Total synthesis of ezetimibe, a cholesterol absorption inhibitor

Article abstract of DOI:10.1021/jo400807c

Ezetimibe (1), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl) -nitrone (8), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N-O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc(OTf)₃-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule 1.

Full text of DOI:10.1021/jo400807c

Article
pubs.acs.org/joc
Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor
́
Marcin Sniezek, Sebastian Stecko, Irma Panfil, Bartłomiej Furman, and Marek Chmielewski*
̇
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: Ezetimibe (1), a strong β-lactamic cholesterol
absorption inhibitor, was synthesized from (R)-6-(4-fluoro-
phenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways
were analyzed in order to select the optimal one, which
involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphen-
yl)-N-(4-fluorophenyl)-nitrone (8), intramolecular nucleo-
philic displacement at the benzylic position of the lactone,
cleavage of the N−O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-
membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective
Sc(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the
cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final
molecule 1.
component had the wrong configuration of both azetidinone
stereogenic centers (Scheme 2).
INTRODUCTION
■
Ezetimibe (1) is a strong β-lactamic cholesterol absorption
inhibitor that reduces plasma low-density lipoprotein fraction
(LDL-C).1−4 It contains three para-substituted phenyl rings, a
chiral benzylic hydroxyl, and two additional stereogenic centers
at the 2-azetidinone scaffold. The three chiral centers give rise
to eight stereoisomers that have been individually characterized
and shown to exhibit significantly different CAI profiles.4 The
stereocontrol of the azetidinone stereocenters (3R,4S) and the
installation of the benzylic hydroxyl with absolute (3′S)
stereochemistry are the most significant synthetic challenges.
Annual worldwide sales of ZETIA for 2010 were $2.3 billion
and $2.0 billion for VYTORIN, which puts ezetimibe high on
the list of valuable drugs and an interesting synthetic target for
many academic and industrial laboratories.3
Most of the known methods for the synthesis of 1 assume
separate formation of stereogenic centers associated with a β-
lactam ring via chiral auxiliary mediated diastereoselective
cyclocondensation between diaryl imine 2 and an ester or
amide enolate and formation of the center in the side chain via
enantioselective reduction of the phenone carbonyl group
(Scheme 1).2−10 Bearing in mind possible industrial
applications, the use of a chiral auxiliary is a serious drawback.
Strategies starting from a nonracemic substrate with complete
atom economy are rare.11−14
There has been one controversial patent report on the direct
formation of ezetimibe via cyclocondensation between p-
benzyloxybenzylidene-p-fluoroaniline 3 and lactone 4.12−14 The
authors, however, have not discussed the stereochemical
pathway of the reaction and did not provide any proof of the
structure or diastereomeric purity of the desired product.12−14
We repeated the reported procedure and found that an
inseparable mixture of two diastereomers 5 and 6 in a ratio of
about 55:45 was obtained in 45% yield. Both products were
trans substituted in the four-membered ring, but the main
Recently, we described a novel approach for the stereo-
controlled formation of ezetimibes’ core β-lactam via the
copper(I)-catalyzed reaction of C-(4-benzyloxyphenyl)-N-(4-
fluorophenyl)nitrone and L-glyceraldehyde acetonide derived
acetylene (Kinugasa reaction).8 Asymmetric induction was
quite good, and moreover two main diastereomeric products
can be used for further steps without separation. Subsequently,
the obtained β-lactamic derivative was transformed in a three-
step sequence into the aldehyde derivative used by Schering-
Plough in their method for the synthesis of ezetimibe.11 Our
synthesis of 1 had, however, the same drawback as all other
reported approaches to ezetimibe: it required the separate
formation of the chiral centers around the β-lactam ring and the
stereogenic center in the side chain.
RESULTS AND DISCUSSION
■
Seeking a more useful method of ezetimibe synthesis, we
revisited our work performed 25 years ago.15 At that time,
before the invention of ezetimibe, we investigated 1,3-dipolar
cycloaddition reactions of α,β-unsaturated sugar lactones with
diaryl nitrones.15 The reactions were performed in boiling
toluene to show, in the case of D-glycero and D-threo lactones,
the exclusive anti addition to the terminal acetoxymethyl group
in the lactone to afford anti-exo and anti-endo adducts with
prevalence of thermodynamic products endo. At that time, using
the known Tufariello approach,16 we have demonstrated the
transformation of adducts into N,4-diaryl β-lactams.15b,c These
studies prompted us to reuse this methodology for the
synthesis of ezetimibe 1.
Received: April 24, 2013
© XXXX American Chemical Society
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Scheme 1. General Strategy for Synthesis of Ezetimibe 1
Scheme 2. Synthesis of 1 via Cyclocondensation between Imine 3 and Lactone 412−14
a
Scheme 3. Possible Synthetic Pathway to Ezetimibe 1 from Lactone 7 and Nitrone 8
a
Ar1 = 4-benzyloxyphenyl, Ar2 = 4-fluorophenyl.
a
Scheme 4. Synthesis of Lactone 7
a
Reagents and conditions: (a) 1 mol % (R,R)-Cr(salen), MTBE, −30°C, yield 97%, 85% ee; (b) NaBH4, CeCl3·7H2O, MeOH/CH2Cl2; (c) MoO3,
30% H2O2, MeCN; (d) Ac2O, Py, yield 52% (2 steps); Ar = 4-fluorophenyl.
The assumed synthetic strategy is presented in Scheme 3.
For this purpose the 1,3-dipolar cycloaddition reactions of
lactones 7/ent-7 to nitrone 8, which has been used for synthesis
of 1 via the Kinugasa reaction,8 were considered as a key step.
Both lactones contain all of the structural elements
corresponding to ezetimibes’ side chain and offer an excellent
atom economy of the synthesis. By varing the reaction
conditions, attractive starting materials suitable for synthesis
of 1 should be provided.
On the basis of our previous experience in cycloaddtions to
sugar-derived lactones, we expected that the reaction should
proceed exclusively anti to the substituent at the lactone
moiety, and therefore the endo addition to (S)-lactone (ent-7)
under thermal conditions should provide the correct
configuration in the side chain and at the stereogenic center
B
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Scheme 5. 1,3-Dipolar Cycloaddition Reaction between Lactone 7 and Nitrone 8 under Thermal and Catalytic Conditions
a
Scheme 6. Three Strategies for Transformation of Isoxazolidine 9 into Ezetimibe 1
a
Ar1 = 4-hydroxyphenyl, Ar2 = 4-benzyloxyphenyl, and Ar3 = 4-fluorophenyl.
next to the nitrogen atom (Scheme 3). On the other hand, the
exo addition to (R)-lactone (7) through kinetic control should
provide the correct configuration at the stereogenic centers that
constitute the geometry of the β-lactam fragment (Scheme 3).
In the first case, the stereogenic center next to the carbonyl
group could be epimerized after formation of the β-lactam ring,
whereas in the second case, the stereogenic center in the side
chain should be inverted at a later step of the synthesis.
Although there are several possible methods17−22 that can be
adopted for synthesis of lactone 7, none of them provided
satisfactory yield or enantioselectivity. The most promising,
direct formation of lactone 7 via condensation of silyl enol of
ethyl crotonate with 4-fluorobenzaldehyde in the presence of
(R)-TolBINAP/Cu(OTf)2 complex, according to Campagne et
al.,22 gave good ee of 84%, but very low yield of 10%.
We found a four-step procedure involving cyclocondensation
between Danishefsky’s diene and 4-fluorobenzaldehyde in the
presence of the Jacobsen’s catalyst to be the most convenient to
provide adduct 10 in 97% yield and 85% ee (Scheme 4).23
Application of modified Jacobsen’s catalyst raised the ee to 91%
but caused a lower yield of 66%.24 Subsequent reduction of the
carbonyl group to glycal 11, followed by the oxidative Ferrier
rearrangement, provided hydroperoxide 12, which in the
presence of an acetic anhydride/pyridine mixture yielded
lactone 7 with 98% ee after crystallization.25 The assignment
of an absolute configuration was done on the basis of the report
by Jacobsen et al.23
The 1,3-dipolar cycloaddition reaction of lactone 7 and
nitrone 8 in boiling toluene led to the exo cycloadduct 9 along
with its endo isomer 13 in ratio 53:47 and yield 41% after 16 h
(Scheme 5). The further extension of the reaction time to 72 h
increased the content of endo adduct to 70% while the reaction
yield decreased to 37%. Such a result indicated the reversibility
of the cycloaddition reaction, which had been observed earlier
for the 2(5H)-furanone derivatives.26 The experiment showed
also that under thermal conditions neither pure endo adduct
(synthesis of 1 from ent-7) nor pure exo (synthesis of 1 from 7)
can be obtained.
Since the endo adduct was always accompanied by the exo
one, we decided to impel the reaction between lactone 7 and
nitrone 8 to promote formation of the kinetic product 9 by
performing it in the presence of a Lewis acid promoter.
