Second generation catalytic asymmetric synthesis of tamiflu: Allylic substitution route

Article abstract of DOI:10.1021/ol062663c

(Chemical Equation Presented) Catalytic asymmetric synthesis of Tamiflu, an important antiinfluenza drug, was achieved. After the catalytic enantioselective desymmetrization of meso-aziridine 3 with TMSN₃, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the C=C double bond were introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile. This second generation route of Tamiflu is more practical than our previously reported route.

Full text of DOI:10.1021/ol062663c

ORGANIC
LETTERS
2007
Vol. 9, No. 2
259-262
Second Generation Catalytic
Asymmetric Synthesis of Tamiflu:
Allylic Substitution Route
Tsuyoshi Mita, Nobuhisa Fukuda, Francesc X. Roca, Motomu Kanai,* and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received October 31, 2006
ABSTRACT
Catalytic asymmetric synthesis of Tamiflu, an important antiinfluenza drug, was achieved. After the catalytic enantioselective desymmetrization
of meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the C C double
d
bond were introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile. This second generation
route of Tamiflu is more practical than our previously reported route.
The antiinfluenza drug Tamiflu (1)1 is extremely important
for protecting humans against a potential future pandemic
of otherwise lethal flu. Considering the amount of Tamiflu
required worldwide, there is an urgent demand to improve
the Tamiflu production process. Currently, three groups have
reported the asymmetric synthesis of Tamiflu:2 Roche’s
commercial route utilizing naturally occurring shikimic acid
as a starting material,3 Corey’s route using the catalytic
asymmetric Diels-Alder reaction developed by his group,4
and a route using the catalytic desymmetrization of meso-
aziridines that was developed by our group.5 In this Letter,
we report an alternative route that significantly improves
upon our initial synthesis.
Our previous synthesis of 1 utilized azido amide 4,
obtained with high enantioselectivity via catalytic desym-
metrization of a meso-aziridine 3 as the starting chiral
building block.5 A yttrium complex derived from ligand 2
was used as the asymmetric catalyst. There were two main
drawbacks to this route: (1) allylic oxidation to introduce
oxygen functionality to a diamine-derivative 10 required a
stoichiometric amount of a toxic selenium reagent and (2)
to effect this allylic oxidation in a synthetically useful yield,
desymmetrized 4 was converted to a C2 symmetric 1,2-
diamine derivative (10: P1, P2 ) Boc), which resulted in
cumbersome protection group shuffling at the later stages
of synthesis. Thus, we planned to develop a more practical
synthetic route to circumvent these two problems (Scheme
1).
(1) 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.
(2) For a recent review of synthetic strategies of Tamiflu, see: Farina,
V.; Brown, J. D. Angew. Chem., Int. Ed. 2006, 45, 7330.
(3) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz,
B.; Zutter, U. Chimia 2004, 58, 621.
(4) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
6310.
(5) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 6312.
10.1021/ol062663c CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/29/2006

