Synthesis of 4-azido-4-deoxy-neu5,7,8,9ac42en1me. A key intermediate for the synthesis of GG167 from D-glucono-δ-lactone

Article abstract of DOI:10.1021/ol0491890

Stereoselective 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, an advanced key intermediate for the synthesis of neuraminidase inhibitor GG167 (Zanamivir, Relenza), was accomplished using D-glucono-δ-lactone as starting material. A highly diastereoselective allyllation of an imine intermediate, a regioselective azide-opening of an aziridine, and chemoselective oxidations of vicinal diols served successfully as key steps.

Full text of DOI:10.1021/ol0491890

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2269-2272
Synthesis of
4-Azido-4-deoxy-Neu5,7,8,9Ac42en1Me. A
Key Intermediate for the Synthesis of
GG167 from D-Glucono-δ-lactone
Ke-Gang Liu, Shi Yan, Yu-Lin Wu, and Zhu-Jun Yao*
State Key Laboratory of Bioorganic and Natural Product Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai
200032, China
yaoz@mail.sioc.ac.cn
Received May 4, 2004
ABSTRACT
Stereoselective 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,
an advanced key intermediate for the synthesis of neuraminidase inhibitor GG167 (Zanamivir, Relenza), was accomplished using D-glucono-
δ-lactone as starting material. A highly diastereoselective allyllation of an imine intermediate, a regioselective azide-opening of an aziridine,
and chemoselective oxidations of vicinal diols served successfully as key steps.
Infection by influenza virus is still a major worldwide health
problem today that causes substantial morbidity and mortal-
ity. Though great advances have been achieved in antiviral
chemotherapies against other pathogens, such as HIV and
herpes, very limited options are available for the treatment
of infection by influenza virus.1 Fortunately, notable progress
has been made in recent years on development of inhibitors
of influenza neuraminidase (NA),2 which is believed to
catalyze the cleavage of terminal sialic acid residues attached
to glycoproteins and glycolipids. This process is necessary
for the release of newly formed virus from infected cells as
well as for efficient spread of virus in the respiratory tract.3
During the past decade, NA has become an attractive target
for developing agents against influenza infection, and various
small molecule-based inhibitors4 have resulted. Among these,
GG1675,6 (zanamivir, relenza, 1) and GS41047 (tamiflu,
oseltamivir, 2) represent two successful examples8 designed
as analogues of the sialic acid derivative Neu5Ac (3, Figure
1). Both agents have been marketed for the treatment of
influenza by Glaxo-Wellcome and Roche, respectively.
(3) (a) Palese, P.; Tobita, K., Ueda, M. Virology 1974, 61, 397-410.
(b) Liu, C.; Air, G. M. Virology 1993, 193, 1-5.
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670.
(5) (a) Kiefel, M., J.; von Itzstein, M. Prog. Med. Chem. 1999, 36, 1-28.
(b) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.;
Jin., B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.; Colman,
P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R. C.; Hotham,
V. J.; Cameron, J. M.; Penn, C. R. Nature 1993, 363, 418-423.
(6) Fleming, D. M. Expert Opin. Pharmacol. 2003, 4, 799-805.
(1) (a) Johnston, S. L. Virus Res. 2002, 82, 147-152. (b) De Cleecq, E.
J. Clin. Virol. 2001, 22, 73-89.
(2) (a) Oxford, J. S.; Lambkin, R. Drug DiscoVery Today 1998, 3, 448-
456. (b) Kiefel, M. J.; von Itzstein, M. Chem. ReV. 2002, 102, 471-490.
(c) Li, L.-S.; Liu, K.-G.; Yao, Z.-J.; Wu, Y.-L. Chin. J. Org. Chem. 2002,
22, 718-734. (d) Li, L.-S.; Wu, Y.-L. Curr. Org. Chem. 2003, 7, 447-
475.
10.1021/ol0491890 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/27/2004

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.
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Org. Lett., Vol. 6, No. 13, 2004

