Highly Stereoselective Conversion of Aryl Peptidyl Ketones into the Corresponding Peptide Alcohols

Article abstract of DOI:10.1002/ejoc.200300563

In this paper we describe the conversion of aryl peptidyl ketones, by a hydride reduction, into the corresponding peptide alcohols. The developed methodology is highly stereoselective and represents a very important application in peptide chemistry for obtaining peptide alcohols. It provides peptide alcohols with definite stereochemistry and in moderate, but satisfactory, yields. The reducing procedure, performed with NaBH₃CN and TiCl₄, probably proceeds via two diastereomeric cyclic intermediates that show different reactivity. The stereochemistry of the resulting alcohols was established after obtaining them by an alternative synthetic procedure. Furthermore, the methodology adopted keeps the urethane protecting group on the amino function of the N-terminal amino acid residue. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300563

FULL PAPER
Highly Stereoselective Conversion of Aryl Peptidyl Ketones into the
Corresponding Peptide Alcohols
Maria Luisa Di Gioia,[a] Antonella Leggio,[a] Adolfo Le Pera,[a] Angelo Liguori,*[a] and
Carlo Siciliano[a]
Keywords: Alcohols / Peptides / Reduction / Stereoselectivity / Titanium
In this paper we describe the conversion of aryl peptidyl ke-
tones, by a hydride reduction, into the corresponding peptide
eric cyclic intermediates that show different reactivity. The
stereochemistry of the resulting alcohols was established
alcohols. The developed methodology is highly stereoselec- after obtaining them by an alternative synthetic procedure.
tive and represents a very important application in peptide
chemistry for obtaining peptide alcohols. It provides peptide
alcohols with definite stereochemistry and in moderate, but
Furthermore, the methodology adopted keeps the urethane
protecting group on the amino function of the N-terminal
amino acid residue.
satisfactory, yields. The reducing procedure, performed with ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
NaBH3CN and TiCl4, probably proceeds via two diastereom- Germany, 2004)
Introduction
Results and Discussion
The aim of this work was the development of a stereose-
lective procedure to convert the carbonyl function of aryl
peptidyl ketones into the alcohol function of peptide al-
cohols. For this purpose we prepared simple peptidyl ke-
tones 1aϪe, made up of two amino acid residues, and stud-
ied their reduction by readily accessible reagents. In particu-
lar, the dipeptidyl ketone N-Fmoc--Ala--Ala-C6H4CH3
(1a) was chosen as a model system to investigate the re-
duction reaction.
Reduction of the dipeptide 1a with an excess of LiAlH4
in dry THF provided two diastereomeric peptide alcohols
2a and 3a in a 1:1 molar ratio, characterized by the opposite
configuration of the carbinol carbon atom. Under these
conditions a preferential attack by the nucleophile on one
of the two faces of the carbonyl group did not occur. How-
ever, the Fmoc group on the amino function was not affec-
ted by LiAlH4, and side products due to the removal of the
Fmoc group were not observed. The removal of the Fmoc
group by LiAlH4, under the conditions mentioned above,
proceeds slowly, as confirmed by treating the N-Fmoc--
valine methyl ester 4 with LiAlH4. The reaction of 4 with
an excess of LiAlH4 in dry THF at room temperature for
17 h afforded, after work up and purification of the crude
product by short column chromatography, N-Fmoc--vali-
nol (5) in 84% yield, a small quantity of the starting mate-
rial (5%) and traces of dibenzofulvene resulting from the
removal of the Fmoc group under basic conditions. This
experiment showed that the Fmoc group is not significantly
affected by this kind of hydride reducing reagent.
Peptide alcohols are important synthetic intermediates of
biologically and pharmaceutically active molecules.[1Ϫ5]
Peptaibols, peptide analogues characterized by the presence
of an alcoholic function at the C-terminal residue of the
peptide chain, are receiving considerable attention because
of their significant activity as antibiotics.[6Ϫ9] Peptide al-
cohols also serve as key synthetic precursors for a number
of peptide aldehydes that are biologically active as enzy-
matic inhibitors.[10Ϫ13] Due to their importance in biology
the stereoselective synthesis of peptide alcohols has become
a goal for many research groups.[14,15] In the peptide al-
cohols, the stereochemistry of the carbon atom could be the
key to their molecular activity, so stereochemical control in
the synthesis of peptide alcohols is an important challenge
in peptide chemistry and pharmacological research.
