Carboxylate Anions Accelerate Pyrrolidinopyridine (PPy)-Catalyzed

Letter pubs.acs.org/OrgLett

Carboxylate Anions Accelerate Pyrrolidinopyridine (PPy)-Catalyzed Acylation: Catalytic Site-Selective Acylation of a Carbohydrate by in Situ Counteranion Exchange Masanori Yanagi, Ayumi Imayoshi, Yoshihiro Ueda,* Takumi Furuta, and Takeo Kawabata* Institute for Chemical Research, Kyoto University, Uji 611-0011, Japan S Supporting Information *

ABSTRACT: Acylpyridinium ions have been known as catalytically active species in acylation reactions catalyzed by 4dimethylaminopyridine and its analogues. Acylpyridinium carboxylates were found to be 800−1300 times more reactive than the corresponding acylpyridinium chlorides. A catalytic cycle was developed, in which acylpyridinium carboxylates were generated by in situ counteranion exchange from the acylpyridinium chlorides. A catalyst loading as low as 0.01 mol % and catalyst turnover number of up to 6700 were achieved for site-selective acylation of a carbohydrate.

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ite-selective catalysis1 has attracted increasing attention because of its potential utility for direct diversification of bioactive natural products and medicinal candidates with multiple functional groups.2 Especially, development of catalysts that can promote the target reaction in a site-selective manner independent from the intrinsic reactivity of the substrates, i.e., catalyst-controlled selectivity, is a challenging objective in current organic synthesis.3 In 2007, we reported site-selective acylation of glucose derivative 2 with organocatalyst 1 (Table 1).4 Acylation of the intrinsically less reactive C(4)−OH in the presence of the primary C(6)−OH proceeds probably via precise molecular recognition between the catalytic intermediate and the substrate. While the reaction has been applied to the direct siteselective derivatization of multifunctionalized natural products5 and a short total synthesis of natural glycosides,6 the relatively high catalyst loading has been a fundamental problem. In general, the inferior reactivity of organocatalysts compared to organometallic catalysts makes it difficult to decrease the catalyst loading to less than 1 mol %.7 For example, the use of 1 mol % of catalyst 1 completed the C(4)−OH-selective isobutyrylation in 24 h (Table 1, entry 2), while the corresponding reaction with 0.1 mol % of 1 did not complete over the same reaction time (entries 2 vs 3). Use of a less reactive acyl donor, benzoic anhydride, required a longer reaction time even in the presence of 10 mol % of 1 (entries 1 vs 5 and 6). Since many natural glycosides contain substituted benzoyl groups,8 their site-selective introduction would be useful for the total synthesis of such natural glycosides. We report here a new catalytic system that enables the catalyst © 2017 American Chemical Society

Table 1. Effects of Catalyst Loading and Acyl Donors in Organocatalytic Site-Selective Acylation of Glucose Derivative 2a

entry

mol % of 1

RCOX

time (h)

monoacylate (%)

site selectivity (6-O:4-O:3-O:2-O)

1 2 3 4 5 6

10 1 0.1 10 10 10

(i-PrCO)2O (i-PrCO)2O (i-PrCO)2O i-PrCOCl (PhCO)2O (PhCO)2O

12 24 24 48 24 168

98 98 66 47 67 95

0:99:1:0 0:99:1:0 0:97:3:0 60:35:5:0 3:94:3:0 3:94:3:0

a

Data quoted from ref 4.

loading to be reduced to 0.01 and 0.1 mol % for the site-selective isobutyrylation and benzoylation of 2, respectively. It could be imagined that the use of a highly reactive acyl donor (acyl chloride) instead of an acid anhydride might be a possible solution to the problem concerning the relatively low efficiency in the catalytic system. However, the use of isobutyryl chloride in Received: April 21, 2017 Published: May 30, 2017 3099

DOI: 10.1021/acs.orglett.7b01213 Org. Lett. 2017, 19, 3099−3102

Letter

Organic Letters the acylation reaction of 2 gave the monoacylates in a low yield with undesired site selectivity even in the presence of 10 mol % of 1 (Table 1, entry 4). The critical difference in the acylation behavior depending on the acyl donor could be explained as shown in Figure 1. The currently accepted catalytic cycle for 4-

Figure 2. (a) Amounts of the acylpyridinium salts formed from PPy and Ac2O, AcCl, Bz2O, and BzCl. (b) Thermodynamic parameters for the equilibrium between PPy and A-PPY. (c) Kinetic profiles of the acylation of 3 with Ac2O and AcCl. (d) Kinetic profiles of acylation of 3 with Bz2O and BzCl.

