Conjugate hydrotrifluoromethylation of α,β-unsaturated acyl-oxazolidinones: Synthesis of chiral fluorinated amino acids

Article abstract of DOI:10.1039/c2ob26810h

A novel conjugate hydrofluoroalkylation of α,β-unsaturated acyl-oxazolidinones is described. Using this method, enantiomerically pure β-trifluoromethylated amino acids were prepared. Trifluorovaline and trifluoroisoleucine were incorporated into peptides and found to show extremely low α-helix propensities.

Full text of DOI:10.1039/c2ob26810h

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Conjugate hydrotrifluoromethylation of α,β-unsaturated acyl-oxazolidinones:
synthesis of chiral fluorinated amino acids†
Holger Erdbrink, Ilona Peuser, Ulla I. M. Gerling, Dieter Lentz, Beate Koksch* and Constantin Czekelius*
Received 14th September 2012, Accepted 25th September 2012
DOI: 10.1039/c2ob26810h
oxazolidinones, a short synthesis of enantiomerically pure fluori-
nated amino acids and their incorporation into peptides.
A novel conjugate hydrofluoroalkylation of α,β-unsaturated
acyl-oxazolidinones is described. Using this method, enantio-
merically pure β-trifluoromethylated amino acids were
prepared. Trifluorovaline and trifluoroisoleucine were incor-
porated into peptides and found to show extremely low
α-helix propensities.
For the stereoselective conjugate trifluoromethylation we
employed the well-established chiral Evans-oxazolidinones.8 We
examined N-(trans-crotonyl)-oxazolidinone 1 as a substrate for
the trifluoromethylation employing CF3I under radical con-
ditions. We considered Et3B and oxygen to be added as radical
initiators at low temperatures and the putatively formed enoyl
radical to be quenched by Bu3SnH.9 The results of these optim-
ization studies are summarized in Table 1. When CH2Cl2 was
used as the sole solvent in the presence of Mg(ClO4)2 product 2
was formed in 33% yield but also 10% of product 3 was formed
(entry 2). This became even more pronounced at elevated temp-
erature (−40 °C, entry 3).9c This by-product formation could be
suppressed by using a mixture of CH2Cl2 and THF together with
ytterbium triflate hydrate. Notably, all reactions occurred with
complete β-regioselectivity. Full conversion of 1 was achieved
by addition of the reagents in batches (up to 3 times). It is impor-
tant to note that the addition of Bu3SnH is not necessary to
obtain the desired hydrotrifluoromethylated product. In fact,
comparable yields of 2 were isolated and no formation of either
the α-iodo-,7e the α-hydroxy-,7d,k or the α-peroxy-substituted
derivatives7d,k was observed (entry 7). This modified procedure
generates no tin waste and greatly facilitates product purification.
The reaction proceeded without diastereoselectivity but the dia-
stereomers could be separated easily in most cases by column
chromatography.10
Using the optimized conditions different substrates were trans-
formed into the β-substituted carboxylic acid derivatives. Alkyl-
substituted derivatives were obtained in 22–70% yield (Table 2,
entries 1–7). The isolated yields largely reflect the degree of
steric hindrance at the β-position. In contrast, substrates with aro-
matic substituents (entry 8) were unreactive. The method was
further extended to the conjugate addition of other perfluoroalkyl
groups. While the addition to crotonyl-oxazolidinones was slow,
the corresponding acryl-oxazolidinones could be transformed in
moderate yields presumably due to competing oligomerization
(entries 9–12).
The chemistry of fluorine-containing organic compounds has
seen a dramatic development in recent years due to the impor-
tance of these substances in both pharmaceutical applications
and materials science.1 The replacement of hydrogen by fluorine
significantly alters the physical, chemical, and metabolic proper-
ties of such molecules. For example, peptides, containing non-
natural fluorinated amino acids, exhibit interesting properties
with respect to folding behaviour and biological activity.2,3
In contrast to the fluoroalkylation of aromatic substrates,4 pro-
tocols for stereoselective trifluoromethylations forming a Csp
–
3