Very recently, we demonstrated that Sc(OTf)3 was a highly
efficient Lewis acid catalyst of the cycloaddition reaction
between C,N-diarylnitrones and sugar-derived α,β-unsaturated
lactones.27 In the presence of scandium salt, lactone 7 with
nitrone 8 provided almost exclusively product 9 (dr 97:3) in
85% yield (Scheme 5). Additionally, purification of 9 did not
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Scheme 7. Synthesis of Aminolactone 17
Scheme 8. Synthesis of 20 through Mitsunobu and Rearrangement Sequence
Scheme 9. Synthesis of 20 via Rearrangement/Mitsunobu Sequence
require any chromatography, and simple crystallization was
sufficient. Moreover, when enantiomerically enriched lactone 7
(85% ee) was subjected to cycloaddition, product 9 with 97%
ee, after crystallization, was obtained.
purification. Due to the presence of the secondary amine
moiety and the double β-substituted carbonyl group, well-
known Barton−McCombie reaction, utilized to remove the free
hydroxyl group in compound 14, was not successful, causing β-
elimination of the amino group 15. The other possibility was to
use β-elimination of a water molecule to afford 16 followed by
reduction of the double bond to afford saturated lactone 17.
Silylation of the hydroxyl group in 14 under standard
conditions followed by treatment with DBU provided the
desired unsaturated lactone 16 in good yield (76%). The
structure of 16 was proved by X-ray analysis (see Supporting
Information).
We expected that reduction of the double bond in 16 with
hydrides, owing to the carbanion intermediate, should afford
thermodynamic product 17 having both substituents of the
lactone located trans diequatorial. Indeed, the best result was
obtained for L-Selectride reduction (1.1 equiv) to provide 17 in
68% yield. The desired product was accompanied, however,
with lactol 18, requiring chromatographical separation. Atempts
to eliminate the unwanted subsequent lactone reduction failed.
However, it was found that temperature during the reduction of
16 must be maintained below −65 °C; otherwise lactol 18,
along with unreacted substrate, would be the only product of
the reaction. Unfortunately, reoxidation of 18 to lactone 17
provided a complicated mixture of products and brought about
reduction of the lactone double bond.
With isoxazolidine 9 in hand, its transformations into
ezetimibe 1 was investigated. As mentioned above, the choice
of (R)-lactone (7) for cycloaddition reaction resulted in the
formation of product 9 with the correct absolute configuration
of two carbon atoms of the isoxazolidine ring that
corresponded to the stereogenic centers of the target β-lactam.
The incorrect absolute configuration at the benzylic position of
lactone 7 was inverted in later steps of the synthesis. Three
routes were considered for the transformation of 9 into target
azetidinone 1 (Scheme 6).
The paths differed in the order of their individual steps
involving N−O bond cleavage, deoxygenation, base-mediated
rearrangement of the six-membered lactone ring into the β-
lactam moiety, and inversion of the configuration at the
benzylic position.
Since compound 9 is highly prone to degradation under
hydrogenation in the presence of Pd/C due to the presence of
multiple benzylic positions, N−O bond cleavage cannot be
done by conventional catalytic reductive methods.28 To
overcome this problem, a protocol reported by Kundig et
̈
al.29 was applied, and isoxazolidine 9 was treated with TMSCl
and KI in wet MeCN (Scheme 7). The corresponding
aminolactone 14 was obtained in 88% yield after extractive
workup and was suitable for use in the next step without further
Next, epimerization of the stereogenic center at the benzylic
position in 17 was made via intramolecular Mitsunobu reaction
D
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(Scheme 8). Opening of the lactone moiety in 17 with LiOH
followed by neutralization to a free carboxylic group and
subsequent treatment with Ph3P and DIAD at 0 °C afforded a
mixture of expected 19 in 62% and substrate 17 in a ratio of
about 3:1, respectively. Chromatographical separation of 19
followed by rearrangement of the δ-lactone ring into a β-lactam
moiety in the presence of t-BuMgCl gave benzyl protected
ezetimibe (20) in 80% yield.
The last two steps could be performed also in reverse order.
Such an approach eliminates the disadvantage related to
selectivity of the intramolecular Mitsunobu reaction by using
the intermolecular procedure, which requires one preparative
step more. Accordingly lactone 17 was transformed into
azetidinone 21, which was subjected to the Mitsunobu reaction
with p-nitrobenzoic acid to afford benzoate 22. Deprotection of
22 gave 20 in 66% overall yield (2 steps, Scheme 9).
Finally, hydrogenolysis of benzyl protected phenolic hydroxyl
in 20 afforded ezetimibe 1 (Scheme 10).
(24:9 dr 9:1). Moreover, the decrease of the reaction
temperature to −10 °C led to further improvement of the
yield (94%) and diasteroselectivity (24:9 dr 97:3). Initially,
product 24 was isolated and purified by chromatography.
However, during scale-up experiments it was found that 24
could be easily isolated by fractional crystallization from i-
PrOH in 63−71% yield. Additionally, the crystallization allowed
enhancement of the enantiomeric excess of product 24 from
85% ee (the crude compound) to 98% ee, in the case when
substrate 9 with 85% ee was used. The correct absolute
configuration of the lactone moiety of 24 was confirmed by X-
ray analysis (see Supporting Information).
The N−O bond cleavage in 24 was performed as above using
TMSCl and KI in wet MeCN to afford aminolactone 25 in 88%
yield, which was suitable for the next step without further
purification.
Due to a conformational equilibrium of the lactone, location
of elements of silanol, probably close to diequatorial, made the
E2-type elimination process difficult in 25. As a solution we
explored elimination using Burgess reagent 27,30 which
proceeded through E1-type elimination. Treatment of 25
with reagent 27 in toluene at 90 °C provided desired
unsaturated lactone 28 in good yield (76%). Hydrogenation
of the double bond in 28, performed over PtO2, proceeded
exclusively anti to the aryl substituent of the lactone to provide
compound 19 (83%, 98% ee) with three stereogenic centers
having absolute configurations identical to those in ezetimibe 1.
Rearrangement of the six-membered ring into the 2-
azetidinone was made, as before, using t-BuMgCl according
to the standard procedure15b and led to product 20 in 80% after
extractive workup. The same reaction can also be performed in
the presence of LDA or KHMDS.
It should be pointed out that stereoselectivity of hydro-
genation of the double bond in 16 and 28 played a secondary
role. This was because rearrangement of the six-membered
lactone ring into the 2-azetidinone one in the presence of LDA
or KHMDS causes epimerization at the stereogenic center next
to the carbonyl group to provide, in both cases, exclusively trans
substituted β-lactams (see Scheme 11).
The final product, ezetimibe (1), was obtained by the known
debenzylation protocol to provide the product with a very high
optical and chemical purity. The structure of the obtained
target molecule was confirmed by X-ray analysis (see
Supporting Information). The overall yield of 1 was 20%, in
8 steps starting from lactone 7.
In our opinion, the last presented route is the optimal
pathway for the synthesis ezetimibe 1. In contrast to known
syntheses, it did not require chiral auxiliaries for asymmetric
induction. In our method, efficient asymmetric induction was
provided by the structure of the obtained product through
hetero-Diels−Alder reaction, which was the single enantiodif-
ferentiation step for the entire synthetic strategy. All other steps
in which formation of new stereocenters or isomerization of
existing ones occur were fully controlled by substrate structure
Scheme 10. Synthesis of Ezetimibe 1
It was also found that it was possible to effect hydrogenation
of the double bond in 16 over PtO2 to afford a diastereomer of
17 (23), which in the presence of LDA underwent rearrange-
ment to β-lactam and simultaneously epimerization at the α-
position to the carbonyl group to provide azetidinone 21
(Scheme 11).
Since routes 1 and 2 (Schemes 7−9) suffer from serious
drawbacks such as lack of control during reduction of 16
leading to unwanted lactol 18 and low efficiency of
epimerization of 17 into 19 via intramolecular Mitsunobu
reaction, and bearing in mind possible industrial applications,
the third synthetic strategy toward 1 was considered.
Therefore, the crucial epimerization at the side-chain
benzylic position was performed at the beginning of the
synthesis just after the cycloaddition step (Scheme 12). In
contrast to previous attempts, at the stage of isoxazolidine 9 an
intramolecular Mitsunobu reaction to epimerize the stereogenic
center at the benzylic position should be the most efficient,
since both side chains taking part in the nucleophilic
substitution were attached syn to the five-membered hetero-
cyclic ring, which should facilitate the displacement.
Indeed, an opening of the lactone moiety in 9 with LiOH
followed by neutralization to a free carboxylic function and
subsequent treatment with Ph3P and DIAD at 0 °C afforded
compound 24 in high yield (80%) and diastereomeric purity
Scheme 11. Synthesis of 21 via Hydrogenolysis/Rearrangement/Epimerization Sequence
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a
Scheme 12. Synthesis of Ezetimibe 1
a
Ar1 = 4-hydroxyphenyl, Ar2 = 4-benzyloxyphenyl, and Ar3 = 4-fluorophenyl.
68.71, H 4.69, F 9.83. GC: InertCap CHIRAMIX 160 °C: racemic
sample rac-10: 32.1 min (S), 33.2 min (R). Assignment was done on
the basis of Jacobsen et al. works.23 Racemic was obtained by reaction
of 4-fluorobenzaldehyde with Danishefsky’s diene in the presence of
Yb(OTf)3. Real sample of 10 (86% ee): 31.8 min (7%, S), 32.4 min
(93%, R). Real sample of 10 after crystallization (91% ee): 32.1 min
(4.6%, S), 32.4 min (95.4%, R).
and were completely stereoselective. Additionally the presented
reaction sequence did not require chromatographical purifica-
tion of intermediates but only crystallization at certain steps.
Finally, all reactions were performed in an optimal temperature
range (mostly at room temperature). These two features are
essential when industrial applications of the described synthesis
are taken into consideration.
(2R)-2-(4-Fluorophenyl)-3,4-dihydro-2H-pyran-4-ol (11). To
a mixture of CeCl3·7H2O (80.74 g, 216.7 mmol) in MeOH (700 mL)
was added 10 (38 g, 197.9 mmol) in CH2Cl2 (700 mL). After cooling
to −20 °C, NaBH4 (8.29 g, 216.7 mmol) was added in portions. After
30 min, reaction was quenched by addition of satd NH4Cl (150 mL).
The reaction mixture was adjusted to room temperature and extracted
with CH2Cl2 (300 mL). After drying over MgSO4 and removal of a
solvent, the crude 11 was used in the next step without further
purification. Analytical sample: 91% ee; [α]20D +60 (c 1.0, AcOEt); 1H
NMR (500 MHz, CDCl3) δ 7.38−7.32 (2H, m), 7.09−7.03 (2H, m),
6.52−6.50 (2H, m), 4,97 (1H, dd, J 11.9, 2.1 Hz), 4.87 (1H, dt, J 6.2,
2.1 Hz), 4.65−4.58 (1H, m), 2.39−2,33 (1H, m), 2.00−1.92 (1H, m);
13C NMR (125 MHz, CDCl3) δ 163.4 and 161.5 (d, JC−F 246.2 Hz),
145.2, 136.1, and 136.1 (d, JC−F 2.9 Hz), 127.8 and 127.7 (d, JC−F 7.8
Hz), 115.5 and 115.3 (d, JC−F 21.4 Hz), 105.8, 76.2, 63.4, 40.0; HRMS
(EI, TOF) m/z calcd for C11H11FO2 [M] 194.0742, found 194.0748.
IR (film) v 3369, 1642, 1607, 1514 cm−1. Anal. Calcd for C11H11FO2:
C 68.03, H 5.71, F 9.78. Found: C 68.15, H 5.52, F 9.87.
(R)-6-(4-Fluorophenyl)-5,6-dihydro-2H-pyran-2-one (7). To a
suspension of 11 (37.8 g, 195 mmol) in 30% H2O2 (400 mL) was
added MoO3 (5.57, 39 mmol) in MeCN (400 mL). After 24 h the
reaction mixture was diluted with water (600 mL) and extracted with
CH2Cl2 (3 × 500 mL). The combined organic phases were washed
with water (5 × 200 mL, to negative result of peroxides test) and dried
over anhydrous Na2SO4. Then, to a solution of crude hydroperoxide
12 in CH2Cl2 was added pyridine dropwise (70 mL) followed by
addition of Ac2O (73 mL), and the mixsture was stirred at room
temperature. After 2 h the reaction mixture was poured into a water/
ice mixture, and the organic phase was separated. The organic phase
was washed with aq Na2SO3 (15 g in 50 mL of H2O), 5% aq HCl (200
mL), 5% aq NaHCO3, water (2 × 150 mL), and finally brine (250
mL). After drying over anhydrous Na2SO4 and removal of solvent,
crude lactone 7 (86% ee) was obtained as a slightly brown solid. It was
dissolved in hot MTBE (50 mL), and heptane (500 mL) was added.
The precipitate was filtered off, washed with heptane, and dried in
vacuum to afford lactone 7 as a white solid (19.46 g, 52%, 98% ee). An
analytical sample was obtained by chromatography on silica gel
(hexane/AcOEt 6:4 v/v). Mp 59−60 °C; [α]20D +220 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.42−7.36 (2H, m), 7.11−7.05 (2H,
m), 7.00−6.94 (1H, m), 6.15 (1H, ddd, J 9.7, 2.4, 1.2 Hz), 5.43 (1H,
dd, J 11.4, 4.9), 2.70−2.56 (2H, m); 13C NMR (125 MHz, CDCl3) δ
163.8 and 161.8 (d, JC−F 263.8 Hz), 163.7 144.7, 134.3, and 134.2 (d,
CONCLUSION
■
We demonstrated a simple, efficient, and stereocontrolled
synthesis of ezetimibe (1) in which, owing to the rigid
transition state of 1,3-dipolar cycloaddition, the absolute
configuration of the starting lactone controls the formation of
other stereogenic centers of the final molecule. In the optimal
reaction sequence epimerization at the benzylic position
proceeded effectively at the stage of isoxazolidine via a simple
opening and closing of the lactone ring, without any additional
protection/deprotection steps. Bearing in mind possible
industrial applications, it should be emphasized that purification
of intermediates did not require chromatography, and only
crystallization at certain steps was sufficient.
EXPERIMENTAL SECTION
■
(R)-2-(4-Fluorophenyl)-2H-pyran-4(3H)-one (10). Molecular
sieves (4 Å, 60 g) were added to a solution of 1.36 g (1% mmol) of
[(R,R)-salen-Cr]BF4 in MTBE (50 mL), the mixture was cooled to
−30 °C, and 4-fluorobenzaldehyde (18.56 g, 200 mmol) was added.
Next, Danishefsky’s diene (37.84 g, 220 mmol) was added slowly.
After 24 h a solution of CF3COOH (10 mL) in 250 mL of CH2Cl2
was added, and the mixture was warmed to room temperature.
Molecular sieves were filtered off, and water (10 mL) was added to the
residue. After 5 h of stirring, the organic phase was washed with 5% aq
NaHCO3 (100 mL) and dried over anhydrous MgSO4. A removal of
solvent provided crude product 10 as a yellowish oil (39.91 g 19.4
mmol, 97%, 86% ee (GC)), which was used in the next step. An
analytical sample was obtained by chromatography on silica gel
(hexanes/AcOEt 4:1 v/v). [α]20 −83 (c 1.1, DCM, ee 91%); H
1
D
NMR (500 MHz, CDCl3) δ 7.47 (1 H, dd, J 6.0, 0.8 Hz), 7.42−7.37
(2H, m), 7.14−7.08 (2H, m), 5.53 (1H, dd, J 6.0, 1.3 Hz), 5.41 (1H,
dd, J 14.4, 3.5 Hz), 2.89 (1H, dd, J 16.8, 14.4 Hz), 2.65 (1H, ddd, J
16.8, 3.5, 1.3 Hz); 13C NMR (125 MHz, CDCl3) δ 191.8, 163.9, and
161.9 (d, JC−F 246.6 Hz), 163.0, 133.7, 133.7 (d, JC−F 3.5 Hz), 128.1
and 127.9 (d, JC−F 8.8 Hz), 115.9 and 115.7 (d, JC−F 22.6 Hz), 107.5,
80.4, 43.3; HRMS (EI, TOF) m/z calcd for C11H9FO2 [M·+]
192.0586, found 192.0583; IR (film) v 3073, 1677, 1606, 1594, 1514
cm−1. Anal. Calcd for C11H9FO2: C 68.75, H 4.72, F 9.89. Found: C
F
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JC−F 3.4 Hz), 128.0 and 127.9 (d, JC−F 7.9 Hz), 121.7, 115.7, and 115.5
(d, JC−F 21.0 Hz), 78.6, 31.7; HRMS (EI, TOF) m/z calcd for
C11H9FO2 [M] 192.0587, found 192.0584; IR (film) v 3071, 1731,
1605, 1511 cm−1. Anal. Calcd for C11H9FO2: C 68.75, H 4.72, F 9.89.
Found: C 68.69, H 4.74, F 9.84. HPLC: Chiralpak OD-H hexane/i-
PrOH (96:4 v/v), flow 1.0 mL/min, UV 207 nm:. Racemic sample rac-
7: 37.2.2 min (R), 39.4 min (S). Real sample of 7 (85% ee): 35.6.0 min
(91%, R-isomer), 39.8 min (9%, S-isomer). Real sample of 7 after
crystallization (96% ee): 37.7 min (98%, R-isomer), 39.6 (2%, S-
isomer).
(3R,3aS,6R,7aS)-3-(4-(Benzyloxy)phenyl)-2,6-bis(4-fluoro-
phenyl)tetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one (13).
