We have coined the 'dentane' name for the exo, exo-fused polynorbornane series of compounds in which the bridges have a syn-facial relationship (Figure 4). It derived this generic name as an extension of the [3]polynorbornane system where the 3­bridges were likened to a trident (see next subsection).

Figure 4

3.1 Tridents, Especially Those with a Central N­bridge (Y = NR)

The trident series is a subsection of the dentane family (see Section 3) of polynorbornanes containing 3-fused norbornanes. They have been so named because the three syn-facial bridges in the [3]polynorbornanes are structurally similar to the top section of a trident.

We have used the trident system as our testing ground for the ACE and aza-ACE methodology in order to assess coupling selectivities. In particular, we have determined the compatibility of juxtaposed heterobridges in these systems with a view of applying this knowledge to larger systems (arc-shaped molecules, polarofacials, Section 3.2, 3.3 respectively).

The stereoselectivity of the aza-ACE coupling reaction has been evaluated using the aziridinocyclobutane 7 as the 4p-reagent and various benzonorbornadienes as the 2p-reagents, following on the early work with norbornadiene (Section 2, Scheme 3).

Scheme 5

A key finding was provided by the reaction of the diacetoxybenzonorbornadiene 15 with aziridine 7 which produced the symmetrically coupled product 16 (Scheme 5). The 1H NMR spectrum of this product was fully symmetrical at room temperature and did not change on heating. This result could be interpreted in a number of ways.

1) The nitrogen substituent is sp2 hybridised and switching very rapidly from one side of the molecule to the other in a degenerate interconversion.

2) The bridge nitrogen is sp2 hybridised.

3) The bridge nitrogen is somewhere in between sp2 and sp3.

In fact, the X-ray structure of 16 indicates that explanation 3 is correct, at least in the solid state. We are currently investigating this feature by 15N NMR spectroscopy as part of a wider investigation of the effect of flanking substituents on the structure of the central N-bridge in the XNY-trident series.

In the first stage of this work, we have been able to show that the aza-ACE coupling reaction is extremely tolerant of the nature of the bridging atom in the 7-position of the benzonorbornadiene and yields trident systems with both the 7-oxa and 7-aza-benzonorbornadienes (Scheme 6).

Scheme 6

We are presently preparing the NNX-tridents and ONX-trident systems (Scheme 6, X= NR and O respectively) as additional models for this study. In addition, we are progressing the program by introducing carbon substituents into the 7-position as part of this study (Scheme 7).

Scheme 7

3.2 Polarofacial Poly(Heterobridged-Norbornanes)

When we first considered the concept of polynorbornanes formed from the assembly of 7­oxanorbornanes, we naively thought that the alicyclic framework would be straight. Accordingly, we envisaged that they could act as ionophores for transport of ions across membranes. This false impression was gained by considering their formation as being derived from two polymethylene chains and linking these alternatively with zero and methylene bridges (see Figure 5). However, molecular modelling showed that this was not the case, and that we are dealing with curved structures.

Figure 5

3.2.1 The Arc-shaped Framework

The concept that polynorbornanes were in fact curved rather than rod-like, had a large bearing on the way we approached the design of rigid molecular architectures. Indeed the positioning of chromophores at the termini of molrac systems composed of polynorbornanes meant that the relative orientation of such effector groups would be changed depending on the geometry of the frame. Indeed, this could be used to aid design and fine tune effector orientation, based on a knowledge of the curvature of the frame. This led to the concept of arc-shaped topography (Figure 6), where the curvature of the arc was governed by the nature of the bridges in the component norbornane subunits.

Figure 6

The curvature of the arc-shape systems was evaluated using molecular modelling conducted at the AM1 level and a selection of polynorbornane systems are displayed in Figure 7.

It is immediately apparent that the radius of curvature of the polynorbornanes differ significantly: the all-carbon system being the most curved while the all-oxygen system has the least curvature. It is of practical significance that the N-bridged systems are almost as curved as the carbon systems, since the former have not been described with more than two fused norbornanes, whereas the all-nitrogen systems are accessible through aza-ACE coupling.

Mixed systems of CN, CO, NO, and CNO have all been prepared and judicious choice of bridge partners allows tuning of the curvature in the polynorbornane system.

