Chiral copper(II) complex-catalyzed reactions of partially protected carbohydrates

Article abstract of DOI:10.1021/ol4033072

Catalyst-controlled regioselective functionalization of partially protected saccharide molecules is a highly important yet under-developed area of carbohydrate chemistry. Such reactions allow for the reduction of protecting group manipulation steps required in syntheses involving sugars. Herein, an approach to these processes using enantiopure copper-bis(oxazoline) catalysts to control couplings of electrophiles to various partially protected sugars is reported. In a number of cases, divergent regioselectivity was observed as a function of the enantiomer of catalyst that is used.

Full text of DOI:10.1021/ol4033072

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6178–6181
Chiral Copper(II) Complex-Catalyzed
Reactions of Partially Protected
Carbohydrates
C. Liana Allen and Scott J. Miller*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven,
Connecticut 06520, United States
scott.miller@yale.edu
Received October 21, 2013
ABSTRACT
Catalyst-controlled regioselective functionalization of partially protected saccharide molecules is a highly important yet under-developed area of
carbohydrate chemistry. Such reactions allow for the reduction of protecting group manipulation steps required in syntheses involving sugars.
Herein, an approach to these processes using enantiopure copperÀbis(oxazoline) catalysts to control couplings of electrophiles to various partially
protected sugars is reported. In a number of cases, divergent regioselectivity was observed as a function of the enantiomer of catalyst that is used.
Sugars are highly important moieties in the development
oftherapeutic agentsduetotheir essentialroleinbiological
processes. The presence of multiple reactive sites on sac-
charide molecules means the synthesis of sugar derivatives
often reliesonextensive protecting groupmanipulations or
the use of enzymes.1 Much effort has been directed toward
regioselective reactions of partially or fully unprotected
carbohydrates, as this is crucial for streamlining the func-
tionalization of such molecules.2 To this end, the diol-
binding affinities of various transition metals3À5 (usually
in a stoichiometric amount) and of boron6 have been
exploited as a method for selective hydroxyl activation.
Organocatalystshave alsobeen appliedtothis challenge.7,8
The more recent use of borinic ester catalysts has provided
an alternative to the use of stoichiometric activating
reagents, while maintaining the same high selectivity.9
While all these methods generally offer high selectivity,
access to regioisomers not inherently produced by a parti-
cular sugar-catalyst combination remains difficult.10 Often,
a specific stereochemical relationship between hydroxyl
groups is strictly required to allow catalyst binding and
subsequent site-specific reaction.11 The development of
reactions which would allow access to all possible regioi-
somers under catalyst control would expand the range of
this important approach to saccharide functionalization.
Tin reagents have received attention in this area, as a switch
(1) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900.
(2) Lee, D.; Taylor, M. S. Synthesis 2012, 44, 3421.
(3) (a) Evtushenko, E. V. Carbohydr. Res. 2012, 359, 111. (b) Osborn,
H. M. I.; Brome, V. A.; Harwood, L. M.; Suthers, W. G. Carbohydr. Res.
2001, 332, 157.
(8) Sun, X.; Lee, H.; Lee, S.; Tan, K. L. Nature Chem. 2013, 5, 790–
795.
(4) Eby, R.; Thresh Webster, K.; Schuerch, C. Carbohydr. Res. 1984,
129, 111.
(9) Gouliaras, C.; Lee, D.; Chan, L.; Taylor, M. S. J. Am. Chem. Soc.
2011, 133, 13926. (b) Lee, D.; Williamson, C. L.; Chan, L.; Taylor, M. S.
J. Am. Chem. Soc. 2012, 134, 8260.
(10) Zhou, Y.; Ramstrom, O.; Dong, H. Chem. Commun. 2012, 48,
5370.
(11) Nashed, M. A.; Anderson, L. Tetrahedron Lett. 1976, 39, 3503.
(12) (a) Muramatsu, W.; Takemoto, Y. J. Org. Chem. 2013, 78, 2336.
(b) Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.;
Moriyama, N.; Onomura, O. Org. Lett. 2008, 10, 5075. (c) Kaji, E.;
Shibayama, K.; In, K. Tetrahedron Lett. 2003, 44, 4881. (d) Boons, G.-J.;
Castle, G. H.; Clase, J. A.; Grice, P.; Ley, S. V.; Pinel, C. Synlett 1993,
913. (e) Wagner, D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem.
1974, 39, 24.
(5) Gangadharmath, U. B.; Demchenko, A. V. Synlett 2004, 12, 2191.
(6) (a) Kaji, E.; Nishino, T.; Ishige, K.; Ohya, Y.; Shirai, Y. Tetra-
hedron Lett. 2010, 51, 1570. (b) Oshima, K.; Aoyama, Y. J. Am. Chem.
Soc. 1999, 121, 2315. (c) James, T. D.; Samankumara Sandanayake,
K. R. A.; Shinkai, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1910.
(7) (a) Ueda, Y.; Muramatsu, W.; Mishiro, K.; Kawabata, T. J. Org.
ꢀ
ꢀ
Chem. 2009, 74, 8802. (b) Sanchez-Rosello, M.; Puchlopek, A. L. A.;
Morgan, A. J.; Miller, S. J. J. Org. Chem. 2008, 73, 1774. (c) Griswold,
K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869. (d) Hu, G.; Vasella, A.
Helv. Chim. Acta 2003, 86, 4369. (e) Mensah, E.; Camasso, N.; Kaplan,
W.; Nagorny, P. Angew. Chem., Int. Ed. 201310.1002/anie.201304298.
r
10.1021/ol4033072
Published on Web 11/26/2013
2013 American Chemical Society

in regioselectivity can be achieved by changing the size of the
alkyl groups on the organotin catalyst. However, this
methodology leads to generation of potentially toxic
alkyltin(IV) byproduct.12 Recently, Tan et al. have shown
that pairs of enantiopure molecules can successfully control
regioselectivity in reactions of carbohydrates by employing
“covalent scaffolding” catalysts.8 The application of enan-
tiopure catalysts to control problems in stereo- and regios-
electivity of all types remains an important approach.13aÀc
Implicit in the effort is the identification of catalysts which can
overcome the different intrinsic reactivities of various sites.13d
As part of our ongoing effort to develop regioselective
functionalizations of carbohydrate substrates,14 we chose
to investigate the use of chiral copperÀ(bis)oxazoline
complexes.15 We were inspired by the work of Onomura
et al., who reported the capacity of such complexes to
influence selectivity in reactions of a variety of polyol
substrates with a range of electrophiles.16 Initial results
proved promising (Table 1, entries 1 and 2), with catalyst-
dependentregioselectivity observed with10mol % catalyst
loading. Further optimization of the reaction conditions
led to anincreaseinselectivity inthe matched case(Table1,
entry 6) when the temperature was decreased to À40 °C,
whereas optimal selectivity was achieved in the mis-
matched case at 0 °C. Change of (bis)oxazoline ligand
(Table 1, entries 8À11), solvent (Table1, entries 12and 13),
or base (Table 1, entries 14 and 15) led to loss of reactivity.
With optimized conditions in hand we turned our
attention to a screen of sugar substrates (Table 2). The
4,6-benzylidene acetal motif was chosen as a convenient
protecting group to block two of the hydroxyl groups of
the hexopyranosides. Pleasingly, in each case, some degree
of regioselectivity is imparted by at least one of the
enantiomers of catalyst (compared with achiral CuCl2 as
catalyst). When the stereochemistry at the anomeric posi-
tion is R, both enantiomers of catalyst affect the regios-
electivity of the reaction, leading to an amplification of the
selectivity observed with CuCl2 as catalyst (Table 2, entries
1, 10, and 17) or an overturn of this selectivity to favor the
other regioisomer (Table 2, entries 2, 9, and 18). However,
when the stereochemistry at the anomeric position is β,
only the (S)-enantiomer of catayst is found to significantly
affect the regioselectivity (Table 2, entries 6 and 14), with
the (R)-enantiomer of catalyst giving approximately the
same results as found with CuCl2 (Table 2, entries 5 and
13). Theseobservations perhaps suggest thatbindingofthe
CuÀBOX catalyst to the diol is sensitive to the stereo-
chemistry at the anomeric position.
The most notable result was observed with methyl 4,6-
benzylidene-R-mannopyranoside (5) as the sugar substrate
(Table 2, entries 17À20). Almost complete selectivity for
benzoylation at the 3-position was found when CuCl2-(R)-
PhBOX was used as catalyst, demonstrating a large am-
plification of the selectivity observed when achiral CuCl2
was used. Pleasingly, CuCl2-(S)-PhBOX was shown to
overturn this selectivity and favor benzoylation at the
2-position in a ratio of 11.5:1 (Table 2, entry 18).
The reaction conditions were found to be applicable to a
range of electrophiles (Table 3). Several acyl chlorides gave
high conversions into the functionalized sugars, albeit with
diminished regioselectivities. Acetyl chloride produced the
best results of the electrophiles tested (Table 3, entries 1
and 2), with high conversion and good regioselectivity
observed with both enantiomers of catalyst. Methyl adi-
poyl chloride (Table 3, entries 7 and 8) and 5-pentenoyl
chloride (Table 3, entries 9 and 10) both gave full conver-
sion with respect to the sugar, but with lower regioselec-
tivity than observed with benzoyl chloride. Although a
catalyst dependency was still clear, substituted benzoyl
chlorides did not provide the same high conversions or
regioselectivities observed with the unsubstituted benzoyl
Table 1. Optimization of Reaction Conditions
entry
catalyst
temp (°C) conve (%) ratioe 1a:1b
1
CuCl2-(R)-PhBOX
CuCl2-(S)-PhBOX
CuCl2
0
0
99
100
93
91
93
92
98
84
92
88
85
31
53
34
0
6.0:1
1:5.7
2
3
0
3.7:1
7.0:1
4
CuCl2-(R)-PhBOX
CuCl2-(S)-PhBOX
CuCl2-(R)-PhBOX
CuCl2-(S)-PhBOX
CuCl2-(R)-BnBOX
CuCl2-(S)-tBuBOX
CuCl2-(R)-Ph-PyBOX
CuCl2-(S)-Ph-PyBOX
À10
À10
À40
À40
À40
À40
À40
À40
À10
À10
À10
À10
5
1:5.3
15.0:1
1:1.2
6
7
8
11.0:1
2.6:1
4.2:1
4.6:1
5.3:1
3.8:1
1.5:1
9
10
11
12a CuCl2-(R)-PhBOX
13b CuCl2-(R)-PhBOX
14c CuCl2-(R)-PhBOX
15d CuCl2-(R)-PhBOX
Conditions: sugar (0.1 mmol, 1 equiv), benzoyl chloride (0.1 mmol,
1 equiv), DIPEA (0.1 mmol, 1 equiv), catalyst (10 mol %), CHCl3
(0.4 mL). a THF as solvent. b PhMe as solvent. c 2,6-Lutidine as base.
d K2CO3 as base. e Determined by 1H NMR spectroscopy.
(13) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1. (b) Kumar, R. R.; Kagan, H. B. Adv. Synth.
Catal. 2010, 352, 231. (c) Lewis, C. A.; Merkel, J.; Miller, S. J. Bioorg.
Med. Chem. Lett. 2008, 18, 6007. (d) Lewis, C. A.; Miller, S. J. Angew.
Chem., Int. Ed. 2006, 45, 5616.
(14) Gould, N. D.; Allen, C. L.; Nam, B. C.; Schepartz, A.; Miller,
S. J. Carbohydr. Res. 2013, 382, 36.
(16) (a) Maki, T.; Ushijima, N.; Matsumura, Y.; Onomura, O.
Tetrahedron Lett. 2009, 50, 1466. (b) Demizu, Y.; Matsumoto, K.;
Onomura, O.; Matsumura, Y. Tetrahedron Lett. 2007, 48, 7605. (c)
Matsumura, Y.; Maki, T.; Tsurumaki, K.; Onomura, O. Tetrahedron
Lett. 2004, 45, 9131. (d) Matsumura, Y.; Maki, T.; Murakami, S.;
Onomura, O. J. Am. Chem. Soc. 2003, 125, 2052.
(15) (a) Gissibl, A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325.
(b) Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. Rev. 2006, 106,
€
3561–3651. (c) Mazet, C.; Roseblade, S.; Kohler, V.; Pfaltz, A. Org. Lett.
2006, 8, 1879. (d) Lee, J. Y.; You, Y. S.; Kang, S. H. J. Am. Chem. Soc.
2011, 133, 1772.
Org. Lett., Vol. 15, No. 24, 2013
6179

