Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu) via the Iron-Catalyzed Stereoselective Olefin Diazidation

Article abstract of DOI:10.1021/jacs.8b06900

We herein report a gram-scale, enantioselective synthesis of Tamiflu, in which the key trans-diamino moiety has been efficiently installed via an iron-catalyzed stereoselective olefin diazidation. This significantly improved, iron-catalyzed method is uniquely effective for highly functionalized yet electronically deactivated substrates that have been previously problematic. Preliminary catalyst structure-reactivity-stereoselectivity relationship studies revealed that both the iron catalyst and the complex substrate cooperatively modulate the stereoselectivity for diazidation. Safety assessment using both differential scanning calorimetry (DSC) and the drop weight test (DWT) has also demonstrated the feasibility of carrying out this iron-catalyzed olefin diazidation for large-scale Tamiflu synthesis.

Full text of DOI:10.1021/jacs.8b06900

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Article
Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu)
via the Iron-Catalyzed Stereoselective Olefin Diazidation
Hongze Li, Shou-Jie Shen, Cheng-Liang Zhu, and Hao Xu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Jul 2018
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Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu) via
the Iron-Catalyzed Stereoselective Olefin Diazidation
Hongze Li,‡ Shou-Jie Shen,‡ Cheng-Liang Zhu, and Hao Xu*
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Department of Chemistry, Georgia State University, 100 Piedmont Avenue SE, Atlanta Georgia 30303, United States.
ABSTRACT: We herein report a gram-scale, enantioselective synthesis of Tamiflu, in which the key trans-diamino moiety
has been efficiently installed via an iron-catalyzed stereoselective olefin diazidation. This significantly improved, iron-
catalyzed method is uniquely effective for highly functionalized yet electronically deactivated substrates that have been
previously problematic. Preliminary catalyst structure–reactivity–stereoselectivity relationship studies revealed that both
the iron catalyst and the complex substrate cooperatively modulate the stereoselectivity for diazidation. Safety assessment
using both differential scanning calorimetry (DSC) and drop weight test (DWT) has also demonstrated the feasibility of
carrying out this iron-catalyzed olefin diazidation for large-scale Tamiflu synthesis.
In Roche’s Tamiflu production route, the starting mate-
INTRODUCTION
rial, shikimic acid 4, is converted to a key homoallylic
Oseltamivir phosphate 1 (Tamiflu), the pro-drug of a
potent viral neuraminidase inhibitor, has been used as an
epoxide intermediate 5 (Scheme 2a).2 The trans-diamino
moiety in Tamiflu is installed through the stereoselective
effective medicine to treat and prevent influenza A and
ring-opening of both epoxide 5 and a homoallylic N-H
influenza B.1a Designed and developed by scientists at
Gilead and Hoffman–La Roche, it effectively mimics the
transition state of enzymatic hydrolysis of terminal sialic
acids 2 from cell-surface glycoconjugates, a step postulat-
aziridine 6 using NaN3 (Scheme 2a).2 Azide-free proce-
dures were later developed from 5 as well; however, addi-
tional epimerization steps are necessary.2c-d To search for
an efficient synthetic strategy from readily available achi-
ed to be necessary for elution of newly formed viruses
ral starting materials, chemists have also extensively in-
from infected cells (Scheme 1a). From a synthetic chemis-
vestigated the de novo enantioselective synthesis of
try perspective, the structure of Tamiflu can be simplified
to a functionalized trans, trans-diamino cyclic allylic al-
Tamiflu.3
Among these efforts, Corey developed a chiral oxazabo-
rolidinium-catalyzed asymmetric Diels–Alder method for
the synthesis of a chiral cyclohexene 7, which then un-
derwent several transformations, including iodo-
lactamization and N-acyl aziridine ring-opening, to fur-
nish 1 (Scheme 2b).3a Shibasaki reported an enantioselec-
tive Tamiflu synthesis that involves an asymmetric ring-
opening of a meso N-acyl aziridine 8 to provide the key
trans-amino azide intermediate 9 (Scheme 2c).3b During
development of several generations of synthetic strate-
gies, he also capitalized on a barium-catalyzed asymmet-
ric Diels–Alder reaction and a stereospecific Curtius rear-
rangement of a trans-diacyl azide intermediate 10 to af-
ford the key oxazolidinone intermediate 11, which was
later converted to 1 (Scheme 2c).3d
cohol 3, in which the stereochemical alignment of three
contiguous stereogenic centers is critical for Tamiflu’s
antiviral activity;1b however, the stereoselective synthesis
of 3 from a readily available starting material is not
straightforward. As a result, numerous efforts have been
devoted to search for an expedient strategy to produce
Tamiflu and a range of efficient Tamiflu syntheses have
been reported (Scheme 2).2,3
