Hexafluoroacetone as a protecting and activating reagent: Synthesis of new types of fluoro-substituted α-amino, α-hydroxy and α-mercapto acids

Article abstract of DOI:10.1055/s-2004-829131

Starting from (S)-aspartic, (S)-malic, (S)-citramalic and (S,R)-thiomalic acid, new types of 4,4-difluoro-substituted α-amino-, α-hydroxy- and α-mercaptopentanoic acids have been synthesized, applying hexafluoroacetone as protecting and activating reagent. The new partially fluorinated α-functionalized carboxylic acids represent interesting monomers for peptide and depsipeptide modification and for rational design and elucidation of secondary structure.

Full text of DOI:10.1055/s-2004-829131

PAPER
1821
Hexafluoroacetone as a Protecting and Activating Reagent: Synthesis of New
Types of Fluoro-Substituted a-Amino, a-Hydroxy and a-Mercapto Acids
Synthesis of
F
e
luoro-Subs
r
d
a
-
g
Amino,
a
-H
e
ydroxyand
j
a
-MercaptoA
N
cids . Osipov,a Torsten Lange,b Pavel Tsouker,b Jan Spengler,b Lothar Hennig,b Beate Koksch,b Stefan Berger,c
Salah M. El-Kousy,d Klaus Burger*b
a
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 18, GSP-1, 117813 Moscow,
Russia
b
Department of Organic Chemistry, University of Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: burger@organik.chemie.uni-leipzig.de
c
Department of Analytical Chemistry, University of Leipzig, Linnéstrasse 3, 04103 Leipzig, Germany
d
Faculty of Science, Minufia University, Shebin El-Kom, Egypt
Received 7 January 2004; revised 5 April 2004
Dedicated to Prof. Dr. W. Steglich on the occasion of his 70th birthday
NMR spectroscopy to address conformational questions,
Abstract: Starting from (S)-aspartic, (S)-malic, (S)-citramalic and
provided that the two fluorine atoms can be assigned indi-
vidually.
(S,R)-thiomalic acid, new types of 4,4-difluoro-substituted a-ami-
no-, a-hydroxy- and a-mercaptopentanoic acids have been synthe-
sized, applying hexafluoroacetone as protecting and activating
reagent. The new partially fluorinated a-functionalized carboxylic
Interactions between the a-hydrogen and carbonyl oxygen
in peptide backbones have been virtually ignored by
acids represent interesting monomers for peptide and depsipeptide
chemists and biologists until recently.8 However, Ca-
modification and for rational design and elucidation of secondary
H···O=C hydrogen bonds seem to be ubiquitous, particu-
structure.
larly in b-sheets and helical proteins. It was postulated
Key words: amino acids, hydroxy acids, mercapto acids, fluorine,
that its strength is up to 3 kcal mol–1, enough to play a con-
peptides
siderable role in determining protein conformation.9 Un-
der these aspects, a-amino acids (A) having additional
carbonyl groups in the side chain (B) (Figure 1) should be
Fluorinated analogues of naturally occurring biologically
of considerable interest, because they are capable of addi-
active compounds often exhibit unique physiological ac-
tional hydrogen bonding, enhancing substrate/enzyme in-
tivities.1,2With increasing success, the design of peptides
teractions and assisting protein folding.10
and proteins of enhanced activity and stability is devel-
oped by incorporation of nonproteinogenic and non-natu-
ral amino acids.3 Therefore, there is a steadily growing
interest in the development of new methodologies for the
incorporation of fluoroamino acids into key positions of
peptides.4,5 The comparable sizes of hydrogen and fluo-
rine preclude undesirable steric inhibition of binding at
Figure 1 Partial structure of amino acids containing additional
moiety in the side chain
the active site of the receptor.6 Incorporation of fluorinat-
ed amino acids into proteins and peptides allows monitor-
ing of the chemical environment of the fluorine-
In this context, amino acids with extra C=O (B) and/or
containing residues by 19F NMR spectroscopy.
CF2 groups (C) in the side chain, should be excellent mod-
Many important structural questions concerning protein
folding cannot be addressed using X-ray crystallography
and therefore have to be solved by NMR spectroscopy in
solution and in solid phase. Introduction of two or three
fluorine atoms into a protein is not expected to significant-
ly perturb its tertiary structure.3However, at least in one
19F NMR study,7 substantial changes have been observed
in protein structure after fluoromodification.
el compounds to study new noncovalent interactions of
type C=O...H and CF2...Hand to find out whether they are
sufficiently strong to have similar impact on the second-
ary structure and on folding like hydrogen-bonding be-
tween Ca-hydrogens and carbonyl groups of the peptide
bond. C(sp3)–F fluorine can enter into stronger hydrogen
bonds than fluorine of a C(sp2)–F moiety.11 Theoretical
calculations estimate the strength of a F...H bond between
2 to 3.2 kcal mol–1.9
In all chiral compounds like amino acids, hydroxy acids,
peptides and depsipeptides, the hydrogen atoms of a
methylene group are diastereotopic. Thus, on displacement
by fluorine diastereotopic fluorine atoms are obtained.
They provide an additional stereochemical tool using
We now report on a new, preparatively simple access to a-
amino acids having CH2C(=O) and CH2CF2 subunits in
the side chain. To enlarge structural diversity of the build-
ing blocks we included a-hydroxy and a-mercapto ana-
logues into our investigations.
Key intermediates of the synthesis are diazoketones 2a–d,
which are obtainable from a-functionalized a,w-dicarbox-
ylic acids 1a–d in three steps. The reaction sequence in-
SYNTHESIS 2004, No. 11, pp 1821–1829
Advanced online publication: 05.07.2004
DOI: 10.1055/s-2004-829131; Art ID: T00204SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
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2
0
0
4

1822
S. N. Osipov et al.
PAPER
cludes hexafluoroacetone protection, conversion into b- sponding a-hydroxy and a-mercapto acids 7b–d via 5b–d
acid chlorides by reaction with thionyl chloride and final- was accomplished using the above protocol (Scheme 2).
ly treatment with an excess of diazomethane ( >3 equiv) The final treatment with propene oxide is not necessary
to give compounds 2a–d in very good yields (90%) since hydrolysis is performed in water–acetonitrile.
(Scheme 1).
Compounds 3a–d were readily converted into 5-bromo-
4,4-difluoropentanoic acid derivatives 8a–d (70–80%) by
fluorodeoxygenation with DAST (diethylaminosulfur tri-
fluoride).15,16 Since hexafluoroacetone protected com-
pounds are carboxy group activated species, simultaneous
deprotection of both functional groups (8 → 9) as well as
simultaneous derivatization of the carboxy group and
deprotection (8 → 10) can be performed already at room
temperature in acceptable yields (65–75%) (Scheme 3).
The debromination of compounds 8a–d could not be
achieved in acceptable yields using the protocol applied
for transformation 3 → 5. Finally, we found tributyltin hy-
dride to be the reagent of choice for reductive debromina-
tion 8 → 11. However, the quantitative removal of the tin
compounds is in some cases laborious. Since hexafluoro-
acetone-protected compounds are carboxy group activat-
ed species, they readily react with various nucleophiles.
Simultaneous deblocking of the carboxy and the adjacent
amino group was accomplished by stirring compounds 11
in a mixture of water–propan-2-ol at room temperature.
The progress of the reaction can be readily controlled by
TLC analysis. The reaction time of the hydrolytic cleav-
age could be reduced to a few hours, when dilute HCl was
used for deblocking (11 → 12) (Scheme 4). Concomitant-
ly with the cleavage of the lactone moiety, deprotection of
the XH function occurred, which can be derivatized selec-
tively in a subsequent step.
Scheme 1
When diazoketones 2a–d were treated with concentrated
HBr at –30 °C in THF spontaneously nitrogen elimination
occurred and the corresponding bromoketones 3a–d were
formed within minutes. The structural assignment is based
on IR, 1H and 13C NMR data. Compounds 3 are versatile
building blocks e.g. for Hantzsch type syntheses of het-
eroaromatic a-functionalized carboxy acids.12–14 Simulta-
neous deprotection of the a-amino and the adjacent
carboxy group could be achieved on heating (bath temper-
ature 50 °C) compounds 3 in an acetonitrile–water mix-
ture.
4-Oxonorvaline (7a)12b was obtained on vigorous stirring
of 3a in boiling toluene under an atmosphere of hydrogen
in the presence of a Pd catalyst, followed by hydrolysis
with dilute HCl at room temperature and finally treatment
with propene oxide (3a → 5a → 6a →7a). The reductive
debromination and deprotection of 3b–d to give the corre-
Scheme 4
Incorporation of the new types of fluorinated amino, hy-
droxy and mercapto acids into small peptides and dep-
sipeptides provides building blocks of high structural
diversity for fragment condensation. When 11 (X = NH)
was reacted with amino acid methyl ester partially fluori-
nated diketopiperazines 13 were formed,17 while in the
case of X = O, S, the open-chain compounds 14 and 15
were stable under the reaction conditions applied
Scheme 2
Scheme 3
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluoro-Substituted a-Amino, a-Hydroxy and a-Mercapto Acids
1823
medicals) was used with solvent systems given in the text. TLC:
compounds were visualized by spraying with ninhydrin (2 mg/mL)
in EtOH or with a mixture of Ce(SO4)2 (0.2%), (NH4)2MoO4 (5%)
and H2SO4 (5%) in H2O followed by heating.
(Scheme 5). Incorporation of a-mercapto acids into pepti-
domimetics adds a new facet to peptide modification, par-
ticulary since disulfide formation offers ready access to
symmetric peptidomimetics.18
Reaction of Diazoketones 2 with Concentrated HBr; General
Procedure
To a stirred solution of diazoketone 2a–d (10.0 mmol) in THF (25
mL) at –30 °C was added conc. HBr (7 mL) dropwise. After gas
evolution ceased, the mixture was warmed up to 0 °C. Solvents and
the excess of HBr were evaporated in vacuo. The residue was dis-
solved in CH2Cl2 (100 mL), washed with cold NaHCO3 solution and
dried (MgSO4). The solvent was evaporated in vacuo and the resi-
due was subjected to column chromatography (eluent: CHCl3–hex-
anes, 10:1) and then recrystallized from CHCl3–pentane.
(4S)-4-(3-Bromo-2-oxopropyl)-2,2-bis(trifluoromethyl)-1,3-ox-
azolidin-5-one (3a)
Yield: 3.18 g (89%); mp 65 °C; [a]D –3.0 (c = 2, CH2Cl2).
IR (KBr): 3355, 1820, 1738 cm–1.
For further spectral data, see Lit.12b,27
(5S)-5-(3-Bromo-2-oxopropyl)-2,2-bis(trifluoromethyl)-1,3-di-
oxolan-4-one (3b)
Yield: 2.73 g (76%); bp 54–56 °C/0.1 Torr, mp 56 °C; [a]D –12.8
(c = 1, acetone).
Scheme 5
IR (KBr): 1845, 1740 cm–1.
For further spectral data, see Lit.27
Examples for the incorporation of a-mercapto acids into
peptide hybrides are rare.19A b-mercapto acid is a subunit
of Captopril, a classical drug for treating hypertension.20
An a-mercapto subunit is present in Omapatrilat and Ge-
mopatrilat, both are vasopeptidase inhibitors which are
currently under clinical evaluation.21Compounds contain-
ing mercapto and mercaptoacyl moieties22often exhibit
strong inhibitory effects on metal-containing enzymes
(metalloenzymes),23 similar to hydroxamic acids.24 Some
of the zinc-containing angiotensin converting enzymes
(ACE) possess an a-mercaptoacyl substructure.25
(5S)-5-(3-Bromo-2-oxopropyl)-2,2-bis(trifluoromethyl)-5-meth-
yl-1,3-dioxolan-4-one (3c)
Yield: 2.80 g (75%); oil; [a]D –49.4 (c = 1.7, CHCl3).
IR (KBr): 1840, 1730 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.74 (s, 3 H, CH3), 3.20 (d,
J = 16.5 Hz, 1 H, CH2), 3.26 (d, J = 16.5 Hz, 1 H, CH2), 3.85 (d,
J = 14.0 Hz, 1 H, CH2Br), 3.91 (d, J = 14.0 Hz, 1 H, CH2Br).
13C NMR (50 MHz, CDCl3): d = 22.8 (CH3), 34.2 (CH2Br), 45.8
(CH2), 79.7 [C(CH3)], 97.5 [sept, J = 36.0 Hz, C(CF3)2], 119.2 (q,
J = 287.0 Hz, CF3), 119.6 (q, J = 289.0 Hz, CF3), 167.2 (lactone
C=O), 195.3 (ketone C=O).
Since a growing number of reports focus on peptidomi-
metic compounds built from two or more different types
of monomers,26 the new building blocks are promising
candidates for rational design of peptidomimetics with the
option of forming weak hydrogen bonds which may play
a substantial role in stabilizing and creating new second-
ary structure motifs and in controlling protein folding.
19F NMR (282 MHz, CDCl3): d = –2.7 (q, J = 7.0 Hz, 3 F, CF3),
–2.3 (q, J = 7.0 Hz, 3 F, CF3).
MS: m/z = 347/345 [M – CO]+, 279 [M – CH2Br]+, 238 [M –
CHCOCH2Br]+, 43 [HCOCH2]+.
4-(3-Bromo-2-oxopropyl)-2,2-bis(trifluoromethyl)-1,3-oxa-
thiolan-5-one (3d)
Yield: 3.07 g (82%); bp 84–87 °C/0.3 Torr; mp 40 °C.
IR (KBr): 1800, 1710 cm–1.
Solvents were purified and dried prior to use. Reagents were used
as purchased. IR spectra were obtained on a Genesis ATI Mattson/
Unicam FTIR spectrophotometer. H NMR spectra were recorded
1
1H NMR (300 MHz, CDCl3): d = 3.25 (dd, J = 19.0, 10.5 Hz, 1 H,
CH2), 3.78 (dd, J = 19.0, 3.0 Hz, 1 H, CH2), 3.95 (s, 2 H, CH2Br),
4.45 (dd, J = 10.0, 3.0 Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 32.6 (CH2Br), 41.0 (CH), 44.1
(CH2), 83.9 [sept, J = 35.0 Hz, C(CF3)2], 121.2 (q, J = 284.0 Hz,
CF3), 121.4 (q, J = 285.0 Hz, CF3), 170.7 (lactone C=O), 198.5 (ke-
tone C=O).
19F NMR (282 MHz, CDCl3): d = 1.0 (q, J = 9.0 Hz, 3 F, CF3), 1.6
(q, J = 9.0 Hz, 3 F, CF3). MS: m/z = 376/374 [M]+, 295 [M – Br]+,
281 [M – CH2Br]+, 253 [M – COCH2Br]+, 87 [M –COCH2Br –
(CF3)2CO]+.
at 200 MHz and 300 MHz. Chemical shifts were reported in ppm
relative to tetramethylsilane (TMS, d = 0); J values are given in
Hertz (Hz). 13C NMR spectroscopy was performed at 50 MHz, 75
MHz with TMS (d = 0.0) as internal standard. 19F NMR spectra
were recorded at 188 MHz and 282 MHz with trifluoroacetic acid
(TFA, d = 0) as external standard. Mass spectra were recorded on a
VG 12-250 (Masslab) electron ionization spectrometer (EI = 70
eV). Optical rotations ([a]D) were measured using a Polatronic po-
larimeter (Schmidt & Haensch) in a 5 cm cell. Melting points were
determined on a Boetius heating table. For C, H, N analyses a
CHNO-Rapid-Elemental-Analyzer (Hereaus) was used. All new
compounds gave satisfactory microanalyses: C 0.54; H 0.45; N,
0.38%. For flash chromatography, silica gel (32–63 mm, ICN Bio-
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

1824
S. N. Osipov et al.
PAPER
Deprotection of Compounds 3; General Procedure
(4S)-4-(2-Oxopropyl)-2,2-bis(trifluoromethyl)-1,3-oxazolidin-
A solution of 3a–d (5 mmol) was heated in the solvent mixture
MeCN–H2O (10 mL, 1:1) for 2 h (50 °C, bath temperature). After
evaporation of the solvent under reduced pressure, the remaining
solid was extracted with Et2O (3 × 20 mL). The combined organic
phase was dried (MgSO4), evaporated to dryness and the residue
was recrystallized from CHCl3 or subjected to column chromatog-
raphy (eluent: CHCl3–hexanes; 10:1).
5-one (5a)12b,27
Yield: 2.15 g (77%); mp 81–82 °C (subl.); [a]D –35.0 (c = 1.0,
CHCl3).
IR (KBr): 3340, 1820, 1720 cm–1.
(5S)-5-(2-Oxopropyl)-2,2-bis(trifluoromethyl)-1,3-dioxolan-4-
one (5b)
Yield: 1.93 g (69%); mp 42 °C; [a]D –11.7 (c = 2.0, CHCl3).
IR (KBr): 3400, 1851, 1728 cm–1.
(2S)-2-Amino-5-bromo-4-oxopentanoic Acid (4a)
Yield: 0.83 g (79%); oil; [a]D –1.7 (c = 1.2, CHCl3).
IR (film): 3700–2500, 1730 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.69–2.75 (m, 1 H, CH2), 2.81–
2.87 (m, 1 H, CH2), 3.25–3.35 (m, 2 H, CH2Br), 3.66–3.74 (m, 2 H,
NH2), 3.92–4.01 (m, 1 H, CH).
1H NMR (200 MHz, CDCl3): d = 2.24 (s, 3 H, CH3CO), 2.97 (dd,
J = 18.3, 6.9 Hz, 1 H, CH2), 3.12 (dd, J = 18.3, 3.7 Hz, 1 H, CH2),
5.08 (dd, J = 6.9, 3.7 Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 25.3 (CH3), 44.2 (CH2), 70.9 (CH),
96.9 [m, C(CF3)2], 119.0 (q, J = 287.0 Hz, CF3), 119.8 (q, J = 289.0
Hz, CF3), 168.0 (acid C=O), 201.1 (ketone C=O).
19F NMR (188 MHz, CDCl3): d = –4.4 (q, J = 8.2 Hz, 3 F, CF3),
–4.1 (q, J = 8.2 Hz, 3 F, CF3).
MS: m/z = 281 [M + H]+, 304 [M + H, Na]+.
13C NMR (50 MHz, CDCl3): d = 34.5 (CH2Br), 40.6 (CH), 41.5
(CH2), 178.0 (acid C=O), 210.6 (ketone C=O).
MS: m/z = 211/209 [M]+, 147/145 [M – CO2 – HF]+, 113 [M – Br –
NH3]+, 100 [M – BrCH2 – NH2]+.
(2S)-5-Bromo-2-hydroxy-4-oxopentanoic Acid (4b)
Yield: 0.89 g (84%); mp 48 °C; [a]D –11.2 (c = 1.0, CHCl3).
IR (KBr): 3700–2500, 1730 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.12 (dd, J = 17.0, 7.0 Hz, 1 H,
CH2), 3.23 (dd, J = 17.0, 4.0 Hz, 1 H, CH2), 4.05 (s, 2 H, CH2Br),
4.61 (dd, J = 7.0, 4.0 Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 34.6 (CH2Br), 43.2 (CH2), 66.3
(CH), 174.3 (acid C=O), 198.9 (ketone C=O).
(5S)-2,2-Bis(trifluoromethyl)-5-methyl-5-(2-oxopropyl)-1,3-di-
oxolan-4-one (5c)
Yield: 2.08 g (71%); oil, [a]D +12.1 (c = 2.0, CHCl3).
IR (film): 3500–3300, 1830, 1722 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.71 (s, 3 H, CH3), 2.21 (s, 3 H,
CH3CO), 3.16 (d, J = 17.9 Hz, 1 H, CH2), 3.35 (d, J = 17.9 Hz, 1 H,
CH2).
13C NMR (50 MHz, CDCl3): d = 22.3 (CH3), 29.4 (CH3), 49.2
(CH2), 79.8 [C(CF3)2], 123.2 (q, J = 286.0 Hz, CF3), 123.5 (q,
J = 285.0 Hz, CF3), 169.7 (acid C=O), 202.9 (ketone C=O).
MS: m/z = 212/210 [M]+, 167/165 [M – CO2H]+, 123/121
[COCH2Br]+, 117 [M – CH2Br]+, 89 [M – CH2Br – CO]+.
19F NMR (282 MHz, CDCl3): d = –2.8 (q, J = 6.0 Hz, 3 F, CF3),
–2.3 (q, J = 6.0 Hz, 3 F, CF3).
MS: m/z = 621 [2 M + K]+, 295 [M + H]+.
(2S)-5-Bromo-2-hydroxy-2-methyl-4-oxopentanoic Acid (4c)
Yield: 0.91 g (81%); oil; [a]D +12.5 (c = 2.4, CHCl3).
IR (film): 3500–3000, 1728 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48 (s, 3 H, CH3), 3.12 (d,
J = 17.0 Hz, 1 H, CH2), 3.34 (d, J = 17.0 Hz, 1 H, CH2), 3.89–4.00
(m, 2 H, CH2Br).
13C NMR (50 MHz, CDCl3): d = 26.0 (CH3), 34.2 (CH2Br), 48.7
(CH2), 72.8 (CCH3), 179.1 (acid C=O), 202.1 (ketone C=O).
2,2-Bis(trifluoromethyl)-4-(2-oxopropyl)-1,3-oxathiolan-5-one
(5d)
Yield: 1.95 g (66%); oil.
IR (film): 2960, 2800, 1810, 1720 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.26 (s, 3 H, CH3CO), 3.01 (dd,
J = 18.6, 11.0 Hz, 1 H, CH2), 3.50 (dd, J = 18.6, 3.0 Hz, 1 H, CH2),
4.19 (dd, J = 11.0, 3.0 Hz, 1 H, CH).
MS: m/z = 226/224 [M]+, 210/208 [M – H – CH3]+, 182/180 [M –
CO2]+, 131 [M – CH2Br]+, 113 [M – CH2Br – H2O]+.
13C NMR (75 MHz, CDCl3): d = 41.3 (CH3), 43.9 (CH2), 55.8 (CH),
83.4–85.2 [m, C(CF3)2], 119.4 (q, J = 284.0 Hz, CF3), 119.7 (q,
J = 284.0 Hz, CF3), 171.0 (acid C=O), 189.0 (ketone C=O).
19F NMR (282 MHz, CDCl3): d = 0.9 (q, J = 9.0 Hz, 3 F, CF3), 1.5
(q, J = 9.0 Hz, 3 F, CF3).
5-Bromo-4-oxo-2-sulfanylpentanoic Acid (4d)
Yield: 0.66 g (58%); oil.
IR (film): 3300–3100, 1712 cm–1.
1H NMR (300 MHz, methanol-d4): d = 2.72 (dd, J = 17.5, 6.9 Hz, 1
H, CH2), 2.80 (dd, J = 17.5, 2.7 Hz, 1 H, CH2), 3.33 (d, J = 16.8 Hz,
1 H, CH2Br), 3.44 (d, J = 16.8 Hz, 1 H, CH2Br), 3.94–4.05 (m, 1 H,
CH).
13C NMR (50 MHz, methanol-d4): d = 37.0 (CH2Br), 42.4 (CH2),
43.0 (CH), 176.7 (acid C=O), 213.2 (ketone C=O).
MS: m/z = 296 [M]+, 593 [2 M + H]+.
(2S)-4-Oxonorvaline Hydrochloride (6a)
Compound 5a (2.0 mmol, 0.56 g) was heated with conc. HCl (1 mL)
in a mixture of THF–H2O (10 mL; 1:1) for 24 h (50 °C bath temper-
ature). After evaporation of the solvent under reduced pressure, the
remaining substance was purified by lyophylization.
MS: m/z = 227/225 [M]+, 251/249 [M + Na]+, 474 [2 M + Na]+.
Debromination of Compounds 3; General Procedure
Yield: 0.23 g (70%); mp 135–137 °C; [a]D +8.0 (c = 1.0, H2O).
IR (KBr): 3700–3300, 1713, 1660 cm–1.
1H NMR (200 MHz; CDCl3): d = 2.11 (s, 1 H, CH3), 3.12–3.24 (m,
2 H, CH2), 4.10–4.20 (m, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 29.2 (CH3), 42.3 (CH2), 48.7 (CH),
171.7 (acid C=O), 209.9 (ketone C=O).
To a solution of 3a–d (10 mmol) in toluene (30 mL) was added the
Pd catalyst (0.5 g 5% Pd on BaSO4). The vigorously stirred solution
was heated for 12 h (100 °C bath temperature), while a stream of H2
was bubbled through the mixture until HBr elimination ceased. The
catalyst was filtered off and the solvent was removed in vacuo. The
remaining colorless liquid was purified by distillation.