Table 2. Screen of Sugars Bearing Vicinal Hydroxyl Groups*
Table 3. Screen of Electrophiles*
* Conditions: sugar (0.1 mmol, 1 equiv), benzoyl chloride (0.1 mmol,
1 equiv), DIPEA (0.1 mmol, 1 equiv), catalyst (10 mol %), CHCl3
(0.4 mL). Results average of two identical runs. a Isolated yield
in parentheses with regioisomer isolated in bold. b Determined by
1H NMR spectroscopy.
chloride (Table 3, entries 11À16). This discrepancy is
conceivably due to a lack of solubility of some benzoyl
chlorides in the reaction solvent.
While acetic anhydride successfully acylated 1, the ratio
of2- to 3-position functionalization was approximately the
same with both enantiomers of catalyst (Table 3, entries 17
and 18). This lack of regioselectivity (and indeed the
diminished regioselectivity observed in other cases) could
possibly be attributed to the electrophile forming a com-
plex with the copper and displacing the chiral ligands,
which would still lead to a reaction but with no element of
regiocontrol. Alkyl halides were not successful in this
reaction, even in the presence of 1 equiv of promotor Ag2O.
Only modest selectivity was observed when attempting to
glycosylate the glucose diol with 2,3,4,6-tetra-O-benzylglyco-
pyranosyl bromide (Table 3, entries 5 and 6).
* Conditions: sugar (0.1 mmol, 1 equiv), electrophile (0.1 mmol,
1 equiv), DIPEA (0.1 mmol, 1 equiv), catalyst (10 mol %), CHCl3
(0.4 mL). Results average of two identical runs. a Isolated yield in
1
parentheses with regioisomer isolated in bold. b Determined by H NMR
spectroscopy. c Ag2O (1 equiv) added to the reacion mixture.
After completion of the reaction of methyl 4,6-benzyl-
idene-R-mannopyranoside with benzoyl chloride, the sol-
vent was removed in vacuo and a hydrogenolysis of the
cyclic benzylidene acetal then immediately performed
In an effort to further streamline the synthesis of monosub-
stituted sugar derivatives, a one-pot, two-step benzoylationÀ
acetal deprotection procedure was attempted (Figure 1).
6180
Org. Lett., Vol. 15, No. 24, 2013

