Superarming of glycosyl donors by combined neighboring and conformational effects

Article abstract of DOI:10.1021/ol402371b

A novel glycosyl donor that combines the concepts of both conformational and electronic superarming has been synthesized. The reactivity and selectivity of the donor have been tested in competition experiments.

Full text of DOI:10.1021/ol402371b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Superarming of Glycosyl Donors
by Combined Neighboring and
Conformational Effects
000–000
†
Mads Heuckendorff, Hemali D. Premathilake, Papapida Pornsuriyasak,
‡
‡
†
,†
,†
Anders Ø. Madsen, Christian M. Pedersen,* Mikael Bols,* and
,‡
Alexei V. Demchenko*
Department of Chemistry, University of Copenhagen, 2100 Copenhagen Ø, Denmark,
and Department of Chemistry and Biochemistry, University of Missouri;St. Louis,
One University Boulevard, St. Louis, Missouri 63121, United States
cmp@chem.ku.dk; bols@chem.ku.dk; demchenkoa@umsl.edu
Received August 19, 2013
ABSTRACT
A novel glycosyl donor that combines the concepts of both conformational and electronic superarming has been synthesized. The reactivity and
selectivity of the donor have been tested in competition experiments.
6
polymer-supported and automated synthesis,
7,8
Traditionally oligosaccharide synthesis relies on protec-
tive group manipulations and the use of orthogonal gly-
cosylation methods, such as different types of glycosyl
donors. Due to the increased interest in biologically
relevant oligosaccharides the development of new meth-
odologies have been impressive during the past couple
of decades and paved the way for more efficient
ionic
surface-
9
,10
11,12
liquid supported,
fluorous tag assisted,
1
3
14
tethered (STICS), and HPLC-assisted syntheses.
The control of the glycosyl donor’s reactivity belongs to
the tools available for improving oligosaccharide synthe-
sis. The armedÀdisarmed concept was introduced by the
1
5
group of Fraser-Reid and utilizes selective activation of
one donor over another with the same anomeric leaving
group. The reactivity of the donor relies on the protective
groups used; more electron-withdrawing groups reduce
(disarm) the donor reactivity and vice versa. Glycosyl
donor A1 is armed (benzylated) whereas A2 is disarmed
1,2
synthesis. These developments include, but are not limited
4,5
3
to, one-pot protection and glycosylation strategies,
†
University of Copenhagen.
University of Missouri;St. Louis.
‡
(
1) Smoot, J. T.; Demchenko, A. V. Adv. Carbohydr. Chem. Biochem.
009, 62, 161–250.
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Lee, C. C.; Chang, K. L.; Hung, S. C. Nature 2007, 446, 896–899.
4) (a) Wang, Y.; Ye, X. S.; Zhang, L. H. Org. Biomol. Chem. 2007, 5,
(more electron-withdrawing protective groups) and acts as
the glycosyl acceptor (Scheme 1A).
2
15,16
(
1
(
(10) Tran, A. T.; Burden, R.; Racys, D. T.; Galan, M. C. Chem.
Commun. 2011, 47, 4526–4528.
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(
2
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189. (b) Francais, A.; Urban, D.; Beau, J.-M. Angew. Chem., Int. Ed.
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2009, 1834–1836.
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2
1
0.1021/ol402371b r XXXX American Chemical Society

With the insight into manipulation of reactivity by protec-
tive groups, new methodologies for oligosaccharides have
been developed; one example is “one-pot” oligosaccharide
strategies, introduced by the groups of Fraser-Reid, Ley,
Scheme 1. Chemoselective Strategies for Oligosaccharide
Synthesis: (A) ArmedÀdisarmed; (B) Conformational
Superarming; (C) Electronic Superarming
17À23
and Wong.
and collaborators
or a disarmed donor varied considerably depending on the
For instance, a very detailed work by Wong
22,23
showed that the reactivity of an armed
24
stereochemistry and whether deoxy groups were present.
The stereochemical effect of hydroxyl groups on the
development of a positive charge in heterocycles has
been further demonstrated using piperidines as the model
compounds. By comparing the pK values for the con-
a
jugate acid it was found that equatorial substituents are
significantly more deactivating (EWD) than their axial
2
5À28
counterparts.
