Deprotection of t-butyl esters of amino acid derivatives by nitric acid in dichloromethane

Article abstract of DOI:10.1016/S0040-4020(00)00280-5

The extension of the deprotection procedure of t-butylated carboxyl function using HNO₃ in CH₂Cl₂ to a number of appropriately selected N-Z- derivatives of natural amino acid esters was investigated. The method was found to work effectively with alanine, phenylalanine, serine and the dipeptide aspartame, but the reagent brought about a number of unwanted transformations with tyrosine, methionine and tryptophan. Suitable protection of functions present in the latter ones allowed selective ester dealkylation, but tyrosine underwent unavoidable fast preliminary ring nitration. 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00280-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3625±3633
Deprotection of t-Butyl Esters of Amino Acid Derivatives by
Nitric Acid in Dichloromethane
*
Paolo Strazzolini, Massimo Scuccato and Angelo G. Giumanini
Department of Chemical Sciences and Technologies, University of Udine, via del Cotoni®cio 108, I-33100 Udine, Italy
Received 24 January 2000; revised 13 March 2000; accepted 30 March 2000
AbstractÐThe extension of the deprotection procedure of t-butylated carboxyl function using HNO3 in CH2Cl2 to a number of appropriately
selected N-Z-derivatives of natural amino acid esters was investigated. The method was found to work effectively with alanine, phenyl-
alanine, serine and the dipeptide aspartame, but the reagent brought about a number of unwanted transformations with tyrosine, methionine
and tryptophan. Suitable protection of functions present in the latter ones allowed selective ester dealkylation, but tyrosine underwent
unavoidable fast preliminary ring nitration. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
presence of a sensitive urethane with the procedure to be
tested (Scheme 1). Moreover, removal of the t-butyl protec-
tion, usually accomplished with CF3COOH (TFA),5
incurred in the formation of side products in some
instances,6 mainly owing to the alkylating action of the
t-butyl cation,7 therefore avoidance of these inconveniences
would be highly desirable. The selection of the six amino
acids to be tested, namely l-alanine (l-Ala, 1a), l-phenyl-
alanine (l-Phe, 2a), l-serine (l-Ser, 3a), l-tyrosine (l-Tyr,
4a), l-methionine (l-Met, 5a) and l-tryptophan (l-Trp, 6a),
as well as the dipeptide N-l-a-aspartyl-l-phenylalanine
1-methyl ester (aspartame, APM, 7a), was effected with
the aim of collecting experimental indications on the viabi-
lity of the use of HNO3 in the presence of a variety of
chemical functions (see Fig. 1).
t-Butylation of free carboxylic acids is a widespread proce-
dure for the protection of the carboxyl function, receiving
continuous attention in many ®elds of chemistry.1 More-
over, this kind of protection has found a variety of applica-
tions in peptide synthesis, both in the semipermanent
masking of the a-carboxyl group of amino acids2 and for
the purpose of protecting some side chain functions.3 We
have recently published a convenient method of deprotec-
tion of t-butyl esters of carboxylic acids employing HNO3 in
CH2Cl2:4 therefore, it appeared of interest to test the proce-
dure with t-butyl esters of amino acids presenting an N-acyl
substituent and possibly bearing sensitive groups in their
side chain.
We chose a common acyl moiety, namely the phenyl-
methoxycarbonyl (benzyloxycarbonyl, Z) group, which is
widely used as an easily removable amino protection in
peptide synthesis, in order to obtain N-acyl derivatives of
a number of natural amino acids: this choice should permit
us to simultaneously observe the compatibility of the
Results and Discussion
In the course of this work, besides the common N-Z-deri-
vatives 3b and 4b of the hydroxylated amino acids outlined
above (3a and 4a), it seemed of interest to prepare the
Scheme 1.
Keywords: amino acids and derivatives; deblocking; esters; nitric acid and derivatives; protecting groups.
* Corresponding author. Tel.: 139-0432-55-8870; fax: 139-0432-55-8803; e-mail: strazzolini@dstc.uniud.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00280-5

3626
P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
Figure 1.
corresponding side chain protected compounds, in the form
of phenylmethoxy carbonates 8 and 9. In the case of l-Tyr
(4a), the goal was easily obtained by using the well estab-
lished Bergmann and Zervas procedure,8 affording the N,O-
diprotected derivative 9 in excellent yield; whereas, under
the same conditions, the corresponding l-Ser derivative 8
was formed only in poor yields. Even direct treatment of Z-
l-Ser (3b) with benzylchloroformate according to a
described method9 gave unsatisfactory results, most likely
owing to the faster decomposition of the acylating agent
caused by the amine used as a catalyst.10 At variance with
an indication reported in the literature,11 we found that the
use of AcCl in CH2Cl212 on 3b gave the O-acetyl protected
N-Z-Ser (10) in excellent yield, which in turn could be
easily transformed into the corresponding t-butyl ester 11;
the acetyl group in the latter could be selectively removed
by hydrazine affording 3c.
likely induced by the presence of DMAP (Scheme 3).17
On the other hand, any attempt at avoiding the use of the
base was unsuccessful, because it is essential to induce the
reaction between formed acylurea 15 and t-BuOH.18
Method B, a priori preferred in transforming the dipeptide
Z-APM (7b) into the ester 7c (88% isolated yield), in the
case of compounds 3b and 4b afforded the corresponding di-
t-butyl derivatives 16 and 17 in good yields; this procedure
proved to be quite ef®cient in converting the O-acetyl deri-
vative of Z-l-Ser (10) and N,O-diZ-l-Tyr (9) into the corre-
sponding esters 11 and 18, respectively, whereas failed with
the di[(phenylmethoxy)carbonyl] derivative 8 which, under
these conditions, evidenced instability of the carbonate
moiety. Method C was then used successfully for the
preparation of 3c, 4c, the nitro derivative 19 and the N,O-
diZ ester 20, although in the latter case some unavoidable
elimination to 14 occurred to depress the yields (Scheme 4).
Convenient preparation of the selected protected amino acid
t-butyl esters implied experiments apt for evaluating the
relative advantages of the use of some procedures among
the many reported in the literature:13 (A) t-BuOH in the
presence of dicyclohexylcarbodiimide (DCC) and 4-di-
methylaminopyridine (DMAP),1b (B) 2-methylpropene
under acid catalysis,14 and (C) t-butyl bromide and K2CO3
in the presence of a phase transfer agent15 (Scheme 2, Table
1). Method A, considered of choice because of its simplicity
on the laboratory scale, gave satisfactory results with Z-l-
Ala (1b), Z-l-Phe (2b), Z-l-Met (5b), Z-l-Trp (6b) and Nin-
formyl-Z-l-Trp (12), but failed with the side chain OH-
unprotected Z-l-Ser (3b), Z-l-Tyr (4b) and 3-nitro-N-Z-l-
Tyr (13) which, as expected,16 gave intractable polymeric
mixtures. The procedure proved to be equally unsuitable in
the case of N,O-diZ-l-Tyr (9), affording a complex mixture
of decomposition products, as well as for l-Ser O-acyl deri-
vatives 8 and 10 which, besides the expected esteri®cation,
underwent an elimination reaction to 1,1-dimethylethyl 2-
[(phenylmethoxy)carbonyl]amino-2-propenoate (14), most
Deprotection of the carboxylic function of the examined
t-butyl esters by the proposed method (Scheme 1) proceeded
smoothly by the action of 3±4 equiv. of HNO3 in CH2Cl2 at
08C during 2 h (Table 2) with some exceptions (see below).
Remarkable features of the procedure are: the optical activ-
ity was fully preserved for all the tested compounds; no ring
nitration occurred on l-Phe derivative 2c; no side chain
oxidation and/or nitration was observed in the case of the
l-Ser derivative 3c; the diacylated l-Ser derivatives 11 and
20 underwent selective removal of the t-butyl group from
the ester function. It is noteworthy that the present condi-
tions effected, although to a partial extent, the seldom
reported19 selective removal of the carboxyl protection on
the di-t-butylated product 16 (Scheme 5, Table 2): the so far
standard deprotection procedure using TFA could not be
induced to exhibit such behaviour to any extent.20 The
case of the t-butyl derivative of APT (7c) is signi®cant
because of the selectivity shown in the removal of only
one alkyl ester group (Scheme 6).
Since we found that the l-Tyr derivatives 4b and 4c under-
went prompt quantitative ring nitration at the 3-position to
13 and 19, respectively, when exposed to only 1 equiv. of
HNO3, it was not surprising that the fully protected deriva-
tive 17 evidenced rapid 3-nitration, although accompanied
by dealkylation of the sole phenol oxygen to yield 19.
Nevertheless, when the nitrolysis reaction was performed
Scheme 2.

P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
Table 1. t-Butyl esters of Z-amino acids and derivatives prepared according to Scheme 2
3627
Entry
Substrate
G
Methoda
Product
G
Yield (%)b
1
2
3
4
5
6
7
8
9
1b
2b
3b
3b
8
10
4b
4b
9
CH3
A
A
C
B
C
B
C
B
B
1c
2c
3c
16
20
11
4c
17
18
CH3
58
71
73
80
30c
70
60
57
63
CH2Ph
CH2OH
CH2OH
CH2OZ
CH2Ph
CH2OH
CH2OCMe3
CH2OZ
CH2OAc
CH2(C6H4)p-OH
CH2(C6H4)p-OC(CH3)3
CH2(C6H4)p-OZ
CH2OAc
CH2(C6H4)p-OH
CH2(C6H4)p±OH
CH2(C6H4)p-OZ
10
11
13
5b
C
A
19
5c
67
58
(CH2)2±S±CH3
(CH2)2-S-CH3
12
13
6b
12
A
A
6c
23
30
82
a See Experimental.
b Yields refer to isolated products.
c Some 12% of 1,1-dimethylethyl 2-[[(Phenylmethoxy)carbonyl]amino]-2-propenoate (14) was also isolated.
Scheme 3.
Scheme 4.
Scheme 5.

