Preparation of C-arylglycals via Suzuki–Miyaura cross-coupling of dihydropyranylphosphates

Article abstract of DOI:10.1016/j.tetlet.2013.10.031

The preparation of C-arylglycals has been accomplished by employing the Suzuki–Miyaura cross-coupling reaction of dihydropyranylphosphates with arylboronate esters. The reaction is tolerant of both electron-donating (EDG) and electron-withdrawing (EWG) gr

Full text of DOI:10.1016/j.tetlet.2013.10.031

Tetrahedron Letters 54 (2013) 6889–6891
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of C-arylglycals via Suzuki–Miyaura cross-coupling
of dihydropyranylphosphates
⇑
Michelle R. Leidy, J. Mason Hoffman, Rongson Pongdee
Department of Chemistry, Sewanee: The University of the South, 735 University Avenue, Sewanee, TN 37383-1000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of C-arylglycals has been accomplished by employing the Suzuki–Miyaura cross-
coupling reaction of dihydropyranylphosphates with arylboronate esters. The reaction is tolerant of both
electron-donating (EDG) and electron-withdrawing (EWG) groups on the aromatic ring and affords the
corresponding C-arylglycals in good to excellent yields (68–97%). Additionally, the ketene acetal
Received 15 September 2013
Revised 5 October 2013
Accepted 7 October 2013
Available online 12 October 2013
phosphate derived from 6-deoxy-3,4-di-O-benzyl-
L
-rhamnal also couples efficiently to yield C-arylglycals
in excellent yields.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Carbohydrates
Deoxysugars
Glycosides
Natural products
Suzuki–Miyaura
C-glycosides are prevalent structural features among
glycosylated secondary metabolites, many of which possess
intriguing and potent biological activities that may find clinical
use for the treatment of a number of infectious diseases.1 Some rep-
resentative examples, shown in Figure 1, include aquayamycin (1),
galtamycin (2), and medermycin (3) to mention only a few.2 This
general class of compounds has attracted considerable attention
from medicinal chemists as biological probes or enzyme inhibitors
due to their increased resistance to chemical or biological degrada-
tion. In addition, investigations by Kishi and co-workers have found
that C- and O-glycosides exhibit similar three-dimensional confor-
mations in solution making C-glycosides ideally suited to serve as
substrate mimics to investigate various biological phenomena.3
Over the years, numerous synthetic approaches have been
reported for the construction of C-arylglycals.4 The development
of these methods has primarily been fueled by the pivotal role that
C-arylglycals perform as synthetic precursors for the establishment
of 2-deoxy-b-C-arylglycosidic linkages. While aspects of these
processes are attractive, potential drawbacks relating to the strong
acidity or basicity of the reaction conditions, the required
stereochemical assembly of the glycosyl donors, the extremely frag-
ile nature of the necessary starting materials, or difficulties associ-
ated with controlling the regiochemical incorporation of the sugar
unit may hinder their applicability for the rapid development of
C-arylglycosides as potential medicinal compounds.
To circumvent these obstacles toward the efficient synthesis of
C-arylglycals, we envisioned the functionalization of sugar lactones
⇑
Corresponding author. Tel.: +1 931 598 1846; fax: +1 931 598 1145.
E-mail address: rpongdee@sewanee.edu (R. Pongdee).
Figure 1. Structures of natural products containing C-glycosides.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.031

