Efficient one-pot formation of amides from benzyl carbamates: Application to solid-phase synthesis

Article abstract of DOI:10.1016/S0040-4020(00)00850-4

A convenient one-pot protocol for the conversion of benzyl carbamates to amides is described. The general applicability of the procedure is illustrated using various types of substrates. This new method proceeds rapidly under mild conditions, in good yields, and without noticeable racemization. This protocol was applied to solid-phase synthesis to prepare amides and esters from Merrifield resin-bound carbamates and carbonates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00850-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8867±8875
Ef®cient One-Pot Formation of Amides from Benzyl Carbamates:
Application to Solid-Phase Synthesis
*
Wen-Ren Li, Ying-Chih Yo and Yu-Sheng Lin
Department of Chemistry, National Central University, Chung-Li 32054, Taiwan
Received 14 August 2000; accepted 21 September 2000
AbstractÐA convenient one-pot protocol for the conversion of benzyl carbamates to amides is described. The general applicability of the
procedure is illustrated using various types of substrates. This new method proceeds rapidly under mild conditions, in good yields, and
without noticeable racemization. This protocol was applied to solid-phase synthesis to prepare amides and esters from Merri®eld resin-bound
carbamates and carbonates. q 2000 Elsevier Science Ltd. All rights reserved.
The selection of a protecting group is a key facet of modern
organic and peptide synthesis. Signi®cant progress has been
made in the development of suitable protecting groups for a
great number of functional groups.1 Although a variety of
protecting groups are available, certain synthetic processes
require to chemoselective transformations of existing
protecting group. The problem of selectivity in functional
group transformations is especially acute in the design and
construction of polyfunctional molecules such as peptides,
polyketides and complex natural products. Therefore, the
availability of methodologies to exchange protecting groups
in a mild, straightforward, and preferably, one-pot pro-
cedure is of great bene®t in terms of time and material
savings.
date, several reports have appeared dealing with the inter-
conversion of carbamates, such as the transformation of a
benzyl carbamate into the Boc group2,3 and the reverse
process4,5 and the conversion of Fmoc into Cbz and
Boc.6,7 However, the transformation of carbamates into
amides has not been previously documented.
In the course of the synthesis of the radiosumin8,9 (Fig. 1), a
trypsin inhibitor to be used in a combinatorial approach, we
needed an ef®cient method of transforming benzyl carba-
mates into acetates in the presence of double bonds. Among
the reported methods for removal of the benzyl carbamates,
catalytic hydrogenolysis or reductive cleavage with a
dissolving metal seemed unsuitable because of the combi-
natorial synthetic strategy and the structural limitations. We
therefore sought to develop an ef®cient procedure for the
Lewis acid catalyzed transformation of benzyl carbamates
to the corresponding amides in high yields. We now
describe a reagent system consisting of acetyl bromide (or
benzoyl chloride) combined with tin(II) bromide and
triethylamine and its practical applications (Scheme 1).
The most useful amino protecting groups are the carba-
mates, developed for the protection of amino acids, and
amides, and used more widely in the syntheses of alkaloids,
peptides and nucleotides. Carbamates utilized in peptide
and protein chemistry include the N-benzyloxycarbonyl
(Cbz), N-¯uorenylmethoxycarbonyl (Fmoc) and the
N-tert-butoxycarbonyl (Boc). These groups exhibit
contrasting chemical stabilities to catalytic hydrogenolysis,
bases and acids.1 The 9-¯uorenylmethyl carbamates (Fmoc)
are usually cleaved by organic bases. N-Boc groups are
stable to bases but removed by acidic hydrolysis whereas
benzyl carbamates (Cbz) are inactive to a variety of reagents
and cleaved by catalytic hydrogenolysis. On the other hand,
amides are exceptionally stable to hydrogenation, acidic or
basic hydrolysis, and are classically hydrolyzed under harsh
conditions by heating in strongly acidic or basic solution. To
Reaction of benzyl carbamates with various Lewis acids,
acetyl bromide and triethylamine (Table 1). Although
several Lewis acids were reported to cleave benzyl
Keywords: benzyl carbamate; selective carbamate cleavage; benzyloxycar-
bonyl linker; Lewis acids; zinc(II) bromide; resin-bound carbamates and
carbonates.
* Corresponding author. Tel.: 1886-3-422-7704; fax: 1886-3-427-7972;
e-mail: ch01@ncu.edu.tw
Figure 1. Radiosumin.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00850-4

8868
W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
Scheme 1.
Table 1. Results obtained from the reaction of N-Cbz-Phe-OMe with acetyl bromide, triethylamine and 0.5 equiv. of various Lewis acids
Entry
Lewis acid
Time (h)
Yield (%)
N-Ac-l-Phe-OMe 1
[a]2D5 (c, solvent)
Mp (8C)
1
2
3
4
5
6
7
8
9
SnBr2
LiI
SnCl2
ZnCl2
ZnBr2
FeCl3
AlCl3
BF3´Et2O
TMSOTf
9
81
33
70
70
71
68
52
31
55
88±89
88±89
88±89
89±90
89±90
88±89
89±90
88±89
87±88
1101.28 (c 2.4, CHCl3)
1101.58 (c 3.4, CHCl3)
1101.68 (c 3.5, CHCl3)
1100.18 (c 3.4, CHCl3)
1100.38 (c 5.7, CHCl3)
1102.38 (c 4.3, CHCl3)
1101.08 (c 2.9, CHCl3)
1101.08 (c 3.0, CHCl3)
1101.28 (c 4.0, CHCl3)
24
24
10
10
7
24
24
15
carbamates,10,11 none of them has been known to convert
carbamates to amides. Therefore, our initial efforts were
directed at selecting the most suitable catalyst and reaction
conditions for this transformation. As shown in Table 1, to
convert benzyl carbamates into their corresponding
N-acetates, the highest yields were obtained by treatment
with acetyl bromide and tin(II) bromide in methylene
chloride, followed by the addition of triethylamine. A
lower yield of the desired products (monoamides) was
observed by adding the triethylamine in one portion and
this lower yield was attributed to the formation of
diamides.
