Sn-free Ni-catalyzed reductive coupling of glycosyl bromides with activated alkenes

Article abstract of DOI:10.1021/ol8028737

A mild, stereoselective method for the Ni-catalyzed synthesis of α-C-alkylglycosides is reported. This approach entails the reductive coupling of glycosyl bromides with activated alkenes at room temperature, with low alkene loading as an important feature. Diastereoselective coupling with 2-substituted acrylate derivatives was made possible through the use of 2,4-dimethyl-3-pentanol as a proton source.

Full text of DOI:10.1021/ol8028737

ORGANIC
LETTERS
2009
Vol. 11, No. 4
879-882
Sn-Free Ni-Catalyzed Reductive
Coupling of Glycosyl Bromides with
Activated Alkenes
Hegui Gong, R. Stephen Andrews, Joseph L. Zuccarello, Stephen J. Lee,† and
Michel R. Gagne´*
UniVersity of North Carolina at Chapel Hill, Department of Chemistry, Chapel Hill,
North Carolina 27599, and U.S. Army Research Office, P.O. Box 12211, Research
Triangle Park, North Carolina 27709
mgagne@unc.edu
Received December 13, 2008
ABSTRACT
A mild, stereoselective method for the Ni-catalyzed synthesis of r-C-alkylglycosides is reported. This approach entails the reductive coupling
of glycosyl bromides with activated alkenes at room temperature, with low alkene loading as an important feature. Diastereoselective coupling
with 2-substituted acrylate derivatives was made possible through the use of 2,4-dimethyl-3-pentanol as a proton source.
The utility of C-glycosides as stabilized biological isosteres
in pharmaceutical or biological research, as well as their
appearance in natural products and their potential as useful
building blocks for complex molecule synthesis, have been
recognized for decades.1,2 This has led to a variety of
synthetic approaches to C-glycosides,3 one of the more
recognizable being the reductive trapping of glycosyl radicals
with activated alkenes. First demonstrated by Giese and
Baldwin for Bu3SnH-mediated radical chain processes,4 it
has since been reported in reactions that employ transition-
metal complexes5 as stoichiometric promoters6 or catalysts.7
A ubiquitous feature in each variant is the stereoselective
formation of an axial C-C linkage between the glycoside
and the coupling partner. Unfortunately, they also suffer from
needing a significant excess (6-20 equiv) of the alkene
partner and the requirement for stoichiometric amounts of a
toxic heavy metal and/or moderate yields.
In light of these limitations, we postulated that a Ni
catalyst, if appropriately tuned and partnered with a conve-
nient and environmentally benign stoichiometric reductant
and proton source, could improve the synthesis of C-
glycosides. Intriguing was the possibility that a glycosyl
(4) (a) Cotanda, K.; Matsugi, M.; SueMura, M.; Ohira, C.; Sano, A.;
Oka, M.; Kita, Y. Tetrahedron 1999, 55, 10315. (b) Giese, B.; Dupuis, J.;
Nix, M. Org. Synth. 1987, 65, 236. (c) Dupuis, J.; Giese, B.; Hartung, J.;
Leising, M.; Korth, H.-G.; Sustmann, R. J. Am. Chem. Soc. 1985, 107,
4332. (d) Giese, B.; Dupuis, J. Angew. Chem., Int. Ed. Engl. 1983, 22,
622. (e) Adlington, R. M.; Baldwin, J. E.; Basak, A.; Kozyrod, R. P.
J. Chem. Soc., Chem. Commun. 1983, 944.
† U.S. Army Research Office.
(1) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon:
Tarrytown, NY, 1995
.
(5) For a leading review on transition-metal-mediated radical reactions,
see: Gansa¨uer, A.; Bluhm, H. Chem. ReV. 2000, 100, 2771.
(6) For Mn, see: (a) DeShong, P.; Slough, G. A.; Elango, V. Carbohydr.
Res. 1987, 171, 342. (b) For Ti, see: Parrish, J. D.; Little, R. D. Org. Lett.