6890
M. R. Leidy et al. / Tetrahedron Letters 54 (2013) 6889–6891
Table 1
With the results of our initial feasibility and optimization study
in-hand, we turned our attention toward exploring the substrate
scope for our newfound process. We envisioned exploring both
substituted electron-poor and electron-rich arylboronate esters
to determine the overall robustness of our method. As depicted
in Table 2, a wide-range of substrates coupled efficiently under
our optimized conditions to provide the corresponding C-arylgly-
cals. Yields were excellent, across the board, and varied marginally
among ortho-(entries 1–3), meta-(entries 4–7), and para-(entries
8–15) substituted arylboronate esters.9 Additionally, the cross-
coupling of electron-rich arylboronate esters, substrates that
sometimes prove difficult, almost universally afforded C-arylgly-
cals in excellent yields. We believe it is worth mentioning that un-
like other palladium-catalyzed syntheses of C-arylglycals
employing either pyranylindium or glycal tin reagents, the use of
ketene acetal phosphate electrophiles did not result in the forma-
tion of any dimerized by-products derived from 4.4g,t Furthermore,
while structurally similar ketene acetal triflates have been utilized
in cross-coupling events, these intermediates suffer from instabil-
ity as well as poor conversions in both their formation and subse-
quent bond-forming reactions.10 On the other hand, cyclic ketene
acetal phosphates enjoy significantly higher stabilities as well as
dramatically improved coupling efficiencies, as witnessed not only
in our method, but in related systems as well.11
Optimization of Suzuki–Miyaura cross-coupling of dihydropyranylphosphate 4
Entry
Catalyst
Base
Solvent
Additive
Et3N
Yield (%)
1
2
3
4
5
Cl2Pd (dppf)
Cl2Pd (dppf)
NiCl2(PCy3)2
(Ph3P)4Pd
Na2CO3
K3PO4
K3PO4
Na2CO3
Na2CO3
THF
THF
Dioxane
THF
THF
51
23
10
94
91
(Ph3P)4Pd
as an ideal method for the construction of this important architec-
tural motif. More specifically, we desired to explore the feasibility
of utilizing carbohydrate-derived ketene acetal phosphates within
the context of a Suzuki–Miyaura cross coupling reaction with
arylboronate esters. Over the years, transition-metal mediated
approaches toward the construction of complex structural frame-
works have undergone exponential growth.5 While the use of
phosphate electrophiles has been previously documented, we were
surprised by the relatively few examples utilizing this functional
group, compared to halogens or sulfonates, despite their ready
availability and ease of preparation.6
Our initial efforts focused on identifying the optimal reaction
conditions for our proposed reaction and are shown in Table 1.
We were pleased to observe that all of the conditions we at-
tempted resulted in the formation of 6a, establishing the feasibility
of our proposed coupling process. Additionally, palladium catalysis
utilizing either Cl2Pd(dppf) or (Ph3P)4Pd, proved substantially
more efficient than NiCl2(PCy3)2, which had been shown to work
well for the coupling of arylphosphates with arylboronic acids.7
Furthermore, the difference in yield was negligible when triethyl-
amine (Et3N) was employed as an additive (entry 5 versus entry
4). However, previous reports from our laboratory had detailed
the beneficial effects of incorporating Et3N in the reaction mixture
and we elected to continue its use in the development of our
method.8
With our survey of substrate scope complete, we next focused
on extrapolating our model system to actual sugar substrates.
Since numerous biologically-active secondary metabolites possess
2,6-dideoxy-b-C-arylglycosidic linkages, we elected to investigate
the coupling of the ketene acetal phosphate derived from
nal as illustrated in Scheme 1.12 Our synthesis originated with 3,
4-di-O-acetyl- -rhamnal (7), which is readily available from
rhamnose via a Fischer–Zach reaction sequence.13 As such, Zém-
plen deacetylation of using catalytic sodium methoxide
(NaOCH3) followed by benzylation of the resulting diol under stan-
L-rham-
L
L-
7
dard conditions (BnBr, NaH) furnished 3,4-di-O-benzyl-L-rhamnal
(8) in excellent overall yield for the two-step process.4x Next,
subjection of glycal 8 to an oxymercuration/demercuration se-
quence, as described by Piancatelli, afforded an anomeric mixture
of C(1)-OH groups that was immediately treated with buffered
pyridinium chlorochromate (PCC) to afford the necessary lactone
Table 2
Substrate scope for Suzuki–Miyaura cross-coupling of dihydropyranylphosphate 4
Entry
Boronate ester
Product
Yield (%)
1
2
3
4
5
6
7
8
5b, R = 2-OCH3
5c, R = 2-N(CH3)2
5d, R = 2-CHO
5e, R = 3-OCH3
5f, R = 3,5-OCH3
5g, R = 3-NO2
5h, R = 3-CN
5i, R = 4-OCH3
5j, R = 4-SCH3
5k, R = 4-C(CH3)3
5l, R = 4-NHBoc
5a, R = 4-NO2
5m, R = 4-C(O)N(CH3)(OCH3)
5n, R = 4-CO2CH3
5o, R = 4-COCH3
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6a
6m
6n
6o
85
68
95
95
90
96
77
95
95
81
89
97
97
92
91
9
10
11
12
13
14
15
Scheme 1. Reaction Conditions: (a) NaOCH3, MeOH (90%); (b) BnBr, NaH, DMF
(89%); (c) Hg(OAc)2, THF/H2O; then NaBH4 (76%); (d) PCC, NaOAc, 4 Å MS, CH2Cl2
(87%); (e) CIP(O)(OPh)2, THF/HMPA, À78 °C; then LHMDS (61%); (f) 5i, 20 mol %
(Ph3P)4Pd, 2 M Na2CO3, Et3N, THF, reflux (88%).

