An alternative synthesis of Tamiflu: a synthetic challenge and the identification of a ruthenium-catalyzed dihydroxylation route

Article abstract of DOI:10.1016/j.tet.2009.05.077

Synthetic studies of Tamiflu and the identification of a ruthenium-catalyzed dihydroxylation route are disclosed. This newly developed synthetic process circumvents the need for a Mitsunobu inversion step and the use of explosive reagents. This

Full text of DOI:10.1016/j.tet.2009.05.077

Tetrahedron 65 (2009) 6017–6024
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Tetrahedron
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An alternative synthesis of TamifluÒ: a synthetic challenge and the identification
of a ruthenium-catalyzed dihydroxylation route
*
*
Kenzo Yamatsugu, Motomu Kanai , Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0013, Japan
a r t i c l e i n f o
a b s t r a c t
Synthetic studies of TamifluÒ and the identification of a ruthenium-catalyzed dihydroxylation route are
disclosed. This newly developed synthetic process circumvents the need for a Mitsunobu inversion step
and the use of explosive reagents. This route, therefore, compares favorably to the previously developed
synthetic process.
Article history:
Received 7 May 2009
Received in revised form 26 May 2009
Accepted 26 May 2009
Available online 3 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
consuming and costly. In addition, dependence on a single syn-
thetic route for the supply of such an important drug is unwise.
Influenza viruses pose a serious threat to public health world-
wide. In particular, the currently spreading avian H5N1 virus strain
is a serious menace due to its high lethality rate and the rapid spread
of this virus to many countries in Asia, Europe, and Africa. There are
now increasing concerns that this virus might acquire the ability to
spread between humans, leading to a worldwide pandemic. Two of
the drugs currently used to treat influenza patients are TamifluÒ
(1, Fig.1) ((ꢀ)-oseltamivir phosphate)1 and RelenzaÒ (2) (zanamivir),2
both of which inhibit viral neuraminidase. TamifluÒ is an orally
active prodrug, whereas RelenzaÒ has low bioavailability and is
administered by inhalation. Because neuraminidase is a funda-
mental enzyme for the life cycle of general influenza viruses,
neuraminidase inhibitors are considered to be effective against
H5N1 virus types. Neuraminidase inhibitors are currently the only
effective molecular weapons available to protect humans against an
influenza pandemic.
There is, therefore, an urgent demand to develop alternative
practical syntheses of TamifluÒ starting from easily available ma-
terials. Several chemists, including our group, are currently in-
volved in developing alternative synthetic methods for TamifluÒ.4,5
Improving synthetic efficiency remains a challenge and is a major
research focus. We report herein the details of our efforts to im-
prove the synthetic process of TamifluÒ, and the identification of
a ruthenium-catalyzed dihydroxylation route is disclosed.
2. Results and discussion
We previously reported4n the development of a Ba–F2–FujiCAPO
complex-catalyzed asymmetric Diels–Alder-type reaction, and
TamifluÒ was successfully synthesized from the cycloadduct via
a Curtius rearrangement, palladium-catalyzed allylic substitution
reaction, and Mitsunobu reaction as key transformations (Scheme 1).
This synthetic process is easily conducted, and gram-scale synthesis
of TamifluÒ can be performed. There is, however, still room for im-
provement of the synthetic efficiency. One area that can be improved
is the use of two Mitsunobu reactions. One Mitsunobu reaction is for
the inversion of allylic alcohol (9 to 10), and the other is for the
synthesis of aziridine (10 to 11). The Mitsunobu reaction is a well-
established reliable process,6 but it generates a large amount of
waste, namely, phosphine oxide and hydrazine byproducts. It usually
requires tedious column chromatography purification of the tar-
geted product.7 Thus, it is desirable to avoid Mitsunobu reactions for
industry-scale processes. In terms of our synthetic process of Tami-
fluÒ, the most straightforward and promising approach to circum-
vent these steps seems to be the direct introduction of a 3-pentyl
ether moiety via an epoxide opening reaction with 8. Thus, we began
our investigation to establish a more efficient synthetic process from
this intermediate.
Figure 1. Structures of TamifluÒ and RelenzaÒ
.
Currently, TamifluÒ is produced and supplied by Roche using
(ꢀ)-shikimic acid as the starting material.3 Production of (ꢀ)-shi-
kimic acid with a consistent purity, however, is both time-
* Corresponding authors.
E-mail address: mshibasa@mol.f.u-tokyo.ac.jp (M. Shibasaki).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.077

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K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
Scheme 1. Previously established synthetic process of TamifluÒ
.
2.1. Epoxide opening reaction of derivatives of 8
butoxycarbonyl group. Therefore, we produced compound 12, in
which we replaced the acetyl group and tert-butoxycarbonyl group
with the TBS group and methoxycarbonyl group, respectively, and
performed a Lewis acid-catalyzed epoxide opening reaction with
this substrate. No reaction occurred, however, and the starting
material was recovered unchanged (entries 4 and 5). Compound 12
was rather inert, and even acid–base combination conditions
[Sc(OTf)3, Pybox, and amine base or alkoxide base] rendered the
starting material unchanged (data not shown).
We next examined the effect of basic conditions, namely, the
formation of metal alkoxide from 3-pentanol and its use as a nu-
cleophile. Metal, solvent, and temperature were screened, and
eventually treatment of 13 with the sodium alkoxide of 3-pentanol
generated by the reaction of 3-pentanol with NaHMDS in dime-
thylformamide (DMF)/tetrahydrofuran (THF) mixed solvent affor-
ded a relatively clean reaction. The obtained product, however, was
imidate 17 (60%), produced by the addition of the alkoxide to
a cyano group (entry 6).
