Glycal assembly by the in situ generation of glycosyl dithiocarbamates

Article abstract of DOI:10.1021/ol301349w

Glycal assembly offers an expedient entry into β-linked oligosaccharides, but epoxyglycal donors can be capricious in their reactivities. Treatment with Et₂NH and CS₂ enables their in situ conversion into glycosyl dithiocarbamates, which can be activated by copper triflate for coupling with complex or sterically congested acceptors. The coupling efficiency can be further enhanced by in situ benzoylation, as illustrated in an 11-step synthesis of a branched hexasaccharide from glucals in 28% isolated yield and just four chromatographic purifications.

Full text of DOI:10.1021/ol301349w

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3380–3383
Glycal Assembly by the in Situ Generation
of Glycosyl Dithiocarbamates
Panuwat Padungros, Laura Alberch, and Alexander Wei*
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette,
Indiana 47907, United States
alexwei@purdue.edu
Received May 17, 2012
ABSTRACT
Glycal assembly offers an expedient entry into β-linked oligosaccharides, but epoxyglycal donors can be capricious in their reactivities.
Treatment with Et2NH and CS2 enables their in situ conversion into glycosyl dithiocarbamates, which can be activated by copper triflate for
coupling with complex or sterically congested acceptors. The coupling efficiency can be further enhanced by in situ benzoylation, as illustrated in
an 11-step synthesis of a branched hexasaccharide from glucals in 28% isolated yield and just four chromatographic purifications.
General strategies for efficient and stereoselective gly-
cosyl couplings continue to provide a challenge for syn-
thetic method development, despite the many mechanistic
insights and technological advances in glycosyl bond
formation.1,2a,b In 1989, Halcomb and Danishefsky intro-
duced an approach for the expedient synthesis of β-linked
oligosaccharides, based on the stereoselective epoxidation
of glycals followed by coupling with glycal acceptors under
mild Lewis acid conditions.3a,b The “glycal assembly”
strategy differs significantly from conventional methods
of carbohydrate synthesis: the intermediate epoxyglycal
donors can be used without workup or purification, and
the C2 substituent of the glycosylation products can be mod-
ified at a later stage, permitting greater flexibility in
synthetic design. Glycals and their epoxides have also
proven amenable to solid-phase oligosaccharide synthesis.4
Despite its potential advantages, the efficiency of glycal
assembly has been limited by the variable reactivity of the
epoxyglycal donors, and by the range of acceptors that can
serve as nucleophiles. For instance, tri-O-benzyl R-epoxy-
glucal is highly sensitive even to mild Lewis acids, and its
use as a glycosyl donor has produced only moderate
yields.3b,5ꢀ7,10 Efforts to improve coupling yields by optimiz-
ing the Lewis acid catalyst or the nucleophilicity of the
acceptor have met with mixed success.8,9a,b Epoxyglycals
can be converted into standard glycosyl donors for activation
by stronger Lewis acid catalysts, but extra steps are needed to
isolate and purify the synthetic intermediates.10,11a,b Further-
more, the use of strong Lewis acids is incompatible with
(7) Fortin, M.; Kaplan, J. P.; Kirk, K., S.; Andrade, R. B. Org. Lett.
2009, 11, 3594.
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4933. (b) Randolph, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 1993,
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S. J. J. Am. Chem. Soc. 1997, 119, 10064. (b) Zheng, C.; Seeberger, P. H.;
Danishefsky, S. J. J. Org. Chem. 1998, 63, 1126.
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1999, 1, 211. (b) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.;
Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545.
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r
10.1021/ol301349w
Published on Web 06/11/2012
2012 American Chemical Society

coupling.18 Furthermore, DTCs can be prepared by the
simple condensation of amines with CS2 in polar
solvents19a,b and are excellent nucleophiles for epoxide
ring-opening. These features suggested to us that glycosyl
DTCs could be ideal surrogates for glycal assembly.