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluoro-Substituted a-Amino, a-Hydroxy and a-Mercapto Acids
1825
MS: m/z = 656 [5 M + H]+, 525 [4 M + H]+, 394 [3 M + H]+, 263 [2
19F NMR (282 MHz, CDCl3): d = – 21.4 (d, 1 F, CF2), –20.1 (d, 1
F, CF2), –3.13 (q, J = 9.0 Hz, 3 F, CF3), –2.49 (q, J = 9.0 Hz, 3 F,
M + H]+, 132 [M + H]+, 74 [M – CH2COCH3]+.
CF3).
Hydrolysis of Compounds 5b–d; General Procedure
MS: m/z = 379 [M – H]+, 310 [ M – CF3 – H]+, 236 [M –
A solution of 5 (5 mmol) was heated in a mixture of MeCN–H2O
(10 mL, 1:1) up to 50 °C (bath temperature) for 24 h. After evapo-
ration of the solvent under reduced pressure, the remaining solid
was extracted with Et2O (3 × 20 mL). The combined organic phase
was dried (MgSO4) and evaporated to dryness.
BrCH2CF2]+, 144 [BrCH2CF2]+, 70 [HCF3]+.
(5S)-(3-Bromo-2,2-difluoropropyl)-2,2-bis(trifluoromethyl)-
1,3-dioxolan-4-one (8b)
Yield: 2.76 g (72%); bp 30 °C/0.07 Torr; [a]D –12.7 (c = 1.5,
CHCl3).
IR (film): 1850 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.62–2.74 (m, 2 H, CH2), 3.55–
3.67 (m, 2 H, CH2Br), 4.95 (dd, J = 10.0, 2.0 Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 30.6 (dd, J = 34.0, 32.0 Hz,
CH2Br), 37.2 (dd, J = 26.0, 25.0 Hz, CH2), 70.4 (dd, J = 7.0, 3.0
Hz, CH), 98.1 [sept, J = 36.0 Hz, C(CF3)2], 118.8 (q, J = 287.0 Hz,
CF3), 119.1 (t, J = 245.0 Hz, CF2), 119.5 (q, J = 289.0 Hz, CF3),
166.7 (C=O).
2-Hydroxy-4-oxopentanoic Acid (7b)
Yield: 0.48 g (73%); oil; [a]D –23.1 (c = 2.0, CHCl3).
IR (film): 3500–3300, 1735 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.23 (s, 3 H, CH3), 2.88 (dd,
J = 16.7, 7.7 Hz, 1 H, CH2), 2.99 (dd, J = 16.7, 4.2 Hz, 1 H, CH2),
4.55 (dd, J = 7.7, 4.2 Hz, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 30.4 (CH3), 46.7 (CH2), 66.6 (CH),
176.9 (acid C=O), 207.9 (ketone C=O).
MS: m/z = 133 [M + H]+, 115 [M – H2O]+.
19F NMR (188 MHz, CDCl3): d = –20.7 (d, 1 F, CF2), –19.1 (d, 1 F,
CF2), –3.3 (m, 6 F, 2 CF3).
MS: m/z = 362/360 [M – HF]+, 69 [CF3]+.
2-Hydroxy-2-methyl-4-oxopentanoic Acid (7c)
Yield: 0.50 g (69%); oil; [a]D +22.1 (c = 2.0, CHCl3).
IR (film): 3500–3300, 2985, 1716 cm–1.
(5S)-(3-Bromo-2,2-difluoropropyl)-2,2-bis(trifluoromethyl)-5-
methyl-1,3-dioxolan-4-one (8c)
Yield: 2.68 g (68%); bp 80 °C/0.56 Torr; [a]D –17.0 (c = 2.0,
CHCl3).
1H NMR (300 MHz, methanol-d4): d = 1.42 (s, 3 H, CH3), 2.18 (s,
3 H, CH3), 2.89 (d, J = 17.0 Hz, 1 H, CH2), 3.12 (d, J = 17.0 Hz, 1
H, CH2).
13C NMR (75 MHz, methanol-d4): d = 25.7 (CH3), 29.6 (CH3), 52.3
(CH2), 73.0 (CCH3), 177.8 (acid C=O), 208.1 (ketone C=O).
MS: m/z = 147 [M + H]+, 169 [M + Na]+.
IR (film): 1845 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 3 H, CH3), 2.57–2.68 (m,
2 H, CH2), 3.51–3.65 (m, 2 H, CH2Br).
13C NMR (75 MHz, CDCl3): d = 22.6 (CH3), 31.2 (dd, J = 33.0,
31.3 Hz, CH2Br), 41.0 (dd, J = 24.7, 37.0 Hz, CH2), 79.5 (C), 97.5
[sept, J = 36.0 Hz, C(CF3)2], 119.1 (q, J = 290.0 Hz, CF3), 119.2 (q,
J = 285.5 Hz, CF3), 119.6 (t, J = 246.0 Hz, CF2), 169.3 (C=O).
4-Oxo-2-sulfanylpentanoic Acid (7d)
Yield: 0.52 g (70%); oil.
IR (film): 3400–2900, 1712 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H, CH3), 2.26 (d, J = 9.3
Hz, 1 H, SH), 2.89 (dd, J = 18.0, 5.1 Hz, 1 H, CH2), 3.15 (dd,
J = 18.0, 9.3 Hz, 1 H, CH2), 3.78 (ddd, J = 9.3, 9.3, 5.1 Hz, 1 H,
CH), 6.3 (br s, 1 H, OH).
13C NMR (50 MHz, CDCl3): d = 29.9 (CH3), 35.0 (CH), 48.3 (CH2),
177.7 (acid C=O), 205.2 (ketone C=O).
19F NMR (282 MHz, CDCl3): d = –18.8 (d, 1 F, CF2), –13.8 (d, 1 F,
CF2), –2.9 (m, 6 F, 2 CF3).
MS: m/z = 396/394 [M – H]+, 376 [M – F]+, 237 [M –
BrCH2CF2CH2], 182 [CO2(CF3)2]+.
(3-Bromo-2,2-difluoropropyl)-2,2-bis(trifluoromethyl)-1,3-oxa-
thiolan-5-one (8d)
Yield: 3.49 g (88%); bp 60 °C/0.07 Torr.
MS: m/z = 149 [M + H]+, 131 [M + H – H2O]+, 130 [M – H2O]+.
Fluorodeoxygenation of Compounds 3; General Procedure
To a solution of the bromoketone 3a–d (10 mmol) in CH2Cl2 (25
mL), was added DAST (11.6 g, 9.5 mL) at –15 °C with stirring. Af-
ter 20 h, the reaction mixture was quenched with an ice/water mix-
ture. The organic layer was washed with aq sat. NaHCO3 solution,
H2O and dried (MgSO4). Then the solvent was evaporated in vacuo.
The residue was purified by distillation under reduced pressure.
IR (CHCl3): 1810 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.67–2.73 (m, 1 H, CH2), 3.25–
3.30 (m, 1 H, CH2), 3.72–3.77 (m, 2 H, CH2Br), 4.55–4.60 (m, 1 H,
CH).
13C NMR (50 MHz, CDCl3): d = 30.5 (dd, J = 33.0, 32.5 Hz,
CH2Br), 38.5 (dd, J = 23.5, 23.0 Hz, CH2), 39.5 (CH), 84.0 [sept,
J = 32.0 Hz, C(CF3)], 119.7 (t, J = 245.0 Hz, CF2), 120.9 (q,
J = 284.0 Hz, CF3), 121.6 (q, J = 284.0 Hz, CF3), 170.2 (C=O).
(4S)-(3-Bromo-2,2-difluoropropyl)-2,2-bis(trifluoromethyl)-
1,3-oxazolidin-5-one (8a)
Yield: 2.66 g (70%); bp 80 °C/0.60 Torr; [a]D –4.0 (c = 1.0,
CHCl3).
19F NMR (188 MHz, CDCl3): d = –22.6 (d, 1 F, CF2), –19.4 (d, 1 F,
CF2), 0.9 (q, J = 9.0 Hz, 3 F, CF3), 1.9 (q, J = 9.0 Hz, 3 F, CF3).
