Heterocyclic ring scaffolds as small-molecule cholesterol absorption inhibitors

Article abstract of DOI:10.1039/b510100j

Enantio- and diastereoselective syntheses of a substituted oxazolidinone, isoxazoline and pyrazoline as β-lactam surrogates are described. The substituted heterocycles were designed to incorporate side chains closely resembling those found in the β-lactam cholesterol absorption inhibitor ezetimibe (1). Additionally, the in vitro inhibitory efficacy of the novel compounds as cholesterol absorption inhibitors is reported using a brush border membrane vesicle assay. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b510100j

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A R T I C L E
Heterocyclic ring scaffolds as small-molecule cholesterol absorption
inhibitors
Tobias Ritter,a Lisbet Kværnø,a Moritz Werder,b Helmut Hauserb and Erick M. Carreira*a
a Laboratorium fu¨r Organische Chemie, ETH-Ho¨nggerberg, CH-8093 Zu¨rich, Switzerland.
E-mail: carreira@org.chem.ethz.ch; Fax: +41 44 632 1328; Tel: +41 44 632 2830
b Lipideon Biotechnology AG, Hermann-Hiltbrunnerweg 25, CH-8713 Uerikon, Switzerland
Received 15th July 2005, Accepted 1st August 2005
First published as an Advance Article on the web 24th August 2005
Enantio- and diastereoselective syntheses of a substituted oxazolidinone, isoxazoline and pyrazoline as b-lactam
surrogates are described. The substituted heterocycles were designed to incorporate side chains closely resembling
those found in the b-lactam cholesterol absorption inhibitor ezetimibe (1). Additionally, the in vitro inhibitory efficacy
of the novel compounds as cholesterol absorption inhibitors is reported using a brush border membrane vesicle assay.
Introduction
Enantio- and diastereoselective methods for the synthesis of
substituted non-aromatic heterocycles are of prime importance.
When incorporating multiple derivatization sites such methods
facilitate diversity oriented synthesis. A recent example is the
drug ezetimibe (1, Fig. 1),1 which inhibits cholesterol absorption
and contains a non-aromatic heterocycle in the form of a b-
lactam ring. In the development of ezetimibe, the b-lactam
was proposed to be essential for inhibitory activity,2,3 with
the corresponding ring-opened b-amino acid derivative being
completely inactive.3 In the course of an ongoing project aimed
at the characterization and further study of intestinal cholesterol
uptake, we became interested in the design of structurally well-
defined, non-aromatic heterocycles which can mimic the b-
lactam scaffold. The b-lactam ring is a rigid, almost planar
Fig. 2 Geometric overlap of oxazolidinone 2 (a), isoxazoline 3 (b), and
pyrazoline 4 (c) with the b-lactam core structure of ezetimibe (1).
heterocycle that defines out of plane vectors from a central
core. Given our objectives of identifying structural congeners
of b-lactams, we focused on generating structures in which
the geometrical alignment of the three exit vectors of the
substituents in the b-lactam are conserved (Fig. 1). Importantly,
we additionally wished to identify b-lactam mimics that would
not be prone to undergo hydrolysis as seen for b-lactams
in general. In this report, we document the enantio- and
diastereoselective syntheses of three b-lactam surrogates, namely
an oxazolidinone, an isoxazoline, and a pyrazoline, which do
not suffer from hydrolytic instability and display a set of exit
vectors closely resembling those found in the b-lactam scaffold.
We furthermore report their activities as cholesterol absorption
inhibitors using our recently developed brush border membrane
vesicle assay.4
the b-lactam ring of ezetimibe. The excellent overlaps of the
substituents are illustrated by superposition of each of the three
heterocycles 2–4 with the b-lactam core found in ezetimibe. In
order to focus on the exit vectors from the heterocyclic core,
the flexible hydroxypropyl side chain in ezetimibe, which is not
expected to strongly favor any single conformation, was replaced
by a methyl group in the calculations.
The synthesis of the desired oxazolidinone 16 commenced
with a Staudinger cycloaddition of imine 66 and the ketene
derived from acid 57 (Scheme 1). The reaction proceeded in 75%
yield (cis:trans = 95:5) to give a mixture of cis-diastereomers 7
and 8 (dr = 2:3 as determined by 1H NMR spectroscopy).8 These
were separable by silica gel chromatography and afforded 8 as
a single isomer. Acid-mediated cleavage of the ketal furnished
a-hydroxy-b-lactam 9 in enantiomerically pure form and 51%
yield. Although yield and diastereoselectivity were modest, the
ready availability of the inexpensive starting materials as well as
the straightforward and scalable reaction protocol were decisive
in our synthetic plan. Cleavage of the b-lactam under alkaline
conditions delivered amino alcohol 10 in 92% yield, which was
converted to oxazolidinone 11 in 89% yield using triphosgene.
The methyl ester in 11 served as an appropriate handle to
attach the 3ꢀ-aryl-3ꢀ-hydroxypropyl side chain found in ezetimibe
(1). Initially, we envisaged reduction of the ester to the aldehyde
and subsequent introduction of the side chain by an aldol con-
densation reaction. However, all attempts to isolate the aldehyde
derived from 11 failed. Reduction of ester 11 or the correspond-
ing Weinreb amide9 with DIBAL-H resulted only in decom-
position products, attributed to the presumed instability of the
product aldehyde. In 1985 Ireland documented the manipulation
Fig. 1 Ezetimibe and the exit vectors of the b-lactam core.
Results and discussion
The oxazolidinone scaffold 2 has previously been suggested to
serve as a structural mimic of the b-lactam of ezetimibe (1).2 Our
ab initio geometry optimizations5 (Fig. 2) additionally suggested
that the isoxazoline 3 and the pyrazoline 4 position three out
of plane exit vectors in a manner that corresponds well to
3 5 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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procedure trans-enone 14 could be conveniently prepared in
89% yield. Hydrogenation of the conjugated double bond
afforded ketone 15, which was diastereoselectively reduced
using the (R)-CBS catalyst14 (dr > 99:1 according to 19F-NMR).
Finally hydrogenolysis of the benzyl ether furnished the targeted
oxazolidinone 16 in 57% yield over three steps. The above
route thus furnished a rapid and straightforward access to the
oxazolidinone scaffold with the desired side chains.
The stereoselective synthesis of the desired isoxazoline 26 was
then pursued (Scheme 2) through a diastereoselective dipolar
cycloaddition reaction of nitrile oxides and optically active
allylic alcohols, which provides access to chiral optically active
isoxazolines.15 However, at the outset of our synthesis it was
far from clear whether allylic alcohols wherein the olefin is
conjugated to a functionalized aromatic ring could be used as
dipolarophiles in this cycloaddition, since the vast majority of
the described magnesium-mediated cycloadditions have been
conducted with non-conjugated allylic alcohols. In order to
test the strategy, the cinnamyl aldehyde 18 was prepared from
commercially available 4-hydroxycinnamic acid (17) in 76%
yield over 4 steps. Subsequent Brown allylation using (+)-
b-allyldiisopinocampheyl borane (19)16 afforded homoallylic
alcohol 20 in 77% yield and 93% ee as determined by chiral
HPLC. Cycloaddition of this allylic alcohol with the nitrile oxide
derived from 22 delivered the product isoxazoline largely derived
from cycloaddition to the terminal double bond. We speculated
that this undesired regioselectivity could be circumvented by
conversion of the terminal double bond to a corresponding di-
substituted olefin, thereby reducing the rate of the cycloaddition
reaction at this site. In this regard, 20 was subjected to Heck
arylation17 to give 21 in 51% yield. In initial investigations of the
cycloaddition reaction we noted a major by-product resulting
from dimerization of the nitrile oxide. In order to minimize the
formation of this by-product, the reaction was conducted at low
concentration of the nitrile oxide in the reaction mixture by slow
addition of the hydroximinoyl chloride (generated from oxime
oxidation with tert-butyl hypochloride) to the dipolarophile over
a period of 30 h. Thus, cycloaddition of allylic alcohol 21 with
the nitrile oxide derived from 22 proceeded completely regio-
and diastereoselectively (dr > 99:1 as determined by NMR) to
give isoxazoline 23 in 36% yield with 46% recovered starting
material. Installation of the desired substituents commenced by
conversion of 23 to aldehyde 24. In analogy to the synthesis of
the oxazolidinone 16 described earlier, aldehyde 24 was allowed
to react with phosphorous ylide 1312 to afford enone 25 (30%
over 4 steps). Hydrogenation of the double bond followed by
diastereoselective ketone reduction (dr > 99:1 as determined
by 1H NMR) using the (R)-CBS catalyst14 afforded the desired
isoxazoline 26 in 75% yield over two steps.
Scheme 1 Reagents and conditions: a) triphosgene, Et3N, CH2Cl2, 0 ◦C
to 23 ◦C. b) CSA, THF–H2O, reflux. c) NaOMe, MeOH. d) Triphosgene,
iPr2NEt, DMAP, CH2Cl2, −78 ◦C to 23 ◦C. e) NaBH4, EtOH. f)
(COCl)2, DMSO, Et3N, CH2Cl2, −78 ◦C. g) 13. h) H2, Pd/C, EtOH.
i) (R)-CBS catalyst, BH3·SMe2, CH2Cl2, −20 ◦C to 0 ◦C.
of unstable aldehydes through in situ Swern oxidation of the
corresponding alcohols and subsequent Wittig reaction.10
Consequently, ester 11 was reduced to the corresponding alcohol
◦
12 by treatment with NaBH4 in ethanol at 23 C. Subsequent
Swern oxidation11 at −78 ◦C for 5 min furnished the intermediate
aldehyde, which was subjected to in situ reaction with stabilized
phosphorous ylide 13.12 The unusu◦al low reaction temperature
for this Wittig reaction (< −40 C)13 underscores the high
electrophilicity of the intermediate aldehyde. Through this
Scheme 2 Reagents and conditions: a) SOCl2, MeOH. b) MsCl, Et3N, THF. c) DIBAL-H, CH2Cl2, 0 ◦C. d) MnO2, CH2Cl2. e) 19, Et2O, −78 ◦C.
f) C6H5I, Pd(OAc)2, PPh3, Et3N, MeCN. g) 22, tBuOCl, iPrOH, EtMgBr, CH2Cl2. h) MsCl, pyr, CH2Cl2. i) DBU, CH2Cl2, reflux. j) K2OsO4·2H2O,
NaIO4, THF–H2O. k) 13. l) H2, Pd/C, MeOH. m) (R)-CBS catalyst, BH3·SMe2, CH2Cl2, −20 ◦C to 0 ◦C.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3
3 5 1 5

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In the approach to the desired substituted pyrazo-
lines, a diastereoselective 1,3-dipolar cycloaddition of TMS-
diazomethane18 was utilized to construct the heterocyclic core
(Scheme 3). The synthesis commenced with a Zn-mediated
enantioselective alkyne addition19 to p-fluorobenzaldehyde 27 to
give propargylic alcohol 28 in 75% yield (96% ee as determined
by chiral HPLC). The yields were higher when the reaction
was conducted slightly below room temperature (8–13 ◦C).
