Large-scale synthesis of all stereoisomers of a 2,3-unsaturated c-glycoside scaffold

Article abstract of DOI:10.1021/jo1022926

All stereoisomers of a highly functionalized 2,3-unsaturated C-glycoside can be accessed in 10-100 g quantities from readily available starting materials and reagents in 3-7 steps. These chiral scaffolds contain three stereogenic centers along with orthogonally protected functional groups for downstream reactivity.

Full text of DOI:10.1021/jo1022926

NOTE
pubs.acs.org/joc
Large-Scale Synthesis of All Stereoisomers of a 2,3-Unsaturated
C-Glycoside Scaffold
Baudouin Gerard, Jean-Charles Mariꢀe, Bhaumik A. Pandya, Maurice D. Lee IV, Haibo Liu, and
Lisa A. Marcaurelle*
Chemical Biology Platform, The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142,
United States
S Supporting Information
b
ABSTRACT: All stereoisomers of a highly functionalized 2,3-unsaturated
C-glycoside can be accessed in 10-100 g quantities from readily
available starting materials and reagents in 3-7 steps. These chiral
scaffolds contain three stereogenic centers along with orthogonally
protected functional groups for downstream reactivity.
s a result of their synthetic versatility and high level of
stereochemical diversity, carbohydrates have served as useful
A
starting points for generating molecular diversity.1 Carbohy-
drate-derived glycals in particular have been employed in multi-
ple diversity-oriented synthesis (DOS) pathways.2 Of interest to
us was the utility of C-alkyl pseudoglycals for developing new
build/couple/pair pathways in the context of library develop-
ment.3 In the present study, we focused on the synthesis of 2,3-
unsaturated C-glycosides 1-4 (Figure 1) that incorporate four
chemical handles: (1) an ester, (2) an alkene, (3) a primary alcohol,
and (4) a secondary alcohol/primary amine, thereby providing a
range of options for subsequent modifications and/or functional
group pairing reactions.4 As partof ourdesignstrategy we sought to
develop methods for the preparation of all eight stereoisomers of
the C-glycoside template to enable the development of stereo/
structure-activity relationships.3b,5 Herein we describe the pre-
paration of C-glycosides 1-4 on large (10-100) scale.
To introduce the ester functionality at C-1 we explored a type I
Ferrier rearrangement6 of tri-O-acetyl-D- and L-glucal to access C-
glycosides 1-4. We elected to focus solely on optimizing the
large-scale Ferrier reaction for the glucal series with the intention
of accessing the galactal-derived material (2) via Mitsunobu
inversion of the C-4 allylic alcohol.7,8 This late stage epimeriza-
tion strategy is an attractive alternative as it requires optimization
of only one Ferrier reaction as well as access to only one un-
natural carbohydrate.
Generally, Lewis acids such as TiCl4,9 BF3 Et2O,10 and
3
Figure 1. Full stereochemical matrix of C-glycosides 1-4.
TMSOTf6c are employed in the Ferrier reaction to promote
rearrangement to form the active glycosyl intermediate. Once
activated, a variety of carbon-based nucleophiles have been
utilized,6d including allyltrimethylsilane,11 trimethylsilylcyanide,12
and various silyl ketene acetals.13 We utilized silylketene acetal 5
(1-(tert-butyldimethylsilyloxy)-1-methoxyethene) as a nucleophile
for generating the C-glycoside as it offers the advantage of installing
an ester side chain without further modifications.