The conversion of tri-O-benzyl glucal 1 into a glycosyl
DTC was achieved in situ, by stereoselective DMDO oxida-
tion followed by treatment with Et2NH and CS2 (premixed
to form the Et2DTC diethylammonium salt) to yield the
desired glycosyl DTC with >95% βselectivity.20 Asurveyof
Lewis acids revealed that glycosyl DTCs were readily acti-
vated by Cu(OTf)2 or CuOTf (C6H6)0.5 at low tempera-
3
tures, using 2,4,6-(tBu)3-pyrimidine (TTBP) as an acid
scavenger. We were pleased to find that Cu(OTf)x activation
could be performed using unpurified glycosyl DTCs and was
also compatible with both acid- and base-sensitive functional
groups, allowing glycal donors to be coupled efficiently with
a variety of acceptors without intermediate workup.
Figure 1. The glycal assembly approach to β-linked glycosides,
aided by the in situ generation of a glycosyl dithiocarbamate
prior to glycosyl coupling and chromatographic purification.
glycal acceptors, defeating a primary merit of the glycal
assembly method.
One-pot glycal couplings were performed using 1 or
Glcβ(1f6)glucal 2 as donors and 1.2ꢀ1.5 equiv of accep-
tors to produce β-glycosides 3ꢀ9 in good yields and
selectivities (Table 1). The stereochemistry of all products
or their 2-O-acetates was confirmed by 1H NMR coupling
constant or pulsed-field gradient (pfg) COSY analysis
(see the Supporting Information).
It is worth noting that the C2 hydroxyl of the inter-
mediate DTC glycoside does not interfere with glycosyl
coupling, as no side products corresponding to self-coupl-
ing or oligomerization could be identified. Instead, the C2
hydroxyl likely plays an active role in promoting β-glycosyla-
tion by generating a tetrahedral intermediate that hinders
nucleophiles from approaching the R face (Figure 2). Com-
plementary studies on the reactivity of glycosyl DTCs sup-
port this argument and will be reported elsewhere.21
While the scope of glycal assembly is substantially
improved by the in situ generation of glycosyl DTCs
(Table 1), this alone is not enough for the efficient coupling
of glycal donors and acceptors into larger oligosacchar-
ides, which is an important objective for its continued
development.3b,4 For instance, some 1,3- and 1,4-linked
disaccharides could only be obtained in fair yields (Table 2,
footnote d). We recognized that a 2-O-benzoate (Bz)
would be useful to enhance donor reactivity, as has been
demonstrated with glycosyl thioimidates.16,22 We thus
developed a chromatography-free method of benzoylation
that retains the processing advantages of glycal assembly.
In situ conversion of glycal donors 1, 10, and 11 into their
corresponding 2-O-Bz glycosyl DTCs proved both facile
and compatible with CuOTf or Cu(OTf)2-mediated
Here we describe coupling conditions that bring the glycal
assembly strategy to its full potential. They are based on the
one-pot conversion of epoxyglycals into glycosyl dithiocar-
bamates (DTCs), by treatment with diethylamine and CS2,
and the selective activation of the glycosyl DTCs with Cu(I)
or Cu(II) triflate to initiate glycosyl coupling (Figure 1).
This procedure is both highly β-selective and compatible
with glycals and other sensitive glycosyl acceptors and does
not require purification of the glycosyl DTC intermediate.
The coupling reaction proceeds with a free C2 hydroxyl
on the glycosyl donor but can be enhanced further by in
situ 2-O-acylation for the expeditious assembly of complex
β-linked oligosaccharides. We demonstrate this with the
concise synthesis of a branched hexasaccharide from the
β-glucan family, whose members have strong immunomo-
dulatory potential but whose structureꢀactivity relation-
ships have not been fully addressed, because of limited
availability of well-characterized structures.12,13
Glycosyl DTCs have been underutilized as donors com-
pared to glycosyl sulfides or thioimidates.1,14ꢀ16 However,
the reduction potentials of DTCs are less than that of
thiols (E0(Et2NCS2ꢀ/thiuram disulfide) = ꢀ302 mV,
versus E0(PhSꢀ/PhSSPh) = ꢀ541 mV),17 indicating facile
ionization and mild activation conditions for glycosyl
(14) Bogusiak, J.; Szeja, W. Carbohydr. Res. 1996, 295, 235.
