α N-O turn induced by fluorinated α-aminoxy diamide: synthesis and conformational studies

Article abstract of DOI:10.1016/j.tet.2009.09.113

Two α-aminoxy diamides with fluorinated side chains were synthesized. Their secondary structures characterization was carried out by ¹H NMR, and IR spectrometries as well as X-ray crystallography studies. α N-O turn secondary structures are ado

Full text of DOI:10.1016/j.tet.2009.09.113

Tetrahedron 65 (2009) 9997–10001
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a
N–O turn induced by fluorinated
a
-aminoxy diamide:
synthesis and conformational studies
,
b
,
a
a
a
Dan-Wei Zhang a , Zheng Luo , Guo-Jun Liu , Lin-Hong Weng
*
a Department of Chemistry, Fudan University, Shanghai 200433, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two
characterization was carried out by 1H NMR, and IR spectrometries as well as X-ray crystallography
studies. N–O turn secondary structures are adopted insusceptibly by side-chain-fluorinated -aminoxy
residues. Thus the fluorinated -aminoxy diamide can be a potential residue as a biological tracer to be
incorporated into aminoxy peptides.
a-aminoxy diamides with fluorinated side chains were synthesized. Their secondary structures
Received 20 August 2009
Received in revised form
24 September 2009
Accepted 29 September 2009
Available online 1 October 2009
a
a
a
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
a
-Aminoxy diamide
Fluorinated side chain
N–O turn
a
Secondary structure
1. Introduction
O
O
H
O
O
N
For several decades, organofluorine chemistry has been an
important area of organic chemistry, especially in the synthesis of
fluorinated biologically active molecules such as peptidomimetics
and drug candidates, and realizing their functions in biosystems
(such as molecular recognition of enzymes).1 Fluorine atom, as
a bioisostere, has been widely used to replace a hydrogen atom or
hydroxyl group of leading compounds, for example, to design
pharmaceutical and bioactive molecules.2 In addition, because of its
extremely rare existence in biological molecules, the fluorine atom
has been used as a biological tracer and mechanistic probe in 19F
NMR spectroscopy for investigation of protein folding pathways,
the structures and properties of enzymes, and the like.1d,3
O
∗
N
H
N
H
HN
∗
O
R
R
α-aminoxy acid residue
α N−O turn
Figure 1.
a
-Aminoxy acid and
a
N–O turn.
bond between adjacent residues of a
-aminoxy peptide, Fig. 1)7 with
no disturbance of the fluorine atom due to its very weak hydrogen
bond acceptor property.8 Thus the residue has the opportunity to be
incorporated into aminoxy peptide as a biological tracer. Hereinafter,
we report the synthesis of two a-aminoxy diamides 1 and 2 (Fig. 2)
with fluoroethyl and fluoropropyl side chains, respectively, and
characterization of their secondary structures.
a
-Aminoxy peptides (a kind of peptidomimetic foldamers4
composed of
-aminoxy acids),5 which have predictable secondary
a
structures depending on the chirality of residues but not the side
chains, have been found to have several bioactive applications, such
as anion receptors and channels.6 Bioactive peptidomimetics design
was of particular interest to us. We intended to introduce one fluo-
O
O
O
O
rineatom intothesidechainof
that the designed compound would adopt an
features an eight-membered-ring with an intramolecular hydrogen
a
-aminoxyacidresidue, andexpected
O
O
N
N
N
N
a
N–O turn (which
Hα
Hβ
Hα
Hβ
F
F
1
2
* Corresponding author. Tel.: þ86 21 6564 3576; fax: þ86 21 6564 3575.
E-mail address: zhangdw@fudan.edu.cn (D.-W. Zhang).
Figure 2. Fluorinated a-aminoxy diamides 1 and 2.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.113

9998
D.-W. Zhang et al. / Tetrahedron 65 (2009) 9997–10001
O
O
O
PBSF, Et3N·(HF)3,
DIEA, THF
1) i-BuOCOCl, NMM, DME,
1) AcCl, reflux,
2h
HO
O
O
0 °C, 2h
OH
O
OBn
O
OBn
HO
O
O
2) NaBH4, H2O, r.t. 1h
2) BnOH, r.t.,
8h
r.t., overnight
OH
OH
OH
3 (58%)
4 (63%)
(S)-malic acid
O
O
O
O
O
K2CO3, MeOH/H2O
r.t., 1h
1) 10% Pd/C, H2, 0.5h
OBn
N
H
N
H
O
O
2) isobutylamine, EDCI,
HOAt, CH2Cl2,
overnight
F
F
F
5 (66%)
6 (70%)
7 (75%)
O
O
O
O
F
1) NH2NH2·H2O, MeOH,
r.t., 5h
PPh3, DIAD,
N
O
O
N
H
N
H
N
H
PhthNOH, THF
2) NaHCO3, PivCl,
CH2Cl2/H2O, 4h
r.t., 6h
O
F
8 (85%)
1 (52%)
Scheme 1. Synthesis of fluoroethyl side-chained
a-aminoxy acid monomer 1.
2. Results and discussion
2.1. Synthesis of fluorinated
As shown in Schemes 1 and 2, fluorinated
to substitute the hydroxy group with a fluorine atom using
perfluorobutanesulphonyl fluoride (PBSF) in the presence of
Et3N$(HF)3 and diisopropyl ethyl amine (DIEA).10 Conventional
protection/deprotection, Mitsunobu reaction, and coupling re-
action were involved to introduce the N–O segment and build up
the amide bond.11,12 When introducing the N–O bond by Mitsunobu
reaction of compound 7 or 17 to produce compound 8 or 18,
a
-aminoxy diamides
a
-aminoxy diamides 1
and 2 were synthesized from (S)-malic acid and L-glutamic acid,
respectively.9 The key step for introducing the fluorine atom was
O
O
H2N
HO
NaNO2, HCl
t-BuOH
OH
OH
O
KOH
OH
O
O
O
O
DCC, DMAP
THF, r.t.,
O
MeOH/H2O,
r.t., 1h
H2O, r.t., 20h
O
O
overnight
9 (83%)
10 (57%)
O
O
OH
11 (64%)
L-Glu
O
O
O
O
O
1) i-BuOCOCl,
NMM, DME,
−20 °C, 0.5h
1) TBDMSCl, Et3N,
DMAP, DCM, r.t.,
15h
HO
O
O
TBAF, THF
r.t., 4h
O
O
O
2) NaBH4, H2O,
1h
2) Ac2O, Pyridine,
10h
OH
OTBS
OH
12 (41%)
13 (92%)
14 (92%)
O
O
O
1) TFA, DCM,
r.t., 3.5h
O
HO
O
PBSF, Et3N·(HF)3
K2CO3
N
H
N
H
O
F
O
MeOH/H2O,
r.t., 1h
O
DIEA, THF,
2) isobutylamine,
EDCI, HOAt,
CH2Cl2, r.t.,
overnight
r.t., overnight
F
F
15 (65%)
16 (92%)
17 (83%)
O
O
O
O
PPh3, DIAD,
1) NH2NH2·H2O,
MeOH, r.t., 7h
N
O
O
N
H
N
H
N
H
PhthNOH, THF
2) K2CO3, PivCl,
CH2Cl2/H2O,
4h
r.t., 6h
O
F
F
18 (69%)
2 (47%)
Scheme 2. Synthesis of fluoropropyl side-chained a-aminoxy acid monomer 2.

D.-W. Zhang et al. / Tetrahedron 65 (2009) 9997–10001
9999
Table 1
separately, the configuration at the
SN2 mechanism.11
a-carbon was inversed via an
Chemical shifts of amide and aminoxy amide protons of 1 and 2 at 25 ꢀC and their
chemical shift changes (Dd) in 1H NMR dilution (dilu.) and DMSO-d6 titration
(DMSO) studies
2.2. Conformational studies
Compound NHa (ppm)
NHb (ppm)
da
Ddb (dilu.) Ddc (DMSO) da Ddb (dilu.) Ddc (DMSO)
2.2.1. 1H NMR dilution and titration studies of diamides 1 and 2. 1H
NMR dilution (Fig. 3) and titration (Fig. 4) studies of diamides 1 and
2 were carried out firstly. Generally, the chemical shift of the proton
on the nitrogen atom varied with the concentration of the sample
and the solvent. At high concentration (e.g., 200 mM), an in-
termolecular hydrogen bond between the NH proton and the car-
bonyl oxygen atom is formed, which induced a strong downfield
chemical shift of NH protons in 1H NMR spectra similar to that of
intramolecular hydrogen bonded NH protons. But at low concen-
tration (1.56–5 mM), almost no intermolecular hydrogen bond is
formed. Thus both intermolecular and intramolecular hydrogen-
bonded NH protons showed downfield shifts at 200 mM in CDCl3,
but only intramolecular hydrogen-bonded NH protons showed
downfield shifts at 1.56 mM concentration. It is the chemical shifts
of the solvent accessible NHs (non-intramolecular hydrogen-
bonded) that significantly upfield shifted upon dilution from
200 mM to 1.56 mM in CDCl3. Moreover, adding the strong hy-
drogen bond acceptor DMSO-d6, which can form hydrogen bonds
with NH protons, to a sample at low concentration in CDCl3 induced
a downfield chemical shift of the solvent accessible NH protons.
Table 1 summarises the results of the 1H NMR studies of diamides 1
and 2, including the chemical shifts of NHs at low concentration
in non-hydrogen bonded solvent, dilution studies with gradual
dilution of the sample from 200 mM to 1.56 mM in CDCl3, and
1
2
8.56 0.73
8.45 0.76
2.04
1.84
8.43 0.07
8.24 0.13
0.12
0.05
a
The value of
d
refers to the chemical shift observed in the 1H NMR spectrum of
the indicated compound in CDCl3 at a concentration of 1.56 mM.
b
The values of Dd were calculated according to the expression dNH (200 mM)ꢁdNH
(1.56 mM).
c
The values of Dd were calculated according to the expression dNH (5 mM in
CDCl3/7% DMSO-d6)ꢁdNH (5 mM in CDCl3).
titration studies carried out by adding 5 ml aliquots of DMSO-d6 to
a 5 mM sample solution in CDCl3. Normally, non hydrogen-bonded
general amide NH has chemical shift ca. 6.5 ppm at low concen-
tration.13 The non-hydrogen-bonded aminoxy amide NH has
chemical shift ca. d
8.5–9.0 ppm.12 At a concentration of 1.56 mM in
CDCl3, the chemical shifts of N-terminal aminoxy amide NHas are
ca. 8.5 ppm, while those of C-terminal general amide NHbs are
downfield (
d¼8.43 ppm for compound 1 and 8.24 ppm for com-
pound 2). Dilution studies showed that the chemical shifts of NHas
apparently moved upfield, whereas the chemical shifts of NHbs
changed very little, upon dilution with CDCl3. The DMSO-d6 titra-
tion study indicated that the NHas at the N-terminus had a dramatic
downfield shift, whereas NHbs at the C-terminus showed little
change upon addition of DMSO-d6. These 1H NMR studies suggest
(a)
(b)
9.5
9.5
O
O
F
O
O
O
O
Hα
N
H
N
H
N
H
N
H
α
β
α
β
Hα
9.0
8.5
8.0
9.0
8.5
8.0
F
1
2
Hβ
Hβ
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
Concentration in CDCl3 (lg)
Concentration in CDCl3 (lg)
Figure 3. The correlation between the chemical shift and concentration’s logarithm of NH in amide functional group of compounds 1 and 2.
(a)
(b)
11.0
10.5
10.0
9.5
11.0
10.5
10.0
9.5
O
O
F
O
O
O
O
Hα
N
H
N
H
N
N
Hα
α
β
Hα
Hβ
F
1
2
9.0
9.0
Hβ
8.5
8.5
Hβ
8.0
8.0
0
10
20
30
40
0
10
20
30
40
volume of DMSO-d6 added (μL)
volume of DMSO-d6 added (μL)
Figure 4. The correlation between the chemical shift of NH (in amide group of compounds 1 and 2) and quantity of DMSO-d6 added.

10000
D.-W. Zhang et al. / Tetrahedron 65 (2009) 9997–10001
O
Hβ
O
Hβ
N
N
w
N
w
N
O
Hα
O
O
Hα
O
H
s
H
s
s: Strong NOE
w: Weak NOE
F
F
1
2
Figure 5. The NOE effects review of compounds 1 and 2 according to their 2D NOESY
spectra (5 mM in CDCl3 at 25 ꢀC).
that the N-terminus NH protons (Ha) of diamides 1 and 2 are sol-
vent accessible, whereas the C-terminus protons (Hb) are in-
tramolecularly hydrogen bonded.
2.2.2. 2D NOESY studies. Nuclear Overhauser effect spectroscopy
(2D NOESY) of compounds 1 and 2 (5 mM in CDCl3) at 25 ꢀC
showed strong nuclear Overhauser effects (NOEs) between NHa and
CaH, but weak NOEs between NHb and CaH, indicating that com-
pounds 1 and 2 adopted a folded structure (Fig. 5), which is the
same as previously reported D-a
-aminoxy peptides.14 This indicated
that the conformation of diamides 1 and 2 in organic solvent does
not change with introduction of fluorine atom into the side chain.
Figure 7. ORTEP structure of compound
hydrogen bond.
1 with atom labels and intramolecular
2.2.3. FTIR spectra studies. FTIR spectra of the N–H stretch region of
compounds 1 and 2 at 2 mM concentration in CH2Cl2 are shown in
Figure 6. For compound 1, the band at 3381 cmꢁ1 corresponds to
the non hydrogen-bonded aminoxy N–Ha at the N-terminus. The
bands in the region of 3305 cmꢁ1 were assigned to the stretching
bands of the hydrogen-bonded amide N–Hb at the C-terminus.7 For
compound 2, similar results were obtained. The band at 3379 cmꢁ1
corresponds to the non hydrogen-bonded aminoxy N–Ha, whereas
absorptions in the region of 3305 cmꢁ1 were assigned to an intra-
molecular hydrogen-bonded amide N–Hb at the C-terminus. Both
compounds 1 and 2 have a weak absorption in the region of
3423 cmꢁ1, which can be assigned to non hydrogen-bonded gen-
eral amide N–Hb stretching. This suggests that the
a-aminoxy
diamides 1 and 2 adopted predominantly the intramolecular eight-
membered-ring hydrogen-bonded conformations in the organic
solvent.
Figure 8. Structure of compound 1 with intra- and intermolecular hydrogen bonds.
2.2.4. X-ray diffraction analysis. X-ray diffraction analysis of com-
pound 1 disclosed the conformation of fluorinated
a-aminoxy
amide in the solid state (Figs. 7 and 8). An intramolecular eight-
membered-ring hydrogen bond is clearly formed between the C-
terminal general amide NHb proton and the N-terminal aminoxy
amide carbonyl oxygen (NHiþ2.O¼Ci, distance 2.30 Å), so that an
also a stabilising factor in the secondary structure formed by
fluorinated aminoxy amide. The side chain of the fluoroethyl group
is almost anti to the N–O bond with dihedral angle :NOCaCs¼
162.57ꢀ. The chirality of the
a N–O turn is also determined by the
a
N–O turn is formed. The C-terminal general amide NHb proton is
configuration of the
a right-handed
a-carbon. For this D-aminoxy acid monomer,
also hydrogen-bonded to the N–O oxygen atom with a distance of
2.36 Å. This intramolecular five-membered-ring hydrogen bond is
a
N–O turn is adopted (dihedral angle :NOCaCO¼
75.28ꢀ). The distance between the N-terminal aminoxy amide NHa
0.008
0.008
Compound 2
Compound 1
3305
3305
0.006
0.006
3379
3381
0.004
0.004
3423
3423
0.002
0.000
0.002
0.000
3450
3400
3350
3300
3250
3450
3400
3350
3300
3250
Wavenumber (cm−1)
Wavenumber (cm−1)
Figure 6. FTIR spectra of the N–H stretch region of compounds 1 and 2 at a 2 mM in CH2Cl2.

D.-W. Zhang et al. / Tetrahedron 65 (2009) 9997–10001
10001
proton and CaH is shorter (O–NHa.HCa, distance 2.36 Å) than that
between the C-terminal general amide NHb proton and -H
(NHb.HCa, distance 3.29 Å). This is in accordance with the 2D
NOESY result that a strong NOE was observed in NHi.HiCa but
NMR (376.2 MHz, CDCl3):
d
¼ꢁ133.5 ppm; IR (CH2Cl2) 3264, 2961,
a
1656, 1553 cmꢁ1; HRMS (ESI) for C14H27FN2O3 (MþþH): calcd
291.2084, found 291.2069.
a weak NOE in NHiþ1.HiCa. The conformation of fluorinated
a-
Acknowledgements
aminoxy amide in the solid state is very similar to that in organic
solvent. The crystal structure of compound 1 indicates that the
incorporated fluorine atom has no effect on the adoption of the
Financial support by the National Natural Science Foundation of
China (Project No. 20202001), Fok Ying Tung Education Foundation
(Project No. 94023) and Key Laboratory of Organofluorine Chem-
istry (SIOC) are gratefully acknowledged. D.-W. Z. thanks Fudan
University for the conferment of the Century Star Award.
a
N–O turn. As shown in Figure 8, the fluorine atom on the side
chain does not form intra- or intermolecular hydrogen bonds with
NH protons.
3. Conclusions
Supplementary data
In conclusion,
adopt the stable secondary structure of
fluorine atom at the end of the side chain does not form a hydrogen
bond with general amide and aminoxy amide NH protons. This
a
-aminoxy diamides with fluorinated side-chains
N–O turn, while the
Synthetic schemes and characterization data of 1–2 and in-
termediates; copies of IR spectra of 1 and 2; crystallographic data of
1. The supplementary data associated with this article can be found
in the online version at doi:10.1016/j.tet.2009.09.113.
a
result suggests that the fluorinated side chain a-aminoxy residues
can be incorporated into peptides without disarranging the back-
bone structure, but acting as a potential biological tracer in bi-
ological studies of aminoxy foldamers.
References and notes
1. (a) Welch, J. T. Tetrahedron 1987, 43, 3123–3197; (b) Biomedicinal Frontiers of
Fluorine Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds. ACS Symposium
Series; American Chemical Society: Washington, DC, 1996, Vol. 639; (c) Asym-
metric Fluoroorganic Chemistry: Synthesis, Applications, and Future Directions;
Ramachandran, P. V., Ed. ACS Symposium Series; American Chemical Society:
Washington, DC, 2000, Vol. 746; (d) Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002,
31, 335–341; (e) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 6711–
6745; (f) Ja¨ckel, C.; Koksch, B. Eur. J. Org. Chem. 2005, 4483–4503; (g) Smits, R.;
Koksch, B. Curr. Top. Med. Chem. 2006, 6, 1483–1498; (h) O’Hagan, D. Chem. Soc.
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Fluorine Chem. 2002, 27–33; (c) Marsh, E. N. G. Chem. Biol. 2000, 7, R153–R157.
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3450–3453; (b) Dalvit, C.; Fagerness, P. E.; Hadden, D. T. A.; Sarver, R. W.;
Stockman, B. J. J. Am. Chem. Soc. 2003, 125, 7696–7703; (c) Wadhwani, P.; Bu¨ rck,
J.; Strandberg, E.; Mink, C.; Afonin, S.; Ulrich, A. S. J. Am. Chem. Soc. 2008, 130,
16515–16517.
4. Experimental section
4.1. General
4.1.1. (R)-2-(N-Pivalylamidoxy)-4-fluoro-N-isobutylbutanamide
(1). White solid; mp 82.5 ꢀC; Rf¼0.34 (EtOAc:hexane¼1:2);
20
[
a]
Dþ10.4ꢀ (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
¼9.29
d
(1H, br s, NHa), 8.50 (1H, br s, NHb), 4.76–4.53 (2H, m, 2JHF¼46.9 Hz,
CH2F), 4.38 (1H, dd, J¼8.8, 3.4 Hz,
a-H), 3.14–3.03 (m, 2H), 2.47–2.30
(m, 1H), 2.16–2.00 (m, 1H), 1.88–1.77 (m, 1H), 1.21 (9H, s, t-Bu), 0.92
(3H, d, J¼6.3 Hz, Me), 0.91 (3H, d, J¼6.3 Hz, Me) ppm; 13C NMR &
DEPT (100 MHz, CDCl3):
d
¼178.5 (C]O), 170.4 (C]O), 83.4 (CH),
80.8 (CH2, d, J¼164.0 Hz), 46.8 (CH2), 38.1 (C), 32.7 (CH2, d,
4. (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015–2022; (b) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173–180.
5. Li, X.; Yang, D. Chem. Commun. 2006, 3367–3379 and references cited therein..
6. Li, X.; Wu, Y.-D.; Yang, D. Acc. Chem. Res. 2008, 41, 1428–1438 and references
cited therein.
J¼20.0 Hz), 28.5 (CH), 27.1 (CH3), 20.2 (CH3) ppm; 19F NMR
(376.2 MHz, CDCl3):
d¼ꢁ130.1 ppm; IR (CH2Cl2) 3234, 2961,
1651 cmꢁ1; HRMS (ESI) for C13H26FN2O3 (MþþH): calcd 277.1928,
found 277.1916.
7. Yang, D.; Ng, F.-F.; Li, Z.-J.; Wu, Y.-D.; Chan, K. W. K.; Wang, D.-P. J. Am. Chem. Soc.
1996, 118, 9794–9795.
8. (a) Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron 1996, 52,
12613–12622; (b) Dunitz, J. D.; Taylor, R. Chem.dEur. J. 1997, 3, 89–98; (c)
Smart, B. E. J. Fluorine Chem. 2001, 3–11; (d) Desiraju, G. R. Acc. Chem. Res. 2002,
35, 565–573.
9. For details, please see the Supporting information.
10. Yin, J.; Zarkowsky, S. D.; Huffman, M. A. Org. Lett. 2004, 6, 1465–1468.
11. Mitsunobu, O. Synthesis 1981, 1–28.
12. (a) Yang, D.; Li, B.; Ng, F.-F.; Yan, Y.-L.; Qu, J.; Wu, Y.-D. J. Org. Chem. 2001, 66,
7303–7312; (b) Shin, I.; Lee, M. R.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem.
2000, 65, 7667–7675.
13. Liang, G. B.; Rito, C. J.; Gellman, S. H. J. Am. Chem. Soc. 1992, 114, 4440–4442.
14. Yang, D.; Qu, J.; Li, B.; Ng, F.-F.; Wang, X.-C.; Cheung, K.-K.; Wang, D.-P.; Wu,
Y.-D. J. Am. Chem. Soc. 1999, 121, 589–590.
4.1.2. (R)-5-Fluoro-2-(N-Pivalylamidoxy)-N-isobutylpentanamide
(2). White solid; mp 89.0 ꢀC; Rf¼0.35 (EtOAc:hexane¼1:2);
20
[
a]
Dþ41.1ꢀ (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d¼8.78
2
(1H, s, NHa), 8.31 (1H, br s, NHb), 4.62–4.41 (2H, m, JHF¼47.4 Hz,
CH2F), 4.27 (1H, dd, J¼7.8, 4.4 Hz,
a-H), 3.15–3.01 (2H, m, NCH2),
2.10–1.78 (5H, m, –CH2CH2– & CHMe2), 1.20 (9H, s, t-Bu), 0.92 (3H,
d, J¼6.4 Hz, Me); 0.91 (3H, d, J¼6.4 Hz, Me) ppm; 13C NMR & DEPT
(100 MHz, CDCl3):
d¼178.5 (C]O), 170.6 (C]O), 86.4 (CH), 84.2
(CH2, d, J¼163.1 Hz), 46.7 (CH2), 38.2 (C), 28.5 (CH), 28.1 (CH2, d,
J¼4.8 Hz), 27.2 (CH3), 26.4 (CH2, d, J¼20.0 Hz), 20.2 (CH3) ppm; 19
F