The same effects were found for glyco-
syl donors and used by Bols and co-workers to conforma-
tionally arm glycosyl donors by changing the equatorial
4
rich C conformation to an axial rich conformation.
29À33
1
The conformational changes were induced by creating
steric congestion at the equatorial C-2, C-3, and C-4
3
4
positions of D-glucosides, resulting in a skew-boat con-
formation (donor B1, Scheme 1B). The new type of donors
showed a 20-fold increase in reactivity as compared to its
3
2
per-O-benzylated counterpart. The superarmed glycosyl
donor B1 could be effectively coupled with “armed”
acceptor B2 promoted by NIS/TfOH at À78 °C to
afford the corresponding disaccharide in 85% yield
reported that a glycosyl donor containing a 2-O-benzoyl
group, instead of a 2-O-benzyl, increased the reactivity
compared with a fully benzylated analogue and hence
be considered “superarmed”. The arming was found to
3
0
41
(
Scheme 1B).
Derived from the discovery of the O2/O5 cooperative
3
effect in glycosylation Demchenko and co-workers
be due to anchimeric assistance, which overrules the
3
6,37
EWD properties of the benzoyl group.
Thus, glycosy-
5
lation with 2-O-benzoyl-3,4,6-tri-O-benzyl protected
S-benzoxazolyl (SBox) glucoside C1 with per-benzylated
“
armed” glycosyl acceptor C2 in the presence of dimethyl-
(
16) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org.
Chem. 1990, 55, 6068–6070.
17) Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.;
Bowen, J. P. J. Am. Chem. Soc. 1991, 113, 1434–1435.
(methylthio)sulfonium triflate (DMTST) provided a
(
disaccharide in 70% yield (Scheme 1C). This concept
for superarming was found to be universally applicable
to common leaving groups including O-pentenyl, S-ethyl,
(
(
18) Wilson, B. G.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 317–320.
19) Douglas, N. L.; Ley, S. V.; L u€ cking, U.; Warriner, S. L. J. Chem.
3
8
Soc., Perkin Trans. 1 1998, 51–66.
20) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734–753.
S-phenyl, S-tolyl, and S-thiazolinyl.
(
With two different approaches to superarm glycosyl
donors, we wondered which superarmed donor is more
reactive. To investigate this, a direct competition experi-
ment was performed wherein the conformationally super-
armed S-phenyl glycosyl donor 1a was set to compete with
electronically superarmed glycosyl donor 1b for cyclohex-
anol (Scheme 2). The most reliable comparison was
achieved in the NIS/TfOH-promoted competition experi-
ment starting at À78 °C and slowly warming up to 0 °C,
essentially the same reaction conditions as reported by
Bols and co-workers. Formation of disaccharide 2a
derived from the conformationally superarmed glycosyl
donor 1a was predominant (2a isolated in 91% yield),
whereas 1b was recovered in 94% yield. This result clearly
indicated that donor 1a has superior reactivity in compar-
ison to donor 1b under these reaction conditions.
(
(
(
21) Ye, X. S.; Wong, C. H. J. Org. Chem. 2000, 65, 2410–2431.
22) Koeller, K. M.; Wong, C. H. Chem. Rev. 2000, 100, 4465–4494.
23) Hsu, Y.; Lu, X.-A.; Zulueta, M. M. L.; Tsai, C.-M.; Lin, K.-I.;
Hung, S.-C.; Wong, C.-H. J. Am. Chem. Soc. 2012, 134, 4549–4552.
24) Premathilake, H. D.; Demchenko, A. V. In Topics in Current
(
Chemistry: Reactivity Tuning in Oligosaccharide Assembly; Fraser-Reid,
B., Lopez, J. C., Eds.; Springer-Verlag: Berlin-Heidelberg, 2011; Vol. 301,
pp 189À221.
(
25) Jensen, H. H.; Lyngbye, L.; Bols, M. Angew. Chem., Int. Ed.
2
2
2
001, 40, 3447–3449.
26) Jensen, H. H.; Lyngbye, L.; Jensen, A.; Bols, M. Chem.;Eur. J.
002, 8, 1218–26.
27) Heuckendorff, M.; Pedersen, C. M.; Bols, M. Chem.;Eur. J.
010, 16, 13982–13994.
