Chiral Benzazaborole-Catalyzed Regioselective Sulfonylation of Unprotected Carbohydrate Derivatives

Article abstract of DOI:10.1002/chem.201903443

Chiral benzazaborole-catalyzed regioselective sulfonylations of unprotected carbohydrate derivatives have been developed. This methodology enables direct regioselective functionalization of the secondary OH group in carbohydrate in the presence of the primary OH group. By using the chiral organoboron catalysis, kinetic resolution of the carbohydrate derivatives was also achieved.

Full text of DOI:10.1002/chem.201903443

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Accepted Article
Title: Chiral Benzazaborole-Catalyzed Regioselective Sulfonylation of
Unprotected Carbohydrate Derivatives
Authors: Satoru Kuwano, Yusei Hosaka, and Takayoshi Arai
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Chiral Benzazaborole-Catalyzed Regioselective Sulfonylation of
Unprotected Carbohydrate Derivatives
Satoru Kuwano,*[a] Yusei Hosaka,[a] and Takayoshi Arai*[a]
Abstract:
Chiral
benzazaborole-catalyzed
regioselective
sulfonylations of unprotected carbohydrate derivatives have been
developed. This methodology enables direct regioselective
functionalization of the secondary OH group in carbohydrate in the
presence of the primary OH group. Using the chiral organoboron
catalysis, kinetic resolution of the carbohydrate derivatives was also
achieved.
Carbohydrate derivatives play essential roles in various
physiological and pathological events such as cell adhesion,
fertilization, and cancer cell metastases.[1] For the synthesis of
various carbohydrates, practical methods involving the catalyst-
controlled regioselective functionalization of one specific OH
group have been extensively investigated and developed.[2] After
the pioneering works such as the development of N-
methylimidazole[3] and 4-pyrrolidinopyridine[4,5] catalysts by Miller
and Kawabata, respectively, several outstanding nucleophilic
catalysts have been developed for the activation of electrophiles
(Scheme 1a).[6] The other approach is the catalyst-controlled
activation of carbohydrates so that they can themselves act as
nucleophiles. Onomura et al. reported the organotin-catalyzed
regioselective acylation through tin-alkoxide formation (Scheme
1b).[7] Although organotin catalysts are widely used, their inherent
potential toxicity poses a problem sometimes.[8] Recently, Dong
et al. reported the iron-catalyzed alkylation of polyols, thus
avoiding the use of tin-based catalysts (Scheme 1c).[9,10]
Organoboron catalysts are among the most nontoxic
compounds.[11] In 2011, Taylor et al. demonstrated that borinic
acids serve as elegant catalysts for the regioselective acylation of
minimally protected carbohydrate derivatives through nucleophile
activation.[12,13] However, to the best of our knowledge, a general
Scheme 1. Regioselective functionalization of unprotected carbohydrate
derivatives.
method
using
organoborons
for
the
regioselective
functionalization of unprotected carbohydrates has not been
reported.[14,15,16] This is because the organoboron catalyst binds
to both cis-1,2-diol and 1,3-diol moieties (Scheme 1e).[12,14] Herein,
we describe the chiral benzazaborole-catalyzed regioselective
sulfonylation of unprotected carbohydrates.[17] Sulfonylated
carbohydrates are used as electrophiles in the synthesis of
biologically interesting pseudosugars and building blocks.[18]
Organoboron species 1 were evaluated as catalysts for the
regioselective sulfonylation of α-D-galactopyranoside 2a (Table
1).[19] While phenyl boronic acid 1a, benzoxaborole 1b,
benzazaborole 1c, and ethanolamine ester of borinic acid (1d)
provided varying degrees of rate enhancement, formations of 6-
O-tosylated product 4a was observed (entries 1–4). In contrast,
heterocyclic borinic acid 1e promoted tosylation at the 3-position,
and 3-O-tosylated product 3a was produced in 19% yield (entry
5). To our delight, the use of chiral benzazaborole 1f was effective
for the regioselective sulfonylation with assistance of NMI,[20] and
product 3a was predominantly furnished in 71% yield (entry 6).[21]
The high catalytic activity of 1f would be derived by the electron-
donation from nitrogen atom onto the boron center. Introduction
of a methoxy substituent on the quinoline ring did not improve the
chemical yield (entry 7).