2002, 4, 1439. (c) Spencer, R. P.; Schwartz, J. J. Org. Chem. 1997, 62,
4204. (d) For Cr, see: Juhasz, Z.; Micskei, K.; Gal, E.; Somsak, L.
Tetrahedron Lett. 2007, 48, 7351.
(2) For recent reviews in C-glycoside biology, see: (a) Lin, C.-H.; Lin,
H.-C.; Yang, W.-B. Curr. Top. Med. Chem. 2005, 5, 1431. (b) Hultin, P. G.
Curr. Top. Med. Chem. 2005, 5, 1299. (c) Zou, W. Curr. Top. Med. Chem.
2005, 5, 1363. (d) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001,
9, 3077. (e) Nicotra, F. Top. Curr. Chem. 1997, 187, 55
.
(3) (a) Meo, P.; Osborn, H. M. I. Best Synthetic Methods: Carbohydrates;
Elsevier Science Ltd.: New York, 2003; p 337. (b) Somsak, L. Chem. ReV.
2001, 101, 81. (c) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998,
54, 9913. (d) Postema, M. H. D. C-Glycoside Synthesis; CRC Press, Inc.:
Boca Raton, FL, 1995.
(7) (a) Catalytic Co/stoichiometric Zn: Scheffold, R.; Abrecht, S.;
Orlinski, R.; Ruf, H.-R. Pure Appl. Chem. 1987, 59, 363. (b) Catalytic Ni(II)/
stoichiometric Mn: Readman, S. K.; Marsden, S. P.; Hodgson, A. Synlett
2000, 1628.
10.1021/ol8028737 CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

Table 1. Optimization of the Reaction Conditions for the
Coupling of Glucosyl Bromide 1 with Methyl Acrylatea
Table 2. Substrate Scope for Coupling of Monosubstituted
Alkenes with Glucosyl Bromide 1a
entry
catalyst/ligand/solvent
product 2 (%)
glucal 3 (%)
1
2
3
4
5
6
7
8
9
Ni(COD)2/6a/DMA
Ni(COD)2/6b/DMA
Ni(COD)2/6c/DMA
Ni(COD)2/(S)-6b/DMA
Ni(COD)2/7a/DMA
Ni(COD)2/7b/DMA
Ni(COD)2/6b/DMF
Ni(COD)2/6b/DMI
Ni(COD)2/6b/THF
Ni(COD)2/6b/CH3CN
Ni(COD)2/none/DMA
none/none/DMA
35
70
69
52
46
54
35
30
trace
40
37
5
12
trace
5
trace
5
8
trace
trace
trace
12
24
major
10
11
12
a Standard reaction conditions used.15
a Standard reaction conditions used.15
by significant amounts of undesired byproducts from ꢀ-e-
limination 3,16 hydrolysis 4, and overaddition 5. Optimization
studies varying ligand and solvent led to a 70% yield of 2
with (R)-Ph-pybox 6b (entry 2), with only trace quantities
of 3, 4, or 5 being observed. Though 6c gave a similar yield,
a slight increase (5%) in glucal 3 was observed (entry 3).
Interestingly, the (S)-enantiomer of 6b reduced the yield to
52% (entry 4), pointing to a stereochemical mismatch
between ligand and sugar. Further changes with respect to
ligand or solvent did not improve the yields (entries 5-10).
Under no conditions was ꢀ-product detected for any reaction.
Control experiments highlighted the critical role of ligand
(entry 11) and Ni(0) (entry 12) for promoting the desired
reactivity in favor of background elimination, which presum-
ably occurs via a glycosyl-Zn species.17
radical8 might be accessible and interceptible from the
reaction of a low-valent Ni source and a glycosyl bromide,
as postulated in the mechanism of our recently disclosed Ni-
catalyzed arylation of glycosyl bromides.9,10 The interme-
diacy of secondary alkyl radicals in Ni-catalyzed cross-
coupling has been previously proposed.11-14
Our investigation began with the reaction of aceto-1-
bromoglucose 1 and methyl acrylate using catalytic
Ni(COD)2, pybox ligand 6a, Zn as the terminal reductant,
NH4Br as a proton source, and DMA as solvent (Table 1,
entry 1).15 Encouraging was the 35% yield of the desired
R-C-glucoside product 2; however, this was accompanied
(13) For examples of SmI2-mediated C-glycoside synthesis invoking
radical intermediates, see: (a) Malapelle, A.; Coslovi, A.; Doisneau, G.;
Beau, J.-M. Eur. J. Org. Chem. 2007, 3145. (b) Yuan, X. J.; Linhardt, R. J.
