Aakanksha Gurawa‡, Manoj Kumar‡ & Sudhir Kashyap

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*Carbohydrate Chemistry Research Laboratory (CCRL), Department of Chemistry, Malaviya National Institute of công nghệ Jaipur, (MNIT), Jaipur-302017, India. E-mail: skashyap.chy

Abstract

A Me3SI-mediated simple & efficient protocol for the chemoselective deprotection of acetyl groups has been developed via employing KMnO4 as an additive. This chemoselective deacetylation is amenable to a wide range of substrates, tolerating diverse & sensitive functional groups in carbohydrates, amino acids, natural products, heterocycles, & general scaffolds. The protocol is attractive because it uses an environmentally benign reagent system khổng lồ perform quantitative and clean transformations under ambient conditions.

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The divergent protection–deprotection approach & extensive functional group manipulation continues khổng lồ serve as an important chemical tool lớn access biologically potent molecules và complex natural products.1 In particular, the hydroxyl moieties & their derivatives are ubiquitous in natural products & recognized as renowned scaffolds because of the overwhelming number of chemical and biological applications that they can be used in.2,3 The selective & orthogonal protection–deprotection of không tính phí hydroxyl group(s) are significant chemical transformations & frequently employed in target-oriented synthesis (TOS).4 Due lớn the widespread use & relative ease of protection–deprotection, introduction of an O-Ac group lớn mask the hydroxyl-moiety has remained as a highly reliable & convenient strategy, especially in synthetic carbohydrate chemistry.1–3 However, the chemoselective deprotection of O-Ac in the presence of analogous and sensitive O-protective groups such as benzoyl (Bz) or pivaloyl (Pv) is a notoriously challenging yet important task.1–3

Thus, considerable effort has been devoted to lớn developing robust and selective methods for the deprotection of the acetate ester. As outlined in Scheme 1, the cleavage of O-Ac is conventionally performed under a homogeneous reagent system including: (a) Brønsted acids/Lewis acids such as HCl/MeOH,5 HBF4·Et2O,6 BF3·Et2O,7 p-TsOH or CSA,8 (b) inorganic/organic basic conditions employing Zemplén hydrolysis (NaOMe/MeOH),1 ammonia solution,9 hydrazine/AcOH/pyridine,10 DBU/PhH,11 guanidine/EtOH/DCM,12 Mg–metal or Mg(OMe)2,13 KCN/EtOH,14 K2CO3/MeOH/H2O,15 NaHCO3/H2O2,16 (c) metallic compounds or oxidants such as MoO2Cl2,17 molecular iodine/MeOH,18a Sm/I2,18b Bu2SnO/heating,19a Bu3SnOMe/DCE.19b Although, the use of heterogeneous catalysts such as CuFe2O4 nanoparticles20 và enzymes21 have also been demonstrated for deacetylation with limited substrate scope. Recently, a tetranuclear zinc cluster, Zn4(OCOCF3)6O has been investigated for use in trans-esterification và deacylation with discriminate selectivity.22


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Scheme 1 Previous advances, và the Me3SI-catalyzed chemoselective deacetylation developed in this work.

Despite the synthetic challenges & demands placed on modern chemistry, advancing green chemical syntheses employing milder and environmentally benign reagent systems remains a constant motivation and is actively pursued. In this context and our continued interest23 developing versatile and selective protocols inspired the development of a simple & chemoselective deacetylation method with remarkable & distinctive synthetic applicability. Recently the dual-reactivity of KMnO4 for selective deacetylation và one-pot deacetylation–oxidation of benzyl-O-acetates under controlled reaction conditions was successfully investigated.23a

