Cyclobutane-derived diamines: Synthesis and molecular structure

Article abstract of DOI:10.1021/jo101271h

Cyclobutane diamines (i.e., cis- and trans-1,3-diaminocyclobutane, 6-amino-3-azaspiro[3.3]heptane, and 3,6-diaminospiro[3.3]heptane) are considered as promising sterically constrained diamine building blocks for drug discovery. An approach to the syntheses of their Boc-monoprotected derivatives has been developed aimed at the preparation of multigram amounts of the compounds. These novel synthetic schemes exploit classical malonate alkylation chemistry for the construction of cyclobutane rings. The conformational preferences of the cyclobutane diamine derivatives have been evaluated by X-ray diffraction and compared with the literature data on sterically constrained diamines, which are among the constituents of commercially available drugs.

Full text of DOI:10.1021/jo101271h

pubs.acs.org/joc
Cyclobutane-Derived Diamines: Synthesis and Molecular Structure
Dmytro S. Radchenko,†,‡ Sergiy O. Pavlenko,†,‡ Oleksandr O. Grygorenko,*,†,‡
Dmitriy M. Volochnyuk,‡,§ Svitlana V. Shishkina,§ Oleg V. Shishkin,§ and
Igor V. Komarov†,‡
†Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64,
Kyiv 01033, Ukraine, ‡Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine, and
§STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, Lenina ave. 60,
Kharkiv 61001, Ukraine
gregor@univ.kiev.ua
Received June 29, 2010
Cyclobutane diamines (i.e., cis- and trans-1,3-diaminocyclobutane, 6-amino-3-azaspiro[3.3]heptane,
and 3,6-diaminospiro[3.3]heptane) are considered as promising sterically constrained diamine
building blocks for drug discovery. An approach to the syntheses of their Boc-monoprotected deri-
vatives has been developed aimed at the preparation of multigram amounts of the compounds. These
novel synthetic schemes exploit classical malonate alkylation chemistry for the construction of
cyclobutane rings. The conformational preferences of the cyclobutane diamine derivatives have been
evaluated by X-ray diffraction and compared with the literature data on sterically constrained
diamines, which are among the constituents of commercially available drugs.
Introduction
their docking to biological targets, which might be useful for
in silico drug discovery.5 And last but not least, the steric
constraints might help to assemble spatial arrangements of
functional groups involved in the intermolecular interaction
which are not attainable in their flexible analogues. This opens
the prospects of more efficient involvement of the target func-
tional groups in drug-target interaction.
Synthesis of sterically constrained molecules involves
constructing a corresponding rigid molecular scaffold, or
the use of presynthesized rigidified building blocks. In drug
design, such building blocks as sterically constrained amino
acids have often been used.6 Sterically constrained diamines,
Restriction of conformational mobility (rigidification) has
long been a design principle for the molecules, the basis of whose
function is the efficiency of their intermolecular noncovalent
interactions. This design principle is especially popular in
current drug discovery.1 Molecular rigidity is widely regarded
as one of the most important properties of approved drugs.2 It
has been suggested that the preorganization arising from steric
constraint in a drug molecule might contribute to the decrease of
the entropy barrier of the intermolecular drug-target interac-
tion, thus increasing the drug’s potency and selectivity. Recent
studies challenged this hypothesis,3 but the number of efficient
sterically constrained drug molecules continues to increase.4
Another beneficial feature of sterically constrained molecules
(compared to their flexible analogues) is the relative facility of
(5) Barril, X.; Solvia, R. In Structure-Based Drug Discovery: An Overview;
Hubbard, R. E., Ed.; RSC Publishing: Cambridge, UK, 2006; pp 54-96.
(6) (a) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med.
Chem. 2004, 11, 2785–2798. (b) Hruby, V. J.; Al-Obeidi, F.; Kazmierski, W.
Biochem. J. 1990, 268, 249–262. (c) Shemyakin, M. M.; Ovchinnikov, Y. A.;
Ivanov, V. T. Angew. Chem., Int. Ed. 1969, 8, 492–499. (d) Komarov, I. V.;
Grigorenko, A. O.; Turov, A. V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73,
785–810. (e) Soloshonok, V. A. Curr. Org. Chem. 2002, 6, 341–364. (f) Qiu,
W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J. Tetrahedron
Lett. 2001, 42, 145–148. (g) Soloshonok, V. A.; Tang, X. J.; Hruby, V. J.;
Meervelt, L. V. Org. Lett. 2001, 3, 341–343.
(1) Mann, A. In Practice of Medicinal Chemistry, 3rd ed.; Wermuth,
C. G., Ed.; Academic Press/Elsevier: Amsterdam, The Netherlands, 2008;
pp 363-379.
(2) Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003, 43,
218–227.
(3) Martin, S. F. Pure Appl. Chem. 2007, 79, 193–200.
(4) MDL Drug Data Report (MDDR); Elsevier MDL, version 2009.2
DOI: 10.1021/jo101271h
r
Published on Web 08/09/2010
J. Org. Chem. 2010, 75, 5941–5952 5941
2010 American Chemical Society

Radchenko et al.
JOCArticle
FIGURE 1. Examples of marketed drugs comprising sterically constrained diamine scaffolds.
FIGURE 2. Rigidification of a carbon chain (a), double bond (b),
cyclopropane (c), and cyclobutane (d) rings.
FIGURE 3. Cyclobutane-derived diamines.
although they seem to offer similar potential in molecular design,7
have received much less attention. Figure 1 depicts several
examples of marketed drugs possessing diamine scaffolds.
These and many other, less successful, examples illustrate the
great potential of sterically constrained diamines in drug
design and stimulate further studies in this area.
In this paper, we wish to report our results on the synthesis
and structural studies of sterically constrained diamines of
low molecular weight. Our approach to achieve restriction of
the conformational mobility in the diamine molecules was
guided by the principle of minimal constitutional changes of
flexible parent molecules. Introducing a double bond as well
as a cyclopropane ring into an aliphatic chain is widely used
to achieve this;8 however, these constitutional changes con-
siderably disturb the electronic properties, leading to rigidi-
fied analogues which differ in chemical reactivity and intra-
molecular interaction from the flexible counterparts.9 This
drawback is alleviated in cyclobutane derivatives less com-
monly exploited to date,10 although the cyclobutane ring
retains some flexibility and can be considered as less rigid
compared to the cyclopropane fragment11 (Figure 2).
illustrating the use of the scaffold 1 in drug discovery were
reported since then; in particular, derivatives of diamine 1 were
evaluated as inhibitors of kinases CDK1,13 CDK2, CDK5,
GSK-3,14 and PLK,13,15 phosphodiesterase PDE4,16 and the
glycine transporter GLyT-1;17 inhibitors of interactions be-
tween Mdm2 and p53 proteins,18 insecticides, and acaricides.19
The design concept described above can be expanded to
spirocyclic compounds, e.g. diamines 2 and 3. Whereas the
first synthesis of 2 was described more than a century ago,20
compound 3 has not been obtained so far (Figure 3).
It should be noted that in order to make selective modi-
fication of diamine building blocks possible, it is essential to
have one of the nitrogen atoms in their molecules protected
(e.g., as Boc derivatives). To the best of our knowledge, no
practical approaches to the derivatives of 1-3 which allow
selective modification of the amino groups have been reported
to date.21 In the present work, we wish to report syntheses
of mono-Boc derivatives of each of the diamines 1a, 1b, 2,
and 3.22 Furthermore, using the results of X-ray diffrac-
tion studies, the molecular structures and conformational
The structures of 1,3-diaminocyclobutanes 1a and 1b are
obtained if the design principle shown in Figure 2d is applied to
construction of rigidified diamines. Compound 1 was reported
first in 1957; it was obtained as a mixture of stereoisomers in ten
steps starting from epibromohydrine.12 A number of examples
(13) Engelhardt, H.; Stadtmueller, H.; Steegmaier, M. PCT Int. Pat. WO
2007115999, 2007.
(14) (a) Helal, C. J.; Kang, Z.; Lucas, J. C.; Bohall, B. R. Org. Lett. 2004,
6, 1853–1856. (b) Ahlijanian, M. K.; Cooper, C. B.; Helal, C. J.; Lau, L.-F.;
Menniti, F.; Sanner, M. A.; Seymour, P. A.; Villalobos, A. PCT Int. Pat. WO
0210141, 2002.
(15) Stadtmueller, H.; Engelhardt, H.; Steegmaier, M.; Baum, A.; Guertler,
U.; Schoop, A.; Quant, J. J.; Solca, F.; Hauptmann, R.; Reiser, U.; Zahn, S. K.
Herfurth, L. PCT Int. Pat. WO 2006021544, 2006.
(16) Kuang, R.; Blythin, D.; Shih, N.-Y.; Shue, H.-J.; Chen, X.; Cao, J.;
Gu, D.; Huang, Y.; Schwerdt, J. H.; Ting, P. C.; Wong, S.-C; Xiao, L. PCT
Int. Pat. WO 2005116009, 2005.
(7) (a) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug. Des. 2006,
67, 101–114. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2580–2627. (c) Levy, J. A. AIDS 2009, 23, 147–160. (d) Yarker,
Y. E.; McTavish, D. Drugs 1994, 48, 761–793. (e) Krishnamoorthy, S.; Lip,
G. Y. Expert Opin. Invest. Drugs 2009, 18, 1191–1196.
(8) (a) Salaun, J. Chem. Rev. 1989, 89, 1247–1270. (b) A. Wessjohann,
L. A.; Brandt, W.; Thiemann, T. Chem. Rev. 2003, 103, 1625–1648.
€
(c) de Meijere, A. Chem. Rev. 2003, 103, 931–932. (d) Salaun, J.; Baird,
M. S. Curr. Med. Chem. 1995, 2, 511–542.
(17) Lowe, J. A.; Sakya, S. M.; Sanner, M., A.; Coe, J. W.; McHardy,
S. F. PCT Int. Pat. WO 2008065500, 2008.
€
(9) Salaun, J. In Small Ring Compounds in Organic Synthesis VI;
de Meijere, A., Kozhushkov, S. I., Eds.; Springer: Berlin/Heidelberg,
(18) Kawato, H.; Miyazaki, M.; Sugimoto, Y.; Naito, H.; Okayama, T.;
Soga, T.; Uoto, K. PCT Int. Pat. WO 2008072655, 2008.
(19) Muehlebach, M.; Jeanguenat, A.; Hall, R. G. PCT Int. Pat. WO
2007080131, 2007.
Germany, 2000; pp 1-67.
(10) (a) Sergeiko, A.; Poroikov, V. V.; Hanus, L. O.; Dembitsky, V. M.
ꢀ
Open Med. Chem. J. 2008, 2, 26–37. (b) Namyslo, J. C.; Kaufmann, D. E.
Chem. Rev. 2003, 103, 1485–1538.
(11) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p 1267.
(12) Avram, M.; Nenitzescu, C. D.; Maxim, M. Chem. Ber. 1957, 90,
1424–1427.
(20) (a) Fecht, H. Ber. 1907, 40, 3883–3888. (b) Janson, S. E.; Pope, W. J.
Proc. R. Soc. 1936, 154, 53–54. (c) Wynberg, H.; Houbiers, J. P. M. J. Org.
Chem. 1971, 36, 834–842.
(21) Synthesis of the mono-Boc derivative of 1a was described without
characterization in the patent literature;16 in this work, an analogous
approach is used.
5942 J. Org. Chem. Vol. 75, No. 17, 2010

