Stereoselective C-glycosidations with achiral and enantioenriched allenylsilanes

Article abstract of DOI:10.1021/ol1019629

Allenylsilanes are used as carbon nucleophiles in highly stereoselective Lewis acid-promoted C-glycosidations, resulting in the introduction of an internal alkyne with an adjacent stereocenter. Both achiral and chiral allenylsilanes form the desired products with high diastereoselectivity, where the nucleophile adds exclusively to the α-face of the intermediate oxonium ion. Reactions with glucal and galactal afford dihydropyran products, while reactions with a ribose derivative yield dihydrofuran products.

Full text of DOI:10.1021/ol1019629

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4624-4627
Stereoselective C-Glycosidations with
Achiral and Enantioenriched
Allenylsilanes
Ryan A. Brawn and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth
AVenue, Boston UniVersity, Boston, Massachusetts 02215, United States
panek@bu.edu
Received August 18, 2010
ABSTRACT
Allenylsilanes are used as carbon nucleophiles in highly stereoselective Lewis acid-promoted C-glycosidations, resulting in the introduction
of an internal alkyne with an adjacent stereocenter. Both achiral and chiral allenylsilanes form the desired products with high diastereoselectivity,
where the nucleophile adds exclusively to the r-face of the intermediate oxonium ion. Reactions with glucal and galactal afford dihydropyran
products, while reactions with a ribose derivative yield dihydrofuran products.
The Ferrier glycal allylic rearrangement allows for the
selective modification of complex carbohydrates.1 Glycosides
bearing a C-glycosidic bond are important building blocks
for synthetic chemistry since many are subunits of biologi-
cally active natural products or potential inhibitors of
enzymes that use carbohydrates as substrates.2
Danishefsky’s initial report on the C-glycosidation of glycals
with allyltrimethylsilane documented that the nucleophile ap-
proached the intermediate oxonium ion predominantly from the
Scheme 1. Additions of Silane Nucleophiles to Glucal
Organosilane reagents have proven to be versatile carbon
nucleophiles for the modification and functionalization of
carbohydrates.3 These reactions favor addition to the R-face
to the sugar, resulting in an axial orientation of the new
carbon bond.
(1) Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153–175.
(2) (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380–1419. (c) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100,
ˇ
2047–2060. (d) Stambasky, J.; Hocek, M.; Kocˇovskyˆ, P. Chem. ReV. 2009,
109, 6729–6764.
(3) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 4976–4978. (b) Panek, J. S.; Sparks, M. A. J. Org. Chem. 1989, 54,
2034–2038. (c) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208–12209. (d) Romero, J. A. C.; Tobacco,
S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168–169.
10.1021/ol1019629  2010 American Chemical Society
Published on Web 09/14/2010