Scheme 1. Enantioselective synthesis of Tamiflu via the
iron-catalyzed stereoselective olefin diazidation
In Fukuyama’s Tamiflu synthesis,3e an organo-catalytic
acrolein Diels–Alder reaction was applied to assemble a
chiral 2-azabicyclo[2.2.2]octene building block 12 (Scheme
2d). Furthermore, a palladium-catalyzed asymmetric al-
lylic alkylation and a rhodium-catalyzed dienoate aziridi-
nation were used to prepare a key intermediate 13 in
Trost’s synthesis of Tamiflu (Scheme 2e).3f Moreover,
Hayashi developed an organo-catalytic conjugate addition
of an α-alkyoxyaldehyde 14 with a nitro-olefin 15 in an
efficient synthesis of 1 (Scheme 2f).3g-h Notably, Ma inde-
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pendently reported the asymmetric conjugate addition of Scheme 3. Retrosynthetic analysis based upon the iron-
1
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14 with (Z)-2-nitroethenamide 16 in another expedient
catalyzed stereoselective olefin diazidation
synthesis of Tamiflu (Scheme 2g).3i
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Scheme 2. Selected examples of the previous Tamiflusyn-
theses
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In 2015, we reported an iron-catalyzed direct diazida-
tion method for a broad range of olefins, in which an iron
catalyst activates TMSN3 in the presence of bench-stable
benziodoxole 19a4 to achieve direct olefin diazidation
(Scheme 4a).5 This reaction occurs at room temperature
and it is effective for a wide variety of olefins, including
those that are incompatible with the previously reported
diazidation methods.6 Coupled with facile reduction, it
readily provides an array of valuable vicinal primary dia-
mines. Recently, we disclosed a second iron-catalyzed
olefin diazidation method via ligand-promoted activation
of bench-stable peroxyesters.7 In this method, nearly a
stoichiometric amount of commercially available tert-
butyl perbenzoate 20 and TMSN3 are sufficient for high-
yielding diazidation of a wide variety of olefins and N-
heterocycles (Scheme 4b).7 These and other concurrent
olefin diazidation methods8 add useful tools in the reper-
toire of synthetic chemists.
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Scheme 4. Iron-catalyzed direct olefin diazidation meth-
ods
Our initial attempts to directly apply these two meth-
ods under the standard conditions to a range of designed
late-stage intermediates for Tamiflu synthesis were not
successful. Most of these complex substrates, including
18, suffer from lack of reactivity, while functionalized 1,4-
cyclohexadiene 17 readily undergoes aromatization.9
Guided by mechanistic analysis, we have improved these
iron-catalyzed methods such that they become effective
with these highly functionalized substrates. Herein, we
disclose these new discoveries that have enabled the iron-
catalyzed stereoselective diazidation of these previously
challenging substrates and thereby facilitated a gram-
scale, enantioselective synthesis of Tamiflu in short steps
(Scheme 1b).
These existing Tamiflu syntheses have showcased the
power of catalytic reactions in assembling stereochemi-
cally complex synthetic targets; however, a strategically
unique synthetic approach has not been reported that can
directly install the trans-diamino moiety within Tamiflu
via stereoselective diamination or diazidation of a highly
functionalized synthetic intermediate, such as 17 or 18
(Scheme 3). Implementation of this diazidation–
diamination strategy will provide a mechanistically dis-
tinct approach for an efficient synthesis of Tamiflu in
complement of the previous syntheses.
RESULTS AND DISCUSSION
To explore the feasibility of achieving an expedient
Tamiflu synthesis via the iron-catalyzed stereoselective
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chiral 1,4-
olefin diazidation, we initially chose
a
Although the chemo- and enzymatic kinetic resolution
of cyclic allylic alcohols have been precedented,11 the ki-
netic resolution of highly functionalized substrates with
three contiguous stereogenic centers has not been report-
ed. We thereby investigated an array of chemo- and en-
zymatic catalysts for the proposed kinetic resolution and
discovered that Amano Lipase from Pseudomonas fluo-
rescens is uniquely effective (Scheme 5): the highly enan-
tio-enriched product (–)-26 (>99% ee) was isolated in
48% yield and the starting material (+)-25 was recovered
in a good yield and excellent ee (44% yield, 98% ee). A
single recrystallization affords (+)-25 essentially in its en-
antio-pure form (40% yield, >99% ee).9
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cyclohexadiene 17 as a possible substrate (Scheme 5).
Since 17 readily underwent aromatization under the dia-
zidation conditions,9 we further targeted a functionalized
chiral cyclic allylic alcohol 18 as an alternative substrate
and expected that facile elimination under mild condi-
tions would unveil the key enoate moiety within Tamiflu
(Scheme 3).
