Diastereoselective synthesis of γ-phthalimido-β-hydroxy esters and n-protected 4-amino-1,3-diols starting from natural α-amino acids

Article abstract of DOI:10.2174/157017810790533869

An efficient diastereoselective synthes.is of γ-phthalimido-β- hydroxy esters and N-protected 4-amino-1,3- diols, starting from natural amino acids is described. The key synthetic strategies involve diastereoselective reduction of γ-phthalimido-β-keto esters with NaBH₄ as hydride reducing. The diastereoselective reduction has been found to be highly selective if carried out in methanol at -78°C. Furthermore, the resulting diastereomeric mixture of the reduced products was successfully and cleanly separated by column chromatography.

Full text of DOI:10.2174/157017810790533869

Letters in Organic Chemistry, 2010, 7, 69-72
69
Diastereoselective Synthesis of ꢀꢁPhthalimido-ꢂ-Hydroxy Esters and
N-Protected 4-Amino-1,3-Diols Startingꢀfrom Natural ꢃ-Amino Acids
Amel Essersi, Ridha Touati and Béchir Ben Hassine*
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (01UR1201), Faculté des Sciences de Monastir,
Avenue de l’Environnement, 5019 Monastir, Tunisie
Received June 10, 2009: Revised November 10, 2009: Accepted November 12, 2009
Abstract: An efficient diastereoselective synthes.is of ꢀꢁphthalimido-ꢂ-hydroxy esters and N-protected 4-amino-1,3-
diols, startingꢀfrom natural amino acidsꢀis described. The key synthetic strategies involve diastereoselective reduction ofꢀ
ꢀꢁphthalimido-ꢂ-keto esters with NaBH4 as hydride reducing. The diastereoselective reduction has been found to be
highly selective if carried out in methanol at -78°C. Furthermore, the resulting diastereomeric mixture of the reduced
products was successfully and cleanly separated by column chromatography.
Keywords: Amino acids, phthalimide analogues, chiral -ꢂ-keto esters, amino acid derivatives, ꢂ-hydroxy esters, N-protected 4-
amino-1,3-diols.
Asymmetric synthesis has emerged as one of the most
rapidly developing research areas in organic chemistry [1].
Among various strategies involved in the asymmetric
synthesis, the use of chiral auxiliaries has been extensively
studied and a number of new auxiliaries have been
successfully used for an efficient asymmetric synthesis [2].
Most of such chiral auxiliaries have been derived from chiral
pools of naturally-occurring compounds namely amino acids
[2,3], terpenes [2], and carbohydrates [2,4].
In addition to their biological importance [17], N-
Protected 2-amino alcohols are valuable starting materials
for the synthesis of optically-active intermediates, such as ꢃ-
amino aldehydes [18], diamines [19] and triamines [20] as
well as for the synthesis of enzyme inhibitors [21], anti-
inflammatory [22] and cytotoxic agents [23].
The generation of optically active amino alcohols from
their masked precursors can easily be achieved through the
known methods [24]. The successful strategy involved the
tagging of a phthalimide as a masking group, since free
amino functions generally cause the inhibition of lipases.
The other advantages of incorporating a phthalimide subunit
are the facilitation of their separation of the resulting
protected compounds and UV detection by HPLC. In
addition, phthalimide analogues are also reported to have
anti-inflammatory [25] analgesic [26], anticonvulsant [27],
herbicidal [28], and insecticidal [29] activities.
Thus, the design of such auxiliaries has been largely
dependent upon the availability of the chiral starting
materials from natural sources. In this connection, we have
initiated a research effort towards the development of novel
chiral auxiliaries based upon highly efficient and reliable
asymmetric transformations [5].
The 1,3-diol structure is a basic subunit for many
bioactive compounds [6]. Therefore, the preparation of this
type of fragment is of much interest, especially if functional
groups are present in the appropriate position in order to
complete the total synthesis of the target molecules.
Although various elegant alternative approaches have also
been reported [7], such as the stereoselective hydrogenation
of ꢂ-diketone [8], the resolution procedures [9] and the aldol
reaction [10] still remain the most versatile strategy leading
to the 1,3 diol structures.ꢀ
For all these reasons, much effort has been devoted to the
development of efficient methods for the asymmetric
synthesis of this kind of molecules [17, 30].
In continuation of our research, which is aimed the
preparation of natural and non-natural compounds of
biomedical importance [31], and in the context of our
medicinal chemistry program dealing with the development
On the other hand, the importance of vicinal amino
alcohols continues to rise interest in the development of new
efficient methods for their synthesis in an enantiomerically
pure form [11], 1,2-Amino alcohols are not only the key
pharmacophores in many drug molecules [11a,12] but also
constitute as substructures in various important natural
products [11a,13-16].
OH
OH
OH
O
R
R
OMe
N
N
O
O
O
O
*Address correspondence to this author at the Laboratoire de Synthèse
Organique Asymétrique et Catalyse Homogène (01UR1201), Faculté des
Sciences de Monastir, Avenue de l’Environnement, 5019 Monastir, Tunisie;
E-mail: bechirbenhassine@yahoo.fr
4
5
Fig. (1).
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Essersi et al.
O
O
O
R
R
OMe
OH
O
O
N
a) ImCOIm, THF, rt, 6 h
O
O
N
O
phtalic anhydride
R
OH
b) Mg(O2CCH2CO2Me)2,
THF, rt, 16 h
Et3N, Toluene. reflux
NH2
1 a-d
2 a-d
a: R= CH3; b:R= (CH3)2CHCH2; c: R=Ph
d: R= PhCH2; e: R= CH3CH2CH(CH3)
3 a-d
Scheme 1.
of a new type of anti-inflammatory, derivatives [32], we
report herein an efficient and easy methodology for the
synthesis of new optically active N-protected ꢀ-amino ꢁ-
hyddroxyesters 4 and their corresponding N-protected 4-
amino 1,3 diols 5 starting from commercially available
natural ꢂ-amino acids (Fig. 1).
protected amino acids was performed using Masamune’s
procedure [31a]. In fact the preparation of this new chiral ꢁ-
keto esters is best carried out by the condensation of N-
Protected amino acids 1 with carbonyldiimidazole and the
magnesium salt of monomethyl malonic acid in anhydrous
THF, to afford the corresponding ꢀ-substituted ꢁ-ketoesters 3
a-e (having a stereogenic center in ꢀ- position) in good yields
(Scheme 1).
The starting N-protected amino acids were prepared by
allowing phthalic anhydride to react with a number of
commercially available amino acids in refluxing nonpolar
solvents such as toluene in the presence of triethylamine and
separating the formed water. The phthalimide derivatives
were prepared in good yield without racemization [33]
(Scheme 1).
Then, we have studied the reduction of these
ꢀꢃphthalimido-ꢁ-keto esters with sodium borohydride
(Scheme 2). The major diastereoisomer is obtained as the
main yields of the product and the diastereoisomeric
excesses are generally good as reported in Table 1.
In the next step and based upon the precedent studies
established in recent reports [31a, 34a], the homologation of
In general, several methods have been reported for the
enhancement of the reactivity and selectivity of this hydride
O
O
OH
O
OH
O
R
R
R
OMe
OMe
>
OMe
NaBH4/ MeOH
T= -78°C
N
N
N
O
O
O
O
O
O
3 a-e
(S,S)-4 a-e
(S,R)-4 a-e
Scheme 2.
Table 1. Asymmetric Reduction of Enantiopure ꢀꢃPhthalimido-ꢁ-Keto Esters 3 with Sodium Borohydridea
d.e (%)b
(S,S)-4/(S,R)-4
Entry
R
Solvent
Temperature
Time (mn)
Yieldc (%)
1
2
3
4
5
6
7
8
9
CH3-
CH3-
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
65
25
10 mn
22 mn
30
38
48
64
68
80
90
82
84
91
68
73
80
84
90
92
89
91
92
CH3-
0
CH3-
-20
-78
-78
-78
-78
-78
34
CH3-
41
(CH3)2CH-CH2-
Ph-
40
40
PhCH2-
(S)-Et-CH3-CH-
43
40
aReaction conditions: 1 mmol of 3, 1 mmol of NaBH4, 10 mL of solvent.
bDetermined by HPLC analysis or 1H NMR of the crude reaction mixture.
cChemical yield of purified and isolated (S,S)-4.

