The catalytic Mannich reaction of 1,1-difluoro-2-trialkyl(aryl)silyl-2- trimethyl-silyloxyethenes: Preparation of β-amino acid derivatives

Article abstract of DOI:10.1021/jo050953l

Catalytic Mannich reactions of 1,1-difluoro-2-trialkyl(aryl)-silyl-2- trimethylsilyloxyethenes (3) with a variety of sulfonylimines were utilized for the preparation of α,α-difluoro-β-amino acid derivatives (7). The influence of the Lewis acid on the reac

Full text of DOI:10.1021/jo050953l

The Catalytic Mannich Reaction of
1,1-Difluoro-2-trialkyl(aryl)silyl-2-trimethyl-
silyloxyethenes: Preparation of â-Amino
Acid Derivatives
FIGURE 1. Two strategies for the formation of fluorinated
â-amino acids.
Woo Jin Chung, Masaaki Omote, and John T. Welch*
Department of Chemistry, University at Albany,
State University of New York, 1400 Washington Avenue,
Albany, New York 12222
tetrahedral transition state mimics may competitively
inhibit serine proteases such as elastase.7
In general, two strategically different approaches to
the incorporation of fluorine in â-amino acids have been
employed, either the R-carbon can be fluorinated (1) or
â-fluoroalkyl groups can be introduced (2) (Figure 1).
The combination of fluorinated â-amino acid moieties
with naturally occurring pharmacophores has led to the
construction of new molecules with enhanced medicinal
properties.8
jwelch@uamail.albany.edu
Received May 12, 2005
The synthesis of â-fluoroalkyl-â-amino acids (1) is
readily tractable via several general approaches.9 On the
other hand, reports of methods for the formation of R,R-
difluoro-â-amino acids (2) are still limited,10 even though
R,R-difluoro-â-amino acids (2) are precursors of fluori-
nated â-lactam antibiotics.11 Ethyl bromodifluoroacetate
has been utilized in Reformatsky-type reactions with
N-tert-butylsulfinimines,10e-g resin-bound imines,10d or
oxazolidines10c as well as in the formation of difluoro-
ketenesilylacetals10a,b that can be utilized in Lewis acid
Catalytic Mannich reactions of 1,1-difluoro-2-trialkyl(aryl)-
silyl-2-trimethylsilyloxyethenes (3) with a variety of sulfo-
nylimines were utilized for the preparation of R,R-difluoro-
â-amino acid derivatives (7). The influence of the Lewis acid
on the reaction was examined. Methods for the conversion
of R,R-difluoroacylsilanes to R,R-difluorocarboxylic acids were
also explored.
â-Amino acids and derivatives, although less abundant
than their R-analogues, have proven utility as building
blocks for molecules with applications in pharmaceutical
and material science.1 â-Amino-R-hydroxy acids are of
considerable importance as crucial functional groups in
taxol2 and bestatin.3 â-Peptides, comprised of â-amino
acids, have found utility in the investigation of the
structure and stabilization of proteins. On substitution
of R-amino acids, â-amino acids only very modestly
perturb the backbone steric demands yet still form amide
bonds capable of participating in intramolecular hydro-
gen bonds.4 This utility has led to significant efforts
toward the synthesis of â-amino acids.5
(6) (a) Fluorine-Containing Amino Acids. Synthesis and Properties;
Kosher, V. P., Soloshonok, V. A., Eds.; John Wiley and Sons Ltd.:
Chichester, UK, 1994. (b) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American Chemical
Society: Washington, DC, 1996. (c) Enantiocontrolled Synthesis of
Fluoro-Organic Compounds: Stereochemical Challenges and Biome-
dicinal Targets; Soloshonok, V. A., Ed.; Wiley: Chichester, UK, 1999.
(7) (a) Rauber, P.; Angliker, H.; Walker, B.; Shaw, E. Biochem. J.
1986, 239, 633. (b) Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25,
3760. (c) Schirlin, D.; Baltzer, S.; Altenburger, J. M.; Tarnus, C.; Remy,
J. M. Tetrahedron 1996, 52, 305.
(8) (a) Uoto, K.; Ohsuki, S.; Takenoshita, H.; Ishiyama, T.; Iimura,
S.; Hirota, Y.; Mitsui, I.; Terasawa, H.; Soga, T. Chem. Pharm. Bull.