One concern about the epoxide opening reaction of derivatives of
8 with 3-pentanol is its regioselectivity. Based on reported pre-
cedents and analogy to the reported reactions of 2,3-epoxy alcohol,8
nucleophiles might attack the C1 position via an intramolecular
metal chelate. We expected, however, that the neighboring acet-
oxydicyanomethyl moiety would exhibit steric bias to achieve C6
position-selective attack of the nucleophiles. Thus, we began by
examining the reaction conditions.
Representative results are shown in Table 1. As the first trial, we
performed a Lewis acid-catalyzed epoxide opening reaction with 8
as the substrate. Only decomposition of the substrate, however, was
observed (entries 1–3). Electrospray ionization-mass spectrometric
(ESI-MS) analysis of the reaction mixture suggested that the acid
lability of 8 was due to the acetoxydicyanomethyl moiety and tert-
Because derivatives of 8 are inert under acidic conditions and
labile under basic conditions, we next examined the reaction under
neutral conditions. When we treated 8 with a substoichiometric
amount of Ni(cod)2 (0.5 equiv) and PBu3 (1 equiv) in THF/3-pen-
tanol mixed solvent, expecting an oxidative addition of Niꢁ to the
epoxide group,9 the obtained product was reduced product 18
(40%) (entry 7). This result might have been due to the ability of the
cyano group to direct a soft metal, Niꢁ in this case, leading to an
oxidative addition to the C–OAc bond and subsequent protonation.
The epoxide groups in the derivatives of 8 were inert under acidic,
basic, as well as neutral conditions, and other functionalities within
the molecule reacted faster than the epoxide group. We, therefore,
abandoned the epoxide opening strategy.
Table 1
Epoxide opening reaction with 3-pentanol
Entry
Substrate
Conditions
Results
2.2. Inversive ether formation from derivatives of 9
1
2
3
4
5
6
7
8
8
8
12
12
13
8
Al(OTf)3, CH2Cl2, rt
Yb(OTf)3, CH2Cl2, rt
BF3$OEt2, Toluene, 60 ꢁ
Decomp.
Decomp.
Decomp.
NR
NR
17 (60%)
18 (40%)
C
Another strategy to avoid the Mitsunobu reaction is inversive
ether formation from the derivatives of 9. Several derivatives of 9
with a variety of leaving groups were produced, and we examined
SN2 displacement of the thus-formed leaving groups by nucleo-
philes derived from 3-pentanol.
Al(OTf)3, DCE, 70 ꢁ
Sc(OTf)3, DCE, 70 ꢁ
C
C
NaHMDS, DMF, THF, ꢀ43 ꢁC
Ni(cod)2, PBu3, THF, rt
First, we examined the reactivity of methanesulfonyl ester 19
(Scheme 2). For the synthesis of 19, alcohol 9 was treated under
standard mesylation conditions (MsCl, NEt3), but only a messy re-
action was observed, and ESI-MS analysis of the reaction mixture
indicated that it was caused by the substitution of a meth-
anesulfonyl ester by chloride anions. Therefore, we tried the Tanabe

K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
6019
Scheme 2. Inversive ether formation under basic conditions.
condition (MsCl, N,N,N0,N0-tetramethyl-1,3-propanediamine),10 and
obtained the desired methanesulfonyl ester 19 in 77% yield. The
thus-produced mesylate 19 was then treated with 3-pentanol and
base (NEt3 or Cs2CO3), but no reaction occurred at room tempera-
ture and only decomposition of the substrate was observed at an
elevated temperature. To increase the reactivity of the substrate, we
tried to produce the corresponding trifluoromethanesulfonyl ester
20, but only the decomposition of 20, due to instability of 20, was
observed.
Next, we examined cyclic sulfamidate as an electrophile. Cyclic
sulfamidate is a very strained functional group, and is therefore
well-known as a very good leaving group. Cyclic sulfamidite 21 was
successfully synthesized from alcohol 9 with thionyl diimidazole in
60% yield.11 The oxidation of sulfamidite 21 to sulfamidate under
several conditions [NaIO4 with ruthenium catalyst in the presence
and absence of ligands, CrO3, phenyliodine bis(trifluoroacetate)
(PIFA), OXONEÒ, and H2O2 with a molybdenum catalyst] did not
afford the desired product. When using NaIO4 with a ruthenium
catalyst as the oxidant, sulfamidite was oxidized to sulfamidate, but
overoxidation at the C–C double bond also occurred. Because the
desired cyclic sulfamidate was not produced, we examined the
reaction of the lithium alkoxide of 3-pentanol with cyclic sulfami-
dite 21 as an electrophile. Ketone 22 was obtained in 50% yield,
however, which was probably generated through ester enolate
Scheme 3. Inversive ether formation under acidic conditions and palladium catalysis.
species. Thus, we examined the addition of copper and zinc alkoxide
to an h
3-allyl palladium species that would be generated by the re-
action of cyclic carbamate 24 and a palladium catalyst. When 24 was
treated with palladium acetate (5 mol %), 2-(di-tert-butylphosphi-
no)biphenyl (7.5 mol %), Et2Zn (0.5 equiv), NH4OAc (10 mol %), and
3-pentanol (1 equiv) in THF, however, no reaction occurred. On
the other hand, when 24 was treated with Pd(PPh3)4 (10 mol %),
2-(di-tert-butylphosphino)biphenyl (40 mol %), (CH3CH2)2CHOLi
(2 equiv), and CuOTf (1 equiv) in THF, cleavage of an acetyl
group (ca. 60%) and the formation of dienamide (probably
formation via deprotonation at the
g position of the a,b-un-
through
b
-hydride elimination of the
h
3-allyl palladium species)
3-allyl palla-
saturated ester group by lithium alkoxide and the subsequent re-
lease of sulfur monoxide.
