Synthesis of C-linked glycopyranosyl serines via a chiral glycine enolate equivalent.

Article abstract of DOI:10.1021/ol026839w

[formula: see text] The stereoselective preparation of C-linked D-gluco- and D-galactopyranosyl L-serines in their alpha and beta forms is herein reported. The syntheses require the conversion of the allyl C-glycopyranosides into their iodoethyl derivativ

Full text of DOI:10.1021/ol026839w

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3963-3965
Synthesis of C-Linked Glycopyranosyl
Serines via a Chiral Glycine Enolate
Equivalent
Ernest G. Nolen,* Micah M. Watts, and Daniel J. Fowler
Department of Chemistry, Colgate UniVersity, Hamilton, New York 13346
enolen@mail.colgate.edu
Received September 2, 2002
ABSTRACT
The stereoselective preparation of C-linked D-gluco- and D-galactopyranosyl L-serines in their r and â forms is herein reported. The syntheses
require the conversion of the allyl C-glycopyranosides into their iodoethyl derivatives, which then undergo substitution with the Williams’
chiral glycine enolate equivalent. Deprotection and acetylation affords Boc-protected amino acids for peptide synthesis.
Posttranslational protein glycosylation not only confers
structural stability to proteins but also is important for
intercellular recognition and has been implicated in tumor
cell metastasis, viral infection, immunogenic responses, and
leukocyte recruitment to sites of inflammation.1 Carbo-
hydrates that are linked to the peptide through the serine or
threonine side-chain oxygen constitute an important class of
O-glycoconjugates. However, the utility of these substances
as therapeutics is hampered in many cases by their degrada-
tion under acidic conditions, by metabolism involving
glycosidase enzymes, and by their propensity to undergo
basic elimination affording dehydroalanine derivatives during
solid-phase synthesis.2 In an attempt to alleviate the stability
issues due to the anomeric oxygen linkage and to provide
analogues for biochemical studies in glycobiology, the
methylene isosteres, D-C-glycopyranosyl L-serines, 1a, 1b,
2a, and 2b have received considerable attention (Figure 1).
Synthetic approaches to carbon-linked glycosyl amino
acids have been reviewed.3 With regard to C-glycopyranosyl
serine syntheses, there are two points of stereocontrol that
must be addressed, namely, the stereocenter at the anomeric
carbon of the C-glycoside and at the R-carbon of the serine.
Many approaches begin with the established stereocenter at
the C-glycoside and add a chiral oxazolidine or oxazolidi-
none, which can later be converted to the amino acid.4
Several groups have used similar chiral oxazolidine or
oxazolidinone precursors to form the C-glycosidic bond, thus
generating the anomeric stereochemistry.5 Others initiate their
(1) (a) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357. (b)
Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A. Science
2001, 291, 2370. (c) Van den Steen, P.; Rudd, P. M.; Dwek, R. A.;
Opdenakker, G. Crit. ReV. Biochem. Mol. Biol. 1998, 33, 151.
(2) (a) Dwek, R. A. Chem. ReV. 1996, 96, 683. (b) Sjolin, P.; Kihlberg,
J. J. Org. Chem. 2001, 66, 2957.
Figure 1. Methylene-isosteres of 1 R- and 2 â-glycosyl L-serine.
(3) Dondoni, A.; Marra, A. Chem. ReV. 2000, 100, 4395.
10.1021/ol026839w CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/05/2002