Not isolated in pure form; H NMR (600 MHz, CDCl3) δ 7.43−
1
7.32 (10H, m), 7.24−6.88 (7H, m), 5.76 (1H, dd, J 11.4, 1.8 Hz), 5.06
(2H, dd, J 11.9, 1.4 Hz), 5.04 (2H, s), 4.89−4.87 (1H, m), 4.34 (1H,
d, J 7.6 Hz), 3.61 (1H, t, J 7.6 Hz), 2.42 (1H, dt, J 15.2, 2.4 Hz), 2.21−
2.15 (1H, m); 13C NMR (150 MHz, CDCl3) δ 169.3, 163.6, and 161.9
(d, JC−F 246.4 Hz), 160.6, 159.1, 159.1, 143.8, 136.7, 134.1, and 134.0
(d, JC−F3.5 Hz), 129.8, 128.8, and 128.6 (d, JC−F 25.4 Hz), 128.0,
127.9, 127.8, 127.5, 120.7, 120.6, 115.8, 115.7, 115.5, 115.4, and 115.3
(d, JC−F 16.2 Hz), 75.9, 74.5, 71.9, 70.6, 56.3, 33.9; HRMS (ESI, TOF)
m/z calcd for C31H25F2NO4Na [M + Na]+ 536.1644, found 536.1650;
IR (film) v 1729 cm−1; HPLC: Chiralpak AD-H hexane/i-PrOH
(50:50 v/v), flow 0.4 mL/min, UV = 231 nm. Racemic sample rac-13:
56.1 min (ent-13) and 82.5 min (13).
Synthesis of C-(4-Benzyloxyphenyl)-N-(4-fluorophenyl)-
nitrone (8). Step 1: To a solution of 4-hydroxybenzaldehyde (122
g, 1 mol) in 600 mL of THF was added benzyl chloride (146 mL, 1.4
mol). Next, K2CO3 (240 g, 1.75 mol) and KI (49.5 g, 300 mmol) were
added. The suspension was refluxed for 20 h. Next, the mixture was
cooled to ambient temperature, and the solid was filtered off and
washed with 100 mL of THF. The solvent was removed under
diminished pressure. The crude product was crystallized from 700 mL
of EtOH to afford 145.3 g of aldehyde. A second crystallization
Cycloaddtion between Nitrone 8 and Lactone 7 under
Catalytic Conditions. A mixture of Sc(OTf)3 (180 mg, 0.37 mmol)
and MS 4 Å (1.46 g) in dry PhMe (28 mL) was stirred for 30 min at
room temperature. Then, solid lactone 7 (0.70 g, 3.66 mmol) and solid
nitrone 8 (1.86 g, 5.48 mmol) were added, and reaction mixture was
kept at 30 °C for 72 h. Molecular sieves were filtered off, and solvent
was removed under diminished pressure. The residue was chromato-
graphed to afford isoxazolidine 9 (dr 97:3, yield 90%, 98.5% ee) was
obtained.
Cycloaddtion between Nitrone 8 and Lactone 7 under
Catalytic Conditions: Scale-up. The mixture of Sc(OTf)3 (3.48 g, 7
mmol) and MS 4 Å (28 g) in PhMe (300 mL) was stirred for 30 min
at room temperature. Then, solid lactone 7 (13.6 g, 70.8 mmol, 85%
ee) and solid nitrone 8 (34.2 g, 106.3 mmol) was added and reaction
mixture was kept at 30 °C for 72 h. Molecular sieves were filtered off
and resulting organic solution was washed with water (250 mL) and
dried (MgSO4). After removal of solvent crude isoxazolidine 9 (39 g,
dr 97:3, yield 85%, 85% ee) was obtained. Crude 9 was used in the
next step without further purification.
(3S,4S,6R,1′S)-[(4-Benzyloxyphenyl)-(4-fluorophenylamino)-
methyl]-6-(4-fluorophenyl)-4-hydroxy-tetrahydro-2H-pyran-2-
one (14). To a mixture of the isoxazolidine 9 (1.00 g, 1.94 mmol) and
KI (0.97 g, 5.85 mmol) in 20 mL of wet acetonitrile at room
temperature was added TMSCl (0.83 mL, 5.85 mmol). After 35 min,
10 mL of saturated aq Na2SO4 was added, and then the product was
extracted with ethyl acetate. After drying of the resulting organic
extracts (MgSO4), the solvent was removed under reduced pressure.
The residue was chromatographed on silica gel (hexane/ethyl acetate
9:1 to 1:1) to provide 0.89 g (1.72 mmol, yield 88%) of aminolactone
14 as a pale yellow solid. Mp 63−65 °C; [α]D +8,8 (c 1.0, MeOH); 1H
NMR (600 MHz, CDCl3) δ 7.40−7.27 (9H, m), 7,08−6.69 (8H, m),
5.81 (1H, dd, J 11.1, 3.6 Hz), 5.42−5,13 (1H, bs), 5,00 (2H, s), 4.72
(1H, d, J 2.4 Hz), 4.63−4.62 (1H, m), 2.37 (1H, dt, J 14.3, 4.0 Hz,)
2.07−2.00 (1H, m); 13C NMR (150 MHz, CDCl3) δ 170.8, 163.4,
161.8, 158.2, 156.6, 141.7, 136.8, 135.1, 131.9, 128.6, 128.3, 128,0,
127.7, 127.6, 127.5, 117.7, 117.6, 115.9, 115.8, 115.7, 115.5, 114.8,
78.3, 70.1, 70.0, 60.5, 53.1, 39.1; HRMS (ESI, TOF) m/z calcd for
C31H27F2NO4Na [M + Na]+ 538.1800, found 538.1810; IR (film) v
3374, 1727, 1609, 1511 cm−1.
1
provided additional 23 g of 4-benzyloxybenzaldehyde. H NMR (400
MHz, CDCl3) δ 5.14 (s, 2 H), 7.07 (d, J 8.50, 2 H), 7.42 (m, 5H), 7.83
(d, J 8.4, 2 H), 9.87 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 190.4,
163.4, 135.7, 131.7, 129.8, 128.4, 127.4, 114.9, 69.9; MS (EI, TOF) m/
z 212 [M+]; IR (KBr) ν 2849, 2745, 1686, 1600, 1509, 1260,
1165,1019 cm−1. Step 2: Zinc dust (39 g, 600 mmol) was added
portionwise to the suspension of p-fluoronitrobenzene (300 mmol,
31.8 mL) in a solution of NH4Cl (390 mmol, 20.9 g) in water (600
mL) at 60 °C. When the last portion of zinc was added, the reaction
mixture was stirred for an additional 15 min. After filtration of zinc
oxide, the residue was saturated with sodium chloride and cooled to 0
°C. After 30 min a yellow precipitate was filtered off, washed with
cooled water, and dried in vacuo. The crude 4-fluorophenylhydroxyl-
amine was used directly in the next step. Step 3: To the solution of
crude 4-fluorophenylhydroxylamine (38.0 g, 300 mmol) in acetone
(300 mL) were added p-benzyloxybenzaldehyde (63.7 g, 300 mmol)
and MsOH (12 droplets) at room temperature. After 2 h the
precipitate was filtered off, washed with acetone (3 × 100 mL, and
dried in vacuo to afford 57.6 g (60%) of nitrone 8 as a white solid. Mp:
193−195 °C (acetone); 1H NMR (500 MHz, DMSO-d6) δ 8.49−8.47
(m, 2H), 8.42 (s, 1H), 7.99−7.95 (m, 2H), 7.50−7.45 (m, 2H), 7.44−
7.32 (m, 5H), 7.13 (d, J 5.0 Hz, 2H), 5.20 (s, 2H); 13C NMR (125
MHz, DMSO-d6) δ 162.2 (d, JC−F 245.6 Hz), 159.9, 144.8 (d, JCF 2.4
Hz), 136.6, 133.0, 130.9, 128.4, 127.9, 127.8, 124.1, 123.6 (d, JC−F 9.3
Hz), 115.7 (d, JCF 22.9 Hz), 114.7, 69.4; HRMS (ESI, TOF) m/z calcd
for C20H16NO2FNa [M + Na]+ 344.1057, found 344.1055. Anal. Calcd
for C20H16FNO2: C, 74.75; H, 5.02; F, 5.91; N, 4.36, found: C, 74.76;
H, 5.08; F, 6.03; N, 4.40.
Cycloaddtion between Nitrone 8 and Lactone 7 under
Thermal Conditions. A solution of nitrone 8 (321 mg, 1 mmol) and
lactone 7 (192 mg, 1 mmol, 98% ee) in toluene (10 mL) was refluxed
for 72 h. After cooling to room temperature and removal of solvent,
the residue was chromatographed on silica gel (30% AcOEt in hexane)
to afford 130 mg of 13 and 60 mg of 9 and (ratio 69:31 overall yield
37%).
O-[(4S,6R)-3-(4-Benzyloxybenzylidene)-6-(4-fluorophenyl)-
tetrahydro-2H-pyran-2-on-4-yl]-1H-imidazol-1-carbotiol, E/Z
Mixture (15). A solution of 14 (513 mg, 1 mmol) and of TCDI
(178 mg, 1 mmol) was refluxed for 4 h. After cooling, solvent was
removed under diminished pressure. The residue was chromato-
graphed on silica gel (hexane/ethyl acetate 7:3) to afford 159 mg (0.3
mmol, yield 30%) of 15 (E/Z mixture) as a pale yellow solid. 1H NMR
(600 MHz, CDCl3) δ 8.09 (0.4 × H, s) 8.08 (0.6 × H, s), 7.70−7.65
(2H, m), 7.45−7.30 (8H, m), 7.08−7.00 (6H, m), 5.83 (1H, m), 5.11
(2H, s), 5.04 (1H, m), 2.15−2.13 (1H, m), 2.07−2.11 (1H, m); 13C
NMR (150 MHz, CDCl3) δ 166.1, 164.6, 161.7, 160.8, 147.5, 147.4,
136.2, 135.1, 132.9, 128.7, 128.3, 128.0, 127.9, 127.8, 127.7, 127.5,
126.4, 123.2, 116.6, 116.5, 115.6, 115.5, 115.4, 75.1, 75.0, 70.1, 62.9,
39.1; IR (KBr) ν 3456, 1693, 1598, 1509, 1172 cm−1.