Radchenko et al.
JOCArticle
SCHEME 1. Synthesis of the Diamine Derivatives 11a and 11ba
aAr is p-nitrophenyl (p-O2NC6H4).
SCHEME 2. Synthesis of Diamine Derivative 18
preferences of these diamine building blocks are established
and discussed.
Results and Discussion
Synthesis. The synthesis of the monoprotected derivatives
of diamines 1 and 2 relies on orthogonal retrosynthetic
transformations of the amino functions. Namely, the Curtius
rearrangement and reductive amination of the carbonyl
compounds can be regarded as the corresponding trans-
forms, ketoacids 4 and 5 therefore being appropriate starting
materials.
Among different published syntheses of compound 4, we
considered the method involving double malonate alkyla-
tion as the most appropriate for multigram preparation.23
Curtius rearrangement of an acyl azide obtained from 4 was
followed by reaction with tert-butanol resulting in the direct
formation of N-Boc-protected aminoketone 7.24 To perform
stereoselective transformation of the ketone moiety in 7 to
an amino function, compound 7 was first reduced with
L-selectride to give alcohol 8a as a single diastereomer.
Compound 8a was the key intermediate in the synthesis of
both isomers 11a and 11b. To obtain the trans-isomer 11a, 8a
was transformed to mesylate 9a, which underwent SN2 reac-
tion with sodium azide followed by catalytic hydrogenation to
afford 11a (7 steps, 19% from 6). Cis-isomer 11b (9 steps, 7%
from 6) was prepared in an analogous manner starting from
alcohol 8b; the latter was obtained by isomerization of 8a with
a Mitsunobu reaction (Scheme 1).21
An analogous approach was applied to the synthesis of the
spirocyclic derivative 18. In this case, the ketoacid 5 was
prepared in five steps from dibromide 6, using the method
reported previously by our group (Scheme 2).25 Curtius
rearrangement of azide obtained from carboxylic acid 5
followed by reaction with tert-butanol led to the formation
of the N-Boc-protected aminoketone derivative 16. The latter
was transformed to oxime 17, which was reduced catalyti-
cally to yield the targeted diamine derivative 18 (9 steps, 15%
from 6).
(22) The preliminary results of this project have been reported previously
by our group: Shivanyuk, A. N.; Volochnyuk, D. M.; Komarov, I. V.;
Nazarenko, K. G.; Radchenko, D. S.; Kostyuk, A.; Tolmachev, A. A. Chem.
Today 2007, 25, 12–13.
(23) Pigou, P. E.; Schiesser, C. H. J. Org. Chem. 1988, 53, 3841–3843.
(24) While the work was in progress, an analogous synthesis of compound
7 was reported elsewhere: Kumar, R. J.; Chebib, M.; Hibbs, D. E.; Kim,
H.-L.; Salam, N. K.; Hanrahan, J. R.; Johnston, G. A. R. J. Med. Chem.
2008, 51, 3825–3840.
We have also considered an approach to the synthesis of
compound 18 via Fecht’s acid dimethyl ester 21 (Scheme 3),
which was previously used to obtain the parent diamine 2.20
(25) Radchenko, D. S.; Grygorenko, O. O.; Komarov, I. V. Tetrahedron:
Asymmetry 2008, 19, 2924–2930.
J. Org. Chem. Vol. 75, No. 17, 2010 5943

Radchenko et al.
JOCArticle
SCHEME 3. Synthesis of the Diamine Derivative 18 via Fecht’s Acid Diester 21
SCHEME 4. Synthesis of Diamine Derivative 37
Compound 21 was prepared by using a modified literature
procedure.26 To modify the carboxyl moieties in the mole-
cule of 21 selectively, mild alkaline hydrolysis was performed
to afford the monoester 22. Compound 22 was transformed
to the amino acid derivative 23 under classical Curtius
rearrangement conditions.27 Hydrolysis of 23 resulted in
the Boc-protected amino acid 24. To achieve Curtius re-
arrangement of the remaining carboxyl group in 24, diphenyl-
phosphoryl azide (DPPA) was used; quenching of the inter-
mediate isocyanate with benzyl alcohol ensured orthogonality
(26) (a) Weatherhead, R. A.; Carducci, M. D.; Mash, E. A. J. Org. Chem.
2009, 74, 8773–8778. (b) Wynberg, H.; Houbiers, J. P. M. J. Org. Chem. 1971,
36, 834–842. (c) Buchta, E.; Merk, W. Liebigs Ann. 1966, 694, 1–8.
(27) A slightly different synthesis of 23 has been reported: Jones, B. C. N.
M.; Drach, J. C.; Corbett, T. H.; Kessel, D.; Zemlicka, J. J. Org. Chem. 1995,
60, 6277–6280.
5944 J. Org. Chem. Vol. 75, No. 17, 2010

Radchenko et al.
JOCArticle
FIGURE 4. (a) Definition of vectors n1, n2 (4-aminopiperidine used as an example); (b) definition of geometric parameters r, j1, j2, and θ.
FIGURE 5. Molecular structure of 38, 11b, 39, and 36 (Ar is p-NO2C6H4).
of the protective groups in the product 25. Finally, selective
monodeprotection of 25 by means of catalytic hydrogena-
tion led to the formation of diamine derivative 18 (7%,
10 steps from 19). In both syntheses of 18 shown in the
Schemes 2 and 3, the product was obtained as a racemate.
A different strategy was developed for the synthesis of
diamine derivative 37 (Scheme 4). In this case, the construc-
tion of the 2-azaspiro[3.3]heptane core was performed by
consequent closure of the cyclobutane and azetidine rings
using bis-alkylation of malonate (compound 28) and tosyl-
amide (compound 31), respectively. After hydrolysis, de-
carboxylation, and detosylation, amino acid 34 was obtained.28
Further steps of the synthesis included Boc-derivatization,
(28) Radchenko, D. S.; Grygorenko, O. O.; Komarov., I. V. Amino Acids
2010, 39, 515–521.
J. Org. Chem. Vol. 75, No. 17, 2010 5945

