Step by Step—From Nonnatural to Biological Molecular Ladders (2003)

Ladderanes were identified recently as membrane lipids (see structural formulas) in two ammonium-oxidizing bacteria, which is an astonishing observation considering the unusual structural motif and the nontrivial synthesis of this class of compounds. The molecular analogue of a ladder can be represented by the structure 11 . When n=0 this structure reduces to cyclobutane (2), which nobody would consider a ladder-type molecule, and when n=1 bicyclo[2.2.0]hexane (3) results. But starting with the “four-runged” tricyclo[4.2.0.02,5]octane (4) on, the analogy between the macroscopic and the molecular object is quite evident. Molecules like 1 and 4 are referred to as ladderanes.1 In fact, the ladder image is somewhat limited for 1, since as the number of rungs increases, the stereochemistry quickly becomes more and more complex. Hydrocarbon 4 can form two diastereomers, anti- and syn-4, which are depicted as 5 and 6, respectively. And even this is a restriction, since the ring junction could in priniciple also have trans stereochemistry, as illustrated in 7. Presumably compounds of this type would be very highly strained, especially if the ladderane would contain more than one trans junction. In the following discussion we will consider only cis-annelated ladderanes, and even then the number of diastereomers still grows quickly. For a polycyclic hydrocarbon containing four cis-fused cyclobutane rings (a pterodactylane, see below) there are three diastereomers, for 1 with n=4 there are five possibilities, and with n=5 the number of possible arrangements is ten. How can these molecules be prepared? And, once they have been obtained, how could they be of interest? Retrosynthetically a ladderane 10 can be cleaved either horizontally or vertically (Scheme 1). Horizonal cleavage would lead ultimately to alkenes (8, first and last rung of the ladder) and alkynes (9, all other rungs). Vertical cleavage would generate the conjugated polyene 11. If the ends of the molecular ladder are unsaturated, then, in principle, this structure could be built up solely from alkynes. Although the simplicity of these starting materials can hardly be surpassed, their actual conversion into ladder-type stuctures is more difficult and in general fails. For example, it has been known since the days of Reppe that acetylene derivatives may be oligomerized, but the resulting products are usually cyclic unsaturated oligomers—benzene derivatives and other arenes, cyclooctatetraenes—not ladder or stair structures. The conversion of 11 into a ladderane would require more or less parallel alignment of the two polyene strands and a separation of 3 to 4 Å, an entropically rather unlikely situation. It is well known that short conjugated polyene chains cyclize preferably to give cyclobutenes, cyclohexadienes, etc. on photochemical or thermal activation, and do not form ladderanes intermolecularly. Clearly either specialized buildings blocks are required or the polyene chains must be held in parallel orientation by a suitable linker unit. Retrosynthetic analysis of ladderanes. One such “specialized” building block is cyclobutadiene (15, Scheme 2). In their pionieering studies on [4n]annulenes Nenitzescu and co-workers showed that 15 can be generated by treatment of cyclobutene dichloride 12 with sodium amalgam.2 The highly reactive antiaromatic intermediate dimerizes under the reaction conditions and yields the syn dimer 17, which on hydrogenation over palladium on charcoal furnishes the syn-[3]ladderane 6. Interestingly, when 12 is treated with lithium amalgam a completely different process takes place (Scheme 2). The resulting anti diene 18 is formed in a stepwise sequence via the lithium derivative 14, which undergoes C–C coupling reactions to give the open dimeric structure 16, the immediate precursor of 18. Hydrogenation of 18 yields the expected anti isomer 5. Reaction sequence for the synthesis of 5 and 6 starting from cyclobutene dichloride (12). Cyclobutadienes were, in fact, also shown to be the intermediates of choice in the synthesis of higher analogues of 5 and 6 (Scheme 3). When cyclobutadiene is liberated from its stored form, metal complex 19, by cerium(iv) oxidation in the presence of the substituted alkyne 20, double addition and formation of the 2:1 adduct 21, which contains four annelated cyclobutane rings, results. Hydrogenation converts these dienes—called pterodactyladienes because of their resemblance to the extinct flying reptiles Pterodactyla—to the tetracyclic products 22.3 Although other substrates such as Dewar benzenes4 and s-tetrazines 235 can replace 20 in cyclobutadiene additions of this type, for the synthesis of the parent hydrocarbon 28 Martin and co-workers had to develop a much more elaborate synthetic sequence (Scheme 3).6 Thus photochemical addition of maleic anhydride (24) to acetylene (9) provided the bisadduct 25. Conventional procedures