Structural and spatial considerations in the N,N′-diacyl- and bis(alkoxycarbonyl)bispidinone series

Article abstract of DOI:10.1021/jo801423a

(Chemical Equation Presented) Diamidic and dicarbamic bispidinones show trans-cis isomerism, the relative population in solution of the cis form increasing with solvent polarity. The mutual proximity of the two amide functions in 4a has no impact on the b

Full text of DOI:10.1021/jo801423a

SCHEME 1. Synthesis of 3,7-Diacyl- and
3,7-Bis(alkoxycarbonyl)-3,7-diazabicyclo[3.3.1]nonan-9-ones 4
Structural and Spatial Considerations in the
N,N′-Diacyl- and Bis(alkoxycarbonyl)bispidinone
Series
Shlomo Levinger, Yifat Sharabi-Ronen, Alexander Mainfeld,
and Amnon Albeck*
Department of Chemistry, Bar-Ilan UniVersity,
Ramat-Gan 52900, Israel
albecka@mail.biu.ac.il
ReceiVed June 30, 2008
Diamidic and dicarbamic bispidinones show trans-cis
isomerism, the relative population in solution of the cis form
increasing with solvent polarity. The mutual proximity of
the two amide functions in 4a has no impact on the barrier
to isomerization. The system represents a peculiar case of
planar chirality posing a challenge to its specification.
in enantioselective catalysis.14-16 Physiologically active alka-
loids with the 1,3-diazaadamantane structure are known,17 and
some synthetic derivatives are sodium channel blockers18 and
κ-opiate and σ-receptor ligands,19 as well as oncolytics.20
Consequently, substantial synthetic efforts have been directed
toward both the bispidine and the 1,3-diazaadamantane scaffolds.
As a result of our interest in these compounds, we have come
across a structural peculiarity of the bispidinone framework that,
to the best of our knowledge, has eluded notice so far and of
which we report here.
Several 6-oxo-1,3-diazaadamantanes 3 have been prepared
by way of the quadruple Mannich cyclocondensation of the
symmetrical ketones 1 with hexamethylenetetraamine (2).21
Opening of the tricyclic cage of 3 was achieved by reaction
with acyl chlorides or with chloroformate esters to yield the
bispidinone derivatives 3,7-diacyl- or 3,7-bis(alkoxycarbonyl)-
3,7-diazabicyclo[3.3.1]nonan-9-ones 4 (Scheme 1).22,23
Both 3,7-diazabicyclo[3.3.1]nonane (DABCN, bispidine) and
1,3-diazaadamantane based compounds exhibit interesting bio-
logical activity. Thus, bispidines possess attractive physiological
properties as antitumor1 and antiarrythmic2-4 agents, as well
as κ-opioid receptor ligands with analgesic activity.5-7 The
bispidine framework constitutes the central ring of a variety of
lupin alkaloids, e.g., (-)-sparteine and (-)-angustifolline, which
are effective muscarinic receptor binding agents.8 Compounds
having the rigid bidentate bispidine nucleus were employed as
ligands for a number of coordinating metals9-13 and were useful
(1) Arutyunyan, G. L.; Chachoyan, A. A.; Shkulev, V. A.; Adamyan, G. G.;
Agadzhanyan, T. E.; Garibdzhanyan, B. T. Khim.-Farm. Zh. 1995, 29, 33–35;
Chem. Abstr. 124:117427.
(2) Garrison, G. L.; Berlin, K. D.; Scherlag, B. J.; Lazzara, R.; Patterson,
E.; Fazekas, T.; Sangiah, S.; Chen, C.-L.; Schubot, F. D.; van der Helm, D.
J. Med. Chem. 1996, 39, 2559–2570.
(3) Ruenitz, P. C.; Mokler, C. M. J. Med. Chem. 1977, 20, 1668–1671.
(4) Smith, G. S.; Thompson, M. D.; Berlin, K. D.; Holt, E. M.; Scherlag,
B. J.; Patterson, E.; Lazzara, R. Eur. J. Med. Chem. 1990, 25, 1–8.
(5) Holzgrabe, U.; Brandt, W. J. Med. Chem. 2003, 46, 1383–1389.
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J. Chem. Soc., Perkin Trans. 2 2001, 2037–2042.
(7) Wang, Y.; Tang, K.; Inan, S.; Siebert, D.; Holzgrabe, U.; Lee, D. Y. W.;
Huang, P.; Li, J.-G.; Cowan, A.; Liu-Chen, L.-Y J. Pharmacol. Exp. Ther. 2005,
312, 220–230; Chem. Abstr. 142:329635.