We report here a convenient and highly stereoselective
synthesis of a class of peptide alcohols by hydride reduction
of precursor aryl peptidyl ketones. The proposed procedure
represents, in peptide chemistry, an interesting synthetic
tool to obtain peptide alcohols with definite stereochem-
istry starting from peptide systems characterized by epimer-
ization problems. A synthetic route to aryl peptidyl ketones
is the acylation of aromatic substrates with N-protected am-
ino acid derivatives. The perfect stereochemical control of
the acylation reaction provides peptidyl ketones in which
the configuration of the asymmetric centres is preserved.[16]
[a]
`
Dipartimento di Scienze Farmaceutiche, Universita degli Studi
della Calabria,
Via P. Bucci Cubo 15/C, 87036 Arcavacata di Rende (CS), Italy
Fax: (internat.) ϩ 39-0984/492-044
E-mail: A.Liguori@unical.it
In an additional experiment the dipeptide 1a was treated
with NaBH3CN in a methanol solution at pH ϭ 3 using
Eur. J. Org. Chem. 2004, 463Ϫ467
DOI: 10.1002/ejoc.200300563
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
463

M. L. Di Gioia, A. Leggio, A. Le Pera, A. Liguori, C. Siciliano
FULL PAPER
1
methyl orange as indicator to monitor the change in pH.
However, the H NMR spectral differences could not be
This reduction reaction gave the conversion of 81% of the used to assign the exact stereochemistry of the new stereog-
starting ketone 1a into the corresponding diastereomeric al- enic centre generated in the reduction of the carbonyl func-
cohols 2a and 3a, which were recovered by short column tion. It is very important to be able to assign the stereo-
chromatography in the molar ratio 1:1. In light of the re- chemistry of the reduction reaction unambiguously, there-
sults obtained, the formation of chelate intermediates was fore we planned an alternative synthesis of the dia-
attempted in order to achieve stereocontrol of the reduction stereomeric dipeptide alcohol 2d resulting from the
process. With this result in mind the reduction reaction of reduction of the dipeptidyl ketone 1d and characterized by
1a was performed using titanium tetrachloride as the chelat- a definite configuration of the carbinol carbon atom (1R).
ing agent and dichloromethane as the solvent. The reaction The target dipeptide alcohol was obtained by treating N-
showed a different course; in fact, only about 50% of 1a Fmoc--alanine chloride (6) with (1R,2S)-norephedrine (8).
was converted into the corresponding diastereomeric al- In this way the configurations of the norephedrine asym-
cohols 2a and 3a (Scheme 1).
metric carbon atoms are unchanged (Scheme 2, Table 2).
Scheme 2
Scheme 1
Table 2. Alternative synthesis of dipeptide alcohols 2dϪe
Moreover, the reaction was highly diastereoselective and
the separation of the product mixture by short column
chromatography afforded the two diastereomeric alcohols
(2a and 3a) in 47 and 2% yields, respectively (Scheme 1,
Table 1).
R1
2[a]
d
e
CH3
85
91
CH3CH2(CH3)CH
[a]
Isolated yield (%).
Table 1. Synthesis of dipeptide alcohols 2aϪe and 3aϪe
TLC analysis of the reaction mixture showed the forma-
R1
R2
R3
2[a]
3[a]
tion of the target dipeptidyl alcohol 2d, which corresponded
perfectly to that obtained, as the major product, by re-
duction of the peptidyl ketone 1d. Furthermore, the 1H
NMR spectra of the two peptide alcohols, obtained by in-
dependent methods, are exactly alike. This result led us to
the conclusion that reduction of the peptidyl ketone 1d af-
fords the corresponding alcohol 2d as the major product.
Based on the results with ketone 1d, we inferred that the
a
b
c
d
e
CH3
CH3
CH3
(CH3)2CH
CH3
CH3
CH3
CH3
CH3
H
47
45
47
45
46
2
2
1
2
2
CH3CH2(CH3)CH
CH3
CH3
CH3CH2(CH3)CH
H
[a]
Isolated yield (%).