MS: m/z = 398/396 [M]+, 397/395 [M – H]+, 316 [M – Br]+, 301
IR (film): 3350, 1820 cm–1.
[M – Br – O]+, 69 [CF3]+.
1H NMR (300 MHz, CDCl3): d = 2.28–2.47 (m, 1 H, CH2), 2.66–
2.84 (m, 1 H, CH2), 3.39 (d, J = 6.0 Hz, 1 H, NH), 3.64 (t, J = 12.9
Hz, 2 H, CH2Br), 4.31–4.36 (m, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 31.5 (dd, J = 32.0, 32.0 Hz,
CH2Br), 38.4 (dd, J = 28.0, 23.0 Hz, CH2), 50.0 (CH), 88.5 [sept,
J = 32.0 Hz, C(CF3)2], 119.0 (q, J = 289.0 Hz, CF3), 120.0 (q,
J = 284.5 Hz, CF3), 122.1 (t, J = 246.0 Hz, CF2), 169.9 (C=O).
Deprotection of Compounds 8; General Procedure
Compound 8 (5 mmol) was heated in a solvent mixture of propan-
2-ol–H2O (10 mL, 1:1) for 5 h (50 °C, bath temperature). After
evaporation of the solvent under reduced pressure, the remaining
solid was extracted with Et2O (3 × 20 mL). The combined organic
phase was dried (MgSO4) and evaporated to dryness. The residue
was recrystallized from CHCl3.
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

1826
S. N. Osipov et al.
PAPER
Methyl 5-Bromo-4,4-difluoro-2-hydroxypentanoate (10b)
(2S)-2-Amino-5-bromo-4,4-difluoropentanoic Acid (9a)
Yield: 0.84 g (72%); mp 181–183 °C; [a]D –9.1 (c = 1.1, DMSO).
IR (KBr): 3500-3000, 1630 cm–1.
Yield: 0.88 g (71%); mp 100–102 °C; [a]D –9.4 (c = 1.7, CHCl3).
IR (KBr): 3500–3100, 1740 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.59–2.63 (m, 1 H, CH2),
2.79–2.85 (m, 1 H, CH2), 3.66 (dt, J = 12.0, 9.0 Hz, 2 H, CH2Br),
4.06 (t, J = 15.0 Hz, 1 H), 4.15–4.20 (m, 1 H, CH), 4.52 (t, J = 7.5
Hz, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 37.1 (CH2Br), 51.5 (CH2), 57.8
(CH), 128.0 (t, J = 244.0 Hz, CF2), 169.5 (C=O).
1H NMR (200 MHz, CDCl3): d = 2.30–2.38 (m, 1 H, CH2), 2.55–
2.61 (m, 1 H, CH2), 3.66–3.75 (m, 2 H, CH2Br), 3.82 (s, 3 H,
OCH3), 4.40–4.49 (m, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 32.1 (t, J = 32.0 Hz, CH2Br), 38.3
(t, J = 25.0 Hz, CH2), 53.2 (OCH3), 66.1 (CH), 120.2 (t, J = 244.0
Hz, CF2), 174.1 (C=O).
19F NMR (188 MHz, CDCl3): d = –18.8 (d, 1 F, CF2), –17.4 (d, 1 F,
CF2).
19F NMR (188 MHz, CDCl3): d = –19.6 (d, 1 F, CF2), –16.3 (d, 1 F,
CF2).
MS: m/z = 460 [2 M – 4 H]+, 232 [M]+, 214 [M – H2O]+.
MS: m/z = 248 [M]+, 209 [M – F2]+, 187 [M – CO2C2H3]+, 167 [M
– Br]+, 89 [CHOHCO2CH3]+, 59 [CO2CH3]+.
(2S)-5-Bromo-4,4-difluoro-2-hydroxypentanoic Acid (9b)
Yield: 0.89 g (75%); mp 80–81 °C; [a]D = –15.0 (c = 1.2, CHCl3).
IR (KBr): 3600–3100, 1730 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.00–2.06 (m, 1 H, CH2), 2.05–
2.10 (m, 1 H, CH2), 3.94 (t, J = 12.0 Hz, 2 H, CH2Br), 4.71–4.76 (m,
1 H, CH).
13C NMR (50 MHz, CDCl3): d = 40.8 (t, J = 35.5 Hz, CH2Br), 44.4
(t, J = 35.0 Hz, CH2), 65.9 (CH), 107.3 (t, J = 245.0 Hz, CF2), 176.7
(C=O).
19F NMR (188 MHz, CDCl3): d = –19.6 (d, 1 F, CF2), –16.7 (d, 1 F,
CF2).
MS: m/z = 465 [2 M – H]+.
GC/MS: m/z = 233 [M]+.
(2S)-Methyl 5-Bromo-4,4-difluoro-2-hydroxy-2-methylpenta-
noate (10c)
Yield: 0.91 g (70%); oil; [a]D –9.0 (c = 1.7, CHCl3).
IR (film): 3600–3100, 1740 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 2.45–2.51 (m,
1 H, CH2), 2.59–2.68 (m, 1 H, CH2), 3.50–3.57 (m, 1 H, CH2Br),
3.58–3.65 (m, 1 H, CH2Br), 3.71 (s, 3 H, OCH3).
13C NMR (50 MHz, CDCl3): d = 27.5 (CH3), 31.4 (t, J = 33.0 Hz,
CH2Br), 43.4 (t, J = 26.0 Hz, CH2), 52.9 (OCH3), 71.8 (CCH3),
120.1 (t, J = 245.0 Hz, CF2), 176.2 (C=O).
19F NMR (188 MHz, CDCl3): d = –20.6 (d, 1 F, CF2), –18.2 (d, 1 F,
CF2).
MS: m/z = 262 [M + H]+, 223 [M – 2 F]+, 181 [M – Br]+, 59
[CO2CH3]+.
(2S)-5-Bromo-4,4-difluoro-2-hydroxy-2-methylpentanoic Acid
(9c)
Methyl 5-Bromo-4,4-difluoro-2-sulfanylpentanoate (10d)
Yield: 0.80 g (61%); oil.
IR (KBr): 3365, 1735 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.28 (d, J = 10.0 Hz, 1 H, SH),
2.48–2.55 (m, 1 H, CH2), 2.80–2.90 (m, 1 H, CH2), 3.50–3.62 (m, 2
H, CH2), 3.65–3.73 (m, 1 H, CH), 3.76 (s, 3 H, OCH3).
13C NMR (50 MHz, CDCl3): d = 31.6 (t, J = 32.0 Hz, CH2Br), 34.4
(CH), 41.0 (t, J = 24.0 Hz, CH2), 53.2 (OCH3), 119.8 (t, J = 244.0
Hz, CF2), 173.1 (C=O).
Yield: 0.85 g (69%); mp >300 °C (dec.); [a]D –2.0 (c = 1.0,
DMSO).
IR (KBr): 3600–3200, 1605 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 3 H, CH3), 2.38–2.43 (m,
2 H, CH2), 3.95–4.02 (m, 2 H, CH2Br).
13C NMR (50 MHz, CDCl3): d = 28.3 (CH3), 35.0 (CH2), 44.9 (t,
J = 35.0 Hz, CH2Br), 71.8 (CH), 121.2 (t, J = 238.0 Hz, CF2), 178.2
(C=O).
19F NMR (188 MHz, CDCl3): d = –20.1 (d, 1 F, CF2), –17.6 (d, 1 F,
CF2).
MS: m/z = 247 [M]+, 205 [M – 2 HF – 2 H]+.
19F NMR (188 MHz, CDCl3): d = –22.1 (m, 2 F, CF2).
MS: m/z = 262 [M – H]+, 232 [M – OCH3]+, 230 [M – SH ]+, 204
[M – CO2CH3]+, 163 [M – Br – HF]+.
5-Bromo-4,4-difluoro-2-sulfanylpentanoic Acid (9d)
Yield: 0.98 g (79%); mp 96–98 °C.
IR (KBr): 3500–2900, 1700 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.38 (dd, J = 10.0 Hz, 1 H, SH),
2.49–2.56 (m, 1 H, CH2), 2.85–2.91 (m, 1 H, CH2), 3.58–3.65 (m, 2
H, CH2Br), 3.71–3.77 (m, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 31.3 (t, J = 32.5 Hz, CH2Br), 31.9
(CH), 40.5 (t, J = 25.0 Hz, CH2), 119.7 (t, J = 244.5 Hz, CF2), 177.7
(C=O).
