Efficient, non-acidolytic method for the selective cleavage of N-Boc amino acid and peptide phenacyl esters linked to a polystyrene resin

Article abstract of DOI:10.1039/a704118g

An efficient, non-acidolytic method for the selective cleavage of phenacyl esters of N-Boc-amino acids and -peptides linked to a polystyrene resin by (CH₃)₃SnOH (TMTOH) or [(n-C₄H₉)₃Sn]₂O (BBTO) is described. We highly recommend the use of trimethyltin hydroxide for the selective cleavage of carboxylic esters based on its favourable properties. The method is compatible with an N-Boc/O-Bn (benzyl ether) strategy and yields enantiomerically pure N-Boc-peptides useful for further manipulation, for segment condensations or for cyclization strategies. A mechanism for the cleavage of methyl phenylacetate in solution by TMTOH is postulated.

Full text of DOI:10.1039/a704118g

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Efficient, non-acidolytic method for the selective cleavage of N-Boc
amino acid and peptide phenacyl esters linked to a polystyrene resin
Ricardo L. E. Furlán, Ernesto G. Mata and Oreste A. Mascaretti*
Instituto de Química Orgánica de Síntesis (CONICET-UNR), Facultad de Ciencias
Bioquímicas y Farmacéuticas, Casilla de Correo 991, 2000 Rosario, Argentina
An efficient, non-acidolytic method for the selective cleavage of phenacyl esters of N-Boc-amino acids and
-peptides linked to a polystyrene resin by (CH3)3SnOH (TMTOH) or [(n-C4H9)3Sn]2O (BBTO) is described.
We highly recommend the use of trimethyltin hydroxide for the selective cleavage of carboxylic esters
based on its favourable properties. The method is compatible with an N-Boc/O-Bn (benzyl ether)
strategy and yields enantiomerically pure N-Boc-peptides useful for further manipulation, for segment
condensations or for cyclization strategies. A mechanism for the cleavage of methyl phenylacetate in
solution by TMTOH is postulated.
Selective deprotection of a particular functional group in the
presence of others is still one of the most important transform-
ations in organic synthesis.1 A typical example is the selective
cleavage of phenacyl (Pac) esters.2,3 The development of new
non-acidolytic reagents for the selective cleavage of benzyl
esters of a variety of heterocyclic structures such as β-lactams,
benzodiazepines, hydantoins, pyrrolidines, thiazolidinones,
diketopiperazines and other small organic molecules, as well as
of biological oligomers such as peptides, oligosaccharides, oligo-
nucleotides and peptidomimetics, from polystyrene resins to
increase synthetic efficiency of final products or intermediate
protected segments continues to attract the attention of syn-
thetic chemists and is one of the most important steps of
solid-phase organic synthesis (SPOS), particularly solid-phase
peptide synthesis (SPPS)4 and its application in the growing
field of combinatorial synthesis.5–8
note we report that trimethyltin hydroxide (TMTOH) and
BBTO cleave, cleanly and efficiently, N-Boc amino acids and
peptides linked through a Pac ester to a polystyrene resin,
giving the corresponding N-Boc amino acids or peptides in high
yield (Scheme 1).
O
C
BBTO or
TMTOH
Boc-AA—OH
Boc AA CH2
R
1 AA = L-Ala-O
2 AA = L-Ala-OH
3 AA = L-Ser(O-Bn)-O
5 AA = L-Phe-L-Pro-O
7 AA = L-Leu-L-Pro-O
4 AA = L-Ser(O-Bn)-OH
6 AA = L-Phe-L-Pro-OH
8 AA = L-Leu-L-Pro-OH
R
= polystyrene resin
Scheme 1
While the benzyl ester linkage is the most frequent mode of
attachment of the first amino acid or non-peptide carboxylic
acid functional molecule to polystyrene chains cross-linked
with divinylbenzene (DVB) as in Merrifield,9 Wang,10 Pam,11
Sasrin12 and Riniker13 resins, the phenacyl ester–polystyrene
resins14 have not been extensively used in SPOS and SPPS,
although this function can be readily introduced into the poly-
styrene resin, is stable to acidic conditions, and therefore is suit-
able for orthogonal deprotection of the N-tert-butoxycarbonyl
(Boc) group and other acid-labile protecting groups.