In a further experiment the same reaction was performed reduction of the dipeptidyl ketones 1aϪe gave the corre-
at room temperature for 48 h with the aim of increasing the sponding alcohols 2aϪe with high stereoselectivity. The dia-
conversion of the starting ketone into the corresponding stereomers 3aϪe were obtained in trace amounts with
alcohol. The conversion of the starting material was still yields lower than 5%. As a further confirmation of the ster-
low. In fact, 45% of the peptidyl ketone 1a was recovered eochemical assignments the dipeptide alcohol 2e was also
unchanged by short column chromatography.
prepared in an alternative way by treating N-Fmoc--iso-
The diastereomers obtained from reduction of 1a could leucine chloride (7) with (1R,2S)-norephedrine (8;
be distinguished by 1H NMR spectroscopy. For example Scheme 2, Table 2). In this case also the TLC analysis and
the protons on the carbinol carbon atoms of 2a and 3a gave 1H NMR spectrum of the obtained product are identical to
1
distinct signals at δ ϭ 4.47 and 4.54 ppm in the H NMR those of the major product formed by the reduction of the
spectrum of the crude reaction product. The relative ratio dipeptidyl ketone 1e with NaBH3CN and TiCl4.
of the diastereomers 2a and 3a was also determined by inte-
gration of these two H NMR signals.
This reduction reaction is characterized by an incomplete
conversion of the starting ketone into the corresponding
1
The reduction reaction was also extended to other sys- alcohol and a high diastereoselectivity. The conversion of
tems. The aryl peptidyl ketones 1bϪe were treated with the starting material into the dipeptide alcohol did not im-
NaBH3CN and TiCl4 under the same conditions as 1a and prove with increased reaction times. The diastereoselectivity
afforded the corresponding peptide alcohols 2bϪe and can be explained by the diastereomeric cyclic intermediates
3bϪe with high stereoselectivity (Scheme 1, Table 1).
A and B, formed from starting material and TiCl4. We pro-
464
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Eur. J. Org. Chem. 2004, 463Ϫ467

Conversion of Aryl Peptidyl Ketones into the Corresponding Peptide Alcohols
FULL PAPER
monitored by TLC using silica gel 60-F254 precoated glass plates.
Short column flash chromatography (SCFC) was performed on
Kieselgel 60 H without gypsum. When required, the reactions were
carried out under N2.
pose that TiCl4 coordinates to the amide nitrogen atom and
the carbonyl oxygen atom of the aryl peptidyl ketone, for-
ming the intermediates A and B in an equimolar ratio (Fig-
ure 1).
Synthesis of 2a؊e and 3a؊e with NaBH3CN/TiCl4: A 1  solution
of TiCl4 in CH2Cl2 (2 mmol, 2 mL) and a 1  methanol solution
of NaBH3CN (6 mmol, 6 mL) were added to a magnetically stirred
solution of the dipeptide 1aϪe (2 mmol) in dry CH2Cl2 (5 mL).
The resulting reaction mixture was maintained at room tempera-
ture and under N2 for 20Ϫ24 h. A 2  NaOH solution was added
and the basified solution was extracted with ethyl acetate (2 ϫ
10 mL). The combined organic extracts were dried with Na2SO4
and the solvents evaporated under vacuum. Subsequent chromato-
graphic purification (chloroform/methanol, 98:2 v/v) afforded the
corresponding alcohols 2aϪe (45Ϫ47%) and 3aϪe (1Ϫ2%).
2a: White solid (47% yield), m.p. 166Ϫ170 °C. IR (KBr): ν˜ϭ 3310,
3061, 2978, 1685, 1654, 1559, 1254, 759, 739 cmϪ1 1H NMR
.
Figure 1. Diastereomeric cyclic intermediates A and B formed from
acryl peptidyl ketones and TiCl4
([D6]DMSO): δ ϭ 0.97 (d, J ϭ 6.6 Hz, 3 H, CH3CHCHOH), 1.03
(d, J ϭ 6.6 Hz, 3 H, CH3CHCONH), 2.25 (s, 3 H, CH3C6H4),
3.80Ϫ4.05 (m, 2 H, CHCH2O and CHCHOH), 4.13Ϫ4.30 (m, 3
H, CHCH2O and CHCONH), 4.47 (dd, J ϭ 4.6 and J ϭ 5.1 Hz,
1 H, CHOH), 5.37 (d, J ϭ 4.6 Hz, 1 H, OH), 7.03Ϫ7.98 (m, 14 H,
CONHCHCHOH, FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 459 (13) [M ϩ H]ϩ, 441 (20), 338 (9), 281 (6), 221 (5),
179 (100), 178 (48), 165 (33), 164 (15). C28H30N2O4 (458.2): calcd.
C 73.34, H 6.59, N 6.11; found C 73.31, H 6.61, N 6.13.
For chelate A, hydride attack on the accessible face of
the carbonyl group produces the major diastereomer 2,
characterized by the (R) configuration of the carbinol car-
bon atom. For chelate B, both faces of the carbonyl groups
are sterically blocked by the group containing titanium and
by the substituent at the α-position. Therefore, chelate A
appears to be the reactive intermediate.