Curr. Top. Med. Chem. 2005, 5, 1393. (c) Miquel, N.; Doisneau, G.; Beau,
J.-M. Chem. Commun. 2000, 2347. (d) Hung, S.-C.; Wong, C.-H. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2671. (e) Hung, S.-C.; Wong, C.-H.
Tetrahedron Lett. 1996, 37, 4903. (f) For an example involving Ni co-
catalysis, see: Miquel, N.; Doisneau, G.; Beau, J.-M. Angew. Chem., Int.
Ed. 2000, 39, 4111.
(8) The glucosyl radical is known to adopt a boat conformation, while
the mannosyl radical is a chair: (a) Korth, H.-G.; Sustmann, R.; Dupuis, J.;
Giese, B. J. Chem. Soc., Perkin Trans. 2 1986, 1453. (b) Dupuis, J.; Giese,
B.; Ru¨egge, D.; Fishcer, H.; Korth, H.-G.; Sustmann, R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 896.
(9) Gong, H.; Gagne´, M. R. J. Am. Chem. Soc. 2008, 130, 12177
.
(14) For mechanistic and computational studies that implicate radical
intermediates in Ni-catalyzed Negishi reactions, see: (a) Lin, X.; Phillips,
D. L. J. Org. Chem. 2008, 73, 3680. (b) Jones, G. D.; Martin, J. L.;
McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.; Brandon, R. J.;
Kanovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem.
Soc. 2006, 128, 13175.
(10) For a related example of Ni-catalyzed C-alkylation, see: Gong, H.;
Sinisi, R.; Gagne´, M. R. J. Am. Chem. Soc. 2007, 129, 1908
.
(11) (a) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (b)
Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594. (c) Powell, D. A.;
Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788. (d) Zhou, J. S.; Fu, G. C.
J. Am. Chem. Soc. 2004, 126, 1340
.
(15) Standard reaction conditions: glycosyl bromide (100 mol %), alkene
(200 mol %), Ni(COD)2 (10 mol %), ligand (15 mol %), proton source
(200 mol %), DMA (0.24 M), rt, 12 h. See the Supporting Informationfor
further details.
(16) Subjection of glucal 3 to the standerd conditions in the presence
of methyl acrylate resulted in no reaction.
(12) For examples of cross-coupling with a putative radical cyclization
prior to C-C bond formation, see: (a) Phapale, V. B.; Bun˜uel, E.; García-
Iglesias, M.; Ca`rdenas, D. J. Angew. Chem., Int. Ed. 2007, 46, 8790. (b)
Gonza´lez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360. (c)
Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510
.
880
Org. Lett., Vol. 11, No. 4, 2009

Table 3. Coupling of Glycosyl Bromides with Methyl Acrylatea
Table 4. Optimization of the Diastereoselectivities for the
Coupling of Glucosyl Bromides and Methyl Methacrylatea
glucosyl
entry bromide ligand
proton
source
yield (%) drb
1
2
3
1
27
1
6b
6b
NH4Br
NH4Br
88
75
72
1.4:1
1.6:1
1:1
(S)-6b NH4Br
4
5
1
1
6c
8
NH4Br
NH4Br
87
63
1.4:1
2:1
6
7
8
9
10
11
12
13
14
15
1
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
(-)-sparteine·H2SO4
H2O
63
55
76
81
80
60
2.3:1
4:1
27
27
27
27
27
27
27
27
1
EtOH
3.2:1
4.2:1
5.0:1
3.5:1
1:1
3.4:1
3.7:1
2:1
iPrOH
iPr2CHOH
tBuOH
(S)-binol
NDc
NDc
NDc
90
(R)-2-butanol
(S)-2-butanol
iPr2CHOH
a Standard reaction conditions used.15 b R ) CH2CH2CO2Me.
a Standard reaction conditions used.15 b The dr refers to the stereocenter
R to the methyl ester;22 in all cases, the stereocenter at the anomeric carbon
was formed with exclusive R selectivity. c Not determined.
