Efficient enantioselective synthesis of orthogonally protected (R)-α-alkylserines compatible with the solid phase peptide synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.08.016

The Sch?llkopf methodology for the asymmetric synthesis of α-amino acids, which was previously not applicable to the construction of quaternary α-amino acids, has been rendered not only suitable but also practical for this purpose and applied to a highly efficient enantioselective synthesis of orthogonally protected (R)-α-alkylserines suitable for the solid phase synthesis.

Full text of DOI:10.1016/j.tetlet.2006.08.016

Tetrahedron Letters 47 (2006) 7339–7341
Efficient enantioselective synthesis of orthogonally protected
(R)-a-alkylserines compatible with the solid phase peptide synthesis
Stamatia Vassiliou,a Athanasios Yiotakisa and Plato A. Magriotisb,*
aDepartment of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
bDepartment of Chemistry, New York University, 110 Washington Square East, New York, NY 10003, USA
Received 5 July 2006; revised 2 August 2006; accepted 7 August 2006
Available online 24 August 2006
Abstract—The Scho¨llkopf methodology for the asymmetric synthesis of a-amino acids, which was previously not applicable to the
construction of quaternary a-amino acids, has been rendered not only suitable but also practical for this purpose and applied to a
highly efficient enantioselective synthesis of orthogonally protected (R)-a-alkylserines suitable for the solid phase synthesis.
Ó 2006 Elsevier Ltd. All rights reserved.
The enantioselective synthesis of a,a-disubstituted (qua-
ternary) a-amino acids has recently received consider-
able attention since their incorporation in modified
peptides often improves both the biological activity
and the pharmacological profile of the latter, due to
the introduction of unusual conformational constraints
which change their secondary or tertiary structure.1 Fur-
thermore, these peptides are rendered more stable meta-
bolically due to the decreased rate of proteolysis,2 and
sometimes quaternary a-amino acids represent powerful
enzyme inhibitors.3 Specifically, chiral nonracemic, suit-
ably protected a-alkylserines such as 4 and 5 (Fig. 1)
have been recognized as important components in the
areas of both synthetic and medicinal chemistry.4
groups, thus rendering a-alkyl serines useful in pepti-
domimetic drug design.5 In addition, the a-substituted
serine unit is contained within several natural products
such as salinosporamide A, myriocin, (+)-lactacystin,
(+)-conangenin, sphingofungin E, altemicidin, and
amicetin.6
Reported methods for the synthesis of a-substituted
serines include rearrangement of chiral (nonracemic)
trichloroacetimidates,6b,7 ring-opening of chiral aziri-
dines,8 enzymatic desymmetrization,6d,9 an intramolecu-
lar version of the asymmetric Strecker reaction,10 phase-
transfer catalytic enantioselective alkylation,11 and
alkylation of chiral amino acid enolate equivalents.4d,12
One of the most notable examples of the latter approach
is the bis-lactim ether methodology developed by
Scho¨llkopf.13 We have recently reported an improved
Scho¨llkopf protocol for the construction of quaternary
a-amino acids and applied it to efficient syntheses of
b-lactams and integrin LFA-1 antagonist BIRT-377.14
Despite its broad utility in both synthetic and medicinal
chemistry,4,5 to the best of our knowledge only one
method has been reported for the synthesis of (S)-Na-
Fmoc-a-methylserine which was not orthogonally
protected (free hydroxyl and carboxyl groups).15
This recognition is attributed to the fact that their
hydroxyl groups stabilize the secondary structure of
peptides by hydrogen bonding with the amide carbonyl
OtBu
OtBu
R
R
H2N
CO2CH3
FmocHN
CO2H
a, R = CH3
b, R = CH2Ph
5
4
In this letter, we report an efficient enantioselective syn-
thesis of orthogonally Na-Fmoc protected (R)-a-alkyl-
serines employing the highly improved Scho¨llkopf
protocol we have developed (Fig. 1).14 Accordingly,
readily available (S)-bislactim ether 116 was deproto-
nated with tert-BuLi (À78°C, THF, 1 h) instead of
n-BuLi used by Scho¨llkopf and co-workers,12c,13 and
Figure 1. The structures of orthogonally protected (R)-a-alkylserines.
Keywords: a,a-Disubstituted a-amino acids; Quaternary a-amino
acids; (R)-a-Alkylserines; Scho¨llkopf methodology; tert-BuLi.
*
Corresponding author. Tel.: +1 212 998 3591; fax: +1 212 260
7905; e-mail: plato.magriotis@nyu.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.016

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S. Vassiliou et al. / Tetrahedron Letters 47 (2006) 7339–7341
alkylated with chloromethyl benzyl ether17 to produce
(3R)-2 in excellent yields (2a:12c 86%, 2b: 90%) and very
high diastereoselectivity (>95%, only one diastereomer
and dioxane, in good yields (5a: 55%, 5b: 65%; two
steps) and very high ee (ꢀ95%).20
1
could be detected by H and 13C NMR). Notably, the
In summary, we have shown that the Scho¨llkopf meth-
odology can be conveniently employed for the enantio-
selective construction of quaternary a-amino acids in a
practical manner,4,13 and we have applied this protocol
to the synthesis of a-alkyl a-amino ester 3 (Scheme
1),21 which has been efficiently converted to orthogo-
nally protected (R)-a-alkylserines 4 and 5, useful for
the solid phase peptide synthesis. The advertized effi-
ciency of this method relies on both the ready availabil-
ity of 1,16 and the two-step, one-pot conversions of 3 to
4 and 4 to 5 in very good overall yields.
yield of 2a using n-BuLi as the deprotonating base was
only 58% as opposed to 91% reported by Scho¨llkopf
and co-workers.12c Consistently, the yield of 2b using
n-BuLi was very low (35%).18 These significant yield dis-
parities are attributed to the exclusively basic action of
tert-BuLi toward the less hindered C-3 hydrogen as
opposed to the C-6 one, as well as its negligible nucleo-
philicity toward the imino esters (Scheme 1).14
The acidic hydrolysis of 2 with 10% trifluoroacetic acid
in acetonitrile/water (2/1) for 10 h at ambient tempera-
ture13c afforded 3 in good yields (3a: 80%, 3b: 85%).
Reductive cleavage of the benzyl group on palladium
in methanol/3% HCl (5/1) proceeded smoothly to pro-
vide the corresponding methyl ester hydrochloride salts,
whose hydroxyl side chain was protected as tert-butyl
ethers 4 in very good yields (4a: 70%, 4b: 80%, Scheme
1, Fig. 1).19
Acknowledgments
This work was supported in part by the Laboratory of
Organic Chemistry of the University of Athens and by
the special account for research grants of the University
of Athens. Professor James W. Canary (NYU) is
warmly thanked for the generous donation of both lab-
oratory space and expendable supplies. Thanks are also
due to Dr. Dionisios Abatis for HPLC assistance.
Hydrolysis of 4 with aqueous NaOH (0.25 N, 0 °C, 2 h)
generated the free a-amino acids which were protected
as their Fmoc derivatives 5 (Fig. 2), after neutralization
(2 N HCl) and addition of Fmoc–Cl in 10% aq Na2CO3
Supplementary data
The experimental procedures and spectral data for prod-
ucts 2–5 as well as HPLC data on the optical purity of
5a and 5b. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2006.08.016.
H3CO
H3CO
1. tert-BuLi, -78 ºC
N
6
N
N
N
2. PhCH2OCH2Cl
3
OCH3
OCH3
R
R
O
References and notes
1
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