Scheme 5. Enantioselective synthesis of highly function-
alized cyclic allylic alcohols for the iron-catalyzed olefin
diazidation
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Scheme 6. Initial attempts for the direct diazidation of
(+)-25 using the standard iron-catalyzed diazidation pro-
cedures
To our surprise, neither of the aforementioned iron-
catalyzed diazidation method was effective for the highly
functionalized (+)-25 when it was directly applied under
the standard reaction conditions (Scheme 6). In the ben-
ziodoxole-mediated diazidation,5 (+)-25 was fully recov-
ered while benziodoxole 19a completely decomposed to
o-iodobenzoic acid.9 Notably, both (+)-25 and tert-butyl
perbenzoate 20 were largely recovered using the iron-
catalyzed, peroxyester-based8 diazidation method.9
b
aNaOAc·3H2O, CH2Cl2, 22 °C, 48 h. Amano Lipase from
Pseudomonas fluorescens (20,000 U/g, 50 wt. %), aq.
Na2HPO4 buffer, 22 °C, 26 h; (+)-25 (40% yield, >99% ee)
after a single recrystallization.
The enantioselective synthesis of both 1,4-
cyclohexadiene 17 and cyclic allylic alcohol 18 has not
been reported; however, the pioneering Danishefsky’s
studies of a Diels–Alder reaction between a siloxy diene 21
and a nitroacrylate 22 have laid the foundation for the
synthesis of 18 as racemate (Scheme 5).10a Since nitroacry-
late 22 tends to decompose under the reaction condition,
we speculated that a more efficient cycloaddition could
be achieved when 22 was gradually generated in situ from
its precursor, bromo-3-nitropropanoate 23 (Scheme 5). As
a promising lead, we discovered that solid NaOAc·3H2O
effectively promotes the reaction between siloxy diene 21a
and 23 at room temperature, which readily affords the
Diels–Alder products 24a and 24b in a high combined
yield, albeit with a low dr. Inspired by this observation,
we further discovered that acetoxy diene 21b undergoes a
highly endo-selective Diels–Alder reaction, delivering 25
as a single diastereomer. Notably, this reaction has been
consistently scaled up to 30 gram-scale and 25 can be
easily purified through recrystallization (Scheme 5).9
In order to significantly improve these iron-catalyzed
methods such that they can become effective with (+)-25,
we carried out detailed mechanistic analysis of both iron-
catalyzed olefin diazidation reactions.5,7 The mechanistic
studies5 have uncovered that TMSN3 may reversibly con-
vert otherwise insoluble benziodoxole 19a to
azidoiodinane 19b, and then to a transient iodine(III)–
diazide species 19c, with which an iron catalyst may be
oxidized to a high-valent iron-azide species that promotes
the stepwise olefin diazidation (Scheme 7). A variety of
experiments suggest that the iron–ligand complexes are
involved in the second C–N3 bond forming step which is
rate-determining.5
Scheme 7. Mechanistic analysis of the iron-catalyzed ole-
fin diazidation using benziodoxole 19a
To search for an enantioselective variant of this trans-
formation, we have explored a range of catalytic enanti-
oselective strategies which prove less effective, presuma-
bly due to the high reactivity associated with nitroacrylate
22. Therefore, as an alternative strategy, we envision that
an efficient kinetic resolution of 25 may provide both of
its enantiomers with high enantio-purity.
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Furthermore, we observed that, in the absence of an ole- 2D–NMR experiments and later corroborated by X-ray
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fin, an iron catalyst completely decomposes benziodoxole
19a together with TMSN3 (Scheme 7), while 19a is stable
towards TMSN3 without an iron catalyst (Scheme 7).8
These results suggest that competing reaction pathways
do exist and they presumably proceed through the iron-
promoted non-productive decomposition of iodine(III)–
diazide species 19c (Scheme 7).8 These competing path-
ways may become particularly detrimental for electroni-
cally deactivated substrates that are less reactive.
crystallographic analysis of 27a (Figure 1).9 A straightfor-
ward hydrolysis–elimination procedure converts 27a to
trans, trans-diazido alcohol 28, which can be easily con-
verted to trans, trans-hydroxyl diaminium tosylates
3·2TsOH via a standard reduction–protonation procedure
(Scheme 8).
Figure 1. X-ray crystallographic analysis of diazide 27a
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Based upon this analysis, we envision that the rate of
olefin diazidation may have an order-dependence on both
[iron catalyst] and [olefin] since the first C–N3 bond form-
ing step is reversible and the second C–N3 bond forming
step is rate-limiting (Scheme 7). Furthermore, the rate of
iron-mediated non-productive decomposition of 19c is
likely dependent on both [19c] and [iron catalyst]
(Scheme 7). Therefore, we suspect that an effective dia-
zidation of (+)-25 may be achieved if a high concentration
of (+)-25 and a low concentration of 19c can be main-
tained at the same time through the reaction such that
non-productive decomposition of 19c can be largely sup-
pressed. Built upon this mechanistic proposal, we have
drastically modulated the previously reported method: to
increase the concentration of (+)-25 up to 0.8 M and to
decrease the concentration of TMSN3 through slow addi-
tion (up to 8 h, Scheme 8).