(ca. 40%) were observed. In the latter case, the
h
dium species should be successfully formed, but weak nucleo-
philicity of the copper alkoxide derived from 3-pentanol, perhaps
due to its steric bulkiness, prevented C–O bond formation.
The failure of the above-mentioned strategies under basic con-
ditions led us to examine a cyclic carbamate or an oxazoline derived
from 9 as electrophiles, expecting acid-activation of these func-
tional groups or the formation of an
h
3-allyl palladium species
(Scheme 3). In these studies, compounds 24 and 26 were used as
model substrates.12 When cyclic carbamate 24 was treated with
a variety of Lewis and Brønsted acids [Sc(OTf)3, AgOTf, Mg(OTf)2,
TMSOTf, and Tf2NH] in 3-pentanol, no reaction occurred at room
temperature, and an acetyl group was cleaved at a higher tem-
perature. In the case of oxazoline 26, no reaction proceeded when
using BF3$OEt2 as the Lewis acid. A Reissert-type reaction was also
tried using Tf2O as an activator of the oxazoline group. The use of 3-
pentanol TMS ether in the presence of a Lewis acid [Et2AlCl,
BF3$OEt2, Gd(OTf)3, or TMSOTf] or a Lewis base (CuF, CuI, AgF, or
tetrabutylammonium difluorotriphenylsilicate) afforded only
a messy reaction.
2.3. Non-inversive ether formation from derivatives of 10
In the above-mentioned strategies, 3-pentanol and its alkoxide
were used as nucleophiles. The desired C–O bond formation did not
occur under any of the conditions examined, because of the low
nucleophilicity of 3-pentanol and its alkoxide, which might be due
to the steric bulkiness of 3-pentanol. Therefore, based on these
results, we changed the strategy to utilize the 3-pentanol unit as an
electrophile and a cyclohexenol core as a nucleophile. Although this
strategy required a Mitsunobu inversion step, the second Mitsu-
nobu aziridine synthesis was avoided, so we thought this strategy
was still advantageous.
At first, the trichloroacetimidate of 3-pentanol was examined as
an electrophile because Fang and co-workers used the same
strategy in their report on the synthesis of TamifluÒ (Scheme 4).4h
Their substrate was different from ours only in the functional group
at the C5 position. They used an azide group as the nitrogen
We then examined palladium catalysis to generate an
h
3-allyl
palladium species, which was expected to be trapped by 3-pentanol
or its alkoxide. Alcohols are generally unfavorable nucleophiles to-
ward an
and Kim13b recently reported that copper alkoxide and zinc alkoxide
are good nucleophiles toward
3-allyl rhodium and palladium
h
3-allyl palladium species, but Evans and Leahy13a and Lee
h
functionality, whereas we used a benzylcarbamate group.

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K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
Table 2
Synthesis of aziridine from 7
Entry
Oxidant
Results
1
2
3
4
5
6
7
8
NBA, THF, rt
33 (>90%)
33 (ca. 60%)
Decomp.
33 (ca. 20%)
NR
NR
NR
NR
NBA, KOtBu, THF, rt
NBA, nBuLi, THF, rt
NBA, PBu3, THF, rt
Chloramine-T, I2, CH3CN, 50 ꢁ
C
tBuOCl, NaI, CH3CN, 50 ꢁ
CF3COOAg, Br2, CCl4, rt
PIFA, MgO, DCE, 60 ꢁC
C
Scheme 4. Non-inversive ether formation from derivatives of 10.
Following their procedure, we treated compound 28 with tri-
chloroacetimidate derived from 3-pentanol in the presence of triflic
acid (1.5 equiv in total, portionwise addition) in CH2Cl2. The desired
ether product, however, was obtained in less than 20% yield. Sol-
vent, temperature, amount of reagents, and the use of triflimide
instead of triflic acid were examined, but there was no improve-
ment. The reasons for the poor results are not known, but subtle
structural differences in the substrates seemed to greatly change
their reactivity.
Other electrophiles (bromide and sulfonate esters) were also
examined with model substrate 30. Compound 30 was reacted with
bromide or tosylate derived from 3-pentanol under 3 equiv of a va-
riety of bases (LHMDS in the presence and absence of CuI, NaH, and
KHMDS) in THF at 0 ꢁC. Only decomposition of the starting material
was observed. On the otherhand, no reaction occurred when several
sulfonate esters derived from 3-pentanol (tosylate, o-nosylate, and
8-quinoline sulfonate) were used under acidic conditions (metal
triflate, see Scheme 4) in CH2Cl2 at room temperature, and cleavage
of a Boc group occurred at an elevated temperature, during which
the desired C–O bond formation was never observed. Thus, we
abandoned the notion of non-inversive ether formation from de-
rivatives of 10.
nucleophilic phosphines or phosphoramidites.14 Thus, we exam-
ined the addition of 1 equiv of tributylphosphine, expecting that the
reactivity of a newly formed brominating reagent would differ from
that of NBA, thereby leading to a change in product selectivity (entry
4). Although the reaction was messy, oxazoline 33 was obtained in
approximately 20% yield. We investigated other oxidants such as
chloramine-T (1 equiv) and I2 (1 equiv) (entry 5),15 tBuOCl (1 equiv)
and NaI (1 equiv) (entry 6),16 CF3COOAg (1 equiv) and Br2 (1 equiv)
(entry 7), and PIFA (3 equiv) in the presence of MgO (entry 8), none
of which promoted the reaction.
Compound 7 was successfully converted to an N-chlorinated
compound. That is, when compound 7 was treated with 1.2 equiv of
trichloroisocyanuric acid (TCCA) in 1,2-dichloroethane at room
temperature, N-chlorinated compound 34 was obtained in 58%
yield (Eq. 1).
