Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Sugar-Based Enones and Their Transformation into 3,5Disubstituted Furans and 2‑Acyl-Substituted 1,2,3-Trideoxy Sugars in the Presence of Lewis Acids Nazar Hussain,†,‡ Monika Bhardwaj,† Ajaz Ahmed,†,‡ and Debaraj Mukherjee*,†,‡ †
Natural Product Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu 180001, India Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India
Org. Lett. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 04/19/19. For personal use only.
‡
S Supporting Information *
ABSTRACT: Pd-catalyzed carbonylative cross-coupling reactions of 2-iodoglycals have been developed for the synthesis of sugar-based arylones and ynones using formic acid as the carbonyl source. Whereas acetyl-protected arylones lead to the formation of highly substituted furan derivatives in the presence of Lewis acid, benzyl-protected arylones furnished the 3-deoxy sugar derivative. In the presence of nucleophiles, an attack took place on the C-1 or C-3 carbon regio- and stereoselectively depending on the nature of the nucleophiles.
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Scheme 1. Art of Launching Carbonyl at the C-2 Position of Glycals and Their Transformation
arbohydrate enol ethers, also known as glycals, are recognized as chiral starting materials in the total synthesis of a wide range of biologically active natural and non-natural products.1 It is well-recognized that the synthetic utility of glycals can be further enhanced through incorporation of other reactive functional groups in addition to the innate ones.2 In this context, 2-C-substituted glycals bearing α,β-unsaturated carbonyl systems, such as 2-C-formyl glycals, have recently emerged as versatile intermediates for the synthesis of bioactive molecules.3 Although much attention has been given to the synthesis and reactivity of 2-C-formyl glycals, to the best of our knowledge, there is no report available on the synthesis and reactivity of the more stable 2-ketoglycal analogues. We envisaged that launching of an electron-withdrawing keto group might give rise to carbohydrate-based enones in which extended conjugation of ring oxygen of the pyran ring with the 1,2-double bond and the keto group might influence the reactivity of glycals under Lewis acidic conditions. Enones such as arylones and ynones, in which the keto functionality is attached to aromatic or alkyne moieties, are abundant in several bioactive natural products, pharmaceuticals, and cosmetics.4 These moieties also offer opportunities for further synthetic modifications.5,6 Based on our experience in glycal chemistry,7 herein, we explore carbonylation using 2iodoglycals8 with different coupling partners such as phenyl boronic acids and acetylene for the first synthesis of sugar-based arylones and ynones (Scheme 1). Once arylones were formed, we investigated their behavior toward Lewis acid in the absence or presence of external nucleophiles for the synthesis of C-2substituted 1,2,3-trideoxy sugars, natural product scaffolds, and 3,5-disubstituted furan derivatives containing a chiral side chain. © XXXX American Chemical Society
We commenced the study by taking 2-iodo-tri-O-acetyl-Dglucal 1a and phenyl boronic acid 2a as model substrates in the presence of a carbonyl source employing different Pd catalysts, and the findings are summarized in Table 1. When 5 mol % of Pd(OAc)2 and 10 mol % of PPh3 were reacted in the presence of 2 equiv of DCC, formic acid, and Et3N (Table 1, entry 1),we obtained 51% of the desired product 3a along with 17% C-2arylated product 3aa at 30 °C. Encouraged by this initial result, we increased the Pd(OAc)2 and PPh3 loading, but it led to reduction of yield (Table 1, entry 2). When the reaction temperature was increased to 80 °C, the C-2 aryl product (3aa) Received: February 22, 2019
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DOI: 10.1021/acs.orglett.9b00680 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 1. Optimization of the Reactiona
entry 1 2c 3 4 5 6 7 8 9 10 11
Pd (mol %) Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(dppf) Cl2 PdCl2 Pd(PPh3)4 Pd(OAc)2 Pd(OAc)2
activator
base
Scheme 2. Utilization of 2-Iodoglycals with Different Boronic Acids/Acetylenesa
temp (°C)
yieldb (%) of 3a/3aa
DCC DCC DCC DCC DIC EDCI DCC
Et3N Et3N Et3N Et3N Et3N Et3N Et3N
30 30 80 50 30 30 30
51/17 47/13 23/67 39/47 39/21 31/23 27/10
DCC DCC DCC DCC
Et3N Et3N Et3N + K2CO3 Et3N + NaHCO3
30 30 30 30
23/11 27/21 72/12 23/12
a Reactions conditions: 1a (1 equiv), 2a (1.2 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), base (2 equiv), DCC (2 equiv), and formic acid (2 equiv) in 5 mL of toluene under N2 atmosphere at 30 °C for 24 h. bIsolated yields after column chromatography. c15 mol % of PPh3 and 10 mol % of Pd(OAc)2 were used.
