the mass spectrum was found to be in full agreement with the presence of a bromine atom in the molecule. Following the removal of this synthetic hurdle, we investigated the substrate scope by carrying out the reaction with various phenylacetylenes and glucal triacetate. In all cases, the reaction was found to proceed smoothly affording the desired halogenated alkenyl C-glycoside in good to excellent yield with high diastereoselectivity (Scheme 1, 3a–3d) except with the p-NO2 substituent 3k (0%) or a pyridyl derivative 3l (0%) probably due to deactivation in 3k and some complex formation in 3l. In general, the yield and diastereoselectivity of the reaction were found to be independent of the nature of the phenylacetylene employed. Extending the study to other glycals like tri-O-acetylD-galactal (Fig. 1, 3e–3h) and di-O-acetyl-L-rhamnal (Scheme 1, 3i–3j) further broadened the scope of the reaction. It is noteworthy that tri-O-acetyl-D-galactal yielded the desired products with better diastereoselectivity than its glucal counterpart. Results obtained from FeBr3 prompted us to study the FeCl3 promoted tandem glycosylation–halogenation reaction (Scheme 2, 4a–4k) In general FeCl3 was found to be slightly better than FeBr3 11410
Chem. Commun., 2013, 49, 11409--11411
Scheme 1 FeBr3 promoted glycosylation–halogenation reaction of various glycals and phenylacetylenes. All the reactions were carried under standardised reaction conditions using 1 mmol of glycal and acetylene, yield refers to isolated yield, d.r. was determined through 1H NMR.
Fig. 1
Stereochemical assignment of product 4h based on NOE.
Scheme 2 FeCl3 promoted glycosylation–halogenation reaction of various glycals and phenylacetylenes. All the reactions were carried under standardised reaction conditions using 1 mmol of glycal and acetylene, yield refers to isolated yield, d.r. was determined through 1H NMR.
in terms of selectivity and yield. It is worth pointing out that in most cases products were formed with high stereoselectivity, This journal is
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Fig. 2 Scheme 3 One pot glycosylation/chlorination of 2-acetoxy-D-glucal to synthesize halo vinyl enone sugars under optimised conditions.
even single isomers being obtained with several substrates. The stereochemistry of the vinyl halo glycoside was deduced by NOE experiments (Fig. 1). With compound 4h (vinyl galactoside), the observed cross peaks between the signal for the anomeric proton (d 4.7) and that of bH-6 (d 4.2) but not a-H-4 (d 5.1) or aH-5 (d 4.25) confirmed the a selectivity at the anomeric centre. Another cross peak between signals for H-10/14 (7.53) of aromatic nucleus and H-1 (4.7) but not H-7 (d 6.13) settled the geometry of the side chain double bond as E. The success story of glycosylation–halogenation motivated us to continue our study in other useful glycals such as 2-acetoxy glucal.10 Accordingly 2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-arabinohex-1-enopyranose (5) was allowed to react with phenylacetylene in the presence of FeCl3. We were intrigued to observe the formation of highly functionalized alkenyl glycoside 5a in moderate yield (51%) with high stereoselectivity. Formation of 5a was confirmed from 1H and 13C NMR spectroscopic analysis. HRMS of the product was in good agreement with the assigned structure. Similar results were obtained with other acetylenes and results are summarized in Scheme 3. Having achieved a convenient synthesis of C-glycosyl alkenyl halides, we wanted to test the possibility of their chain elongation by palladium catalyzed C–C bond formation employing Suzuki11 and Heck12 reactions to generate intermediates required for pyran embedded natural product synthesis. Towards this objective, vinyl bromide 3a was subjected to undergo coupling with various substituted phenylboronic acids under various conditions (Table S1, ESI†). It was found that the use of Pd(OAc)2 in PEG-400–H2O (1 : 3) in the presence of K3PO4 was the best condition to afford the corresponding coupling products 6a–6c in moderate to good yield. Following the literature procedure13 vinyl bromide 3a was also allowed to undergo the Heck coupling reaction with m-nitro styrene (Scheme 4) to afford fully substituted conjugated glycoside 7a in 57% yield. In accordance with our own experimental results and literature precedent,8,10 it can be assumed that the Lewis acid plays
Scheme 4 Suzuki and Heck coupling of vinyl glycoside 3a. (a) Pd(OAc)2 (10 mol%), PEG:400–H2O (1 : 3), K2CO3. (b) Pd(OAc)2, PEG:2000, Et3N.