ð1Þ
This substrate seemed appealing for the synthesis of aziridine
through either homolytic or heterolytic cleavage of the N–Cl bond.
Therefore, we examined the reaction conditions.
2.4. Aziridine synthesis without using a Mitsunobu reaction
We tested the use of 3-pentanol derivatives as both nucleophiles
and electrophiles toconstructa stericallybulky3-pentyl ethermoiety,
but it was unsuccessful. Thus, the only available method to construct
a 3-pentyl ether moiety was via aziridine 11. We therefore examined
the synthesis of aziridine without the use of a Mitsunobu reaction.
Compound 7 was selected as a substrate because oxidation of the
C–C double bond (e.g., formation of a halonium ion) would be fol-
lowed by cyclization of the neighboring acetamide group to form
aziridine (Table 2). When compound 7 was treated with 3 equiv of
N-bromoacetamide (NBA) at room temperature, cyclization oc-
curred. The obtained product, however, was not aziridine 32, but
oxazoline 33 (entry 1). Because solvent screening revealed no spe-
cific solvents with beneficial effects, we examined the effect of
several additives on product selectivity. The addition of 1 equiv of
KOtBu did not change the product selectivity (entry 2), and 1 equiv
of nBuLi resulted in decomposition of the starting material (entry 3).
Recently, Ishihara and co-workers reported enantioselective halo-
cyclization of polyprenoids induced by N-halosuccinimide and
At first, homolytic cleavage of the N–Cl bond followed by trapping
of the thus-formed amidyl radical by the C–C double bond was ex-
amined (Table 3). Although a toluene solution of 34 was heated at
100 ꢁC in the presence of AIBN, no reaction took place (entry 1). When
we heated a mesitylene solution of 34 at 160 ꢁC, 34 was completely
consumed, but the product was 7, which was reduced (entry 2).
Copper chloride was then used as a single electron reductant to fa-
cilitate generation of an amidyl radical.17 Only decomposition of the
starting material, however, was observed (entry 3). In the case of
entry 2, an amidyl radical might have been generated, however,
which did not react with the neighboring C–C double bond, resulting
in H-abstraction, probably from the solvent.
Representative results of our examination of heterolytic cleavage
of the N–Cl bond are summarized inTable 4. Treatment of compound
34 with K2CO3 in EtOH was expected to generate potassium dien-
olate by unmasking the ester-equivalent moiety, followed by
deprotonation at the
a position of the thus-formed ethoxycarbonyl
group, and intramolecular reaction with the N–Cl acetamide group,

K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
6021
Table 3
Synthesis of aziridine through homolytic cleavage of the N–Cl bond
Entry
Conditions
Results
1
2
3
AIBN, toluene, 100 ꢁ
Mesitylene, 160 ꢁC
CuCl, MeOH, 60 ꢁC
C
NR
7
Decomp.
Scheme 5. Synthesis of a-ether 42.
Table 4
Synthesis of aziridine through heterolytic cleavage of the N–Cl bond
Entry
Conditions
Results
1
2
3
K2CO3, EtOH, rt
37 (>80%)
NR
38 (58%)
AgNO3, CH3CN, 80 ꢁ
C
Pd2(dba)3$CHCl3, K2CO3, DMF, 65 ꢁ
C
Scheme 6. Synthesis of pentylidene acetal.
a thermodynamically more stable -ether under basic conditions (via
b
deprotonation at the position of a,b-unsaturated ester) or a transi-
g
tion metal-catalyzed process. Alcohol 40 was converted to pentyli-
dene hemiaminal 41 using 20 equiv of 3-pentanone dimethyl acetal
in the presence of 0.3 equiv of CSA in toluene at 60 ꢁC (Scheme 5). A
reductive opening reaction of the resulting pentylidene hemiaminal
proceeded well using 3 equiv of BH3$SMe2 as the reductant, and
1.1 equiv of TMSOTf and 1.1 equiv of CSA as acids in CH2Cl2 at 0 ꢁC.19
thus leading to the formation of aziridine. The afforded product was
not aziridine 11, however, but 37, which was produced by pro-
tonation of the potassium dienolate at the
g
position (entry 1).18
When 34 was reacted with AgNO3 in CH3CN at 80 ꢁC to activate the
N–Cl bond, there was no reaction (entry 2). We anticipated that
oxidative addition of Pdꢁ to the N–Cl bond and intramolecular aza-
Wacker reaction with a neighboring C–C double bond would lead to
the formation of aziridine, and we therefore treated 34 with
10 mol % of Pd2(dba)3$CHCl3 in the presence of K2CO3 in DMF at
65 ꢁC. The obtained product was compound 38, which was gener-
ated by a reduction of the N–Cl bond and the elimination of HCN
(entry 3). N–Cl Acetamide 34 was rather labile and easily reduced to
the corresponding N–H acetamide under homolytic and heterolytic
cleavage of the N–Cl bond. Thus, we abandoned the notion of N–Cl
acetamide 34 as a precursor of aziridine.
With the
a-ether in hand, we next examined the isomerization of 42
to b-ether 29 under a variety of reaction conditions (Table 5).
Table 5
Isomerization of a-ether 42 to b-ether 29
2.5. Pentylidene acetal (hemiaminal) opening strategy
Entry
Conditions
Results
1
2
3
4
5
6
7
EtONa, EtOH, rt
NR
Decomp.
