A room temperature Negishi cross-coupling approach to C-alkyl glycosides

Article abstract of DOI:10.1021/ja068950t

Glycosyl halides serve as effective alkyl halides for room temperature Negishi cross-coupling reactions using functionalized alkyl zinc reagents. The catalyst for these reactions is in situ generated (PyBox)NiCl₂. The functional group tolerance on the zinc reagent is typically high, and both benzyl and ester protecting groups on the carbohydrate are tolerated. Anomer selectivities are modest for glucosyl halides but high for mannosyl halides. Copyright

Full text of DOI:10.1021/ja068950t

Published on Web 01/30/2007
A Room Temperature Negishi Cross-Coupling Approach to C-Alkyl
Glycosides
Hegui Gong, Riccardo Sinisi, and Michel R. Gagne´*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Received December 14, 2006; E-mail: mgagne@unc.edu
Table 1. Ligand Screening Results for the Cross-Coupling of
O-Acetyl-R-bromo-D-glucose and MeZn-I
C-Glycosides represent an important class of bioactive com-
pounds that are resistant to metabolic processing.1,2 Although cross-
coupling reactions are obvious approaches to these compounds, the
sensitivity of C1-substituted organometallics to â-elimination pro-
cesses (hydride or alkoxy) is the generally accepted reason why
fully oxygenated and saturated structures are not typically accessible
via these methods.3-5 This notion is generally true of the synthetic
methods that generate nucleophilic character at C1.6 The contrast-
ingly high number of methods for the synthesis of 2-deoxy
C-glycosides2a reinforces the notion of an elimination problem in
C1 organometallics.7
Recent investigations of pincer-ligated organometallic complexes
have shown that these ligands can effectively inhibit â-H elimination
reactions by occupying the cis coordination sites required for
elimination.8,9 Fu has recently shown that iPr-PyBox/Ni (NiCl2,
NiBr2, Ni(COD)2) effectively catalyzes the cross-coupling of 2°
alkyl halides with alkyl zinc reagents without competing â-H
elimination.10 These catalysts therefore seemed the ideal starting
point for the search for cross-coupling methods applicable to the
synthesis of C-glycosides.11
entrya
ligand
yield (
R
:
â)
glucal
1
2
3
4
5
6b
7
8
S-iPr-PyBox
R-iPr-PyBox
S-sBu-PyBox
S-Ph-PyBox
PyBox
terpy
Py-bisimine
terthiophene
50% (1:1.5)
50% (1:1.5)
20% (1:1.5)
trace
76% (1:2.2)
30% (â-only)
NR
10%
9%
trace
NA
6%
trace
NA
trace
major
a Typical reaction conditions: glucosyl bromide (0.24 mmol, 0.24 M in
DMI), NiCl2•DME (0.024 mmol), ligand (0.036 mmol), at room temperature
for 12 h. b NiBr2•glyme in DMI was used.
Table 2. Cross-Coupling Results Using a Primary Alkyl Zinc
Reagent with Various Aceto-Protected R-Bromo Sugars
Because of the widespread use of acetate-protected carbohydrates,
we initiated our studies using aceto-R-bromo-D-glucose and MeZn-I
(Table 1). An initial screen of solvents indicated that DMI (N,N′-
dimethylimidazolone), THF, and DMA (N,N′-dimethylacetamide)
were acceptable, with the former being optimal; nonpolar solvents
acceleratedcompetingeliminationprocesses.Additionally,NiCl2•DME
and NiBr2•glyme could be used interchangeably. In the absence of
a Ni catalyst, oligomeric baseline products were formed.
entrya
sugar
ligand
yield (
R
:
â
)
glycal
1
2
3
glucose
mannose
galactose
PyBox
PyBox
PyBox
53% (1:2.5)
75% (8:1)
43% (1:2)
9%
9%
trace
Table 1 collects results for a variety of tridentate ligands,
including a variety of PyBox ligands (entries 1-5), terpyridine
(terpy, entry 6),12 a pyridyl bisimine (entry 7),12a and a terthiophene
(entry 8). The best ligand was the unsubstituted PyBox ligand,
which gave the desired product in 76% yield along with traces of
the glucal elimination product.13 The higher yields for the smaller
ligand suggested that steric effects in the catalyst were important.
In each of the cases, the diastereomeric ratio modestly favored the
â-anomer, with the exception of terpy, where only the â-anomer
was observed, though, unfortunately, at the expense of yield.14
a Typical reaction conditions: glycosyl bromide (0.24 mmol, 0.19 M in
DMI), NiCl2•DME (0.024 mmol), ligand (0.036 mmol), RZnBr in DMI at
room temperature for 12 h.