Radchenko et al.
JOCArticle
TABLE 1. Values of the Parameters r, j1, j2, and θ Obtained from X-ray Diffraction Data on the Sterically Constrained Diamine Derivatives
ꢁ
˚
r, A
entry no.
derivative
diamine
piperazine
piperazine
piperazine
4-aminopiperidine
4-aminopiperidine
40
40
41
42
43
1a
1b
2
j1, deg
j2, deg
θ, deg
ref
1
2
3
4
5
6
7
8
9
10
11
12
13
14
44
zopiclone
aripiprazole
astemizole
2.838
2.842
2.871
4.261
4.242
4.311
4.219
4.150
4.228
3.072
4.485
4.585
6.810
5.490
23.6
22.3
25.7
41.4
35.1
27.9
40.1
50.0
41.4
72.8
33.4
31.3
23.3
5.9
23.6
26.9
24.2
25.7
19.9
9.0
0.0
177.4
179.9
0.6
33
34
35
36
37
38
38
39
40
41
demethoxycisapride
45
46
1.2
178.2
166.0
1.2
0.6
2.1
179.2
1.8
112.7
131.1
3.5
tropapridea
27.3
25.7
68.1
10.5
30.9
12.1
17.9
47a
48
38
this work
this work
this work
this work
11b
39b
36
3
aHydrochloride. bThe data are given for the (aR)-isomer.
FIGURE 7. Some sterically constrained diamines: constituents of
marketed drugs.
Curtius rearrangement, and selective monodeprotection
allowing the diamine derivative 37 to be obtained (18%,
11 steps from 26).
Conformational Preferences. Current rational drug design
aims at finding the optimal disposition of the molecular
fragments in the potential drug candidates or the scaffolds
of which they are constructed. This idea was embodied in
the pharmacophore concept, which correlates the potential
ligand molecule with a combination of steric and electronic
features necessary to ensure optimal interaction with the
biological target.29 From this viewpoint, the diamine scaf-
folds can be characterized by relative spatial orientation of
the amino functions, the role of the carbon framework being
reduced to providing this orientation. The disposition of the
amino functions of the diamine can be represented by two
vectors;30 namely, the nitrogen atoms (N1 and N2) can be
regarded as the starting points of the vectors, whereas to
define their direction the C-N bond and the bisector
C-N-C angle can be used for the primary and secondary
amino groups, respectively (Figure 4a). The relative spatial
orientation of two vectors n1 and n2 thus obtained for the
diamine scaffold can be described by four parameters: the
distance between the nitrogen atoms r, the plane angles j1
(between vectors n1 and N2N1) and j2 (between n2 and N1N2),
FIGURE 6. The chemical space covered by sterically constrained
diamines discussed in this work: (a) r-θ representation (polar
coordinates); (b) j1-θ and j2-θ representations (shown in the same
plot, Cartesian coordinates). Derivatives of piperazine and 4-amino-
piperidine are shown in black, the bicyclic diamines 40-43 are in green,
cyclobutane diamines 1-3 are in red. I and I0: “piperazine” regions
(θ ≈ 0° and 180°, respectively). II: “4-aminopiperidine” region.
(29) Wermuth, C.-G.; Langet, T. In 3D QSAR in drug design: theory,
methods and applications; Kubiniyi, H., Ed.; ESCOM Science Publishers:
Leiden, Holland, 1993; pp 117-136.
(30) To be more precise, bound unit vectors, see: Tang, K.-T. Mathematical
methods for engineers and scientist 2: vector analysis, ordinary differential equations
and Laplace transforms; Springer-Verlag: Berlin/Heidelberg, Germany, 2007;
pp 3-22.
5946 J. Org. Chem. Vol. 75, No. 17, 2010

Radchenko et al.
JOCArticle
FIGURE 8. Derivatives of sterically constrained diamines studied by X-ray diffraction (literature data).
and the dihedral angle θ defined by vectors n1, N1N2, and n2
(Figure 4b).31
Amino-derived substituents in the cyclobutane rings of
11b, 36, 38, and 39 adopt an equatorial position (except the
tert-butyloxycarbonylamino group in 38, which is axial). The
values of the corresponding torsion angles are as follows:
147.2(2)° (N(1)-C(1)-C(2)-C(3)) and 143.7(2)° (N(2)-
C(3)-C(4)-C(1)), 11b; 134.1(1)° (N(2)-C(1)-C(4)-C(3))
and 104.7(1)° (N(1)-C(3)-C(4)-C(1)), 38;-142.4(1)° (C(2)-
C(3)-C(4)-N(2)), 36; and 136.6(1)° (N(1)-C(6)-C(7)-C(1))
and 145.5(1)° (C(1)-C(2)-C(3)-N(3)), 39.
Amide and carbamate fragments of the diamine deriva-
tives discussed herein exhibit almost perfect planarity (the
sum of the bond angles centered at the nitrogen atoms ω0(N) =
358.5-360°). For 36, this fact is remarkable as it has been
shown previously that the nitrogen atom in many azetidine
derivatives tends to be pyramidalized.32 As could be expected,
The range of theoretically possible values of j1 and j2 is
between 0° and 180°, although most of the numbers are less
than 90°, whereas θ can vary from -180° to 180°. The sign of
θ is rather important as it is the only parameter that is
affected by the chirality of the diamine molecule. In parti-
cular, enantiomers have equal values of r, j1, and j2, as well
as the absolute values of θ, but differ in the sign of θ. It should
be noted that all the compounds encountered in this study are
either racemic or nonchiral; thus both enantiomers or enantio-
meric conformations (respectively) are observed for any set of
the values of r, j1, j2, and (θ. In the further discussion, we
shall consider only positive values of θ, keeping in mind that the
corresponding negative values are also possible.
To establish the above-defined geometrical parameters of
the diamine scaffolds 1-3, X-ray diffraction studies of the
derivatives 11b, 36, 38, and 39 were performed (Figure 5). All the
cyclobutane rings in the molecules of 11b, 36, 38, and 39 adopt
puckered conformation (puckering angle is 19.8° (38), 29.1°
(11b), 34.8° (the C(1)-C(2)-C(3)-C(4) torsion angle of 39),
25.5° (theC(1)-C(5)-C(6)-C(7) torsion angle of 39), and29.9°
(32) See, for example: (a) Fong., C. W.; Grant, H. G. Aust. J. Chem. 1981,
34, 2307–2312. (b) Jhon, J. S.; Kang, Y. K. J. Phys. Chem. B 2007, 111, 3496–
3507. (c) Burkhard, J. A.; Gurot, C.; Knust, H.; Rogers-Evans, M.; Carreira,
E. M. Org. Lett. 2010, 12, 1944–1947.
(33) Zheng, P.-W.; Wang, W.; Duan, X.-M. Acta Crystallogr., Sect. E
2005, 61, o2513.
(34) Shankland, N.; David, W. I. F.; Shankland, K.; Kennedy, A. R.;
Frampton, C. S.; Florence, A. J. Chem. Commun. 2001, 2204–2205.
(35) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Tessadri, R.; Wieser, J.;
Griesser, U. J. Cryst. Growth Des. 2009, 9, 1054–1065.
˚
(36)), whereas the azetidine ring of 36 is planar within 0.02 A.
(31) In principle, this description can be extended to any conformation-
ally constrained scaffolds possessing two functional groups. It should be
noted, however, that due to some flexibility characteristic to any organic
molecule (especially to cyclobutane derivatives described in this work), the
values of the above-defined geometric parameters can be useful only for
semiquantitative considerations. See the Supporting Information for more
detailed discussion.
(36) Peeters, O. M.; Blaton, N. M.; De Ranter, C. J. Acta Crystallogr.,
Sect. C 1995, 51, 2132–2135.
(37) Collin, S.; Vercauteren, D. P.; Evrard, G.; Durant, F.; Tollenaere,
J. P.; Moereels, H. J. Mol. Struct. 1989, 214, 159–175.
(38) de Meijere, A.; Williams, C. M.; Kourdioukov, A.; Sviridov, S. V.;
Chaplinski, V.; Kordes, M.; Savchenko, A. I.; Stratmann, C.; Noltemeyer,
M. Chem.;Eur. J. 2002, 8, 3789–3801.
J. Org. Chem. Vol. 75, No. 17, 2010 5947