(
3
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(
(
28) Jensen, H. H.; Bols, M. Acc. Chem. Res. 2006, 39, 259–265.
oꢀ pez, O.; Murphy, P.; Fern ꢀa ndez Bola n~ os,
(29) McDonnell, C.; L
J. G.; Hazell, R.; Bols, M. J. Am. Chem. Soc. 2004, 126, 12374–85.
30) Pedersen, C. M.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc.
007, 129, 9222–35.
31) Jensen, H. H.; Pedersen, C. M.; Bols, M. Chem.;Eur. J. 2007,
3, 7576–82.
32) Pedersen, C. M.; Marinescu, L. G.; Bols, M. Chem. Commun.
008, 2465–7.
33) Heuckendorff, M.; Pedersen, C. M.; Bols, M. J. Org. Chem.
012, 77, 5559–68.
34) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron
Lett. 1996, 37, 663–666.
35) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215–3218.
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2
1
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(
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(
2106.
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(
(
B
Org. Lett., Vol. XX, No. XX, XXXX

Since 1c has incorporated a 2-O-benzoyl substituent, the
stereoselectivity was expected to be excellent due to neigh-
boring group participation. The stereoselectivity obtained
with donor 1a having a nonparticipating TBS-group at
O-2 is normally excellent with poor acceptors, such as
other carbohydrates, but can be reduced when using
Scheme 2. Competition Experiment between Conformationally
Superarmed Donor 1a and Electronically Superarmed Donor 1b
3
0
simple alcohols as acceptors. The results of this study
are summarized in Table 1. All glycosylations were giving
good-to-excellent yields and for entries 2 and 3 complete
β-selectivity was observed, whereas donor 1a (entry 1)
was less selective. Glycosylations of benzylated “armed”
glycosyl acceptors equipped with the S-phenyl anomeric
group with donor 1c gave moderate-to-good yields
and complete stereoselectivity (entries 5 and 6), with an
acceptor site. The lower yield observed with the primary
acceptor (entry 5) is mainly due to migration of the TBS
protective group from donor 1c to the acceptor. The new
donor can therefore be considered superarmed, as it is
more reactive than a conventionally armed donor.
With the glycosylation properties of donor 1c estab-
lished, its reactivity was studied by competition experi-
ments with donors 1a and 1b using essentially the
same reaction conditions as those described in Scheme 2.
From the first experiment between the hybrid donor 1c
and the electronically superarmed donor 1b, it was obvious
that compound 1c was significantly more reactive; i.e.,
complete conversion of 1c to glycoside 2c and almost
full recovery of unreacted 1b was observed (Scheme 3).
Competition between donor 1c and the conformationally
superarmed donor 1a revealed that donor 1a was much
more reactive. The high conversion of donor 1a to glyco-
side 2a was observed, whereas most of donor 1c was
recovered.
This result lead to the question of whether further
enhancement in reactivity could be achieved by using
a combination of both conformational and electronic
effects. To address this question and with the goal of
incorporating all key structural features from both ap-
proaches into a single hybrid donor, 1c, equipped with
both the 2-O-benzoyl substituent and remote O-TBS sub-
stituents at 3,4-positions in combination with 6-O-benzyl
(
its synthesis), was obtained. The conformation of donor
glycosyl donor 1c; see the Supporting Information (SI) for
1
c was investigated by H NMR, where the coupling
1
constants suggested a skew-boat conformation similar to
3
0
the one found for conformationally armed donors.
The conformation was further proved by obtaining
the first reported crystal structure of the superarmed donor
1
3
a, which has similar (to 1c) J coupling constants in its
1
H NMR (Figure 1). The crystal structure confirms the
suggested skew-boat conformation and confirms that 1c is
3
9,40
in a similar conformation.
a
Table 1. Comparative Study of Glycosyl Donors 1aÀc
Figure 1. Crystal structure of 1a.
Having established that 1c indeed has changed the con-
formation to an axial-rich skew-boat, the properties of the
hybrid donor 1c could be investigated in more detail. For
this purpose, glycosyl donors 1aÀc were compared under
standard reaction conditions (NIS/TfOH, À78 to 0 °C).
(
(
39) Walford, C.; Heath, S. L. Chem. Commun. 1997, 1855–1856.