the method described in the general procedure. As shown in
Table 2, the yields and the reaction rates of the various
substrates show a de®nite pattern. Benzamides usually
were obtained in better yields. Faster transprotection
occurred with acetyl bromide (9±20 h) as compared to
benzoyl chloride (24±36 h).
The ester groups, the sul®de bond and the peptide bonds
were stable under these conditions. We also observed that
the tert-butyldimethyl silyl ether was rapidly converted to
the corresponding acetate (3) using SnBr2/AcBr/Et3N. This
protocol complements the direct deprotection by ¯uoride,
followed by acylation, and further illustrates the unexplored
potential of this reagent system. In the present study,
racemization was not detected after comparison of the
optical rotations of the pure amides with those reported in
the literature.
The amount of by-products was catalyst-dependent, with
aluminum(III) chloride and boron tri¯uoride etherate giving
the most by-products. Iron(III) chloride, zinc(II) halides and
tin(II) chloride afforded the product but the overall yields
and the reaction rates were not as good as with tin(II)
bromide. With catalysts, such as lithium iodide and
trimethylsilyl tri¯ate the reaction did not go to completion.
Addition of tetrabutylammonium bromide or potassium
iodide did not enhance the yield or reaction rate in this
`transprotection' with tin(II) bromide.
The catalyst and solvent effect (Table 3). When the
reaction was carried out in the presence of tin(II) bromide
(0.5 equiv.), the reaction rate increased and only 9 h were
needed to reach total conversion. Screening various reaction
conditions, we found that CH2Cl2 was the most suitable
solvent. Other solvents such as Et2O and DMF gave low
yields and decreased the reaction rate. Therefore, this
reaction does not seem to proceed in protic or lone pair
electron rich solvents such as alcohols, N-methyl-2-pyrroli-
dinone (NMP) and acetone.
The transprotection: synthesis of amides (Table 2). A
variety of substrates were examined to evaluate the scope
of the reaction. The acetamides and benzamides were
prepared from the corresponding benzyl carbamates using
Table 2. One-pot conversion of benzyl carbamates into the corresponding amides
Entry
Substrate
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
N-Cbz-l-Phe-OMe
N-Cbz-l-Met-OBn
N-Cbz-l-Ser(OTBDMS)-OMe
N-Cbz-l-Ala-l-Ile-OEt
N-Cbz-l-Phe-l-Leu-OMe
N-Cbz-l-Ala-OMe
N-Cbz-l-Leu-OMe
N-Cbz-l-Pro-OMe
N-Cbz-l-Phe-l-Leu-OMe
9
Ac-l-Phe-OMe (1)
Ac-l-Met-OBn (2)
Ac-l-Ser(OAc)-OMe (3)
Ac-l-Ala-l-Ile-OEt (4)
Ac-l-Phe-l-Leu-OMe (5)
Bz-l-Ala-OMe (6)
Bz-l-Leu-OMe (7)
Bz-l-Pro-OMe (8)
Bz-l-Phe-l-Leu-OMe (9)
81
79
80
68
73
86
84
80
76
12
10
20
15
36
34
24
36

W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
8869
Table 3. Catalyst and solvent in¯uence on the reaction of N-Cbz-Phe-OMe
with acetyl bromide, tin(II) bromide and triethylamine
Table 4. Results obtained from the cleavage of resin-bound carbamate of
phenylalanine methyl ester with acetyl bromide, triethylamine and various
Lewis acids
Entry
Equivalent of SnBr2
Solvent
Time (h)
Yield (%)
Entry
Lewis Acid
Time (h)
Yield of N-Ac-l-Phe-OMe 1 (%)
1
2
3
4
5
6
7
0.02
0.1
0.5
0.5
0.5
0.5
0.5
CH2Cl2
CH2Cl2
CH2Cl2
DMF
THF
Et2O
48
48
9
48
48
48
24
46
61
81
14
21
28
66
1
2
3
4
5
6
7
9
ZnBr2
SnBr2
SnCl2
FeCl3
AlCl3
BF3´Et2O
BBr3
TMSOTf
24
24
24
20
20
24
20
15
81
49
28
42
45
36
23
25
CH3CN
Application to solid-phase synthesis. Use of a carbamate
linker to attach amines to Wang resin has been widely
applied to prepare various compounds for biological test-
ing.12±19 The susceptibility of Wang resin-bound carbamate
linker to cleave by mild acids limits the range of solid-phase
chemistry which can be performed. Merri®eld resin-bound
carbamates, being much less labile towards acid than those
linked to Wang resins, are more versatile in the solid-phase
combinatorial synthesis. However, cleavage of these carba-
mates by acids is more dif®cult.20±22 It is also desirable from
a synthetic point of view that amines, released from the solid
support, immediately react with acyl halides and provide
amides in a one-pot reaction.23,24 This type of `traceless'
cleavage method should ®nd broad application in solid-
phase synthesis and stimulate the wider use of the Merri®eld
resin. In order to enhance the acidic stability of Wang resin-
bound carbamate linker and add another dimension to the
strategy of solid-phase synthesis, we sought to develop a
mild method which would allow an ef®cient one-pot forma-
tion of amides from Merri®eld resin-bound carbamates and
broaden the application of this resin. Because of the success
of the solution method, we decided to apply the same proto-
col to combinatorial solid-phase synthesis. Unfortunately,
several attempts to use tin(II) bromide to promote the
conversion of Merri®eld resin-bound carbamate to amide
1 suffered from incomplete cleavage and proceeded in
poor yields (Scheme 2).
