Chain extension of sugar delta-lactones with the enolate of tert-butyl bromoacetate and elaboration into functionalized C-ketosides, C-glycosides, and C-glucosyl glycines.

Article abstract of DOI:10.1021/ol0102343

[structure: see text] We describe the synthesis of a series of exocyclic sugar epoxides 1 prepared in a one-step procedure from sugar delta-lactones with the enolate of tert-butyl bromoacetate. Ring opening of the sugar oxiranes provides C-ketosides while

Full text of DOI:10.1021/ol0102343

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4115-4118
Chain Extension of Sugar δ-Lactones
with the Enolate of tert-Butyl
Bromoacetate and Elaboration into
Functionalized C-Ketosides,
C-Glycosides, and C-Glucosyl Glycines
,†
Frank Schweizer* and Toshiyuki Inazu
The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan
frank.schweizer@ualberta.ca
Received October 16, 2001
ABSTRACT
We describe the synthesis of a series of exocyclic sugar epoxides 1 prepared in a one-step procedure from sugar δ-lactones with the enolate
of tert-butyl bromoacetate. Ring opening of the sugar oxiranes provides C-ketosides while reduction affords functionalized C-glycosides
bearing an r-hydroxy ester moiety. The r-hydroxy ester can be converted into C-glucosyl glycine analogues 2.
Glycoconjugates which are involved in several biological
events such as tumor metastasis, inflammation, and immune
response have a significant pharmaceutical potential.1 Of
particular interest are glycoproteins and glycopeptides con-
taining modified glycosylamino acids, thus exhibiting new
properties. C-Glycosylamino acids promise to be attractive
building blocks due to their enhanced stability toward
chemical and enzymatic degradation.2 In a few cases
C-glycopeptides have also been isolated from natural sources.3
We present here a novel method for the chain elongation of
a series of aldono-lactones into exocyclic epoxides which
can be used as precursors for the synthesis of functionalized
C-glycosides and C-glycosylamino acids.
Our initial interest focused on the synthesis of C-
glycosylamino acids where the R-C-atom of glycine is fused
to a glucopyranoside, refered to as C-glycosyl glycines. Few
reports deal with the synthesis of pyranoside-based C-
glycosyl glycines.4 Most of these have significant drawbacks
such as low diastereoselectivity4a-c (R-carbon), unspecified
stereochemistry4b,c (R-carbon), and multistep synthesis.4a,c
Recently, we explored the Claisen condensation of tert-butyl
acetate enolate with 2,3,4,6-tetra-O-benzyl-D-galactono-1,5-
lactone and found that 2-deoxyoct-3-ulopyransonates could
† Current address: Department of Chemistry, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2.
(1) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Lee, Y. C.; Lee, R. T.
Acc. Chem. Res. 1995, 28, 322.
(2) Marcaurelle, L. A.; Bertozzi, C. R. Chem. Eur. J. 1999, 5, 1384.
(3) (a) Hofsteenge, J.; Mu¨ller, D. R.; Beer, T.; Lo¨ffler, A.; Richter, W.
J.; Vliegenhart, J. F. G. Biochemistry 1994, 33, 13524. (b) Beer, T.;
Vliegenhart, J. F. G.; Lo¨ffler, A.; Hofsteenge, J. Biochemistry 1995, 34,
11785. (c) Lo¨ffler, A.; Doucey, M.-A.; Jansson, A. M.; Mu¨ller, D. R.; Beer,
T.; Hess, D.; Meldal, M.; Richter, W. J.; Vliegenhart, J. F. G.; Hofsteenge,
J. Biochemistry 1996, 35, 12005. (d) Doucey, M.-A.; Hess, D.; Blommers,
M. J. J.; Hofsteenge, J. Glycobiology 1999, 9, 435.
(4) (a) Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.; Scher-
rmann, M.-C.; Tejero, T. J. Org. Chem. 1997, 62, 5484. (b) Simchen, G.;
Pu¨rkner, E. Synthesis 1990, 525. (c) Rosenthal. A.; Brink, A. J. J. Carbohydr.
Nucleosides Nucleotides 1975, 2, 343. (d) Colombo, L.; Casiraghi, G.;
Pittalis, A. J. Org. Chem. 1991, 56, 3897.
10.1021/ol0102343 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/20/2001

