N-methyl-N-nosyl-β3-amino acids

Article abstract of DOI:10.1021/jo070438i

(Chemical Equation Presented) N-Methyl-β³-amino acids are important building blocks in the synthesis of biologically active molecules. A very simple and efficient approach to transform natural α-amino acids into their corresponding N-methyl-β

Full text of DOI:10.1021/jo070438i

N-Methyl-N-nosyl-â3-amino Acids
Emilia Belsito, Maria L. Di Gioia, Antonella Greco, Antonella Leggio, Angelo Liguori,*
Francesca Perri, Carlo Siciliano, and Maria C. Viscomi
Dipartimento di Scienze Farmaceutiche, UniVersita` della Calabria, Via P. Bucci, Cubo 15/C,
I-87036 ArcaVacata di Rende (CS) - Italy
A.Liguori@unical.it
ReceiVed March 2, 2007
N-Methyl-â3-amino acids are important building blocks in the synthesis of biologically active molecules.
A very simple and efficient approach to transform natural R-amino acids into their corresponding N-methyl-
â3-amino acids is here presented. In the method, the key intermediates N-methyl-N-nosyl-R-aminoacyl-
diazomethanes are prepared in only one step, by a simple treatment of the corresponding N-nosyl-R-
aminoacyl chlorides with diazomethane. The synthetic route takes advantage from the use of the nosyl
group. This N-masking moiety activates the NH function, and the N-methylation can directly occur during
the acylation step of diazomethane, rendering useless a second step that instead is shown to be necessary
in all the classical procedures already reported for the preparation of N-methyl-â3-amino acids. The Wolff
rearrangement of N-methyl-N-nosyl-R-aminoacyldiazomethanes provides the corresponding N-methyl-
N-nosyl-â3-amino acids with total retention of the chiral configuration of the starting R-amino acids. No
epimerization of the chiral carbon atom is observed also when N-methyl-N-nosyl-â3-amino acids are
transformed into chlorides and coupled with R-amino acid methyl esters to achieve model scaffolds for
biologically important modified peptides.
Introduction
â3-amino acid.7 Another peculiar aspect lies in the fact that â3-
amino acids are nonmutagenic. All these features confer to
â-peptides valuable characteristics to be promising candidates
in pharmaceutical applications as peptidomimetics.
â3-Amino acids are widely encountered in nature, especially
in compounds having marine origin, and they are representative
building blocks in the design of biologically active substances
having peptidic morphology.
Pharmaceutical target molecules, such as peptide structure-
based drugs, many natural products,1 and a vast array of
metabolites,2 contain optically active â-amino acid residues.
Furthermore, â3-amino acids are considered as the ideal precur-
sors of â-lactam antibiotics.3
Numerous studies dealing with peptides and other biologically
active substances containing a â3-amino acid framework are
reported in the literature.4 These molecules, the â-peptides, are
able to fold into well-defined three-dimensional structures.5
â-Peptides have shown increased stability against the degrad-
ing action of mammalian proteases,6 due to the inability of
proteolytic enzymes to cleave the amide bonds adjacent to the
Due to the importance of â3-amino acids, their N-methyl
derivatives are potentially useful amino acid surrogates for
incorporation in lead therapeutic agents having â-peptide
(4) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (b) Cheng,
R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101, 3219-3232.
(c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1,
1111-1239. (d) Stephens, O. M.; Kim, S.; Welch, B. D.; Hodson, M. E.;
Kay, M. S.; Schepartz, A. J. Am. Chem. Soc. 2005, 127, 13126-13127. (e)
Schmitt, M. A.; Choy, S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem.
Soc. 2005, 127, 13130-13131.
