An efficient method for the synthesis of enantiopure ω-amino acids with proteinogenic side chains

Article abstract of DOI:10.1055/s-2002-33647

An efficient method for the synthesis of enantiopure ω-amino acids with proteinogenic side chains, starting from the corresponding natural α-amino acids, was developed. N-Protected amino aldehydes, obtained from the corresponding amino alcohols by oxidati

Full text of DOI:10.1055/s-2002-33647

PAPER
1735
An Efficient Method for the Synthesis of Enantiopure -Amino Acids with
Proteinogenic Side Chains
An
E
fficient Met
a
t
Synthe
e
sis of
E
na
n
r
tiopur
e
i
-Amin
n
o Acids with
a
Proteinogenic
S
N
ide
C
hains oula, Vassilios Loukas, George Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
Fax +30(107)274761; E-mail: gkokotos@cc.uoa.gr
Received 8 February 2002; revised 6 June 2002
In recent years, N-protected amino alcohols, which are
easily obtained from -amino acids,13,14 have been used
for the synthesis of a variety of optically active com-
pounds, for example -amino aldehydes,15 triamines,16 or
Abstract: An efficient method for the synthesis of enantiopure
-
amino acids with proteinogenic side chains, starting from the corre-
sponding natural -amino acids, was developed. N-Protected amino
aldehydes, obtained from the corresponding amino alcohols by ox-
idation with NaOCl in the presence of 4-acetamido-2,2,6,6-tetra- peptide nucleic acids.17 Our strategy to synthesize -ami-
methylpiperidine-1-yloxy free radical (AcNH-TEMPO), reacted
no acids was based on a Wittig-type olefination reaction
of N-protected -amino aldehydes, leading to chain ho-
with the ylides generated from TrO(CH2)nP+Ph3I–. Catalytic hydro-
genation produced N-protected -amino alcohols. Boc-Protected
-
mologation. Wittig olefination of N-protected -amino al-
dehydes with non-functionalized ylides has been
reported.18,19 N-Protected -amino aldehydes may be pre-
pared either by reduction of a carboxy derivative of amino
acids or by oxidation of 2-amino alcohols.15 It was decid-
ed to prepare -amino aldehydes by oxidation of 2-amino
alcohols, using NaOCl in the presence of a catalytic
amount of a 2,2,6,6-tetramethylpiperidine-1-yloxy free
radical (TEMPO) derivative, a method which appears su-
perior to the reductive methods in terms of preservation of
the enantiomeric purity.20
amino acids were obtained in high yields by the oxidation of these
alcohols using NaOCl in the presence of a catalytic amount of
AcNH–TEMPO and Bu4N+HSO4 . The present route to -amino
–
acids permits the insertion of any chain length between the amino
and carboxy functionalities depending on the chain length of the
starting ylide used for the Wittig olefination reaction.
Key words: amino acids, amino alcohols, amino aldehydes, Wittig
reactions, ylides
Non-proteinogenic amino acids play an important role in
the design and synthesis of pharmacologically relevant
molecules, peptide mimetics and enzyme inhibitors.1 In
consequence, a large effort has been devoted to the prep-
aration of enantiopure amino acids, a subject already cov-
ered by general reviews.2 It is of special interest that
oligopeptides containing unnatural amino acids are able to
form well-defined secondary structures. Recent investiga-
tions by Seebach,3,4 Gellman5 and Hanessian6,7 have
shown that peptides constructed from - and -amino ac-
ids can adopt helix, sheet or reverse turn conformations in
solution or in the solid state as evidenced by NMR, CD,
X-ray and modeling studies. The surprising difference be-
tween the natural -, and the analogous - and -peptides
is that the helix stability increases upon homologation of
the residues.4 The complete stability of - and -peptides
against common proteases8 is of considerable importance
as it suggests that - and -peptides may be suitable for
pharmaceutical applications.
N-tert-Butoxycarbonyl-L-phenylalanine and -methyl N-
tert-butoxycarbonyl-L-glutamate were converted into al-
cohols 1a,b by reduction with NaBH4 via either their cor-
responding mixed anhydrides13 or via their corresponding
acyl fluorides,14 as previously described by the authors.