results for the one-pot transformation of benzyl carbamates
into amides in solution, including ZnBr2, SnCl2, FeCl3,
AlCl3, and TMSOTf (Table 1). In search of a more ef®cient
catalyst, investigations on the solid-phase were conducted
on the resin-bound carbamate of phenylalanine methyl
ester, to parallel the experiments in solution phase. As
shown in Tables 1 and 4, a surprising solid-phase effect
was observed.
In the solution phase, N-Cbz-Phe-OMe was converted
smoothly to the corresponding acetate with most of Lewis
acids/acetyl bromide/triethylamine reagent systems. In
contrast, on the solid-phase, the Merri®eld resin-bound car-
bamate of phenylalanine methyl ester only reacted with the
zinc(II) bromide catalyzed reagent system to give a high
yield (81%) of the desired product 1.26 The precise
mechanism of action of these reagent systems are unknown.
However, the ability of tin bromide or zinc bromide to act as
a Lewis acid in solution or solid-phase is probably an impor-
tant factor. For comparison to the reported method,12 Wang
resin27 was converted to an activated carbamate and treated
with phenylalanine methyl ester to afford polymer 10
(Scheme 2). After tri¯uoroacetic acid cleavage and acetyl-
ation with Ac2O/Et3N, this protocol delivered N-Ac-l-Phe-
OMe 1 in a similar overall yield.
Our recent publication exploring the zinc(II) bromide
assisted release of Merri®eld resin-bound ethers prompted
us to reinvestigate the catalyst effect on solid support.25
Therefore, we examined reagents known to produce good
To verify the applicability of the method to solid-phase
synthesis, we have synthesized Ac-l-Phe-l-Leu-OMe 5
(Scheme 3) and various amides listed in Table 5 on the
Merri®eld resin. As shown in Table 5, the p-nitrophenol
Scheme 2.

8870
W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
Table 5. Synthesis of amides 14a and esters 14b by Lewis acids assisted cleavage of resin-bound carbamates 13a and carbonates 13b
Entry
1
Resin 13: R1±Y groupˆ
Base used
Cleavage conditionsa
Product 14: R2 group
Overall yieldsb (%)
DIPEA
DIPEA
A
B
R2ˆCH3 (1)
R2ˆPh (15)
81
86
2
DIPEA
DIPEA
A
B
R2ˆCH3 (5)
R2ˆPh (9)
72
78
3
4
DIPEA
DIPEA
A
B
R2ˆCH3 (16)
R2ˆPh (17)
72
74
DIPEA
DIPEA
A
B
R2ˆCH3 (18)
R2ˆPh (19)
77
80
5
DIPEA
DIPEA
A
B
R2ˆCH3 (20)
R2ˆPh (21)
70
75
6c
7
DIPEA
A
R2ˆCH3 (22)
74
Cs2CO3
Cs2CO3
C
D
R2ˆCH3 (23)
R2ˆPh (24)
93
97
8
Cs2CO3
Cs2CO3
C
C
R2ˆCH3 (25)
75
68
9
R2ˆCH3 (26)
10
DMAP
DBU
NaH
C
C
C
R2ˆCH3 (27)
R2ˆCH3 (27)
R2ˆCH3 (27)
97
40
10
a Cleavage conditions: A. ZnBr2/AcBr/Et3N/CH2Cl2; B. ZnBr2/BzCl/Et3N/CH2Cl2; C. ZnBr2/AcBr/CH2Cl2; D. ZnBr2/BzCl/ CH2Cl2.
b Overall yields are isolated yields based on the loading of hydroxymethyl resin. All compounds gave satisfactory 200 MHz 1H NMR spectra and the correct
molecular ion by MS.
c Distilled technical grade 3-phenyl-1-propylamine was used.
was replaced by a variety of nucleophiles in the presence of
different bases to afford resin-bound carbamates. Various
types of the resin-bound carbamates were then cleaved
with the zinc bromide/acyl halide/triethylamine reagent
system to provide the corresponding amides in good yields.
It is noteworthy that the cleavage proceeded faster with
acetyl bromide but benzamides were obtained in better
yield in both solid and solution reactions. The chemoselec-
tivity of cleavage between benzyl carbamate and less reac-
tive benzyl ester was excellent under the present conditions
(entries 3±5).28 No epimerization was observed when the
cleavage of Merri®eld resin-bound carbamates was

W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
8871
Scheme 3.
conducted with ZnBr2/AcBr or BzCl/Et3N reagent systems.