(5) (a) Fernande´z-Santin, J. M.; Mun˜oz-Guerra, S.; Rodriguez-Galan, A.;
Aymami, J.; Lloveras, J.; Subirana, J. A.; Giralt, E.; Ptak, M. Macromol-
ecules 1987, 20, 62-68. (b) Fernande´z-Santin, J. M.; Aymami, J.;
Rodriguez-Galan, A.; Mun˜oz-Guerra, S.; Subirana, J. A. Nature 1984, 311,
53-54. (c) Iverson, B. L. Nature 1997, 385, 113-115. (d) Koert, U. Angew.
Chem., Int. Ed. 1997, 36, 1836-1837. (e) Gademann, K.; Hintermann, T.;
Schreiber, J. V. Curr. Med. Chem. 1999, 6, 905-925. (f) Seebach, D.;
Matthews, J. L. Chem. Commun. 1997, 2015-2022.
* Corresponding author: tel +39 0984 492042; fax +39 0984 492855.
(1) (a) Bewley, C. A.; Faulkner, D. J. Angew. Chem., Int. Ed. 1998, 37,
2162-2178. (b) Berks, A. H. Tetrahedron 1996, 52, 331-375.
(2) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117-128.
(3) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org. Chem. 2000, 563-
572.
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A. K.; Schild, H.; Schulz, H.; Hennecke, H.; Woessner, R.; Bitsch, F. Chimia
1998, 52, 734-739. (b) Werder, M.; Hauser, H.; Abele, A.; Seebach, D.
HelV. Chim. Acta 1999, 82, 1774-1783. (c) Huang, L.; Lee, A.; Ellman, J.
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10.1021/jo070438i CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/01/2007
4798
J. Org. Chem. 2007, 72, 4798-4802

N-Methyl-N-nosyl-â3-amino Acids
TABLE 1. Synthesis of
N-Methyl-N-nosyl-r-aminoacyldiazomethanes 3a-h
SCHEME 1
compd
R1
R2
yield (%)
3a
3b
3c
3d
3e
3f
H
CH3
H
H
H
CH3
H
CH(CH3)2
CH2(C6H5)
CH(CH3)CH2CH3
H
CH2CH(CH3)2
(CH2)4NHFmoc
78
81
73
77
81
89
77
69
CH(CH3)CH2CH3
H
H
3g
3h
Recently we have developed a very simple and efficient
approach for preparing N-methyl-R-amino acid methyl esters
using the nosyl group to protect the starting R-amino acid methyl
esters.15 The methylation reaction simply requires the treatment
of nosyl derivatives with an ethereal solution of diazomethane.
In addition, this procedure has been successfully employed for
site-specific N-methylation of the terminal amino function of
N-nosyl peptides.16
structure and characterized by an increased lipophilicity and
bioavailability. The resulting conformational rigidity of N-
methylated peptides8 may produce compounds with improved
binding characteristics and new receptor subtype selectivity.9
Furthermore, N-methylation of optically pure â3-amino acids
could be straightforward in making available monomers useful
for the developments of new foldamers,10 as well as in the
synthesis of biologically active peptidomimetic drugs.11 For
example, it is known12 that introduction of an N-methyl-â3-
amino acid at the fourth position of tetrapeptide analogues of
dermorphin, a potent natural analgesic with long-lasting opio-
idlike activity, provides molecules stable to proteolytic enzymes.
Substitution also improves receptor affinity, selectivity, and
analgesic activity.
N-Methyl-â3-amino acids could also generate appropriate
modified â-peptide scaffolds useful to enlighten the mechanisms
regulating the gastrointestinal high-affinity carrier system of â3-
amino acids in human and mammalian organisms.13 Conse-
quentially, it is crucial to provide optically pure N-methyl-â3-
amino acids with a large supply. However, only a few methods
have been developed for the synthesis of N-methyl-â3-amino
acids.14 Some of these approaches are characterized by harsh
reaction conditions or numerous synthetic steps.