the presence of LiClO4 in Et2O, addition of 5 to tri-O-acetyl-D-
glucal leads predominantly to the formation of the R-anomer
(ratio 3:1, R:β).13b In contrast, Csuk et al. reported that treat-
ment of tri-O-acetyl-D-glucal with silylketene acetal 5 in the
presence of TMSOTf in CH2Cl2 affords the β-anomer as the
major product (ratio 1:2, R:β).13c Since we discovered that the
R- and β-glycosides could be easily separated by silica gel
The stereochemical outcome of Lewis acid mediated C-
glycosidation reactions is, in general, highly dependent on the
conditions employed.6d For example, it has been reported that in
Received: November 17, 2010
Published: February 22, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo1022926 J. Org. Chem. 2011, 76, 1898–1901
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimization of the Ferrier Reaction
Scheme 2. Mitsunobu Inversion of C-4 Allylic Alcohol
entry Lewis acid
solvent
ratio (R:β)c
yield (%)
45d
73d
65d
72 (39:33)e
77 (42:35)e
1a
2a
3a
4a
5b
BF3 Et2O CH2Cl2
1:2
1:1.5
1.5:1
1.2:1
1.2:1
3
TMSOTf
CH2Cl2
CH3CN
TMSOTf
TMSOTf
TMSOTf
CH2Cl2/CH3CN (1:1)
Table 2. Introduction of C-4 Amine via Mitsunobu Reaction
CH2Cl2/CH3CN (1:1)
a 1.2 equiv of Lewis acid, 0.15 M, 2.5 mmol scale. b 1.2 equiv of Lewis
c
acid, 0.15 M, 735 mmol scale. Ratio between R and β stereoisomers
determinated by 1H NMR. d Isolated yield for the mixture of R-D-6 and
β-D-6. e Isolated yield for each anomer (R-D-6:β-D-6)
Scheme 1. Deacetylation and TBDPS-Protection
entry
SM
product
PR3
yield (%)a
1
2
3
4
5
6
R-D-1
β-D-1
R-D-1
β-D-1
R-D-2
β-D-2
R-D-7
β-D-7
R-D-7
β-D-7
R-D-8
β-D-8
PPh3
PPh3
PBu3
PBu3
PPh3
PPh3
62
54
75
84
85
89
a Isolated yield after silica gel chromatography.
alcohols R-L-1 and β-L-1 were displaced with p-nitrobenzoic acid
in the presence of PBu3 and DIAD at 0 °C (Scheme 2).
Hydrolysis of the resulting benzoates cleanly afforded the
enantiopure allylic alcohols R-L-2 and β-L-2 in 68% and 76%
yield over two steps, respectively. This procedure could then be
applied to allylic alcohols R-D-1 and β-D-1 to afford glycosides R-
D-2 and β-D-2, thereby completing the full matrix of eight
stereosiomers.
Conversion of allylic alcohols 1 and 2 to amines 3 and 4 was
our final task to prepare the desired scaffolds. Introduction of an
azido substituent as a precursor to the amine was initially
considered using diphenylphosphoryl azide (DPPA)17 or the
zinc complex Zn(N3)2Py2,18 but neither of these options proved
useful on multigram scale. In most cases, complex mixtures were
obtained and the desired products were isolated in low yield.
Successful introduction of the C-4 amine was achieved using
phthalimide as a nitrogen nucleophile19 via a Mitsunobu reaction
(Table 2). Essential to reproducible high yields and selectivity
was the use of PBu3, which proved to be more efficient than
triphenylphosphine (PPh3) for the Mitsunobu reaction of glucal-
based derivatives R-D-1 and β-D-1 to yield R-D-7 and β-D-7 in
75% and 84% yield, respectively (entries 3 and 4). Under these
conditions, the formation of undesired SN20 byproducts,19,20
which had been observed during the PPh3-mediated Mitsunobu
reactions, was diminished. By contrast, for the C-4 epimeric
glycosides (R-D-2 and β-D-2) PPh3 proved to be the optimal
Mitsunobu reagent affording allylic phthalimides R-D-8 and β-D-
8 in 85% and 89% yield (entries 5 and 6).21
chromatography and we required access to equal quantities of
both anomers, we elected to develop reaction conditions that
would achieve a closer to 1:1 R:β ratio.
As shown in Table 1, we evaluated the Ferrier reaction of tri-O-
acetyl-D-glucal with 5 under a range of conditions, mainly focused
on varying the nature of the Lewis acid and solvent. Use of
BF3 Et2O as the Lewis acid in CH2Cl2 led to the formation of C-
3
glycoside 6 in 45% yield as a 1:2 mixture of anomers favoring the
β-anomer (entry 1). Changing the Lewis acid to TMSOTf led to
a higher isolated yield (73%) and a more favorable ratio of
anomers of 1:1.5 (entry 2). Using TMSOTf we next investigated
the effect of solvent on reaction selectivity. When CH3CN was
employed as a solvent the formation of the R-anomer was slightly
favored (R/β ratio = 1.5:1) and a lower yield was obtained (65%,
entry 3). The yield of the glycosidation reaction could be
improved to 77% on large scale (200 g), using CH2Cl2 as a
cosolvent (entries 4 and 5), providing a 1.2:1 mixture of anomers.
The R/β isomers could be easily separated by silica gel chroma-
tography to provide 42% of the R-anomer (R-D-6) and 35% of
the β-anomer (β-D-6).14 Deacetylation and subsequent selective
6-O-TBDPS protection provided allylic alcohols R-D-1 and β-D-1
in 90% yield over two steps (Scheme 1). This protocol was also
applied to tri-O-acetyl-L-glucal15 on 100-g scale to afford allylic
alcohols R-L-1 and β-L-1.16
We next investigated the conversion of R/β-D-1 and R/β-L-1
to the corresponding C-4 epimers via Mitsunobu inversion.8
After varying parameters such as phosphine, solvent, and tem-
perature, we arrived at a reliable and robust protocol for the
Mitsunobu reaction. Focusing initially on the L-series, allylic
Lastly, removal of the phthalimide protecting group was
achieved via treatment with ethylenediamine22 to afford allylic
amines 3 and 4 (Scheme 3). Application of these conditions to all
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dx.doi.org/10.1021/jo1022926 |J. Org. Chem. 2011, 76, 1898–1901

The Journal of Organic Chemistry
NOTE
Scheme 3. Phthalimide Removal To Yield Amines 3 and 4
(m, 1H), 2.45 (m, 1H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
171.2, 135.8, 135.7, 132.9, 132.8, 130.1, 129.7, 129.6, 128.9, 128.0, 127.8,
77.7, 71.3, 66.7, 66.3, 51.9, 40.4, 27.0, 19.3; HRMS (ESIþ) calcd for
C25H32O5Si [M þ H2O]þ 458.2363, found 458.2359
Representative Procedure for Mitsunobu Inversion at C-4:
Allylic Alcohol (1S,4S,5S)-(þ)-r-L-2. To an oven-dried 3-neck 1-L
round-bottom flask equipped with a 150 mL oven-dried addition funnel
and placed under argon was added a solution of (þ)-R-L-1 (29.0 g, 65.8
mmol, 1.0 equiv) and p-nitrobenzoic acid (12.1 g, 72.4 mmol, 1.1 equiv)
in dry THF (370 mL). The mixture was degassed with argon (sparged
for 30 min) and then cooled to 0 °C. PBu3 (24.4 mL, 99.0 mmol, 1.5
equiv) was added via syringe to the reaction mixture and a solution of
DIAD (19.5 mL, 99.0 mmol, 1.5 equiv) in degassed THF (70 mL) was
slowly added via addition funnel over 30 min. After stirring at rt
overnight, the solvents were removed in vacuo and the crude product
was taken onto the next step without purification.
A 1-L round-bottom flask was charged with the crude p-nitrobenzoic
ester as a solution in CH2Cl2 (130 mL) and MeOH (530 mL) and
K2CO3 (455 mg, 3.3 mmol, 0.05 equiv) was added. The resulting dark
orange mixture was stirred at rt for 2 h and then AcOH (0.57 mL, 9.9
mmol, 0.15 equiv) was added. After evaporation of the solvents, the
crude product was dissolved in Et2O and washed with sat. NH4Cl aq.
