Syntheses of α- and β-C-glucopyranosyl serines from a common intermediate

Article abstract of DOI:10.1021/ol802009v

(Chemical Equation Presented) A versatile synthesis leading to either C-linked α- or β-glucopyranosyl serines is presented from a common, advanced synthetic intermediate. Cyclization of the penultimate carbinol onto the alkene and methanolysis of the lactone yields selectively the α-linkage. A transposition of these last steps leads to the α-linked isomer selectively.

Full text of DOI:10.1021/ol802009v

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4911-4914
Syntheses of r- and
ꢀ-C-Glucopyranosyl Serines from a
Common Intermediate
Ernest G. Nolen,* Laurence A. Donahue, Rebecca Greaves, Trevor A. Daly, and
David R. Calabrese
Department of Chemistry, Colgate UniVersity, 13 Oak DriVe,
Hamilton, New York 13346
enolen@colgate.edu
Received August 27, 2008
ABSTRACT
A versatile synthesis leading to either C-linked r- or ꢀ-glucopyranosyl serines is presented from a common, advanced synthetic intermediate.
Cyclization of the penultimate carbinol onto the alkene and methanolysis of the lactone yields selectively the r-linkage. A transposition of
these last steps leads to the ꢀ-linked isomer selectively.
Protein glycosylation, often via an oxygen linkage to serine/
threonine, is of biochemical significance because it alters the
physicochemical properties and activity of proteins and the
carbohydrates themselves act as receptors on the cell surface.1
Cell surface carbohydrates play important roles in the
modulation of cellular interactions. Of particular interest, the
R-linkage to O-GalNAc Ser/Thr, known as Tn antigen, forms
the foundation for eight core structures of the heavily
glycosylated proteins known as mucins. These structures are
key immunological recognition features directly involved in
antibody-antigen interactions, in pathogen binding, and
serve as tumor markers. In addition, Hart has reviewed the
significance of ꢀ-linked O-GlcNAc in cellular regulation on
cytosolic and nuclear proteins and the implication of its
misregulation in neurodegenerative diseases and diabetes.2
The stereochemical aspect of the anomeric linkage (R or ꢀ)
is essential to biochemical activity, and it has been shown,
for example, that replacement of the natural R-O-GalNAc
in mucin glycopeptides with a ꢀ-O-GalNAc results in
structural disorder.3
Many groups have sought to mimic these glycoconjugates
to better understand their glycobiology and to produce
potential therapeutic agents. Toward that end, convenient
syntheses of catabolically stable glycosyl amino acid mimics
are desired. One approach has been the substitution of the
linking oxygen with a methylene to form the so-called
C-glycosides. These mimics are robust to degradation by
(1) (a) Marth, J.; Lowe, B. J.; VarkiA. In Essentials of Glycobiology;
Varki, A., Cummings, R., Esko, J., Freeze, H., Hart, G., Marth, J., Eds.;
Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 1999. (b)
Sears, P.; Wong, C.-H. Cell. Mol. Life Sci. 1998, 54, 223–252. (c) Dwek,
R. A. Chem. ReV. 1996, 96, 683–720.
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(b) Comer, F. I.; Hart, G. W. J. Biol. Chem. 2000, 275, 29179–29182.
(3) Pratt, M. R.; Bertozzi, C. R Chem. Soc. ReV. 2005, 34, 58–68.
10.1021/ol802009v CCC: $40.75
Published on Web 09/27/2008
2008 American Chemical Society