Alcohols 1a,b were oxidized to the corresponding alde-
hydes (Scheme, Table 1) by NaOCl in the presence of a
catalytic amount of 4-acetamido-TEMPO.21 The alde-
hydes were directly used for the Wittig-type reaction,
without any purification. The Wittig olefination of N-pro-
tected -amino aldehydes with carboxy ylides may direct-
ly lead to -amino acids. The reaction of hexanal and
benzaldehyde with triphenylphosphonium ylides contain-
ing anionic nucleophilic groups in their side chain has
been studied.22 Following the procedure proposed by that
study the reaction of the aldehyde obtained from 1a with
the ylide generated from the phosphonium salt of 10-bro-
modecan-1-ol was tested. However, the desired product
2a was only obtained in very low yield (17%). Thus, it
was decided to use ylides containing an -protected hy-
droxy group in subsequent procedures. Monotrityl 1,4-bu-
tanediol and 1,10-decanediol23 were converted into the
corresponding iodides and subsequently into triphe-
nylphosphonium salts by treatment with PPh3 in MeCN
under reflux.
Methods for the enantioselective synthesis of -amino ac-
ids have been reviewed.9 -Amino acids may be prepared
either by modification of glutamic acid or by homologa-
tion of -amino acids.4,10–12 The aim of this work was to
develop an efficient method for the synthesis of enan-
tiopure -substituted -amino acids with proteinogenic
side chains starting from -amino acids.
Boc-Protected amino aldehydes, prepared by the oxida-
tion of 1a,b, reacted at –78 °C with the ylides, that were
generated by treatment of TrtO(CH2)nP+Ph3I– (n = 4, 10)
with KHMDS in toluene at 0 °C (Scheme 1). Compounds
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1735,1739,ftx,en;T01702SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1736
C. Noula et al.
PAPER
R1
OR2
R1
lents of NaOCl in the presence of AcNH-TEMPO and tet-
rabutylammonium hydrogensulfate as a phase transfer
catalyst, the -substituted -amino acids 5a,b were ob-
tained in high yield.
a, b
OH
( )n
NHBoc
NHBoc
1a,b
2a-d
It should be noticed that in the 1H NMR (CDCl3) spectra
of Boc-protected amino acids 5a,b, two signals corre-
spond to the carbamate NH proton, attributed to the exist-
ence of rotamers. As it has been proposed for -amino
acid carbamate derivatives,25 the high field peak corre-
sponds to anti-rotamer 6a and the low field peak corre-
sponds to syn-rotamer 6b. The syn-rotamer is possibly
stabilized by the formation of intermolecular H-bond
complexes with another carboxylic acid moiety, as is
shown in the Figure 1.
c
O
a
R1
R1
( )n
NHBoc
( )n
H
OH
NHBoc
3a-c
4
d
O
R1
( )n
OH
NHBoc
O
NHBoc
H
5a,b
10
O
R
O
R
Scheme 1 Reagents and conditions: (a) AcNH–TEMPO, NaOCl,
NaHCO3, NaBr, H2O/EtOAc/PhCH3, –5 °C; (b) R2O(CH2)n + 1P+Ph3I–
/KHMDS, PhCH3, –78 °C; (c) H2, 10% Pd/C; (d) AcNH-TEMPO,
O
R
O
H
ButO
N
O
–
ButO
N
H
OH
NaOCl, NaHCO3, NaBr, Bu4N+HSO4 , H2O/CH2Cl2, 0 °C
10
OH
10
1
6a
6b
2b–d were identified as Z-olefins according to H NMR
analysis as was expected. The use of KHMDS under such
experimental conditions for the generation of nonsta-
bilized ylides is known to lead to high Z-selectivity.24 Cat-
alytic hydrogenation of the double bond of 2b–d with
simultaneous removal of the trityl group produced the N-
protected amino alcohols 3a–c. Oxidation of 3a with 1.1
equivalent of NaOCl in the presence of AcNH–TEMPO
led to -amino aldehyde 4. However, using 2.5 equiva-
Figure 1
It is known that N-protected -amino aldehydes present a
high tendency for racemization. The enantiomeric purity
of the final products depends on the conditions used for
both the preparation of -amino aldehydes and the Wittig
reaction. To confirm if any racemization had occurred to
the stereogenic center, compounds 2b,c were deprotected
and converted almost quantitatively into MTPA amides
by coupling with (S)-(–)- and (R)-(+)- -methoxy- -tri-
fluoromethyl phenylacetic acid (MTPA)26 using 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride as a condensing agent in the presence of 1-hydroxy-
benzotriazole. 1H and 19F NMR analysis of Mosher
amides indicated an enantiomeric excess >95%. Further-
more, compounds 2b,c were deprotected and converted
quantitatively into fluorenylmethoxycarbonyl (Fmoc) de-
rivatives. HPLC analysis of the Fmoc derivatives, using a
ChiraDex® column, confirmed that the enantiomeric puri-
ty was at least 95%. Thus, the production of -amino al-
dehydes by NaOCl/TEMPO oxidation, in combination
with the generation of ylide by KHMDS, leads to products
of high enantiomeric purity.
