First synthesis of totally orthogonal protected α-(trifluoromethyl)- and α-(difluoromethyl)arginines

Article abstract of DOI:10.1021/jo0009043

The first synthesis of a series of totally orthogonal protected racemic α-(trifluoromethyl)- and α-(difluoromethyl)arginines is described. The key steps of the synthesis are the mild guanidinylation procedure and the selective hydrogenation of a CC triple bond in the presence of a Cbz-group.

Full text of DOI:10.1021/jo0009043

130
J . Org. Chem. 2001, 66, 130-133
F ir st Syn th esis of Tota lly Or th ogon a l P r otected
r-(Tr iflu or om eth yl)- a n d r-(Diflu or om eth yl)a r gin in es
Maurizio Moroni,*,† Beate Koksch,† Sergey N. Osipov,‡ Marcello Crucianelli,§
Massimo Frigerio,§ Pierfrancesco Bravo,§ and Klaus Burger†
Institute of Organic Chemistry, University of Leipzig, J ohannisallee 29, D-04103 Leipzig, Germany,
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str.28,
GSP-1, V-334, Rus-117813 Moscow, Russia, and CNR, Department of Chemistry of the Politecnico,
via Mancinelli 7, I-20131 Milan, Italy
moroni@organik.chemie.uni-leipzig.de
Received J une 14, 2000
The first synthesis of a series of totally orthogonal protected racemic R-(trifluoromethyl)- and
R-(difluoromethyl)arginines is described. The key steps of the synthesis are the mild guanidinylation
procedure and the selective hydrogenation of a CC triple bond in the presence of a Cbz-group.
In tr od u ction
fundamental therapeutic interest. Incorporation of R-Tfm-
or R-Dfm-amino acids into key positions of biological
active peptides increases metabolic stability, stabilizes
secondary structures, improves lipophilicity,6 and pro-
vides an useful NMR label for secondary structure
elucidation.
The two known routes to R-fluoroalkylated arginines
are low yielding and provide the modified arginine either
already incorporated into peptides or partially unpro-
tected.7,8
The amino acid arginine exhibits several potentially
beneficial properties.1,2 However, the effect of arginine
on tumor growth is a controversial issue; the vast
majority of collected data from animal experiments
provides favorable results with natural killer cells giving
increased cytolytic activity, enhanced macrophage tumor
cytotoxicity, stimulation of the protein synthesis in the
host but not in the tumor, and a decrease in tumor
growth.3 In contrast, little is known on the effect of
arginine on human tumors.4
Arginine is a constituent of biological relevant peptides,
like RGD peptides, well-known as an universal binding
and recognition sequence involved in cell-cell and cell-
matrix interactions, inducing blood platelet aggregation,
tumor cell adhesion, and osteoporosis.5
In this paper, we wish to disclose a convenient,
preparatively simple three step synthesis of fully or-
thogonal protected R-Tfm- and R-Dfm-arginines starting
from readily available partially fluorinated N-acylimines.
Resu lts a n d Discu ssion
Replacement of the R-H by trifluoromethyl (Tfm) or
difluoromethyl (Dfm) groups in natural amino acids has
received considerable attention recently, because several
â-fluoro-containing R-amino acids are biologically active,
exhibiting antibacterial, antihypertensive, cancerostatic,
and cytotoxic effects. R-Dfm-ornithine seems to be a
superior drug for treatment of the “sleeping sickness”.
â-Fluoro-substituted amino acids in general are potent
irreversible inhibitors of pyridoxal phosphate-depending
enzymes, like decarboxylases, transaminases, and race-
mases. Regulation of enzymatic decarboxylation reactions
of amino acids by using highly specific inhibitors is of
To obtain orthogonally protected R-Tfm- and R-Dfm-
arginines 7a -d , we tested two synthetic routes. First,
we introduced a side chain of five-carbon atoms having
a CC double bond in the terminal position via Grignard
addition into Boc- and Cbz-protected imines of trifluoro-
and difluoropyruvate (1 f 2), respectively6,8,9 (Scheme 1).
Then the CC double bond was oxidized with KMnO4/H2-
SO4, and the carboxylic acids obtained (3a ,c) were
activated with pentafluorophenol (PfpOH) and trans-
formed into amides 4a ,c on treatment with NH4OH/DCC.