Scheme 1. Synthetic Plan
Scheme 2. Preliminary Optimization of the Allylic
Substitution Route of Tamiflu
The bulky 3-pentyloxy group should be introduced at a
late stage with a ring-opening reaction of aziridine 5, which
was produced from amido alcohol 6 under Mitsunobu
conditions.5 Compound 6 containing a â-OH group would
be obtained via suprafacial allylic rearrangement of cyano-
phosphate 7,6 which could be synthesized from enone 8 via
cyanophosphorylation. Enone 8 would be synthesized from
1,2-trans-diamine derivative 10 through halocyclization
followed by elimination, hydrolysis, and oxidation. As
reported previously, 10 can be synthesized with excellent
enantioselectivity through catalytic enantioselective desym-
metrization of meso-aziridine 3. To avoid protection group
shuffling, two amino groups of 10 should be differentiated,
preferably with the protecting group P1 to be an acetyl.
On the basis of this synthetic plan, enantiomerically pure
11 was synthesized through catalytic desymmetrization of 3
with TMSN3 as a key step (Scheme 2). This catalytic reaction
led to two new findings. First, the reaction was performed
with 1 mol % of catalyst in the presence of 1 equiv of 2,6-
dimethylphenol in a 30-g scale. The reaction rate was faster
than in the previously reported conditions in the absence of
a protic additive, and the enantioselectivity was comparable
(89% ee).7 Second, chiral ligand 2 was recovered in 81%
yield after the reaction through extraction with a base. A
catalyst prepared from the recovered 2 produced almost
comparable results to the first cycle with regard to catalyst
activity and enantioselectivity.
Next, reduction of the azide with Ph3P and acetylation of
the resulting amine produced unsymmetrically protected
diamine derivative (10: P1 ) Boc, P2 ) Ac). Iodocyclization
proceeded selectively on the acetamide carbonyl oxygen
atom, and the following elimination of HI with DBU
produced dihydrooxazine 12. In the iodocyclization step, the
product resulting from the cyclization of N-Boc urethane
carbonyl oxygen while maintaining the acetamidesa more
favorable reaction pathway for the Tamiflu synthesisswas
produced only as a minor component. The dihydrooxazine
moiety was hydrolyzed in the presence of CbzCl,8 producing
acetate 13. Hydrolysis of the acetate followed by Dess-
Martin oxidation produced the key enone 14 in high overall
yield.
Cyanophosphorylation of enone 14 proceeded stereo-
selectively with use of diethylphosphoryl cyanide (DEPC)9
in the presence of a catalytic amount of LiCN,10 affording
cyanophosphate 15.11 The crucial allylic rearrangement was
(6) (a) Bartlett, P. A.; McQuaid, L. A. J. Am. Chem. Soc. 1984, 106,
7854. (b) Kurihara, T.; Miki, M.; Yoneda, R.; Harusawa, S. Chem. Pharm.
Bull. 1986, 34, 2747.
(7) Previously, 4 was produced in 96% yield with 91% ee, using 2 mol
% of the catalyst in the absence of 2,6-dimethylphenol (reaction time ) 48
h). For beneficial effects of a protic additive in a catalytic asymmetric
conjugate addition of an azide, see: Guerin, D. J.; Miller, S. J. J. Am. Chem.
Soc. 2002, 124, 2134.
(8) Dalko, P. I.; Langlois, Y. Tetrahedron Lett. 1998, 39, 2107.
(9) Yamada, S.; Kasai, Y.; Shioiri, T. Tetrahedron Lett. 1973, 1595.
(10) Harusawa, S.; Yoneda, R.; Kurihara, T.; Hamada, Y.; Shioiri, T.
Tetrahedron Lett. 1984, 25, 427.
260
Org. Lett., Vol. 9, No. 2, 2007

