Crestey et al.
JOCNote
R-lithiation and subsequent electrophilic trapping of N-Boc
piperazines.12
SCHEME 1. Modular Synthesis of Piperazine, 1,4-Diazepane,
and 1,4-Diazocane Building Blocks
While a survey of the literature did not reveal many studies
concerning synthesis of chiral diazocanes,13 a few papers
describe routes to chiral 1,4-diazepanes,14 which may be
commonly prepared either by reduction of the correspond-
ing diketo-1,4-diazepanes obtained via intermolecular con-
densation of R- and β-amino acid derivatives15 or by
condensation of a ditriflate with a resin-bound diamine in
a solid-phase synthesis (SPS).16 Therefore, a short and
versatile sequence allowing preparation of such selectively
N-protected chiral heteroalicyclic building blocks for com-
binatorial applications is of particular interest.
As part of our ongoing investigations within aziridine
chemistry17 we were intrigued by the apparent lack of
systematic solution-phase studies concerning influence of
ring size and bulkiness of substituents,18 and we decided to
devise a general method for the construction of chiral
monoprotected piperazines I. In addition, we intended to
explore the possibilities for obtaining larger heterocyclic
rings as well as establish the potential of the method for
gram-scale preparations. Thus, in the present work we report
on intramolecular Fukuyama-Mitsunobu cyclization of
protected β-aminosulfonamides II obtained by nucleophilic
ring-opening of activated aziridines III with ω-amino alco-
hols. The protocol was found also to provide access to novel
1,4-diazepane and 1,4-diazocane derivatives IV and V
(Scheme 1), albeit with less efficiency.
Our initial focus was on optimizing the synthesis of
piperazine 3 by a four-step sequence only requiring chroma-
tographic purification after the final step. Nucleophilic
opening of (S)-N-(p-nitrobenzenesulfonyl)-2-benzylaziri-
dine 2a19 with 2-aminoethanol (n=1)20 in 1,2-dichloroethane
(DCE) was monitored by TLC and HPLC-DAD (254 nm),
and complete conversion of the starting aziridine was ob-
served after 30 min at room temperature. Subsequent re-
moval of excess 2-aminoethanol by a simple extraction was
followed directly by N-Boc-protection of the crude product,
using Boc2O and triethylamine. Subsequent Fukuyama-
Mitsunobu cyclization21 was accomplished with diisopro-
pyl azodicarboxylate (DIAD)22 and triphenylphosphine
(Ph3P) during 3 h at room temperature.23 A simple Boc-
deprotection in TFA-CH2Cl2 provided N-nosylated piper-
azine 3 in good yield (Table 1, entry 1).
To obtain piperazines 4-6, the conditions for ring-open-
ing of the requisite aziridines were modified. Thus, aziridines
bearing i-Bu (2b), CH2cHex (2c), and i-Pr (2d) as substituents
required heating with 2-aminoethanol at 40 °C for 1 h to
reach full conversion. Sequential N-protection and cycliza-
tion similarly afforded the corresponding piperazines in
good overall yields (Table 1, entries 2-4). Having obtained
these promising results, the scope of the protocol was further
explored to include preparation of homologous ring systems.
Thus, sequences involving initial aminolysis of the enantio-
meric aziridines 2a and 2f with 3-aminopropan-1-ol (n=2) or
4-aminobutan-1-ol (n=3) provided monoprotected chiral R-
substituted enantiomeric 1,4-diazepanes 7 and 9 and 1,4-
diazocanes 8 and 10, respectively, in good overall yields
(Table 1, entries 5-8). Measurement of the optical rotation
of enantiomers 7 and 9 gave the same value but with opposite
sign. Likewise, the enantiomers 8 and 10 exhibited identical
numerical [R]D values confirming the validity of this proto-
col.24 In addition, the reactivity and selectivity of an amino
diol was examined.25 Hence, after ring-opening of
2a with (2R)-3-aminopropan-1,2-diol and subsequent pro-
tection, the resulting Boc-protected β-aminosulfonamide
(12) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer D. J.; Terpstra,
J. W.; Hiemstra, H.; Iwena Bakker, W. I.; van den Hoogenband, A.;
van Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369–2371.
(13) Hidaka, H.; Nishio, M.; Sumi, K. U.S. 08064681, 2008; Chem.
Abstr. 2008, 148, 331572.