3628
P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
Table 2. Nitrolysis of t-butyl esters of Z-amino acids and derivatives
according to Scheme 1
on the diacylated ester 18, a suitable building block in
peptide synthesis,21 ring nitration did not occur and selective
deblocking of the carboxyl function was achieved affording
9. The l-Met derivatives 5b and 5c under nitrolytic condi-
tions underwent faster transformation to the corresponding
sulfoxides 21 and 22, after a well known pattern of reac-
tion.22
a
Entry Substrate HNO3
Conversion (%)b Product Yield (%)c
1
2
3
4
5
6
7
8
1c
2c
3c
16
20
11
4c
17
18
5c
22
6c
23
7c
3
3
3
3
4
4
3
3
4
3
4
3
4
3
98
98
96
84
94
95
99
68
95
99
92
99
94
95
1b
2b
3b
25
8
10
4b
4b
9
5b
21
6b
12
7b
95
96
89
47d
82
91
0e
The sulfoxide 22 was then completely and selectively
deprotected at the ester function to 21: this reaction
might be of use in some peptide syntheses when l-
Met, due to its known sensitivity to oxidation,23 is
®rst introduced in the form of its sulfoxide to be even-
tually reduced.24
0f
9
91
0g
85
0h
91
89
10
11
12
13
14
As could be expected by the ascertained sensitivity of
the indole system to the action of strong acids,25 the
nitrolysis procedure on the l-Trp derivative 6c gave
an intractable tarry reaction mixture. Following the indi-
cation reported in the literature25 that Nin-formylation is
widely employed as a suitable protection of the ring, we
prepared the Nin-protected derivative 23 as reported in
Scheme 7. Subsequent nitrolysis of the ester 23
proceeded as desired to 12.
a HNO3 (mol) per mole of substrate.
b Reported conversions were determined by 1H NMR, on intact reaction
mixtures after dilution with CH2Cl2, washing with 30% aqueous NaCl,
drying over Na2SO4, evaporation of the solvent and redissolution in
CDCl3.
c Yields refer to isolated products.
d Compounds 3b (22%) and 3c (15%) were also formed.
e Complete 3-nitration accompanied by some 36% nitrolysis of the ester
was observed. Compounds 4b and 4c were promptly 3-nitrated in the
presence of 1.1 equiv. of HNO3.
f Essentially compound 19 was formed.
g Complete oxidation to sulfoxide was observed. Compound 5b was
transformed into the sulfoxide 21 by treatment with 1.2 equiv. of
HNO3.
In conclusion, the present work has ®rmly established the
feasibility of the selective nitrolysis deprotection of amino
acid t-butyl esters in general and supplied alternatives in the
cases where it could not be applied.
h An intractable tarry mixture was obtained.
Scheme 6.
Scheme 7.

P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
3629
Experimental
MeOH). [Lit.29: mp 120±1228C; [a]2D0ˆ214.8 (cˆ0.5;
1
MeOH)]. H and 13C NMR.30
General
N-[(Phenylmethoxy)carbonyl]-l-serine
phenylmethyl
carbonate (8). The compound was obtained by the classic
Bergmann and Zervas's procedure.8 Benzyl chloroformate
(168.0 mmol) was added dropwise during 30 min into a well
stirred solution of l-serine (3a, 80.0 mmol) in 4 M NaOH
(20.0 mL) at 08C, maintaining constant pH by simultaneous
addition of 4 M NaOH (42.0 mL). After completion of the
addition, the reaction mixture was allowed to reach room
temperature, left under stirring for 1 h, washed with Et2O
(2£100 mL) and the pH adjusted to ca. 3 by careful addition
of concentrated HCl. The obtained suspension was extracted
with EtOAc (3£100 mL), then the combined organic phase
was washed with 30% aqueous NaCl, dried over Na2SO4
and the solvent evaporated off: pure 8 was obtained by
repeated fractional crystallizations of the oily residue.
White solid (27% yield): mp (from C6H6) 738C;
[a]2D0ˆ15.0 (cˆ1.0; EtOH). [Lit.31: mp 83±848C;
[a]2D0ˆ14.4 (cˆ1.0; EtOH)].
Unless otherwise speci®ed, reagents and solvents were
commercially available (Aldrich Italia, Milano, Italy) and
used as received. Commercial 100% HNO3 (dˆ1.51) was
purchased from Hydro Chemicals France (Nanterre, France)
and kept at 48C in the dark to avoid decomposition; the acid
was freshly distilled and its titre, averaging ca. 24 M, alka-
limetrically checked prior to use. Anhydrous K2CO3 was
®nely ground and activated by keeping it in vacuo at
1508C for 1 h. TLC analyses and column chromatography
were performed on silica gel 60 from Merck (Darmstadt,
Germany). The course of all the described reactions was
1
monitored by TLC and by a parallel accurate H NMR
quantitative evaluation. Melting points were determined in
open ended capillary tubes by using a Mettler FP 61 auto-
matic apparatus and are uncorrected. Elemental analyses
were obtained by a Carlo Erba CHN/OS 1106 analyzer for
all isolated compounds and found satisfactory. Optical
activities were measured at 208C by an Atago Polax-D
polarimeter at 589 nm in a 1.0 dm tube. IR spectra were
recorded on a Nicolet FTIR Magna 550 spectrophotometer
using the KBr technique. Unless otherwise indicated, 1H and
13C NMR spectra were recorded in CDCl3 on a Bruker AC-
200 spectrometer at 200 and 50 MHz, respectively (s: sing-
let, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad,
sym: symmetrical). The proton chemical shifts are reported
in ppm on the d scale relative to TMS as an internal refer-
ence (0.00); the carbon chemical shifts are reported in ppm
relative to the center line of the CDCl3 triplet (77.00) or,
when Me2SO-d6 was the solvent, the center line of the corre-
sponding heptet (39.50). The coupling constants are given in
Hz. MS measurements were carried out with a Fisons TRIO-
2000 apparatus, working in the positive-ion electron impact
mode (70 eV), by direct introduction of the sample into the
ion source and heating from 50 to 3008C. The ®ve most
intense peaks and the molecular peak for each individual
compound with bracketed intensity values are reported.
