Time Economical Total Synthesis of (-)-Oseltamivir

Article abstract of DOI:10.1021/acs.orglett.6b01595

A time economical 60 min total synthesis of (-)-oseltamivir was accomplished in a single reaction vessel over five steps. One of the key issues is reduction in the number of steps by eliminating lengthy reaction steps with substitution of a rapid epimerization step. A catalytic system consisting of three reagents, namely, diphenylprolinol silyl ether, thiourea, and acid, was developed for a rapid asymmetric Michael reaction with excellent diastereo- and enantioselectivities. All reactions were optimized in terms of not only yield and selectivity but also reaction time.

Full text of DOI:10.1021/acs.orglett.6b01595

Letter
pubs.acs.org/OrgLett
Time Economical Total Synthesis of (−)-Oseltamivir
Yujiro Hayashi* and Shin Ogasawara
Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki-Aza Aoba-ku, Sendai, Miyagi 980-8578,
Japan
S
* Supporting Information
ABSTRACT: A time economical 60 min total synthesis of
(−)-oseltamivir was accomplished in a single reaction vessel
over five steps. One of the key issues is reduction in the
number of steps by eliminating lengthy reaction steps with
substitution of a rapid epimerization step. A catalytic system
consisting of three reagents, namely, diphenylprolinol silyl
ether, thiourea, and acid, was developed for a rapid asymmetric
Michael reaction with excellent diastereo- and enantioselectiv-
ities. All reactions were optimized in terms of not only yield and selectivity but also reaction time.
ime is money. This is true not only in our daily life but
considered in the optimization. Moreover, not only a single
Talso in the synthesis of molecules. It is one of the goals reaction but also all reactions in the complete synthetic
scheme should be optimized in view of time. Thus, to realize
the ultimate synthesis with time economy, a key is the
selection of a synthetic strategy with a small number of rapid
reactions under fast reaction conditions using a small number
of reaction vessels.
We have been investigating the synthesis of (−)-oseltamivir
and reported three-pot and two-pot syntheses in 200910 and
2010,11 respectively, using an asymmetric Michael reaction of
aldehyde and nitroalkene catalyzed by diphenylprolinol silyl
ether as a key step.12 Recently, we have accomplished a one-
pot synthesis1a without solvent swap with a single purification
using (Z)-nitroalkene 2 developed by Ma,1b Sebesta,1c and
Lu1d independently. Even though it is a one-pot procedure, it
still takes 57 h for the completion of all of the synthetic
transformations. In this communication, we demonstrate the
realization of time economy in the very rapid synthesis of
(−)-oseltamivir within only 60 min.
Scheme 1 summarizes our 60 min time economical total
synthesis of (−)-oseltamivir. An asymmetric Michael reaction
of nitroalkene 2 and α-alkoxyaldehyde 3 proceeds smoothly in
the presence of three catalysts, such as diphenylprolinol silyl
ether 4, Schreiner’s thiourea 5,13 and formic acid at 20 °C for
30 min to afford the Michael product 6. The product was
isolated with excellent syn- and enantioselectivity when the
reaction was quenched at this step (Table 1, entry 1). If any
one of these catalysts is lacking, the reaction does not proceed
well in terms of reaction speed, yield, and selectivity (entries 2
and 3). Diphenylprolinol silyl ether 4 is key for the generation
of enamine,12,14 the reactive intermediate, while thiourea 5
activates nitroalkene 2 via hydrogen bonding.13 The acid is for
suppression of side reactions, such as the generation of an
unreactive cyclobutane intermediate.15 These three catalysts
for a chemist to synthesize a molecule as quickly as possible.
However, this is not easy because some of the single reactions
take a long time, and several hours and days are usually
necessary to carry out several reactions. For instance, there are
more than 60 syntheses1,2 of (−)-oseltamivir phosphate
(Tamiflu),3 a neuraminidase inhibitor, which is one of the
most effective drugs for the treatment of influenza, and the
total reaction time for the previous syntheses are more than
30 h. This number only includes the reaction time, and a
much longer time is needed, considering the postprocessing
operations. It is a great challenge to synthesize a molecule
within a short time period in current synthetic organic
chemistry. Recently, Jamison reported a remarkable 3 min
synthesis of ibuprofen using continuous flow technology.4
The most time-consuming operations in the synthesis of
organic molecules are those such as quenching, extracting, and
purifying after the reaction. To minimize these postprocessing
operations, it is synthetically advantageous to carry out several
reaction steps in a single reaction vessel sequentially, and we
recently proposed the importance of pot economy.5
There are several economies6 in syntheses, such as atom
economy,7 step economy,8 and redox economy.9 The
selection of a synthetic strategy with a small number of
steps according to step economy and redox economy is
essential for efficient synthesis as well as performing the
reactions in a single vessel, reducing the postprocessing
operations according to pot economy. Step, redox, and pot
economies are all concerned with reducing the reaction time,
but these are not enough for a rapid synthesis. The reaction
itself has to be fast, and selection of a rapid reaction and
reaction conditions is also essential for the success of time
economy. In some cases, new catalytic systems have to be
developed. Optimization of reactions is routinely performed
mostly in terms of yield, selectivity, and greenness, the last
one being especially important in industry. Time should be
Received: June 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01595
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. 60 Minute Time Economical Synthesis of (−)-Oseltamivir
Table 1. Asymmetric Michael Reaction of 2 and 3
a
Catalyzed by Diphenylprolinol Silyl Ether 4
Figure 1. Structure of 10.
reduction of the nitro group (11 → 12), the retro-Michael
reaction of thiol proceeded to provide (−)-oseltamivir (14 h).