Subsequent silylation was immediately followed by sequential
reduction of the triple bond and removal of the benzyl group
to give alcohol 29 in 80% overall yield. This was necessary
because the intermediary propargylic silyl ether proved unstable
and difficult to isolate. The propensity of the benzylic and
propargylic C–OSi bond to undergo hydrogenolytic cleavage
necessitated stepwise hydrogenation of the alkyne prior to re-
moval of the benzyl group. Subsequent Dess–Martin oxidation20
(80% yield) and Horner–Wadsworth–Emmons olefination using
the camphorsultam derived phosphonate 3021,22 and LiCl–
DBU23 afforded the (E)-olefin 31 in 71% yield. The pyrazoline
heterocyclic core was generated using a diastereoselective 1,3-
dipolar cycloaddition of TMS-diazomethane,18 which furnished
the desired pyrazoline 32 in 94% combined yield (89:11 dr based
on the yields of the isolated diastereomers). The diastereomeric
products were readily separated by chromatography on silica gel
to afford diastereomerically pure 32.
Optimal yields (63%) were obtained using the organobismuth
reagent, (p-FC6H4)3Bi, which was readily obtained by reaction
of p-fluorophenylmagnesium bromide with BiCl3. With this
intermediate 33 in hand, we envisioned a rapid synthesis of
various analogues by conversion of the carboxylic acid derivative
into an oxazole as a substitute for the phenol substituent of
ezetimibe. In this regard, substitution of the camphorsultam
auxiliary with glycine catalyzed by KCN27 (75%) and dehy-
dration using the water-soluble DCC analogue 3528 afforded
the desired, but rather unstable, oxazolone 36 in 39% isolated
yield. Generation of the oxazole 37 was effected by benzene
sulfonate ester formation and desilylation in 40% and 39% yields,
respectively.
As an alternative pyrazoline derivatization, the chiral cam-
phorsultam auxiliary of 33 was reductively removed (LiAlH4,
76% yield) to give a primary alcohol which, following tosylation
(83% yield), was subjected to nucleophilic displacement of the
sulfonate by hydroquinone in 86% yield (Scheme 5). Subsequent
desilylation afforded the pyrazoline 38 in 99% yield featuring an
oxymethylene linker between the pyrazoline and the aromatic
ring substituent.
Scheme 5 Reagents and conditions: a) LiAlH4, THF, −78 ◦C. b) TsCl,
DMAP. Et3N, CH2Cl2. c) Hydroquinone, Cs2CO3, DMF, 80 ◦C. d)
HF·pyr, pyr, THF.
The heterocyclic compounds 16, 26, and 37–38 were subse-
quently evaluated for inhibition of intestinal cholesterol uptake
using our recent brush border membrane vesicle in vitro assay
(Fig. 3).4 We were pleased to observe that oxazolidinone 16
showed a similar in vitro activity (19% inhibition) to ezetimibe
(1) (16% inhibition). Despite previous promising in vitro results
for a wide range of sulfonate ester phenolic derivatives of
ezetimibe,4b the sulfonate ester substituted isoxazoline (26)
and pyrazoline (37) did not show any activity as cholesterol
absorption inhibitors. The remaining pyrazoline 38 was likewise
void of inhibitory activity. This attests that small changes of the
Scheme 3 Reagents and conditions: a) Zn(OTf)2, (+)-N-methyle-
phedrine, Et3N, toluene, 8–13 ◦C. b) TBDMSCl, imidazole, DMF. c)
H2, Pd/C, Na2CO3, EtOH. d) H2, Pd/C, EtOH. e) Dess–Martin periodi-
nane, CH2Cl2. f) 30, DBU, LiCl, MeCN. g) TMSCHN2, toluene–hexane;
then TFA, CH2Cl2.
Typical conditions employed in Pd-mediated N-arylations24
proved incompatible with the camphorsultam imide. However,
a Cu-mediated N-arylation proceeded successfully employing ei-
ther a boronic acid25 or a triarylbismuth derivative26 (Scheme 4).
Scheme 4 Reagents and conditions: a) (p-FC6H4)3Bi, Cu(OAc)2, Et3N,
CH2Cl2. b) Glycine, KCN, MeOH, 50 ◦C. c) 35, CH2Cl2, reflux. d)
PhSO2Cl, Et3N, CH2Cl2. e) HF·pyr, pyr, THF.
Fig. 3 Percentage inhibition in the brush border membrane vesicle
assay using rabbit small intestine at nominal concentrations of 6 lM.4
The average standard deviations were 3% inhibition.
3 5 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3

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heterocyclic core can result in marked differences as cholesterol
absorption inhibitors even though the geometric deviations of
the exit vectors are only subtle (Fig. 2).
5.00 eq.) followed by imine 66 (28.1 g, 92.1 mmol, 1.00 eq.).
The solution was cooled to −20 ◦C and triphosgene (16.4 g,
55.8 mmol, 0.600 eq.) was added in 50 ml CH2Cl2 over a period
of 20 min. The solution was warmed to 23 ◦C over a period of
8 h and stirred for an additional 10 h at this temperature. The
solution was poured onto 600 ml ice water and 200 ml CH2Cl2.
The aqueous phase was extracted with CH2Cl2 (3 × 100 ml).
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel eluting with hexane–EtOAc
(3:2 to 1:2 gradient) and then chromatography on silica gel
eluting with EtOAc–CH2Cl2 (7:1 to 3:1 gradient) to afford
b-lactam 8 as a colorless solid in 45% yield along with 30% yield
of the undesired diastereomer 7. Mp: 132 ◦C. Rf = 0.38 [hexane–
Conclusions
We have documented the enantio- and diastereoselective syn-
theses of three b-lactam surrogates with side chains resembling
those found in the cholesterol absorption inhibitor ezetimibe
(1). In the course of these investigations we expanded the
substrate scope of the highly diastereoselective hydroxyl-directed
nitrile oxide cycloadditions. The pyrazoline synthesis featured a
diastereoselective dipolar cycloaddition of TMS-diazomethane
and a copper-mediated N-arylation using an organobismuth
reagent as the key steps. When evaluated in the brush border
membrane vesicle assay, the oxazolidinone 16 showed similar
activity as ezetimibe (1) as a cholesterol absorption inhibitor.
This promising result suggests that an oxazolidinone ring
scaffold could effectively replace the b-lactam of ezetimibe.
Synthesis of additional analogues and their biological evaluation
are underway and will be reported in due course.
◦
1
EtOAc 1:1 (v/v)]. aD30.5 = +77 , (c 1.075 in CHCl3). H-NMR
(300 MHz, CDCl3): d 7.46–7.07 (16 H, m), 6.92–6.84 (2 H, m),
5.34 (1 H, d, J = 5.3 Hz), 5.06 (2 H, s), 4.95 (1 H, d, J = 5.3 Hz),
4.60 (1 H, d, J = 2.5 Hz), 3.23–3.14 (1 H, m), 2.90 (3 H, s), 1.70
(3 H, s), 0.83 (3 H, d, J = 6.2 Hz). 13C-NMR (75 MHz, CDCl3):
d 165.4, 165.0, 159.3 (d, J = 244 Hz), 159.1, 137.1 (d, J = 5 Hz),
133.7, 129.9, 128.9, 128.6, 128.3, 128.0, 127.7, 125.7, 119.0 (d,
J = 8 Hz), 116.0 (d, J = 23 Hz), 115.1, 100.1, 76.9, 71.2, 70.1,
62.2, 59.0, 33.8, 23.6, 12.4. IR (thin film): 2938, 1756, 1667,
1612, 1511, 1382, 1223, 1177, 1112, 1092, 834, 734. HRMS
Experimental
+
General experimental details
(EI): found, 580.2369. C35H33FN2O5 requires 580.2374.
Reactions in anhydrous solvents were all performed using
oven dried glassware under an atmosphere of argon. Reagent
grade solvents were all purchased from chemical companies
and used without prior purification. Anhydrous THF, ether,
toluene, CH3CN and CH2Cl2 were dried and purified through
activated alumina columns as described.29 Diisopropylamine,
triethylamine and pyridine were distilled from KOH. For chro-
matographic purification, technical grade solvents were distilled
prior to use. TLC was performed using Machery-Nagel Alugram
Sil G/UV254 or Merck 0.25 mm silica gel 60 F254 TLC glass plates.
Visualization of the developed chromatogram was performed by
UV fluorescence at 254 nm and oxidative stain by either ceric am-
monium molybdate solution, KMnO4–NaHCO3 water solution,
phosphomolybdic acid or H2SO4–MeOH. Chromatographic
purification of products was accomplished by dry column
vacuum chromatography30 on either Merck silica gel 60 (15–
(3S,4R)-4-(4-Benzyloxyphenyl)-1-(4-fluorophenyl)-3-hydroxy-
azetidin-2-one (9). To a solution of ketal 8 (17.0 g, 29.0 mmol,
1.00 eq.) in THF (242 ml) and water (48 ml) was added p-
toluenesulfonic acid monohydrate (55.7 g, 293 mmol, 10.0 eq.).
The solution was heated to reflux for 5 h. The solution
was concentrated to an approximate volume of 60 ml and
then poured onto EtOAc (150 ml) and water (250 ml). The
aqueous phase was extracted with EtOAc (4 × 100 ml).
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(3:2 to 2:3 gradient), to afford b-lactam 9 as a colorless solid
in 51% yield. Mp: 168 ◦C. Rf = 0.26 [hexane–EtOAc 3:2
(v/v)]. a2D9.5 = −129◦, (c 1.22 in acetone). 1H-NMR (300 MHz,
acetone-d6): d 7.50–7.47 (2 H, m), 7.42–7.29 (5 H, m), 7.10–7.01
(4 H, m), 5.33 (1 H, d, J = 5.3 Hz), 5.27 (1 H, dd, J = 7.2 Hz,
5.3 Hz), 5.11 (2 H, s), 5.07 (1 H, d, J = 7.2 Hz). 13C-NMR
(75 MHz, acetone-d6): d 166.5, 159.2, 159.0 (d, J = 241 Hz),
137.7, 134.7, 129.6, 128.6, 128.0, 127.8, 118.9 (d, J = 8 Hz),
115.8 (d, J = 23 Hz), 114.8, 78.0, 69.8, 62.3. IR (thin film):
3120, 1756, 1667, 1612, 1511, 1382, 1223, 1177, 1112, 1092,
˚
40 lm) or Brunschwig silica 18–32, 60 A (18–32 lM) or by flash
chromatography on silica gel 60 (230–400 mesh, 0.04–0.063 mm)
from Merck at rt and 0.3–0.5 mbar air pressure. Concentration
under◦reduced pressure was performed by rotary evaporation
at 40 C and the purified compounds were subsequently dried
under high vacuum (<0.5 Torr). NMR spectra were recorded on
a Varian Mercury 300 MHz apparatus operating at 300 MHz,
75 MHz and 282 MHz for 1H, 13C/DEPT and 19F, respectively,
and chemical shifts (d) were referenced to the internal solvent
+
834, 734. HRMS (EI): found, 363.1268. C22H18FNO3 requires
363.1271. Anal.: found, C, 77.73; H, 5.20; N, 3.91. C22H18FNO3
requires C, 72.72; H, 4.99; N, 3.85%.
(2S,3R)-3-(4-Benzyloxyphenyl)-3-(4-fluorophenylamino)-2-
hydroxypropionic acid methyl ester (10). To a suspension of
b-lactam 9 (2.00 g, 5.50 mmol, 1.00 eq.) in methanol (55.0 ml)
was added sodium methoxide (1.49 g, 27.5 mmol, 5.00 eq.). The
suspension was stirred at 23 ◦C for 2 h. To the forming solution
was added NH4Cl(s) and the suspension was concentrated in
vacuo. To the solid was added EtOAc (50 ml) and water (50 ml).
