Synthesis of a new oseltamivir derivative through late-stage catalytic C-H functionalization

Article abstract of DOI:10.3987/COM-12-S(N)94

N-Boc-protected oseltamivir 5 was converted to olefin insertion product 4 via a ruthenium-catalyzed C(sp²)-H functionalization reaction using its ester functionality as a directing group. The addition of a catalytic amount of (p-CF₃C

Full text of DOI:10.3987/COM-12-S(N)94

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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1565 - 1574. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 9th July, 2012, Accepted, 13th August, 2012, Published online, 16th August, 2012
DOI: 10.3987/COM-12-S(N)94
SYNTHESIS OF A NEW OSELTAMIVIR DERIVATIVE THROUGH
LATE-STAGE CATALYTIC C–H FUNCTIONALIZATION
Kenta Saito1,2 and Motomu Kanai1,2,*
1 Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1
2
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
ERATO Kanai Life Science
Catalysis Project, JST. E-mail: kanai@mol.f.u-tokyo.ac.jp
Abstract – N-Boc-protected oseltamivir 5 was converted to olefin insertion
product 4 via a ruthenium-catalyzed C(sp2)–H functionalization reaction using its
ester functionality as a directing group. The addition of a catalytic amount of
(p-CF3C6H4)3P in the presence of the RuH2(CO)(PPh3)3 catalyst significantly
improved the yield for this specific conversion. Tamao-Fleming oxidation
followed by deprotection concisely produced a new oseltamivir analog 16.
Drug lead optimization generally requires labor-intensive molecular structural derivatizations. The ability
to diversify the structures of readily available organic molecules containing significant biological
activities—e.g., abundant natural products or inexpensive commercial drugs—at a late stage would
markedly facilitate the lead optimization process (Figure 1).1 Realization of this attractive and emerging
lead optimization approach requires a truly powerful C–H functionalization catalysis. Specifically, C–H
functionalization methods applicable to multifunctional molecules should proceed under mild conditions
with high functional group tolerance and predictable regioselectivity. This interdisciplinary field of
catalysis and drug development is still in its infancy. Here we describe the late-stage catalytic
derivatization of an anti-influenza drug, oseltamivir.
This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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Figure 1. Late-stage C–H functionalization of practically available biologically active compounds (such
as commercial drugs) is a potentially ideal pipeline for lead optimization compared to conventional
analog synthesis via a key intermediate.
Oseltamivir phosphate (Tamiflu®: 1),2 the sole orally-active commercial anti-influenza drug available to
date, is widely used. The high-rate of emergence of oseltamivir-resistant viruses, however, is a serious
problem. Although zanamivir (Relenza®: 2),3 the first-in-class potent neuraminidase inhibitor, is still
effective against oseltamivir-resistant viruses, new analogues are in high demand. We consider analogues
possessing a hydrogen bond donor (X) attached through a linker to the C-2 position of oseltamivir (such
as 3: X = OH) to be interesting candidates.4 Molecular modeling studies suggest that the position of X is
constrained at the anti position to the bulky 3-pentyloxy group at C-3 (Figure 2). The introduction of an
additional interaction site with functionally important polar amino acid side chains in the hydrophilic
catalytic site of neuraminidases (such as Glu277 and Tyr406)5,6 would increase the binding affinity of the
analog. The additional interaction might override the repulsion between the drug and mutated
neuraminidase,7 resulting in possible maintenance of the anti-influenza activity.8 Based on this hypothesis,
we designed 3 containing a hydroxyethyl group at the C-2 position of oseltamivir.
Figure 2. Structures of oseltamivir phosphate (1), zanamivir (2), and designed oseltamivir analog 3

