Synthesis of N-protected α-amino aldehydes from their morpholine amide derivatives

Article abstract of DOI:10.1016/S0040-4039(99)01818-3

A new method for the synthesis of N-protected α-amino aldehydes was developed. N-Protected α-amino amides of morpholine were easily prepared and then reduced with LiAlH₄ to produce clean N-protected α-amino aldehydes. This new scheme of synthesis can be used with Boc, Z and Fmoc amino-protecting groups.

Full text of DOI:10.1016/S0040-4039(99)01818-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 37–40
Synthesis of N-protected α-amino aldehydes from their
morpholine amide derivatives
Céline Douat,a Annie Heitz,b Jean Martinez a,∗ and Jean-Alain Fehrentz a
aLAPP, associé au CNRS-Universités Montpellier I and II, Faculté de Pharmacie, 15 av. C. Flahault, 34060 Montpellier,
France
bUnité Mixte CNRS, Faculté de Pharmacie, Montpellier, France
Received 6 August 1999; accepted 21 September 1999
Abstract
A new method for the synthesis of N-protected α-amino aldehydes was developed. N-Protected α-amino
amides of morpholine were easily prepared and then reduced with LiAlH4 to produce clean N-protected α-amino
aldehydes. This new scheme of synthesis can be used with Boc, Z and Fmoc amino-protecting groups. © 1999
Elsevier Science Ltd. All rights reserved.
Enantiomerically pure α-amino aldehydes are starting materials for asymmetric synthesis of numerous
compounds and for pseudopeptide bond formation. They are mainly obtained by oxidation of their
corresponding alcohols or by reduction of α-amino acid derivatives with various reducing agents.
Reduction of Weinreb amide1,2 or 3,5-dimethyl pyrazolide3 of N-protected amino acid derivatives is
the method of choice compared to the reduction of α-amino esters.4 The two first derivatives have the
major advantage of avoiding alcohol formation during the reduction which proceeds through a stable
metal-chelated intermediate. Morpholine amides have already been used with success for nucleophilic
acylation reactions from simple carboxylic acids.5,6 In a recent paper7 the use of amino acid morpholine
amide derivatives for the synthesis of enantiopure α-amino ketones has been described by reaction with
organolithium reagents at −78°C. We have investigated the reduction of morpholine amide derivatives of
N-protected amino acids. In this report we describe the preparation and the use of N-protected α-amino
morpholine amides to generate the corresponding α-amino aldehydes.
N-Boc and N-Z α-amino acids were converted into their morpholine amides by conventional coupling
with morpholine and using any method of activation (phosphonium or uronium salts, chloroformiates,
DCC/HOBt, etc.) with a preference for phosphonium or uronium salts; when N-Fmoc α-amino acids
are used, the reaction must go to completion rapidly as morpholine, a secondary amine, is able to cleave
the N-Fmoc protecting group. In this case we found that the use of isobutylchloroformate (IBCF) as
activating agent to preform the mixed anhydride before the addition of morpholine was the best solution.
∗
Corresponding author. Fax: 33 4 67 41 20 17; e-mail: martinez@colombes.pharma.univ-montp1.fr
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01818-3

38
Using these conditions, we have prepared N-Fmoc α-amino morpholine amides. Reduction of the amides
was performed with five equivalents of hydride (that means 1.25 equivalents of LiAlH4) to produce
within a short time (10 to 20 min) the corresponding aldehydes in various conditions of temperature
(−70°C, −15°C and 0°C). We focused our attention on the eventual formation of the corresponding
alcohols and on the optical purity of the aldehydes. At −70°C, the reaction was incomplete even after
90 min while at 0°C it was complete within 20 min. Because traces of alcohol were observed by TLC
in all reaction conditions, we preferred to perform the reduction at 0°C. Formation of the corresponding
alcohols was very minor, suggesting that a strong stable metal-chelated tetrahedral intermediate was
formed (Scheme 1) avoiding the release of the formed aldehydes in the medium and, consequently,
an over-reduction of the aldehyde. After hydrolysis, the desired carbonyl components were recovered
1
by a classical work-up. All compounds were characterized by H NMR and mass spectrometry. The
enantiomeric purity was checked after purification on silica gel flash chromatography in non-racemizing
conditions.8
Scheme 1. Reduction of the morpholine amides into aldehydes
This method was tested with some Boc, Z and Fmoc amino acids to check their stability in the
reaction conditions. Various N-protected α-amino morpholine amides were prepared in good yields using
different coupling conditions (Table 1). These amides were then treated at 0°C with LiAlH4 as reducing
Table 1
Yields and optical purity of morpholine amide derivatives and N-protected α-amino aldehydes