(3S,3aS,6R,7aS)-3-(4-(Benzyloxy)phenyl)-2,6-bis(4-fluoro-
phenyl)tetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one (9).
Mp: 64−66 °C; 98.5% ee; [α]20 −96 (c 1, MeOH); 1H NMR
D
(600 MHz, CDCl3) δ 7.52−7.49 (2H, m), 7.41−7.30 (5H, m), 7.14−
6.97 (10H, m), 5.42 (1H, d, J 9.1 Hz), 5.06 (2H, dd, J 11.9, 1.4 Hz),
5.04 (2H, s), 4,81 (1H, ddd, J 9.1, 3.8, 1.4 Hz), 3.95 (1H, t, J 9.1 Hz),
2.30−2.27 (1H, m) 2.10−2.05 (1H, m); 13C NMR (150 MHz,
CDCl3) δ 168.0, 163.5, and 161.9 (d, JC−F 246 Hz), 159.8 and 158.2
(d, JC−F 242 Hz), 158.7, 145.1, 145.0, 136.7, 133.9, and 133.8 (d, JC−F
2.9 Hz), 128.7, 128.6, and 128.6 (d, JC−F 15.5 Hz), 128.0, 127.9, 127.5,
116.6, 116.5, 116.0, and 115.9 (d, JC−F 22.5 Hz), 115.7 and 115.5 (d,
JC−F 21.1 Hz), 114.9, 75.7, 73.5, 71.5, 70.0, 53.2, 34.4; HRMS (ESI,
TOF) m/z calcd for C31H25F2NO4Na [M + Na]+ 536.1644, found
536.1656. Anal. Calcd for C31H25F2NO4: C 72.50, H 4.91, F 7.40, N
2.73. Found: C 72.74, H 4.93, F 7.61, N 2.51; IR (film) v 3033, 1729,
1609, 1513, 1501 cm−1.
(1′R,6R)-3-[(4-Benzyloxyphenyl)-(4-fluorophenylamino)-
methyl]-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one (16).
A solution of amicolactone 14 (420 mg, 0.82 mmol) and imidazol
G
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(114.8 mg, 1.64 mmol) in CH2Cl2 (20 mL) was treated with TMSCl
(295 μL, 2.05 mmol). After 30 min the solid was filtred off, and DBU
(245 μL, 1.64 mmol) was added. After 15 min the reaction mixture
was portioned between water (10 mL) and CH2Cl2 (50 mL). The
aqueous phase was additionally washed with CH2Cl2 (30 mL). The
combined organic phases were dried over anhydrous MgSO4. After
removal of drying agent, MeOH (100 mL) was added, and solvents
were removed under diminished pressure (350 mbar, 55 °C).
Remaining methanolic solution was slowly cooled to an ambient
temperature, and the precipitate was collected after 5 h. Yield of 16,
298 mg (0.60 mmol, 73%) as a colorless crystals. Mp 170−172 °C
(MeOH); [α]D −60.3 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ
7.43−7.31 (9H, m), 7.08−6.79 (8H, m), 6.51−6.47 (2H, m), 5.29
(1H, dd, J 12.1, 3.9 Hz), 5.05 (2H, s), 2.73−2.66 (1H, m) 2.67−2.58
(1H, m); 13C NMR (150 MHz, CDCl3) δ 164.0, 163.7, 161.7, 158.7,
138.5, 136.8, 134.1, 134.0, 132.7, 128.8, 128.6, 128.1, 128.0, 127.5,
115.8, 115.7, 115.6, 115.5, 115.2, 78.2, 70.1, 57.9, 31.9; HRMS (ESI,
TOF) m/z calcd for C31H25F2NO3Na [M + Na]+ 520.1695, found
520.1710; IR (film) v 3395, 1714, 1609, 1509 cm−1.
163.3, and 161.7 (d, JC−F 250 Hz), 158.3, 157.0, and 155.4 (d, JC−F 237
Hz), 143.2, 136.8, 134.7, 134.6, 132.6, 128.6, 128.5, 128.0, 127.6, and
127.5 (d, JC−F 13.8 Hz), 127.5, 116.1, 116.0, 115.7, 115.63, and 115.48
(d, JC−F 22.8 Hz), 115.60 and 115.45 (d, JC−F 21.5 Hz), 115.3, 115.2,
114.9, 79.5, 70.1, 58.8, 45.1, 29.3, 20.8. HRMS (ESI, TOF) m/z calcd
for C31H25F2NO3Na [M + Na]+ 522.1851, found 522.1864; IR (film) v
3349, 1610, 1512 cm−1. Anal. Calcd for C31H27F2NO3: C 74.53, H
5.45, N 2.80, F 7.61. Found: C 74.42, H 5.51, N 2.76, F 7.54.
Method 2. PtO2 (109 mg) was added to the solution of the lactone
28 (4.80 g, 9.65 mmol) in toluene (100 mL), and the resulting
suspension was saturated with hydrogen for 24 h. A filtration through
Celite and removal of solvent under diminished pressure provided
lactone 19 (4.29 g, 89%) as white solid.
(3R,4S,3′R)-1-(4-Fluorophenyl)-4-(4-hydroxyphenyl)-3-[3′-
(4-fluorophenyl)-3′-hydroxy-propyl]-azetidin-2-one (21).
Method 1. To a cooled (0 °C) solution of the lactone 17 (100 mg,
0.2 mmol) in 8 mL of dry diethyl ether was added 100 μL (0.4 mmol)
of a 2 M solution of t-BuMgCl in Et2O. After 15 min 3 mL of aq
NH4Cl was added. The aqueous layer was extracted with ether (10
mL), then the organic layer was dried (MgSO4), and the solvent was
removed under reduced pressure. The residue was chromatographed
on silica gel (hexane/ethyl acetate 7:3) to afford 81 mg (0,16 mmol,
yield 80%) of 21 as a white solid. Mp 129−132 °C [α]D +10.8 (c 1.1,
CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.42−7.20 (11H, m), 7.02−
6.90 (6H, m), 5.04 (2H, s), 4.72−4.68 (1H, m) 4.55 (1H, d J 2.2 Hz),
4.55 (1H, dt J 7.1, 2.2 Hz) 2.05−1.93 (3H, m) 1.89−1.82 (2H, m);
13C NMR (125 MHz, CDCl3) δ 167.6, 163.0, 161.4, 159.8, 159.0,
(1′S,3R,6R)-3-[(4-Benzyloxyphenyl)-(4-fluorophenylamino)-
methyl]-6-(4-fluorophenyl)-tetrahydro-2H-pyran-2-one (17). A
solution of the lactone 16 (480 mg, 0.96 mmol) in dry THF (100 mL)
was cooled to −78 °C, and then 0.96 mL (0.96 mmol) of L-Selectride
was slowly added. After 2 h the reaction was quenched by addition of
aq NH4Cl (10 mL). Then, the mixture was adjusted to room
temperature and alkalized (to pH about 8) with aq NaHCO3. After
extraction with ethyl acetate (2 × 30 mL), the organic layer was dried
over anhydrous MgSO4. After removal of solvent, the residue was
chromatographed on silica gel (hexane/ethyl acetate 8:2) to afford 328
mg of 17 (0.66 mmol, yield 68%, white solid) and 52 mg (11%) of
lactol 18 and unreacted 16 (47 mg, 9%). Compound 17: mp 51−53
158.1, 140.0, 139.9, 136.6, 133.9, 129.6, 128.6, 128,1, 127.5, 127.4,
127.4, 127.2, 118.4, 118.3, 115.8, 115.7, 115.5, 115.4, 115.3, 73.3, 70,1,
61,1, 60.3, 36.5, 25,0; HRMS (ESI, TOF) m/z calcd for
C31H27F2NO3Na [M + Na]+; 522.1851, found 522.1870; IR (KBr) v
3441, 1743, 1609, 1510 cm−1.
