A new strategy for the synthesis of α-difluoromethyl-substituted α-hydroxy and α-amino acids

Article abstract of DOI:10.1021/jo9608331

A new method for the preparation of α-chlorodifluoromethyl-, α-bromodifluoromethyl-, and α-difluoromethyl-substituted α-hydroxy and α-amino acid esters 11, 19-21 is described. The key step of the synthesis is the regioselective alkylation of ketones 5, 7-9 and imines 16-18 with C-nucleophiles. The ketones 7-9 are readily available from 3,3,3-trifluorolactate 1 by a five-step procedure. Subsequent removal of the protecting groups from 19-21 provides the corresponding free amino acids 25, 26, 28.

Full text of DOI:10.1021/jo9608331

J . Org. Chem. 1996, 61, 7521-7528
7521
A New Str a tegy for th e Syn th esis of r-Diflu or om eth yl-Su bstitu ted
r-Hyd r oxy a n d r-Am in o Acid s
Sergey N. Osipov,† Alexander S. Golubev,† Norbert Sewald,‡ Thomas Michel,‡
Alexey F. Kolomiets,† Alexander V. Fokin,† and Klaus Burger*,‡
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28,
GSP-1, V-334, RUS-117813 Moscow, Russia, and Institute of Organic Chemistry, University of Leipzig,
Talstrasse 35, D-04103 Leipzig, Germany
Received May 6, 1996X
A new method for the preparation of R-chlorodifluoromethyl-, R-bromodifluoromethyl-, and
R-difluoromethyl-substituted R-hydroxy and R-amino acid esters 11, 19-21 is described. The key
step of the synthesis is the regioselective alkylation of ketones 5, 7-9 and imines 16-18 with
C-nucleophiles. The ketones 7-9 are readily available from 3,3,3-trifluorolactate 1 by a five-step
procedure. Subsequent removal of the protecting groups from 19-21 provides the corresponding
free amino acids 25, 26, 28.
In tr od u ction
R-amino acids6 can be divided into two groups. Direct
substitution of an R-hydrogen of a natural R-amino acid
by fluoromethyl substituents consists of CH-insertion of
the fluorine-containing carbene generated in situ from
the corresponding freon under strongly basic conditions
in a late step of the reaction sequence.7 The second
method involves the transformation of functional groups
(e.g. fluorodehydroxylation) and includes the applica-
tion of special fluorinating agents such as DAST, SF4,
CF3OF, HF, and others.8 In both cases the introduction
of fluorine is accomplished using highly reactive species
which may cause undesired transformations of other
functional groups present in the molecule. Consequently,
control of regio- and stereoselectivity is often difficult to
achieve. Therefore, it is necessary to protect the func-
tional groups, which requires additional synthetic steps.
The most important standard protective groups (e.g. Boc
and Cbz) for peptide synthesis are not applicable for these
purposes as the remaining proton of the amino function
can be attacked by the fluorinating reagent. Moreover,
many of the currently used fluorinating reagents are
expensive, toxic, corrosive, and sometimes explosive.
Regulation of enzymatic decarboxylation reactions of
amino acids by using specific inhibitors is of fundamental
therapeutic interest.1 In this context a number of
â-fluorine-containing R-amino acids has received consid-
erable attention during the last 15 years.2 Among them
special attention is paid to R-difluoromethyl-substituted
R-amino acids possessing promising properties as ir-
reversible mechanism-based inhibitors of the correspond-
ing pyridoxal phosphate dependent R-amino acid decar-
boxylases.3 Several representatives of this class of
compounds exhibit antibacterial, antihypertensive, can-
cerostatic, and cytotoxic activity. For instance, R-difluo-
romethyl ornithine (eflornithine) is of therapeutic rel-
evance for the treatment of African sleeping disease4 and
of Pneumocystis carinii pneumonia,5 the most frequent
opportunistic infection associated with the acquired
immune deficiency syndrome (AIDS).
The known synthetic routes for R-fluoromethyl (e.g.
R-monofluoromethyl, R-difluoromethyl, R-trifluoromethyl)
The building block strategy represents an attractive
alternative route to R-fluoromethyl R-amino acids. We
developed a preparative method for the synthesis of
R-trifluoromethyl R-amino acids based on the amidoalkyl-
ation of carbon nucleophiles with highly electrophilic
imines of methyl 3,3,3-trifluoropyruvate.9 This enables
direct synthesis of R-trifluoromethyl R-amino acids with
orthogonal protective groups and renders this method
† Russian Academy of Sciences.
‡ University of Leipzig.
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) (a) Douglass, W. W. In The Pharmacological Basis of Therapeu-
tics; Goodman, L. S., Gilman, A., Eds.; MacMillan: New York, 1975;
590 ff. (b) Russell, D. H. In Polyamines in Normal and Neoplastic
Growth; Russell, D. H., Ed., Raven: New York, 1973; 1 ff. (c)
Quemener, V.; Blanchard, Y.; Chamaillard, L.; Havouis, R.; Cipolla,
B.; Moulinoux, J .-P. Anticancer Res. 1994, 14, 443.
(2) (a) Kollonitsch, J .; Patchett, A. A.; Marburg, S.; Maycock, A. L.;
Perkins, L. M.; Doldouras, G. A.; Duggan, D. E.; Aster, S. D. Nature
1978, 274, 906. (b) Bey, P. Ann. Chim. Fr. 1984, 9, 695. (c) Walsh, C.
Tetrahedron 1982, 38, 871.
(3) (a) Palfreyman, M. G.; Bey, P.; Sjoerdsma, A. Essays Biochem.
1987, 23, 28. (b) Schirlin, D.; Ducep, J . B.; Baltzer, S.; Bey, P.; Piriou,
F.; Wagner, J .; Hornsperger, J . M.; Heydt, J . G.; J ung, M. J .; Danzin,
C.; Weiss, R.; Fischer, J .; Mitschler, A.; De Cian, A. J . Chem. Soc.,
Perkin Trans. 1 1992, 1053. (c) Shen, H. J .; Xie, Y. F.; Li, R. T. Plant
Growth Regul. 1994, 14, 1. (d) Reddy, R. L.; Reddy, B. F.; Kumar, P.;
Reddy, P. R. K. J . Reprod. Biol. Comp. Endocrinol. 1993, 5, 8. (e)
Helleboid, S.; Couillerot, J .-P.; Hilbert, J .-L.; Vasseur, J . Planta 1995,
196, 571. (f) Leubner-Metzger, G.; Amrhein, N. Z. Naturforsch., C:
Biosci. 1994, 49, 781. (g) Meyskens, F. L., J r.; Gerner, E. W. J . Cell.
Biochem. 1995 (Suppl. 22), 126.
(6) Sewald, N.; Burger, K. In Fluorine-containing Amino Acids:
Synthesis and Properties; Kukhar’, V. P.; Soloshonok, V. A., Eds.; J ohn
Wiley and Sons: Chichester, 1995; p 139 and references cited therein.
(7) (a) Bey, P.; Vevert, J .-P. Tetrahedron Lett. 1978, 14, 1215. (b)
Bey, P.; Vevert, J .-P.; Van Dorsselaer, V.; Kolb, M. J . Org. Chem. 1979,
44, 2732.
(8) (a) Kollonitsch, J .; Marburg, S. US Patent 4,215,221; 1980; Chem.
Abstr. 1981, 94, 16081. (b) Kollonitsch, J .; Marburg, S.; Perkins, L. M.
J . Org. Chem. 1979, 44, 771. (c) Kollonitsch, J .; Patchett, A. A.;
Marburg, S. S. Afr. Patent 78 03,121; 1979; Chem. Abstr. 1980, 93,
8515. (d) Zembower, D. E.; Gilbert, J . A.; Ames, M. M. J . Med. Chem.
1993, 36, 305. (e) Kollonitsch, J .; Barash, L. J . Am. Chem. Soc. 1976,
98, 5591. (f) Kollonitsch, J .; Marburg, S.; Perkins, L. M. J . Org. Chem.
1976, 41, 3107.
(9) (a) Burger, K.; Ho¨ss, E.; Gaa, K.; Sewald, N.; Schierlinger, C. Z.
Naturforsch. 1991, B46, 361. (b) Burger, K.; Gaa, K. Chem.-Ztg. 1990,
114, 101. (c) Burger, K.; Sewald, N. Synthesis 1990, 115. (d) Osipov,
S. N.; Chkanikov, N. D.; Kolomiets, A. F.; Fokin A. V. Bull. Acad. Sci.
USSR, Chem. Sect. (Eng.) 1986, 1256. (e) Osipov, S. N.; Kolomiets, A.
F.; Fokin, A. V. Russ. Chem. Rev. 1992, 61, 798.
(4) (a) Dibari, C.; Pastore, G.; Roscigno, G.; Schechter, P. J .;
Sjoerdsma, A. Ann. Intern. Med. 1986, 105, 83. (b) Bacchi, C. J .;
Goldberg, B.; Garofalo-Hannan, J .; Rattendi, D.; Lyte, P.; Yarlett, N.
Biochem. J . 1995, 309, 737.
(5) (a) Gilman, T. M.; Paulson, Y. J .; Boylen, C. T.; Heseltine, P. N.
R.; Sharma, O.P. J . Am. Med. Assoc. 1986, 256, 2197. (b) Chowdhury,
S. R.; Guha, S.; Sen, U. Neoplasma 1994, 41, 159. (c) Gunaratna, P.
C.; Wilson, G. S.; Slavik, M. J . Pharm. Biomed. Anal. 1994, 12, 1249.
S0022-3263(96)00833-X CCC: $12.00 © 1996 American Chemical Society

7522 J . Org. Chem., Vol. 61, No. 21, 1996
Osipov et al.
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
convenient for the preparation of free amino acids as well
as for their incorporation into peptides10 (Scheme 1).
Furthermore, the building block strategy provides
access to homochiral R-trifluoromethyl R-amino acids via
alkylation of in situ formed homochiral cyclic R-trifluo-
romethyl acyl imines with C-nucleophiles11 or via the
alkylation of R-trifluoromethyl imines with homochiral
carbanions.12
In this paper, we wish to disclose a new convenient
synthesis for R-difluoromethyl R-hydroxy and R-amino
acids and for the virtually unknown R-chlorodifluoro-
methyl and R-bromodifluoromethyl R-hydroxy and R-ami-
no acids, respectively, via 3,3-difluoropyruvate, 3-chloro-
3,3-difluoropyruvate, and 3-bromo-3,3-difluoropyruvate
or via the corresponding acyl imines.
of 4 into ketone 5 were unsuccessful so far. Conversion
up to 30% only is observed on treatment of 4 with Et3N
in CH2Cl2. Compound 6 is the main product of this
reaction as the result of an aldol-type condensation
(Scheme 3). Nevertheless, methyl 3,3-difluoropyruvate
(5) was separated from the mixture and characterized
by NMR spectra and chemical transformations (Scheme
5 and 6).
