1,2-trans Glycosylation via Neighboring Group Participation of

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

1,2-trans Glycosylation via Neighboring Group Participation of 2‑O‑Alkoxymethyl Groups: Application to One-Pot Oligosaccharide Synthesis Milandip Karak,‡ Yohei Joh,‡ Masahiko Suenaga, Tohru Oishi, and Kohei Torikai* Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Downloaded via UNIV OF WINNIPEG on January 29, 2019 at 14:52:11 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: The use of 2-O-alkoxymethyl groups as effective stereodirecting substituents for the construction of 1,2-trans glycosidic linkages is reported. The observed stereoselectivity arises from the intramolecular formation of a five-membered cyclic architecture between the 2-Oalkoxymethyl substituent and the oxocarbenium ion, which provides the expected facial selectivity. Furthermore, the observed stereocontrol and the extremely high reactivity of 2O-alkoxymethyl-protected donors allowed development of a one-pot sequential glycosylation strategy that should become a powerful tool for the assembly of oligosaccharides.

I

The design of this stereoselective glycosylation using alkoxymethyl-protected donors is illustrated in Scheme 1. We

n carbohydrate chemistry, the stereoselective formation of glycosidic bonds has become one of the most important fields of research due to their essential functions in diverse biological processes.1 Despite the availability of numerous extraordinary strategies for the efficient synthesis of oligo- and polysaccharides, anomeric stereochemical control during the construction of glycosidic linkages remains a fundamental challenge.2 To date, one of the most robust and commonly used strategies for the stereoselective formation of glycosidic bonds is neighboring group participation (NGP).3 In general, an ester-type participating group, typically a 2-O-acyl functionality, affords a stable cyclic acyloxonium ion that blocks nucleophilic attacks from the covered face, thus facilitating the predominant formation of the 1,2-transglycoside.4 During this NGP, 2-O-acyl groups are considered to stabilize the cationic intermediate, but very mildly, since acyl protecting groups are electron-withdrawing by nature. Furthermore, the difficulties associated with the selective removal of the 2-O-acyl group, especially for targets possessing other acyl groups, occasionally increase the number of reaction steps. In contrast, ether-type substituents endow the donor with a higher reactivity, but the stereocontrol remains difficult even when solvent effects are fully taken into account. Thus, to facilitate the glycochemistry, we have decided to pursue new protecting groups that (i) can be orthogonally used with acyl groups, (ii) enhance the glycosylation reactivity by the more powerful stabilization of the cationic intermediate, and (iii) simultaneously control the stereoselectivity. Herein, we report a 1,2-trans-selective glycosylation using alkoxymethyl functionalities as protecting groups that undergo NGP, as well as its application to natural products and one-pot oligosaccharide syntheses. © XXXX American Chemical Society

Scheme 1. Proposed NGP Using 2-O-Alkoxymethyl Groupsa

a

LG = leaving group.

hypothesized that alkoxymethyl groups such as methoxymethyl (MOM), benzyloxymethyl (BOM), and our recently developed 2-naphthylmethoxymethyl (NAPOM)5 groups could engage with the C1 anomeric carbon atom via their acetalic oxygen atoms to form five-membered cyclic intermediates, which accept the attack of alcohols exclusively from the uncovered face. To verify this hypothesis, we initially examined the glycosylation of phenylthioglucosides 1 and 3 (Scheme 2). As expected, glycosylation of 2-O-Me thioglucoside 1 by treatment with ICl and In(OTf)3 afforded a 1:1 anomer mixture of 2 (51%).6 Under identical conditions, the glycosylation of 2-O-BOM substrate 3 afforded 4 in a stereoselective manner and higher yield; i.e., the β-anomer was obtained exclusively in 75% yield. Received: January 18, 2019

A

DOI: 10.1021/acs.orglett.9b00220 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Comparison of the Stereoselectivity of the Glycosylation of 2-O-Me- and 2-O-BOM-Substituted Thioglucosides 1 and 3

Table 1. Substrates Scope for the 2-O-Alkoxymethyl Group Protected Glycosylation (PG= protecting group)