Organic azides, especially those with lower molecular
weights, may present potential safety concerns for their
handling, with regard to their thermo- and mechanical
impact stabilities.12 In order to explore the feasibility of
the iron-catalyzed olefin diazidation for Tamiflu produc-
tion on a larger scale, it is imperative to carry out chemi-
cal hazard assessment of this olefin diazidation process. A
reactive chemical hazard assessment refers the identifica-
tion and possibly quantification of dangerous energy re-
lease scenarios for a chemical process of interest. Differ-
ential Scanning Calorimetry (DSC) is one of the most
commonly applied thermal stability testing methods for
organic compounds, while Drop Weight Test (DWT) has
been routinely applied to detect the sensitivity of a chem-
ical towards mechanical impact. In 2017, we reported a
process safety assessment of the iron-catalyzed olefin dia-
zidation using benziodoxole 19a.13 DSC analysis of the
corresponding reagents, intermediates presented in suffi-
cient concentrations, and a list of representative diazide
products revealed that all of them are thermal stable at
the reaction temperature.13 Based upon these results, we
carried out DSC analysis of 27a and observed that it does
not decompose occur until 189 °C, which allows for a con-
venient operating margin in carrying out the diazidation
at room temperature. Most notably, the diazide 27a is
insensitive to mechanical impact during DWT studies.
Encouraged by these results, this iron-catalyzed diazida-
tion has been consistently scaled up to 5 gram-scale with-
out compromising the yield and dr of the product
(Scheme 8).9
Scheme 8. Iron-catalyzed stereoselective diazidation of
(+)-25 for the expedient synthesis of 3·2TsOH
aFe(OAc)2 (5 mol %), L1 (5 mol %), 19a (2 equiv),
CH2Cl2/MeCN (10:1), 0.8 M, 22 °C, TMSN3 (5 equiv) added
gradually within 8 h and subsequently quenched with satu-
b
rated NaHCO3 solution. MsOH, EtOH, 55 °C, 7 h, then Li-
OH·H2O, EtOH, 0 °C, 0.5 h. cPPh3, H2O, THF, 22 °C, 8 h, then
TsOH·H2O, 1 h. Standard safety precautions about handling
TMSN3 should be taken; see SI for details.
Scheme 9. The proposed reversible azido-radical addition
step during the diazidation of (+)-25
We discovered that the Fe(OAc)2–L1 catalyst (5 mol %)
effectively promotes the stereoselective diazidation of (+)-
25 with a good combined yield and excellent dr (dr: 7.4:1).
Notably, an array of control experiments revealed that
deviation from the newly discovered condition leads to an
incomplete reaction. The desired trans, trans-diazide 27a
can be readily separated from the cis, trans-diazide 27b
through either recrystallization or flash-column chroma-
tography. Their structures were initially assigned with
OAc
N3
CO2Et azido-radical
addition
azido-radical
addition
CO2Et
NO2
O2N
AcO
O2N
4
3
CO2Et
AcO
N3
29a
(+)-25
29b
The observed promising stereoselectivity at both C3 (dr:
7.4:1) and C4 (dr >20:1) positions is mechanistically inter-
esting. During the diazidation (Scheme 9), we envision
that, based upon electronic effect, β-azido-C3 carboradi-
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is gradually released under the diazidation condition, 33a
cal 29a, a putative intermediate reversibly generated from
1
2
3
4
5
6
7
8
is likely derived from 34 by the residue TMSN3 and it is
unlikely the diazidation product from 32.
(+)-25, is likely more reactive than β-azido-C4 carboradi-
cal 29b towards the rate-determining oxidative C–N3
bond formation; therefore, we suspect that the dr at C3
may be further improved through structural modulation
of both iron catalysts and substrates.
The excellent stereoselectivity achieved with (+)-26
urged us to further evaluate 24b and 35, two exo-Diels–
Alder products, for the diazidation (Scheme 10). Interest-
ingly, both 24b and 35 present excellent reactivity and
stereoselectivity, affording either a trans, cis-diazido silyl
ether 36 or an alcohol 37 as a single diastereomer (dr >20:1
at both C3 and C4 positions in 36 and 37). Again, a small
amount of TMS-protected allyl silyl ether 38 was also ob-
tained (dr >20:1).
