A sequential indium-mediated aldehyde allylation/palladium-catalyzed cross-coupling reaction in the synthesis of 2-deoxy-β-aryl glycosides

Article abstract of DOI:10.1021/ol901353f

Image Presented Indium-mediated allylation of aldehydes with 2-chloro-3-iodopropene, followed by a palladium-catalyzed cross-coupling reaction with triarylindium reagents or arylboronic acids, leads to aryl-substituted homoallylic alcohols in good to exce

Full text of DOI:10.1021/ol901353f

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3734-3737
A Sequential Indium-Mediated Aldehyde
Allylation/Palladium-Catalyzed
Cross-Coupling Reaction in the
Synthesis of 2-Deoxy-ꢀ-C-Aryl
Glycosides
John Alec Moral, Seong-Jin Moon, Samuel Rodriguez-Torres, and
Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State UniVersitysNorthridge,
Northridge, California 91330
thomas.minehan@csun.edu
Received June 16, 2009
ABSTRACT
Indium-mediated allylation of aldehydes with 2-chloro-3-iodopropene, followed by a palladium-catalyzed cross-coupling reaction with triarylindium
reagents or arylboronic acids, leads to aryl-substituted homoallylic alcohols in good to excellent yields and diastereoselectivities. The products
obtained from reactions conducted with D-glyceraldehyde acetonide can be transformed into 2-deoxy-ꢀ-C-aryl ribofuranosides in high overall
yields. Similarly, 2-deoxy-ꢀ-C-aryl allopyranosides may be prepared efficiently from 2,4-O-benzylidene erythrose.
C-Aryl glycosides are an important class of naturally
occurring compounds with unique chemical and biological
properties.1 Possessing a carbon-carbon bond between
aromatic and carbohydrate moieties, these substances are
endowed with remarkable stability toward acid and enzymatic
hydrolysis; this affords them a sufficient intracellular lifetime
to allow trafficking to the nucleus, where they bind DNA to
form stable complexes.2 Indeed, numerous members of the
glycosyl arene family have been shown to possess antibacte-
rial, antitumor, and antifungal activities. These characteristics,
in addition to limited availability from natural resources,
mark these compounds as intriguing and timely targets for
total synthesis.
Many previous approaches to the synthesis of C-aryl
glycosides focus on achieving efficient formation of the
aryl-glycosidic carbon-carbon bond.3 Refinement of acti-
vating groups,4 the use of lanthanide Lewis acids as
(3) (a) Jaramillo, C.; Knapp, S. Synthesis 1994, 1, 1. (b) Levy, D. E.;
Tang, C. The Chemistry of C-glycosides; Elsevier Science: Tarrytown, NY,
1995. (c) Postema, M. H. D. C-Glycoside Synthesis; Rees, C. W., Ed.; CRC
Press: Boca Raton, FL, 1995. (d) Nicotra, F. Top. Curr. Chem. 1997, 187,
55. (e) Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54, 9913.
(4) (a) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1988,
29, 6935. (b) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. Tetrahedron
Lett. 1989, 30, 6185. (c) Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron
Lett. 1990, 31, 4629. (d) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K.
J. Am. Chem. Soc. 1991, 113, 6982.
(1) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249, and
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(2) Hacksell, U.; Daves, G. D. Prog. Med. Chem. 1985, 22, 1.
10.1021/ol901353f CCC: $40.75
Published on Web 07/24/2009
 2009 American Chemical Society