Table 1
R1
n
R2
1a
1b
2a
2b
2c
2d
3a
3b
3c
4
CH2Ph
(CH2)2CO2Me
CH2Ph
9
9
9
3
9
9
3
9
9
9
H
CH2Ph
Trt
Trt
Trt
(CH2)2CO2Me
CH2Ph
CH2Ph
(CH2)2CO2Me
CH2Ph
In conclusion, a simple and efficient method for the syn-
thesis of enantiopure -amino acids with proteinogenic
side chains from the corresponding natural -amino acids
was developed. The present route permits the insertion of
any chain length between the amino and carboxy func-
tionalities depending on the chain length of the starting
ylide used for the Wittig olefination reaction. In addition,
-amino alcohols and aldehydes, which are useful chiral
intermediates, may be prepared.
CH2Ph
5a
5b
CH2Ph
(CH2)2CO2Me
Synthesis 2002, No. 12, 1735–1739 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Method for the Synthesis of Enantiopure -Amino Acids with Proteinogenic Side Chains
1737
Mps were determined on a mp apparatus and are uncorrected. Spe-
cific rotations were measured at 25 °C on a polarimeter using a 10
cm cell. NMR spectra were recorded on a 200 MHz spectrometer.
All amino acid derivatives were of L-configuration and were pur-
chased from Fluka Chemical Co. TLC plates (silica gel 60 F254) and
silica gel 60 (70–230 or 230–400 mesh) for column chromatogra-
phy were purchased from Merck. Visualization of spots was effect-
ed with UV light and/or phosphomolybdic acid and/or ninhydrin,
both in EtOH stain. THF, toluene, and Et2O were dried by standard
procedures and stored over molecular sieves or Na. All other sol-
vents and chemicals were of reagent grade and were used without
further purification. The phosphonium salt HO(CH2)10P+Ph3Br–
was prepared by refluxing PPh3 and bromodecan-1-ol in EtOH and
was used in the Wittig reaction without purification.
NH), 5.18 (m, 1 H, CHCH=CH), 5.41 (m, 1 H, CH=CHCH2), 7.15-
7.50 (m, 20 H, 4 C6H5).
13C NMR (50 MHz, CDCl3) = 26.3, 27.7, 28.3, 29.2, 29.3, 29.4,
29.5, 30.0, 42.2, 49.5, 63.7, 79.2, 86.2, 126.7, 127.7, 128.7, 129.7,
133.0, 137.7, 144.5, 155.0.
FAB MS: m/z (%) = 654 (M+ + Na, 20), 316 (47), 243 (100).
Anal. Calcd. for C43H53NO3: C, 81.73; H, 8.45; N, 2.22. Found: C,
81.59; H, 8.62; N, 2.30.
Methyl (4S,5Z)-15-Trityloxy-4-[(tert-butoxycarbonyl)amino]-
pentadec-5-enoate (2c)
Yield: 0.64 g (51%); oil; [ ]D25 + 5.6 (c 1.9, CHCl3).
