Iron(iii) chloride-catalyzed activation of glycosyl chlorides

Article abstract of DOI:10.1039/c8ob02413h

Glycosyl chlorides have historically been activated using harsh conditions and/or toxic stoichiometric promoters. More recently, the Ye and the Jacobsen groups showed that glycosyl chlorides can be activated under organocatalytic conditions. However, thos

Full text of DOI:10.1039/c8ob02413h

Organic &
Biomolecular Chemistry
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Iron(III) chloride-catalyzed activation of glycosyl
chlorides†
Cite this: Org. Biomol. Chem., 2018,
16, 9133
Scott A. Geringer and Alexei V. Demchenko
*
Received 27th September 2018,
Accepted 6th November 2018
DOI: 10.1039/c8ob02413h
rsc.li/obc
Glycosyl chlorides have historically been activated using harsh for glycosylation,28,29 we observed that glycosidation of chlo-
conditions and/or toxic stoichiometric promoters. More recently, rides can be achieved in the presence of catalytic amounts of
the Ye and the Jacobsen groups showed that glycosyl chlorides iron(III) chloride (FeCl3 aka ferric chloride). This discovery is at
can be activated under organocatalytic conditions. However, those the basis of this communication.
reactions are slow, require specialized catalysts and high tempera-
FeCl3 is naturally abundant, inexpensive and relatively
tures, but still provide only moderate yields. Presented herein is a benign.30 Ferric chloride has been employed in the introduc-
simple method for the activation of glycosyl chlorides using abun- tion of protecting groups in carbohydrates.31,32 The appli-
dant and inexpensive ferric chloride in catalytic amounts. Our pre- cation of FeCl3 in O-glycosylation has also emerged, most pro-
liminary results indicate that both benzylated and benzoylated gly- minently for the activation of glycosyl donors bearing the
cosyl chlorides can be activated with 20 mol% of FeCl3.
anomeric acetate.33–42 Other applications for the activation of
aryl glycoside,43 pivaloate,44 bromide,45 imidate,46 or hemiace-
tal donors (as a co-catalyst)47 have also been explored. Using
this prior knowledge, we theorized that glycosyl chlorides may
also offer a promising new substrate for the catalytic activation
with FeCl3. To test this hypothesis, we chose known per-benzy-
lated glucosyl chloride donor 123 to couple with the standard
glycosyl acceptor 2.48 The glycosylation was set-up in the pres-
ence of molecular sieves (4 Å) in dichloromethane. For this
preliminary study we chose excess of donor 1 (2.0 equiv.) simi-
larly to that used by Ye et al.26 and Jacobsen et al.27 After a
brief preliminary experimentation, we established that
20 mol% of FeCl3 provides the most favorable balance between
yields and the reaction time. Thus, the coupling of donor 1
with acceptor 248 provided disaccharide 3 in 67% yield in only
2 h (Table 1, entry 1). Also, glycosidations of chloride 1 with
secondary acceptors 4, 6, and 848 were conducted under essen-
tially the same reaction conditions. These reactions were
slower (3–16 h), but the respective disaccharides 5, 7 and 9
have successfully been obtained in 47–80% yields (entries
2–4). This preliminary set of experiments has demonstrated
both the advantages and limitations of this approach. The
main advantage of this approach is the availability and low
cost of the catalytic activator. Also the reaction times are
notably shorter than those reported for the organocatalytic
reactions and even for the traditional heavy metal-based stoi-
chiometric activators. Somewhat average yields for the for-
mation of all products, perhaps except 9, still on a par with tra-
ditional approaches and the results reported by Ye et al.26 and
Introduced by Michael in 18791 and subsequently studied by
many, glycosyl chlorides have been very influential building
blocks that helped to establish basic principles of carbo-
hydrate chemistry.2,3 Once prominent glycosyl donors, in
recent years glycosyl chlorides have been outshadowed by
other, more powerful glycosyl donors,4–11 and for a reason.
Traditionally, the activation of glycosyl chlorides demanded
stoichiometric and often toxic reagents, such as silver(I)2,12,13
or mercury(II) salts.14 This, along with a fairly high propensity
to hydrolysis, hampered the application of glycosyl chlorides in
recent years. Glycosyl chlorides, however, have many positive
traits. They can be obtained using a variety of substrates and
methods,15–25 many chlorides are stable, and recent studies by
Ye et al.26 and Jacobsen et al.27 have demonstrated that these
compounds can be activated without toxic promoters under
organocatalytic conditions using urea- or thiourea-based cata-
lysts. Good stereoselectivity was obtained using various addi-
tives26 or with complex chiral catalytic constructs,27 but these
reactions are slow (24–48 h), require high temperatures and
provide practical yields only with highly reactive (alkylated)
chlorides. In an active pursuit of catalytic activation methods
Department of Chemistry and Biochemistry, University of Missouri – St Louis, One
University Boulevard, St Louis, Missouri 63121, USA.
E-mail: demchenkoa@umsl.edu
†Electronic supplementary information (ESI) available: Experimental details and
characterization data for all new compounds. See DOI: 10.1039/c8ob02413h
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Table 1 Iron(III) chloride-catalyzed glycosylations
Entry
1
Donor
Acceptor
Time
2 h
Product
Yield
67%
α/β ratio
1.1/1
2
1
16 h
47%
1.2/1
3
4
1
1
3 h
60%
80%
1.5/1
1.0/1
16 h
5
6
2
4
0.5 h
0.5 h
88%
57%
1/1.4
1.6/1
10
7
8
10
10
6
8
0.5 h
16 h
80%
90%
1.3/1
1/2.7
9
2
4
6
8
2 h
80%
66%
56%
95%
4.5/1
10
11
12
15
15
15
16 h
16 h
16 h
α-Only
α-Only
2.6/1
13
14
2
4
16 h
16 h
98%
80%
β-Only
β-Only
20
