Coupling of sterically hindered aldehyde with fluorinated synthons: Stereoselective synthesis of fluorinated analogues of salinosporamide A

Article abstract of DOI:10.1016/j.jfluchem.2012.01.003

Salinosporamide A is an irreversible inhibitor of the β-subunits of the 20S proteasome. Its C-5 cyclohexenyl moiety is the key to its affinity and potency as an anticancer agent. Here we describe the synthesis of C-5 difluoromethylated and trifluoromethyl

Full text of DOI:10.1016/j.jfluchem.2012.01.003

Journal of Fluorine Chemistry 136 (2012) 12–19
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Coupling of sterically hindered aldehyde with fluorinated synthons:
Stereoselective synthesis of fluorinated analogues of salinosporamide A
Zeng-Hao Chen a, Bing-Lin Wang a, Andrew J. Kale b, Bradley S. Moore b, Ruo-Wen Wang a,
Feng-Ling Qing a,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
b Scripps Institution of Oceanography and the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Salinosporamide A is an irreversible inhibitor of the
b-subunits of the 20S proteasome. Its C-5
Received 30 December 2011
Received in revised form 14 January 2012
Accepted 16 January 2012
Available online 24 January 2012
cyclohexenyl moiety is the key to its affinity and potency as an anticancer agent. Here we describe the
synthesis of C-5 difluoromethylated and trifluoromethylated analogues of salinosporamide A and their
biological evaluation as proteasome inhibitors against purified yeast 20S proteasome. The synthetic
strategy featured the stereoselective coupling reaction of sterically hindered aldehyde 3 with fluorinated
organolithium reagents.
Keywords:
ß 2012 Elsevier B.V. All rights reserved.
Salinosporamide A
20S proteasome
Fluorinated analogues
1. Introduction
time in complex with the 20S proteasome core particle [12,13].
While the C-2 chloroethyl group is key to salinosporamide A’s
Currently more than half of the pharmaceuticals in use are
derived from natural products [1–3]. The synthesis of natural
product analogues by removing suspected sites of toxicity or by
introducing additional functionalities may enhance potency or
stability of natural medicines [4,5]. In this regards, many
fluorinated analogues of natural compounds have been synthe-
sized due to the special properties of the fluorine atom, such as
strong electronegativity, capacity to enhance metabolic stability,
small size and low polarisability of the C–F bond [6]. From 1957,
more than 150 fluorinated drugs have come into the market and
now make up about 20% of all pharmaceuticals [7,8].
irreversible binding mechanism, its C-5 cyclohexenyl ring is
integral to salinosporamide A’s binding affinity to the 5-subunit
b
of the 20S proteasome [14,15]. In view that the hydrophobic
property of the cyclohexenyl ring is important to the biological
activity of salinosporamide A [14], we sought to replace the
cyclohexenyl ring with fluorinated groups to probe its structure–
activity relationship since fluorinated groups possess significant
hydrophobicity. Herein we report the stereoselective synthesis of
difluoromethylated and trifluoromethylated analogues of salinos-
poramide A, compounds 1A, 1B and 1C (Fig. 1).
Salinosporamide A (1), isolated by Fenical and co-workers in
2003 from the marine bacterium Salinispora tropica [9], is a potent
anticancer agent that recently entered phase I human clinical trials
for the treatment of multiple myeloma and other cancers [10].
Because of its novel chemical structure and promising biological
properties, many synthetic and biosynthetic studies have been
reported towards it and its analogues [11]. One of such studies
involved fluorine substitution at C-13 to replace the reactive
chlorine substituent that acts as a leaving group during the drug’s
2. Results and discussion
The retrosynthetic analysis of analogues 1A–1C is shown in
Scheme 1. The key step is the stereoselective reaction of aldehyde 3
with fluorinated alkyl metal reagents, affording alcohol 40. 1A–1C
could be accomplished by Tamao-Fleming oxidation, ester
hydrolysis, lactone formation, chlorination of primary alcohol
and PMB cleavage from 40. Aldehyde 3 can be synthesized from cis-
fusedlactam 2 [16].
covalent attachment to the proteasome
b-subunits [12]. In that
Our synthesis began with L-threonine, from which silyl ether 2
case, fluorine substitution slows down salinosporamide’s two-step
irreversible binding reaction pathway and increases its residence
was prepared in 12 steps [16]. Hydrogenation of benzyl ether 2 and
followed by Dess-Martin periodinane oxidation provided the
aldehyde 3 in 85% overall yield (Scheme 2).
With aldehyde 3 in hand, the coupling of 3 with 3-bromo-3,3-
fluoropropene 17 was investigated [17–20]. Indium or zinc
mediated coupling of 17 with general aldehyde proceeds smoothly
* Corresponding author. Fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.01.003

Z.-H. Chen et al. / Journal of Fluorine Chemistry 136 (2012) 12–19
13
Fig. 1. Design of fluorinated analogues of salinosporamide A.
Scheme 1. Retrosynthetic analysis of target molecules.
to give an alcohol in high yield, but alcohol 4 could not be prepared
by these easy handling methods from aldehyde 3 and 17 (Table 1,
entries 1–4). This might be induced by the extreme steric
hindrance of the aldehyde 3. Thus a more reactive organolithium
reagent, gem-difluoroallyllithium [21,22], was tested for the
coupling reaction with aldehyde 3. Two equiv. of n-butyllithium
in n-hexane was added slowly to a mixture of 17 and aldehyde 3 in
THF/Et2O/pentane at ꢀ98 8C. To our delight, the gem-difluoroal-
lyllithium in situ generated reacted with aldehyde 3 to give alcohol
4 was prepared in 50% yield (entry 5). The Diastereoisomer of
alcohol 4 was not found, which meant the coupling of aldehyde 3
with organolithium is a stereoselective reaction. Furthermore, the
yield of compound 4 was improved to 75% when 3.0 equiv. of both
17 and n-butyl lithium were used (entry 6).
Ring opening of silyl ether 4 with hydrogen peroxide and
sodium hydrogen carbonate in a mixture of methanol and THF
afforded triol 5 in 85% yield [23,24]. Accordingly, ester 5 was
hydrolyzed to the corresponding lactam-carboxylic acid using 3 N
lithium hydroxide in aqueous THF at 5 8C. The resulting crude acid
was then treated with pyridine and bis-(2-oxo-3-oxazolidinyl)
phosphinic chloride (BOPCl) at 23 8C under argon for 1 h to afford
compound 7 in 52% yield in 2 steps. Chlorination of compound 7
with triphenylphosphine dichloride (Ph3PCl2) in anhydrous
CH3CN/pyridine (1:1) at 23 8C for 12 h provided 8 in 80% yield

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Z.-H. Chen et al. / Journal of Fluorine Chemistry 136 (2012) 12–19
Table 1
Direct coupling of sterically hindered aldehyde 3 with gem-difluoroallyl synthon 17.
Scheme 2. Synthesis of aldehyde 3. Reagents and conditions: (i) H2, Pd (OH)2/C, THF;
(ii) Dess-Martin periodinanes, CH2Cl2, 85%.
Entry
Metal
Solvent
Temp.
Yieldd
1a
2a
3a
4a
5b
6c
Zn (4.0 equiv.)
Zn (4.0 equiv.)
In (4.0 equiv.)
In (4.0 equiv.)
nBuLi (2.0 equiv.)
nBuLi (3.0 equiv.)
DMF
0 8C to rt
0 8C to rt
0 8C to rt
0 8C to rt
ꢀ98 8C
NR
as a colourless oil. Finally, oxidative cleavage of the PMB group
gave the target molecule 1A in 40% yield (Scheme 3). Notably, if the
PMB group was removed from 5, the following hydrolyzation of the
methyl ester 6 could not lead to desired acid and the starting
material 6 was totally decomposed.
With the established synthetic route to 1A, target molecules 1B
and 1C were readily obtained from building blocks 9 and 12
correspondingly. As shown in Scheme 4, ester 9 was prepared from
compound 5 by hydrogenation in the presence of Pd(OH)2/C, and
was eventually converted to target molecule 1B by the same
procedures for compound 5 as described in Scheme 3.
THF
NR
DMF
NR
THF:H2O = 4:1
NR
THF:pentane:Et2O = 10:1:1
THF:pentane:Et2O = 10:1:1
50%
75%
ꢀ98 8C
a
BrCF2CH5CH2 (4.0 equiv.).
BrCF2CH5CH2 (2.0 equiv.).
BrCF2CH5CH2 (3.0 equiv.).
Isolated yield.
b
c
d
Building block 12 was synthesized stereoselectively by the
coupling of aldehyde 3 with in situ generated 3,3,3-trifluoropro-
pyllithium [25] in pentane at ꢀ78 8C (Scheme 5). As equivalent to
compound 4 in Scheme 3, alcohol 12 was converted smoothly to
target molecule 1C by the same procedures.
The absolute configuration of 12 at C-5 position was deter-
mined as S by the X-ray crystal structure (Fig. 2) [26], which is
coincident with Cram–Felkin–Anh rule for the reaction of
aldehydes with nucleophiles [27,28]. Therefore, the absolute
configuration of target molecules1A, 1B and 1C at C-5 position
could be determined as R, R and S correspondingly according to the
absolute configuration of compound 12, as the chiral centre at C-5
of all the compounds were generated by a similar stereoselective
coupling of aldehyde 3 with organolithium reagents.
Scheme 4. Synthesis of target molecule 1B. Reagents and conditions: (i) H2, Pd (OH)2/
C, THF, 90%.
With the fluorinated analogues in hand, we next evaluated the
biological activities of compounds 1A, 1B and 1C in comparison
with salinosporamide A in inhibition assays against the
b5-subunit
of the purified yeast 20S proteasome. The results are illustrated in
Scheme 3. Synthesis of target molecule 1A. Reagents and conditions: (i) KF, NaHCO3, H2O2, THF, MeOH, 85%; (ii) LiOH, THF, H2O, 5 8C; (iii) BOPCl, CH2Cl2, Py; (iv) Ph3PCl2,
CH3CN, Py, 42% for 3 steps; (v) CAN, MeCN, H2O, 0 8C, 1 h, 40%.

Z.-H. Chen et al. / Journal of Fluorine Chemistry 136 (2012) 12–19
15
Table 2
IC50 for inhibition of chymotrypsin-like activity of the purified 20S proteasome of
Saccharomyces cerevisiae.
Compound
Proteasome inhibition [nM]
Salinosporamide A (1)
0.80 ꢁ 0.04
240 ꢁ 21
94 ꢁ 9
Difluorosalinosporamide (1A)
Difluorosalinosporamide (1B)
Trifluorosalinosporamide (1C)
220 ꢁ 20
Scheme 5. Synthesis of target molecule 1C. Reagents and conditions: (i) 3-bromo-
1,1,1-trifluoropropane, ether, pentane, tert-butyllithium, ꢀ78 8C, 62%.
Table 2 and show >100-fold loss in activity as previously observed
with aliphatic, straight chain C-5 salinosporamide derivatives [29].
Introduction of the fluorinated groups did not lead to any
significant improvement in inhibitory activity in comparison to
the biosynthtically prepared, non-fluorinated derivative of 1B that
had a reported 245 ꢁ 38 nM IC50 value [29], as the gem-difluor-
omethylene at C-5 may increase the acidity of the vicinal hydroxyl
group and subsequently decrease the hydrophobicity of the molecule.
Therefore, fluorination of the salinosporamide C-5 side chain does not
afford improved activity in this molecular series.
In summary, we accomplished the synthesis of three new
fluorinated analogues of salinosporamide A. The key synthetic
transformation involved the stereoselective coupling of aldehyde 3
with organolithium reagents for the introduction of fluorinated
groups at the C-5 position.
an argon atmosphere. Tetrahydrofuran (THF) and diethyl ether
(Et2O) were distilled under argon with sodium/benzophenone
ketyl and dichloromethane (CH2Cl2) with calcium hydride.
Petroleum ether refers to the fraction of light petroleum ether
with bp 60–908C. 1H NMR and 13C NMR spectra were recorded on
Bruker AM-300, Bruker AM-400 or Varian Mercury-300 spectro-
meters. 19F NMR was recorded on a Bruker AM-300 spectrometer
(FCCl3 as outside standard and low field is positive). Chemical
shifts (d) are reported in parts per million, and coupling constants
(J) are in hertz. Optical rotations were measured using a Perkin-
Elmer 241 or 341 polarimeter. Crystallographic data were analyzed
with Rigaku FCR Diffractimer. All melting points are uncorrected.
3.2. Preparation of (4aR,7R,7aS)-methyl7-((R)-2,2-difluoro-1-
hydroxybut-3-en-1-yl)-6-(4-methoxybenzyl)-2,2,7a-trimethyl-5-
oxooctahydro-[1,2]oxasilino[5,6-c]pyrrole-7-carboxylate (4)
3. Experimental
A
solution of 3 (230 mg, 0.57 mmol) and 3-bromo-3,3-
difluoropropene (267 mg, 1.71 mmol) in THF/Pentane/Et2O
(6 mL/0.3 mL/0.3 mL) under nitrogen at ꢀ95 8C was added n-
butyllithium slowly. After being stirred for 90 min, the reaction
was quenched with water then extracted with ethyl acetate. The
3.1. General description of materials and methods
All reactions were carried out using commercially available
starting materials and solvents without further purification under
Fig. 2. The X-ray crystallographic structure of compound 12 and the absolute configuration of 1A–1C.

16
Z.-H. Chen et al. / Journal of Fluorine Chemistry 136 (2012) 12–19
combined solvents were evaporated by a rotary evaporator, and
the obtained crude product was purified by column chromatog-
raphy on silica gel (eluent:EtOAc/PE = 1:1) to afford compound 4
solution and organic layers were dried over Na2SO4. The solvent was
removed in vacuo to give the crude product which was purified by
column chromatography on silica gel (eluent:ethyl acetate) giving
(207 mg, 75%) as a clear oil. [
NMR (300 MHz, CDCl3):
a
]
26 = ꢀ28.7 (c1.2, CHCl3); 1H
the pure 6 (78 mg, 72%) as a white solid. [a D
]
25 = 29.7 (c0.8, MeOH);
6.14–5.96 (m, 1H,
D
d
7.39 (br, 2H, ArH), 6.80 (d, J = 8.5 Hz,
M.p. 207–208 8C. 1H NMR (300 MHz, MeOD)
d
2H, ArH), 6.09–5.91 (m, 1H, CH55CH2), 5.64 (d, J = 17.3 Hz, 1H,
CH55CHH), 5.49 (d, J = 10.9 Hz, 1H, CH55CHH), 4.76–4.43 (m, 3H,
CF2CHOH and NCH2Ar), 4.17–4.14 (s, 1H, OH), 3.78 (s, 3H,
ArOCH3), 3.59 (br, 3H, COOCH3), 2.79 (s, 1H, CH), 2.36–2.30 (m,
1H, CHHCH2Si), 2.36–2.31 (m, 1H, CHHCH2Si), 1.64 (s, 3H, CCH3),
0.63–0.50 (m, 1H, CH2CHHSi), 0.39–0.34 (m, 1H, CH2CHHSi),
0.14 (s, 3H, CH3Si CH3), 0.05 (s, 3H, CH3SiCH3); 13C NMR
CH55CHH),5.66(d, J = 17.3 Hz, 1H,CH55CHH),5.55(d, J = 11.0 Hz, 1H,
CH55CHH), 4.39 (dd, J = 13.3, 7.0 Hz, 1H, CF2CHOH), 3.74 (s, 3H,
COOCH3), 3.74–3.71 (m, 2H, CH2CH2OH), 2.86 (dd, J = 8.1, 4.9 Hz, 1H,
CH), 1.90–1.69 (m, 2H, CH2CH2OH), 1.59 (s, 3H, CCH3); 13C NMR
(75 MHz, MeOD)
d 180.8 (CO), 170.8 (CO), 131.9 (t, JC-F = 23.3 Hz,
CH55CH2), 121.5 (t, JC-F = 7.5 Hz, CH55CH2), 118.1 (t, JC-F = 246.2 Hz,
CF2), 82.5 (NCCOOMe), 74.6 (CF2CHOH), 61.9 (HOC), 52.6
(CH2CH2OH), 27.9 (CH2CH2OH), 20.4 (CH3); 19F NMR (282 MHz,
(75 MHz, CDCl3)
d 176.3 (CO), 158.1 (CAr), 131.4 (t, JC-
F = 25.4 Hz, CH55CH2), 131.4 (CAr), 128.8 (CAr), 121.1 (t, JC-
F = 9.3 Hz, CH55CH2), 121.1 (CAr), 119.0 (t, JC-F = 246.5 Hz, CF2),
113.1 (CAr), 84.2 (NCCOOMe), 79.2 (SiOC), 74.8 (t, JC-F = 26.4 Hz,
CF2CHOH), 55.4 (ArOCH3), 51.7 (COOCH3), 48.3 (NCH2), 48.0
(CH), 22.1 (CH3), 17.3 (SiCH2CH2), 7.6 (SiCH2CH2), 0.2 (SiCH3),
MeOD)
IR (thin film)
d
ꢀ101.3 (d, J = 253.31 Hz, 1F), ꢀ111.9 (d, J = 255.00 Hz, 1F);
n
max 3316, 1737, 1676, 1421, 1042, 798 cmꢀ1; MS (ESI)
m/z 324.1 [M+H]+; HRMS (ESI) Calcd. for C13H20F2NO6: 324.1265,
found 324.1253.
0.03 (SiCH3); 19F NMR (282 MHz, CDCl3)
d
ꢀ102.0 (br, 1F),
3.5. Preparation of (1R,4R,5S)-4-(2-chloroethyl)-1-((R)-2,2-difluoro-
1-hydroxybut-3-en-1-yl)-2-(4-methoxybenzyl)-5-methyl-6-oxa-2-
azabicyclo[3.2.0]heptane-3,7-dione (8)
ꢀ110.7 (d, J = 247.65 Hz, 1F); IR (thin film) nmax 3323, 1865,
1680, 1514, 1053 cmꢀ1; MS (ESI) m/z 484.3 [M+H]+; HRMS (ESI)
Calcd. for C23H31F2NO6SiNa: 506.1791, found 506.1781.
A solution of ester 5 (100 mg, 0.226 mmol) in 3 N aq LiOH
(1.7 mL) and THF (0.58 mL) was stirred for 12 h until hydrolysis was
complete. The reaction mixture was acidified with phosphoric acid
(to pH 3.5). The solvent was removed in vacuo and the residue was
extracted with EtOAc, separated, and concentrated in vacuo to give a
crude carboxylic acid. The crude acid was suspended in dry CH2Cl2
(0.90 mL), treated with pyridine (0.28 mL) and stirred vigorously at
23 8C for 5 min. To this solution was added BOPCl (149 mg,
0.59 mmol) at 23 8C under argon, and stirring was continued for
3 h. The solvent was removed under high vacuum and the residue
was suspended in dry CH3CN (0.57 mL) and pyridine (0.57 mL). To
this solution was added PPh3Cl2 (183 mg, 0.55 mmol) at 23 8C under
argon with stirring. After 1 h the solvent was removed in vacuo. The
crude product was purified by column chromatography on silica gel
(eluent:EtOAc/PE = 1:2.5) to yield 8 (38.6 mg, 42% for 3 steps) as a
3.3. Preparation of (2R,3S,4R)-methyl2-((R)-2,2-difluoro-1-
hydroxybut-3-en-1-yl)-3-hydroxy-4-(2-hydroxyethyl)-1-(4-
methoxybenzyl)-3-methyl-5-oxopyrrolidine-2-carboxylate (5)
To a solution of 4 (280 mg, 0.145 mmol) in THF (0.4 mL) and
MeOH (0.4 mL) at 23 8C was added NaHCO3 (49 mg, 0.58 mmol)
and KF (26 mg, 0.44 mmol). Hydrogen peroxide (30% in water,
0.4 mL) was then introduced to this mixture. The reaction mixture
was vigorously stirred at 23 8C for 18 h, the reaction mixture was
quenched carefully with NaHSO3 solution. The mixture was
extracted with ethyl acetate and the combined organic layers
were washed with water and dried over Na2SO4. The solvents were
evaporated by a rotary evaporator, and the resulting crude product
was purified by column chromatography on silica gel
(eluent:CH2Cl2/MeOH = 6:1) to yield 5 as a clear oil (200 mg,
clear oil. [a]D d 7.19
23 = 0.7 (c0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
85%). [
a
]
26 = 11.0 (c1.3, CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.32
(d, J = 8.6 Hz, 2H, ArH), 6.82 (d, J = 8.6 Hz, 2H, ArH), 5.88–5.79 (m, 1H,
CH55CH2), 5.64 (d, J = 17.3 Hz, 1H, CH55CHH), 5.52 (d, J = 10.7 Hz, 1H,
CH55CHH), 4.82 (d, J = 15.4 Hz, 1H, NCHHAr), 4.62 (dd, J = 18.9,
7.5 Hz, 1H, CF2CHOH), 4.27 (d, J = 15.4 Hz, 1H, NCHHAr), 4.30–4.25
(m, 1H, CH2CHHCl), 3.87–3.82 (m, 1H, CH2CHHCl), 3.78 (s, 3H,
ArOCH3), 2.89 (dd, J = 8.1, 5.5 Hz, 1H, CH), 2.34–2.23 (m, 1H,
CHHCH2Cl), 2.16–2.04 (m, 1H, CHHCH2Cl), 1.92 (s, 3H, CH3); 13C
D
(d, J = 7.3 Hz, 2H, ArH), 6.82 (d, J = 6.8 Hz, 2H, ArH), 6.02–5.89 (m,
1H, CH55CH2), 5.66 (d, J = 17.4 Hz, 1H, CH55CHH), 5.51 (d,
J = 10.9 Hz, 1H, CH55CHH), 4.70–4.41 (m, 3H, CF2CHOH and
NCH2Ar), 4.32 (s, 1H, CF2CHOH), 4.16 (s, 1H, OH), 3.77 (s, 3H,
ArOCH3), 3.77–3.77 (m, 2H, CH2CH2OH), 3.66 (s, 3H, COOCH3), 3.11
(br, 1H, OH), 2.98–2.94 (m, 1H, CH), 1.88–1.72 (m, 2H, CH2CH2OH),
1.63 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3)
d
178.20 (CO), 168.41
NMR (101 MHz, CDCl3) d 174.1 (CO), 166.0 (CO), 159.3 (CAr), 130.0
(CO), 158.12 (CAr), 131.08 (t, JC-F = 26.1 Hz, CH55CH2), 130.58 (CAr),
128.29 (CAr), 122.34 (CAr), 121.41 (t, JC-F = 9.5 Hz, CH55CH2),
118.96 (t, JC-F = 241.5 Hz, CF2), 113.48 (CAr), 81.13 (NCCOOMe),
78.87 (HOC), 74.69 (t, JC-F = 26.4 Hz, CF2CHOH), 61.32 (CH2CH2OH),
55.36 (ArOCH3), 52.25 (COOCH3), 50.60 (NCH2), 48.1 (CH), 26.88
(CAr), 129.6 (t, JC-F = 24.9 Hz, CH55CH2), 127.7 (CAr), 121.9 (t, JC-
F = 231.1 Hz, CH55CH2), 121.60 (t, JC-F = 9.6 Hz), 114.1 (CAr), 86.1
(NCCO), 80.0 (COOC), 68.41 (dd, JC-F = 32.3, 28.2 Hz, CF2CHOH), 55.2
(ArOCH3), 45.4 (NCH2), 44.9 (CH), 42.4 (CH2CH2Cl), 28.2 (CH2CH2Cl),
20.0 (d, JC-F = 6.9 Hz, CH3); 19F NMR (282 MHz, CDCl3)
J = 251.53, 12.70 Hz, 1F), ꢀ107.6 (dt, J = 254.07, 12.42 Hz, 1F); IR
d
ꢀ103.5 (dt,
(CH2CH2OH), 21.16 (CH3); 19F NMR (282 MHz, CDCl3)
J = 249.23 Hz, 1F), ꢀ110.7 (ddd, J = 248.65, 19.36, 10.96 Hz, 1F); IR
d
ꢀ102.5 (d,
(thinfilm)n
max 3392, 1834, 1682, 1514, 1034, 820 cmꢀ1; MS (ESI)m/
(thin film)
n
max 3339, 1763, 1672, 1514, 1038, 812 cmꢀ1; MS (ESI)
z 430.1 [M+H]+; HRMS (ESI) Calcd. for C22H22ClF2NO5Na: 452.1059,
m/z 444.1 [M+H]+; HRMS (ESI) Calcd. for C21H28F2NO7: 444.1839,
found 452.1047.
found 444.1828.
3.6. Preparation of (1R,4R,5S)-4-(2-chloroethyl)-1-((R)-2,2-difluoro-
1-hydroxybut-3-en-1-yl)-5-methyl-6-oxa-2-
3.4. Preparation of (2R,3S,4R)-methyl 2-((R)-2,2-difluoro-1-
hydroxybut-3-en-1-yl)-3-hydroxy-4-(2-hydroxyethyl)-3-methyl-5-
oxopyrrolidine-2-carboxylate (6)
azabicyclo[3.2.0]heptane-3,7-dione (1A)
Using the same conditions as described for compound 6,
compound 1A (9 mg, 40%) was prepared as a white solid from
compound 7 (40 mg, 0.093 mmol) (eluent:CH2Cl2/EtOAc = 10:1–
Toa solutionof5(150 mg, 0.339 mmol)inacetonitrile(2.0 mL)at
0 8C was added a pre-cooled solution of ceric ammonium nitrate
(CAN) (559 mg, 1.02 mmol in 0.7 mL H2O). TLC analysis showed the
complete consumption of starting material of 5. The reaction
mixture was diluted with ethyl acetate, washed with saturated NaCl
4:1). [a D
]
24 = ꢀ15.4 (c0.5, MeOH); M.p. 145–147 8C. 1H NMR
(300 MHz, MeOD)
d 6.22–6.06 (m, 1H, CH55CH2), 5.73 (d,
J = 17.3 Hz, 1H, CH55CHH), 5.59 (d, J = 11.1 Hz, 1H, CH55CHH), 4.37

Z.-H. Chen et al. / Journal of Fluorine Chemistry 136 (2012) 12–19
17
(dd, J = 16.8, 9.3, Hz, 1H, CF2CHOH), 3.97–3.77 (m, 2H, CH2CH2Cl),
2.76 (d, J = 7.0 Hz, 1H, CH), 2.24–2.04 (m, 2H, CH2CH2Cl), 1.86 (s, 3H,
(dd, JC-F = 7.3, 5.1 Hz, CF2CH2CH3); 19F NMR (282 MHz, CDCl3)
ꢀ104.4 (dm, J = 250.77 Hz, 1F), ꢀ108.2 (dtd, J = 252.46, 19.77,
9.88 Hz, 1F); IR (thin film) nmax 3379, 1832, 1678, 1514, 1040,
812 cmꢀ1; MS (ESI) m/z 436.1 [M+Na]+; HRMS (ESI) Calcd. for
d
CH3);13CNMR(101 MHz, MeOD)
d176.2(CO), 166.8(CO), 130.7(t, JC-
F = 24.9 Hz, CH55CH2), 120.2 (t, JC-F = 10.6 Hz, CH55CH2), 119.8 (t, JC-
F = 243.1 Hz, CF2), 86.3 (NCCO), 76.7 (COOC), 68.5 (dd, JC-F = 31.4,
27.2 Hz, CF2CHOH), 45.3 (CH), 41.8 (CH2CH2Cl), 28.0 (CH2CH2Cl),
C20H25F2NO6Na: 436.1545, found 436.1542.
18.7 (d, JC-F = 2.6 Hz, CH3); 19F NMR (282 MHz, MeOD)
d
ꢀ104.6 (dt,
3.9. Preparation of (1R,4R,5S)-4-(2-chloroethyl)-1-((R)-2,2-difluoro-
1-hydroxybutyl)-2-(4-methoxybenzyl)-5-methyl-6-oxa-2-
azabicyclo[3.2.0]heptane-3,7-dione (11)
J = 252.18, 11.58 Hz, 1F), ꢀ109.2 (dt, J = 251.05, 15.5 Hz, 1F); IR (thin
film)n
max 3358, 1834,1710, 1421,1082,960,831 cmꢀ1;MS (ESI)m/z
364.2 [M+MeOH+Na]+; HRMS (ESI) Calcd. for C13H18ClF2NO5:
364.0743, found 364.0734.
Compound 10 (35.8 mg, 0.087 mmol) was suspended in dry
CH3CN (0.42 mL) and pyridine (0.42 mL). To this solution was
added PPh3Cl2 (136 mg, 0.41 mmol) at 23 8C under argon with
stirring. After 1 h the solvent was removed in vacuo. The crude
product was purified by column chromatography on silica gel
(eluent:EtOAc/PE = 1:3) to yield 11 (30.7 mg, 82%) as a clear oil.
3.7. Preparation of (2R,3S,4R)-methyl 2-((R)-2,2-difluoro-1-
hydroxybutyl)-3-hydroxy-4-(2-hydroxyethyl)-1-(4-methoxybenzyl)-
3-methyl-5-oxopyrrolidine-2-carboxylate (9)
A solution of 5 (170 mg, 0.384 mmol) in THF (5 mL) at 23 8C was
treated with 20% Pd(OH)2-C (90 mg). The mixture was treated with
H2 (1 atm, H2 balloon) gas for 18 h. The resulting crude product
was purified by column chromatography on silica gel
(eluent:CH2Cl2/MeOH = 25:1) to 9 (158 mg, 90%) as a clear oil.
[a] d 7.18 (d,
25 = 4.5 (c1.6, CHCl3); 1H NMR (300 MHz, CDCl3)
D
J = 8.4 Hz, 2H, ArH), 6.82 (d, J = 8.4 Hz, 2H, ArH), 4.83 (d, J = 15.5 Hz,
1H, NCHHAr), 4.54 (d, J = 22.2 Hz, 1H, CF2CHOH), 4.27 (d,
J = 15.5 Hz, 1H, NCHHAr), 4.05–3.97 (m, 1H, CH2CHHOH), 3.87–
3.81 (m, 2H, CH2CHHOH and OH), 3.77 (s, 3H, ArOCH3), 2.98–2.83
(m, 1H, CH), 2.34–2.23 (m, 1H, CHHCH2Cl), 2.16–2.04 (m, 1H,
CHHCH2Cl), 1.90–1.65 (m, 2H, CF2CH2CH3), 1.88 (s, 3H, CCH3), 0.97
[a]
26 = 16.5 (c7.8, MeOH); M.p. 142–145 8C. 1H NMR (300 MHz,
D
MeOD)
d 7.27 (d, J = 8.2 Hz, 2H, ArH), 6.76 (d, J = 8.6 Hz, 2H, ArH),
4.60–4.50 (m, 3H, CF2CHOH and NCH2Ar), 3.71 (s, 5H, ArOCH3 and
CH2CH2OH), 3.58 (s, 3H, COOCH3), 2.88 (t, J = 6.6 Hz, 1H, CH), 1.78–
1.76 (m, 4H, CF2CH2CH3 and CH2CH2OH), 1.63 (s, 3H, CCH3), 1.00 (t,
J = 7.4 Hz, 3H, CF2CH2CH3); 13C NMR (75 MHz, MeOD)
d 178.7 (CO),
168.7 (CO), 157.9 (CAr), 130.9 (CAr), 127.8 (CAr), 123.6 (t, JC-
F = 247.8 Hz, CF2), 112.6 (CAr), 80.5 (NCCOOMe), 78.7 (HOC), 72.5
(t, JC-F = 24.2 Hz, CF2CHOH), 60.5 (CH2CH2OH), 54.4 (ArOCH3), 50.8
(COOCH3), 49.2 (NCH2), 48.6 (CH), 28.2 (t, JC-F = 21.3 Hz,
CF2CH2CH3), 27.4 (CH2CH2OH), 19.8 (CH3), 4.9 (t, JC-F = 4.8 Hz,
(t, J = 7.4 Hz, 3H, CF2CH2CH3); 13C NMR (75 MHz, CDCl3)
d 174.3
(CO), 167.0 (CO), 159.5 (CAr), 129.9 (CAr), 128.0 (CAr), 124.4 (dd, JC-
F = 249.3, 245.1 Hz, CF2), 114.1 (CAr), 86.7 (NCCO), 80.5 (COOC),
67.5 (dd, JC-F = 33.2, 26.3 Hz, CF2CHOH), 55.4 (ArOCH3), 45.3 (d, JC-
F = 4.2 Hz, NCH2), 45.0 (d, CH), 42.6 (CH2CH2Cl), 28.4 (CH2CH2Cl),
27.9 (t, JC-F = 23.6 Hz, CF2CH2CH3), 19.9 (d, JC-F = 8.3, Hz, CH3), 5.6 (t,
JC-F = 5.6 Hz, CF2CH2CH3); 19F NMR (282 MHz, CDCl3)
J = 251.05 Hz, 1F), ꢀ108.3 (dtd, J = 253.03, 22.87, 8.75 Hz, 1F); IR
d
ꢀ104.6 (dm,
(thin film) n
max 3397, 1834, 1681, 1515, 1040, 820 cmꢀ1; MS (ESI)
CF2CH2CH3); 19F NMR (282 MHz, MeOD)
(d, J = 243.43 Hz, 1F); IR (thin film) nmax 3399, 1763, 1670, 1514,
1040, 976, 831 cmꢀ1; MS (ESI) m/z 468.3 [M+Na]+; HRMS (ESI)
Calcd. for C21H29F2NO7Na: 468.1823, found 468.1804.
d
ꢀ106.0 (br, 1F), ꢀ111.4
m/z 432.1 [M+Na]+; HRMS (ESI) Calcd. for C20H25ClF2NO5:
432.1395, found 432.1384.
3.10. Preparation of (1R,4R,5S)-4-(2-chloroethyl)-1-((R)-2,2-
difluoro-1-hydroxybutyl)-5-methyl-6-oxa-2-
azabicyclo[3.2.0]heptane-3,7-dione (1B)
3.8. Preparation of (1R,4R,5S)-1-((R)-2,2-difluoro-1-hydroxybutyl)-
4-(2-hydroxyethyl)-2-(4-methoxybenzyl)-5-methyl-6-oxa-2-
azabicyclo[3.2.0]heptane-3,7-dione (10)
Using the same conditions as described for compound 1A,
compound 1B (12 mg, 56%) wasprepared from compound 11 (31 mg,
A solution of triol ester 9 (75 mg, 0.167 mmol) in 3 N aq LiOH
(1.3 mL) and THF (0.43 mL) was stirred for 12 h until hydrolysis
was complete. The reaction mixture was acidified with phosphoric
acid (to pH 3.5). The solvent was removed in vacuo and the residue
was extracted with EtOAc, separated, and concentrated in vacuo to
give the crude trihydroxy carboxylic acid. The crude acid was
suspended in dry CH2Cl2 (0.67 mL), treated with pyridine (0.21 mL)
and stirred vigorously at 23 8C for 5 min. To this solution was
added BOPCl (110 mg, 0.44 mmol) at 23 8C under argon, and
stirring was continued for 3 h. The solvent was removed under
high vacuum and the crude product was purified by column
chromatography on silica gel (eluent:EtOAc/PE = 2:3) to yield 10
0.072 mmol) (eluent:CH2Cl2/EtOAc = 10:1–4:1).
[
a D
]
27 = ꢀ19.3
(c0.40, MeOH); M.p. 148–150 8C. 1H NMR (300 MHz, MeOD)
d 4.35
(dd, J = 20.7, 7.6 Hz, 1H, CF2CHOH), 4.40–3.79 (m, 2H, CH2CH2Cl), 2.78
(t, J = 7.0 Hz, 1H, CH), 2.23–1.94 (m, 4H, CF2CH2CH3 and CH2CH2Cl),
1.84 (s, 3H, CCH3), 1.05 (t, J = 7.5 Hz, 3H, CF2CH2CH3); 13C NMR
(75 MHz, MeOD)
d 177.7 (CO), 168.4 (CO), 126.1 (t, JC-F = 246.5 Hz,
CF2), 87.7 (NCCO), 78.2 (COOC), 68.6 (dd, JC-F = 31.8, 26.3 Hz,
CF2CHOH), 46.6 (CH), 43.2 (CH2CH2Cl), 29.4 (CH2CH2Cl), 28.3 (t, JC-
F = 25.0 Hz, CF2CH2CH3),20.0 (d, JC-F = 4.2 Hz, CH3), 5.9(t, JC-F = 6.9 Hz,
CF2CH2CH3); 19F NMR (282 MHz, MeOD)
d
ꢀ108.0 (dtd, J = 241.65,
18.91, 7.34 Hz, 1F), ꢀ111.9 (ddd, J = 248.99, 34.44, 18.91 Hz, 1F); IR
(thin film) n
max 3366, 1834, 1703, 1390, 985, 830 cmꢀ1; MS (ESI) m/z
(35.8 mg, 52% for 3 steps) as a clear oil. [
a
]
23 = 4.5 (c1.0, MeOH);
366.1 [M+MeOH+Na]+; HRMS (ESI) Calcd. for C13H20ClF2NO5Na:
366.0902, found 366.0890.
D
1H NMR (300 MHz, CDCl3)
d
7.18 (d, J = 8.4 Hz, 2H, ArH), 6.81 (d,
J = 8.5 Hz, 2H, ArH), 4.90 (d, J = 15.0 Hz, 1H, NCHHAr), 4.74 (br, 1H,
OH), 4.55 (d, J = 22.5 Hz, 1H, CF2CHOH), 4.24 (d, J = 15.5 Hz, 1H,
NCHHAr), 4.21 (br, 1H, OH), 3.97–3.81 (m, 2H, CH2CH2OH), 3.76 (s,
3H, ArOCH3), 2.81 (t, J = 6.5 Hz, 1H, CH), 1.98–1.70 (m, 4H,
CF2CH2CH3 and CH2CH2OH), 1.86 (s, 3H, CCH3), 0.97 (t,
3.11. Preparation of (4aR,7R,7aS)-methyl 6-(4-methoxybenzyl)-
2,2,7a-trimethyl-5-oxo-7-((S)-4,4,4-trifluoro-1-
hydroxybutyl)octahydro-[1,2]oxasilino[5,6-c]pyrrole-7-carboxylate
(12)
J = 7.4 Hz, 3H, CF2CH2CH3); 13C NMR (101 MHz, MeOD)
d 176.9
(CO), 167.7 (CO), 160.8 (CAr), 131.0 (CAr), 130.7 (CAr), 126.7 (t, JC-
F = 243.3 Hz, CF2), 114.8 (CAr), 87.7 (NCCO), 82.0 (COOC), 67.7 (t, JC-
F = 28.0 Hz, CF2CHOH), 60.4 (CH2CHOH), 55.7 (ArOCH3), 46.5
(NCH2), 46.0 (d, JC-F = 5.7 Hz, CH), 29.0 (CH2CH2OH), 28.5 (t, JC-
F = 24.6 Hz, CF2CH2CH3), 20.5 (d, JC-F = 10.1 Hz, CH3), 5.8
tert-Butyllithium (1.6 M in pentane, 2.2 mL) was slowly added
at ꢀ78 8C to a stirred solution of 3-bromo-1,1,1-trifluoropropane
(524.5 mg, 2.96 mmol) in ether (2 mL) and pentane (3 mL). The
solution was then stirred 2 h at ꢀ78 8C. Then compound 3 (200 mg,
0.49 mmol) in ether (1.2 mL) was slowly added to the mixture.

18
Z.-H. Chen et al. / Journal of Fluorine Chemistry 136 (2012) 12–19
After stirred at ꢀ78 8C for 3 h, the solution was quenched (NH4Cl),
extracted (EtOAc) and dried, then purified by silica gel column
chromatography (eluent:EtOAc/PE = 1:3) to give 12 (152 mg, 62%)
(282 MHz, CDCl3)
d
ꢀ66.8 (t, J = 9.88 Hz, 3F); IR (thin film) nmax
3224, 1826, 1687, 1514, 1024, 822 cmꢀ1; MS (ESI) m/z 504.2
[M+MeOH+Na]+; HRMS (ESI) Calcd. for C21H27ClF3NO6Na:
504.1392, found 504.1371.
as a white solid. [
a
]
D
25 = ꢀ19.2 (c1.2, CHCl3); M.p. 67–69 8C. 1H
NMR (300 MHz, CDCl3):
d
7.33 (d, J = 8.4 Hz, 2H, ArH), 6.83 (d,
J = 8.1 Hz, 2H, ArH), 4.76 (d, J = 15.0 Hz, 1H, NCHHAr), 4.64 (d,
J = 15.3 Hz, 1H, NCHHAr), 4.16 (t, J = 8.1 Hz, 1H, CF3CH2CHOH), 3.79
(s, 3H, ArOCH3), 3.74–3.60 (br, 1H, OH), 3.67 (3H, s, COOCH3), 2.17
(t, J = 3.0 Hz, 1H, CH), 2.35–152 (m, 6H, CF3CH2CH2 and SiCH2CH2),
1.60 (3H, s, CCH3), 0.59 (td, J = 14.4, 5.1, 1H, SiCHHCH2), 0.41 (dt,
J = 15.1, 3.7, 1H, SiCHHCH2), 0.14 (3H, s, CH3SiCH3), 0.05 (3H, s,
3.14. Preparation of (1R,4R,5S)-4-(2-chloroethyl)-5-methyl-1-((S)-
4,4,4-trifluoro-1-hydroxybutyl)-6-oxa-2-azabicyclo[3.2.0]heptane-
3,7-dione (1C)
Using the same conditions as described for compound 1A,
compound 1C (10 mg, 68%) was prepared as white solid from
compound 15 (20 mg, 0.045 mmol) (eluent:CH2Cl2/EtOAc = 10:1–
CH3SiCH3); 13C NMR (101 MHz, CDCl3)
d 176.8 (CO), 169.6 (CO),
158.6 (CAr), 131.2 (CAr), 128.7 (CAr), 125.7 (q, JC-F = 273.9 Hz),
113.8 (CAr), 83.1 (NCCOOMe), 82.9 (SiOC), 72.9 (CF3CHOH), 55.4
(ArOCH3), 51.8 (COOCH3), 48.4 (NCH2), 48.3 (CH), 31.5 (q, JC-
F = 29.1 Hz, CF3CH2CH2), 27.1 (CF3CH2CH2), 22.5 (CCH3), 17.0
(SiCH2CH2), 7.5 (SiCH2CH2), 0.3 (SiCH3), 0.2 (SiCH3); 19F NMR
4:1). [
(300 MHz, MeOD):
a
]
23 = ꢀ49.4 (c0.50, MeOH); M.p. 164–165 8C. 1H NMR
D
d
4.15 (dd, J = 11.0, 2.4 Hz, 1H,
CF3CH2CH2CHOH), 3.95–3.77 (m, 2H, CH2CH2Cl), 2.83 (t,
J = 7.1 Hz, 1H, CH), 2.50–1.93 (m, 5H, CF3CH2CH2, CH2CH2Cl and
CF3CH2CHH), 1.85–1.71 (m, 1H, CF3CH2CHH), 1.80 (s, 3H, CCH3);
(282 MHz, CDCl3)
d
ꢀ66.7 (t, J = 8.47 Hz, 3F); IR (thin film) nmax
13C NMR (101 MHz, CDCl3)
F = 273.4 Hz, CF2), 85.6
d
177.1 (CO), 168.2 (CO), 127.4 (q, JC-
(NCCO), 78.5 (COOC), 64.5
3359, 1757, 1676, 1514, 1026 cmꢀ1; MS (ESI) m/z 504.4 [M+H]+;
HRMS (ESI) Calcd. for C23H32F3NO6SiNa: 526.1844, found
526.1843.
(CF3CH2CH2CHOH), 45.5 (CH), 41.2 (CH2CH2Cl), 29.9 (q, JC-
F = 29.5 Hz, CF3CH2CH2), 28.1 (CH2CH2Cl), 24.3 (t, JC-F = 3.3 Hz,
CF3CH2CH2), 18.1 (CCH3); 19F NMR (282 MHz, CDCl3)
J = 11.00 Hz, 3F); IR (thin film) nmax 3352, 1826, 1705, 1016,
809 cmꢀ1; MS (ESI) m/z 328.0 [MꢀH]ꢀ; HRMS (ESI) Calcd. for
C12H14ClF3NO4: 328.0560, found 328.0569.
d
ꢀ68.3 (t,
3.12. Preparation of (2R,3S,4R)-methyl 3-hydroxy-4-(2-
hydroxyethyl)-1-(4-methoxybenzyl)-3-methyl-5-oxo-2- ((S)-4,4,4-
trifluoro-1-hydroxybutyl)pyrrolidine-2-carboxylate (13)
Using the same conditions as described for compound 5,
compound 13 (92 mg, 77%) was prepared as a clear oil from
compound 12 (130 mg, 0.26 mmol) (eluent:CH2Cl2/MeOH = 25:1).
3.15. 20S proteasome inhibition assays
Salinosporamide A and synthetic analogues 1A–1C were assayed
for inhibition of the Saccharomyces cerevisiae 20S proteasome
b
5-subunit as previously described except 0.5 g mLꢀ1 proteasome
was used [29]. Data were plotted on SigmaPlot 11.0 and fit with a ‘‘4
parameter logistic’’ curve to obtain IC50 values with standard errors.
[a] d 7.30 (d,
24 = 4.4 (c1.6, MeOH); 1H NMR (300 MHz, MeOD):
D
J = 8.6 Hz, 2H, ArH), 6.80 (d, J = 8.6 Hz, 2H, ArH), 4.70 (d, J = 15.9 Hz,
1H, NCHHAr), 4.57 (d, J = 15.9 Hz, 1H, NCHHAr), 4.27 (d, J = 10.2 Hz,
1H, CF3 CH2 CH2CHOH), 3.76–3.72 (m, 2H, CH2CH2OH), 3.74 (s, 3H,
ArOCH3), 3.72 (s, 3H, COOCH3), 2.89 (dd, J = 7.5, 5.5 Hz, 1H, CH),
2.36–2.03 (m, 2H, CF3CH2CH2), 1.86–1.72 (m, 2H, CH2CH2OH),
1.68–1.41 (m, 2H, CF3CH2CH2), 1.61 (s, 3H, CCH3); 13C NMR
Acknowledgements
(101 MHz, MeOD) d 180.2 (CO), 171.0 (CO), 159.7 (CAr), 128.6 (q, JC-
We thank the National Natural Science Foundation of China
(21072028 and 20832008) and the National Institutes of Health
(CA127622) for funding this work.
F = 275.9 Hz, CF2), 114.3 (CAr), 83.8 (NCCOOMe), 80.6 (COH), 72.7
(CF3CH2CH2CHOH), 61.8 (CH2CH2OH), 55.7 (ArOCH3), 52.3
(COOCH3), 50.5 (NCH2), 49.2 (CH), 32.0 (q, JC-F = 29.1 Hz,
CF3CH2CH2), 28.3 (CH2CH2OH), 28.0 (CF3CH2CH2), 21.3 (CCH3);
19F NMR (282 MHz, MeOD)
n
d
ꢀ66.2 (t, J = 9.88 Hz, 3F); IR (thin film)
References
max 3361, 1755, 1673, 1515, 1037, 815 cmꢀ1; MS (ESI) m/z 464.3
[M+H]+; HRMS (ESI) Calcd. for C21H29F3NO7: 464.1889, found
464.1891.
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3.13. Preparation of (1R,4R,5S)-4-(2-chloroethyl)-2-(4-
methoxybenzyl)-5-methyl-1-((S)-4,4,4-trifluoro-1-hydroxybutyl)-6-
oxa-2-azabicyclo[3.2.0]heptane-3,7-dione (15)
Using the same conditions as described for compound 8,
compound 15 (16 mg, 37%) was prepared as a clear oil from
compound 13 (40 mg, 0.09 mmol) (eluent:EtOAc/PE = 1:1).
[
a
]
25 = ꢀ61.8 (c0.75, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.21
D
(d, J = 8.5 Hz, 2H, ArH), 6.86 (d, J = 8.6 Hz, 2H, ArH), 5.11 (d,
J = 15.3 Hz, 1H, NCHHAr), 4.13–4.04 (m, 2H, CH2CHHCl and CF3
CH2CH2CHOH), 4.00 (d, J = 15.2 Hz, 1H, NCHHAr), 3.87–3.81 (m,
1H, CH2CHHCl), 3.78 (s, 3H, ArOCH3), 2.92 (dd, J = 7.8, 6.0 Hz, 1H,
CH), 2.52 (d, J = 6.2 Hz, 1H, OH), 2.37–1.99 (m, 3H, CF3CH2CH2 and
CHHCH2Cl), 1.89 (s, 3H, CCH3), 1.48–1.38 (m, 1H, CHHCH2Cl), 1.25–
[16] L.R. Reddy, P. Saravanan, E.J. Corey, J. Am. Chem. Soc. 126 (2004) 6230–6231.
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(2000) 8275–8280.
1.12 (m, 2H, CF3CH2CH2); 13C NMR (101 MHz, CDCl3)
d 174.3 (CO),
168.0 (CO), 160.0 (CAr), 129.5 (CAr), 128.8 (CAr), 126.5 (q, JC-
F = 263.0 Hz, CF2), 114.7 (CAr), 84.8 (NCCOOMe), 82.7 (COOC), 66.8
(CF3CH2CH2CHOH), 55.5 (ArOCH3), 45.5 (NCH2), 45.1 (CH), 42.6
(CH2CH2Cl), 30.7 (q, JC-F = 29.4 Hz, CF3CH2CH2), 28.3 (CH2CH2Cl),
22.7 (dd, JC-F = 5.5, 2.6 Hz, CF3CH2CH2), 19.8 (CCH3); 19F NMR
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19
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