N-[(Phenylmethoxy)carbonyl]-l-serine ethanoate (10).
The compound was obtained by a described procedure.12
Pale brownish solid (93% yield): mp (from cyclohexane±
EtOAc) 868C; [a]2D0ˆ220.0 (cˆ2.0; DMF). [Lit.32: mp 88±
1
898C; [a]2D0ˆ218.5 (cˆ2.0; DMF)]. H NMR.33
N-[(Phenylmethoxy)carbonyl]-l-tyrosine phenylmethyl
carbonate (9). The compound was obtained by the proce-
dure employed for 8, the only modi®cation being the careful
control of pH between 9 and 11 during the whole course of
the reaction. White solid (85% yield): mp (from CCl4)
1158C; [a]2D0ˆ15.0 (cˆ10.0; AcOH). [Lit.34: mp 85±
868C; [a]2D0ˆ13.7 (cˆ10.0; AcOH)].
3-Nitro-N-[(phenylmethoxy)carbonyl]-l-tyrosine (13).
The nitro derivative was obtained by direct nitration of the
N-protected amino acid 4b.35 A solution of 100% HNO3
(16.0 mmol) in CH2Cl2 (1.5 mL) was added dropwise into
a stirred solution of 4b (15.0 mmol) in CH2Cl2 (8.5 mL) at
08C. After completion of the addition, the reaction mixture
was allowed to reach room temperature, left under stirring
for 1 h, diluted with CH2Cl2 (100 mL), washed with 30%
aqueous NaCl, dried over Na2SO4 and the solvent evapo-
rated off. Yellow solid (85% yield): mp (from cyclohex-
aneÐt-butyl methyl ether) 1098C; [a]2D0ˆ110.0 (cˆ1.0;
MeOH). [Lit.36: mp 1108C; [a]2D0ˆ112.5 (cˆ2.9; MeOH)].
Occasionally, we prepared large amounts of the N-[(phenyl-
methoxy)carbonyl]-l-amino acids 1b±6b, essentially
according to a described procedure,26 encountering some
dif®culties in obtaining consistently reproducible yields,
probably due to the known aptitude of these compounds
to form very stable complexes with the corresponding
salts.27 A de®nite improvement was obtained by pouring
the ®nal basic reaction mixtures in one lot into an excess
of well stirred 1 M HCl at room temperature. Some of the
substrates (4a, 6a and 7a), were initially dissolved in the
NaHCO3±H2O system by heating and, in the ®rst two
instances, kept in solution on cooling and during the course
of the reaction by the addition of an equal volume of MeOH,
the latter being evaporated at reduced pressure previous to
the ®nal work up. In the case of the tyrosine derivative 6b, in
order to reverse the unavoidable formation of the diacylated
derivative 9 (ca. 11%), the procedure described by Ismai-
lov28 was successfully employed.
4-(Methylsul®nyl)-2-[[(Phenylmethoxy)carbonyl]amino]-
(2S)-butanoic acid (21). The sulfoxide 21 (as diastereo-
isomeric mixture) was prepared by direct oxidation of the
protected amino acid 5b according to a reported proce-
dure.37 Orange oil (98% yield): [a]2D0ˆ211.1 (cˆ0.9;
MeOH). [Lit.38: mp 89±1048C; [a]2D0ˆ1(0.5±5.5)
(AcOH)]. IR (®lm) nmax: 3316s, br; 1715s; 1534m;
1455w; 1410w; 1229s; 1050w; 1003m; 739w; 700w cm21
.
1H NMR d (ppm): 9.14 (br s, 111H, COOH); 7.45±7.20 (m,
515H, C6H5); 6.17 (d, Jˆ7.5 Hz, 1H, NH); 6.09 (d,
Jˆ7.5 Hz, 1H, NH); 5.08 (s, 212H, PhCH2); 4.55±4.28
(m, 111H, CH); 2.98±2.67 (m, 212H, OSCH2); 2.59 (s,
3H, OSCH3); 2.55 (s, 3H, OSCH3); 2.43±2.03 (m, 212H,
CH2). 13C NMR d (ppm): 172.951172.89; 156.081156.12;
N-[N-[(Phenylmethoxy)carbonyl]-l-a-aspartyl]-l-phenyl-
alanine 1-methyl ester (7b). Pale brownish solid (89%
yield): mp (from Et2O) 1178C; [a]2D0ˆ215.9 (cˆ1.6;

3630
P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
136.05; 128.46; 128.13; 128.06; 66.97; 52.81152.53;
49.10149.02; 37.23137.12; 25.79125.35. MS (Tˆ1008C)
m/z: 91 (100); 108 (57); 79 (52); 107 (40); 77 (33); 299 (M1,
,1). Anal. Calcd for C13H17NO5S: C, 52.16; H, 5.73; N,
4.68. Found: C, 51.33; H, 5.87; N, 4.52.
(10.0 mmol) and benzyltriethylammonium chloride
(10.0 mmol) in N,N-dimethylacetamide (75 mL) and the
resulting suspension kept under vigorous mechanical stir-
ring. 2-Bromo-2-methylpropane (480 mmol) was added
dropwise and the resulting mixture stirred at 558C for
24 h. After that time, the reaction mixture was cooled at
room temperature, poured under stirring into cold H2O
(1000 mL) and the oily residue which separated was
extracted with EtOAc (2£200 mL). The combined organic
phase was washed with 30% aqueous NaCl (2£200 mL),
dried and processed as for Method A.
1-Formyl-N-[(phenylmethoxy)carbonyl]-l-tryptophan
(12). Compound 12 was obtained starting from 1-formyl-l-
tryptophan monohydrochloride (24),39 according to a
reported method (Scheme 7).40 White solid (88% yield):
mp (from diisopropyl ether) 808C; [a]2D0ˆ14.5 (cˆ1.1;
MeOH). [Lit.40: mp 108±1108C]. IR (pellet) nmax: 3325s,
br; 2971s, br; 1702s; 1522w; 1459m; 1385m; 1335w;
N-[(Phenylmethoxy)carbonyl]-l-alanine 1,1-dimethyl-
ethyl ester (1c). Colourless oil (58% yield): [a]2D0ˆ222.9
(cˆ1.2; EtOH). [Lit.42: [a]2D0ˆ223.8 (cˆ3.6; EtOH)].
1196s; 1053m; 793w; 747m; 697w cm21 1H NMR d
.
(ppm): (isomer ratio due to formyl protection
E:Zˆ1:1.8)41 9.23 [br s, 0.35H, CHO (E)]; 9.07 (br s, 1H,
COOH); 8.87 [br s, 0.65H, CHO (Z)]; 8.42±8.20 (m 0.65H,
indole-H (Z)]; 7.75±7.12 (m, 8.35H, indole-H1C6H5); 7.06
[br s, 0.65H, indole 2-H (Z)]; 6.74 [br s, 0.35H, indole 2-H
(E)]; 5.59 (d, Jˆ7.9 Hz, 1H, NH); 5.15±4.92 (m, 2H,
PhCH2); 4.83±4.52 (m, 1H, CH); 3.39±2.97 (m, 2H,
CH2). 13C NMR d (ppm): [predominant isomer (Z)]
174.73; 159.79; 156.03; 135.87; 134.07; 131.19; 128.45;
128.19; 128.02; 125.37; 124.55; 118.87; 118.15; 116.07;
109.61; 67.12; 53.53; 27.34. MS (Tˆ1208C) m/z: 130
(100); 158 (74); 77 (26); 108 (24); 79 (23); 366 (M1,
,1). Anal. Calcd for C20H18N2O5: C, 65.57; H, 4.95; N,
7.65. Found: C, 65.43; H, 5.02; N, 7.29.
N-[(Phenylmethoxy)carbonyl]-l-phenylalanine 1,1-di-
methylethyl ester (2c). White solid (71% yield): mp
(from petroleum ether±EtOAc) 828C; [a]2D0ˆ27.5 (cˆ1.0;
EtOH). [Lit.43: mp 81±828C; [a]2D0ˆ27.8 (cˆ1.0; EtOH)].
N-[(Phenylmethoxy)carbonyl]-l-serine
1,1-dimethyl-
ethyl ester (3c). White solid (73% yield): mp (from hex-
ane±Et2O) 958C; [a]D20ˆ215.9 (cˆ1.1; EtOH). [Lit.11: mp
93±958C; [a]2D0ˆ216.5 (cˆ1.0; EtOH)].
O-(1,1-Dimethylethyl)-N-[(phenylmethoxy)carbonyl]-l-
serine 1,1-dimethylethyl ester (16).20 White solid (80%
yield): mp (from hexane±CH2Cl2) 658C; [a]2D0ˆ15.0
(cˆ1.4; CH2Cl2). IR (pellet) nmax: 3445s, br; 2977w;
1729s; 1508m; 1387w; 1368m; 1343w; 1157m; 1068w;
Synthesis of 1,1-dimethylethyl esters.
1
740w; 697w cm21. H NMR d (ppm): 7.42±7.27 (m, 5H,
General procedure. Method A.1b A solution of dicyclohex-
ylcarbodiimide (DCC, 20.8 mmol) in CH2Cl2 (4.0 mL) was
added dropwise at 08C and under vigorous stirring into a
solution containing the substrate (20.0 mmol), 2-methyl-2-
propanol (40.0 mmol) and 4-(dimethylamino)pyridine
(DMAP, 3.2 mmol) in CH2Cl2 (8.0 mL). After the addition
was complete, the reaction mixture was allowed to reach
room temperature and stirred overnight; the formed dicyclo-
hexylurea (DCU) was ®ltered off, the solvent evaporated
and the residue dissolved in Et2O (40 mL). The obtained
solution was additionally ®ltered, if necessary, washed
with 0.5 M HCl (3£20 mL), 5% aqueous NaHCO3
(2£20 mL), 30% aqueous NaCl (20 mL), dried over
Na2SO4 and the solvent evaporated off. The obtained esters
were suitably puri®ed by column chromatography; yields
are reported in Table 1.
C6H5); 5.59 (d, Jˆ9.1 Hz, 1H, NH); 5.12 (s, 2H, PhCH2);
4.35 (ddd, Jˆ9.1, 3.0, 2.7 Hz, 1H, CH); 3.79 (dd, Jˆ8.7,
2.7 Hz, 1H, t-BuOCHH); 3.53 (dd, Jˆ8.7, 3.0 Hz, 1H, t-
BuOCHH); 1.46 [s, 9H, COOC(CH3)3]; 1.13 [s, 9H,
CH2OC(CH3)3]. 13C NMR d (ppm): 169.57; 156.11;
136.45; 128.46; 128.06 (2 overlapped signals); 81.71;
73.02; 66.82; 62.26; 54.95; 27.99; 27.28. MS (Tˆ508C)
m/z: 91 (100); 57 (64); 148 (63); 209 (57); 150 (42). Anal.