Emerging from these precedents, the Me3SI-catalyzed, simple và chemoselective removal of O-acetate, an elegant & promising alternative approach for the deprotection of the acetate ester (Scheme 1d) is presented herein. Inspired by recent research,23f an initial experiment employing Me3SI(OAc)2, generated in situ oxidative transfer of the acetyl groups from PhI(OAc)2 lớn Me3SI, which gave the regioselective 2-iodoglycosylation of enol ether functionality in 3,4,6-tri-O-acetyl-D-glucal (1a) with methanol together with traces of the deacetylated product 1 (Table 1, entry 1). The preliminary results led khổng lồ the exploration of the possibility of using sulfonium iodate salts in the selective removal of the O-acetyl protection group. As summarized in Table 1, subsequent optimization of the reaction was performed by altering the reagents và solvent systems. Accordingly, the reactions of TOAc-glucal 1a using varying amounts of Me3SI and NaIO4 in the presence of MeOH facilitated the smooth deacetylation providing the desired hàng hóa 1 with excellent efficiency under ambient conditions (Table 1, entries 2–5). It is worth noting, that the use of Me3SI in combination with NaIO4 in MeOH as the solvent, promoted the deprotection of acetates in a chemoselective manner, however the direct 1,2-addition product, 2-deoxy-glycoside was not detected.23f,g Meanwhile, the reaction using 0.2 equiv. Of both Me3SI và NaIO4 was found lớn suffice for obtaining the complete deacetylation of 1a after 40 min (Table 1, entry 4).


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EntryCatalyst (equiv.)Additive (equiv.)SolventTimeYieldba Reaction conditions: 1a (1.0 equiv.), salt (0.1 to 1.0 equiv.), additive (0.1 to lớn 1.0 equiv.), solvent (1 mL) in open-air at room temperature.b The isolated and unoptimized yields, based on the starting material 1a.c Increasing the amount of both salt & additive up lớn 1.0 equiv., 24 h. NR = no reaction.
1Me3SI (1.0)PhI(OAc)2 (1.0)MeOH24 hTrace
2Me3SI (1.0)NaIO4 (1.0)MeOH10 min100%
3Me3SI (0.4)NaIO4 (0.4)MeOH30 min100%
4Me3SI (0.2)NaIO4 (0.2)MeOH40 min100%
5Me3SI (0.1)NaIO4 (0.1)MeOH12 h95%
6n-Bu4NI (0.1)NaIO4 (0.1)MeOH12 h90%
7KI (0.1)NaIO4 (0.1)MeOH12 h50%
8NaI (0.1)NaIO4 (0.1)MeOH16 h90%
9cMe3SOI (0.1)NaIO4 (0.1)MeOH12 hNR
10cMe3SBr (0.1)NaIO4 (0.1)MeOH12 hNR
11cn-Bu4NBr (0.1)NaIO4 (0.1)MeOH12 hNR
12cKBr (0.1)NaIO4 (0.1)MeOH12 hNR
13Me3SI (0.1)KMnO4 (0.1)MeOH5 min100%
14Me3SI (0.1)KMnO4 (0.1)MeCN24 hNR
15Me3SI (0.1)KMnO4 (0.1)Toluene24 hNR
16Me3SI (0.1)KMnO4 (0.1)THF24 hNR
17Me3SI (0.1)KMnO4 (0.1)DCM24 hNR
18Me3SI (0.1)K2S2O8 (0.1)MeOH12 hTrace
19Me3SI (0.1)Oxone (0.1)MeOH12 hTrace
20Me3SI (0.1)KBrO3 (0.1)MeOH12 hTrace
21Me3SI (0.1)NaBO3·H2O (0.1)MeOH12 h40%
22Me3SI (0.1)Na3BO3 (0.1)MeOH12 hTrace

