Equatorial anomeric triflates from mannuronic acid esters

Article abstract of DOI:10.1021/ja905008p

(Chemical Equation Presented) Activation of mannuronic acid esters leads to a conformational mixture of -anomeric triflates, in which the equatorial triflate (¹C₄ chair) is formed preferentially. This unexpected intermediate clearly

Full text of DOI:10.1021/ja905008p

Published on Web 08/07/2009
Equatorial Anomeric Triflates from Mannuronic Acid Esters
Marthe T. C. Walvoort,† Gerrit Lodder,† Jaroslaw Mazurek,‡ Herman S. Overkleeft,†
Jeroen D. C. Code´e,*,† and Gijsbert A. van der Marel*,†
Leiden Institute of Chemistry, Leiden UniVersity, P.O. Box 9502, 2300 RA Leiden, The Netherlands, and AVantium
Technologies B.V., Zekeringstraat 29, 1014 BV Amsterdam, The Netherlands
Received June 18, 2009; E-mail: marel_g@chem.leidenuniv.nl; jcodee@chem.leidenuniv.nl
The stereoselective construction of 1,2-cis glycosidic bonds
continues to be one of the largest challenges in synthetic carbo-
hydrate chemistry. Because the glycosidic bond forming process
can proceed via different (SN1- and SN2-like) reaction pathways
and through the intermediacy of different reactive species (e.g.,
anomeric triflates, oxacarbenium ions), it is exceedingly difficult
to identify and control the exact reaction pathway. In the course of
our research toward the construction of anionic oligosaccharides,
we have recently reported that condensations of 1-thio mannuronate
ester donors proceed with excellent 1,2-cis selectivity to provide
ꢀ-linked products.1 On the one hand, this selectivity can be
explained by invoking an axial R-anomeric triflate (1a, Scheme 1)
as a product forming intermediate, which is substituted in an SN2-
like manner. The axial anomeric triflate is preferentially formed
following the dictates of the anomeric effect.2,3 On the other hand,
an oxacarbenium ion intermediate may be formed that preferentially
selectivity. These results are comparable in stereoselectivity to those
obtained for 2-O-Bn mannuronate donor 1.1
Table 1. Results from the Glycosylation of Donor 2
Next, we set out to identify possible reactive intermediates
formed upon activation of uronate 2 by low-temperature NMR
spectroscopy. A mixture of ꢀ-thiodonor 2 and Ph2SO (1.3 equiv)
in DCM-d2 (0.05 M) at -80 °C was treated with Tf2O (1.3 equiv),
3
adopts the H4 half-chair conformation 1b. In this half-chair the
1
and a H NMR spectrum was recorded. The donor was instanta-
C-5 carboxylate occupies a pseudoaxial position to allow a through
space stabilization of the positive charge at the anomeric center.1c
The other ring substituents are also in their most favorable
orientation: the C-3 and C-4 substituents are positioned axially,
and the C-2 functionality is positioned equatorially.4 The incoming
nucleophile attacks this half chair along a pseudoaxial trajectory
on the ꢀ-face of the molecule to produce a 1,2-cis linkage. The
neously consumed to yield the spectrum shown in Figure 1,
displaying two distinct sets of signals. When the reaction mixture
was warmed to -40 °C, the two resonance sets coalesced to one
averaged set of signals (see Supporting Information). Upon cooling
to -80 °C, the two resonance sets appeared again, indicating a
dynamic equilibrium of two species. Above -40 °C decomposition
was observed. Using 2D COSY and HSQC measurements all
pyranosyl peaks were assigned as reported in Figure 1.
4
alternative H3 half-chair 1c, which would lead to the R-linked
product, is strongly disfavored due to misplacement of all ring
substituents.
Scheme 1. Intermediates in the Glycosylation of Donors 1 and 2
To gain more insight into the mechanism underlying the
exceptional 1,2-cis selectivity, we set out to study the behavior in
glycosylations of 1-thio mannosaziduronate donor 2, bearing an
electron-withdrawing azide functionality at C-2. Its natural equiva-
lent, mannosaminuronic acid, is found in various (bacterial) polysac-
charides,5 in which it generally is ꢀ-linked. First, the stereoselectivity
of donor 2 was assessed in three condensation reactions with acceptors
3, 4 and 5 using the Ph2SO-Tf2O activator system.6 The primary
acceptor 3 gave disaccharide 6 in high yield and excellent selectivity
(Table 1). Also the secondary acceptors 4 and 5 were coupled with
high ꢀ-selectivity, with acceptor 5 being superior in yield and
Figure 1. Part of the 1H NMR spectrum obtained after activation of
mannuronic acid esters 2 and 9 at -80 °C.