The proposed model explains the reaction yields, which
are about 50% for all used systems, and the high stereoselec-
tivity as well.
3a: White solid (2% yield), m.p. 187Ϫ191 °C. IR (KBr): ν˜ϭ 3312,
3060, 2977, 1673, 1652, 1560, 1262, 760, 741 cmϪ1 1H NMR
.
([D6]DMSO): δ ϭ 0.99 (d, J ϭ 6.7 Hz, 3 H, CH3CHCHOH), 1.06
(d, J ϭ 6.8 Hz, 3 H, CH3CHCONH), 2.23 (s, 3 H, CH3CHCONH),
3.81Ϫ4.05 (m, 2 H, CH3C6H4), 4.14Ϫ4.32 (m, 3 H, CHCH2O and
CHCONH), 4.54 (dd, J ϭ 4.1 and J ϭ 4.6 Hz, 1 H, CHOH), 5.42
(d, J ϭ 4.1 Hz, 1 H, OH), 7.04Ϫ7.98 (m, 14 H, CONHCHCHOH,
FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA): m/z (%) ϭ 459 (15)
[M ϩ H]ϩ, 441 (25), 338 (7), 281 (5), 221 (6), 179 (100), 178 (46),
165 (32), 164 (17). C28H30N2O4 (458.2): calcd. C 73.34, H 6.59, N
6.11; found C 73.32, H 6.61, N 6.12.
Conclusion
The reduction of aryl peptidyl ketones represents a gen-
eral method for the preparation of aryl peptide alcohols.
The reduction reaction, performed using NaBH3CN/TiCl4
as the reagent system, shows a remarkably high stereoselec-
tivity. These results suggest that chelation of the ketone oxy-
gen atom and the amide nitrogen atom to titanium tetra-
chloride is the key to the stereochemical control. Our results
also show that, under the reaction conditions used, the pep-
tide alcohols obtained keep the Fmoc protecting group on
the amino function. The most important aspect of the pro-
posed methodology is the highly stereoselective formation
of peptide alcohols using modified peptide systems as start-
ing materials.
2b: White solid (45% yield), m.p. 193Ϫ196 °C. IR (KBr): ν˜ϭ 3313,
3059, 2976, 1681, 1657, 1557, 1250, 760, 740 cmϪ1 1H NMR
.
([D6]DMSO): δ ϭ 0.66 [d, J ϭ 6.1 Hz, 3 H, CH3CH2(CH3)CH],
0.74 [dd, J ϭ 6.9 and J ϭ 7.8 Hz, 3 H, CH3CH2(CH3)CH], 0.97
(d, J ϭ 6.9 Hz, 3 H, CH3CHCHOH), 1.19Ϫ1.30 [m, 2 H,
CH3CH2(CH3)CH], 1.60 [m, 1 H, CH3CH2(CH3)CH], 2.25 (s, 3 H,
CH3C6H4), 3.83 (dd, J ϭ 7.8 and J ϭ 8.6 Hz, 1 H, CHCH2O), 3.95
(m,
1 H, CHCHOH), 4.15Ϫ4.36 (m, 3 H, CHCH2O and
CHCONH), 4.47 (dd, J ϭ 4.3 and J ϭ 5.2 Hz, 1 H, CHOH), 5.30
(d, J ϭ 4.3 Hz, 1 H, OH), 7.01Ϫ7.92 (m, 14 H, CONHCHCHOH,
FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA): m/z (%) ϭ 501 (18)
[M ϩ H]ϩ, 483 (31), 380 (8), 279 (6), 179 (100), 178 (58), 165 (13),
164 (8). C31H36N2O4 (500.3): calcd. C 74.37, H 7.25, N 5.60; found
C 74.34, H 7.27, N 5.61.