1
°C; [α]D +30 (c 1.0, MeOH); H NMR (600 MHz, C6D6) δ 7.25−
7,18 (4H, m), 7.19−6.68 (13H, m), 6.46−6.43 (2H, m), 4.88 (1H, d, J
5.3 Hz) 4.63 (2H, s), 4.40−4.37 (1H, m), 1.32−1,17 (4H, m) 1.09−
1.03 (1H, m); 13C NMR (150 MHz, CDCl3) δ 170.2, 163.3, 161.7,
158.6, 137.0, 135.7, 128.8, 128.3, 115.7, 115.5, 115.5, 115.1, 114.9,
96.1, 80.8, 69.7, 59.5, 46,1, 30.6, 22,1; HRMS (ESI, TOF) m/z calcd
for C31H27F2NO3Na [M + Na+] 522.1851, found 522.1878; IR (film) v
3349, 1610, 1512 cm−1. Compound 18 (mixture): 1H NMR (600
MHz, CDCl3) δ 7.43−7.26 (10H, m), 7.21−7.16 (3H, m), 7.01−6.98
(3H, m), 6.94−6.90 (3H, m), 6.80−6.75 (3H, m), 6.55−6.52 (1H, m),
6.46−6.42 (2H, m), 5.03−4.98 (4.5 × H, m), 4.81 (0.6 × H, d, J 8.1
Hz), 4.42−4.36 (1.5 × H, m), 4.22 (0.4 × H, d, J 8.1 Hz), 2.15−2.04
(2H, m), 1.89−1.84 (1.4 × H, m), 1.77−1.72 (0.4 × H, m), 1.62−1.44
(4H, m); 13C NMR (150 MHz, CDCl3), δ 162.9, 161.3, 158.2, 157.9,
138.2, 136.9, 136.8, 128.6, 128.6, 128.5, 128.0, 127.9, 127.7, 127.6,
127.6, 127.5, 127.4, 116.6, 115.6, 115.5, 115.2, 115.0, 114.9, 114.8,
110.3, 92.8, 77.4, 70.3, 70.1, 70.0, 46.5, 45.6, 34.1, 33.2, 25.7, 22.6; MS
(ESI, TOF) m/z 524.2 [M + Na]+, 540.1 [M + K]+.
(1′S,3R,6S)-3-[(4-Benzyloxyphenyl)-(4-fluorophenylamino)-
methyl]-6-(4-fluorophenyl)-tetrahydro-2H-pyran-2-ol (19).
Method 1. To a solution of the lactone 17 (100 mg, 0.2 mmol) in
5 mL of THF were added LiOH (6 mg, 0.22 mmol) and 0.5 mL of
water. After 18 h, the solvent was evaporated, and 3 mL of 5% aq HCl
was added. Next, the mixture was neutralized with NaHCO3 solution
and extracted with CH2Cl2 (3 × 10 mL). After drying of the organic
layer with anhydrous Na2SO4 and removal of the solvent, the residue
(80 mg of a yellowish solid) was dissolved in 10 mL of THF. Next, 50
mg (0.19 mmol) of Ph3P was added. The reaction mixture was cooled
to 0 °C, and then 40 μL (0.19 mmol) of DIAD was added. After 3 h,
the solvent was removed, water was added to the obtained residue, and
the mixture was extracted with CH2Cl2 (3 × 15 mL). Then, the
organic layer was dried (MgSO4), solvent was removed, and the
residue was chromatographed on silica gel (hexane/ethyl acetate 7:3)
to afford 74 mg (62%, white solid) of 19 and 20 mg of 17 (19/17 ratio
3.7:1). Compound 19: mp 52−54 °C; [α]20D −8.6 (c 1.3, CHCl3); 1H
NMR (600 MHz, CDCl3) δ 7.41−7.28 (8H, m), 7.19−6.68 (6H, m),
6.55−6.52 (2H, m), 5.31 (1H, dd, J 10.0, 3.6 Hz) 5.02 (2H, s), 4.66
(1H, d, J 6.5 Hz), 3.10−3.06 (1H, m), 2.10−2.03 (1H, m), 1.99−1.90
(1H, m), 1.89−1.78 (2H, m); 13C NMR (125 MHz, CDCl3) δ 172.8,
Method 2. A solution of the lactone 23 (350 mg, 0.7 mmol) and
DMPU (4 mL) in 10 mL of dry THF mL was cooled to −50 °C, and 1
mL of a 0.7 M solution of LDA in THF was added. After 15 min
solution was warmed to −20 °C. After 3 h aq NH4Cl (5 mL) was
added. The aqueous layer was extracted with ether (60 mL). Organic
phase was washed with satd NaHCO3 (50 mL) and dried (MgSO4),
and the solvent was removed under diminished pressure. The residue
was chromatographed on silica gel (hexanes/AcOEt 7:3) to afford 213
mg (61%) of 21.
(3S,6RL)-3-(S)-(4-Benzyloxyphenyl)-(4-fluorophenyl)amino-
methyl-6-(4-fluorophenyl)-tetrahydro-2H-piran-2-one (23).
PtO2 (2 mg, 5 mol %) was added to the solution of the lactone 16
(100 mg, 0.2 mmol) in toluene (5 mL), and the resulting suspension
was saturated with hydrogen for 24 h. A filtration through Celite and
removal of solvent under diminished pressure provided lactone 23 (79
mg, 79%) as white solid. An analytical sample was obtained by
chromatography on silica gel (hexane/AcOEt 4:1). Mp 65 °C; [α]D
+14.3 (c 0.6, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.41−7.28 (8H,
m), 7.19−6.65 (6H, m), 6.65 (2H, bs), 5.39 (1H, dd, J 7.3, 4.4 Hz),
5.02 (2H, s), 4.61 (1H, d, J 3.7 Hz), 3.40 (1H, bs), 2.13−2.08 (1H,
m), 1.99−1.90 (1H, m), 1.81−1.70 (3H, m); 13C NMR (150 MHz,
CDCl3) δ 172.8, 158.7, 136.7, 134.7, 129.4, 128.6, 128.1, 127.5, 127.3,
127.2, 115.8, 115.6, 115.5, 115.3, 115.0, 79.7, 70.1, 44.5, 30.9, 29.6,
19.8; HRMS (EI, TOF) m/z calcd for C31H27F2NO3 [M] 499.1959,
found 499.1938; IR (film) v 3384, 1609, 1510 cm−1.
(3S,3aS,6S,7aS)-3-(4-(Benzyloxy)phenyl)-2,6-bis(4-fluoro-
phenyl)tetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one (24).
To a solution of isoxazolidine 9 (150 mg, 0.29 mmol) in 5 mL
THF were added LiOH·H2O (7 mg, 0.30 mmol) and 0.5 mL of water.
After 18 h, the solvent was removed, 3 mL of 5% aq HCl was added,
and then the mixture was neutralized with aq NaHCO3. Subsequently,
the mixture was extracted with methylene chloride (3 × 10 mL). The
combined organic solutions were dried (Na2SO4). Removal of solvent
provided 114 mg of pale yellow solid, which was dissolved in 10 mL of
THF. Then 56 mg (0.21 mmol) of PPh3 was added, and the obtained
mixture was cooled to 0 °C. Next, 45 μL (0.21 mmol) of DIAD was
added. After 3 h, the solvent was removed, water was added to the
obtained residue, and the mixture was extracted three times with
H
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CH2Cl2. After drying (MgSO4), solvent was removed, and the residue
was chromatographed on silica gel (hexane/AcOEt 7:3) to provide 94
mg (0.18 mmol, 62%) of isoxazolidine 24 as a white solid; mp 152−
154 °C; [α]20D −111 (c 1.84, CHCl3); 1H NMR (600 MHz, CDCl3) δ
7.52−7.49 (2H, m), 7.41−7.30 (5H, m), 7.14−6.97 (10H, m), 5.23
(1H, d, J 8.2 Hz), 5.09 (2H, dd, J 12.6, 2.1 Hz), 5.06 (2H, s), 4.81
(1H, m), 3.80 (1H, dt, J 9.6, 8.4 Hz), 2.37 (1H, ddd, J 13.9, 6.2, 2.1
Hz) 1.97−1.90 (1H, m); 13C NMR (150 MHz, CDCl3) δ 168.4, 163.6,
and 161.9 (d, JC−F 248 Hz),159.9 and 158.3 (d, JC−F 245 Hz), 158.5,
146.3, 146.3, 136.8, 133.9, and 133.8 (d, JC−F 3.5 Hz), 129.5, 128.9,
128.6, 128.0, and 127.9 (d, JC−F 8.7 Hz), 127.5, 116.9, 116.8, 115.8,
and 115.66 (d, JC−F 22.6 Hz), 115.72 and 115.6 (d, JC−F 21.9 Hz),
114.7, 77.5, 73.2, 71.5, 70.0, 50.5, 35.7; HRMS (ESI, TOF) m/z calcd
for C31H25F2NO4Na [M + Na]+ 536.1644, found 536.1631. Anal.
Calcd for C31H25F2NO4: C 72.50, H 4.91, F 7.40, N 2.73. Found: C
72.01, H 5.00, F 7.36, N 2.63.
Large Scale Synthesis of 24. Crude 9 (39 g, 57 mmol, 85% ee)
was dissolved in 400 mL of THF and treated with LiOH·H2O (4.9 g,
117 mmol) and water (10 mL). After 18 h solvent was removed. The
residue was treated with 5% aq HCl (30 mL), extracted with 300 mL
AcOEt, and washed with water (20 mL with 200 mg NaHCO3). The
combined organic phases were dried over anhydrous Na2SO4. After
removal of AcOEt, the residue was dissolved in 500 mL of THF, PPh3
was added (18.34 g, 70 mmol), and the mixture was cooled to −10 °C.