CF3-bond are more limited in number and mostly focus on
nucleophilic attack on carbonyl groups5 or electrophilic addition
to electron-rich or unactivated alkenes.6 Only a few methods
have been reported for the conjugate perfluoroalkylation of
α,β-unsaturated carboxylic acid derivatives and related sub-
strates, thereby mostly focusing on iodoperfluoroalkylations of
terminal CvC bonds.7 However, reactions of RfI with internal
electron-deficient olefins are known to be difficult, due to oligo-
mer formation, respectively.7b,l In 2007, Yajima and Nagano
obtained optically active fluorinated α-amino acids by iodo-
perfluoroalkylation of acryl camphor sultams, but no example
was reported in which a new stereocenter in the β-position was
formed.7e,j We envisioned that the development of a reductive
trifluoromethylation protocol of internal electron-deficient
alkenes would allow for new access to optically active
β-trifluoromethylated carboxylic acids and amino acids. Herein,
we report the hydrofluoroalkylation of α,β-unsaturated acyl-
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3,
D-14195 Berlin, Germany. E-mail: cczekeli@chemie.fu-berlin.de;
Fax: (+49)30-838-53625; Tel: (+49)30-838-52625
†Electronic supplementary information (ESI) available: Syntheses,
X-ray crystallographic details for 2a, 25a, 26a, and additional data.
CCDC 887849–887851. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob26810h
Although the exact mechanism for product formation is not
clear at the present stage we assume that the first step is the gen-
eration of CF3-radicals by Et3B/O2.11 Following conjugate attack
of the Michael system the putatively formed enoyl radical
may react with free Et3B to form the transient diethylboron
This journal is © The Royal Society of Chemistry 2012
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Table 1 Optimization reactions for the conjugate trifluoromethylation
Entry
Solvent
Lewis acid
Additive
Yield 2/%
dr
Rec. 1/%
Yield 3/%
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2–THF 4 : 1
CH2Cl2–THF 4 : 1
CH2Cl2–THF 1 : 1
CH2Cl2–THF 1 : 1
—
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
—
25
33
13
40
46
60
70
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
43
16
—
7
26
4
—
10
57
6
—
—
—
2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Yb(OTf)3·nH2O
Yb(OTf)3·nH2O
Yb(OTf)3·nH2O
3a
4
5
6b
7b
—
a The reaction was performed at −40 °C. b The reagents were added three times.
Table 2 Radical conjugate trifluoromethylation of acyl-oxazolidinonesa
Entry
1
R
CmFnI
CF3I
Productb
Yield/%
70
dr
Me (1)
1 : 1
2
3
Et (4)
CF3I
CF3I
51
56
1 : 1
1 : 1
n-Hexyl (6)
4
5
CH2CH2Ph (8)
CF3I
CF3I
40
22
1 : 1
1 : 1
cyclo-Hexyl (10)
6
7
–(CH2)3OBn (12)
CF3I
CF3I
38
42
1 : 1
1 : 1
–(CH2)4COOEt (14)
8
Ph (16)
H (18)
H (18)
H (18)
H (18)
CF3I
0
34
33
27
17
—
—
—
—
—
9
CF3I
10
11
12
CF3CF2CF2I
CF3(CF2)3I
CF3CFICF3
a Conditions: −78 °C in THF–CH2Cl2 1 : 1, Yb(OTf)3·nH2O (2 equiv.), CmFnI (3 times 9 equiv.), Et3B in hexane (3 times 5 equiv.); entries 9–12,
reagents were added only once. b Xc = (S)-N-benzyl-oxazolidinonyl.
enolate.11b–d The presence of water in the reaction mixture
results in rapid in situ hydrolysis of the intermediate enol bori-
nate liberating the corresponding product. Hydrotrifluoromethyl-
ation in the presence of Yb(OTf)3 under anhydrous conditions
resulted in the incorporation of deuterium in the α-position upon
workup with D2O, whereas the use of deuterium-labeled solvents
did not.
The β-trifluoromethylated carboxylic acid derivatives are very
useful synthetic building blocks. This is exemplified in the
synthesis of fluorinated α-amino acids via diastereoselective
8584 | Org. Biomol. Chem., 2012, 10, 8583–8586
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Scheme 1 Synthesis of enantiomerically pure, fluorinated amino
acids.13
Fig. 2 Circular dichroism spectra of the peptides KVal, KIle, K(3S)-
43-F3Val, K(3R)-43-F3Val, and K4′3-F3Ile at pH 7 (273 K) in 1 mM
phosphate, borate, and citrate with 1 M NaCl.
Table 3 Ellipticity [Θ] at 222 nm was taken from normalized CD data.
Fraction helix [fhelix] and helix propensities [w] were calculated from