were used to convert 25 into the bisthioether 26, which after chlorination with N-chlorosuccinimide (NCS) and oxidation gave the bissulfone 27 as a mixture of isomers. A final Ramburg–Bäcklund ring contraction yielded pterodactyladiene 28. General approach to the ladderanes and the synthesis of the parent hydrocarbon 28 according to Martin et al.6 Considering the high reactivity of cyclobutadienes, it should in principle be possible to prepare still higher ladderanes by omitting a second addition partner altogether, that is, by letting cyclobutadienes react with themselves. This strategy was first demonstrated by Mehta and co-workers, who on oxidation of diester 29 obtained a product mixture in acceptable yield (55 %) containing the ladderane derivatives 30–32 in a 3:2:1 ratio (Scheme 4).7 Later this approach was extended to the preparation of [9]- to [13]ladderane derivatives8 as well other esters such as 33.9 Synthesis of higher ladderanes starting from iron cyclobutadiene complexes. CAN=ceric ammonium nitrate. The parent reaction for the polyene route to ladderanes (11→10, Scheme 1) is the solid-state photodimerization of cinnamic acid, a process investigated thoroughly by Schmidt and co-workers.10 In this well-known photodimerization, topochemical control is practically built in since the process only takes place when the distance between the reacting (parallel) double bonds does not exceed ca. 3.5 to 4 Å. This critical distance is provided and maintained in the crystal lattice but breaks down in solution. Hence cinnamic acids do not undergo [2+2]photodimerization in solution. On the other hand, if a rigid spacer is used to hold appropriate functional groups in correct orientation, high-yield photoaddition should also be possible in solution. Such a spacer is provided by the “layered” [2.2]paracyclophane system, in which the distance between the aromatic rings is roughly 3.1 Å. Indeed, when “cinnamic acid dimer” 34 is irradiated in ethanol, the cyclobutane derivative 35 is formed quantitatively, with the highest quantum yield ever measured for such a process (Scheme 5).11 Spacer-directed ladderanes synthesis. a) Diisobutylaluminum hydride, Et2O, N2, −80→0 °C; b) MnO2, CH2Cl2, N2, room temperature; c) NaH, (EtO)2P(O)CH2COOEt, THF, N2, room temperature. The bisvinylogous diester 36 could be obtained readily from 34 in good yield in a few simple steps, and subsequent irradiation gave the [3]ladderane 37, again in excellent yield. Even at this point the controlling influence of the [2.2]paracyclophane unit has not yet been exhausted; irradiation of the still further extended hexaene diester 38 provides the [5]ladderane derivative 39 (Scheme 5).12 The ladderanes discussed here have all been all typical “nonnatural” or “designed” compounds. However, it was recently discovered that ladderanes also occur as the dominant membrane lipids of two anaerobic ammonium-oxidizing (anammox) bacteria.13 These lipids are found in the anammoxosome, the dedicated intracytoplasmic compartment where anammox catabolism takes place. These naturally occurring “ladderane lipids”, with structures such as 40 and 41-4 , generate an exceptionally dense membrane, helping to contain toxic intermediates such as hydrazine and hydroxylamine. The (unknown) biosynthesis of these biomolecules certainly requires a unique set of enzymes and—considering the high strain energy of a even single cyclobutane ring—very likely has a high energetic cost. Another recent development concerns the study of acyclic and cyclic sigmatropic “shiftamers” derived from [n]ladderanes. Hoffmann and Tantillo have suggested that a formal [2+2]cycloreversion in ladderane 42-4 would give rise to compound 43, which has a local “defect” consisting of two parallel double bonds.14 Diene 43 could isomerize via the boatlike transition state 44 to 45, which, of course, for the parent systems would be equivalent to 43. If this process would be continued along the parallel chains “to infinity”, it would lead to a pair of double bonds zipping down the polymer chain. Indeed, B3LYP6-31G(d) calculations suggest that the barrier to the Cope rearrangement is low enough to make the shiftamer 43 fluxional at room temperature. Shiftamers do not necessarily have linear structures. All-cis fusion of the cyclobutane rings of a ladderane would eventually generate cyclic molecules in which the moving double bonds would “run around in circles”. The ladderane motif—until recently not more than an idea—has gained interest as a spacer unit allowing large variations in rigidity, three-dimensional structure, and intermolecular distances. Not only could ladderanes lead to novel materials with unusual electronic and bonding properties but they also occur in nature. Having access to reliable synthetic methods to prepare these unusual ladders, we might now expect to climb them quickly and gain interesting perspectives on new preparative transformations, materials, and compounds of biological interest.