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Our synthetic plan to access 3 is shown in Scheme 1. Tamao-Fleming oxidation of 4 followed by
hydrolysis of the ester moiety should afford 3.9 The key precursor 4 would be synthesized through
catalytic activation of the C(sp2)–H bond at the C-2 position of 5 followed by the insertion of vinylsilane
6 using the ester group at C-1 as a directing group. Substrate 5 should then be produced through
protection of commercially available oseltamivir phosphate (1). Thus, the key to the success of this
synthesis is the development of a robust C–H activation catalyst applicable to late-stage substrate 5
possessing multiple polar functional groups.
Scheme 1. Retrosynthetic analysis
To achieve this catalytic transformation, we anticipated that the conditions originally reported by Murai
and Kakiuchi10 would be a reasonable starting point. Despite recent intensive studies of C(sp2)–H
activation, there are still few methods that utilize an ester group as a directing group.11,12 The Murai
reaction is one such rare example. There are, however, no previous examples of the application of the
reaction to substrates with significant structural complexity, such as 5. Due to the existence of multiple
coordinating sites in the substrate to the catalyst, the use of 5 in the C–H functionalization reaction is very
challenging.
Our hypothesis for the design of an activated catalyst is based on the reported reaction mechanism (Figure
3).13 First, ruthenium dihydride catalyst 8 is activated though hydrogenation of an olefin substrate (e.g., 6)
to generate 16-electron ruthenium complex 9. An -unsaturated ester substrate then coordinates to 9,
and the C–H activation process proceeds from 10, either through a ruthena-Michael reaction followed by
hydride migration to the metal or oxidative addition of the C–H bond to the metal, generating 11. Olefin
insertion to 11 followed by reductive elimination from 12 produces the product with regenerating active
complex 9. Although structural modulation of catalyst 8 is difficult, Darses reported an alternative in situ
active catalyst generation method from readily available dinuclear ruthenium chloride complex 13 (Figure
3).14 Darses’ method allows for the catalyst properties to be tuned by changing the phosphine ligands. The
use of electron-deficient tri(p-trifluoromethylphenyl)phosphine produced the best results. We envisioned
that the C–H activation step would be further facilitated by making an electronically asymmetric catalyst

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using a mixture of electron-deficient and electron-donating ligands in Darses’ method (10).15 Due to the
trans effect, the Lewis acidity of the coordination site trans to an electron-deficient ligand L2 (site A)
should be enhanced. Therefore, coordination of an -unsaturated ester to site A should be facilitated.
While, the coordination site trans to an electron-donating ligand L1 (site B) should be more electron-rich,
which would facilitate the C–H activation.
Figure 3. Proposed catalytic cycle of ruthenium-catalyzed C(sp2)–H functionalization and our catalyst
design
Based on this catalyst design of electronic asymmetry, we investigated mixed ligand catalysts generated
in situ by Darses’ method using model substrate 14 (Figure 4). As expected, a catalyst prepared by using
a
combination
of
electron-rich
tri(p-methoxyphenyl)phosphine
and
electron-deficient
tri(p-trifluoromethylphenyl)phosphine in a 1:2 ratio under [Ru] = 2.5 mol % loading markedly improved
product yield (77%) compared to Murai’s and Darses’ conditions (17 and 41%, respectively).