Figure 1. Catalytic cycle for DMAP-catalyzed acylation with (a) acid anhydrides and (b) acyl chlorides. (c) A proposed catalytic cycle for DMAP-catalyzed acylation with an acyl chloride−carboxylate system.

measurement with the corresponding acid anhydride and PPy due to the fast equilibrium at 20 °C. In order to gain insights into the equilibrium process, the thermodynamic parameters of the process were determined to be ΔH = −7.27 kcal/mol, ΔS = −32.6 cal/mol·K and ΔH = −8.75 kcal/mol, ΔS = −44.8 cal/ mol·K with acetic anhydride and benzoic anhydride, respectively, by variable-temperature 1H NMR measurement (Figure 2b; also see the SI). Based on these parameters, equilibrium constants for the formation of A-PPY (R = Me) and A-PPY (R = Ph) were calculated to be 0.017 and 5.2 × 10−4 mol−1, respectively at 20 °C. Accordingly, the former and the latter were assumed to be generated in 0.12% yield and 3.6 × 10−3% yield, respectively based on the amount of PPy (Figure 2a). Only a small amount of acylpyridinium salts were found to be formed when acid anhydrides were used, while the salts were quantitatively formed from PPy and acyl chlorides. Kinetic studies were performed to estimate the reactivity of the acylpyridinium salts (Figure 2c and 2d; details can be found in the SI). An acetylation reaction of 2,2-dimethyl-1-phenyl-1propanol (3) was run under the pseudo-first-order conditions with 10 equiv of an acyl donor and 15 equiv of PPy in CHCl3 at 0 °C. The reaction with Ac2O proceeded 2.5 times faster than that with AcCl (Figure 2c, kAc2O/kAcCl = 2.5). The amount of A-PPY (R = Me) formed under the conditions in Figure 2c was calculated to be 0.33% yield based on the amounts of employed Ac2O (0.22% yield based on the amounts of employed PPy). These kinetic and thermo dynamic data indicate that A-PPY (R = Me) is about 800 times more reactive than B-PPY (R = Me) for acetylation of 3. The kinetic study for benzoylation of 3 was performed in a similar manner resulting in the relative rate of kBz2O/kBzCl = 0.16 (Figure 2d). The amount of A-PPY (R = Ph) formed under these conditions was calculated to be 1.2 × 10−2 % yield based on the amounts of employed Bz2O (8.0 × 10−3 % yield based on the amounts of employed PPy). Considering the kinetic and thermodynamic data, A-PPY (R = Ph) is expected to be 1300 times more reactive than B-PPY (R = Ph). These results clearly show that acylpyridinium carboxylate A-PPY has much

dimethylaminopyridine (DMAP)-catalyzed acylation of alcohols with acid anhydrides consists of two key steps (Figure 1a).9 The first key step is the setup of an equilibrium between DMAP and acylpyridinium salts A (step 1), and the second one is the irreversible nucleophilic attack of an alcohol on the carbonyl group in A (step 2). The similar catalytic cycle with acyl chlorides may be drawn as shown in Figure 1b. The efficiency of the DMAP-catalyzed acylation depends not only on the concentration of acylpyridinium salts A and B but also on the rate of the individual step 2. We expected that while the concentration of A is lower than that of B,10 TS-A would be much more favorable than TS-B,9,11 because of the stronger basicity of the carboxylate anion than the chloride anion as well as the proximity effect of the carboxylate anion due to the C(2)-H···OC hydrogen bonding. Accordingly, while step 1 with acyl chlorides is more favorable than that with acid anhydrides, step 2 in the latter is much more favorable than the former. Overall, it is understandable that the acylation of 2 with isobutyric anhydride resulted in proceeding more smoothly than that with isobutyryl chloride (Table 1, entries 1 vs 4) because of the critical importance of step 2. With this background in mind, we envisaged a new catalytic system, in which both steps 1 and 2 are favorable (Figure 1c). High catalytic performance could be expected if acylpyridinium salt B could be generated in high concentration by the use of an acyl chloride, and it could be converted to a highly reactive acylpyridinium salts A′ by in situ counteranion exchange. We investigated two key factors of the catalytic cycle using 4pyrolidinopyridine (PPy) as the nucleophilic catalyst: (1) efficiency of the formation of the acylpyridinium ion depending on the acyl donor, and (2) relative reactivity of the acylpyridinium salts depending on the counteranion. Quantitative formation of acylpyridinium chloride B-PPY was observed by 1H NMR spectroscopy by mixing the acyl chloride and PPy in a 1:1 ratio in CDCl3 at 20 °C (Figure 2a; also see the Supporting Information (SI)).10 On the other hand, acylpyridinium carboxylate A-PPY was not detected in a similar NMR 3100