In the Merrifield protocol involving Boc-peptides, the
method of cleavage of the benzyl ester linkage from the resin
involves anhydrous hydrogen fluoride (HF).15,16 The cleavage
step in the more acid-labile resins, such as Wang,17 Sasrin17,18
and Riniker,19 is effected by trifluoroacetic acid (TFA). In these
acidolytic methods all protective groups sensitive to acid are
cleaved in the process to yield the free (or unprotected) peptide.
Cleavage of Boc peptide Pac ester–polystyrene resins by
tetrabutylammonium fluoride (TBAF) was reported by Kiso
et al.20
In a recent series of papers, we have documented the utility
of bis(tributyltin) oxide21 (henceforth abbreviated BBTO) as
a useful, non-acidolytic reagent for the selective cleavage of
primary alkyl carboxylic esters, double esters such as (pivaloyl-
oxy)methyl carboxylates22a–c as well as phenacyl, benzyl and
methyl esters of simple N-protected amino acid and dipeptides
and N-protected amino acid benzyl esters linked to Wang and
Pam resins.22d We also investigated the cleavage, in solution, of
methyl and isopropyl phenylacetates by trialkyltin, triaryltin
and dialkyltin oxides as well as triaryltin and trialkyltin hydrox-
ides under classical heating and microwave irradiation.23 In this
Results and discussion
The 2-bromoacetyl resin (BrCH2COC6H4-resin) was obtained
from reaction of the polystyrene resin (copolystyrene, 3% DVB)
beads (200–400 mesh)24 with 2-bromoacetyl bromide in the
presence of AlCl3. The incorporation of N-Boc amino
acids and dipeptides into the resin was achieved by stirring the
2-bromoacetyl resin with a slight excess of their respective
triethylammonium salts in ethyl acetate.14 The loading of 2-
bromoacetyl resin and the degree of incorporation of Boc
amino acid or peptide in N-Boc-AA-CO2-CH2COC6H4-resin
were verified by the modified Volhard method.25
Table 1 summarizes the experimental results and illustrates
the efficiency of the present cleavage method. Treatment of
Boc--Ala-Pac-polystyrene resin 1 with BBTO in refluxing 1,2-
dichloroethane [(CH2Cl)2] afforded Boc--Ala-OH26 2 in quan-
titative yield (entry 1). When a mixture of substrates 1, BBTO
and dimethylformamide (DMF) was subjected to microwave
irradiation at 650 W for 50 min, compound 2 was isolated in
83% yield (entry 2). Treatment of compound 1 with TMTOH
in refluxing (CH2Cl)2 for 15 h furnished compound 2 in 96%
yield (entry 3). The Pac ester of Boc--serine(O-benzyl)-Pac-
polystyrene resin 3 was also cleaved with TMTOH, yielding
Boc--ser(O-benzyl)-OH in 96% yield (entry 5). This result
demonstrated that the cleavage of the Pac ester by TMTOH
proceeded with complete retention of both the N-Boc and the
side-chain O-Bn26 protecting groups of serine. Cleavage of
compound 3 with the sterically hindered BBTO (entry 4),
required a longer reaction time and the yield was lower.
We have also studied the cleavage of the N-Boc dipeptide
J. Chem. Soc., Perkin Trans. 1, 1998
355

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Lewis acid,22a,23 which implies that the ‘hard’ oxygen atom
of TMTOH coordinates with the ‘hard’ electrophilic carbonyl
carbon, through a polar transition state.
Most of the organotin oxides and hydroxides and their by-
products are highly soluble in nonpolar solvents and very
insoluble in water. TMTOH is the only organotin compound
soluble in water and very insoluble in most organic solvents.