The aqueous phase was extracted with EtOAc (3 × 20 ml).
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(3:2 to 1:1 gradient), to afford amino alcohol 10 as a colorless
1
signals for H and 13C. Multiplicities are reported as follows:
1H: s = singlet, bs = broad singlet, d = doublet, t = triplet,
q = quartet, p = pentet, m = multiplet; 13C: C, CH, CH2, CH3
(determined by DEPT); coupling constants are reported in Hz.
Melting points were measured on a Bu¨chi 510 apparatus in open
capillaries and all melting points are uncorrected. IR-Spectra
were recorded in CHCl3 on a Perkin Elmer Spectrum RX I
FT-IR apparatus (thin films on NaCl plates) and are reported
as absorption maxima in cm−1. Optical rotations are reported
in 10−1deg cm2 g−1. Elemental analysis was performed by the
Mikroelementaranalytisches Laboratorium at the ETH, Zu¨rich.
High resolution matrix-assisted laser desorption ionization mass
spectrometry (MALDI-MS) and electrospray ionization (ESI-
MS) were performed by the mass spectrometry service of the
LOC at the ETH, Zu¨rich.
◦
solid in 89% yield. Mp: 103 C. Rf = 0.45 [hexane–EtOAc 3:2
(v/v)]. a2D5.3 = +13.9◦, (c 1.10 in CH2Cl2). 1H-NMR (300 MHz,
CDCl3): d 7.44–7.24 (4 H, m), 6.97–6.91 (2 H, m), 6.84–6.76
(2 H, m), 6.53–6.46 (2 H, m), 5.02 (2 H, s), 4.81 (1 H, s), 4.60
(1 H, s), 4.46 (1 H, m), 3.79 (3 H, s), 3.07 (1 H, d, J = 3.7 Hz).
13C-NMR (75 MHz, CDCl3): d 158.2, 155.8 (d, J = 233 Hz),
142.5, 136.8, 131.0, 128.5, 127.9, 127.9, 127.4, 155.5 (d, J =
22 Hz), 114.9, 114.8, 74.6, 70.0, 59.1, 53.1, 114.8, 78.0, 69.8,
(2S,5R,6S)-2-[(1S,2R)-2-(4-Benzyloxyphenyl)-3-(4-fluoro-
phenyl)-4-oxocyclobutoxy]-2,4,5-trimethyl-6-phenylmorpholin-3-
one (8). To a solution of acid 57 (30.0 g, 102 mmol, 1.11 eq.) in
CH2Cl2 (600 ml) was added triethylamine (64.0 ml, 461 mmol,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3
3 5 1 7

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62.3. IR (thin film): 3390, 1737, 1610, 1510, 1221, 1113, 823.
MS (EI): 306.1748 (2.54%), 186.2356 (18.8%), 91.0908 (100%).
Anal.: found, C, 69.88; H, 5.78; N, 3.54. C23H22FNO4 requires
C, 69.86; H, 5.61; N, 3.54%.
solution. The aqueous phase was extracted with CH2Cl2.
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(2:1 to 1:1 gradient), to afford enone 14 as a colorless solid in
89% yield. Mp: 152 ◦C. Rf = 0.56 [hexane–EtOAc 3:2 (v/v)].
a2D5.6 = +100◦, (c 0.60 in CHCl3). 1H-NMR (300 MHz, CDCl3):
d 8.06–7.99 (2 H, m), 7.42–7.06 (14 H, m), 7.00–6.92 (4 H, m),
5.05–5.00 (4 H, m). 13C-NMR (75 MHz, CDCl3): d 187.1, 165.9
(d, J = 254 Hz), 159.8 (d, J = 243 Hz), 159.4, 154.8, 140.0,
136.2, 133.2, 132.3, 131.4 (d, J = 9 Hz), 128.6, 128.1, 128.1,
127.9, 127.4, 125.8, 123.5 (d, J = 9 Hz), 115.9 (d, J = 24 Hz),
115.8 (d, J = 24 Hz), 115.8, 80.5, 70.2, 66.0. IR (thin film):
1760, 1675, 1597, 1511, 1385, 1227. HRMS (MALDI): found,
534.1482. C31H23F2NO4Na+ requires 534.1493. Anal.: found,
C, 72.51; H, 4.78; N, 2.73. C31H23F2NO4 requires C, 72.79; H,
4.53; N, 2.74%.
(4R,5S)-4-(4-Benzyloxyphenyl)-3-(4-fluorophenyl)-2-oxooxa-
zolidine-5-carboxylic acid methyl ester (11). To a solution
of amino alcohol 10 (1.92 g, 4.86 mmol, 1.00 eq.) in
CH2Cl2 (24.0 ml) was added diisopropylethylamine (2.54 ml,
14.6 mmol, 3.00 eq.) and 4-N,N-dimethylaminopyridine
(59.0 mg, 0.486 mmol, 0.10 eq.). The solution was cooled to
−78 ◦C and triphosgene (1.44 g, 4.86 mmol, 1.00 eq.) in CH2Cl2
(4.0 ml) was added over a period of 5 min. The solution was
warmed to 23 ◦C over 8 h and stirred at this temperature for an
additional 5 h. To this solution was added water (50 ml) and
concentrated aqueous ammonium hydroxide solution (3 ml).
The aqueous phase was extracted with CH2Cl2 (3 × 20 ml).
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(2:1 to 1:1 gradient), to afford methyl ester 11 as a colourless
(4R,5R)-3-(4-Fluorophenyl)-5-[(S)-3-(4-fluorophenyl)-3-hy-
droxypropyl]-4-(4-hydroxyphenyl)oxazolidin-2-one (16). To
enone 14 (910 mg, 1.78 mmol, 1.00 eq.) in ethanol (15.0 ml)
was added, at 23 ◦C, Pd on carbon (10%) (100 mg). The
suspension was vigorously stirred under 1 atm of hydrogen gas
for 3 h. The suspension was filtered through a pad of celite,
eluting with EtOAc, concentrated and the residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(2:1 to 1:1 gradient). A portion of the resulting benzyl ether
15 (310 mg, 0.604 mmol, 1.00 eq.) was dissolved in CH2Cl2
and cooled to −20 ◦C. (R)-3,3-Diphenyl-1-methyltetrahydro-
3H-pyrrolo-oxazaborole-2-methyl oxazaborolidine [solution
in toluene (0.5 M) 0.600 ml, 0.302 mmol, 0.50 eq.] was
added, followed by borane–dimethylsulfide complex (0.0◦80 ml,
0.905 mmol, 1.50 eq.). The solution was stirred at −20 C for
2 h, then warmed to 0 ◦C and quenched with methanol. To
the solution was added saturated aqueous Na2HCO3 solution
and CH2Cl2. The aqueous phase was extracted with CH2Cl2.
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(3:2 to 1:1 gradient). A portion of the resulting alcohol (53 mg,
0.10 mmol, 1.0 eq.) was dissolved in ethanol and Pd on carbon
(10 mg) was added. The suspension was vigorously stirred
under an atmosphere of hydrogen for 2.5 h. The suspension
was filtered through a plug of celite eluting with EtOAc.
The residue was purified by chromatography on silica gel
eluting with hexane–EtOAc (1:1 to 1:2 gradient) to afford
◦
solid in 82% yield. Mp: 118 C. Rf = 0.54 [hexane–EtOAc 3:2
◦
(v/v)]. a2D9.3 = +18 , (c 1.10 in CHCl3). H-NMR (300 MHz,
CDCl3): d 7.40–7.32 (7 H, m), 7.29–7.22 (2 H, m), 6.98–6.93
(4 H, m), 5.33 (1 H, d, J = 4.4 Hz), 5.03 (2 H, s), 4.73 (1 H,
d, J = 4.4 Hz), 3.89 (3 H, s). 13C-NMR (75 MHz, CDCl3): d
168.9, 160.1 (d, J = 244 Hz), 159.7, 154.3, 136.7, 132.7, 129.5,
128.9, 128.4, 127.8, 127.7, 123.2 (d, J = 8 Hz), 116.1 (d, J =
22 Hz), 116.0, 77.9, 70.3, 36.6, 53.5. IR (thin film): 1769, 1552,
1388, 1227, 1099, 834. HRMS (MALDI): found, 444.1224.
C24H20FNO5Na+ requires 444.1224. Anal.: found, C, 68.18; H,
4.91; N, 3.38. C24H20FNO5 requires C, 68.40; H, 4.78; N, 3.32%.
1
(4R,5S)-4-(4-Benzyloxyphenyl)-3-(4-fluorophenyl)-5-hydroxy-
methyloxazolidin-2-one (12). To a suspension of methyl ester
11 (1.68 g, 3.99 mmol, 1.00 eq.) in ethanol (27.0 ml) was added,
at 23 ◦C, sodium borohydride (226 mg, 5.98 mmol, 1.50 eq.).
The suspension was stirred for 2 h at this temperature after
which point all solids had dissolved. To this solution was
added NH4Cl(s) and the volume was concentrated to 5 ml
in vacuo. To this suspension was added water (50 ml) and
EtOAc (50 ml). The aqueous phase was extracted with EtOAc.
The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with hexane–EtOAc
(1:1 to 2:3 gradient), to afford alcohol 12 as a colorless solid in
92% yield. ◦Mp: 143 ◦C. Rf = 0.40 [hexane–EtOAc 2:3 (v/v)].
oxazolidinone 16 as a colorless solid in 57% yield from enone
1
a3D2.4 = −16 , (c 1.54 in CHCl3). H-NMR (300 MHz, CDCl3):
◦
14. Mp: 98 C. Rf = 0.41 [hexane–EtOAc 2:3 (v/v)]. aD27.6
=
−1◦, (c 0.84 in CHCl3). 1H-NMR (300 MHz, acetone-d6):
d 7.47–7.35 (4 H, m), 7.29–7.24 (2 H, m), 7.09–6.97 (4 H,
m), 6.85–6.79 (2 H, m), 5.15 (1 H, d, J = 6.7 Hz), 4.76–4.68
(1 H, m), 4.43–4.34 (2 H, m), 2.02–1.76 (4 H, m). 13C-NMR
(75 MHz, acetone-d6): d 162.0 (d, J = 243 Hz), 159.5 (d, J =
242 Hz), 157.9, 155.3, 142.2 (d, J = 3 Hz), 134.3 (d, J = 2 Hz),
129.1, 128.7, 127.8 (d, J = 8 Hz), 123.8 (d, J = 9 Hz), 116.1,
115.2 (d, J = 23 Hz), 114.9 (d, J = 21 Hz), 82.4, 72.3, 65.6,
35.0, 30.3. IR (thin film): 3316, 2925, 1726, 1603, 1511, 1224,
835. HRMS (MALDI): found, 448.1326. C24H21F2NO4Na+
requires 448.1337. The diastereoselectivity of the CBS reduction
was established by integration of the fluorine signals in the
19F-NMR spectrum by comparison to a mixture of 16 and
(4R,5R)-3-(4-fluorophenyl)-5-[(R)-3-(4-fluorophenyl)-3-hy-
droxypropyl]-4-(4-hydroxyphenyl)oxazolidin-2-one, obtained
by NaBH4 reduction of the corresponding ketone.
d 7.42–7.19 (9 H, m), 6.97–6.90 (4 H, m), 5.26 (1 H, d, J =
6.5 Hz), 5.02 (2 H, s), 4.39 (1 H, m), 3.99 (1 H, d, J = 12.5 Hz),
3.74 (1 H, d, J = 12.5 Hz), 2.77 (1 H, s). 13C-NMR (75 MHz,
CDCl3): d 159.7 (d, J = 245 Hz), 159.0, 136.4, 132.7, 129.4,
128.5, 128.0, 127.9, 127.4, 123.6 (d, J = 8 Hz), 115.6 (d, J =
22 Hz), 115.6, 82.0, 70.1, 61.6, 61.2. IR (thin film): 3418,
2930, 2871, 1748, 1611, 1512, 1394, 1234. HRMS (EI): found,
+
393.1389. C23H20FNO4 requires 393.1376. Anal.: found, C,
70.26; H, 5.21; N, 3.61. C23H20FNO4 requires C, 70.22; H, 5.12;
N, 3.56%.
(4R,5R)-4-(4-Benzyloxyphenyl)-3-(4-fluorophenyl)-5-[(E)-3-
(4-fluorophenyl)-3-oxopropenyl]oxazolidin-2-one (14). To
a
solution of oxalyl chloride (508 mg, 4.00 mmol, 2.00 eq.) in
CH2Cl2 (15.0 ml) was added, at −78 ◦C, dimethyl sulfoxide
(0.355 ml, 5.00 mmol, 2.50 eq.). After 10 min at −78 ◦C, alcohol
12 (787 mg, 2.00 mmol, 1.00 eq.) in CH2Cl2 (15.0 ml) was
added over a period of 5 min. After an additional 5 min at
this temperature, triethylamine (1.14 ml, 8.00 mmol, 8.00 eq.)
was added. After 5 min, 1-(4-fluorophenyl)-2-(triphenyl-k5-
phosphanylidene)ethanone 131◦2 was added and the resulting
suspension was warmed to 20 C and stirred for an additional
30 min. To the solution was added saturated aqueous Na2HCO3
Methanesulfonic acid 4-[(E)-3-oxopropenyl]phenyl ester (18).
To a suspension of 4-hydroxycinnamic acid 17 (8.85 g,
53.5 mmol, 1.00 eq.) in methanol (70 ml) at 0 ◦C was added
dropwise thionyl chloride (6.40 g, 53.5 mmol, 1.00 eq.). The
ice bath was removed and the solution was stirred at 23 ◦C
for 16 h. A stream of air was bubbled through the solution
3 5 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3

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for 2 h and the solution was concentrated in vacuo to afford
an off-white solid. This solid was dissolved in THF (75 ml)
and triethylamine (6.05 g, 60.0 mmol, 1.20 eq.) was added and
the solution was cooled to 0 ◦C. To this solution was added
methanesulfonyl chloride (6.30 g, 55.0 mmol, 1.10 eq.). The ice
1.10 eq.), and allyl alcohol 20 (980 mg, 3.65 mmol, 1.00 eq.).
The suspension was heated at reflux for 4 h. The solution was
concentrated in vacuo and the residue was dissolved in EtOAc
(20 ml) and filtered over a plug of silica gel, eluting with EtOAc.
The solution was concentrated in vacuo and the residue was
recrystallized from toluene (4 ml). The crystals were filtered
off, washed with toluene (3 ml), and dried in vacuo to afford
the target compound as a beige solid (51% yield). Rf = 0.35
0.85 in CH2Cl2). 1H NMR (300 MHz, acetone-d6): d 7.55–7.51
(2 H, m), 7.40–7.37 (2 H, m), 7.30–7.16 (5 H, m), 6.68 (1 H,
dd, J = 15.9 Hz, 1.0 Hz), 6.53–6.33 (3 H, m), 4.46–4.38 (1 H,
m), 4.10 (1 H, d, J = 4.7 Hz), 3.26 (3 H, s), 2.55–2.51 (2 H, m).
13C NMR (75 MHz, acetone-d6): d 149.4, 138.4, 137.3, 135.3,
132.7, 129.1, 128.4, 128.2, 127.6, 127.5, 126.7, 123.0, 72.3, 42.3,
37.5. IR (thin film) 3370, 3029, 2935, 1501, 1375, 1356, 1197,
1178, 1151, 969, 872, 777, 748, 695 (cm−1). HRMS-EI (m/z):
157.0344 (84.80%), 114.0275 (62.10%), 113.0204 (54.88%),
17.9497 (100%). Anal.: found, C, 66.41; H, 5.84. C19H20O4S
requires C, 66.26; H, 5.85%.
◦
bath was removed and the suspension was stirred at 23 C for
2 h. This suspension was poured onto saturated, aqueous NH4Cl
(25 ml), water (50 ml), and EtOAc (150 ml). The phases were
separated and the aqueous phase was extracted with EtOAc
(3 × 30 ml). The combined organic phase was washed with
brine, dried (Na2SO4) and concentrated in vacuo. The residue
was recrystallized from hexane–EtOAc (1:3, 200 ml) to afford a
colorless solid. The solid was suspended in CH2Cl2 (100 ml) and
the suspension was cooled to 0 ◦C. To this suspension was added,
over a period of 15 min, DIBAl-H (15.3 g, 108 mmol, 2.15 eq.)
and the solution was stirred at 0 ◦C for 15 min. To this solution
was added saturated, aqueous NaK-tartrate solution (100 ml)
followed by Et2O (100 ml). This emulsion was vigorously stirred
for 12 h. The phases were separated and the aqueous phase was
extracted with Et2O. The combined organic phase was washed
with brine, dried (Na2SO4) and concentrated in vacuo to afford
a yellow solid. This solid was dissolved in CH2Cl2 (200 ml) and
MnO2 (34.7 g, 400 mmol, 8.00 eq.) was added and the suspension
was stirred for 6 h. The suspension was filtered over a plug
of celite, eluting with CH2Cl2. The filtrate was concentrated in
vacuo. The residue was purified by chromatography on silica
gel, eluting with hexane–EtOAc (1:1 to 2:3 gradient), to afford
the target compound as a bright yellow solid in 76% yiel◦d (four
◦
[hexane–EtOAc 1:1 (v/v)]. Mp (toluene) 134 C. a2D9.0 −4◦ (c
Methanesulfonic acid 4-{(4S,5S)-3-(4-fluorophenyl)-5-[(E)-(S)-
1-hydroxy-4-phenylbut-3-enyl]-4,5-dihydroisoxazol-4-yl}phenyl
ester (23). To allyl alcohol 21 (600 mg, 1.74 mmol, 1.00 eq.)
in CH2Cl2 (8.5 ml) at 0 ◦C was added isopropanol (345 mg,
5.75 mmol, 3.30 eq.) followed by ethylmagnesium bromide
(3.0 M) (1.74 ml, 5.23 mmol, 3.00 eq.). The solution was
allowed to warm to 23 ◦C. Separately, 4-fluorobenzaldehyde
oxime 22 (303 mg, 2.18 mmol, 1.25 eq.) was dissolved in
CH2Cl2 (8.5 ml). This solution was cooled to −78 ◦C and
tert-butyl hypochloride (239 mg, 2.18 mmol, 1.25 eq.) was
added. The ice bath was removed and the solution allowed to
1
steps). Rf = 0.35 [hexane–EtOAc 1:1 (v/v)]. Mp: 78 C. H
NMR (300 MHz, CDCl3): d 9.69 (1 H, d, J = 7.5 Hz), 7.62–7.60
(2 H, m), 7.45 (1 H, d, J = 15.9 Hz), 7.36–7.33 (2 H, m), 6.67
(1 H, dd, J = 15.6 Hz, 7.8 Hz), 3.18 (3 H, s). 13C NMR (75 MHz,
CDCl3): d 193.6, 151.0, 150.8, 133.5, 130.4, 129.7, 123.0, 38.0.
IR (thin film) 3035, 2939, 2826, 2744, 1678, 1627, 1600, 1504,
1367, 1177, 1155, 1126, 974, 873, 775, 693, 526 (cm−1). HRMS-
EI (m/z): found, 226.0301. C10H10O4S requires 226.0300. Anal.:
found, C, 53.14; H, 4.56. C10H10O4S requires C, 53.09; H, 4.45%.
◦
reach 23 C. This solution was added over a period of 30 h by
syringe pump to the solution containing allyl alcohol 23. To
the solution was added 10% aqueous HCl (10 ml). The phases
were separated and the aqueous phase was extracted with
CH2Cl2. The combined organic phase was washed with brine,
dried (Na2SO4) and concentrated in vacuo to afford a yellow
oil. The residue was purified by chromatography on silica gel,
eluting with toluene–EtOAc (4:1 to 2:1 gradient), to afford the
target compound as a colorless solid (36% yield, dr > 99:1) and
starting material 21 (46%). Rf = 0.37 [hexane–EtOAc 1:1 (v/v)].
Mp 78 ◦C. a2D9.0 +147◦ (c 0.65 in CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 7.56–7.50 (2 H, m), 7.36–7.18 (9 H, m), 7.00–6.93
(2 H, m), 6.51 (1 H, d, J = 15.9 Hz), 6.24 (1 H, dd, J = 15.9 Hz,
6.2 Hz), 4.79 (1 H, d, J = 5.6 Hz), 4.51 (1 H, dd, J = 5.6 Hz,
3.4 Hz), 3.90–3.82 (1 H, m), 3.13 (3 H, s), 2.62–2.58 (2 H, m),
2.14 (1 H, d, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3): d 161.2
(d, J = 242 Hz), 157.4, 148.4, 138.0, 136.8, 133.6, 129.2, 129.1,
128.5, 127.4, 126.1, 124.7, 123.0, 115.8 (d, J = 24 Hz), 91.9,
72.1, 55.9, 37.7, 37.3. IR (thin film) 3387, 3027, 2936, 1603,
1512, 1502, 1368, 1235, 1177, 1151, 969, 913, 871, 838, 772,
749 (cm−1). HRMS-EI (m/z): found, 481.1355. C26H24FNO5
requires 481.1359.
Methanesulfonic acid 4-[(E)-(S)-3-hydroxyhexa-1,5-dienyl]-
phenyl ester (20). To (+)-b-chloro diisopinocampheyl borane
(8.24 g, 25.6 mmol, 1.25 eq.) in Et2O (50 ml) at −78 ◦C was added
allylmagnesium bromide (1.0 M in Et2O, 24.7 ml, 24.7 mmol,
1.20 eq.). The emulsion was warmed to 23 ◦C and stirred at this
temperature for 2 h to afford a grey slurry. This slurry was cooled
to −78 ◦C and aldehyde 18 was added portionwise over a period
of 15 min. The yellow slurry was stirred at −78 ◦C for 2 h. The
reaction was quenched with methanol (1.0 ml), 10% aqueous
NaOH (25 ml), and H2O2 (30%) (25 ml). The emulsion was
vigorously stirred for 20 h. The phases were separated and the
aqueous phase was extracted with Et2O. The combined organic
phase was washed with brine, dried (Na2SO4) and concentrated
in vacuo to afford a yellow oil. The residue was purified by
chromatography on silica gel, eluting with hexane–EtOAc (2:1
to 1:2 gradient), to afford the target compound as a colorless
oil (77% yield, 93% ee). Rf = 0.35 [hexane–EtOAc 1:1 (v/v)].
1H NMR (300 MHz, CDCl3): d 7.42–7.38 (2 H, m), 7.24–7.20
(2 H, m), 6.59 (1 H, d, J = 16.2 Hz), 6.22 (1 H, dd, J = 15.9 Hz,
5.9 Hz), 5.91–5.77 (1 H, m), 5.22–5.15 (2 H, m), 4.39–4.32
(1 H, m), 3.13 (3 H, s), 2.44–2.36 (2 H, m). 13C NMR (75 MHz,
CDCl3): d 148.3, 136.0, 133.7, 132.9, 128.5, 127.8, 122.1, 118.7,
71.3, 42.0, 37.4. IR (thin film) 3370, 3029, 1501, 1375, 1356, 1178,
1151, 969, 872, 695 (cm−1). HRMS-EI (m/z): found, 268.0760.
C13H16O4S requires 268.0769. Chiral HPLC (Daicel Chiralpak
AD-H, hexane–i-PrOH = 9:1, flow rate = 1.00 ml min−1) tR =
21.0 min (major), tR = 18.9 min (minor).
Methanesulfonic acid 4-{(4S,5R)-3-(4-fluorophenyl)-5-[(E)-3-
(4-fluorophenyl)-3-oxopropenyl]-4,5-dihydroisoxazol-4-yl}phenyl
ester (25). To homoallyl alcohol 23 (80.0 mg, 0.155 mmol,
1.00 eq.) in CH2Cl2 (1.5 ml) at 25 ◦C was added pyridine
(24.6 mg, 0.310 mmol, 2.00 eq.) followed by methanesulfonyl
chloride (26.◦7 mg, 0.233 mmol, 1.50 eq.). The solution was
stirred at 23 C for 16 h, then diluted with CH2Cl2 and water.
The phases were separated and the aqueous phase was extracted
with CH2Cl2. The combined organic phase was washed with
brine, dried (Na2SO4) and concentrated in vacuo. The residue
was dissolved in EtOAc and passed over a small plug of silica
gel, eluting with EtOAc. The solution was concentrated in vacuo.
The residue was dissolved in CH2Cl2 (1.0 ml) and DBU (0.10 ml)
was added. The solution was heated at reflux for 12 h, then
cooled and diluted with saturated aqueous NH4Cl and CH2Cl2.
The phases were separated and the aqueous phase was extracted
Methanesulfonic acid 4-[(1E,5E)-(S)-3-hydroxy-6-phenylhexa-
1,5-dienyl]phenyl ester (21). To Pd(OAc)2 (82.0 mg,
0.365 mmol, 0.10 eq.) in acetonitrile (14.0 ml) at 25 ◦C
was added triphenylphosphine (192 mg, 0.730 mmol, 0.20 eq.),
triethylamine 140 (7 ml), iodobenzene (820 mg, 4.02 mmol,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3
3 5 1 9

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with CH2Cl2. The combined organic phase was washed with
brine, dried (Na2SO4) and concentrated in vacuo. The residue
was dissolved in EtOAc and passed over a small plug of silica
gel, eluting with EtOAc. The solution was concentrated in vacuo.
The residue was dissolved in THF (2.6 ml) and water (2.6 ml)
and NaIO4 (222 mg, 1.04 mmol, 8.00 eq.) was added followed by
K2OsO4·2H2O (9.5 mg, 26 lmol, 0.20 eq.). The suspension was
stirred for 14 h, then diluted with EtOAc and saturated aqueous
Na2SO3. The phases were separated and the aqueous phase
was extracted with EtOAc. The combined organic phase was
washed with brine, dried (Na2SO4) and concentrated in vacuo.
The residue was immediately dissolved in CH2Cl2 (2.0 ml) and
1-(4-fluorophenyl)-2-(triphenyl-k5-phosphanylidene)ethanone
1312 (200 mg, 0.516 mmol, 3.30 eq.) was added. The solution
was stirred at 23 ◦C for 30 min and then concentrated in vacuo.
The residue was purified by chromatography on silica gel,
eluting with hexane–EtOAc (3:2 to 1:1 gradient), to afford the
target compound as a colorless solid (30% yield, four steps).
(5.556 g, 38.00 mmol) was added in one portion. After 20 min
stirring, the mixture was transferred to a pre-cooled acetone
bath (8 ◦C), stirred for 5 min and p-FC6H4CHO (3.632 g,
29.26◦mmol) was added in one portion. After 15 h stirring at
9–12 C, the suspension was diluted with EtOAc (125 ml) and
washed with sat. aq. NH4Cl (2 × 30 ml) and brine (30 ml).
The organic layer was evaporated on celite and purified by dry
column vacuum chromatography (5.4 × 5.5 cm) on silica gel,
eluting with a gradient of 0–50% EtOAc in hexane (v/v), to give
alcohol 28 (5.896 g, 75%) as a light yellow oil. Enantiomeric
excess as determined by HPLC analysis: 96% ee; tR 20 min (R-
28), 28 min (S-28) (Chiracel OD-H 25 cm, 6% iPrOH in hexane,
flow 1.0 ml min−1, 254 nm). Rf [EtOAc–hexane 1:3 (v/v)] 0.28.
1H-NMR (300 MHz, CDCl3): d 7.50 (2 H, dd, J = 5.6, 8.7 Hz),
7.38–7.32 (5 H, m), 7.06 (2 H, t, J = 8.7 Hz), 5.48 (1 H, s),
4.60 (2 H, s), 4.26 (2 H, s), 2.84 (1 H, s). 13C-NMR (75 MHz,
CDCl3): d 164.01, 160.75, 136.95, 136.04 (C), 128.30, 128.21,
127.92, 127.81, 115.43, 115.13 (CH), 86.13, 82.62 (C), 71.74
(CH2), 63.74 (CH), 57.35 (CH2). 19F-NMR (282 MHz, CDCl3):
d −113.28 (1 F, septet, J = 4.3 Hz). IR (cm−1): 3390, 3066, 3032,
2859, 1604, 1508, 1455, 1413, 1386, 1355, 1224, 1158, 1121, 1096,
1072, 1028, 1014, 842, 772, 744, 699, 592, 561, 498. MALDI-
MS: found, 293.0947 [MNa]+. C17H15FO2Na requires 293.0954.
Anal.: found, C, 75.39; H, 5.62. C17H15FO2 requires C, 75.54; H,
5.59%.
◦
Rf = 0.51 [hexane–EtOAc 1:1 (v/v)]. Mp (MeOH) 64 C. aD27.8
+255◦ (c 1.00 in CH2Cl2). 1H NMR (300 MHz, CDCl3): d
8.03–7.99 (2 H, m), 7.58–7.54 (2 H, m), 7.35–6.96 (8 H, m),
5.20 (1 H, ddd, J = 4.7 Hz, 4.7 Hz, 1.6 Hz), 4.62 (1 H, d, J =
5.0 Hz), 3.16 (3 H, s). 13C NMR (75 MHz, CDCl3): d 187.7,
165.7 (d, J = 255 Hz), 163.6 (d, J = 251 Hz), 156.6, 148.6,
142.6, 136.9, 133.4, 131.3 (d, J = 9 Hz), 129.2 (d, J = 9 Hz),
129.0, 125.2, 123.9, 123.2, 116.0 (d, J = 22 Hz), 115.8 (d, J =
22 Hz), 88.4, 59.4, 37.8. IR (thin film) 3028, 2938, 1672, 1626,
1598, 1511, 1369, 1235, 1153, 972, 872, 838 (cm−1). HRMS-EI
(m/z): found, 483.0948. C25H19F2NO5S requires 483.0952.
4-(tert-Butyldimethylsilanyloxy)-4-(4-fluorophenyl)butan-1-ol
(29). Alcohol 28 (4.108 g, 15.20 mmol) was dissolved in
anhydrous DMF (50 ml). Imidazole (2.123 g, 31.1 mmol) and
TBDMSCl (3.590 mg, 23.8 mmol) were added sequentially and
the solution was stirred for 3.5 h, followed by addition of 50%
sat. aq. NaHCO3 (150 ml). After extraction with ether (4 ×
50 ml), the combined organic phase was washed successively
with sat. aq. NaHCO3 (50 ml) and H2O (50 ml), evaporated and
dried shortly under high vacuum. The residue was dissolved in
EtOH (40 ml). Na2CO3 (3.229 g, 30.5 mmol) and Pd/C [10%
(w/w), 223 mg] were added and the suspension was evacuated
4 times with H2 and stirred under an H2 atmosphere for 19 h.
The suspension was diluted with 10% EtOAc–hexane [250 ml
(v/v)] and filtered through a short plug of silica gel [2 ×
25 ml 20% EtOAc–hexane washings (v/v)], evaporated and
dried shortly under high vacuum. The residue was dissolved in
EtOH (40 ml). Pd/C [10% (w/w), 142 mg] was added and the
suspension was evacuated 4 times with H2 and stirred under an
H2 atmosphere for 1 h. Additional Pd/C [10% (w/w), 190 mg]
was added and the suspension was evacuated 4 times with H2
and stirred under an H2 atmosphere for 1.25 h. The suspension
was evaporated on celite and purified by dry column vacuum
chromatography (5.2 × 5.5 cm) on silica gel, eluting with a
gradient of 0–25% EtOAc in hexane (v/v), to give alcohol 29
(3.643 g, 80%) as a light yellow oil. Rf [EtOAc–hexane 1:3
(v/v)] 0.37. 1H-NMR (300 MHz, CDCl3): d 7.24 (2 H, dd,
J = 5.6, 8.7 Hz), 6.97 (2 H, t, J = 8.7 Hz), 4.69 (1 H, dt, J =
1.2, 5.0 Hz), 3.59 (2 H, dt, J = 1.2, 6.2 Hz), 2.18 (1 H, bs),
1.77–1.45 (4 H, m), 0.87 (9 H, s), 0.02 (3 H, s), −0.15 (3 H, s).
13C-NMR (75 MHz, CDCl3): d 163.37, 160.13, 140.96, 140.91
(C), 127.32, 127.23, 114.94, 114.64, 74.16 (CH), 62.76, 37.19,
28.47 (CH2), 25.76 (CH3), 18.15 (C), −4.71, −5.05 (CH3). IR
(cm−1): 3339, 2954, 2930, 2885, 2858, 1606, 1510, 1472, 1463,
1362, 1252, 1223, 1156, 1092, 1060, 984, 890, 836, 776, 668,
560. MALDI-MS: found, 321.1643 [MNa]+. C16H27FO2SiNa
requires 321.1662. Anal.: found, C, 64.36; H, 9.15. C16H27FO2Si
requires C, 64.39; H, 9.12%.
Methanesulfonic acid 4-{(4S,5R)-3-(4-fluorophenyl)-5-[(S)-
3-(4-fluorophenyl)-3-hydroxypropyl]-4,5-dihydroisoxazol-4-yl}-
phenyl ester (26). To alkene 25 (6.7 mg, 14 lmol) in methanol
(1.3 ml) was added Pd on carbon (10%) (2 mg). The atmosphere
was changed to hydrogen (1 atm) and the suspension was stirred
for 10 min at 23 ◦C. The suspension was diluted with EtOAc
(15 ml) and filtered through a plug of silica gel, eluting with
EtOAc. The filtrate was concentrated in vacuo and redissolved
in CH2Cl2 (0.50 ml). The solution was cooled to −20 ◦C and
(R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo-oxazaborole-
2-methyl-oxazaborolidine (solution in toluene, 0.5 M) (10 ll,
5.0 lmol, 0.50 eq.) was added, followed by borane–dimethyl-
sulfide complex (1.5 mg, 20 lmol, 2.0 eq.). The solution was
stirred at −20 ◦C for 2 h, then warmed to 0 ◦C and stirred
for an additional 1 h. To this solution was added methanol
(50 ll) followed by saturated aqueous NaHCO3 solution and
CH2Cl2. The phases were separated and the aqueous phase
was extracted with CH2Cl2. The combined organic phase was
washed with brine, dried (Na2SO4) and concentrated in vacuo.
The residue was purified by chromatography on silica gel,
eluting with hexane–EtOAc (1:1 to 1:2 gradient), to afford the
target compound as a colorless solid (75% yield, two steps).
◦
Rf = 0.44 [hexane–EtOAc 1:2 (v/v)]. Mp 68 C. a2D6.2 +135◦
1
(c 0.25 in CH2Cl2). H NMR (300 MHz, CDCl3): d 7.55–7.51
(2 H, m), 7.33–7.24 (6 H, m), 7.06–6.95 (4 H, m), 4.75–4.71 (1 H,
m), 4.52–4.46 (1 H, m), 4.36 (1 H, d, J = 5.0 Hz), 3.14 (3 H, s),
1.99–1.82 (5 H, m). 13C NMR (75 MHz, CDCl3): d 163.8 (d,
J = 250 Hz), 162.5 (d, J = 245 Hz), 157.1, 148.7, 140.2, 138.4,
129.3 (d, J = 9 Hz), 129.2, 127.6 (d, J = 8 Hz), 125.0, 123.3,
116.2 (d, J = 22 Hz), 115.7 (d, J = 22 Hz), 90.7, 73.7, 59.3,
37.8, 35.1, 31.6. IR (thin film) 3388, 2930, 1604, 1151, 1368,
1222, 1151, 871, 837 (cm−1). HRMS-EI (m/z): found, 487.1256.
C25H23F2NO5S requires 487.1265.
4-Benzyloxy-1-(4-fluorophenyl)but-2-yn-1-ol (28). A 50 ml
Olefin (31). Alcohol 29 was dissolved in CH2Cl2 (50 ml).
Dess–Martin periodinane (5.658 g, 13.3 mmol) was added and
the milky solution was stirred at room temperature for 1.5 h.
Sat. aq. Na2SO3 (100 ml) was added and the layers were swirled
until the solid had dissolved. The layers were separated and
the aqueous phase was extracted with CH2Cl2 (2 × 40 ml). The
combined organic phase was evaporated on celite and purified by
Schlenk flask was charged with Zn(OTf)2 (12.647 g, 34.79 mmol)
◦
and heated to 120 C under high-vacuum (0.2 Torr) for 3.5 h.
After cooling, (+)-N-methylephedrine (6.595 g, 36.79 mmol)
was added and the flask was purged with Ar for 15 min. Anhy-
drous toluene (14 ml) followed by Et3N (3.874 g, 38.3 mmol)
were added and, after 3 h stirring, benzyl propargyl ether31
3 5 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3

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dry column vacuum chromatography (5.1 × 5.5 cm) on silica gel,
eluting with a gradient of 0–10% EtOAc in hexane (v/v), to give
the intermediary aldehyde (2.093 g, 80%) as a light yellow oil. Rf
[EtOAc–hexane 1:3 (v/v)] 0.63. 1H-NMR (300 MHz, CDCl3): d
9.73 (1 H, d, J = 1.5 Hz), 7.25 (2 H, dd, J = 5.6, 8.7 Hz), 6.99(2 H,
t, J = 9.0 Hz), 4.74 (1 H, dt, J = 5.0, 6.8 Hz), 2.52–2.35 (2 H, m),
2.06–1.88 (2 H, m), 0.88 (9 H, s), 0.02 (3 H, s), −0.16 (3 H, s). 13C-
NMR (75 MHz, CDCl3): d 201.91 (CH), 163.35, 160.10, 140.13
(C), 127.20, 127.10, 115.04, 114.75, 73.03 (CH), 39.69, 33.11
(CH2), 25.85 (CH3), 18.21 (C), −4.61, −4.95 (CH3). IR (cm−1):
2955, 2938, 2888, 2858, 2720, 1727, 1606, 1509, 1472, 1464, 1412,
1390, 1362, 1254, 1223, 1156, 1090, 1014, 837, 776, 670, 540.
Anal.: found, C, 64.95; H, 8.36. C16H25FO2Si requires C, 64.82;
H, 8.50%. LiCl (140.8 mg, 3.32 mmol) was heated shortly with
a heat gun under high-vacuum and, after cooling, anhydrous
CH3CN (5 ml), phosphonate 3021 (660 mg, 1.68 mmol) and
DBU (221 mg, 1.45 mmol) were added sequentially. After 3 min
stirring, the aldehyde (407.3 mg, 1.37 mmol) was added and the
suspension was stirred at room temperature for 2.5 h, followed
by addition of 50% sat. aq. NaHCO3 (60 ml). After extraction
with ether–hexane [1:1 (v/v), 4 × 25 ml], the combined organic
phase was washed with brine (25 ml), evaporated on celite and
purified by dry column vacuum chromatography (4.6 × 3.3 cm)
on silica gel, eluting with a gradient of 0–20% EtOAc in hexane
(v/v), to give olefin 31 (520.7 mg, 71%) as a colourless oil. Rf
[EtOAc–hexane 1:3 (v/v)] 0.43. 1H-NMR (300 MHz, CDCl3): d
7.25 (2 H, dd, J = 5.6, 8.7 Hz), 7.10–6.94 (3 H, m), 6.53 (1 H,
d, J = 14.9 Hz), 4.65 (1 H, dd, J = 5.0, 7.5 Hz), 3.91 (1 H,
dd, J = 5.6, 6.8 Hz), 3.50 (1 H, d, J = 13.7 Hz), 3.42 (1 H,
d, J = 13.7 Hz), 2.30–2.23 (2 H, m), 2.09–2.02 (2 H, m), 1.90–
1.70 (5 H, m), 1.43–1.30 (2 H, m), 1.15 (3 H, s), 0.95 (3 H, s),
0.85 (9 H, s), 0.01 (3 H, s), −0.20 (3 H, s). 13C-NMR (75 MHz,
CDCl3): d 163.88, 163.39, 160.14, 150.06, 140.63 (C), 127.35,
127.26, 120.91, 114.98, 114.69, 73.24, 64.99 (CH), 53.04 (CH2),
48.33, 47.67 (C), 44.58 (CH), 38.61, 38.39, 32.71, 28.32, 26.40
(CH2), 25.72, 20.72, 19.78 (CH3), 18.04 (C), −4.74, −5.10 (CH3).
IR (cm−1): 2956, 2885, 2859, 1684, 1640, 1605, 1509, 1472,
1414, 1374, 1332, 1295, 1250, 1220, 1165, 1134, 1083, 1049, 995,
970, 860, 836, 774, 544. MALDI-MS: found, 558.2479 [MNa]+.
C28H42FNO4SSiNa requires 558.2486. Anal.: found, C, 62.84;
H, 7.78; N, 2.58. C28H42FNO4SSi requires C, 62.77; H, 7.90; N,
2.61%.
H, 7.83; N, 7.16. C29H44FN3O4SSi requires C, 60.28; H, 7.67;
N, 7.27%. 32A: Rf [EtOAc–hexane 1:3 (v/v)] 0.11. H-NMR
1
(300 MHz, CDCl3): d 7.21 (2 H, dd, J = 5.3, 8.4 Hz), 6.96 (2
H, t, J = 8.7 Hz), 6.62 (1 H, s), 6.14 (1 H, d, J = 3.1 Hz), 4.59
(1 H, dd, J = 5.0, 6.8 Hz), 4.39 (1 H, dd, J = 3.1, 7.5 Hz),
3.90 (1 H, dd, J = 5.0, 7.5 Hz), 3.52 (1 H, d, J = 13.7 Hz),
3.45 (1 H, d, J = 13.7 Hz), 3.37 (1 H, dd, J = 6.2, 13.7 Hz),
2.08–1.13 (2 H, m), 1.00 (3 H, s), 0.96 (3 H, s), 0.85 (9 H, s), 0.00
(3 H, s), −0.19 (3 H, s). MALDI-MS: found, 600.2691 [MNa]+.
C29H44FN3O4SSiNa requires 600.2704.
(p-FC6H4)3Bi. p-FC6H4Br (5.446 g, 31.1 mmol) dissolved in
anhydrous ether (100 ml) was added to Mg turnings (844 mg,
34.7 mmol) and I2 (28 mg, 0.11 mmol) and the suspension was
refluxed for 1 h 20 min and cooled to 0 ◦C. BiCl3 (3.931 g,
12.5 mmol) was added and, after 15 min stirring at 0 ◦C, the
suspension was refluxed for 4 h. The suspension was cooled,
H2O (3 ml) was added and the suspension was evaporated
on celite and purified by dry column vacuum chromatography
(4.8 × 5.5 cm) on silica gel, eluting with a gradient of 0–14%
EtOAc in hexane (v/v), to give (p-FC6H4)3Bi (2.862 g, 56%) as a
light yellow solid. Rf [EtOAc–hexane 1:9 (v/v)] 0.42. 1H-NMR
(300 MHz, CDCl3): d 7.72 (2 H, dd, J = 6.2, 8.1 Hz), 7.13 (2 H,
t, J = 9.0 Hz). 13C-NMR (75 MHz, CDCl3): d 164.19, 160.92,
149.36 (C), 139.02, 138.92, 117.96, 117.70 (CH). 19F (282 MHz,
CDCl3): d −111.97 (1 F, m).
N-Aryl pyrazoline (33). Pyrazoline 32 (409.8 mg,
0.709 mmol), Cu(OAc)2 (296 mg, 1.63 mmol) and (p-FC6H4)3Bi
(950 mg, 1.92 mmol) were dissolved in anhydrous CH2Cl2
(5 ml). Anhydrous Et3N (165 mg, 1.63 mmol) was added and
the dark green suspension was stirred at room temperature for
12.5 h. After evaporation on celite the residue was purified by
dry column vacuum chromatography (4.5 × 3.3 cm) on silica
gel, eluting with a gradient of 0–30% EtOAc in hexane (v/v), to
give pyrazoline 33 (320.8 mg, 63%) as a light yellow foam. Rf
[EtOAc–hexane 1:3 (v/v)] 0.33. 1H-NMR (300 MHz, CDCl3): d
7.24 (2 H, dd, J = 5.3, 8.4 Hz), 7.01–6.94 (4 H, m), 6.89 (2 H, t,
J = 8.7 Hz), 6.68 (1 H, d, J = 1.9 Hz), 5.05 (1 H, d, J = 3.7 Hz),
4.62 (1 H, t, J = 5.3 Hz), 3.85 (1 H, dd, J = 4.4, 7.5 Hz), 3.59
(1 H, d, J = 14.3 Hz), 3.58 (1 H, d, J = 14.3 Hz), 3.41–3.35
(1 H, m), 1.98–1.78 (5 H, m), 1.72–1.60 (3 H, m), 1.41–1.23
(3 H, m), 1.21 (3 H, s), 0.98 (3 H, s), 0.88 (9 H, s), 0.04 (3 H, s),
−0.17 (3 H, s). 13C-NMR (75 MHz, CDCl3): d 169.54, 163.38,
160.14, 158.46, 155.30 (C), 142.10 (CH), 140.75 (C), 127.32,
127.22, 115.71, 115.40, 114.96, 114.67, 114.22, 114.12, 73.99,
65.48, 64.93 (CH), 53.02 (CH, CH2), 49.05, 47.77 (C), 44.31
(CH), 37.98, 36.95, 32.76, 27.79, 26.25 (CH2), 25.75, 20.37,
19.77 (CH3), 18.07 (C), −4.77, −5.01 (CH3). 19F (282 MHz,
CDCl3): d −116.27 (1 F, m), −125.73 (1 F, septet, J = 4.3 Hz).
IR (cm−1): 2957, 2857, 1699, 1606, 1510, 1471, 1413, 1362, 1334,
1268, 1250, 1221, 1166, 1136, 1113, 1088, 1063, 987, 836, 776,
759, 538. MALDI-MS: found, 540.2127 [MH − TBDMSOH]+.
C29H32F2N3O3S requires 540.2132; found, 694.2909 [MNa]+.
C35H47F2N3O4SSiNa requires 694.2922. Anal.: found, C, 62.37;
H, 7.05; N, 6.03. C35H47F2N3O4SSi requires C, 62.56; H, 7.05;
N, 6.25%.
Pyrazoline (32). Olefin 31 was dissolved in anhydrous
toluene (2.0 ml). TMSCHN2 (2 M in hexanes, 1.50 ml, 3.0 mmol)
was added and the solution was stirred at room temperature for
64 h. After evaporation, the residue was dissolved in CH2Cl2
(10 ml). TFA (202 mg, 1.77 mmol) was added and the solution
was stirred for 20 min. Sat. aq. NaHCO3 (1.5 ml) was added
and the mixture was evaporated on celite and purified by dry
column vacuum chromatography (4.5 × 3.3 cm) on silica gel,
eluting with a gradient of 0–40% EtOAc in hexane (v/v), to give
diastereomeric pyrazolines 32 (468 mg, 84%) and 32A (54.3 mg,
10%) as light yellow foams. 32: Rf [EtOAc–hexane 1:3 (v/v)]
1
0.25. H-NMR (300 MHz, CDCl3): d 7.21 (2 H, dd, J = 5.6,
8.7 Hz), 6.95 (2 H, t, J = 8.7 Hz), 6.60 (1 H, s), 6.16 (1 H, d,
J = 5.6 Hz), 4.65 (1 H, t, J = 5.0 Hz), 4.33 (1 H, dd, J = 5.9,
9.7 Hz), 3.87 (1 H, dd, J = 5.0, 7.5 Hz), 3.67–3.62 (1 H, bs), 3.53
(1 H, d, J = 13.7 Hz), 3.44 (1 H, d, J = 13.7 Hz), 2.15–1.99 (2 H,
m), 1.91–1.86 (3 H, m), 1.66–1.51 (3 H, m), 1.47–1.21 (3 H,
m), 1.14 (3 H, s), 0.95 (3 H, s), 0.86 (9 H, s), 0.01 (3 H, s),
−0.17 (3 H, s). 13C-NMR (75 MHz, CDCl3): d 167.96, 163.12,
159.89 (C), 146.91 (CH), 140.52, 140.49 (C), 127.15, 127.05,
114.83, 114.54, 73.37, 66.44, 65.09 (CH), 52.81 (CH2), 48.91 (C),
48.04 (CH), 47.79 (C), 44.33 (CH), 37.98, 37.79, 32.55, 26.76,
26.45 (CH2), 25.82, 20.68, 19.84 (CH3), 18.16 (C), −4.64, −4.90
(CH3). IR (cm−1): 3360, 2955, 2857, 1700, 1604, 1509, 1472,
1390, 1329, 1273, 1250, 1236, 1221, 1166, 1134, 1086, 1066, 994,
939, 836, 775, 694, 542. MALDI-MS: found, 600.2691 [MNa]+.
C29H44FN3O4SSiNa requires 600.2704. Anal.: found, C, 60.25;
Carboxylic acid (34). Pyrazoline 33 (228.5 mg, 0.340 mmol)
was dissolved in anhydrous MeOH (5 ml), glycine (226 mg,
3.01 mmol) and KCN (305 mg, 4.68 mmol) were added and the
suspension was stirred at 50 ◦C in a sealed flask for 19 h. After
cooling, the suspension was evaporated on celite and purified
twice by dry column vacuum chromatography (4.8 × 2.0 cm)
on silica gel, eluting first with a gradient of 0–60% MeOH in
EtOAc and second with 0–20% MeOH in CH2Cl2 (v/v), to give
carboxylic acid 34 (135.6 mg, 75%) as a light yellow oil. Rf
[MeOH–EtOAc 1:3 (v/v)] 0.38. 1H-NMR (300 MHz, CDCl3): d
7.33 (2 H, dd, J = 5.6, 8.7 Hz), 7.01–6.93 (6 H, m), 6.80 (1 H,
s), 4.78–4.73 (1 H, m), 3.95–3.78 (3 H, m), 3.40–3.32 (1 H, m),
1.88–1.65 (4 H, m), 0.86 (9 H, s), 0.04 (3 H, s), −0.17 (3 H, s).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3
3 5 2 1

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13C-NMR (75 MHz, CDCl3): d 174.55, 165.01, 161.79, 160.58
(C), 145.83 (CH), 144.14, 144.11, 142.57, 142.53 (C), 128.94,
128.82, 116.58, 116.34, 116.24, 115.95, 115.66, 74.91, 70.88,
55.50 (CH), 42.25, 38.40, 30.07 (CH2), 26.38 (CH3), 19.06 (C),
−4.40, −4.71 (CH3). 19F (282 MHz, CDCl3): d −116.75 (1 F, m),
−125.36 (1 F, septet, J = 4.3 Hz). IR (cm−1): 3325, 2954, 2930,
2858, 1737, 1671, 1606, 1508, 1472, 1410, 1361, 1252, 1224, 1157,
1088, 1006, 984, 835, 776, 760, 668, 608, 554. MALDI-MS: 576.2
[M − H + 2Na]+.
129.44, 128.62, 127.39, 115.76, 115.65, 115.45, 115.37, 114.92,
114.82, 112.28, 73.17, 63.09, 53.68, 35.69, 28.19. 19F (282 MHz,
CD3OD): d −114.03 (1 F, m), −123.73 (1 F, p, J = 6.4 Hz). IR
(cm−1): 3300, 2926, 1606, 1509, 1450, 1396, 1224, 1192, 1090,
998, 828, 736, 685, 618, 578.
4-{2-(4-Fluorophenyl)-4-[3-(4-fluorophenyl)-3-hydroxypropyl]-
3,4-dihydro-2H-pyrazol-3-ylmethoxy}phenol (38). Pyrazoline
33 (101.5 mg, 0.151 mmol) was dissolved in anhydrous THF
(5 ml) −78 ◦C, LiAlH4 (33 mg, 0.87 mmol) was added and the
2-{2-(4-Fluorophenyl)-4-[3-(4-fluorophenyl)-3-hydroxypropyl]-
◦
suspension was stirred at −78 C for 4.5 h. Sat. aq. NaHCO3
3,4-dihydro-2H-pyrazol-3-yl}-4H-oxazol-5-one
(36). Car-
(1 ml) was added and the mixture was evaporated on celite and
purified twice by dry column vacuum chromatography (4.6 ×
2.0 cm) on silica gel, eluting with a gradient of 0–30% EtOAc
in hexane (v/v), to give the intermediary alcohol (52.7 mg,
76%) as a light yellow oil. Rf [EtOAc–hexane 1:3 (v/v)] 0.23.
1H-NMR (300 MHz, CDCl3): d 7.23 (2 H, dd, J = 5.6, 8.7 Hz),
7.04–6.92 (6 H, m), 6.67 (1 H, d, J = 1.2 Hz), 4.64 (1 H, t, J =
5.9 Hz), 3.81 (1 H, dd, J = 4.0, 11.5 Hz), 3.68–3.58 (2 H, m),
3.12 (1 H, dd, J = 6.2, 6.8 Hz), 1.86 (1 H, bs), 1.77–1.67 (2 H,
m), 1.58–1.48 (2 H, m), 0.86 (9 H, s), 0.00 (3 H, s), −0.17
(3 H, s). 13C-NMR (75 MHz, CDCl3): d 163.47, 160.22, 158.83,
155.68 (C), 144.84 (CH), 142.35, 140.67, 140.62 (C), 127.26,
127.16, 115.75, 115.46, 115.11, 115.06, 114.96, 114.83, 73.76,
66.81 (CH), 62.37 (CH2), 50.05 (CH), 37.72, 28.28 (CH2), 25.75
(CH3), 18.12 (C), −4.67, −5.01 (CH3). 19F (282 MHz, CDCl3):
d −115.25 (1 F, septet, J = 4.3 Hz), −124.25 (1 F, septet, J =
4.3 Hz). IR (cm−1): 3401, 2953, 2930, 2885, 2858, 1672, 1605,
1509, 1472, 1463, 1416, 1362, 1296, 1252, 1223, 1156, 1086,
1006, 979, 938, 861, 835, 776, 666, 608, 554. MALDI-MS:
found, 429.2175 [M − CH2OH]. C24H31F2N2O2Si requires
429.2174. Found, 459.2279 [M − H]+. C25H33F2N2O2Si requires
459.2279. This alcohol (70.8 mg, 0.154 mmol) was dissolved in
anhydrous CH2Cl2 (5 ml), anhydrous Et3N (0.50 ml, 3.9 mmol),
DMAP (6.8 mg, 0.056 mmol) and TsCl (69 mg, 0.36 mmol)
were added and the solution was stirred at room temperature
for 12.5 h, evaporated on celite and purified by dry column
vacuum chromatography (4.4 × 2.0 cm) on silica gel, eluting
with a gradient of 0–20% EtOAc in hexane (v/v), to give the
intermediary tosylate (78.4 mg, 83%) as a colourless oil. Rf
boxylic acid 34 (22.0 mg, 0.041 mmol) was dissolved in
anhydrous CH2Cl2 (5 ml), N-cyclohexyl-Nꢀ-2-(N-methyl-
morpholinio)ethylcarbodiimide p-toluenesulfonate 35 (19.0 mg,
0.045 mmol) was added and the mixture was stirred at reflux
for 2 h. The solution was cooled, diluted with CH2Cl2 (10 ml),
washed with sat. aq. NaHCO3 (10 ml) and H2O (10 ml),
dried (Na2SO4), filtered through a short plug of silica gel
[15 ml EtOAc–hexane washings, 1:1 (v/v)] and evaporated to
give the oxazolone 36 (8.3 mg, 39%) as a colourless oil. Rf
1
[EtOAc–hexane 1:1 (v/v)] 0.58. H-NMR (300 MHz, CDCl3):
d 7.23 (2 H, dd, J = 5.6, 8.7 Hz), 7.06–6.93 (6 H, m), 6.73 (1 H,
s), 4.68–4.64 (1 H, m), 4.39 (1 H, d, J = 6.2 Hz), 4.21 (2 H,
s), 3.47–3.39 (1 H, m), 1.80–1.57 (4 H, m), 0.86 (9 H, s), 0.00 (3 H,
s), −0.17 (3 H, s). 13C-NMR (75 MHz, CDCl3): d 174.69, 165.28,
163.58, 160.32, 159.11, 155.94, 142.46, 141.30, 140.28, 127.29,
127.18, 115.89, 115.60, 115.26, 114.97, 114.87, 114.76, 73.61,
63.26, 54.23, 52.64, 37.50, 29.70, 27.96, 25.78, 18.14, −4.63,
−5.0. 19F (282 MHz, CDCl3): d −115.81 (1 F, m), −124.45 (1 F,
septet, J = 4.3 Hz). IR (cm−1): 2930, 2858, 1835, 1674, 1606,
1509, 1472, 1362, 1252, 1224, 1157, 1088, 1021, 905, 836, 777,
736, 608, 553. MALDI-MS: 429.2 [M − C3H2NO2]+.
Benzenesulfonic acid 2-{2-(4-fluorophenyl)-4-[3-(4-fluorophenyl)-
3-hydroxypropyl]-3,4-dihydro-2H-pyrazol-3-yl}oxazol-5-yl ester
(37). Oxazolone 36 (24 mg, 0.047 mmol) was dissolved in
anhydrous CH2Cl2 (5 ml), Et3N (0.2 ml, 1.4 mmol) followed by
PhSO2Cl (0.1 ml, 0.78 mmol) were added and the mixture was
stirred at room temperature for 22 h. Sat. aq. NaHCO3 (1 ml)
was added and the mixture was evaporated on celite and purified
by dry column vacuum chromatography (4.5 × 2.0 cm) on silica
gel, eluting with a gradient of 0–60% EtOAc in hexane (v/v), to
give the intermediary oxazole (12.2 mg, 40%) as a yellow oil. Rf
[EtOAc–hexane 1:3 (v/v)] 0.29. 1H-NMR (300 MHz, CDCl3): d
7.76 (2 H, d, J = 8.1 Hz), 7.63 (1 H, tt, J = 1.2, 7.5 Hz), 7.42 (2 H,
dd, J = 7.5, 8.7 Hz), 7.21 (2 H, dd, J = 5.3, 8.4 Hz), 6.99 (2 H, t,
J = 8.7 Hz), 6.91 (4 H, d, J = 6.2 Hz), 6.66 (1 H, d, J = 1.2 Hz),
6.52 (1 H, s), 4.64–4.60 (1 H, m), 4.51 (1 H, d, J = 7.5 Hz), 3.35–
3.30 (1 H, m), 1.74–1.53 (4 H, m), 0.85 (9 H, s), 0.01 (3 H, s),
−0.18 (3 H, s). 13C-NMR (75 MHz, CDCl3): d 157.31, 142.38,
135.27, 129.41, 128.62, 127.29, 127.18, 115.73, 115.44, 115.21,
114.90, 114.81, 112.25, 73.56, 63.05, 53.78, 27.75, 25.78, 18.14,
−4.65, −5.02. 19F (282 MHz, CD3OD): d −115.91 (1 F, m),
−124.69 (1 F, p, J = 6.4 Hz). IR (cm−1): 2930, 2857, 1606, 1509,
1451, 1398, 1224, 1193, 1157, 1090, 999, 914, 829, 777, 752, 685,
618, 578, 554. This oxazole (12.0 mg, 0.018 mmol) was dissolved
in anhydrous THF (1.0 ml, teflon bottle), anhydrous pyridine
(0.20 ml) followed by HF·pyridine complex (0.20 ml) were added
and the solution was stirred at room temperature for 10 h, diluted
with ether (10 ml) and washed with sat. aq. NaHCO3 (2 × 5 ml).
The organic layer was evaporated on celite and purified by dry
column vacuum chromatography (3.2 × 2.0 cm) on silica gel,
eluting with a gradient of 0–100% EtOAc in hexane (v/v), to
give oxazole 37 (3.9 mg, 39%) as a light brown oil. Rf [EtOAc–
1
[EtOAc–hexane 1:3 (v/v)] 0.44. H-NMR (300 MHz, CDCl3):
d 7.68 (2 H, d, J = 8.7 Hz), 7.25 (4 H, t, J = 8.1 Hz), 6.99
(2 H, t, J = 8.7 Hz), 6.92–6.80 (4 H, m), 6.64 (1 H, d, J =
1.2 Hz), 4.65 (1 H, dd, J = 4.4, 6.8 Hz), 4.12 (1 H, dd, J =
2.5, 9.3 Hz), 3.92–3.81 (2 H, m), 3.08–3.01 (1 H, m), 2.42
(3 H, s), 1.80–1.43 (4 H, m), 0.87 (9 H, s), 0.01 (3 H, s),
−0.17 (3 H, s). 13C-NMR (75 MHz, CDCl3): d 163.49, 160.24,
158.59, 155.43, 145.16 (C), 143.40 (CH), 140.54, 132.21 (C),
129.84, 127.82, 127.32, 127.21, 115.79, 115.48, 115.12, 114.83,
114.31, 114.22, 73.50 (CH), 67.45 (CH2), 62.42, 50.74 (CH),
37.35, 27.87 (CH2), 25.77, 21.59 (CH3), 18.10 (C), −4.67, −5.01
(CH3). 19F (282 MHz, CDCl3): d −116.01 (1 F, m), −125.40
(1 F, septet, J = 4.3 Hz). IR (cm−1): 3055, 3034, 2953, 2930,
2886, 2857, 1603, 1509, 1472, 1463, 1365, 1307, 1294, 1252,
1223, 1190, 1177, 1156, 1096, 979, 862, 835, 775, 666, 608,
555. MALDI-MS: found, 483.1559 [MH − TBDMSOH]+.
C26H25F2N2O3S requires 483.1554. Found, 637.2330 [MNa]+.
C32H40F2N2O4SSiNa requires 637.2344. This tosylate was
dissolved in anhydrous DMF (2.5 ml), hydroquinone (263 mg,
2.39 mmol) and Cs2CO3 (102.1 mg, 0.313 mmol) were added
and the suspension was stirred at 80 ◦C for 12 h. EtOAc
(30 ml) was added and the organic phase was washed with sat.
aq. NaHCO3 (10 ml) and H2O (10 ml), evaporated on celite
and purified by dry column vacuum chromatography (4.5 ×
2.0 cm) on silica gel, eluting with a gradient of 0–30% EtOAc
in hexane (v/v), to give the intermediary phenol (70.9 mg,
86%) as a colourless oil. Rf [EtOAc–hexane 1:3 (v/v)] 0.33.
1H-NMR (300 MHz, CDCl3): d 7.24 (2 H, dd, J = 5.3, 8.4 Hz),
7.06–6.93 (6 H, m), 6.75–6.68 (5 H, m), 4.67 (1 H, dd, J = 4.4,
6.8 Hz), 4.10–3.98 (2 H, m), 3.74 (1 H, dd, J = 1.2, 7.5 Hz),
1
hexane 1:1 (v/v)] 0.19. H-NMR (300 MHz, CDCl3): d 7.76
(2 H, d, J = 7.5 Hz), 7.64 (1 H, t, J = 7.5 Hz), 7.44 (2 H, t, J =
7.8 Hz), 7.34–7.25 (2 H, m), 7.03 (2 H, t, J = 8.4 Hz), 6.92 (4 H,
d, J = 6.2 Hz), 6.69 (1 H, d, J = 1.9 Hz), 6.52 (1 H, s), 4.66–4.62
(1 H, m), 4.57 (1 H, d, J = 7.5 Hz), 3.42–3.36 (1 H, m), 1.90–1.53
(4 H, m). 13C-NMR (75 MHz, CDCl3): d 142.30, 139.76, 135.32,
3 5 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3

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3.17–3.11 (1 H, m), 1.86–1.54 (4 H, m), 0.88 (9 H, s), 0.02 (3 H,
s), −0.15 (3 H, s). 13C-NMR (75 MHz, CDCl3): d 163.32,
160.08, 158.48, 155.35, 152.31, 149.86 (C), 143.85 (CH), 141.52,
141.49, 140.63 (C), 127.23, 127.12, 115.99, 115.73, 115.51,
115.44, 115.04, 114.75, 114.67, 114.57, 73.78 (CH), 67.79 (CH2),
63.88, 51.51 (CH), 37.77, 28.38 (CH2), 25.89 (CH3), 18.25 (C),
−4.46, −4.80 (CH3). 19F (282 MHz, CDCl3): d −115.31 (1 F,
m), −124.71 (1 F, septet, J = 4.3 Hz). IR (cm−1): 3350, 3056,
2953, 2930, 2885, 2858, 1605, 1509, 1472, 1462, 1362, 1297,
1226, 1156, 1100, 1086, 1050, 1006, 939, 828, 776, 667, 609,
553, 518. MALDI-MS: found, 421.1720 [MH − TBDMSOH]+.
C25H23F2N2O2 requires 421.1728. Found, 553.2677 [MH]+.
C31H39F2N2O3Si requires 553.2698. Found, 575.2505 [MNa]+.
C31H38F2N2O3SiNa requires 575.2517. This phenol (18.4 mg,
0.0333 mmol) was dissolved in anhydrous THF (1.0 ml, teflon
bottle) at 0 ◦C, anhydrous pyridine (0.20 ml) followed by
HF·pyridine complex (0.20 ml) were added and the solution
was allowed to warm to room temperature over several hours
and stirred at room temperature for 22 h. Ether (20 ml) was
added and the solution was washed with sat. aq. NaHCO3
(2 × 5 ml), evaporated on celite and purified by dry column
vacuum chromatography (4.5 × 2.0 cm) on silica gel, eluting
with a gradient of 0–60% EtOAc in hexane (v/v), to give diol
38 (14.4 mg, 99%) as a colourless oil. Rf [EtOAc–hexane 1:1
(v/v)] 0.27. 1H-NMR (300 MHz, CDCl3): d 7.29 (2 H, dd, J =
5.3, 8.4 Hz), 7.06–6.93 (6 H, m), 6.75–6.67 (5 H, m), 4.70 (1 H,
t, J = 6.5 Hz), 4.09–4.03 (2 H, m), 3.72 (1 H, t, J = 10.0 Hz),
3.18 (1 H, dd, J = 4.4, 6.2 Hz), 1.99–1.50 (4 H, m). 13C-NMR
(75 MHz, CDCl3): d 163.72, 160.47, 155.31, 152.26, 149.95
(C), 143.53 (CH), 141.41, 139.78 (C), 127.41, 127.29, 116.01,
115.77, 115.51, 115.23, 114.54, 114.42, 73.49 (CH), 67.60 (CH2),
63.67, 51.35 (CH), 35.89, 28.70 (CH2). 19F (282 MHz, CDCl3):
d −114.89 (1 F, septet, J = 4.3 Hz), −124.64 (1 F, septet, J =
4.3 Hz). IR (cm−1): 3320, 2927, 1604, 1508, 1453, 1366, 1225,
1157, 1102, 1044, 910, 826, 733, 609. MALDI-MS: found,
421.1717 [MH − H2O]+. C25H23F2N2O2 requires 421.1728.
Found, 438.1755 [M]+.C25H24F2N2O3 requires 438.1755. Found,
439.1825 [MH]+. C25H25F2N2O3 requires 439.1833. Found,
461.1650 [MNa]+. C25H24F2N2O3Na requires 461.1653.
5 Ab initio calculations: initial energy-minimization by molecular
mechanics using MacroModel v. 7.0 [pseudosystematical Monte
Carlo conformational search (100 steps, limit 30 kJ mol−1) with
CHCl3 as solvent, MMFFs force field] was followed by a quantum-
mechanical geometry optimization using Jaguar v. 4.2 (B3LYP/6-
31G*) in Maestro v. 4.1.
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Acknowledgements
This research was supported by a KTI grant (6813.2 BTS-LS)
and Lipideon AG. L. K. was supported by a fellowship from
The Technical University of Denmark. T. R. thanks the Fonds
der Chemischen Industrie for a Kekule´ Fellowship.
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50, 779–790.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 1 4 – 3 5 2 3
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