The anomeric H-1 signal at 6.00 ppm was a singlet as expected
for a manno H-1. The H-1* doublet at 6.22 ppm however displayed
a coupling constant of 3JH1-H2 ) 8.8 Hz indicating a trans-diaxial
relationship between H-1* and H-2*. In mannosyl pyranosides such
a large coupling constant is caused by a change in conformation
4
1
from the C1 to the C4 chair. This ring flip was supported by the
coupling constants of the other ring protons. The chemical shifts
of the two anomeric signals H-1 and H-1* are both indicative of
an anomeric triflate.7 Strikingly, this suggests that activation of
† Leiden University.
‡ Avantium Technologies B.V.
9
12080 J. AM. CHEM. SOC. 2009, 131, 12080–12081
10.1021/ja905008p CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
mannosazide uronate 2 leads to a conformational mixture of
anomeric triflates in which the 1C4 chair product 2a*, which
accommodates the anomeric triflate in the equatorial position, is
predominantly formed (2a*:2a ) 3:1).
nucleophile. Thus, both the anomeric triflate and the formation of the
3H4 oxacarbenium ion contribute to the excellent ꢀ-selectivity observed
in the condensation of mannuronates 1 and 2.
To confirm that the spectrum displayed in Figure 1 indeed
belongs to a conformational mixture of R-anomeric triflates,
N-(phenyl)trifluoroacetimidate 9 was activated in a low-temperature
NMR experiment. When donor 9 was treated with an equimolar
amount of TfOH in DCM-d2 at -80 °C, the imidate was
immediately consumed and the resulting spectrum matched the one
shown in Figure 1. Activation of 1-thio mannuronate 2 and imidate
9 thus lead to an identical mixture of anomeric R-triflates in which
the equatorial triflate 2a* prevails.8
Whereas axial anomeric triflates have been frequently character-
ized by NMR studies,9 equatorial anomeric triflates have up to now
never been spectroscopically detected. Nonetheless, they have been
invoked as product forming intermediates during glycosylation.10,11
With electron-withdrawing substituents at the anomeric center,
pyranosyl ring inversion has been observed before, but always to
profit from the stabilizing anomeric effect.2,3 Since the preference
for an electronegative substituent to reside in an axial anomeric
position is more pronounced in mannosides than in other glyco-
sides,3 the finding that mannosaziduronic acid ester preferentially
forms the equatorial triflate 2a* is highly unexpected. In addition
to the lack of anomeric stabilization, this structure also places three
of the five substituents in a sterically disfavored axial position.
We rationalize this atypical behavior by taking into account that
this species carries a significant amount of positive charge on its
anomeric carbon atom; the presence of the anomeric triflate, the
C-5 ester, and the C-2 azide together render the anomeric center
of the mannosyl core electron-deficient. Consequently, the structure
of the equatorial triflate 2a* approximates the structure of the
Figure 2. X-ray crystallographic structure of lactone 10 and proposed
transition state 11.
In conclusion, activation of mannosyl methyl uronates leads to
the predominant formation of equatorial mannosyl triflates. This
finding contrasts with conventional wisdom that the anomeric effect
is of decisive influence on both the conformation of glycosides and
their behavior in glycosylations.
Acknowledgment. This work was supported by Top Institute
Pharma and The Netherlands Organization of Scientific Research
(NWO, veni grant). The authors thank C. Erkelens and F. Lefeber
for their assistance with executing the NMR experiments.
Supporting Information Available: Spectroscopic data of the
reported compounds, low-temperature NMR spectra and X-ray crystal-
lographic data of 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
3
corresponding oxacarbenium ion 2b. In analogy to the H4 half-
(1) (a) van den Bos, L. J.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel,
G. A. J. Am. Chem. Soc. 2006, 128, 13066–13067. (b) Code´e, J. D. C.;
van den Bos, L. J.; de Jong, A.-R.; Dinkelaar, J.; Lodder, G.; Overkleeft,
H. S.; van der Marel, G. A. J. Org. Chem. 2009, 74, 38–47. (c) Dinkelaar,
J.; de Jong, A.-R.; van Meer, R.; Somers, R.; Lodder, G.; Overkleeft, H. S.;
Code´e, J. D. C.; van der Marel, G. A. J. Org. Chem. 2009, 74, 4982–4991.