dominated and the carbonyl-inserted product 3a was isolated in only 23% yield (Table 1, entry 3). When we used DIC/EDCI instead of DCC, further reduction in the yield of 3a was observed (Table 1, entries 5 and 6). After screening different palladium sources (Table 1, entries 7−9), we came to the conclusion that Pd(OAc)2 is the best catalyst, and hence selected it for further optimization studies. Screening different solvents revealed that toluene is the best solvent compared to tetrahydrofuran, dimethylforamide, and dioxane. Gratifyingly, when we used potassium carbonate (2 equiv) with triethylamine (2 equiv), the yield of the desired product was enhanced up to 72% (Table 1, entry 10). Replacing K2CO3 with NaHCO3 leads to decreased yield (Table 1, entry 11). Finally, we came to the conclusion that 5 mol % of Pd(OAc)2 and 10 mol % of PPh3 along with 2 equiv of each of DCC, formic acid, triethylamine, and K2CO3 in toluene at 30 °C are the optimal reaction conditions for further exploration. We explored the substrate scope of carbonylation by taking different aromatic phenyl boronic acids with 2-iodoglycals under optimized conditions (Scheme 2). When 2-iodotri-O-acetyl-Dglucal reacted with a panel of m-, o-, and p-substituted phenyl boronic acids, desired carbonylative products (3a−3f) were obtained in moderate to good yields irrespective of substitutions on the aryl rings. Disubstituted aryl boronic acid such as 2,4dimethoxyphenylboronic acid also gave the desired product (3g) in slightly lower yield (53%). To our satisfaction, etherprotected glycals, such as compound 1b, were capable of producing desired products (3h and 3i) in good to moderate yield while reacting with phenyl boronic acid and 3-thienyl boronic acid. Even glycals other than glucal, such as 2-iodo-Dxylal and 2-iodo-D-galactal, were compatible under the reaction conditions, and the corresponding products (3j and 3k) were obtained in good yield. We extended the current methodology with different substituted phenyl acetylenes for the synthesis of sugar-based ynones. Toward this endeavor, we facilitated an initial reaction of 2-iodoglycals with 4-ethyl phenyl acetylene under the
a Reaction conditions: 1a (1 equiv) and 2 or 4 (1.5 equiv) in 5 mL of toluene under N2 atmosphere at 30 °C for 24 h.
optimized reaction conditions described above and obtained only 51% yield. In an attempt to increase the yield, we used triethylamine alone instead of the triethylamine potassium carbonate combination used earlier and obtained an improved yield of 5a (68%). Once we completed a slight modification in the optimization study, we created an assembly of ynones with various acetylene sources and glycals, as shown in Scheme 2. Gratifyingly, unactivated aliphatic acetylene-like cyclopropyl acetylene was compatible, though in lower yield (5e, 51%). However, a strongly electron-withdrawing group on phenyl acetylene, such as nitro and cyano, prevented the reaction from taking place. Ether-protected glycals, such as 2-iodo-D-galactal, were next examined, and the corresponding ynone (5f) was obtained in 63% yield. After successfully launching a keto aryl/alknyl group at the C2 position of glycal, we investigated how these derivatives (3a, 3j, 3k, 3h) behave toward Lewis acid in the absence or presence of external nucleophiles, vis-à-vis unsubstituted glycals, and the results are summarized in Scheme 3.When arylone 3a was exposed to 20 mol % of TfOH, we found complete conversion of the starting material and formation of a new, fast-moving product by TLC. After spectroscopic analysis, we characterized the new product as 3,5-disubstituted furan derivative 6a containing a chiral side chain (Scheme 3A). Considering the fact that 3,5-disubstituted furans have immense biological B
DOI: 10.1021/acs.orglett.9b00680 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
took place at an anometic carbon (Scheme 3C, 10, 10a, 11) to produce a normal Ferrier α-glycosylated product in good yield. Stereoselective generation of a hydroxyl group flanked between the pyran and aryl moieties (Scheme 4, 12a/12b)
Scheme 3. Reactivity of 2-Acyl Glycal in Lewis Acid in the Presence and Absence of Nucleophiles
Scheme 4. Stereoselective Synthesis of an α-Hydroxyl Group Flanked by Pyran and Aryl Moieties