1H NMR (200 MHz, CDCl3):
= 1.21–1.39 [m, 12 H,
CHCH2(CH2)6], 1.43 [s, 9H, C(CH3)3], 1.50–1.69 (m, 2 H,
CH2CH2O), 1.69–1.92 (m, 2 H, COCH2CH2), 1.98–2.21 (m, 2 H,
CH=CHCH2), 2.31–2.38 (m, 2 H, COCH2CH2), 3.04 (t, J = 6.6 Hz,
2 H, CH2O), 3.66 (s, 3 H, CH3O), 4.22–4.53 (m, 2 H, CH, NH), 5.16
(m, 1 H, CHCH=CH), 5.48 (m, 1 H, CH=CHCH2), 7.18–7.47 (m,
15 H, 3 C6H5).
13C NMR (50 MHz, CDCl3): = 26.2, 27.8, 28.3, 29.3, 29.5, 30.0,
30.5, 31.1, 47.6, 51.6, 63.6, 79.3, 86.2, 126.7, 127.6, 128.7, 129.3,
133.0, 144.5, 155.1, 173.8.
Compounds 2a–d; General Procedure
To a solution of N-protected 2-amino alcohol 1a,b (2.00 mmol) in a
mixture of toluene–EtOAc (1:1; 12 mL) were added a solution of
NaBr (0.22 g, 2.1 mmol) in H2O (1 mL) and subsequently AcNH-
TEMPO (4 mg, 0.02 mmol). To the resulting biphasic system,
which was cooled to –5 °C, an aq solution of NaOCl (0.35 M; 6.3
mL, 2.2 mmol) containing NaHCO3 (0.50 g, 6 mmol) was added un-
der vigorous stirring, dropwise at –5 °C over 1 h. After the mixture
was stirred for an additional 15 min at 0 °C, EtOAc (12 mL) and
H2O (4 mL) were added. The aq layer was separated and washed
with EtOAc (12 mL). The combined organic layers were washed
with aq citric acid (5%; 12 mL) containing KI (0.07 g), aq Na2S2O3
(10%; 12 mL) and brine and dried (Na2SO4). The solvents were
evaporated under reduced pressure and the obtained crude aldehyde
was immediately used in the next step.
FAB MS: m/z (%) = 650 (M+ + Na, 55), 406 (4), 243 (100), 165
(37), 57 (75).
Anal. Calcd. for C40H53NO5: C, 76.52; H, 8.51; N, 2.23. Found: C,
76.39; H, 8.68; N, 2.11.
(2S,3Z)-7-Trityloxy-N-(tert-butoxycarbonyl)-1-phenylhept-3-
en-2-amine (2d)
To a stirred suspension of the phosphonium salt (2.40 mmol) in an-
hyd toluene (12 mL) was added a solution of KHMDS (0.5 M; 4.80
mL, 2.40 mmol) in toluene dropwise over a period of 5 min at 0 °C
under N2. The bright red solution was stirred for another 15 min and
cooled to –78 °C, when the solution of the aldehyde in anhyd tolu-
ene (4 mL) was instantly added, and the temperature was left to rise
from –78 °C to r.t. The light yellow mixture was stirred at r.t. for 20
h. The reaction mixture was quenched with sat. aq NH4Cl (20 mL)
and extracted with Et2O (3 6 mL). The combined organic phases
were washed with brine and dried (Na2SO4). The solvent was re-
moved, and the residue was purified by column chromatography
[EtOAc–petroleum ether (bp 40–60 °C), 1:9].
Yield: 0.59 g (54%); oil; [ ]D25 –1.0 (c 3.6, CHCl3).
1H NMR (200 MHz, CDCl3): = 1.38–1.65 [m, 11 H, C(CH3)3,
CH2CH2O], 1.90–2.16 (m, 2 H, CH=CHCH2), 2.60–3.05 (m, 4 H,
C6H5CH2, CH2O), 4.40–4.60 (m, 2 H, CH, NH), 5.17 (m, 1 H,
CHCH=CH), 5.39 (m, 1 H, CH=CHCH2), 7.11–7.48 (m, 20 H, 4
C6H5).