Radchenko et al.
JOCArticle
pyramidalization of the free amino group in 11b is much more
pronounced (ω0(N) = 341°).
added SOCl2 (96 mL, 1.32 mol) dropwise upon vigorous stir-
ring. The resulting mixture was refluxed for 1.5 h. After cooling,
the solvent was evaporated under reduced pressure. The residue
was dissolved in CCl4 (2 ꢀ 120 mL) and evaporated to remove
HCl and SOCl2. The crude product was dissolved in acetone
(120 mL), and the resulting solution was added dropwise to a
solution of NaN3 (58.1 g, 0.89 mol) in H2O (175 mL) at 0 °C over
30 min. The mixture was stirred for 1 h at 0 °C, then ice (600 g)
was added, and the product was extracted with Et2O (3 ꢀ
150 mL), dried over MgSO4, and concentrated to 340 mL
under reduced pressure. The resulting solution was added to
toluene (700 mL), and the mixture was heated to 90 °C. After the
residual ether was distilled off, the mixture was stirred at 90 °C
for 30 min until evolution of N2 ceased. Then tert-butanol
(140 mL) was added, and the mixture was heated at 90 °C for
12 h. After cooling, the solvent was removed under reduced
pressure. The crude product (67.9 g) was recrystallized from
EtOH; an additional amount was obtained from the mother
liquor after dilution with hexane. Yield 57.3 g (69%). White
crystals, mp 77-78 °C. For spectral and physical data, see ref 24.
tert-Butyl (cis-3-Hydroxycyclobutyl)carbamate (8a). Com-
pound 7 (40 g, 0.216 mol) was dissolved in dry THF (1000 mL)
under an argon atmosphere, and the solution was cooled to -78 °C
upon stirring. L-Selectride (1 M in THF, 324 mL, 0.324 mol) was
added dropwise over 1 h period. The mixture was kept at -78 °C for
1 h, and a solution of NaOH (13.0 g) in H2O (160 mL) was added
dropwise over 30 min followed by 30% aqueous H2O2 (120mL) over
2 h. The resulting mixture was warmed to rt and then diluted with
EtOAc (2 L), washed with 10% aqueous Na2SO3 and brine, and
dried over MgSO4.The solvent was evaporated in vacuo. The crude
product (38 g) was purified by recrystallization (hexane-EtOAc
(1:1)) to give 8a (31 g) as yellowish needles. An additional amount of
8a (2.5 g) was obtained from the mother liquor. The combined yield
of the product was 33.5 g (83%). Mp 117 °C. MS (m/z, EI) 172
(Mþ - CH3), 143 (Mþ - CO2), 87, 57 (C(CH3)3þ). Anal. Calcd for
C9H17NO3: C 57.73, H 9.15, N 7.48. Found: C 57.68, H 9.01, N 7.73.
1H NMR (CDCl3) δ 1.42 (s, 9H, C(CH3)3), 1.79 (br s, 2H, 2- and
4-CHH), 2.43 (br s, 1H, OH), 2.73 (br s, 2H, 2- and 4-CHH), 3.63
(br s, 1H, 1-CH), 3.99 (quint, J = 6.9 Hz, 1H, 3-CH), 4.72 (br s, 1H,
NH). 13C NMR (CDCl3) δ 28.4 (C(CH3)3), 37.3 (CH2), 41.8
(C(CH3)3), 60.9 (CH), 79.7 (CH), 155.1 (COOC(CH3)3).
The values of the parameters r, j1, j2, and θ are summar-
ized in Table 1 and plotted in Figure 6. In addition, the
corresponding parameter values were also elucidated from
the literature data available for the derivatives of several sterically
constrained diamine scaffolds widely used in drug discovery (i.e.,
piperazine, 4-aminopiperidine, as well as diamines 40-43 which
are constituents of trovafloxacin, maraviroc, granisetron, and
ambasilide, respectively (Figures 7 and 8).
The data in the Table 1 show that the nearly coplanar
orientation of n1 and n2 which corresponds to θ ≈ 0° or 180°
is frequently encountered in the derivatives of diamines:
constituents of marketed drugs. In particular, three regions
can be outlined in the r-θ representation of the chemical
space covered by sterically constrained diamines: they cor-
respond to piperazine (θ ≈ 0°; θ ≈ 180°) and 4-aminopiper-
idine (θ ≈ 0°) derivatives (Figure 6). It should be noted that in
the case of parent 4-aminopiperidine, only θ ≈ 0° values are
observed, which comply with the equatorial position of the
4-amino substituent. θ ≈ 180° values (which can be referred
to the axial position of the substituent) are often met in the
derivatives of some bicyclic constrained analogues of 4-ami-
nopiperidine, e.g. diamine 40.
As could be deduced from Figure 6, the geometric para-
meters of 1b derivatives are similar to those of 4-aminopiper-
idine. This allows one to assume that 1b might be considered
as a 4-aminopiperidine replacement, although comprising an
additional rotatable bond. Analogously, trans-isomer 1a can be
regarded as an analogue of a less stable conformation of
4-aminopiperidine with an axial position of the substituent,
as also observed in 6-amino-3-azabicyclo[3.1.1]hexane (40)
derivatives. Diamines 2 and 3 provide access to less explored
regions of the chemical space covered by sterically constrained
diamines which correspond to noncoplanar, three-dimensional
molecular structure.42
Conclusions
cis-3-[(tert-Butoxycarbonyl)amino]cyclobutyl Methanesulfo-
nate (9a). Compound 8a (44.2 g, 0.236 mol) was dissolved in
CH2Cl2 (950 mL), triethylamine (49.4 mL, 0.708 mol) was added,
and the solution was cooled to -30 °C upon vigorous stirring.
Mesyl chloride (21.9 mL, 0.283 mol) was added dropwise over a
20 min period, and the mixture was warmed to ambient tempera-
ture, then washed with water (200 mL), 10% aqueous citric acid
(200 mL) and brine, dried over Na2SO4, and evaporated to yield
crude 9a (59 g). The product was purified by recrystallization
(EtOAc) to give 9a (48.7 g) as yellowish crystals. An additional
amount of 8a (8.8 g) was obtained from the mother liquor. Total
yield was 57.5 g (0.205 mol, 87%). Mp 155-156 °C. MS (m/z, EI)
250 (Mþ - CH3), 122, 79, 55 (C(CH3)3þ). Anal. Calcd for
C10H19NO5S: C 45.27, H 7.22, N 5.28, S 12.08. Found: C 45.06,
H 7.51, N 5.54, S 12.33. 1H NMR(CDCl3) δ1.43 (s, 9H, C(CH3)3),
1.64 (br s, 1H, NH), 2.19 (m, 2H, 2- and 4-CHH), 2.91 (br s, 2H, 2-
and 4-CHH), 2.99 (s, 3H, CH3SO2), 3.83 (br s, 1H, 3-CH), 4.70
(quint, J = 7.1 Hz, 1H, 1-CH). 13C NMR (CDCl3) δ 28.4
(C(CH3)3), 37.9 (3-CH), 38.2 (CH2), 39.7 (CH3SO2), 67.9 (1-CH),
79.9 (C(CH3)3), 155.4 (COOC(CH3)3).
Practical syntheses of the cyclobutane-derived diamines 1-3as
their mono-Boc-protected derivatives which allow selective che-
mical modification of the amino functions were developed. The
chemical space covered by these sterically constrained diamines is
analyzed by using the parameters of three-dimensional molecular
structures determined by X-ray crystallography. The results of
these studies show that monocyclic cyclobutane diamines 1a
and 1b can be used as surrogates of 4-aminopiperidine, whereas
spirocyclic derivatives 2 and 3 open a route into less explored
three-dimensional molecular structures.
Experimental Section
tert-Butyl (3-Oxocyclobutyl)carbamate (7). To a solution of
the carboxylic acid 423 (50.6 g, 0.44 mol) in CH2Cl2 (370 mL) was
(39) Collin, S.; Patiny, A.; Evrard, G.; Durant, F. Bull. Soc. Chim. Belg.
1987, 96, 337–338.
(40) Collin, S.; Evrard, G.; Durant, F. Acta Crystallogr., Sect. C 1987,
C43, 697–699.
(41) Levina, O. I.; Potekhin, K. A.; Kurkutova, E. N.; Struchkov, Yu. T.;
Palyulin, V. A.; Zefirov, N. S. Dokl. Akad. Nauk SSSR 1984, 277, 367.
(42) The 3-Azaspiro[3.3]heptane scaffold has been recently considered as
a possible replacement for piperidine, see: (a) Meyers, M. J.; Muizebelt, I.;
van Wiltenburg, J.; Brown, D. L.; Thorarensen, A. Org. Lett. 2009, 11, 3523–
tert-Butyl (trans-3-Azidocyclobutyl)carbamate (10a). Com-
pound 9a (55.4 g, 0.209 mol) was dissolved in DMF (570 mL),
NaN3 (57.4 g, 0.863 mol) was added, and the mixture was stirred
at 70 °C for 18 h. After cooling, water (1 L) was added, and the
mixture was extracted with EtOAc (3 ꢀ 300 mL). The combined
organic phases were washed with water (2 ꢀ 200 mL) and brine,
dried over Na2SO4, and evaporated to yield 10a (46.2 g, 100%),
€
3525. (b) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.;
Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524–3527.
5948 J. Org. Chem. Vol. 75, No. 17, 2010

