A novel and efficient method for cleavage of phenacylesters by magnesium reduction with acetic acid

Article abstract of DOI:10.1021/ol050209n

(Equation Presented) In the present study, we use magnesium turnings as a new deprotection reagent for the phenacyl group during orthogonal organic synthesis in the presence of other esters and sensitive protecting groups. By applying the new magnesium turnings/acetic acid deprotection method, phenacyl group can be more easily combined with other protecting groups that are not compatible with the zinc/acetic acid method.

Full text of DOI:10.1021/ol050209n

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1723-1724
A Novel and Efficient Method for
Cleavage of Phenacylesters by
Magnesium Reduction with Acetic Acid
Stella Kokinaki,† Leondios Leondiadis,*,‡ and Nikolas Ferderigos*,†
Laboratory of Organic Chemistry, Chemistry Department, UniVersity of Athens, 157 71
Greece, and Mass Spectrometry and Dioxin Analysis Lab, IRRP, National Centre for
Scientific Research “Demokritos”, Athens, 153 10 Greece
leondi@rrp.demokritos.gr; nferder@chem.uoa.gr
Received February 1, 2005
ABSTRACT
In the present study, we use magnesium turnings as a new deprotection reagent for the phenacyl group during orthogonal organic synthesis
in the presence of other esters and sensitive protecting groups. By applying the new magnesium turnings/acetic acid deprotection method,
phenacyl group can be more easily combined with other protecting groups that are not compatible with the zinc/acetic acid method.
Since its first use, the phenacyl group has proved to be an
important reagent for protecting carboxyl functions during
orthogonal organic synthesis in the presence of other esters
and sensitive protecting groups (such as alkyl, benzyl esters,
Boc, Z, Fmoc).1 Phenacyl esters are generally solids that are
easily prepared, purified and handled and soluble in most
common solvents.The phenacyl group has been used in
peptide synthesis for the temporary protection of the â- and
γ-carboxy group of aspartic and glutamic acids.2,3 In addition,
in the segment condensation peptide synthesis method, the
segments were protected as phenacyl esters at the carboxyl
termini.4 In solid-phase peptide synthesis, 4-(Boc-amino-
acyloxymethyl)-phenylacetic acid phenacyl esters have been
used as key intermediates to anchor the first amino acid to
the polymer support.5
high concentrations of hydrogen chloride or hydrogen
bromide in acetic acid.2 It is readily cleaved (a) by nucleo-
philes such as sodium thiophenoxide,6 KCN/18-crown-6,7
hydrazine,8 and tetrabutylammonium fluoride,9 (b) by hy-
drogenolysis with H2/Pd-C,2 or (c) by reduction with zinc
in acetic acid10 or with zinc with acetylacetone and pyridine.11
It can also be removed by photolysis12 and CuII/O2/DMF-
H2O,13 but these methods are somewhat too complicated to
be used in synthesis.
In the course of the synthesis of Fmoc-glycyl-4-oxy-
methylphenoxy acetic acid as an intermediate for loading
solid-phase peptide synthesis resins by the Fmoc strategy,
we observed that the reduction of the intermediate compound
phenacyl ester (Figure 1) either by the standard activated
(6) Sheehan, J. C.; Daves, G. D., Jr. J. Org. Chem. 1964, 29, 2006-
2008.
(7) Tam, J. P.; Cunningham-Rundles, W. F.; Erickson, B. W.; Merrifield,
R. B. Tetrahedron Lett. 1977, 4001-4004.
(8) Kimura, Τ.; Takai, M.; Masui, Y.; Morikawa, T.; Sakakibara, S.
Biopolymers 1981, 20, 1823-1832.
The phenacyl group is stable in 50% trifluoroacetic acid
in methylene chloride and to HF (0 °C, 1 h),3 as well as in
† University of Athens.
‡ National Centre for Scientific Research “Demokritos”.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; J. Wiley & Sons: New York, 1999; pp 393-394, 728.
(2) Stelakatos, G. C.; Zervas, L. J. Chem. Soc. C 1966, 1191-1199.
(3) Yang, C. C.; Merrifield, R. B. J. Org. Chem. 1976, 41, 1032-1041.
(4) Kimura, Τ.; Morikawa, T.; Takai, M.; Sakakibara, S. J. Chem. Soc.,
Chem. Commun. 1982, 340-341.
(9) (a) Ueki, M.; Kai, K.; Amemiya, M.; Horino, H.; Oyamada, H. J.
Chem. Soc., Chem. Commun. 1988, 414-415. (b) Namikoshi, M.; Kundu,
B.; Rinehart, K. L. J. Org. Chem. 1991, 56, 5464-5466.
(10) Hendrickson, J. B.; Kandall, C. Tetrahedron Lett. 1970, 343-344.
(11) Hagiwarwa, D.; Neya, M.; Hashimoto, M. Tetrahedron Lett. 1990,
31, 6539-6542.
(5) Mitchell, A. R.; Kent, S. B. H.; Engelhard, M.; Merrifield, R. B. J.
Org. Chem. 1978, 43, 2845-2852.
(12) Sheehan, J. C.; Umezawa, K. J. Org. Chem. 1973, 21, 3771-3774.
(13) Ram, R. N.; Singh, L. Tetrahedron Lett. 1995, 36, 5401-5404.
10.1021/ol050209n CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/24/2005