Debromination of Compounds 8a–d with Tributyltin Hydride;
General Procedure
To a solution of 8 (10 mmol) in anhyd benzene (5 mL) in an inert
gas atmosphere were added Bu3SnH (2.90 g, 10 mmol) and AIBN
(2,2¢-azobisisobutyronitrile, 50 mg, 0.3 mmol) in anhyd benzene (4
mL) dropwise during 10 min. The resulting mixture was stirred at
r.t. overnight. The solvent was evaporated in vacuo, and the residue
was purified by column chromatography.
(4S)-4-(2,2-Difluoropropyl)-2,2-bis(trifluoromethyl)-1,3-oxazo-
lidin-5-one (11a)
19F NMR (188 MHz, CDCl3): d = –20.5 (m, 2 F, CF2).
Yield: 1.98 g (66%) ; bp 65 °C/5 Torr; [a]D –18.3 (c = 2.0, CHCl3).
IR (film): 3450–3350, 1832 cm–1.
MS: m/z = 249 [M]+, 227 [M – F – 3 H]+, 203 [M – COOH – H]+.
Alcoholysis of Compounds 8b–d; General Procedure
Compound 8b–d (5 mmol) was reacted with an excess of MeOH
(20 mL) for 2 h at 50 °C. Then the solvent was evaporated in vacuo,
the residue was washed with Et2O and purified by flash chromatog-
raphy (eluent: EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.72 (t, J = 18.8 Hz, 3 H, CH3),
2.08–2.25 (m, 1 H, CH2), 2.42–2.60 (m, 1 H, CH2), 3.38 (d, J = 4.8
Hz, 1 H, NH), 4.27–4.33 (m, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 24.0 (t, J = 26.6 Hz, CH3), 41.5 (t,
J = 24.0 Hz, CH2), 50.2 (CH), 88.6 [sept, J = 34.5 Hz, C(CF3)2],
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluoro-Substituted a-Amino, a-Hydroxy and a-Mercapto Acids
1827
121.3 (q, J = 286.6 Hz, 2 CF3), 122.9 (t, J = 238.0 Hz, CF2), 170.5
(2S)-4,4-Difluoronorvaline (12a)
(acid C=O).
Yield: 0.46 g (60%); colorless crystals; mp 230 °C; [a]D –4.6
(c = 2.0, CHCl3).
19F NMR (282 MHz, CDCl3): d = –14.8 (d, 1 F, CF2), –13.1 (d, 1 F,
CF2), –3.1 (q, J = 9.0 Hz, 3 F, CF3), –2.5 (q, J = 9.0 Hz, 3 F, CF3),
IR (KBr): 3100–3000, 1599 cm–1.
MS: m/z = 261 [M – K]+ 238 [M – CH3CF2]+, 136 [M – HFA]+.
1H NMR (300 MHz, methanol-d4): d = 1.76 (t, J = 19.2 Hz, 3 H,
CH3), 2.39–2.45 (m, 1 H, CH2), 2.66–2.79 (m, 1 H, CH2), 3.84 (dd,
J = 11.1, 2.4 Hz, 1 H, CH).
(5S)-5-(2,2-Difluoropropyl)-2,2-bis(trifluoromethyl)-1,3-diox-
olan-4-one (11b)
Yield: 2.29 g (76%); bp 104 °C/250 Torr; [a]D –6.2 (c = 2.0,
CHCl3).
IR (film): 3500–3200, 2990, 1820 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.74 (t, J = 18.5 Hz, 3 H, CH3),
2.28–2.41 (m, 1 H, CH2), 2.49–2.59 (m, 1 H, CH2), 4.92 (d, J = 9.6
Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 25.5 (t, J = 26.0 Hz, CH3), 40.3 (t,
J = 24.7 Hz, CH2), 52.4 (d, J = 2.7 Hz, CH), 126.7 (t, J = 235.1 Hz,
CF2), 175.7 (acid C=O).
19F NMR (282 MHz, CDCl3): d = –13.6 (d, 1 F, CF2), –10.4 (d, 1 F,
CF2).
MS: m/z = 154 [M + H]+, 88 [M – CH3CF2]+.
13C NMR (50 MHz, CDCl3): d = 23.9 (t, J = 26.5 Hz, CH3), 40.4 (t,
J = 27.3 Hz, CH2), 70.9 (CH), 97.6 [sept, J = 37.4 Hz, C(CF3)2],
118.7 (q, J = 287.2 Hz, CF3), 119.5 (q, J = 288.7 Hz, CF3), 121.4 (t,
J = 240.3 Hz), 167.2 (C=O).
19F NMR (282 MHz, CDCl3): d = –14.2 (d, 1 F, CF2), –11.2 (d, 1 F,
CF2), –3.5 (q, J = 6.0 Hz, 3 F, CF3), –3.3 (q, J = 6.0 Hz, 3 F, CF3),
(2S)-4,4-Difluoro-2-hydroxypentanoic Acid (12b)
Yield: 0.53 g (69%); colorless crystals; mp 73 °C; [a]D +11.5
(c = 2.0, CHCl3).
IR (KBr): 3400–3200, 3000, 1719 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.72 (t, J = 19.0 Hz, 3 H, CH3),
2.25–2.33 (m, 1 H, CH2), 2.44–2.54 (m, 1 H, CH2), 4.57 (d, J = 6.5
Hz, 1 H, CH), 7.42 (br s, 1 H, OH).
MS: m/z = 605 [2 M + H]+, 325 [M + Na]+, 303 [M + H]+.
13C NMR (50 MHz, CDCl3): d = 24.1 (t, J = 26.5 Hz, CH3), 41.5 (t,
J = 25.4 Hz, CH2), 66.5 (s, CH), 123.4 (t, J = 237.6 Hz, CF2), 177.7
(acid C=O).
19F NMR (282 MHz, CDCl3): d = –11.7 (d, 1 F, CF2), –9.8 (d, 1 F,
CF2).
(5S)-5-(2,2-Difluoropropyl)-2,2-bis(trifluoromethyl)-5-methyl-
1,3-dioxolan-4-one (11c)
Yield: 2.05 g (65%); bp 78 °C; [a]D +18.9 (c = 2.0, CHCl3).
IR (film): 3000, 1843 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.70 (t, J = 18.0 Hz, 3 H, CH3),
1.72 (s, CH3), 2.24–2.36 (m, 1 H, CH2), 2.41–2.59 (m, 1 H, CH2).
MS: m/z = 153 [M – H]+, 89 [M – CH3CF2]+.
13C NMR (50 MHz, CDCl3): d = 22.4 (s, CH3), 24.4 (t, J = 26.7 Hz,
CH3), 44.0 (dd, J = 28.8 Hz, CH2), 79.7 [d, J = 7.7 Hz, C(CH3)],
97.4 [sept, J = 35.9 Hz, C(CF3)2], 119.2 (q, J = 288.3 Hz, CF3),
119.3 (q, J = 289.8 Hz, CF3), 122.2 (t, J = 238.8 Hz, CF2), 169.7
(acid C=O).
19F NMR (282 MHz, CDCl3): d = –10.5 (d, 1 F, CF2), –9.7 (d, 1 F,
CF2), –3.1 (m, 6 F, 2 CF3).
(2S)-4,4-Difluoro-2-hydroxy-2-methylpentanoic Acid (12c)
Yield: 0.60 g (72%); colorless crystals; mp 108 °C; [a]D +4.1
(c = 2.0, CHCl3).
IR (KBr): 3420, 3000, 1728 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.47 (s, 3 H, CH3), 1.69 (t,
J = 19.2 Hz, 3 H, CH3), 2.21–2.34 (m, 1 H, CH2), 2.44–2.59 (m, 1
H, CH2).
13C NMR (50 MHz, CDCl3): d = 24.8 (t, J = 27.1 Hz, CH3), 27.9
(CH3), 47.6 (t, J = 30.0 Hz, CH2), 72.8 (t, J = 6.1 Hz, C), 124.6 (t,
J = 236.5 Hz, CF2), 178.7 (acid C=O).
HRMS: m/z = 316 [M]+.
4-(2,2-Difluoropropyl)-2,2-bis(trifluoromethyl)-1,3-oxathiolan-
5-one (11d)
Yield: 2.13 g (67%); bp 88 °C/50 Torr.