With optimized reaction conditions in hand, the scope of
the alkene partner was examined (Table 2). Reaction with
acrylate derivatives such as tert-butyl acrylate and acryloni-
trile smoothly produced the desired products 9 and 10,
respectively, in good yields (entry 1 and 2), while (E)-methyl
penta-2,4-dienoate gave the nonconjugated R-glucosyl ester
11 in 65% yield (entry 3). As anticipated, however, styrene-
derived alkenes proved more challenging (entry 4). Reaction
with styrene and 4-methoxystyrene generated only trace
amounts of 12 and 13, respectively, with pyranose 4 being
the major product.18 Given the nucleophilic character of the
glycosyl radical,19 we predicted that electron-poor styrenes
would be more reactive (entry 4, products 14-21), and this
was indeed the case, especially for 4-carbomethoxy- and
4-cyanostyrene.
We next turned our attention to 1,1-disubstituted and
trisubstituted alkenes, with diastereocontrol as an important
goal. To this end, the coupling of glucosyl bromides 1 and
27 with methyl methacrylate was utilized as a probe system
(Table 4). Using the previously optimized conditions, C-
glycoside 28 was obtained in high yield and with excellent
selectivity for the R anomer, but with poor diastereoselec-
tivity (1.4:1) at the stereocenter R to the methyl carboxylate
(entry 1). Use of Bz-protected 27 did not significantly
improve the dr (entry 2), nor did variation of the chiral ligand
(entries 3-5). Chiral, enantiopure methacryloyl esters such
as bornyl or menthyl methacrylate (not shown) also failed
to affect the diastereoselection.
Since protonation of a transition-metal enolate intermediate
was presumed to be stereodetermining, we then examined
the proton source itself. While the use of sterically hindered
ammonium salts such as (-)-sparteine·H2SO4 resulted in
diastereoselectivities only slightly greater than 2:1 (entry 6),
alcohols elucidated clear improvement (entries 7-15).22
Increases in steric bulk and branching improved the dr to
5:1 with iPr2CHOH (entry 10),23 but chiral alcohols (entries
12-14) were inferior. Finally, reaction of Ac-protected 1
In addition to 1, the Ni-catalyzed reductive coupling with
methyl acrylate was successfully extended to other acetate-
protected glycosyl bromides (Table 3, entries 1-3). The R-C-
mannoside and R-C-galactoside products 22 and 23 were
obtained in 76% and 60% yield, respectively, while the
5-dealkylated C-arabinoside was provided in 61% yield with
diminished stereoselectivity.20 Benzoate-protected sugars
were similarly well-behaved (entry 4), while Bn-protected
glucosyl bromide was particularly prone to hydrolysis.21
i
using the Pr2CHOH proton source (entry 15) resulted in
lower diastereoselectivity than that observed for the Bz-
protected 27 (entry 10).
(17) The Zn-mediated reductive elimination of aceto-1-glycosyl bromides
is well known from the Fischer-Zach glycal synthesis: Fischer, E.; Zach,
K. Sitzungsber. Kl. Preuss. Akad. Wiss. 1913, 27, 311.
(18) Attempts to suppress hydrolysis product 4 through the use of
desiccants (molecular sieves, etc.) were unsuccessful.
(21) Attempts to improve yields by using the Bn-protected glucosyl or
mannosyl chlorides failed (no reaction).