glycosidases, reaction with glycosyltransferases, acid hy-
drolysis of the former anomeric acetal, and ꢀ-elimination
from the serine.
ically the R- or ꢀ-anomeric C-linkage, 4 and 5, respectively,
from the common intermediate 6.
The known gluco-heptenitol 2 was available in one step
by addition of divinylzinc to 2,3,5-tri-O-benzyl arabinose.9
The divinylzinc addition is remarkably stereoselective, and
the crude product is used directly in the next step. The
metathesis partner, allyl glycine 3, was produced by protec-
tion of the commercially available allyl glycine. As shown
in Scheme 1, Yamaguchi or DCC-activated esterification of
Several syntheses of R-C-glycopyranosyl serines4 and ꢀ-C-
glycopyranosyl serines4a,e,5 have been reported. In most
cases, the stereochemistry of the C-linkage to the carbohy-
drate is first established with a pendant functional group,
which is utilized to elaborate the amino acid moiety. The
one exception being the exoalkylidene hydrogenation to
afford the ꢀ-C-linkage.5e,f In addition to these strategies,
cross-metathesis (CM) has been employed to join C-vinyl
glycosides with vinyl glycine surrogates to furnish glycosyl
serine mimics. In general, these have only produced low
yields of CM product.6
Scheme 1. Nonselective Esterification of Diol 2
Previously, we have reported the synthesis of R-C-glycosyl
serine 4 through an intramolecular hydroalkoxylation of the
(E)-4-decenoate 1.7 This cyclization precursor was prepared
by CM of the readily available gluco-heptenitol 2 and L-allyl
glycine 3, as illustrated in Figure 1. Unfortunately, both
the heptenitol 2 with the acid 3 yielded mixtures of products
with a slight preference for the nonallylic ester 7 over the
allylic ester 8 in a ∼3:2 ratio by mass after separation of
products. Neither Bu2SnO10 nor Ag2O,11 which are useful
for selective reaction of vicinal diols, were of any use in
(4) (a) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1999, 64, 933–
944. (b) Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J. J. Am.
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J.-M. Chem. Commun. 1998, 955–956. (d) Rohrig, C. H.; Takhi, M.;
Schmidt, R. R. Synlett 2001, 1170–1172. (e) Dondoni, A.; Marra, A.; Massi,
A. Chem. Commun. 1998, 1741–1742. (f) Ben, R. N.; Orellana, A.; Arya,
P. J. Org. Chem. 1998, 63, 4817–4820. (g) Dorgan, B. J.; Jackson, R. F. W.
Synlett 1996, 859–861. (h) Dondoni, H.; Catozzi, N.; Marra, A. J. Org.
Chem. 2004, 69, 5023–5036. (i) Nolen, E. G.; Watts, M. M.; Fowler, D. J.
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Raynham, T. M. Chem. Commun. 1999, 1599–1600. (d) Ohnishi, Y.;
Ichikawa, Y. Bioorg. Med. Chem. Lett. 2002, 12, 997–999. (e) Modica, E.;
Compostella, F.; Colombo, D.; Franchini, L.; Cavallari, M.; Mori, L.; De
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2001, 2129–2137.
Figure 1. Retrosynthetic plan and the common intermediate.
(6) (a) McGarvey, G. J.; Benedum, T. E.; Schmidtmann, F. W. Org.
Lett. 2002, 4, 3591–3594. (b) Nolen, E. G.; Kurish, A. J.; Wong, K. A.;
Orlando, M. D. Tetrahedron Lett. 2003, 44, 2449–2453. (c) Chen, G.;
Schmieg, J.; Tsuji, M.; Franck, R. W. Org. Lett. 2004, 6, 4077–4080.
(7) (a) Nolen, E. G.; Kurish, A. J.; Potter, J. M.; Donahue, L. A.;
Orlando, M. D. Org. Lett. 2005, 7, 3383–3386. Structures related to
compound 11 have been reported for the preparation of dysiherbaine and
neodysiherbaine. (b) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K.
J. Am. Chem. Soc. 1997, 119, 4112–4116. (c) Sakai, R.; Koike, T.; Sasaki,
M.; Shimamoto, K.; Oiwa, C.; Yano, A.; Suzuki, K.; Tachibana, K.; Kamiya,
H. Org. Lett. 2001, 3, 1479–1482.
metathesis partners are of type I8 and thus are highly reactive,
so significant amounts of the two self-metathesis products
were obtained. This was circumvented by using a 4:1 ratio
of the heptenitol to the allyl glycine, providing the decenoate
1 and a large amount of the easily separated heptenitol self-
metathesis product. While this strategy was tenable for the
readily available gluco-heptenitol 2, it was not feasible for
other heptenitols that may require greater synthetic effort.
To avoid this limitation, we present here a ring-closing
metathesis strategy that not only allows for a 1:1 stoichio-
metric ratio between the metathesis partners but also presents
the option of diverting the synthesis to yield stereospecif-
(8) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
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53, 4181–4185.
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69, 5774–5777.
4912
Org. Lett., Vol. 10, No. 21, 2008