13C NMR (50 MHz, CDCl3): = 24.5, 28.3, 29.7, 41.9, 49.4, 63.0,
79.3, 86.3, 126.7, 127.7, 128.6, 129.5, 131.8, 137.6, 144.8, 155.0.
FAB MS: m/z (%) = 570 (M+ + Na, 40), 243 (100), 165 (23), 91 (5),
57 (56).
Anal. Calcd. for C37H41NO3: C, 81.13; H, 7.54; N, 2.56. Found: C,
81.01; H, 7.62; N, 2.64.
(10Z,12S)-12-[(tert-Butoxycarbonyl)amino]-13-phenyltridec-
10-en-1-ol (2a)
Yield: 0.13 g (17%); oil; [ ]D25 –1.7 (c 0.9, CHCl3).
Compounds 3a–c; General Procedure
1H NMR (200 MHz, CDCl3): = 1.02–1.48 [m, 21 H, C(CH3)3,
(CH2)9], 1.48–1.62 (m, 2 H, CH2CH2OH), 1.80–2.04 (m, 2 H,
CH=CHCH2), 2.65–2.97 (m, 2 H, CH2C6H5), 3.64 (t, J = 6.6 Hz, 2
H, CH2OH), 4.30–4.65 (m, 2 H, CH, NH), 5.18 (m, 1 H,
CHCH=CH), 5.40 (m, 1 H, CH=CHCH2), 7.15–7.35 (m, 5 H,
C6H5).
13C NMR (50 MHz, CDCl3): = 25.7, 27.7, 28.3, 29.1, 29.2, 29.3,
29.4, 32.8, 42.1, 49.3, 63.0, 79.2, 126.2, 128.1, 128.9, 129.7, 132.8,
137.7, 155.0.
To a solution of 2b–d (1.00 mmol) in MeOH (10.0 mL), 10% Pd/C
(10 mg, 0.009 mmol) was added. The reaction mixture was stirred
under H2 for 3 days. The catalyst was removed by filtration through
a pad of Celite and the organic solvent was evaporated under re-
duced pressure. The product was purified by column chromatogra-
phy (EtOAc–petroleum ether, 1:1).
(12R)-12-[(tert-Butoxycarbonyl)amino]-13-phenyltridecan-1-ol
(3a)
Yield: 0.36 g (92%); white solid; mp 58–59 °C; [ ]D25 10.7 (c 1.2,
FAB MS: m/z (%) = 390 (M+ + H, 5), 334 (10), 290 (4), 288 (16),
198 (93), 91 (46) 57 (100).
CHCl3).
1H NMR (200 MHz, CDCl3): = 1.20–1.70 [m, 29 H, C(CH3)3,
(CH2)10], 2.76 (d, J = 6.0 Hz, 2 H, CH2C6H5), 3.64 (t, J = 6.6 Hz, 2
H, CH2OH), 3.80 (m, 1 H, CH), 4.30 (d, J = 7.8, 1 H, NH), 7.15–
7.35 (m, 5 H, C6H5).
13C NMR (50 MHz, CDCl3): = 25.7, 25.9, 28.3, 29.4, 29.5, 32.8,
34.2, 41.3, 51.5, 63.0, 79.0, 126.0, 128.2, 129.5, 138.3, 155.5.
(2S,3Z)-13-Trityloxy-N-(tert-butoxycarbonyl)-1-phenyltridec-
3-en-2-amine (2b)
Yield: 0.97 g (77%); oil; [ ]D25 –1.2 (c 1, CHCl3).
1H NMR (200 MHz, CDCl3):
= 1.12–1.40 [m, 12 H,
CH=CHCH2(CH2)6], 1.44 [s, 9 H, C(CH3)3], 1.56–1.66 (m, 2 H,
CH2CH2O), 1.80–2.00 (m, 2 H, CH=CHCH2), 2.65–3.02 (m, 2 H,
CH2C6H5), 3.06 (t, J = 6.6 Hz, 2 H, CH2O), 4.38–4.65 (m, 2 H, CH,
FAB MS: m/z (%) = 392 (M+ + H, 7), 336 (26), 318 (8), 292 (52),
200 (63), 91 (38), 57 (95).
Synthesis 2002, No. 12, 1735–1739 ISSN 0039-7881 © Thieme Stuttgart · New York

1738
C. Noula et al.
PAPER
Anal. Calcd for C24H41NO: C, 73.61; H, 10.55; N, 3.58. Found: C,
73.54; H, 10.78; N, 3.52.
10 mL) and brine and dried (MgSO4). The organic solvent was
evaporated under reduced pressure and the residue was purified by
column chromatography (CHCl3–MeOH, 98:2).
Methyl (4R)-15-Hydroxy-4-[(tert-butoxycarbonyl)amino]pen-
tadecanoate (3b)
(12R)-12-[(tert-Butoxycarbonyl)amino]-13-phenyltridecanoic
Yield 0.26 g (68%); oil; [ ]D25 +2.5 (c 0.8 CHCl3).
Acid (5a)
Yield: 0.37 g (91%); white solid; mp 60–62 °C; [ ]D25 + 3.3 (c 1.6,
1H NMR (200 MHz, CDCl3): = 1.22–1.94 [m, 31 H, C(CH3)3,
(CH2)10, CHCH2CH2COO], 2.38 (t, J = 7.2 Hz, 2 H, CH2COO),
3.46–3.70 (m, 6 H, CH, CH2OH, OCH3), 4.27 (d, J = 9.4 Hz, 1 H,
NH).
13C NMR (50 MHz, CDCl3): = 25.7, 25.8, 28.3, 29.3, 29.4, 30.6,
30.8, 32.8, 35.8, 50.3, 51.6, 63.0, 79.0, 155.7, 174.2.
CHCl3).
1H NMR (200 MHz, CDCl3): = 1.08–1.57 [m, 25 H, C(CH3)3,
(CH2)8], 1.57–1.78 (m, 2 H, CH2), 2.35 (t, J = 7.2 Hz, 2 H,
CH2COOH), 2.76 (d, J = 6.0 Hz, 2 H, CH2C6H5), 3.75 (br, 1 H, CH),
4.32 (d, J = 8.2 Hz, 2/3 H, NH), 5.92 (m, 1/3 H, NH), 7.15–7.34 (m,
5 H, C6H5).
13C NMR (50 MHz, CDCl3): = 24.7, 25.9, 28.3, 29.4, 29.7, 34.2,
41.3, 51.1, 79.0, 126.0, 128.1, 129.6, 138.3, 155.5, 179.2.
FAB MS: m/z (%) = 388 (M+ + H, 4), 332 (4), 302 (22), 288 (69),
57 (100).
Anal. Calcd for C21H41NO5: C, 65.08; H, 10.66; N, 3.61. Found: C,
65.13; H, 10.39; N, 3.77.
FAB MS: m/z (%) = 428 (M+ + Na, 12), 406 (M+ + 1, 3), 350 (30),
306 (100), 271 (23), 214 (58), 91 (45), 57 (92).
(6R)-6-[(tert-Butoxycarbonyl)amino]-7-phenylheptan-1-ol (3c)
Yield: 0.22 g (71%); white solid; mp 55–57 °C; [ ]D25 11.8 (c 1.1,
CHCl3).
Anal. Calcd for C24H39NO4: C, 71.07; H, 9.69; N, 3.45. Found: C,
70.98; H, 9.77; N, 3.21.
(12R)-12-[(tert-Butoxycarbonyl)amino]-15-methoxy-15-oxo-
pentadecanoic Acid (5b)
1H NMR (200 MHz, CDCl3): = 1.25–1.62 [m, 15 H, C(CH3)3,
(CH2)4], 1.62–1.83 (m, 2 H, CH2), 2.76 (d, J = 6.4 Hz, 2 H,
CH2C6H5), 3.61 (t, J = 6.4 Hz, 2 H, CH2OH), 3.84 (m, 1 H, CH),
4.33 (d, J = 8.6 Hz, 1 H, NH), 7.15–7.35 (m, 5 H, C6H5).
Yield 0.31 g (77%); oil; [ ]D25 + 0.8 (c 1.0 CHCl3).