Scheme 1a
a Reagents and conditions: (a) CHBrCO2C(CH3)3 (4.1 equiv), LiN(SiMe3)2 (4.0 equiv), THF, -78 °C; (b) 1. TFA (1 equiv), wet THF;
2. Tf2O, pyridine, 0 °C, 2 h; (c) TFA (catalytic), wet THF, 1 d; (d) SiEt3H (2 equiv), TMSOTf (catalytic), CH2Cl2, -78 °C, 12 h; (e) 1.
SiEt3H (3 equiv), TMSOTf (4 equiv), CH2Cl2, 0 °C; 2. Cs2CO3, BnBr.
be prepared in high yields.5 Encouraged by these results, we
further investigated the reaction of a variety of R-substituted
tert-butyl acetate enolates generated under two conditions
(Table 1). Surprisingly, we found that the enolate of tert-
butyl bromoacetate (4 equiv) generated from lithium bis-
(trimethylsilyl)amide [(CH3)3Si]2NLi in THF at -78 °C
reacted with the lactone 3 to form the exocyclic epoxide 4
in 81% isolated yield. It is noteworthy that the conditions
for enolate generation, as well as the nature of the R-sub-
stitutent, had a strong influence on the outcome of the
reaction. For instance, attempts to use LDA as base (condi-
tion A) resulted in complete recovery of the starting lactone
3. In addition, when the enolate of R-chloro tert-butyl acetate
(condition B) was exposed to the lactone 3, only starting
material (70%) together with a small amount of C-ketoside
16 could be isolated after workup (aqueous NH4Cl).
Table 1. Claisen Condensation of Sugar Lactone 3 with the
Enolate of tert-Butyl Bromoacetate To Give Epoxide 4a
ester
cond. A
cond. B
CH3COOC(CH3)3
91%
Xb
c
c
CH2N(Bn)2COOC(CH3)3
CH2ClCOOC(CH3)3
CH2BrCOOC(CH3)3
Xb
Xd
81%
Xb
a Condition A: ester (4.1 equiv), THF, LDA (4 equiv), -78 °C, 3 (1
equiv), 1 h. Condition B: ester (4.1 equiv), THF, LiN(SiMe3)2 (4 equiv),
-78 °C, 3 (1 equiv), 1 h. b Only starting material was recovered. c Reaction
was not carried out. d Starting material (70%) and products (<15%) resulting
from hydrolysis of the epoxide were isolated.
(5) Schweizer, F.; Lohse, A.; Otter, A.; Hindsgaul, O. Synlett 2001, 1434.
4116
Org. Lett., Vol. 3, No. 25, 2001