(11) Comba, P.; Nuber, B.; Ramlow, A. J. Chem. Soc., Dalton Trans. 1997,
347–352.
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Chem. 1993, 65, 473–476.
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Soc., Dalton Trans. 1995, 3705–3708.
(14) Vrancken, E.; Alexakis, A.; Mangeney, P. Eur. J. Org. Chem. 2005,
1354–1366.
(15) Kocienski, P. J.; Christopher, J. A.; Bell, R.; Otto, B. Synthesis 2005,
75–84.
(8) Michael, J. P. Nat. Prod. Rep. 1997, 14, 21–41.
(9) Black, D. S. C.; Deacon, G. B.; Rose, M. Tetrahedron 1995, 51, 2055–
2076.
(10) Comba, P.; Kanellakopulos, B.; Katsichtis, C.; Lienke, A.; Pritzkow,
H.; Rominger, F. J. Chem. Soc., Dalton Trans. 1998, 3997–4002.
(16) Allen, B. D.; Cintrat, J.-C.; Faucher, N.; Berthault, P.; Rousseau, B.;
O’Leary, D. J. J. Am. Chem. Soc. 2005, 127, 412–420.
(17) Nuzillard, J.-M.; Connolly, J. D.; Delaude, C.; Richard, B.; Zeches-
Hanrot, M.; Le Men-Olivier, L. Tetrahedron 1999, 55, 11511–11518.
10.1021/jo801423a CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7793–7796 7793

TABLE 1. Equilibrium Constant (K) and Free Energy (∆G°) of
Bispidinone 4a at 301 K in Different Solvents
solvent
relative permittivity, εra K ([cis]/[trans]) ∆G°, kcal mol-1
d-chloroform
d6-acetone
d4-methanol
d3-acetonitrile
d6-DMSO
4.81b
20.7c
32.6c
37.5b
0.026
0.080
0.13
0.15
0.20
2.19
1.51
1.23
1.12
0.95
47b
a Reference 25; data correspond to the nondeuterated solvent. b At 293
K. c At 298 K.
FIGURE 1. MM2 minimized 3D model of trans- (left) and cis-3,7-
diacetyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one 4a; gray )
C, red ) O, blue ) N; hydrogen atoms are omitted for clarity.
These diamidic and dicarbamic bispidinones were obtained
as crystalline materials in 66-100% overall yields. Their
NMR spectra support a twin chair conformation of the
bispidinone skeleton. As a typical case, the proton spectrum
of bisacetamide 4a displays a single set of phenyl group
signals as well as one singlet for the two acetamide methyls
in the higher field region (δ ) 2.2 ppm). Two AB systems
(δ ) 5.71; 3.53 and 4.48; 3.97 ppm), each of four protons
and with a ∼14 Hz geminal coupling constant and a ∼3 Hz
long-range coupling constant, represent the four methylenes.
The 13C NMR spectrum features one set of signals for the
phenyl groups, as well as one set for the acetamide function
(methyl and carbonyl) and one signal for the quaternary
carbon R to the ketone (δ ) 52.5 ppm), while the four
methylene carbons are represented by two signals (δ ) 58.2;
52.1 ppm). These spectra are consistent with a double chair
conformation of the bispidinone skeleton, holding the two
acetamide functionalities in a trans mutual relationship
(Figure 1).
Stereoelectronic factors have been invoked to explain the
propensity of the 3,7-diazabicyclo[3.3.1]nonane system for the
twin chair conformation in derivatives possessing trigonal
nitrogens (amide, carbamate, and N-nitroso), as judged from
X-ray crystallography.24 The possibility of a rapid interconver-
sion in solution between two degenerate boat-chair conforma-
tions seems unlikely in light of the overwhelming preference
for the trans arrangement of the amide groups, as evidenced
from the NMR spectra in less polar solvents: the mutual
proximity of these groups in the double chair conformation is
expected to yield a strong dipole-dipole repulsion in the case
of a cis arrangement, whereas such an interaction would have
been insignificant in the boat-chair conformation where the
amide groups are widely separated from each other. Indeed,
increasing the polarity of the solvent resulted in NMR spectra
that show, in addition to the major set of signals of the trans
FIGURE 2. Equilibrium constant (K, [cis]/[trans]) of bispidinone 4a
at 301 K as a function of solvent permittivity.
diamide, a minor set of resonances belonging to the cis rotamer.