Freshly chromatographed bromide was key to obtaining reproduc-
ibly high yields.
Benzyl-protected glycosyl halides were also examined; however,
the R-bromides were too reactive and under the standard PyBox/
Ph(CH2)3Zn-Br conditions resulted in diminished yields, the mass
balance primarily consisting of hydrolysis products. The R-chlo-
rides, however, were more stable, and excellent yields and high
R-selectivities could be obtained; the R-mannosyl chloride gave
no detectable â-anomer (>10:1). As shown in Table 3, glycosyl
chlorides effectively partnered with a variety of functionalized
primary alkyl zinc reagents, including alkene, acetal, ester, and
heteroaromatic and phthalimide functional groups.
As a general rule, “fully armed” sugars were best matched to
chloride leaving groups, and “disarmed” acetate-protected sugars
worked best as the bromide (the chlorides were unreactive).
Mannosides uniformly provided high R-selectivity, while glucosides
were much less so, and while acetals, phthalimides, and esters were
uniformly effective, the Zn-pentenyl and alkyl-thiophene reagents
consistently gave reduced yields and higher levels of glucal, perhaps
due to chelation effects in a key organo-Ni intermediate.
Since PyBox provided the most encouraging results with MeZn-
I, it was tested with a primary alkyl zinc reagent. Results for several
R-bromo sugars are collected in Table 2. Particularly encouraging
was aceto-R-bromo mannose, which selectively provided the
R-product in good yield, perhaps a consequence of anchimeric
assistance or additional stereoelectronic control by the axial OAc.
9
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J. AM. CHEM. SOC. 2007, 129, 1908-1909
10.1021/ja068950t CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. C-Alkylation with Functionalized Alkyl Zinc Reagents
catalyst control over anomer selectivity in C-glycoside synthesis
may be achievable.
Acknowledgment. We warmly thank the National Science
Foundation for partial support of this work (CHE-0315203), and
Profs. Antony Fairbanks and George Fleet (Oxford University) for
helpful discussions.
Supporting Information Available: Full synthetic and character-
ization details. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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(13) In the course of the screening experiment, it was occasionally observed
that â-H elimination can occur, but this product is absent in the indicated
entries.
a Typical reaction conditions: glycosyl bromide (0.24 mmol, 0.19 M in
DMI), NiCl2•DME (0.024 mmol), ligand (0.036 mmol), RZnBr (in DMI),
at room temperature for 12 h. b No â-isomer detected by TLC or NMR.
(14) Additional optimization of this reaction indicated that DMA improved
the yields to 60%, while maintaining the high â-selectivity. Unfortunately,
high selectivity was not maintained with larger reagents (Ph(CH2)3-
t
Zn-Br). Bu3terpy, which significantly improves alkyl-alkyl Negishi
cross-couplings (see ref 12a), did not yield the C1-methyl product in DMA,
though it was observed in THF (∼40% with high â-selectivity).
(15) Preliminary experiments with aryl zinc reagents indicate that some C1-
aryl product can be obtained using the standard protocol (∼40%).
Experiments to optimize the reaction conditions are underway and will
be reported in due course. In contrast, preliminary experiments with
BnZnBr did not give the C-glycoside.
(16) In the case of aceto-R-bromo-D-mannose and Ph(CH2)3Zn-Br a lower
catalyst loading (5 mol %) was also tolerated with minimal diminution in
yield and diastereoselectivity.
In summary, we report herein a cross-coupling method for the
synthesis of fully oxygenated, fully saturated C-alkyl glycosides
that utilizes glycosyl halides and functionalized alkyl zinc reagents
as the reacting partners.15 Unsubstituted PyBox ligands provide good
yields of products, and mannosyl halides were particularly diaste-
reoselective for retentive C1-alkylation.16 In contrast, terpy (and
MeZnI) provided the invertive C1-alkyl as the sole product,
suggesting that cross-coupling methodologies capable of exercising
JA068950T
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