Consequently, TOAc-glucal 1a was subjected to various complementary halide salts employing NaIO4 (0.1 equiv.) in MeOH under ambient reaction conditions (Table 1, entries 6–12). Use of the catalytic n-Bu4NI và KI provided the desired product with good khổng lồ modest transformation, 90% and 1/2 yields, respectively (Table 1, entries 6 & 7 vs. 5). It was found that NaI can efficiently promote the deacetylation in improved yields (90%) after 16 h under the present conditions (Table 1, entry 8). In contrast, Me3SOI & bromide salts such as Me3SBr, n-Bu4NBr, & KBr failed khổng lồ deliver the deacetylated sản phẩm even after increasing the amount of the salts & additive NaIO4 to lớn 1.0 equiv. And a prolonged reaction time (Table 1, entries 9–12). Remarkably, switching to lớn KMnO4 (0.1 equiv.) as the additive in a Me3SI-catalyzed reaction led to lớn simple deacetylation of 1a with almost quantitative yields (100%), within 5 min (Table 1, entry 13). A rapid screening of common organic solvents including CH3CN, toluene, THF or CH2Cl2 were unsuccessful & did not give any desired transformations (Table 1, entries 14–17). Further optimization employing analogous additives such as K2S2O8, oxone, KBrO3, NaBO3·H2O, & Na3BO3 were found khổng lồ be too sluggish or resulted in poor conversions (Table 1, entries 18–22).

Having improved & optimized the reagent system, the generality và limitation of Me3SI-catalyzed selective deacetylation protocol was investigated next, & the results are summarized in Scheme 2. Of the particular note, diverse & commonly used O-protecting groups in D-glucal comprising benzoyl (1b), benzyl (1c), methyl (1d), and tert-butyldimethylsilyl ether (1e) were fully tolerated, thus unambiguously establishing the potential synthetic applicability of the representative chemoselective procedure. Subsequently, the selective deacetylation of several per-O-acetylated glycals: D-galactal (2a), D-rhamnal (3a), L-rhamnal (4a), D-xylal (5a), D-arabinal (6a) và L-arabinal (7a), also disaccharide derived glycals bearing 1,4-glycosidic linkages, for example D-lactal (8a) & D-maltal (9a), were performed successfully to lớn obtain the corresponding products 2–9 in excellent yields.


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Scheme 2 The study of the substrate scope & a functional group compatibility investigation for the chemoselective deacetylation. Reaction conditions: 1a–23a (1.0 equiv.), Me3SI (0.1 equiv.), additive (0.1 equiv.), MeOH (1 mL), 25 °C under atmospheric pressure, 1–12 h. The isolated & unoptimized yields are shown.

Furthermore, the substrates bearing O-TIPS (10a), O-Bn (11a–13a), & 4,6-O-benzylidene (14a) in carbohydrate substrates were uniformly sustained under selective deacetylation conditions giving the hydroxyl products 10–14, respectively, (up khổng lồ 98% yields). Indeed, the glycosides comprising sensitive O-isopropylidene linkages in D-galactopyranose (15a), D-glucofuranose (16a), D-ribose (17a), và unprotected uridine (18a) were selectively deacetylated to generate the corresponding free-hydroxyl compounds 15–18 in good yields. Importantly, the amino acid derivatives 19a–23a including relatively subtle or labile substituents such as tert-butylcarbamate (Boc), fluorenylmethoxycarbonyl (Fmoc) carbobenzoxy (Cbz), & methyl ester (–CO2Me), underwent efficient chemoselective deacetylation giving the desired products 19–23 in good khổng lồ excellent yields.

Encouraged by these results, the scope of the selective protocol was extended by performing the systematic deacetylation of substrates involving benzylic, alkylic, allylic, phenolic, naphthyl, hetereocyclic, alicyclic, spirocyclic, natural-products, long chain aliphatic, và aminoxy moieties. As illustrated in Scheme 3, a series of substrates enclosing comparatively susceptible and electronically diverse O-protecting groups (O-Ac; 24a vs. O-Piv; 24b, O-Boc; 24c, O-Ms; 24d, O-THP; 24e, O-Tr; 24f) were well protected under present conditions, further confirming the effectiveness of the chemoselective method. The Me3SI-catalyzed simple removal of acetyl groups, in menthyl (25a), geranyl (26a), cholesteryl (27a), và diversely substituted aryl substrates 28a–35a, was conducted khổng lồ efficiently obtain the desired products 25–35 in good-to-excellent yields (90–99%). It is worth noting, that the selective deacetylation for a substrate consisting of two electronically different acetates was accomplished successfully (cleavage of O-acetate vs. N-acetate in 29a).