(19) For example, see: (a) Liu, Y.; Gallagher, T. Org. Lett. 2004, 6,
2445. (b) SanMartin, R.; Tavassoli, B.; Walsh, K. E.; Walter, D. S.;
Gallagher, T. Org. Lett. 2000, 2, 4051.
(22) Bz-protected products simplified the assessment of dr by 1H NMR;
for this reason, glucosyl bromide 27 was used thereafter.
(23) The configuration of the stereocenter R to the methyl ester in the
major isomer of 29 was determined by single-crystal X-ray analysis (see
the Supporting Information).
(20) For examples of the known difficulty in obtaining high selectivity
in reactions of arabinosyl-type radicals, see refs 1 and 6d.
Org. Lett., Vol. 11, No. 4, 2009
881

Table 5. Coupling of Substituted Alkenes with Glucosyl
Bromides 1 and 27a
Scheme 1.
Ni-Catalyzed Coupling of 27 with 40a
a Standard reaction conditions used,15 with glucosyl bromide 27, ligand
6b, and NH4Br.
(1.2:1 dr) (entry 5), indicating a greater electron-withdrawing
requirement for these more hindered partners.
In addition to the exquisite R-selectivity for the glucosyl
and mannosyl substrates and the need for activated (elec-
trophilic) alkene acceptors,4 the coupling of vinyl cyclopropyl
malonate 40 (Scheme 1) with 27 generated the ring-opened
41 rather than cyclopropane product 42. While the interme-
diacy of radicals explains each of our observations, a
mechanism relying on olefin insertion into a Ni-glycosyl
intermediate followed by transmetalation to zinc cannot be
rigorously ruled out.26
In summary, we have demonstrated a mild, Sn-free Ni-
catalyzed reductive coupling of glycosyl bromides with
electron deficient alkenes featuring low alkene stoichiometry
requirements. The diastereoselectivity of reactions with
2-substituted acrylate derivatives was significantly improved
through the use of iPr2CHOH as a proton source. Efforts to
expand this method are ongoing.
a Standard reaction conditions used.15 b In all cases, the anomeric
stereocenter was formed with exclusive R selectivity. c The R-stereocenter
is drawn by analogy to the crystallographically characterized 29, which
was additionally corroborated by conversion of 33 to 29.25
Acknowledgment. We thank Andrew Parsons (UNC-CH)
for his generous donation of compound 40. J.L.Z. thanks
the National Research Council for a Postdoctoral Fellowship,
S.J.L. thanks the ARO for Staff Research Funding, and
M.R.G. thanks the Department of Energy (DE-FG02-
05ER15630) for generous support.
The optimal conditions for diastereoselective coupling
were then applied to various geminally disubstituted alkenes
(Table 5). Reaction of 27 with R-methylene-γ-butyrolactone
and 3-methacryloyloxazolidin-2-one24 proceeded smoothly
and with good dr (entries 1 and 2). More sterically demand-
ing alkenes like methyl 2-phenylacrylate and (1S,4R)-3-
methylenebicyclo[2.2.1]heptan-2-one (entries 3-4) pro-
ceeded successfully, with applicability to enones being
demonstrated by the latter. Although 3-substituted or trisub-
stituted methyl acrylates generally demonstrated poor reac-
tivity, dimethyl 2-ethylidenemalonate gave 39 in 56% yield
Supporting Information Available: Experimental pro-
cedures and spectra of new compounds and CIF data for
29. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL8028737
(25) Transesterification conditions: Sm(OTf)3 (catalytic), MeOH, CH2Cl2,
rt, 48 h. See: Evans, D. A.; Coleman, P. J.; Carlos Dias, L. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2738.
(26) For recent examples of Ni-catalyzed reductive coupling reactions
involving transmetalation with dialkylzinc species, see: (a) Montgomery,
J.; Sormunen, G. J. Top. Curr. Chem. 2007, 279, 1. (b) Cozzi, P. G.;
Mignogna, A.; Zoli, L. Pure Appl. Chem. 2008, 80, 891.
(24) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984.
882
Org. Lett., Vol. 11, No. 4, 2009