NR
NR
NR
We tested the use of 3-pentanol derivatives as both nucleophiles
and electrophiles, and the synthesis of aziridine without a Mitsu-
nobu reaction to construct a sterically bulky ether moiety, none of
which was successful. To overcome this difficulty, we tried an in-
direct introduction of a sterically bulky alkyl group in a masked
form, followed by structural modification to construct a 3-pentyl
ether unit, and among the possible tactics, reductive opening of
pentylidene acetal was appealing. Two options were considered,
hemiaminal 41 (Scheme 5) and acetal 45 (Scheme 6) as substrates,
and we started the examination with 41 because it could be pro-
duced from alcohol 40 in a straightforward manner.
NaH, THF, 40 ꢁC
La(OTf)3, Et3N, DCE, rt
TfOH, EtOH, 70 ꢁC
[RhCl(PPh3)3], DABCO, wet-EtOH, 70 ꢁ
C
[RhH(PPh3)4], TFA, EtOH, 70 ꢁ
C
NR
NR
Fe(CO)5, xylene, 130 ꢁ
C
In the first trial, compound 42 was treated with 5 equiv of EtONa
in EtOH, but the starting material remained unchanged (entry 1).
When 5 equiv of sodium hydride was used as a base, decomposition
of the substrate was observed (entry 2). Thus, we examined an
We expected that reductive opening product 42, which would
be produced from hemiaminal 41, would be isomerized to
acid–base combination to activate
increasing the acidity of the protons at the
a
,
b
-unsaturated ester, thereby
g
position. No reaction

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K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
occurred, however, using 0.42 equiv of La(OTf)3 and 0.84 equiv of
Et3N in 1,2-dichloroethane at room temperature (entry 3). We then
examined acidic conditions, but 1 equiv of TfOH afforded no iso-
merized products (entry 4). Because both the basic and acidic
conditions failed, we next tried a transition metal-catalyzed
isomerization of allyl ether. Both rhodium and iron catalysts were
expected covalent bond formation between the carboxylic acid and
Lewis acid to activate the desired counterpart of the oxygen atom.
Carboxylic acid 47 was synthesized from compound 45 in 99% yield
(Et3N$3HF in THF/H2O).
When ester 46 was used as a substrate, the reductive opening
reaction proceeded under almost identical conditions (3 equiv of
BH3$SMe2 in the presence of 1.1 equivof TMSOTf) toafford a reduced
product in 60% yield. Again, however, the product obtained was 52,
and the regiochemistry produced was undesirable (Table 6, entry 6).
On the other hand, when using carboxylic acid 47 as a substrate, the
use of TMSOTf as a Lewis acid afforded a complex reaction mixture
(entry 7). Re-examination of a couple of Lewis acids indicated that
the reaction proceeded with the use of 1.1 equiv of TiCl4 to afford
a reduced product in 40% yield. The obtained product was 53, which
was also an undesired regioisomer (entry 8). The use of Ti(OiPr)2Cl2,
expecting the formation of a covalent bond between titanium and
carboxylic acid, resulted in decomposition of the starting material
(entry 9). Therefore, altering the regioselectivity seemed difficult,
and we abandoned the reductive opening strategy.
examined, but no reaction occurred and the desired b-ether was
not obtained. At this point, we abandoned the isomerization
strategy, and proceeded to the other option, the use of acetal 45.
Acetal 45 was synthesized from compound 43 by a ruthenium-
catalyzed dihydroxylation reaction (Scheme 6). Olefin 43 was
treated with 1.5 equiv of NaIO4 in the presence of 1.5 mol % of RuCl3
catalyst and 20 mol % of H2SO4 cocatalyst at 0 ꢁC to afford
b-cis diol
44.20 In the case of epoxidation (10 equiv of trifluoroacetic anhy-
dride, 20 equiv of urea$H2O2, and 15 equiv of Na2HPO4 in CH2Cl2),
in situ generated trifluoroperacetic acid attacked C–C double bond
from the
tween peracid and acetamide group to afford
and 13). On the other hand, catalytically generated RuO4 attacked
the C–C double bond from sterically less congested face to afford
-cis diol. Diol 44 was converted to pentylidene acetal 45 in 56%
a
face of the molecule through hydrogen bonding be-
a
epoxide (e.g., 8, 12,
b
b
2.6. Identification of a ruthenium-catalyzed dihydroxylation
route
yield (for two steps) with 5 equiv of 3-pentanone dimethyl acetal
and 0.2 equiv of TsOH$H2O. With the desired acetal in hand, we
began to examine the reaction conditions for the reductive opening
of this acetal (Table 6).
Although the strategy for a reductive opening of pentylidene
acetal (hemiaminal) was not fruitful,
intermediate. In our previous work,4n epoxidation of olefin 7 pro-
ceeded from the face, which eventually led to the -alcohol 9 after
unveiling the ester-equivalent moiety (Scheme 1). Therefore, in-
version of the thus-formed -alcohol to -one with a Mitsunobu
reaction (from 9 to 10) was required. In that sense, -cis diol was
b-cis diol 44 was an appealing
Several combinations of reductant and acid were examined using
45 as a substrate (entries 1–5). We found that when using 6 equiv of
BH3$SMe2 in the presence of 1.1 equiv of TMSOTf, a reductive
opening reaction of the pentylidene acetal proceeded (entry 5). The
desired 48 was not obtained but its regioisomer 51 was exclusively
obtained in 50% yield, likely because the neighboring acetamide
group directed the Lewis acid, which led to activation of the un-
desired counterpart of an oxygen atom in the acetal moiety.21
Although the desired regiochemistry was not achieved, we
successfully attained a promising reductive opening reaction that
proceeded well. Therefore, we tried to reverse the regioselectivity
by modifying the structure of the substrate. Expecting coordination
ability and reduced steric bulkiness, we considered ester 46 to be
a promising candidate, which was produced from compound 45 in
quantitative yield (Et3N$3HF in EtOH) (Scheme 6). Furthermore,
carboxylic acid 47 was also an appealing substrate, because we
a
a
a
b
b
quite appealing because we could circumvent the Mitsunobu in-
version step with this substrate. Thus, we examined the synthesis
of b-alcohol 10 from b-cis diol.