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Plausible mechanism of tandem glycosylation–halogenation.
two major roles when phenyl acetylene and glucal triacetates are reacted. It hastens the elimination of the allylic acetoxy group of the glycals affording a glycosyl oxocarbenium ion intermediate which is acted upon from the a-face by the alkyne with concomitant attack of a halide ion released from the Lewis acid (Fig. 2). While the nucleophile prefers to approach from the a-face of the oxocarbenium ion as that would lead to the energetically favoured half chair conformer,8e linkage of the halide ion takes place in an anti-periplanar fashion to generate Ea as the kinetically controlled product at lower temperature. In conclusion, we have developed an operationally simple and practical protocol to access C-vinyl glycosides from glycals and unactivated aryl acetylenes by a highly regio- and stereoselective tandem process featuring the use of metal halogenated Lewis acids. In addition, a method for carbon chain elaboration of stereo-defined trisubstituted alkenes has been achieved through Pd-catalyzed cross coupling reactions. Application of the methodology for the synthesis of microbial natural products and for conventional glycosylation from various glycosyl donors are in progress and will be reported in due course.
Notes and references 1 (a) X. Zhu and R. R. Schmidt, Angew. Chem., Int. Ed., 2009, 48, 1900, and references cited therein; (b) D. P. Galonic and D. Y. Gin, Nature, 2007, 446, 1000. 2 (a) S. Hanessian, Total Synthesis of Natural Products: The Chiron Approach, Pergamon Press, Oxford, 1984; (b) M. Isobe, R. Nishizawa, S. Hosokawa and T. Nishizawa, Chem. Commun., 1998, 2665; (c) J. Zeng, J. Ma, S. Xiang, S. Cai and X. W. Liu, Angew. Chem., Int. Ed., 2013, 52, 5134. 3 A. K. Kusunuru, T. Madhubabu, S. K. Yousuf and D. Mukherjee, Chem. Commun., 2013, 49, 10154. 4 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457. 5 L. Nicolas, P. Angibaud, I. Stansfield, P. Bonnet, L. Meerpoel, S. Reymond and J. Cossy, Angew. Chem., Int. Ed., 2012, 51, 11101. 6 (a) M. C. P. Yeh, C. W. Fang and H. H. Lin, Org. Lett., 2012, 14, 1830; (b) M. C. P. Yeh, C. J. Liang, C. W. Fan, W. H. Chiu and J. Y. Lo, J. Org. Chem., 2012, 77, 9707, and references therein. 7 A. T. Biju, N. E. Wurz and F. Glorius, J. Am. Chem. Soc., 2010, 132, 5970, and references cited therein. 8 (a) D. Mukherjee, B. A. Shah, P. Gupta and S. C. Taneja, J. Org. Chem., 2007, 72, 8965; (b) D. Mukherjee, S. K. Yousuf and S. C. Taneja, Org. Lett., 2008, 10, 4831; (c) M. Tatina, S. K. Yousuf and D. Mukherjee, Org. Biomol. Chem., 2012, 10, 5357; (d) S. K. Yousuf, D. Mukherjee and S. C. Taneja, J. Org. Chem., 2010, 75, 3097; (e) S. K. Yousuf, D. Mukherjee, L. Mallikharjunarao and S. C. Taneja, Org. Lett., 2011, 13, 576. 9 P. O. Miranda, D. D. Dı´az, J. I. Padron, J. Bermejo and V. S. Martın, Org. Lett., 2003, 5, 1979. 10 (a) M. Hayashi, S. Nakayama and H. Kawabata, Chem. Commun., 2000, 1329; (b) P. Gupta, N. Kumari, A. Agarwal and Y. D. Vankar, Org. Biomol. Chem., 2008, 6, 3948; (c) T. G. Alexander, S. E. Elena, S. V. Leonid and T. A. Genrikh, Mendeleev Commun., 1991, 4, 133; (d) R. Crespo, M. G. Bravo, P. A. Colinas and R. D. Bravo, Bioorg. Med. Chem. Lett., 2010, 20, 6469. 11 A. Suzuki, J. Organomet. Chem., 1999, 576, 147. 12 N. J. Whitcomb, K. K. Hii and S. E. Gibson, Tetrahedron, 2001, 57, 7449. 13 Z. P. Sun, H. Yang, L. Lu, H. Yan, M. Creus and J. Mao, Eur. J. Org. Chem., 2012, 4831. Chem. Commun., 2013, 49, 11409--11411
11411
COMMUNICATION
Cite this: Chem. Commun., 2013, 49, 11409 Received 10th September 2013, Accepted 12th October 2013 DOI: 10.1039/c3cc46914j
View Article Online View Journal | View Issue
Tandem regio- and diastereo-selective synthesis of halogenated C-vinyl glycosides from unactivated arylacetylenes† Madhubabu Tatina,ab Anil Kumar Kusunuru,ab Syed Khalid Yousuf*c and Debaraj Mukherjee*ab
www.rsc.org/chemcomm
A highly regio- and diastereo-selective synthesis of halogenated C-vinyl glycosides has been achieved from glycals and unactivated aryl acetylenes in the presence of halogenated Lewis acids via a tandem glycosylation–halogenation reaction. The Lewis acid used served the dual purpose of activating the allylic acetoxy group of glycals and serving as halogen source for Markovnikov addition across the triple bond, which makes the process atom economic. The synthesized glycosyl vinyl halides have been used as precursors for various Pd catalyzed C–C cross coupling reactions.