The 3-chloro-3,3-difluoro-, 3-bromo-3,3-difluoro-, 3-iodo-
3,3-difluoropyruvates, respectively, can be synthesized in
a stepwise procedure starting from enol 4, which readily
reacts with halogens (or ICl) to give a mixture of the
corresponding ketone (7-9) and the hydrogen halide
adduct 1018 (Scheme 4) in a ratio of 3:1 (X ) Cl), 3:2 (X
) Br), 1:1 (X ) I). The HX adducts 10 can be trans-
formed into 7-9.
Two pathways for the formation of 10 seem to be
plausible: either the adducts are formed independently
as a result of decomposition of the initially formed
halogenonium ion or they are the products of a secondary
reaction of 7-9 with the corresponding hydrogen halide.
The undesired byproducts 10a or 10c are converted
into 7 or 9, respectively, by distillation of the reaction
mixture under ambient pressure. HBr elimination from
10b is accomplished by treatment of the mixture with 1
equiv of quinoline. Subsequent distillation under re-
duced pressure gives pure 8. Thus, ketones 7-9 are
obtained from readily available lactate 1 by a five-step
procedure in 50, 47, and 35% overall yield, respectively.
In addition, every stage has been optimized on a 100 g
scale.
Our interest in R-difluoromethyl R-hydroxy acids is
connected with the fact that several R-fluoromethyl
R-hydroxy acids have been applied as important compo-
nents of antiandrogenic compounds.19 Some of them were
used for the synthesis of monomers for piezoelectric
polymers20 as well as for the preparation of fluorine-
containing sugars.21
Resu lts a n d Discu ssion
In the context with our interest in new fluorine
containing building blocks,13 we recently described a new
metastable fluorinated enol, 3,3-difluoro-2-hydroxyacryl-
ate (4),14 using methyl 3,3,3-trifluorolactate (1)15 as
starting material (Scheme 2), which can be obtained from
easily accessible methyl 3,3,3-trifluoropyruvate.16
The trifluoroacetyl derivative 2 is obtained in 91% yield
on treatment of 1 with trifluoroacetic anhydride (TFAA)
in quinoline. Dehydrofluorination with BF3‚NEt3 pro-
vides acrylate 3 in good yield even on a 100 g scale.
Essentially quantitative deprotection of 3 is achieved on
treatment with MeOH. Enol 4 is a stable compound and
can be distilled (bp 130-133 °C) without substantial
decomposition.
The enol of pentafluoroacetone (as an analog of 4)
quantitatively isomerizes to give the ketone in boiling
MeOH.17 All attempts to induce complete transformation
(10) (a) Sewald, N.; Hollweck, W.; Mu¨tze, K.; Schierlinger, C.;
Seymour, L. C.; Gaa, K.; Burger, K.; Koksch, B.; J akubke, H. D. Amino
Acids 1995, 8, 187. (b) Burger, K.; Hollweck, W. Synlett 1994, 751. (c)
Hollweck, W.; Burger, K. J . Prakt. Chem. 1995, 337, 391.
(11) Sewald, N.; Seymour, L. C.; Burger, K.; Osipov, S. N.; Kolomiets,
A. F.; Fokin, A. V. Tetrahedron: Asymmetry 1994, 5, 1051.
(12) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.;
Kukhar’, V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5,
2009.
As expected, the ketones 5, 7-9 react regioselectively
with Grignard reagents at -78 °C to give R-hydroxy
esters 11 (Scheme 5) in high yields.
(13) (a) Burger, K.; Geith, K.; Sewald, N. J . Fluorine Chem. 1985,
29, 213. (b) Osipov, S. N.; Sewald, N.; Kolomiets, A. F.; Fokin, A. V.;
Burger, K. Tetrahedron Lett. 1996, 37, 615.
(14) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Kolomiets, A. F.;
Fokin, A. V.; Burger, K. Synlett 1995, 1269.
(15) von dem Bussche-Hu¨nnefeld, C.; Cescato, C.; Seebach, D. Chem.
Ber. 1992, 125, 2795.
(18) An analogous adduct was obtained on bromination of pentafluo-
roacetone enol. See Bekker, R. A.; Melikyan, G. G.; Dyatkin, B. L.;
Knunyants, I. L. Zh. Org. Khim. 1975, 8, 1604; Chem. Abstr. 1975,
83, 178185r.
(16) (a) Knunyants, I. L.; Shokina, V. V.; Tyuleneva, V. V. Dokl.
Akad. Nauk SSSR 1966, 169, 594; Chem. Abstr. 1966, 65, 15218e. (b)
Sianesi, D.; Pasetti, A.; Tarli, F. J . Org. Chem. 1966, 31, 2312.
(17) Bekker, R. A.; Melikyan, G. G.; Dyatkin, B. L.; Knunyants, I.
L. Zh. Org. Khim. 1975, 11, 1370; English (Plenum) 1975, 1356.
(19) Morris, J . J .; Hughes, L. R.; Glen, A. T.; Taylor, P. J . J . Med.
Chem. 1991, 34, 447.
(20) Hu¨bel, M.; O’Hagan, D. Liebigs Ann. 1995, 583.
(21) Wucherpfennig, U.; Logothetis, T. A.; Eilitz, U.; Burger, K.
Tetrahedron 1996, 52, 143.

R-Difluoromethyl-Substituted R-Hydroxy and R-Amino Acids
J . Org. Chem., Vol. 61, No. 21, 1996 7523
Ta ble 1. Con ver sion of Im in es 16-18 in to r-Am in o Acid
Ester s 19-21
Sch em e 5
entry
X
R
R1
product
yield (%)
1
2
3
4
5
6
7
8
9
H
t-Bu
PhCH2
Me
PhCH2
PhCH2
Me
PhCH2
i-Bu
Ph
19e
20a
20b
20c
21a
21b
21c
21d
21e
21f
21g
72
73
92
80
78
68
63
62
61
80
86
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
PhCH2
PhCH2
t-Bu
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
t-Bu
Allyl
Me
PhCH2
10
11
t-Bu
Sch em e 8
Sch em e 6
Sch em e 9
Sch em e 7
A protocol described by us earlier for the synthesis of
the corresponding R-trifluoromethyl derivatives9 can be
applied for the synthesis of R-difluoromethyl R-amino acid
derivatives from ketones 5, 7-9 (Schemes 6 and 7). The
ketones 5, 7-9 readily form the stable hemiamidals 12-
15 on reaction with benzyl and tert-butyl carbamates. The
reactions proceed in CH2Cl2 or CHCl3 at rt and are
complete within 16 h. This process is significantly
accelerated (1 h) when the reaction temperature is
increased to 50-60 °C. The conversion of compounds
12-15 into imines 16-18 is carried out with trifluoro-
acetic anhydride/pyridine as dehydrating agent. Usually,
the imines obtained do not require further purification.
However, some of them can be distilled under reduced
pressure. In analogy to their precursors 5 and 7-9, the
imines 16-18 smoothly react with Grignard reagents at
-78 °C and the corresponding amino acid derivatives
19-21 are obtained in good to excellent yields (Table 1).
1-2 h. Reduction of compounds 21a -d in boiling THF
reaches completion within 2-4 h.
The chloro derivatives 13b, 20a ,b are also reduced with
n-Bu3SnH in boiling THF. However, the conversion
remained incomplete under the reaction conditions tested
(also in the presence of AIBN). Furthermore, partial
decomposition is observed especially in the case of
hemiamidal 13b, presumably via elimination of benzyl
carbamate.
In order to check the perspectives for the utilization
of these protected amino acid derivatives for peptide
synthesis we tested methods for the removal of protective
groups using standard peptide chemistry protocols.
Selective deprotection of the carboxy group of Cbz-
protected derivatives 19-21 under mildly basic condi-
tions (KOH/MeOH, rt, 24 h or LiOH/MeOH, 5 °C, 24 h)
readily gives the corresponding acids 22-24. Subsequent
catalytic hydrogenation (Pd/C, MeOH, 12 h) affords free
amino acids 25 and 26. In the case of the bromo
derivative 24a hydrogenation results in simultaneous
reduction of the CF2Br- and cleavage of Cbz-group to give
R-difluoromethyl alanine 25a (Scheme 9).
The reactions of the imines with the Grignard reagents
proceed regioselectively. Addition to the ester groups or
isomerization of 16a to the enamide are not observed.
As mentioned above, this sequence is of limited value
for the synthesis of R-difluoromethyl-substituted R-hy-
droxy and R-amino acids because of the low yield of 5.
Therefore, we developed an alternative route via radical
reduction of the BrCF2-group at the end of the reaction
sequence. The (R-BrCF2)-groups in hemiamidals 14 and
R-amino esters 21 are readily reduced on treatment with
1.3 equiv of n-Bu3SnH (Scheme 8) in THF. In the case
of the hemiamidals 14 the reaction proceeds at rt within
Direct hydrolysis of Boc-protected derivatives 19e, 20c
(6 N HCl, 80 °C, 10 h) proceeds in good yield to give

7524 J . Org. Chem., Vol. 61, No. 21, 1996
Osipov et al.
Sch em e 10
Con clu sion
We developed a new convenient route to 3-chloro-3,3-
difluoropyruvate 7 and 3-bromo-3,3-difluoropyruvate 8
via halogenation of enol 4. The latter is readily prepared
via a three-step procedure from 3,3,3-trifluorolactate 1.
The new ketones 7, 8 are highly electrophilic synthons
which can be efficiently used as building blocks for the
synthesis of various derivatives of biologically valuable
R-difluoromethyl-substituted R-hydroxy and R-amino
acids. Scale-up synthesis of these compounds can easily
be achieved, thus making them available in sufficient
quantities to study their potential pharmacological and
therapeutic properties.
Sch em e 11
Exp er im en ta l Section
1H NMR spectra were recorded on 200 and 300 MHz
spectrometers with Me4Si as internal standard. 13C NMR
spectroscopy was performed at 50, 75, and 100 MHz. 19F NMR
spectra were obtained at 188 and 282 MHz with trifluoroacetic
acid as external standard, downfield shifts being designated
as positive. Mass spectra were obtained using EI ionization
at 70 eV. Elemental microanalyses were carried out by the
microanalytical laboratory of the chemistry department, Uni-
versity of Leipzig. All compounds have been fully character-
ized and gave correct microanalytical data [(0.4%, except 5
(unstable), 10 (undesired side products), 28 (contains salt), 29
(hygroscopic)]. All reactions were routinely monitored with
the aid of 19F NMR spectroscopy or TLC. Analytical TLC was
performed using Merck precoated silica gel 60F-254 plates
(0.25 mm). For flash chromatography, silica gel 60 (30-60
µm) was used with hexanes/ethyl acetate solvent systems.
Organic solvents were dried and distilled prior to use.
Sch em e 12
Meth yl O-(Tr iflu or oa cetyl)-3,3,3-tr iflu or ola cta te (2).