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a 14 was added after preactivating the catalyst for 1 h by heating 8 and 6 in degassed toluene under reflux
conditions.13 Using 5 mol % catalyst, the yield of 15 was 97%.11 b A mixture of 13, (p-CF3C6H4)3P (7.5
mol %), HCO2Na (15 mol %), 6, and 14 in degassed dioxane was heated at 100 oC.14 c A mixture of 13,
(p-CF3C6H4)3P (5 mol %), (p-MeOC6H4)3P (2.5 mol %), HCO2Na (15 mol %), 6, and 14 in degassed
dioxane was heated at 100 oC. The precise catalyst structure is unknown.
Figure 4. Comparison of three conditions in Ru-catalyzed C(sp2)–H functionalization reaction of model
substrate 14
Although the mixed ligand system in Darses’ method markedly improved the product yield of the
reaction using simple model substrate 14, application of this catalyst to substrate 5 had no positive
effects; yields of 4 were only moderate (ca. 30%) under the three conditions. Even after intensive
optimization of the reaction conditions using various ligand combinations, hydride sources (other than
HCO2Na), and solvents, a synthetically useful yield of 4 was not realized.16 Therefore, the optimized
conditions using simple model substrate 14 were not applicable to multifunctional substrate 5.
Because catalyst 8 is already electronically asymmetric (ligands = Ph3P and CO), we switched our
approach to enhance the asymmetry by introducing additive ligands to 8, expecting that a catalyst with
higher activity might be generated in the reaction mixture through dynamic ligand exchange. We initially
considered that the addition of an electron-rich ligand would be suitable. In this case, triphenylphosphine
would be replaced by an additive electron-rich ligand. As a result, the coordination site B of the
electron-deficient C=C double bond and/or the C–H bond of the substrate should become more
electron-rich (10) compared to the original catalyst 8 (see Figure 3).
The feasibility of this hypothesis was tested using oseltamivir-derived substrate 5 (Figure 5, eq 1).
Contrary to our expectation, however, we observed a significant yield improvement using
electron-deficient tri(p-trifluoromethylphenyl)phosphine (78% in the presence of the additive phosphine
vs. 41% in the absence of any additive). Using triphenylphosphine and tri(p-methoxyphenyl)phosphine as

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additives, the yield was still slightly improved compared to that of the reaction in the absence of an
additive. Surprisingly, however, the addition of phosphine ligand decreased the catalyst activity in the
case of simple substrate 14 (Figure 5, eq 2). Therefore, the addition of phosphine is only effective for
substrate 5. The origin of the acceleration effects by the addition of phosphine in the case of substrate 5 is
not clear, but it is likely related to the structure of 5. Our current hypothesis is that the addition of
phosphine protects the catalyst from non-productive coordination by the amide oxygen atom of 5.
Figure 5. Ru-catalyzed C(sp2)–H functionalization of N-Boc protected oseltamivir 5 and model substrate
14
Having developed the synthetically useful C–H functionalization, our next task was to convert 4 to 3
(Scheme 2). Tamao-Fleming oxidation in the presence of KHF2 and peracetic acid generated in situ
afforded lactone 16 in 85% yield. Cleavage of the N-Boc group was achieved using trifluoroacetic acid
(TFA) in moderate yield. Unfortunately, all attempts to convert 17 to 3 failed. Hydrolysis of the lactone
moiety of 17 was possible under basic conditions (1 M NaOH aq in THF, based on TLC analysis). 3 was
not stable, however, and it was readily converted back to 17 under acidic, basic, and even neutral
conditions. Our current ongoing biological studies utilize 17 as a prodrug in the presence of an esterase.
Evaluation of anti-influenza activity of 17 in the presence of esterases is currently under investigation.