Cyclic carbamate 54 was reacted with masked acyl anion
equivalent 5522 using 2 equiv of 55, 2 mol % of Pd2(dba)3$CHCl3, and
8 mol % of dppf to afford olefin 56 in 88% yield (Scheme 7). Com-
pound 56 was converted to b-cis diol 57 via a ruthenium-catalyzed
dihydroxylation reaction.20 Intensive examination of the reaction
conditions indicated that the dihydroxylation reaction best pro-
ceeded with the use of 0.5 mol % of RuCl3, 1.5 equiv of NaIO4, and
0.2 equiv of H2SO4 in an EtOAc/CH3CN/H2O mixed solvent system at
Table 6
Reductive opening of the pentylidene acetal
Entry
Substrate
Reductant
Acid
Temp (ꢁC)
Results
1
2
3
4
5
6
7
8
9
45
45
45
45
45
46
47
47
47
Dibal-H
Et3SiH
d
ꢀ78 to rt
ꢀ20 to 60
ꢀ78 to rt
ꢀ78 to rt
ꢀ20 to rt
ꢀ40 to 0
ꢀ20
No TM
NR
TMSOTf
BF3$OEt2
TiCl4
BH3$SMe2
BH3$SMe2
BH3$SMe2
BH3$SMe2
BH3$SMe2
BH3$SMe2
BH3$SMe2
No TM
No TM
51 (50%)
52 (60%)
No TM
53 (40%)
Decomp.
TMSOTf
TMSOTf
TMSOTf
TiCl4
ꢀ20 to rt
ꢀ20 to rt
Ti(OiPr)2Cl2

K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
6023
500 MHz for 1H NMR and 125.65 MHz for 13C NMR. Chemical shifts
were reported in parts per million on the d scale relative to residual
CHCl3
(d
¼7.24 for 1H NMR and
d
¼77.0 for 13C NMR) as an internal
reference. Optical rotations were measured on a JASCO P-1010
polarimeter. ESI-MS spectra were measured on a Waters-ZQ4000.
FAB mass spectra were measured on a JEOL JMS-BU20 GCmate or
a JEOL JMS-700V. Column chromatography was performed with
silica gel Merck 60 (230–400 mesh ASTM). Reactions were per-
formed in dry solvents under an argon atmosphere, unless other-
wise stated. Dry solvents of THF and dichloromethane (CH2Cl2)
were purchased from KANTO CHEMICAL Co., Inc. 3-Pentanol was
distilled from CaH2 before use. Other reagents were used as re-
ceived from commercial sources, unless otherwise stated.
4.2. tert-Butyl (1S,2S,5S)-2-acetamido-5-((tert-
butyldimethylsilyloxy)dicyanomethyl)cyclohex-3-
enylcarbamate (56)
Scheme 7. Ruthenium-catalyzed dihydroxylation route to b-alcohol 10.
4 ꢁC. In the case of substrates with other protective groups (Ac, Piv,
Bz, or MOM) instead of a TBS group at the ester-equivalent moiety,
the dihydroxylation reaction resulted in a substantially lower yield.
At room temperature, 55 (24.0 ml, 0.135 mmol) was added to
a stirred solution of 54 (20.0 mg, 0.0675 mmol), Pd2(dba)3$CHCl3
(1.4 mg, 0.00135 mmol), and dppf (3.0 mg, 0.00541 mmol) in toluene
(2.00 ml), and the resulting solution was stirred at 60 ꢁC for 60 min.
After cooling the reaction mixture to room temperature, the mixture
was filtered through an SiO2 pad, and the filtrate was concentrated to
afford crude 56, which was purified with preparative TLC (Hexane/
AcOEt¼1/1) to afford 56 (26.6 mg, 0.0592 mmol, 88% yield) as a pale
Then, b-cis diol 57 was transformed to acetonide 58 under standard
conditions (5 equiv of 2,2-dimethoxypropane in the presence of
0.4 equiv of TsOH$H2O in toluene at 55 ꢁC) in 56% yield in two steps.
In the next step, the thus-formed acetonide group functions as
a leaving group. We, therefore, tried to produce a couple of com-
pounds with leaving groups other than acetonide group, such as
yellow amorphous. 1H NMR (CDCl3, 500 MHz)
d 6.31–5.84 (m, 3H),
a
carbonate group (through a
reaction with 1,10-carbon-
4.57 (d, J¼7.9 Hz, 1H), 4.35 (m, 1H), 3.97 (m, 1H), 2.94 (m, 1H), 2.15–
yldiimidazole: decomp.) and a thiocarbonate group (through a re-
action with 1,10-thiocarbonyldiimidazole: y. 46%), but the formation
of acetonide afforded the best results. Acetonide 58 was treated with
1.4 equiv of Et3N$3HF in EtOH at room temperature to unmask the
ester-equivalent moiety, and successive addition of 7.2 equiv of DBU
1.89 (m, 5H), 1.42 (s, 9H), 0.93 (s, 9H), 0.38 (s, 3H), 0.36 (s, 3H); 13C
NMR (CDCl3, 125 MHz)
d 170.4, 155.7, 134.2, 123.5, 114.9, 114.6, 80.1,
67.0, 51.0, 47.1, 45.2, 28.4, 27.2, 25.4, 23.4, 18.3, ꢀ4.5, ꢀ4.5; IR (neat,
cmꢀ1) 3299, 2957, 2932, 2860, 2242, 1698, 1659; ESI-MS: m/z 471.3
[MþNa]þ; FAB-HRMS: m/z calcd for C22H36CsN4O4Si [MþCs]þ:
successfully afforded b-alcohol 10 through b-elimination of acetone
25
581.1555, found: 581.1564. [
a
]
ꢀ10.1 (c 1.15, CHCl3).