our esterification. Although we were unable to achieve a
satisfactory esterification, others have shown modest selec-
tivity for the allylic hydroxyl in reactions on diol 2 by
alkylation with p-methoxybenzyl chloride12 and benzoylation
in a two-phase system to supply modest selectivity, 3.5:1.13
Interestingly, Crumpstey has reported a highly selective (10:
1) 3,4-dimethoxybenzylation on a structurally similar octeni-
tol with preference for etherification of the non-allylic
hydroxyl.14 A report using trimethylorthoformate and cam-
phorsulfonic acid followed by reduction with diisobutyla-
luminum hydride15 was promising as there exhibited a
preference for MOM protection of a non-allylic hydroxyl in
the presence of an allyic hydroxyl, yet in our hands, the initial
acid-catalyzed step of this procedure directly yielded the
C-vinyl arabinose 916 by SN2 displacement at the allylic
position.
olefin geometry of nonenolides was critically dependent on
the protecting groups, with allylic hydroxyl favoring the (Z)-
alkene and PMB protection affording the E-isomer.
With both esters 7 and 8 leading to the same Z-
configuration, the selectivity issues of the esterification were
not of concern providing that the (Z)-decenoate 11 leads on
the desired product. However, we were more interested in
the synthetic versatility of the oxepenone 6. The esterification
selectivity issue described in Scheme 1 was avoided by an
alternative route, shown in Scheme 3, through a dithioacetal
Scheme 3
.
Alternative Selective Synthesis of the Common
Intermediate 6
With esters 7 and 8 in hand, albeit unselectively at this
point, we conducted the RCM using 5 mol % of Grubbs
second generation catalyst (G2) in refluxing dichloromethane
(see Scheme 2). Both esters gave good yields of cyclized
Scheme 2. RCM and Convergent Synthesis of Decenoate 11
to supply the starting aldehyde 12.19 While reproducing the
literature procedure, we explored two modifications. Attempts
to prepare the initial dithioacetal via an odorless protocol20
were unsuccessful; however, the removal of the diethyl
dithioacetal using NBS, CH3CN, and H2O21 nicely replaced
the need for mercury salts to unmask the aldehyde of 12.
Divinylzinc addition by Nicotra’s method9 yielded the gluco-
heptenitol 13 as the major isomer. Lowering the temperature
of the reaction from rt to 0 °C improved the selectivity of
vinyl addition from 3:1 to 5:1 in favor of the gluco-
configuration over the manno-isomer. Chelation control with
the adjacent benzyl ether dictates the gluco-configuration,
and proof of the diastereoselection was accomplished by
removal of the silyl protecting group in 85% yield using
Bu4NF to supply the aforementioned gluco-heptenitol 2.
Conversion of 13 into 6 was accomplished by esterification
products. The oxepenone 6 was produced in 94% yield and
the oxecenone 10 in 89% yield. Obviously, RCM of the
allylic ester 8 can only afford the Z-geometry within
the seven-membered oxepenone framework, but presumably
the nonallylic ester 7 could produce a mixture of (E)- and
(Z)-alkenes in the 10-membered ring; however, we observed
only the Z-isomer. The assignment was confirmed by
methanolysis of each of the lactones to yield the same acyclic
(Z)-alkene 11. We were surprised to find that only the
Z-geometry of 10 was obtained in view of the mixtures
observed in other RCM reactions leading to 10-membered
rings, such as that found in microcarpalide syntheses.17
Recently, a report by Mohapatra and Grubbs18 observed the
(12) Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41, 7801–
7803.
(13) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry
2001, 12, 1807–1809.
(14) Crumpstey, I. Tetrahedron Lett. 2005, 46, 6257–6259.
(15) Friesen, R. W.; Vanderwal, C. J. Org. Chem. 1996, 61, 9103–9110.
(16) Persky, R.; Albeck, A. J. Org. Chem. 2000, 65, 5632–5638.
(17) (a) Ghosh, S.; Rao, R. V.; Shashidhar, J. Tetrahedron Lett. 2005,
46, 5479–5481. (b) Prasad, K. R.; Penchalaiah, K.; Choudhary, A.;
Anbarasan, P. Tetrahedron Lett. 2007, 48, 309–311. (c) Garcia-Fortanet,
J.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A. J. Org. Chem. 2005, 70,
9822–9827.
(18) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M. A.; Chorghade,
M. S.; Gurjar, M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48, 2621–
2625.
(19) Payette, D. R.; Just, G. Can. J. Chem. 1981, 59, 269–282.
(20) Ouyang, Y.; Dong, D.; Zheng, C.; Yu, H.; Liu, Q.; Fu, Z. Synthesis
2006, 22, 3801–3804.
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Org. Lett., Vol. 10, No. 21, 2008
4913