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Scheme 3 Extended scope of the Me3SI-catalyzed selective deacetylation. Reaction conditions: 24a–55a (1.0 equiv.), Me3SI (0.1 equiv.), additive (0.1 equiv.), MeOH (1 mL), 25 °C under atmospheric pressure, 1–12 h. The isolated and unoptimized yields are shown.

Next, the diversely substituted phenolic or naphthylic O-acetates 36a–42a, eugenyl 43a, vanillyl 44a, & estrone acetate 45a were subjected, under ambient conditions, to lớn access the corresponding free-phenols 36–45 in acceptable yields (72–96%). Likewise, the reaction employing heterocyclic furfuryl acetate (46a), 2-amino-(Cbz)-ethyl acetate (47a), & alicyclic substrates with different ring sizes (five, six, or seven) 48a–50a proceeded smoothly providing the corresponding products 46–50 (80–99% yields). Additionally, long chain aliphatic acetates 51a and 52a, a spirocycle bearing sensitive dioxa moiety 53a, sterically hindered adamantyl 54a, và aminoxy-O-acetate 55a were competent, when used in the applied protocol, of producing their corresponding hydroxyls 51–55 in satisfactory yields (90–99%).

To gain further insight into the Me3SI-promoted deacetylation, the reaction of TOAc-glucal 1a was performed with equimolar amounts of trimethylsulfonium iodide and an additive (0.1 equiv. Each) employing deuterated methanol (CD3OD) as the solvent (Fig. 1). The 1H-NMR analyses of the crude reaction mixture revealed the presence of a distinctive resonance which was due khổng lồ an anomeric proton (δ 6.42 dd, J1-2 = 6.10, 1.4 Hz, H-1) and other characteristic chemical shifts which conformed with that of the desired sản phẩm 1′ (tri-O-2H-D-glucal).


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Fig. 1 Experiments with deuterated methanol và 1H-NMR analyses, used to lớn provide mechanistic rationalization for Me3SI-promoted deacetylation.

With no variance, the acetyl protons of methyl acetate (CH3CO-OCD3) were found at δ 2.10 (s, 9H) which potentially resulted from the methanolysis of the acetate groups with CD3OD. In addition, substantial amounts of trimethylsulfonium hydroxide species were observed consistently at δ 3.05 as a singlet (vs. Me3SI at δ 1.56),24 & this established the role of trimethylsulfonium iodide in selective & simple cleavage of acetates. A mix of control experiments were performed lớn identify the possible intermediate iodine species in this transformation. The studies revealed the absence of molecular iodine in the present reaction conditions as confirmed by a negative starch solution kiểm tra (the màu sắc did not change khổng lồ an intense xanh color).24 Indeed, the standard Me3SI-mediated deacetylation reaction employing a common radical scavenger such as TEMPO (a stable aminooxy radical) or 2,6-di-tert-butyl-4-methylphenol (BHT) preceded smoothly, & further ruled out a radical pathway in the process. Although, attempting a reaction of TOAc-glucal 1a using a catalytic amount of iodine in methanol solvent was inconsistent (50–60% conversion) resulting in the mono-deacetylation of the primary acetate (6-OAc) even after a prolonged reaction time (48 h).18a It is worth noting that the characteristic Lewis acidity of molecular iodine (I2) has been exploited in the selective O-Ac as well N-Boc protection of diverse substrates.25