Furthermore, in a previous work, we have realized the direct
homologation of N-Fmoc-R-amino acids into the corresponding
â3-amino acids, according to the Arndt-Eistert procedure and
using Fmoc-amino acid chlorides as starting materials.17
On the other hand, the stability of the nosyl group toward
acids allows the activation of carboxyl function as chloride;16
therefore, the N-nosyl-R-aminoacyl chlorides could be the ideal
starting substrates in the Arndt-Eistert reaction. The nosyl group
enhances the acidity of the NH function, so that N-nosyl-R-
aminoacyl chlorides should react with diazomethane at both the
NH moiety and the carbonyl group, achieving in only one step
the formation of the N-methyldiazoketones.
Results and Discussion
By use of previously published procedures,16 N-nosyl-R-
amino acids 1a-g were prepared from the corresponding
R-amino acids and p-nitrobenzenesulfonyl chloride and then
treated with thionyl chloride to give the corresponding N-nosyl-
R-aminoacyl chlorides 2a-g in quantitative yields (Scheme 1).
N-Nosyl-R-aminoacyl chlorides 2a-g were transformed into
N-methyl-N-nosyl-R-aminoacyldiazomethanes 3a-g upon treat-
ment with a methylene chloride solution of diazomethane.
Reaction was complete after 50-70 min, and 3a-g were
recovered in 73-89% overall yields, after column chromatog-
raphy (Scheme 1, Table 1). The one-step formation of com-
pounds 3a-g, due to the methylation of the protected NH
function that simultaneously occurs during the acylation of
diazomethane, was confirmed by NMR spectroscopy. 1H NMR
spectrum of each compound showed singlets resonating in the
ranges of 2.81-2.92 and 5.50-5.83 ppm, attributable to the
NCH3 and CHN2 protons, respectively.
(7) (a) Hintermann, T.; Seebach, D. Chimia 1997, 50, 244-247. (b)
Franckenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; Seebach, D. ChemBio-
Chem 2001, 2, 445-455.
(8) (a) Mark, J. E.; Goodmann, M. Biopolymers 1967, 5, 809-814. (b)
Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem. 1995, 2,
654-686.
(9) (a) Rajeswaran, W. J.; Hocart, S. J.; Murphy, W. A.; Taylor, J. E.;
Coy, D. H. J. Med. Chem. 2001, 44, 1305-1311. (b) Rajeswaran, W. J.;
Hocart, S. J.; Murphy, W. A.; Taylor, J. E.; Coy, D. H. J. Med. Chem.
2001, 44, 1416-1421.
(10) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893-4011.
(11) EnantioselectiVe Synthesis of â-Amino Acids, 2nd ed.; Juaristi, E.,
Soloshonok, V., Eds.; John Wiley & Sons: New York, 2005.
(12) (a) Ogawa, T.; Miyamae, T.; Murayama, K.; Okuyama, K.;
Okayama, T.; Hagiwara, M.; Sakurada, S.; Morikawa, T. J. Med. Chem.
2002, 45, 5081-5089. (b) Ogawa, T.; Miyamae, T.; Okayama, T.; Hagiwara,
M.; Sakurada, S.; Morikawa, T. Chem. Pharm. Bull. 2002, 50, 771-780.
(c) Masakatsu, E. Med. Res. ReV. 2004, 24, 182-212.
With the protected precursors 3a-g in hand, we evaluated
their conversion into the corresponding N-methyl-N-nosyl-â3-
homoamino acids. The homologation reaction was performed
initially under experimental conditions already reported in the
(13) Munck, L. K.; Grøndahl, M. L.; Skadhauge, E. Biochim. Biophys.
Acta 1995, 1238, 49-56.
(14) (a) Hintermann, T.; Mathes, C.; Seebach, D. Eur. J. Org. Chem.
1998, 2379-2387. (b) Farra`s, J.; Ginesta, X.; Sutton, P. W.; Taltavull, J.;
Egeler, F.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron 2001, 57, 7665-
7674. (c) Govender, T.; Arvidsson, P. I. Tetrahedron Lett. 2006, 47, 1691-
1694. (d) Hughes, A. B.; Sleebs, B. E. Aust. J. Chem. 2005, 58, 778-784.