DOI: 10.1021/acs.orglett.7b01213 Org. Lett. 2017, 19, 3099−3102

Letter

Organic Letters Table 2. Effects of in Situ Counteranion Exchange on Catalytic Performance for Site-Selective Acylation of 2

a

entry

mol % of 1

RCOX

additive

base

time

monoacylate

site selectivity

TONa

1 2 3 4c 5 6 7 8 9 10

0.1 0.1 0.02 0.02 0.01 10 10 0.1 0.02 0.01

i-PrCOCl (2.2) (i-PrCO)2O (1.1) i-PrCOCl (2.2) i-PrCOCl (2.2) i-PrCOCl (2.2) PhCOCl (2.2) (PhCO)2O (1.1) PhCOCl (2.2) PhCOCl (2.2) PhCOCl (2.2)

PivOH (2.2) none PivOH (2.2) PivOH (2.2) PivOH (2.2) PivOH (2.2) none PivOH (2.2) PivOH (2.2) PivOH (2.2)

DIPEA (3.3) collidine (1.5) DIPEA (3.3) DIPEA (3.3) DIPEA (3.3) DIPEA (3.3) collidine (1.5) DIPEA (3.3) DIPEA (3.3) DIPEA (3.3)

5 min 5 min 25 min 60 min 21 h 5 min 15 min 15 min 12 h 24 h

99 traceb 97 89 73 85 8 87 76 69

0:98:2:0 − 0:96:4:0 2:95:3:0 4:92:4:0 0:96:4:0 0:96:4:0 1:95:4:0 0:95:5:0 0:94:6:0

980 − 4600 4200 6700 8 0.8 830 3600 6500

Turnover number for the production of the 4-O-acylate. bSubstrate 2 was recovered in 99%. cReaction using 5 g of 2.

results by the present catalytic system are compared with the previous ones (entries 3−5 vs entry 2, entries 8−10 vs entry 7). The newly developed catalytic cycle (method I) was applied to the introduction of various substituted benzoyl groups (Table 3).

higher reactivity than the corresponding acylpyridinium chloride B-PPY, while the former is generated in much smaller amounts than the latter. Benzoylation was observed to proceed in a rather sluggish manner (Table 1, entries 5 and 6). This could be explained by the formation of a very low concentration of the acylpyridinium salt along with the low electrophilicity of its benzoyl group. The observed phenomena on acylpyridinium salts A and B seem to support the validity of the proposed catalytic cycle (Figure 1c), where B is generated quantitatively by using an acyl chloride as an acyl donor and converted to the acylpyridinium salt A′ with much higher reactivity by in situ exchange of the counteranion. According to the proposed catalytic cycle, the effects of the source of the carboxylate ion on the catalytic performance of the acylation reaction were examined (Table 2). Acylation catalyzed by only 0.1 mol % of 1 with isobutyryl chloride was complete within only 5 min in the presence of pivalic acid (PivOH) and N,N-diisopropylethtylamine (DIPEA) as the carboxylate ion source (99% yield and 98% site selectivity, entry 1). Only a trace amount of the desired 4-O-acylate was obtained over the same reaction time under the previously established conditions5a with an isobutyric anhydride/collidine system (entry 2; also see Table 1, entry 3). These results clearly show that the counteranionexchange method dramatically increased the catalytic performance. Even in the presence of 0.02 mol % of 1, the reaction was complete within 25 min (entry 3). The high catalytic performance was maintained in a gram-scale reaction (entry 4). A further decrease in the catalyst loading to 0.01 mol % resulted in a prolonged reaction time (entry 5), with the desired 4-O-acylate being obtained selectively in an acceptable yield with a high catalyst turnover number (TON) of 6700. Site-selective benzoylation was investigated. In the presence of 10 mol % of 1, the 4-O-benzoate was obtained in 80% yield (85% yield for the combined monoacylates) and 94% site selectivity within 5 min (entry 6). The catalytic performance of the present method was again much improved compared to the previously established conditions6a with benzoic anhydride/collidine (entries 6 vs 7; also see Table 1, entry 5). The benzoylation was also complete within 15 min, with preservation of the high site selectivity under the conditions with decreased catalyst loading to 0.1 mol % (entry 8). Use of only 0.01 mol % of catalyst 1 was still effective for the highly site-selective benzoylation of 2 with TON of 6500, although the reaction required a longer reaction time (24 h) (entry 10). Superior catalytic performance is obvious when the

Table 3. Site-Selective Introduction of Substituted Benzoyl Groups into 2

entry

Ar

mol % of 1

method

time (h)

yield of 4 (%)

TONa

1 2 3 4 5 6

p-CF3-C6H4p-CF3-C6H4p-F-C6H4p-OMe-C6H4p-NMe2-C6H4p-NMe2-C6H4-

0.1 0.1 0.1 1 10 10

I II I I I II

2 2 4 2 15 48

76 7 80 83 46 3

760 70 800 83 5 0.3

a

Turnover number for the production of the 4-O-acylate.