With the prospect of an alkoxymethyl-driven 1,2-trans glycosylation in hand, the reaction conditions were optimized. After considerable experimentation, we found that the use of NIS/In(OTf)3 at −78 to −30 °C afforded the best yield with an excellent stereoselectivity (for details, see Table S3). Thus, we decided to examine the scope of donors and acceptors in these optimized conditions (Table 1). As shown in entries 1, 3, and 5, the 2,3-O-BOM-protected phenyl thioglucoside donor 3 can be efficiently and selectively coupled with a variety of acceptors such as 5, 9, and 12 to afford the corresponding 1,2trans glycosides 6, 10, and 13 in 79−81% yield. Likewise, the 2,3-O-MOM-protected donor 7 (entries 2, 4, and 6) afforded 1,2-trans glycosides 8, 11, and 14 in 76−85% yield. It is worth noting that the β-selectivity is also guaranteed for the reactions involving secondary alcohols (entries 5 and 6), i.e., acceptor 12 reacted with the 2-O-BOM (3) and 2-O-MOM (7) donors smoothly to form β-glycosides 13 (81%) and 14 (76%), respectively. As a different acceptor, the more challenging fully benzoylated galactose 15 was selected and coupled with donor 3 (entry 7). Even in this case, the glycosylation proceeded smoothly to give the desired disaccharides 16 in 54% yield with high 1,2-trans-selectivity (9:1). As we had obtained good results using 4,6-O-benzylideneprotected cyclic donors, we next focused on donors possessing acyclic protecting groups at the 4,6-O-positions. The glycosylation of fully armed donor7 2-O-BOM-3,4,6-O-benzyl glucopyranoside 17 with fully armed acceptor 9 resulted in the highly stereoselective (7:1) formation of 1,2-trans glycosides 18 (69%, entry 8). Moreover, the glycosylation of donor 17 with fully disarmed acceptor 19 was also very promising, i.e., 1,2-trans glycosides 20 was obtained in a yield and stereoselectivity that is similar to those obtained from entry 8 (66%, 8:1; entry 9). Even when rather disarmed donor 2-O-BOM3,4,6-O-benzoyl glucopyranoside 21 was used in combination with acceptor 9, the desired 1,2-trans glycosides 22 were isolated in good yield (75%; entry 10) with high β-selectivity (11:1). This established strategy was then successfully applied to the synthesis of glucopyranoside natural products (entry 11). The coupling of donor 23 with highly reactive alcohols, e.g., MeOH, EtOH, and 3-phenylpropanol (5), resulted in the exclusive formation of β-glucosides 24−26 in high yield (76− 83%). Subsequent orthogonal removal of all BOM and benzyl protecting groups from 24 and 25, in the presence of an acyl group, afforded β-D-glucopyranoside natural products S12 and S13 (for more details, see the SI). Next, we expanded the scope to 2,3,4,6-O-BOM galactopyranoside donor 27 (entry 12). Although a comparatively lower selectivity (β/α = 4:1) was observed, the reaction still afforded the disaccharides 28 in good yield (78%). As all these glycosylations lead predominantly to the formation of 1,2-trans glycosides, it should be B

DOI: 10.1021/acs.orglett.9b00220 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. continued

Table 2. Feasibility of the Glycosylation with Different Leaving Groups

a

All reactions were quenched when complete donor consumption was detected by TLC and HRMS. bFor the sake of clarity, only the major isomer (β) is shown together with the β/α ratio. cIsolated yields after column chromatography. dDetermined by 1H NMR and COSY analysis of the mixture of β/α isomers. eSolvent: hexane/CH2Cl2 = 3/ 2 (v/v).

expected that the NGP of alkoxymethyl groups effectively controls the stereoselectivity. Having obtained excellent results via the NGP of 2-O-BOM and -MOM groups, we turned our attention to a 2-ONAPOM-protected donor. The NAPOM group is an alkoxymethyl-type protecting group that can be removed selectively in the presence of p-methoxybenzyl or benzyl groups, which should be advantageous for the synthesis of carbohydrates. However, the reaction using 2-O-NAPOM donor 29 and the primary alcohol 9 furnished the desired product 30 only in 43% yield (entry 13), and a five-membered cyclic acetal 33 (Scheme 3) was obtained in 53% yield as a byproduct.

a

For the sake of clarity, only the major isomer (β) is shown together with the β/α ratio. PG = protecting group. bIsolated yield after column chromatography. cDetermined by 1H NMR and COSY analysis of the mixture of β/α isomers. dThe reaction was also performed with NIS (1.5 equiv) and TfOH (0.3 equiv) in CH2Cl2 at −20 °C for 3 h (79% yield; β/α = 9:1).

