New polymer-supported allyloxycarbonyl (Alloc) and propargyloxycarbonyl (Proc) amino-protecting reagents

Article abstract of DOI:10.1055/s-2003-38726

New polymer-supported reagents, Alloc-P-OSu and Proc-P-OSu, have been prepared from a polymeric N-hydroxysuccinimide (P-HOSu), and used as solid-supported reagents for the allyloxycarbonyl (Alloc) and propargyloxycarbonyl (Proc) protection of the amino group. These new polymeric reagents are safe and stable, the residual P-HOSu generated after the protection reaction can be easily separated by simple filtration and reused.

Full text of DOI:10.1055/s-2003-38726

LETTER
809
New Polymer-Supported Allyloxycarbonyl (Alloc) and Propargyloxycarbonyl
(Proc) Amino-Protecting Reagents
New
P
olymer-Su
a
pported
A
m
f
ino-Pro
a
tecting Rea
e
gents l Chinchilla, David J. Dodsworth, Carmen Nájera,* José M. Soriano
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: cnajera@ua.es
Received 21 January 2003
the use of Alloc-Cl for the N-protection of amino acids
Abstract: New polymer-supported reagents, Alloc-P-OSu and
Proc-P-OSu, have been prepared from a polymeric N-hydroxysuc-
cinimide (P-HOSu), and used as solid-supported reagents for the al-
lyloxycarbonyl (Alloc) and propargyloxycarbonyl (Proc) protection
can induce the formation of protected dipeptide by-prod-
ucts.1d Other more stable reagents for the introduction of
the Alloc group have been developed, such diallyl dicar-
of the amino group. These new polymeric reagents are safe and sta- bonate (3),6 allyl succinimidyl carbonate (Alloc-OSu, 4),7
allyl 1-benzotriazolyl carbonate (Alloc-OBt, 5)6,8 and al-
ble, the residual P-HOSu generated after the protection reaction can
be easily separated by simple filtration and reused.
lyl 1-[6-(trifuoromethyl)]benzotriazolyl carbonate (6).9 In
Key words: amino acids, polymers, protecting reagents, solid-sup-
ported reagents
addition, the Proc group has also been introduced using
propargyl pentafluorophenyl carbonate (Proc-OPfp, 7).4e
Recently, the polymer-supported Alloc-protecting reagent
Alloc-OBt-6-carboxamidomethyl polystyrene (8) has
The allyloxycarbonyl (Alloc or Aloc) group shows a been commercialized (Figure 1).10
growing interest nowadays as a protecting group for pri-
mary and secondary amines and especially for amino ac-
ids in the synthesis of peptides due to its stability to acidic
1, R =
O
and some basic conditions, thus allowing selective depro-
2, R =
Cl
OR
tection of other groups such as Boc or Fmoc.1 The remov-
al of the Alloc group was originally achieved employing
rather inconvenient methods such as the use of metallic
sodium in liquid ammonia.2 However, the development of
mild deprotection methods mainly based on the palladi-
um(0)-catalyzed allyl transfer1 boosted the use of the Al-
loc protecting group, especially for the synthesis of highly
sensitive structures such as glycopeptides.3 These com-
pounds are crucial components of the oligosaccharide
coat in the lipid and protein surface components of cell
membranes, and provide the basis for the recognition by
the immune system.