promoters,5 and improvements in transition-metal-mediated
couplings6 have now made possible the total synthesis of
complex natural products possessing the C-aryl glycoside
functional group. Despite this progress, concerns about the
use and disposal of environmentally hazardous reagents,
solvents, and heavy metals have motivated chemists to
investigate alternative “green” methods for forming carbon-
carbon bonds, the backbone of all organic compounds.
dehyde acetonide (1a) with 2,3-dihalopropenes. Stirring a
DMF (or 1:1 DMF:H2O) solution of 1a with 1.5 equiv of
2,3-dibromopropene 2a and 1 equiv of indium metal led to
the desired homoallylic alcohol product in a disappointing
20% yield (Scheme 1). Careful study of the reaction revealed
Scheme 1. Glyceraldehyde Allylation with 2,3-Dihalopropenes
Organoindium compounds have been shown to participate
in a wide range of transition-metal-mediated processes for
carbon-carbon bond formation.7 These environmentally
benign reagents are air- and moisture-stable and can undergo
cross-coupling reactions in an atom-efficient manner.8 Fur-
thermore, the indium-mediated allylation of aldehydes and
ketones in aqueous media is a powerful and stereoselective
process that has been applied to the synthesis of a variey of
complex natural products.9 In this letter, we detail our
findings on a sequential indium-mediated carbon-carbon
bond-forming process that efficiently establishes the carbon
backbone of 2-deoxy-C-aryl glycosides.
Motivated by the studies of Otera and Alcaide10 and
others11 on the tin-mediated Barbier-type allylation of
aldehydes with 2,3-dibromopropene, and hoping to avoid the
use of toxic metals and acidic conditions required for such
couplings, our initial investigations centered around the
indium-mediated allylation of readily available D-glyceral-
that addition of the indium metal to 2a in the presence or
absence of glyceraldehyde acetonide led to a vigorous
exothermic reaction and the visible production of gas. We
reasoned that, upon formation, the 2-bromoallylindium
reagent undergoes a rapid decomposition to indium bromide
and allene. In contrast, Li has previously reported the high-
yielding allylation of aldehydes with 3-bromo-2-chloropro-
pene in water.12 Since 2,3-dichloropropene is commercially
available and inexpensive, we decided to investigate the
allylation of D-glyceraldehyde acetonide with this reagent
in the presence of an iodide source to generate the more
reactive 3-iodo-2-chloropropene in situ. Indeed, addition of
indium metal (1 equiv) and TBAI (1 equiv) to a 2 M DMF
solution of glyceraldehyde and 2,3-dichloropropene (2b, 1.5
equiv) led to homoallylic alcohol 4 in 92% yield and 7:1
diastereoselectivity; the major diastereomer was assigned the
anti stereochemistry in analogy with previously reported
indium allylations of glyceraldehyde.13 The allylation reac-
tion takes place with similar efficiency (89% yield) and
diastereoselectivity (dr ) 6.5:1) in 1:1 DMF:H2O when
2-chloro-3-iodopropene14 is employed as the allyl source.
Subsequent cross-coupling of 4 with 1 equiv of Ph3In in the
presence of Pd(dppf)Cl2 (5 mol %) at 80 °C for 18 h
proceeded uneventfully,7j providing an 83% yield of 5a, the
spectral data of which matched closely those reported for
the same compound by Wang et al.13 Similarly, treatment
of Garner’s aldehyde 1d with 2b in the presence of indium
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to promote C-aryl glycosidations. See: Toshima, K.; Matsuo, G.; Tatsuta,
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(14) 2-Chloro-3-iodopropene was prepared by treatment of commercially
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Org. Lett., Vol. 11, No. 16, 2009
3735