syntheses from the established C-glycosides and carry out a
de novo synthesis of the serine stereocenter in the final steps.6
Our work falls in the latter category, as the readily available
R- or â-allyl tetra-O-benzyl C-glucose and C-galactose
precursors provide configurationally defined substrates on
which to build.7 This report demonstrates the utility of the
optically active Boc-protected 5,6-diphenyl-2,3,5,6-tetra-
hydro-4H-1,4-oxazin-2-one (available in 99% ee) as a chiral
glycine equivalent to provide the R-serine stereochemistry
via enolate alkylation. This chiral oxazinone enolate has been
thoroughly developed by Williams,8 and in this paper we
report the successful use of this enolate for the preparation
of D-C-glucosyl and D-C-galactosyl N-Boc L-serines.
and sodium periodate to cleanly provide the aldehydes. While
some of these aldehydes have been previously reported,10 it
has been shown that carbonyls in the side chain of C-
glycosides may equilibrate the anomeric position by elimina-
tion and Michael addition of the pyranose oxygen.11 There-
fore, our aldehydes were immediately reduced using NaBH4
in methanol to give the corresponding alcohols 5a, 5b, 6a,
and 6b.12 Conversion to iodides 7a, 7b, 8a, and 8b was
achieved by the action of triphenylphosphine, imidazole, and
iodine.13
â-Iodoethyl C-glycosides 8a and 8b are stable for extended
periods of time at 4 °C, although they are prone to
elimination to the C-vinyl glycoside if kept at room tem-
perature. Interestingly, in the R-anomer series, C-glycoside
7b forms bicyclic structure 9 with concomitant loss of the
C-2 O-benzyl group over the course of 1 month at 4 °C
(Scheme 2). It has been observed that this process can be
The conversion of the allyl side chain into the iodoethyl
substituent was accomplished in the same manner for both
anomers and both C-glycosides (Scheme 1).9 R-Alkenes 3a
Scheme 1
Scheme 2
catalyzed by use of excess iodine in the step leading to 7b.
Presumably the more stable cis-fused 6,5-ring system,
possible only with the R-anomers, affords a lower energy
reaction pathway to the cyclization product. A closely related
5-exo-type cyclization with a cis-ring fusion has been
reported by Nicotra.14
With the iodides in hand, the key C-C bond-forming step
entailed the stereoselective alkylation of a chiral, nonracemic
(5S,6R)-oxazinone enolate by the iodides, illustrated on the
R-Gal iodide 7b (Scheme 3). As prescribed by Williams,
and 3b, available by deacetylation and benzylation of the
C-allyl tetra-O-acetylglycosides, and â-alkenes 4a and 4b
were oxidatively cleaved using catalytic osmium tetroxide
Scheme 3
(4) (a) Bertozzi, C. R.; Hoeprich, P. D., Jr.; Bednarski, M. D. J. Org.
Chem. 1992, 57, 6092. (b). Bertozzi, C. R.; Cook, D. G.; Kobertz, W. R.;
Gonzalez-Scarano, F.; Bednarski, M. D. J. Am. Chem. Soc. 1992, 114,
10639. (c) Campbell, A. D.; Paterson, D. E.; Raynham, T. M.; Taylor, R.
J. K. Chem. Commun. 1999, 1599. (d) Paterson, D. E.; Griffin, F. K.;
Alcaraz, M.-L.; Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1323. (e) Dondoni,
A.; Marra, A.; Massi, A. Tetrahedron 1998, 54, 2827. (f) Dondoni, A.;
Giovannini, P. P.; Marra, A. J. Chem. Soc., Perkin Trans. 1 2001, 2380.
(5) (a) Dondoni, A.; Marra, A.; Massi, A. Chem. Commun. 1998, 1741.
(b) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1999, 64, 933. (c)
Urban, D.; Skrydstrup, T.; Beau, J. M. Chem. Commun. 1998, 955. (d)
Dorgan, B. J.; Jackson, R. F. W. Synlett 1996, 859. (e) Dondoni, A.; Mariotti,
G.; Marra, A.; Massi, A. Synthesis 2001, 2129.
(6) (a) Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J. J.
Am. Chem. Soc. 1997, 119, 9897. (b) Debenham, S. D.; Cossrow, J.; Toone,
E. J. J. Org. Chem. 1999, 64, 9153. (c) Fuchss, T.; Schmidt, R. R. Synthesis
1998, 753. (d) Arya, P.; Ben, R. N.; Qin, H. Tetrahedron Lett. 1998, 39,
6131. (e) Ben, R. N.; Orellana, A.; Arya, P. J. Org. Chem. 1998, 63, 4817.
(f) Lay, L.; Meldal, M.; Nicotra, F.; Panza, L.; Russo, G. Chem. Commun.
1997, 1469. (g) Sutherlin, D. P.; Stark, T. M.; Hughes, R.; Armstrong, R.
W. J. Org. Chem 1996, 61, 8350.
the base, LiHMDS, was added slowly to the solution of 7b,
oxazinone, and HMPA in THF due to enolate instability.
Using a 1:1:1 mixture of 7b, oxazinone, and base led to
recovery of more than 50% of the starting iodide; therefore,
(8) (a) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276.
(b) Williams, R. M.; Fegley, G. J.; Gallegos, R.; Schaefer, F.; Pruess, D.
L. Tetrahedron 1996, 52, 1149.
(9) For similar transformations on carbohydrates, see: (a) Notz, W.;
Hartel, C.; Waldscheck, B.; Schmidt, R. R. J. Org. Chem. 2001, 66, 4250.
(b) Richter, P. K.; Tomaszewski, M. J.; Miller, R. A.; Patron, A. P.;
Nicolaou, K. C. Chem. Commun. 1994, 1151 and ref 4e.
(10) Sparks, M. A.; Panek, J. S. Tetrahedron Lett. 1989, 30, 407 and ref
6e.
(7) R-Anomers: (a) Ponten, F.; Magnusson, G. J. Org. Chem. 1996, 61,
7463. (b) Hosomi, A.; Sakata, Y.; Sakurai, H. Carbohydr. Res. 1987, 171,
223. (c) Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26, 1479.
â-Anomers: (d) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 4976.
3964
Org. Lett., Vol. 4, No. 22, 2002