with L-allyl glycine 3, RCM to yield the oxepenone, and
TMSOTf deprotection of the silyl ether.22
Turning now to the key closure of the pyranosyl ring, we
envisioned a mercury(II)-mediated cyclization of the pen-
ultimate carbinol onto the alkene as described in our earlier
work,7a which was modeled after Nicotra’s C-methyl gly-
cosides.9 As shown in Scheme 4, treatment of 6 with
Scheme 4. Divergence from 6 to Afford R- and ꢀ-C-Glc Ser
Figure 2
.
Suggested origin of the cyclization stereochemistry.
1
Specifically, the H NMR resonance for H-2 (glycoside
numbering) of compound 16 in CDCl3 appears as a doublet
of doublets (J1,2 ) 5.7 Hz) at 5.07 ppm, which is charac-
4
teristic of the R-anomer in the C1 conformation.
In contrast, when the cyclization was conducted, after
methanolysis of 6, on the aforementioned acyclic (Z)-alkene
11, the ꢀ-C-glucopyranosyl serine 5 was observed. Presum-
ably, the steric repulsion of the hydroxyl and the cis-
methylene disfavors the inside alkoxy model, allowing bond
rotation to position the smaller C-H bond into the plane of
the double bond, giving rise to cyclization from the opposite
face of the alkene, as shown in Figure 2. Confirmation of
the ꢀ-isomer was supported by transformation to the tet-
1
raacetate and comparison to the H NMR spectrum of the
known compound.4i In particular, for compound 17 in CDCl3,
the NMR resonance of H-2 at δ 4.89 ppm appears as a triplet
with J1,2 ) 9.6 Hz, in agreement with axial-axial coupling
constants, as expected for the ꢀ-isomer.
In summary, the oxepenone 6 is available through a RCM
strategy and can be diverted to prepare mimics of O-glycosyl
serines in either anomeric configuration. From the oxepenone,
hydroalkoxylation and methanolysis afford the R-C-glucopy-
ranosyl serine, and a reversal of the sequence of the final
two reactions leads to the ꢀ-C-glucopyranosyl serine.
mercury(II) trifluoroacetate in an ice bath, followed by
removal of mercury with BEt3 and NaBH4 produced a
23
single stereoisomer. The stereoselectivity of the addition was
controlled by the stereochemistry at the allylic position,
which orients the cyclizing chain to one face of the alkene.
Essentially, the lactone ring locks the allylic C-O bond into
the inside alkoxy orientation that has been explanatory for
other intramolecular additions to alkenes24 (see Figure 2).
Finally, methanolysis of the lactone provided the R-C-
glucopyranosyl serine 4. The stereochemical assignment was
only possible by hydrogenolysis and acetate formation to
furnish the tetraacetate 16, which was identical to material
synthesized by a stereochemically unambiguous route.4i
Acknowledgment. Support for this work was provided
by ACS-PRF. R.G. and D.C. thank Bristol-Myers Squibb
Co. for summer support.
(22) Bou, V.; Vilarrasa, J. Tetrahedron Lett. 1990, 31, 567–568.
(23) Kang, S. H.; Lee, J. H.; Lee, S. B. Tetrahedron Lett. 1998, 39,
59–62.
Supporting Information Available: Experimental pro-
cedures and characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(24) (a) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Jager,
V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880–3882.
(b) Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J. J. Am.
Chem. Soc. 1987, 109, 672–677.
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