metal led to anti-vinyl chloride 6c in 62% yield and 2.5:1
diastereoselectivity, in line with the previous allylation
studies of Paquette;15 palladium-catalyzed cross-coupling of
6c with Ph3In furnished alcohol 7 in 71% yield. However,
allylation of either 2-O-benzyl-L-glyceraldehyde16a (1b) or
2-O-triisopropylsilyl-L-glyceraldehyde16b (1c) was essentially
nondiastereoselective (dr ) 1.2-1.5:1), producing vinyl
chlorides 6a and 6b, respectively, in moderate yields.
Ultimately, it was revealed that both the allylation and
cross-coupling reactions could be performed sequentially
without purification of the intermediate homoallylic alcohol:
crude 4 obtained from a simple extractive work up of the
allylation reaction was directly treated with the reagents for
cross-coupling, and the reaction was heated for 16-36 h.
To explore the scope of this process, we tested cross-coupling
with a variety of aryl- and heteroarylindium reagents. Both
electron-rich (Table 1, entries 2 and 6) and electron-deficient
Employing tributylindium (entry 13) in the cross-coupling
led to the formation of reduced products due to a facile
ꢀ-hydride elimination/reductive elimination sequence. How-
ever, arylboronic acids could be efficiently used in place of
arylindium reagents (entries 8-10) when slightly modified
reaction conditions were employed for the cross-coupling
(1.5 equiv of ArB(OH)2, 3 of equiv Na2CO3 (2 M), 3:1
toluene:EtOH, 90 °C, 18-21 h). Optimal yields were
obtained with 1 equiv of triarylindium reagent or 1.5 equiv
of arylboronic acid. Employing decreased amounts of these
reagents led to significantly increased reaction times and
lower overall yields.
Although this method did not furnish products containing
sterically encumbered, ortho-substituted aryl groups, these
substrates could be prepared by an alternate route involving
Xiao’s R-regioselective Heck arylation of allyl alcohol,18
allylic iodide formation, and indium-mediated glyceraldehyde
allylation in aqueous media (Scheme 2). This procedure
Table 1. Scope of the Sequential Glyceraldehyde Allylation/
Arylindium Cross-Coupling Reactiona
Scheme 2. Synthesis of Substrates Containing
Sterically-Hindered Aryl Moieties
5b (% yield
entry
R
temp (°C) time (h)
5
from 1a)
1
2
3
4
5
6
7
8
Ph
80
80
80
80
80
80
80
90
90
18
16
36
17
18
22
20
18
21
18
48
48
24
a
b
c
d
e
f
g
h
i
75
68
78
86
88
65
58
87
69
51
<10
<5
--
4-MeO-C6H4
4-Me-C6H4
4-Cl-C6H4
3-F-C6H4
afforded alcohols 5k,l in ∼40% overall yield and 3:1
diastereoselectivity.
2-Deoxy-ꢀ-C-aryl glycofuranosides have recently gained
heightened importance as non-natural nucleoside ana-
logues.19,20 Given that our arylated products contain the
carbon backbone of 2-deoxyribose, we envisioned that they
could be transformed into C-aryl ribofuranosides in a
straightforward manner. Benzylation of 5a, acetonide depro-
tection, and regioselective silylation of the primary hydroxyl
group took place in 80% overall yield. Oxidative cleavage
of the alkene (cat. OsO4, NMO, acetone/H2O; KIO4, pH 6.5
buffer) gave 9a as a mixture of C.1 anomers; stereoselective
ketol reduction (Et3SiH, TESOTf, CH2Cl2, -78 °C) then
provided the target 1-phenyl-2-deoxyribofuranoside 10a with
>10:1 ꢀ:R stereoselectivity. The undesired diastereomer at
2-furyl
3-CF3-C6H4
2-naphthylc
4-CO2Me-C6H4
3-pyridylc
2-Me-C6H4
1-naphthyl
Bu
c
9
10
11
12
13
90
j
k
l
100
100
80
m
a Reaction conditions: (a) 2,3-dichloropropene (1.5 equiv), In (1 equiv),
TBAI (1 equiv), DMF (2 M), rt, 6 h. b Isolated yield after silica gel
chromatography. c The corresponding arylboronic acid (ArB(OH)2) was
employed for the cross-coupling reaction. Conditions: 1.5 equiv of
ArB(OH)2, 3 equiv of Na2CO3 (2 M), 5 mol % of Cl2Pd(dppf), 3:1 toluene:
EtOH, 90 °C, 18-21 h.
(16) (a) Steuer, B.; Wehner, V.; Lieberknecht, A.; Jager, V. Org. Synth.
1997, 71, 1. (b) McNulty, J.; Mao, J. Tetrahedron Lett. 2002, 43, 3857.
(17) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020. (b) Singh, R.; Viciu, M. S.; Kramareva, N.; Navarro, O.; Nolan, S. P.
Org. Lett. 2005, 7, 1829.
(entries 4, 5, and 7) arylindiums cross-couple efficiently.
However, sterically hindered arylindiums (entries 11 and 12)
such as tris-2-tolylindium or tris-1-naphthylindium provided
negligible yields (<10%) of coupled products even at elevated
temperatures (100 °C) and with extended reaction times (48
h). The use of alternative catalyst systems, such as Fu’s P(t-
Bu)3/Pd2(dba)3 and PCy3/Pd(OAc)2 systems17a or Nolan’s
NHC/Pd(OAc)2 complexes,17b afforded no significant im-
provement in the yields of 5k and 5l obtained (∼10-20%).
(18) (a) Mo, J.; Xu, L.; Ruan, J.; Liu, S.; Xiao, J. Chem. Commun. 2006,
34, 3591. (b) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751.
(c) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45, 4152.
(19) (a) Schweitzer, B. A.; Kool, E. T. J. Org. Chem. 1994, 59, 7238.
(b) Schweitzer, B. A.; Kool, E. T. J. Org. Chem. 1995, 60, 8326. (c) Ren,
X.-F.; Schweitzer, B. A.; Sheils, C. J.; Kool, E. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 743. (d) Ren, X.-F.; Chaudhuri, N. C.; Kool, E. T. J. Am.
Chem. Soc. 1996, 118, 7671
(20) (a) Schweitzer, B. A.; Kool, E. T. J. Am. Chem. Soc. 1995, 117,
1863. (b) Moran, S.; Rem, R. X.-F; Rumney, S.; Kool, E. T. J. Am. Chem.
.
(15) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.; Schomer,
W. W. J. Org. Chem. 1997, 62, 4293.
Soc. 1997, 119, 2056.
3736
Org. Lett., Vol. 11, No. 16, 2009

