In-line proximity effects in extended 7-azanorbornanes. 1. a new concept for modifying effector group separation based on the control of N-invertomer geometry

Article abstract of DOI:10.1021/ol9910969

(figure presented) X,Y = CH₂ ≈ spirocyclopropyl > C=CMe₂ > NZ > O sentinel dominance control (X>Y) Control of N-substituent geometry in fused 7-azanorbornane systems is based on the dominance of one proximate bridge (sentinel X) over the other (sentinel Y) relative to the N-bridge; the N-inversion equilibrium can effectively be displaced in favor of a single invertomer. This study has used a combination of synthesis, crystallography, and molecular modeling to establish stereostructures.

Full text of DOI:10.1021/ol9910969

ORGANIC
LETTERS
2000
Vol. 2, No. 6
721-724
In-Line Proximity Effects in Extended
7-Azanorbornanes. 1. A New Concept
for Modifying Effector Group Separation
Based on the Control of N-Invertomer
Geometry
Douglas N. Butler,* Malcom L. A. Hammond,† Martin R. Johnston,†
,†
,‡
,†
Guangxing Sun,† John R. Malpass,* John Fawcett,‡ and Ronald N. Warrener*
Centre for Molecular Architecture, Central Queensland UniVersity,
Rockhampton, Queensland, 4702, Australia, and Department of Chemistry,
UniVersity of Leicester, Leicester, LE1 7RH, U.K.
r.warrener@cqu.edu.au
Received September 28, 1999
ABSTRACT
Control of N-substituent geometry in fused 7-azanorbornane systems is based on the dominance of one proximate bridge (sentinel X) over the
other (sentinel Y) relative to the N-bridge; the N-inversion equilibrium can effectively be displaced in favor of a single invertomer. This study
has used a combination of synthesis, crystallography, and molecular modeling to establish stereostructures.
The ability of nature to maximize host/guest interactions
using conformational changes within the host is a well-
established tenet in enzyme substrate selectivity. A series
of leading articles covering the concepts of supramolecular
science has recently appeared.1-5 Host flexibility has been
advocated as a necessary feature in unnatural host design,5
and several examples have been reported which support this
concept. Changes in shape which involve methylene chain
conformations are usually too imprecise, and improvement
has been gained by using conformational changes within six-
membered rings.6-8 Similarly, guest flexibility can play a
role in some host/guest interactions, e.g., bis-intercalating
agents. The role of nitrogen in determining conformation in
N-alicyclic systems has been well established.9 However, our
present study demonstrates that N-invertomer preferences can
be controlled and thereby adds a new element into the design
and use of fused 7-azanorbornanes.
Recently, we described a new class of “windscreen wiper”
molecules having two 7-azanorbornanes linked together by
a rigid carbocyclic frame.10 Such molecules have the potential
to exhibit a significant degree of substituent mobility
associated with nitrogen inversion. Since the rest of the
† Central Queensland University.
‡ Leicester University.
(1) Smith, D. K.; Diederich, F. Chem. Eur. J. 1998, 4, 1353-1361.
(2) Chambron, J.-C.; Sauvage, J.-P. Chem. Eur. J. 1998, 4, 1362-1366.
(3) Hartgerink. J. D.; Clark, T. D.; Ghadiri, M. R. Chem. Eur. J. 1998,
4, 1367-1372.
(4) de Mendoza, J. Chem. Eur. J. 1998, 4, 1373-1377.
(5) Sanders, J. K. M. Chem. Eur. J. 1998, 4, 1378-1383.
(6) Tokunaga, Y.; Rudkevich, D. M.; Santamaria, J.; Hilmersson, G.;
Rebek, J., Jr.; Chem. Eur. J. 1998, 4, 1449-1457.
(7) Ashton, P. R.; Girreser, U.; Giuffrida, D.; Kohnke, F. H.; Mathias,
J. P.; Raymo, F. M.; Slawin, A. M. Z.; Stoddart, J. F.; Williams, D. J. J.
Am. Chem. Soc. 1993, 115, 5422-5429.
(8) Klarner, F.-G.; Benkhoff, J.; Boese, R.; Burkert, U.; Kamieth, M.;
Naatz, U.Angew. Chem., Int. Ed. Engl. 1996, 35, 1130-1133.
(9) Alder, R. W.; East, S. P. Chem. ReV. 1996, 96, 2097-2111.
(10) Malpass, J. R.; Sun, G.; Fawcett, J.; Warrener, R. N. Tetrahedron
Lett. 1998, 39, 3038-3086.
10.1021/ol9910969 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/03/2000

carbocyclic frame of the molecule is rigidly fused, displace-
ments at nitrogen occur within a plane bisecting the long
axis of the molecule (Figure 1). This inversion process, if
Scheme 1
Figure 1. Windscreen wiper molecule 1 and fixed invertomer
systems in (linked) 7-azanorbornanes.
the molecule can be forced to adopt one of the conformations,
opens up the opportunity to form three distinct isomers with
R,R separations corresponding to d1 (out,out-invertomer), d2
(in,out-invertomers), and d3 (in,in-invertomers). In practice,
the N-substituents in 2 are forced to assume the out,out-
configuration owing to the steric interaction with the H-
substituents on the inside of the frame,11 so we sought
alternative ways to control the N-invertomer preference and
report herein the role of sentinel groups on either side of
the 7-azanorbornane to achieve this goal.
To allow individual control of “in” or “out” invertomer
positioning, it was important to have an understanding of
the geometry and mobility of N-substituents in 7-azanor-
bornanes. Preliminary molecular modeling (AM1) indicated
that placement of proximate groups (sentinel bridges X or
Y) on each side of the N-bridge within a [3]polynorbornane
frame XNY12 offered such an opportunity (Figure 1). The
constraints that the sentinel bridges exert in the dynamic
XNX series are also supported by molecular modeling (see
discussion in the accompanying Letter13). This effect mani-
fests itself in the motion of the substituent on the N-bridge
such that the distances between the inner and outer limits
reduce as X becomes larger and tend more and more toward
that expected for a planar nitrogen system.
In this Letter, we report the synthesis of syn-facial aza-
[3]polynorbornanes 12-25 in which five different sentinel
groups (spirocyclopropyl, methylene, isopropylidene, aza,
and oxa) have been incorporated as X,Y bridges about the
central N-benzyl-7-azanorbornane. We also discuss how the
sentinel groups X and Y affect N-substituent conformations,
e.g., invertomer 3a versus invertomer 3b, using a combina-
1
tion of X-ray, modeling, and H NMR techniques.
The synthesis of 14 different N-bridged [3]poly norbor-
nanes 12-2514 was achieved by application of our recently
(14) Physical properties of representative new compounds: 11e 57%;
mp 158-159 °C; 1H NMR δ 2.50 (2H, s), 3.51 (6H, s), 3.78 (6H, s), 3.82
(2H, s), 5.83 (2H, s), 7.12-7.18 (3H, m), 7.25-7.29 (4H, m), 7.46 (2H, d,
J ) 7.45 Hz); 13C NMR δ 48.83, 52.38, 52.43, 55.15, 79.75, 80.91, 119.58,
126.51, 126.77, 127.68, 127.99, 139.02, 144.42, 146.66, 164.24, 167.35,
HRMS calcd for C29H27O9N 533.1686, found 533.1685. 12 43%; mp 299-
(11) The out,out-sterochemistry in 2 has been established by X-ray
crystallography.10
(12) We describe the particular [3]polynorbornanes using a three-letter
prefix as a shorthand notation to designate the bridges (see Scheme 1 for
the one-letter abbreviations for each bridge type), i.e., CNC[3]poly
norbornane refers to the symmetrical product 24 in which the aza bridge is
flanked by methylene bridges, whereas the ONπ[3]polynorbornane indicates
an unsymmetrical product 14 in which the aza bridge is flanked by an
oxygen bridge on one side and a 7-isopropylidene group on the other. For
the bent isomers 27-33, the bent bridge is designated in parentheses, e.g.,
the CN(N) adduct 32 has the carbon and the N-benzyl bridge syn-related
and the second NZ bridge on the underside of the [3]polynorbornane.
(13) Malpass, J. R.; Butler, D. N.; Johnston, M. R.; Hammond, M. L.
A.; Warrener, R. N. Org. Lett 2000, 2, 725-728.
1
300 °C; H NMR δ 2.13 (4H, s), 3.71 (6H, s), 4.16 (2H, s), 5.38 (4H, s),
7.06-7.08 (4H, m), 7.11 (1H, t, J ) 7.85 Hz), 7.16-7.18 (4H, m), 7.25
(2H, t, J ) 7.85 Hz), 7.70 (2H, d, J ) 7.85 Hz); 13C NMR δ 51.87, 52.45,
56.67, 75.00, 79.64, 119.18, 125.04, 126.73, 127.21, 127.26, 144.11, 146.29,
170.75; HRMS calcd for C33H29O6N 535.1994, found 535.1998. 25 4%;
1
mp 221-222 °C; H NMR δ 0.01 (2H, t, J ) 7.85 Hz), 1.12 (2H, t, J )
7.85 Hz), 1.17 (1H, d, J ) 8.88 Hz), 1.89 (2H, s), 2.27 (2H, s), 2.85 (2H,
s), 3.16 (3H, m), 3.89 (6H, s), 4.38 (2H, s), 6.92-6.95 (4H, m), 7.00-7.03
(4H, m), 7.21 (1H, t, J ) 7.51 Hz), 7.31 (2H, t, J ) 7.51 Hz), 7.54 (2H, d,
722
Org. Lett., Vol. 2, No. 6, 2000

reported aza-ACE coupling reaction15 that employs the [4π
+ 2π] addition of benzonorbornadienes 4a-4e to the 1,3-
dipoles 10a-10e formed by ring opening of the appropriate
aziridinocyclobutenes 9a-9e (Scheme 1). The 15th possible
syn-facial aza[3]polynorbornane ∆N∆ 26 could not be
prepared by this method. The required aziridines 9a-9e were
synthesized in three steps from the appropriate benzonor-
bornadiene 4a-4e using the sequence: (i) conversion to the
related cyclobutene 1,2-diester by ruthenium-catalyzed ad-
dition of dimethyl acetylenedicarboxylate (DMAD) 5; (ii)
addition of benzyl azide 7 to the resultant cyclobutenes; (iii)
photoinduced deazetization of the triazoline adducts (see
Scheme 1 and Table 1).
zonorbornadiene 4c was used as the dipolarophile, but rarely
with the others. The two-bridged systems 11a-11e14 were
prepared by heating the appropriate aziridine 9a-9e with
excess DMAD 5 at 120 °C.
Each of the XNY products could be formed in two ways,
since the X bridge could be part of the aziridine 9 and reacted
with the Y-bridged dipolarophile 4 or the Y bridge could be
incorporated into the aziridine reagent 9 and reacted with
the X-bridged dipolarophile. Table 1 shows that the different
modes of coupling gave vastly different yields for the same
product in several cases. Two factors contribute to this
difference: (a) the dipolarophilicity of the benzonorborna-
dienes 4 (O > NZ > π . CH2 > ∆); (b) the relative stability
of the 1,3-dipoles toward a competitive fragmentation process
(O, π, NZ, others stable).16
The stereostructures of the [3]polynorbornanes was es-
tablished by X-ray crystallography (Figure 2) or by spectral
Table 1. Yields and Melting Points of XNY 12-25a
a Yields are isolated and formed by the benzene reflux method unless
stated otherwise. * ) bent-frame isomer. ** ) symmetrical XNX
compounds are on diagonal and are boxed in bold.
Formation of the extended-frame aza[3]polynorbornanes
12-25 was achieved by thermal reaction of the aziridino
cyclobutenes 9a-9e with the benzonorbornadienes 4a-4e
[benzene at reflux or heating the reagents neat at 120 °C
(melt method)]. In several reactions a second stereoisomer
was formed in which the attacking dipolarophile has its
bridge located in an anti-relationship to the others, viz 27-
33. This bent-frame stereoisomer was always formed as well
as the extended-frame isomer when 7-isopropylidene ben-
Figure 2. X-ray structures of extended-frame adducts 13, 15, and
16 and bent-frame adduct 32 (X-ray data for these structures,
together with CNN 19 and CNC 24,13 are available from the author).
data. The NOE between the endo-bridgehead protons Ha and
Hb (Figure 3) was used to confirm the extended-frame
J ) 7.51 Hz); HRMS calcd for C37H35O4N 557.2566, found 557.2559. 29
34%; mp 210-211 °C; 1H NMR δ 0.14 (2H, t, J ) 7.83 Hz), 1.01 (6H, s),
1.12 (2H, t, J ) 7.83 Hz), 2.10 (2H, s), 2.57 (2H, s), 2.85 (2H, s), 3.55
(6H, s), 3.71 (2H, s), 3.77 (2H, s), 7.00-7.07 (6H, m), 7.16 (2H, m), 7.15-
7.21 (3H, m), 7.26 (2H, t, J ) 7.34 Hz), 7.34 (2H, d, J ) 7.34 Hz); HRMS
calcd for C40H39O4N 597.2879, found 597.2880. 35 90%; mp 157-159
°C; 1H NMR δ 2.75 (4H, s), 3.75 (12H, s), 3.95 (4H, s), 5.64 (4H, s),
7.26-7.34 (10H, m); 13C NMR δ 42.73, 50.16, 53.39, 59.00, 73.81, 81.92,
128.44, 128.54, 129.43, 136.91, 167.15, 167.36; HRMS calcd for C40H34N2O13
726.2061, found 726.2061. 36 54%; mp 280-282 °C; 1H NMR δ 1.43
(4H, s), 1.99 (2Hs, s), 2.25 (4H, s), 2.86 (2H, s), 3.70 (12H, s), 3.91 (4H,
s), 5.32 (4H, s), 7.12-7.43 (18H, m); 13C NMR δ 30.94, 42.37, 52.34,
54.09, 58.24, 58.60, 76.78, 80.03, 120.09, 126.47, 127.47, 127.95, 129.28,
143.75, 147.30, 171.47; HRMS calcd for C53H50N2O10 874.3465, found
874.3452. 38 35%; mp 274-275 °C; 1H NMR δ 0.87 (2H, d, J ) 8.1 Hz),
1.71 (4H, s), 2.56 (4H, s), 2.61 (4H, s), 3.12 (2H, d, J ) 8.1 Hz), 3.74
(12H), 3.76 (4H, s), 5.08 (4H, s), 6.07 (4H, s), 7.15-7.40 (10H, m).
Figure 3. NOE measurements used in the structure determination
and invertomer position fo r[3]poly norbornanes 12-25. Similar
NOEs were used to assign invertomer geometry to 36 and 38.
Org. Lett., Vol. 2, No. 6, 2000
723

geometry of the XNY adducts having different sentinel
groups. For the C2V-symmetrical compounds XNX, the
simplicity of the H NMR spectra provided the required
Scheme 2
1
support.
Sentinel Dominance Control. Since the sentinel groups
are different in XNY systems, the invertomers are not
isoenergetic and one invertomer is strongly favored in these
systems17 except for CN∆, 25 which is dynamic (see
accompanying Letter13). A priority order can be established
in which the dominant sentinel group (CH2 ≈ ∆ > π > NZ
≈ O) repels the central N-substituent, thereby providing a
method for controling the invertomer geometry by varying
the sentinel bridges.
The N-invertomer preference in solution for the XNY
systems was established using NOE measurements involving
the benzylic methylene protons and only one of the bridge-
head protons (interaction with Hc on the proximate norbor-
nane subunit shown in Figure 3, but not Hd on the remote
bridgehead). These preferences correspond to those found
in the solid state by X-ray crystallographic analysis of
compounds 13, 15, 16, 19, and 24 and are reinforced by AM1
modeling studies. 1H NMR, X-ray, and AM1 measurements
are in concert and fully validate the order of sentinel effects.
Aza-ACE coupling of bis-aziridine 3418 with 7-oxaben-
zonorbornadiene 5e yields the “windscreen wiper” 3615 in
which the N-substituents are outward-facing (out,out-inver-
tomer), so positioned by the dominance of the central
methylene bridge (Scheme 2). Coupling of norbornadiene
37 with bis-aziridine 35 yields the “windscreen wiper” 38,15
where the dominance of the methylene bridge again exerts
itself, this time forcing the N-substituent to adopt the in,in-
invertomer geometry.
sentinel bridge exhibit decisive invertomer preferences and
always direct the N-substituent away from the sentinel bridge.
This effect provides an additional way to obtain predictable
invertomer geometry.
The advent of the aza-ACE cycloaddition reaction has
allowed entry to aza[n]polynorbornanes, a new class of
heteroalicycles not hitherto available by any other route. The
substantial array of bridged polynorbornanes reported herein
has allowed us to study proximity-based (sentinel) effects
on the geometry of the N-substituents in fused 7-azanorbor-
nanes and determine how to control invertomer geometry.
These outcomes have direct bearing on the fundamental
question of nitrogen inversion and hybridization in a confined
environment and should allow these findings to be taken into
the field of molecular architecture and drug design (bis-
intercalators are currently under study in our laboratories).
Compounds such as 11a-11e which lack the second
(15) Butler, D. N.; Malpass, J. R.; Margetic, D.; Russell, R. A.; Sun,
G.; Warrener, R. N. Synlett 1998, 588-589.
(16) Warrener, R. N.; Hammond, M. L. A.; Butler, D. N. 1999,
unpublished results.
(17) Not only do the sentinels control the invertomer preference, they
also cause flattening of the nitrogen pyramid and a concomitant change in
hybridization of the N-bridge. These changes have been examined in more
detail using 15N NMR spectroscopy, and this aspect will be discussed
elsewhere.
(18) Warrener, R. N.; Margetic, D.; Sun, G.; Amarasekara, A. S.; Foley,
P.; Butler, D. N.; Russell, R. A. Tetrahedron Lett. 1999, 40, 4111-4114.
Acknowledgment. We thank Central Queensland Uni-
versity (Grant support) and the Australian Research Council
(Large Grant to CMA and International Project Travel Award
to J.R.M.).
OL9910969
724
Org. Lett., Vol. 2, No. 6, 2000