solution. The aqueous phase was extracted with Et2O and the combined
organic layers were washed with brine, dried over MgSO4, filtered and
concentrated. The crude product was purified by silica gel chromatog-
raphy (hexanes to 7:3 hexanes/EtOAc) to afford allylic alcohol R-L-2
(19.8 g, 68% yield, over two steps) as a thick colorless oil. [R]20D þ78.2
(c 1.5, CHCl3); IR (film) v 2930, 2856, 1735, 1428, 1361, 1272, 1200,
1100, 1086; 1H NMR (300 MHz, CDCl3) δ 7.67 (m, 4H), 7.39 (m, 6H),
6.08 (ddd, J = 9.9, 5.5, 1.5, 1H), 5.89 (dd, J = 10.1, 3.2 Hz, 1H), 4.73 (m,
1H), 3.96 (dd, J = 8.7, 6.1 Hz, 1H), 3.86 (dd, J = 8.8, 4.4 Hz, 1H), 3.77
(m, 1H), 3.62 (s, 3H), 2.66 (d, J = 15.2, 9.0 Hz, 1H), 2.43 (d, J = 15.3, 5.5
Hz, 1H), 1.85 (d, J = 8.9 Hz, 1H), 1.04 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 171.2, 135.8, 135.8, 133.6, 133.5, 131.8, 130.0, 129.9, 127.9,
127.8, 127.6, 72.4, 70.1, 63.6, 62.2, 52.0, 37.4, 27.0, 19.3; HRMS (ESIþ)
calcd for C25H32O5Si [M þ H]þ 441.2097, found 441.2100.
stereoisomers led to isolation of the desired eight allylic amines in
high yield (>90%).(See Supporting Information.)
In summary, we have demonstrated that all possible stereo-
chemical permutations of two highly functionalized C-glycosides
can be prepared from tri-O-acetyl-D- and L-glucal on large scale.
The use of these 16 pyran scaffolds for library synthesis is forth-
coming.23
’ EXPERIMENTAL SECTION
Representative Procedure for Ferrier Reaction: C-Glycosides
(1R,4S,5R)-(þ)-r-D-6 and (1S,4S,5R)-(þ)-β-D-6. Into a 5-L flask
containing CH2Cl2 (1.8 L) and CH3CN (2.0 L) was added. tri-O-acetyl-
D-glucal (200 g, 735 mmol). The reaction mixture was cooled to -5 °C
and silyl ketene acetal 5(135 mL, 882 mmol, 1.2 equiv) was added slowly so
as to maintain a constant temperature. A solution of TMSOTf (153 mL,
845 mmol, 1.1 equiv) in CH2Cl2 (200 mL) was added slowly via an addi-
tion funnel over 30 min. After complete addition of the Lewis acid, the bath
temperature was kept at -5 °C for 2 h. The reaction mixture was poured
slowly into sat. aq. NaHCO3 solution (1.5 L). Excess solvent was removed
in vacuo and the crude yellow mixture was extracted with CH2Cl2 (3 ꢀ 1L).
The combined organic layers were washed with brine and then dried over
MgSO4. Solvent was removed in vacuo and the crude material was purified
by silica gel chromatography (hexanes/EtOAc 95:5 to 70:30) to afford first
73 g (35%) of β-D-6 and then 88 g (42%) of R-D-6 as yellow oils.14
Representative Procedure for Deacetylation/TBDPS Protec-
tion: Allylic Alcohol (1S,4S,5R)-(þ)-β-D-1. To a 5-L flask contain-
ing β-D-6 (95 g, 332 mmol) dissolved in 4:1 MeOH/CH2Cl2 (3.3 L) was
added K2CO3 (2.30 g, 16.6 mmol, 0.05 equiv). The reaction mixture was
stirred at rt for 100 min and then AcOH (3.80 mL, 66.4 mmol, 0.2 equiv)
was added. Solvent was removed in vacuo and the product was filtered
through a column of silica gel and eluted with 1 L of 70% hexanes/
EtOAc followed by 3 L of straight EtOAc to provide the desired diol,
which was isolated as a yellow oil (67 g, 99% yield).