The carbamide linkage was able to tolerate some stringent
conditions such as LAH, NaOMe at room temperature, and
therefore was a useful functionality in many aspects of
organic synthesis. With these results in hand, we extended
this protocol to the synthesis of acetates and benzoates from
alcohol and phenols on solid support.29 In contrast to the
Merri®eld resin-bound carbamate cleavage method, it was
found that the triethylamine was not necessary to drive the
reaction to completion when the resin-bound carbonates
were cleaved (Table 5, entries 7±10). It should be noted
that direct treatment of salicylaldehyde in CH2Cl2 with ace-
tyl bromide in the absence of triethylamine for 24 h suffered
incomplete acetylation (65% yield) and entry 9 also gave a
moderate one-pot solid-phase synthesis of a O-acylated
salicylaldehyde. This result is presumably due to
hydrogen bonding between the carbonyl group and the
hydrogen of the hydroxyl group, which retarded acylation
of the alcohol.
Experimental
General procedures
All solvents were reagent grade and distilled before use.
Analytical thin-layer chromatography (TLC) was
performed on Merck silica gel (60 F254) plates (0.25 mm).
Visualization was effected with ultraviolet light or any of
the following reagents: ninhydrin, phosphomolybdic acid
and anisaldehyde. Chromatography was carried out on
Merck silica gel 60 (particle size 240±400 mesh). Melting
points (mp) were determined with a Mel±Temp II melting
point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on a Brucker DRX-200 spectrometer.
Chemical shifts were measured in parts per million (d)
relative to tetramethylsilane (TMS) or chloroform as the
internal standard. Coupling constants (J values) are in
Hertz (Hz). Multiplicities are designated as singlet (s),
broad singlet (br s), doublet (d), triplet (t), quartet (q), and
multiplet (m). Infrared spectra (IR) were obtained on a Bio-
Rad FTS 155 spectrometer. Absorptions are reported in
wave numbers (cm21) and the spectra are calibrated against
the 1601 cm21 band of a polystyrene ®lm. Optical rotations
(in degrees, 8) were recorded on a Perkin±Elmer Model 343
polarimeter at the sodium D line. Concentrations were
reported in g/100 mL. High resolution mass spectra
(HRMS) were obtained on JEOL SX-102A, using either
ammonia chemical ionization (CI) or electron impact (EI).
In conclusion, we have developed novel and useful cleavage
methods for the Merri®eld resin based carbamates and
carbonates which require no additional linker for anchoring
amines, phenols, and alcohols to the resin other than the
functional group constructed during the synthesis. This
Merri®eld resin-bound benzyloxycarbonyl linkage is stable
to moderately strong bases such as piperidine, and it shows
better stability against acids such as dilute tri¯uoroacetic
acid. The direct transformation of benzyl carbamates and
benzyloxycarbonyl resins into amides and esters has various
advantages including mild and ef®cient reaction conditions,
experimental convenience, and material ef®ciency. This
methodology also gives high yields and purity, ensures
total preservation of the stereochemistry, and therefore
permits the construction of long chains of chiral amides
and esters. The Merri®eld resin-bound benzyloxycarbonyl
linkers would also allow the construction of both peptide
and organic combinatorial libraries in a bi-directional
fashion. This protocol should expand the utility of com-
mercially available Merri®eld resin and hydroxymethyl
resin and tremendously broaden the scope of the new
synthetic procedure to the solid-phase combinatorial synthe-
sis of natural products of pharmacological interest.
Currently, we are in the process of using this Lewis acid
catalyzed cleavage method to the combinatorial synthesis of
radiosumin libraries and those results will be reported in due
course.
General procedure for the conversion of benzyl
carbamates into amides
To a stirred solution of benzyl carbamates (0.46 mmol) in
CH2Cl2 (2.3 mL) was added, under an argon atmosphere,
tin(II) bromide (0.25 mmol) followed by acetyl bromide
or benzoyl chloride (2.3 mmol) at room temperature. After
the carbamates disappeared, a solution of triethylamine
(0.69 mmol) in 2.5 mL CH2Cl2 was introduced dropwise
and the mixture was then stirred at room temperature until
the reaction was completed. The reaction was monitored by
TLC using MeOH/CH2Cl2 (20:80) or EtOAc/hexane
(30:70) as eluting system. After dilution with EtOAc, the
mixture was washed with 5% NaHCO3, 5% HCl and satu-
rated NaCl solutions. The organic layer was dried (Na2SO4),
®ltered, and concentrated. The resulting crude products
were puri®ed by column chromatography and eluted with
a EtOAc/hexane system to afford the pure products.

8872
W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
General procedure for the synthesis of dipeptides such as
Z-alaninylisoleucine ethyl ester
(m, 1H), 4.60±4.67 (m, 1H), 6.61 (br d, 1H Jˆ7.4 Hz), 7.02
(br d, 1H, Jˆ8.4 Hz); 13C NMR (CDCl3/TMS) d 11.56,
14.14, 15.41, 18.49, 23.00, 25.00, 37.58, 48.70, 56.63,
61.14, 169.91, 171.53, 172.40; HRMS Calcd for
C13H24N2O4 (M1) 272.1736, found 272.1755.
Isoleucine (1.17 g, 8.93 mmol) was dissolved in EtOH
(40 mL) in a ¯ame-dried ¯ask equipped with a magnetic
stirrer. To this stirred solution was added dropwise, under
argon, a solution of thionyl chloride in EtOH (5 mL, 7 M).
The reaction mixture was re¯uxed for 6 h, and then concen-
trated under reduced pressure. The resulting crude material
was dissolved in CH2Cl2 (30 mL). To this solution was
added triethylamine (1.8 mL, 13.39 mmol) at 08C. The
reaction was stirred for 15 min. and Z-alanine (1.99 g,
8.93 mmol) in CH2Cl2 (20 mL) was added via a cannula.