differences were 0.98 ppm for anti-isomer 10a, whereas the
syn-isomer had a ∆δ of 0.61 ppm, in accordance with the
observation by Williams.
Table 1. Williams’ Chiral Glycine Enolate Alkylation Results
and Yield of the Deprotection Step
The original C-glycosidic stereocenter is maintained
throughout these transformations, as indicated by the down-
field chemical shifts of the C-1 proton for all R-isomers
(4.05-4.24 ppm) in comparison to H-1 on the â-glycosides
(3.35-3.56 ppm). Furthermore, the H-1 to H-2 coupling
constants for the R-isomers are in agreement with an axial
to equatorial coupling; the J1,2 ) 3.8 Hz for 10b is
representative.
Table 1 summarizes the nonoptimized alkylation step and
the final deprotection results to afford C-glucosyl and
C-galactosyl N-Boc L-serines. The removal of the oxazinone
chiral auxiliary requires treatment with lithium in ammonia,
which deprotects the glycoside benzyl ethers as well. Workup
with acetic anhydride and pyridine supplies products suitable
for peptide synthesis on the free carboxylic acid (Scheme
4). The products were characterized as their methyl esters
iodide
alkylation yield
deprotection yield
R-Glc 7a
R-Gal 7b
â-Glc 8a
â-Gal 8b
10a 71%a
10b 87%
11a 76%b
11b 73%
12a 73%
12b 77%
13a 86%
13b 68%
a Recovered 16% starting iodide and 8% elimination product. b Only 90%
pure, contaminated with unreacted oxazinone.
a 3-fold excess of oxazinone and base were employed
supplying a 76% yield of alkylation product 10b in 6 h with
13% recovered starting material. Extending the reaction time
to 14 h led to an 87% yield of product.15 Use of the sodium
enolate, generated with NaHMDS, was explored but led to
complex mixtures. The lithium enolate yielded cleaner
reactions in all cases as judged by TLC and isolated yield
of desired product.
Scheme 4
As expected, the alkylation occurs on the less hindered
top-face of the enolate, opposite the phenyl substituents, to
give anti-addition product 10b, which was the only isolated
product in this case. The stereochemical assignment was
based on the difference in chemical shift between H-5 and
H-6 on the oxazinone moiety in DMSO-d6 at 368 K.
Williams has reported the empirical observation that the anti-
isomers have a ∆δ of 0.94-1.10 ppm, while the ∆δ values
for the syn-isomers are 0.60-0.70 ppm.16 In our alkylations,
only R-Glc iodide 7a led to any isolated syn-isomer. In this
case, the anti:syn ratio was 93:7. The chemical shift
by treatment with diazomethane and provided spectroscopic
data in agreement with the results of others.4d,f,5e,6a
The well-precedented allyl C-glycosides, in both R- and
â-forms, afford convenient starting substrates, and the ability
to achieve excellent diastereoselection in the key oxazinone
alkylation and the relatively short, five-step synthesis make
this an attractive route for the preparation D-C-glycosyl
N-Boc L-serines. Furthermore, the unnatural D-serines, via
the antipodal oxazinone, would also be available through this
versatile route.
(11) (a) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A.
J. Chem. Soc., Perkin Trans. 1 1989, 1275. (b) Ohrui, H.; Jones, G. H.;
Moffatt, J. G.; Maddox, M. L.; Christensen, A. T.; Byram, S. K. J. Am.
Chem. Soc. 1975, 97, 4602.
(12) Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107, 4289.
See also refs 11a and 4d.
Acknowledgment. The authors thank Pfizer, Inc., for the
Summer Undergraduate Research Fellowship to D.J.F. and
James A. Kelly of the NCI-Frederick for mass spectral
analysis. Partial support for this work was provided by the
National Science Foundation’s CCLI Program under grant
DUE-0088227.
(13) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866.
(14) Cipolla, L.; Lay, L.; Nicotra, F. J. Org. Chem. 1997, 62, 6678.
(15) A solution of iodide (0.501 mmol) and 4-(tert-butoxycarbonyl)-
5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (0.492 g, 1.50 mmol)
in THF (14 mL) was cooled to -78 °C, and to this was added a 1 M solution
of LiHMDS (1.50 mmol). The reaction mixture was allowed to warm to
room temperature overnight. Brine was added (3 mL), and the mixture was
diluted with EtOAc (30 mL). The organic layer was separated, washed with
more brine, dried with MgSO4, concentrated, and chromatographed.
(16) Williams, R. M.; Sinclair, P. J.; Zhai, S.; Chen, S. J. Am. Chem.
Soc. 1988, 110, 1547.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 5a,b-13a,b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL026839W
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3965