Experimental Section
General Remarks: All solvents were purified and dried by standard
procedures and distilled prior to use. Melting points were deter-
mined with a Kofler hot-stage apparatus and are uncorrected. IR
spectra were obtained using KBr pellets. 1H NMR spectra were
recorded with a Bruker Avance 300 instrument at 300 MHz. Unless
3b: White solid (2% yield), m.p. 180Ϫ182 °C. IR (KBr): ν˜ϭ 3311,
1
3060, 2980, 1683, 1657, 1555, 1250, 759, 740 cmϪ1. H NMR: δ ϭ
0.67 [d, J ϭ 6.3 Hz, 3 H, CH3CH2(CH3)CH], 0.78 [dd, J ϭ 6.8 and
J ϭ 7.6 Hz, 3 H, CH3CH2(CH3)CH], 0.99 (d, J ϭ 6.7 Hz, 3 H,
CH3CHCHOH), 1.20Ϫ1.27 [m, 2 H, CH3CH2(CH3)CH], 1.61 [m,
otherwise indicated, [D6]DMSO was used as the NMR solvent. 1 H, CH3CH2(CH3)CH], 2.23 (s, 3 H, CH3C6H4), 3.83 (dd, J ϭ
Mass spectra were recorded with a Vacuum Generators ZAB-2F 7.7 and J ϭ 8.7 Hz, 1 H, CHCH2O), 3.95 (m, 1 H, CHCHOH),
spectrometer, using 3-nitrobenzyl alcohol as matrix, by fast-atom 4.15Ϫ4.36 (m, 3 H, CHCH2O and CHCONH), 4.52 (dd, J ϭ 4.3
bombardment (FABϩ MS), with a neutral Xenon beam operating
and J ϭ 4.7 Hz, 1 H, CHOH), 5.41 (d, J ϭ 4.3 Hz, 1 H, OH),
at 8 keV and a total current of 10 µA. Reaction mixtures were 7.02Ϫ7.95 (m, 14 H, CONHCHCHOH, FmocNH and Ar-H) ppm.
Eur. J. Org. Chem. 2004, 463Ϫ467
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M. L. Di Gioia, A. Leggio, A. Le Pera, A. Liguori, C. Siciliano
FULL PAPER
FAB-MS (ϩ, NBA): m/z (%) ϭ 501 (23) [M ϩ H]ϩ, 483 (27), 380
3e: White solid (2% yield), m.p. 175Ϫ177 °C. IR (KBr): ν˜ϭ 3311,
1
(10), 279 (5), 179 (100), 178 (67), 165 (22), 164 (12). C31H36N2O4 3058, 2985, 1685, 1659, 1562, 1257, 761, 739 cmϪ1. H NMR: δ ϭ
(500.3): calcd. C 74.37, H 7.25, N 5.60; found C 74.33, H 7.27,
N 5.62.
0.66 (d, J ϭ 6.8 Hz, 3 H, CH3CH2(CH3)CH], 0.76 [dd, J ϭ 6.8 and
J ϭ 7.8 Hz, 3 H, CH3CH2(CH3)CH], 0.98 (d, J ϭ 5.9 Hz, 3 H,
CH3CHCHOH), 1.20Ϫ1.31 (m, 2 H, CH3CH2(CH3)CH], 1.57 [m,
1 H, CH3CH2(CH3)CH], 3.80 (dd, J ϭ 7.8 and J ϭ 8.7 Hz, 1 H,
CHCH2O), 4.01 (m, 1 H, CHCHOH), 4.19Ϫ4.32 (m, 3 H,
CHCH2O and CHCONH), 4.58 (dd, J ϭ 4.3 and J ϭ 5.0 Hz, 1
H, CHOH), 5.40 (d, J ϭ 4.3 Hz, 1 H, OH), 7.17Ϫ7.93 (m, 15 H,
CONHCHCHOH, FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 487 (21) [M ϩ H]ϩ, 469 (15), 380 (10), 279 (6), 179
(100), 178 (73), 165 (32), 164 (12). C30H34N2O4 (486.3): calcd. C
74.05, H 7.04, N 5.76; found C 74.01, H 7.06, N 5.77.
2c: White solid (47% yield), m.p. 168Ϫ171 °C. IR (KBr): ν˜ϭ 3316,
1
3060, 2958, 1689, 1654, 1559, 1251, 760, 738 cmϪ1. H NMR: δ ϭ
0.80 [d, J ϭ 6.8 Hz, 6 H, (CH3)2CH], 0.90 (d, J ϭ 6.9 Hz, 3 H,
CH3CH), 2.10 [m, 1 H, (CH3)2CH], 2.25 (s, 3 H, CH3C6H4),
3.85Ϫ3.92 (m, 2 H, CHCH2O and CHCONH), 4.10Ϫ4.30 (m, 3
H, CHCHOH and CHCH2O), 4.34 (dd, J ϭ 4.1 and J ϭ 5.3 Hz,
1 H, CHOH), 5.28 (d, J ϭ 4.1 Hz, 1 H, OH), 7.02Ϫ7.94 (m, 14 H,
CONHCHCHOH, FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 487 (11) [M ϩ H]ϩ, 469 (30), 366 (10), 276 (6), 179
(100), 178 (69), 165 (32), 164 (14). C30H34N2O4 (486.3): calcd. C
74.05, H 7.04, N 5.76; found C 74.02, H 7.06, N 5.77.