[Θ] by using modified Lifson–Roig theory
Peptide
[Θ222 nm
]
fhelix
w
KVal
KIle
−13 054 452
−13 876 186
−2685 526
−3887 547
−3602 130
0.38 0.01
0.40 0.01
0.08 0.02
0.11 0.02
0.10 0.01
0.41 0.04
0.53 0.05
0
0
0
K[(3S)-43-F3Val ]
K[(3R)-43-F3Val ]
K[(3S)-4′3-F3Ile]
Fig. 1 Molecular structures (ORTEP14) of protected trifluorovaline 25a
(left) and trifluoroisoleucine 26a (right).
amination (Scheme 1). All four diastereomers of N-Boc-
protected trifluorovaline (TfV, 43F3Val) and trifluoroisoleucine
(TfI, 4′3-F3Ile) were prepared in enantiomerically pure form via
the corresponding α-azides.8b,12 This methodology complements
the fast access to β-trifluoromethylated amino acids by rhodium-
catalyzed asymmetric reduction of dehydroamino acids.12c The
absolute configuration of the amino acids was confirmed by
crystal structure determination of intermediate 2a, 25a, and 26a
based on the known auxiliary configuration (Fig. 1).
222 nm, whereas the peptides containing the fluorinated ana-
logues do not form helical structures (Fig. 2). The α-helix pro-
pensity [w] was calculated from CD data by using modified
Lifson–Roig theory (Table 3).15d–f The helix propensities of Val
and Ile are comparable to previously published values,15f but for
(3S)-43-F3Val, (3R)-43-F3Val, and (3S)-4′3-F3Ile we obtained
slightly negative values, which are therefore interpreted as zero.
Val and Ile are known to be better accommodated within
β-sheet structures,15c,16b,c which is also reflected by their rela-
tively low w-value. Ile with the more flexible ethyl group on the
β-carbon shows a slightly higher helix propensity compared to
Val. Due to its branching on the β-carbon atom the rigid side
chain atoms come in close proximity to the peptide backbone,18
thereby destabilizing α-helical structures. This effect is amplified
for the two diastereomers of TfV ((3S)-43-F3Val, (3R)-43-F3Val )
which have the larger CF3 group on the β-carbon atom. The
close proximity of this sterically demanding group to the peptide
backbone strongly impedes the formation of α-helical structures.
As a result these amino acids show a helix propensity of zero.
In summary, we have developed a new method for the conju-
gate trifluoromethylation of α,β-unsaturated acyl-oxazolidinones.
The addition of iodoperfluoroalkanes utilizing triethylborane,
which presumably serves as an initiator and radical terminator,
occurs in a reductive fashion. All four diastereomers of trifluoro-
valine and L-trifluoroisoleucine were readily prepared from the
corresponding products in an enantiomerically pure form. It was
found that both diastereomers of L-trifluorovaline and L-trifluoro-
isoleucine show extremely low α-helix propensities. These
findings reinforce earlier conclusions made by Cheng et al. that
The peptide sequence Ac-YGGKAAAAKAXAAKAAAAK-
̲
NH2 (KX) has previously been designed as a monomeric α-helix
to enable helix propensity determination of the amino acid in the
guest position X 15a,d
Cheng et al. investigated fluorinated amino
̲
acids using this model and concluded that they exhibit reduced
helix propensity compared to their hydrocarbon analogues.15a,b
TfV has mostly been incorporated as diastereomeric mixtures
into peptides.16a,b Here, we have determined the helix propensi-
ties of each diastereomer separately. The amino acids (3S)-43-
F3Val, (3R)-43-F3Val, and (3S)-4′3-F3Ile were introduced into the
guest position of the model peptide and their helix propensities
[w] were determined and compared to the values of their res-
pective non-fluorinated analogues valine (Val) and isoleucine
(Ile). The Boc-protected amino acids were converted into the
Fmoc analogues by standard procedures (see ESI†). The peptides
were synthesized following standard protocols for solid-phase
peptide synthesis (SPPS).17 The identity of the peptides was
confirmed by high resolution mass spectroscopy (HR-ESI-
ToF MS).
The CD-spectra of the referenced peptides KVal and KIle indi-
cate helical structures as evidenced by the minima at 208 and
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8583–8586 | 8585

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