Calcd for C19H29NO5: C, 64.94; H, 8.32; N, 3.99. Found: C,
66.11; H, 8.46; N, 3.85.
N-[(Phenylmethoxy)carbonyl]-l-serine
phenylmethyl
carbonate 1,1-dimethylethyl ester (20). White solid
(30% yield): mp (from hexane±CH2Cl2) 888C;
[a]2D0ˆ120.0 (cˆ1.0; CH2Cl2). IR (pellet) nmax: 3361m,
br; 2978w; 1751s; 1515m; 1457w; 1371w; 1269s; 1157m;
1
1062w; 755w; 698m cm21. H NMR d (ppm): 7.39±7.27
Method B.14 An excess of 2-methylpropene (ca. 20 mL) was
condensed at 2258C into a solution of the substrate
(10.0 mmol) in CH2Cl2 (25 mL) and, after the addition of
0.3 mL of 96% H2SO4, the reaction mixture was transferred
into a pressure vessel, allowed to reach room temperature
and vigorously stirred for 12 h. After this time, the excess of
2-methylpropene and the solvent were carefully evaporated
at reduced pressure and room temperature and the residue
dissolved in Et2O (50 mL); the obtained solution was
washed with 5% aqueous NaHCO3 (2£30 mL), 30%
aqueous NaCl (30 mL), dried and processed as for Method
A.
(m, 10H, C6H5); 5.60 (d, Jˆ6.9 Hz, 1H, NH); 5.13 (s, 2H,
PhCH2); 5.10 (s, 2H, PhCH2); 4.60±4.33 (m, 3H, CH±CH2);
1.42 [s, 9H, OC(CH3)3]. 13C NMR d (ppm): 167.84; 155.72;
154.68; 136.12; 134.92; 128.55 (2 overlapped signals);
128.46; 128.29; 128.11; 128.03; 83.11; 69.88; 67.64;
67.04; 53.89; 27.81. MS (Tˆ658C) m/z: 91 (100); 107
(38); 92 (20); 57 (16); 181 (14). Anal. Calcd for
C23H27NO7: C, 64.32; H, 6.34; N, 3.26. Found: C, 65.73;
H, 6.42; N, 3.18.
1,1-Dimethylethyl 2-[[(phenylmethoxy)carbonyl]amino]-
2-propenoate (14). Side product from the preparation of
20. Colourless oil (12% yield). IR (®lm) nmax: 3412m;
2928m; 1743s; 1708s; 1640w; 1516s; 1371w; 1334s;
Method C.15 Finely ground anhydrous K2CO3 (260 mmol)
was added in one lot into a solution of the substrate

P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
3631
1228w; 1164m; 1068s; 893w; 747w; 698m cm21. 1H NMR
d (ppm): 7.43±7.29 (m, 5H, C6H5); 7.27 (br s, 1H, NH);
6.16 [s, 1H, NCvCH (Z)]; 5.69 [d, Jˆ1.5 Hz, 1H, NCvCH
(E)]; 5.15 (s, 2H, PhCH2); 1.51 [s, 9H, OC(CH3)3]. 13C
NMR d (ppm): 162.67; 153.13; 135.94; 132.11; 128.53;
128.26; 128.13; 104.87; 82.75; 66.85; 27.86. MS
(Tˆ258C) m/z: 91 (100); 57 (46); 176 (37); 92 (21); 41
(20). Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N,
5.05. Found: C, 64.86; H, 6.99; N, 4.98.
3-Nitro-N-[(phenylmethoxy)carbonyl]-l-tyrosine
1,1-
dimethylethyl ester (19). Orange oil (67% yield):
[a]2D0ˆ214.5 (cˆ0.7; MeOH). IR (®lm) nmax: 3332m, br;
2980m; 1734s; 1630w; 1540s; 1430w; 1327w; 1217m;
1156m; 1082w; 843w; 754m; 698w cm21 1H NMR d
.
(ppm): 10.41 (s, 1H, ArOH); 7.88 (d, Jˆ2.0 Hz, 1H,
ArH); 7.44±7.21 (m, 6H, C6H51ArH); 7.04 (d, Jˆ8.6 Hz,
1H, ArH); 5.37 (d, Jˆ7.8 Hz, 1H, NH); 5.09 (sym m, 2H,
PhCH2); 4.51 (sym m, 1H, CH); 3.08 (sym m, 2H, TyrCH2);
1.44 [s, 9H, OC(CH3)3]. 13C NMR d (ppm): 169.88; 155.47;
154.06; 138.92; 136.16; 133.17; 128.67; 128.51; 128.23;
128.09; 125.34; 119.92; 83.05; 66.98; 54.97; 37.14; 27.96.
MS (Tˆ508C) m/z: 91 (100); 57 (44); 152 (24); 92 (20); 41
(14); 416 (M1, ,1). Anal. Calcd. for C21H24N2O7: C, 60.57;
H, 5.81; N, 6.73. Found: C, 58.23; H, 5.95; N, 6.81.
