De novo synthesis of tamiflu via a catalytic asymmetric ring-opening of meso-aziridines with TMSN3

Article abstract of DOI:10.1021/ja061696k

An asymmetric ring-opening reaction of meso-aziridines with TMSN₃ was developed using a catalyst prepared from Y(OⁱPr)₃ and chiral ligand 2 in a 1:2 ratio. Excellent enantioselectivity was realized from a wide range of substrates with a practical catalyst loading. The products were efficiently converted to enantiomerically enriched 1,2-diamines, which are versatile chiral building blocks for pharmaceuticals and chiral ligands. This reaction was applied to a catalytic asymmetric synthesis of Tamiflu, a very important anti-influenza drug containing a chiral 1,2-diamino functionality. Copyright

Full text of DOI:10.1021/ja061696k

Published on Web 04/25/2006
De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of
meso-Aziridines with TMSN3
Yuhei Fukuta, Tsuyoshi Mita, Nobuhisa Fukuda, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan
Received March 10, 2006; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Optimization of Reaction Conditions
Due to the recent emergence of avian flu, which has the potential
to infect humans, an outbreak of influenza virus is a serious
worldwide concern. Tamiflu (oseltamivir phosphate 1) is an orally
active anti-influenza drug that potently inhibits neuramidase, an
enzyme crucial for the release and spread of the influenza virus
from infected cells.1 Many nations have planned to stock a
significant amount of 1 to protect against a possible influenza
outbreak. The current commercial synthetic route of 1 uses naturally
occurring (-)-shikimic acid as a starting material.2 For constant
and large-scale supply of 1, however, a more reliable source is
desired. We describe an asymmetric synthesis of 1 utilizing a
general catalytic enantioselective ring-opening of meso-aziridines
with TMSN3.
a DMP ) 2,6-dimethylphenol (1 equiv was used). TFA ) trifluoroacetic
acid (5 mol % was used). b Isolated yield. c Determined by chiral HPLC.
The optimized reaction conditions were then applied to various
meso-aziridines (Table 2). High enantioselectivity was produced
from a wide range of substrates, including cyclic and acyclic
aziridines, using 1-10 mol % catalyst. Thus, this is the most general
CDMA with TMSN3 reported to date. The absolute configuration
of products was the same as that of CDMA with TMSCN.6
Therefore, the present reaction should proceed through a mechanism
similar to the previously reported CDMA with TMSCN:6 generation
of a reactive yttrium azide from TMSN3 through transmetalation7
and intramolecular transfer of the azide to an activated acylaziridine
by a Lewis acidic yttrium in the same poly Y catalyst.8 Products
were converted to optically active C2 symmetric 1,2-diamines in
excellent yield (Scheme 1).
Optically active 1,2-diamines are versatile chiral building blocks
for many useful molecules, including pharmaceuticals and chiral
ligands.3 Desymmetrization of meso-aziridines by a nitrogen
nucleophile is a direct method to access these compounds. Only
one catalytic enantioselective method has been reported in this
category from Jacobsen’s group using a tridentate Schiff base
Cr(III) complex as a catalyst.4 Considering the high utility of the
products, however, there remains room for improvement in terms
of enantioselectivity, substrate generality, and catalyst loading.5 On
the basis of our recent development of catalytic desymmetrization
of meso-aziridines (CDMA) with TMSCN using a poly Gd complex
derived from ligand 2,6 we investigated the possibility of extending
this catalysis to using TMSN3 as a nucleophile.
Previously optimized conditions for CDMA with TMSCN
involve a catalytic amount of trifluoroacetic acid (TFA) and a
stoichiometric amount of 2,6-dimethylphenol (DMP) as additives.6
We proposed that TFA tuned the catalyst by forming a TFA-
containing polymetallic complex, and DMP facilitated the catalyst
turnover step. When those conditions were applied to a ring-opening
reaction of N-4-nitrobenzoylaziridine (3a, optimum substrate for
CDMA with TMSCN6) with TMSN3, the reaction proceeded slowly,
giving product 4a with only 46% ee (Table 1, entry 1). In the
absence of any additives, enantioselectivity improved to 66% ee
without changing the reaction rate (entry 3). To enhance the