1997, 45, 1793. (b) Kuznetsova, L.; Ungureanu, I. M.; Pepe, A.; Zanardi,
I.; Wu, X.; Ojima, I. J. Fluorine Chem. 2004, 125, 487-500.
(9) (a) Soloshonok, V. A.; Kirilenko, A. G.; Fokina, N. A.; Shishkina,
I. P.; Galushko, S. V.; Kukhar, V. P.; Svedas, V. K.; Kozolova, E. V.
Tetrahedron: Asymmetry 1994, 5, 1119. (b) Soloshonok, V. A.; Kirilenko,
A. G.; Fokina, N. A.; Kukhar, V. P.; Galushko, S. V.; Svedas, V. K.;
Resnati, G. Tetrahedron: Asymmetry 1994, 5, 1225. (c) Soloshonok, V.
A.; Kukhar, V. P. Tetrahedron 1996, 52, 6953. (d) Soloshonok, V. A.;
Ono, T.; Soloshonok, I. V. J. Org. Chem. 1997, 62, 7538. (e) Soloshonok,
V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas, V. K. J. Org. Chem.
1998, 63, 1878. (f) Volonterio, A.; Bravo, P.; Zanda, M. Org. Lett. 2000,
2, 1827. (g) Volonterio, A.; Bravo, P.; Moussier, N.; Zanda, M.
Tetrahedron Lett. 2000, 41, 6517. (h) Fustero, S.; Salavert, E.; Pina,
B.; Ramirez de Arellano, C.; Asensio, A. Tetrahedron 2001, 57, 6475.
(i) Pesenti, C.; Arnone, A.; Bellosta, S.; Bravo, P.; Canavesi, M.; Corradi,
E.; Frigerio, M.; Meille, S. V.; Monetti, M.; Panzeri, W.; Viani, F.;
Venturini, R.; Zanda, M. Tetrahedron 2001, 57, 6511.
Selective introduction of fluorine is a well-established
strategy for the modulation of the pharmacological
properties of biologically active molecules.6 For example,
peptidomimetics in which the scissile amide bond in
peptides is replaced by a gem-difluoroketone group often
exhibit improved activities relative to nonfluorinated
compounds. Fluorination at the R-position can promote
formation of stable hydrates and hemiacetals, which as
* To whom correspondence should be addressed. Phone: +1-518-
442-4455. Fax: +1-518-442-3462.
(1) (a) Enantioselective Synthesis of â-Amino acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 101, 3219.
(10) (a) Taguchi, T.; Kitarawa, O.; Suda, Y.; Ohkawa, S.; Hashimoto,
A.; Iitaka, Y.; Kobayashi, Y. Tetrahedron Lett. 1988, 29, 5291. (b) Iseki,
K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto, S.; Kobayashi,
Y. Tetrahedron 1997, 53, 10271. (c) Marcotte, S.; Pannecoucke, X.;
Feasson, C.; Quirion, J.-C. J. Org. Chem. 1999, 64, 8461. (d) Vidal, A.;
Nefzi, A.; Houghten, R. A. J. Org. Chem. 2001, 66, 8268. (e) Soloshonok,
V. A.; Ohkura, H.; Sorochinsky, A.; Voloshin, N.; Markovsky, A.; Belik,
M.; Yamazaki, T. Tetrahedron Lett. 2002, 43, 5445. (f) Staas, D. D.;
Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R. G. J. Org. Chem.
2002, 67, 8276. (g) Sorochinsky, A.; Voloshin, N.; Markovsky, A.; Belik,
M.; Yasuda, N.; Uekusa, H.; Ono, T.; Berbasov, D. O.; Soloshonok, V.
A. J. Org. Chem. 2003, 68, 7448.
(2) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
1994, 33, 15.
(3) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.; Takeuchi, T.
J. Antibiot. 1976, 29, 97.
(4) (a) Iverson, B. L. Nature 1997, 385, 113. (b) Seebach, D.;
Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997, 2015. (c)
Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (d) Gademann, K.;
Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999, 6. 605. (e)
Degrado, W. F.; Schneider, J. P.; Hamuro, Y. J. Peptide Res. 1999, 54,
206.
(5) (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117.
(11) (a) van de Steen, F. H.; van Koten, G. Tetrahedron 1991, 47,
7503. (b) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447.
