Development of new stereodiverse diaminocyclitols as inhibitors of influenza virus neuraminidase

Article abstract of DOI:10.1021/ol902438f

"Chemical Equation Presented" A concise and modular approach to synthesize a new type of cyclopentene-based diaminocyclitol library from D-serine and L-serine has been developed, and key steps in this synthesis are an aza-Claisen rearrangement, a ring-closing metathesis, and a Baylis-Hillman reaction. The developed chemistry may offer a unique way to investigate the neuraminidase (NA) mutation by systematically mapping the changes within its binding sites.

Full text of DOI:10.1021/ol902438f

ORGANIC
LETTERS
2010
Vol. 12, No. 1
4-7
Development of New Stereodiverse
Diaminocyclitols as Inhibitors of
Influenza Virus Neuraminidase
Yi Cui,† Zhaodong Jiao,† Jianxian Gong,† Quan Yu,‡ Xiaofeng Zheng,‡
Junmin Quan,*,† Ming Luo,*,†,§ and Zhen Yang*,†,|
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking UniVersity Shenzhen Graduate School, Shenzhen 518055, China, College of
Life Science, Peking UniVersity, Beijing 100871, China, Department of Microbiology
and Center for Biophysical Sciences and Engineering, UniVersity of Alabama at
Birmingham, Birmingham, Alabama 35294, and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education and Beijing National
Laboratory for Molecular Science (BNLMS), College of Chemistry and the State Key
Laboratory, Peking UniVersity, Beijing 100871, China
zyang@pku.edu.cn; ming@cbse.uab.edu; quanjm@szpku.edu.cn
Received June 25, 2009
ABSTRACT
A concise and modular approach to synthesize a new type of cyclopentene-based diaminocyclitol library from D-serine and L-serine has been
developed, and key steps in this synthesis are an aza-Claisen rearrangement, a ring-closing metathesis, and a Baylis-Hillman reaction. The
developed chemistry may offer a unique way to investigate the neuraminidase (NA) mutation by systematically mapping the changes within
its binding sites.
The outbreak of 2009 H1N1 influenza A virus that is believed
to have originated in Mexico is rapidly spreading across the
globe.1 This virus is spreading from person-to-person,
probably in much the same way that regular seasonal
influenza viruses spread. Thus, influenza is one of the most
deadly viruses known to humans.2
vaccines that are effective against the newly emerged
influenza virus will have many difficulties, and the efficacy
of the vaccines is difficult to test thoroughly because of low
incidences of human infection at an early stage. It may be
too late to use it in control of an influenza pandemic if the
vaccine is not effective when administered to humans.
Therefore, the development of small molecular based anti-
viral drugs is even more important in the event that new
Current prevention and treatment of influenza rely on
vaccines and antiviral drugs. However, development of new
† Peking University Shenzhen Graduate School.
‡ College of Life Science, Peking University.
§ University of Alabama at Birmingham.
(3) World Health Organization, Fact Sheet No. 211, March 2003.
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Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681. (b) Stittelaar,
K. J.; Tisdale, M.; van Amerongen, G.; van Lavieren, R. F.; Pistoor, F.;
Simon, J.; Osterhaus, A. D. AntiViral Res. 2008, 80, 225.
| College of Chemistry and the State Key Laboratory, Peking University.
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10.1021/ol902438f  2010 American Chemical Society
Published on Web 12/09/2009