Then, DIAD (14.15 g, 70 mmol) was added slowly. After 3 h, 500 mL
of wet i-PrOH was added, and THF was removed under diminished
pressure (550 mbar) at 55 °C. The obtained mixture was left for 16 h
at room temperature. The precipitation was collected, washed with
cold i-PrOH (10 °C, ∼100 mL), and dried to afford 19.39 g of
isoxazolidine 24 (62%, >99% ee, dr 98:2) as a off-white solid.
(3S,4S,6S)-3-((S)-(4-(Benzyloxy)phenyl)(4-fluorophenyl-
amino)methyl)-6-(4-fluorophenyl)-4-hydroxytetrahydro-2H-
pyran-2-one (26). To the mixture of the isoxazolidine 24 (13.0 g,
25.3 mmol) and KI (12.6 g, 75.9 mmol) in 200 mL of acetonitrile at
room temperature were added TMSCl (10.9 mL, 75.9 mmol) and
water (1 mL). After 35 min, 50 mL of saturated aq Na2SO4 was added,
and then the product was extracted with AcOEt. After drying of
resulting organic extracts (MgSO4), the solvent was removed under
reduced pressure to afford amino alcohol 25 as a pale yellow solid
and 115.5 (d, JC−F 21.9 Hz), 115.2, 115.0, 114.7, 114.6, 78.1, 70.1,
58.4, 31.5, 26.9; HRMS (EI, TOF) m/z calcd for C31H25F2NO3 [M]
497.1803, found 497.1824; IR (film) v 3383, 1714, 1608, 1509 cm−1.
Anal. Calcd for C31H25F2NO3: C 74.84, H 5.06, N 2.82, F 7.64. Found:
C 74.93, H 5.11, N 2.78, F 7.61.
(3S,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-
(4-fluorophenyl)-3′-hydroxypropyl)azetidin-2-one (20). Meth-
od 1. To a cooled (0 °C) solution of lactone 19 (2.0 g, 4 mmol) in
160 mL of dry diethyl ether was added 12 mL of 1 M solution of t-
BuMgCl in diethyl ether. After 2 h, 30 mL of aq NH4Cl was added.
The aqueous layer was extracted with ether (160 mL), the organic
layer was washed with satd NaHCO3 (50 mL) and dried (MgSO4),
and the solvent was removed under reduced pressure. Crude product
20 (1.64 g, 82%) obtained as a yellowish solid was used in the next
step without further purification. An analytic sample was obtained by
chromatography on silica gel (hexanes/ethyl acetate 7:3). Mp 130−
133 °C [lit.11 132−134 °C]; [α]20 −42.2 (c 1.2, CHCl3); H NMR
1
D
(600 MHz, CDCl3) δ 7.42−7.20 (11H, m), 7.02−6.90 (6H, m), 5,04
(2H, s), 4.72−4.68 (1H, m), 4.55 (1H, d J 2.2 Hz), 3.07 (1H, dt J 7.1,
2.2 Hz), 2.05−1.93 (3H, m) 1.89−1.82 (2H, m); 13C NMR (150
MHz, CDCl3) δ 167.6, 163.0, and 161.4 (d, JC−F 244.2 Hz), 159.8 and
158.1 (d, JC−F 241.8 Hz), 159.0, 140.0, 139.9, 136.6, 133.9, and 133.8
(d, JC−F 2.9 Hz), 129.6, 128.6, 128.1, 127.5, 127.4 and 127.4, (d, JC−F
8.0 Hz), 127.2, 118.4, 118.3, 115.8, 115.8, and 115.7 (d, JC−F 22.0 Hz),
115.5, 115.4, and 115.3 (d, JC−F 21.3 Hz), 73.3, 70.1, 61.1, 60.3, 36.5,
25.0; HRMS (ESI, TOF) m/z calcd for C31H27F2NO3Na [M + Na]+
522.1851, found 522.1862; IR (KBr) v 3441, 1743, 1609, 1510 cm−1.
Anal. Calcd for C31H27F2NO3: C 74.53, H 5.45, N 2.80, F 7.61. Found:
C 74.40, H 5.53, N 2.74, F 7.56.
Method 2. PPh3 (58 mg, 0.22 mmol) was added to a cooled (0 °C)
solution of 2-azetidionone 21 (100 mg, 0.2 mmol) and p-nitrobenzoic
acid (37 mg, 0.22 mmol) in 10 mL of THF. Next, DIAD (40 μL, 0.22
mmol) was added. After 3 h solvent was removed, and the residue was
chromatographed (hexane to hexane/ethyl acetate 8:2) to afford 101
mg (0.16 mmol, yield 78%) of 22 as a low-melting white solid. [α]20
D
+8.6 (c 0.49, CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.29−8.17 (4H,
m) 7.43−7.31 (7H, m), 7.23−7.19 (4H, m), 7.05−7.01 (2H, m),
6.98−6.88 (4H, m), 5.96 (1H, t J 6.9 Hz), 5.04 (2H, s), 4.54 (1H, d J
2.3 Hz), 3.10 (1H, dt, J 7.7, 2.3 Hz), 2.25−2.19 (2H, m); 1.98−1.86
(2H, m); 13C NMR (150 MHz, CDCl3) δ 166.8, 163.6, 159.1, 150.6,
136.6, 135.3, 133.7, 130.7, 129.4, 128.6, 128.4, 128.3, 128.1, 127.4,
127.1, 123.6, 118.4, 118.3, 115.9, 115.8, 115.7, 115.7, 115.6, 76.6, 70.1,
60.9, 59.9, 33.5, 24.9; HRMS (ESI, TOF) m/z calcd for
C38H30F2N2O6Na [M + Na]+ 671.1964, found 671.1976; IR (KBr) v
1747, 1725, 1608, 1528, 1509, 1270. To a solution of 22 (20 mg, 0.03
mmol) in 4 mL of MeOH was added 5 mg of K2CO3. After 30 min, 30
mL of EtOAc was added and 20 mL of water. Organic layer was
separated and dried over MgSO4. After removal of solvent the residue
was chromatographed on silica gel (hexanes/AcOEt 6:4) to afford 13
mg of 20 (84%).
(11.46 g, 88%), which was used in the next step without further
1
purification. Mp 69 °C; [α]20 −23.6 (c 1.5, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.42−7.29 (9H, m), 7.09−7.03 (2H, m), 6.95−6.72
(6H, m), 5.18 (1H, dd, J 11.9, 4.7 Hz), 5.00 (2H, s), 4.86 (1H, d J 3.0
Hz), 4.80−4.73 (1H, m), 3.17 (1H, bs), 2.68−2.59 (1H, m) 2.11−2.02
(1H, m); 13C NMR (125 MHz, CDCl3) δ 171.2, 163.8, and 161.8 (d,
JC−F 246.1 Hz), 158.4, 136.8, 133.7, and 133.6 (d, JC−F 3.0 Hz), 128.7,
128.6, 128.3, 128.2, and 128.0 (d, JC−F 23.8 Hz), 127.5, 118.1, 115.9,
and 115.77 (d, J 22.1 Hz), 115.78 and 115.6 (d, JC−F 21.6 Hz), 115.1,
115.0, 70.0, 68.9, 60.1, 50.9, 40.6; HRMS (ESI, TOF) m/z calcd for
C31H27F2NO4Na [M + Na]+ 538.1800, found 538.1810; IR (film) v
3374, 1727, 1609, 1511, 1454, 1230 cm−1. Anal. Calcd for
C31H27F2NO4: C 72.22, H 5.28, F 7.37, N 2.72. Found: C 72.30, H
5.22, N 2.70, F 7.34.
Ezetimibe (1). 2-Azetidinone 20 (1.64 g, 3.3 mmol) was dissolved
in a mixture of AcOEt/MeOH (1:1, 100 mL), and 20 mg of 10% Pd/
C was added. The mixture was saturated with hydrogen for 18 h. After
filtration through Celite and silica, solvent was removed. Crude 1 was
dissolved in hot MTBE (10 mL), and hexane (3 mL) was added.
Collected solid was dissolved in hot methanol (10 mL), and water (1
mL) was added to provide (after drying) ezetimibe 1 (1.08 g, 80%) as
(6S)-3-((R)-(4-(Benzyloxy)phenyl)(4-fluorophenylamino)-
methyl)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one (28).
To a solution of 26 (11.46 g, 22.2 mmol) in dry PhMe (100 mL)
was added Burgess reagent 27 (5.81 g, 24.4 mmol), and the mixture
was kept at 90 °C for 18 h. After the mixture cooled to room
temperature, water (100 mL) was added and extracted with AcOEt (2
× 200 mL). After drying over MgSO4, organic solution was reduced to
20% of starting volume and filtered through silica gel pad, which was
subsequently washed with Et2O. Removal of solvent provided
a white solid. Mp 164−166 °C [lit.11 155−157 °C]; 99% ee; [α]20
D
−28.1 (c 0.15, MeOH) [lit.11 −32.6 (c 0.34, MeOH)]; 1H NMR (600
MHz, DMSO-d6) δ 9.49 (1H, s), 7.28−7.24 (2H, m), 7.19−7.16 (4H,
m), 7.11−7.07 (4H, m), 6.75−6.71 (2H, m), 5.25 (1H, d, J 4.3 Hz),
4.77 (1H, d, J 2.2 Hz), 4.49−4.59 (1H, m), 3.07−3.04 (1H, m) 1.84−
1.66 (4H, m); 13C NMR (150 MHz, CDCl3) δ 167.8, 162.3, and 160.7
(d, JC−F 240.3 Hz), 159.3, 157.9, 157.7, 142.5, 134.4, 128.7, 128.3,
128.0, 127.9, 118.7, and 118.6 (d, JC−F 8.1 Hz), 116.3, 116.2, 115.2,
and 115.0 (d, JC−F 20.7 Hz), 71.5, 60.0, 59.9, 36.8, 24.9; HRMS (EI,
TOF) m/z calcd for C24H21F2NO3 [M] 409.1489 found 409.1478.