1,3-Diisopropylcarbodiimide (DIC) (1.53 mL, 9.82 mmol)
was then added with stirring. After 24 h, the reaction
mixture was concentrated, and the resulting solid was
washed with cold EtOAc. The ®ltrate was concentrated
under reduced pressure and diluted with ether (250 mL).
The ether layer was washed with 10% HCl (40 mL), 5%
NaHCO3 (40 mL), and saturated NaCl (40 mL) solutions.
The organic layer was dried (Na2SO4), ®ltered, and concen-
trated. The resulting crude oil was puri®ed by column
chromatography eluting with EtOAc/hexane (40:60).
Z-alaninylisoleucine methyl ester (2.3 g, 92%) was obtained
as a white solid.
Ac-l-Phe-l-Leu-OMe (5). Mp 126±1288C; [a]2D5ˆ218.28
(c 4.0, MeOH); IR (CHCl3): nˆ3285, 3077, 2963, 1744,
;
1657, 1549, 1200, 1153 cm21 1H NMR (200 MHz,
CDCl3) d 0.88 (d, 6H, Jˆ5.5 Hz), 1.46±1.59 (m, 3H),
1.96 (s, 3H), 3.06 (d, 2H, Jˆ6.9 Hz), 3.69 (s, 3H), 4.48±
4.55 (m, 1H), 4.60±4.81 (m, 1H), 6.34±6.43 (m, 2H), 7.23±
7.25 (m, 5H); 13C NMR (CDCl3/TMS) d 21.87, 22.63,
23.08, 24.72, 38.28, 41.34, 50.90, 52.22, 54.30, 126.95,
128.56, 129.31, 136.42, 169.95, 170.71, 172.62; HRMS
Calcd for C18H26N2O4 (M1) 334.1893, found 334.1895.
Bz-l-Ala-OMe (6). Mp 52±538C; [a]2D5ˆ138.68 (c 2.9,
CHCl3); IR (CHCl3): nˆ3318, 2988, 1744, 1643, 1543,
1
1454 cm21; H NMR (200 MHz, CDCl3) d 1.52 (d, 3H,
Jˆ7.2 Hz), 3.78 (s, 3H), 4.71±4.91 (m, 1H), 6.83 (br d,
1H, Jˆ5.5 Hz), 7.39±7.51 (m, 3H), 7.78±7.83 (m, 2H);
13C NMR (CDCl3/TMS) d 18.56, 48.41, 52.52, 126.99,
128.51, 131.67, 133.82, 166.76, 173.65; HRMS Calcd for
C11H13NO3 (M1) 207.0895, found 207.0898.
Bz-l-Leu-OMe (7). Mp 102.5±103.58C, lit.34 103±1048C;
[a]D25ˆ222.78 (c 6.25, EtOH), lit.34 [a]2D5ˆ2228 (c 3.6,
EtOH); IR (CHCl3): nˆ3285, 3069, 2955, 1751, 1637,
Spectral data
Ac-l-Phe-OMe (1). Mp 88±898C, lit.30 87±88.58C;
[a]D25ˆ1101.28 (c 2.4, CHCl3), lit.30 [a]2D5ˆ1105.38 (c 1,
CHCl3), lit.31 [a]D25ˆ196.48 (c 1, CHCl3); IR (CHCl3):
1
1541, 1228, 1163 cm21; H NMR (200 MHz, CDCl3) d
0.96±1.01 (m, 6H), 1.62±1.81 (m, 3H), 3.78 (s, 3H),
4.84±4.88 (m, 1H), 6.55 (br d, 1H, Jˆ7.3 Hz), 7.40±7.52
(m, 3H), 7.78±7.83 (m, 2H); 13C NMR (CDCl3/TMS) d
22.00, 22.79, 24.93, 41.80, 51.06, 52.34, 127.01, 128.52,
131.68, 133. 86, 167.05, 173.69; HRMS Calcd for
C14H19NO3 (M1) 249.1365, found 249.1364.
nˆ3331, 3036, 2963, 1784, 1651, 1535, 1221 cm21; H
1
NMR (200 MHz, CDCl3) d 1.98 (s, 3H), 3.09±3.14 (m,
2H), 3.72 (s, 3H), 4.88 (m, 1H), 5.95 (br d, 1H, Jˆ
6.0 Hz), 7.06±7.11 (m, 2H), 7.23±7.34 (m, 3H)32; 13C
NMR (CDCl3/TMS) d 23.11, 37.79, 52.30, 53.06, 127.10,
128.55, 129.19, 135.77, 169.57, 172.06; HRMS Calcd for
C12H15NO3 (M1) 221.1052, found 221.1036.
Bz-l-Pro-OMe (8). Mp 90±918C, lit.35 89±918C;
[a]D25ˆ299.38 (c 5.85, MeOH), lit.35 [a]2D5ˆ2100.18 (c
1.17, MeOH); IR (CHCl3): nˆ2951, 2878, 1742, 1624,
Ac-l-Met-OBn (2). [a]2D5ˆ225.78 (c 1.7, MeOH); IR
(CHCl3): nˆ3285, 3063, 2920, 1744, 1655, 1541,
1
1572, 1448 cm21; H NMR (200 MHz, CDCl3) d 1.81±
1
1211 cm21; H NMR (200 MHz, CDCl3) d 1.88±2.17 (m,
2.34 (m, 4H), 3.50±3.71 (m, 2H), 3.77 (s, 3H), 4.36±4.68
(m, 1H), 7.36±7.59 (m, 5H)36; 13C NMR (CDCl3/TMS) d
25.33, 29.34, 49.87, 52.20, 59.08, 126.46, 127.24, 128.18,
129.72, 130.13, 136.13, 169.62, 172.72; HRMS Calcd for
C13H15NO3 (M1) 233.1052, found 233.1063.