Figure 7

3.2.2 The Poly(7­oxanorbornanes)

In earlier approaches to the synthesis of poly(7-oxanorbornanes) we had explored the reaction of isobenzofurans with 7-oxanorbornenes and found that both exo,exo-isomers and exo,endo-isomers were produced. The stereoselectivity of these cycloadditions could be influenced by modification of the bridgehead position of the isobenzofuran, and we exploited this in the preparation of bis(crown ethers). While it was appropriate to use unsubstituted crown-isobenzofurans for the preparation of cavity shaped bis(crown ethers) (see Section 4, Scheme 29), formation of extended frame products required the use of arylated isobenzofurans. Thus, reaction of the bis­alkene 31 with arylated isobenzofuran 30 provided access to the extended frame product 32 with four contiguous O-bridges, together with the half-bent isomer 33 (Scheme 8). Such isobenzofuran reagents were inappropriate, however, for the production of more extended bis-crowns until appropriate bis(7-oxanorbornenes) were available. Work in this area has been largely overtaken by the successes of the BLOCK protocols described later (Section 4).

Scheme 8

The opportunity to use BLOCK coupling techniques in this work appeared promising when the ACE coupling reaction was found to produce exclusively extended-frame products on reaction cyclobutene epoxides with norbornenes (vide supra, Scheme 1). We were hopeful that similar stereoselectivity would be obtained with 7­oxanorbornenes, however, this was not to be, and both stereoisomers 35 and 36 were produced in the reaction of 7-oxabenzonorbornadiene 11 and the cyclobutene epoxide 34 (Scheme 9). It is interesting to note that the adverse oxygen, oxygen orbital interactions which contribute to the production of the bent-frame isomers such as 36 are apparently not as strong in nitrogen, oxygen or nitrogen, nitrogen systems (currently under theoretical study). Accordingly, reaction of 7-azabenzonorbornadiene with cyclobutene epoxides again exhibits extended-frame stereoselectivity (vide supra).

Scheme 9

Notwithstanding the lack of stereoselectivity of the ACE reaction with 7-oxanorbornenes, we pressed on to make the oxygen-bridged bis-epoxide reagent 39 (Scheme 10). This was achieved by reaction of the previously reported bis-alkene 37 with DMAD in the presence of a ruthenium catalyst to produce the bis(cyclobutene-1,2-diester) 38, which was epoxidised (tBuO2H,MeLi, -78 oC) to form the bis-epoxide 39.

Scheme 10

The reaction of 7-oxabenzonorbornadiene 11 with the bis-epoxide 39 was found to produce three isomeric cycloaddition compounds 42-44 in a 1:1:2 ratio (Scheme 11). The major product 44 is readily identified (four singlet CH resonances, three oxa-bridgehead resonances and two ester methyl resonances), however, the C2v symmetry of the other products 42, 43 renders their spectra both simple and similar. The distinction cannot be made reliably on chemical shift data alone and was achieved using nOe data. The required polarofacial system 42 shows a clear nOe between protons Ha and Hb on the lower face of the molecule, thereby clinching its stereochemistry.

Scheme 11

The ACE coupling is very specific regarding the nature of the epoxide which will participate in the reaction. To date it is restricted to cyclobutene epoxides containing two ester activating groups and simple changes, eg removal of one ester 45, both esters 46 or their replacement with phenyl sulfonyl groups 47, negates their participation (Figure 8). Further, norbornene epoxides 48 do not participate and can be incorporated into the ACE reagent with immunity. We have exploited this fact to increase the length of the oxygen substituted face of these polarofacials.

Figure 8

The required ACE BLOCKs containing the non-participating norbornene epoxide are each prepared from the 2:1-adduct 50, obtained from reaction of furan with perfluorobut-2-yne. It is interesting to note that the nucleophilic epoxidation conditions used to convert the cyclobutene-1,2-diester to their epoxides, also effects epoxidation of the trifluoromethyl-substituted p­bond in 50. This does not occur in related norbornene systems and clearly involves participation of the oxygen bridge. A mechanism for this transformation is outlined in Scheme 12, and finds recent precedent in the attack of carbanions onto 7-oxanorbornenes.ref

Scheme 12

Ruthenium-catalysed addition of DMAD to the 7-oxanorbornene 50 occurs site selectively at the unsubstituted alkene to yield the cyclobutene-1,2-diester 53 (Scheme 13). Treatment with tertiary butyl peroxide under the normal low temperature conditions causes epoxidation to occur at both p-centres of 53 to form bis-epoxide 55; controlled epoxidation allows isolation of the mono-epoxide 54, showing there is a clear preference for attack at the cyclobutene p-centre.

Scheme 13

Having ACE BLOCKs of each type with inbuilt epoxides has allowed the preparation of several new polarofacial systems. Compound 56, with five juxtaposed oxygen bridges, was prepared in two ways, one where the epoxide was provided by the alkene BLOCK (Scheme 14, mode 1 ) and the other where it was an end component of the cyclobutene epoxide BLOCK 55 (Scheme 14, mode 2). In each coupling mode, the required polarofacial target 56 was accompanied by roughly equal amounts of an isomer, the structure of which depended on the mode of coupling, eg 57 from mode 1 and 58 from mode 2 (Scheme 14).