Scheme 2.
Additions of Enantioenriched Allenylsilanes to Tri-O-acetyl-D-glucal and Galactala
a Reaction conditions: TMSOTf (1.0 equiv) was added to a solution of allenylsilane (1.0 equiv) and carbohydrate (1.2 equiv) in MeCN (0.5 M) at -40
b
1
°C and stirred for 1 h. Isolated yields after chromatographic purification. Diastereomeric ratios determined by H NMR analysis of crude material.
R-face.4 When chiral crotylsilane reagents were used, a double
stereodifferentiation was observed, wherein the stereochemistry
of the silane nucleophile affected the diastereomeric ratio of
the C-glycosidation products (Scheme 1).5
relative and absolute stereochemistry of the products was
assigned by analogy to known products.9
Achiral allenylsilanes 4a-4c were prepared using a
Fleming SN2′ displacement of the appropriate propargyl
mesylate,10 while 4d was obtained by a Johnson orthoester
Claisen rearrangement.6g These achiral allenylsilanes under-
went C-glycosidation with tri-O-acetyl-D-glucal, giving the
desired dihydropyrans in moderate to high yield (Table 1).
Recently, allenylsilanes have reemerged as an important class
of carbon nucleophiles. These allenes have demonstrated their
versatility in nucleophilic additions to oxonium and iminum
ions, leading to the stereospecific formation of functionalized
alkynes.6 Despite the recent advances exploring the synthesis
and reactivity of allenylsilanes, there are no reports of these
nucleophiles (or similar allenylmetal reagents) in C-glycosida-
tion reactions. Herein we report an efficient and highly
stereoselective C-glycosidation of glycals with allenylsilanes,
forming glycosides containing an internal alkyne.7
Table 1. Additions of Achiral Allenylsilanes to
Tri-O-acetyl-D-glucal
We have recently reported the multigram synthesis of both
enantiomers of allenylsilane 1.6d The C-glycosidations of tri-
O-acetyl-D-glucal with allenylsilanes (Ra)-1 and (Sa)-1, mediated
by TMSOTf in MeCN,8 gave the desired R-C-glycoside
products in good yields as single diastereomers (Scheme 2).
Both the (Ra) and (Sa) enantiomers display exceptional face
selectivity, as the axial chirality of the allene overrides the
inherent chirality of the glycal. In other words, the “matched”
or “mismatched” reaction partners, which were observed with
chiral crotylsilanes, were not observed with the allenes.5 The
relative and absolute stereochemistry of the products was
assigned based on comparison to known products, confirming
the expected R-addition to the carbohydrate.9
Enantioenriched allenylsilanes 1 also underwent C-gly-
cosidation reactions with tri-O-acetyl-D-galactal, providing
the diastereomeric dihydropyran products in slightly lower
yield than the analogous glucal additions (Scheme 2). As
before, the products were formed as a single observed
diastereomer, with both allene enantiomers exibiting similar
levels of diastereoselectivity. However, it is interesting to
note that the Sa-enantiomer provided lower yields in both
additions, so it is possible that the mismatched reaction
partners are less reactive than the matched counterparts. The
allene
R
yielda
drb
product
4a
4b
4c
4d
Me
Et
Ph
93
88
54
65
>20:1
>20:1
>20:1
>20:1
5a
5b
5c
5d
CH2CO2Me
a Isolated yield after chromatographic purification. b Diastereomeric ratios
determined by H NMR analysis of crude material.
1
The products of these reactions were again formed as a single
diastereoisomer, with preferential addition to the R-face.
Achiral allenylsilanes 4a-4d also provided the desired
C-glycosidation adducts when added to tri-O-acetyl-D-
galactal in the presence of TMSOTf (Table 2). The galactal-
derived products were isolated in slightly lower yields than
(5) Panek, J. S.; Schaus, J. V. Tetrahedron 1997, 53, 10971–10982.
(6) (a) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3927–
3929. (b) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem.
1986, 51, 3870–3878. (c) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000,
65, 630–633. (d) Brawn, R. A.; Panek, J. S. Org. Lett. 2007, 9, 2689–
2692. (e) Felzmann, W.; Castagnolo, G.; Rosenbeiger, D.; Mulzer, J. J.
Org. Chem. 2007, 72, 2182–2186. (f) Brawn, R. A.; Panek, J. S. Org. Lett.
2009, 11, 4362–4365. (g) Brawn, R. A.; Welzel, M.; Lowe, J. T.; Panek,
J. S. Org. Lett. 2010, 12, 336–339. (h) Marchart, S.; Gromov, A.; Mulzer,
J. Angew. Chem., Int. Ed. 2010, 49, 2050–2053.
(4) (a) Danishefsky, S. J.; Kerwin, J. F. J. Org. Chem. 1982, 47, 3803–
3805. (b) Danishefksy, S. J.; Armistead, D. M.; Wincott, F. E.; Selnick,
H. G.; Hungate, R. J. Am. Chem. Soc. 1987, 109, 8117–8119.
Org. Lett., Vol. 12, No. 20, 2010
4625