Scheme 2. Aziridine-Opening by Sodium Azide
Scheme 3. Synthesis of Sugar Derivative 16
presence of NH4Cl proved to be optimal, opening aziridine
9 regioselectively at the less hindered position. This afforded
the desired azide 10 in 62% yield (Scheme 2). One advantage
of this reaction is its ease of scale-up. Acetylation of amine
10 gave compound 11 as a highly crystalline solid (88%).
X-ray crystallographic studies on 11 (see Supporting Infor-
mation) confirmed its absolute stereochemistry of 11 unam-
biguously. This also defined the stereochemistry of the
previous addition product 5.
Next, the terminal olefin in 11 was efficiently dihydroxy-
lated by catalytic OsO4 in the presence of NMO in acetone-
H2O; diol 12 was formed in 96% yield (Scheme 3). The
primary hydroxyl of diol 12 was selectively oxidized under
TEMPO-based conditions12 using Ca(ClO)2 as a co-oxidant.
The resulting acid was immediately converted into its methyl
ester 13 (80%). Dess-Martin oxidation of the remaining
hydroxyl group of 13 provided the R-ketocarboxylic acid
methyl ester 14. Interestingly, elimination of one molecule
of HN3 occurred during silica gel purification of 14, giving
the conjugated olefin 15. It is noteworthy that Swern
oxidation of 13 also afforded 15 as the sole product in high
yield. Without purification, crude 14 derived from Dess-
Martin oxidation was directly treated with 40% HF in MeCN
(5% in volume)10a to give the sugar derivative 16 (52% for
two steps).
The sugar derivative 16 was fully acetylated with acetic
anhydride in pyridine to yield 17 (Scheme 4).13 By analogy
to referenced methods,14 replacement of the R-acetoxyl group
of 17 with chloride (18, 76%) was accomplished by bubbling
HCl (g) in DCM. Subsequent elimination of HCl from 18
was achieved, employing DBU in DCM to afford azide 19
(97%), which is a known advanced intermediate for the
synthesis of GG167 (1). All the physical data on 19 coincided
with literature reports.9
of chemoselective oxidations were developed and/or opti-
mized as the key steps in the synthesis. An advantage of
this route is its use of an inexpensive sugar as a starting
material, which may strengthen industrial interest in this
route. The presented work also represents a successful
application of our general [6 + 3] approach toward sialic
acids and their analogues. Finally, all the intermediates
produced in this route provide further opportunities to
develop new NA inhibitors for related antiviral chemo-
therapy.
Scheme 4. Completion of Synthesis of
4-Azido-4-deoxy-Neu5,7,8,9Ac42en1Me (19)
In summary, we have accomplished a new 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), which is an advanced intermediate in the preparation
of the influenza drug GG167 (Zanamivir, Relenza, 1). A
highly diastereoselective imine addition, a regioselective and
mild aziridine ring-opening using sodium azide, and a series
(11) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.; Prasad, A. R.
Synthesis 2002, 1061-1064.
(12) Ikunaka, M.; Matsumoto, J.; Nishimoto, Y. Tetrahedron: Asymmetry
2002, 13, 1201-1208.
(13) Marra, A.; Sinay, P. Carbohydr. Res. 1989, 190, 317-322.
(14) Gregar, T. Q.; Gervay-Hague, J. J. Org. Chem. 2004, 69, 1001-
1009.
Org. Lett., Vol. 6, No. 13, 2004
2271

Acknowledgment. The Major State Basic Research and
Development Program (G2000077500), NSFC Team Pro-
gram Grant (20321202), Chinese Academy of Sciences
(KGCX2-SW-209), and Shanghai Municipal Commission of
Science and Technology (03DZ19203) were greatly appreci-
ated for the financial support. The authors thank Dr. Terry
Burke at NCI and Mr. Yan-Tao He at SIOC for help with
manuscript preparation.
Supporting Information Available: Experimental details
with full characterization of compounds, copies of 1H NMR
of compounds 7-11, 14, and 17-19, a copy of 13C NMR
of compound 19, and an ORTEP drawing of compound 11
derived from X-ray crystallographic analysis and CIF file.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0491890
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Org. Lett., Vol. 6, No. 13, 2004