Radchenko et al.
JOCArticle
which was used in the next step without further purification.
Mp 84 °C. MS (m/z, CI) 185 (MHþ - N2), 129 (MHþ - N2 -
i-C4H8). Anal. Calcd for C9H16N4O2: C 50.93, H 7.60, N 26.40.
Found: C 50.59, H 7.26, N 26.03. 1H NMR (CDCl3) δ 1.43 (s,
9H, C(CH3)3), 2.26 (br s, 2H, CH2), 2.43 (br s, 2H, CH2), 4.06
(m, 1H, CH), 4.24 (br s, 1H, CH), 4.71 (br s, 1H, NH). 13C NMR
(CDCl3) δ 28.4 (C(CH3)3), 37.1 (CH2), 43.2 (1-CH), 52.3(3-CH),
79.9 (C(CH3)3), 154.9 (COOC(CH3)3).
tert-Butyl (trans-3-Aminocyclobutyl)carbamate (11a). Com-
pound 10a (14.8 g, 65 mmol) was dissolved in MeOH saturated
with NH3 (150 mL), 10% Pd/C (3 g) was added, and H2 was
bubbled through the reaction mixture for 2 h. The catalyst was
filtered off, and the filtrate was evaporated under reduced
pressure. The crude product (12.8 g) was distilled in vacuo to
yield 11a (9.8 g, 48 mmol, 75%) as a clear solid. Bp 102 °C/
0.5 mmHg. MS (m/z, EI) 186 (Mþ), 129 (Mþ - C(CH3)3), 113
(Mþ - OC(CH3)3). Anal. Calcd for C9H18N2O2: C 58.04, H
9.74, N 15.04. Found: C 57.83, H 9.91, N 14.74. 1H NMR
(CDCl3) δ 1.42 (s, 9H, C(CH3)3), 1.47 (br s, 2H, NH2), 2.06 (br s,
2H, CH2), 2.14 (br s, 2H, CH2), 3.59 (m, 1H, CH), 4.15 (br s, 1H,
CH), 4.73 (br s, 1H, NH). 13C NMR (CDCl3) δ 28.4 (C(CH3)3),
40.4, 42.5, 44.3, 79.3 (C(CH3)3), 155.3 (COOC(CH3)3).
trans-3-[(tert-Butoxycarbonyl)amino]cyclobutyl 4-Nitrobenzoate
(12). To a solution of 8a (16.3 g, 87 mmol) and p-nitrobenzoic acid
(16 g, 96 mmol) in dry THF (400 mL) were added triphenylpho-
sphine (34 g, 0.13 mol) and DEAD (25.8 mL, 0.163 mol) subse-
quently at 0 °C (exothermic reaction upon DEAD addition).
The resulting mixture was stirred at rt overnight. The solution
formed was concentrated in vacuo, and the residue was subjected
to column chromatography on silica gel (hexane-EtOAc (2:1) as
an eluent) to afford 12 (18.9 g, 64%) as a white solid. Mp 163-
164 °C. MS (m/z, CI) 237 (MHþ - CO2 - C4H8), 122 (C6H4-
NO2þ). Anal. Calcd for C16H20N2O6: C 57.14, H 5.99, N 8.33.
Found: C 56.94, H 6.39, N 8.02. 1H NMR (CDCl3) δ 1.44 (s, 9H,
C(CH3)3), 2.46 (m, 2H, CH2), 2.61 (m, 2H, CH2), 4.39 (br s, 1H,
3-CH), 4.87 (br s, 1H, NH), 5.36 (m, 1H, 1-CH), 8.20 (dd, 2H, J =
8.0 Hz, C6H4), 8.27 (dd, 2H, J = 8.0 Hz, C6H4). 13C NMR (CDCl3)
δ 29.5 (C(CH3)3), 38.7 (CH2), 69.9, 70.1, 81.2 (C(CH3)3), 124.6,
131.9, 136.6, 151.8, 155.4 (COOC(CH3)3), 165.5 (COOC6H4NO2).
tert-Butyl (trans-3-Hydroxycyclobutyl)carbamate (8b). To a
mixture of K2CO3 (11.7 g, 85 mmol), H2O (80 mL), and
methanol (400 mL) was added compound 12 (18.9 g, 56 mmol).
The resulting mixture was refluxed for 1.5 h, cooled, and filtered,
and the filtrate was evaporated under reduced pressure. The
product 8b (10.2 g, 64%) was obtained as a white solid that was
used in the next step without further purification. Mp 112 °C.
MS (m/z, EI) 172 (Mþ - CH3), 143 (Mþ - CO2), 87, 57
(C(CH3)3þ). Anal. Calcd for C9H17NO3: C 57.73, H 9.15, N
7.48. Found: C 57.99, H 9.37, N 7.41. 1H NMR (CDCl3) δ 1.42
(s, 9H, C(CH3)3), 1.78 (br s, 2H, CH2), 2.61 (br s, 1H, OH), 2.73
(br s, 2H, CH2), 3.63 (br s, 1H, 1-CH), 3.99 (br s, 1H, 3-CH),
4.74 (br s, 1H, NH). 13C NMR (CDCl3) δ 28.4 (C(CH3)3), 37.4
(1-CH), 42.3 (CH2), 60.9 (3-CH), 79.7 (C(CH3)3), 154.9
(COOC(CH3)3).
trans-3-[(tert-Butoxycarbonyl)amino]cyclobutyl Methane-
sulfonate (9b). Compound 8b (10 g, 53 mmol) was dissolved in
CH2Cl2 (100 mL), triethylamine (11.2 mL, 81 mmol) was added,
and the solution was cooled to -30 °C upon stirring. Mesyl chloride
(5 mL, 64 mmol) was added dropwise over a 20 min period, then the
mixture was warmed to ambient temperature, washed with water
(30 mL), 10% aqueous citric acid (30 mL), and brine, dried over
Na2SO4, and evaporated in vacuo to yield 9b (13.9 g, 98%) as a
colorless solid that was used in the next step without purification.
Mp 104 °C. MS (m/z, EI) 250 (Mþ - CH3), 186 (Mþ - CH3SO2),
143, 122, 79, 57 (C(CH3)3þ). Anal. Calcd for C10H19NO5S: C 45.27,
H 7.22, N 5.28, S 12.08. Found: C 45.15, H 7.47, N 5.17, S 11.80.
1H NMR (CDCl3) δ 1.42 (s, 9H, C(CH3)3), 2.42 (br s, 2H, 2- and
4-CHH), 2.63 (br s, 2H, 2- and 4-CHH), 2.98 (s, 3H, CH3SO2), 4.24
(br s, 1H, 3-CH), 4.87 (br s, 1H, NH), 5.15 (br s, 1H, 1-CH). 13
C
NMR (CDCl3) δ 28.2 (C(CH3)3), 37.9 (CH2), 37.9(CH3SO2), 42.1
(C(CH3)3), 72.9 (3-CH), 79.8 (1-CH), 155.1 (CdO).
tert-Butyl (cis-3-Azidocyclobutyl)carbamate (10b). Compound
9b (13.7 g, 52 mmol) was dissolved in DMF (60 mL), NaN3 (5.03 g,
77 mmol) was added, and the mixture was stirred at 85 °C for 18 h.
After cooling, water (110 mL) was added, and the mixture was
extracted with EtOAc (3 ꢀ 60 mL). The combined organic extracts
were washed with water (2 ꢀ 60 mL) and brine, dried over Na2SO4,
and evaporated in vacuo to yield 10b (7.8 g, 71%) that was used in
the next step without further purification. Mp 95 °C. MS (m/z, EI)
184 (Mþ - N2), 170 (Mþ - N3), 57 (C(CH)3)3). Anal. Calcd for
C9H16N4O2: C 50.93, H 7.60, N 26.40. Found: C 51.13, H 7.75, N
26.09. 1H NMR (CDCl3) δ 1.43 (s, 9H, C(CH3)3), 1.90 (m, 2H, 2-
and 4-CHH), 2.73 (br s, 2H, 2- and 4-CHH), 3.55 (quint, J = 7.3
Hz, 1H, 1-CH), 3.85 (br s, 1H, NH), 4.69 (br s, 1H, 3-CH). 13C
NMR (CDCl3) δ 28.3 (C(CH3)3), 37.1 (CH2), 43.1 (1-CH), 52.3
(3-CH), 80.0 (C(CH3)3), 155.2 (COOC(CH3)3).
tert-Butyl (cis-3-Aminocyclobutyl)carbamate (11b). Compound
10b (7.66 g, 36 mmol) was dissolved in MeOH saturated with
NH3 (70 mL). The resulting solution was added dropwise to a
suspension of Pd/C (2.5 g) in MeOH (70 mL) while H2 was bubbled
through the mixture under ambient pressure. The reaction mixture
was filtered, and the filtrate was evaporated under reduced pressure.
The crude product (6.1 g) was purified by column chromatography
on silica gel (hexane:EtOAc (2:1) as an eluent, Rf 0.51) to give 11b
(5.86 g, 86%) as a white solid. Mp 111-112 °C. MS (m/z, EI) 129
(Mþ - C(CH3)3), 113 (Mþ - OC(CH3)3), 57 (C(CH3)3). Anal.
Calcd for C9H18N2O2: C 58.04, H 9.74, N 15.04. Found: C 58.37, H
9.56, N 15.09. 1H NMR (CDCl3) δ 1.41 (br s, 9H, C(CH3)3), 1.45
(br s, 2H, CH2), 1.49 (br s, 2H, NH2), 2.68 (br s, 2H, CH2), 3.09
(m, 1H, CH-NH2), 3.70 (br s, 1H, CH-NHBoc), 4.68 (br s, 1H,
NH). 13C NMR (CDCl3) δ 28.4 (C(CH3)3), 38.8, 41.6, 42.9, 79.4,
155.1 (CdO).
tert-Butyl (6-Oxospiro[3.3]hept-2-yl)carbamate (16). 6-Oxospiro-
[3.3]heptane-2-carboxylic acid25 (5) (26 g, 0.169 mol) was dissolved
in CH2Cl2 (300 mL). SOCl2 (37 mL, 0.51 mol) was added dropwise
over a 10 min period upon vigorous stirring. The mixture was
refluxed for 1.5 h then cooled to rt, and the solvent was removed
under reduced pressure. The residue was dissolved with CCl4 (2 ꢀ
40 mL) and evaporated to remove the residual HCl. The crude
product was distilled in vacuo to give colorless oil (25.5 g, bp 112 °C/
1 mmHg). It was dissolved in acetone (70 mL), and the solution was
added dropwise to a solution of NaN3 (28.8 g, 0.443 mol) in H2O
(106 mL) at 0 °C over a 30 min period. The mixture was stirred for
1hat0°C, then ice (400 g) was added, and the product was extracted
with CH2Cl2 (3 ꢀ 120 mL). The combined organic extracts were
dried over Na2SO4, and the solution was concentrated to 60 mL
under reduced pressure. The residue was added to toluene (500 mL)
and heated to 90 °C. The residue of CH2Cl2 was distilled off, and the
mixture was stirred at 90 °C for 30 min until evolution of N2 ceased.
Then tert-butanol (58 mL) was added, and the mixture was heated at
90 °C for 16 h. After cooling, the solvent was removed in vacuo to
give 16 (62 g, 96%) that was used in the next step without further
purification. Mp 94 °C. MS (m/z, EI) 210 (Mþ - CH3), 108 (Mþ -
NHBoc). Anal. Calcd for C12H19NO3: C 63.98, H 8.50, N 6.22.
Found: C 64.26, H 8.29, N 6.00. 1H NMR (CDCl3) δ 1.41 (s, 9H,
C(CH3)3), 2.13 (t, J = 11.7 Hz, 0.5 ꢀ 2H, CHH), 2.13 (t, J = 11.7
Hz, 0.5 ꢀ 2H, CHH), 2.54 (br s, 2H, CHH), 3.03 (s, 2H, CH2), 3.11
(s, 2H, CH2), 4.12 (br s, 1H, 2-CH), 4.76 (br s, 1H, NH). 13C NMR
(CDCl3) δ 26.8 (C(CH3)3), 28.4, 42.7, 58.1, 58.9, 79.5, 154.9
(COOC(CH3)3), 206.6 (6-CdO).
tert-Butyl [6-(Hydroxyimino)spiro[3.3]hept-2-yl]carbamate (17).
To a solution of 16 (2 g, 8.8 mmol) and pyridine (2.87 mL, 35.2
mmol) in 2-propanol (15 mL) was added a solution of NH2OH
3
HCl (0.93 g, 13.4 mmol) in 2-propanol (7 mL). The reaction
mixture was refluxed for 3 h, cooled to rt, and evaporated under
reduced pressure. The residue was diluted with water (20 mL) and
J. Org. Chem. Vol. 75, No. 17, 2010 5949