N-[(Phenylmethoxy)carbonyl]-l-serine ethanoate 1,1-
dimethylethyl ester (11). Yellowish oil (70% yield):
[a]2D0ˆ135.0 (cˆ1.0; CHCl3). IR (®lm) nmax: 3347m, br;
2981m; 1734s; 1522m; 1457w; 1370w; 1227s; 1158m;
1059m; 845w; 754m; 698w cm21 1H NMR d (ppm):
.
7.40±7.22 (m, 5H, C6H5); 5.60 (d, Jˆ7.7 Hz, 1H, NH);
5.12 (s, 2H, PhCH2); 4.56±4.23 (m, 3H, CH±CH2); 2.02
(s, 3H, CH3); 1.46 [s, 9H, OC(CH3)3]. 13C NMR d (ppm):
170.31; 168.23; 155.66; 136.09; 128.45; 128.12; 128.06;
82.86; 67.00; 64.36; 53.78; 27.80; 20.48. MS (Tˆ508C)
m/z: 91 (100); 57 (38); 108 (15); 92 (14); 107 (13). Anal.
Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C,
62.20; H, 6.71; N, 3.98.
N-[(Phenylmethoxy)carbonyl]-l-methionine 1,1-dimethyl-
ethyl ester (5c). Yellowish oil (58% yield): [a]2D0ˆ229.0
(cˆ2.8; EtOH). [Lit.44: [a]D20ˆ114.0 (cˆ2.1; CHCl3)].
1,1-Dimethylethyl 4-(methylsul®nyl)-2-[[(phenylmethoxy)-
carbonyl]amino]-(2S)-butanoate (22). The sulfoxide 22
(as diastereoisomeric mixture) was prepared by direct
oxidation of the ester 5c as previously described for 21.
Pale yellowish oil (98% yield): [a]2D0ˆ243.9 (cˆ0.6;
MeOH). [Lit.44: [a]2D0ˆ219.3 (cˆ1.3; MeOH)].
N-[(Phenylmethoxy)carbonyl]-l-tyrosine 1,1-dimethyl-
ethyl ester (4c). Pale brownish solid (60% yield): mp
(from hexane±Et2O) 868C; [a]2D0ˆ20.5 (cˆ1.0; EtOH).
[Lit.15: mp 888C; [a]2D0ˆ20.4 (cˆ1.0; EtOH)].
N-[(Phenylmethoxy)carbonyl]-l-tryptophan 1,1-dimethyl-
ethyl ester (6c). White solid (30% yield): mp (from
hexane±CH2Cl2) 688C; [a]2D0ˆ25.0 (cˆ1.0; EtOH).
[Lit.13b: mp 70±718C; [a]2D0ˆ25.2 (cˆ1.0; MeOH)].
O-(1,1-Dimethylethyl)-N-[(phenylmethoxy)carbonyl]-l-
tyrosine 1,1-dimethylethyl ester (17).20 Yellowish oil
(57% yield): [a]2D0ˆ131.5 (cˆ1.1; CH2Cl2). IR (®lm)
n
max: 3342m, br; 2379m; 1725s; 1609w; 1507s; 1368m;
1-Formyl-N-[(phenylmethoxy)carbonyl]-l-tryptophan
1,1-dimethylethyl ester (23). Pale yellowish oil (82% yield
based on 12):40 [a]D20ˆ15.0 (cˆ1.0; MeOH). IR (pellet)
1237m; 1161s; 1057m; 899w; 847w; 751w; 698w cm21
.
1H NMR d (ppm): 7.38±7.28 (m, 5H, C6H5); 7.09±6.99
(m, 2H, HOC6H4); 6.94±6.83 (m, 2H, HOC6H4); 5.29 (d,
Jˆ8.3 Hz, 1H, NH); 5.09 (s, 2H, PhCH2); 4.50 (sym m, 1H,
CH); 3.03 (d, Jˆ6.1 Hz, 2H, CH2); 1.37 [s, 9H,
COOC(CH3)3]; 1.32 [s, 9H, CH2OC(CH3)3]. 13C NMR d
(ppm): 170.49; 155.47; 154.25; 136.30; 129.84; 129.01;
128.40; 128.03; 127.97; 123.96; 82.09; 78.24; 66.74;
55.20; 37.78; 28.73; 27.82. MS (Tˆ708C) m/z: 107 (100);
91 (86); 220 (79); 164 (61); 57 (36); 427 (M1, ,1). Anal.
Calcd for C25H33NO5: C, 70.23; H, 7.78; N, 3.28. Found: C,
69.65; H, 7.83; N, 3.25.
n
max: 3344m, br; 2980m; 1717s; 1609w; 1522m; 1459m;
1370s; 1231s; 1156s; 1050m; 845w; 793w; 751m; 698w
cm21. 1H NMR d (ppm): (isomer ratio due to formyl protec-
tion E:Zˆ1:1.8)41 9.36 [br s, 0.35H, CHO (E)]; 8.97 [br s,
0.65H, CHO (Z)]; 8.37 (d, Jˆ7.3 Hz, 0.65H, indole-H (Z)];
7.74±7.18 (m, 8.7H, indole-H1C6H5); 7.12 [br s, 0.65H,
indole 2-H (Z)]; 5.48 (d, Jˆ7.8 Hz, 1H, NH); 5.19±4.98
(m, 2H, PhCH2); 4.64 (sym m, 1H, CH); 3.22 (sym m,
2H, CH2); 1.36 [s, 9H, OC(CH3)3]. 13C NMR d (ppm):
[predominant isomer (Z)] 170.39; 159.02; 155.58; 136.14;
134.05; 131.27; 128.39; 128.06; 128.00; 125.31; 124.39;
119.05; 118.47; 115.97; 109.43; 82.50; 66.77; 54.07;
27.92; 27.75. MS (Tˆ608C) m/z: 158 (100); 91 (74); 130
(72); 215 (38); 57 (20); 422 (M1, ,1). Anal. Calcd for
C24H26N2O5: C, 68.23; H, 6.20; N, 6.63. Found: C, 67.96;
H, 6.35; N, 6.62.