O
O
O
O
O
N
O
O
O
O
4
3
F
F
O
N
N
F
O
O
N
O
R
O
F
F
In addition, the propargyloxycarbonyl (Proc or Poc) group
has appeared recently as an alternative amino protecting
group to the Alloc.4 Thus, the Proc group can also resist
acidic and mild basic conditions, but can be cleaved under
neutral conditions using benzylammonium tetrathiomo-
lybdate under ultrasonic irradiation,4a with Amberlite-
bound tetrathiomolybdate,4d Co2(CO)84b and with various
other metal reagents.4c
7
5, R = H
6, R = CF3
O
O
O
O
N
N
H
N
N
The N-protection of amines with the Alloc or Proc groups
is generally achieved by reaction of the amine with the
corresponding chloroformates Alloc-Cl (1)1 or Proc-Cl
(2).4a–4d These reagents are very sensitive to moisture,
therefore handling and storage precautions have to be tak-
en and the reagents may contain varying amounts of very
toxic phosgene.5 Furthermore, it has been observed that
8
Figure 1
Amongst all the safer and more convenient alternatives to
Alloc-Cl (1) or Proc-Cl (2), probably Alloc-OSu (4) and
its non-described counterpart Proc-OSu are the more
promising from an economical point of view. These re-
agents would be even more valuable if an easy separation
of the liberated N-hydroxysuccinimide (HOSu) from the
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0809,0812,ftx,en;D01803ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

810
R. Chinchilla et al.
LETTER
protected substrate could be achieved, a feature especially
interesting when working on a small scale. In this respect,
and with attention to the growing interest in the develop-
ment of polymer-supported reagents for organic synthe-
sis,11 our group has recently reported the facile
preparation of an economical reagent which incorporates
the N-hydroxysuccinimide moiety into a polymer.12 This
polymeric HOSu (P-HOSu, 9) has been employed as a
solid supported racemization-lowering additive for DCC-
mediated peptide formation.12 In addition, P-HOSu (9)
has also been used for the preparation of reagents for the
protection of amino groups with the 9-fluorenylmethoxy-
carbonyl (Fmoc)13 or 2,7-di-tert-butyl-9-fluorenyl-
methoxycarbonyl (Dtb-Fmoc)14 groups. Furthermore,
ammonium salts obtained from P-HOSu (9) have been
employed as amino releasing and racemization-lowering
reagents in carbodiimide-mediated amidations.15 In all
cases, these polymeric reagents are rather soluble in polar
organic solvents and the P-HOSu (9) can be easily re-
moved from the reaction mixture by simple filtration and
reused. Using these precedents, we envisaged that P-
HOSu (9) could be suitable for the preparation of new ad-
vantageous and economical polymer-supported reagents
for the Alloc- and Proc-N-protection of amino acids relat-
ed to Alloc-OSu (4) and its propargylic counterpart Proc-
OSu.
Ph
n
1
O
O
K2CO3
N
O
CH2Cl2/H2O
O
Ph
n
O
10
O
O
N
Ph
OH
9
n
2
O
O
O
N
O
K2CO3
CH2Cl2/H2O
O
11
Scheme 1
Table 1 Alloc and Proc-N-protected Amines and Amino Acids Us-
ing 10 and 11
25c,d
Entry
1
Product
Reagent
10
Yield (%)a,b [α]D
AllocNHnBu
AllocAlaOH
Alloc-ValOH
AllocPheOH
AllocPheOEt
AllocPheOBn
AllocAibOH
ProcNHnBu
ProcAlaOH
ProcValOH
ProcPheOH
ProcPheOBn
ProcAibOH
76
Polymer-supported Alloc-OSu (Alloc-P-OSu, 10) was
prepared by reaction of P-HOSu (9)16 with allyl chlorofor-
mate (1) using triethylamine as organic base in dichlo-
romethane as solvent (Scheme 1). The related polymeric
Proc-OSu (Proc-P-OSu, 11) was prepared from P-HOSu
(9) and propargyl chloroformate (2) using the same meth-
odology (Scheme 1). The polymers Alloc-P-OSu (10) and
Proc-P-OSu (11) were isolated as white solids and showed
two strong C=O stretching IR bands at 1785 cm–1 and
1735 cm–1, whereas the starting P-HOSu presented only a
C=O band at 1707 cm–1. In addition, polymer 11 showed
a new IR stretching band at 2134 cm–1, typical of a car-
bon-carbon triple bond. These reagents proved to be very
stable, no appreciable decomposition or loss of effective-
ness being observed after storage for months at room
temperature without any special precautions.