We have used these properties extensively to purify carboxylic
acids and alcohols.22a,23
Table 1 Cleavage of Boc-amino acid and -dipeptide Pac ester linked
to polystyrene resin by BBTO and TMTOH
Entry Starting material Producta Conditionsb
Yield (%)d
1
2
3
4
5
6
7
8
9
1
1
1
3
3
5
5
7
7
2
2
2
4
4
6
6
8
8
BBTO, 25 h
100
83
96
45
96
58
80
67
78
BBTO, 50 mc
TMTOH, 15 h
BBTO, 22 h
TMTOH, 15 h
BBTO, 15 h
TMTOH, 13 h
BBTO, 15 h
In conclusion we have described an application of TMTOH
and BBTO for the selective cleavage of Pac esters of N-Boc-
amino acids or -dipeptides linked to a polystyrene resin, render-
ing N-Boc-amino acids and -peptides. The TMTOH reagent
overcame the limitations of the BBTO reagent, including the
steric congestion, which is reflected in the rate of cleavage of
hindered carboxylic esters and N-Boc-amino acid benzyl esters
bound to the Merrifield resin.22d We highly recommend the use
of TMTOH based (i) on the simplicity in the separation of
TMTOH and its organotin by-products; (ii) on the high yield of
products and (iii) because the cleavage of Pac ester N-Boc-
amino acids and N-Boc-dipeptides linked to polystyrene resins
with TMTOH afforded N-Boc-amino acids and N-Boc-
dipeptides with complete retention of enantiomeric purity. The
method is compatible with an N-Boc/O-Bn ether strategy (i.e.,
for protection on the side-chain) yielding protected peptides
useful for further manipulation, for segment condensations or
for cyclization strategies.28
The postulated reaction mechanism of the acyl-oxygen bond-
cleavage regiochemistry, supported by the products 10 and
methanol, involves attack of the ‘hard’ oxygen atom on the
carbonyl carbon, followed by attack of the ‘hard’ nucleophilic
oxygen of the carbinol moiety on the ‘hard’ electrophilic hydro-
gen atom, in analogy with our previously published mechanism
for BBTO.22a,23
The present reaction with TMTOH provides a synthetic
method for the selective cleavage of Pac esters linked to
polystyrene resins, which we hope will be useful for further
applications to solid-phase synthesis and to production of
combinatorial libraries, in particular of small organic com-
pounds where acid-sensitive functional groups are present.
We are currently exploiting the TMTOH reagent for the
cleavage of larger peptides with a variety of side-chain func-
tional groups linked through phenacyl and benzyl esters of
polymeric resins.
TMTOH, 15 h
a Comparison of TLC, 1H NMR, 13C NMR and [α]D with authentic
samples confirmed the identity of the products. b All reactions were
performed with 2.2 mol equiv. of reagent in 1,2-dichloroethane at
83 ЊC, unless otherwise indicated. c Reaction performed under micro-
wave irradiation at 650 W in DMF. d Yields reported correspond to
isolated compounds that were pure by NMR spectroscopy.
Pac-polystyrene resins 5 and 7. Treatment of Boc--Phe--Pro-
Pac-resin 5 with TMTOH in refluxing (CH2Cl)2 for 15 h led to
detachment of Boc--Phe--Pro-OH 6 from the solid matrix in
80% yield (entry 7), while the cleavage with BBTO provided
acid 6 in 58% yield after treatment for 15 h (entry 6). In the
cleavage of peptide-resin 5 with TMTOH or BBTO there was
no evidence of free Pro-OH, demonstrating that the peptide
bond is unaffected. A similar result was obtained in the cleav-
age of Boc--Leu--Pro-Pac resin 7 by TMTOH and BBTO,
which yielded the corresponding N-Boc-dipeptide Boc--Leu-
-Pro-OH 8 in 78 and 67%, respectively (entries 8 and 9). Based
on a comparison of the yield of products 4, 6 and 8 it may be
concluded that the cleavage reaction of resins 3, 5 and 7 with
BBTO is hampered by steric hindrance around the carboxyl
and carbinol carbons as previously evidenced.22a These results
indicate that the versatile TMTOH reagent is much more
efficient than BBTO for the cleavage of the Pac ester of these
resins.
Anchoring of N-Boc-amino acids and dipeptides through
Pac esters to the 2-bromoacetyl resin and subsequent cleavage
with TMTOH occurs without noticeable racemization. For
example, the optically active N-Boc-amino acids 2, 4 (entries 3
and 5) and N-Boc-dipeptides 6 and 8 (entries 7 and 9) were
obtained without loss of enantiomeric purity.