highly virulent strains can lead to global pandemics resulting
in millions of deaths.3
Currently, oseltamivir (Tamiflu) and zanamivir (Relenza)
are influenza neuraminidase (NA) inhibitors4 that are highly
effective to all strains of influenza viruses. However, the
recent emergence of oseltamivir (A in Figure 1) resistant
oriented synthesis of its library. To this end, we carried out
a preliminary computational analysis (see Supporting Infor-
mation for details). Since scaffold C has three chiral centers,
we wished that our developed chemistry could allow us to
stereoselectively synthesize its corresponding eight stereoi-
somers.
Synthetically, we would like to explore the RCM reaction
as a key step to construct the framework of C because of its
operational simplicity, high chemoselectivity, and remarkable
tolerance for functional group substitution,11 and this syn-
thetic strategy has been successfully demonstrated by Yao
and co-workers12 in the syntheses of six-membered-ring
based diaminocyclitols.
Our synthesis started with the syntheses of diamines 3
and 4 from 1, which can be easily made from L-serine13
(Scheme 1).
Figure 1. Structures of antiviral drugs.
Synthetically, alcohol 1 was first oxidized by CrO3-
pyridine to its aldehyde, which then reacted with methyl
2-(dimethoxyphosphoryl) acetate to afford an ester, followed
by DIBAl-H/BF3·Et2O reduction to afford allylic alcohol 2
in overall 58% yield in three steps. To make diamines 3,
alcohol 2 was reacted with 2,2,2-trichloroacetonitrile in the
presence of NaH to form an allyl trichloroacetimidate, which
underwent Pd-catalyzed aza-Claisen rearrangement14 to
diastereoselectively afford an anti-diamine in 65% yield,
which was then subjected to a hydrolysis to remove its
trichloroacetyl group, followed by protection with a Cbz
group and removal of THP with PTSA/MeOH to give
compound 3 in 61% yield. Mechanistically, this aza-Claisen
rearrangement might proceed through a formation of a Pd
complex, which also might trigger the rearrangement as
illustrated in Scheme 1.
influenza virus variants5 underscores an urgent need for
studying neuraminidase mutation.6 Given the significant
sequence variations across strains and the unpredictable
mutations by gene reassortment and random mutations,7 the
understanding of inhibitor-neuraminidase interactions at the
molecular level represents the main goal of the current
research.8 Herein we report our effort for the development
of a concise strategy for the modular synthesis of diverse
diaminocyclitols; the developed chemistry offers an alterna-
tive approach to the existing strategies for NA mutation and
identification of NA inhibitors in response to emerging drug-
resistant influenza viruses.
The scaffold selection of our NA inhibitors was based on
the structures of oseltamivir (A) and peramivir (B).9 Because
all the existing NA inhibitors have a carboxylate group and
an acetyl-amino group at the opposite ends of the ring
system,10 we therefore selected C as our synthetic target in
consideration of its potential as a scaffold for diversity-
To make syn-diamine,15 we applied a thermal aza-
Claisen rearrangement16 to obtain compound 4. To this
end, alcohol 2 was first reacted with trichloroacetonitrile
in the presence of NaH; the formed adduct then refluxed
in o-xylene to afford diamines as a pair of diastereoisomers
(1/1 ratio), which without purification were subjected to
hydrolysis, followed by Cbz protection and removal of
THP with PTSA/MeOH to give anti-diamine 3 and syn-
diamine 4 (1/1 ratio) in a combined yield of 48% in four
steps.
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Org. Lett., Vol. 12, No. 1, 2010
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Scheme 1
.
Syntheses of Diaminocyclitols 9-20
Scheme 2. Syntheses of Compounds 3bb and 4bb
With this general aza-Claisen rearrangement protocol to
access anti- and syn-diamines 3 and 4 in hand, we next
pursued their transformation to the corresponding dienes 5,
6, 7, and 8 through a sequential oxidation and a Baylis-Hill-
man reaction.17 In this maneuver, 3 was first oxidized to its
aldehyde in 98% yield, and the formed aldehyde then
underwent Baylis-Hillman reaction to give almost equal
amounts of compounds 5 and 6 in a combined yield of 39%.
Both compounds were separated by a silica gel chromatog-
raphy. To circumvent the issue of this low yield, we profiled
the reaction conditions according to the reported procedure,18
but no improvement was observed. Since the starting material
is stable under the reaction conditions, we can recycle it by
chromatography. Following the same approach, dienes 7 and
8 were made from cis-diamine 4 in a combined yield of 35%
and separated by a silica gel chromatography.
With those dienes, we then started to investigate their
cyclization. An initial attempt was made by treatment of
substrate 5 with both first and second generation Grubbs
catalysts. Quite interestingly, the present system consisting
of methyl acrylate exhibited a remarkable reactivity toward
the second generation of Grubbs catalyst, enabling the
catalytic cyclization of 5 in CH2Cl2 to afford the desired
product 9 in 77% yield at room temperature.
To profile the reaction scope, compounds 6, 7, and 8 were
subjected to the same conditions mentioned above, and the
desired products 10, 11, and 12 were also obtained in good
yields. However, no reaction proceeded when first generation
Grubbs catalyst was utilized, and only starting materials were
recovered. The relative stereochemistry of compounds 9, 10,
1
thiones 3bb and 4bb by the chemistries illustrated in Scheme
2. Accordingly, the free hydroxyl groups in 3 and 4 were
protected as their acetate 3aa and 4aa, which were then
treated with TMSI in CH3CN at room temperature to remove
their protecting groups Boc and Cbz, followed by reaction
with thiophosgene in the presence of base to give their
corresponding 3bb and 4bb, respectively. 2D NMR (NOE-
SY) studies showed that the correlation between Ha and Hb
was observed in 3bb, indicating their cis-relationship between
Ha and Hb of 3bb. On the other hand, no correlation between
Ha and Hb in 4bb was observed, indicating their trans-
relationship between Ha and Hb of 4bb (see Supporting
Information for details).
11, and 12 was determined by H NMR and NOE experi-
ments (see Supporting Information for details).
Having succeeded in the formation of 9, 10, 11, and 12,
we then turned our attention to test the functional group
interconversion. Selective removal of the Boc group in the
presence of a Cbz group from substrates 9, 10, 11, and 12
was achieved in high yields using HCl/MeOH. An initial
attempt to carry out their acylation with organic bases (such
(17) (a) Aggarwal, V. K.; Dean, D. K.; Mereu, A. R.; Williams, R. J.
Org. Chem. 2002, 67, 510. (b) Zhu, S.; Hudson, T. H.; Kyle, D. E.; Lin, A.
J. Med. Chem. 2002, 45, 3491.
(18) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811.
6
Org. Lett., Vol. 12, No. 1, 2010