(e) Hughes, A. B.; Sleebs, B. E. HelV. Chim. Acta. 2006, 89, 2611-2637.
(f) Gademann, K.; Ernst, M.; Seebach, D.; Hoyer, D. HelV. Chim. Acta
2000, 83, 16-33. (g) Matthews, J. L.; Overhand, M.; Ku¨hnle, F. N. M.;
Ciceri, P. E.; Seebach, D. Liebigs Ann./Rec. 1997, 1371-1379.
(15) Di Gioia, M. L.; Leggio, A.; Le Pera, A.; Liguori, A.; Napoli, A.;
Siciliano, C.; Sindona, G. J. Org. Chem. 2003, 68, 7416-7421.
(16) Di Gioia, M. L.; Leggio, A.; Liguori, A. J. Org. Chem. 2005, 70,
3892-3897.
(17) Leggio, A.; Liguori, A.; Procopio, A.; Sindona, G. J. Chem. Soc.,
Perkin Trans. 1 1997, 1969-1971.
J. Org. Chem, Vol. 72, No. 13, 2007 4799

Belsito et al.
TABLE 2. Synthesis of N-Methyl-N-nosyl-â3-homoamino Acids
SCHEME 2
4a-h
compd
R1
R2
yield (%)
4a
4b
4c
4d
4e
4f
H
CH3
H
H
H
CH(CH3)CH2CH3
H
H
CH3
H
CH(CH3)2
CH2(C6H5)
CH(CH3)CH2CH3
H
CH2CH(CH3)2
(CH2)4NHFmoc
83
82
60
70
65
68
74
62
literature.17,18 In particular, 1 mmol of N-methyl-N-nosyl-
alanyldiazomethane 3a, chosen as model system, was dissolved
in a 1,4-dioxane/water mixture and subjected to treatment with
catalytic amounts of silver benzoate, at 70 °C. After 5 h, the
catalyst was filtered off and the solvent was removed. Hydrolytic
workup of the crude mixture afforded N-methyl-N-nosyl-â3-
homo-L-alanine (4a) in only 30% total yield. Unexpectedly, the
main reaction product was N-methyl-4-nitrobenzenesulfonamide.
After a careful optimization of the reaction conditions, we
found that yields and kinetic of the homologation were
significantly improved when silver benzoate was dissolved in
triethylamine and the resulting homogeneous solution was added
to a 1,4-dioxane/water system containing N-methyl-N-nosyl-
alanyldiazomethane (3a). The use of excess triethylamine
together with catalytic amounts of silver benzoate at room
temperature for 20 min led to the rearrangement product 4a in
higher yield (78%). Probably silver benzoate dissolved in
triethylamine acts as a homogeneous catalyst.19 On the other
hand, it was recently demonstrated that triethylamine helps the
formation of silver nanoclusters,20 which are the species
responsible for the catalysis in the Wolff rearrangement of
diazoketones.21 In principle, the presence of the coreagent
triethylamine favors the formation of N-methyl-N-nosyl-â3-
amino acid rather than N-methyl-4-nitrobenzenesulfonamide.
The catalyst system triethylamine/silver benzoate produces only
traces of the sulfonamide in the reaction mixture.
In light of the excellent results obtained with 3a, treatment
with silver benzoate and triethylamine in 1,4-dioxane/water was
then extended to the other N-methyldiazoketones 3b-g. In all
cases, the reaction performed at room temperature was complete
in a few minutes and the corresponding N-methyl-N-nosyl-â3-
amino acids 4b-g were recovered pure without need of
chromatography, and in yields variable between 65% and 83%
(Scheme 2, Table 2).
For completeness, we investigated the application of the
described procedure to N-nosyl-L-lysine protected on the
ꢀ-amino function with the Fmoc group. The selection of the
base-labile masking group in the side chain of lysine was
necessary as a protection compatible with the developed
methodology. In fact, the Fmoc group is stable under the acidic
conditions required for preparation of amino acid chlorides.