These steps need long reaction times, although the yield and
the 5R/5S selectivity are excellent. In terms of a rapid
synthesis, these slow Michael and retro-Michael reactions of
thiol should be removed. As this step is for the epimerization
from 5R to 5S, an additional rapid and efficient epimerization
step is necessary. After intensive screening, we found that
equilibrium was reached within 20 min in the presence of
TBAF to provide a 1:1 mixture of 5R and 5S isomers 9,
although complete epimerization cannot be achieved. Time
for the equilibrium was further reduced to 5 min under
microwave (MW) irradiation.
b
c
d
e
f
entry acid
thiourea
time (min) yield (%)
syn/anti
ee
1
2
3
yes
yes
no
30
90
90
>95
80
6:1
7:1
97
99
yes
no
yes
<5
a
Unless noted otherwise, reactions were performed by employing 2
(0.15 mmol) and 3 (0.3 mmol) in chlorobenzene (0.5 mL) at 20 °C
b
for the indicated time. Formic acid (0.06 mmol, 40 mol %) was
c
employed. Thiourea 5 (0.015 mmol, 10 mol %) was employed.
d
Conversion yield from the 1H NMR of the reaction mixture.
e
f
1
Determined by H NMR analysis. See the Supporting Information
for determination of enantioselectivity.
The last step is reduction of the nitro group to an amine
using Zn, which took 100 min at 70 °C, but the reaction was
greatly accelerated under MW irradiation.16 The reduction
was completed within only 5 min.
work in different ways in good harmony to achieve a dramatic
acceleration of the reaction.
Domino Michael and Horner−Wardsworth−Emmons re-
actions proceed smoothly by addition of ethyl acrylate
derivative 7, t-BuOK, and EtOH in the same vessel at 0 °C
for 20 min to provide cyclohexene 8, while this trans-
formation took 3.5 h using Cs2CO3 in chlorobenzene
followed by the addition of EtOH in the previous synthesis.1a
The base is essential for the rapid reaction. Changing the base
to t-BuOK greatly reduced the reaction time.
Next, protonation occurs on the nitronate ion instantly at
−40 °C by reaction with HCl, which was generated from
trimethylsilyl chloride in situ. A mixture of 5R and 5S isomers
of nitrocyclohexene 9 was obtained with predominant
formation of undesired 5R isomer (5S/5R = 1:4−5).
Epimerization from the 5R to 5S isomer is the next step.
A previous ab initio calculation study of the similar
compound 10 (Figure 1) in our second-generation synthesis
of (−)-oseltamivir indicated that the 5R and 5S isomers are
energetically similar.11a That is why a three-step procedure
was developed for the complete epimerization from the 5R to
the 5S isomer1 (Scheme 2): the Michael reaction of thiol to 9,
followed by the epimerization from 5R to 5S (48 h). After
Overall, (−)-oseltamivir was obtained in 15% total yield via
a one-pot procedure starting from 120 mg of nitroalkene 2.
The procedure is very simple, adding the reagents successively
without solvent swap. The total reaction time is just 60 min.
As MW irradiation was used in Scheme 1, the scale is limited
to the apparatus.17 A gram-scale synthesis was investigated
without MW irradiation (Scheme 3). MW was employed in
the last two steps: epimerization and reduction of the nitro
group. As described previously, it takes 20 and 100 min for
each step without MW irradiation. (−)-Oseltamivir can be
prepared still within a short time period (170 min) in similar
yield (14%) in a gram-scale experiment without MW
irradiation.
In summary we have accomplished a 60 min time
economical total synthesis of (−)-oseltamivir in a single
reactor over five steps: (1) asymmetric Michael reaction (2 +
3 → 6), (2) domino Michael and Horner−Wardsworth−
Emmons reaction (6 + 7 → 8), (3) protonation (8 → 9), (4)
epimerization (5R isomer → 5S isomer), and (5) reduction of
a nitro group (9 → 1). There are several noteworthy features
B
DOI: 10.1021/acs.orglett.6b01595
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Epimerization of 5R to 5S in the Previous Synthesis
Scheme 3. Gram-Scale Synthesis of (−)-Oseltamivir without Using MW Irradiation
(2) For Tamiflu syntheses published after ref 1, see; (a) Chen, C.-
A.; Fang, J.-M. Org. Biomol. Chem. 2013, 11, 7687. (b) Chavan, S. P.;
Chavan, P. N.; Khairnar, L. B. RSC Adv. 2014, 4, 11417.
(c) Furutachi, M.; Kumagai, N.; Watanabe, T.; Shibasaki, M.