Alternative Synthesis of 2dϪe: (1R,2S)-Norephedrine (1 mmol) in
an aqueous 5% solution of Na2CO3 (5 mL) was added to a solution
of N-Fmoc--alanine chloride (6; 1 mmol) or N-Fmoc--isoleucine
chloride (7; 1 mmol) in ethanol-free chloroform (10 mL). The re-
sulting mixture was stirred at room temperature for 1 h, and then
HCl (1 ) was added. The chloroform layer was separated and the
acidified aqueous solution was extracted with two additional por-
tions of chloroform (2 ϫ 5 mL). The combined chloroform extracts
were washed with brine, dried with Na2SO4 and the solvents evapo-
rated under vacuum to afford the corresponding aryl peptide al-
cohols 2dϪe in 84Ϫ88% yields. The compound characterization
data for 2dϪe are identical to those obtained with the NaBH3CN/
TiCl4 procedure.
3c: White solid (1% yield), m.p. 178Ϫ180 °C. IR (KBr): ν˜ϭ 3313,
1
3065, 2964, 1687, 1650, 1558, 1245, 762, 739 cmϪ1. H NMR: δ ϭ
0.82 [d, J ϭ 6.8 Hz, 6 H, (CH3)2CH], 0.93 (d, J ϭ 6.9 Hz, 3 H,
CH3CH), 2.14 [m, 1 H, (CH3)2CH], 2.24 (s, 3 H, CH3C6H4),
3.84Ϫ3.92 (m, 2 H, CHCH2O and CHCONH), 4.13Ϫ4.31 (m, 3
H, CHCHOH and CHCH2O), 4.39 (dd, J ϭ 4.0 and J ϭ 5.7 Hz,
1 H, CHOH), 5.37 (d, J ϭ 4.0 Hz, 1 H, OH), 7.02Ϫ7.94 (m, 14 H,
CONHCHCHOH, FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 487 (10) [M ϩ H]ϩ, 469 (35), 366 (8), 276 (5), 179 (100),
178 (77), 165 (46), 164 (18). C30H34N2O4 (486.3): calcd. C 74.05,
H 7.04, N 5.76; found C 74.02, H 7.06, N 5.77.
Synthesis of Aryl Peptidyl Ketones 1aϪe: Aryl peptidyl ketones
1aϪc were synthesised as reported in the literature.[16] Peptides 1d,e
were obtained as follows: AlCl3 (3 mmol) was added to a magneti-
cally stirred solution of N-Fmoc--alanine chloride (1 mmol) in dry
benzene (15 mL). The reaction mixture was maintained at room
temperature under N2 for 5 h. HCl (1 ) was added, and the acidi-
fied solution was extracted with diethyl ether (3 ϫ 10 mL). The
aqueous phase was basified with saturated aqueous Na2CO3. The
basic liquors, containing the α-aminoalkyl phenyl ketone, were
treated with a solution of N-Fmoc--alanine chloride (1 mmol) or
N-Fmoc--isoleucine chloride (1 mmol) in ethanol-free chloroform
(10 mL). The resulting mixture was stirred at room temperature for
1 h, and then the chloroform layer was separated. The aqueous
phase was extracted with three additional portions of chloroform
(3 ϫ 10 mL). The combined chloroform extracts were dried with
Na2SO4 and the solvents evaporated under vacuum to afford the
aryl peptidyl ketones in 84Ϫ87% yields.
2d: White solid (45% yield), m.p. 181Ϫ183 °C. IR (KBr): ν˜ϭ 3313,
1
3060, 2981, 1686, 1653, 1557, 1258, 761, 738 cmϪ1. H NMR: δ ϭ
1.01 (d, J ϭ 6.8 Hz, 6 H, CH3CHCONH and CH3CHCHOH),
3.91Ϫ4.08 (m, 2 H, CHCH2O and CHCHOH), 4.17Ϫ4.28 (m, 3
H, CHCH2O and CHCONH), 4.50 (dd, J ϭ 4.9 and J ϭ 5.0 Hz,
1 H, CHOH), 5.46 (d, J ϭ 4.9 Hz, 1 H, OH), 7.19Ϫ7.94 (m, 15 H,
CONHCHCHOH, FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 445 (26) [M ϩ H]ϩ, 427 (31), 338 (8), 267 (4), 207 (3),
179 (100), 178 (63), 165 (29), 164 (14). C27H28N2O4 (444.2): calcd.
C 72.95, H 6.35, N 6.30; found C 72.93, H 6.36, N 6.31.