8H), 2.41±2.50 (m, 2H), 4.70±4.81 (m, 1H), 5.18 (d, 2H,
Jˆ1.9 Hz), 6.27 (br d, 1H, Jˆ7.4 Hz), 7.32±7.45 (m, 5H);
13C NMR (CDCl3/TMS) d 15.44, 23.16, 29.83, 31.73,
51.68, 67.36, 128.34, 128.56, 128.64, 135.11, 169.84,
171.90; HRMS Calcd for C14H19NO3S (M1) 281.1086,
found 281.1079.
Bz-l-Phe-l-Leu-OMe (9). Mp 144±1478C, lit.37 163±
1668C; [a]2D5ˆ245.98 (c 4.35, MeOH); IR (CHCl3):
nˆ3291, 3067, 2957, 1751, 1637, 1543, 1489, 1207 cm21
;
Ac-l-Ser(OAc)-OMe (3). Mp 55±568C; [a]2D5ˆ168.48 (c
4.85, CHCl3); IR (CHCl3): n ˆ3299, 3063, 2949, 1744,
1H NMR (200 MHz, CDCl3) d 0.77 (d, 6H, Jˆ5.14 Hz),
1.35±1.55 (m, 3H), 3.12 (m, 2H), 3.64 (s, 3H), 4.43±4.52
(m, 1H), 4.84±5.00 (m, 1H), 6.50 (br d, 1H, Jˆ7.5 Hz), 6.64
(br d, 1H, Jˆ8.8 Hz), 7.01±7.66 (m, 10H); 13C NMR
(CDCl3/TMS) d 21.84, 22.62, 24.72, 38.30, 41.29, 50.98,
52.28, 54.59, 127.02, 128.64, 129.45, 131.82, 133.71,
136.43, 167.20, 170.66, 172.66; HRMS Calcd for
C23H28N2O4 (M1) 396.2049, found 396.2057.
1657, 1543, 1375, 1227 cm21
;
1H NMR (200 MHz,
CDCl3) d 2.05 (s, 6H), 3.78 (s, 3H), 4.30±4.51 (m, 2H),
4.82±4.90 (m, 1H), 6.25 (br d, 1H, Jˆ6.0 Hz)33; 13C NMR
(CDCl3/TMS) d 20.47, 22. 79, 51.56, 52.66, 63.74, 169.97,
170.46; HRMS Calcd for C8H13NO5 (M1) 203.0794, found
203.0784.
Ac-l-Ala-l-Ile-OEt (4). Mp 103±1068C; [a]2D5ˆ219.38 (c
4.75, CHCl3); IR (CHCl3): nˆ3285, 2963, 1744, 1643,
Resin-bound phenylalanine lithium salt (11).20,38 The
hydroxymethyl resin39 (300 mg, 0.48 mmol) was suspended
in dry CH2Cl2 (1.9 mL) and treated with p-nitrophenyl
chloroformate (290.3 mg, 1.44 mmol) and DIPEA
1543, 1448, 1259, 1024 cm21
;
1H NMR (200 MHz,
CDCl3) d 0.85±0.92 (m, 6H), 1.18±1.41 (m, 8H), 1.87±
1.97 (m, 1H), 1.99 (s, 3H), 4.12±4.24 (m, 2H), 4.45±4.53

W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
8873
(0.26 mL, 1.44 mmol) under an argon atmosphere. The
Spectral data
mixture was agitated for 8 h at room temperature, ¯ushed
and washed with DMF (2 mL£2) and CH2Cl2 (2 mL£2).
The resulting resin was dried in vacuo to provide p-nitro-
phenyl carbonate resin. The carbonate resin (300 mg,
0.48 mmol) was then treated with freshly prepared phenyl-
alanine lithium salt (246.5 mg, 1.44 mmol) in DMF
(1.5 mL) at room temperature. The mixture was agitated
for 24 h, ®ltered and washed with H2O (2 mL£2), DMF
(2 mL£2) and CH2Cl2 (2 mL£2) to afford the resin-bound
phenylalanine lithium salt 11.
Bz-l-Phe-OMe (15). [a]2D5ˆ180.58 (c 1.89, CH2Cl2); IR
(CH2Cl2): nˆ3318, 3063, 3030, 2952, 1744, 1643, 1535,
1489, 1217, 700 cm21 1H NMR (200 MHz, CDCl3) d
;
3.13±3.38 (m, 2H), 3.76 (s, 3H), 5.09 (q, 1H, Jˆ7.50 Hz),
6.62 (d, br, Jˆ7.25 Hz), 7.12±7.74 (m, 10H); 13C NMR
(CDCl3/TMS) d 37.76, 52.28, 53.46, 126.92, 127.06,
128.48, 128.50, 129.21, 131.64, 133.77, 135.81, 166.763,
171.97; HRMS Calcd for C17H17NO3 (M1) 283.1208,
found 283.1214.