TFAA (190.0 g, 0.90 mol) was added at 0 °C to a stirred
solution of 1 (130 g, 0.82 mol) in quinoline (380.0 g, 2.90 mol).
The mixture was stirred at 0 °C for 1 h and then at rt for 1 h.
The reaction flask was connected to a distillation apparatus,
and the product was transferred under reduced pressure (1
Torr) into a cooled (-78 °C) receiver. The contents of the
receiver was allowed to warm up to rt. Distillation gave 190.1
R-difluoromethyl and R-chlorodifluoromethyl amino acids
25b, 26b (Scheme 10). Bromo derivatives 21f,g decom-
pose under these conditions. Treatment of 21f,g with
40% HBr in acetic acid (20 °C, 3 h) results only in
deprotection of the amino group to give 27a ,b.
g (91%) of 2: bp 72 °C/70 Torr; n20 1.3202. 1H NMR (CDCl3)
D
δ 3.93 (s, 3H); 5.58 (q, J HF ) 6.5 Hz, 1H). 13C NMR (CDCl3)
3
A different strategy was used for the preparation of
free R-bromodifluoromethyl R-amino acids 28a ,b: depro-
tection of the amino group in the corresponding Boc-
derivatives 21f,g with trifluoroacetic acid (TFA), followed
by cleavage of the methyl esters 27a ,b (LiOH/MeOH)
(Scheme 11). All attempts to purify acids 28a ,b (also by
ion-exchange chromatography with ion-exchange resin
DOWEX 50W-X2) failed. They were characterized spec-
troscopically as hydrochlorides in a mixture with LiCl.
Noteworthy, the free R-BrCF2-containing R-amino acids
are unstable toward heating or basic reagents. However,
being protected either on the amino or the carboxy
function, they are quite stable compounds.
R-Difluoromethyl-substituted R-amino acids can be
readily incorporated into peptides by standard peptide
synthesis procedures as demonstrated by the synthesis
of dipeptide 30 from Boc-protected L-phenylalanine and
methyl R-(difluoromethyl)alaninate (29)22 using the mixed
anhydride strategy (Scheme 12). The diastereomers can
be separated by flash-chromatography. Investigations
concerning SPPS (solid phase peptide synthesis) with
R-difluoromethyl-substituted R-amino acids are in
progress.
2
1
δ 54.1; 71.3 (q, J CF ) 35.2 Hz); 113.9 (q, J CF ) 284.7 Hz);
1
2
120.2 (q, J CF ) 281.2 Hz); 155.6 (q, J CF ) 42.6 Hz); 160.8.
19F NMR (CDCl3) δ 3.22 (s, 3F); 5.03 (d, J HF ) 6.5 Hz, 3F).
3
Meth yl 3,3-Diflu or o-2-(tr iflu or oa cetoxy)a cr yla te (3). A
mixture of 2 (20.0 g, 0.079 mol), silica gel (Merck, 63-200 µm,
1.6 g), and Et3N‚BF3 (40.0 g, 0.23 mol) was heated to 120 °C
for 2 h. The reaction flask was then connected to a distillation
apparatus, and the volatiles were transferred under reduced
pressure (1 Torr) into a cooled (-78 °C) receiver, while the
temperature was raised from rt to 90 °C. The contents of the
receiver was subjected once more to thermolysis at 120 °C for
42 h with the same amount of Et3N‚BF3 (this time without
silica gel). The product was collected as above. Distillation
gave 12.8 g (70%) of pure 3: bp 40-42 °C/50 Torr; n20D 1.3456.
1H NMR (CDCl3) δ 3.89 (s, 3H). 13C NMR (CDCl3) δ 53.1; 106.1
1
2
(m); 114.1 (q, J CF ) 285.9 Hz); 158.8; 158.9 (q, J CF ) 21.3
Hz); 159.0 (dd, J CF ) 308.4, 303.4 Hz). 19F-NMR (CDCl3) δ
-2.14 (d, J FF ) 6.1 Hz, 1F); 3.29 (d, J FF ) 6.1 Hz, 1F); 3.40
(s, 3F).
1
2
2
Meth yl 3,3-Diflu or o-2-h yd r oxya cr yla te (4). MeOH (5.8
g, 0.18 mol) in 5 mL of CH2Cl2 was added at -10 °C to a stirred
solution of 3 (40.0 g, 0.17 mol) in CH2Cl2 (15 mL). The mixture
was allowed to warm up to rt and was stirred for 16 h.
Volatiles were removed under reduced pressure (60 Torr).
Distillation of the residue gave 22.3 g (94%) of 4: bp 65-66
°C/60 Torr. 1H NMR (CDCl3) δ 3.92 (s, 3H); 4.54 (br s, 1H).
13C NMR (CDCl3) δ 53.3; 109.6 (dd, 2J CF ) 35.4, 19.3 Hz); 156.1
(22) Compound 29‚HBr was especially obtained from compound 21a
by hydrogenation (Pd/C, MeOH, 12 h) as result of simultaneous
cleavage of the Cbz-protective group and reduction of the bromodi-
fluoromethyl group to a difluoromethyl group (see Experimental
Section).
1
3
(dd, J CF ) 295.0, 298.2 Hz); 164.7 (dd, J CF ) 10.3, 7.9 Hz).
19F NMR (CDCl3) δ -19.16 (d, J FF ) 29.0 Hz, 1F); -9.34 (d,
2
2J FF ) 29.0 Hz, 1F). IR (neat): ν (cm-1) 3400 (OH), 1760
(CdC), 1750 (CdO). MS (EI, m/z) 138 (M+); 107 (39); 79 (74).

R-Difluoromethyl-Substituted R-Hydroxy and R-Amino Acids
J . Org. Chem., Vol. 61, No. 21, 1996 7525
Isom er iza t ion of 4. A solution of Et3N (3-4 drops) in
CH2Cl2 (3 mL) was added at rt to a solution of 4 (10.0 g, 7.24
mmol) in CH2Cl2 (10 mL). The mixture was stirred for 10 h.
After evaporation of the solvent, the residue was distilled
under reduced pressure to give two fractions: methyl 3,3-
difluoropyruvate (5) (3.1 g, bp 78-80 °C/25 Torr) and dimethyl
4-(difluoromethyl)-3,3-difluoro-4-hydroxy-2-oxopentanedi-
oate (6) (4.2 g, bp 101-103 °C/15 Torr).
pressure, and the crude product was purified by flash chro-
matography.
Met h yl 3,3-d iflu or o-2-h yd r oxy-2-p h en ylp r op ion a t e
(11a ): yield 68%; oil. 1H NMR (CDCl3) δ 3.87 (s, 1H); 3.91 (s,
2
3H); 6.23 (t, J HF ) 54.4 Hz, 1H); 7.41 (m, 3H); 7.69 (m, 2H).
2
13C NMR (CDCl3) δ 54.47; 78.61 (t, J FC ) 21.2 Hz); 115.18 (t,
1J FC ) 248.9 Hz); 126.45; 129.14; 129.64; 135.01; 171.15. 19F
2
2
NMR (CDCl3) δ -55.97 (ddABX, J FF ) 278.3 Hz, J HF ) 54.4
2
2
1
2
Hz, 1F); -51.22 (ddABX, J FF ) 278.3 Hz, J HF ) 54.4 Hz, 1F).
Meth yl 2-(d iflu or om eth yl)-2-h yd r oxy-3-p h en ylp r op i-
on a te (11b): yield 74%; oil. 1H NMR (CDCl3) δ 3.11 (s, 2H);
5: H NMR (CDCl3) δ 3.98 (s, 3H); 6.40 (t, J HF ) 52.9 Hz,
2
1H). 19F NMR (CDCl3) δ -53.21 (d, J HF ) 52.9 Hz). An
analytically pure sample was not obtained. 6‚H2O: 1H NMR
(CDCl3) δ 3.92 (s, 3H); 3.95 (s, 3H); 4.52 (br s, 3H); 6.17 (dd,
2J HF ) 54.9, 53.1 Hz, 1H). 13C NMR (CDCl3) δ 54.55; 54.85;
2
3.43 (br s, 1H); 3.80 (s, 3H); 5.86 (t, J HF ) 55.1 Hz, 1H); 7.25
(m, 5H). 13C NMR (CDCl3) δ 39.42 (t, J CF ) 3.0 Hz); 53.87;
3
2
1
2
1
77.25 (m); 92.64 (t, J CF ) 29.6 Hz); 112.31 (t, J CF ) 252.9
78.81 (t, J CF ) 21.0 Hz); 115.41 (t, J CF ) 250.2 Hz); 127.91;
1
2
Hz); 115.64 (t, J CF ) 276.1 Hz); 167.19 (t, J CF ) 3.5 Hz);
168.10. 19F NMR (CDCl3) δ -53.53 (ddt, 2J FF ) 293.9 Hz, 2J HF
) 53.2, 4J FF ) 12.0 Hz, 1F); -50.40 (ddt, 2J FF ) 293.9 Hz, 2J HF
) 53.2, J FF ) 12.0 Hz, 1F); -38.84 (dt, J FF ) 274.8, J FF
12.0 Hz, 1F); -37.73 (dt, J FF ) 274.9, J FF ) 12.0 Hz, 1F).
128.85; 130.67; 134.03; 171.29. 19F NMR (CDCl3) δ -55.82
2
2
(ddABX, J FF ) 282.4 Hz, J HF ) 55.1 Hz, 1F); -49.97 (ddABX
,
2J FF ) 282.4 Hz, J HF ) 55.1 Hz, 1F). MS (EI, m/z) 230 (M+);
2
4
2
4
)
212 (18); 91 (100).
2
4
Meth yl 3-ch lor o-3,3-d iflu or o-2-h yd r oxy-2-p h en ylp r o-
p ion a te (11c): yield 82%; oil. 1H NMR (CDCl3) δ 3.98 (s, 3H);
4.47 (s, 1H); 7.20 (m, 3H); 7.92 (m, 2H). 13C NMR (CDCl3) δ
Meth yl 3-Ch lor o-3,3-d iflu or o-2-oxop r op ion a te (7).
cold (-50 °C) solution of chlorine (23.2 g, 32.6 mmol) in
CH2Cl2 (100 mL) was added under nitrogen in one portion to
a stirred solution of 4 (30.0 g, 21.7 mmol) in CH2Cl2 (50 mL)
at -78 °C. The reaction mixture was stirred for 2 h at -60
°C, warmed up to rt, and stirred overnight. The solvent was
removed under reduced pressure. The residue was a mixture
of 7 and methyl 2,3-dichloro-3,3-difluoro-2-hydroxypropionate
(10a ) (ratio of 3:1; as measured by NMR). 10a : 1H NMR
(CDCl3) δ 3.96 (s, 3H), 4.81 (br s, 1H). 19F (CDCl3) δ 11.39
A
2
1
55.14; 81.64 (t, J CF ) 27.3 Hz); 122.59 (t, J CF ) 303.3 Hz);
127.74; 128.85; 130.14; 133.52; 170.26. 19F NMR (CDCl3) δ
15.07 (dAB, J FF ) 165.4 Hz, 1F); 17.20 (dAB, J FF ) 165.4 Hz,
1F).