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(15) Fugedi, P.; Garegg, P. J.; Oscarson, S.; Rosen, G.; Silwanis,
B. A. Carbohydr. Res. 1991, 211, 157.
(16) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2103.
(17) Nichols, P. J.; Grant, M. W. Aust. J. Chem. 1982, 35, 2455.
(18) Yamago, S.; Kokubo, K.; Hara, O.; Masuda, S.; Yoshida, J.-i.
J. Org. Chem. 2002, 67, 8584.
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(19) (a) Zhao, Y.; Perez-Segarra, W.; Shi, Q.; Wei, A. J. Am. Chem.
Soc. 2005, 127, 7328. (b) Zhu, H.; Coleman, D. M.; Dehen, C. J.; Geisler,
I. M.; Zemlyanov, D.; Chmielewski, J.; Simpson, G. J.; Wei, A.
Langmuir 2008, 24, 8660.
(20) We note that while the DMDO oxidation of the glucal provides
the R-epoxyglycal with 90% facioselectivity (ref 3), epoxide ring opening
provides additional kinetic resolution to produce glycosyl DTCs with
>95% β selectivity. See: Alberch, L.; Cheng, G.; Seo, S.-K.; Li, X.;
Boulineau, F. P.; Wei, A. J. Org. Chem. 2011, 76, 2532.
(21) Padungros, P.; Alberch, L.; Wei, A. manuscript in preparation.
(22) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115.
(24) Zhang, Q.; Zhao, Y.; Wang, B.; Feng, R.; Liu, X.; Cheng, T.
Steroids 2002, 67, 347.
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P. T.; Franco-Rodrıguez, G.; Espartero, J. L.; Irastorza-Iribas, A.;
Gil-Serrano, A. M. Carbohydr. Res. 1997, 303, 453. (b) Velasco, S. E.;
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guez-Carvajal, M. A.; Mateo,
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Areizaga, J.; Irastorza, A.; Duenas, M. T.; Santamaria, A.; Munoz,
M. E. J. Agric. Food Chem. 2009, 57, 1827.
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Gualtieri, P. Nat. Prod. Rep. 2011, 28, 457.
(27) Albersheim, P.; Darvill, A.; Augur, C.; Cheong, J.-J.; Eberhard,
S.; Hahn, M. G.; Marfa, V.; Mohnen, D.; O’Neill, M. A.; Spiro, M. D.;
York, W. S. Acc. Chem. Res. 1992, 25, 77.
(23) Di Bussolo, V.; Kim, Y. J.; Gin, D. Y. J. Am. Chem. Soc. 1998,
120, 13515.
Org. Lett., Vol. 14, No. 13, 2012
3381

Table 1. One-Pot Glycal Coupling via in Situ Glycosyl Dithio-
carbamate (DTC) Formation
Table 2. Oligosaccharide Assembly via in Situ Benzoylation of
Glycosyl DTC Intermediates
a Standard conditions: (i) DMDO (1.5 equiv), 0 °C, CH2Cl2; (ii) CS2
(1.05 equiv), Et2NH (2.1 equiv), MeOH, rt; (iii) BzCl (4 equiv, 0.4 M),
pyridine, rt; (iv) [Donor] = 0.15 M; Cu(OTf)x, TTBP (2 equiv each), 4 A
mol sieves, ꢀ50 °C, 1:1 CH2Cl2/C2H4Cl2; acceptor added at ꢀ50 °C;
reaction quenched at 10 °C. (A) Cu(OTf)2 and 1.5 equiv of acceptor; (B)
CuOTf and 1.5 equiv of acceptor; (C) CuOTf and 1.4 equiv donor.
b Isolated yields of β isomer, unless stated otherwise. c Also isolated 1,2-
orthobenzoate byproduct (6%). d Yields in parentheses for glycosyl
couplings without in situ 2-O-benzoylation, shown for comparison.
e 1.3 equiv of acceptor. f DMDO (1.5 equiv), ꢀ55 °C. g Glycosyl coupling
without in situ 2-O-benzoylation produces a 5:1 β:R mixture.