Finally, 4a ,c were converted into the R-Tfm- and R-Dfm-
ornithines 5a ,c via a Hofmann-type degradation with 1,1-
bis(trifluoroacetoxy)iodobenzene (TIB). Since compounds
5a ,c are only stable as salts or as δ-N-protected deriva-
tives, they are readily transformed under the basic
conditions of the guanidinylation step into δ-lactams
* To whom correspondence should be addressed. Phone: (Germany)
+49-341-9736555. Fax: (Germany) +49-341-9736599.
† University of Leipzig.
‡ Russian Academy of Sciences.
§ Polytechnic of Milan.
(1) Barbul, A. J . Parent. Enteral. Nutr. 1986, 10, 227-238.
(2) Barbul, A. Nutrition 1990, 6, 53-58.
(6) (a) Koksch, B.; Sewald, N.; J akubke, H.-D.; Burger, K. Synthesis
and Incorporation of R-Trifluoromethyl-Substituted Amino Acids into
Peptides. In Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J . R., Welch, J . T., Eds; American Chemical Society:
Washington, DC, 1996; pp 42-58. (b) Hollweck, W.; Sewald, N.; Michel,
T.; Burger, K. Liebigs Ann. Chem. 1997, 2549-2551.
(3) (a) Oka, T.; Ohwada, K.; Nagao, M.; Kitazato, K. J . Parent.
Enteral Nutr. 1993, 17, 375-383. (b) Oka, T.; Ohwada, K.; Nagao, M.;
Kitazato, K.; Kyshino, Y. J . Parent. Enteral Nutr. 1994, 18, 491-496.
(c) Reynolds, J . V.; Daly, J . M.; Zhang, S. Surgery 1988, 104, 142-
151. (d) Reynolds, J . V.; Daly, J . M.; Shou, J .; Sigal, R.; Ziegler, M. M.;
Naji, A. Ann. Surg. 1990, 211, 202-210.
(4) Imoberdorf, R. Support Care Cancer 1997, 5, 381-386.
(5) (a) McDowell, R. S.; Gadek, T. R. J . Am. Chem. Soc. 1992, 114,
9245-9253. (b) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee,
L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.;
Thorsett, E. D.; Tischler, M.; Webb, R. R., II; Venuti, M. C. J . Am.
Chem. Soc. 1994, 116, 5077-5083.
(7) Bey, P.; Vevert, J .-P.; Van Dorsselaer, V.; Kolb, M. J . Org. Chem.
1979, 44, 2732-2742.
(8) Dal Pozzo, A.; Muzi, L.; Moroni, M.; Rondanin, R.; de Castiglione,
R.; Bravo, P.; Zanda, M. Tetrahedron 1998, 54, 6019-6028.
(9) (a) Burger, K.; Gaa, K. Chemiker-Zeitung 1990, 114, 101-104.
(b) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel, T.; Kolomiets, A.
F.; Fokin, A. V.; Burger, K. J . Org. Chem. 1996, 61, 7521-7528.
10.1021/jo0009043 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/13/2000

Synthesis of R-(Trifluoromethyl)- and R-(Difluoromethyl)arginines
J . Org. Chem., Vol. 66, No. 1, 2001 131
Sch em e 1
Sch em e 2
nylated at room temperature at pH 8 without the risk of
the unwanted lactamization.
A particularly critical step is the catalytic hydrogena-
tion. If hydrogenation of the CC triple bond of compounds
8 is performed in the presence of Pd/C before guanidi-
nylation, a spontaneous lactamization accompanied by
a simultaneous loss of the Cbz-group yielding 2-piperi-
done derivatives in high yield is observed. Ring opening
of the 2-piperidone system and simultaneous cleavage of
the Boc-group can be achieved under acid conditions and
affords the unprotected ornithines.11 They are less stable,
and guanidinylation experiments gave low yields.
Therefore, it is advantageous to perform the guanidi-
nylation step before hydrogenation of the CC triple bond
and to use a modified catalyst. When the commercial
catalyst (5% Pd/C) was treated with a 10-fold excess (vs
Pd metal of Pd/C) of ethylenediamine as described by
Hirota et al.,12 a catalyst was obtained (Pd(en)/C),
perfectly suitable for a selective hydrogenation of the CC
triple bond in the presence of the Cbz-group. Hydrogena-
tion of compounds 9a -d gave the fully orthogonal
protected R-Tfm- and R-Dfm-arginines 7a -d in about
95% yield.