2
2
Meth yl 2-(br om odiflu or om eth yl)-2-h ydr oxypr opion ate
(11d ): yield 70%; oil. 1H NMR (CDCl3) δ 1.61 (s, 3H); 3.91 (s,
3H); 3.97 (s, 1H). 13C NMR (CDCl3) δ 20.00; 54.71; 79.93 (t,
2J CF ) 24.2 Hz); 123.76 (t, 1J CF ) 315.9 Hz); 171.30. 19F NMR
2
2
(dAB
,
2J FF ) 164.4 Hz, 1F); 15.93 (dAB
,
2J FF ) 164.4 Hz, 1F).
(CDCl3) δ 18.67 (dAB, J FF ) 162.2 Hz, 1F); 21.18 (dAB, J FF )
The mixture was distilled to give 31.1 g (83%) of pure 7 (bp
129-130 °C). 1H NMR (CDCl3) δ 3.98 (s, 3H). 13C NMR
(CDCl3) δ 54.02; 118.27 (t, 1J CF ) 304.1 Hz); 157.14; 173.87 (t,
2J CF ) 33.2 Hz). 19F NMR (CDCl3) δ 11.31 (s, 2F). MS (EI,
m/z) 172 (M+); 160 (18); 132 (28); 95 (31); 86 (92); 59 (100).
162.2 Hz, 1F).
Meth yl 3-br om o-3,3-d iflu or o-2-h yd r oxy-2-p h en ylp r o-
p ion a te (11e): yield 74%; oil. 1H NMR (CDCl3) δ 3.98 (s, 3H);
4.54 (s, 1H); 7.42 (m, 3H); 7.85 (m, 2H). 13C NMR (CDCl3) δ
2
1
55.21; 82.40 (t, J CF ) 24.1 Hz); 123.09 (t, J CF ) 316.0 Hz);
127.72; 128.81; 130.10; 133.44; 170.00. 19F NMR (CDCl3) δ
20.85 (dAB, J FF ) 162.4 Hz, 1F); 23.48 (dAB, J FF ) 162.4 Hz,
1F).
Meth yl 3-Br om o-3,3-d iflu or o-2-oxop r op ion a te (8).
A
2
2
solution of bromine (50.0 g, 31.25 mmol) in CH2Cl2 (100 mL)
was slowly (within 1 h) added to a vigorously stirred solution
of 4 (40.0 g, 28.9 mmol) in CH2Cl2 (50 mL) at -30 °C under
nitrogen. The reaction mixture was stirred for 12 h at rt. After
removal of the solvent, the residue was distilled under reduced
pressure (bp 41-43 °C/10 Torr) to afford 74.5 g of a slightly
yellow liquid which was a mixture of 8 and methyl 2,3-
dibromo-3,3-difluoro-2-hydroxypropionate (10b) (according to
Meth yl 2-(br om od iflu or om eth yl)-2-h yd r oxy-3-p h en yl-
p r op ion a te (11f): yield 61%; oil. 1H NMR (CDCl3) δ 3.20 (dAB
,
2
2J HH ) 13.4 Hz, 1H); 3.33 (dAB, J HH ) 13.4 Hz, 1H); 3.82 (s,
3H); 3.94 (s, 1H); 7.25 (m, 5H). 13C NMR (CDCl3) δ 38.03;
2
1
54.02; 83.02 (t, J CF ) 23.4 Hz); 122.79 (t, J CF ) 316.7 Hz);
127.62; 128.38; 130.42; 133.24; 169.60. 19F NMR (CDCl3) δ
NMR spectra) in a ratio of 3:2. 10b: 1H NMR (CDCl3) δ 3.98
19.62 (dAB, J FF ) 162.0 Hz, 1F); 22.22 (dAB, J FF ) 162.0 Hz,
1F). MS (EI, m/z) 308 (M+); 290 (5); 211 (17); 91 (100).
Gen er a l P r oced u r e for P r ep a r a tion of Hem ia m id a ls
12-15. A mixture of the corresponding ketone (10 mmol) and
benzyl carbamate (or tert-butyl carbamate; 10 mmol) in dry
CHCl3 was stirred at rt for 16 h. The solution was concen-
trated in vacuo, and the crude product was purified by
recrystallization from CHCl3/hexanes.
2
2
2
(s, 3H); 5.46 (br s, 1H). 19F NMR (CDCl3) δ 19.29 (dAB, J FF
)
162.0 Hz, 1F); 26.17 (dAB, 2J FF ) 162.0 Hz, 1F). A 37.4 g (28.9
mmol) amount of quinoline was added at 10 °C to this mixture.
After stirring for 1 h the reaction flask was connected to a
distillation apparatus and the product was transferred under
reduced pressure (1 Torr) into a cooled (-78 °C) receiver, while
the temperature of the reaction flask was slowly raised from
rt to 50 °C. The product was redistilled from a small amount
of phosphorus pentoxide to give 65.7 g (80%) of pure 8 (bp 70-
71 °C/70 Torr). 1H NMR (CDCl3) δ 4.00 (s, 3H). 13C NMR
(CDCl3) δ 54.00; 111.36 (t, 1J CF ) 317.9 Hz); 156.88; 173.73 (t,
2J CF ) 29.6 Hz). 19F NMR (CDCl3) δ 13.88 (s, 2F). MS (EI,
m/z): 216 (M+); 176 (13); 129 (52); 82 (31); 59 (100).
Meth yl 2-[N-(ter t-bu tyloxycar bon yl)am in o]-3,3-diflu or o-
2-h yd r oxyp r op ion a te (12a ): yield 83%; mp 68-70 °C. 1H
NMR (CDCl3) δ 1.45 (s, 9H); 3.91 (s, 3H); 4.92 (s, 1H); 5.65 (s,
1H); 5.87 (t, 2J HF ) 52.0 Hz). 13C NMR (CDCl3) δ 27.60; 53.77;
2
1
80.70 (t, J CF ) 24.2 Hz); 81.70; 112.11 (t, J CF ) 242.3 Hz);
153.88; 167.53. 19F NMR (CDCl3) δ -57.01 (ddABX, 2J FF ) 288.1
2
2
2
Meth yl 3-Iod o-3,3-d iflu or o-2-oxop r op ion a te (9). By
analogy to the procedure for 7, 17.1 g of a mixture of 9 and
methyl 2-chloro-3-iodo-3,3-difluoro-2-hydroxypropionate (10c)
in a ratio of 1:1 were obtained from 10.0 g (7.24 mmol) of 4
and 13.0 g (8.0 mmol) of ICl. 10c: 1H NMR (CDCl3) δ 3.96 (s,
Hz, J HF ) 52.0 Hz, 1F); -52.85 (ddABX, J FF ) 288.1 Hz, J HF
) 52.0 Hz, 1F).
Meth yl 2-[N-(ben zyloxyca r bon yl)a m in o]-3,3-d iflu or o-
2-h yd r oxyp r op ion a te (12b): yield 74%; mp 108-109 °C. 1H
NMR (CDCl3) δ 3.90 (s, 3H); 4.89 (s, 1H); 5.11 (dAB, )
2J HH
3H); 4.45 (br s, 1H). 19F NMR (CDCl3) δ 20.54 (dAB
,
2J FF
)
12.0 Hz, 1H); 5.15 (dAB, 2J HH ) 12.0 Hz, 1H); 5.87 (s, 1H); 5.90
2
(t, J HF ) 55.3 Hz, 1H); 7.37 (m, 5H). 13C NMR (CDCl3) δ
2
185.3 Hz, 1F); 23.58 (dAB, J FF ) 185.3 Hz, 1F). The mixture
was converted into pure 9 (12.8 g, 67%) on distillation under
reduced pressure (bp 57-59 °C/12 Torr). 1H NMR (CDCl3) δ
3.99 (s, 3H). 19F NMR (CDCl3) δ 16.05 (s, 2F).
2
1
54.82; 68.34; 81.76 (t, J CF ) 25.0 Hz); 112.89 (t, J CF ) 252.0
Hz); 128.82, 129.05; 129.11; 135.70; 155.61; 167.98. 19F NMR
(CDCl3) δ -57.00 (ddABX, 2J FF ) 294.3 Hz, 2J HF ) 55.3 Hz, 1F);
2
2
-52.92 (ddABX, J FF ) 294.3 Hz, J HF ) 55.3 Hz, 1F).
Gen er a l P r oced u r e for th e P r ep a r a tion of r-Hyd r oxy
a cid s 11a -f. A Grignard reagent (solution in THF, 10.0
mmol) was added dropwise to a stirred solution of 10.0 mmol
of ketone 5, 7, 8, 9, respectively, in dry THF (25 mL) at -78
°C. After 1 h at -78 °C the reaction mixture was allowed to
warm up to rt within 2 h. The reaction was quenched with
1 N HCl and extracted with ether (2 × 25 mL). The combined
organic layer was washed with brine (25 mL), dried over
MgSO4, and filtered. The solvent was removed under reduced
Meth yl 2-[N-(ter t-bu tyloxyca r bon yl)a m in o]-3-ch lor o-
3,3-d iflu or o-2-h yd r oxyp r op ion a te (13a ): yield 89%; mp
83-84 °C. 1H NMR (CDCl3) δ 1.46 (s, 9H); 3.94 (s, 3H); 5.58
(br s, 1H); 5.73 (m, 1H). 13C NMR (CDCl3) δ 28.09; 54.74;
2
1
82.57; 83.96 (t, J CF ) 28.6 Hz); 126.38 (t, J CF ) 303.4 Hz);
154.03, 167.01. 19F NMR (CDCl3) δ 11.39 (dAB, J FF ) 164.1
2
Hz, 1F); 11.78 (dAB,
2J FF ) 164.1 Hz, 1F). MS (EI, m/z) 271
(M+ - H2O); 256 (34); 217 (23); 57 (100).

7526 J . Org. Chem., Vol. 61, No. 21, 1996
Osipov et al.
2
Meth yl 2-[N-(ben zyloxyca r bon yl)a m in o]-3-ch lor o-3,3-
d iflu or o-2-h yd r oxyp r op ion a te (13b): yield 91%; mp 106-
108 °C. 1H NMR (CDCl3) δ 3.91 (s, 3H); 5.11 (dAB, 2J HH ) 12.2
128.07; 133.35; 149.85 (t, J CF ) 27.2 Hz); 154.70; 157.44. 19F
NMR (CDCl3) δ 21.29 (s, 2F).
P r oced u r e for th e P r ep a r a tion of Am in o Ester s 19-
21. The R-amino esters 19-21 were obtained by Grignard
reaction according to the procedure for the synthesis of
R-hydroxy esters 11.