39
agent to yield after 15–25 min complete reduction of the starting material.10 After classical work-up,
the crudes were examined by TLC and compared in some cases with the crudes resulting from the
corresponding Weinreb amide reductions which were synthesized in parallel. These crudes were found as
pure as the ones obtained from Weinreb amide reductions and with similar yields. They were purified by
silica gel chromatography with eluent systems containing 0.1% pyridine to avoid racemization to measure
their optical purity (Table 1). To check that N-protected α-amino aldehydes were not racemized when
prepared by this method, the synthesis of a reduced dipeptide, e.g. Boc-L-AlaΨ(CH2NH)L-Phe-NH2,
was carried out by condensation of crude Boc-L-Ala-H with H-L-Phe-NH2, as previously described9
1
(Scheme 2). Examination of the H NMR spectrum showed a single signal for the NH, Cα and methyl
protons of the alanine residue corresponding to the (LL) diastereoisomer, supporting the idea that this
method was free of racemization during the preparation of the aldehyde. Moreover, the measured [α]D
of the reduced dipeptide was found identical to that of compounds prepared by various methods.11
Scheme 2. Synthesis of the reduced dipeptide Boc-L-AlaΨ(CH2NH)L-Phe-NH2
In conclusion, this method of preparation of N-protected α-amino aldehyde is comparable with the
Weinreb amide one and provides an interesting alternative. The high cost of N,O-dimethylhydroxamate
hydrochloride made this new approach attractive since morpholine amides could be easily prepared at
low cost. We have also shown the reduction condition compatibility with most of the commonly used
N-protecting groups.
References
1. Nahm, S.; Weinreb, S. Tetrahedron Lett. 1981, 39, 3815–3818.
2. Fehrentz, J. A.; Castro, B. Synthesis 1983, 676–678.
3. Nishizawa, R.; Saino, T. J. Med. Chem. 1977, 20, 510–515.
4. Rich, D. H.; Sun, E. T.; Boparai, A. S. J. Org. Chem. 1978, 43, 3624–3626.
5. Kurosu, M.; Kishi, Y. Tetrahedron Lett. 1998, 39, 4793–4796.
6. Martin, R.; Romea, P.; Tey, C.; Urpf, F.; Vilarrassa, J. Synlett 1997, 1414–1415.
7. Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999, 40, 4107–4110.
8. Ho, P. T.; Ngu, K. J. Org. Chem. 1993, 58, 2313–2316.
9. Martinez, J.; Bali, J. P.; Rodriguez, M.; Castro, B.; Magous, R.; Laur, J.; Lignon, M. F. J. Med. Chem. 1985, 28, 1874–1879.
10. General method of preparation of the N-Boc or N-Z morpholine amide derivatives: Boc-Ala-OH (945 mg, 5
mmol) was dissolved in dichloromethane (50 mL), then BOP [(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate] (2.21 g, 5 mmol) and diisopropylethylamine (DIEA: 1.72 mL, 10 mmol) were added followed by
morpholine (0.478 mL, 5.5 mmol). After 90 min stirring, the mixture was concentrated in vacuo and ethyl acetate was
added. The organic layer was washed with acidic, then basic and neutral aqueous solutions, dried over sodium sulfate
and concentrated in vacuo. The compound obtained as an oil was purified by silica gel flash chromatography. BOP could
be replaced by N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-
oxide (HBTU) or other phosphonium or uronium salts. Chloroformates were also useful especially in the case of Fmoc-
α-amino acids; DCC/HOBt coupling mixture was found less suitable. In the case of coupling with BOP, HBTU, etc.
on N-Boc or N-Z-amino acids, the tertiary amine (DIEA, NEt3, etc.) could advantageously be replaced by an excess of
morpholine (4 equiv.). General method of preparation of the N-Fmoc morpholine amide derivatives: Fmoc-Ala-OH (3.11
g, 10 mmol) were dissolved in 25 mL DME and placed at −15°C. IBCF (1.31 mL, 10 mmol) and NMM (1.01 mL, 10
mmol) were then added; the formed precipate was eliminated by filtration and morpholine (0.87 mL, 10 mmol) was added
to the solution. After one hour the reaction was complete and treated as previously described. After flash chromatography,
3.4 g of a foam were obtained (yield: 90%). General method of preparation of amino aldehydes: As an example, reduction

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of Boc-Phe-morpholine amide is reported. Starting from 3 mmol of amide (1.00 g) dissolved in 30 mL of anhydrous THF
and placed under stirring in an ice bath, 47.5 mg (3.75 mmol) of LiAlH4 were added. The reaction was checked by TLC
examination (eluent system ethyl acetate/hexane (v/v)) of an aliquot which was separately hydrolyzed. After 15 min, the
reaction was hydrolyzed with 5% KHSO4 aqueous solution (5 mL) and extracted with diethyl ether. After classical work-
up, 675 mg of a white solid were obtained (yield 91%) which were purified by column chromatography on silica gel with
ethyl acetate/hexane (v/v) containing 0.1% pyridine as eluent. Pure material (510 mg) was obtained (68%).
11. Fehrentz, J. A.; Pothion, C.; Califano, J. C.; Loffet, A.; Martinez, J. Tetrahedron Lett. 1994, 35, 9031–9034.