[a]
Dr. S. Kuwano, Y. Hosaka, Prof. Dr. T. Arai
Soft Molecular Activation Research Center (SMARC)
Chiba Iodine Resource Innovation Center (CIRIC)
Molecular Chirality Research Center (MCRC)
Synthetic Organic Chemistry, Department of Chemistry, Graduate
School of Science, Chiba University
1-33 Yayoi, Inage, Chiba 263-8522 (Japan)
E-mail: skuwano@chiba-u.jp
tarai@faculty.chiba-u.jp
Supporting information for this article is given via a link at the end of
the document.
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Table 1: Optimization of reaction conditions.
Table 2: Chiral benzazaborole 1f-catalyzed regioselective fuctionalization
of carbohydrate derivatives having cis-1,2-diol moiety.
Yield
(%)[a]
Entry
1
Substrate
Product
71[d]
2
70[e]
3
84[f]
88
4[b]
5[b]
82
3a[a]
(%)
4a[a]
(%)
5a[a]
(%)
Entry
1
Solvent
base
1
2
1a
1b
1c
1d
1e
1f
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtCN
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Li2CO3
2
11
16
12
37
6
2
6
7
6
7
8
60
88
98
3
2
2
4
1
24
27
18
22
20
9
5
19
71
60
31
9
6
1
7
1g
1h
1i
<1
<1
13
<1
<1
3
8
9
10
11
12
13
14
15
16
17
18
19
20
1f
23
52
34
11
33
58
29
23
13
10
<1
4
1f
K2CO3
17
7
1f
NaHCO3
Et3N
9
>99
1f
23
5
14
5
1f
DIPEA
1f
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
<1
<1
<1
<1
<1
<1
18
21
2
1f
DCM
10[c]
81
67
1f
THF
1f
toluene
EtOAc
MeCN
<1
4
1f
none
<1
11[b]
[a] NMR yield.
When benzazaborole 1h was employed as a pseudo-enantiomer
of 1f, the yield of 3a decreased to 31% (entry 8). This result
indicated a matching/mismatching between the chirality of the cis-
1,2-diol moiety on the carbohydrates and chiral catalysts. The use
of chiral 2-aminomethyl phenyl boronic acid 1i did not increase
the reactivity and selectivity (entry 9). Examination of the base
effect revealed that Na2CO3 was the optimal choice for this
reaction (entries 10–14). Among the tested solvents, acetonitrile
gave the best result (entries 15–19). In the absence of
organoboron catalyst, reaction did not proceed at all (entry 20).
12[b]
62
[a] Isolated yield. [b] Reaction was performed in the absence of NMI. [c] TsCl
(4 eq), Na2CO3 (4 eq), and MS3A were used. [d] 18% of ditosylate were
produced. [e] 15% of ditosylate were produced. [f] 8% of ditosylate were
produced.
With the optimized conditions in hand, we next explored the
substrate scope of the 1f-catalyzed regioselective sulfonylation of
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carbohydrate derivatives (Table 2). Besides the α-anomer of a
galactose derivative (2a), the β-anomer (2b) also gave
monosulfonate ester 3b in good yield (entry 2). Thioglycoside 2c,
which was utilized as a glycosyl donor, was smoothly converted
into the corresponding monosulfonate esters, and various
sulfonate esters were obtained in 82%–88% yields (entries 3–5).
N-Boc protected D-galactosamine derivative 2d could also be
employed in this regioselective reaction in the presence of a free
6-OH group (entry 6). Derivatives of L-arabinose and L-rhamnose,
which do not have a free primary OH group, readily afforded
products 3e and 3f in high yields (entries 7 and 8). This method
was suitable for the regioselective sulfonation of triol 6a prepared
from quinic acid, a carbohydrate-like structure present in
numerous bioactive natural products (entry 9). Upon the addition
of excess sulfonyl chloride, 2a was converted into disulfonate
ester 3aa in 81% yield (entry 10). In addition to the regioselective
sulfonylation, the catalyst system was applicable to regioselective
acylation of unprotected carbohydrates (entries 11 and 12).
When D-mannose derivative 2g was applied to the 1f-
catalyzed regioselective sulfonylation, the corresponding product
3g was obtained in only 24% yield. Because the cis-1,2-diolmoiety
of 2g has enantiomeric stereochemistry relative to D-galactose
derivative 2a, a pseudo- enantiomeric catalyst 1h was selected
for the “matched” pair. In the presence of benzazaborole 1h,
mannopyranoside 2g was smoothly converted into sulfonate
ester 3g in good yield (Table 3, entry 1). The use of 1h was
effective for the regioselective sulfonylation of carbohydrate
derivatives possessing the same cis-1,2-stereochemistry as 2g.