(14) For synthesis of tetraaza macrocycles bearing a chiral diazepane
ring, see: Kang, S.-G.; Choi, J.-S.; Nam, K.; Chun, H.; Kim, K. Inorg. Chim.
Acta 2004, 357, 2783–2790.
€
€
(15) (a) Bedurftig, S.; Wunsch, B. Eur. J. Med. Chem. 2009, 44, 519–525.
(b) Keenan, T. P.; Kaplan, A. P. US 07203124, 2007; Chem. Abstr. 2007, 147,
323014. (c) Revesz, L.; Bollbuck, B.; Buhl, T.; Eder, J.; Esser, R.; Feifel, R.;
Heng, R.; Hiestand, P.; Jachez-Demange, B.; Loetscher, P.; Sparrer, H.;
Schlapbach, A.; Waelchli, R. Bioorg. Med. Chem. Lett. 2005, 15, 5160–5164.
(16) Li, D.; Hall, D. G. Tetrahedron: Asymmetry 2005, 16, 1733–1736.
(17) (a) Ottesen, L. K.; Olsen, C. A.; Witt, M.; Jaroszewski, J. W.;
Franzyk, H. Chem.;Eur. J. 2009, 15, 2966–2978. (b) Crestey, F.; Ottesen,
L. K.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron Lett. 2008, 49, 5890–
5893. (c) Crestey, F.; Witt, M.; Frydenvang, K.; Stærk, D.; Jaroszewski,
J. W.; Franzyk, H. J. Org. Chem. 2008, 73, 3566–3569. (d) Olsen, C. A.;
Christensen, C.; Nielsen, B.; Mohamed, F. M.; Witt, M.; Clausen, R. P.;
Kristensen, J. L.; Franzyk, H.; Jaroszewski, J. W. Org. Lett. 2006, 8, 3371–
3374.
(21) For a recent review on Fukuyama-Mitsunobu reactions, see:
Golantsov, N. E.; Karchava, A. V.; Yurovskaya, M. A. Chem. Heterocycl.
Compd. 2008, 44, 263–294.
(22) When diethyl azodicarboxylate (DEAD) was employed in this
Fukuyama-Mitsunobu reaction,
a similar yield was obtained. Cf.:
€
Kummerle, A. E. Synlett 2008, 2373–2374.
(23) For recent examples on Fukuyama-Mitsunobu reactions, see:
(a) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48–56.
(b) Demmer, O.; Dijkgraaf, I.; Schottelius, M.; Wester, H.-J.; Kessler, H.
Org. Lett. 2008, 10, 2015–2018. (c) Leach, S. G.; Cordier, C. J.; Morton, D.;
McKiernan, G. J.; Wariner, S.; Nelson, A. J. Org. Chem. 2008, 73, 2753–
2759. (d) Zapf, C. W.; Del Valle, J. R.; Goodman, M. Bioorg. Med. Chem.
Lett. 2005, 15, 4033–4036.
(24) For complete optical rotation data, see the Supporting Information.
(25) For recent examples on Fukuyama-Mitsunobu and Mitsunobu
reactions with diols, see: (a) Valeur, E.; Roche, D. Tetrahedron Lett. 2008,
49, 4182–4185. (b) Garcıa-Delgado, N.; Riera, A.; Verdaguer, X. Org. Lett.
2007, 9, 635–638. (c) Wilkinson, M. C.; Bell, R.; Landon, R.; Nikiforov,
(18) For synthesis of a disubstituted piperazine from an aziridine, see:
Letavic, M. A.; Barberia, J. T.; Carty, T. J.; Hardink, J. R.; Liras, J.;
Lopresti-Morrow, L. L.; Mitchell, P. G.; Noe, M. C.; Reeves, L. M.; Snow,
S. L.; Stam, E. J.; Sweeney, F. J.; Vaughn, M. L.; Yu, C. H. Bioorg. Med.
Chem. Lett. 2003, 13, 3243–3246.
(19) For complete data on aziridine building blocks 2a-e, see ref 17c. For
further details on aziridine 2f, see the Supporting Information.
(20) To avoid possible repeated ring-opening of aziridine building blocks
by the secondary amine formed in the reaction, a large excess of the amino
alcohol was used during the first step of the sequential protocol.
€€
P. O.; Walker, A. J. Synthesis 2006, 2151–2153. (d) Hovinen, J.; Sillanpaa, R.
Tetrahedron Lett. 2005, 46, 4387–4389.
J. Org. Chem. Vol. 74, No. 15, 2009 5653