10.1021/jo050953l CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/19/2005
7784
J. Org. Chem. 2005, 70, 7784-7787

SCHEME 1. Synthesis of Fluorinated Acylsilanes (4-5) and
1,1-Difluoro-2-trialkyl(aryl)silyl-2-trimethylsilyloxyethenes (3)
TABLE 1. Influence of Lewis Acid
promoted aldol condensations where the aldol product
can be subjected to Mitsunobu amination. New fluori-
nated building blocks based on relatively inexpensive and
readily available trifluoroethanol have been developed
and the relevant transformations of those materials into
R,R-difluoro-â-amino acids are described below.
We recently reported the synthesis of novel 1,1-
difluoro-2-trialkyl(aryl)silyl-2-trimethylsilyloxyethenes (3)
and fluorinated acylsilanes (4, 5) (Scheme 1).12 Acylsi-
lanes are versatile synthetic intermediates easy to trans-
form to carboxylic acids under basic oxidizing condi-
tions,13 or to aldehydes under basic conditions14a-c or by
catalytic reduction.14d 1,1-Difluoro-2-trialkyl(aryl)silyl-2-
trimethylsilyloxyethenes (3) are synthetic equivalents of
R,R-difluoroacylsilanes, and therefore synthetic precur-
sors to R,R-difluorocarbonyl compounds such as alde-
hydes, carboxylic acids, and derivatives.
The Mannich reaction, a classic and attractive method
for the synthesis of â-amino acid derivatives involving
convergent assembly of two units of similar complexity
by carbon-carbon bond formation,15 can be effected under
asymmetric and catalytic protocols as well.16 In our initial
experiments, the condensation of 1,1-difluoro-2-trialkyl-
(aryl)silyl-2-trimethylsilyloxyethenes (3) and N-benzy-
lidineaniline was investigated employing an assortment
of Lewis acids and reaction conditions. In contrast to
reactions with aldehydes,17 recovery of 3 without the
formation of adduct was observed in every case, while
the reaction of 3 with a variety of aldehydes had been
shown previously to form aldol adducts in good to
moderate yields. It was apparent that the simple aldi-
mines did not possess sufficient reactivity and required
activation to react with 3. This is in contrast to the
entry
Lewis acid
stoichiometry
yield of 7aa (%)
1
2
TiCl4
125 mol %
125 mol %
125 mol %
10 mol %
125 mol %
10 mol %
125 mol %
10 mol %
125 mol %
125 mol %
10 mol %
10 mol %
10 mol %
125 mol %
125 mol %
125 mol %
125 mol %
125 mol %
41
44
69
66
79
91
88
87
82
85
76
72
72
0
BF3‚OEt2
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Y(OTf)3
Y(OTf)3
TES-OTf
TMS-OTf
TMS-OTf
Triflic acid
Cu(OTf)2
La(OTf)3
ZnI2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
0
SnCl2
0
FeI2
0
SmI2
0
a isolated yield; characterized by 1H, 13C, 19F, and elemental
analysis.
reported observations that silyl difluoro enamines react
well with imines.18
Easy to prepare and proven effective, various aromatic
and aliphatic N-sulfonylaldimines were synthesized by
known methods.19 It is worth noting that aliphatic
aldehyde-derived p-toluenesulfonylimines were formed in
high yields, as solids more easily manipulated and
convenient to handle than the corresponding benzene-
sulfonylimines.
Reaction of N-benzylidinebenzenesulfonamide (6a, 1
equiv) and 1,1-difluoro-2-trimethylsilyl-2-trimethyloxy-
ethene (3a, 1.25 equiv) with TiCl4 (1.25 equiv) in CH2Cl2
at room temperature resulted in the formation of adduct
in 41% yield. A series of Lewis acids were scrutinized to
optimize reaction conditions (Table 1). Reactions with
strong Lewis acids such as TiCl4 and BF3‚OEt2 (entries
1 and 2) gave the sulfonylamine adduct in low yields.
Apparently adventitious hydrolysis of the reactant 6a to
an aldehyde subsequently led to aldol condensation. This
competing process was suppressed by employing mild
Lewis acids.
(12) (a) Chung, W. J.; Welch, J. T. J. Fluorine Chem. 2004, 125,
543-658. (b) Higashiya, S.; Chung, W. J.; Lim, D. S.; Ngo, S. C.;
Toscano, P. J.; Welch, J. T. J. Org. Chem. 2004 69, 6323-6328.