reactivity of the substrate, N-3,5-dinitrobenzoylaziridine 3b was
used. Although the reaction time decreased little, enantioselectivity
significantly improved to 85% ee (entry 4). Screening of rare earth
alkoxides as the catalyst metal source (entries 5-9) indicated that
Y(OiPr)3 was optimum, giving the product in 90% yield with 92%
ee in 1 h (entry 9).
Our next focus was to achieve a catalytic asymmetric synthesis
of Tamiflu (1) using this reaction as a basic methodology (Scheme
2). We selected 4e as a starting compound (Table 2, entry 5). The
main tasks required for the synthesis of 1 from 4e were the
introduction of an oxygen functionality at the allylic position and
an ethoxycarbonyl group at the olefin. After obtaining enantio-
merically enriched 4e by recrystallization, C2 symmetric diamide
9
5 was synthesized in four steps. Allylic oxidation of 5 with SeO2
in the presence of Dess-Martin periodinane produced a mixture
of enone 6 and allylic alcohol 7 (ca. 2:3),10 which was treated
without purification by Dess-Martin periodinane, giving 6 in 68%
yield. Enantiomerically pure (>99% ee) 6 was obtained at this stage
by recrystallization. A 1,4-addition of TMSCN in the presence of
10 mol % of Ni(COD)211 followed by treatment with NBS and Et3N
produced γ-keto nitrile 8, which was selectively reduced with a
bulky aluminum reagent12 to give alcohol 9. Aziridine formation
under Mitsunobu conditions and BF3‚EOEt2-mediated aziridine
opening with 3-pentanol1 afforded 10 in good yield. Treatment of
10 with TFA, followed by protection of the sterically less hindered
9
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10.1021/ja061696k CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Catalytic Asymmetric Synthesis of Tamiflua
Table 2. Catalytic Enantioselective Desymmetrization of
meso-Aziridines with TMSN3
a Reagents and conditions: (a) recrystallized from iPrOH, 72%; (b) Boc2O
(1.5 equiv), DMAP (0.5 equiv), CH3CN, rt, 3 h; (c) 4 M NaOH, rt, 2 h,
98% (2 steps); (d) Ph3P (1.1 equiv), CH3CN, 50 °C, 3 h; H2O, 40 °C, 2 h;
(e) Boc2O (2 equiv), Et3N (5 equiv), CH2Cl2, rt, 2 h, 90% (2 steps); (f)
SeO2 (1 equiv), Dess-Martin periodinane (1.5 equiv), dioxane, 80 °C, 12
h; (g) Dess-Martin periodinane (1.5 equiv), CH2Cl2, 4 °C, 68% (2 steps);
recrystallized from iPr2O-hexane, >99% ee, 62%; (h) Ni(COD)2 (10 mol
%), COD (10 mol %), TMSCN (3 equiv), THF, 60 °C, 65 h; (i) NBS (1.05
equiv), THF, 20 min; Et3N (14 equiv), 4 °C, 40 min; (j) LiAlH(OtBu)3 (5
equiv), THF, 4 °C, 30 min, 60% (>20:1) (3 steps); (k) DEAD (2.5 equiv),
Ph3P (2.5 equiv), THF, 4 °C, 1 h, 87%; (l) 3-pentanol, BF3‚OEt2 (1.5 equiv),
4 °C, 1 h, 52%; (m) TFA (20 equiv), CH2Cl2, 4 °C to rt, 3 h; (n) Boc2O
(1.1 equiv), Et3N (5 equiv), CH2Cl2, 4 °C, 30 min, 63% (2 steps); (o) Ac2O
(2 equiv), DMAP (0.5 equiv), py, rt, 1 h, 84%; (p) 4.2 M HCl-EtOH, 60
°C, 4 h; H2O, 4 °C, 3 h, 53%; (q) 85% H3PO4 (1 equiv), EtOH; cryst,
50%.
References
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a Isolated yield. b Determined by chiral HPLC. c Three equivalents of
TMSN3 was used. d The absolute configuration was determined as shown.
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Scheme 1. Typical Conversion to 1,2-Diamines
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amine with a Boc group, acetylation, conversion of the nitrile to
ethoxycarbonyl in acidic ethanol concomitant with removal of Boc
group, and H3PO4 salt formation afforded 1. To our knowledge,
this is the first enantioselective synthesis of Tamiflu using an
artificial asymmetric catalyst.
In conclusion, we developed a general CDMA with TMSN3 using
a Y complex of chiral ligand 2. This reaction was applied to a
catalytic asymmetric synthesis of Tamiflu. Further improvement
of the synthetic efficacy of Tamiflu, particularly, in the allylic
oxidation and the Ni-catalyzed cyanide conjugate addition, and
investigation of an alternative route are currently ongoing.
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of over-oxidized allylic diol (∼30%) as a byproduct.
Acknowledgment. Financial support was provided by a Grant-
in-Aid for Specially Promoted Research of MEXT.
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Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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