Our efforts were directed at determining some mechanistic
aspects of the reaction with TMTOH. A 0.05  aq. solution
of TMTOH was shown to have pH 7.6. The regiochemistry of
the acyl-oxygen bond cleavage was documented when methyl
phenylacetate 9 was treated with TMTOH and the product of
Experimental
General details
1
reaction was analyzed using IR spectroscopy, and H, 13C and
The IR spectrum of compound 10 was run on a Bruker IF525
FTIR spectrophotometer. NMR spectra were measured in
CDCl3 or (CD3)2SO ([2H6]DMSO) at 200 MHz for protons and
20.15 MHz for 13C, on a Bruker AC200 spectrometer. J-Values
are in Hz. Optical rotations were measured with a JASCO
DIP-1000 polarimeter at ambient temperature using a 1-ml
capacity cell. [α]D-Values are in 10Ϫ1 deg cm2 gϪ1. TLC and
spectral analyses (1H and 13C NMR) indicated that all prod-
ucts were identical with commercial authentic material. Boc--
Ala-OH, N-Boc--Ser-(OBn)-OH, Boc--Phe--Pro-OH and
Boc--Leu--Pro-OH were purchased from Bachem Bioscience
Inc. The polystyrene/3% divinylbenzene resin (Bio-Beads S-X3)
was purchased from Bio-Rad. The BrCH2COC6H4-resin was
prepared using a literature procedure14 and was analyzed using
the modified Volhard method.25
119Sn NMR spectroscopy to reveal C6H5CH2CO2Sn(CH3)3 10 as
the only organotin product isolated27 (Scheme 2). On the basis
O
δ+
δ−
O
CH3
O
R
CH2
O
δ−
C
O
δ+
O
CH3
H
9
Sn(CH3)3
H
polar transition state
H3C Sn
H3C
CH3
O
CH2
C
HOCH3
OSn(CH3)3
10
Representative procedure for the attachment of the preformed
Boc-amino acid or Boc-peptide derivatives to resin
Scheme 2
Bromoacetyl resin (1.0 g) containing 1.94 mmol equiv. Br/g was
stirred with 6 ml of AcOEt for 30 min. To this was added a
solution of Boc--Ala (488 mg, 2.58 mmol) and Et3N (290 mg,
286 mmol) in 3 ml of AcOEt, and the mixture was stirred for
of the above information it is likely that the mechanism of
cleavage of carboxylic esters with the weakly basic TMTOH
is similar to the proposed mechanism with BBTO, a weak
356
J. Chem. Soc., Perkin Trans. 1, 1998

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22 h at room temp. The esterified resin was then collected by
filtration and washed successively with AcOEt, CHCl3, 1,4-
dioxane–water (3:1, v/v), water, 1,4-dioxane and MeOH, and
dried overnight at reduced pressure to give 1.21 g of resin 1.
Similarly prepared were the resin analogues of N-Boc-(OBn)-
-Ser (3), Boc--Phe--Pro (5) and Boc--Leu--Pro (7).
CH2Cl2 and AcOEt. The combined organic solution was evap-
orated to dryness under reduced pressure and the resultant
residue was dissolved in 15 ml of AcOEt and the solution was
extracted with 5% aq. NaHCO3 (3 × 5 ml). The combined
aqueous solution was acidified to pH 4.5 with 0.5  aq. KHSO4
and extracted with AcOEt (3 × 10 ml). The AcOEt solution was
dried (Na2SO4) and evaporated to dryness to give pure Boc-
Ala-OH 2 as a solid (0.0275 g, 83%).
Determination of N-Boc-L-Ala residue on resin 1
A 0.2 g portion of resin 1 was stirred with 2.5  dry HCl/AcOEt
for 40 min and collected by filtration. The resin was then
washed successively with AcOEt, 1,4-dioxane, aq. 1,4-dioxane,
water and MeOH. The resulting alanyloxyacetyl-resin hydro-
chloride was suspended in DMF and treated with 10 ml of
DMF containing 1 ml of Et3N, filtered, and washed with DMF.