Extensive explorations of a range of iron catalysts and
ligands for the diazidation of (+)-25 provided modest im-
provement over the dr: notably, the Fe(NTf2)2–ligand
complexes induced an even lower dr at C3 position (dr:
4.8:1).9 We thereby investigated the possibility of achiev-
ing enhanced stereoselectivity via substrate control.
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Scheme 11. Catalyst structure–reactivity relationship
studies of the polymeric iron-azide complex (Fe(L1)(N3)2)n
Scheme 10. Substrate structure–stereoselectivity relation-
ship studies for the iron-catalyzed olefin diazidation
Et
O
O
a) Fe(OAc)2 (5 mol %)
L1
TMSN3 (5.0 equiv)
slow addition
22 °C, c = 0.8 M
dr : 2.2:1
O
Et
N
L1
39
(Fe( )(N3)2)n
Fe(OAc)2
TMSN3
(1.0 equiv)
+
+
N3 CO2Et
N3 CO2Et
N3
(5 mol %)
NO2
N
N
(15 mol %)
L1
O2N
RO
O2N
+
Me
Me
Me
+
19a
IR stretches:
2047,2060 cm-1
Me
CO2Et
(15 mol %)
N3
RO
31a
31b
30
57% R: 3-pentyl 28%
OTMS
NO2
N3 CO2Et
N3 CO2Et
N3
a)
O2N
RO
O2N
+
+
+
19a
19a
dr : 1.7:1
CO2Et
N3
RO
33a
33b
32
55% R: TMS
N3 CO2Et
32%
OH
N3 CO2Et
NO2
b)
O2N
HO
O2N
+
dr >20:1
CO2Et
(+)-26
N3
RO
N
OH
a) 39 (5 mol %)
TMSN3 (3.6 equiv)
slow addition
34
33a
3
O
N3
N3
CO2Et
+
CO2Et
N3
NO2
70%
6%
R: TMS
O2N
HO
O2N
O
+
OTBS
OTBS
I
22 °C, c = 0.8 M
dr >20:1
CO2Et
NO2
NO2
N3
TMSO
N3
N3
a)
OH
(+)-26
19a
19b
34
70%
33a
8%
+
+
19a
19a
dr >20:1
CO2Et
CO2Et
O
O
N3
CO2Et
N3
24b
36
75%
39
(20 mol %)
b)
O2N
HO
+
(+)-26
OH
OTMS
OH
I
22 °C, c = 0.8 M
NO2
NO2
NO2
N3
N3
N3
34
17%
dr >20:1
21% conversion
N3
a)
+
dr >20:1
CO2Et N3
CO2Et
CO2Et
35
37
38
a39 (5 mol %), 19a (1.5 equiv), CH2Cl2/MeCN (10:1), 0.8 M,
22 °C, TMSN3 (3.6 equiv) added gradually within 8 h. b39
(20 mol %), 19b (1.5 equiv), CH2Cl2/MeCN (10:1), 0.8 M, 22
°C.
58%
18%
aFe(OAc)2 (5 mol %), L1 (5 mol %), 19a (2 equiv),
CH2Cl2/MeCN (10:1), 0.8 M, 22 °C, TMSN3 (5 equiv) added
gradually within 8 h. bFe(OAc)2 (5 mol %), L1 (5 mol %), 19a
(1.5 equiv), CH2Cl2/MeCN (10:1), 0.8 M, 22 °C, TMSN3 (3.6
equiv) added gradually within 8 h. The reactions were subse-
quently quenched with saturated NaHCO3 solution.
These observations evidently suggest that both iron
catalysts and substrates cooperatively influence the stere-
oselectivity of the diazidation. In order to propose a plau-
sible stereochemical model, the possible structure of a
catalytically active iron complex needs to be considered.