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Scheme 2. Conversion of 4 to a new oseltamivir analogue 17
In conclusion, we identified two approaches to enhance catalyst activity in the ester group-directed C–H
functionalization reaction. One approach was to use a combination of electron-rich and electron-deficient
phosphine ligands to enhance the electronic asymmetry in the C–H activation step. This approach was
only effective for simple model substrate 14. For substrate 5 possessing multiple functional groups,
another approach introducing electron-deficient additive phosphine ligand was effective, and the target
compound 4 was obtained in a synthetically useful yield. This C–H functionalization reaction provided
rapid access to a new oseltamivir analog 17. This is the first example of application of the
ruthenium-catalyzed C–H activation to a complex substrates. Our findings demonstrated that a catalytic
C–H functionalization strategy can be a powerful new method for the structural derivatization of complex
molecules. This strategy will also facilitate the drug development process. Studies aimed in this direction
are ongoing in our laboratory.
EXPERIMENTAL
(3R,4R,5S)-Ethyl
4-acetamido-5-[(tert-butoxycarbonyl)amino]-3-(pentan-3-yloxy)cyclohex-1-
enecarboxylate (Boc-oseltamivir: 5): To a solution of oseltamivir (1.25 g, 4.0 mmol) in dry toluene (80
mL), N-methylimidazole (320 µL, 4.0 mmol) and Boc2O (1.1 mL, 4.8 mmol) were added at room
temperature. The reaction was stirred at the same temperature for an hour under argon atmosphere. After
the reaction was completed, the solution was quenched with diluted HCl aqueous solution. The organic
layer was separated, and the aqueous layer was extracted with EtOAc. Combined organic layers were
washed with brine, dried over Na2SO4, and concentrated to give white solid, which was purified by
column chromatography (silica gel EtOAc/hexane = 1/3 to 1/2) to give 5 (1.50 g, 91%) as white solid.
Spectra data were previously reported.17
(3R,4R,5S)-Ethyl
4-acetamido-5-[(tert-butoxycarbonyl)amino]-3-(pentan-3-yloxy)-2-[2-
(triethoxysilyl)ethyl]cyclohex-1-enecarboxylate (4): To a flame-dried test-tube filled with argon, 5
(82.5 mg, 0.2 mmol), Ru(PPh3)3H2(CO) (18.4 mg, 0.02mmol) and (p-CF3C6H4)3P (18.7 mg, 0.04 mmol)

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were added, followed by the addition of addition of dry toluene (0.8 mL) and 6 (84 µl, 0.4 mmol). The
solution was degassed with freeze-pump-thaw procedure, charged with argon, and the mixture was stirred
at reflux temperature for 20 h under argon atmosphere. The reaction mixture was passed through a short
pad of silica gel with DCM/ MeOH = 9/1 as eluent. Solvent was evaporated to give dark blown oily solid.
1
The yield of 4 was determined by H NMR using TMS2O as an internal standard (78%). The crude
mixture was applied to silica gel column, and eluted with DCM/hexane = 1/1, followed by with
EtOAc/hexane = 2/1. The eluent was concentrated to give brown solid. The residue was further purified
by reversed-phase preparative HPLC (MeOH/THF/H2O = 2/1/2, wave length: 230 nm, column size: 20
mm×250 mm, flow rate: 10 mL/min, tR: 55 min), to give 4 (80 mg, 66%) as white solid. IR (KBr) ν 3336,
3274, 3106, 2977, 1720, 1684, 1651, 1573, 1524, 1233, 1171, 1079 cm-1; 1H NMR (CDCl3, 500 MHz) δ
5.91 (d, J = 8.0 Hz, 1H), 5.55 (d, J = 10.2 Hz, 1H), 4.25-4.33 (m, 1H), 4.16-4.24 (m, 2H), 4.10-4.16 (m,
1H), 3.83-3.88 (m, 1H), 3.76-3.83 (m, 6H), 3.23-3.33 (m, 1H), 2.78-2.92 (m, 1H), 2.37-2.48 (m, 2H),
2.15-2.25 (m, 1H), 1.94 (s, 3H), 1.43-1.57 (m, 4H), 1.40 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.0
13
Hz, 9H), 0.90-1.01 (m, 2H), 0.88 (t, J = 7.6 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H); C NMR (CDCl3, 126
MHz) δ 169.80, 168.33, 155.68, 145.28, 123.94, 81.47, 79.23, 71.01, 60.55, 58.39, 51.19, 50.39, 29.62,
28.32, 25.77, 24.15, 23.19, 18.19, 14.12, 9.38, 9.15; HRMS (ESI): m/z calculated for C29H54N2NaO9Si+
[M+Na]+: 625.3496, found: 625.3498.
tert-Butyl [(5R,6R,7S)-6-acetamido-1-oxo-5-(pentan-3-yloxy)-3,4,5,6,7,8-hexahydro-1H-isochromen-
7-yl]carba-mate (16): To a solution of 4 (230 mg, 0.38 mmol) in DMF (3.8 mL), KHF2 (59.3 mg, 0.76
mmol), Ac2O (217 µL, 2.30 mmol) and 30% H2O2 aqueous solution (0.3 mL, 2.30 mol) were added at
room tempretature. The mixture was stirred at 60 oC for 16 h. The reaction mixture was cooled in an ice
bath, and saturated Na2S2O3 aqueous solution was added slowly. The mixture was stirred for 20 min, and
products were extracted with DCM for three times. Combined organic layers were washed with brine,
dried over Na2SO4, and concentrated to give white solid. The residue was purified by column
chromatography (silica gel, 100% DCM to DCM/EtOAc = 3/1, 1/1 and 1/2) to give 16 (133 mg, 85%) as
1
a white solid. IR (KBr) ν 3360, 3276, 2970, 1720, 1685, 1654, 1523, 1169 cm-1; H NMR (CDCl3, 500
MHz) δ 6.09 (d, J = 6.3 Hz, 1H), 5.65 (d, J = 9.2 Hz, 1H), 4.29-4.41 (m, 2H), 4.23-4.29 (m, 1H),
4.12-4.22 (m, 1H), 3.76-3.88 (m, 1H), 3.28 (m, 1H), 2.45-2.63 (m, 2H), 2.27-2.45 (m, 2H), 1.96 (s, 3H),
1.45-1.56 (m, 4H), 1.42 (s, 9H), 0.88 (t, J = 7.5 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 126
MHz) δ 170.31, 164.99, 156.09, 149.06, 122.22, 81.23, 80.01, 71.58, 66.12, 52.42, 51.93, 28.28, 27.60,
+
26.03, 25.65, 25.59, 23.18, 9.53, 9.11; HRMS (ESI): m/z calculated for C21H34N2NaO6 [M+Na]+:
433.2315, found: 433.2309.
N-((5R,6R,7S)-7-Amino-1-oxo-5-(pentan-3-yloxy)-3,4,5,6,7,8-hexahydro-1H-isochromen-6-yl)aceta-
mide (17): To a solution of 16 (24 mg, 0.058 mmol) in DCM (5.8 mL), TFA (1.2 mL, 20%v/v) was

