enantio- and diastereocontrolled synthesis of the four
stereoisomers of orthogonally protected cyclobutane-1,2-
diamine in view of opening a new access for a wide range of
useful enantiopure molecules containing this moiety.
Three syntheses of racemic trans-cyclobutane-1,2-diamine
had been reported previously, but in most cases, yields
were low.9 Resolution of the racemic mixture was accom-
plished in one instance also in modest yield by using
L-tartaric acid.9a
Scheme 1. Retrosynthetic Analysis of the Orthogonally Pro-
tected Four Stereoisomers of Cyclobutane-1,2-diamine (1 and 2)
The retrosynthetic analysis of the target molecules
points to readily available optically pure half-ester 65c,10
as the only chiral precursor (Scheme 1). From 6, enantio-
divergent synthetic routes lead to the two enantiomers of
the key intermediate diprotected cyclobutane β-amino
acid, (1R,2S)- and (1S,2R)-5. These compounds allow
the preparation of enantiomeric cis-derivatives 1 through
acids 3 by hydrolysis and subsequent Curtius rearrange-
ment. In turn, trans-diastereoisomers 2 come from trans-
acids 4, which result from epimerization of the R-carbonyl
position in both enantiomers of 5.
Orthogonal protection in target molecules 1 and 2 is
crucial for further chemoselective manipulation of the two
amino groups. This allows retention of the chirality in cis-
diastereomers 1 that, otherwise, would become meso.
Therefore, the sequential order of the synthetic transfor-
mations is the key to successfully accomplish the stereo-
controlled synthesis of bothenantiomers of cis-1 and trans-
2 diamine derivatives.
both enantiomers of orthogonally protected cis-diamine 1
were obtained in 48% and 50% yields, respectively (three
steps) (see the Supporting Information).
The two enantiomers of cis-1 were obtained from 5.5c
First, the diprotection of the amino group was necessary in
order to avoid the formation of cyclic ureas during Curtius
rearrangement of monoprotected amines (Scheme 2).
These byproducts are formed through intramolecular nu-
cleophilic attack of the carbamate nitrogen to the carbon
of the transient isocyanate with concomitant ring-closure,
due to the kinetically favorable cyclization to the five-
membered urea ring.11 This process is not favorable with
trans-derivatives so they do not need amine diprotection.
Scheme 2 shows the diastereodivergent synthetic path-
ways for the preparation of cis-(1S,2R)-1 and trans-(1S,2S)-2
from cis-amino acid derivative (1R,2S)-5. The double
protection was achieved by treating 5 with Boc anhydride
(2 equiv) in the presence of DMAP and triethylamine.
Saponification of the methylesterwas carried out to obtain
quantitatively cis-3. After that, the carboxylic acid was
activated as a mixed anhydride by reaction with ethyl
chloroformate and then sodium azide was added to form
an acyl azide that was not isolated. This intermediate was
submitted to Curtius rearrangement by heating to reflux in
toluene and in the presence of benzyl alcohol. In this way,
The syntheses of both enantiomers of trans-diamine 2
were also conducted from amino acid derivative 5. Activa-
tion of the carboxylic acid as a mixed anhydride by
reaction with ethyl chloroformate and subsequent treat-
ment with ammonium hydrogencarbonate in pyridine
yielded an amide,12 which was heated under strong basic
conditions to afford monoprotected trans-amino acid 4.
From this intermediate and following procedures similar
to those described above for cis-diastereomers, both en-
antiomers of orthogonally protected trans-2 were obtained
in 67% and 69% overall yield (three steps), respectively.
For the purpose of proving that the synthesized ortho-
gonally protected cyclobutane 1,2-diamine derivatives
could be used for further functionalization, their selective
deprotections were carried out (Scheme 3). Thus, elimina-
tion of the two tert-butoxycarbonyl groups in cis-diamine
(1S,2R)-1 was achieved quantitatively giving amine hydro-
chloride (1S,2R)-10. In a similar way, both enantiomers of
trans-amine hydrochloride 10 were obtained in quantita-
tive yield from diprotected trans-diamines (1R,2R)- and
(1S,2S)-2, respectively. Alternatively, the benzyl carba-
mate group in (1S,2S)-2 was hydrogenolyzed in the pre-
sence of Pd(OH)2/C to afford (1S,2S)-12 in 82% yield.
Products 10 and 12 are suitable for the chemo-
selective introduction of structural units containing
additional functional groups. As a preliminary instance,
(9) (a) Daly, A. M.; Gilheany, D. G. Tetrahedron: Asymmetry 2003,
14, 127. (b) Vergne, F.; Partogyan, K.; Aitken, D. J.; Husson, H.-P.
Tetrahedron 1996, 52, 2421. (c) Buchman, E. R.; Reims, A. O.; Skei, T.;
Schlatter, M. J. J. Am. Chem. Soc. 1942, 64, 2696.
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(10) (a) Dıaz de Villegas, M. D.; Galvez, J. A.; Etayo, P.; Badorrey,
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R.; Lopez-Ram-de-Vıu, P. Chem. Soc. Rev. 2011, 40, 5564. (b) Atodiresei,
I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683. (c) Bolm, C.; Schiffers,
I.; Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron: Asymmetry 2003, 14,
3455.
(12) (a) Fernandes, C.; Pereira, E.; Faure, S.; Aitken, D. J. J. Org.
Chem. 2009, 74, 3217. (b) Fernandes, C; Gauzy, C.; Yang, Y.; Roy, O.;
Pereira, E.; Faure, S.; Aitken, D. J. Synthesis 2007, 14, 2222.
ꢁ
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(11) Gorrea, E.; Nolis, P.; Alvarez-Larena, A.; Da Silva, E.; Branchadell,
~
V.; Ortuno, R. M. Tetrahedron: Asymmetry 2010, 21, 339.
B
Org. Lett., Vol. XX, No. XX, XXXX
Sans, Marta