Stereoselective formation of C-glycosidic linkages constitutes the fundamental process of synthetic carbohydrate chemistry.1 The introduction of a carbon chain into sugar chiron paves the way to achieve the synthesis of various pyran embedded marine natural products like ciguatoxin, tautomycin etc.,2 enumerating their use as a chiral pool. However, the requirement of only strong nucleophiles with stoichiometric amounts of Lewis acids is the prerequisite of the glycosylation process which restricts the wide utilisation of the reaction. Our recent success on the direct synthesis of alkynylglycosides from glycals and unactivated aryl acetylenes3 prompted us to study further transformations of alkenyl glycosides to alkenyl halides with the anticipation that the latter can participate in halogen–metal exchange reactions4 and would be amenable for conversion to stereodefined trisubstituted alkenes, intermediates for the synthesis of marine natural products having cyclic ethers fused with a pyran ring as their main structural feature.2 We initially considered the possibility of hydrohalogenation of the C–C triple bond which is one of the most fundamental reactions in organic chemistry. However, this reaction usually does not proceed in a preparatively useful manner due to the formation of some regio- and stereoisomers that are difficult to separate. a
Academy of Scientific and Innovative Research, CSIR-IIIM, India. E-mail: [email protected]; Fax: +91-011-256-9111 b Indian Institute of Integrative Medicine, Jammu, 180001, India c Indian Institute of Integrative Medicine Br., Srinagar, 190005, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Detailed experimental procedures and compound characterization data. See DOI: 10.1039/c3cc46914j
This journal is
c
The Royal Society of Chemistry 2013
In fact, attempts to hydrohalogenate sugar acetylene derivatives with different halogenating agents were unsuccessful. There is no literature precedent for the synthesis of trisubstituted vinyl glycosides except the cobalt catalysed cross coupling of acetobromosugar and substituted vinyl magnesium bromides.5 However, the major limitation of the vinyl magnesium bromide coupling method lies in the fact that it is restricted to methyl/ hydrogen substituents only which could not be used for further chain elongation. To overcome this synthetic challenge, we then decided to use metal halogen containing reagents capable of acting as both Lewis acids and nucleophilic halide sources.6 We proposed that the Lewis acid may facilitate the removal of the allylic acetoxy group of the glycals affording a glycosyl oxocarbenium ion intermediate under Ferrier conditions. Anti-addition of the glycosyl cation and a halide ion (released by the Lewis acid itself) across the alkyne with concomitant generation of the C(sp2)–X bond may then follow, constituting a new entry to stereodefined trisubstituted halo-vinyl glycosides. This would then be a new example of cascade reactions,7 wherein more than one useful transformation can be carried out in one vessel under the same reaction conditions without adding additional reagents and catalysts, making the process atom economic. In continuance of our recent interest towards the development of one-pot reaction strategies in carbohydrate chemistry,8 herein we report a halogenated Lewis acid promoted tandem glycosylation– halogenation of aryl acetylenes with glycals to form stereo defined a,E-trisubstituted halo vinyl glycosides and their subsequent application in Pd-catalyzed cross-coupling reactions. To test our hypothesis tri-O-acetyl-D-glucal (1) and phenylacetylene (2) were chosen as the model substrates. FeBr3 was selected as a metal halogen reagent due to its advantages such as low cost, nontoxicity, good stability, and easy handling.9 After initial experimentation, we noticed that the addition of 0.35 equiv. of FeBr3 to an equimolar mixture of 1 and 2 in dichloroethane at room temperature yielded 87% of 3 (Table 1, entry 4) within 18 minutes. Careful spectroscopic analysis revealed that the product is an inseparable mixture of four different diastereomers, namely Ea : Eb : Za : Zb (ESI,† Fig. S1A) with the general structure 3 making the process inapplicable for synthetic purposes. In order to Chem. Commun., 2013, 49, 11409--11411
11409
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Communication
Published on 14 October 2013. Downloaded by University of California - Santa Cruz on 30/10/2014 03:43:20.