Scheme 3. Plausible Pathway for the Formation of the Acetal by Product 33

proceeded to afford the glycoside 37 under predominant formation of β-anomer (8:1) and excellent yield (86%; entry 3). Sato and co-workers have previously reported that the reaction of MOM ether 36 and donor 19, using NIS and TfOH in CH2Cl2 at −20 °C, afforded the α-isomer as the major product (α/β = 15:1, 90%).8 However, in our hands under the stipulated conditions, these glycosylation experiments always resulted in the formation of disaccharides 37 in a highly β-selective manner (β/α = 9:1, 79%). Since we carefully isolated 37β and determined its structure unambiguously by COSY and NOESY experiments, we confidently report that 2O-MOM-protected glucopyranoside donors afford 1,2-trans glycosides as the major products (for a detailed assignment and the determination of the absolute configuration, see the SI). Subsequently, we applied our newly developed method to a one-pot synthesis of oligosaccharides. Before launching this project, we noticed that, at low temperature (ca. −40 °C), 2-OBOM thioglucosides quite selectively react with acceptors in the presence of 2-O-benzoyl donors (for details, see the SI); in other words, our 2-O-alkoxymethylated donors seemed to be more reactive than the conventionally armed, and even the superarmed 2-O-acyl, donors reported by Mydock and Demchenko.7b,9 We envisaged that the sequential one-pot glycosylation7a,b,10 of thioglucosides might be successful if the 2-O-alkoxymethylated donors are initially coupled with a 1phenylthio-2-O-acyl acceptor at low temperature in order to form a disaccharide intermediate. The latter could then be treated with a second acceptor at higher temperature for the second glycosylation of the 2-O-acyl thioglucoside moiety to proceed. Thus, we started our synthesis with the coupling between acceptor 38 and donor 3 using the aforementioned optimized conditions (Scheme 4). After the first glycosylation had been completed at −40 °C, the reaction temperature was raised to 0 °C, where the disaccharide intermediate engaged in the second glycosylation and coupled with acceptors 5, 9, and

The cyclic acetal byproduct is likely formed via an attack of the nucleophile (R1OH) on the C7 methylene carbon atom (CH2−R′′; blue ball) of the NAPOM-protected intermediate (path b), instead of on the desired C1 carbon atom (red ball) at the anomeric position (path a). The formation of 33 indicated that the C1−O1 bond in the NAPOM intermediate (C1−O1NAPOM) is stronger than the C7−O1NAPOM bond and those in the MOM and BOM intermediates. Furthermore, in silico analyses suggested that the solvent effects may increase the yield of 30 (for details, see the SI). After considerable investigations, we found that conducting the reaction in hexane/CH2Cl2 (3/2, v/v, Table 1, entry 13) increased the yield of 30 to 63%, while that of byproduct 33 decreased to 27%. Moreover, a substrate with a benzyl group instead of a NAPOM group at the C3 position (31) afforded the desired glycoside 32 in 73% yield (entry 14). As this yield was comparable to those of MOM and BOM substrates, it was concluded that 2-O-NAPOM-protected donors can be readily attached to the substrates of this 1,2-trans-selective glycosylation, thanks to the addition of hexane. For the broader application, we next investigated the use of 2-O-alkoxymethyl-protected donors having different leaving groups (Table 2). The reaction between the glycosyl fluoride 34 and the acceptor 9 proceeded smoothly to afford the desired glycoside 10 with absolute β-selectivity and good yield (64%; entry 1). Similarly, the glycosylation of trichloroacetimidate 35 also afforded disaccharide 10 under exclusive formation of the β-anomer (68%; entry 2). Moreover, the glycosylation of ethylthio donor 36 with acceptor 19 C

DOI: 10.1021/acs.orglett.9b00220 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Notes

Scheme 4. Sequential One-Pot Synthesis of 1,2-Trans Oligosaccharides Using the Double-Glycosylation Strategy

The authors declare the following competing financial interest(s): A patent regarding this work is pending (Kyushu University, PCT Application No. PCT/JP2017/46800).