40) Yamada, H.; Nakatani, M.; Ikeda, T.; Marumoto, Y. Tetrahe-
a c
Hexanol = cyclohexanol.
dron Lett. 1999, 40, 5573–5576.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Competition Experiment between the Hybrid Donor
1
Scheme 4. Competition Experiment between Donor 1c and
Donor 1e as well as Donor 1f
c and Previously Developed Donors 1a and 1b
Puzzled by the lower reactivity of the hybrid donor 1c
the question arose whether the trans-vicinal 2-O-benzoyl
group in 1c is able to increase the reactivity by the
anchimeric effect or if it is overall disarming due to its
electron-withdrawing nature. To investigate this, the
R-counterpart 1e of β-donor 1c was synthesized (see the SI
for its synthesis). Due to the 1,2-cis orientation in donor 1e,
the 2-O-benzoyl group is unable to provide the anchimeric
assistance. Therefore, if this effect prevails R-linked donor 1e
would be less reactive than its β-linked counterpart 1c.
A competition experiment between donors 1c and 1e
carried out under the standard conditions clearly showed
that β-linked donor 1c (80% conversion) was more reac-
tive than its R-linked conterpart 1e (10% conversion). The
higher reactivity of 1c compared to 1e suggests that the
arguably due to the altered axial-rich conformation, which
results in a smaller electron-withdrawing effect from sub-
stituents on the sugar ring. The altered, and not so flexible,
conformation could, however, also diminish the effect of
the anchimeric assistance since the 2-O-benzoyl is not
perfectly antiperiplanar to the anomeric leaving group in
the skew-boat conformation.
In conclusion, we have successfully synthesized a new
type of donor 1c that combines conformational arming
and anchimeric assistance effects. Glycosylations with this
donor are high yielding and stereoselective. From this
work it is clear that conformational arming is the more
powerful tool when it comes to increasing the reactivity of
the glycosyl donor. Anchimeric assistance does not in-
crease the reactivity further in this particular case, but does
lead to stereocontrol. Thus the combined donor obtained
is highly reactive (superarmed), useful in one-pot glycosy-
lations, and stereoselective. Alternative promoter systems
for thioglycosides were investigated, but without providing
additional insight; the NIS/TfOH promotor system re-
mains the most successful in terms of yields and simplicity.
2
-O-benzoyl group is providing an arming effect by means
4
1
of the anchimeric assistance. On the other hand, the
reactivity difference between 1c and 1e could also be partly
due tothe anomeric effect lowering the ground state energy
4
2,43
of the R-anomer.
In the absence of the anchimeric
assistance, axial thioglycosides have been found to be
more reactive than their equatorial counterparts. This
has been explained with the importance of an antiperipla-
nar arrangement between the leaving group and one of the
4
4,43
ring-oxygen lone pairs.
To gain a better understanding of the effects caused by
the 2-O-protective group, 2-O-benzyl superarmed donor
1
3
f was synthesized. A competition experiment between
0
donors 1c and 1f was performed (Scheme 4), and in this
case donor 1f (80% conversion) was found to be more
reactive than donor 1c (10% conversion). This result
suggests that the 2-O-benzoyl in 1c is having an overall
disarming effect in comparison to that of the 2-O-benzyl
group in donor 1f.
Since donor 1c is more reactive than 1e, but less reactive
than 1f, the arming anchimeric assistance of the 2-O-
benzoyl group is overruled by the electron-withdrawing
properties. The higher reactivity of 1c compared to 1b is
Acknowledgment. A.V.D. thanks NIGMS (Award
GM077170) for supporting this work. H.D.P. is grateful
to UMSL Graduate School for proving her with the
Dissertation Fellowship. Dr. Winter and Mr. Kramer
(UM;St. Louis) are thanked for HRMS determinations.
M.H. thanks FTP for supporting this work.
(
41) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115–4118.
(
42) Heuckendorff, M.; Pedersen, C. M.; Bols, M. Org. Lett. 2011,
Supporting Information Available. Experimental de-
tails for preparation of new compounds, NMR spectra,
and X-ray crystal data. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
3, 5956–5959.
(
cated when having conformational restricted glycosyl donors. See:
Heuckendorff, M.; Pedersen, C. M.; Bols, M. J. Org. Chem. 2013, 78,
43) The reactivity difference between anomers can be more compli-
7
234–7248 for a discussion of this.
44) Mydock, L. K.; Kamat, M. N.; Demchenko, A. V. Org. Lett.
011, 13, 2928–2931.
(
2
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX