Fluorine-decoupled carbon spectroscopy for the determination of configuration at fully substituted, trifluoromethyl- and perfluoroalkyl-bearing carbons: Comparison with 19F-1H heteronuclear overhauser effect spectroscopy

Article abstract of DOI:10.1021/jo502677a

The synthesis of a series of α-trifluoromethylcyclohexanols and analogous trimethylsilyl ethers by addition of the Ruppert-Prakash reagent to substituted cyclohexanones is presented. A method for the assignment of configuration of such compounds, of relat

Full text of DOI:10.1021/jo502677a

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Article
Fluorine-Decoupled Carbon Spectroscopy (FDCS) for the
Determination of Configuration at Fully Substituted, Trifluoromethyl
and Perfluoroalkyl Bearing Carbons. Comparison with 19F-1H
Heteronuclear Overhauser Effect Spectroscopy (HOESY)
Appi Reddy Mandhapati, Takayuki Kato, Takahiko Matsushita,
Bashar Ksebati, Andrea Vasella, Erik C Boettger, and David Crich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502677a • Publication Date (Web): 05 Jan 2015
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FluorineꢀDecoupled Carbon Spectroscopy (FDCS) for
the Determination of Configuration at Fully Substituted,
Trifluoromethyl and Perfluoroalkyl Bearing Carbons.
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Comparison with Fꢀ H Heteronuclear Overhauser
Effect Spectroscopy (HOESY)
a,‡
a,‡
a
a
b
Appi Reddy Mandhapati, Takayuki Kato, Takahiko Matsushita, Bashar Ksebati, Andrea Vasella,
c
a,
Erik C. Böttger, and David Crich *
a: Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
b: Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland
c: Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland
‡These authors contributed equally.
dcrich@chem.wayne.edu
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Abstract. The synthesis of a series of αꢀtrifluoromethylcyclohexanols and analogous trimethylsilyl
ethers by addition of the RuppertꢀPrakash reagent to substituted cyclohexanones is presented. A method
for the assignment of configuration of such compounds and of related αꢀ
trifluoromethylcyclohexylamines and of quaternary trifluoromethylꢀsubstituted carbons is described
3
13
based on the determination of the J coupling constant between the fluorine decoupled CF3
CH
resonance and the vicinal hydrogens. This method is dubbed FluorineꢀDecoupled Carbon Spectroscopy
and abbreviated FDCS. The method is also applied to the configurational assignment of substances
bearing monoꢀ, diꢀ, and perfluoroalkyl rather than trifluoromethyl groups. The configuration of all
1
19
substances was verified by either H, F heteronuclear Overhauser spectroscopy (HOESY) or by Xꢀray
2
3
crystallography. The relative merits of FDCS and HOESY are compared and contrasted. J , J , and
CH
CH
4
19
JCH to F decoupled CF groups in alkenes and arenes have also been determined and should prove
3
useful in the structural assignment of trifluoromethylated alkenes and arenes.
Introduction.
1
ꢀ6
The longꢀappreciated beneficial properties of the trifluoromethyl group in medicinal chemistry and
the imperatives of green chemistry provide the impetus for the current resurgence of interest in the
7
ꢀ36
development of trifluoromethylation methods.
The ability to produce ever more complex
trifluoromethylated substances gives rise to the need for efficient methods to unambiguously assign their
constitution, configuration, and conformation. Current projects in our laboratory necessitated the
synthesis and configurational assignment of pairs of diastereomeric αꢀtrifluoromethylcyclohexanols and
related compounds. While such compounds may be readily accessed by reaction of the RuppertꢀPrakash
3
7ꢀ38
39ꢀ45
reagent,
or other systems delivering a nucleophilic CF moiety,
it became apparent that assigning
2
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the configuration relative to an existing stereogenic center in such compounds is not straightforward in
the absence of crystals suitable for Xꢀray analysis. Thus, in previous work the relative configuration of
diastereomeric pairs of αꢀtrifluoromethyl tertiary alcohols, if assigned at all, was based on considerations
of relative polarities, differences in IR stretching frequencies of the OH group, NMR chemical shift
differences of the tertiary alcohols or of their derivatives, NOE measurements of derivatives, and
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considerations of inherent face selectivity in the precursors.
To address this problem we considered
two potential solutions: i) the application of heteronuclear NOE type experiments (HOESY) between the
5
2ꢀ55
CF ꢀgroup and proximal substituents, and ii) the Karplusꢀtype correlation
of the dihedral angle (φ)
3
subtended by the CF group and axial or equatorial hydrogen atoms at the vicinal position (HꢀCꢀCꢀCF )
3
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with the J heteronuclear coupling constants (Fig 1). Heteronuclear J coupling constants are
CH
CH
widely applied in carbohydrate chemistry for the determination of glycosidic bond and hydroxymethyl
5
6ꢀ62
63
group torsion angles,
and also enable the determination of torsion angles about CCꢀOH bonds.
64ꢀ68
However, with the exception of their use for the configurational assignment of sialic acid glycosides,
3
heteronuclear J coupling constants do not find wide application in the conformational analysis of
CH
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9ꢀ72
3
cyclic systems.
We report here on the successful development of a straightforward JCH
heteronuclear coupling method for the determination of configuration in trifluoromethylated tertiary
alcohols and related compounds which we believe will also be of use in determining the relative
1
3
1
configuration of a broad range of CF ꢀbearing quaternary centers. We also report related vicinal Cꢀ H
3
coupling constants in olefinic systems which should apply in the assignment of configuration of
trifluoromethyl alkenes.
3
13
1
Figure 1. Variation of vicinal J heteronuclear Cꢀ H couplings with the dihedral angle.
Results and Discussion
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Synthesis. Reaction of the RuppertꢀPrakash reagent with the series of representative cyclohexanones
ꢀ6 in the presence of either tetrabutylammonium fluoride or cesium fluoride gave rise to the αꢀ
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trifluoromethylated cyclohexanols or the corresponding trimethylsilyl ethers 9ꢀ14 with the yields and
selectivities listed in Table 1, entries 1ꢀ6. Similarly, reaction of the RuppertꢀPrakash reagent with the
gluconolactone 7 gave the ketose 15 (Table 1, entry 7). Reaction of the RuppertꢀPrakash reagent with
0
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3ꢀ74
the imine 8 formed in situ from 4ꢀtertꢀbutylcyclohexanone and benzylamine,
followed by
hydrogenolysis, gave the diastereoisomeric αꢀtrifluoromethylamines 16 (Table 1, entry 8). Reaction of
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5
pentafluoroethyltrimethylsilane with 4ꢀtertꢀbutylcyclohexanone catalyzed by tetrabutylammonium
fluoride gave the αꢀpentafluoroethyl 4ꢀtertꢀbutylcyclohexanols 17 (Table 1, entry 9).
Table 1. Synthesis of αꢀTrifluoromethylated Cyclohexanols, Amines, Trimethylsilyl Ethers, and
Related Substances by Reaction of Perfluoroalkyl Trimethylsilanes with Ketones and an Imine.
a
Entry Substrate
Product, yield
ax CF :eq CF
3
3
b
1
4:1
b
2
4:1
c
3
ax only
c
4
ax only
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d
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eq only
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3:1
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eq only
e
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1:1
7:3
f
a) All reactions with the exception of entry 9 were conducted with 2.0 equiv TMSCF in THF in the
3
presence of either 0.1 equiv TBAF or CsF. b) Promoted with TBAF and worked up with 6N HCl. c)
Promoted with TBAF. d) Promoted with CsF and worked up with 2 equiv TBAF. e) Promoted with 0.8
equiv KHF and 1.5 equiv TMSCF in acetonitrile, followed by hydrogenolysis over Pd/C in MeOH. f)
2
3
3
.0 Equiv TMSCF CF in THF in the presence of 0.3 equiv TBAF were employed.
2 3
In addition, a diastereomeric mixture of two steroids 19 containing a quaternary carbon in which one
of the four ligands is a trifluoromethyl group was prepared as described by Blazejewski and
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coworkers, by radical reaction of allyltrimethylstannane with the Sꢀmethyl xanthate ester 18 derived
from the tertiary trimethylsilyl ether 11 (Scheme 1).
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Scheme 1. Preparation of a CF ꢀBearing Quaternary Center
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Stereoselectivity in the Addition of the Trifluoromethide Anion to Cyclohexanones and 1,5ꢀ
Lactones. Although not the primary focus of this Article, it is noteworthy and bears comment that
kineticallyꢀcontrolled reaction of the RuppertꢀPrakash reagent with five of the six cyclohexanones
studied is selective for the formation of the axial trifluoromethyl derivatives. The use of both 4ꢀtertꢀ
butyl and 4ꢀphenylcyclohexanone as substrate gave approximate 4:1 mixtures of adducts favoring
introduction of the CF group syn to the remote substituent, with the products retaining essentially
3
1
undistorted chair conformations in the solution phase as determined by analysis of the HꢀNMR spectra
despite the axial location of the bulky CF group. Previously, the major product from the reaction with
3
4
ꢀphenylcyclohexanone was assigned the opposite configuration (CF trans to phenyl) on the basis of
3
4
8
chemical shift differences in the derived xanthate esters of the two isomers.
In view of this
discrepancy, and in support of the FDCS NMR method discussed below, we obtained an Xꢀray crystal
structure of the major isomer from reaction with 4ꢀphenylcyclohexane (Supporting Information and
CCDC 1032684), which confirms its chair conformation and the axial location of the CF group. The
3
CF ꢀC1 bond adopts a perfectly staggered conformation in this structure. This assignment corrects the
3
4
8
earlier literature, focuses attention on the ambiguities arising from the assignment of configuration in
such αꢀtrifluoromethyl tertiary alcohols on the basis of chemical shift arguments alone, and underlines
the need for unambiguous methods for assignment of configuration that are preferably based on the
analysis of coupling constants.
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In their original report on the reaction of trifluoromethyltrimethysilane with aldehydes and ketones
Prakash and coworkers noted the formation of a single but unassigned diastereomeric product in the
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reaction with cholestanone 3. Subsequent workers reported a 96:4 ratio of isomers favoring the 3αꢀ
47
CF epimer, but did not provide any basis for the attribution of configuration. In our hands a single
3
diastereomer 11 was formed (Table 1, entry 3) to which we assign the 3αꢀCF configuration on the basis
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of the FDCS method discussed below and which is further confirmed by HOESY. Similarly, the
triterpenoid methyl ester 4 gives a single isomer of the adduct 12 with an axial CF group (Table 1, entry
3
4
) as determined by FDCS and confirmed by the HOESY relationship of the CF group to a single of the
3
two vicinal methyl groups. The glucopyranoseꢀ4ꢀone derivative 5 reacts in a highly selective manner
with the RuppertꢀPrakash reagent but affords the galactoꢀconfigured trimethylsilyl ether 13 with the
equatorial CF group (Table 1, entry 5). The configuration of this derivative was assigned by the FDCS
3
method below, and is confirmed by NOESY correlations between the trimethylsilyl methyl groups and
the axial hydrogen at position 2 as well as by HOESY correlations between the CF group and the axial
3
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hydrogens at positions 3 and 5. With the apramycinone derivative 6, as reported previously, a return to
axial selectivity is observed (Table 1, entry 6) as confirmed by HOESY measurements.
The axial selectivity observed for the introduction of the CF group into cyclohexanones 1ꢀ4, and 6 is
3
7
8
interesting in view of the steric bulk of the CF group itself (Steric A value 2.37) and more pertinently
3
ꢀ
ꢀ 38,79
of the presumed penta coꢀordinate species (R COꢀSiMe ꢀCF or FꢀSiMe ꢀCF )
that transfers the
2
3
3
3
3
CF group to the ketone. Presumably, this selectivity arises from the coꢀordination/activation of the
3
7
9
ketone to the trimethylsilyl group of the RuppertꢀPrakash reagent, as suggested by Prakash and Yudin;
in much the same way the facial selectivity of alkyllithium attack on cyclohexanones can be reversed
from the equatorial face to the axial face by complexation of the ketone with sterically bulky Lewis
8
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acids. The equatorial selectivity observed in the formation of 13 is consistent with that observed for
81
the addition of the bulky trichloromethide anion to 13 and it’s αꢀanomer, and for the reduction of the
8
2
permethyl analog of 13 by sodium borodeuteride. Less hindered acetylide nucleophiles, on the other
8
3
hand, are axial selective in their reactions with 13. The single diastereomer observed in the formation
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of the sixꢀmembered cyclic βꢀtrifluoromethyl hemiacetal 15 presumably is due to mutarotation
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subsequent to the initial attack and so reflects both the steric bulk of the CF group and the influence
3
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4
of the exoꢀanomeric effect.
The reduced selectivity observed in the trifluoromethylation of the Nꢀbenzylimine 8, as compared to
reaction with the corresponding ketone 1 (Table 1, entries 1 and 8), presumably arises from the weaker
coꢀordination of the imine nitrogen than the ketone oxygen to the reagent resulting in a smaller effective
bulk and more facile accommodation of the CꢀN bond in the axial position. Consistent with the greater
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steric bulk of the pentafluoroethyl group (Steric A value 2.67) reaction of 4ꢀtertꢀbutylcyclohexanone 1
7
5
with pentafluoroethyltrimethylsilane
(Table 1, entry 9) was less selective than with
trifluoromethyltrimethylsilane (Table 1, entry 1) resulting in a greater proportion of the adduct 17 with
the equatorial fluoroalkyl group.
FluorineꢀDecoupled Carbon Spectroscopy Method (FDCS) and Assignment of Configuration.
3
In the sialic acids the measurement of J coupling constants between the anomeric carboxyl carbon
CH
and the axial H3 is a rapid and reliable method for the determination of anomeric configuration (Figure
6
4ꢀ68
2
).
which are a variation on standard
methyl esters and are carried out with selective low power decoupling of the methoxycarbonyl protons
Such experiments, which we dub Single Frequency OffꢀResonance Decoupling (SFORD), and
8
5ꢀ88
offꢀresonance decoupling methods, are usually conducted on the
3
13
to facilitate identification of the desired residual J coupling constant in the C NMR spectrum as
CH
illustrated in Figure 3A. An axial CO Me group, with its antiperiplanar relation to the axial H3 typically
2
displays a vicinal coupling constant of 5ꢀ7 Hz, while its equatorial counterpart flanked by two gauche
hydrogens is usually devoid of coupling (Figure 2).
CO Me
OR
O
CO Me
2
R'
O
OR
R'
2
AcHN
AcHN
H
3eq
H
3eq
PO
PO
H3ax
H3ax
3JC,H3ax = 3JC,H3eq = 0 Hz
3JC,H3ax = 5-7 Hz
3JC,H3eq = 0 Hz
R = aglycone, R' = CH(OP)-CH(OP)-CH OP;
2
P = H or protecting group
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Figure 2. Diagnostic vicinal CH couplings in the sialic acid glycosides.
1
2
3
4
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6
7
3
Inspired by this method we developed an analogous protocol for the determination of J coupling
CH
13
1
constants between the carbon of a CF group and its vicinal hydrogen atoms, which we dub the Cꢀ H
3
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FluorineꢀDecoupled Coupling Constant (FDCS) method. In this experiment a fully Hꢀcoupled
C
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observed spectrum was acquired with selective F irradiation as illustrated in Figure 3B. In this manner
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the CF resonance is observed free of J coupling, thereby revealing the diagnostic J couplings in
3
CF
CH
an unobstructed manner.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Pulse sequences employed in the SFORD, and FDCS determinations and in the
confirmatory HOESY experiments.
13
A) Pulse sequence for single frequency offꢀresonance decoupling (SFORD) experiment. C was the
1
observed nucleus and the desired H was irradiated with low power single frequency continuous wave
1
3
1
13
(CW) pulse. B) Pulse sequence for the Cꢀ H FDCS experiment. C spectrum was the observed
19
nucleus and F signal was selectively decoupled with a Waltzꢀ16 composite decoupling scheme. C)
1
9
1
Pulse sequence for the Fꢀ{ H} 2DꢀHOESY experiment. The standard pulse sequence from the
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VNMRJ 3.2 software library was used, with 0.3 s mixing time and 4.0 s relaxation delay. The
acquisition time was 0.17 s, with 16 or 32 scans for each of 128 increments. D) Pulse sequence for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
19
the Hꢀ{ F} 1DꢀHOESY experiment. The standard pulse sequence from the VNMRJ 3.2 software
19
library was used. For the HꢀF NOE difference experiment, two FIDs were recorded, one with F
1
9
selective low power irradiation and the second FID without F irradiation. The resulting two spectra
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
were subtracted digitally to observe the HꢀF NOE spectrum.
Application of the FDCS method to the various αꢀtrifluoromethyl cycloalkanols or their trimethylsilyl
1
3
1
ethers displayed in Table 2 supports the initial premise that the Cꢀ H heteronuclear coupling constant
is a function of the torsion angle. Thus, an axial CF group exhibits a coupling constant of 7.3ꢀ10.4 Hz
3
o
with vicinal axial hydrogen atoms (φ 180 ) (Table 2, entries 1, 3, 5, 6, and 8). The vicinal coupling
o
constant between an axial CF group and an equatorial hydrogen atom (φ 60 ) is typically ≤1 Hz but
3
ranges as high as 4.2 Hz in the steroidal and triterpenoid examples (Table 2, entries 1, 3, 5, 6, and 8).
An equatorial CF group exhibits a vicinal coupling constant of ≤1 Hz with vicinal axial and equatorial
3
o
hydrogen atoms (φ 60 ) in the systems studied (Table 2, entries 2, 4, 7, 9, and 10). In the case of both
o
o
the 180 and 60 dihedral angles, the larger coupling constants in the observed ranges are found in the
conformationally more rigid systems (Table 2, entries 5 and 6). This suggests that the smaller coupling
constants observed in the simple cyclohexyl systems are the result of an appreciable population of nonꢀ
chair conformers at room temperature consistent with the most recent estimates of the steric A value for
the CF group, which suggest that it is more bulky than an isopropyl group but less so than a tertꢀbutyl
3
7
8
group. Although the present data set is not sufficiently extensive for careful calibration, we also note
3
54
that, as is well appreciated in homonuclear J
coupling and as has been demonstrated in other
H,H
3
72,89
heteronuclear J systems,
the general Karplusꢀtype relationship correlating the magnitude of F Cꢀ
3
CH
CꢀCꢀH coupling constant with torsion angle will be modulated by the nature and orientation of
substituents.
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The
FDCS
method
is
readily
extended
from
trifluoromethylcyclohexanols
to
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
trifluoromethylcyclohexylamines and allows the assignment of axial and equatorial CF groups in the αꢀ
3
1
3
trifluoromethyl amines 16 (Table 2, entries 11 and 12). By way of example, Figure 4 shows the C
resonances of the two CF groups in a mixture of the diastereomeric amines 16 before (Fig 4A) and after
3
1
9
(
Fig 4B) decoupling of the F atoms.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Figure 4. CF Resonances in a diasteromeric mixture of trifluoromethylamines 16 before (Fig 4A)
3
19
and after (Fig 4B) F decoupling with a partial expansion (Fig 4C).
The analysis of the FDCS spectra of the inseparable diastereomeric trifluoromethylated steroid
derivatives 19 in which the trifluoromethyl group is appended to a quaternary carbon were complicated
3
13
by the additional J coupling of the CF resonances to the allylic methylene protons in addition to
CH
3
the diagnostic couplings to the vicinal hydrogens in the steroidal A ring (Table 2, entries 15 and 16; Fig
1
3
5
). Nevertheless, application of the standard FDCS sequence to the standard C spectrum (Fig 5A)
gave a simplified spectrum (Fig 5B) displaying a downfield CF resonance as a broad multiplet for one
3
isomer and a narrower more upfield multiplet for the second isomer. The broader multiplet, expanded in
Fig 5C, clearly represents the axial CF group with its diaxial couplings to the axial hydrogens at the
3
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vicinal 2ꢀ and 4ꢀpositions, while the narrower multiplet lacks such large couplings to the vicinal
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
hydrogens in the steroidal A ring. Although both multiplets are convoluted with additional J
CH
3
couplings to the two allylic hydrogens, which renders actual measurement of the diagnostic J
CH
couplings constants difficult, the clear difference in the width at half height of the two multiplets (w1/2
=
1
7.2 and 26.3 Hz) allows relative configuration to be assigned. To confirm this assignment a SFORD
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
experiment was conducted in which the allylic hydrogens were selectively decoupled giving rise to the
partial spectrum in Fig 5D. The signals in this SFORD experiment retain the quartet due to coupling to
1
9
the C F resonances and also display coupling to the vicinal hydrogens at positions 2 and 4 in the A
3
ring. The lines that make up the more downfield quartet are broader than those in the upfield quartet as
3
they display the larger JCH couplings to the axial hydrogens at the 2ꢀ and 4ꢀpositions, which is
observable on the expansion (Fig 5E). Further confirmation of these assignments was achieved by
NOESY experiments showing the spatial proximity of the vinylic hydrogens with the axial hydrogen at
the 1ꢀposition in the A ring of the major isomer.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Figure 5. CF Resonances in a diasteromeric mixture of trifluoromethylsteroids 19.
3
1
9
19
13
A) Before F decoupling. B) After F decoupling. C) Expansion of B. D) C SFORD experiment.
E) Expansion of D.
1
3
The FDCS method is not limited to CF groups, as demonstrated by its application to the
3
diastereomeric αꢀpentafluoroethyl cyclohexanols 17 (Table 2, entries 13 and 14) involving observation
13
2
of the CF resonance. The FDCS spectra of the two isomers of 17 contain an additional J quartet
2
CF
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coupling to the CF group, but as the extra coupling constant is significantly larger it is of no
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
consequence and does not complicate interpretation. The FDCS method was also applied to the known
9
0
91
αꢀmonoꢀ and diꢀ fluoromethylcyclohexanols 20 and 21 (Table 2, entries 17ꢀ20), which were donated
by Drs Lewis Mtashobya and Bruno Linclau at the University of Southampton. The spectra of 20 and
1
2
1 are complicated by convolution of the vicinal coupling constants with the JCH couplings but spectral
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
interpretation is not difficult as the vicinal coupling constants are more than an order of magnitude
13
1
smaller. Commercially available αꢀtrifluoromethyl ethanol 22 allowed the determination of the Cꢀ H
vicinal coupling constant between a hydrogen atom and a CF group in a freely rotating acyclic system
3
(Table 2, entry 21).
1
9
13
Table 2. Multiplicity and Coupling Constants of F Decoupled CF Resonances and Method of
3
Confirmation of Configuration.
Method of
1
3
CF Signal Multiplicity and
a
b
Confirmation
of
Entry Compound
Coupling Constants (Hz)
Configuration
3
Triplet, J
= 9.0 Hz,
CF3,2Hax
1
2
3
HOESY
HOESY
3
JCF3,2Heq <1 Hz
3
Broad singlet, J
3
<1 Hz,
CF3,2Hax
JCF3,2Heq <1 Hz
3
HOESY,
Xꢀray
Triplet, J
3
= 7.3 Hz,
CF3,2Hax
JCF3,2Heq <1 Hz
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Broad singlet, J
3
<1 Hz,
CF3,2Hax
4
5
6
HOESY
HOESY
HOESY
JCF3,2Heq <1 Hz
3
Triplet of triplet, J
= 9.6
CF3,2Hax
3
Hz, J
= 4.2 Hz
CF3,2Heq
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Doublet of doublet, J
=
CF3,Hax
3
9
.8 Hz, J
= 3.1 Hz
CF3,Heq
HOESY,
NOESY
3
7
8
Triplet, J
= 1.1 Hz
= 8.1 Hz
CF3,2Hax
c
3
HOESY
Triplet, J
CF3,2Hax
c
3
9
1
HOESY
HOESY
Broad singlet, J
<1 Hz
CF3,2Hax
3
0
Broad singlet, J
<1 Hz
CF3,Hax
3
Triplet of triplets, J
=
d
d
CF3,2Hax
11
12
HOESY
HOESY
3
10.4 Hz, J
= 3.4 Hz
CF3,2Heq
3
Broad singlet, J
<1 Hz,
CF3,2Hax
3
JCF3,2Heq <1 Hz
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e
Quartet of triplet of triplet,
1
2
2
3
1
3
HOESY
HOESY
JCF2,CF3 = 28.4 Hz, J
=
CF2,2Hax
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
7
.3 Hz, J
= 3.3 Hz
CF2,2Heq
e
Broad quartet,
2
3
14
15
JCF2,CF3 = 33.4 Hz, J
<1
CF2,2Hax
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, J
<1 Hz
CF2,2Heq
f
HOESY
Broad multiplet
Narrow multiplet
HOESY,
NOESY
f
16
17
Triplet of triplet of triplet,
1
3
NOESY
NOESY
NOESY
NOESY
JCF,CH2F = 150 Hz, J
=
CF,2Hax
3
7.6 Hz, J
= 3.1 Hz
CF,2Heq
,
Triplet of quintet
1
3
1
8
9
JCF,CH2F = 150 Hz, J
=
CF,2Hax
3
1
.5 Hz, J
= 1.5 Hz
CF,2Heq
Doublet of triplet of triplet,
1
3
1
JCF2,CHF2 = 180.7 Hz, J
CF2,2Hax
3
=
8.1 Hz, J
= 3.1 Hz
CF2,2Heq
Broad doublet,
1
3
2
2
0
1
JCF2,CHF2 = 186.3 Hz, J
CF2,2Hax
3
=
<1 Hz, J
= <1 Hz
CF2,2Heq
Quartet of doublet,
3
2
JCF3,CH3 = 4.8 Hz, J
= 3.6
CF3,CH
Hz
a) Unless otherwise stated spectra were recorded in CDCl ; b) The descriptors ax and eq refer to the
3
axial or equatorial location of the fluoroalkyl groups and of the vicinal hydrogens to which they are
77
coupled; c) All NMR experiments of 14 were recorded in D O after complete deprotection; d)
2
1
3
Recorded in CD OD; e) Multiplicity of the CF resonance; f) Owing to complications arising from
3
2
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1
3
convolution with additional CF coupling to the allylic hydrogens multiplicity and coupling constants
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
are difficult to assign for 19ax and 19eq (see text for clarification).
Comparison of FDCS with HOESY. As discussed above (Table 2) the configuration of a number of
9
2ꢀ95
the samples employed in this study was confirmed by heteronuclear Overhauser effect (HOESY)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
measurements between CF groups and spatially proximal hydrogen atoms. These measurements enable
3
a comparison of the FDCS and HOESY methods. HOESY spectra were acquired using an autoꢀtriple
1
19
resonance broadband probe (ATB), which is simultaneously tuned to H and F on the high band RF
coil. 2D HOESY experiments used the manufacturer supplied FHꢀHOESY pulse sequence implemented
1
19
in the VNMRJ 3.2 software (Figure 3C). H Observed, F irradiated 1D HOESY experiments used the
FH decoupling pulse sequence from the VNMRJ 3.2 software (Figure 3D). The main limitation of the
HOESY method as implemented in these experiments is the requirement for the three channel or ATB
type probe and of a spectrometer with three channel capabilities. When such hardware is on hand, the
HOESY method – 1D or 2D – provides a rapid means of assessing the spatial proximity of the CF and
3
adjacent protons and therefore of inferring configuration and/or conformation. Because the 1D HOESY
19
sequence is observed by the proton channel and the 2D HOESY sequence by the F channel, sensitivity
is correspondingly high and data acquisition times are relatively short. The FDCS sequence on the other
hand employs a standard two channel probe and can be implemented on any modern spectrometer. It
1
13
gives direct information on the dihedral angle subtended by the coupled H and CF spins, and so on
3
the conformation and/or configuration of the substance under investigation. The FDCS spectrum is
1
3
acquired through the C channel and data acquisition is correspondingly slow. Overall, FDCS and
HOESY provide complementary information, and the combination of the two is a powerful tool for
studying the configuration and conformation of CF and other fluoroalkylꢀcontaining molecules.
3
Application of FDCS to Alkenes and Arenes. Although the primary focus of this investigation is
the development of the FDCS method for the assignment of configuration in saturated systems carrying
CF groups, using commercially available compounds, we also briefly investigated its application to
3
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unsaturated molecules. Thus, as illustrated in Fig 6, the FDCS method allows distinction of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
regioisomers in trifluoromethylated arenes, as the CF group only exhibits a measureable Cꢀ H
3
coupling to an orthoꢀhydrogen. Likewise, the FDCS method may be applied to the determination of
3
configuration of trifluoromethylꢀsubstituted alkenes, as the transꢀ J coupling constant is more than
CH
2
double that of the corresponding cis coupling constant; J couplings are even smaller and should not
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH
complicate assignment of configuration (Fig 6).
2
Figure 6. FluorineꢀDecoupled Carbon Spectroscopy in sp ꢀHybridized Systems.
Conclusion
The fluorineꢀdecoupled carbon spectroscopy method is readily implemented on standard two channel
NMR spectrometers and provides a facile method for the determination of the configuration and/or
conformation of CF ꢀ and other fluoroalkylꢀsubstituted molecules. Based on the Karplusꢀtype relation
3
1
13
1
19
of the HꢀCꢀCꢀ CF torsion angle to the coupling constant, the method is an alternative to H, F
3
HOESY. Earlier methods for the assignment of configuration of CF ꢀsubstituted tertiary alcohols based
3
on chemical shift differences in derived xanthate esters are unreliable and should be succeeded by the
FDCS and/or HOESY methods.
Experimental
General Experimental: All reactions were performed using oven dried glassware under an atmosphere
of argon. All reagents and solvents were purchased from commercial suppliers and were used without
further purification unless otherwise specified. All organic extracts were dried over sodium sulfate and
concentrated under vacuum. Chromatographic purifications were carried out over silica gel (230ꢀ400
mesh). Reactions were monitored by analytical thinꢀlayer chromatography on preꢀcoated glass backed
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plates (w/UV 254) and visualized by UV irradiation (254 nm) or by staining with 25% H SO in EtOH
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
or ceric ammonium molybdate solution. Specific rotations were obtained using a digital polarimeter in
the solvent specified. High resolution mass spectra were recorded with an electrospray source coupled to
1
13
19
a timeꢀofꢀflight mass analyzer. H, C, F, HOESY and FDCS spectra were recorded on a 400 or 600
MHz spectrometer using VNMRJ 3.2 as processing software. Commercial NMR solvents were used
without more purification. Chemical shifts are given in ppm (δ) and coupling constants J are given in
Hz.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
ꢀtransꢀtertꢀButylꢀ1ꢀtrifluoromethylꢀrꢀ1ꢀcyclohexanol (9ax) and 4ꢀcisꢀtertꢀButylꢀ1ꢀtrifluoromethylꢀ
4
8
rꢀ1ꢀcyclohexanol (9eq). Compounds 9ax and 9eq were prepared according to the literature protocol
using 4ꢀtertꢀbutylcyclohexanone (400 mg, 2.6 mmol) and (trifluoromethyl)trimethylsilane (740 mg, 5.2
mmol) in tetrahydrofuran (3.0 mL) at room temperature with a catalytic amount of tetrabutylammonium
fluoride (0.25 mL, 1.0 M in tetrahydrofuran). Chromatographic purification (gradient elution of diethyl
º
ether /pentane: 2% to 10%), gave 9eq (70 mg, 12%, mp: 48.0ꢀ49.5 C) as an offꢀwhite solid, and 9ax
º
(290 mg, 50%, mp: 94.5ꢀ95.5 C) as a white solid.
1
9
eq: H NMR (600 MHz, CDCl ): δ 1.82 (dd, J = 14.3, 2.2 Hz, 2H), 1.73 (br s, 1H), 1.67 (m, 2H), 1.59
3
1
3
(
dt, J = 13.5, 4.0 Hz, 2H), 1.36 (m, 2H), 1.00 (tt, J = 12.1, 2.9 Hz, 1H), 0.88 (s, 9H); C NMR (150
1
2
MHz, CDCl ): δ 126.0 (q, J = 284.4 Hz, CF ), 72.2 (q, J = 28.1 Hz, C ), 47.0, 32.3, 30.2, 27.3,
3
CF
3
CF
1
1
9
2
9
2
1.1; F NMR (564 MHz, CDCl ): δ ꢀ87.4 (s, CF ); FDCS (150) MHz, CDCl ): δ 131.5 (br s).
3
3
3
1
ax: H NMR (600 MHz, CDCl ): δ 2.20 (m, 3H), 1.70 (d, J = 13.5 Hz, 2H), 1.48 (dt, J = 13.9, 2.2 Hz,
3
1
3
H), 1.30 (q, J = 12.4 Hz, 2H), 1.08 (tt, J = 12.1, 2.9 Hz, 1H), 0.84 (s, 9H); C NMR (150 MHz,
1
2
19
CDCl ): δ 126.8 (q, J = 286.1 Hz, CF ), 71.8 (q, J = 27.5 Hz, C ), 46.3, 33.3, 32.2, 27.4, 23.0; F
3
CF
3
CF
1
NMR (564 MHz, CDCl ): δ ꢀ80.4 (s, CF ); FDCS (150 MHz, CDCl ): δ 131.5 (tt, J = 8.9, 3.6 Hz).
3
3
3
4
ꢀtransꢀPhenylꢀ1ꢀtrifluoromethylꢀrꢀ1ꢀcyclohexanol (10ax) and 4ꢀcisꢀPhenylꢀ1ꢀtrifluoromethylꢀrꢀ1ꢀ
48
cyclohexanol (10eq). Compounds 10ax and 10eq were prepared according to the literature protocol
using 4ꢀphenylcyclohexanone (1.0 g, 5.7 mmol) and (trifluoromethyl)trimethylsilane (1.6 g, 11.2 mmol)
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in tetrahydrofuran (5.0 mL) at room temperature with a catalytic amount of tetrabutylammonium
fluoride (0.6 mL, 1.0 M in tetrahydrofuran). The residue was purified by column chromatography
(eluting with dichloromethane) followed by recrystallization from IPA: water (7:1) to give 10eq (90 mg,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
º
º
8
%, mp: 75.0ꢀ76.5 C) as an offꢀwhite solid, and 10ax (356 mg, 24%, mp: 70.5ꢀ71.3 C) as a white solid,
and mixture of both isomers (750 mg, 52%).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
2
8
1
0eq: H NMR (600 MHz, CDCl ): δ 7.33 (t, J = 7.7 Hz, 2H), 7.25 (m, 3H), 2.55 (tt, J = 11.7, 4.0 Hz,
3
1
3
1
H), 1.93 (m, 3H), 1.85 (m, 6H); C NMR (150 MHz, CDCl ): δ 146.1, 125.5, 126.7, 126.6 (q, J
=
3
CF
2
19
84.4 Hz, CF ), 126.3, 72.0 (q, J = 28.1 Hz, C ), 43.2, 30.1, 27.7; F NMR (564 MHz, CDCl ): δ ꢀ
3
CF
1
3
7.3 (s, CF ); FDCS (150MHz, CDCl ): δ 131.5 (br s).
3
3
1
0ax: H NMR (600 MHz, CDCl ): δ 7.33 (m, 2H), 7.26 (m, 3H), 2.77 (br s, 1H), 2.18 (m, 3H), 1.96
3
1
3
1
(m, 4H), 1.69 (m, 2H); C NMR (150 MHz, CDCl ): δ144.7, 128.5, 126.8, 126.7 (q, J = 285.5 Hz,
3
CF
2
19
CF ), 126.1, 72.0 (q, J = 25.8 Hz, C ), 40.4, 31.0, 28.0; F NMR (564 MHz, CDCl ): δ ꢀ82.2 (s,
3
CF
1
3
CF ); FDCS (150 MHz, CDCl ): δ 124.2 (t, J = 7.3 Hz).
3
3
3
αꢀTrifluoromethylꢀ3βꢀtrimethylsilanoxycholestane (11ax). To a stirred solution of cholestanꢀ3ꢀone
(400 mg, 1.0 mmol) in tetrahydrofuran (3.0 mL) was added (trifluoromethyl)trimethylsilane (300 mg,
2.1 mmol) and a catalytic amount of tetrabutylammonium fluoride (27 mg, 0.1 mmol, 1.0 M in
tetrahydrofuran) at room temperature. The resulting reaction mixture was stirred at room temperature for
2
h. The solvent was evaporated under reduced pressure and the residue was dissolved in
dichloromethane (5.0 mL), washed with water followed by brine, dried over Na SO , and concentrated
2
4
under reduced pressure. The residue was purified by column chromatography on silica gel eluting with
3
8
º
20
EtOAc: hexanes (2% to 10%) to afford 11ax (482 mg, 90%, mp: 103ꢀ104 C) as a white solid. [α]
=
D
1
+
20.4 (c =3.7, dichloromethane); H NMR (600 MHz, CDCl ): δ 2.08 (td, J = 14.6, 1.8 Hz, 1H), 1.95
3
(td, J = 12.8, 2.9 Hz, 1H), 1.85ꢀ1.77 (m, 2H), 1.65 (m, 2H), 1.61ꢀ1.42 (m, 6H), 1.39ꢀ1.29 (m, 6H), 1.28ꢀ
.20 (m, 3H), 1.20ꢀ0.94 (m, 11H), 0.89 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 2.6 Hz, 3H), 0.83 (s, 3H), 0.67
1
1
3
1
(
dd, J = 12.4, 4.0 Hz, 1H), 0.64 (s, 3H), 0.14 (s, 9H); C NMR (150 MHz, CDCl ): δ 126.6 (q, J
=
3
CF
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2
2
87.2 Hz, CF ), 75.2 (q, J = 26.9 Hz, C ), 56.3, 56.2, 53.9, 42.6, 41.8, 39.9, 39.5, 36.8, 36.1, 35.8,
3 CF 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
3
5.4, 35.2, 34.8, 31.7, 30.1, 28.6, 28.2, 27.9, 24.1, 23.8, 22.8, 22.6, 21.1, 18.6, 12.0, 11.7, 2.2; F NMR
(564 MHz, CDCl ): δ ꢀ80.3 (s, CF ); FDCS (150 MHz, CDCl ) δ: 131.5 (tt, J = 9.6, 4.1 Hz).
3
3
3
Methyl 3αꢀtrifluoromethylꢀ3βꢀtrimethylsilanoxyꢀoleanꢀ12ꢀenꢀ28ꢀoate (12ax). A solution of methyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
6
3
ꢀketooleanꢀ12ꢀenꢀ28ꢀoate (40 mg, 0.08 mmol) and (trifluoromethyl)trimethylsilane (66.2 mg, 0.46
mmol) in tetrahydrofuran (1.5 mL) was treated with a catalytic amount of tetrabutylammonium fluoride
4.4 mg, 0.02 mmol, 1.0 M in tetrahydrofuran) at room temperature. The resulting reaction mixture was
(
stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue
was dissolved in dichloromethane (2.0 mL), washed with water followed by brine, dried over Na SO ,
2
4
and concentrated under reduced pressure. The residue was subjected to flash column chromatography
º
(gradient elution of EtOAc /Hexanes: 2% to 20%) to afford 12ax (42 mg, 82%, mp 178ꢀ179 C) as a
20
1
white solid. [α] = +62.1 (c =1.4, dichloromethane); H NMR (600 MHz, CDCl ): δ 5.26 (t, J = 3.6
D
3
Hz, 1H), 3.60 (s, 3H), 2.84 (dd, J = 13.9, 4.4 Hz, 1H), 1.99ꢀ1.78 (m, 5H ), 1.70ꢀ1.54 (m, 5H), 1.51 (m,
2H), 1.44 (m, 2H), 1.31 (m, 3H), 1.24 (m, 2H), 1.18 (t, J = 12.2 Hz, 2H ), 1.12 (m, 1H), 1.11 (s, 3H),
13
0
.96 (br s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H), 0.71 (s, 3H), 0.11 (s, 9H); C NMR
1
2
(150 MHz, CDCl ): δ 178.2, 143.8, 127.2 (q, J = 291.7 Hz, CF ), 122.1, 81.0 (q, J = 24.6 Hz, C ),
3
CF
3
CF
3
5
2
1.4, 51.2, 47.5, 46.7, 45.8, 41.7, 41.6, 41.3, 39.2, 36.3, 35.4, 33.8, 33.0, 32.8, 32.3, 30.6, 27.7, 24.1,
1
9
3.5, 23.3, 23.0, 21.1, 19.1, 16.9, 15.5, 2.1; F NMR (564 MHz, CDCl ): δ ꢀ69.5 (s, CF ); FDCS (150
3
3
+
MHz, CDCl ): δ 124.6 (dd, J = 9.8, 3.1 Hz); ESIHRMS calcd for C H O F SiNa ([M + Na] )
3
35 57
3 3
6
33.3916, found 633.3927.
Methyl 2,3,6ꢀtri-Oꢀbenzylꢀ4ꢀtrifluoromethylꢀ4ꢀOꢀtrimethylsilylꢀβꢀ
D
ꢀgalactopyranoside (13eq) To a
.
97
solution of methyl 2,3,6ꢀtriꢀOꢀbenzylꢀβꢀ
D
ꢀglucopyranoside (296 mg, 0.54 mmol) in anhydrous
dichloromethane (2.5 mL) was added Dess–Martin periodinane (296 mg, 0.69 mmol) at room
temperature. The resulting reaction mixture was stirred at room temperature for 3 h, then quenched with
saturated aqueous NaHCO (3.0 mL), and washed with water (3.0 mL), and brine (3.0 mL). The solvent
3
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was evaporated under reduced pressure to give the 4ꢀketone as yellow oil, which was taken forward to
the next step without further characterization. To a solution of this ketone (220 mg, 0.47 mmol) in
anhydrous tetrahydrofuran (4.0 mL) was added a catalytic amount of cesium fluoride (7.0 mg, 0.04
mmol) followed by (trifluoromethyl)trimethylsilane (700 mg, 4.90 mmol) at room temperature. The
resulting reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under
reduced pressure and the residue was dissolved in dichloromethane (5.0 mL), washed with water (5.0
mL) followed by brine (5.0 mL), dried over Na SO , and concentrated under reduced pressure. The
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
residue was purified by silica gel column chromatography eluting with 10% EtOAc in hexanes to give
2
5
1
1
3eq (198 mg, 69%) as an oil. [α]D = +36.5 (c= 4.9, dichloromethane); H NMR (600 MHz, CDCl ): δ
3
7
.38ꢀ7.25 (m, 15H), 4.97 (dd, J = 9.9, 5.1 Hz, 2H), 4.74 (d, J = 10.6 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H),
4.60 (d, J = 9.9 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.33 (d, J = 7.7 Hz, 1H), 3.96 (dd, J = 11.4, 2.2 Hz,
1
9
1
7
H), 3.81 (dd, J = 7.3, 2.2 Hz, 1H), 3.74 (d, J = 9.5 Hz, 1H), 3.69 (dd, J = 11.3, 7.7 Hz, 1H), 3.65 (d, J =
1
3
.2 Hz, 1H), 3.64 (s, 3H), 0.04 (s, 9H); C NMR (150 MHz, CDCl ): δ 138.3, 138.1, 137.5, 128.7,
3
1
28.4, 128.3, 128.2, 128.1, 127.7, 127.7, 127.6, 127.6, 124.6 (q, JCF = 291.1 Hz, CF ), 104.5, 80.3,
3
2
19
9.5, 78.5 (q, J = 25.2 Hz, C ), 76.4, 75.6, 74.8, 73.7, 69.3, 57.2, 1.8; F NMR (564 MHz, CDCl ): δ
CF
4
3
ꢀ
64.7 (s, CF ); FDCS (150 MHz, CDCl ): δ 122.1 (d, J = 1.1 Hz); ESIHRMS calcd for C H O F SiNa
3
3
32 39
6 3
+
(
[M + Na] ) 627.2366, found 627.2341.
2,3,4,6ꢀTetraꢀOꢀbenzylꢀ1ꢀtrifluoromethylꢀαꢀDꢀglucopyranose (15eq). To a solution of 2,3,4,6ꢀtetraꢀ
9
8
Oꢀbenzylꢀ
D
ꢀgluconoꢀ1,5ꢀlactone (200 mg, 0.47 mmol) in anhydrous tetrahydrofuran (4.0 mL), was
added
a
catalytic amount of cesium fluoride (6.0 mg, 0.04 mmol) followed by
(trifluoromethyl)trimethylsilane (1.0 g, 7.40 mmol) at room temperature. The resulting reaction mixture
was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the
residue was dissolved in dichloromethane (4.0 mL), washed with water (4.0 mL) followed by brine (4.0
mL), dried over Na SO , and concentrated under reduced pressure. The residue was dissolved in
2
4
tetrahydrofuran (3.0 mL) and was treated with tetrabutylammonium fluoride (170 mg, 0.65 mmol, 1.0 M
in THF) at room temperature. The resulting reaction mixture was stirred for 1 h. at room temperature.
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The solvent was evaporated under reduced pressure and the residue was purified by silica gel column
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
5
chromatography eluting with 10% EtOAc in hexanes to give 15eq (142 mg, 65%) as an oil. [α]D
=
1
+
50.3 (c= 8.0, dichloromethane); H NMR (600 MHz, CDCl ): δ 7.40ꢀ7.27 (m, 17H), 7.26ꢀ7.22 (m,
3
3
H), 4.97 (d, J = 11.0 Hz, 1H), 4.90 (d, J = 2.9 Hz, 1H), 4.87 (br s, 1H), 4.85 (d, J = 10.6 Hz, 1H), 4.75
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(d, J = 9.9 Hz, 1H), 4.69 (dd, J = 10.6, 7.7 Hz, 1H), 4.59 (d, J = 12.5 Hz, 1H), 4.05 (d, J = 9.9 Hz, 1H),
3
3
1
.94 (br s, 1H), 3.93 (d, J = 5.1 Hz, 1H), 3.92 (br s, 1H), 3.85 (dd, J = 11.4, 3.6 Hz, 1H), 3.81 (m, 1H),
1
3
.76 (dd, J = 11.7, 1.8 Hz, 1H); C NMR (150 MHz, CDCl ): δ 138.2, 138.1, 137.9, 136.9, 128.5,
3
1
28.5, 128.4, 128.3, 128.3, 128.2, 127.9, 127.8, 127.7, 127.7, 127.6, 127.5, 122.4 (q, JCF = 287.2 Hz,
2
19
CF ), 94.3 (q, J = 31.9 Hz, C ), 83.4, 78.3, 76.8, 75.9, 75.7, 75.1, 73.4, 72.9, 67.8; F NMR (564
3
CF
1
MHz, CDCl ): δ ꢀ85.8 (s, CF ); FDCS (150 MHz, CDCl ): δ 122.1 (br s); ESIHRMS calcd for
3
3
3
+
C H O F Na ([M + Na] ) 631.2283, found 631.2264.
3
5
35
6 3
4
ꢀtransꢀtertꢀButylꢀ1ꢀtrifluoromethylꢀrꢀ1ꢀcyclohexylamine
(16ax)
and
4ꢀcisꢀtertꢀButyl
ꢀ1ꢀ
trifluoromethylꢀrꢀ1ꢀcyclohexylamine (16eq). A suspension of 4ꢀtertꢀbutylcyclohexanone (1.0 g, 6.49
mmol), benzylamine (1.0 g, 9.71 mmol), and dry powdered magnesium sulfate (4.0 g, 33.3 mmol) in
dichloromethane (10 mL) was stirred at room temperature for 48 h. The reaction mixture was filtered
through Celite, washed with water and the solvent was removed under reduced pressure and the residue
was directly subjected to next reaction without further purification. To a stirred solution of the crude
intermediate imine in acetonitrile (10 mL) were added trifluoroacetic acid (0.8 mL, 10.0 mmol),
º
potassium bifluoride (405.0 mg, 5.19 mmol), and N,Nꢀdimethylformamide (2.0 mL) at 0 C. The
reaction mixture was stirred for 10 min, then was treated with (trifluoromethyl)trimethylsilane (1.4 g,
9
.8 mmol) at 0 ºC and the mixture was stirred at room temperature for 48 h. The reaction mixture was
quenched with saturated aqueous Na CO solution (3 mL), and diluted with water (25.0 mL), and
2
3
extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water and
brine, dried over Na SO and evaporated under reduced pressure. The residue was dissolved in MeOH
2
4
(10.0 mL) and the solution was stirred for 36 h with Pd/C (10 mg, 10% mol) under 1 atm of hydrogen
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(
balloon). After completion, the reaction mixture was filtered through Celite, and the filtrate was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
evaporated under reduced pressure. The residue was dissolved in 2M HCl/MeOH and then concentrated
to dryness. The resulting hydrochloride salt was crystallized from acetonitrile (3.0 mL), filtered and
washed with diethyl ether to afford the HCL salts of 16ax and 16eq (154 mg, 68%, mp: 240ꢀ242 ºC) in
1
1
:1 ratio, as a white solid. H NMR (600 MHz, CD OD): δ 2.37 (d, J = 14.3 Hz, 2H), 2.06 (d, J = 12.8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Hz, 2H), 1.95ꢀ1.83 (m, 6H), 1.75 (t, J = 13.5 Hz, 2H), 1.40ꢀ1.27 (m, 4H), 1.16 (m, 2H), 0.92 (s, 9H),
1
3
1
1
0
.88 (s, 8H); C NMR (150 MHz, CD OD): δ 125.5 (q, J = 284.9 Hz, CF ), 125.2 (q, J = 282.2
3
CꢀF
3
CF
2
2
Hz, CF ), 58.4 (q, J = 25.8 Hz, C ), 57.2 (q, J = 28.0 Hz, C ), 46.5, 45.5, 31.7, 31.6, 29.6, 27.6,
3
CF
1
CF
1
1
9
2
6.3, 26.2, 22.0, 20.3; F NMR (564 MHz, CD OD): δ ꢀ73.4 (s, CF ), ꢀ80.8 (s, CF ); FDCS (150 MHz,
3
3
3
+
CD OD): δ 125.3 (tt, J = 10.4, 3.4 Hz), 124.9 (br s); ESIHRMS calcd for C H NF ([M + H] )
3
11 21
3
2
24.1626, found 224.1629.
4ꢀtransꢀtertꢀButylꢀ1ꢀpentafluoroethylꢀrꢀ1ꢀcyclohexanol
pentafluoroethylꢀrꢀ1ꢀcyclohexanol (17eq). To a stirred solution of (pentafluoroethyl)trimethylsilane
507 mg, 2.6 mmol) in tetrahydrofuran (1.5 ml) were added 4ꢀtertꢀbutylcyclohexanꢀ1ꢀone (136 mg, 0.88
(17ax)
and
4ꢀcisꢀtertꢀButyl
ꢀ1ꢀ
(
mmol) and tetrabutylammonium fluoride (0.26 mL, 0.26 mmol, 1.0 M tetrahydrofuran) at room
temperature. After 2 h of stirring, 6 M HCl (1 mL) was added and the reaction mixture was stirred for 1
h at room temperature. The aqueous layer was separated and extracted with diethyl ether (3 × 3.0 mL).
The combined organic layer was washed with saturated aqueous NaHCO (10.0 ml) and brine (10.0 mL)
3
and dried over MgSO . The crude products were purified by flash column chromatography (gradient
4
elution with nꢀpentane:diethyl ether = 98:2, 96:4, 94:6, 92:8) to give a white solid 17ax (116 mg, 54%;
o
mp: 74 C) as the major isomer and a colorless oil 17eq (54 mg, 25%) as the minor isomer. Neither
1
7ax nor 17eq was amenable to ionization by either electrospray or electron impact mass spectrometry.
1
17ax: H NMR (600 MHz, CDCl ): δ 2.37ꢀ2.30 (m, 2H), 2.26 (br s, 1H, OH), 1.73ꢀ1.66 (m, 2H), 1.48
3
13
(td, J = 13.8, 4.2 Hz, 2H), 1.35 (tdd, J = 14.3, 8.3, 2.8 Hz, 2H), 1.17ꢀ1.09 (m, 1H), 0.84 (s, 9H); C
1
2
1
NMR (150 MHz, CDCl ): δ 119.4 (qt, J = 280 Hz, J = 31.9 Hz, CF CF ), 116.3 (tq, J = 260 Hz,
3
CF
CF
3
2
CF
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2
19
J = 28.4 Hz, CF CF ), 72.2 (t, J = 22.7 Hz, C ), 46.0, 34.0, 32.3, 27.4, 22.8; F NMR (564 MHz):
CF
3
2
CF
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ ꢀ81.4 (s, 3F, CF CF ), ꢀ121.9 (s, 2F, CF CF ); FDCS (150 MHz, CDCl ): δ 116.3 [qtt, J = 28.4 Hz
3
2
3
2
3
(from fluorine), 7.3 Hz (from axial hydrogen), 3.3 Hz (from equatorial hydrogen)].
1
1
7eq: H NMR (600 MHz, CDCl ): δ 1.91ꢀ1.85 (m, 2H), 1.76 (s, 1H, OH), 1.71ꢀ1.59 (m, 4H), 1.38 (m,
3
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2H), 1.00 (tt, J = 12.4, 3.1 Hz, 1H), 0.86 (s, 9H); C NMR (150 MHz, CDCl ): δ 119.5 (qt, J = 288.0
3 CF
2
1
2
2
Hz, J = 31.9 Hz, CF CF ), 114.8(tq, J = 258.0 Hz, J = 33.4 Hz, CF CF ), 73.2 (t, J = 22.7 Hz,
CF
3
2
CF
CF
3
2
CF
1
9
C ), 47.0, 32.3, 30.3, 27.3, 21.1; F NMR (564 MHz): δ ꢀ80.9 (s, 3F, CF CF ), ꢀ129.5 (s, 2F,CF CF );
1
3
2
3
2
FDCS (150 MHz, CDCl ): δ 119.5 Broad quartet [J = 33.4 Hz (from fluorine)].
3
SꢀMethyl 3ꢀ(trifluoromethyl)ꢀ3βꢀcholestanyl xanthate (18). A solution of 11ax (350 mg, 0.66 mmol)
in tetrahydrofuran (3.0 mL), was treated with 2N HCl (0.6 mL) and stirred for 5 h at room temperature.
The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (5.0
mL), washed with saturated aqueous NaHCO solution (5.0 mL), water (5.0 mL) followed by brine (5.0
3
mL), dried over Na SO , and concentrated under reduced pressure afford the 3ꢀ(trifluoromethyl)ꢀ3βꢀ
2
4
3
8
cholestanol, which was taken forward to the next reaction without further purification. A suspension of
3
ꢀ(trifluoromethyl)ꢀ3βꢀcholestanol (135 mg, 0.29 mmol) and potassium hydride (24 mg, 0.60 mmol) in
tetrahydrofuran (6.0 mL) was stirred for 10 min at room temperature followed by addition of carbon
disulfide (115 mg, 1.47 mmol) then methyl iodide (420 mg, 2.95 mmol) at 65 ºC. The resulting reaction
mixture was stirred for 1 h at 65 ºC, then was cooled to 0 ºC and quenched with water (5.0 mL). After
extraction into dichloromethane (2×8 mL), the combined organic layer was washed with water (10.0
mL) followed by brine (10.0 mL), and dried over Na SO . The solvent was evaporated under reduced
2
4
pressure and the residue was purified by silica gel column chromatography eluting with hexanes to give
2
5
1
1
8 (119 mg, 74%, mp 95.5ꢀ96.0 ºC) as a white solid. [α]D = +25.4 (c= 0.7, dichloromethane); H NMR
(
600 MHz, CDCl ): δ 3.34 (dt, J = 14.3, 5.5 Hz, 1H), 3.14 (t, J = 14.3 Hz, 1H), 2.45 (s, 3H), 1.99 (td, J =
3
14.3, 2.2 Hz, 1H), 1.95 (td, J = 12.8, 3.3 Hz, 1H), 1.83ꢀ1.75 (m, 2H), 1.71 (dd, J = 13.5, 4.4 Hz, 1H),
1
.66 (m, 1H), 1.57ꢀ1.40 (m, 5H), 1.38ꢀ1.18 (m, 9H), 1.16ꢀ1.00 (m, 6H), 1.00ꢀ0.93 (m, 5H), 0.88 (d, J =
6
.6 Hz, 3H), 0.85 (d, J = 2.9 Hz, 3H), 0.84 (d, J = 2.9 Hz, 3H), 0.69 (dt, J = 12.5, 4.0 Hz, 1H), 0.64 (s,
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1
3
1
2
3
H); C NMR (150 MHz, CDCl ): δ 211.4, 125.7 (q, J = 286.7 Hz, CF ), 91.6 (q, J = 27.5 Hz,
3
CF
3
CF
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
C ), 56.3, 56.2, 53.5, 42.5, 42.5, 39.8, 39.4, 36.1, 35.7, 35.4, 35.3, 35.1, 31.7, 28.8, 28.5, 28.2, 27.9,
3
19
2
4.1, 23.8, 22.8, 22.5, 22.4, 21.2, 19.0, 18.6, 12.6, 12.1; F NMR (564 MHz, CDCl ): δ ꢀ76.7 (s, CF ).
3
3
4
7
3
βꢀ(2ꢀPropenyl)ꢀ3αꢀ(trifluoromethyl)cholestane
(19ax)
and
3αꢀ(2ꢀPropenyl)ꢀ3βꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
7
(trifluoromethyl)cholestane (19eq).
To a stirred solution of xanthate 18 (102 mg, 0.18 mmol) in
allyltributyltin (433.0 mg, 1.30 mmol), was added triethylborane (20.0 mg, 0.20 mmol) at ꢀ30 ºC. The
resulting reaction mixture was stirred for 1 h at ꢀ30 ºC, quenched with diisopropyl azodicarboxylate
(DIAD) (452.0 mg, 2.23 mmol) and stirred for 3 h at room temperature. Column chromatography of the
reaction mixture (silica gel, pentane) afforded a mixture of 19ax and 19eq along with allyltributyltin.
The residue was dissolved in anhydrous dichloromethane (2.0 mL), and propionaldehyde (84 mg, 1.44
mmol) was added. The reaction mixture was cooled to 0 ºC and boron trifluoride diethyl etherate (205
mg, 1.44 mmol) was added and resulting reaction mixture was stirred at 0 ºC for 1 h, quenched with
saturated aqueous NaHCO solution (2.0 mL), washed with water (2.0 mL) and brine (2.0 mL). The
3
solvent was evaporated under reduced pressure and the residue was purified by silica gel column
chromatography eluting with hexanes to obtain a mixture of 19ax and 19eq (49.2 mg, 55%, mp: 51ꢀ52
2
5
1
ºC) in 1:2.5 ratio, as a white solid. [α]D = +16.4 (c= 2.2, dichloromethane); H NMR (600 MHz,
CDCl ): δ 5.71 (m, 2H), 5.11 (dd, J = 10.3, 2.2 Hz, 1H), 5.07 (dd, J = 13.9, 1.8 Hz, 1H), 2.37 (d, J = 7.3
3
Hz, 2H), 2.16 (m, 1H), 1.96 (m, 2H), 1.81 (m, 2H), 1.72 (dd, J = 13.9, 4.4 Hz, 1H), 1.67 (m, 2H), 1.62ꢀ
1.41 (m, 11H), 1.40ꢀ1.17 (m, 17H), 1.17ꢀ1.03 (m, 9H), 1.03ꢀ0.94 (m, 4H), 0.91ꢀ0.88 (m, 7H), 0.88ꢀ0.85
13
1
(
m, 8H), 0.79 (s, 3H), 0.66ꢀ0.63 (m, 4H); C NMR (150 MHz, CDCl ): δ 133.7, 132.8, 129.8 (q, J =
3
CF
1
286.1 Hz, CF ), 129.3 (q, J = 283.3 Hz, CF ), 111.8, 117.7, 56.5, 56.4, 56.3, 56.2, 54.3, 54.0, 42.5,
3
CF
3
4
2
1.0, 40.1, 39.9, 39.5, 36.1, 35.8, 35.5, 35.5, 35.4, 34.9, 34.6, 32.9, 31.9, 31.7, 30.0, 29.2, 28.5, 28.2,
1
9
8.0, 27.4, 25.2, 24.1, 23.8, 23.4, 22.8, 22.5, 20.9, 18.6, 13.7, 12.0, 11.7, 8.7; F NMR (564 MHz,
CDCl ): δ ꢀ73.1 (s, CF ), ꢀ79.3 (s, CF ); FDCS (150 MHz, CDCl ): δ 19eq, 128.5 (narrow multiplet),
3
3
3
3
1
9ax, 129.0 (broad multiplet).
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Acknowledgments.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Drs Lewis Mtashobya and Bruno Linclau, University of Southampton, UK, are thanked for the
synthesis and generous donation of compounds 20ꢀ21. The NMR laboratory of the Wayne State
University School of Pharmacy is acknowledged for the loan of the ATB probe for recording of the
HOESY spectra. We thank the University of Zurich, Wayne State University, and the NIH (GM62160)
for partial support of this work, and the NSF (MRIꢀ084043) for funds toward the purchase of the 600
MHz NMR spectrometer in the Lumigen Instrument Center at Wayne State University.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
Supporting Information. Full experimental details and copies of H and C NMR spectra of all
compounds and of all FDCS and HOESY spectra. This material is available free of charge via the
Internet at http://pubs.acs.org. CCDC 1032684 contains the supplementary crystallographic data for
compound 10 and can be obtained from the Cambridge Crystallographic Data Center via
www.ccdc.ac.uk/data_request/cif.
References
(1)
Mueller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881ꢀ1886.
(
2)
3)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 320ꢀ330.
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359ꢀ4369.
(
(4)
Wang, J.; SánchezꢀRoselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432ꢀ2506.
5) Siodła, T.; Ozimiński, W. P.; Hoffmann, M.; Koroniak, H.; Krygowski, T. M. J. Org. Chem.
2014, 79, 7321ꢀ7331.
6) Böhm, H.ꢀJ.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; ObstꢀSander, U.; Stahl,
M. ChemBioChem 2004, 5, 637ꢀ643.
7) Prakash, G. K. S.; Wang, F. In Organic Chemistry ꢀ Breakthroughs and Perspectives; Ding, K.,
Dai, L.ꢀX., Eds.; WileyꢀVCH: Weinheim, 2012, p 413ꢀ477.
(
(
(
(
8)
9)
Sato, K.; Tarui, A.; Omote, M.; Ando, A.; Kumadaki, I. Synthesis 2010, 1865ꢀ1882.
Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921ꢀ930.
ACS Paragon Plus Environment
(
28

29
Page 29 of 33
The Journal of Organic Chemistry
(
10) Nie, J.; Guo, H.ꢀC.; Cahard, D.; Ma, J.ꢀA. Chem. Rev. 2011, 111, 455ꢀ529.
11) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475ꢀ4521.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
(12) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214ꢀ8264.
13) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P.
S. Proc. Natl. Acad. Sci., USA 2011, 108, 14411ꢀ14415.
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(14) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224ꢀ228.
(15) Shibata, N.; Suzuki, S.; Furukawa, T.; Kawai, H.; Tokunaga, E.; Yuan, Z.; Cahard, D. Adv.
Synth. Catal. 2011, 353, 2037ꢀ2041.
(
16) Besset, T.; Cahard, D.; Pannecoucke, X. J. Org. Chem. 2014, 79, 413ꢀ418.
17) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem. Int. Ed. 2012, 51, 5048ꢀ5050.
(
(18) Dong, X.; Sun, J. Org. Lett. 2014, 16, 2450ꢀ2453.
(
19) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Angew. Chem. Int. Ed. 2014, 53, 7144ꢀ7148.
20) Cantillo, D.; de Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O. Org. Lett. 2014, 16, 896ꢀ
(
899.
(
(
(
(
21) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem. Int. Ed. 2014, 53, 539ꢀ542.
22) Lin , J.ꢀS.; Liu , X.ꢀG.; Zhu , X.ꢀL.; Tan, B.; Liu, X.ꢀY. J. Org. Chem. 2014, 79, 7084ꢀ7092.
23) Wang , F.; Wang , D.; Mu , X.; Chen , P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 10202ꢀ10205.
24) Gao, P.; Shen, Y.ꢀW.; Fang, R.; Hao, X.ꢀH.; Qiu, Z.ꢀH.; Yang, F.; Yan, X.ꢀB.; Wang, Q.; Gong,
X.ꢀJ.; Liu, X.ꢀY.; Liang, Y.ꢀM. Angew. Chem. Int. Ed. 2014, 53, 7629ꢀ7633.
25) He, Y.ꢀT.; Li, L.ꢀH.; Zhou, Z.ꢀZ.; Hua, H.ꢀL.; Qiu, Y.ꢀF.; Liu, X.ꢀY.; Liang, Y.ꢀM. Org. Lett.
014, 16, 3896ꢀ3899.
(
2
(26) Xiong, Y.ꢀP.; Wu, M.ꢀX.; Zhang, X.ꢀY.; Ma, C.ꢀL.; Huang, L.; Zhao, L.ꢀJ.; Tan, B.; Liu, X.ꢀY.
Org. Lett. 2014, 16, 1000ꢀ1003.
(27) Hang, Z.; Li, Z.; Liu, Z.ꢀQ. Org. Lett. 2014, 16, 3648ꢀ3651.
(28) Prakash, G. K. S.; Wang, F.; Zhang, Z.; Haiges, R.; Rahm, M.; Christe, K. O.; Mathew, T.; Olah,
G. A. Angew. Chem. Int. Ed. 2014, 53, 11575ꢀ11578.
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