2
10
77
72
80
88
98
75
76
75
70
71
87
62
–19
–10
–9
3
10
4
10
5
10
–15
–12
6
10
7
10
8
11
9
11
–25
–21
–20
–18
10
11
12
13
11
11
The polymers Alloc-P-OSu (10) and Proc-P-OSu (11)
prepared as shown were employed as solid-supported Al-
loc- and Proc-protecting reagents for the amino group of
different substrates. Thus, amines, free amino acids or
11
11
a All compounds gave satisfactory spectroscopic data (1H and
amino acid esters reacted with 10 or 11 in the presence of 13C NMR, MS).
b Isolated pure compounds (1H, 13C NMR) after filtration and aqueous
triethylamine using refluxing dichloromethane as solvent
to give the corresponding crude pure Alloc- or Proc-pro-
tected derivatives in good yields (62–98%), after filtration
and work-up (Table 1), even with hindered systems such
as aminoisobutyric acid (Table 1, entries 7 and 13). The
filtered solid was washed with 2 M HCl allowing the
quantitative recovery of P-HOSu (9), which was recycled
for the preparation of new polymeric reagents 10 and 11.
work up.
c For crude products.
d c 1, EtOH.
In order to compare the results obtained with the poly-
meric Alloc-protecting reagent 10 with other reagents
normally used, we performed the protection reaction of
Phe-OH using the toxic chloroformate 1 under the typical
Schötten–Baumann reaction conditions,2 the isolated
yield was found to be higher (95%). In addition, when we
Synlett 2003, No. 6, 809–812 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Polymer-Supported Amino-Protecting Reagents
811
suspension of 10 or 11 in CH2Cl2 was added the corresponding
amine (0.4 mmol) and the mixture was stirred at 40 ºC for 1 day.
The solid was filtered off and the filtrate was evaporated (15 Torr)
affording the pure N-protected amine.
prepared Alloc-OSu (4) from N-hydroxysuccinimide and
the chloroformate 1,7 and used the product for the protec-
tion of the same amino-acid, the isolated yield of Alloc-
Phe-OH was 92%, whereas when the carbonate 3 was
used for protection the yield was 94%. In general, some-
what higher yields and faster reaction times were obtained Acknowledgment
using non-polymeric reagents, whereas good results were
We thank the Dirección General de Enseñanza Superior e Investig-
obtained compared to the polymer-supported reagent 8.
Thus, when the commercial polymeric reagent 8 was em-
ployed for the Alloc-protection of Phe-OH under the typ-
ical reaction conditions used for 10, only a 52% yield was
obtained, rising to 60% isolated yield when 2 equivalent
of 8 were employed. Moreover, we also performed the Al-
loc-protection reaction of Phe-OBn using Alloc-P-OSu
(10) and obtained the corresponding Alloc-Phe-OBn in
practically quantitative yield (Table 1, entry 6) whereas
only a 76% yield is reported when using the polystyrene-
bound reagent 8.10
ación Científica (project no. 1FD97-0721) of the Ministerio de Edu-
cación y Cultura (MEC) and the Conselleria de Cultura Educació i
Ciència of the Generalitat Valenciana (project no. GV99-33-1-02)
for financial support. We thank MEDALCHEMY S. L. for a ge-
nerous gift of chemicals.
References
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Organic Synthesis; J. Wiley & Sons: New York, 1999, 526–
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We also compared the performance of the polymeric re-
agent 11 in the Proc-protection of Phe-OH with the corre-
sponding chloroformate 2, which afforded a 90% yield of
Proc-Phe-OH. In addition, we prepared Proc-OSu in 93%
yield from N-hydroxysuccinimide and the chloroformate
2 following the same reported procedure as for Alloc-OSu
(4),7 its use affording a 90% yield of Proc-Phe-OH.