Our mechanistic studies have revealed that the Fe(OAc)2–
L1 complex readily reacts with TMSN3, furnishing an iron-
azide complex 39 (Scheme 11).14 IR analysis of 39 uncov-
ered strong azido group absorptions (2047 and 2060 cm-1)
shifted to lower energy in comparison to free azide, char-
acteristic of iron-azide complexes.15 Subsequent X-ray
crystallographic analysis of 39 revealed a unique iron co-
ordination polymer with all iron centers equivalent and
generated by symmetry–(Fe(L1)(N3)2)n (Scheme 11).14 In
additional to the rigid tridentate ligand L1, three remain-
ing coordination sites of the iron center are occupied by
three azides with one being terminal and the other two
azides cis to each other bridging adjacent iron centers to
form the coordination polymer.14 Importantly, this poly-
meric iron catalyst 39 is catalytic active and it catalyzes
the diazidation of (+)-26 with essentially the same yield
The diazidation of a 3-pentyl-substituted allylic ether
30 was first evaluated since it could lead to a more
streamlined Tamiflu synthesis (Scheme 10). We observed
that the Fe(OAc)2–L1 catalyst promotes an efficient dia-
zidation of 30, albeit with a low dr at C3 (dr: 2.2:1). Con-
sidering the β-branch effect that might be associated with
30, we further explored the reaction with a TMS-
protected allyl silyl ether 32; however, a modest level of dr
was again observed (dr: 1.7:1). To our surprise, the iron
catalyst promotes a highly stereoselective diazidation
with an unprotected allylic alcohol (+)-26, affording a
trans, trans-diazido alcohol 34 and a small amount of its
TMS-protected ether 33a with excellent dr (dr >20:1 at
both C3 and C4 positions in 33a and 34). It is worth not-
ing that (+)-26 is evidently more reactive than (+)-25 and
acid workup readily converts 33a back to 34. Since TMSN3
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to approach the β-azido carboradical species 45 from its α
and dr (Scheme 11). Surprisingly, 39 can also promote dia-
1
2
3
4
5
6
7
8
zidation of (+)-26 with 19b in the absence of TMSN3, albeit
with a low yield (Scheme 11, 17% yield, dr >20:1). Therefore,
it is likely that iron-azide complex 39 gets oxidized to a
high-valent iron-azide species that facilitates the olefin
diazidation and that the terminal iron–azide bond in 39
may be involved in the rate-limiting azido-group transfer.
face regardless of the R substituent.
With the success of this improved diazidation method
using benziodoxole 19a, we further explored the possibil-
ity of developing a new peroxyester-based diazidation
approach for the synthesis of trans, trans-diazido alcohol
28. Under the standard peroxyester-based diazidation
conditions, both (+)-25 and tert-butyl perbenzoate 20
were largely recovered (Scheme 6), which suggests that
the energy barrier of rate-determining step may be too
high for this electronically deactivated substrate.
Scheme 12. Proposed stereochemical model for the iron-
catalyzed olefin diazidation of cyclic allylic alcohols
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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57
58
59
60
Based upon our mechanistic studies,7 we envision that
Fe(NTf2)2–ligand complex may reductively cleave the O–
O bond in a peroxyester 20 to generate a tert-butoxyl rad-
ical that is associated with a high-valent iron complex 47
i
(Scheme 13a). PrOH presumably facilitates gradual re-
lease of HN3 from TMSN3, and tert-butoxyl radical may
thereby be rapidly sequestered by HN3 to liberate azido
radical. The azido radical may reversibly add to an olefin
to afford carbo-radical species 48 and TMSN3 may also
convert the iron(III) species 47 to a high-valent iron-azide
species 49, which presumably mediates the rate-
determining azido-group transfer to the carbo-radical
species 48 and afford the diazidation product.7
Based upon these catalyst structure–reactivity relation-
ship studies, a plausible stereochemical model that fits
the observations is presented in Scheme 12. We envision
that the endo-Diels-Alder product 40 can adopt either of
the two conformations (40a and 40b) that may be in rap-
id equilibrium. Since the azido-radical addition to 40 is
reversible and it likely occurs at C4 position from the axial
trajectory in order to avoid a twist-boat conformation
(Scheme 9),16 β-azido carboradical species 42a and 42b
may be two reactive intermediates in equilibrium. In the
subsequent rate-determining C–N3 bond forming step,
the bulky iron(III) azide species derived from 39 may oxi-
dize 42a or 42b through direct azido-ligand transfer from
the iron center.5,7 Considering the significant unfavorable
1,3-diaxial interactions that may build up in 42b (between
the iron-azide complex and the CO2Et or NO2 group)
along the reaction trajectory, it is less likely that this oxi-
dation occurs with 42b from either the α or β face.
Scheme 13. a) Mechanistic working hypothesis of the
Fe(NTf2)2-catalyzed olefin diazidation using peroxyesters
and b) iron-catalyzed peroxyester activation for diazida-
tion of (+)-25
However, the azido-group transfer may occur with 42a
in which these unfavorable interactions no long exist. If R
is a less-sterically demanding group, such as hydrogen or
acetyl group, the iron complex may readily deliver the
azido-group to 42a from the α face.16 The axial hydroxyl
group may also direct the iron catalyst to achieve an en-
hanced α-selectivity. Alternatively, when R becomes more
sterically demanding, the iron complex may thereby be
forced to deliver the azido-group from the β face. There-
fore, excellent stereoselectivity can be achieved with an
unprotected allylic alcohol (+)-26 using a bulky polymeric
iron-azide catalyst (Fe(L1)(N3)2)n 39.
aFe(NTf2)2 (10 mol %), (±)-L2 (10 mol %), 50 (2.5 equiv),
iPrOH (0.2 equiv), TMSN3 (3.5 equiv), CH2Cl2/MeCN (9:1),
0.5 M, 22 °C, 12 h. The reactions were subsequently
quenched with saturated NaHCO3 solution.