As expected from its structure, this isomer features two sets of
phenyl signals in its 1H and 13C spectra as well as two distinct
signals in the 13C spectrum for the quaternary bridgehead
carbons of the bispidinone framework (δ ) 52.2; 51.9 ppm in
d6-DMSO). Solvent-solute dipolar interactions are expected to
stabilize the more polar cis-diamide in preference to the trans
rotamer, thus increasing the cis to trans equilibrium constant
1
(calculated from the relative peak areas in the H spectra) as
solvent polarity increases (Table 1 and Figure 2).
Plotting the equilibrium constants versus other solvent polarity
parameters (polarizability, dipole moment) resulted in excellent
linear correlations, as well.
Dicarbamate 4c exhibits a similar trend, although the respec-
tive values for the [cis]/[trans] equilibrium constants are higher
(e.g., K ) 0.22 in d-chloroform at 300 K), while the dependency
of K on solvent polarity is less pronounced. Both facts are in
accordance with the smaller dipole moment of the carbamate
function relative to amides.
In view of the compactness of the 3,7-diazabicyclo[3.3.1]
nonane double chair skeleton, it was interesting to check whether
a possible mutual interaction between the proximal amide groups
in the N,N′-disubstituted bispidinones 4 can be detected.
Assuming that such an interaction would manifest itself in an
abnormal barrier to internal rotation about the amide bonds, we
followed the kinetics of this rotation in bispidinone 4a by
dynamic NMR spectroscopy. For simplicity reasons we exam-
ined the skeletal methylene and quaternary carbons’ region in
the 13C NMR spectrum. Spectra were taken in d6-DMSO, and
upon raising the temperature, broadening of the methylene
signals of the trans rotamer was observed until full coalescence
occurred at 150 °C. This broadening was accompanied by
disappearance of the minor resonances pertaining to the cis
rotamer. Using the method of line shape analysis (LSA), the
spectra taken at different temperatures were fitted to traces
calculated from guessed rate constants. After a correction for
the data at temperatures remote from coalescence has been made
(applying the 2D procedure of exchange spectroscopy (EXSY)
(18) Yamawaki, I.; Bukovac, S. W.; Sunami, A. Chem. Pharm. Bull. 1994,
42, 2365–2369.
(19) Brandt, W.; Drosihn, S.; Haurand, M.; Holzgrabe, U.; Nachtsheim, C.
Arch. Pharm. (Weinheim, Ger.) 1996, 329, 311–323.
(20) Arutyunyan, G. L.; Chachoyan, A. A.; Agadzhanyan, T. E.; Garibdzh-
anyan, B. T. Pharm. Chem. J. (Engl. Transl.) 1996, 30, 739–741; Chem. Abstr.
127:29297.
(21) Kuznetsov, A. I.; Basargin, E. B.; Moskovkin, A. S.; Ba, M. K.;
Miroshnichenko, I. V.; Botnikov, M. Y.; Unkovskii, B. V. Khim. Geterotsikl.
Soedin. 1985, 1679–1685; Chem. Abstr. 105:42136.
(22) Chiavarelli, S.; Settimj, G. Gazz. Chim. Ital 1958, 88, 1234–1245; Chem.
Abstr. 53:122272.
(23) Stetter, H.; Schafer, J.; Dieminger, K. Chem. Ber. 1958, 91, 598–604.
(24) McCabe, P. H.; Milne, N. J.; Sim, G. A. J. Chem. Soc., Chem. Commun.
1985, 625–626.
7794 J. Org. Chem. Vol. 73, No. 19, 2008

Molecular chirality caused by the presence of a stereogenic
plane is typically encountered in the fields of cyclophanes and
ansa compounds, annulenes, trans-cycloalkenes,27 arenemetal,28,29
and olefinmetal complexes,30 and the specification of this kind
of chirality has been dealt with already in the monumental paper
by Cahn, Ingold, and Prelog.31 However, the assignment in our
case is not trivial, as the generic system in question is not
considered explicitly by the original CIP rules31 nor could we
find any precedence in later literature. Thus, in accordance with
the sequence rules (precedence of Z over E), we define as pilot
atom, for each chiral (amide) plane in the trans form of Figure
1, that bridgehead skeletal carbon (C1 or C5) that is bonded to
the methylene carbon collateral (Z) with the amide oxygen rather
than with the amide methyl. Following then the selection rule
for planar chirality31 and the general sequence rule, both amide
planes in the trans rotamer of Figure 1 become of pR
configuration. Accordingly, the frontal amide plane in the cis
rotamer of Figure 1 is of the pS configuration, while the rear
one is pR.
