LETTER
2803
Applications of the N-tert-Butylsulfonyl (Bus) Protecting Group in Amino Acid
and Peptide Chemistry
Applications
o
t
f
the
N
e
-
tert-Butyls
p
ulfonyl (Bus
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)
Protecting
e
G
roup n Hanessian,* Xiaotian Wang
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
E-mail: stephen.hanessian@umontreal.ca
Received 17 July 2009
Dedicated to Professor Steven Weinreb for his scholarly contributions to organic chemistry
Surprisingly, the utility of the N-Bus protecting group has
Abstract: The utility of the tert-butylsulfonyl group (Bus) for the
temporary protection of amino acids and peptides is reported. Com-
patibility and orthogonality in the presence of other N- and O-pro-
tecting groups were studied.
not been systematically explored in amino acid and pep-
tide chemistry. We report herein our efforts in the prepa-
ration a variety of N-Bus derivatives of common amino
acids and peptides. We further show the combination of
N-Bus and other common N-protecting groups, and the
prospects of performing orthogonal deprotections. The re-
sults for the formation and cleavage of the N-Bus amino
acid esters are shown in Table 1 (compounds 3a–g).
Key words: tert-butylsulfonyl group, amino-group protection,
amino acids, orthogonal N-protection
N-Protecting groups are of primary importance in the uti-
lization of amino acids and organic molecules containing
amino groups in synthesis.1 Among the more popular N-
protecting groups that can also benefit from an orthogonal
deprotection strategy are the N-Boc, N-Cbz, and N-Fmoc
groups. With the exception of the N-o-nitrophenylsulfo-
nyl group introduced by Fukuyama,2 other commonly
available sulfonamides are not as versatile, due to the
harsh conditions required for their removal. In 1997 Sun
and Weinreb3 reported the use of the N-tert-butylsulfonyl
group as a new protecting group for amines. Their prepa-
ration consisted of a two-step procedure involving reac-
tion of an amine with the commercially available tert-
butylsulfinyl chloride, followed by oxidation of the result-
ing sulfinamide with a variety of oxidants to give the cor-
responding tert-butylsulfonamides in excellent overall
yield. Sun and Weinreb also showed that the N-Bus group
could be cleaved with TFA/anisole at room temperature to
regenerate the amine salt in good yields.
We next studied the formation and cleavage of N-Bus de-
rivatives of functionalized amino acids (Table 2, 5a–f).
Selective deprotection of N-Boc, N-Cbz, N-Fmoc, and
benzyl ethers groups could be achieved in the presence of
the N-Bus group (Table 2, 6a–f). However, deprotection
of the N-Bus group with TfOH in CH2Cl2 also cleaved N-
Boc, N-Cbz, and benzyl ether groups (Table 2, 5a–e). The
N-Fmoc group was not affected under the conditions of
deprotection (Table 2, 6g).
The formation and cleavage of N-Bus dipeptides contain-
ing other N-protecting groups is shown in Scheme 1. L-
Proline methyl ester was coupled to N-Bus-O-Bn-L-Ser
(7) and N-Bus-O-Bn-L-Tyr (8), respectively, and the
products were hydrogenated to the dipeptides 11 and 12.
Similar coupling with N6-Boc-L-Lys-OMe led to the
dipeptides 13 and 14. Hydrogenolysis of the benzyl ether
or deprotection of the N-Boc gave 15–18. Dipeptides 21–
24 were prepared from N6-Boc (or Cbz)-L-Lys-OMe by
coupling with N-Bus-L-Ala-OH and N-Bus-L-Phe-OH (19
and 20). Selective cleavage of the N6-Boc or N6-Cbz
group with TFA/CH2Cl2 or hydrogenolysis gave 25 and
26, respectively. The same sequence was also achieved
with N-Bus-D-Ala-OH and N-Bus-D-Phe-OH to give 29–
34 in essentially identical yields.
Only limited use has been made of this versatile N-pro-
tecting group since its initial report in 1997. For example,
Sharpless and coworkers4 have shown that tert-butyl sul-
fonamide is an effective nitrogen source for catalytic ami-
nohydroxylation and aziridination of olefins. The
resulting N-Bus products could be cleaved to the corre-
sponding amino alcohols and aziridines, respectively.
Other applications have involved addition reactions to N-
Bus imines5,6 and lithiation–electrophile trapping of ter-
minal N-Bus aziridines and related applications.7 The re-
gioselective opening of an aziridine intermediate with
CeCl3 during the total synthesis of chlorodysinosin A8
was only possible with the N-Bus protection. Other sul-
fonamides led to mixture of chloro products.
Orthogonal deprotections in the tripeptide series are
shown in Scheme 2. Thus N-Bus-L-Pro-OMe (35) was hy-
drolyzed to the acid 36, then coupled with N6-Cbz-L-Lys-
OMe to give 37. Hydrolysis to the acid 38, followed by
coupling with N6-Boc-L-Lys-OMe afforded 39, which
was subjected to hydrogenolysis to give 40. Subsequent
treatment with methanolic HCl gave 41. Alternatively
cleavage of the N6-Boc group in 39 with TFA/CH2Cl2
gave 42. Finally, global deprotection of N-Bus, N-Boc,
and N-Cbz groups in 39 could be achieved to give the tri-
peptide methyl ester 43 in excellent yield.
SYNLETT 2009, No. 17, pp 2803–2808
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Advanced online publication: 30.09.2009
DOI: 10.1055/s-0029-1217996; Art ID: S08309SS
© Georg Thieme Verlag Stuttgart · New York
Hanessian, Stephen