IR (film): 3000, 1824 cm–1.
19F NMR (282 MHz, CDCl3): d = –9.7 (d, 1 F, CF2), –5.2 (d, 1 F,
CF2).
MS: m/z = 169 [M + H]+, 149 [M + H – HF]+, 133 [M + H – 2 F]+.
1H NMR (300 MHz, CDCl3): d = 1.73 (t, J = 18.4 Hz, 3 H, CH3),
2.30–2.39 (m, 1 H, CH2), 2.83–3.00 (m, 1 H, CH2), 4.41 (d, J = 11.1
Hz, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 23.8 (t, J = 26.9 Hz, CH3), 39.8 (d,
J = 4.0 Hz, CH), 42.3 (t, J = 24.6 Hz, CH2), 83.5 [sept, J = 35.5 Hz,
C(CF3)2], 120.9 (q, J = 284.6 Hz, CF3), 121.5 (q, J = 283.4 Hz,
CF3), 121.8 (t, J = 237.3 Hz, CF2), 170.5 (acid C=O).
19F NMR (282 MHz, CDCl3): d = –16.1 (d, 1 F, CF2), –12.7 (d, 1 F,
CF2), 0.8 (q, J = 9.1 Hz, 3 F, CF3), 1.9 (q, J = 9.1 Hz, 3 F, CF3).
MS: m/z = 318 [M]+, 299 [M – F]+, 267 [M – HCF2]+.
4,4-Difluoro-2-sulfanylpentanoic Acid (12d)
Yield: 0.53 g (62%); colorless crystals; mp 95 °C.
IR (KBr): 3500–3300, 3000, 1749, 1660 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.64 (t, J = 18.9 Hz, 3 H, CH3),
2.21–2.36 (m, 1 H, CH2), 2.34 (d, J = 9.6 Hz, 1 H, SH), 2.62–2.81
(m, 1 H, CH2), 3.84 (ddd, J = 9.6, 3.9 Hz, 1 H, CH), 8.1 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.8 (t, J = 27.1 Hz, CH3), 34.5 (t,
J = 4.2 Hz, CH), 43.6 (t, J = 25.5 Hz, CH2), 122.3 (t, J = 239.6 Hz,
CF2), 178.7 (C=O).
19F NMR (282 MHz, CDCl3): d = –13.5 (d, 1 F, CF2), –12.9 (d, 1 F,
Hydrolysis of Compounds 11a–d; General Procedure
A solution of 11 (5 mmol) was heated in a solvent mixture of
MeCN–H2O (10 mL; 1:1) up to 50 °C (bath temperature) for 24 h.
After evaporation of the solvent under reduced pressure, the re-
maining solid was extracted with Et2O (3 × 20 mL). The combined
organic phase was dried (MgSO4) and evaporated to dryness and the
residue was recrystallized from CHCl3.
CF2),
MS: m/z = 169 [M]+, 104 [M – CH3CF2]+.
Aminolysis of Compounds 11a–d; General Procedure
A solution of 11 (1.5 mmol) and amine (2.0 mmol) in a minimum
amount of anhyd MeCN was stirred at r.t. for 48 h. The solvent was
evaporated in vacuo, and the residue was purified by column chro-
matography.
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

1828
S. N. Osipov et al.
PAPER
(3S,6S)-3-Benzyl-6-(2,2-difluoropropyl)-2,5-diketopiperazine
(13a)
Yield: 0.30 g (72%); mp 174 °C; [a]D +3.4 (c = 2.0, MeCN).
IR (KBr): 3450–2900, 1678 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.50 (t, J = 19.2 Hz, 3 H, CH3),
1.72–1.89 (m, 2 H, CH2Ph), 2.90 (dd, J = 13.5, 4.9 Hz, 1 H, CH2),
3.15 (dd, J = 13.5, 4.0 Hz, 1 H, CH2), 3.84 (d, J = 8.7 Hz, 1 H, CH),
4.20–4.29 (m, 1 H, CH), 7.15–7.35 (m, 5 H, C6H5), 7.87 (s, 1 H,
NH), 8.35 (s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 22.9 (t, J = 26.5 Hz, CH3), 38.1
(CH2Ph), 41.1 (t, J = 24.8 Hz, CH2), 49.9 (t, J = 4.0 Hz, CH), 55.3
(CH), 123.6 (t, J = 236.9 Hz, CF2), 126.7, 128.2, 130.4, 136.1
(C6H5), 166.3 (2 C=O).
13C NMR (50 MHz, CDCl3): d = 23.9 (t, J = 26.9 Hz, CH3), 36.6
(CH2Ph), 37.9 (CH), 43.8 (t, J = 25.0 Hz, CH2), 52.5 (OCH3), 53.7
(CHNH), 123.4 (t, J = 235.0 Hz, CF2), 127.3, 128.7, 129.6, 135.7
(C6H5), 171.4 (C=O), 171.7 (C=O).
19F NMR (282 MHz, CDCl3): d = –13.5 (d, 1 F, CF2), –11.8 (d, 1 F,
CF2).
MS: m/z = 330 [M – H]+, 314 [M – OH]+.
Benzyl N-[(2S)-2-Amino-4,4-difluoropentanoyl]azaglycinate
(15a)
Yield: 0.32 g (72%); mp 157 °C; [a]D –17.2 (c = 2.0, MeOH).
IR (KBr): 3400–3000, 1716, 1522 cm–1.
1H NMR (300 MHz, methanol-d4): d = 2.01 (s, 3 H, CH3), 2.87–
2.99 (m, 2 H, CH2), 3.33–3.35 (m, 1 H, CH), 5.25 (s, 2 H, CH2Ph),
7.36–7.43 (m, 5 H, C6H5).
19F NMR (282 MHz, DMSO-d6): d = –9.2 (d, 1 F, CF2), –7.5 (d, 1
F, CF2).
MS: m/z = 281 [M – H]+.
13C NMR (50 MHz, CDCl3): d = 17.7 (CH3), 38.2 (CH2), 68.2
(CH2Ph), 77.1–77.7 (m, CH), 121.5 (q, J = 286.4 Hz, CF2), 129.2,
129.3, 129.5, 137.6 (C6H5), 156.6 (urethane C=O), 170.5 (hydrazide
C=O).
Methyl N-[(2S)-4,4-Difluoro-2-hydroxypentanoyl]phenylalani-
nate (14b)
Yield: 0.30 g (63%); mp 55 °C; [a]D –12.4 (c = 2.0, MeOH).
IR (KBr): 3380, 3300, 1731, 1639 cm–1.
19F NMR (282 MHz, methanol-d4): d = –11.4 (d, 1 F, CF2), –9.7 (d,
1 F, CF2).
1H NMR (300 MHz, methanol-d4): d = 1.60 (t, J = 19.0 Hz, 3 H,
CH3), 1.82–2.03 (m, 1 H, CH2), 2.09–2.29 (m 1 H, CH2), 3.02 (dd,
J = 14.0, 5.5 Hz, 1 H, CH2Ph), 3.18 (dd, J = 14.0, 8.0 Hz, 1 H,
CH2Ph), 3.69 (s, 3 H, OCH3), 4.21 (dd, J = 1.8, 9.4 Hz, 1 H, CH),
4.74 (dd, J = 5.5, 8.0 Hz, 1 H, CH), 7.10–7.35 (m, 5 H, C6H5).
MS: m/z = 300 [M – H]+.
Benzyl N-[(2S)-4,4-Difluoro-2-hydroxypentanoyl]azaglycinate
(15b)
Yield: 0.27 g (60%); mp 74 °C; [a]D +3.4 (c = 2.0, MeOH).
13C NMR (50 MHz, CDCl3): d = 23.0 (t, J = 26.9 Hz, CH3), 37.2
(CH2Ph), 41.9 (t, J = 25.8 Hz, CH2), 51.8 (OCH3), 53.3 (CH), 67.5
(t, J = 5.7 Hz, COH), 123.6 (t, J = 236.5 Hz, CF2), 126.9, 128.4,
129.2, 136.6 (C6H5), 172.0 (C=O), 174.5 (C=O).
19F NMR (188 MHz, methanol-d4): d = –13.2 (d, 1 F, CF2), –9.6 (d,
1 F, CF2).
IR (KBr): 3400, 3200, 1688, 1662 cm–1.