HETEROCYCLES, Vol. 86, No. 2, 2012
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added at room tempretature. The mixture was stirred for 2 h, and the solvent was evaporated to give
slightly yellow oily residue. The residue was dissolved in DCM, washed with saturated NaHCO3 aqueous
solution for three times and brine. The organic layer was dried over Na2SO4, and concentrated to give 17
1
(10 mg, 55%) as a slightly yellow oil. IR (KBr) ν 3291, 2964, 1705, 1654, 1550, 1084 cm-1; H NMR
(CDCl3, 500 MHz) δ 5.64 (d, J = 7.5 Hz, 1H), 4.31-4.44 (m, 2H), 3.95-4.03 (m, 1H), 3.82-3.88 (m, 1H),
3.31 (m, 1H), 3.23-3.29 (m, 1H), 2.79-2.88 (m, 1H), 2.52-2.60 (m, 1H), 2.41-2.49 (m, 1H), 2.00 (s, 3H),
1.44-1.58 (m, 3H), 1.39 (m, 1H), 0.88 (t, J = 7.5 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 126
MHz) δ 170.39, 165.32, 151.87, 121.06, 80.62, 71.43, 66.28, 55.74, 54.76, 27.11, 26.17, 25.80, 23.52,
+
9.76, 9.20; HRMS (ESI): m/z calculated for C16H27N2O4 [M+H]+: 311.1971, found: 311.1984.
ACKNOWLEDGEMENTS
We thank Professor Shinji Murai (Nara Institute of Science and Technology) and Professor Fumitoshi
Kakiuchi (Keio University) for fruitful discussions and providing us catalyst 8 (FK). Ms. Seiko Kitahara
in our laboratory is acknowledged for her assistance in molecular modeling. This work is supported by
The Uehara Memorial Foundation and ERATO from JST.
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