2
Hz, 1H); 5.17 (dAB, J HH ) 12.2 Hz, 1H); 5.53 (br s, 1H); 6.01
(br s, 1H); 7.37 (m, 5H). 13C NMR (CDCl3) δ 54.94; 68.09; 84.00
(t, 2J CF ) 28.1 Hz); 126.19 (t, 1J CF ) 303.4 Hz); 128.46; 128.71;
128.73; 135.05; 154.67; 166.60. 19F NMR (CDCl3) δ 11.34 (dAB
,
Meth yl N-(ter t-bu tyloxyca r bon yl)-2-(d iflu or om eth yl)-
2J FF ) 164.3 Hz, 1F); 11.74 (dAB
,
2J FF ) 164.3 Hz, 1F). MS
p h en yla la n in a te (19e): yield 72%; oil. 1H NMR (CDCl3) δ
(EI, m/z) 305 (M+ - H2O); 263 (5); 107 (20); 91 (100).
2
2
1.48 (s, 9H); 3.29 (d, J HH ) 13.4 Hz, 1H); 3.74 (d, J HH ) 13.4
2
Meth yl 2-[N-(ter t-bu tyloxyca r bon yl)a m in o]-3-br om o-
3,3-d iflu or o-2-h yd r oxyp r op ion a te (14a ): yield 86%; mp
92-95 °C. 1H NMR (CDCl3) δ 1.46 (s, 9H); 3.94 (s, 3H); 5.60
(very br.); 5.72 (br s, 1H). 13C NMR (CDCl3) δ 28.53; 55.21;
Hz, 1H); 3.86 (s, 3H); 5.47 (br s, 1H); 6.42 (t, J HF ) 55.8 Hz,
1H); 7.09 (m, 2H); 7.29 (m, 3H). 13C NMR (CDCl3) δ 27.82;
34.55; 52.75; 65.71 (t, 2J CF ) 21.4 Hz); 80.04; 113.10 (t, 1J CF
)
250.9 Hz); 127.03; 128.10; 129.58; 133.63; 153.82; 168.11. 19F
2
1
2
83.01; 84.80 (t, J CF ) 26.5 Hz); 121.20 (t, J CF ) 315.4 Hz);
NMR (CDCl3) δ -50.34 (d, J HF ) 55.8 Hz, 2F).
154.33; 167.16. 19F NMR (CDCl3) δ 16.80 (dAB, J FF ) 162.2
2
Met h yl
N-(b en zyloxyca r b on yl)-2-(ch lor od iflu or o-
Hz, 1F); 18.35 (dAB,
2J FF ) 162.2 Hz, 1F). MS (EI, m/z) 317
m eth yl)a la n in a te (20a ): yield 73%; oil. 1H NMR (CDCl3) δ
(M+ - H2O); 243 (11); 215 (13); 57 (100).
1.91 (s, 3H); 3.82 (s, 3H); 5.11 (s, 2H); 5.62 (s, 1H); 7.36 (s,
5H). 13C NMR (CDCl3) δ 19.16; 54.15; 67.20 (t, J CF ) 24.9
2
Meth yl 2-[N-(ben zyloxyca r bon yl)a m in o]-3-br om o-3,3-
d iflu or o-2-h yd r oxyp r op ion a te (14b): yield 93%; mp 99-
100 °C. 1H NMR (CDCl3) δ 3.91 (s, 3H); 5.11 (dAB, 2J HH ) 12.1
Hz); 67.80; 129.21 (t, 1J CF ) 302.5 Hz); 128.71; 128.85; 129.07;
136.28; 154.80; 168.01. 19F NMR (CDCl3) δ 15.67 (dAB, 2J FF
)
2
2
Hz, 1H); 5.16 (dAB, J HH ) 12.1 Hz, 1H); 5.52 (br s, 1H); 5.97
164.2 Hz, 1F); 16.74 (dAB, J FF ) 164.2 Hz, 1F).
(br s, 1H); 7.37 (m, 5H). 13C NMR (CDCl3) δ 54.92; 68.07; 84.00
(t, 2J CF ) 28.6 Hz); 126.21 (t, 1J CF ) 303.1 Hz); 128.48; 128.60;
Meth yl N-(ben zyloxyca r bon yl)-2-(ch lor od iflu or om eth -
yl)p h en yla la n in a te (20b): yield 92%; mp 51-52 °C. 1H
NMR (CDCl3) δ 3.04 (d, 2J HH ) 13.8 Hz, 1H); 3.84 (s, 3H); 4.29
128.72; 135.07; 154.72; 166.65. 19F NMR (CDCl3) δ 16.77 (dAB
,
2
2J FF ) 135.5 Hz, 1F); 18.22 (dAB, J FF ) 135.5 Hz, 1F).
2
2
(d, J HH ) 13.8 Hz, 1H); 5.05 (dAB, J HH ) 12.2 Hz, 1H); 5.26
2
Meth yl 2-[N-(ben zyloxyca r bon yl)a m in o]-3-iod o-3,3-d i-
flu or o-2-h yd r oxyp r op ion a te (15): yield 64%; mp 91-92 °C.
1H NMR (CDCl3) δ 3.91 (s, 3H); 5.11 (dAB, 2J HH ) 12.1 Hz, 1H);
(dAB, J HH ) 12.2 Hz, 1H); 6.01 (s, 1H); 7.08 (m, 5H); 7.19 (m,
5H). 13C NMR (CDCl3) δ 33.40; 54.38; 67.47; 72.21 (t, J CF
)
2
25.6 Hz); 128.03; 128.85; 128.99; 129.03; 129.05; 129.09; 130.41
2
(t, 1J CF ) 314.4 Hz); 134.07; 135.22; 154.51; 167.58. 19F NMR
5.16 (dAB, J HH ) 12.1 Hz, 1H); 5.47 (s, 1H); 5.83 (s, 1H); 7.38
(m, 5H). 13C NMR (CDCl3) δ 55.39; 68.55; 85.05 (t, 2J CF ) 22.5
Hz); 102.10 (t, 1J CF ) 321.7 Hz); 128.75; 128.97; 129.17; 135.53;
2
2
(CDCl3) δ 19.00 (dAB, J FF ) 160.1 Hz, 1F); 20.48 (dAB, J FF
)
160.1 Hz, 1F).
2
154.83; 165.93. 19F NMR (CDCl3) δ 16.77 (dAB, J FF ) 135.5
Met h yl N-(ter t-b u t yloxyca r b on yl)-2-(ch lor od iflu or o-
m eth yl)p h en yla la n in a te (20c): yield 80%; mp 62-63 °C. 1H
NMR (CDCl3) δ 1.49 (s, 9H); 3.46 (d, 2J HH ) 12.6 Hz, 1H); 3.86
2
Hz, 1F); 18.22 (dAB, J FF ) 135.5 Hz, 1F).
Gen er a l P r oced u r e for th e P r ep a r a tion of Im in es 16-
18. Trifluoroacetic anhydride (4.5 mL, 31.9 mmol) was added
at 0 °C to a vigorously stirred solution of a hemiamidal (29
mmol) in dry ether (100 mL) over a period of 0.5 h. After
stirring for 0.5 h, pyridine (5.2 mL, 64 mmol) was added slowly.
Stirring was continued for additional 2 h. The reaction
mixture was cooled to -20 °C and the precipitated pyridinium
trifluoroacetate was filtered off under an inert gas atmosphere.
The filtrate was concentrated in vacuo and triturated with 50
mL of hexanes (4 × 50 mL) to dissolve the imine and separate
it from residual pyridinium trifluoroacetate. The combined
hexane solutions were evaporated. Frequently, the purity of
the products is sufficient for further transformations. If
necessary, the imines 16-18 can easily be purified by distil-
lation in vacuo.
2
(s, 3H); 4.27 (d, J HH ) 12.6 Hz, 1H); 5.72 (s, 1H); 7.22 (m,
5H). 13C NMR (CDCl3) δ 28.72; 33.79; 54.23; 72.07 (t, J CF
)
2
1
25.1 Hz); 80.97; 127.96; 128.87; 129.32 (t, J CF ) 307.4 Hz);
130.53, 134.45; 153.82, 167.80. 19F NMR (CDCl3) δ 19.29 (dAB
,
2J FF ) 160.0 Hz, 1F); 20.63 (dAB, J FF ) 160.0 Hz, 1F).
2
Met h yl
N-(b en zyloxyca r b on yl)-2-(b r om od iflu or o-
m eth yl)a la n in a te (21a ): yield 78%; bp 120-122 °C/0.05 Torr.
1H NMR (CDCl3) δ 1.90 (s, 3H); 3.82 (s, 3H); 5.12 (s, 2H); 5.68
(br s, 1H); 7.37 (m, 5H). 13C NMR (CDCl3) δ 18.95; 53.82; 67.51
2
1
(t, J CF ) 31 Hz); 67.81; 123.10 (t, J CF ) 317 Hz); 128.26;
128.42; 128.62; 135.80; 154.21; 167.40. 19F NMR (CDCl3) δ
2
2
22.21 (dAB, J FF ) 161.0 Hz, 1F); 23.82 (dAB, J FF ) 161.0 Hz,
1F).
Meth yl N-(ben zyloxyca r bon yl)-2-(br om od iflu or om eth -
yl)p h en yla la n in a te (21b): yield 68%; mp 61-63 °C. 1H
NMR (CDCl3) δ 3.44 (d, 2J HH ) 13.6 Hz, 1H); 3.85 (s, 3H); 4.29
Meth yl 2-[N-(ter t-bu tyloxyca r bon yl)im in o]-3,3-d iflu o-
r op r op ion a te (16a ): yield 88%, bp 68-70 °C/0.25 Torr. 1H
2
NMR (CDCl3) δ 1.49 (s, 9H); 3.85 (s, 3H); 6.35 (t, J HF ) 53.3
2
2
(d, J HH ) 13.6 Hz, 1H); 5.07 (dAB, J HH ) 12.2 Hz, 1H); 5.27
Hz). 13C NMR (CDCl3) δ 28.22; 53.91; 85.14; 110.20 (t, 1J CF
)
2
(dAB, J HH ) 12.2 Hz, 1H); 6.03 (s, 1H); 7.19 (m, 5H); 7.40 (m,
247.1 Hz); 150.92 (t, 2J CF ) 25.9 Hz); 157.26, 158.39. 19F NMR
5H). 13C NMR (CDCl3) δ 33.26; 54.48; 67.55; 73.54 (t, J CF
)
2
2
(CDCl3) δ -46.33 (d, J HF ) 53.3 Hz, 2F).
1
22.8 Hz); 123.41 (t, J CF ) 321.8 Hz); 128.06; 128.62; 128.83;
129.00; 129.08; 130.37; 134.08; 136.67; 154.42; 167.75. 19F
Meth yl 2-[N-(ter t-bu tyloxyca r bon yl)im in o]-3-ch lor o-
3,3-d iflu or op r op ion a te (17a ): yield 92%; bp 60-62 °C/0.25
Torr. 1H NMR (CDCl3) δ 1.58 (s, 9H); 3.96 (s, 3H). 13C NMR
2
NMR (CDCl3) δ 25.40 (dAB, J FF ) 156.5 Hz, 1F); 27.56 (dAB
,
2J FF ) 156.5 Hz, 1F). MS (EI, m/z) 441 (M+); 350 (5); 211 (13);
1
(CDCl3) δ 28.21; 54.21; 85.68; 121.07 (t, J CF ) 294.6 Hz);
151 (12); 91 (100).