a Standard conditions: (i) DMDO (1.5 equiv), 0 °C, CH2Cl2;
(ii) CS2 (1.05 equiv), Et2NH (2.1 equiv), MeOH, rt; (iii) [Donor] =
0.15 M; Cu(OTf)x, TTBP (2 equiv each), 4 A mol sieves, ꢀ50 °C,
1:1 CH2Cl2/C2H4Cl2, then acceptor (1.5 equiv); reaction quenched
at 10 °C. (A) Cu(OTf)2; (B) CuOTf. b Isolated yields of β isomer, unless
stated otherwise. c Yields in parentheses (reported in refs 3ꢀ5) are shown
for comparison. d 1.3 equiv of acceptor. e Reaction quenched at ꢀ30 °C.
f Obtained as a 9:1 β:R mixture. g DMDO, ꢀ55 °C. h [Donor] = 0.2 M;
1.2 equiv of acceptor. i Also isolated R isomer (7%).
with an increase in overall yields by more than 30%.
Such modifications effectively remove any limitations
previously associated with the efficiency of glycal assem-
bly, including the formation of β-1,2-, β-1,3-, and
β-1,4-linked oligosaccharides.10,23
The modified glycal assembly conditions can be
applied to a variety of naturally occurring β-linked
oligosaccharides and glycoconjugates. For example,
glycal 15 is a precursor for the branched tetrasaccharide
of a pregnane glycoside (Glcβ(1f6)[Glcβ(1f2)]Glcβ-
(1f6)Glcβ-) isolated from Stelmatocrypton khasianum.24
To determine whether modified glycal assembly could
provide an efficient entry into sterically congested glycans,
we designed a synthetic route toward oligomers of
[Glcβ(1f3)[Glcβ-(1f2)]Glcβ(1f3)]n-, a trisaccharide re-
peat unit of a branched β-glucan produced by probiotic
strains of the Pediococcus genus.30 The diverse biological
Figure 2. Cu-mediated activation of the glycosyl DTC inter-
mediate (L = coordination ligand). The participation of the C2
hydroxyl promotes the formation of β-glycosides.
glycosylation directly after workup. This allowed com-
pounds 12ꢀ17 to be produced in high yields and with
exclusive β selectivity (Table 2).
Benzoylation of the intermediate DTC glycoside was
particularly beneficial in couplings involving less reactive
glycal donors such as conformationally locked glucal 11,
(28) Miller, K.; Kennedy, E.; Reinhold, V. Science 1986, 231, 48.
(29) Lequette, Y.; Rollet, E.; Delangle, A.; Greenberg, E. P.; Bohin,
J. P. Microbiology 2007, 153, 3255.
(30) (a) Descroix, K.; Ferrieres, V. J.; Yvin, F., J.-C.; Plusquellec, D.
Mini-Rev. Med. Chem. 2006, 6, 1341. (b) Zeng, Y.; Ning, J.; Kong, F.
Tetrahedron Lett. 2002, 43, 3729. (c) Zeng, Y.; Ning, J.; Kong, F.
Carbohydr. Res. 2003, 338, 307.
3382
Org. Lett., Vol. 14, No. 13, 2012

activities of branched β-glucans have gained prominence in
recent years and include a broad range of human health
benefits12,13,26 as well as regulatory functions in plants27 and
bacterial biofilm formation.28,29 The crowded 1,2;1,3-link-
age provides a stringent test for glycosyl coupling, as the
steric congestion around the branched acceptor impedes
both coupling efficiency and stereoselectivity.30
Scheme 1. Synthesis of a Branched β-Glucan by Modified
Glycal Assembly
The p-methoxybenzyl (PMB)-protected glucal donor 18
was coupledwith glucal acceptor 19using a slightvariation
of the previous reaction conditions. Epoxidation was
performed using a modest excess of DMDO, followed by
treatment with 1.3 equiv of Et2DTC in MeOH (Scheme 1).
In this case, the DTC salt also served as a DMDO
scavenger to prevent overoxidation of the 3-O-PMB ether.
