As MBBs are to be connected in a three-dimensional fashion, one needs to find rigid and three-dimensional molecules which could serve as skeletons. But apart from the fact that the overwhelming bulk of molecules that chemists deal with are of a floppy and chain-like nature, the few rigid and compact cages (like cubane, adamantane, dodecahedrane, the norbornanes, and the fullerenes) are very difficult to functionalize in a systematic and useful way because these molecules are very inert once synthesized. The step-wise syntheses of these skeletons often face severe steric problems at one or more steps, they often have lengthy syntheses, give low yields, and harsh conditions are employed which many functional groups would not tolerate. The most promising structures would be the norbornanes, which usually are assembled in one step by a Diels-Alder cycloaddition reaction, starting with two substrate materials that could be functionalized with some limited degree of flexibility.
But even if this group of compact cage skeletons were easily accessible, one could raise doubts on their usefulness because they might be too small for practical purposes. They might not provide enough potential attachment sites for functional groups. One of the more interesting types of chemistries to link the MBBs together are electrocyclic additions of the Diels-Alder type. The problem there would be that in order to just anchor one link, one would have to occupy two adjacent functional group attachment sites, at least for the diene component. With small skeletons such as adamantane and norbornane, one would encounter severe problems in incorporating diene structures.
The small sizes of the compact cages could also make them not immunogenic enough, which is of importance because the receptors for these MBBs will presumably be antibody fragments. On the other hand, antibodies to a hapten of comparable smallness, 2,4-dinitrophenolate, have been successfully generated and are commercially available.
If the compact cage skeletons are too small, one would simply have to use larger skeleton structures. But what are the problems one runs into here ? In the literature, there is an intriguing lack of syntheses of stiff larger cage structures that might be suitable. There is quite a range of cavitands, carcerands, and similar complexing agents, but the functional groups of these compounds generally all look towards the interior, and/or are chemically identical and indistinguishable, and are provided in insufficient quantity (many large compounds hardly have three or four functionalities).
Ideally, one would like to have a dedicated construction kit for the MBBs themselves, to build a variety of them, having different and asymmetric functionalization patterns. This kit would consist of a number of miniature building-blocks, each able to carry, say, one decorational functional group that is to end up in the final MBB, plus functional groups needed to link up with other minis to establish the skeleton structure. Such an approach has been tried recently with some success [WuLeeMoo92] by using phenylacetylene-units as the minis, which can be joined in a sequentially controllable polymerization scheme. In principle, one could custom-tailor the phenyl-units to contribute decorational functional groups.
In order to create stiff, non-floppy, cage-like structures, one invariably will end up pinning down a potentially flexible "planar" structure by a tripod. This whole construct will end up being rigid and sturdy only if the legs of the tripod do not contain too many joints. Namely, one joint seems to be fine as is nicely illustrated by adamantane, where a "planar" cyclohexane ring is being held in one conformation by a tripod which has one joint per each leg. (Cubane is a "planar" cyclohexane ring being held in one conformation by two tripods which have zero joints in the legs and are grasping the cyclohexane from both sides and holding at it alternating sites.) But with more than just one joint per leg, the tripod will become floppy. Each joint will be where an atom sits, and this statement can be also reversed: as there are no atomic bonding geometries in organic chemistry that are linear (except for sp1-carbons), every atom will introduce angles and become a joint that is able to wiggle the leg into undesired conformations, unless strictly confined, by e. g. a tripod that does not have legs which contain more than one intervening joint. Building sturdy structures using these minimal tripods invariably leads to cyclic structures that contain about six atoms, which is precisely the domain of the compact cages mentioned earlier. So then, nothing would have been gained. It is fairly difficult to conceive of larger cages that can be put together in a modular fashion so that the result is still rigid enough. In [WuLeeMoo92] the large cage was constructed by not using single atoms as the joints, but phenyl-units instead. The architecture used might be described as two mutually opposed tripods, which seem to be able to restrict each others conformational freedom sufficiently in some cases. This however led to a fairly empty and airy cage which leaves some desire for more structural rigidity.
There is an additional problem. As any individual mini-building-block has to be incorporated into the skeleton in a rigid and confined fashion, it usually will have to be attached by at least three bonds. If this mini then provides one additional functional group that will actually appear on the MBB, then in the overall analysis, three functional groups have been consumed for one that has been delivered. If one looks at the totally and completely assembled MBB, one finds that essentially nothing has been gained in terms of providing more potential functionalization sites which would have been desirable for increased design flexibility, and which was the reason why one wanted larger cages in the first place. The functional groups needed for tying together the minis into the skeleton are lost because usually the atoms for such a bond cannot engage in any further activity other than the bond-formation itself. Similarly, nothing is gained in additional functionality by using sp1-carbons (the only linear joint type available as mentioned above), because the resulting acetylenic structures only make the cage larger and more airy.
These problems seem to constitute a rather sinister law in organic chemistry which explains in part why modularily enhancing the number of functionalization sites by making larger (but still rigid) cages fails so easily. After more than a hundred years of synthetic efforts, one would have expected large cages to be more prevalent unless there do exist serious obstacles.