Con clu sion
(6a ,c, 60%). The arginine derivatives 7a ,c could only be
isolated as byproducts (35%).
We developed a new preparatively simple high-yielding
three-step synthesis of racemic orthogonally protected
R-Tfm- and R-Dfm-arginines 7a -d . They are stable
compounds and can be stored for a long time. Scale-up
of the synthesis can be easily achieved, thus making
these compounds available in sufficient quantities to
study their chemical and biological properties; in fact,
any biological data are available so far on protected
arginines of this type. They can be selectively deprotected
In a second approach, again we started from Boc- and
Cbz-protected imines of trifluoro- and difluoropyruvates
1a -d . The side chain of arginine consisting of three
carbon atoms was introduced together with the δ-amino
group via addition of readily available lithium N,N-bis-
(trimethylsilyl)aminomethyl acetylide,10 which gave the
corresponding adducts 8a-d in quantitative yield (Scheme
2). The presence of the triple bond prevents ring closure.
The δ-amino group is deblocked on workup and guanidi-
(11) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Burger, K. Tetrahe-
dron Lett. 1997, 345965-5966.
(12) Sajiki, H.; Hattori, K.; Hirota, K. J . Org. Chem. 1998, 63, 7990-
7992.
(10) Cappella, L.; Degl’Innocenti, A.; Reginato, G.; Ricci, A.; Tadei,
M. J . Org. Chem. 1989, 54, 1473-1476.

132 J . Org. Chem., Vol. 66, No. 1, 2001
Moroni et al.
Cbz)-S-methylisothiourea (1.742 g and 2.150 g, respectively)
were added. The reaction was allowed to stay at room
temperature overnight, and then the solvent was evaporated
in vacuo and the crude product purified by flash chromatog-
raphy (eluent: n-hexane/ethyl acetate 80:20) to obtain pure
9.
to provide useful building blocks for peptide modification
and combinatorial chemistry.
Exp er im en ta l Section
Gen er a l Rem a r k s. 1H NMR, 13C NMR, and 19F NMR
1
9a : 3.272 g, 5.6 mmol, yield 93%; H NMR (CDCl3) δ 1.48
spectra were recorded at 360, 90, and 339 MHz, respectively.
(s, 18H), 3.85 (s, 3H), 4.31 (d, 2J ) 26 Hz, 2H), 5.12 (s 2H),
1
TMS was used as internal standard for H NMR and 13C NMR
2
5.84 (s, 1H), 7.34 (s, 5H), 8.47 (t, J ) 26 Hz, 1H), 11.42 (br s,
spectra. 19F NMR spectra were recorded 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,
University of Leipzig. All compounds have been fully charac-
terized and gave correct microanalytical data ((0.4%). All
reactions were routinely monitored by 19F NMR spectroscopy
or TLC. Analytical TLC was performed using Merck silica gel
60F-254 plates (0.25 mm). For flash chromatography, silica
gel 60 (30-60 µm) was used with hexane/ethyl acetate or
CHCl3/MeOH as eluent system. Organic solvents were dried
and distilled prior to use.
1H); 19F NMR (CDCl3) δ 2.64 (s, 3F); MS (EI, 70 eV) m/z 586
(M+, 3), 384 (100), 369 (11), 234 (37). Anal. Calcd for
C
26H33F3N4O8: C, 53.23; H, 5.67; N, 9.55. Found: C, 53.31; H,
5.65; N, 9.51.
1
9b: 3.425 g, 5.5 mmol, yield 92%; H NMR (CDCl3) δ 1.44
2
2
(s, 9H), 3.84 (s, 3H), 4.32 (d, J ) 26.2 Hz, 2H), 5.20 (d, J )
2
12.4 Hz, 4H), 5.83 (s, 1H), 7.38 (s, 10H), 8.50 (t, J ) 26.2 Hz,
1H), 11.85 (br s, 1H); 19F NMR (CDCl3) δ 2.60 (s, 3F); MS (EI,
70 eV) m/z 620 (M+, 6), 519 (100), 504 (18), 234 (12). Anal.
Calcd for C29H31F3N4O8: C, 56.13; H, 5.04; N, 9.03. Found: C,
56.25; H, 5.02; N, 8.99.
