LETTER
1791
Hexadienyloxycarbonyl (Hdoc) – A Mild Acid Labile Protecting Group for
Amines
up Lingard,a,1 Gurdip Bhalay, Mark Bradley*a
b
N
Ie w
A
m
a
ine Protec
t
i
ing Gro
n
a
Department of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK
Fax +44(2380)596766; E-mail: J.Quinn-Parsons@soton.ac.uk.
b
Novartis Pharmaceuticals, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK
Received 28 July 2003
O
Abstract: Hexadienyloxycarbonyl is an amine protecting group
(3), Et N R
3
N
O
R-NH2
R=Ph
which can be cleaved with 1% TFA in CH Cl . It is stable to Pd(0)
2
2
H
and basic conditions and is proposed as a useful alternative to the
trityl and Bpoc protecting groups.
4
5
6
7
8 R=Ph 81%
9 R=CH2Ph 96%
10 R=CH2CH2CH2Ph 94%
11 R=CH(CH2Ph)CO2H 69%
R=CH2Ph
R=CH2CH2CH2Ph
R=CH(CH2Ph)CO2H
Key words: protecting groups, amines, amino acids, cleavage,
protonations
Scheme 2 Hdoc protection of amines (4–8)
Protecting groups are essential tools for the synthetic
chemist in the construction of complex organic molecules.
The usefulness of any protecting group relies on its ease
of synthesis and introduction, its stability to a range of re-
action conditions, and the selectivity, efficiency and rela-
tive ‘orthogonality’ of its cleavage with respect to other
It was found that the Hdoc group could be readily cleaved
from the amino acid under a variety of acidic conditions
(
Table 1, entries 1–6), returning phenylalanine. The moi-
ety was found to be stable to all of the other conditions in-
vestigated, but RP-HPLC analysis showed that reaction
with iodine caused modification to the molecule (entry
2
protecting groups. Here we report the synthesis, intro-
duction and cleavage of a protecting group, observed to be
1
2) and treatment of this modified compound with 10%
TFA in CH Cl failed to cleave the protecting group.
2
2
‘
orthogonal’ to a wide variety of existing protecting
The mild acid cleavage of the group can be explained by
resonance stabilisation of the cation across the conjugated
diene system and the generation of carbon dioxide (cf. to
the Boc group). Proton abstraction from any of the reso-
nance structures would lead to the formation of 1,3,5-
hexatriene as the by product, however GC-MS analysis of
the cleavage products suggested that the cation was
quenched by reaction with TFA yielding a mixture of
hexadienyltrifluoroacetates, although it was not possible
to confirm the identity of these by-products by NMR.
groups, yet readily cleaved under mildly acidic condi-
tions.
The protecting group was readily incorporated using E,E-
3
2
,4-hexadienyl-(4-nitrophenyl) carbonate (3) which was
readily prepared by the reaction of E,E-hexadien-1-ol (1)
with p-nitrophenylchloroformate (2) in the presence of
DIPEA (Scheme 1). This activated carbonate could be
stored at –20 °C for three months without degradation.
NO2
O
The non-cleavage modification of Hdoc-Phe-OH by pal-
ladium(0) was somewhat unexpected due to the similarity
with the Aloc group, which is selectively cleaved by treat-
ment with palladium(0). One could surmise that the Hdoc
group would be cleaved in a similar manner, or modified
by complexation of the palladium by the diene moiety. In
order to confirm that this was not the case, the treatment
of Hdoc-Phe-OH with palladium(0) was repeated on a
larger scale and the product isolated. HPLC-MS and
NMR confirmed the recovery of unmodified Hdoc-Phe
OH in 87% yield following purification and work-up, sug-
OH +
Cl
O
1
2
DIPEA/CH2Cl2
8%
6
NO
2
O
O
O
3
Scheme 1 Synthesis of the activated reagent for Hdoc protecting
group introduction.
Amino protection of a variety of amines [aniline (4), ben- gesting that it is essentially stable to these conditions.
zylamine (5), 3-phenylpropylamine (6) and phenylalanine
In summary, the hexadienyloxycarbonyl or Hdoc group is
(
7)] with the Hdoc moiety was easily achieved by reaction
a new mild acid cleavable protecting group for amines. It
is stable to a wide variety of conditions, including many
that are used for the removal of other protecting groups.
The group may be a useful alternative to the trityl group
where the latter’s steric bulk may cause synthetic difficul-
ties or provide a more acid labile variant of the widely
used Boc group.
with 1 equivalent of compound 3 in the presence of trieth-
ylamine (Scheme 2).
SYNLETT 2003, No. 12, pp 1791–1792
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41501; Art ID: D09903ST
©
Georg Thieme Verlag Stuttgart · New York
Lingard, Iain