(13) Ricci, A.; Degl’Innocenti, A. Synthesis 1989, 647. (b) Bulman
Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147.
(14) (a) Brook, A. G.; Vanderson, T. J.; Limburg, W. Can. J. Chem.
1978, 56, 2758. (b) Schinzer, D.; Heathcock, C. H. Tetrahedron Lett.
1981, 22, 1881. (c) Pietropaolo, D.; Fiorenza, M.; Rucci, A.; Todder, M.
J. Organomet. Chem. 1980, 197, 7. (d) Cirillo, P. F.; Panek, J. S.
Tetrahedron Lett. 1991, 32. 457.
(15) (a) Tramontini, M.; Angiolini, L. Mannich-Bases, Chemistry and
Uses; CRC, Boca Raton, FL, 1994. (b) Tramontini, M.; Angiolini, L.
Tetrahedron 1990, 46, 1791. (c) Tramontini, M. Synthesis 1973, 703.
(d) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044.
(16) (a) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org. Chem.
2000, 4, 563. (b) Denmark, S.; Nicaise, J.-C. In Comprehensive
Asymmetric Catalyst; Jacobsen, E., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, p 954. (c) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
(17) Chung, W. J.; Ngo, S. C.; Higashiya, S.; Welch, J. T. Tetrahedron
Lett. 2004, 45, 5403-5406.
(18) (a) Chemal, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
(b) Love, B. E.; Raje, P. S.; Williams, T. C. Synlett 1994, 493.
(19) Kobayashi, T.; Nakagawa, T.; Amii, H.; Uneyama, K. Org. Lett.
2003, 5, 4297-4300.
J. Org. Chem, Vol. 70, No. 19, 2005 7785

TABLE 2. Influence of Trialkylsilyl Substituents
TABLE 3. Influence of Substituents on Aryl of the
Sulfonyl Group
entry
SiR3
SiEt3
Lewis acid stoichiometry yield of 7a (%)
1
2
Sc(OTf)3
TMSOTf
Sc(OTf)3
TMSOTf
Sc(OTf)3
TMSOTf
Sc(OTf)3
TMSOTf
Sc(OTf)3
TMSOTf
Sc(OTf)3
TMSOTf
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
125 mol %
125 mol %
7b: 77
7b: 85
7c: 80
7c: 74
7d: 82
7d: 84
7e: 86
7e: 88
7f: 0
entry
R
Lewis acid
yield of 7a (%)
t
3
SiMe2 Bu
1
2
3
OCH3 (6b)
CH3 (6c)
NO2 (6d)
TMSOTf (10 mol %)
TMSOTf (10 mol %)
Cu(OTf)2 (200 mol %)
7g: 75
7h: 79
7i: 85
4
t
5
SiPh2 Bu
6
a Isolated yield; characterized by 1H, 13C, 19F, and elemental
analysis.
7
SiPh3
SiiPr3
8
9
10
11
12
7f: 29
7f: 62
7f: 68
TABLE 4. Influence of Substituents on Aromatic Ring
a Isolated yield; characterized by 1H, 13C, 19F, and elemental
analysis.
Rare earth triflates and lanthanide triflates have
unique properties in comparison with typical Lewis
acids.20 Not only mildly acidic but also stable in aqueous
media, rare earth and lanthanide triflates can be em-
ployed in catalytic quantities in some cases. Yb(OTf)3,
Sc(OTf)3, and Y(OTf)3 mediated reactions in stoichiomet-
ric (entry 3, 5, and 7) or catalytic quantities (entry 4, 6,
and 8) yielded the desired condensation product without
the formation of aldol product. Intriguingly, reaction in
the presence of catalytic quantities of triflic acid gave 7a
in good yield (entry 12). Ikeda et al.21 have postulated
that trimethylsilyl triflate, formed by reaction of 3a with
triflic acid, could initiate a catalytic reaction. Trialkylsilyl
triflates (entry 9-11) did promote reaction in either
catalytic or stoichiometric amounts in good yields. Cu-
(OTf)2 was also scrutinized in consideration of the
potential applicability to asymmetric reactions in the
presence of chiral auxiliaries.22 Other Lewis acids such
as La(OTf)3, ZnI2, SnCl2, FeI2, and SmI2 resulted in
recovery or decomposition of 3a without formation of 7a.