as Et3N and pyridine) and acetic anhydride or acyl chloride
in anhydrous solvents (such as THF, CH2Cl2, and DMF) did
not result in the formation of the desired product, but instead,
the starting materials were converted to unidentified products.
Since the results could be attributed to the free hydroxyl
group at the allylic position of substrates, which could
compete with acylation under anhydrous conditions, and the
formed products might cause decomposition, we therefore
performed the reaction using MeOH as a solvent. As a result,
the desired amides 13, 14, 15, and 16 were obtained in good
yields in the presence of Na2CO3 as a base with AcCl as an
acylating agent.19
Scheme 3. Synthesis of Diaminocyclitols 23 and 24
Since the C-4 position is uniformly occupied by basic
groups such as an amine or guanidine in all known
inhibitors,20 we therefore explored the reaction conditions
to remove the Cbz group in compounds 13, 14, 15, and 16.
Fortunately, TMSI was found to be an effective agent to
remove the Cbz, and the desired products 17, 18, 19, and
20 were obtained in good yields.
Thus, we developed a concise and modular synthetic
approach to synthesize four diaminocyclitols 17-20 from
L-serine, and the developed chemistry was successfully
applied to constructing their enantiomers from D-serine. The
details for their syntheses are provided in the Supporting
Information.
Given diaminocyclitols 17-20 as potential scaffolds to
probe NA mutation, we then chose 15 as a model to convert
it to the oseltamivir-type molecules. To this end, 15 was first
reacted with 3,4-dihydro-2H-pyran in the presence of PTSA
to give 22 in 79% yield, followed by reaction with Et3SiH
in the presence of Pd(OAc)2 and Et3N21 to afford the
corresponding amine 24 in 86% yield. In addition, 15 could
also undergo sequential benzylation and hydrogenation to
give product 24 in high yields (Scheme 3).
The large synthetic opportunity offered by this work could
be realized by the facile syntheses of all the valuable chiral
compounds with the relative and absolute stereochemistry
around scaffold C. Therefore, we can anticipate that our
program for synthesis of stereodiverse diaminocyclitols may
find application in synthesis of useful probes for the study
of viral mutation and in the development of small molecules
as therapeutic agents against influenza virus variants.
Acknowledgment. Financial support from the RRDCC
basic research grant of Roche R&D Center (China) Ltd., the
National Science and Technology Major Project “Develop-
ment of Novel Vaccines, Antibodies and Therapeutic Agents
against Influenza Infection” (2009ZX10004-016), and the
National Science Foundation of China (grants 20272003,
20325208, 20852002) is gratefully acknowledged.
In summary, we have developed an efficient and concise
method for diversity-oriented synthesis of a new type of
diaminocyclitols. The synthetic protocol embodies aza-
Claisen rearrangement, ring-closing metathesis, and Baylis-
Hillman reactions and is accomplished in a modular manner.
Note Added after ASAP Publication. Part of the
acknowledgment was incorrect in the version published
ASAP December 9, 2009; the corrected version was pub-
lished on the web December 28, 2009.
Supporting Information Available: Experimental pro-
cedure and NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Chand, P.; Babu, Y. S.; Bantia, S.; Rowland, S.; Dehghani, A.;
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T. H. J. Med. Chem. 2004, 47, 1919.
(20) Lew, W.; Chen, X.; Kim, C. U. Curr. Med. Chem. 2000, 7, 663.
(21) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1992, 57, 5813.
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