Derivatives of D-lyxose 2h and L-fucose 2i were quantitatively
transformed to the corresponding products 3h and 3i (entries 2
and 3). The reaction using 1,6-anhydrogalactopyranose 2j
resulted in monosulfonylation at the C4 position of an unbridged
galactopyranoside (entry 4). Monosaccharide Helicid, which
contains a cis,cis-1,2,3-triol and formyl group, gave disulfonate
ester 3k in good yield when using three equivalents of TsCl (entry
5). Interestingly, the free primary OH group was not functionalized,
and the formyl group was tolerated under the reaction conditions.
To expand the utility of the benzazaborole-catalyzed
regioselective sulfonylation, we applied this reaction to the kinetic
resolution of carbohydrate derivatives. In general, separation of
structurally similar carbohydrates by simple methods such as
silica gel column chromatography and recrystallization is difficult
because of the similar polarity and solubility of these compounds.
Recently, enzyme, Sn-, and Cu-catalyzed methods have been
developed for the aforesaid separation,[22] but there is no report
on the use of an organocatalyst for this purpose. First, the kinetic
resolution of D-galactose derivative 2c and D-glucose derivative
9a was investigated (Table 4, entry 1). When a mixture of 2c and
9a was stirred in the presence of benzazaborole 1f, 2c was
selectively converted to sulfonate ester 3ca in 80% yield.
Remarkably, the primary OH group in D-glucopyranoside was not
tosylated, and 99% of the unreacted 9a was recovered. Our
method could also be used for the resolution of L-arabinose
derivative 2e and D-xylose derivative 9b, or L-rhamnose derivative
Table 3: Chiral benzazaborole 1h-catalyzed regioselective sulfonylation of
carbohydrate derivatives having “enantiomeric” cis-1,2-diol moiety.
Table 4: Chiral benzazaborole-catalyzed kinetic resolution of carbohydrate
derivatives.
Entry
1
Substrate
Product
Yield (%)[a]
66
2
>99
3
>99
84
Recovered 9
Yield of 3
Entry
2
9
1
(%)[a]
(%)[a]
4[b]
1
2
3
4
5
2c
2e
2f
9a
9b
9a
9a
9b
1f
1f
80
84
97
97
99
99
88
98
95
94
1f
2h
2i
1h
1h
5[c]
74
[a] Isolated yield.
[a] Isolated yield. [b] TsCl (2 eq) was used. [c] TsCl (3 eq) and Na2CO3 (3
eq) were used.
2f and D-glucose derivative 9a (entries 2 and 3). In addition, the
resolutions of D-lyxose derivative 2h and D-glucose derivative 9a,
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[7]
[8]
a) F. Iwasaki, T. Maki, O. Onomura, W. Nakashima, Y. Matsumura, J.
Org. Chem. 2000, 65, 996; b) Y. Demizu, Y. Kubo, H. Miyoshi, T. Maki,
Y. Matsumura, N. Moriyama, O. Onomura Org. Lett. 2008, 10, 5075.
a) W. Muramatsu, S. Tanigawa, Y. Takemoto, H. Yoshimatsu, O.
Onomura, Chem. Eur. J. 2012, 18, 4850; b) W. Muramatsu, J. Org. Chem.
2012, 77, 8083; c) W. Muramatsu, H. Yoshimatsu, Adv. Synth. Catal.
2013, 355, 2518; d) M. Giordano, A. Iadonisi, J. Org. Chem. 2014, 79,
213; e) H. Xu, Y. Lu, Y. Zhou, B. Ren, Y. Pei, H. Dong, Z. Pei, Adv. Synth.
Catal. 2014, 356, 1735; f) W. Muramatsu, Org. Lett. 2014, 16, 4846.
B. Ren, O. Ramstrꢀm, Q. Zhang, J. Ge, H. Dong, Chem. Eur. J. 2016,
22, 2481.
or L-fucose derivative 2i and D-xylose derivative 9b were
effectively promoted when using 1h (entries 4 and 5).
[9]
Scheme 2. Ns group as orthogonal protective group.
[10] a) B. Ren, J. Lv, Y. Zhang, J. Tian, H. Dong, ChemCatChem 2017, 9,
950; b) B. Ren, N. Yan, L. Gan, RSC Adv. 2017, 7, 46257.
Finally, deprotection of Ns group in 10 was examined
(Scheme 2). Use of PhSH and K2CO3 in MeCN gave deprotected
compound 11 in good yield, and side reactions (substitution,
elimination, or 1,2-acyl migration) were not observed in the mild
basic conditions.