FIGURE 3. Temperature dependence of the barrier to rotation about
the amide bonds in bispidinone 4a compared to that in model amide 5;
data from dynamic NMR spectroscopy in d6-DMSO solution.
at room temperature), a standard enthalpy of activation (∆Hq)
of 16 kcal mol-1 and a standard activation entropy (∆Sq) of
-6 eu were determined (Figure 3).
In summary, the trans form in N,N′-diacyl- and di(alkoxy-
carbonyl)bispidinones 4 is more stable than its cis isomer due
to dipole-dipole opposition, the difference in stability depending
on solvent polarity. Despite the mutual proximity of the amide
groups in 4a, the barrier to rotation about the C(O)-N bonds is
found to be essentially the same as in isolated amides. A chair-
to-boat conversion upon rotation is postulated to account for
this fact. Diamides and dicarbamates 4 represent a special case
of planar chirality accompanied by a specification issue for
which a solution is suggested.
Both of these values are very similar to the corresponding
activation parameters (∆Hq ) 16 kcal mol-1; ∆Sq ) -4 eu)
obtained for the rotation barrier in a model amide, 1-acetyl-4-
piperidone 5 (Figure 3), indicating that there is no interference
of the amide groups in bispidinone 4a with each other’s rotation
dynamics. A chair-to-boat inversion of one of the six membered
rings, concomitant with nitrogen pyramidalization en route to
the transition state for amide rotation, may provide an explana-
tion, as such process would push the two amide groups away
from mutual hindrance. The preference for a boat-chair con-
formation in bispidinones featuring pyramidal nitrogens has been
observed24 and the barrier to the chair-to-boat inversion in this
system is expected to be considerably lower than that to amide
rotation.26
Experimental Section
Preparation of 6-Oxo-1,3-diazaadamantanes (3). General
Procedure.21 A solution of hexamethylenetetraamine 2 (3.51 g,
25 mmol) in ethanol (10 mL) at 0 °C was neutralized by the slow
addition of glacial acetic acid (∼3 mL), and then the ketone 1 (25
mmol) and additional ethanol (20 mL) were added. The resulting
suspension was heated gently under reflux for a period of time
varying according to the ketone employed (8 h to 5 d). The cooled
reaction mixture was worked up by one of the following methods:
Method A. The product that crystallized out of the reaction
mixture was collected and washed with ethanol.
Method B. The reaction mixture was diluted with ether (300
mL), the pH was adjusted to 3 with 70% aqueous perchloric acid,
and the mixture was then stored overnight at -4 °C. The solid
precipitate was removed by suction filtration and the fitrate was
evaporated to yield the crude product.
It is noteworthy that 180° rotations about both of the amide
(or carbamate) C-N bonds of the trans bispidinones 4 amounts
to a transition between two enantiomers of the trans form,
passing through an achiral cis intermediate. The stereochemical
relationships in the diamide or dicarbamate 4 are best conceived
as resulting from the presence of two chiral planes in the
molecule, each identified with one of the amide (or carbamate)
groupings. A mutual trans conformation of the two planar
functions conveys identical sense to their chiralities, thus
imparting chirality to the whole of the structure, which then
possesses a C2 symmetry axis, colinear with the ketone carbonyl
bond. On the other hand, when the two amide (carbamate)
functions are cis to each other, their planar chiralities are
mutually opposing and the entire molecule is achiral as a result
of a mirror plane lying in between the individual chiral planes
and coplanar with the ketone carbonyl plane.
5,7-Bis(phenylmethyl)-1,3-diazatricyclo[3.3.1.13,7]decan-6-one
(3d). This compound was prepared from 1,5-diphenyl-3-pentanone
(5.96 g, 25 mmol) following the general procedure above. The
reaction mixture was refluxed overnight and then worked up
according to method A to give 4.07 g (49%) of the clean product
1
(3d). Mp: 199-200 °C (EtOH); H NMR (300 MHz, CDCl3) δ
7.34-7.19 (m, 6H, m,p-Ph), 7.17-7.10 (m, 4H, o-Ph), 3.88 (s, 2H,
NCH2N), 3.26 and 3.02 (AB q, Jgem ) 12.6 Hz, 8H, CCH2N), 2.82
(s, 4H, CH2Ph);13C NMR (75.5 MHz, CDCl3) δ 210.6 (C, CO),
136.3 (C, ipso-Ph), 130.6 (CH, o-Ph), 128.4 (CH, m-Ph), 126.6
(27) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley:
New York, 1994; p 1166.