Table 1. Removal of Protecting Group with Magnesium
[R]25D (deg)
(c 1, DMF)
rxn std
entry
starting material
producta
Figure 1.
1
2
3
4
5
6
7
8
Boc Phe OPac
Boc Asp(Bn) OPac
Boc Val OPac
Boc Leu OPac
Boc Pro OPac
Boc Glu(Bn) OPac
Boc Asn OPac
Z Phe OPac
Boc Phe OH
Boc Asp(Bn) OH
Boc Val OH
Boc Leu OH
Boc Pro OH
Boc Glu(Bn) OH
Boc Asn OH
Z Phe OH
-20.3 -20.8
-20.1 -19.8
-10.2 -10.0
-29.5 -29.8
-46.2 -46.0
-16.6 -16.3
zinc/acetic acid method or by the modified method was
problematic. Indeed, the reaction was sluggish, and the
formation of the desired product was accompanied by several
byproducts. Fmoc-glycine was identified as one of these and
is the result of the cleavage of the ester bond between the
Fmoc-glycine and the 4-(oxymethyl)-phenoxy acetic acid
We attributed this cleavage to the significant Lewis acidity
of the zinc salts generated during the reaction. To alleviate
this problem, we considered reducing the phenacyl esters
by utilizing a different metal that would produce, upon
reduction, less acidic salts. We chose for this purpose
magnesium, the common Grignard reagent, which is a more
reductive reagent than zinc and generates less acidic salts.
To prove our hypothesis, we tried reducing phenacyl esters
of common Z, Boc and Fmoc NR-protected amino acids by
magnesium turnings in a variety of solvents and with acetic
acid as proton donor (Scheme 1).14 The results obtained are
-7.5
-7.6
-37.8 -38.0
-38.7 -39.0
9
Fmoc Phe OPac
Fmoc Phe OH
10
11
12
13
14
15
17
18
FmocGlu(Bu)OPac Fmoc Glu(Bu) OH -19.1 -19.0
Fmoc Ala OPac Fmoc Ala OH -19.3 -19.2
FmocLys(Boc)OPac Fmoc Lys(Boc) OH -6.4 -6.6
Fmoc Val OPac Fmoc Val OH -17.9 -17.5
Fmoc Ser(Bu) OPac Fmoc Ser(Bu) OH -2.6 -2.4
Fmoc Tyr(Bu) OPac Fmoc Tyr(Bu) OH -30.1 -30.0
Fmoc Trp OPac
Fmoc Met OPac
Fmoc Trp OH
Fmoc Met OH
-29.6 -29.5
-30.8 -31.2
a MeOH/DMF (8:2) was used as solvent.
corroborate this observation, phenacylester was removed
from the synthesized dipeptide Boc-(L)-Phe-(L)-OPac. After
Boc deprotection, the resulting free dipeptide was analyzed
by HPLC. No peak was detected at the time corresponding
to the (L)-Phe-(D)-LeuOH isomer compared to control
chromatograms of (L)-Phe-(L)-LeuOH (tR ) 13.908 min) and
(L)-Phe-(D)-LeuOH (tR ) 16.702 min) isomers. This fact
indicates that no racemization took place during derivatiza-
tion with phenacyester and subsequent deprotection.
Scheme 1
Finally, Fmoc-glycyl-4-oxymethylphenoxy acetic acid was
prepared in high yield (87%) and purity by magnesium
turnings reductive cleavage of its corresponding phenacyl
ester (Figure 1). No detection of the side product Fmoc-
Glycine was observed by TLC under these conditions.
In conclusion, we proved that magnesium is a more
convenient reagent than zinc for the deprotection of the
phenacyl temporary protecting group. Magnesium turnings
need no activation before use, and the generated salts are
soluble and do not produce side products by cleaving acid-
sensitive ester bonds. Finally, the deprotection reaction can
be performed in organic solvents such as DMF and MeOH
and in the absence of water. By applying the magnesium
turnings/acetic acid deprotection method, phenacyl group can
be more readily combined with other protecting groups that
are not compatible with the zinc/acetic acid method.
summarized in Table 1. All isolated yields were more than
80%; the products were of high purity (>95%) and were
1
characterized by elemental analysis and H and 13C NMR.
Of the solvents used, methanol was the most efficient
(reaction time 60 min). When DMF was used more time was
needed for full deprotection (120 min). Because some Fmoc
amino acid phenacyl esters are insoluble in methanol, we
used a mixture of MeOH/DMF (8:2) with no significant
increase of deprotection time (75 min).
No racemization has been reported to date in the removal
of phenacyl esters by the zinc/acetic acid method. In the
present study, the deprotection products by magnesium
turnings have the same specific rotation as the original
compounds. Thus, racemization is not a problem. To
Acknowledgment. This work was supported by funds
from “Special Account for Research Grants” of the National
and Capodistrian University of Athens.
(14) Typical Procedure. To a solution of protected amino acid (2 mmol)
in MeOH/DMF (8:2, 15 mL) were added acetic acid (1.5 mL, 24 mmol)
and magnesium turnings (300 mg, 13 mmol). The solution was stirred for
60-100 min (checked by TLC; CHCCl3/MeOH ) 9:1) at room temperature.
The reaction mixture was filtered, and the filtrate was concentrated in vacuo.
The residue was diluted with 5% NaHCO3 (10 mL) and ether/EtOAc (1:1,
10 mL) and the organic layer was extracted with 5% NaHCO3 (2 × 10
mL). The aqueous extract was acidified to pH 2-3 with saturated KHSO4
and extracted with EtOAc (2 × 10 mL). The organic layer was washed
with brine (2 × 10 mL), dried with sodium sulfate, and filtered. The filtrate
was evaporated in vacuo, and the product was crystallized with petroleum
ether (40-60).
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for all com-
pounds described. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL050209N
1724
Org. Lett., Vol. 7, No. 9, 2005