Scheme 14

The coupling of the ACE BLOCKs 52 and 55 which each carry the inert epoxide functionality can also be achieved and this leads to the seven oxygen-bridged system 59; again it was accompanied by its stereoisomeric shadow (Scheme 15). This is the most extended oxa-bridged polarofacial system ever made, although the methodology does allow the potential to form more extended systems.

Scheme 15

3.2.3 The Aza-bridged Polarofacial systems

The major advantage of working in the nitrogen-bridged series is that the coupling reactions are all stereoselective and, as a consequence, single products are formed. As presented earlier (Scheme 3), the aza-ACE reaction proceeds with exo,exo-stereochemistry to afford extended-frame products. On the experimental side, the aza-ACE reaction occurs at a significantly lower temperature (80 oC) than the ACE reaction (140-160 oC) and this means that the reaction can be achieved by reflux in benzene without recourse to sealed tube conditions.

We find that the 7-substituent of the benzonorbornadiene effects the rate of reaction (dipolarophilicity) towards aza-bridged aziridines in the aza-ACE reaction. 7­Oxa-benzonorbornadiene 11 is the most reactive, while 7-isopropylidene-benzonorbornadiene 22 is the least reactive; other substituted members are of intermediate reactivity (see Scheme 16).

Scheme 16

The basis for the entry to all-heterobridged systems was provided by N-bridged aziridine BLOCK 61 which yielded the NNN-trident 62 on reaction with the N-bridged benzonorbornadiene 17 and the NNO­trident 63 by coupling with 7-oxabenzonorbornadiene 11 (Scheme 17). Again, the 1H NMR spectra of these products are complicated by loss of symmetry associated with N-substituent mobility at room temperature and only return to C2v or Cs-symmetry at higher temperature.

Scheme 17

The larger mixed oxygen, nitrogen systems have been produced using ACE coupling on dual epoxide BLOCKs and N-bridged benzonorbornadienes. Thus, reaction of bis-epoxide 40 with Boc-7-azabenzonorbornadiene 17 (140 oC, DCM) produced the pentadentane 64 (Scheme 18).

Scheme 18

For the study of multiple N-bridged dentane structures, we have again drawn on the dual coupling protocol. In particular, we have prepared the bis-aziridine 68, using the method outlined in Scheme 19. In this case, addition of azide could only be achieved using high-pressure conditions and then, with only moderate efficiency. A mixture of C2 and s-isomeric bis-triazolines 66 and 67 were produced but these were not separated as each yielded the required dual BLOCK 68 upon irradiation.

Scheme 19

Reaction of the N-bridged benzonorbornadiene 17 with dual aziridine 68 was conducted in benzene solution at reflux and produced the [5]polynorbornane 70 in which four of the syn-facial bridges are nitrogen (Scheme 20).

Scheme 20

The synthesis of the dual oxygen-bridged BLOCK 73 in the cyclobutene epoxide series was prepared in two steps from the known bis-alkene 71 according to our standard protocol (Scheme 21). This complements the single oxygen bridged system 39 described earlier.

Scheme 21

To date, we have not been successful in obtaining the bis-aziridines corresponding to epoxides 39 and 43 as addition of benzylazide fails to add onto the oxa-bridged cyclobutene-1,2-diesters 38 and 72. We are presently investigating alternative ways of converting cyclobutene-1,2-diesters to aziridinocyclobutanes.

The preparation of sexadentane systems have been successfully approached using ACE chemistry on the bis-epoxide 73. The feasibility of this approach was established using the coupling of naphthonorbornadiene 5 with bis-epoxide 73 which provided the CO4C-dentane 74 (Scheme 22). The stereochemistry of the coupling protocol was established by NMR spectroscopy, where the C2v-symmetry combined with the typical downfield shift of the methylene bridge proton Ha confirmed its proximity with the oxygen bridge (steric compression) as required in the assigned structure 74.

Scheme 22

In a related reaction with bis-epoxide 73, it was found that 7-azabenzonorbornadiene 17 produced a single 2:1-adduct 75 (Scheme 23). The dynamics of the N-bridges in this product precluded the use of NMR spectroscopy to confirm the structure, and its assignment rests on the analogy provided in the previous reaction with the carbon-bridged dipolarophile. Notwithstanding, structure 75 is the largest of the hetero polynorbornanes we have yet prepared and contain six contiguous 7-heteronorbornanes.

Scheme 23
Table of Contents
4. The Cavity Systems