D
in 76% yield. As a result, b-alcohol 10, which was the intermediate in
our previous synthesis of TamifluÒ,4n was obtained from cyclic car-
4.3. tert-Butyl (1S,2R,3S,4R,5S)-2-acetamido-5-((tert-
butyldimethylsilyloxy)dicyanomethyl)-3,4-dihydroxy-
cyclohexylcarbamate (57)
bamate 54 without the need of a Mitsunobu inversion step.
3. Conclusion
A 1 M H2SO4 aqueous solution (22.3
added to a stirred suspension of NaIO4 (35.8 mg, 0.167 mmol) in
H2O (86
l). The mixture was cooled down to 4 ꢁC, and 0.1 M RuCl3
(5.6 l, 0.000557 mmol) aqueous solution was added. The mixture
was stirred for 5 min at the same temperature, and AcOEt (341 l)
was added. After stirring for 5 min, CH3CN (341 l) was added, and
the mixture was stirred for an additional 5 min. Then, 56 (50.0 mg,
0.111 mmol) was added, and the resulting mixture was stirred for
80 min at the same temperature. AcOEt, saturated NaHCO3 aqueous
solution, and saturated Na2S2O3 solution were added at the same
temperature, and the mixture was stirred for 10 min at room
temperature. The aqueous layer was extracted with AcOEt three
times, and the combined organic layer was washed with brine,
dried over Na2SO4, and concentrated to afford crude 57 (63.4 mg) as
a pale yellow film, which was used for the next reaction without
further purification.
ml, 0.0223 mmol) was
We examined a number of strategies to construct the sterically
bulky 3-pentyl ether moiety in TamifluÒ in a more efficient manner,
i.e., avoiding Mitsunobu reactions, such as an epoxide opening re-
m
m
action with 3-pentanol, inversive ether formation from
a-alcohol,
m
non-inversive ether formation from -alcohol, synthesis of aziridine
b
m
without a Mitsunobu reaction, and reductive opening of pentyli-
dene acetal (hemiaminal). These synthetic studies eventually led to
the identification of a ruthenium-catalyzed dihydroxylation route
(Scheme 7). Although this established process still requires a single
Mitsunobu reaction for the synthesis of aziridine, the second Mit-
sunobu inversion step was circumvented. Additionally, the ruthe-
nium-catalyzed dihydroxylation reaction requires only 0.5 mol % of
ruthenium catalyst, compared to the rather high amounts of re-
agents (10 equivof TFAA and 20 equiv of urea$H2O2) required for the
epoxidation in the previously developed synthetic route.4n The use
of explosive trifluoroperacetic acid, which is generated in situ, was
also avoided. Thus, the newly established synthetic process is con-
sidered advantageous.
4.4. tert-Butyl (3aS,4R,5S,7S,7aR)-4-acetamido-7-((tert-
butyldimethylsilyloxy)dicyanomethyl)-2,2-dimethyl-
hexahydrobenzo[d][1,3]dioxol-5-ylcarbamate (58)
4. Experimental
4.1. General
2,2-Dimethoxypropane (58.3
(7.2 mg, 0.0379 mmol) were added to a stirred solution of crude 57
ml, 0.474 mmol) and TsOH$H2O
(63.4 mg) in toluene (474 ml) at room temperature, and the resulting
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier
transform infrared spectrophotometer. NMR spectra were recorded
on a JEOL JNM-LA500 or ECX500 spectrometer, operating at
mixture was stirred for 30 min at 50 ꢁC. After cooling the mixture to
room temperature, AcOEt and saturated NaHCO3 aqueous solution
were added. The aqueous layer was extracted with AcOEt three times,

6024
K. Yamatsugu et al. / Tetrahedron 65 (2009) 6017–6024
4. (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310; (b) Fu-
kuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 6312; (c) Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365; (d) Mita, T.;
Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259; (e) Ya-
matsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2007,
48, 1403; (f) Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.; Kann, N.
Chem. Commun. 2007, 3183; (g) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T.
Angew. Chem., Int. Ed. 2007, 46, 5734; (h) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai,
K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J. Am. Chem.
Soc. 2007, 129, 11892; (i) Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.;
Iwagawa, T. Org. Lett. 2008, 10, 815; (j) Trost, B. M.; Zhang, T. Angew. Chem., Int.
Ed. 2008, 47, 3759; (k) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008,
73, 4895; (l) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem., Int. Ed. 2008, 47,
5788; (m) Matveenko, M.; Willis, A. C.; Banwell, M. G. Tetrahedron Lett. 2008,
49, 7018; (n) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2009, 48, 1070; (o) Ishikawa, H.; Suzuki, T.; Hayashi, Y.