3d: White solid (2% yield), m.p. 175Ϫ177 °C. IR (KBr): ν˜ϭ 3318,
1
3063, 2984, 1690, 1655, 1555, 1252, 760, 738 cmϪ1. H NMR: δ ϭ
1.02 (d, J ϭ 6.8 Hz, 6 H, CH3CHCONH and CH3CHCHOH),
3.89Ϫ4.07 (m, 2 H, CHCH2O and CHCHOH), 4.18Ϫ4.30 (m, 3
H, CHCH2O and CHCONH), 4.55 (dd, J ϭ 4.6 and J ϭ 5.4 Hz,
1 H, CHOH), 5.54 (d, J ϭ 4.6 Hz, 1 H, OH), 7.21Ϫ7.95 (m, 15 H,
CONHCHCHOH, FmocNH and Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 445 (22) [M ϩ H]ϩ, 427 (33), 338 (6), 267 (4), 207 (4),
179 (100), 178 (60), 165 (31), 164 (12). C27H28N2O4 (444.2): calcd.
C 72.95, H 6.35, N 6.30; found C 72.93, H 6.36, N 6.31.
1d: White solid (84% yield), m.p. 125Ϫ127 °C. IR (KBr): ν˜ϭ 3294,
3059, 2986, 1719, 1690, 1640, 1549, 1260, 760, 739 cmϪ1. 1H NMR
(CDCl3): δ ϭ 1.40 (d, J ϭ 7.4 Hz, 6 H, CH3CHCONH and
CH3CHCOC6H5), 4.22 (m, 1 H, CHCH2O), 4.39Ϫ4.48 (m, 3 H,
CHCH2O and CHCONH), 5.51 (m, 1 H, CHCOC6H5), 5.64 (d,
J ϭ 7.4 Hz, 1 H, FmocNH), 7.14 (d, J ϭ 6.9 Hz, 1 H,
CONHCHCOC6H5), 7.25Ϫ7.95 (m, 13 H, Ar-H) ppm. FAB-MS
(ϩ, NBA): m/z (%) ϭ 443 (35) [M ϩ H]ϩ, 337 (7), 294 (4), 265 (5),
223 (13), 179 (100), 178 (75), 165 (38), 164 (22). C27H26N2O4
(442.2): calcd. C 73.28, H 5.92, N 6.33; found C 73.25, H 5.93,
N 6.34.
2e: White solid (46% yield), m.p. 190Ϫ192 °C. IR (KBr): ν˜ϭ 3312
cmϪ1, 3060, 2983, 1687, 1654, 1559, 1251, 760, 738 cmϪ1 1H
.
NMR: δ ϭ 0.63 [d, J ϭ 6.8 Hz, 3 H, CH3CH2(CH3)CH], 0.74 [dd,
J ϭ 6.8 and J ϭ 7.8 Hz, 3 H, CH3CH2(CH3)CH], 0.99 (d, J ϭ
5.9 Hz,
3
H, CH3CHCHOH), 1.18Ϫ1.30 [m,
2
H,
CH3CH2(CH3)CH], 1.59 [m, 1 H, CH3CH2(CH3)CH], 3.82 (dd,
J ϭ 7.8 and J ϭ 8.7 Hz, 1 H, CHCH2O), 3.97 (m, 1 H, CHCHOH),
4.19Ϫ4.35 (m, 3 H, CHCH2O and CHCONH), 4.52 (dd, J ϭ 3.9 1e: White solid (87% yield), m.p. 169Ϫ171 °C. IR (KBr): ν˜ϭ 3296,
and J ϭ 4.8 Hz, 1 H, CHOH), 5.40 (d, J ϭ 3.9 Hz, 1 H, OH), 3060, 2974, 1718, 1687, 1644, 1545, 1258, 762, 740 cmϪ1. 1H NMR
7.18Ϫ7.93 (m, 15 H, CONHCHCHOH, FmocNH and Ar-H) ppm. (CDCl3): δ ϭ 0.85Ϫ0.98 [m, 6 H, CH3CH2(CH3)CH], 1.22 [m, 1
FAB-MS (ϩ, NBA): m/z (%) ϭ 487 (25) [M ϩ H]ϩ, 469 (19), 380
(11), 279 (6), 179 (100), 178 (63), 165 (28), 164 (14). C30H34N2O4 1.50 [m,
(486.3): calcd. C 74.05, H 7.04, N 5.76; found C 74.01, H 7.06,
N 5.77.