To a 5-L flask containing diol (67 g, 332 mmol) was added CH2Cl2
(1.5 L) followed by Et3N (93 mL, 664 mmol, 2.0 equiv) and DMAP
(4.06 g, 33.2 mmol, 0.1 equiv). The reaction mixture was cooled to 0 °C
and TBDPS-Cl (90 mL, 349 mmol, 1.05 equiv) was slowly added. The
reaction was slowly warmed to rt and stirred for 46 h. The solvent was
removed in vacuo and the crude oil was diluted with Et2O and filtered
through Celite to remove the resulting white solid. The mixture was
concentrated and the resulting oil was redissolved in Et2O, washed with
sat. NH4Cl and brine. After drying over MgSO4, the solvent was
removed in vacuo. The yellow oil was then purified by silica gel
chromatography (hexanes/EtOAc 95:5 to 70:30) to afford allylic alcohol
β-D-1 as a colorless oil (131 g, 90% yield). [R]20D þ4.1 (c 1.0, CHCl3).
IR (film) v 2930, 2858, 1736, 1427, 1361, 1277, 1200, 1111, 1088; 1H
NMR (300 MHz, CDCl3) δ 7.67 (m, 4H), 7.40 (m, 6H),
5.83 (m, 1H), 5.73 (m, 1H), 4.52 (m, 1H), 4.27 (m, 1H), 3.90 (dd,
J = 10.2, 5.1 Hz, 1H), 3.76 (dd, J = 10.2, 7.2 Hz, 1H), 3.64 (s, 3H), 3.50
Representative Procedure for Phthalimide Mitsunobu
Reaction: Allylic Phthalimide (1S,4R,5S)-(-)-β-D-7. To an
oven-dried 3-neck 2-L round-bottom flask equipped with a 250-mL
addition funnel was added a solution of (þ)-β-D-1 (46.5 g, 106 mmol,
1.0 equiv) and phthalimide (23.3 g, 158 mmol, 1.5 equiv) in dry THF
(800 mL). The mixture was degassed with argon (sparged for 60 min)
and then cooled to 0 °C. Tributylphosphine (35.0 mL, 137.1 mmol, 1.3
equiv) (or triphenylphosphine, 1.3 equiv) was added, followed by a
solution of DIAD (28.7 mL, 137.1 mmol, 1.3 equiv) in degassed THF
(200 mL) via addition funnel (over 60 min). After stirring at rt
overnight, the solvent was removed in vacuo and the crude product
was purified by silica gel chromatography (hexanes to 7:3 hexanes/
EtOAc) to afford allylic phthalimide β-D-7 (50.7 g, 84% yield). [R]20
-
D
86.2 (c 1.0, CHCl3). IR (film) v 2926, 2856, 1716, 1352, 1112; 1H NMR
(500 MHz, CDCl3) δ 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 7.67 (dd, J = 5.5, 3.1
Hz, 2H), 7.57 (dd, J = 7.9, 1.4 Hz, 2H), 7.49 (dd, J = 7.9, 1.1 Hz, 2H),
7.37 - 7.25 (m, 4H), 7.17 (t, J = 7.5 Hz, 2H), 6.09 (d, J = 10.0 Hz, 1H),
5.78 (ddd, J = 10.0, 5.5, 2.0 Hz, 1H), 4.81 (br d, J = 3.6 Hz, 1H), 4.67 (br
t, J = 6.9 Hz, 1H), 3.97 (td, J = 6.0, 3.5 Hz, 1H), 3.67 (s, 3H), 3.65 (dd, J =
10.8, 5.7 Hz, 3H), 3.59 (dd, J = 10.8, 6.5 Hz, 1H), 2.89 (dd, J = 15.8, 7.4
Hz, 1H), 2.71 (dd, J = 15.8, 6.5 Hz, 1H), 0.92 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 171.5, 167.8, 135.5, 135.4, 133.9, 133.8, 133.2, 133.1,
131.8, 129.5, 129.4, 127.5, 127.4, 123.1, 121.4, 75.9, 71.5, 63.6, 51.6, 44.7,
38.8, 26.6, 18.9; HRMS (ESIþ) calcd for C33H35NO6Si [M þ Na]þ
592.2131, found 592.2134.