■

ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI (Grant Nos. JP15K21210, JP18K05462) and grants from the Heiwa Nakajima Foundation (Japan) and the Nakamura Jishiro Ikueikai Foundation (Japan) to K.T. M.K. thanks Heiwa Nakajima Foundation (Japan) and Takeda Science Foundation (Japan) for research fellowships. We are grateful to Mr. Takaaki Torikai, Ms. Rumiko Torikai, Mr. Motoaki Yamaoka, Ms. Michie Yamaoka, Ms. Kimiko Komiya, and Dr. Kazuhiro Matsunaga for their generous personal financial donations.

■

12. As a result, target compounds 39−41 were readily obtained in 64−54% yield as single isolable isomers. Despite the use of only a single combination of the activation method (NIS/ In(OTf)3) and a leaving group (−SPh), this novel strategy perfectly controls both the stereoselectivity of the glycosidic linkages and the sequence of saccharides via the temperature. Although further investigation is needed for the full rationalization, the extremely higher reactivity of our 2-Oalkoxymethylated donors may relate to the direct (from the C7H2 to O1 to C1 atom of Scheme 3) and/or indirect (through the C8H2 to O2 to C2 to C1 atom) electrondonating character of the alkyl groups in the alkoxymethyl groups. In summary, we have developed a practical and general method for the formation of 1,2-trans-glycosidic linkages using the neighboring group participation of 2-O-alkoxymethyl protecting groups. Easy removal of the 2-O-alkoxymethyl groups in the presence of an intact ester moiety further demonstrated the utility of these orthogonal protecting groups, evident from the syntheses of two natural β-D-glucopyranosides. Finally, the extremely high reactivity of 2-O-alkoxymethylated donors enabled us to develop a novel one-pot 1,2trans-selective glycosylation method using building blocks equipped with a single leaving group. Further studies on the properties of alkoxymethylated saccharides and their application scope are currently in progress in our laboratory.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00220. Experimental procedures, spectral data, as well as 1H and 13 C NMR spectra of all new compounds (PDF)