[11] a) K. Ishihara, H. Yamamoto, Eur. J. Org. Chem. 1999, 527; b) K.
Ishihara in Lewis Acids in Organic Synthesis Vol. 1 (Eds.: H. Yamamoto,
Wiley-VCH, Weinheim, 2000, pp. 89−190); c) K. Ishihara, H. Yamamoto
in Modern Aldol Reactions (Eds.: R. Mahrwald, Wiley-VCH, Weinheim,
2004, pp. 25−68).
[12] D. Lee, M. S. Taylor, J. Am. Chem. Soc. 2011, 133, 3724.
[13] a) L. Chan, M. S. Taylor, Org. Lett. 2011, 13, 3090; b) C. Gouliaras, D.
Lee, L. Chan, M. S. Taylor, J. Am. Chem. Soc. 2011, 133, 13926; c) D.
Lee, C. L. Williamson, L. Chan, M. S. Taylor, J. Am. Chem. Soc. 2012,
134, 8260; d) E. Dimitrijevic, M. S. Taylor, Chem. Sci. 2013, 4, 3298; e)
S. O. Bajaj, E. U. Sharif, N. G. Akhmedov, G. A. O’Doherty, Chem. Sci.
2014, 5, 2230; f) K. A. D'Angelo, M. S. Taylor, J. Am. Chem. Soc. 2016,
138, 11058; g) S. Izumi, Y. Kobayashi, Y. Takemoto, Org. Lett. 2019, 21,
665.
In conclusion, we have developed a chiral benzazaborole-
catalyzed
regioselective
sulfonylation
of
unprotected
carbohydrate derivatives. This methodology enables direct
regioselective functionalization of the secondary OH groups in the
carbohydrate derivatives in the presence of the primary OH
groups. This organoboron catalysis could also be used for the
kinetic resolution of carbohydrate derivatives.
[14] For pioneering example using organoboron compounds, see: a) K.
Oshima, Y. Aoyama, J. Am. Chem. Soc. 1999, 121, 2315; b) R.-Z. Li, H.
Tang, L. Wan, X. Zhang, Z. Fu, J. Liu, S. Yang, D. Jia, D. Niu, Chem.
2017, 3, 834.
Acknowledgements
This work was financially supported by Toray Award in Synthetic
Organic Chemistry, Japan, and JSPS KAKENHI Grant Number
19K15553.
[15] Boronic acid-catalyzed glycosylation via SNi-type strategy, see: M.
Tanaka, A. Nakagawa, N. Nishi, K. Iijima, R. Sawa, D. Takahashi, K.
Toshima, J. Am. Chem. Soc. 2018, 140, 3644.
[16] Diarylborinic acid-catalyzed, site-selective sulfation of carbohydrate
derivatives was reported during the preparation of our manuscript
(Scheme1d). see: D. Gorelik, Y. C. Lin, A. I. Briceno-Strocchia, M. S.
Taylor, J. Org. Chem. 2019, 84, 900.
Keywords: chiral benzazaborole • organoboron catalyst •
regioselective sulfonylation
•
carbohydrate derivatives
•
cooperative catalysis
[17] a) X. Sun, H. Lee, S. Lee, K. L. Tan, Nat. Chem. 2013, 5, 790; b) C. L.
Allen, S. J. Miller, Org. Lett. 2013, 15, 6178; c) I.-H. Chen, K. G. M. Kou,
D. N. Le, C. M. Rathbun, V. M. Dong, Chem. Eur. J. 2014, 20, 5013.
[18] a) S. J. Danishefsky, M. P. DeNinno, S. Chen, J. Am. Chem. Soc. 1988,
110, 3929; b) Y. Tsuda, M. Nishimura, Y. Ito, Chem. Pharm. Bull. 1991,
39, 1983; c) S. R. Sanapala, S. S. Kulkarni, J. Am. Chem. Soc. 2016,
138, 4938.
[1]
[2]
For examples, see: a) T. Feizi, Nature 1985, 314, 53; b) H.-J. Gabius, S.
Gabius Lectins and Cancer (Springer-Verlag: New York, 1991.); c) P. R.
Crocker, T. Feizi, Curr. Opin. Struct. Biol. 1996, 6, 679; d) G. S. Kansas,
Blood 1996, 88, 3259; e) S. Liedtke, H. Geyer, M. Wuhrer, R. Geyer, G.
Frank, R. Gerardy-Schahn, U. Zahringer, M. Schachner, Glycobiology
2001, 11, 373; f) S. Brodesser, P. Sawatzki, T. Kolter, Eur. J. Org. Chem.
