Synthesis of a homologous series of side-chain-extended orthogonally protected aminooxy-containing amino acids

Article abstract of DOI:10.1055/s-2008-1078600

Practical methodology is reported for the synthesis of a homologous series of side-chain-extended amino acids containing aminooxy functionality bearing orthogonal protection suitable for Fmoc peptide synthesis. These reagents may be useful for the preparation of libraries containing fragments joined by peptide linkers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078600

2432
PAPER
Synthesis of a Homologous Series of Side-Chain-Extended Orthogonally
Protected Aminooxy-Containing Amino Acids
Homologous
S
a
eries of
S
ide Cha
L
in Extende
d
A
m
i
ino A
u
Laboratory of Medicinal Chemistry, CCR, NCI-Frederick, NIH, Bldg. 376, 1050 Boyles St., Frederick, MD 21702, USA
Fax +1(301)8466033; E-mail: tburke@helix.nih.gov
Received 21 March 2008; revised 24 April 2008
Cross metathesis (CM) has found wide application for
coupling through highly efficient carbon–carbon bond
formation.6 A CM approach for the synthesis of target
compounds 1d–f required the N-Boc-protected aminooxy
building blocks 4a–c,7 which could be obtained by reac-
tion of the corresponding bromides 3a–c with N-Boc-hy-
droxylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in CH2Cl2 (Scheme 1).8 The CM coupling of N-
Fmoc-L-allylglycine O-benzyl ester (5)6c with five equiv-
alents of the respective substrates 4a–c in refluxing
CH2Cl2 using 5% Grubbs 2nd generation catalyst,
[((PCy3)(Im(Mes)2)Ru=CHPh)]9 provided the products
6a–c (Scheme 2), which were contaminated with small
quantities of unwanted material resulting from ho-
modimerization of reagent 4. It was advantageous to sub-
ject the crude mixtures directly to hydrogenation to
provide the easily purified final products 1d–f. Based on
combined yields over two steps, it was found that CM ef-
ficiency improved with increasing substrate chain length
(1d, 40% yield; 1e, 53% yield and 1f, 72% yield).
Abstract: Practical methodology is reported for the synthesis of a
homologous series of side-chain-extended amino acids containing
aminooxy functionality bearing orthogonal protection suitable for
Fmoc peptide synthesis. These reagents may be useful for the prep-
aration of libraries containing fragments joined by peptide linkers.
Key words: oxime, peptidomimetic, aldehydes, combinatorial
chemistry
Fragment-based approaches to drug discovery have
gained increasing importance in the pharmaceutical in-
dustry.1 Tethered libraries represent a subclass of frag-
ment-based methodologies. However, to date, tethered
libraries have typically employed structurally simple link-
er elements, consisting mainly of polymethylene seg-
ments bearing terminal aminooxy groups that serve as
anchoring points for fragment attachment.2 However, in-
creased library complexity, leading potentially to en-
hanced bioactivities, may be possible by combining the
structural diversity of peptide scaffolds together with
linker-based functionalized oxime ethers. Amino acids
1a–f and 2a were designed to serve as key components of
linker-based peptide libraries by providing protected ami-
nooxy groups appended onto the peptide backbone via
methylene chains of increasing lengths (Figure 1). Final
tethered products would be obtained by acid-catalyzed
oxime ether deprotection and conjugation with fragment
libraries. However, only the core structures of 1a,3 1c4,
and 1d5 are known in the literature and efficient syntheses
of the series 1a–f and 2a have not yet been reported. Prac-
tical methodology for the preparation of 1a–f and 2a bear-
ing orthogonal protection designed for Fmoc-based
peptide synthesis was the focus of the current study.
Br
Boc
O
a
N
H
n
n
3
4
a, n = 1; b, n = 2; c, n = 3
a, n = 1; b, n = 2; c, n = 3
Scheme 1 Reagents and conditions: (a) Boc-NHOH, DBU, CH2Cl2.
Boc
O
CO2Bn
Fmoc
CO2Bn
Fmoc
4a–c
N
H
n
N
N
a
H
H
6
5
a, n = 1; b, n = 2; c, n = 3
b
1d (40%); 1e (53%); 1f (72%)
[yields are for two steps]
H
Scheme 2 Reagents and conditions: (a) Grubbs 2nd generation ca-
talyst, CH2Cl2, D; (b) H2, Pd/C, EtOH.
N
CO2H
Fmoc
R
O
n
N
H
The shorter homologues 1a–c were prepared from L-
serine (Ser), L-homoserine (HSer) and L-glutamic acid
(Glu), respectively. Near quantitative conversion of Ser to
N-Trt-L-serine O-methyl ester (N-Trt-Ser-OMe, 710) and
reaction with N-hydroxyphthalimide under Mistunobu
conditions, provided the globally-protected product 8
(79% yield, Scheme 3). Use of the N-Trt group was to
minimize unwanted b-elimination during the Mitsunobu
reaction.11 Having served its purpose, the N-Trt group was
1, R = Boc: 2, R = Mtt
a, n = 1; b, n = 2; c, n = 3;
d, n = 4; e, n = 5; f, n = 6
Figure 1 Structures of protected aminooxy amino acid analogues
SYNTHESIS 2008, No. 15, pp 2432–2438
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1078600; Art ID: M01608SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PAPER
Homologous Series of Side-Chain-Extended Amino Acids
2433
O
tion with Boc anhydride (near quantitative yields for two
steps, Scheme 5). Cleavage of the amino acid methyl es-
ters of 17 and 18 (LiOH in aqueous THF) followed by Cbz
hydrogenolysis and reprotection as the N-Fmoc deriva-
tives provided the final products 1a and 1b in 58% and
81% yields over three steps. Hydrogenation of 19 and N-
Fmoc reprotection gave 1c directly (47% yield).
N
OH
CO2Me
Trt
CO2H
NH2
O
a, b
HO
HO
N
c
H
(91 %)
Ser
7
H
1a (58%)
1b (81%)
1c (47%)
a, b
c, d, e
O
O
N
CO2R
Cbz
O
O
9, 15, 16
Boc
O
n
N
CO2Me
Cbz
N
N
CO2Me
Trt
d, e
H
O
N
17 n = 1; R = Me
18 n = 2; R = Me
19 n = 3; R = Bn
O
N
H
H
(84%)
(79%)
9
8
Scheme 5 Reagents and conditions: (a) MeNHNH2, CH2Cl2; (b)
Boc2O, Et3N, THF; (c) LiOH, THF, H2O; (d) H2, Pd/C, MeOH; (e)
FmocOSu, dioxane.
Scheme 3 Reagents and conditions: (a) HCl, MeOH; (b) TrtCl,
Et3N; (c) Ph3P, DEAD; (d) HCl (37%), CH2Cl2; (e) CbzCl, THF, H2O.
To determine whether the DBU/DMF conditions resulted
in racemization at the a-amino center, 1c was evaluated
for enantiomeric purity as follows. Phenylalanine dipep-
tides were prepared by solid-phase techniques (Figure 2),
and the resulting diastereomers were separated by re-
verse-phase HPLC (Figure 3). Analysis of the racemic
D,L-phenylalanine containing dipeptides 20 indicated
good separation of diastereomers. The dipeptide 22, pre-
pared using enantiomerically pure L-phenylalanine, did
not show detectable diastereomeric contamination, indi-
cating that the ee value of 1c is >98%.
replaced by Cbz protection to provide intermediate 9
(84% yield).
Conversion of HSer to N-Cbz-L-homoserine O-methyl es-
ter (N-Cbz-HSer-OMe, 10) was by literature procedures,12
while the side chain-elongated analogue 12 was obtained
from commercially available N-Cbz-Glu-OBn (11)13 by
reduction of the free carboxylic acid group (Scheme 4).14
When direct transformation of 10 to the phthalimidooxy
product 15 under Mitsunobu conditions was accompanied
by poor yields and the formation of cyclized by-products,
the alcohols 10 and 12 were converted in quantitative
yield to the corresponding mesyl esters 13 and 14.15 Sub-
sequent nucleophilic displacement using N-hydroxy-
phthalimide provided 15 and 16, respectively, in
approximately 60–70% yields.12
D-, L-Phe
L-Phe
1c
NH2
O
NH2
O
MsO
CO2R
Cbz
R2
CO2R1
a
n
n
N
O
O
N
O
O
H
H
N
H
Cbz
H
N
N
NH2
N
NH2
10, n = 1; R1 = Me; R2 = OH
11, n = 1; R1 = Bn; R2 = CO2H
12, n = 2; R1 = Bn; R2 = OH
13, n = 1; R = Me (100%)
14, n = 2; R = Bn (100%)
H
H
O
O
c
22
21
O
Figure 2 Determination of enantiomeric purity of 1c
O
N
O
OH
O
CO2R
Cbz
Use of the Boc-protected aminooxy-containing analogue
1a in solid-phase peptide synthesis is potentially limited
by b-elimination during piperidine-mediated Fmoc depro-
tection. Indeed, attempted incorporation on NovaSyn®
TGR resin of 1a in place of threonine in the Tsg101-bind-
ing peptide, FITC-Ava-PEPTAPPEE-amide16 gave only
product resulting from b-elimination.17 Therefore, the
aminooxy Boc protecting group in 1a was replaced with
the more electron-donating 4-methyltriphenylmethyl
(Mtt) (final product 2a). This was achieved by deprotec-
tion of phthalamide 9 using methylhydrazine in CH2Cl2
followed by reaction with MttCl (i-Pr2EtN, CH2Cl2) to
give the corresponding Mtt-protected aminooxy analogue
20 in quantitative yield (Scheme 6). Conversion to the
N
n
N
H
O
b
15, n = 1; R = Me (71%)
16, n = 2; R = Bn (61%)
Scheme 4 Reagents and conditions: (a) MsCl, Et3N, CH2Cl2; (b)
DBU, DMF; (c) ClCO2Et, 4-methylmorpholine, THF followed by
NaBH4, MeOH.
To complete the synthesis of the target compounds, the
phthalimidooxy intermediates 9, 15, and 16 were cleaved
by treatment with methylhydrazine in CH2Cl2 at 0 °C,
then protected as their N-Boc derivatives 17–19 by reac-
Synthesis 2008, No. 15, 2432–2438 © Thieme Stuttgart · New York

2434
F. Liu et al.
PAPER
side CA, 92521. Optical rotations were measured on a Jasco P-1010
polarimeter at 589 nm and IR spectra were obtained neat using a
Jasco FT-IR/615 spectrometer.
Compounds 4a–c; General Procedure
To a mixture of alkenyl bromide 3a–c (10 mmol) and N-Boc-hy-
droxylamine (25 mmol) in CH2Cl2 (1.0 mL) at 0 °C, was added
DBU (7.5 mL) carefully. The mixture was warmed to r.t. and stirred
overnight. The mixture was diluted with EtOAc (150 mL), washed
with H2O (50 mL) and brine (50 mL), and purified by silica gel col-
umn chromatography (hexanes–EtOAc) to yield 4a–c as colorless
oils.
N-(Prop-2-en-1-yloxy)carbamic Acid 1,1-Dimethylethyl Ester
(4a)7
Prepared from 3a; yield: 1.18 g (68%).
IR (KBr): 3290.9, 2979.5, 2361.4, 1717.3, 1456.0, 1368.3, 1249.7,
1165.8, 1107.9, 928.6 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.28 (br s, 1 H), 5.88 (m, 1 H),
5.28–5.18 (m, 2 H), 4.27 (dd, J = 6.2, 1.0 Hz, 2 H), 1.41 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 156.74, 132.52, 119.54, 81.37,
77.24, 28.08.
ESI-MS (+): m/z = 196.1 (M + Na)+.
Figure 3 HPLC chromatograms of 21 (top) and 22 (bottom). Iden-
tity of the 3 major peaks were confirmed by ESI mass spectra [337.1
(M + H)+ and 359.1 (M + Na)+]
N-(But-3-en-1-yloxy)carbamic Acid 1,1-Dimethylethyl Ester
(4b)7
Prepared from 3b; yield: 1.10 g (59%).