N-[(Phenylmethoxy)carbonyl]-l-tyrosine phenylmethyl
carbonate 1,1-dimethylethyl ester (18). White solid
(63% yield): mp (from hexane±CH2Cl2) 1188C;
[a]2D0ˆ115.0 (cˆ1.0; CH2Cl2). IR (pellet) nmax: 3357m,
br; 2979m; 1763m; 1725s; 1509s; 1457w; 1370w; 1243s;
1
1156w; 1055m; 913w; 847w; 737m; 698w cm21. H NMR
d (ppm): 7.48±7.28 (m, 10H, C6H5); 7.19±7.03 (m, 4H,
ZOC6H4); 5.28 (d, Jˆ8.0 Hz, 1H, NH); 5.26 (s, 2H,
OCOOCH2Ph); 5.10 (s, 2H, NCOOCH2Ph); 4.51 (sym m,
1H, CH); 3.07 (d, Jˆ6.1 Hz, 2H, CH2); 1.38 [s, 9H,
OC(CH3)3]. 13C NMR d (ppm): 170.32; 155.50; 153.51;
150.12; 136.31; 134.76; 133.97; 130.47; 128.72; 128.66;
128.47 (2 overlapped signals); 128.13; 128.09; 120.87;
82.47; 70.28; 66.87; 55.13; 37.79; 27.90. MS (Tˆ1508C)
m/z: 91 (100); 197 (45); 92 (19); 107 (16); 108 (8). Anal.
Calcd for C29H31NO7: C, 68.90; H, 6.18; N, 2.77. Found: C,
66.26; H, 6.33; N, 2.71.
N-[N-[(Phenylmethoxy)carbonyl]-l-a-aspartyl]-l-phenyl-
alanine 4-(1,1-dimethylethyl) 1-methyl ester (7c). White
solid (88% yield): mp (from hexane±CH2Cl2) 718C;
[a]2D0ˆ215.0 (cˆ1.0; MeOH). [Lit.45: mp 71±738C;
[a]2D0ˆ216.2 (cˆ1.0; MeOH)].
Nitrolysis of 1,1-dimethylethyl esters.4
General procedure. A chilled solution of 100% HNO3 in
CH2Cl2 (60.0 mmol in 8.0 mL) was added dropwise at 08C
and under stirring to a solution of the substrate (Scheme 1,

3632
P. Strazzolini et al. / Tetrahedron 56 (2000) 3625±3633
B. F.; Johansen, N. L.; Vo¤ lund, A.; Markussen, J. Int. J. Peptide
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23, 287±291. (j) Kemp, D. S.; Fotouhi, N.; Boyd, J. G.; Carey, R. I.;
Ashton, C.; Hoare, J. Int. J. Peptide Protein Res. 1988, 31, 359±
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Table 2) in CH2Cl2 (20.0 mmol in 12.0 mL) and the homo-
geneous mixture was stirred for 2 h at 08C with protection
from the light. Then, the reaction mixture was diluted with
CH2Cl2 (100 mL), washed with 30% aqueous NaCl
(2£100 mL), dried over anhydrous Na2SO4 and the solvent
fully evaporated. The obtained residue was suitably puri-
®ed, when needed, by crystallization or column chromato-
graphy: results and yields are reported in Table 2. In order to
complete the deprotection reaction, some substrates (11, 18,
20, 22 and 23) required 4 equiv. of HNO3.
Hydrazinolysis of N-[(phenylmethoxy)carbonyl]-l-
serine ethanoate 1,1-dimethylethyl ester (11). Hydrazine
monohydrate (30.0 mmol) was added dropwise to a solution
of the acetyl derivative 11 in EtOH (15.0 mmol in 30 mL) at
08C under stirring. The reaction mixture was allowed to
reach room temperature and stirring was continued until
complete conversion was observed (12 h); then EtOH was
evaporated at reduced pressure and the yellowish oily resi-
due dissolved in EtOAc (50 mL), washed with 1 M HCl
(30 mL), 30% aqueous NaCl (30 mL) and dried over
Na2SO4. The white solid residue from evaporation of the
solvent (91% yield) was found to be identical to 3c.
7. Svanholm, U.; Parker, V. D. J. Chem. Soc, Perkin Trans. 1
1973, 562±566.
8. Bergmann, M.; Zervas, L. Chem. Ber. 1932, 65B, 1192±1201.
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12. Strazzolini, P.; Giumanini, A. G.; Verardo, G. Tetrahedron
1994, 50, 217±254.
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Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 1063±1066. (h)
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Acknowledgements
This work was supported in part by research grants to P. S.
and A. G. G. from M.U.R.S.T. (1998±99), Rome, Italy. We
are indebted to Prof G. Verardo for MS data collection and
to Dr P. Martinuzzi for recording the NMR spectra.
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