2003, 11, 2021.
[19] For chiral boronic acid catalyst, see; a) K. Arnold, B. Davies, D. Hꢁrault,
A. Whiting, Angew. Chem. Int. Ed. 2008, 47, 2673; b) D. Lee, S. G.
Newman, M. S. Taylor, Org. Lett. 2009, 11, 5486; c) T. Hashimoto, A. O.
Gꢂlvez, K. Maruoka, J. Am. Chem. Soc. 2015, 137, 16016; d) N. Hayama,
T. Azuma, Y. Kobayashi, Y. Takemoto, Chem. Pharm. Bull. 2016, 64,
704; e) N. Hayama, R. Kuramoto, T. Fꢀldes, K. Nishibayashi, Y.
Kobayashi, I. Pꢂpai, Y. Takemoto, J. Am. Chem. Soc. 2018, 140, 12216.
[20] a) S. Kuwano, Y. Hosaka, T. Arai, Org. Biomol. Chem. 2019, 17, 4475;
b) N. Mannville, H. Alite, F. Haeffner, A. H. Hoveyda, M. L. Snapper, Nat.
Chem., 2013, 5, 768.
a) D. Lee, M. S. Taylor, Synthesis 2012, 44, 3421; b) W. Muramatsu,
Trends Glycosci. Glycotechnol. 2016, 28, J1; c) Y. Ueda, T. Kawabata,
Top. Curr. Chem. 2015, 372, 203; d) M. W. Giuliano, S. J. Miller, Top.
Curr. Chem. 2015, 372, 157; e) C. R. Shugrue, S. J. Miller, Chem. Rev.
2017, 117, 11894; f) V. Dimakos, M. S. Taylor, Chem. Rev. 2018, 118,
11457.
[3]
[4]
K. S. Griswold, S. J. Miller, Tetrahedron 2003, 59, 8869.
T. Kawabata, W. Muramatsu, T. Nishio, T. Shibata, H. Schedel, J. Am.
Chem. Soc. 2007, 129, 12890.
[21] DATB catalyst having an azaborine ring, see; a) H. Noda, M. Furutachi,
Y. Asada, M. Shibasaki, N. Kumagai, Nat. Chem. 2017, 9, 571; b) H.
Noda, Y. Asada, M. Shibasaki, N. Kumagai, J. Am. Chem. Soc.
2019, 141, 1546.
[5]
a) Y. Ueda, W. Muramatsu, K. Mishiro, T. Furuta, T. Kawabata, J. Org.
Chem. 2009, 74, 8802; b) H. Takeuchi, K. Mishiro, Y. Ueda, Y. Fujimori,
T. Furuta, T. Kawabata, Angew. Chem., Int. Ed. 2015, 54, 6177; c) Y.
Ueda, T. Furuta, T. Kawabata, Angew. Chem., Int. Ed. 2015, 54, 11966;
d) M. Yanagi, A. Imayoshi, Y. Ueda, T. Furuta, T. Kawabata, Org. Lett.
2017, 19, 3099.
[22] a) J. García, A. Díaz-Rodríguez, S. Fernandez, Y. S. Sanghvi, M. Ferrero,
V. Gotor, J. Org. Chem. 2006, 71, 9765; b) J. Maity, G. Shakya, S. K.
Singh, V. T. Ravikumar, V. S. Parmar, A. K. Prasad, J. Org. Chem. 2008,
73, 5629; c) W. Muramatsu, Y. Takemoto, J. Org. Chem. 2013, 78, 2336;
d) C. L. Allen, S. J. Miller, Org. Lett. 2013, 15, 6178.
[6]
a) G. Xiao, G. A. Cintron-Rosado, D. A. Glazier, B. Xi, C. Liu, P. Liu, W.
Tang, J. Am. Chem. Soc. 2017, 139, 4346; b) Heterocycles 2019, 98,
304.
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Entry for the Table of Contents
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S. Kuwano,* Y. Hosaka, T. Arai*
Page No. – Page No.
Chiral Benzazaborole-Catalyzed
Regioselective Sulfonylation of
Unprotected Carbohydrate
Derivatives
Regioselective functionalization: Chiral benzazaborole-catalyzed regioselective
sulfonylations of unprotected carbohydrate derivatives have been developed. This
methodology enables direct regioselective functionalization of the secondary OH
groups in carbohydrates in the presence of the primary OH groups. Using the chiral
organoboron catalysis, kinetic resolution of the carbohydrate derivatives was also
achieved.
This article is protected by copyright. All rights reserved.