1H NMR (300 MHz, methanol-d4): d = 2.21 (t, J = 14.8 Hz, 3 H,
CH3), 2.19–2.26 (m, 1 H, CH2), 2.30–2.48 (m, 1 H, CH2), 4.39–4.42
(m, 1 H, CH), 5.18 (s, 2 H, PhCH2), 7.30–7.45 (m, 5 H, C6H5).
13C NMR (75 MHz, methanol-d4): d = 23.1 (t, J = 27.5 Hz, CH3),
42.0 (t, J = 25.8 Hz, CH2), 67.2 (CH2Ph), 67.3 (COH), 123.6 (t,
J = 237.6 Hz, CF2), 127.9, 128.1, 128.4, 136.5 (C6H5), 157.3 (ure-
thane C=O), 174.6 (hydrazide C=O).
MS: m/z = 314 [M – H]+, 254 [M – CH3CF2]+.
Methyl N-[(2S)-4,4-Difluoro-2-hydroxy-2-methylpenta-
noyl]phenylalaninate (14c)
Yield: 0.33 g (67%); mp 77 °C; [a]D +26.0 (c = 2.0, MeOH).
IR (KBr): 3395, 3380, 3200, 1750, 1670, 1538 cm–1.
19F NMR (282 MHz, methanol-d4): d = –10.8 (d, 1 F, CF2), –6.7 (d,
1 F, CF2).
MS: m/z = 301 [M – H]+.
1H NMR (300 MHz, methanol-d4): d = 1.40 (s, CH3), 1.53 (t,
J = 19.5 Hz, 3 H, CH3), 2.05–2.20 (m, 1 H, CH2), 2.40–2.55 (m, 1
H, CH2), 3.12 (d, 1 H, CH2Ph), 3.15 (d, 1 H, CH2Ph), 3.73 (s, 3 H,
OCH3), 4.73 (t, J = 6.6 Hz, 1 H, CH), 7.20–7.35 (m, 5H, C6H5).
13C NMR (50 MHz, methanol-d4): d = 24.5 (t, J = 26.9 Hz, CH3),
28.0 (CH3), 38.3 (CH2Ph), 47.0 (t, J = 25.0 Hz, CH2), 52.8 (OCH3),
54.6 (CH), 73.7 (COH), 124.7 (t, J = 235.9 Hz, CF2), 128.0, 129.6,
130.3, 137.6 (C6H5), 173.1 (C=O), 177.7 (C=O).
19F NMR (282 MHz, methanol-d4): d = –5.8 (d, 1 F, CF2), –2.8 (d,
1 F, CF2).
MS: m/z = 328 [M – H]+.
Benzyl N-[(2S)-2-Hydroxy-4,4-difluoro-2-methylpenta-
noyl]azaglycinate (15c)
Yield: 0.34 g (71%); mp 67 °C; [a]D +29.1 (c = 2.0, MeOH).
IR (KBr): 3400–3250, 1682 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51 (s, 1 H, CH3), 1.66 (t,
J = 19.5 Hz, 3 H, CH3), 2.01–2.35 (m, 1 H, CH2), 2.55–2.71 (m, 1
H, CH2), 5.17 (s, 2 H, PhCH2), 7.18 (s, 1 H, NH), 7.25–7.45 (m, 5
H, C6H5), 8.79 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 24.8 (t, J = 26.9 Hz, CH3), 27.7
(CH3), 45.6 (t, J = 23.5 Hz, CH2), 68.2 (CH2Ph), 74.3 (t, J = 2.9 Hz,
COH), 124.4 (t, J = 238.2 Hz, CF2), 128.5, 128.7, 128.8, 135.7
(C6H5), 156.6 (urethane C=O), 175.1 (hydrazide C=O).
Methyl N-[(2S)-4,4-Difluoro-2-sulfanylpentanoyl]phenylalani-
nate (14d)
Yield: 0.31 g (64%); mp 102 °C; 1:1 diastereomeric mixture.
IR (KBr): 3325, 2950, 1736, 1647 cm–1.
19F NMR (282 MHz, CDCl3): d = –9.1 (d, 1 F, CF2), –6.0 (d, 1 F,
CF2).
MS: m/z = 339 [M + Na]+, 665 [2 M + Na]+.
1H NMR (300 MHz, CDCl3): d = 1.53 (t, J = 18.6 Hz, 3 H, CH3),
2.13–2.16 (m, 1 H, CH2), 2.17–2.20 (m, 1 H, CH2), 2.64–2.77 (m, 1
H, CH2), 3.04–3.08 (m, 1 H, CH2Ph), 3.11–3.13 (m, 1 H, CH2Ph),
3.34–3.42 (m, 1 H, CHNH)), 3.66 (s, 3 H, OCH3), 4.78–4.85 (m, 1
H, CH), 6.42 (d, J = 7.4 Hz, 1 H, NH), 7.05–7.35 (m, 5 H, C6H5).
Benzyl N-(4,4-Difluoro-2-sulfanylpentanoyl)azaglycinate (15d)
Yield: 0.37 g (77%); oil; 1:1 diastereomeric mixture.
IR (KBr): 3400–3200, 3020, 1700, 1530 cm–1.
1H NMR (300 MHz, methanol-d4): d = 1.64 (t, J = 18.4 Hz, 3 H,
CH3), 2.32–2.38 (m, 1 H, CH2), 2.72–2.81 (m, 1 H, CH2), 3.51–3.72
(m, 1 H, CH), 5.17 (s, 2 H, PhCH2), 7.25–7.50 (m, 5 H, C6H5).
Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluoro-Substituted a-Amino, a-Hydroxy and a-Mercapto Acids
1829
13C NMR (75 MHz, methanol-d4): d = 22.7 (t, J = 26.9 Hz, CH3),
33.5 (CH), 43.2 (t, J = 25.8 Hz, CH2), 67.3 (CH2Ph), 122.9 (t,
J = 237.3 Hz, CF2), 127.9, 128.2, 128.4, 136.2 (C6H5), 157.2 (ure-
thane C=O), 173.7 (hydrazide C=O).
19F NMR (282 MHz, methanol-d4): d = –14.3 (d, 1 F, CF2), –10.7
(d, 1 F, CF2).
(11) (a) Smart, B. E. Characteristics of C–F Systems, In
Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E., Ed.; Plenum: New York, 1994.
(b) Dixon, D. A.; Smart, B. E. Selective Fluorination in
Organic and Bioorganic Chemistry, ACS Symposium Series
456; Welch, J. T., Ed.; , American Chemical Society:
Washington DC, 1991. (c) Dixon, D. A.; Smart, B. E. J.
Phys. Chem. 1991, 95, 1602.
MS: m/z = 319 [M + H]+, 341 [M + Na]+, 357 [M + K]+.
(12) (a) Burger, K.; Gold, M.; Neuhauser, H.; Rudolph, M.; Höß,
E. Synthesis 1992, 1145. (b) Burger, K.; Rudolph, M.;
Neuhauser, H.; Gold, M. Synthesis 1992, 1150.
(13) Burger, K.; Windeisen, E.; Heistracher, E.; Lange, T.; Abdel
Aleem, A. A. H. Monatsh. Chem. 2002, 133, 41.
(14) Pumpor, K.; Windeisen, E.; Burger, K. J. Heterocycl. Chem.
2003, 61, 259.
Acknowledgment
We thank Stiftung Volkswagenwerk, Hannover, for financial sup-
port. S. M. El-Kousy is grateful to DFG for a grant.
(15) (a) Hudlický, M. Org. React. 1988, 34, 513. (b) Chemistry
of Organic Fluorine Compounds, ACS Monograph 187;
Hudlický, M.; Pavlath, A. E., Eds.; American Chemical
Society: Washington DC, 1995, 240; and references cited
therein.
(16) Houben-Weyl, Organo-Fluorine Compounds, Vol. E;
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Stuttgart, 2000, 10a, 87; and references cited therein.
(17) Burger, K.; Rudolph, M.; Windeisen, E.; Worku, A.; Fehn,
S. Monatsh. Chem. 1993, 124, 453.
(18) Burger, K.; Radics, G., unpublished results.
(19) Kraus, G. A.; Bae, J.; Choudhury, P. K. Synthesis 2003, 19.
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Synthesen - Patente – Anwendungen; Thieme: Stuttgart,
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Synthesis 2004, No. 11, 1821–1829 © Thieme Stuttgart · New York