The influence of trialkyl(aryl)silyl substituents on the
reactivity and selectivity of 3 was investigated under
optimized conditions employing either Sc(OTf)3 or trim-
ethylsilyl triflate (TMS-OTf). As summarized in Table 2,
the steric influence of the substituents is particularly
noteworthy in the case of the triisopropylsilyl group
(entries 9-12). Even with longer reaction times of more
than a day, reactions were incomplete with no formation
of 7f or of the aldol product (entry 9) but rather only low
yields of 7f (entry 10). However, with greater than
stoichiometric quantities of Lewis acid (125 mol %) 7f
was isolated in moderate yields.
entry
X
yield of 7a (%)
1
2
3
4
5
4-Cl
7j: 72
7k: 71
7l: 51
7m: 56
7n: 49
4-CH3
4-NO2
4-OCH3
2-CH3
a Isolated yield; characterized by 1H, 13C, 19F, and elemental
analysis.
conditions. However, reaction of phenylmethylidene-4-
nitrobenzenesulfonamide (6d) under the same conditions
resulted in the formation of only limited quantities of 7i
with a large portion of unreacted 6d remaining even with
extended reaction times (1 week). The best results with
6d were obtained in reactions with 2 equiv of 3a and an
excess of Cu(OTf)2.
The generality of the reactions of 3a was explored
further with various substituted N-benzylidinebenzene-
sulfonamides (6). As summarized in Table 4, the desired
â-amino acid precursors (7j-n) were obtained in good to
moderate yields. Reaction of substrates bearing substitu-
ent at the para position (entries 1-4) resulted in better
yields than reaction where there was an ortho substituent
(entry 5). Presumably steric inhibition to reaction was
significant. Substituents with heteroatoms, either elec-
tron donating or withdrawing, gave low yields (entries 3
and 4). The presence of the sulfonyl group led to trouble-
free purification of 7 by simple recrystallization in
hexane.
As mentioned above, p-toluenesulfonylimines derived
from aliphatic aldehydes were easier to handle than
benzenesulfonylimines. Reaction of 3a with N-cyclohexy-
lmethylene-4-methylbenzenesulfonamide under the con-
ditions previously optimized for reactions of N-benzy-
lidinebenzenesulfonamides formed 7o in low yield due
to the higher reactivity of N-alkylidine-4-methylbenze-
nesulfonamide than the N-benzylidinebenzenesulfona-
mide. Better results were obtained on lowering the
reaction temperature from -78 °C, whereupon the â-ami-
no acid derivatives (7o-r) were formed in moderate
yields (Table 5).
The aryl substituents also modulated the reactivity of
the sulfonylimines. Sulfonylimines bearing a 4-methoxy
(6b) or 4-methyl substituent (6c) reacted to form the
desired adducts (7g and 7h, respectively) with complete
conversion of the sulfonylimines under the optimized
(20) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209.
(21) Ikeda, K.; Achiwa, K.; Sekiya, M. Tetrahedron Lett. 1983, 24,
913.
(22) (a) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002,
4. 143. (b) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa,
H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. (c) Nakamura, Y.;
Matsubara, R.; Kiyohara, H.; Kobayashi, S. Org. Lett. 2003, 5, 2481.
As mentioned earlier, R,R-difluoroacylsilanes are syn-
thetic precursors of R,R-difluorocarbonyl compounds such
7786 J. Org. Chem., Vol. 70, No. 19, 2005

SCHEME 2
TABLE 5.
SCHEME 3
entry
R
yield of 7a (%)
1
2
3
4
cyclohexyl
isopropyl
isobutyl
butyl
7o: 63
7p: 49
7q: 51
7r: 54
presence of K2CO3 to give 11 without defluorination
(Scheme 3).23
In conclusion, we have described a new pathway to R,R-
difluoro-â-amino acid derivatives where condensation of
3 with various sulfonylimines (4) gave 7 in good to
moderate yields. Conversion of the acylsilane moiety of
7 resulted in the formation of â-amino acid ester 8.
Consequent reaction of resultant 8 with either amine or
amino acid formed amide (9) or dipeptides (10). Depro-
tection of 9b gave 11 without defluorination. The syn-
thetic applications to obtain chiral 7 and peptide con-
taining R,R-difluoro-â-amino acid moiety are still under
investigation.
a Isolated yield; characterized by 1H, 13C, 19F, and elemental
analysis.