Radchenko et al.
JOCArticle
filtered to give white solid (1.67 g). The crude product was
recrystallized from ethanol to give 17 (1.48 g, 69%). Mp 160 °C.
MS (m/z, EI) 209 (Mþ - 31), 184 (Mþ - i-C4H8), 123, 57
(C(CH3)3þ). Anal. Calcd for C12H20N2O3: C 59.98, H 8.39, N
11.66. Found: C 60.24, H 8.07, N 11.54. 1H NMR (CDCl3) δ 1.43
(s, 0.5 ꢀ 9H, C(CH3)3), 1.66 (s, 0.5 ꢀ 9H, C(CH3)3), 1.97(td, J =
8.8 and 1.0 Hz, 2H, CH2), 2.50 (m, 2H, CH2), 2.89 (m, 2H, CH2),
evaporated under reduced pressure. Compound 22 (20.5 g, 95%)
was obtained as a yellow oil that was used in the next step without
further purification. For spectral and physical data, see ref 27.
Methyl 6-[(tert-Butoxycarbonyl)amino]spiro[3.3]heptane-2-
carboxylate (23). To a solution of compound 22 (20.5 g, 0.104 mol)
inCH2Cl2 (200 mL) was added SOCl2 (30mL, 0.41 mol) dropwise
upon vigorous stirring. The resulting mixture was refluxed for
1 h. After cooling, the solvent was evaporated under reduced
pressure. The residue was diluted with CCl4 (2 ꢀ 70 mL) and
evaporated to remove the rest of the SOCl2. The crude product
was dissolved in acetone (60 mL) and added dropwise to a
solution of NaN3 (19.5 g, 0.3 mol) in H2O (90 mL) over 30
min. The mixture was stirred at 0 °C for 1 h, then ice (60 g) was
added, and the product was extracted with Et2O (3 ꢀ 75 mL). The
combined extracts were dried over MgSO4 and concentrated to
60 mL under reduced pressure. The residue was added to toluene
(250 mL). After the residual Et2O was distilled off, the mixture
was stirred for 30 min until N2 evolution ceased. tert-Butanol
(17 mL) was added, and the mixture was heated at 90 °C for an
additional 12 h. After cooling, the solvent was removed in vacuo
to give 23 (21.0 g, 75%) pure enough for the next step. For
spectral and physical data, see ref 27.
6-[(tert-Butoxycarbonyl)amino]spiro[3.3]heptane-2-carboxylic
Acid (24). To a solution of 23 (49.6 g, 0.184 mol) in MeOH
(200 mL) was added a solution of NaOH (29.5 g, 0.77 mol) in a
mixture of MeOH (170 mL) and water (20 mL). The reaction
mixture was stirred at rt for 5 h, and the solvent was removed
under reduced pressure. Water (100 mL) was added to the
residue, and the mixture was adjusted to pH 3-3.5 with 10%
aqueous citric acid. The product was extracted with CH2Cl2 (4 ꢀ
80 mL). The combined organic extracts were washed with brine,
dried over Na2SO4, and evaporated under reduce pressure. The
crude product was recrystallized from EtOH to give 24 (41.1 g,
87%) as a white solid. Mp 101-104 °C. MS (m/z, EI) 238 (Mþ - 17),
55 (C(CH3)3þ). Anal. Calcd for C13H21NO4: C 61.16, H 8.29,
N 5.49. Found: C 60.92, H 8.06, N 5.67. 1H NMR (CDCl3) δ 1.41
(s, 9H, C(CH3)3), 1.84 (m, 2H, CH2), 2.15 (br s, 1H, CH2), 2.31
(m, 4H, CH2), 2.47 (br s, 1H, CH2), 3.02 (quint, J = 8.3 Hz, 1H,
6-CH), 3.98 (br s, 1H, CH), 4.65 (br s, 1H, NH).
Benzyl tert-Butylspiro[3.3]heptane-2,6-diylbiscarbamate (25).
To a solution of 24 (18.1 g, 70.9 mmol) in toluene (200 mL) were
added triethylamine (11.8 mL, 85 mmol) followed by DPPA
(16.8 mL, 78 mmol) dropwise. The mixture was heated to 80 °C
and stirred at this temperature for 1 h. Next benzyl alcohol
(14.7 mL, 0.142 mmol) was added, then the mixture was left for
12-16 h and evaporated under reduced pressure. Aqueous
KOH (100 mL, 10%) was added to the residue, and the product
was extracted with EtOAc (3 ꢀ 100 mL). The combined organic
extracts were washed with water (50 mL) and brine, dried over
Na2SO4, and evaporated under reduced pressure. The crude
product (19.4 g) was recrystallized from hexane-EtOAc to yield
25 (8.6 g, 62%) as a colorless solid. Mp 132 °C. MS (m/z, CI) 361
(MHþ), 261 (MHþ - CO2 - C(CH3)3) Anal. Calcd for C20H28-
N2O4: C 66.64, H 7.83, N 7.77. Found: C 66.60, H 7.67, N 7.41.
1H NMR (DMSO-d6) δ 1.42 (s, 9H, C(CH3)3), 1.84 (m, 2H,
2-CH2), 2.27 (br s, 2H, 4-CH2), 2.45 (br s, 2H, CH2), 4.04 (m,
2H, CH), 4.59 (br s, 1H, NH), 4.81 (br s, 1H, NH), 5.04 (s, 2H,
CH2O), 7.3-7.4 (m, 5H, C6H5). 13C NMR (DMSO-d6) δ 28.4
(C(CH3)3), 30.8 (CH2), 41.8 (CH), 42.2 (CH), 42.8 (CH2), 43.0
(CH2), 43.1 (CH2), 43.2 (CH2), 66.7 (CH2OC6H5), 79.3
(C(CH3)3), 127.9 (C6H5), 128.1 (C6H5), 128.4 (C6H5), 136.8
(ipso-C of C6H5), 154.9 (COOCH2C6H5), 155.4 (COOC(CH3)3).
tert-Butyl (6-Aminospiro[3.3]hept-2-yl)carbamate (18). Method B
(from 25). Compound 25 (15.3 g, 42.5 mmol) was dissolved in EtOH
(150 mL), and 10% Pd/C (5 g) was added. The suspension was
hydrogenated under 50-70 bar of H2 at 45 °C for 20 h. The cata-
lyst was filtered of, and the filtrate was evaporated under reduced
pressure, diluted with CH2Cl2 (150 mL) and washed with 10%
2.94 (m, 2H, CH2), 4.08 (br s, 1H, NH), 4.69 (br s, 1H, OH). 13
C
NMR (CDCl3) δ 28.4 (C(CH3)3), 29.7, 31.0, 41.0, 43.2, 44.2, 79.6,
154.9 (COO-t-Bu), 155.6 (CdN).
tert-Butyl (6-Aminospiro[3.3]hept-2-yl)carbamate (18). Method A
(from 17). To the solution of 17 (1.48 g, 6.2 mmol) in MeOH
saturated with NH3 (20 mL) was added Raney Ni (0.5 g). The
reaction mixture was stirred under 100 psi of H2 for 3 h. The catalyst
was filtered off carefully, and the filtrate was evaporated under
reduced pressure. The crude product (1.3 g) was recrystallized from
ethanol to give 18 as a white solid (1.16 g, 84%). Mp 119 °C. MS
(m/z, EI) 226 (Mþ), 169 (Mþ - C(CH3)3), 153 (Mþ - OC(CH3)3).
Anal. Calcd for C12H22N2O2: C 63.69, H 9.80, N 12.38. Found: C
63.69, H 9.80, N 12.38. 1H NMR (DMSO-d6) δ 1.42 (s, C(CH3)3),
1.68 (m, 2H, CH2), 1.79 (t, J = 9.8 Hz, 2H, CH2), 2.24 (m, 2H,
CH2), 2.39 (m, 2H, CH2), 3.30 (quint, J = 7.8 Hz, 1H, CH), 3.39
(br s, 1H, CH), 4.60 (br s, 1H, NH). 13C NMR (DMSO-d6) δ 28.7
(C(CH3)3), 29.5, 41.6, 42.6, 43.1, 44.2, 45.9, 46.4, 77.9, 154.9
(COOC(CH3)3).
Dimethyl Spiro[3.3]heptane-2,6-dicarboxylate (21). Fecht acid
dimethyl ester 21 was prepared from compound 2043 by using
a modified literature procedure.26 Diethyl malonate (255 g,
1.59 mol) was added dropwise to a stirred suspension of NaH
(70 g, 1.75 mol) in dry DMF (1.5 L) over 0.5 h. Then compound
20 (300 g, 0.4 mol) was added, and the resulting mixture was
heated at 110-120 °C for 20 h, then cooled, diluted with
saturated aqueous NH4Cl (2 L), and extracted with EtOAc
(3 ꢀ 0.6 L). The combined organic extracts were washed with
water (2 ꢀ 0.5 L), dried over Na2SO4, and evaporated under
reduced pressure. The resulting orange oil (150 g) contained
approximately 85% of the product (NMR data) and was used in
the next step without purification. It was dissolved in EtOH
(0.3 L) and added to a solution of NaOH (94 g, 2.35 mol) in
EtOH (0.8 L). The mixture was refluxed for 1.5 h, then cooled,
and the precipitate was filtered, washed with cold water (50 mL),
and dissolved in water (200 mL). The solution was adjusted to
pH <2 with 6 N aqueous HCl and extracted with EtOAc (3 ꢀ
150 mL). The combined organic extracts were dried over
Na2SO4 and evaporated under reduced pressure. The crude acid
(100 g) was used in the next step without purification. It was
dissolved in pyridine (1 L), and the solution was refluxed for
14 h. Pyridine was removed in vacuo, and 6 N aqueous HCl was
added carefully to the residue to adjust pH <2. The product was
extracted with EtOAc (3 ꢀ 100 mL), dried over Na2SO4,
and evaporated under reduced pressure. The crude Fecht’s acid
(42.4 g) was dissolved in MeOH (200 mL), and SOCl2 (67 mL,
0.92 mol) was added dropwise. The resulting mixture was
refluxed for 2.5 h, then evaporated under reduced pressure,
diluted with CCl4 (3 ꢀ 100 mL), and evaporated again to remove
the residual HCl. The crude product was distilled in vacuo (bp 84-
89 °C/0.5 mmHg). Compound 21 (25.8 g, 30% from 20) was obtai-
ned as a colorless oil. For spectral and physical data, see ref 26.
6-(Methoxycarbonyl)spiro[3.3]heptane-2-carboxylic Acid (22).
Compound 21 (23 g, 108 mmol) was dissolved in EtOH (100 mL)
and added to the solution of NaOH (4.33 g, 108 mmol) in EtOH
(100 mL). The reaction mixture was refluxed for 1 h, then cooled,
the precipitate was filtered, washed with cold water (20 mL), and
dissolvedinwater (100 mL). The solution was adjustedtopH5-6
with 3 N aqueous HCl and extracted with EtOAc (3 ꢀ 100 mL).
The combined organic extracts were dried over Na2SO4 and
(43) Herzog, H. L. Org. Synth. 1951, 31, 82.
5950 J. Org. Chem. Vol. 75, No. 17, 2010