(28) Schloegl, K. Top. Stereochem. 1967, 1, 39–91.
(29) Schloegl, K. Pure Appl. Chem. 1970, 23, 413–432.
(30) Donohoe, T. J.; Harji, R. R.; Moore, P. R.; Waring, M. J. J. Chem.
Soc., Perkin Trans. 1 1998, 819–834.
(31) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966,
5, 385–415.
(32) IUPAC Compendium of Chemical Terminology; electronic version: http://
goldbook.iupac.org/R05273.html.
(25) (a) Relative permittivity (formerly called dielectric constant) is the ratio
of the electric field strength in vacuum to that in a given medium.32. (b) Values
taken from CRC Handbook of Chemistry and Physics, 72nd ed.; Lide, D. R.,
Ed.; CRC Press: Boca Raton, 1991-1992; pp 8-49; 9-27.
ˆ
(26) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH: Deerfield Beach, Florida, 1985; pp 334-335.
J. Org. Chem. Vol. 73, No. 19, 2008 7795

(CH, p-Ph), 72.9 (CH2, NCH2N), 63.3 (CH2, CCH2N), 49.4 (C,
CCH2Ph), 37.4 (CH2, CH2Ph); HRMS (DCI+ CH4) m/z (%)
332.1889 (100) [M]+ (calcd for C22H24N2O 332.1889).
4H, ax CCH2N); 13C NMR (75.5 MHz, CDCl3) δ [major (trans)
rotamer] 207.8 (C, CO), 155.0 (C, NCO2), 135.9 (C, ipso-Ph), 132.8
(CH, vinylic), 128.4 (CH, Ph), 127.9 (CH, p-Ph), 127.5 (CH, Ph),
118.2 (CH2, vinylic), 66.9 (CH2, allylic), 55.8 (br CH2, CH2N),
55.3 (br CH2, CH2N), 53.1 (C, CPh); HRMS (DCI+ CH4) m/z (%)
460.2019 (18) [M]+ (calcd for C27H28N2O5 460.1998). Anal. Calcd
for C27H28N2O5: C, 70.45; H, 6.08; N, 6.09. Found: C, 70.24; H,
6.39; N, 5.79.
Preparation of 3,7-Diacyl- and 3,7-Bis(alkoxycarbonyl)-3,7-
diazabicyclo[3.3.1]nonan-9-ones (4). General Procedure.22,23 To a
6-oxo-1,3-diazaadamantane 3 (1.0 mmol) in chloroform (10 mL)
was added an acyl chloride or a chloroformate ester (2.0 mmol).
The solution was stirred for 5 d at room temperature and then
partitioned between water and chloroform. The combined organic
phase was washed with saturated NaCl solution, dried over MgSO4,
and concentrated to afford the product 4.
Acknowledgment. Partial support from the Raoul Wallenberg
Chair in Immunological Chemistry is gratefully acknowledged.
We thank Dr. Hugo E. Gottlieb for his help with the NMR
experiments.
1,5-Diphenyl-3,7-bis[(2-propenyloxy)carbonyl]-3,7-diaza-
bicyclo[3.3.1]nonan-9-one (4d). This compound was prepared
from 3c (0.305 g, 1.0 mmol) and allyl chloroformate (0.241 g, 2.0
mmol), following the general procedure above, to furnish the clean
Supporting Information Available: Characterization data
not included in the Experimental Section, copies of 1H and 13
C
1
product (4d) quantitatively. Mp: 123-124 °C (EtOH); H NMR
(300 MHz, CDCl3) δ [major (trans) rotamer] 7.41-7.24 (m, 10H,
Ph), 5.97 (ddt, J ) 17.0, 10.6, 5.9 Hz, 2H, internal vinylic), 5.33
(dq, J ) 17.4, 1.5 Hz, 2H, terminal vinylic), 5.23 (dq, J ) 10.4,
1.3 Hz, 2H, terminal vinylic), 5.10 (br d, J ) 12.4 Hz, 2H, eq
CCH2N), 4.91 (br d, J ) 12.6 Hz, 2H, eq CCH2N), 4.78-4.62 (br
m, 2H, allylic), 4.62-4.45 (br m, 2H, allylic), 3.84-3.64 (br m,
NMR spectra of isolated products, and reproduction of the
temperature dependence of the 13C NMR spectrum of 4a
together with fitted, calculated spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO801423A
7796 J. Org. Chem. Vol. 73, No. 19, 2008