Representative Procedure for Phtalimide Removal: Allylic
Amine (1S,4R,5S)-(-)-β-D-3. A 2-neck 2-L flask equipped with a reflux
condenser was charged with the allylic phthalimide β-D-7 (25 g, 43.9 mmol,
1900
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The Journal of Organic Chemistry
NOTE
1.0 equiv) in THF (44 mL) and 1,2-ethylenediamine (8.8 mL, 131.7 mmol,
3.0 equiv) was added at rt via syringe. The reaction mixture was stirred at rt for
2-4 h and then MeOH (835 mL) was added. The reaction mixture was
stirred at 60 °Cfor16h, bywhichtimeawhiteprecipitatehadformedandthe
reaction was deemed complete (LC-MS). The solvents were partially
evaporated and Et2O was added to the crude product. After filtration through
a pad of Celite, the solvents were partially evaporated and the process was
repeated once more to remove any excess of white byproduct. The solution
was evaporated to dryness and the crude product was purified by silica gel
chromatography (CH2Cl2/MeOH 100:0 to 90:10) to afford allylic amine β-
D-3 as a pale yellow oil (17.6 g, 91% yield). [R]20D -44.2 (c 1.2, CHCl3). IR
(film) v2930, 2856, 1740, 1428, 1168, 1112; 1H NMR (500 MHz, CDCl3) δ
7.66 (d, J = 6.6 Hz, 2H), 7.63 (d, J = 6.5 Hz, 2H), 7.42 - 7.35 (m, 6H), 6.02
(dd, J=9.8, 5.6Hz, 1H), 5.69(d,J= 10.1 Hz, 1H), 4.46 (br t, J= 5.8 Hz, 1H),
3.82 (dd, J = 14.6, 10.0 Hz, 1H), 3.73 - 3.66 (m, 2H), 3.63 (s, 3H), 3.24 (br
d, J = 5.2 Hz, 1H), 2.50 (dd, J = 15.4, 7.5 Hz, 1H), 2.43 (dd, J = 15.4, 5.8 Hz,
1H), 1.21 (br s, 2H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 171.0,
135.5, 133.3, 133.2, 130.0, 130.0, 129.7, 129.6, 127.7, 127.6, 77.2, 71.9, 62.7,
51.6, 45.0, 40.0, 26.8, 19.1; HRMS (ESIþ) calcd for C25H33NO4Si
[M þ H]þ 440.2257, found 440.2252.
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’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and characterization for all new compounds, including
copies of 1H and 13C NMR spectra. Crystallographic information
files in CIF format of compounds β-D-7 and R-D-8. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) (a) Balamurugan, R.; Koppolu, S. R. Tetrahedron 2009, 65,
8139–8142. (b) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett.
2003, 5, 3579–3582.
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’ AUTHOR INFORMATION
(13) (a) Tulshian, D. B.; Fraser-Reid, B. J. Org. Chem. 1984, 49, 518–
522. (b) Pearson, W. H.; Schkeryantz, J. M. J. Org. Chem. 1992, 57,
2986–2987. (c) Csuk, R.; Schaade, M.; Krieger, C. Tetrahedron 1996, 52,
6397–6408.
Corresponding Author
*E-mail:lisa@broadinstitute.org.
(14) Curran, D. P.; Suh, Y. G. Carbohydr. Res. 1987, 17, 161–192.
(15) Although tri-O-acetyl-L-glucal is commercially available, be-
cause of cost considerations we opted to produce this material in house
from L-glucose, which can be prepared in two steps starting from L-
arabinose; see: Swoden, J. C.; Fischer, H. O. J. Am. Chem. Soc. 1947, 69,
1963–1965.
(16) Application of the optimized Ferrier conditions to tri-O-acetyl-
D-galactal likewise afforded a ∼1:1 mixture of R/β-anomers (see
Supporting Information); however, the isomers could not be easily
separated until after TBDPS protection.
’ ACKNOWLEDGMENT
The authors gratefully thank Dr. Peter M€uller for X-ray
crystallography, as well Dr. Jason Lowe for helpful reading of
this manuscript. This work was funded in part by the NIGMS-
sponsored Center of Excellence in Chemical Methodology and
Library Development (Broad Institute CMLD; P50 GM069721).
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