■

REFERENCES

(1) For the biological relevance of glycosylations, see: (a) Krasnova, L.; Wong, C.-H. Annu. Rev. Biochem. 2016, 85, 599−630. (b) Ouerfelli, O.; Warren, J. D.; Wilson, R. M.; Danishefsky, S. J. Expert Rev. Vaccines 2005, 4, 677−685. (c) Galonić, D. P.; Gin, D. Y. Nature 2007, 446, 1000−1007. (2) For recent reviews on O-glycosylations, see: (a) Williams, R.; Galan, M. C. Eur. J. Org. Chem. 2017, 2017, 6247−6264. (b) Sangwan, R.; Mandal, P. K. RSC Adv. 2017, 7, 26256−26321. (c) van der Vorm, S.; Hansen, T.; Overkleeft, H. S.; van der Marel, G. A.; Codée, J. D. C. Chem. Sci. 2017, 8, 1867−1875. (d) Das, R.; Mukhopadhyay, B. ChemistryOpen 2016, 5, 401−433. (e) Yang, Y.; Zhang, X.; Yu, B. Nat. Prod. Rep. 2015, 32, 1331−1355. (f) Seeberger, P. H. Acc. Chem. Res. 2015, 48, 1450−1463. (g) Mydock, L. K.; Demchenko, A. V. Org. Biomol. Chem. 2010, 8, 497−510. (h) Crich, D. Acc. Chem. Res. 2010, 43, 1144−1153. (i) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900−1934. (3) For selected examples on the stereoselective glycosylation via neighboring group participation, see: (a) Speciale, G.; Farren-Dai, M.; Shidmoossavee, F. S.; Williams, S. J.; Bennet, A. J. J. Am. Chem. Soc. 2016, 138, 14012−14019. (b) Elferink, H.; Mensink, R. A.; White, P. B.; Boltje, T. J. Angew. Chem., Int. Ed. 2016, 55, 11217−11220. (c) Buda, S.; Nawój, M.; Gołębiowska, P.; Dyduch, K.; Michalak, A.; Mlynarski, J. J. Org. Chem. 2015, 80, 770−780. (d) Singh, G. P.; Watson, A. J. A.; Fairbanks, A. J. Org. Lett. 2015, 17, 4376−4379. (e) Cox, D. J.; Singh, G. P.; Watson, A. J. A.; Fairbanks, A. J. Eur. J. Org. Chem. 2014, 2014, 4624−4642. (f) Buda, S.; Gołębiowska, P.; Mlynarski, J. Eur. J. Org. Chem. 2013, 2013, 3988−3991. (g) Fascione, M. A.; Kilner, C. A.; Leach, A. G.; Turnbull, W. B. Chem. - Eur. J. 2012, 18, 321−333. (h) Chao, C.-S.; Lin, C.-Y.; Mulani, S.; Hung, W.C.; Mong, K.-k. T. Chem. - Eur. J. 2011, 17, 12193−12202. (i) Crich, D.; Cai, F. Org. Lett. 2007, 9, 1613−1615. (j) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem., Int. Ed. 2005, 44, 7123−7126. (k) Bérces, A.; Enright, G.; Nukada, T.; Whitfield, D. M. J. Am. Chem. Soc. 2001, 123, 5460−5464. (l) Jiao, H.; Hindsgaul, O. Angew. Chem., Int. Ed. 1999, 38, 346−348. (m) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield, D. M. J. Am. Chem. Soc. 1998, 120, 13291−13295. (4) Jensen, K. J. J. Chem. Soc., Perkin Trans. 2002, 1, 2219−2233. (5) (a) Sato, T.; Joh, Y.; Oishi, T.; Torikai, K. Tetrahedron Lett. 2017, 58, 2178−2181. (b) Sato, T.; Oishi, T.; Torikai, K. Org. Lett. 2015, 17, 3110−3113. (6) Salmasan, R. M.; Manabe, Y.; Kitawaki, Y.; Chang, T.-C.; Fukase, K. Chem. Lett. 2014, 43, 956−958. (7) For selected examples of the armed/disarmed concepts, see: (a) Bandara, M. D.; Yasomanee, J. P.; Rath, N. P.; Pedersen, C. M.; Bols, M.; Demchenko, A. V. Org. Biomol. Chem. 2017, 15, 559−563. (b) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2107− 2110. (c) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115−4118. (d) Pedersen, C. M.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc. 2007, 129, 9222−9235. (e) Mootoo, D. R.; Konradsson, P.;

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Milandip Karak: 0000-0001-9998-5994 Tohru Oishi: 0000-0002-3057-9354 Kohei Torikai: 0000-0002-9928-4300 Author Contributions ‡

M.K. and Y.J. contributed equally. D

DOI: 10.1021/acs.orglett.9b00220 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Udodong, U.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 5583− 5584. (8) Sato, K.; Akai, S.; Sakai, K.; Kojima, M.; Murakami, H.; Idoji, T. Tetrahedron Lett. 2005, 46, 7411−7414. (9) For the reactivity comparison between 2-O-BOM and 2-O-Bz donors at low temperature, see the SI. (10) For recent reviews on one-pot glycosylations, see: (a) Kulkarni, S. S.; Wang, C.-C.; Sabbavarapu, N. M.; Podilapu, A. R.; Liao, P.-H.; Hung, S.-C. Chem. Rev. 2018, 118, 8025−8104. (b) Panza, M.; Pistorio, S. G.; Stine, K. J.; Demchenko, A. V. Chem. Rev. 2018, 118, 8105−8150. (c) Wang, Y.; Ye, X.-S.; Zhang, L.-H. Org. Biomol. Chem. 2007, 5, 2189. (d) Codée, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft, H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005, 34, 769−782.

E

DOI: 10.1021/acs.orglett.9b00220 Org. Lett. XXXX, XXX, XXX−XXX