K. Yamatsugu et al. / Tetrahedron Letters 48 (2007) 1403–1406
1405
oxazolidin-2-one 16 was produced exclusively. The suc-
3. Experimental
cess of this step was due to the rapid intramolecular trap
of the intermediate isocyanate by the neighboring a-allyl
alcohol, followed by the intermolecular addition of
t-BuOH to the other isocyanate. The intramolecular
isocyanate trap was so fast that neither di-tert-butylcar-
bamate derived from double intermolecular addition of
t-BuOH nor the intramolecular addition of tert-butyl-
carbamate to the other isocyanate (protected urea
formation) was detected. Hydrolysis of the cyclic carba-
mate moiety of 16, followed by N-acetylation, pro-
ceeded uneventfully to afford 17. Oxidation of 17 was,
however, unexpectedly problematic. After intensive
studies, modified Moffat conditions using bulky isobu-
tyric anhydride7,8 as an activator of DMSO were deter-
mined to be optimum. Under the optimized conditions,
enone 3 was obtained in a 53% yield via four steps from
acyl azide 15.
3.1. (1S*,2R*,3S*)-3-Hydroxy-cyclohex-4-ene-1,2-dicar-
bonyl diazide (15)
Fumaryl chloride (8: 7.5 ml, 69.6 mmol) was added
slowly to a stirred solution of 1-(trimethylsilyloxy)-1,3-
butadiene (14: 12.3 ml, 70.3 mmol) in THF (352 ml) at
room temperature, and the mixture was stirred at the
same temperature for 2 h. TMSN3 (19.6 ml, 148 mmol)
and DMAP (800 mg, 7.0 mmol) were carefully added
at room temperature, and the mixture was stirred at
the same temperature for additional 2 h. After cooling
to 4 °C, 1 N HCl aq (70.3 ml, 70.3 mmol) was carefully
added, and the mixture was stirred at the same temper-
ature for 10 min. The organic layer was separated and
the aqueous layer was extracted twice with AcOEt
(500 ml). The combined organic layers were washed with
saturated NaHCO3 solution (150 ml) and brine (150 ml),
dried over Na2SO4, and concentrated to give crude 15,
which was purified by silica gel column chromatography
(SiO2 200 g, hexane/AcOEt = 4/1 to 2/1) to give 15
(9.1 g, 38.5 mmol; 55% yield) as a colorless oil. 1H
NMR (CDCl3, 500 MHz) d 6.92–5.86 (m, 2 H), 4.48
(m, 1 H), 2.96 (ddd, J = 5.3, 11.6, 12.0 Hz, 1H), 2.87
(dd, J = 4.0, 12.0 Hz, 1H), 2.49 (ddd, J = 5.2, 5.3,
17.7 Hz, 1H), 2.10–2.03 (m, 1H); 13C NMR (CDCl3,
125 MHz) d 181.9, 179.3, 128.7, 127.0, 63.8, 49.6, 37.9,
28.7; IR (neat, cmꢁ1) 3412, 2260, 2146, 1710; FAB-
HRMS calcd for C8H9N6O3 [M+H]+: 237.0731, found:
237.0726.
At this stage, the resolution of intermediate 3 using chiral
HPLC [Daicel Chiralpak AD-H, 2-propanol/hexane 1/9,
flow 0.6 mL/min, detection at 254 nm: tR 15.4 min
26
(desired, ½aꢀD ꢁ149.2 (c 0.313, CHCl3)) and 18.4 min
27
(undesired, ½aꢀD +140.9 (c 0.313, CHCl3)) was per-
formed, and enantiomerically pure 3 was obtained.
The remaining steps from enantiomerically pure enone 3
to Tamiflu were (1) introduction of the ethoxy carbonyl
group at the b-position of the enone and (2) introduction
of the 3-pentyloxy group. The first step was accom-
plished with 1,4-addition of TMSCN to the enone, fol-
lowed by the oxidation of the resulting TMS-enol
ether. Thus, compound 3 was treated with TMSCN in
the presence of Ni(cod)2 (50 mol %) and 1,5-cyclooctadi-
ene (50 mol %). The resulting enol silyl ether was sub-
jected to a-bromination, and the subsequent HBr
elimination with triethylamine afforded b-cyanoenone
18.4 Stereoselective reduction of the ketone with LiAl-
(Ot-Bu)3H proceeded cleanly to produce 2 in 44% yield
in three steps. Aziridine formation under Mitsunobu
conditions, followed by the ring-opening reaction of
the resulting aziridine with 3-pentanol, afforded
compound 19.4 Ethanolysis of the cyanide and cleavage
of the Boc group proceeded in one pot under acidic
ethanol. The free amine form of 1 was formed after
3.2. (2-Oxo-2,3,3ab,4a,5,7ab-hexahydro-benzoxazol-4-
yl)-carbamic acid tert-butyl ester (16)
The solution of 15 (8.7 g, 36.8 mmol) in distilled
t-BuOH (74 ml) was stirred at refluxing temperature
for 5.5 h. Removal of the solvent under reduced pressure
gave crude 16 (9.4 g, 36.8 mmol) as a white solid, which
was used for the next reaction without further purifica-
tion. 1H NMR (CD3OD, 500 MHz) d 6.10 (m, 1H),
5.88–5.86 (m, 1H), 5.04–5.03 (m, 1H), 3.77–3.73 (m,
1H), 3.55–3.50 (m, 1H), 2.37 (ddd, J = 5.2, 5.5,
17.2 Hz, 1H), 2.01–1.96 (m, 1H), 1.44 (s, 9H); 13C
NMR (CD3OD, 125 MHz) d 161.4, 158.1, 132.7,
123.7, 80.5, 75.3, 56.4, 51.0, 29.8, 28.7; IR (KBr,
cmꢁ1) 3370, 3243, 1747, 1683; ESI-MS m/z 277
[M+Na]+; FAB-HRMS calcd for C12H19N2O4
[M+H]+: 255.1339, found: 255.1332.
9
basification. Treatment of the free amine with H3PO4
produced 1.
In summary, we developed a third generation synthesis
of Tamiflu. An appropriately functionalized cyclohex-
ene skeleton was synthesized through the Diels–Alder
reaction between commercially available diene and
dienophile. The unsymmetrically protected 1,2-trans-
diamine derivative 16 was constructed via Curtius rear-
rangement and subsequent intramolecular trapping of
the resulting isocyanate. These two key reactions
allowed for rapid (12 steps) access to the core structure
of Tamiflu. As a preliminary study, we separated enan-
tiomers using chiral HPLC at the stage of 3. Asymmetric
synthesis of Tamiflu utilizing the catalytic asymmetric
Diels–Alder reaction and investigation of the more
efficient conversion of enone 3 to b-cyanoenone 18 are
currently ongoing.
Acknowledgments
Financial support was provided by a Grant-in-Aid for
Specially Promoted Research of MEXT. Y.S. thanks
JSPS for a research fellowship.
References and notes
1. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel,