C. Körner et al. / Tetrahedron Letters 51 (2010) 6381–6383
6383
1. PMB-Br, DIPEA
2. iPr3SiH, 1% TFA
H
H
H
4, NaBH3CN, 1% AcOH
COOPMB
COOH
NHFmoc
COOPMB
N
R
MttHN
H2N
O
91% (2 steps)
NAloc
NHFmoc
NHFmoc
3
7, R = H
Boc2O, DMAP, THF, 6 h
59% (2 steps)
8, R = Boc
1. TEMPO/BAIB,
PTSA, MeOH, 20 h
MeCN:H2O 1:1, 6 h
H
H
H
COOPMB
NHFmoc
AlocHN
COOPMB
NHFmoc
N
N
HO
Boc
Boc
2. Cs2CO3,
MeOH, then allyl
bromide
NHAloc
AllylOOC
9
2
40% (3 steps)
Scheme 2. Synthesis of protected lysinoalanine.
Driscoll, P. C.; Tabor, A. B. J. Org. Chem. 2003, 68, 8193–8198; (c) Bregant, S.;
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462–463.
to 75 C these resolved to give single peaks (Supplementary data),
as was seen with the aldehyde 4, clearly indicating that a single
diastereoisomer of the protected lysinoalanine derivative had been
formed.
In summary, we have developed a synthetic route to lysinoala-
nine via the reductive amination of a novel Aloc-protected Garner’s
aldehyde derivative. The synthetic strategy ensures that the two
carboxylic acid groups, and three amino groups, remain differenti-
ated throughout, allowing the preparation of an orthogonally pro-
tected bis-amino acid. We envisage that this will be useful in the
solid-phase preparation of a range of constrained peptides.
7. (a) Smith, N. D.; Goodman, M. Org. Lett. 2003, 5, 1035–1037; (b) Zhu, X.;
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Acknowledgements
This work was supported by an Erasmus Grant from the
European Commission (to C.K.), a BBSRC Grant BB/D005469/1
(to E.-A.R.), an EPSRC LSI Doctoral Training Centre Studentship
(to D.C.N.) Grant EP/F500416/1, and an EPSRC Advanced Research
Fellowship EP/E052789/1 (to T.S.).
13. (a) Beaulieu, L. P.; Schiller, P. W. Tetrahedron Lett. 1988, 29, 2019–2022; (b)
Baxter, A. D.; Murray, P. J.; Taylor, R. J. K. Tetrahedron Lett. 1992, 33, 2331–2334;
(c) Barco, A.; Benetti, S.; Spalluto, G.; Casolari, A.; Pollini, G. P.; Zanirato, V. J.
Org. Chem. 1992, 57, 6279–6286.
Supplementary data
14. (a) Moriwake, T.; Hamano, S.; Saito, S.; Torii, S. Chem. Lett. 1987, 2085–2088;
(b) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Synthesis 1994, 31–33.
15. Meffre, P.; Durand, P.; Branquet, E.; Le Goffic, F. Synth. Commun. 1994, 24,
2147–2152.
Supplementary data (experimental procedures, characteriza-
tion data and 1H and 13C NMR spectra for all compounds, VT 1H
NMR spectra for aldehyde 4 and VT 1H and 13C spectra for the pro-
tected bis-amino acid 2) associated with this article can be found,
16. Dondoni, A.; Perrone, D. Synthesis 1997, 527–529.
17. At 25 °C a doubling of the aldehyde and methyl signals was observed in the 1
H
NMR spectrum, however, on heating to 75 °C single, sharp peaks were
observed (Supplementary data) indicating that at the lower temperature
there is restricted rotation around one or more bonds. This behaviour has been
observed previously, see: Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361–
2364.
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