Based on the previously mentioned experimental observations và with reference to precedents in the literature, a plausible mechanistic rationalization for a Me3SI-catalyzed reaction is postulated in Scheme 4. Initially, KMnO4 showed rapid disproportionation, resulting in permanganic acid (HMnO4 ↔ H+ + MnO4−) & potassium methoxide (KOMe ↔ K+ + MeO−) ions in the presence of methanol, which was attributed to lớn the reducing behavior of methanol in the present system.26 The main oxidizing reagent Mn(VII)O4− was capable of inverting the polarity of the reactivity of the halide salt Me3SI in slightly acidic conditions which resulted in the iodate (I+) species , & was disproportionate to Mn(IV)O2 và H2O. The reduced Mn(IV) species would then readily oxidize back to the higher Mn(VI)O4− in a slightly basic medium (KOMe/H2O) under the normal atmosphere26c và this was likely to lớn facilitate the release of trimethylsulfonium hydroxide. Meanwhile, the incipient electrophilic intermediate initiated from the oxidation of Me3SI coordinated with the oxygen atoms of the carbonyl functionality (CH3CO2–) in the acetate compound <1a> lớn generate a transient species .25b,25c,27 This significantly induced the polarization of the C"/>O double bond & increased the electrophilicity of the carbonyl carbon as well contributing towards the bond lengthening of the carbonyl C"/>O moiety in .


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Scheme 4 A plausible mechanism for Me3SI-promoted selective deacetylation.

Subsequent coordination of the K+ ion with alkyl-oxygen (RO−) and attack of methoxide (MeO−) as the nucleophile on the electrophilic carbon in , would then eventually produce the tetrahedral intermediate . Following the elimination of the penultimate transient species và simultaneously trapping of the respective alkoxide ion (RO−) in a hydrolytic environment would unambiguously lead to the formation of the respective alkanol (ROH) <1> with the liberation of potassium methoxide. The proposed intermediate finally displaced the corresponding methyl acetate (CH3CO2Me) by releasing the required iodate species which presumably participated in another catalytic cycle en route to the selective deacetylation process.

In summary, a catalytic and practical procedure for chemoselective deacetylation with a general substrate scope employing environmentally benign reagents under ambient reaction conditions is reported. It is worth noting that the catalytic protocol is broadly applicable khổng lồ numerous substrates, including carbohydrates, amino acids, and natural products, tolerating orthogonal và sensitive groups (esters, ethers, silyl ethers, carbamates, carboxybenzyl, mesyl, 2-tetrahydropyranyl, trityl, aldehydes, và also alkenes). Furthermore, the method is advantageous as it involves a safe và convenient reaction, ensuring smooth và quantitative conversion as well as preventing trans-esterification.

Experimental

Representative procedure for chemoselective deacetylation

To a previously prepared solution of acetate substrate (50 mg, 1.0 equiv.) in MeOH (1 mL) was added Me3SI (0.1 equiv.) and KMnO4 (0.1 equiv.). The mixture was stirred at room temperature in an open-air environment and the reaction progress was monitored by TLC. After the complete consumption of the starting material had occurred, typically 5 min to lớn 12 h, the reaction mixture was filtered and washed with EtOAc (10 mL). The filtrate was treated with saturated aqueous NaHCO3 (5 mL), & the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were then washed with water và brine, dried over anhydrous Na2SO4, và concentrated in vacuo khổng lồ obtain the analytically pure products.

Conflicts of interest

There are no conflicts to declare.

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Acknowledgements

SK gratefully acknowledges the Department of Science and Technology, India for the Early Career Research Award và Research Grant for Young Scientists (SERB-ECR/2017/001477). SK thanks TEQIP-III for their generous support and MRC MNIT (Advanced Analytical & Characterization Centre) for providing the NMR spectroscopic và analytical data. The authors are also grateful lớn the Director of MNIT for providing the necessary infrastructure for this research. AG acknowledges a UGC Fellowship.

Notes & references