Radchenko et al.
JOCArticle
TABLE 2. The Crystallographic Data and Experimental Parameters for Compounds 11b, 36, 38, and 39
parameter
11b
36
38
39
ꢁ
˚
a, A
9.9889(7)
11.4918(8)
9.6399(7)
90
90
90
8.1775(6)
11.2741(8)
11.5261(7)
74.860(6)
71.782(6)
75.209(6)
956.7(1)
372
triclinic
P1
2
0.084
1.203
60
11279
5572
0.029
15.128(3)
5.980(1)
19.539(4)
90
107.58(2)
90
9.929(1)
12.674(1)
15.774(2)
90
90.00(1)
90
ꢁ
˚
b, A
ꢁ
˚
c, A
R, deg
β, deg
γ, deg
3
ꢁ
˚
V, A
1106.6(1)
408
orthorhombic
Pna21
4
0.079
1.118
60
6206
3077
1684.9(5)
712
monoclinic
P21/c
4
0.099
1.322
60
17198
4920
1984.8(3)
888
monoclinic
P21/n
4
0.106
1.420
60
12149
5790
F(000)
crystal system
space group
Z
μ, mm-1
Dcalc, g/cm3
2Θmax, grad
no. of measured reflcns
no. of independent reflcns
Rint
no. of Reflcns with F > 4σ(F)
no. of parameters
0.033
1899
129
0.100
1482
228
0.042
1702
288
1739
233
R1
wR2
S
CCDC no.
0.054
0.134
0.954
778485
0.036
0.078
0.641
778486
0.039
0.077
0.640
778487
0.037
0.067
0.625
778488
aqueous KOH (50 mL). The organic layer was washed with brine,
dried over Na2SO4, and evaporated under reduced pressure. The
crude product (10.1 g) was recrystallized from EtOH to give 18
(7.6 g, 34 mmol, 79%) as a white solid. The spectral and physical
data are described above.
(7 mL) and10% Pd/C(30mg) was added. Hydrogenwas bubbled
though the mixture over 10 min upon stirring, the catalyst was
filtered off, and the filtrate was evaporated under reduced
pressure to give 37 (29 mg, 97%) as a white solid. Mp 115 °C.
MS(m/z, EI) 212(Mþ), 197(Mþ - 15), 156 (Mþ - i-C4H8). Anal.
Calcd for C11H20N2O2: C 62.24, H 9.50, N 13.20. Found: C 62.01,
H 9.50, N 13.55. 1H NMR (CDCl3) δ 1.40 (s, 9H, C(CH3)3), 1.72
(br s, 2H, NH2), 1.80 (m, 2H, CH2), 2.46 (m, 2H, CH2), 3.30 (br
m, 1H, 6-CH), 3.79 (s, 2H, CH2), 3.87 (s, 2H, CH2). 13C NMR
(CDCl3) δ 28.4 (C(CH3)3), 30.7 (2-CH2), 43.1 (6-CH), 44.3 (4-C),
44.5 (CH2), 79.3 (C(CH3)3), 156.2 (CdO).
tert-Butyl {trans-3-[(4-Nitrobenzoyl)amino]cyclobutyl}-
carbamate(38). Compound11a (200 mg, 1.1 mmol) was dissolved
in dioxane (10 mL), and NEt3 (0.22 mL, 3 mmol) was added
followed by 4-nitrobenzoyl chloride (200 mg, 1.1 mmol). The
mixture was refluxed for 1.5 h, then diluted with water (20 mL)
and filtrered. The precipitate was washed with cold water (5 mL)
and ether (10 mL). The crude product was recrystallized from
EtOAc (5 mL). Compound 38 (340 mg, 94%) was obtained as a
white solid. Mp 240 °C. MS (m/z, CI) 335 (Mþ). Anal. Calcd for
C16H21N3O5: C57.30, H 6.31, N 12.53. Found:C 57.01, H 6.62, N
12.59. 1H NMR (CDCl3) δ 1.44 (s, 9H, C(CH3)3), 2.43 (m, 4H,
CH2), 4.31 (br s, 1H, CH), 4.62 (br s, 1H, CH), 4.81 (br s, 1H,
NHBoc), 6.42 (br s, 1H, NHC6H4NO2), 7.95 (dd, 2H, J = 8.0 Hz,
C6H4NO2), 8.23 (dd, 2H, J = 8.0 Hz, C6H4NO2). 13C NMR
(CDCl3) δ 28.3(C(CH3)3), 38.5(CH2), 39.2 (CH), 40.2 (CH), 78.2
(C(CH3)3), 123.7 (CH), 128.0 (CH), 139.9 (C), 149.5 (C), 155.0
(COOC(CH3)3), 164.3 (COO).
6-[(tert-Butoxycarbonyl)amino]spiro[3.3]heptane-2-carboxylic
Acid (35). To the solution of NaOH (0.542 g, 13.6 mmol) in
water (25 mL) were added hydrochloride of 3428 (2.4 g, 13.5
mmol) and Boc2O (6.23 mL, 30 mmol). The reaction mixture
was stirred at rt for 1.5 h and washed with Et2O (2 ꢀ 10 mL). The
aqueous phase was adjusted to pH 3.5-4 with 10% aqueous
citric acid and extracted with CH2Cl2 (3 ꢀ 12 mL). The
combined organic extracts were washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The crude
product (2.9 g) was recrystallized from ethanol (5 mL) to give 35
(2.7 g, 83%) as a white solid. Mp 95-97 °C. MS (m/z, EI) 224
(Mþ - OH), 200, 199, 182, 96, 57 (C(CH3)3þ). Anal. Calcd for
C12H19NO4: C 59.73, H 7.94, N 5.80. Found: C 59.90, H 8.22,
N 5.53. 1H NMR (CDCl3) δ 1.42 (s, 9H, C(CH3)3), 2.46 (m, 4H,
CH2), 3.01 (quint, J = 8.0 Hz, 1H, CH), 2.73 (br s, 2H, CH2),
3.69 (s, 2H, CH2), 3.93 (s, 2H, CH2), 4.74 (br s, 1H, NH); COOH
is not observed due to exchange. 13C NMR (CDCl3) δ 28.4
(C(CH3)3), 32.5 (2-CH), 34.8 (3-C), 35.8 (CH2), 61.2 (CH2), 61.6
(CH), 79.8 (C(CH3)3), 156.2 (COOC(CH3)3), 179.4 (CO2H).
tert-Butyl 6-{[(Benzyloxy)carbonyl]amino}azetidine-2-azaspiro-
[3.3]heptane-2-carboxylate (36). Compound 35 (1 g, 4.13 mmol)
and triethylamine (0.7 mL, 4.95 mmol) were dissolved in toluene
(15 mL). The reaction mixture was heated to 95 °C, then DPPA
(1 mL, 4.55 mmol) was added dropwise, and the mixture was stirred
for 1.5 h. Then benzyl alcohol (0.9 mL, 8.33 mmol) was added,
and the resulting mixture was stirred for 16 h. The solution was
evaporated under reduced pressure, and the residue was recrystal-
lized from EtOH to give 36 (0.47 g, 62%) as a white solid. Mp
128-129 °C. MS (m/z, EI) 291(Mþ - i-C4H8), 248(Mþ - i-C4H8 -
CO2). Anal. Calcd for C19H26N2O4: C 65.88, H 7.56, N 8.09. Found:
C 66.17, H 7.51, N 7.84. 1H NMR (CDCl3) δ 1.42 (s, 9H, C(CH3)3),
2.03 (br s, 2H, CH2), 2.56 (br s, 2H, CH2), 3.82 (s, 2H, CH2), 3.93
(s, 2H, CH2), 4.03 (br s, 1H, 6-CH), 4.92 (br s, 1H, NH), 5.07 (s, 2H,
CH2C6H5), 7.32-7.38 (m, 5H, C6H5). 13C NMR (CDCl3) δ 28.4
(C(CH3)3), 31.6, 41.4, 41.8, 66.9, 80.1, 128.1, 128.2, 128.6, 136.2,
155.5 (CdO), 156.2 (CdO).
N,N0-Spiro[3.3]heptane-2,6-diylbis(4-nitrobenzamide) (39).
Compound 18 (310 mg, 1.37 mmol) was dissolved in 3 N HCl
(8 mL) and the solution was stirred for 0.5 h. The mixture was
evaporated under reduced pressure, diluted with water (2 ꢀ
10 mL), and evaporated to remove the residual HCl. The solid
was dissolved in preheated dimethylformamide (10 mL), and
NEt3 (0.6 mL, 4.12 mmol) was added followed by 4-nitro-
benzoyl chloride (510 mg, 2.74 mmol). The mixture was heated
at 80 °C for a 1 h, and then cooled. The product was filtered, then
washed with cold water (2 ꢀ 25 mL) and ether (20 mL). The
crude product was recrystallized from dimethylformamide to
give 39 (510 mg, 88%) as orange needles. Mp 289 °C. MS (m/z,
CI) 423 (M- - 1). Anal. Calcd for C21H20N4O6: C 59.43, H 4.75,
1
tert-Butyl 6-Amino-2-azaspiro[3.3]heptane-2-carboxylate (37).
Compound 36 (50 mg, 0.14 mmol) was dissolved in dry MeOH
N 13.20. Found: C 59.27, H 4.70, N 13.51. H NMR (CDCl3)
δ 2.21 (m, 4H, CH2), 2.34 (br s, 2H, CH2), 4.36 (m, 2H, CH),
J. Org. Chem. Vol. 75, No. 17, 2010 5951