attempted under thermal conditions.6b,12 Unexpectedly, a
cyclic carbamate was cleanly produced via intramolecular
SN2′ allylic substitution. After reprotection of the nitrogen
atom of the cyclic carbamate with a Boc group to afford 16,
the less sterically hindered carbamate was cleaved by a
catalytic amount of Cs2CO3 in MeOH, producing the
corresponding R-OH allylic alcohol. The stereochemistry of
the allylic position was inverted through an oxidation-
stereoselective reduction5 sequence, affording trans amido
alcohol 17 containing the suitable stereo-requirement for the
following aziridine formation via the Mitsunobu reaction.13
The Mitsunobu reaction proceeded in high yield. The
resulting aziridine 18 was subjected to a ring-opening
reaction with 3-pentanol in the presence of BF3‚OEt2,14 and
the successive cleavage of the N-Boc group followed by
N-acetylation afforded 19 in 81% yield. Hydrolysis of the
N-Cbz group and ethanolysis of the nitrile proceeded
concomitantly in acidic ethanol. Basification and H3PO4 salt
formation15 completed the synthesis of Tamiflu (1).
Scheme 3. Optimized Allylic Substitution Route
Although this preliminary synthetic route avoided allylic
oxidation with the toxic selenium reagent, protection group
manipulation was still cumbersome and the synthesis was
lengthy due to undesired iodocyclization with the acetamide
group at the initial stage of the synthesis. To address this
problem, we investigated a modified route involving iodo-
cyclization of azido amide 11 (Scheme 3). Ttreatment of 11
with I2 in the presence of K2CO3, followed by subjecting
the resulting cyclic carbamate to an elimination reaction of
HI with DBU, produced 20 in 85% yield. Protection of the
carbamate nitrogen atom with a Boc group and reductive
acetylation of the azide with AcSH16 produced 21, which
was selectively hydrolyzed and oxidized with Dess-Martin
periodinane to produce enone 22. Cyanophosphorylation of
enone 22 proceeded with DEPC in the presence of LiCN,
and cyanophosphate 23 was obtained as a single detectable
isomer.
oxazoline opening of 29 with 3-pentanol, we next turned
our attention to an intermolecular nucleophilic substitution
of the allylic phosphate of 28. After several trials,18
a
synthetically useful yield (78%) of R-allylic alcohol 24 was
produced by the addition of saturated aqueous NH4Cl
solution to 28.
The key allylic rearrangement of 23 was studied under
thermal conditions (Scheme 4). Heating a toluene solution
of 23 to 140 °C in a sealed tube produced a labile and
unisolatable â-allyl phosphate 28 as an initial product, whose
structure was estimated by ESI-MS without isolation.17
Addition of 1 M NaOH solution to the reaction mixture
produced stable oxazoline 29 as a major product in 38%
yield, together with allylic alcohol 24 (23%) produced
through an SN2 attack of a hydroxide anion to the phosphate.
Because we could not find any conditions that affect the
Scheme 4. Allylic Rearrangement-Substitution Sequence
(11) Configuration of the tetrasubstituted carbon of 15 was temporarily
assigned as shown based on the structure of 29 (see Scheme 4).
(12) Pd(II)-catalyzed allylic rearrangement (ref 6a) did not afford the
desired product.
(13) Ho, M.; Chung, J. K. K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513.
(14) Ring-opening reaction of cyclic carbamate 16 with 3-pentanol was
intensively studied in the presence of a variety of Lewis acids. The desired
product, however, was not produced in these reactions.
(15) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org.
Process Res. DeV. 2004, 8, 86.
(16) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J.
Am. Chem. Soc. 2003, 125, 7754.
On the basis of the above findings, asymmetric synthesis
of Tamiflu was completed from 24 as follows (Scheme 3).
(17) The stereochemistry of the allylic position of 28 was temporarily
assigned based on Bartlett and Kurihara’s previous findings (ref 6), in which
allylic rearrangement of R-cyanophosphate proceeded in a suprafacial
fashion.
(18) Neither direct addition of 3-pentanol to 28 nor aziridine formation
from 28 proceeded under various conditions.
Org. Lett., Vol. 9, No. 2, 2007
261

After the R-allyl alcohol of 24 was inverted via the
Mitsunobu reaction with p-nitrobenzoic acid followed by
hydrolysis of the p-nitrobenzoate in one pot, the resulting
â-allylic alcohol 25 was subjected to aziridine formation
through Mitsunobu conditions, producing 26. Introduction
of 3-pentanol was conducted with an aziridine opening
reaction to produce 275 in 56% yield. Ethanolysis of the
cyanide and cleavage of the Boc group under acidic ethanol,
followed by basification and H3PO4 treatment,15 produced
1. This route solves the two main problems (allylic oxidation
and protection group shuffling) of the previously reported
synthetic route.5 In addition, the synthetic scheme is shorter
than that of the previously reported synthesis5 (15 steps from
aziridine 3).
ature. Careful optimization of the synthetic scheme made it
possible to avoid protection group shuffling, which was a
drawback in our first generation synthesis.5 The allylic
oxygen functionality required for 3-pentyl ether formation
was introduced by rearrangement of an allylic phosphate
followed by substitution with a hydroxyl group. Thus, the
other drawback of our previous synthesissi.e., the use of a
toxic selenium reagent in the allylic oxidationswas also
overcome. Further improvement of the synthetic efficacy by
using a completely different strategy is currently under
investigation.
Acknowledgment. Financial support was provided by a
Grant-in-Aid for Specially Promoted Research of MEXT.
In summary, we developed our second generation synthesis
of Tamiflu. This route utilizes a catalytic enantioselective
desymmetrization of meso-aziridine 3 with TMSN3 as the
initial key step. The reaction was performed with 1 mol %
of chiral Y catalyst derived from ligand 2 at room temper-
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062663C
262
Org. Lett., Vol. 9, No. 2, 2007