Table 1 reaction
ChemComm
Optimization of the one-pot tandem glycosylation–halogenation
Entry
Solventa
t (1C)
1 2 3 4 5 6 7 8 9 10
CH3CN DCM DCE DCE DCE DCE DCE THF DCE DCE
rt rt rt 0 25 80 25 rt 25 25
Time (h)
Yieldb (%)
MX3 (mmol)
Ea : Eb : Za : Zbc
1 5 0.3 0.3 1 24 1 12 1 1
0 52 87 87 85 72 26 Trace 34 30
0.35 0.35 0.35 0.35 0.35 0.35 0.1 0.35 0.35d 0.35e
ND 6.6 : 1.6 : 1 : 1.5 6.6 : 1.6 : 1 : 1.5 6.6 : 1.6 : 1 : 1.5 11 : 1 : 0 : 0 6.6 : 1.6 : 1 : 1.5 11 : 1 : 0 : 0 ND 11 : 1 : 0 : 0 7:1:0:0
a In all the cases tri-O-acetyl-D-glucal (1 mmol), phenyl acetylene (1.05 mmol), and iron(III) halide (0.35 mmol) were used with 10 mL solvent. b Isolated yields after column chromatography. c Determined from 1H NMR. ND = not determined. d InCl3 used as a halide source. e SnCl4 used as a halide source.
overcome this demerit, the effect of various components was studied (Table 1). Gratifyingly, lowering the temperature of the reaction to 25 1C led to the formation of the kinetically controlled product 3a (Ea) as the major isomer (ESI,† Fig. S1B) with excellent yield (85%) and stereoselectivity (Table 1, entry 5), whereas decrease in the amount of FeBr3 to 0.1 equiv. lowered the yield substantially (Table 1, entry 7). Use of more polar solvents such as THF or CH3CN failed to effect the transformation (Table 1, entries 1 and 8). The use of other Lewis acids such as InCl3 or SnCl4 in DCE at 25 1C decreased the yield of product 3a (Table 1, entries 9 and 10). The basic skeleton of product 3a was confirmed by an upfield shift of the anomeric proton signal from d 6.6 to 4.6, indicating the formation of a C-glycosidic linkage. The occurrence of peaks at d 6.36 (d, J = 9.5, 1H) and d 5.83 (m, 2H) assignable to the exocyclic vinylic proton and H-2, H-3 of the pseudo glucal double bond, respectively, proved the formation of the bromovinyl glycoside 3a. Finally, the mass spectrum was found to be in full agreement with the presence of a bromine atom in the molecule. Following the removal of this synthetic hurdle, we investigated the substrate scope by carrying out the reaction with various phenylacetylenes and glucal triacetate. In all cases, the reaction was found to proceed smoothly affording the desired halogenated alkenyl C-glycoside in good to excellent yield with high diastereoselectivity (Scheme 1, 3a–3d) except with the p-NO2 substituent 3k (0%) or a pyridyl derivative 3l (0%) probably due to deactivation in 3k and some complex formation in 3l. In general, the yield and diastereoselectivity of the reaction were found to be independent of the nature of the phenylacetylene employed. Extending the study to other glycals like tri-O-acetylD-galactal (Fig. 1, 3e–3h) and di-O-acetyl-L-rhamnal (Scheme 1, 3i–3j) further broadened the scope of the reaction. It is noteworthy that tri-O-acetyl-D-galactal yielded the desired products with better diastereoselectivity than its glucal counterpart. Results obtained from FeBr3 prompted us to study the FeCl3 promoted tandem glycosylation–halogenation reaction (Scheme 2, 4a–4k) In general FeCl3 was found to be slightly better than FeBr3 11410
Chem. Commun., 2013, 49, 11409--11411
Scheme 1 FeBr3 promoted glycosylation–halogenation reaction of various glycals and phenylacetylenes. All the reactions were carried under standardised reaction conditions using 1 mmol of glycal and acetylene, yield refers to isolated yield, d.r. was determined through 1H NMR.