Anal. Calcd for C24H21F2NO3: C 70.41, H 5.17, F 9.28, N 3.42. Found:
C 70.46, H 5.23, F 9.24, N 3.34.
unsaturated lactone 28 (8.16 g, 76%) as an off-white solid. Mp 61
1
°C; [α]20 +40.8 (c 0.49, CHCl3); H NMR (600 MHz, CDCl3) δ
D
7.44−7.27 (11H, m), 7.05−6.84 (7H, m), 6.55−6.50 (2H, m), 5.44−
5.38 (1H, m), 5.30 (1H, s), 5.04 (2H, s), 2.70−2.67 (2H, m); 13C
NMR (150 MHz, CDCl3) δ 163.9, 163.5, and 161.8 (d, JC−F 246 Hz),
158.4, 156.9, and 155.4 (d, JC−F 235 Hz), 142.8, 139.6, 136.9, 134.2,
and 134.1 (d, JC−F 3.5 Hz), 133.4, 132.4, 132.4, 128.8, 128.6, 128.4,
128.0, 127.9, 129.8, 127.5, 115.8, and 115.61 (d, JC−F 22.2 Hz), 115.65
I
dx.doi.org/10.1021/jo400807c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(19) Kadlcí
̌
kova,
́
A.; Hrdina, R.; Valterova,
́
I.; Kotora, M. Adv. Synth.
ASSOCIATED CONTENT
* Supporting Information
GC and/or HPLC analysis of 1, 7, 9, 10, and 24; copies of H
and 13C NMR spectra; CIF files for 1, 16, and 24. This material
is available free of change via the Internet at http://pubs.acs.
org.
■
Catal. 2009, 351, 1279−1283.
(20) Broustal, G.; Ariza, X.; Campagne, J.-M.; Garcia, J.; Georges, Y.;
Marinetti, A.; Robiette, R. Eur. J. Org. Chem. 2007, 2007, 4293−4297.
(21) Wach, J.-Y.; Guttinger, S.; Kutay, U.; Gademann, K. Bioorg. Med.
S
1
̈
Chem. Lett. 2010, 20, 2843−2846.
́
(22) Bazan-Tejeda, B.; Bluet, G.; Broustal, G.; Campagne, J.-M.
Chem.Eur. J. 2006, 12, 8358−8366.
(23) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
̊
AUTHOR INFORMATION
Corresponding Author
*E-mail: chmiel@icho.edu.pl.
Notes
■
403−405.
(24) Chaładaj, W.; Kwiatkowski, P.; Jurczak, J. Synlett 2006, 2006,
3263−3266.
(25) (a) Mieczkowski, J.; Jurczak, J.; Chmielewski, M.; Zamojski, A.
Carbohydr. Res. 1977, 56, 180−182. (b) Chmielewski, M.; Jurczak, J. J.
Org. Chem. 1981, 46, 2230−2233.
The authors declare no competing financial interest.
́ ́
(26) (a) Stecko, S.; Pasniczek, K.; Jurczak, M.; Urbanczyk-Lipkowska,
ACKNOWLEDGMENTS
■
Z.; Chmielewski, M. Tetrahedron: Asymmetry 2006, 17, 68−78.
(b) Stecko, S.; Pasniczek, K.; Jurczak, M.; Urbanczyk-Lipkowska, Z.;
Chmielewski, M. Tetrahedron: Asymmetry 2007, 18, 1085−1093.
Financial support for this work was provided through the
National Center of Research and Development INITECH
Project No. ZPB/51/64927/IT/10.
́
́
́
́
(27) Sniezek, M.; Stecko, S.; Panfil, I.; Furman, B.; Urbanczyk-
̇
Lipkowska, Z.; Chmielewski, M. Tetrahedron: Asymmetry 2013, 24,
89−103.
REFERENCES
■
(28) (a) Jones, R. C.; Martin, J. N. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; Wiley & Sons, Inc.: New
York, 2002; pp 1−81. (b) Grigor’ev, I. A. Nitrones: Novel Strategies in
Synthesis. In Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis; John Wiley & Sons, Inc.: New York, 2007; pp 129−434.
(c) Feuer, H., Nitrile Oxides, Nitrones and Nitronates in Organic
Synthesis: Novel Strategies in Synthesis, 2nd ed.; Wiley: Weinhaim, 2008.
(1) (a) Bays, H. E.; Moore, P. B.; Drehobl, M. A.; Rosenblatt, S.;
Toth, P. D.; Dujovne, C. A.; Knopp, R. H.; Lipka, L. J.; LeBeaut, A. P.;
Yang, B.; Mellars, L. E.; Cuffie-Jackson, C.; Veltri, E. P. Clin. Ther.
2001, 23, 1209−1230. (b) Knopp, R. H.; Gitter, H.; Truitt, T.; Bays,
H.; Manion, C. V.; Lipka, L. J.; LeBeaut, A. P.; Suresh, R.; Yang, B.;
Veltri, E. P. Eur. Heart J. 2003, 24, 729−741.
(2) Thiruvengadam, T. K.; Sudhakar, A. R.; Wu, G. In Process
Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G., Ed.;
Marcel Dekker: New York, 1999; pp 221−242 and references therein.
(3) Rosenblum, S. B. Cholesterol absorpion inhibitors: ezetimibe. In
The Art of Drug Synthesis; Johnson, D. J., Li, J. J., Eds.; Wiley-
Intersience: NJ, 2007; pp 183−196 and references therein.
(4) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R.; Yumibe,
N.; Clader, J. W.; Burnett, D. A. J. Med. Chem. 1998, 41, 973−980.
(5) Fu, X.; McAllister, T. L.; Thiruvengadam, T. K.; Tann, C.-H.; Su,
D. Tetrahedron Lett. 2003, 44, 801−804.
(29) Badoiu, A.; Bernardinelli, G.; Mareda, J.; Kundig, E. P.; Viton, F.
̆
̈
Chem. Asian J. 2008, 3, 1298−1311.
(30) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744−
4745.
(6) Sanchez, C. C.; Dobarro, R. A.; Bosch, C. J.; Garcia, D. D. Patent
WO2012004382A1, 2012.
(7) Sasikala, C. H. V. A.; Reddy Padi, P.; Sunkara, V.; Ramayya, P.;
Dubey, P. K.; Bhaskar Rao Uppala, V.; Praveen, C. Org. Process Res.
Dev. 2009, 13, 907−910.
(8) Michalak, M.; Stodulski, M.; Stecko, S.; Mames, A.; Panfil, I.;
Soluch, M.; Furman, B.; Chmielewski, M. J. Org. Chem. 2011, 76,
6931−6936.
(9) Shankar, B. B.; Kirkup, M. P.; McCombie, S. W.; Clader, J. W.;
Ganguly, A. K. Tetrahedron Lett. 1996, 37, 4095−4098.
̌
̌ ̌
A.; Pecar, S.; Casar, Z.; Gobec, S.
(10) Sova, M.; Mravljak, J.; Kovac,
Synthesis 2010, 2010, 3433−3438.
(11) Wu, G.; Wong, Y.; Chen, X.; Ding, Z. J. Org. Chem. 1999, 64,
3714−3718.
(12) Karooti, K. K. G. S.; Rathod, P. D.; Aryan, R. C.; Kumar, Y.
Patent WO2004099132A2, 2004.
(13) Talley, J.; Martinez, E.; Zimmer, D.; Lundrigan-Soucy, R. Patent
WO2006102674A2, 2006.
(14) Talley, J. J.; Barden, T. C. Patent WO2008061238A2, 2008.
(15) (a) Panfil, I.; Chmielewski, M. Tetrahedron 1985, 41, 4713−
4716. (b) Panfil, I.; Chmielewski, M.; Bełzecki, C. Heterocycles 1986,
̇
24, 1609−1617. (c) Panfil, I.; Belzecki, C.; Chmielewski, M. J.
Carbohydr. Chem. 1987, 6, 463−470. (d) Panfil, I.; Belzecki, C.;
Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 1991, 47,
10087−10094.
(16) (a) Tufariello, J. J.; Tette, J. P. J. Org. Chem. 1975, 40, 3866−
3869. (b) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396−403.
(17) Doucet, H.; Santelli, M. Tetrahedron: Asymmetry 2000, 11,
4163−4169.
(18) Ramachandran, P. V.; Prabhudas, B.; Chandra, J. S.; Reddy, M.
V. R. J. Org. Chem. 2004, 69, 6294−6304.
J
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