Figure 1. NA inhibitors GG167 (1), GS4104 (2), and Neu5Ac
(3).
All literature approaches9 toward GG167 (1) pass through
common intermediates and require approximately 15 steps,
starting from Neu5Ac (3). The major differences between
these routes are the reproducibility of certain steps, reagents,
and yields. Considering the cost of Neu5Ac, it would be of
considerable value to establish an alternative route to GG167
that started from less costly starting materials. In recent years,
we have developed a general [6 + 3] sugar-extension strategy
that has been successfully applied to the syntheses of several
sialic acid analogues.10 All of these targets present common
structural features such as R-ketocarboxylic acids bearing
cyclic internal hemi-acetal moieties or dehydrated variants.
Structurally, GG167 presents these characteristics, being a
typical R-ketocarboxylic acid sugar derivative (2,6-anhydro
form) with a nine-carbon skeleton (Figure 2). Presented
herein is our recent synthesis of 5-acetamido-7,8,9-tri-O-
acetyl-2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycero-D-galacto-
non-2-enonic acid methyl ester (19), a key advanced
intermediate en route to GG167 (1), using the inexpensive
starting material, D-glucono-δ-lactone. The synthesis utilizes
as key steps, addition of allylmagnesium bromide to an imine
intermediate, as well as an efficient aziridine-opening by
sodium azide.
Figure 2. Retrosynthetic analysis of GG167 (1) and its key
intermediate 19.
in a range of solvents at various temperatures. Finally, it
was found that the addition of allylmagnesium bromide in
ether at 0-25 °C gave a single diastereomer 5 in satisfactory
yield (56%).10b The stereochemistry of imine addition was
ultimately confirmed by X-ray crystallography at a later stage
(Scheme 2). N-Acetylation of amine 5 with acetic anhydride
provided the acetamide 6 (88%). Deprotection of both benzyl
groups in 6 was carried out using lithium-liquid ammonia
(82%). The resultant alcohol 7 was then converted into the
key aziridine intermediate 9 through a two-step procedure
(MsCl/Et3N and NaH/THF) in 69% overall yield.
With aziridine 9 in hand, a variety of ring-opening reagents
and conditions were tried in order to accomplish the
transformation to the corresponding vicinal syn-azidoamine
derivative. These conditions included NaN3/DMF, LiN3/
DMF, TMSN3/ZnBr2, TMSN3/BF3‚OEt2, TMSN3/InBr3,11
and TMSN3/TMSOTf. All of these gave either negative
results or caused de-N-acetylation. Finally, concise and mild
conditions using NaN3 in refluxing EtOH-H2O in the
The synthesis started from inexpensive commercially
available D-glucono-δ-lactone, which was converted to the
imine 4 according to ref 10b (Scheme 1). Several reagents
and sets of conditions were examined with this imine before
the chain extension could be achieved. Conditions examined
included propargyl bromide-Zn dust, propargylmagnesium
bromide, allyl bromide-Zn dust, and allylmagnesium bromide
Scheme 1. Synthesis of Aziridine 9
(7) (a) McClellan, K.; Perry, C. M. Drug 2001, 61, 263-283. (b) 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.; Laver, W. G.;
Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681-690. (c) Kim, C. U.;
Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P. A.;
Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451-
2460.
(8) (a) Wang, G. T. Expert Opin. Ther. Pat. 2002, 12, 845-861. (b)
Dreitlein, W. B.; Maratos, J.; Brocavich, J. Clin. Ther. 2001, 23, 327-
355.
(9) (a) Scheigetz, J.; Zamboni, R.; Bernstein, M. A., Roy, B. Org. Prep.
Proc. Int. 1995, 27, 637-644. (b) von Itzstein, M.; Jin, B.; Wu, W.-Y.;
Chandler, M. Carbohydr. Res. 1993, 244, 181-185. (c) Schreiber, E.; Zbiral,
E.; Kleineidam, R. G.; Schauer, R. Liebigs Ann. Chem. 1991, 129-134.
(d) Chandler, M.; Bamford, M. J.; Conroy, R.; Lamont, B.; Patel, B.; Patel,
V. K.; Steeples, I. P.; Storer, R.; Weir, N. G.; Wright, M.; Williamson, C.
J. Chem. Soc., Perkin Trans. 1. 1995, 1173-1179.
(10) (a) Liu, K.-G.; Yan, S.; Wu, Y.-L.; Yao, Z.-J. J. Org. Chem. 2002,
67, 6758-6763. (b) Liu, K.-G.; Zhou, H.-B.; Wu, Y.-L.; Yao, Z.-J. J. Org.
Chem. 2003, 68, 9528-9531. (c) Liu, K.-G.; Hu, S.-G.; Wu, Y.; Yao, Z.-
J.; Wu, Y.-L. J. Chem. Soc., Perkin. Trans. 1. 2002, 1890-1895.
2270
Org. Lett., Vol. 6, No. 13, 2004