N-Nosyl- and N-Fmoc-N-Methyl-R-amino Acids
SCHEME 2
TABLE 2. Results of the Solid-Phase Synthesis of N-Fmoc-N-
methyl-r-amino Acids 7a-l
pylethylamine (DIPEA) in dichloromethane (DCM) for 2 h
(Scheme 1). Unreacted remaining trityl chlorides were converted
to the corresponding inert methyl ethers by washing the resin
with a solution of DCM/MeOH/DIPEA (80:15:5).16N-Methy-
lation of the resulting resin-bound sulfonamides was then
performed using 8 equiv of diazomethane10,11 in a dichlo-
romethane solution for 4 h (Scheme 1).
entry
R1
R2
yield (%)a
7a
7b
7c
7d
7e
7f
7g
7h
7i
CH(CH3)CH2CH3
CH3
CHCH2(CH3)2
CH(CH3)2
H
H
H
H
89
82
75
77
76
70
76
73
75
72
H
CH2Ph
Cleavage from the resin was, at this stage, the most
comprehensive method to test the efficacy of the methodology.
Treatment with trifluoroethanol (TFE)/acetic acid (AcOH)/DCM
(1:1:3)17 afforded the crude products 5a-e in 78-83% yields
(CH2)4NH-(Boc)
CH2O-(t-Bu)
CH2C6H4O-(t-Bu)
CH2S-CH2Ph
CH2CONH-(Trt)
H
H
H
H
H
7l
1
(Scheme 1, Table 1). GC/MS and H NMR analysis revealed
a Isolated yield.
the presence of N-nosyl-N-methyl-R-amino acids 5a-e as the
sole reaction products.
In light of these results, we then planned the removal of the
nosyl protective group and the subsequent introduction of the
Fmoc group in order to obtain the desired N-Fmoc-N-R-
methylamino acids. To this end, the nosyl-protected lipophilic
amino acids were attached to the 2-chlorotrityl chloride resin
in the presence of DIPEA in dichloromethane: in a second step
N-methylation was achieved with diazomethane. The removal
of the nosyl group from the intermediate N-methylated sul-
fonamide 4a-e was accomplished via aromatic nucleophilic
substitution (SNAr) by treatment with thiophenol/potassium
carbonate2c in DMF (Scheme 2).
Deprotection was easily followed by simple visual inspection
of the released yellow chromophore.2c The reaction was also
monitored by the chloranil test that enables a reliable qualitative
detection of secondary amino groups.18 The reaction went to
completion in 2 h. The procedure was repeated once more to
ensure complete deprotection in every case.
The Fmoc protecting group was introduced by treatment
with FmocCl (4 equiv) and DIPEA (6 equiv) in DCM for 2 h.
The N-Fmoc-N-methyl-R-amino acids 7a-e were cleaved
from the resin under the usual acidic conditions (Scheme 2,
Table 2).
To investigate the stereochemical aspects of the entire
methodology the L-isoleucine was subjected to the adopted
procedure affording the N-nosyl-N-methylisoleucine (5a) and
N-Fmoc-N-methylisoleucine (7a). GC/MS analysis performed
on the N-nosyl-N-methylisoleucine revealed 5a as the single
product; moreover, 1H NMR analysis performed on 5a and 7a
clearly showed the presence of signals corresponding to one
diastereoisomer only thus excluding any possible racemiza-
tion process of the chiral substrates during the entire synthetic
process. Moreover, H NMR analysis performed on 7a was
identical to that of a commercially available authentic
sample.
1
The applicability of this method was then tested for a set of
amino acids containing functionalized side chains with acid-
labile protecting groups (e.g., Boc, t-Bu, trityl) to make the
adopted procedure general. The initial preparation of the
nosyl-protected derivatives required particular attention to the
acid-sensitive side chain protecting groups. Therefore, the
protection of the R-amino function with the nosyl group was
realized by treatment of the side chain-protected amino acids
1f-l with nosyl chloride in a dioxane/water solution in the
presence of a large excess of triethylamine. Workup was
performed with a 5% solution of KHSO4 to avoid undesired
removal of the acid-sensitive side chain protecting groups
(Scheme 3, Table 3).
Attachment of side-chain-protected NR-nosyl-R-amino acids
2f-l to the 2-chlorotrityl chloride resin was performed under
the adopted conditions and then the obtained products were
treated with diazomethane to provide the resin-bound N-
(19) (a) Stewart, W. E.; Siddall, T. H. Chem. ReV. 1970, 70, 517-551.
(b) Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2000, 65, 2309-2318.
(c) Pettit, G. R.; Singh, S. B.; Srirangam, J. K.; Hogan-Pierson, F.; Williams,
M. D. J. Org. Chem. 1994, 59, 1796-1800.
(20) (a) Barlos, K.; Knipp, B. PCT Int. Appl. 2004, WO 2004056883,
A2 20040708, CAN 141:106893, AN 2004:546536. (b) Harre, M.; Nickisch,
K.; Tilstam, U. React. Funct. Polym. 1999, 41, 111-114.
(16) Chiva, C.; Vilaseca, M.; Giralt, E.; Albericio, F. J. Pept. Sci. 1999,
5(3), 131-140.
(17) Barlos, K.; Gatos, D.; Kallitsis, J.; Papaphotiu, G.; Sotiriu, P.;
Wenging, Y.; Schaefer, W. Tetrahedron Lett. 1989, 30, 3943-3946.
(18) (a) Vojkovsky, T. Pept. Res. 1995, 8, 236-237. (b) Christensen,
T. Acta Chem. Scand. 1979, 33, 763-766.
J. Org. Chem, Vol. 72, No. 10, 2007 3725