The combined filtrate and washings were evaporated to dryness
under reduced pressure and the residue, triethylamine hydro-
chloride, was analyzed by the Volhard method and found to
have a substitution level of 1.38 mmol Boc-Ala/g.
Boc-L-Phe-L-Pro-OH 6. [α]D20 Ϫ32.0 (c 1.0, EtOH) [lit.,29 Ϫ32.2
(c 1.0, EtOH)]; δH([2H6]DMSO) 1.30 (br s, 9 H), 1.79–2.25 (m, 4
H), 2.69–3.01 (m, 2 H), 3.45–3.75 (m, 2 H), 4.25–4.49 (m, 2 H),
6.97 (d, J 8.3, 1 H) and 7.26 (m, 5 H); δH(CDCl3) 1.38 (s, 9
H), 1.81–2.38 (m, 5 H), 2.94–3.07 (m, 2 H), 3.56–3.73 (m, 1 H),
4.49–4.72 (m, 2 H), 5.40–5.50 (br s, 1 H) and 7.25 (br s, 5
H); δC(CDCl3) 174.35, 171.98, 155.18, 136.03, 129.45, 128.27,
126.83, 79.69, 59.15, 53.29, 47.00, 38.80, 28.18, 28.11 and 24.57.
Boc-L-Leu-L-Pro-OH 8. [α]D20 Ϫ71.5 (c 2.0, MeOH) [lit.,29
Ϫ72.0 (c 2.0, MeOH)]; δH(CDCl3) 0.94 (d, J 6.28, 3 H), 0.98 (d,
J 6.28, 3 H), 1.43 (s, 9 H), 1.20–1.80 (m, 3 H), 2.00–2.25 (m,
4 H), 3.50–3.85 (m, 2 H), 4.40–4.63 (m, 2 H) and 5.20–5.35 (m,
1 H); δC(CDCl3) 173.69, 173.43, 155.63, 79.67, 59.16, 50.24,
47.03, 41.46, 28.21, 28.01, 24.73, 24.41, 23.21 and 21.59.
C6H5CH2CO2Sn(CH3)3 10. The data for compound 10 are as
follows: νmax(KBr)/cmϪ1 1576, 1428, 1206 and 775; δH(CDCl3)
0.52 [CH3Sn, J(Sn,H) 58.2, 9 H], 3.62 (s, 2 H) and 7.28 (s, 5
H); δC(CDCl3) 129.12, 128.27, 126.48, 41.77 and Ϫ2.59; 119Sn
δSn(C6D6; Me4Sn internal standard) 118.66. The IR and 1H
spectra of CH3CO2Sn(CH3)3 are identical with those reported
in ref. 27.
Representative procedure for the cleavage of Boc-amino acids and
Boc-peptide-Pac-polystyrene resin by BBTO
To a stirred suspension of Boc--Ala resin 1, 1.16 mmol equiv.
Boc-Ala/g of resin (0.151 g, 0.175 mmol), in 1 ml of (CH2Cl)2
was added BBTO (178 ml, 0.350 mmol) at room temp. under
nitrogen. The reaction mixture was then refluxed (83 ЊC) for 25
h and the resulting suspension was filtered, and washed succes-
sively with CH2Cl2 and AcOEt. The combined organic solution
was evaporated to dryness in vacuo and the resultant residue
was dissolved in 20 ml of AcOEt and then extracted with 5%
aq. NaHCO3 (3 × 5 ml). The combined aqueous solution was
acidified to pH 4.5 with 0.5  aq. KHSO4 and extracted with
AcOEt (3 × 10 ml). The AcOEt solution was dried (Na2SO4)
and evaporated to dryness to give 0.0331 g (100%) of N-Boc-
Ala-OH 2 as a solid, [α]D20 Ϫ26.3 (c 2.0, AcOH) [lit.,29 Ϫ26.2 (c
2.0, AcOH)]; δH([2H6]DMSO) 0.97 (d, J 7.34, 3 H), 1.12 (s, 9 H),
3.66 (m, 1 H) and 6.78 (d, J 7.62, 1 H).