M. R. Leidy et al. / Tetrahedron Letters 54 (2013) 6889–6891
6891
intermediate 9 in good yield.13–15 Employing similar conditions for
the formation of model phosphate 4, lactone 9 was smoothly con-
verted to ketene acetal phosphate 10 employing lithium bis(tri-
methylsilyl)amide (LHMDS) and diphenylphosphoryl chloride.16
At this juncture, we were now poised to examine the applicability
of our method to a real sugar substrate. Disappointingly, our initial
attempts at the conversion of phosphate 10 to C-arylglycal 11
proved unsuccessful. After careful consideration, we postulated
that chelation of the palladium catalyst to the electron-rich oxygen
atoms present in 10 was inhibiting the progress of the reaction.4i,17
With this in-mind, we were gratified to observe the formation of C-
arylglycal 11 in excellent yield (88%) upon increasing the catalyst
loading to twenty mole percent.
In summary, we have developed an efficient and robust method
for the construction of C-arylglycals from dihydropyranylphos-
phates with arylboronate esters under Suzuki–Miyaura conditions.
Our method is flexible and is tolerant of various electron-donating
and electron-withdrawing groups at the ortho-, meta-, and para-
positions on the aromatic ring. Additionally, carbohydrate-derived
ketene acetal phosphates work equally well to produce more com-
plex C-arylglycals as exemplified by the synthesis of 11. Further-
more, the endocyclic olefin of 11 can be readily reduced to afford
the corresponding 2-deoxy-b-C-arylglycosidic linkage, prevalent
among angucycline antitumor antibiotics, employing either cata-
lytic hydrogenation over Adams’ catalyst (H2/PtO2) or sodium cya-
noborohydride (NaBH3CN) in ethanolic hydrochloric acid.4i,t,18 Our
application of this method within the context of natural product
synthesis will be reported in due course.
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Acknowledgments
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of cases. Additionally, the current method has also allowed for an expansion of
substrate scope as C-arylglycals that were previously inaccessible using
arylboronic acids (5c, 5e, 5f, 5k, 5m) are efficiently produced employing
arylboronate esters. Most importantly, the use of arylboronic acids failed to
produce any C-arylglycals when carbohydrate-derived ketene acetal phosphate
10 was employed under a variety of reaction conditions.
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This Letter is dedicated to Professor Carmelo J. Rizzo of Vander-
bilt University on the occasion of his 51st birthday. We gratefully
acknowledge financial support from the National Institute of Al-
lergy and Infectious Diseases (R15, AI084075-02). Additionally,
we thank the National Science Foundation, as part of its Major Re-
search Instrumentation (MRI) Program (CHE-1126231), for the
acquisition of a JEOL ECS-400 Nuclear Magnetic Resonance Spec-
trometer. Accurate mass measurements were performed by Dr.
William Boggess of the Mass Spectrometry and Proteomics Facility
at the University of Notre Dame.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.031.
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