Ac-l-Ile-OBn (16). [a]2D5ˆ1144.58 (c 0.87, CH2Cl2); IR
(CH2Cl2): nˆ3306, 3065, 2870, 1670, 1543, 1460,
Resin-bound phenylalaninylleucine methyl ester (12). To
a suspension of resin-bound phenylalanine lithium salt 11
(200 mg, 0.32 mmol) in DMF (2.3 mL) was added HBTU
(364.1 mg, 0.96 mmol) followed by leucine methyl ester
1
1211 cm21; H NMR (200 MHz, CDCl3) d 0.84 (d, 3H,
Jˆ7.4 Hz), 0.87 (t, 3H, Jˆ7.0 Hz), 1.13±1.38 (m, 2H),
1.85±1.95 (m, 1H), 2.01 (s, 3H), 4.66 (dd, 1H,
Jˆ4.92 Hz), 5.08±5.23 (m, 2H), 6.33 (d, 1H, Jˆ8.54 Hz),
7.28±7.38 (m, 5H); 13C NMR (CDCl3/TMS) d 11.31, 15.21,
22.77, 24.85, 37.63, 56.26, 66.66, 128.06, 128.17, 128.32,
135.11, 169.95, 171.99; HRMS Calcd for C15H21NO3 (M1)
263.1521, found 263.1521.
(173.8 mg,
0.96 mmol)
and
DIPEA
(0.366 mL,
1.92 mmol) under an argon atmosphere. The mixture was
agitated for 3 h at room temperature. The resin was then
¯ushed free of the liquids, washed with DMF (2£2 mL)
followed by CH2Cl2 (2£2 mL) and DMF (2£2 mL) to afford
the polymeric Phe-Leu-OMe 12.
Bz-l-Ile-OBn (17). [a]2D5ˆ1268.38 (c 0.87, CH2Cl2); IR
(CH2Cl2): nˆ3331, 3065, 3033, 2966, 2935, 2877, 1739,
General procedure for the preparation of resin-bound
carbamates 13a and carbonates 13b
1
1644, 1603, 1185, 712 cm21; H NMR (200 MHz, CDCl3)
d 0.90 (d, 3H, Jˆ7.31 Hz), 0.96 (t, 3H, Jˆ3.85 Hz), 1.21±
1.49 (m, 2H), 2.00±2.06 (m, 1H), 4.89 (dd, 1H, Jˆ4.85,
4.89 Hz), 5.13±5.29 (m, 2H), 6.78 (d, 1H, Jˆ8.42 Hz),
7.37±7.82 (m, 10H); 13C NMR (CDCl3/TMS) d 11.47,
15.41, 25.13, 38.15, 56.72, 66.97, 126.93, 128.24, 128.33,
128.44, 128.47, 131.55, 134.00, 135.148, 167.05, 171.93;
HRMS Calcd for C20H23NO3 (M1) 325.1678, found
325.1676.
(A) Amines. The hydroxymethyl resin (200 mg, 0.32 mmol)
was swelled with CH2Cl2 (1.5 mL) and treated with p-nitro-
phenyl chloroformate (193.5 mg, 0.96 mmol) and DIPEA
(0.17 mL, 0.96 mmol) under an argon atmosphere. The
mixture was agitated for 8 h at room temperature, ¯ushed
and washed with DMF (2 mL£2) and CH2Cl2 (2 mL£2).
The resin was dried in vacuo to provide p-nitrophenyl
carbonate resin. The resulting carbonate resin (300 mg,
0.48 mmol) in DMF (1.9 mL) was added to the desired
substrate hydrochloride amine salt (1.44 mmol) and N,
N-diisopropylethylamine (0.5 mL, 2.88 mmol) and left to
shake at room temperature for 6 h. The resin was then
washed with DMF (2 mL£3) and CH2Cl2 (2 mL£3). (B)
Phenols. Same as condition A, except DIPEA was changed
to Cs2CO3 and the mixture was agitated for 24 h. (C)
Aliphatic alcohol. Same as condition B, except Cs2CO3
was changed to DMAP.
Ac-l-Pro-OBn (18). [a]2D3ˆ264.48 (c 1.79, CH2Cl2); IR
(CH2Cl2): nˆ3466, 2959, 1741, 1634, 1451, 1172 cm21
;
1H NMR (200 MHz, CDCl3) d 1.92±2.07 (m, 2H), 2.10
(s, 3H), 2.15±2.20 (m, 2H), 3.49±3.68 (m, 2H), 4.52±4.57
(m, 1H), 5.16±5.53 (m, 2H), 7.30±7.35 (m, 5H); 13C NMR
(CDCl3/TMS) d 22.15, 24.66, 29.28, 47.65, 58.52, 66.63,
127.94, 128.44, 128.69, 169.36, 172.10; HRMS Calcd for
C14H17NO3 (M1) 247.1208, found 247.1209.
Bz-l-Pro-OBn (19). [a]2D5ˆ256.98 (c 2.21, CH2Cl2); IR
(CH2Cl2): nˆ3466, 3036, 1742, 1624, 1570, 1495,
1
787 cm21; H NMR (200 MHz, CDCl3) d 1.81±2.07 (m,
General procedure for the cleavage of resin-bound
carbamates 13a and carbonates 13b
2H), 2.23±2.34 (m, 2H), 3.49±3.84 (m, 2H), 4.70±4.76
(m, 1H), 5.02±5.29 (m, 2H), 7.26±8.08 (m, 10H); 13C
NMR (CDCl3/TMS) d 25.13, 29.16, 49.77, 59.11, 66.65,
127.053, 127.90, 128.07, 128.16, 129.80, 130.04, 133.06,
135.89, 169.67, 171.88; HRMS Calcd for C19H19NO3
(M1) 309.1365, found 309.1363.