Fig. 1
Stereochemical assignment of product 4h based on NOE.
Scheme 2 FeCl3 promoted glycosylation–halogenation reaction of various glycals and phenylacetylenes. All the reactions were carried under standardised reaction conditions using 1 mmol of glycal and acetylene, yield refers to isolated yield, d.r. was determined through 1H NMR.
in terms of selectivity and yield. It is worth pointing out that in most cases products were formed with high stereoselectivity, This journal is
c
The Royal Society of Chemistry 2013
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Fig. 2 Scheme 3 One pot glycosylation/chlorination of 2-acetoxy-D-glucal to synthesize halo vinyl enone sugars under optimised conditions.
even single isomers being obtained with several substrates. The stereochemistry of the vinyl halo glycoside was deduced by NOE experiments (Fig. 1). With compound 4h (vinyl galactoside), the observed cross peaks between the signal for the anomeric proton (d 4.7) and that of bH-6 (d 4.2) but not a-H-4 (d 5.1) or aH-5 (d 4.25) confirmed the a selectivity at the anomeric centre. Another cross peak between signals for H-10/14 (7.53) of aromatic nucleus and H-1 (4.7) but not H-7 (d 6.13) settled the geometry of the side chain double bond as E. The success story of glycosylation–halogenation motivated us to continue our study in other useful glycals such as 2-acetoxy glucal.10 Accordingly 2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-arabinohex-1-enopyranose (5) was allowed to react with phenylacetylene in the presence of FeCl3. We were intrigued to observe the formation of highly functionalized alkenyl glycoside 5a in moderate yield (51%) with high stereoselectivity. Formation of 5a was confirmed from 1H and 13C NMR spectroscopic analysis. HRMS of the product was in good agreement with the assigned structure. Similar results were obtained with other acetylenes and results are summarized in Scheme 3. Having achieved a convenient synthesis of C-glycosyl alkenyl halides, we wanted to test the possibility of their chain elongation by palladium catalyzed C–C bond formation employing Suzuki11 and Heck12 reactions to generate intermediates required for pyran embedded natural product synthesis. Towards this objective, vinyl bromide 3a was subjected to undergo coupling with various substituted phenylboronic acids under various conditions (Table S1, ESI†). It was found that the use of Pd(OAc)2 in PEG-400–H2O (1 : 3) in the presence of K3PO4 was the best condition to afford the corresponding coupling products 6a–6c in moderate to good yield. Following the literature procedure13 vinyl bromide 3a was also allowed to undergo the Heck coupling reaction with m-nitro styrene (Scheme 4) to afford fully substituted conjugated glycoside 7a in 57% yield. In accordance with our own experimental results and literature precedent,8,10 it can be assumed that the Lewis acid plays
Scheme 4 Suzuki and Heck coupling of vinyl glycoside 3a. (a) Pd(OAc)2 (10 mol%), PEG:400–H2O (1 : 3), K2CO3. (b) Pd(OAc)2, PEG:2000, Et3N.
This journal is
c
The Royal Society of Chemistry 2013
Plausible mechanism of tandem glycosylation–halogenation.
two major roles when phenyl acetylene and glucal triacetates are reacted. It hastens the elimination of the allylic acetoxy group of the glycals affording a glycosyl oxocarbenium ion intermediate which is acted upon from the a-face by the alkyne with concomitant attack of a halide ion released from the Lewis acid (Fig. 2). While the nucleophile prefers to approach from the a-face of the oxocarbenium ion as that would lead to the energetically favoured half chair conformer,8e linkage of the halide ion takes place in an anti-periplanar fashion to generate Ea as the kinetically controlled product at lower temperature. In conclusion, we have developed an operationally simple and practical protocol to access C-vinyl glycosides from glycals and unactivated aryl acetylenes by a highly regio- and stereoselective tandem process featuring the use of metal halogenated Lewis acids. In addition, a method for carbon chain elaboration of stereo-defined trisubstituted alkenes has been achieved through Pd-catalyzed cross coupling reactions. Application of the methodology for the synthesis of microbial natural products and for conventional glycosylation from various glycosyl donors are in progress and will be reported in due course.
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