C.3 formed in the allylation step could be easily separated
at this stage by silica gel chromatography; the overall yield
of 10a from compound 5a was 58% (Scheme 3). Compounds
Scheme 5. Synthesis of 2-Deoxy ꢀ-C-Aryl Glycosides 15a-c
Scheme 3. Synthesis of 2-Deoxy-C-arylfuranosides 10 from 5
of 12 with triphenylindium led to styrene 13a in 70% yield.
Suzuki coupling of 12 with 3-fluorophenylboronic acid or
2-naphthaleneboronic acid gave rise to 13b and 13c in 56%
and 88% yields, respectively.
5e, 5g, 5h, and 5i can be transformed into C-aryl glycosides
10e, 10g, 10h, and 10i in an analogous manner in 51-70%
overall yields. The stereochemistry of the products was
confirmed by analysis of cross peaks observed in the NOESY
spectrum of 10h (see Supporting Information for details).
To extend this process to the synthesis of C-aryl pyrano-
sides, we investigated allylation reactions of glucose-derived
aldehyde 1121 with 2,3-dichloropropene under our standard
conditions. Vinyl chloride 12 was obtained in low (30%)
yield; however, when 2-chloro-3-iodopropene 2c was used
as the allyl source and the reaction was conducted under
aqueous conditions (1:1 DMF:H2O), a 78% yield of 12 was
obtained. In both cases, only a single diastereomer was
Compound 13a, containing the carbon backbone of
2-deoxyallose, was then subjected to standard olefin oxidative
cleavage conditions, and subsequent silyl protection of the
C.3 alcohol produced ketol 14a. Treatment with excess
Et3SiH and TESOTf at -78 °C led to reduction of the C.1
ketol and opening of the benzylidene acetal in a regioselec-
tive fashion to provide ꢀ-C-aryl glycoside 15a in 80% overall
yield from 13a (Scheme 5). Compounds 13b and 13c could
be similarly transformed into C-glycosides 15b and 15c in
69-90% overall yields. The 11.2 Hz coupling constant
observed for the anomeric protons in 15a-c confirmed the
ꢀ-orientation of the aryl groups at C.1 of the carbohydrates.
Importantly, the differential protection of the three hydroxyl
groups on glycosides 15a-c allows for regioselective
unmasking for subsequent O-glycosylation reactions.
1
evident by H NMR, indicating <95:5 diastereoselectivity
for the reactions. We suspect that a highly organized
transition state, such as that represented by structure A in
Scheme 4, is responsible for the high level of diastereose-
The sequential indium-mediated aldehyde allylation/pal-
ladium-catalyzed cross-coupling process efficiently estab-
lished the carbon backbone of 2-deoxy-C-aryl ribofuranosides
and allopyranosides, and subsequent transformations stereo-
selectively furnish glycosides with differential hydroxyl
protection. We are currently exploring the utility of this
method in the context of natural product synthesis.
Scheme 4
.
Diastereoselective Allylation of 2,4-O-Benzylidene
Erythrose 11
Acknowledgment. We thank the National Institutes of
Health (SC2 GM081064-01), the ACS Petroleum Research
Fund (No. PRF 45277-B1), and the Henry Dreyfus Teacher-
Scholar Award for their generous support of our research
program.
Supporting Information Available: Detailed experimen-
lection observed in this process.13d The resulting 2,3-anti,
3,4-anti stereorelationship was deduced by analysis of the
NOESY spectrum of acetonide derivative 16a (vide infra,
Scheme 5). Subsequent palladium-catalyzed cross-coupling
1
tal procedures, spectroscopic data, and H and 13C NMR
spectra for all compounds in Table 1 and Schemes 1-5, as
well as NOESY spectra for compounds 10h and 16a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003,
125, 492.
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