Scheme 2.a Synthesis of C-Glucosyl Amino Acids by
Displacement of Triflates with Primary Amines. The Newman
Projection of the Predominant (>90%) Conformers of 27 and 29
Are Also Shown
Table 2. Characteristic (Un)Observed NOEs at 600 MHz
NMRi and Reaction Yields for Compounds 4, 5, 7, 9, 10, 12,
14, and 15
characteristic observed (obs)
cmpd
and unobserved (uobs) NOEs
yield
81%
4a
obs: H-2/H-7; H-2/H-5; tert-butyl/H-7;
tert-butyl/H-8a. uobs: H-2/C-4OCH2Ph
obs: H-2/H-5; tert-butyl/H-7; tert-butyl/H-8a;
H-2/C-4OCH2Ph. uobs: H-2/H-7
obs: H-2/H-5; tert-butyl/H-7; tert-butyl/H-8a;
H-2/C-4OCH2Ph
obs: H-2/H-4; H-2/H-5; tert-butyl/H-7;
tert-butyl/H-8a,b. uobs: H-2/H-7
obs: H-2/H-7 (strong); H-2/H-4 (weak);
H-2/H-5 (weak)
obs: H-2/H-5 (strong); H-2/H-7 (weak);
tert-butyl/H-7; tert-butyl/Me
obs: H-2/H-4 (strong); H-2/H5.
uobs: H-2/H-7
obs: H-2/H-7 (strong); H-2/H-5 (weak).
uobs: H-2/H-4
5b
7a
55%d
61%e
42%f
10%f
50%g
51%h
10%h
9c
10b
12c
14c
15c
i Solvents: aDMSO. bCDCl3. cC6D6. d For conversion from 4 to 5. e 35%
starting material was recovered. f Compounds 9 and 10 were obtained as a
mixture (ratio 9:10 ) 4:1) together with 35% recovered starting material.
g 40% starting material was recovered. h Compound 14 and 15 were obtained
as a mixture (ratio 14:15 ) 5:1) together with 30% recovered starting
material.
The stereochemistry of compound 4 was deduced from
the TROESY spectrum (600 MHz; DMSO, see Table 2).
The observed NOEs between H-2 and H-5 and H-7 as well
as the tert-butyl group and H-7 and one of the C-8 methylene
protons are consistent with this structural assignment. By
comparison, epimeric epoxide 5 was synthesized by a two-
step procedure from epoxide 4 (epoxide opening: TFA (2
equiv) in 4:1 THF/H2O and activation of the resulting
secondary hydroxyl function as the activated trifluoromethane-
sulfonate ester followed by concomitant intramolecular
cyclization with trifluoromethanesulfonic anhydride in py-
ridine, Scheme 1) showed NOEs from H-2 to H-5 and H-4,
respectively, but no NOE to H-7 was observed. In addition,
an NOE between H-2 and the benzylic proton attached to
the hydroxyl group at C-4 was observed which was absent
in epoxide 4 (Table 2).
Encouraged by these results we then subjected the series
of lactones 6, 8, 11, and 13 to the enolate of R-bromo tert-
butyl acetate (4 equiv) generated from lithium bis(trimeth-
ylsilyl)amide, [(CH3)3Si]2NLi, in THF at -78 °C and isolated
the epoxides 7, 9, 10, 12, 14, and 15 in modest yields (41-
61% for the major isomer after column chromatography,
Table 2, and Scheme 1). The stereochemistry was assigned
on the basis of observed (or not observed) characteristic
NOEs shown in Table 2. In all cases, the epoxides 4, 5, 7,
9, 10, 12, 14, and 15 could easily be opened by treatment
with catalytic amounts of trifluoroacetic acid in wet THF,
affording the C-ketosides 16-20 and 24-26 as a single
stereoisomer, respectively, in quantitative yields (Scheme 1).6
Treatment of the epoxides 4, 5, and 7 with triethylsilane (2
equiv) under TMSOTf-promoted conditions at -78 °C in
a Reagents and conditions: (a) 1. Tf2O, pyridine, 0 °C; 2. RNH2,
CH2Cl2, 3 d; (b) Pd(OH)2, H2, HCl, MeOH; (c) Pd(OH)2, H2,
MeOH.
CH2Cl2 afforded the functionalized C-glycosides 21-23,
respectively, in yields averaging 50% (Scheme 1).7 Similarly,
the R-hydroxybenzyl ester 31 was obtained by treatment with
a mixture of TMSOTf and triethylsilane at 0 °C (reduction
and ester cleavage) followed by treatment with Cs2CO3 and
BnBr in DMF in 35% isolated yield (Scheme 1). The
R-hydroxy esters 21, 22, and 31 were further selected for
conversion into the C-glycosyl glycine esters (Scheme 2).
At first, the alcohols 21, 22, and 31 were activated as
trifluoromethanesulfonate esters using standard conditions
(Tf2O, pyridine), followed by subsequent inversion of the
ester by primary amines (benzylamine and cyclopentylamine;
(6) The stereochemistry at C-2 of compounds 16-20 and 24-26 was
assigned by assuming that the epoxide opening proceeds via a carboxonium
ion intermediate with retention at C-2. The C-ketosides 16-20 and 24-27
exist as a single conformer with an axial hydroxy group at C-3 in CDCl3
on the basis of NOE contacts between H-2 and H-4 and absent NOEs
between H-2 and H-5 or H-7.
(7) The starting material and hydrolysis products resulting from ester
hydrolysis and epoxide opening were isolated in a total yield of 35%. The
stereochemistry at C-2 in 23 has not been determined yet.
Org. Lett., Vol. 3, No. 25, 2001
4117