could be of high pharmacological importance. The αhydroxylpyran A/E/F and a pyrrothine were isolated from a marine bacterium Alteromonasrava SANK 73390, with antimicrobial activity against both Gram-positive and Gramnegative bacteria.10 Hence, we thought that 12a/12b could be very useful in the design of improved second-generation thiomarinol analogues. We therefore reduced 3h with sodium borohydride and cerium chloride in ethanol at room temperature, which provided 12a and 12b in a separable 1:1 diastereomeric ratio in good yield (77%). Plausible mechanisms for the downstream products from 2acylglycals are summarized in Scheme 5. TfOH accelerates oxocarbonium ion A formation with the elimination of a C-3 acetyl group, which in the absence of any external nucleophiles probably converted into bicyclic xylosan-type intermediate B by the attack of oxygen at C-4 to the anomeric carbon. The unstable Scheme 5. Plausible Reaction Mechanisms
importance and are extensively used in the field of agrochemicals, pharmaceuticals, and cosmetics,9 we used other glycals to investigate the above transformation. Interestingly, both glucal- and xylal-based arylones 3a and 3k were compatible under the reaction condition and provided the desired furans 6a and 6b in moderate yield, but in case of galactal-based arylone 3j, only 10% yield of furan 6a was observed (Scheme 3A). Other Lewis acids, such as BF3Et2O, produced the same result in comparatively lower yield (see Table S1). Under a similar set of reaction conditions, benzyl-protected glucal 3h yielded 3deoxypyran derivative 7 (Scheme 3A) with simultaneous benzyl deprotection at the 6-position. In the presence of an external nucleophile, such as 2-bromothiophenol, substitution occurred at the C-3 position of compound 3a (Scheme 3B) in SN2 fashion with complete stereocontrol. A similar result was observed with AlCl3, which acted both as a Lewis acid and as a chlorine source to obtain compound 8 (64%). In the case of stronger nucleophiles, such as allylsilane and triethylsilane, the attack C
DOI: 10.1021/acs.orglett.9b00680 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters intermediate B opens up11 by the push of the bridgehead oxygen lone pair to form oxocabonium ion D in acidic medium. Finally, aromatization by deprotonation and C-5 transesterification7h leads to 3,5-disubstituted furan derivative 6 (Scheme 5I). To explain the formation of the 3-deoxy sugar, we have proposed the following pathway (Scheme 5II). A Lewis acid, such as BF3Et2O, in addition to selective 6-OBn deprotection,12 coordinates with a carbonyl oxygen at C-2 and benzyl oxygen at C-3 to form chelate complex E, which facilitates the formation of oxocarbonium ion F with elimination of benzaldehyde and formation of 3-deoxy derivative 7 by H− attack. In the presence of nucleophiles, extended conjugation of the ring oxygen of the pyran ring with the 1,2-double bond and the keto group makes both C-3 or C-1 susceptible to nucleophilic attack. Relatively stronger nucleophiles, such as triethylsilyl hydride and allylsilane, attack at anomeric carbon to form compounds 10 and 11, whereas softer nucleophiles, such as thiophenol and chloride, prefer a C-3 attack to produce compounds 8 and 9. In summary, we have developed a new Pd-catalyzed carbonylative strategy for the synthesis of sugar-based arylones and ynones from 2-iodoglycals using formic acid as a CO source. The carbonylation method works well with an ester protecting group which is otherwise not possible in formylation reactions. Behavior of arylone-based glycals toward Lewis acids is found to be different than that from 2-unsubstituted glycals. Some of the downstream products can be used as precursors for the synthesis of natural product scaffolds.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00680.
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Experimental procedures, 1H and 13C NMR spectra, and characterization of all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Debaraj Mukherjee: 0000-0002-2162-7465 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are thankful to DST-India (EMR-2016-004710) for funding. N.H. and A.A. thank UGC New Delhi for SRF/JRF. IIIM Publication No. IIIM/2188/2019.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b00680 Org. Lett. XXXX, XXX, XXX−XXX