Diastereoselective Synthesis of ꢀ Phthalimido-ꢁ-Hydroxy Esters
OH
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
OH OH
71
O
R
R
OMe
N
O
O
N
O
O
NaBH4, MeOH
r.t. 5 h
(S,S)-5 a-e
(S,S)-4 a-e
Scheme 3.
reducing reagent in the organic synthesis which has been
reviewed by Periasamy and Thirumalaikumar [35].
groups, the stereogenic centers in ꢀ-and ꢂ-position does not
undergo any racemerization during the process or the
isolation.
The effect of the solvent on the reaction was first
investigated. After the screening of solvents for the reduction
of 3, methanol turned out to be the most appropriate solvent.
ACKNOWLEDGEMENT
On the other hand, although the reaction can be
conducted successfully at room temperature in some cases,
the best results were obtained while working at a low
temperature. In fact, when the temperature was decreased
(entries 3-5), a significant increase in the diastereofacial
discrimination was observed, leading to the corresponding
ꢀꢁphthalimido-ꢂ-hydroxy ester with an excellent diastereo-
selectivity (over 85%).
The authors are grateful to DGRSRT (Direction Générale
de la Recherche Scientifique et de la Rénovation
Technologique) of the Tunisian Ministry of Higher
Education, Scientific Research and Technology for the
financial support.
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