9c: 2.743 g, 4.45 mmol, yield 89%; 1H NMR (CDCl3) δ 1.30
(t, J ) 7.2 Hz, 3H), 1.43 (s, 9H), 3.48 (d, 2J ) 26.2 Hz, 2H),
All reagents used were purchased from commercial suppli-
ers and used without further purification. Boc- and Cbz-imines
1a -d , lithium N,N-bis(trimethylsilyl)aminomethyl acetylide,
and Pd(en)/C were synthesized by published methods.9-12
Spectroscopical data of the lactams 6a ,c and of other products
from Scheme 1 are available as Supporting Information.
Gen er a l P r oced u r e for P r ep a r a tion of 8a -d . To a
cooled solution (-78 °C) of 8 mmol of lithium N,N-bis-
(trimethylsilyl)aminomethyl acetylide (1.643 g) in situ pre-
pared10 in 20 mL of dry THF, under argon atmosphere were
added 6.7 mmol of imine 1 (a , 1.937 g; b, 1.709 g; c, 1.683 g;
d , 1.817 g) dissolved in 5 mL of dry THF. The temperature of
reaction mixture was allowed to increase slowly to room
temperature; afterward the solution was stirred overnight. The
reaction was quenched at 0 °C with 80 mL of 1 M HCl and
then adjusted to pH ) 8 by addition of a 5% aqueous solution
of NaHCO3; finally, diethyl ether was added. The organic layer
was separated and the aqueous phase extracted with diethyl
ether (3 × 20 mL). The collected organic layer was dried over
anhydrous MgSO4 and the solvent evaporated under reduced
pressure. The purity of products 8 was sufficient for further
reactions.
2
4.31 (q, J ) 7.2 Hz, 3H), 5.19 (dAB, J ) 12.0 Hz, 4H), 5.51 (br
s, 1H), 6.21 (t, 2J HF ) 56.0 Hz, 1H), 7.39 (s, 10H), 8.50 (t, 2J )
26.2 Hz, 1H), 11.80 (br s, 1H); 19F NMR (CDCl3) δ -50.48
2
2
(ddABX, J FF ) 276.1 Hz, J FH ) 56.0 Hz, 1F), -47.90 (ddABX
,
2J FF ) 276.1 Hz, J FH ) 56.0 Hz, 1F); MS (EI, 70 eV) m/z 616
2
(M+, 12), 587 (56), 486 (100), 351 (18). Anal. Calcd for
C
30H34F2N4O8: C, 58.43; H, 5.56; N, 9.09. Found: C, 58.66; H,
5.53; N, 9.05.
1
9d : 3.138 g, 5.5 mmol, yield 92%; H NMR (CDCl3) δ 1.50
2
(s, 9H), 1.52 (s, 9H), 3.71 (d, J ) 25.9 Hz, 2H), 3.92 (s, 3H),
5.11 (dAB, 2J ) 12.4 Hz, 2H), 5.53 (br s, 1H), 6.19 (t, 2J HF)58.4
2
Hz, 1H), 7.36 (s, 5H), 8.49 (t, J ) 25.9 Hz, 1H), 10.98 (br s,
1H). 19F NMR (CDCl3) δ -48.91 (ddABX, J FF ) 296.1 Hz, J FH
2
2
2
) 58.4 Hz, 1F), -50.50 (ddABX
,
2J FF ) 296.1 Hz, J FH ) 58.4
Hz, 1F); MS (EI, 70 eV) m/z 568 (M+, 7), 336 (61), 316 (100),
134 (21). Anal. Calcd for C26H34F2N4O8: C, 54.92; H, 6.03; N,
9.85. Found: C, 55.04; H, 6.01; N, 9.81.
Gen er a l P r oced u r e for Syn th esis of P r otected r-Tfm -
a n d r-Dfm -a r gin in es (7a -d ). To a solution of 4 mmol of 9
(a , 2.346 g; b, 2.482 g; c, 2.466 g; d , 2.274 g) in 8 mL of MeOH
was added a catalytic amount of freshly prepared Pd(en)/C
(10% of the weight of the substrate) under an atmosphere of
argon with stirring. Then the solution was stirred overnight
under an atmosphere of hydrogen. The solid material was
filtered off, and the organic layer was evaporated to dryness
in vacuo. The crude product was purified by flash chromatog-
raphy (eluent: CHCl3/MeOH) to provide the pure fluorinated
arginine derivatives 7.