Radchenko et al.
JOCArticle
8.08 (dd, J = 8.0 Hz, 4H), 8.30 (dd, J = 8.0 Hz, 4H), 8.86 (br s,
2H, NH). 13C NMR (CDCl3) δ 31.4 (C(CH3)3), 41.2 (CH),
42.1 (CH2), 42.4 (CH2), 123.9 (CH), 129.2 (CH), 140.6 (C),
149.5 (C), 164.2 (COO).
Positions of hydrogen atoms were located from electron den-
sity difference maps and refined with use of the riding model
with Uiso =nUeq (n=1.5 for methyl groups and 1.2 for other
hydrogen atoms), except the H-atoms at nitrogen which were
refined within isotropic approximation. The crystallographic
data and experimental parameters are listed in Table 2. Final
atomic coordinates, geometrical parameters, and crystallo-
graphic data have been deposited with the Cambridge Crystal-
lographic Data Centre, 11 Union Road, Cambridge, CB2 1EZ,
UK (fax þ44 1223 336033; e-mail deposit@ccdc.cam.ac.uk).
The deposition numbers are given in Table 2.
X-ray Diffraction Studies of 11b, 36, 38, and 39. The crystals for
X-ray diffraction studies were obtained by slow crystallization from
EtOAc (11b and 38), EtOH (36), and dimethylformamide (39).
X-ray diffraction studies were performed on an automatic
“Xcalibur 3” diffractometer (graphite monochromated Mo KR
radiation, CCD-detector, ω-scanning, 2θmax = 60°). The struc-
ture was solved by direct method with the SHELXTL
package.44 The restrains were applied to the lengths of C-C bonds
˚
in the tert-butyl substituents (1.54(1) A) for the structure 11b.
Supporting Information Available: Copies of NMR spectra
and crystallographic information files. This material is available
free of charge via the Internet at http://pubs.acs.org.
(44) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, A64, 112–122.
5952 J. Org. Chem. Vol. 75, No. 17, 2010