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Table 1 (Contd.)
Entry
15
Donor
Acceptor
Time
16 h
Product
Yield
52%
α/β ratio
β-Only
20
6
16
20
8
16 h
73%
β-Only
Jacobsen et al.,27 are mainly attributed to a substantial for-
mation of a side product of 1,6-anhydro-2,3,4-tri-O-benzyl-β-D-
glucopyranose. While somewhat unexpected in this particular
setting, the formation of 1,6-anhydro sugars in the presence of
FeCl3 has been reported.49 As evident from Table 1, all
four disaccharides have been produced with poor selectivity
(α/β = 1–1.5/1); our method, however, does not employ stereo-
directing functionalities, additives,26 or complex chiral
catalytic constructs27 at this stage.
Following the general success of glucosyl chloride donor 1
we investigated galactosyl chloride 1023 that provided even
faster reaction times (entries 5–8), probably due to the gener-
ally higher reactivity of the galactosyl donors versus similarly
equipped glucose counterparts, and a noticeable increase in
yields. The latter could be attributed to the entire absence of
Scheme 1 Proposed mechanism of the activation of glycosyl chlorides
with ferric chloride.
the 1,6-anhydro side-product that hampered the yields with when donor 20 was glycosidated with acceptor 2 a slower reac-
donor 1. tion time 16 h (entry 13, Table 1) was recorded in comparison
Thus, primary acceptor 2 led to the formation of disacchar- to that with the benzylated glucosyl donor 1 (2 h, see entry 1).
ide 11 in a respectable yield of 88% (entry 5). For comparison, Nevertheless, the reaction still proceeded to completion and
glucosyl chloride donor 1 produced the 1→6 linked disacchar- provided disaccharide 21 in an impeccable yield of 98% and
ide 3 in 67% (see entry 1). A similar enhancement in yields (up no indication for the side product formation. The glycosida-
to 90%) and decrease in the reaction time have been observed tion of donor 20 also proceeded well with the secondary accep-
for the secondary acceptors to produce the respective disac- tors 4, 6, and 8 providing the corresponding disaccharides
charides 12–14 (entries 6–8). Expectedly, mannosyl donor 1513 22–24 in respectable yields of 52–80% and complete
showed lower reactivity than its glucosyl and galactosyl β-selectivity due to the neighboring group participation. It is
counterparts. This was reflected by the increase in reaction noteworthy that neither Ye’s nor Jacobsen’s conditions were
times; nevertheless, we obtained respectable yields (up to able to activate these deactivated benzoylated chlorides.
95%) for the synthesis of disaccharides 16–19 (entries 9–12).
In conclusion, we have shown that a variety of glycosyl
No formation of the 1,6-anhydro side product was detected in chlorides can be activated with catalytic iron(III) chloride. This
this case either. We believe this reaction follows a traditional method allows for a cheap and relatively benign activation of
Lewis acid-catalyzed mechanistic pathway depicted in glycosyl chlorides compared to previous methods using
Scheme 1. Presumably, this reaction follows the traditional harsher and less environmentally friendly conditions. While
unimolecular SN1 mechanism according to which the catalyst- the yield of glycosylation reactions are still far from being
mediated leaving group departure results in the formation of ideal, a majority of results obtained herein are on a par with
the oxacarbenium ion. The latter exists in a flattened half-chair recently developed organocatalytic reactions reported by Ye
conformation that explains poor stereoselectivity observed.
et al.26 and Jacobsen et al.27 The stereoselectivity obtained in
Having demonstrated that FeCl3-catalyzed reactions work reactions with benzylated chlorides is unimpressive, which is
reasonably well with per-benzylated sugars, we wanted to not a surprise because we do not currently employ any
investigate whether electronically deactivated benzoylated directing auxiliaries, catalysts, or additives as in other similar
chloride 20 could be activated using our method. As expected, studies. However, our study employs a very inexpensive activa-
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tor, and this method can serve as a basis for refining stereo- 13 K. Matsuoka, M. Terabatake, A. Umino, Y. Esumi,
selectivity in the future. One of the possible directions for this
K. Hatano, D. Terunuma and H. Kuzuhara,
to explore the known effect of stoichiometric FeCl3 that is
Biomacromolecules, 2006, 7, 2274.
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15 V. D. Grob, T. G. Squires and J. R. Vercellotti, Carbohydr.
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Res., 1969, 10, 595.
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reported in due course. Our preliminary attempt to broaden 19 Z. Zhang and G. Magnusson, Carbohydr. Res., 1996, 925,
the scope of this reaction by investigating SnCl4, BF3–OEt2, 41.
and Fe(OTf)3 indicated similar reaction yields and reaction 20 S. Sugiyama and J. M. Diakur, Org. Lett., 2000, 2, 2713.
4903.
times to those reported herein.
21 F. M. Ibatulin and S. I. Selivanov, Tetrahedron Lett., 2002,
43, 9577.
22 L. Encinas and J. L. Chiara, J. Comb. Chem., 2008, 10, 361.
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Conflicts of interest
There are no conflicts to declare.
25 M. B. Tatina, D. T. Khong and Z. M. A. Judeh, Eur. J. Org.
Chem., 2018, 2208.
26 L. Sun, X. Wu, D. C. Xiong and X. S. Ye, Angew. Chem., Int.
Ed., 2016, 55, 8041.
Acknowledgements
This work was supported by the National Institute of General
Medical Sciences (GM120673) and the National Science 27 Y. Park, K. C. Harper, N. Kuhl, E. E. Kwan, R. Y. Liu and
Foundation (CHE-1800350).
E. N. Jacobsen, Science, 2017, 355, 162.
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