(A) Carbamates. To the carbamate resin (200 mg,
0.32 mmol), swelled in CH2Cl2 (1.6 mL), was added dry
zinc(II) bromide (36 mg, 0.16 mmol) and acetyl bromide
or benzoyl chloride (0.07 mL, 0.96 mmol) under an argon
atmosphere. The mixture was stirred for 24 h at room
temperature, then a solution of triethylamine (0.07 mL,
0.48 mmol) in 0.38 mL CH2Cl2 was added dropwise. After
the reaction was completed, the resin was collected by ®ltra-
tion. The ®ltrate was washed with 5% NaHCO3, 5% HCl
and saturated NaCl solutions. The organic layer was dried
(MgSO4), concentrated, and chromatographed on silica gel
to yield the desired amides 14a. (B) Carbonates. Same as
condition A, except the addition of triethylamine was
omitted.
Ac-l-Leu-l-Pro-OBn (20). [a]2D4ˆ283.38 (c 2.07,
CH2Cl2); IR (CH2Cl2): nˆ3466, 3063, 2961, 2866, 1742,
1
1632, 1537, 1441, 1373, 1169, 1093, 738 cm21; H NMR
(200 MHz, CDCl3) d 1.04 (dd, 6H, Jˆ6.834, 7.026 Hz),
1.60±1.64 (m, 2H), 1.75±1.84 (m, 1H), 1.88 (s, 3H),
2.04±2.28 (m, 4H), 3.73±3.92 (m, 2H), 4.69 (t, 1H,
Jˆ5.24 Hz), 4.92 (q, 1H, Jˆ8.43 Hz), 5.16±5.31 (m, 2H),
6.37 (d, 1H, Jˆ8.54 Hz), 7.37±7.42 (m, 5H); 13C NMR
(CDCl3/TMS) d 22.02, 22.93, 24.72, 24.85, 28.98, 41.46,

8874
W.-R. Li et al. / Tetrahedron 56 (2000) 8867±8875
46.90, 49.14, 59.00, 66.79, 128.05, 128.22, 128.51, 135.87,
169.78, 171.59, 171.70; HRMS Calcd for C20H28N2O4
(M1) 360.2049, found 360.2049.
171.01; HRMS Calcd for C11H14O2 (M1) 178.0994,
found 178.1007.
Bz-l-Leu-l-Pro-OBn (21). [a]2D5ˆ253.68 (c 0.75,
CH2Cl2); IR (CH2Cl2): nˆ3425, 2958, 1744, 1579, 1450,
Acknowledgements
1
1170 cm21; H NMR (200 MHz, CDCl3) d 0.97 (dd, 6H,
The authors are grateful to the National Science Council,
ROC, for the ®nancial support (NSC 87-2113-M-008-008)
of this work.
Jˆ6.438, 6.350 Hz), 1.58±1.76 (m, 3H), 1.99±2.10 (m,
2H), 2.23±2.25 (m, 2H), 3.68±3.91 (m, 2H), 4.61 (m,
1H), 5.06±5.25 (m, 3H), 7.26±7.45 (m, 10H), 8.09 (d, 1H,
Jˆ6.87 Hz); 13C NMR (CDCl3/TMS) d 21.83, 23.37, 24.71,
28.98, 41.74, 46.97, 49.34, 58.98, 66.96, 127.14, 128.15,
128.32, 128.55, 130.00, 131.58, 133.80, 135.45, 167.19,
171.62, 171.82; HRMS Calcd for C25H30N2O4 (M1)
422.2206, found 422.2205.
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1448, 1292, 744, 698 cm21; H NMR (200 MHz, CDCl3)
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nˆ3499, 3028, 1755, 1707, 1439, 1277, 1163, 1117, 914,
860, 760 cm21; 1H NMR (200 MHz, CDCl3) d 2.32 (s, 3H),
3.91 (s, 3H), 7.14±7.20 (m, 2H), 8.04±8.10 (m, 2H); 13C
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Â
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1
nˆ1718, 1597, 1502, 1282, 1265, 1169 cm21; H NMR
Â
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(200 MHz, CDCl3) d 3.93 (s, 3H), 7.28±7.33 (m, 2H),
7.48±7.65 (m, 3H), 8.09±8.22 (m, 4H); 13C NMR (CDCl3/
TMS) d 52.12, 121.68, 127.68, 128.59, 129.01, 130.15,
131.14, 133.80, 154.54, 164.54, 166.25; HRMS Calcd for
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3077, 3003, 1761, 1680, 1591, 1489, 1435, 1360, 1283,
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1
3H), 2.57 (s, 3H), 7.27±7.82 (m, 4H); 13C NMR (CDCl3/
TMS) d 20.78, 26.42, 121.19, 125.54, 126.22, 129.43,
138.25, 150.59, 169.02, 196.64; HRMS Calcd for
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Â
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Lett. 1998, 39, 3429.
1769, 1697, 1603, 1456, 1368, 1188 cm21 1H NMR
;
(200 MHz, CDCl3) d 2.39 (s, 3H), 7.15±7.89 (m, 4H),
10.1 (s, 1H); 13C NMR (CDCl3/TMS) d 20.78, 123.42,
126.06, 131.28, 134.61, 135.28, 151.10, 169.26, 188.83;
HRMS Calcd for C9H8O3 (M1) 164.0473, found 164.0420.
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3-Phenylpropyl acetate (27). IR (CH2Cl2): nˆ3059, 3027,
1736, 1495, 1446, 1389, 1367, 1238, 1036, 742, 694 cm21
;
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7.16±7.28 (m, 5H); 13C NMR (CDCl3/TMS) d 20.90,
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