H, CH3CH2(CH3)CH], 1.40 (d, J ϭ 6.9 Hz, 3 H, CH3CHCOC6H5),
H, CH3CH2(CH3)CH], 1.89 [m, H,
CH3CH2(CH3)CH], 4.16Ϫ4.25 (m, H, CHCH2O and
CHCONH), 4.39Ϫ4.45 (m, 2 H, CHCH2O), 5.52 (m, 1 H,
1
1
2
466
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 463Ϫ467

Conversion of Aryl Peptidyl Ketones into the Corresponding Peptide Alcohols
CHCOC6H5), 5.75 (d, J ϭ 8.6 Hz, 1 H, FmocNH), 7.12 (d, J ϭ peptidyl ketone 1a (1 mmol) in dry MeOH (5 mL). A trace of a 1
FULL PAPER
7.8 Hz, 1 H, CONHCHCOC6H5), 7.22Ϫ7.92 (m, 13 H, Ar-H)
 ethanol solution of methyl orange was added and 2  HCl in
ppm. FAB-MS (ϩ, NBA): m/z (%) ϭ 485 (31) [M ϩ H]ϩ, 379 (2), methanol was added dropwise to maintain the red colour. The re-
336 (3), 307 (9), 179 (100), 178 (67), 165 (34), 164 (18). Anal. Calcd. sulting reaction mixture was maintained at room temperature un-
For C30H32N2O4 (484.2): calcd. C 74.36, H 6.66, N 5.78; found C
74.34, H 6.68, N 5.79.
der N2 for 36 h, then the methanol was evaporated in vacuo. Brine
was added and the aqueous phase was extracted with diethyl ether
(3 ϫ 5 mL). The combined organic extracts were dried with
Na2SO4 and the solvents evaporated in vacuo. The subsequent
chromatographic purification (chloroform/methanol, 98:2 v/v) af-
forded the corresponding alcohols 2a and 3a as a 1:1 dia-
stereomeric mixture.
Reduction of Aryl Peptidyl Ketone 1a with LiAlH4: LiAlH4
(3 mmol) was added to a magnetically stirred solution of aryl pepti-
dyl ketone 1a (1 mmol) in dry THF (10 mL). The resulting reaction
mixture was maintained at room temperature under N2 for 15 min,
then 1  KHSO4 (5 mL) was added. The THF was evaporated un-
der vacuum and the aqueous phase was extracted with dichloro-
methane (3 ϫ 5 mL). The combined organic extracts were dried
with Na2SO4 and the solvents evaporated under vacuum. Sub-
sequent chromatographic purification (chloroform/methanol, 98:2
v/v) afforded the corresponding alcohols 2a and 3a as a 1:1 dia-
stereomeric mixture. The compound characterisation data for 2a
and 3a are identical to those obtained with the NaBH3CN/TiCl4
procedure.
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reaction mixture was maintained at room temperature and N2 for
17 h. H2O (10 mL) was added and the aqueous phase was extracted
with diethyl ether (2 ϫ 5 mL). The combined organic extracts were
washed with 1  HCl (1 ϫ 5 mL) then dried with Na2SO4 and the
solvents evaporated under vacuum. Subsequent chromatographic
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[10]
3348, 3066, 2965, 1667, 1540, 1273, 763, 738 cmϪ1 1H NMR
.
[11]
(CDCl3): δ ϭ 0.98 [d, J ϭ 6.8 Hz, 3 H, CH(CH3)2], 1.03 [d, J ϭ
6.8 Hz, 3 H, CH(CH3)2], 1.93 [m, 1 H, CH(CH3)2], 3.55 (m, 1 H,
CHNH), 3.66Ϫ3.80 (m, 2 H, CH2OH), 4.29 (m, 1 H, CHCH2O),
4.42Ϫ4.59 (m, 2 H, CHCH2O), 5.10 (d, J ϭ 9.2 Hz, 1 H,
FmocNH), 7.35Ϫ7.88 (m, 8 H, Ar-H) ppm. FAB-MS (ϩ, NBA):
m/z (%) ϭ 326 (18) [M ϩ H]ϩ, 179 (100), 178 (87), 165 (23), 164
(8). C20H23NO3 (325.2): calcd. C 73.82, H 7.12, N 4.30; found C
73.79, H 7.14, N 4.31.
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Reduction of Aryl Peptidyl Ketone 1a with NaBH3CN: NaBH3CN
(1.1 mmol) was added to a magnetically stirred solution of aryl
G. Sindona, J. Org. Chem. 2001, 66, 7002Ϫ7007.
Received September 5, 2003
Eur. J. Org. Chem. 2004, 463Ϫ467
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
467