IR (KBr): 3297.7, 2979.5, 1721.2, 1478.2, 1368.3, 1245.8, 1165.8,
1108.9, 773.3 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37 (s, 1 H), 5.74 (m, 1 H), 5.03
(m, 1 H), 4.96 (m, 1 H), 3.81 (t, J = 6.8 Hz, 2 H), 2.30 (m, 2 H), 1.39
(s, 9 H).
13C NMR (100 MHz, CDCl3): d = 156.90, 134.31, 116.64, 81.36,
75.45, 32.40, 28.09.
N-Fmoc final product 2a was as described above for the
preparation of target compounds 1a–c. Repeating the syn-
thesis of the Tsg101-binding peptide described above us-
ing 2a rather than 1a gave the desired aminooxy-
containing peptide as the major product with no b-elimi-
nation side product as detected by HPLC.18
ESI-MS (+): m/z = 210.1 (M + Na)+.
H
N
CO2Me
Cbz
a, b
c, d, e
Mtt
O
N-(Pent-4-en-1-yloxy)carbamic Acid 1,1-Dimethylethyl Ester
9
2a (58%)
(4c)7
N
H
20
Prepared from 3c; yield: 1.20 g (60%).
Scheme 6 Reagents and conditions: a) MeNHNH2, CH2Cl2; (b)
MttCl, i-Pr2EtN, CH2Cl2; (c) LiOH, THF, H2O; (d) H2, Pd/C, MeOH;
(e) FmocOSu, dioxane.
IR (KBr): 3300.6, 2978.5, 1721.2, 1368.3, 1246.8, 1166.7, 1108.9,
912.2, 775.2 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.41 (s, 1 H), 5.71 (m, 1 H), 4.92
(m, 1 H), 4.86 (m, 1 H), 3.75 (t, J = 6.6 Hz, 2 H), 2.04 (m, 2 H), 1.62
(m, 2 H), 1.38 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 156.90, 137.80, 114.90, 81.41,
75.96, 29.92, 28.13, 27.12.
In conclusion, the practical synthesis of a homologous se-
ries of aminooxy-containing amino acid analogues has
been reported herein. These analogues are intended to
serve as valuable building blocks for the post solid-phase
construction of tethered oxime-based peptide libraries.
ESI-MS (+): m/z = 224.1 (M + Na)+.
Amino Acids 1d–f; General Procedure
All experiments involving moisture-sensitive compounds were con-
ducted under dry conditions (positive argon pressure) using stan-
dard syringe, cannula, and septa protocols. All anhydrous solvents
were obtained commercially (Aldrich) and used directly. HPLC-
grade hexanes, EtOAc, CH2Cl2, and MeOH were used in chroma-
tography. Analytical TLC was performed using Analtech precoated
plates (Uniplate, silica gel GHLF, 250 microns) containing a fluo-
rescence indicator. NMR spectra were recorded using a Varian Ino-
va 400 MHz spectrometer. Coupling constants are reported in hertz,
and peak shifts are reported in d (ppm). Low-resolution mass spec-
tra (ESI) were measured with using an Agilent 1200 LC/MSD-SL
system, and high-resolution mass spectra (ESI or APCI) were mea-
sured by the University of California Riverside Mass Spectrometry
Facility, Department of Chemistry, University of California, River-
A solution of alkene 4a–c (5.0 equiv) and the protected allylglycine
5
6c (1.0 equiv) in anhyd CH2Cl2 (20 mL) was degassed under argon
(5 min), then the Grubbs 2nd generation catalyst
[(PCy3)(Im(Mes)2)Ru=CHPh]9 (0.05 equiv) was added and the
mixture was refluxed for 8 h. The solvent was evaporated by rotary
evaporation and the residue was purified by silica gel column chro-
matography (hexanes–EtOAc) to yield crude 6a–c as colorless oils.
Without further purification, a solution of 6 in EtOH (10 mL) was
hydrogenated at r.t. under 1 atm H2 over 10% Pd/C (1 h). The cata-
lyst was removed by filtration and the filtrate was concentrated and
purified by silica gel column chromatography (CH2Cl2–MeOH) to
yield 1d–f as white waxes.
Synthesis 2008, No. 15, 2432–2438 © Thieme Stuttgart · New York

PAPER
Homologous Series of Side-Chain-Extended Amino Acids
2435
(3S)-3-Carboxy-12,12-dimethyl-10-oxo-8,11-dioxa-2,9-diaza-
decanoic Acid 1-(9H-Fluoren-9-ylmethyl) Ester (1d)
Prepared from 4a in 40% yield over 2 steps; [a]D +9.60 (c 0.70,
CHCl3).
g, 10.22 mmol) and the mixture was stirred overnight at r.t. The
mixture was diluted with EtOAc (200 mL), washed with H2O (50
mL) and brine (50 mL). The solvent was evaporated and the residue
purified by silica gel column chromatography (hexanes–EtOAc) to
yield 7 as a white solid (3.20 g, 91%); [a]D20 +3.02 (c 1.80, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.48–7.44 (m, 6 H), 7.27–7.17 (m,
9 H), 3.69 (m, 1 H), 3.55 (m, 2 H), 3.27 (s, 3 H), 2.96 (br s, 1 H),
2.29 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 173.90, 145.57, 128.72, 127.91,
126.59, 70.94, 64.92, 57.78, 51.96.
ESI-MS (+): m/z = 384.1 (M + Na)+.
20
IR (KBr): 3296.7, 2923.6, 1701.9, 1522.5, 1449.2, 1160.9, 909.3,
733.8 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.75 (d, J = 7.55 Hz, 2 H), 7.59
(dd, J = 7.07, 4.13 Hz, 2 H), 7.38 (t, J = 7.46 Hz, 2 H), 7.29 (t,
J = 7.45 Hz, 2 H), 7.18 (br s, 1 H), 5.67 (d, J = 7.95 Hz, 1 H), 4.40–
4.38 (m, 3 H), 4.20 (m, 1 H), 3.84 (t, J = 5.97 Hz, 2 H), 1.91 (m, 1
H), 1.76 (m, 1 H), 1.68–1.59 (m, 3 H), 1.54–1.46 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 176.16, 157.53, 156.35, 143.75,
143.61, 141.24, 127.67, 127.04, 125.05, 119.93, 82.30, 76.09,
67.17, 53.60, 47.05, 31.71, 28.16, 27.24, 21.58.
O-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-N-(triphenylmeth-
yl)-L-serine Methyl Ester (8)
To a solution of alcohol 7 (2.80 g, 7.76 mmol), N-hydroxyphthalim-
ide (2.53 g, 15.51 mmol), and Ph3P (4.50 g, 17.06 mmol) in THF
(100 mL) at 0 °C under argon was slowly added diethyl azodicar-
boxylate (DEAD) (40% in toluene, 7.80 mL, 17.06 mmol). The
mixture was warmed to r.t. and stirred overnight. The mixture was
diluted with EtOAc (200 mL), washed with H2O (2 × 50 mL) and
brine (50 mL), and dried (Na2SO4). Purification by silica gel column
chromatography (hexanes–EtOAc) provided 8 as a white wax;
3.10 g (79%); [a]D20 +39.6 (c 1.34, CHCl3).
ESI-MS (+): m/z = 507.2 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C26H32N2O7 + Na (M + Na)+:
507.2107; found: 507.2104.
(3S)-3-Carboxy-13,13-dimethyl-11-oxo-9,12-dioxa-2,10-diaza-
decanoic Acid 1-(9H-Fluoren-9-ylmethyl) Ester (1e)
Prepared from 4b in 53% yield over 2 steps; [a]D +7.04 (c 0.48,
CHCl3).
20
IR (KBr): 2360.4, 1735.6, 1026.9, 701.0 cm–1.
IR (KBr): 3285.1, 2933.2, 2364.3, 1700.9, 1521.6, 1449.2, 1162.8,
909.3, 732.8 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.83–7.81 (m, 2 H), 7.74–7.72 (m,
2 H), 7.55–7.52 (m, 6 H), 7.27–7.23 (m, 6 H), 7.19–7.15 (m, 3 H),
4.48 (dd, J = 9.2, 4.0 Hz, 1 H), 4.13 (dd, J = 9.2, 6.0 Hz, 1 H), 3.70
(m, 1 H), 3.42 (s, 3 H), 3.10 (d, J = 10.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 172.51, 162.94, 145.58, 134.46,
128.82, 128.72, 127.90, 126.49, 123.48, 80.18, 71.20, 55.74, 52.15.
ESI-MS (+): m/z = 529.1 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C31H26N2O5 + Na (M + Na)+:
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 7.55 Hz, 2 H), 7.66–
7.50 (m, 3 H), 7.37 (m, 2 H), 7.29 (t, J = 7.41 Hz, 2 H), 5.54 (d,
J = 8.13 Hz, 1 H), 4.55–4.30 (m, 3 H), 4.19 (m, 1 H), 3.82 (m, 2 H),
1.88 (m, 1 H), 1.72 (m, 1 H), 1.64–1.55 (m, 2 H), 1.46 (s, 9 H), 1.44–
1.35 (m, 3 H), 1.30 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 176.23, 157.51, 156.22, 143.76,
143.61, 141.24, 127.69, 127.04, 125.04, 119.93, 82.16, 76.44,
67.11, 53.66, 47.06, 31.96, 28.17, 27.50, 25.30, 24.77.
529.1739; found: 529.1760.
ESI-MS (+): m/z = 521.2 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C27H34N2O7 + Na (M + Na)+:
521.2264; found: 521.2261.
O-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-N-[(phenyl-
methoxy)carbonyl]-L-serine Methyl Ester (9)
To a solution of 8 (2.00 g, 3.95 mmol) in CH2Cl2 (50 mL) at r.t. was
added 37% HCl (0.50 mL) and the suspension was stirred for 1 h
and then quenched by the addition of sat. NaHCO3 (10 mL). The
mixture was extracted with CH2Cl2 (2 × 50 mL) and the combined
organic layers were washed with brine (50 mL) and dried (Na2SO4).
The solvent was removed by rotary evaporation and the residue was
dissolved in THF (30 mL) with H2O (10 mL). To this solution was
added NaHCO3 (498 mg, 5.92 mmol) and benzyl chloroformate
(0.59 mL, 4.15 mmol) and the mixture was stirred overnight at r.t.
THF was removed by rotary evaporation and the resulting aqueous
phase was extracted with EtOAc (2 × 100 mL). The combined or-
ganic layer was washed with H2O (2 × 50 mL) and brine (50 mL),
and dried (Na2SO4). The residue obtained after evaporation of the
solvent was purified by silica gel column chromatography (hex-
anes–EtOAc) to yield 9 as a viscous colorless oil (1.32 g, 84%);
[a]D20 +31.8 (c 0.75, CHCl3).
(3S)-3-Carboxy-14,14-dimethyl-12-oxo-10,13-dioxa-2,11-diaza-
decanoic Acid 1-(9H-Fluoren-9-ylmethyl) Ester (1f)
Prepared from 4c in 72% yield over 2 steps; [a]D +7.67 (c 1.11,
CHCl3).
20
IR (KBr): 3292.9, 2928.4, 1702.8, 1450.2, 1248.7, 1162.9, 1107.9,
909.3, 731.9 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.73 (d, J = 7.47 Hz, 2 H), 7.64–
7.51 (m, 3 H), 7.37 (t, J = 7.32 Hz, 2 H), 7.29 (d, J = 2.29 Hz, 2 H),
5.55 (br s, 1 H), 4.57–4.27 (m, 3 H), 4.19 (t, J = 6.84 Hz, 1 H), 3.80
(t, J = 6.44 Hz, 2 H), 1.86 (m, 1 H), 1.70 (m, 1 H), 1.64–1.52 (m, 2
H), 1.52–1.41 (m, 10 H), 1.41–1.19 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 157.31, 156.15, 143.70, 141.24,
127.67, 127.04, 125.10, 119.93, 113.43, 81.82, 76.60, 67.04, 47.10,
32.13, 28.76, 28.20, 27.74, 25.49, 24.94.
ESI-MS (+): m/z = 535.2 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C28H36N2O7 + Na (M + Na)+:
IR (KBr): 3366.1, 2954.4, 2363.3, 1727.9, 1516.7, 1211.1, 1054.9,
876.5, 698.1 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.75–7.73 (m, 2 H), 7.67–7.65 (m,
2 H), 7.30–7.20 (m, 5 H), 6.26 (d, J = 8.8 Hz, 1 H), 5.07 (s, 2 H),
4.73 (dd, J = 10.6, 3.0 Hz, 1 H), 4.57 (m, 1 H), 4.33 (dd, J = 10.6,
3.4 Hz, 1 H), 3.63 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.56, 163.19, 156.11, 136.21,
134.76, 128.56, 128.45, 128.06, 127.97, 123.71, 77.61, 67.11,
53.45, 52.80.
535.2420; found: 535.2414.
N-(Triphenylmethyl)-L-serine Methyl Ester (7)10
To cooled MeOH (100 mL) at 0 °C was added acetyl chloride (10.0
mL) dropwise. The resulting solution was stirred for 15 min, then L-
Serine (5.0 g, 47.6 mmol) was added and the solution was stirred at
reflux for 2 h and then cooled to r.t. The solvent was evaporated to
provide H-Ser-OMe·HCl as a white solid (7.40 g, quant). To a sus-
pension of this material (1.50 g, 9.74 mmol) in CH2Cl2 (50 mL) at
0 °C was added Et3N (3.0 mL, 21.4 mmol) and trityl chloride (2.90
HR-ESI/APCI MS: m/z calcd for C20H18N2O7 + Na (M + Na)+:
421.1011; found: 421.1007.
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2436
F. Liu et al.
PAPER
Mesyl Esters 13 and 14; General Procedure
IR (neat): 3324, 3066, 3033, 2965, 2936, 2361, 2336, 1725, 1698,
1539, 1276, 1186, 1127, 1018, 876, 736, 696 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.83–7.80 (m, 2 H), 7.76–7.73 (m,
2 H), 7.40–7.29 (m, 10 H), 5.47 (d, J = 8.0 Hz, 1 H), 5.20 (s, 2 H),
5.10 (s, 2 H), 4.49 (m, 1 H), 4.19 (m, 2 H), 2.16 (m, 1 H), 2.02 (m,
1 H), 1.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 171.95, 163.57, 155.94, 136.23,
135.23, 134.45, 128.86, 128.56, 128.44, 128.38, 128.23, 128.06,
127.98, 123.50, 67.20, 66.91, 53.63, 28.83, 24.28.
To a solution of N-Cbz-L-homoserine O-methyl ester (10)12 or 5-hy-
droxy-N-[(phenylmethoxy)carbonyl]-L-norvaline (12;14 1.0 equiv)
in CH2Cl2 (30 mL) at 0 °C was added Et3N (1.5 equiv) and
MeSO3Cl (1.2 equiv) and the mixture was stirred for 1 h. The mix-
ture was diluted with CH2Cl2 (100 mL), the CH2Cl2 layer was
washed with H2O (50 mL) and brine (50 mL), dried (Na2SO4), and
the solvent evaporated. Purification of the residue obtained by silica
gel column chromatography (hexanes–EtOAc) provided 13 (from
10) and 14 (from 12) as viscous colorless oils.
HR-ESI/APCI MS: m/z calcd for C28H26N2O7 + Na (M + Na)+:
525.1638; found: 525.1641.
N-Benzyloxycarbonyl-O-mesyl-L-serine Methyl Ester (13)
Prepared from 10 (2.70 g, quant); [a]D20 +5.0 (c 0.30, CHCl3).
Protected Amino Esters 17–20; General Procedure
IR (KBr): 3327.6, 2940.0, 1696.1, 1538.0, 1341.3, 1172.5, 1005.7,
740.5 cm–1.
To a solution of intermediates 9, 15, or 16 (1.0 equiv) in CH2Cl2 (20
mL) at 0 °C was added methylhydrazine (1.5 equiv) and the mixture
was stirred at 0 °C (1 h). The mixture was passed through Celite and
the filtrate was concentrated and dried under high vacuum (30 min).
For product 20 see below. For products 17–19, the residue was re-
dissolved in THF (50 mL) and to this was added Et3N (2.0 equiv)
and Boc2O (2.0 equiv) and the solution was stirred overnight at r.t.
The mixture was diluted with EtOAc (200 mL) and washed with
H2O (2 × 50 mL) and brine (50 mL), and dried (Na2SO4). Purifica-
tion by silica gel column chromatography (hexanes–EtOAc) pro-
vided 17–19 as viscous colorless oils. For product 20, the residue
mentioned above prepared by the treatment of 9 with methylhydra-
zine was dissolved in CH2Cl2 (10 mL) and to this was added DIPEA
(2.0 equiv) and 4-methyltrityl chloride (1.2 equiv) and the mixture
was stirred for 1 h at r.t. The mixture was diluted with EtOAc (100
mL) and washed with H2O (50 mL) and brine (50 mL), and dried
(Na2SO4). Purification of the residue obtained by evaporation of the
solvent by column chromatography (hexanes–EtOAc) using Et3N-
pretreated silica gel provided 20 as a white wax.
1H NMR (400 MHz, CDCl3): d = 7.36–7.30 (m, 5 H), 5.61 (d,
J = 6.0 Hz, 1 H), 5.11 (s, 2 H), 4.50 (m, 1 H), 4.28 (m, 2 H), 3.76 (s,
3 H), 2.96 (s, 3 H), 2.33 (m, 1 H), 2.14 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 173.73, 171.86, 155.93, 135.97,
128.55, 128.29, 128.12, 67.21, 65.69, 52.76, 50.76, 37.14, 31.79.
ESI-MS (+): m/z = 368.0 (M + Na)+.
5-[(Methylsulfonyl)oxy]-N-[(phenylmethoxy)carbonyl]-L-nor-
valine Phenylmethyl Ester (14) Prepared from 12 (3.95 g, quant).
This material was used in the next step without further purification.
1H NMR (400 MHz, CDCl3): d = 7.40–7.30 (m, 10 H), 5.36 (d,
J = 8.0 Hz, 1 H), 5.18 (m, 2 H), 5.11 (s, 2 H), 4.45 (q, J = 8.0 Hz, 1
H), 4.20 (t, J = 8.0 Hz, 2 H), 2.95 (s, 3 H), 2.01 (m, 1 H), 1.84–1.70
(m, 3 H).
ESI-MS: m/z = 525.1 (M + Na+).
Phthalimidoxy Intermediates 15 and 16; General Procedure
To a solution of N-hydroxyphthalimide (2.0 equiv) in DMF (10 mL)
at r.t. was added a solution of DBU (2.0 equiv) in DMF (10 mL).
The mixture was cooled to 0 °C and stirred for 30 min, then a solu-
tion of either 13 (to prepare 15) or 14 (to prepare 16) (1.0 equiv) in
DMF (10 mL) was added dropwise. The mixture was warmed to r.t.
and stirred for 2 d. The solution was diluted with EtOAc (200 mL)
and the organic layer was washed with H2O (50 mL) and brine (50
mL), and dried (Na2SO4). Purification of the residue obtained by
evaporation of the solvent by silica gel column chromatography
(hexanes–EtOAc) provided products 15 and 16 as white solids.
3-{[(1,1-Dimethylethoxy)carbonyl]aminooxy}-N-[(phenyl-
methoxy)carbonyl]-L-serine Methyl Ester (17)
Prepared from 9 (1.05 g, 95%); [a]D20 –11.7 (c 1.33, CHCl3).
IR (KBr): 3297.7, 2978.5, 2361.4, 1716.3, 1519.6, 1210.1, 1055.8,
775.2 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.54 (s, 1 H), 7.31–7.23 (m, 5 H),
6.18 (d, J = 8.4 Hz, 1 H), 5.09 (s, 2 H), 4.54 (m, 1 H), 4.19 (dd,
J = 7.2, 4.4 Hz, 1 H), 4.03 (dd, J = 11.0, 3.4 Hz, 1 H), 3.70 (s, 3 H),
1.42 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 170.54, 156.87, 156.32, 136.24,
O-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-N-[(phenyl-
methoxy)carbonyl]-L-homoserine Methyl Ester (15)12
Prepared from 13 (2.20 g, 71%); [a]D20 +8.6 (c 1.95, CHCl3).
128.44, 128.06, 127.97, 82.30, 75.89, 67.00, 53.18, 52.60, 28.09.
ESI-MS (+): m/z = 391.1 (M + Na)+.
IR (KBr): 3331.4, 2364.3, 2343.1, 1725.0, 1682.6, 1529.3, 1216.9,
698.1 cm–1.
HR-ESI/APCI MS: m/z calcd for C17H24N2O7 + Na (M + Na)+:
391.1481; found: 391.1482.
1H NMR (400 MHz, CDCl3): d = 7.77–7.74 (m, 2 H), 7.71–7.67 (m,
2 H), 7.31–7.22 (m, 5 H), 6.16 (d, J = 8.4 Hz, 1 H), 5.07 (s, 2 H),
4.58 (q, J = 6.8 Hz, 1 H), 4.26 (m, 2 H), 3.70 (s, 3 H), 2.27 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 172.02, 163.47, 156.14, 136.39,
134.60, 128.74, 128.40, 127.97, 127.91, 123.60, 74.98, 66.85,
52.55, 51.44, 30.19.
ESI-MS (+): m/z = 435.1 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C21H20N2O7 + Na (M + Na)+:
4-{[(1,1-Dimethylethoxy)carbonyl]aminooxy}-N-[(phenyl-
methoxy)carbonyl]-L-homeserine Methyl Ester (18)
Prepared from 15 (0.90 g, 97%); [a]D20 +5.8 (c 0.65, CHCl3).
IR (KBr): 3308.3, 2977.6, 2361.4, 1703.8, 1527.4, 1246.7, 1162.9,
739.6 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.46 (s, 1 H), 7.37–7.26 (m, 5 H),
6.10 (d, J = 7.6 Hz, 1 H), 5.12 (s, 2 H), 4.52 (dd, J = 13.6, 6.4 Hz, 1
H), 4.00–3.87 (m, 2 H), 3.73 (s, 3 H), 2.12 (m, 2 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 172.56, 156.94, 156.13, 136.34,
128.41, 128.00, 127.91, 81.88, 72.87, 66.81, 52.44, 51.62, 30.28,
28.12.
435.1168; found: 435.1176.
5-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-N-[(phenyl-
methoxy)carbonyl]-L-norvaline Phenylmethyl Ester (16)
Prepared from 14 (2.70 g, 61%); [a]D20 –16.34 (c 0.35, CHCl3); mp
101–105 °C.
ESI-MS (+): m/z = 405.1 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C18H26N2NaO7 + Na (M + Na)+:
405.1638; found: 405.1647.
Synthesis 2008, No. 15, 2432–2438 © Thieme Stuttgart · New York

PAPER
Homologous Series of Side-Chain-Extended Amino Acids
2437
5-{[(1,1-Dimethylethoxy)carbonyl]aminooxy}-N-[(phenyl-
methoxy)carbonyl]-L-norvaline Phenylmethyl Ester (19)
Prepared from 16 (1.85 g, 80%); [a]D20 –5.92 (c 0.58, CHCl3).
(3S)-3-Carboxy-9,9-dimethyl-7-oxo-5,8-dioxa-2,6-diaza-
decanoic Acid 1-(9H-Fluoren-9-ylmethyl) Ester (1a)
Prepared from 17 (0.62 g, 58% yield over 3 steps); [a]D +4.4 (c
1.30, CHCl3).
20
IR (neat): 3310, 3065, 3034, 2976, 2940, 2881, 1711, 1523, 1454,
1367, 1247, 1165, 1110, 1044, 911, 734, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.28 (m, 10 H), 7.15 (s, 1 H),
5.56 (d, 1 H, J = 8.0 Hz), 5.22–5.13 (m, 2 H), 5.10 (s, 2 H), 4.42 (q,
J = 8.0 Hz, 1 H), 3.81 (t, J = 6.0 Hz, 2 H), 2.23–1.92 (m, 1 H), 1.90–
1.80 (m, 1 H), 1.72–1.60 (m, 2 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 172.15, 157.00, 156.05, 136.22,
135.27, 128.56, 128.44, 128.39, 128.23, 128.07, 81.70, 75.74,
67.09, 66.93, 53.77, 29.00, 28.14, 27.57, 23.93.
IR (KBr): 3288.0, 2977.6, 2364.3, 1700.9, 1521.6, 1449.2, 1160.0,
734.7 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.97 (br s, 1 H), 7.30 (d, J = 7.6
Hz, 2 H), 7.65–7.50 (m, 2 H), 7.37 (t, J = 7.6 Hz, 2 H), 7.30–7.17
(m, 2 H), 6.48 (br s, 1 H), 4.54 (m, 1 H), 4.37 (m, 2 H), 4.28 (dd,
J = 11.4, 3.4 Hz, 1 H), 4.22 (d, J = 7.2 Hz, 1 H), 4.02 (dd, J = 11.4,
5.4 Hz, 1 H), 1.46 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 158.29, 156.56, 143.70, 143.56,
141.25, 127.72, 127.07, 125.14, 119.95, 83.81, 75.79, 67.45, 52.73,
46.98, 28.02, 27.55.
ESI-MS: m/z = 495.1 (M + Na+).
HR-ESI/APCI MS: m/z calcd for C25H32N2O7 + Na (M + Na)+:
ESI-MS (+): m/z = 465.1 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C23H26N2O7 + Na (M + Na)+:
495.2107; found: 495.2110.
3-[(Diphenyl-p-tolylmethyl)aminooxy]-N-[(phenyl-
methoxy)carbonyl]-L-serine Methyl Ester (20)
465.1638; found: 465.1636.
Prepared from 9 (1.31 g, quant); [a]D20 +6.5 (c 1.08, CHCl3).
(3S)-3-Carboxy-10,10-dimethyl-8-oxo-6,9-dioxa-2,7-diaza-
decanoic Acid 1-(9H-fluoren-9-ylmethyl) Ester (1b)
Prepared from 18 (1.60 g, 81% yield over 3 steps); [a]D +9.0 (c
0.79, CHCl3).
IR (KBr): 3402.8, 2949.6, 1717.3, 1509.0, 1208.2, 1058.7, 698.1
cm–1.
20
1H NMR (400 MHz, CDCl3): d = 7.33–7.16 (m, 15 H), 7.13 (AB,
JA,B = 8.4 Hz, 2 H), 7.05 (AB, JA,B = 8.4 Hz, 2 H), 6.69 (s, 1 H), 5.40
(d, J = 8.8 Hz, 1 H), 5.06 (m, 2 H), 4.52 (m, 1 H), 3.91 (dd, J = 10.8,
4.8 Hz, 1 H), 3.84 (dd, J = 10.8, 3.6 Hz, 1 H), 3.59 (s, 3 H), 2.28 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 171.1, 156.0, 144.2, 141.1, 136.6,
136.3, 129.1, 129.0, 128.6, 128.5, 128.2, 128.1, 127.8, 127.0, 73.9,
67.0, 53.8, 52.5, 21.0.
IR (KBr): 3296.7, 2977.6, 2355.6, 1700.9, 1523.5, 1160.9, 1106.9,
909.3, 735.7 cm–1
.
1H NMR (400 MHz, CDCl3): d = 7.73 (d, J = 7.6 Hz, 2 H), 7.69–
7.60 (m, 2 H), 7.52 (m, 1 H), 7.36 (t, J = 7.4 Hz, 2 H), 7.27 (t, J = 7.6
Hz, 2 H), 6.67 (br s, 1 H), 4.55 (m, 1 H), 4.43–4.28 (m, 2 H), 4.20
(t, J = 7.4 Hz, 1 H), 3.96 (m, 2 H), 2.15 (m, 2 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 175.64, 157.92, 156.86, 143.81,
143.67, 141.23, 127.68, 127.07, 125.21, 119.91, 106.60, 82.81,
73.12, 67.37, 51.77, 47.00, 29.68, 28.12, 27.54.
ESI-MS (+): m/z = 547.2 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C32H32N2O5 + Na (M + Na)+:
ESI-MS (+): m/z = 479.1 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C24H28N2O7 + Na (M + Na)+:
547.2209; found: 547.2213.
Amino Acids 1a–c and 2a; General Procedure
479.1794; found: 479.1808.
To a solution of intermediates 17, 18, or 20 (1.0 equiv) in THF (10
mL) containing H2O (10 mL) at 0 °C was added LiOH·H2O (1.2
equiv) and the mixture was stirred at 0 °C (2 h). THF was removed
by rotary evaporation and the residual aqueous phase was washed
with Et2O (50 mL) and then acidified to pH 3–4 by the addition of
aq 1 N HCl (Note: For 20 aq sat. NH4Cl was used rather than aq 1
N HCl.) The mixture was extracted with EtOAc (3 × 50 mL) and the
combined EtOAc extracts were washed with H2O (50 mL) and brine
(50 mL), and dried (Na2SO4). The organic phase was concentrated
and the residue was dissolved in MeOH (20 mL) and stirred with
10% Pd/C under 1 atm H2 (2 h). (Note: The preparation of 1c began
at this point by the direct hydrogenation of 19.) The Pd/C was re-
moved by filtration and the filtrate was concentrated and the residue
was dissolved in dioxane (10 mL) and H2O (10 mL). To this was
added 9-fluorenylmethylsuccinimidyl carbonate (FmocOSu) (1.1
equiv) and NaHCO3 (2.0 equiv) and the mixture was stirred over-
night at r.t. The reaction solution was acidified to pH 3–4 by the ad-
dition of aq 1 N HCl (Note: For 2a aq sat. NH4Cl was used rather
than aq 1 N HCl.) The mixture was extracted with EtOAc (3 × 50
mL) and the combined EtOAc extracts were washed with H2O (50
mL) and brine (50 mL), and dried (Na2SO4). Purification by silica
gel column chromatography (CH2Cl2–MeOH) provided final prod-
ucts 1a–c and 2a as viscous colorless oils. Lyophilization from
MeCN–H2O provided white powders, which were suitable for
solid-phase applications.