1
8a : 2.191 g, 6.4 mmol, yield 95%; H NMR (acetone-d6) δ
2
2.91 (br s, 2H), 3.81 (s, 3H), 4.11 (s, 2H), 5.16 (dAB, J ) 12.0
Hz, 2H), 7.41 (m, 5H), 8.09 (br s, 1H). 19F NMR (acetone-d6) δ
3.32 (s, 3F); MS (EI, 70 eV) m/z 344 (M+, 10), 329 (100), 367
(12), 238 (30), 169 (23). Anal. Calcd for C15H15F3N2O4: C, 52.33;
H, 4.39; N, 8.14. Found: C, 52.47; H, 4.38; N, 8.11.
1
7a : 2.267 g, 3.8 mmol, yield 96%; 1H NMR (CDCl3) δ 1.35-
1.53 (m, 1H), 1.44 (s, 9H), 1.45 (s, 9H), 1.54-172 (m, 1H), 2.12-
2.27 (m, 1H), 2.35-2.40 (m, 2H), 2.75-2.91 (m, 1H), 3.87 (s,
8b: 1.891 g, 6.1 mmol, yield 91%; H NMR (CDCl3) δ 1.44
(s, 9H), 1.62 (br s, 2H), 3.48 (s, 2H), 3.90 (s, 3H) 5.49 (br s,
1H); 19F NMR (CDCl3) δ 2.48 (s, 3F); MS (EI, 70 eV) m/z 310
(M+, 7), 253 (100), 238 (27), 169 (11). Anal. Calcd for
2
3H), 5.11 (s, 2H), 5.91 (s, 1H), 7.36 (s, 5H), 8.47 (t, J ) 26.1
Hz, 1H), 11.42 (br s, 1H); 19F NMR (CDCl3) δ 3.07 (s, 3F); MS
(EI, 70 eV) m/z 590 (M+, 6), 476 (100), 461 (77), 370 (8). Anal.
Calcd for C26H37F3N4O8: C, 52.88; H, 6.32; N, 9.48. Found: C,
53.07; H, 6.30; N, 9.44.
C
12H17F3N2O4: C, 46.45; H, 5.52; N, 9.03. Found: C, 46.53; H,
5.50; N, 8.99.
1
8c: 1.908 g, 6.2 mmol, yield 93%; H NMR (CDCl3) δ 1.30
(t, J ) 7.2 Hz, 3H), 1.43 (s, 9H), 1.62 (br s, 2H), 3.48 (s, 2H),
2
7b: 2.398 g, 3.8 mmol, yield 96%; 1H NMR (CDCl3) δ 1.36-
1.54 (m, 1H), 1.45 (s, 9H), 1.55-174 (m, 1H), 2.12-2.27 (m,
1H), 2.33-2.40 (m, 2H), 2.75-2.91 (m, 1H), 3.86 (s, 3H), 5.19
4.31 (q, J ) 7.2 Hz, 2H), 5.51 (br s, 1H), 6.21 (t, J HF ) 56.0
Hz, 1H). 19F NMR (CDCl3) δ -50.48 (ddABX, J FF ) 276.2 Hz,
2
2J FH ) 56.0 Hz, 1F), -47.90 (ddABX
,
2J FF ) 276.2 Hz, J FH
)
2
56.0 Hz, 1F); MS (EI, 70 eV) m/z 306 (M+, 8), 249 (100), 220
(44), 169 (30). Anal. Calcd for C13H20F2N2O4: C, 50.98; H, 6.58;
N, 9.14. Found: C, 51.17; H, 6.56; N, 9.10.
2
2
(dAB, J ) 13 Hz, 4H), 5.90 (s, 1H), 7.38 (s, 10H), 8.47 (t, J )