Angew. Chem., Int. Ed. 2009, 48, 1304; (p) Mandai, T.; Oshitari, T. Synlett 2009,
783; (q) Oshitari, T.; Mandai, T. Synlett 2009, 787; (r) Satoh, N.; Akiba, T.;
Yokoshima, S.; Fukuyama, T. Tetrahedron 2009, 65, 3239; (s) Nie, L.-D.; Ko, X.-X.;
Ko, K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970; (t) Sullivan, B.; Carrera, I.; Drouin,
M.; Hudlicky, T. Angew. Chem., Int. Ed. 2009, 48, 4229.
and the combined organic layer was washed with brine, dried over
Na2SO4, and concentrated to afford crude 58 (57.1 mg), which was
purified with silica gel column chromatography (SiO2¼2.5 g, hexane/
AcOEt¼1/1 to 1/2) to afford 58 (32.8 mg, 0.0627 mmol, 56% yield for
two steps) as a colorless film. 1H NMR (CDCl3, 500 MHz)
d 5.80
(d, J¼8.1 Hz, 1H), 5.13 (d, J¼8.1 Hz, 1H), 4.29 (dd, J¼7.4, 5.8 Hz, 1H),
4.12–4.05 (m, 2H), 3.70 (m, 1H), 2.60 (m, 1H), 2.02–1.90 (m, 5H), 1.50
(s, 3H), 1.39 (s, 9H), 1.33 (s, 3H), 0.91 (s, 9H), 0.37 (s, 3H), 0.36 (s, 3H);
13C NMR (CDCl3, 125 MHz)
d 171.2, 156.0, 114.6,114.3,110.7, 80.1, 77.4,
73.2, 65.5, 52.8, 48.2, 46.1, 28.4, 27.8, 27.6, 25.7, 25.4, 23.5, 18.3, ꢀ4.5,
ꢀ4.5; IR (neat, cmꢀ1) 3302, 2933, 2860, 2362, 2242, 1696, 1662; ESI-
MS: m/z 545.2 [MþNa]þ; FAB-HRMS: m/z calcd for C25H42CsN4O6Si
23
[MþCs]þ: 655.1923, found: 655.1943. [
a]
þ7.2 (c 1.00, CHCl3).
D
4.5. (3R,4R,5S)-Ethyl 4-acetamido-5-(tert-butoxycarbonyl-
amino)-3-hydroxycyclohex-1-enecarboxylate (10)
5. For reviews, see: (a) Farina, V.; Brown, J. D. Angew. Chem., Int. Ed. 2006, 45,
7330; (b) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
6. Mitsunobu, O. Synthesis 1981, 1.
7. Many modified reagents to facilitate the purification of a targeted product have
been reported. For a review, see: But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2,1340.
8. Hanson, R. M. Chem. Rev. 1991, 91, 437.
9. Oxidative addition of Ni(cod)2 catalyst to an epoxide group was proposed.
Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076.
A 0.67 M solution of 3HF$NEt3 in EtOH (112
added to a stirred solution of 58 (28.1 mg, 0.0538 mmol) in EtOH
(438 l) at room temperature, and the resulting solution was stirred
for 10 min at the same temperature. DBU (57.8 l, 0.387 mmol) was
ml, 0.0750 mmol) was
m
m
then added at room temperature, and the resulting solution was
stirred for an additional 36 h at the same temperature. AcOEt and
saturated NH4Cl aqueous solution were added, and the mixture was
stirred for 10 min at the same temperature. The aqueous layer was
extracted with AcOEt three times, and the combined organic layer
was washed with brine, dried over Na2SO4, and concentrated to af-
ford crude 10 (17.9 mg), which was purified with silica gel column
chromatography (SiO2¼0.40 g, hexane/AcOEt¼1/4 to AcOEt) to af-
ford 10 (14.0 mg, 0.0409 mmol, 76% yield) as a white solid. 1H NMR
10. Yoshida, Y.; Shimonishi, K.; Sakakura, Y.; Okada, S.; Aso, N.; Tanabe, Y. Synthesis
1999, 1633.
11. When using thionyl chloride, dimerization of the substrate predominantly
occurred.
12. In our previous reports,4b,d,e a cyano group was used as an ester equivalent, and
these model substrates were synthesized from intermediates in those reports.
13. (a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882; (b) Kim, H.; Lee, C.
Org. Lett. 2002, 4, 4369.
14. Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
15. Morino, Y.; Hidaka, I.; Oderaotoshi, Y.; Komatsu, M.; Minakata, S. Tetrahedron
2006, 62, 12247.
(CDCl3, 500 MHz)
d
7.31 (d, J¼5.5 Hz, 1H), 6.78 (m, 1H), 4.98 (m, 1H),
16. Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M. Org. Lett. 2006, 8, 3335.
17. Schulte-Wu¨lwer, I. A.; Helaja, J.; Go¨ttlich, R. Synthesis 2003, 1886.
18. Compound 39, which was synthesized by the reaction of a corresponding
acetamide with TCCA, was also examined for the synthesis of aziridine.
Treatment with 2 equiv of KHMDS in THF at ꢀ78 ꢁC or 4 equiv of NaH in THF at
4.83 (d, J¼7.9 Hz,1H), 4.30–4.26 (m,1H), 4.21–4.13 (m, 2H), 3.85–3.77
(m, 1H), 3.74–3.66 (m, 1H), 2.84–2.76 (m, 1H), 2.20–2.12 (m, 1H), 1.99
(s, 3H), 1.44 (s, 9H), 1.26 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
ꢁC afforded the reduced product 37 in good yield.
d
173.8, 166.0, 157.8, 139.2, 127.8, 81.1, 73.8, 61.2, 60.8, 48.2, 31.0, 28.4,
4
23.2, 14.3; IR (neat, cmꢀ1) 3330, 2979, 2933, 1717, 1678; ESI-MS: m/z
365.4 [MþNa]þ; FAB-HRMS: m/z calcd for C16H27N2O6 [MþH]þ:
28
343.1864, found: 343.1877. [
a]
ꢀ11.0 (c 0.91, CHCl3).
D
Acknowledgements
Financial support was provided by a Grand-in-Aid for Specially
Promoted Research of MEXT and Grant-in-Aid for Scientific Re-
search (S) and (B) from JSPS. K.Y. thanks JSPS for the research
fellowships.
References and notes
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