(3S)-3-Carboxy-11,11-dimethyl-9-oxo-7,10-dioxa-2,8-diaza-
decanoic Acid 1-(9H-Fluoren-9-ylmethyl) Ester (1c)
Prepared from 19 (0.82 g, 47% yield over 2 steps); [a]D20 +0.152 (c
0.77, CHCl3); mp 55–65 °C.
IR (neat): 3295, 2977, 2941, 2879, 1710, 1525, 1451, 1368, 1249,
1165, 1110, 1043, 758, 739, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.75 (d, J = 7.6 Hz, 2 H), 7.62–
7.56 (m, 2 H), 7.39 (t, J = 6.8 Hz, 2 H), 7.30 (t, J = 7.2 Hz, 2 H),
5.74 (s, 1 H), 4.56–4.32 (m, 3 H), 4.22 (t, J = 6.8 Hz, 1 H), 3.91 (s,
2 H), 2.16–2.04 (m, 1 H), 1.96–1.84 (m, 1 H), 1.78–1.68 (m, 2 H),
1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 157.44, 156.49, 143.85, 141.20,
127.63, 127.04, 125.14, 119.88, 82.09, 75.80, 67.12, 53.72, 47.05,
38.33, 30.89, 28.76, 28.17, 23.90.
ESI-MS: m/z = 493.1 (M + Na+).
HR-ESI/APCI MS: m/z calcd for C25H30N2O7 + Na (M + Na)+:
493.1951; found: 493.1957.
3-[(Diphenyl-p-tolylmethyl)aminooxy]-N-{[(9H-fluoren-9-yl-
methyl)oxy]carbonyl}-L-serine (2a)
Prepared from 20 (0.40 g, 58% yield over 3 steps); [a]D –9.4 (c
0.75, CHCl3).
20
IR (KBr): 3404.7, 2365.3, 1706.7, 1508.1, 1229.4, 1056.8, 700.0
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.91 (dd, J = 7.4, 2.2 Hz, 1 H),
7.71 (t, J = 5.4 Hz, 1 H), 7.65 (m, 1 H), 7.45–7.16 (m, 16 H), 7.09–
Synthesis 2008, No. 15, 2432–2438 © Thieme Stuttgart · New York

2438
F. Liu et al.
PAPER
7.00 (m, 5 H), 5.02 (dd, J = 16.2, 12.6 Hz, 1 H), 4.32–4.18 (m, 3 H),
(7) Yang, Y.-K.; Tae, J. Synlett 2003, 2017.
3.84 (m, 1 H), 3.60 (t, J = 9.6 Hz, 1 H), 2.25 (s, 1.6 H), 2.21 (s, 1.4
H).
(8) Jones, D. S.; Hammaker, J. R.; Tedder, M. E. Tetrahedron
Lett. 2000, 41, 1531.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
13C NMR (100 MHz, DMSO-d6): d = 172.4, 156.6, 145.1, 144.3,
142.0, 141.2, 137.4, 136.0, 129.2, 128.8, 128.5, 128.2, 128.1, 127.9,
127.5, 127.0, 125.7, 120.5, 74.1, 73.4, 66.3, 65.9, 54.3, 47.0, 21.0.
ESI-MS (+): m/z = 621.2 (M + Na)+.
HR-ESI/APCI MS: m/z calcd for C38H34N2O5 + Na (M + Na)+:
1999, 1, 953.
(10) Kelleher, F.; Proinsias, K. O. Tetrahedron Lett. 2007, 48,
4879.
(11) Peluso, S.; Imperiali, B. Tetrahedron Lett. 2001, 42, 2085.
(12) Wolfe, S.; Wilson, M.-C.; Cheng, M.-H.; Shustov, G. V.;
Akuche, C. I. Can. J. Chem. 2003, 81, 937.
621.2365; found: 621.2368.
(13) Available from Novabiochem, Inc.
(14) Jiang, S.; Li, P.; Lai, C. C.; Kelley, J. A.; Roller, P. P. J. Org.
Chem. 2006, 71, 7307.
(15) Easmon, J.; Heinisch, G.; Holzer, W.; Matuszczak, B. Arch.
Pharm. (Weinheim, Ger.) 1995, 328, 367.
Acknowledgment
This research was supported by the Intramural Research Program of
the NIH, Center for Cancer Research, NCI-Frederick.
(16) (a) Liu, F.; Stephen, A. G.; Adamson, C. S.; Gousset, K.;
Aman, M. J.; Freed, E. O.; Fisher, R. J.; Burke, T. R. Jr. Org.
Lett. 2006, 8, 5165. (b) Liu, F.; Stephen, A. G.; Fisher, R. J.;
Burke, T. R. Bioorg. Med. Chem. Lett. 2008, 18, 1096.
(17) The major fraction obtained by HPLC purification of the
peptide resulting using 1a to replace the Thr residue,
provided a mass spectral molecular ion (m/z = 1422.4) that
was 31 amu lower than expected for the correct product
(m/z = 1453.5). This is consistent with b-elimination of
HONH2 followed by reduction of the resulting double bond
during under the reducing conditions of resin cleavage using
triethylsilane.
(18) The major fraction obtained by HPLC purification of the
peptide resulting from the use of 2a to replace the Thr
residue, provided mass spectral molecular ions consistent
with the desired peptide product [m/z = 1454.5, (M + H) and
1476.5 (M + Na)].
References
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(3) Spetzler, J. C.; Hoeg-Jensen, T. J. Pept. Sci. 1999, 5, 582.
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Synthesis 2008, No. 15, 2432–2438 © Thieme Stuttgart · New York