TABLE 6.
entry
R
yield of 10a (%)
Experimental Section
1
2
H
CH3
10a: 73
10b: 72
General Procedure for the Formation of 7.24 To a mixture
of sulfonylimine (6, 0.8 mmol) and trimethylsilyl trifluoromethane-
sulfonate (18 mg, 0.08 mmol) in 3 mL of dichloromethane was
added a solution of 3 (1 mmol) in 2 mL of dichloromethane at 0
°C. The resulting mixture was stirred at room temperature for
24 h, quenched with 10 mL of saturated sodium bicarbonate
solution, and then extracted with dichloromethane (2 × 20 mL).
The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated. Recrystallization in hexane provided com-
pound 7 as solid.
a Isolated yield; characterized by 1H, 13C, 19F, and elemental
analysis.
as aldehydes or carboxylic acid derivatives. Conversion
of the acylsilane to the ester (8) was achieved in good
yields by treatment of 7 with tetrabutylammonium fluo-
ride (TBAF) in the presence of hydrogen peroxide (H2O2),
followed by esterification of the intermediate acid with
ethanol under reflux in the presence of chlorotrimethyl-
silane (TMSCl). Reaction of 8 with ethylamine resulted
in the formation of amide (9) in good yields (Scheme 2).
Successful conversion of ester (8) to amide group (9)
by simple treatment with ethylamine prompted us to
investigate the direct coupling reaction with a C-protect-
ed amino acid for the formation of dipeptide. Peptide-
coupling reaction of 8a with glycine ethyl ester hydro-
chloride in the presence of triethylamine in dichloro-
methane under reflux for 1 day gave dipeptide 10a in
good yield (Table 6, entry 1). However, reaction with
L-alanine ethyl ester hydrochloride proceeded more slowly.
Longer reaction times were needed to obtain dipeptide
(10b) in 72% conversion as a mixture of diastereomers
(46:54) (Table 6, entry 2).
N-(2,2-Difluoro-3-oxo-1-phenyl-3-trimethylsilylpropyl)-
benzenesulfonamide (7a). White solid: mp 114-115 °C; 1H
NMR (CDCl3) δ 7.66 (d, J ) 7.8 Hz, 2H), 7.39 (t, J ) 7.0 Hz,
1H), 7.27 (t, J ) 7.8 Hz, 2H), 7.16-7.05 (m, 5H), 6.00 (d, J )
9.6 Hz, 1H), 4.95 (td, J ) 13.1, 9.6 Hz, 1H), 0.04 (s, 9H); 13C
2
NMR (CDCl3) δ 236.3 (t, JC-F ) 35.9 Hz), 140.1, 132.5, 132.4,
1
128.7, 128.6, 128.5, 127.0, 115.3 (t, JC-F ) 259.0 Hz), 57.9 (t,
2JC-F ) 24.7 Hz), -3.6; 19F NMR (CDCl3) δ -111.2 (dd, J )
276.2, 12.2 Hz, 1F), -112.8 (dd, J ) 276.2, 13.7 Hz, 1F). Anal.
Calcd for C18H21F2NO3SSi: C, 53.39; H, 5.32. Found: C, 54.51;
H, 5.49.
Acknowledgment. It is a pleasure to acknowledge
the helpful comments and suggestions of Prof. Kenji
Uneyama. We thank the National Institutes of Health
(grant AI052777-02) for financial support of this re-
search.
Supporting Information Available: Experimental pro-
cedure for the synthesis of compounds 3, 7, 8, 9, 10, and 11 as
well as characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Excision of the arylsulfonyl group of 9 is required to
reveal the â-amino group. Reductive cleavage of sulfona-
mide with SmI2 was not suitable for formation of 9 as
reaction at the reactive R,R-difluorinated carbonyl led
predominately to defluorination under those reaction
conditions. However, deprotection in high yield was
possible by the reaction of 9b with thiophenol in the
JO050953L
(23) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Wilson, M. E.; Nowick, J. S. Tetrahedron Lett. 1998,
39, 6613.
(24) Full experimental details and compound characterization ap-
pear in the Supporting Information.
J. Org. Chem, Vol. 70, No. 19, 2005 7787