The starting NR-nosyl-Nꢀ-Fmoc-L-lysine (1h) was prepared
by treatment of commercial Nꢀ-Fmoc-R-L-amino acid with
p-nitrobenzensulfonyl chloride in a 1,4-dioxane/water solution
containing triethylamine. Reaction of 1h with thionyl chloride
4g
4h
TABLE 3. Synthesis of N-Methyl-N-nosyldipeptides 6a,b
compd
R1
R2
yield (%)
6a
6b
H
CH3
CH3
H
75
64
furnished 2h (Scheme 1), which was in turn converted into the
corresponding N-methyldiazoketone 3h under experimental
conditions similar to those used for the preparation of 3a-g
(Scheme 1, Table 1). Column chromatography was necessary
to recover pure 3h in 69% yield. Homologation of 3h under
the catalytic conditions optimized as previously described
proceeded at room temperature for 20 min, giving the desired
NR-methyl-NR-nosyl-Nú-Fmoc-â3-homo-L-lysine (4h) in 62%
yield, without need of chromatography (Scheme 2, Table 2).
In order to exploit the stereochemical features of the novel
synthetic approach here proposed, we synthesized the diaster-
eomers N-methyl-N-nosyl-L-isoleucyldiazomethane (3e) and
N-methyl-N-nosyl-D-allo-isoleucyldiazomethane (3f). Com-
pounds 3e,f were obtained in 81% and 89% total yields,
respectively, by the described procedure (Scheme 1, Table 1).
The 1H and 13C NMR analysis of each compound showed
resonances attributable to only one diastereomer,22 proving that
the stereochemistry of the original chiral carbon atom is totally
retained during the preparation of diazoketones 3e,f. The
spectroscopic analysis performed on a mixture of the two
compounds 3e,f showed instead the presence of all spin systems
attributable to both products.22
In addition, we investigated if racemization could occur
during the conversion of diazomethane derivatives into the
corresponding â3-amino acids. In analogy to the spectral study
performed on 3e,f, H and 13C NMR spectroscopies were able
1
to determine the presence of the corresponding unwanted
diastereomer in the samples of N-methyl-N-nosyl-â3-homo-L-
isoleucine (4e) and its epimer 4f. The spectral information led
to the conclusion that also homologation is not affected by
racemization. Gas chromatographic-mass spectrometric (GC-
MS) analysis of the single products 4e,f, injected after their
conversion into the corresponding methyl esters by treatment
with a methylene chloride solution of diazomethane, definitively
confirmed the presence of only one diastereomer in both
samples. As expected, GC-MS analysis of a sample containing
a mixture of the two methyl esters clearly showed the presence
of only two distinguishable peaks corresponding to the couple
of diastereomeric methyl esters.22
(18) Babu, V. V. S.; Gopi, H. N.; Ananda, K. J. Pept. Res. 1999, 53,
308-313.
(19) Newman, M. S.; Beal, P. F. J. Am. Chem. Soc. 1950, 72, 5163-
5165.
We completed our studies by verifying the possible applica-
tions of N-methyl-â3-amino acids as building blocks in the
synthesis of modified peptides. N-methyl-N-nosyl-â3-homoam-
ino acids 4a,b were converted quantitatively into the corre-
sponding acyl chlorides 5a,b by treatment with thionyl chloride,
(20) Sudrik, S. G.; Maddanimath, T.; Chaki, N. K.; Chavan, S. P.;
Chavan, S. P.; Sonawane, H. R.; Vijayamohanan, K. Org. Lett. 2003, 5,
2355-2358.
(21) (a) Sudrik, S. G.; Sharma, J.; Chavan, V. B.; Chaki, N. K.;
Sonawane, H. R.; Vijayamohanan, K. P. Org. Lett. 2006, 8, 1089-1092.