5 equiv, rt, CH2Cl2, 3 d) to afford the amino esters 27, 29,
and 35 as single stereoisomers respectively in isolated yields
averaging 80% without detectable epimerization at C-2
(Scheme 2).8 In the case of the benzyl ester 31, the amino
ester 32 (52%) and the amide 34 (25%) were isolated as
products. Subsequent deblocking of the amino esters 27, 29,
and 32 was achieved by hydrogenation using Pearlman’s
catalyst (Pd(OH)2) in acidified (HCl) methanol to afford the
C-glycosyl glycines 28, 30, and 33 in quantitative yield.
The present Claisen condensation of sugar lactones with
the enolate of tert-butyl bromoacetate generated from lithium
bis(trimethylsilyl)amide is an effective route toward exocyclic
sugar epoxides. Ring opening of the oxiranes provides entry
to novel C-ketosides, while reduction affords functionalized
C-glycosides (R-hydroxy esters) in modest yields. Activation
of the R-hydroxy esters as trifluoromethanesulfonate esters
and subsequent inversion with primary amines yields C-
glucosylamino acids without epimerization.
Acknowledgment. Financial support was provided by a
Grant-in Aid for JSPS Fellows. We thank Dr. Kazunori Toma
and Ms. Shoko Higuchi (Noguchi Institute) (MM2 calcula-
tions), Prof. Michio Murata (Osaka University) (HMBC),
and Dr. Albin Otter (University of Alberta) (TROESY) for
assistance.
(8) The absolute stereochemistry at C-2 in compounds 27 and 29 was
deduced by MM2 calculations and CD and HMBC measurements. MM2
calculations on compounds 27 and 29 revealed that both compounds exist
as single rotamers with antiperiplanar orientation C-1/H-3 (for 27) and
antiperiplanar orientation for C-1/C-4 (for 29) (see Scheme 2). NMR in
Supporting Information Available: Characteristic spec-
troscopic and analytical data for compounds 4, 5, 7, 9, 10,
12, 14, 15, 27, and 29 and experimental procedures for the
synthesis of oxiranes, C-ketosides, and C-glycosides. This
material is available free of charge via the Internet at
http://pubs.acs.org.
conjunction with HMBC measurements (500 MHz, C6D6) revealed the
3
following homo- and heteronuclear coupling constants. 27: JH-2,H-3
)
3
3
3
1.7 Hz; JC-4,H-2 ) 2.0 Hz, JC-1,H-3 ) 5.5 Hz. 29: JH-2,H-3 ) 2.2 Hz;
3JC-4,H-2 ) 1.4 Hz, 3JC-1,H-3 ) 2.5 Hz. In addition, 27 showed a negative
Cotton effect, while 29 displayed a positive Cotton effect in MeOH which
is consistent with reported values for this class of amino acids (see:
Rosenthal, A.; Shudo, K. J. Org. Chem. 1972, 37, 4391). By comparison,
the unprotected R-hydroxy ester 36 showed a positive Cotton effect while
ester 37 exhibited a negative Cotton effect in H2O.
OL0102343
4118
Org. Lett., Vol. 3, No. 25, 2001