(2) Stevens, C. M.; Watanabe, R. J. Am. Chem. Soc. 1950, 72,
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We conclude that Alloc-P-OSu (10) and Proc-P-OSu (11)
are new safe, stable and efficient economical solid sup-
ported reagents for the Alloc- and Proc-protection of the
amino group. The use of these polymeric reagents pre-
sents the advantage that, compared to other reagents cur-
rently employed, of the easy separation and recycling of
the P-HOSu (9) liberated after the protection reaction. The
results obtained are better than those obtained using cur-
rently available and more expensive solid-supported Al-
loc-protecting reagents.17
(5) Herrinton, P. M. In Encyclopedia of Reagents for Organic
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Procedure for the Synthesis of Polymeric Reagents Alloc-P-OSu
(10) and Proc-P-OSu (11)17
A mixture of P-HOSu16 (9) (4 g, 4 mmol) and K2CO3 (1.1 g, 8
mmol) in water (30 mL) was stirred at room temperature for 30 min.
A solution of allyl chloroformate (1) (1.75 mL, 16 mmol) or prop-
argyl chloroformate (2) (1.62 mL, 16 mmol) in acetone (30 mL) was
added and the resulting suspension was stirred at room temperature
for 1 day. Hexane (30 mL) was added and the solid was filtered,
washed with a mixture of acetone/water/hexane (10/10/10 mL) and
dried in an oven (70 ºC) under vacuum (0.1 Torr) affording 4.2 g of
Alloc-P-OSu (10) or 4.2 g of Proc-P-OSu (11).
(9) Takeda, K.; Tsuboyama, K.; Hoshino, M.; Kishino, M.;
Ogua, H. Synthesis 1987, 557.
(10) Novabiochem (2002/3 catalogue: 5 g, 162 ).
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Tetrahedron 1996, 52, 4527. (b) Früchtel, J. S.; Jung, G.
Angew. Chem., Int. Ed. Engl. 1996, 35, 17. (c) Hermkens,
P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron
1997, 53, 5643. (d) Brown, R. Contemp. Org. Synth. 1997,
216. (e) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97,
489. (f) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K.
Synthesis 1997, 1217. (g) Lorsbach, B. A.; Kurth, M. J.;
Brown, R. C. D. J. Chem. Soc., Perkin Trans. 1 1998, 3293.
(h) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
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Commun. 1999, 1917. (j) Brown, A. R. Chem. Rev. 1999,
Procedure for the Alloc- or Proc-N-protection Using 10 or 11
To a suspension of Alloc-P-OSu (10) (400 mg, 0.4 mmol) or Proc-
P-OSu (11) (400 mg, 0.4 mmol) in CH2Cl2 (20 mL) was added a so-
lution of the corresponding free amino acid (0.4 mmol) and K2CO3
(39 mg, 0.4 mmol) in water (15 mL). The mixture was stirred under
reflux for 1 day and the solvents were evaporated (15 Torr). The re-
sulting solid was suspended in water (20 mL) and filtered. The solid
consisted of HOSu (9), which was quantitatively recovered after
washing with 2 M HCl. The filtrate was acidified with concd HCl
and extracted with AcOEt (3 × 20 mL). The organics layers were
dried (Na2SO4) and evaporated (15 Torr) affording pure Alloc- or
Proc-amino acids. In the case of the N-protection of amines, to the
Synlett 2003, No. 6, 809–812 ISSN 0936-5214 © Thieme Stuttgart · New York

812
R. Chinchilla et al.
LETTER
99, 1549. (k) James, I. W. Tetrahedron 1999, 55, 4855.
(l) Shuttleworth, S. J.; Allin, S. M.; Wilson, R. D.; Nasturica,
D. Synthesis 2000, 1035. (m) Ley, S. V.; Baxendale, I. R.;
Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D.
A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem.
Soc., Perkin Trans. 1 2000, 3815. (n) Orain, D.; Ellard, J.;
Bradley, M. J. Comb. Chem. 2002, 4, 1.
(13) (a) Chinchilla, R.; Dodsworth, D. J.; Nájera, C.; Soriano, J.
M. Tetrahedron Lett. 2001, 42, 7579. (b) Chinchilla, R.;
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(16) The loading of P-HOSu(9) was 1.0 mmol/g, as it was
determined by the assay of the OH group content:
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(17) Available from MEDALCHEMY S. L.
Synlett 2003, No. 6, 809–812 ISSN 0936-5214 © Thieme Stuttgart · New York