(b) Sudrik, S. G.; Chaki, N. K.; Chavan, V. B.; Chavan, S. P.; Chavan, S.
P.; Sonawane, H. R.; Vijayamohanan, K. Chem.sEur. J. 2006, 12, 859-
864.
(22) See the Supporting Information.
4800 J. Org. Chem., Vol. 72, No. 13, 2007

N-Methyl-N-nosyl-â3-amino Acids
SCHEME 3
amino acids with acid-labile groups in the side chain, through
the homologation of the corresponding N-nosyl-protected
R-amino acids, is now under investigation.
Experimental Section
Synthesis of N-Methyl-N-nosyl-R-aminoacyldiazomethanes
3a-h: General Procedure. A solution of the appropriate N-nosyl-
R-aminoacyl chloride 2a-h (1 mmol) in dry methylene chloride
was added dropwise to a stirred 0.66 M methylene chloride solution
of diazomethane (10 mmol) at 0 °C. The mixture was maintained
under stirring for about 50-60 min, until thin-layer chromatogr-
taphic (TLC) analysis (chloroform/diethyl ether 90:10 v/v) of the
reaction mixture showed complete conversion of the precursor into
the corresponding N-methyldiazoketone. The organic solvent was
removed under vacuum and the oily residue was purified by column
chromatography to afford the respective N-methyl-N-nosyl-R-
aminoacyldiazomethane 3a-h in 69-89% yield.
under the same conditions adopted for the R-analogues13
(Scheme 3). Dipeptides 6a,b were then obtained by coupling
of N-methyl-N-nosyl-â3-homoamino acid chlorides 5a,b, dis-
solved in ethanol-free methylene chloride, with L-alanine methyl
ester hydrochloride dissolved in an aqueous basic solution
(Scheme 3). The reactions proceeded at room temperature and
went to completion in about 25-30 min. Dipeptides 6a,b were
isolated in 75% and 64% yields, respectively (Table 3) and in
high purity.
The single diastereomeric dipeptides 6a,b, and then a mixture
of the two compounds, were characterized by GC-MS analysis.
Each diastereomer showed a unique peak, while the mixture
presented two peaks well resolved. 1H NMR spectroscopy
definitively excluded the formation of epimerized products in
the coupling reaction.
Synthesis of N-Methyl-N-nosyl-â3-homoamino Acids 4a-h:
General Procedure. A solution of silver benzoate (0.13 mol equiv)
dissolved in freshly distilled triethylamine (the volume of triethy-
1
lamine was adjusted to /8 that of the 1,4-dioxane/water solution)
was added dropwise to a solution (0.1 M) of the appropriate
N-methyl-N-nosyl-R-aminoacyldiazomethane 3a-h in 1,4-dioxane/
water (4:1 v/v). The resulting mixture was stirred at room
temperature for 20-30 min, until TLC analysis (chloroform/
methanol 90:10 v/v) of the reaction mixture showed complete
conversion of the precursor into the corresponding N-methyl-â3-
homoamino acid. The reaction mixture was filtered and the solvent
was removed under vacuum. The residue was dissolved in saturated
aqueous sodium hydrogen carbonate (20 mL) and washed with
diethyl ether (3 × 10 mL). The aqueous layer was acidified to pH
2 by adding 1 N aqueous hydrochloric acid (10 mL) and extracted
with ethyl acetate (3 × 20 mL). The combined organic layers were
washed once with brine (10 mL) and dried over Na2SO4. Evapora-
tion of the solvent under vacuum afforded the respective N-methyl-
N-nosyl-â3-homoamino acid 4a-h in 62-83% yield, without need
of chromatography. The N-methyl-N-nosyl-â3-homoamino acids
4a-g were analyzed by GC-MS after their conversion into the
corresponding methyl esters by treatment with a methylene chloride
solution of diazomethane.