Since the O–O bond cleavage is unlikely rate-
determining, we suspect that a more electron-deficient
iron(III) species 49 may accelerate the rate-determining
C–N3 bond forming step. Therefore, we evaluated peroxy-
ester 50 with a more-electron-withdrawing acyl group
and observed that the Fe(NTf2)2–racemic L2 catalyst pro-
motes an efficient diazidation with (+)-25, affording 27 in
an excellent yield albeit moderate dr (Scheme 13b). It is
worth noting that no significant match/mismatch effect
was observed using enantio-pure L2 ligand,9 and that a
This proposed model can also rationalize the excellent
stereoselectivity observed with exo-Diels–Alder product
44 (Scheme 12). Locked in a conformation where the OR,
CO2Et, and NO2 groups all reside in equatorial positions,
the polymeric iron(III)-azide intermediate should be able
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Given the pitfalls of alkylation with diazido alcohol 28,
high concentration of TMSN3 is necessary for the reactivi-
1
2
3
4
5
6
7
8
ty. Further evaluation of the unprotected allylic alcohol
(+)-26 under the newly discovered condition furnished
decreased stereoselectivity, presumably due to the readily
conversion of (+)-26 to its TMS-protected ether 32 in situ.
we further evaluated bis-carbamates that are more nucle-
ophilic. Straightforward reduction of 28 and N-Boc pro-
tection affords 55, which demonstrates excellent reactivity
in the acid-catalyzed alkylation with trichloroacetimidate
51; however, N-Boc groups surprisingly participate in the
alkylation as well (Scheme 14). Fortunately, bis-methyl
carbamate 57 can be engaged in this alkylation and it was
converted to 58 in an excellent yield (Scheme 14). White
crystalline solid 58 can be further converted to 59, the
penultimate synthetic target, via a gram-scale procedure
that involves TMSCl–NaI-mediated carbamate deprotec-
tion18 and selective N-acylation19 of both Boc and Ac
groups. Subsequently, N-Boc deprotection of 59 using
H3PO4 in hot EtOH readily affords Tamiflu 1 (Scheme 14).
Scheme 14. Expedient Tamiflu synthesis from 3·2TsOH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSIONS
Scheme 15. Summary of the enantioselective synthesis of
Tamiflu via the iron-catalyzed stereoselective olefin dia-
zidation
b
aMsOH, 51, CH2Cl2, 22 °C, 22 h. TfOH (0.4 equiv), 51, 5
c
Å MS, CH2Cl2, 28 °C, 22 h. Methyl chloroformate, Na-
d
HCO3, H2O, 22 °C, 2 h. TMSCl, NaI, CH3CN, 40 °C, 12 h.
eBoc2O, CH2Cl2, 0 °C, 1.5 h then Ac2O, Et3N, DMAP, 22 °C,
2 h. fH3PO4, EtOH, 0.5 M, 78 °C, 12 h.
In conclusion, we have reported a gram-scale, enanti-
oselective Tamiflu synthesis, in which the key trans-
diamino moiety within Tamiflu has been efficiently in-
stalled via an iron-catalyzed stereoselective olefin diazida-
tion (Scheme 15). This improved, iron-catalyzed method
is effective for highly functionalized yet electronically
deactivated substrates that have been otherwise problem-
The gram-scale preparation of trans, trans-diazido al-
cohol 28 in short steps and high enantio-purity has al-
lowed us to explore the selective incorporation of both 3-
pentyl and acetyl groups for a short Tamiflu synthesis
(Scheme 14). Although a list of standard 3-pentyl-derived
electrophiles are unreactive towards this diazido cyclic
allylic alcohol 28, alkylation with trichloroacetimidate 51
proves uniquely effective under acidic conditions.17
atic.
Preliminary
catalyst
structure–reactivity–
stereoselectivity relationship studies revealed that both
the iron catalyst and the complex substrate cooperatively
modulate the stereoselectivity for diazidation. Most nota-
bly, an oligomeric iron-azide catalyst proves unique effec-
tive for the stereoselective diazidation. Process safety as-
sessment using both differential scanning calorimetry
(DSC) and drop weight test (DWT) has also demonstrated
the feasibility of carrying out this iron-catalyzed olefin
diazidation for large-scale Tamiflu synthesis.
We observed that MsOH promotes the difficult alkyla-
tion of 28 to afford 52, albeit in a low yield (Scheme 14);
however, 3-pentylmesylate 53, generated in situ, is an in-
effective electrophile towards 28. We subsequently dis-
covered that a catalytic amount of TfOH promotes the
alkylation of diazido allylic alcohol 28; however, a small
amount of regio-isomeric 2-pentyl-alkylation product 54
was formed as an inseparable mixture with 52.9 We sus-
pected that 54 may be generated from 52 via TfOH-
catalyzed rearrangement, which was confirmed by a sub-
sequent experiment (Scheme 14).