25.2 Hz, 1H), 11.50 (br s, 1H); 19F NMR (CDCl3) δ 3.02 (s, 3F);
MS (EI, 70 eV) m/z 624 (M+, 5), 567 (70), 475 (100), 384 (25),
370 (10). Anal. Calcd for C29H35F3N4O8: C, 55.77; H, 5.65; N,
8.97. Found: C, 55.89; H, 5.64; N, 8.93.
1
8d : 2.033 g, 6.2 mmol, yield 93%; H NMR (CDCl3) δ 2.00
2
(br s, 2H), 3.70 (s, 2H), 3.90 (s, 3H), 5.11 (dAB, J ) 12.4 Hz,
2
1
2H) 5.51 (br s, 1H), 6.20 (t, J HF ) 55.1 Hz, 1H), 7.36 (s, 5H);
7c: 2.358 g, 3.8 mmol, yield 95%; H NMR (CDCl3) δ 1.29
19F NMR (CDCl3) δ -48.00 (ddABX
,
2J FF ) 276.3 Hz, J FH
)
2
(t, 2J ) 7.0 Hz, 3H), 1.44-1.53 (m, 1H), 1.50 (s, 9H), 1.60-
1.67 (m, 1H), 2.05-2.12 (m, 1H), 2.43-2.51 (m, 1H), 3.44-
3.52 (m, 1H), 3.55-3.63 (m, 1H), 4.01 (q, 2J ) 7.0 Hz, 2H),
2
2
55.1 Hz, 1F), -50.50 (ddABX, J FF ) 276.3 Hz, J FH ) 55.1 Hz,
1F); MS (EI, 70 eV) m/z 326 (M+, 11), 311 (100), 268 (17), 133
(42). Anal. Calcd for C15H16F2N2O4: C, 55.21; H, 4.94; N, 8.58.
Found: C, 55.28; H, 4.92; N, 8.54.
2
5.20 (s, 4H), 6.03 (br s, 1H), 6.21 (t, J HF ) 57.7 Hz, 1H), 7.40
(s, 10H), 8.69 (br s, 1H), 11.49 (br s, 1H). 19F NMR (CDCl3) δ
2
2
Gen er a l P r oced u r e for P r ep a r a tion of 9a -d . To a
solution of 6 mmol of 8 (a , 2.065 g; b, 1.861 g; c, 1.531 g; d ,
1.957 g) in 30 mL of THF was added 6 mmol of N,N′-di(Boc or
-51.37 (ddABX, J FF ) 279.4 Hz, J FH ) 57.7 Hz, 1F), -52.67
2 2
(ddABX, J FF ) 279.4 Hz, J FH ) 57.7 Hz, 1F); MS (EI, 70 eV)
m/z 620 (M+, 8), 563 (100), 534 (68), 352 (28). Anal. Calcd for

Synthesis of R-(Trifluoromethyl)- and R-(Difluoromethyl)arginines
J . Org. Chem., Vol. 66, No. 1, 2001 133
C30H38F2N4O8: C, 58.06; H, 6.17; N, 9.03. Found: C, 58.18; H,
6.15; N, 8.99.
ches Signal und biologische Antwort”), the European
Community (TMR: “Fluorine as a Unique Tool for
Engineering Molecular Properties”), MURST COFIN
(Rome), and the Vigoni Program 1999 for financial
support of this research.
7d : 2.130 g, 3.7 mmol, yield 93%; 1H NMR (CDCl3) δ 1.45-
1.55 (m, 1H), 1.50 (s, 9H), 1.51 (s, 9H), 1.60-1.67 (m, 1H),
2.00-2.10 (m, 1H), 2.41-2.51 (m, 1H), 3.44-3.52 (m, 1H),
3.55-3.63 (m, 1H), 3.91 (s, 3H), 5.1 (br s, 2H), 6.03 (br s, 1H),
6.21 (t, 2J HF ) 55.7 Hz, 1H), 7.34 (s, 5H), 8.69 (br s, 1H), 11.49
(br s, 1H). 19F NMR (CDCl3) δ -50.27 (ddABX, 2J FF ) 279.4 Hz,
2
2J FH ) 55.7 Hz, 1F), -51.57 (ddABX
,
2J FF ) 279.4 Hz, J FH
)
Su p p or tin g In for m a tion Ava ila ble: Spectral data of the
lactams 6a ,c and of the products 4-5 (a ,c) from Scheme 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
55.7 Hz, 1F); MS (EI, 70 eV) m/z 572 (M+, 5), 458 (100), 367
(22), 352 (30). Anal. Calcd for C26H38F2N4O8: C, 54.54; H, 6.69;
N, 9.78. Found: C, 54.68; H, 6.67; N, 9.74.
Ack n ow led gm en t. We are grateful to Deutsche
Forschungsgemeinschaft (Innovationskolleg: “Chemis-
J O0009043