(2) Juaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019–5087.
(3) Levy, D. E.; Fu¨gedi, P. The Organic Chemistry of Sugars; CRC Press:
Boca Raton, FL, 2006.
(4) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc.
2000, 122, 168–169. (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521–
15528. (c) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641–
2647.
(5) For example: Deng, L.; Anderson, J. S. J. Biol. Chem. 1997, 272, 479–
485.
(6) Code´e, J. D. C.; Stubba, B.; Schiattarella, M.; Overkleeft, H. S.; van Boom,
J. H.; van der Marel, G. A. J. Am. Chem. Soc. 2005, 127, 3767–3773.
(7) Crich, D.; Sun, S. X. J. Am. Chem. Soc. 1997, 119, 11217–11223.
(8) Activation of mannuronate 1 with Tf2O at-80 °C also produces a
conformational mixture of R-anomeric triflates, albeit in a ratio of 1:1.4 in
favor of the 1C4 conformation (see Supporting Information).
(9) See amongst others: (a) Eby, R.; Schuerch, C. Carbohydr. Res. 1974, 34,
79–90. (b) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681–1690. (c)
Nokami, T.; Shibuya, A.; Tsuyama, H.; Suga, S.; Bowers, A. A.; Crich,
D.; Yoshida, J.-i. J. Am. Chem. Soc. 2007, 129, 10922–10928. (d) Kim,
K. S.; Fulse, D. B.; Baek, J. Y.; Lee, B.-Y.; Jeon, H. B. J. Am. Chem. Soc.
2008, 130, 8537–8547. (e) Zeng, Y.; Wang, Z.; Whitfield, D.; Huang, X.
J. Org. Chem. 2008, 73, 7952–7962.
chair 2b, the 1C4 triflate 2a* places the C-5 methyl uronate as well
as C-3 and C-4 substituents in a pseudo-axial position to stabilize
the partially electron-positive anomeric center.12 Notably, this
stabilizing effect is strong enough to overrule both the anomeric
effect and the unfavorable 1,3-diaxial interactions. The preferential
1
flip of the electron-deficient mannuronate core to the C4 chair
conformation thus supports the model we proposed for the lower
3
ground-state energy of the H4 half-chair mannuronate oxacarbe-
nium ion.1b
To endorse the postulation that the developing positive charge
at C-1 is the driving force for the inversion of chair conformation,
mannuronate lactone 10 was synthesized. As in the mannuronate
oxacarbenium ion, the C-1 of the lactone is sp2-hybridized and
carries a partial positive charge. Analysis by NMR spectroscopy
revealed that lactone 10 adopts a flattened 1C4 chair at room
temperature, as depicted in Figure 2. X-ray crystallography cor-
roborated this structure (Figure 2).
The existence of the conformational mixture of R-anomeric
triflates provides support for a glycosylation pathway having both
SN1- and SN2-character. Substitution of the triflate is accompanied
by the development of significant oxacarbenium ion character at
the anomeric center. To accommodate this (partial) positive charge,
the mannuronates 1 and 2 adopt a conformation approaching the
3H4 half chair, as illustrated by the asymmetric exploded transition
state 11 (Figure 2).13 The (stereo)electronic effects stabilizing this
conformation are already apparent in the neutral triflate 2a* and
lactone 10 and will become more important with increasing positive
charge at C-1. In this glycosylation scenario, the amount of SN1- and
SN2-like character is determined by the reactivity of the incoming
(10) (a) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291–1297. (b)
Crich, D.; de la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68, 8142–
8148.
(11) Once a ꢀ-triflate was postulated which adopted a 1S5 twist boat conforma-
tion, placing the triflate in a pseudo-axial position to benefit from the
anomeric effect (ref 7).
(12) Electronegativity of the C5 substituent itself is not the cause of ring
inversion, as an L-rhamnoside with a CF3 moiety at C-5 has been shown to
form a stable triflate without inducing a conformational change. Crich, D.;
Vinogradova, O. J. Am. Chem. Soc. 2007, 129, 11756–11765.
(13) Krumper, J. R.; Salamant, W. A.; Woerpel, K. A. Org. Lett. 2008, 10,
4907–4910.
JA905008P
9
J. AM. CHEM. SOC. VOL. 131, NO. 34, 2009 12081