2
149.55 (t, J CF ) 30.4 Hz); 156.46; 157.37. 19F NMR (CDCl3)
Meth yl N-(ben zyloxyca r bon yl)-2-(br om od iflu or om eth -
δ 18.45 (s, 2F).
yl)leu cin a te (21c): yield 63%; oil. 1H NMR (CDCl3) δ 0.79
2
2
Meth yl 2-[N-(ben zyloxyca r bon yl)im in o]-3-ch lor o-3,3-
d iflu or op r op ion a te (17b): yield 98%; oil. 1H NMR (CDCl3)
δ 3.78 (s, 3H); 5.34 (s, 2H); 7.42 (m, 5H). 13C NMR (CDCl3) δ
(d, J HH ) 6.6 Hz, 3H); 0.95 (d, J HH ) 6.1 Hz, 3H); 1.63 (m,
1H); 2.03 (m, 1H); 2.93 (m, 1H); 3.87 (s, 3H); 5.12 (m, 2H);
6.18 (s, 1H); 7.38 (m, 5H). 13C NMR (CDCl3) δ 21.87; 23.55;
1
2
54.03; 69.59; 120.48 (t, J CF ) 295.2 Hz); 128.77; 129.02;
24.54; 35.76; 53.92; 67.01; 71.54 (t, J CF ) 22.9 Hz); 123.69 (t,
2
129.11; 134.43; 155.78 (t, J CF ) 31.3 Hz); 155.78; 158.51. 19F
1J CF ) 322.3 Hz); 128.16; 128.29; 128.58; 136.17; 153.56;
168.67. 19F NMR (CDCl3) 24.00 (dAB, 2J FF ) 155 Hz, 1F); 26.49
NMR (CDCl3) δ 18.23 (s, 2F).
2
Meth yl 3-br om o-2-[N-(ter t-bu tyloxyca r bon yl)im in o]-
3,3-d iflu or op r op ion a te (18a ): yield 94%; bp 78-80 °C/0.25
Torr. 1H NMR (CDCl3) δ 1.58 (s, 9H); 3.95 (s, 3H). 13C NMR
(dAB, J FF ) 155 Hz, 1F).
Met h yl
N-(b en zyloxyca r b on yl)-2-(b r om od iflu or o-
m eth yl)-2-p h en ylglycin a te (21d ): yield 62%; mp 85-86 °C.
1
1H NMR (CDCl3) δ 3.78 (s, 3H); 5.11 (s, 2H); 6.06 (s, 1H); 7.40
(CDCl3) δ 28.21; 54.20; 85.61; 112.90 (t, J CF ) 309.2 Hz);
2
150.20 (t, J CF ) 27.7 Hz); 156.39; 157.28. 19F NMR (CDCl3)
(m, 10H). 13C NMR (CDCl3) δ 54.26; 68.11; 72.72 (t, J CF
)
2
1
δ 21.67 (s, 2F).
21.7 Hz); 124.21 (t, J CF ) 321.0 Hz); 127.64, 128.80; 128.90;
Meth yl 2-[N-(ben zyloxyca r bon yl)im in o]-3-br om o-3,3-
d iflu or op r op ion a te (18b): yield 95%; oil. 1H NMR (CDCl3)
δ 3.78 (s, 3H); 5.34 (s, 2H); 7.40 (m, 5H). 13C NMR (CDCl3) δ
129.07; 129.12; 129.90; 133.37; 136.22; 154.55; 166.72. 19F
2
NMR (CDCl3) δ 26.42 (dAB, J FF ) 159.0 Hz, 1F); 28.16 (dAB
,
2J FF ) 159.0 Hz, 1F). MS (EI, m/z) 427 (M+); 254 (5); 199 (7);
1
52.99; 68.53; 111.28 (t, J CF ) 308.9 Hz); 127.72; 127.97;
108 (20); 91 (100).

R-Difluoromethyl-Substituted R-Hydroxy and R-Amino Acids
J . Org. Chem., Vol. 61, No. 21, 1996 7527
2
2
Met h yl-2-[N-(ben zyloxyca r b on yl)a m in o]-2-(b r om od i-
flu or om eth yl)-4-p en ten oa te (21e): yield 61%; oil. 1H NMR
(CDCl3) δ 2.95 (m, 1H); 3.73 (m, 1H); 3.87 (s, 3H); 5.09 (m,
1H); 5.14 (m, 2H); 5.16 (m, 1H); 5.55 (m, 1H); 6.03 (s, 1H);
7.38 (m, 5H). 13C NMR (CDCl3) δ 32.74; 54.12; 67.12; 71.64
(t, 2J CF ) 23.0 Hz); 120.90; 122.76 (t, 1J CF ) 320.4 Hz); 128.16;
128.31; 128.59; 130.09; 136.05; 153.61; 167.40. 19F NMR
) 276.0 Hz, J HF ) 55.7 Hz, 1F); -50.17 (ddABX, J FF ) 276.0
2
Hz, J HF ) 55.7 Hz, 1F).
Met h yl N-(b en zyloxyca r b on yl)-2-(d iflu or om et h yl)-
p h en ylglycin a te (19d ): yield 60%; mp 83-85 °C. 1H NMR
2
(CDCl3) δ 3.81 (s, 3H); 5.11 (s, 2H); 5.93 (s, 1H); 6.72 (t, J HF
) 56.0 Hz, 1H); 7.39 (m, 10H). 13C NMR (CDCl3) δ 53.90; 67.63
2
1
(t, J CF ) 22.6 Hz); 67.95; 113.42 (t, J CF ) 249.2 Hz); 127.21;
2
2
(CDCl3) δ 24.21 (dAB, J FF ) 157.3 Hz, 1F); 26.16 (dAB, J FF
157.3 Hz, 1F).
)
128.65; 128.86; 129.07; 129.36; 129.73; 135.57; 136.27; 155.52;
169.30. 19F NMR (CDCl3) δ -50.44 (ddABX, J FF ) 281.2 Hz,
2
2J HF ) 56.0 Hz, 1F); -47.99 (ddABX
,
2J FF ) 281.2 Hz, J HF
)
2
Met h yl N-(ter t-b u t yloxyca r b on yl)-2-(b r om od iflu or o-
m eth yl)a la n in a te (21f): yield 80%; mp 52-53 °C. 1H NMR
(CDCl3) δ 1.45 (s, 9H); 1.85 (s, 3H); 3.83 (s, 3H); 5.29 (s, 1H).
56.0 Hz, 1F). MS (EI, m/z) 349 (M+); 254 (5); 180 (7); 108 (22);
91 (100).
2
13C NMR (CDCl3) δ 20.03; 28.62; 53.95; 67.88 (t, J CF ) 22.2
Gen er a l P r oced u r e for th e Sa p on ifica tion of Am in o
Ester s 19a -c, 20a ,b, a n d 21a . A solution of an R-amino acid
ester (2 mmol) in ether (20 mL) was stirred with a 1:1 mixture
of 1 N aqueous KOH/MeOH (15 mL) for 12 h (method A) or
with 10 mmol of LiOH‚H2O in MeOH/water (3:1) for 15 h at
5 °C (method B). The reaction mixture was concentrated to
approximately 7 mL, acidified with 2 N HCl to pH 1, and
extracted twice with ether (25 mL). The combined organic
layer was washed with brine, dried over MgSO4, and concen-
trated. The residue was purified by recrystallization from
CHCl3/hexanes.
1
Hz); 81.51; 123.92 (t, J CF ) 316.6 Hz); 154.08; 167.93. 19F
2
NMR (CDCl3) δ 22.51 (dAB, J FF ) 162.0 Hz, 1F); 23.89 (dAB
,
2J FF ) 162.0 Hz, 1F).
Met h yl N-(ter t-b u t yloxyca r b on yl)-2-(b r om od iflu or o-
m eth yl)p h en yla la n in a te (21g): yield 86%; mp 66-67 °C. 1H
NMR (CDCl3) δ 1.49 (s, 9H); 3.44 (d, 2J HH ) 12.0 Hz, 1H); 3.86
2
(s, 3H); 4.28 (d, J HH ) 12.0 Hz, 1H); 5.74 (s, 1H); 7.22 (m,
2
5H). 13C NMR (CDCl3) δ 28.29; 33.01; 53.84; 72.88 (t, J CF
)
1
22.6 Hz); 80.52; 123.28 (t, J CF ) 322.3 Hz); 127.51; 128.42;
130.03; 134.01; 153.30; 167.45. 19F NMR (CDCl3) δ 25.79 (dAB
,
2J FF ) 155.1 Hz, 1F); 27.81 (dAB, J FF ) 155.1 Hz, 1F).
2
N-(Ben zyloxycar bon yl)-2-(diflu or om eth yl)alan in e (22a)
(method A): yield 97%; mp 79-81 °C. 1H NMR (CDCl3) δ 1.65
Red u ction of Br om o Der iva tive 14a w ith n -Bu 3Sn H.
Freshly prepared n-Bu3SnH (13.6 g, 46.7 mmol) was added to
a stirred solution of 14a (12.0 g, 36 mmol) in THF (100 mL)
over a period of 10 min. During the addition, the reaction
warmed up to 50 °C. The mixture was heated to reflux for
1 h to complete the reaction. THF was removed under reduced
pressure. The residue was redissolved in ether (80 mL) and
treated with a saturated aqueous solution of KF (50 mL) for
0.5 h. Precipitated n-Bu3SnF was filtered off. The aqueous
layer was separated and extracted with ether (2 × 20 mL).
The combined organic layer was dried over MgSO4 and
evaporated. The residue was recrystallized from CHCl3/
hexanes to give 5.6 g of pure 12a . The mother liquor was
evaporated and purified by flash chromatography (SiO2,
EtOAc/hexanes) to give further 2.0 g (total yield 75%) of 12a ,
whose spectral and analytical data were identical with those
reported above. Compound 12b was obtained in the same
manner from bromo derivative 14b in 83% yield.
Red u ction of Br om o Der iva tive 21a w ith n -Bu 3Sn H.
Freshly prepared n-Bu3SnH (0.65 g, 2.2 mmol) was added to
a stirred solution of 21a (0.62 g, 1.7 mmol) in THF (10 mL).
The mixture was heated to reflux until TLC analysis indicated
completion, and workup was done as above. Purification by
flash chromatography (SiO2, EtOAc/hexanes) gave 0.27 g (66%)
of pure 19a . Compounds 19b-d were obtained in the same
manner from bromo derivatives 21b-d , respectively.