stable to chromatographic purification and can be fromed
from readily available starting materials.
C-Glycosidation reactions of 2,3-dihydrofuran 7 with both
enantiomers of allenylsilane 1 provided the desired trans-
dihydrofuran products in moderate yields (Scheme 4). These
reactions displayed excellent diastereoselectivity as the
Table 2. Additions of Achiral Allenylsilanes to
Tri-O-acetyl-D-galactal
Scheme 4
.
Additions of Chiral Allenylsilanes to Dihydrofuran
allene
R
yielda
drb
product
7a
4a
4b
4c
4d
Me
Et
Ph
82
86
39
63
>20:1
>20:1
>20:1
>20:1
6a
6b
6c
6d
CH2CO2Me
a Isolated yield after chromatographic purification. b Diastereomeric ratios
determined by H NMR analysis of crude material.
1
the corresponding glucal products, but the desired pyran
diastereomer was the exclusive product in all cases.
While C-glycosidation reactions with commercially avail-
able glucal and galactal have been well developed, there are
fewer examples that utilize furanose derivitives as the
electrophile.11 While bis-O-acetyl-D-ribose derivitive 7 is a
known compound, previous syntheses report that it is
unstable and readily decomposes during synthesis. Conse-
quently, it has not been used as an electrophile reaction
partner in C-glycosidations.12 Herein, we describe a modified
and reproducible procedure for the synthesis of furanose 7
a Isolated yield after chromatographic purification. Diastereomeric ratios
determined by H NMR analysis of crude material.
1
isolated products were diastereomerically pure when either
allene enantiomer was employed.
Reactions with achiral allenylsilanes and 2,3-dihydrofuran
7 also resulted in the formation of the desired 3,4-dihydro-
furan products in moderate to high yield (Table 3). All of
Scheme 3.
Synthesis of Dihydrofuran 7a
Table 3. Additions of Achiral Allenylsilanes to Dihydrofuran 7
a Isolated yield after chromatographic purification.
in three steps from D-ribose (Scheme 3). While the product
yield is moderate (33% over three steps), the material is
allene
R
yielda
drb
product
4a
4b
4c
4d
Me
Et
Ph
93
88
45
54
>20:1
>20:1
>20:1
>20:1
9a
9b
9c
9d
(7) For the synthesis of C-glycosides with an allene or alkyne functional-
ity, see: (a) Ichikawa, Y.; Isobe, M.; Goto, T. Tetrahedron Lett. 1984, 25,
5049–5052. (b) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbohydr.
Res. 1987, 171, 193–199. (c) Tsukiyama, S.; Isobe, M. Tetrahedron Lett.
1992, 33, 7911–7914. (d) Saeeng, R.; Isobe, M. Org. Lett. 2005, 7, 1585–
1588. (e) Vieira, A. S.; Fiorante, P. F.; Hough, T. L. S.; Ferreira, F. P.;
Lu¨dtke, D. S.; Stefani, H. A. Org. Lett. 2008, 10, 5215–5218.
(8) Reactions carried out in other solvents (DCM, THF, toluene) gave
poor yields.
CH2CO2Me
a Isolated yield after chromatographic purification. b Diastereomeric ratios
determined by H NMR analysis of crude material.
1
the cases examined exhibited very high diastereoselectivity,
further demonstrating the utility of this electrophile as a route
to the stereoselective formation of functionalized 2,5-trans-
dihydrofurans. The stereochemistry of the products was
assigned based on 2D NMR studies.9
In conclusion, we have reported the stereoselective C-
glycosidation of glycal derivitives with achiral and enan-
tioenriched allenylsilanes. The reactions proceed with mod-
erate to high yield with excellent diastereoselectivity, with
(9) See Supporting Information for assignment of relative and absolute
stereochemical assignments.
(10) (a) Fleming, I.; Terrett, N. K. J. Organomet. Chem. 1984, 264,
99–118. (b) Fleming, I.; Newton, T. W. J. Chem. Soc., Perkin Trans. 1
1984, 1805–1808.
(11) For some examples of C-glycosidation reactions with furanose
derivitives see: (a) ref 1. (b) ref.3c (c) Cameron, M. A.; Cush, S. B.;
Hammer, R. P. J. Org. Chem. 1997, 62, 9065–9069. (d) Singh, I.; Seitz, O.
Org. Lett. 2006, 8, 4319–4322.
(12) Strauss, C. R.; Scott, J. L.; Saylik, D.; Malic, N. Resolution of
chiral alcohols via transacetalization with enantiomerically pure chiral
auxiliaries. PCT Int. Appl. WO 2005070911 A1, Aug 4, 2005.
4626
Org. Lett., Vol. 12, No. 20, 2010

selective addition to the R-face of the oxonium ion regardless
of the nucleophile. The products of these glycosidations will
be exploited as building blocks for complex molecules and
library production of potentially biologically active com-
pounds.
2009-2010 graduate fellowship. Financial support was
provided by the National Institutes of Health (NIH
CA53604).
Supporting Information Available: Experimental data
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The authors would like to thank Paul
Ralifo (Boston University) for assistance with structural
assignments. R.A.B. is grateful to AstraZeneca for a
OL1019629
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