Further elongation of dipeptide chain can be easily ac-
complished by removal of the sulfonamide group followed by
a coupling with activated amino acids.16
Conclusions
We developed a highly efficient and simple methodology for
the homologation of N-nosyl-protected R-amino acids into the
corresponding N-methyl-â3-amino acids. The nosyl protecting
group is used straightforwardly in the synthetic method, since
it offers great advantages in the preparation of N-methyl-â3-
amino acids. In fact, the sulfonamide masking group enhances
the NH proton acidity, allowing the formation of diazoketones
and the simultaneous methylation of the amino function during
the treatment of N-nosyl-R-aminoacyl chlorides with diaz-
omethane. N-Methyl-N-nosyl-R-aminoacyldiazomethanes are
then smoothly converted into the corresponding â3-amino acids
by Wolff rearrangement. With respect to the other procedures
already reported in the literature, our methodology allows us
to easily obtain N-methyl-â3-amino acids in a few synthetic steps
and under very mild conditions. Another advantage is the
efficient conversion of N-methyl-N-nosyl-â3-amino acids into
their corresponding chlorides, which can be used as building
blocks in the synthesis of modified peptides. It is worth noting,
moreover, that the entire synthetic procedure does not cause
any detectable racemization of the stereocenters present in the
precursors. Although synthesis of N-methyldiazoketones by the
acid chloride method is not applicable when acid-labile groups
are used to protect reactive amino acid side chains, the strategy
can also be applied to functionalized R-amino acids bearing on
side chains base-labile protecting groups compatible with the
nosyl chemistry. The synthesis of functionalized N-methyl-â3-
Synthesis of N-Methyl-N-nosyl-â3-homoamino Acid Chlorides
5a,b: General Procedure. Thionyl chloride (12 mmol) was added
to a solution of the appropriate N-methyl-N-nosyl-â3-homoamino
acid 4a,b (1 mmol) dissolved in dry ethanol-free methylene chloride
(15 mL). The resulting mixture was stirred under reflux for 20-
30 min, until TLC analysis (chloroform/methanol 90:10 v/v) showed
complete conversion of the precursor. Evaporation of the solvent
under vacuum afforded the respective N-methyl-N-nosyl-â3-ho-
moamino acid chlorides 5a,b in quantitative yield, each one as a
yellowish amorphous solid.
Synthesis of N-Methyl-N-nosyldipeptides 6a,b: General Pro-
cedure. The appropriate N-methyl-N-nosyl-â3-homoamino acid
chloride 5a,b (1 mmol) was dissolved in ethanol-free methylene
chloride (10 mL) and treated with a solution of L-alanine methyl
ester hydrochloride (1 mmol) in 5% aqueous sodium hydrogen
carbonate (10 mL). The mixture was stirred at room temperature
for 25-30 min, until TLC analysis (chloroform/methanol 95:5 v/v)
showed complete conversion of the precursor. The organic layer
was separated and the aqueous phase was extracted with methylene
chloride (3 × 10 mL). The combined organic extracts were washed
once with 1 N aqueous hydrochloric acid (10 mL) and once with
brine (10 mL) and then dried over Na2SO4. The solvent was
evaporated under vacuum to afford the corresponding N-nosyl-
dipeptides 6a,b in 64-75% yield.
Acknowledgment. This work was supported by grants from
Ministero Italiano dell’Universita` e della Ricerca (MIUR).
J. Org. Chem, Vol. 72, No. 13, 2007 4801

Belsito et al.
Supporting Information Available: Characterization of com-
pounds 1h, 3a-h, 4a-h, and 6a,b; GC-MS analysis of the methyl
of dipeptides 6a and 6b; GC-MS analysis of methyl esters of
compounds 4e,f. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
esters of compounds 4a-g; H NMR spectra of compounds 3a,
1
3c-h, 4a, 4c-h, and 6a,b; H NMR spectra of a mixture of 3e
and 3f and a mixture of 4e and 4f; 1H NMR spectrum of a mixture
JO070438I
4802 J. Org. Chem., Vol. 72, No. 13, 2007