Tetrahedron 2014, 70, 9113. (d) Kongkathip, B.; Akkarasamiyo, S.;
Kongkathip, N. Tetrahedron 2015, 71, 2393. (e) Tisovsky, P.;
Penaska, T.; Meciarova, M.; Sebesta, R. ACS Sustainable Chem. Eng.
2015, 3, 3429.
(3) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. M.;
Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119,
681.
in the synthesis. In the synthetic design, the total number of
steps is reduced to five, in line with step economy, and only a
single reactor was employed throughout the five steps, which
satisfies pot economy. The reaction was optimized in view of
not only yield and selectivity but also reaction time. A new
catalyst cocktail, in which three catalysts act cooperatively, was
developed for the rapid asymmetric Michael reaction in
excellent yield with excellent diastereo- and enantioselectiv-
ities. To consider the efficiency in the ideal organic
synthesis,18 there are several factors to consider, such as
yield, selectivity, and greenness. We propose that time
economy should be considered in the synthesis.
(4) Snead, D. R.; Jamison, T. F. Angew. Chem., Int. Ed. 2015, 54,
983.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01595.
(5) (a) Hayashi, Y.; Umemiya, S. Angew. Chem., Int. Ed. 2013, 52,
3450. (b) Hayashi, Y.; Sakamoto, D.; Okamura, D. Org. Lett. 2016,
18, 4. (c) Hayashi, Y. Chem. Sci. 2016, 7, 866.
(6) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev.
2009, 38, 3010.
(7) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(8) (a) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006,
62, 7505. (b) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T.
H. Acc. Chem. Res. 2008, 41, 40. (c) Wender, P. A. Nat. Prod. Rep.
2014, 31, 433.
■
S
Experimental procedures and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(9) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854.
(10) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed.
2009, 48, 1304.
*E-mail: yhayashi@m.tohoku.ac.jp.
Notes
The authors declare no competing financial interest.
(11) (a) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi,
Y. Chem. - Eur. J. 2010, 16, 12616. (b) Ishikawa, H.; Bondzic, B. P.;
Hayashi, Y. Eur. J. Org. Chem. 2011, 2011, 6020.
(12) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212.
(13) (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289. (b) Zhang,
Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
(14) (a) Hayashi, Y.; Okamura, D.; Yamazaki, T.; Ameda, Y.;
Gotoh, H.; Tsuzuki, S.; Uchimaru, T.; Seebach, D. Chem. - Eur. J.
2014, 20, 17077. (b) Gotoh, H.; Uchimaru, T.; Hayashi, Y. Chem. -
Eur. J. 2015, 21, 12337.
(15) (a) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.;
Seebach, D.; Hayashi, Y. Helv. Chim. Acta 2011, 94, 719. (b) Seebach,
D.; Sun, X.; Sparr, C.; Ebert, M.-O.; Schweizer, W. B.; Beck, A. K.
Helv. Chim. Acta 2012, 95, 1064. (c) Seebach, D.; Sun, X.; Ebert, M.-
ACKNOWLEDGMENTS
■
We thank Dr. T. Uchimaru at National Institute of Advanced
Industrial Science and Technology (AIST) for the ab initio
calculation. This work was supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
REFERENCES
■
(1) (a) Mukaiyama, T.; Ishikawa, H.; Koshino, H.; Hayashi, Y.
Chem. - Eur. J. 2013, 19, 17789 and references cited therein.
(b) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010,
49, 4656. (c) Rehak, J.; Hut’ka, M.; Latika, A.; Brath, H.; Almassy,
A.; Hajzer, V.; Durmis, J.; Toma, S.; Sebesta, R. Synthesis 2012, 44,
2424. (d) Weng, J.; Li, Y.-B.; Wang, R.-B.; Lu, G. ChemCatChem
2012, 4, 1007.
O.; Schweizer, W. B.; Purkayastha, N.; Beck, A. K.; Duschmale,
Wennemers, H.; Mukaiyama, T.; Benohoud, M.; Hayashi, Y.; Reiher,
M. Helv. Chim. Acta 2013, 96, 799. (d) Bures, J.; Armstrong, A.;
́
J.;
́
C
DOI: 10.1021/acs.orglett.6b01595
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Blackmond, D. G. J. Am. Chem. Soc. 2011, 133, 8822. (e) Bures
Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134, 6741.
(f) Bures, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc.
2012, 134, 14264. (g) Bures, J.; Armstrong, A.; Blackmond, D. G.
Pure Appl. Chem. 2013, 85, 1919. (h) Sahoo, G.; Rahaman, H.;
Madarasz, A.; Papai, I.; Melarto, M.; Valkonen, A.; Pihko, P. M.
́
, J.;
́
́
̀
̀
Angew. Chem., Int. Ed. 2012, 51, 13144; Angew. Chem. 2012, 124,
13321.
(16) Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.; Ramana,
A. V. Tetrahedron Lett. 2004, 45, 6517.
(17) Microwave irradiations were performed in Biotage Initiator+.
The largest volume of a reaction mixture is about 20 mL.
(18) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657.
D
DOI: 10.1021/acs.orglett.6b01595
Org. Lett. XXXX, XXX, XXX−XXX