1H NMR (200 MHz, CDCl3):
= 1.20–1.38 [m, 14 H,
CHCH2(CH2)7], 1.43 [s, 9 H, C(CH3)3], 1.52–1.71 (m, 4 H, CHCH2,
CH2CH2CO2H), 1.72–2.00 (m, 2 H, CH2CH), 2.27–2.46 (m, 4 H, 2
CH2CO), 3.52 (m, 1 H, CH), 3.67 (s, 3 H, OCH3), 4.30 (d, J = 9.8
Hz, 3/4 H, NH), 5.55 (m, 1/4 H, NH).
13C NMR (50 MHz, CDCl3): = 24.6, 25.8, 28.3, 29.0, 29.1, 29.4,
30.5, 30.8, 33.9, 35.8, 50.4, 51.6, 79.1, 155.7, 174.3, 179.0.
13C NMR (50 MHz, CDCl3): = 25.2, 25.5, 28.3, 32.5, 34.3, 41.5,
51.1, 62.5, 79.1, 126.2, 128.3, 129.5, 138.2, 155.6.
FAB MS: m/z (%) = 308 (M+ + 1, 12), 252 (76), 208 (88), 160 (68),
116 (70), 91 (38), 57 (95).
Anal. Calcd for C18H29NO3: C, 70.32; H, 9.51; N, 4.56. Found: C,
70.41; H, 9.58; N, 4.47.
FAB MS: m/z (%) = 402 (M+ + 1, 12), 370 (5), 346 (22), 302 (90),
252 (15), 214 (13), 116 (32), 57 (100).
(12R)-12-[(tert-Butoxycarbonyl)amino]-13-phenyltridecanal (4)
Boc-Protected 12-amino alcohol 3a was converted into the alde-
hyde 4 as described above and was purified by column chromatog-
raphy (EtOAc–petroleum ether, 1:4).
Anal. Calcd for C21H39NO6: C, 62.81; H, 9.79; N, 3.49. Found: C,
62.96; H, 9.63; N, 3.56.
Yield: 0.58 g (74%); white solid; mp 48–50 °C; [ ]D25 10.2 (c 1.0,
CHCl3).
Acknowledgement
V.L. thanks the Greek Government and the European Commission
for a fellowship (E.P.E.A.E.K.). This work was supported in part by
the University of Athens (Special Account for Research Grants).
1H NMR (200 MHz, CDCl3): = 1.15–1.46 [m, 25 H, C(CH3)3,
(CH2)8], 1.46–1.65 (m, 2 H, CH2CH2CHO), 2.40 (dt, J = 7.4, 1.6
Hz, 2 H, CH2CHO), 2.73 (d, J = 6.2 Hz, 2 H, CH2C6H5), 3.76 (br, 1
H, CH), 4.27 (d, J = 9.0 Hz, 1 H, NH), 7.13–7.32 (m, 5 H, C6H5),
9.74 (t, J = 1.8 Hz, 1 H, CHO).
13C NMR (50 MHz, CDCl3): = 22.0, 25.9, 28.3, 29.1, 29.3, 29.4,
29.5, 34.2, 41.4, 43.9, 51.5, 79.0, 126.2, 128.4, 129.5, 138.4, 155.5,
203.0.
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FAB MS: m/z (%) = 390 (M+ + H, 5), 334 (48), 316 (44), 290 (30),
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Anal. Calcd for C24H39NO3: C, 73.99; H, 10.09; N, 3.59. Found: C,
73.85; H, 9.94; N, 3.76.
Boc-Protected -Amino Acids (5a,b); General Procedure
To a 0 °C, rapidly stirred solution of 3a,b (1 mmol) in CH2Cl2 (2.5
mL) and H2O (0.5 mL) were subsequently added AcNH-TEMPO (2
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–
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mmol), containing NaHCO3 (355 mg) was added and the mixture
was stirred vigorously for 20 min. The organic solvent was evapo-
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EtOAc (20 mL) and aq citric acid (10%; 10 mL) containing KI (60
mg). The aqueous phase was re-extracted with EtOAc (10 mL) and
the combined organic phases were washed with aq Na2S2O3 (10%;
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Synthesis 2002, No. 12, 1735–1739 ISSN 0039-7881 © Thieme Stuttgart · New York