Use of 0.1 mol % of catalyst 1 was effective for introducing substituted benzoyl groups with electron-withdrawing substituents such as CF3 and F to give the desired 4-O-acylates in relatively short reaction times (2−4 h, TON = 760−800, entries 1 and 3). The previously established protocol (method II)5a with the same catalyst loading (0.1 mol %) gave the 4-O-acylate in only 7% yield in 2 h (entry 2). Method I was also effective for the site-selective introduction of a p-methoxybenzoyl group. The reaction required a 1 mol % catalyst loading because introduction of an arylcarbonyl group with electron-donating groups usually only proceed in a sluggish manner. Introduction of arylcarbonyl groups with a further strongly electron-donating group, the 4-dimethylaminobenzoyl group (σpara for p-NMe2: −0.83), has been quite difficult due to the extremely low reactivity of the corresponding acylpyridinum intermediate. The reaction of 2 with (p-NMe2C6H4CO)2O in the presence of 10 mol % of 1 gave the 4-O-acylate in only 3% yield after 48 h by method II (entry 6). In contrast, the 4-Oacylate was obtained in a moderate 46% yield in 15 h by method I (entry 5). The established new catalytic cycle may be applicable to the acylation of various mono- and oligosaccharides4−6,12 at least in principle. 3101

DOI: 10.1021/acs.orglett.7b01213 Org. Lett. 2017, 19, 3099−3102

Organic Letters

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ACKNOWLEDGMENTS This research was financially supported by Grants-in-Aids for Scientific Research (S) (JP26221301), Young Scientists (B) (JP15K18827), and Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” (JP23105008) and “Middle Molecular Strategy” (JP16H01148). A.I. acknowledges the financial support through JSPS Research Fellowships for Young Scientists (JP15J10954).

We have established a new catalytic cycle with high performance for site-selective acylation. We supposed that acylpyridinium carboxylate A′ (Figure 1c) generated by in situ counteranion exchange would be the reactive intermediate. However, the possibility that A′ was generated by the reaction between the catalyst and a mixed anhydride formed by the acyl chloride and carboxylate5c could not be eliminated, since the mixed anhydride was often obtained as a side product in the present method. In order to examine this possibility, a mixed anhydride was independently prepared from BzCl, PivOH, and DIPEA and used for the catalytic site-selective acylation of 2 (Scheme 1). Only a trace amount of the 4-O-acylate was obtained

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by this procedure, whereas the corresponding conditions by the present protocol gave the 4-O-acylate in 83% yield (Table 2, entry 8). These results strongly suggest that a reactive acylpyridinium carboxylate is generated by in situ counteranion exchange of the corresponding acylpyridinium chloride as shown in Figure 1c. In this protocol, 2.2 equiv of the carboxylate source are required for the completion of the acylation. This is because the formation of the unreactive mixed anhydride is unavoidable as a side product in the present catalytic cycle for acylation. In conclusion, we have found that the catalytic reactivity of acylpyridinium ions is highly dependent on the counteranion. Acylpyridinium carboxylates were found to be ∼1300 times more reactive than the corresponding acylpyridinium chlorides. The former was expected to be generated by in situ counteranion exchange from the latter in the present catalytic cycle. A highly efficient catalytic cycle was developed for the site-selective acylation of a carbohydrate with a 0.01 mol % catalyst loading and catalyst turnover number of up to 6700. It is worth noting that a significant improvement in the catalytic performance was achieved without structural modification of the original catalyst,13,14 which seems to be the key for maintaining high site selectivity for acylation of carbohydrates.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01213. Details of NMR experiment, kinetic studies, experimental procedures, analytical data, and copies of the new products (PDF)

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REFERENCES

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Scheme 1. Attempted Acylation of 2 with a Mixed Anhydride

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Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Takeo Kawabata: 0000-0002-9959-0420 Notes

The authors declare no competing financial interest. 3102

DOI: 10.1021/acs.orglett.7b01213 Org. Lett. 2017, 19, 3099−3102