the use of modified carbohydrates; however, these com-
pounds are challenging to synthesize and are likely to bind
to many CLECs.
arrangement mirrors that of shikimic acid, yet shikimic
acidfallsshortasascaffoldfor L-fucosemimetics. Shikimic
acid lacks a simple means of installing a group that cor-
responds to the fucose anomeric substituent. Thus, to
generate L-fucose surrogates, a different building block is
required. We reasoned that (ꢀ)-4-epi-shikimic acid 3 could
serve in this capacity, if it could be converted to com-
pounds like 4 (Figure 1b). Accordingly, we sought a facile
synthesis of (ꢀ)-4-epi-shikimic acid.
Scheme 1. Retrosynthetic Analysis of (ꢀ)-4-epi-Shikimic Acid
Figure 1. Glycomimetic scaffolds designed to mimic (A) man-
nose and (B) fucose. Hydroxyl groups typically involved in
C-type lectin binding are highlighted in red.
While routes to (ꢀ)-4-epi-shikimic acid 3 have been
reported,10 our goal was to devise a divergent synthetic
strategy that could access any desired epimer. We envi-
sioned using a ring-closing metathesis (RCM) of a trihy-
droxy precursor such as 5 (Scheme 1). We postulated that 5
could be attained from iodosugar 6 via a tandem reductive
ring opening followed by Barbier reaction.11 The iodosu-
gar needed to generate (ꢀ)-4-epi-shikimic acid could be
obtained from D-arabinose 8. The feasibility of this ap-
proach depended upon developing effective conditions for
generating the iodosugar derivative and the efficiency of
the key steps. Indeed, a concern at the outset was the ring-
closing metathesis, as 1,1-disubstituted acrylates are rela-
tively unreactive.
Our first objective was to synthesize the necessary pre-
cursor for the Barbier reaction. We initiated our route with
a high yielding acid-catalyzed ring contraction, in which
the pyranose form of D-arabinose is converted to furanose
9 (Scheme 2). The primary 5-hydroxyl group was con-
verted into an iodide using Mitsunobu conditions. All
remaining hydroxyl groups were masked by triethylsilyl
group protection, so that they would not interfere with the
subsequent organometallic transformation. In a two-step,
one-pot sequence, zinc-mediated reductive ring opening
afforded an intermediate aldehyde, which was trapped by
a Barbier reaction to afford 11a. We examined several
Given the utility of CLEC probes, we sought to develop
a general synthetic strategy to assemble noncarbohydrate
glycomimetics as CLEC ligands. (ꢀ)-Shikimic acid 1 has
served as a building block in the synthesis of biologically
active compounds.7 Previously, we demonstrated that (ꢀ)-
shikimic acid 1 can be converted into R-D-mannose mimics.8
We generated active compounds by coupling amino acids
to the shikimic acid carboxylate followed by thiol con-
jugate addition to install a pseudoanomeric group. This
approach afforded glycomimetics 2 that have the requisite
axialꢀequatorialꢀequatorial display of hydroxyl groups
present in mannosides (Figure 1a).8a These mimetics also
possess additional substituents that can enhance CLEC
binding affinity and selectivity. We postulated that epimers
of shikimic acid could be used to access scaffolds with the
necessary hydroxyl group stereochemistry to mimic other
carbohydrates. Like D-mannose, L-fucose possesses an
axialꢀequatorialꢀequatorial display of hydroxyl groups
that it can use for CLEC binding.9 As described, this
(7) (a) Tan, D. S.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.;
Schreiber, S. L. J. Am. Chem. Soc. 1999, 121, 9073–9087. (b) Nie, L.; Shi,
X.; Ko, K.; Lu, W. J. Org. Chem. 2009, 74, 3970–3973. (c) Kim, C. U.;
Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.;
Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y. J. Am. Chem.
Soc. 1997, 119, 681–690. (d) Srinivas, R.; Karmali, P. P.; Pramanik, D.;
Garu, A.; Venkata Mahidhar, Y.; Majeti, B. K.; Ramakrishna, S.;
Srinivas, G.; Chaudhuri, A. J. Med. Chem. 2010, 53, 1387–1391.
(8) (a) Schuster, M. C.; Mann, D. A.; Buchholz, T. J.; Johnson,
K. M.; Thomas, W. D.; Kiessling, L. L. Org. Lett. 2003, 5, 1407–1410.
(b) Garber, K. C. A.; Wangkanont, K.; Carlson, E. E.; Kiessling, L. L.
Chem. Commun. 2010, 46, 6747–6749.
(10) (a) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1973, 95,
7821–7828. (b) Pornpakakul, S.; Pritchard, R. G.; Stoodley, R. J. Tetra-
ꢀ
ꢀ
hedron Lett. 2000, 41, 2691–2694. (c) Sanchez-Abella, L.; Fernandez,
S.; Armesto, N.; Ferrero, M.; Gotor, V. J. Org. Chem. 2006, 14,
5397–5399.
(11) (a) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000, 122, 8444–
8452. (b) Vankarand coworkershavedescribed arelated approachto(ꢀ)-
shikimic acid and (ꢀ)-5-epi-shikimic acid. See: Kancharla, P. K.; Doddi,
V. R.; Kokatla, H.; Vankar, Y. D. Tetrahedron Lett. 2009, 50, 6951.
(9) Guo, Y.; Feinberg, H.; Conroy, E.; Mitchell, D. A.; Alvarez, R.;
Blixt, O.; Taylor, M. E.; Weis, W. I.; Drickamer, K. Nat. Struct. Mol.
Biol. 2004, 11, 591–8.
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