Figure 1. In situ 4,6-acetal deprotection.
using Adam’s catalyst/H2. After workup, methyl 3-benzoyl-
R-mannopyranoside was isolated in 83% yield (along with
an inseparable 8% methyl 6-benzoyl-R-mannopyranoside
impurity).
Three competition reactions were then run in an effort to
gain insight into how the relative stereochemistry of each
hydroxyl on the sugar ring affects the binding of the
catalyst (if it is indeed forming a complex with the diol
in situ). First, a 1:1 mixture of methyl 4,6-benzylidene-
R-glucopyranoside and methyl 4,6-benzylidene-R-galacto-
pyranoside (stereochemistry different at the 4-position)
was subjected to the standard reaction conditions with
1 equivalent of benzoyl chloride. No preference for either
sugar was observed with either catalyst. Each substrate
reached approximately 50% conversion with regioselectivity
ratios very similar to those reported in Table 1. Second,
a 1:1 mixture of methyl 4,6-benzylidene-R-galactopyra-
noside and methyl 4,6-benzylidene-β-galactopyranoside
(stereochemistry different at the 1-position) was subjected
to the same conditions. In this case, the (R)-enantiomer of
catalyst appeared to show a preference for the β anomer,
with this substrate reaching 48% conversion compared
with the R anomer which only reached 2% conversion.
Moreover, the β anomer reacted preferentially at the
3-position in a 1:20 ratio (2:3 position benzoylation). The
same site selectivity was observed previously with this
substrate (Table 1, entry 13). Conversely, the (S)-enantiomer
catalyst only showed a slight bias toward the β anomer, with
no strong regioselectivity displayed.
Figure 2. Competition reactions.
attributed to the different stereochemical relationship be-
tween the two sets of free hydroxyls on the sugar substrates;
the glucose derivative bears a trans vicinal diol and the
mannose derivative bears a cis vicinal diol (Figure 2).
In summary, we have shown that enantiopure copper
complexes can influence the regioselectivity of reactions of
partially protected sugars. These complexes can lead to a
significant enhancement of the “inherent” reactivity of the
sugar or, in some cases, an overturn of this selectivity to
favor the other, less accessible regioisomer. The current
reaction conditions were also shown to be compatible with
several different electrophiles. One-pot, orthogonal depro-
tection of the benzylidene acetalwas demonstrated. Efforts
toimprovethe regioselectivityand scopeofthe reaction via
modification of the catalyst continue in our laboratory.
Acknowledgment. We are grateful to the W. M. Keck
Foundation for financial support and to Professor Alanna
Schepartz for helpful discussions.
Lastly, a 1:1 mixture of methyl 4,6-benzylidene-R-gluco-
pyranoside and methyl 4,6-benzylidene-R-mannopyranoside
(stereochemistry different at the 2-position) was subjected to
the reaction conditions. Strikingly, with both enantiomers
of catalyst, complete selectivity for methyl 4,6-benzylidene-
R-mannopyranoside was observed. This observation also
demonstrates a significant difference from when the achiral
catalyst CuCl2 was used. The observed selectivity may be
Supporting Information Available. Procedures and
characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 24, 2013
6181