2
(s, 3H); 5.13 (s, 2H); 5.50 (br s, 1H); 6.25 (t, J HF ) 56.0 Hz,
1H); 7.36 (m, 5H); 7.63 (br s, 1 H). 13C NMR (CDCl3) δ 17.23;
2
1
61.47 (t, J CF ) 23.1 Hz); 68.29; 113.56 (t, J CF ) 249.0 Hz);
128.68; 128.96; 129.12; 135.88; 155.93; 174.18. 19F NMR
(CDCl3) δ -53.16 (ddABX, 2J FF ) 282.1 Hz, 2J HF ) 56.0 Hz, 1F);
2
2
-51.24 (ddABX, J FF ) 282.1 Hz, J HF ) 56.0 Hz, 1F).
N -(Be n zyloxyca r b on yl)-2-(d iflu or om e t h yl)p h e n yl-
a la n in e (22b) (method A): yield 91%; mp 100-101 °C. 1H
2
2
NMR (CDCl3) δ 3.31 (d, J HH ) 13.8 Hz, 1H); 3.73 (d, J HH
)
)
13.8 Hz, 1H); 5.05 (dAB, 2J HH ) 12.2 Hz, 1H); 5.23 (dAB, 2J HH
2
12.2 Hz, 1H); 5.65 (s, 1H); 6.45 (t, J HF ) 55.2 Hz, 1H); 7.20
(m, 10H); 9.21 (br s, 1H). 13C NMR (CDCl3) δ 35.06; 66.20 (t,
2J CF ) 22.1 Hz); 67.37; 113.26 (t, J CF ) 251.3 Hz); 127.65;
1
128.33; 128.47; 128.53; 128.64; 130.00; 133.12; 135.83; 155.00;
171.21. 19F NMR (CDCl3) δ -50.37 (m, 2F).
N-(Ben zyloxycar bon yl)-2-(diflu or om eth yl)leu cin e (22c)
(method A): yield 80%; mp 127-129 °C.1H NMR (CDCl3) δ
3
3
0.87 (d, J HH ) 5.9 Hz, 3H); 0.93 (d, J HH ) 5.9 Hz, 3H); 1.70
(m, 1H); 1.90 (m, 1H); 2.45 (m, 1H); 5.12 (s, 2H); 5.90 (s, 1H);
6.27 (t, J HF ) 56.2 Hz, 1H); 7.05 (br s, 1H); 7.36 (m, 5H). 13C
2
NMR (CDCl3) δ 22.97; 24.03; 24.42; 37.72; 65.23 (t, 2J CF ) 20.5
Hz); 67.82; 113.99 (t, 1J CF ) 252.6 Hz); 128.63; 128.91; 129.10;
136.19; 155.18; 173.74. 19F NMR (CDCl3) δ -51.36 (ddABX, 2J FF
2
2
) 278.2 Hz, J HF ) 56.2 Hz, 1F); -50.29 (ddABX, J FF ) 278.2
2
Hz, J HF ) 56.2 Hz, 1F).
N -(Be n zyloxyca r b on yl)-2-(ch lor od iflu or om e t h yl)-
a la n in e (23a ) (method A): yield 75%; mp 75-77 °C. 1H NMR
Met h yl N-(b en zyloxyca r b on yl)-2-(d iflu or om et h yl)-
a la n in a te (19a ): yield 56%; oil. 1H NMR (CDCl3) δ 1.62 (s,
3H); 3.80 (s, 3H); 5.10 (s, 2H); 5.46 (s, 1H); 6.22 (t, 2J HF ) 56.0
Hz, 1H); 7.36 (s, 5H). 13C NMR (CDCl3) δ 17.30; 53.68; 61.64
(CDCl3) δ 1.92 (s, 3H); 4.26 (br s, 1H); 5.13 (s, 2H); 5.71 (s,
1H); 7.37 (s, 5H). 13C NMR (CD3OD) δ 20.85; 67.31 (t, J CF
)
2
24.2 Hz); 68.18; 129.71; 129.43; 129.82; 131.56 (t, 1J CF ) 302.5);
2
1
138.10; 157.05; 170.38. 19F NMR (CDCl3) δ 15.90 (dAB, 2J FF
)
(t, J CF ) 22.5 Hz); 67.76; 113.82 (t, J CF ) 248.9 Hz); 128.61;
128.84; 129.07; 136.27; 155.31; 170.23. 19F NMR (CDCl3) δ
2
165.2 Hz, 1F); 16.86 (dAB, J FF ) 165.2 Hz, 1F).
2
2
-52.98 (ddABX, J FF ) 279.0 Hz, J HF ) 56.0 Hz, 1F); -50.95
N-(Ben zyloxyca r bon yl)-2-(ch lor od iflu or om eth yl)p h e-
n yla la n in e (23b) (method A; reaction time 72 h): yield 93%;
2
2
(ddABX, J FF ) 279.0 Hz, J HF ) 56.0 Hz, 1F).
mp 138-139 °C. 1H NMR (CDCl3) δ 3.52 (d, J HH ) 14.4 Hz,
2
Met h yl N-(b en zyloxyca r b on yl)-2-(d iflu or om et h yl)-
p h en yla la n in a te (19b): yield 84%; mp 59-60 °C. 1H NMR
2
2
1H); 4.24 (d, J HH ) 14.4 Hz, 1H); 5.08 (dAB, J HH ) 12.1 Hz,
1H); 5.24 (dAB, 2J HH ) 12.1 Hz, 1H); 5.99 (s, 1H); 7.17 (m, 5H);
7.40 (m, 5H); 8.74 (s, 1H). 13C NMR (CDCl3) δ 33.37; 67.50;
71.56 (t, 2J CF ) 24.3 Hz); 127.67; 128.41; 128.42 (t, 1J CF ) 307.7
Hz); 128.48; 128.58; 128.64; 130.08; 133.11; 135.80; 154.32;
2
2
(CDCl3) δ 3.29 (d, J HH ) 13.3 Hz, 1H); 3.74 (d, J HH ) 13.3
Hz, 1H); 3.86 (s, 3H); 5.06 (dAB, 2J HH ) 12.4 Hz, 1H); 5.23 (dAB
,
2J HH ) 12.4 Hz, 1H); 5.74 (s, 1H); 6.44 (t, 2J HF ) 55.3 Hz, 1H);
7.10 (m, 5H); 7.44 (m, 5H). 13C NMR (CDCl3) δ 35.41; 53.87;
2
1
169.80. 19F NMR (CDCl3) δ 19.24 (dAB, J FF ) 160.8 Hz, 1F);
2
66.85 (t, J CF ) 22.1 Hz); 67.55; 113.87 (t, J CF ) 250.9 Hz);
127.97; 128.61; 128.77; 128.56; 129.09; 130.34; 134.10; 136.58;
155.17; 168.69. 19F NMR (CDCl3) δ -50.20 (m, 2F). MS (EI,
m/z) 363 (M+); 272 (10); 212 (23); 51 (10); 91 (100).
2
20.56 (dAB, J FF ) 160.8 Hz, 1F).
N -(Be n zyloxyca r b on yl)-2-(b r om od iflu or om e t h yl)-
a la n in e (24a ) (method B): yield 61%; oil. 1H NMR (CDCl3)
δ 1.89 (s, 3H); 5.12 (s, 2H); 5.88 (br s, 1H); 7.35 (s, 5H); 8.63
Meth yl N-(ben zyloxyca r bon yl)-2-(d iflu or om eth yl)leu -
(s, 1H). 13C NMR (CDCl3) δ 19.69; 67.87 (t, J CF ) 22.0 Hz);
2
3
cin a te (19c): yield 61%; oil. 1H NMR (CDCl3) δ 0.80 (d, J HH
1
2
68.25; 123.62 (t, J CF ) 317.1 Hz); 128.78; 129.00; 129.15;
) 6.6 Hz, 3H); 0.92 (d, J HH ) 6.6 Hz, 3H); 1.61 (m, 1H); 1.85
135.89; 155.34; 170.86. 19F NMR (CDCl3) δ 22.71 (dAB, 2J FF
)
(m, 1H); 2.48 (m, 1H); 3.85 (s, 3H); 5.10 (s, 2H); 6.00 (s, 1H);
2
2
6.23 (t, J HF ) 55.7 Hz); 7.36 (m, 5H). 13C NMR (CDCl3) δ
162.6 Hz, 1F); 24.01 (dAB, J FF ) 162.6 Hz, 1F).
2
22.71; 24.11; 24.29; 37.63; 53.82; 65.31 (t, J CF ) 21.3 Hz);
Hyd r ogen a tion . A mixture of 22a (0.135 g, 0.5 mmol) and
10% Pd/C (0.4 g) in methanol (25 mL) was stirred for 14 h
under an atmosphere of hydrogen. The catalyst was filtered
1
67.45; 114.13 (t, J CF ) 251.5 Hz); 128.55; 128.77; 129.05;
136.53; 154.85; 170.10. 19F NMR (CDCl3) δ -51.28 (ddABX, 2J FF

7528 J . Org. Chem., Vol. 61, No. 21, 1996
Osipov et al.
off, and the filtrate was concentrated under reduced pressure.
The remaining solid was triturated with ether to give 72 mg
of 25a . Purification was performed by sublimation.
adjusted to pH 1 with 2 N HCl and evaporated to give 0.4 g of
28a ‚xLiCl. 1H NMR (D2O) δ 1.79 (s, 3H). 13C NMR (D2O) δ
2
1
18.65; 68.25 (t, J FC ) 21.8 Hz); 121.48 (t, J FC ) 311.4 Hz);
2-(Diflu or om eth yl)a la n in e (25a ): yield 99%; mp 256 °C
169.68. 19F NMR (D2O) δ 21.43 (dAB
,
2J FF ) 171.7 Hz, 1F);
2
2
dec. 1H NMR (D2O) δ 1.46 (s, 3H); 6.17 (t, J HF ) 53.0 Hz,
22.31 (dAB, J FF ) 171.7 Hz, 1F).
1H). 13C NMR (D2O) δ 16.65; 61.73 (t, 2J CF ) 18.3 Hz); 114.92
2-(Br om od iflu or om et h yl)p h en yla la n in e h yd r och lo-
1
(t, J CF ) 245.2 Hz); 170.49. 19F NMR (D2O) δ -55.44 (ddABX
,
)
r id e (28b) was obtained in analogy to 28a as a mixture with
2J FF ) 279.1 Hz, J HF ) 53.0 Hz, 1F); -49.18 (ddABX
279.1 Hz, J HF ) 53.0 Hz, 1F).
,
2J FF
LiCl. 1H NMR (D2O) δ 3.07 (d, J ΗΗ ) 16.6 Hz, 1H); 3.58 (d,
2
2
2
2J HH ) 16.6 Hz, 1H); 7.25 (m, 5H).13C NMR (D2O) δ 36.45;
2
1
Compounds 25b,c, 26a ,b were obtained in the same manner
starting from Cbz-derivatives 22b,c, 24a , respectively.