The crude glycosyl DTC intermediate was benzoylated,
then subjected to CuOTf-mediated coupling with 1.5 equiv
of 19to produce disaccharide glycal20in 71% overall yield
from 18 after chromatography.
The 20-O-Bz ester was saponified and subjected to a one-
pot coupling with 2 equiv of 1 using our modified glycal
assembly conditions, to produce branched trisaccharide
glycal 14 in 92% yield from 20.31 Acceptor 21 (1.2 equiv)
was prepared from donor 14 by oxidative cleavage of the
30-O-PMB ether in 90% yield and then subjected to CuOTf-
mediated coupling to produce 22 in 47% isolated yield
(Scheme 1). The synthesis of hexasaccharide glycal 22 from
glucals 18 and 19 wasachievedin11stepsandwithonlyfour
chromatographic purifications, in an overall yield of
28%. Furthermore, 22 was produced as a single dia-
stereomer despite the creation of 10 stereocenters. In
this regard, we note that the DMDO epoxidation of
disaccharide glycal 20, trisaccharide glycal 14, and
hexasaccharide glycal 22 all furnished glycosyl DTCs
with >95% β selectivity.20
and also by key dipolar couplings between rings B and D
via 2D-ROESY analysis. It is worth mentioning that
hexasaccharide glycal 22 could also be oxidized into an
epoxyglycal with DMDO and coupled with trisacchar-
ide acceptor 21 using modified glycal assembly condi-
tions (see the Supporting Information for partial
characterization). However, the expected nonasacchar-
ide glycal could not be isolated by chromatographic
separation, possibly because of the sensitivity of the
strained β-1,3-linkages.
Remarkably, the internal β-glucoside at the newly
formed 1,3-linkage (ring D) of hexasaccharide 22 was
significantly distorted from a chair (4C1) conformation
(J1,2 = 5.3 Hz), despite the torsional constraints imposed
by the 4,6-benzylidene acetal. Additional NMR analysis of
ring D suggested a twist-boat conformation, which may
serve to alleviate steric interactions with neighboring re-
sidues on ring B (see the Supporting Information). This is
in accord with earlier reports of anomalously low J1,2
values for one or more pyranosides in protected derivatives
of 1,3-linked β-glucans.32 The β configuration of ring D
was eventually confirmed by 13C NMR analysis of its
anomeric carbon (δ(C1D) 99.8 ppm; 1JCH = 166.1 Hz)33
In conclusion, glycal assembly via the in situ generation of
2-O-Bz glycosyl DTCs is competitive with standard methods
of preparing β-linked oligosaccharides while reducing the
burden of isolating and purifying synthetic intermediates.
Glycal donors can be coupled with sterically congested
acceptors under mild conditions to enable the expedient
assembly of complex β-glucans, including those whose inter-
nal linkages exhibit considerable torsional strain.
Acknowledgment. Financial support was provided by
the National Institutes of Health (GM-06982), the National
Science Foundation (CHE-0957738), and a predoctoral
scholarship from the Royal Thai government for P.P. We
also acknowledge NMR and MS support from the Purdue
University Center for Cancer Research and Dr. John
Harwood for assistance with 2D NMR experiments.
(31) We note that glycal coupling with donor as the limiting agent is
also high-yielding (Table 2, entry 3) and permits recovery of excess
acceptor, but limiting the acceptor is more practical in this case because
of ease of purification.
(32) (a) Collins, P. M.; Ali, M. H. Tetrahedron Lett. 1990, 31, 4517.
Supporting Information Available. Complete experi-
mental details and NMR spectra of enumerated com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢁ
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(b) Jamois, F.; Ferrieres, V.; Guegan, J.-P.; Yvin, J.-C.; Plusquellec, D.;
Vetvicka, V. Glycobiology 2005, 15, 393. (c) Mo, K. F.; Li, H. Q.; Mague,
J. T.; Ensley, H. E. Carbohydr. Res. 2009, 344, 439. (d) Tanaka, H.;
Kawai, T.; Adachi, Y.; Ohno, N.; Takahashi, T. Chem. Commun. 2010,
46, 8249.
(33) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem. 1983,
41, 27.
The authors declare no competing financial interest.
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