ASSOCIATED CONTENT
Supporting Information
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Foderaro, T.; Hughes, R. C. "Research and Development
Experimental procedure, characterization data for all new
compounds, selected NMR spectra and HPLC traces. This
material is available free of charge via the Internet at
http://pubs.acs.org.
of a Second-Generation Process for Oseltamivir Phos-
phate, Prodrug for a Neuraminidase Inhibitor." Org. Pro-
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ficient Access to Oseltamivir Phosphate (Tamiflu) via the
O-Trimesylate of Shikimic Acid Ethyl Ester." Angew.
Chem., Int. Ed. 2009, 48, 5760.
1
2
3
4
AUTHOR INFORMATION
5
6
7
8
9
Corresponding Author
(3) For selected references of Tamiflu synthesis from aca-
demic labs, see: (a) Yeung, Y. Y.; Hong, S.; Corey, E. J. "A
Short Enantioselective Pathway for the Synthesis of the
Anti-Influenza Neuramidase Inhibitor Oseltamivir from
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128, 6310; (b) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.;
Shibasaki, M. "De Novo Synthesis of Tamiflu via a Cata-
lytic Asymmetric Ring-Opening of meso-Aziridines with
TMSN3." J. Am. Chem. Soc. 2006, 128, 6312; (c) Mita, T.;
Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. "Second
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Oseltamivir." Angew. Chem., Int. Ed. 2008, 47, 3759; (g)
Ishikawa, H.; Suzuki, T.; Hayashi, Y. "High-Yielding Syn-
thesis of the Anti-Influenza Neuramidase Inhibitor (−)-
Oseltamivir by Three “One-Pot” Operations." Angew.
Chem., Int. Ed. 2009, 48, 1304; (h) Hayashi, Y.; Ogasawa-
ra, S. "Time Economical Total Synthesis of (−)-
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Wang, Y.; Ma, D. "Organocatalytic Michael Addition of
Aldehydes to Protected 2-Amino-1-Nitroethenes: The
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the Chemoenzymatic Synthesis of Oseltamivir (Tamiflu)
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4229; (l) Bromfield, K. M.; Graden, H.; Hagberg, D. P.;
Olsson, T.; Kann, N. "An Iron Carbonyl Approach to the
Influenza Neuraminidase Inhibitor Oseltamivir." Chem
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Influenza Agent Tamiflu." Tetrahedron Lett. 2008, 49,
7018; (n) Mandai, T.; Oshitari, T. "Efficient Asymmetric
Synthesis of Oseltamivir from d-Mannitol." Synlett 2009,
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L. "Efficient Formal Synthesis of Oseltamivir Phosphate
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vir Phosphate (Tamiflu) via Enzymatic Desymmetrization
of a meso-1,3-Cyclohexanedicarboxylic Acid Diester." J.
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J. "Ring-Closing Metathesis-Based Synthesis of
(3R,4R,5S)-4-Acetylamino-5-amino-3-hydroxy-cyclohex-
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* hxu@gsu.edu ORCID: 0000-0001-5029-8392
Author Contributions
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12
13
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16
17
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19
20
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22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡These authors contributed equally.
Funding Sources
This research was supported by the National Institutes of
Health (GM110382).
Notes
The subject matter described in this article is included in
patent applications filed by Georgia State University.
ACKNOWLEDGMENT
We thank Luca Arosio, Dr. Roberto Villa, and Professor Ma-
rino Nebuloni for the DSC and DWT safety assessment of
compound 27a. We thank Peijing Jia and Naixin Qian for
their assistance in lipase-catalyzed kinetic resolution of 25. P.
J. and N. Q. were supported by a Li-Yun Summer Under-
graduate Research Scholarship.
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Palladium-Catalyzed Intermolecular Oxidative Diazida-
tion of Alkenes. Chin. J. Chem. 2017, 35, 876; c) Zhou, H.;
Jian, W.; Qian, B.; Ye, C.; Li, D.; Zhou, J.; Bao, H. Copper-
Catalyzed Ligand-Free Diazidation of Olefins with
TMSN3 in CH3CN or in H2O. Org. Lett. 2017, 19, 6120. For
a recent review for olefin azidation, see: d) Wu, K.; Liang,
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Electrocatalytic Approach to the Radical Difunctionaliza-
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(9) For experimental details, see Supporting Information.
(10) (a) Danishefsky, S.; Prisbylla, M. P.; Hiner, S. "The Use of
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(11) For selected example of asymmetric synthesis of chiral
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Ikeda, M.; Sharpless, K. B. "Kinetic Resolution of Racemic
Allylic Alcohols by Enantioselective Epoxidation. A Route
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