2-(Diflu or om eth yl)p h en yla la n in e (25b): yield 89%; mp
72.47 (t, J FC ) 22.1 Hz); 119.75 (t, J FC ) 312.4 Hz); 128.83;
129.51; 130.53; 131.34; 167.06. 19F NMR (D2O) δ 22.49 (dAB
,
2J FF ) 177.0 Hz, 1F); 23.46 (dAB, J FF ) 177.0 Hz, 1F).
2
2
220 °C. 1H NMR (D2O) δ 2.97 (d, J HH ) 14.3 Hz, 1H); 3.36
Met h yl 2-(d iflu or om et h yl)a la n in a t e h yd r ob r om id e
(29‚HBr) was obtained from 21a by hydrogenation (procedure
see 25a ) and purified by recrystallization from CHCl3: yield
77%; mp 124-126 °C. 1H NMR (acetone-d6) δ 1.07 (s, 3H);
2
2
(d, J HH ) 14.3 Hz, 1H); 6.29 (t, J HF ) 53.0 Hz, 1H); 7.23 (m,
5H). 13C NMR (D2O) δ 36.65; 66.87 (t, 2J CF ) 19.2 Hz); 115.37
1
(t, J CF ) 249.5 Hz); 128.42; 129.25; 130.22; 132.10; 169.23.
19F NMR (D2O) δ -54.32 (ddABX, J FF ) 280.3 Hz, J HF ) 53.0
3.95 (s, 3H); 6.71 (t, J HF ) 54.1 Hz, 1H). 13C NMR (acetone-
2
2
2
2
2
1
Hz, 1F); -49.34 (ddABX
,
2J FF ) 280 Hz, J HF ) 53.0 Hz, 1F).
d6) δ 16.72; 54.55; 62.58 (t, J CF ) 23.7 Hz); 114.48 (t, J CF )
2-(Diflu or om eth yl)leu cin e (25c): yield 95%; mp 228-229
250.2 Hz); 166.96. 19F NMR (acetone-d6) δ -47.40 (ddABX, 2J FF
2 2
°C. 1H NMR (D2O) δ 0.75 (d, 3J HH ) 6.4 Hz, 3H); 0.79 (d, 3J HH
) 286.8 Hz, J HF ) 54.1 Hz, 1F); -45.72 (ddABX, J FF ) 286.8
) 6.4 Hz, 3H); 1.65 (m, 3H); 6.06 (t, J HF ) 53.8 Hz, 1H). 13C
Hz, J HF ) 54.1 Hz, 1F).
2
2
2
NMR (D2O) δ 21.69; 23.10; 23.69; 39.01; 65.60 (t, J CF ) 20.7
Syn t h esis of Met h yl N-(ter t-Bu t yloxyca r b on yl)-L-
p h en yla la n yl-a m bo-r-(d iflu or om eth yl)a la n in a te (30a ,b).
A solution of Boc-Phe-OH (0.26 g, 1.0 mmol) in dry THF (5
mL) was cooled to -15 °C and neutralized with N-methylmor-
pholine (0.10 g, 1.0 mmol). Isobutyl chloroformate (0.16 g, 1.2
mmol) was added. After 10 min at -15 °C, a mixture of methyl
R-(difluoromethyl)alaninate hydrobromide (0.23 g, 1.0 mmol)
and N-methylmorpholine (0.10 g, 1.0 mmol) in DMF (5 mL)
was added. The reaction mixture was stirred for 4 h at
-15 °C and then warmed up to rt. The salts were removed
by filtration and washed with THF. The solution was con-
centrated under reduced pressure and the residue partitioned
between water (20 mL) and ethyl acetate (30 mL). The organic
layer was washed with 0.5 N KHSO4 (20 mL), water (20 mL),
1 N NaHCO3 (20 mL), and water (20 mL) and dried over
MgSO4. Evaporation of the solvent afforded 0.24 g (59%) of
30 as a mixture of diastereomers. The diastereomers were
separated by flash chromatography (SiO2, EtOAc/hexanes).
Hz); 115.66 (t, J CF ) 246.1 Hz); 170.20. 19F NMR (D2O) δ
1
2
2
-55.13 (ddABX, J FF ) 276.1 Hz, J HF ) 53.8 Hz, 1F); -49.15
2
2
(ddABX, J FF ) 276.1 Hz, J HF ) 53.8 Hz, 1F).
2-(Ch lor od iflu or om eth yl)a la n in e (26a ): yield 71%; mp
> 250 °C. 1H NMR (D2O) δ 1.56 (s, 3H). 13C NMR (D2O) δ
2
1
20.15; 69.66 (t, J CF ) 25.1 Hz); 130.00 (t, J CF ) 297.8 Hz);
171.16. 19F NMR (D2O) δ 15.55 (dAB
,
2J FF ) 170.9 Hz, 1F);
2
16.53 (dAB, J FF ) 170.9 Hz, 1F).
2-(Ch lor odiflu or om eth yl)ph en ylalan in e (26b): yield 93%;
mp 188-189 °C. 1H NMR (D2O) δ 3.25 (d, J HH ) 14.3 Hz,
2
1H); 3.76 (d, 2J HH ) 14.3 Hz, 1H); 7.41 (m, 5H). 13C NMR (D2O)
δ 36.21; 71.39 (t, 2J CF ) 22.9 Hz ); 127.13 (t, 1J CF ) 298.7 Hz);
128.68; 129.39; 130.43; 131.42; 166.99. 19F NMR (D2O) δ 17.33
(s, 2F).
P r oced u r e for Dir ect Hyd r olysis of 19e, 20c. A solution
of Boc-protected amino acid ester 19e (0.5 g, 1.5 mmol) in 6 N
HCl (15 mL) was heated at 80 °C for 10 h. The reaction
mixture was evaporated under reduced pressure, dissolved in
EtOH (10 mL), and stirred with an excess of propylene oxide
for 10 h. The volatiles were removed under reduced pressure
to give 0.27 g (83%) of amino acid 25b. Purification was
performed by sublimation (100 °C, 0.1 Torr). Compound 26b
was obtained in the same manner starting from Boc-derivative
20c in 75% yield. NMR spectra of the compounds 25b and
26b were identical with those reported above.
Diastereomer 1: mp 158-158.5 °C; [R]21 ) -36.4 (c 1,
D
CH2Cl2). 1H NMR (CDCl3) δ 1.39 (s, 9H); 1.46 (s, 3H); 3.01 (d,
2J HH ) 7.0 Hz, 2H); 3.75 (s, 3H); 4.33 (m, 1H); 5.10 (br s, 1H);
2
6.19 (t, J HF ) 55.9 Hz, 1H); 6.72 (br s, 1H); 7.10-7.35 (m,
5H). 13C NMR (CDCl3) δ 16.19; 28.22; 37.78; 53.04; 55.46;
2
2
60.82 (t, J CF ) 23.8 Hz); 80.60; 112.84 (t, J CF ) 248.0 Hz);
127.08; 128.72; 129.39; 136.40; 155.58; 169.35; 171.38. 19F
2
2
NMR (CDCl3) δ -53.27 (ddABX, J FF ) 281.7 Hz, J HF ) 55.9
2
2
Meth yl 2-(br om od iflu or om eth yl)a la n in a te (27a ). A 10
mL volume of TFA was added in one portion to a solution of
21f (1.0 g, 2.86 mmol) in CH2Cl2 (20 mL). The reaction
mixture was stirred for 15 min at 25 °C, volatiles were
evaporated and the residue was dissolved in ether and washed
with NaHCO3. The aqueous solution was extracted with ether
(2 × 20 mL), and the combined organic layer was dried over
MgSO4, filtered, and concentrated to afford 0.57 g (80%) of 27a
as an oil. 1H NMR (CDCl3) δ 1.75 (s, 3H); 2.02 (s, 2H); 3.91
(s, 3H). 13C NMR (CDCl3) δ 20.93; 53.32; 66.89 (t, 2J CF ) 21.7
Hz, 1F); -50.41 (ddABX, J FF ) 281.7 Hz, J HF ) 55.9 Hz, 1F).
Diastereomer 2: mp 120-121 °C; [R]21 ) -57.1 (c 1,
D
CH2Cl2). 1H NMR (CDCl3) δ 1.39 (s, 9H); 1.48 (s, 3H); 2.90-
2
3.05 (m, 2H); 3.75 (s, 3H); 4.38 (m, 1H); 5.18 (d, J HH ) 8.0
2
Hz, 1H); 6.21 (t, J HF ) 55.9 Hz, 1H); 6.92 (br s, 1H); 7.10-
7.35 (m, 5H). 13C NMR (CDCl3) δ 16.52; 28.66; 38.32; 53.49;
2
2
56.00; 61.34 (t, J CF ) 23.8 Hz); 81.05; 113.25 (t, J CF ) 248.0
Hz); 127.50; 129.12; 129.79; 136.79; 156.06; 169.96; 171.98. 19
F
2
2
NMR (CDCl3) δ -53.12 (ddABX, J FF ) 281.7 Hz, J HF ) 55.9
Hz, 1F); -50.13 (ddABX, J FF ) 281.7 Hz, J HF ) 55.9 Hz, 1F).
2
2
1
Hz); 125.94 (t, J CF ) 316.3 Hz); 169.70. 19F NMR (CDCl3) δ
2
2
Ack n ow led gm en t. We thank Volkswagen-Stiftung
and Deutsche Forschungsgemeinschaft (Innovationskol-
leg “Chemisches Signal und biologische Antwort” for
financial support and Hoechst AG, Frankfurt/Main, for
a generous supply with chemicals. Special thanks to
Mrs. J . Ortwein for NMR experiments.
20.46 (dAB, J FF ) 157.2 Hz, 1F); 21.89 (dAB, J FF ) 157.2 Hz,
1F).
Meth yl 2-(br om odiflu or om eth yl)ph en ylalan in ate (27b)
(procedure see 27a ): yield 85%; oil. 1H NMR (CDCl3) δ 1.91
2
2
(s, 2H); 2.97 (d, J HH ) 13.0 Hz, 1H); 3.51 (d, J HH ) 13.0 Hz,
1H); 3.78 (s, 3H); 7.22 (m, 5H). 13C NMR (CDCl3) δ 39.28;
2
1
53.67; 71.66 (t, J FC ) 20.9 Hz); 125.74 (t, J FC ) 318.8 Hz);
128.22; 129.17; 130.76; 134.21; 169.79. 19F NMR (CDCl3) δ
Su ppor tin g In for m ation Available: Microanalytical data
(1 page). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
2
2
21.47 (dAB, J FF ) 156.1 Hz, 1F); 23.96 (dAB, J FF ) 156.1 Hz,
1F).
2-(Br om od iflu or om eth yl)a la n in e Hyd r och lor id e (28a ).
A 0.3 g (1.3 mmol) amount of 27a was treated with 7.0 mmol
of LiOH‚H2O in MeOH/water (3:1) for 72 h at 10 °C. Methanol
was evaporated under reduced pressure. The residue was
J O9608331