Acknowledgements
We thank Professor Ernest L. Eliel (The University of North
Carolina at Chapel Hill) for his critical reading of the manu-
script, and Professor José Barluenga (Universidad de Oviedo)
for recording the 119Sn NMR spectrum. One of us (R. L. E. F.)
thanks CONICET (Consejo Nacional de Investigaciones
Científicas y Técnicas) for a fellowship.
Representative procedure for the cleavage of Boc-amino acids and
peptide-Pac-polystyrene resin by TMTOH
To a stirred suspension of Boc--ser-(OBn)-resin 3, 0.8 mmol
equiv. Boc-Ser-(OBzl)/g of resin (0.141 g, 0.113 mmol) in 1 ml of
(CH2Cl)2, was added TMTOH (0.068 g, 0.249 mmol) at room
temp. under nitrogen. The reaction mixture was then refluxed
(83 ЊC) for 15 h and the resulting suspension was filtered, and
washed successively with (CH2Cl)2, CH2Cl2 and AcOEt. The
combined organic solution was evaporated to dryness under
reduced pressure and the resultant residue was dissolved in 10
ml of AcOEt, washed with 0.5  HCl (3 × 5 ml), and dried with
Na2SO4. The solvent was removed by rotatory evaporator to
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19 For the cleavage of Fmoc-peptide benzyl esters linked to the Riniker
resin with a solution of 1% (v/v) TFA in CH2Cl2, see: I. Dalcol,
F. Rabanal, M. D. Ludevid, F. Albericio and E. Giralt, J. Org. Chem.,
1995, 60, 7575.
1988, 36, 5024; Y. Kiso, T. Kimura, Y. Fujiwara, H. Sakikawa and
K. Akaji, Chem. Pharm. Bull., 1990, 38, 270.
21 The naming of organotin compounds follows the trivial system
using ‘tin’ as a suffix, as in ref. 22a.
22 (a) C. J. Salomon, E. G. Mata and O. A. Mascaretti, J. Org. Chem.,
1994, 59, 7259. For preliminary communications see (b) E. G. Mata
and O. A. Mascaretti, Tetrahedron Lett., 1988, 29, 6893; C. J.
Salomon, E. G. Mata and O. A. Mascaretti; (c) Tetrahedron Lett.,
1991, 32, 4239; (d) J. Chem. Soc., Perkin Trans. 1, 1996, 995.
23 R. L. E. Furlán, E. G. Mata and O. A. Mascaretti, Tetrahedron
Lett., 1996, 37, 5229.
24 Polystyrene 3% DVB resin (Bio-Beads S-X3) was purchased from
Bio-Rad.
25 J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis,
Freeman, San Francisco, 1969, p. 113.
26 Abbreviations used in this paper for amino acids and for the
designation of peptides follow the rules of the IUPAC–IUBC
Commission of Biochemical Nomenclature in J. Biol. Chem., 1972,
247, 977. Other abbreviations are as follows: Bn, benzyl; Boc, tert-
butoxycarbonyl; DVB, divinylbenzene.
27 In another experiment we isolated CH3CO2Sn(CH3)3. The IR and
1H NMR spectra were identical with those reported by P. B. Simons
and W. A. Graham, J. Organomet. Chem., 1967, 8, 479.
28 For recent reviews on convergent solid-phase peptide synthesis, see:
P. L. Williams, F. Albericio and E. Giralt, Tetrahedron, 1993, 49,
11 065; H. Benz, Synthesis, 1994, 337.
29 [α]D-Values for compounds 2, 4, 6 and 8 were taken from the
Analytical Data Sheet from Bachem Feinchemikalien AG
(Switzerland).
Paper 7/04118G
Received 12th June 1997
Accepted 11th September 1997
20 For the cleavage of Boc-peptide phenacyl esters, linked to a
polystyrene-DVB resin, by fluoride ion, see: Y. Kiso, T. Kimura,
Y. Fujiwara, M. Shimokura and A. Nishitani, Chem. Pharm. Bull.,
358
J. Chem. Soc., Perkin Trans. 1, 1998