Synthesis of a chlorin with annelated lactam ring as subunit for artificial photosynthetic reaction centres

A chlorin with an annelated cyclic ketone moiety was synthesized from a tricyclic nickel complex and appropriate pyrrole building blocks. Ketone functionality of the target chlorin allows Beckmann rearrangement to yield chlorin lactams. Lactam moieties on the chlorin represent masked amino acid structures which should allow formation of peptide-like backbones, along which chlorin pigments are arranged. Due to the “natural” chlorin chromophores and the peptide backbone the devices should represent artificial mimetics of natural photosynthesis systems.


Introduction
The elementary step of photosynthesis in bacteria, algae and, plants consists of a light-induced electron transfer from so-called special pair chlorophylls along a chain of further chlorophyll pigments to quinone acceptors.The so-formed hydroquinone structure provisionally stores two electrons for subsequent biochemical transformations. 1-3The process of light induced-electron transfer is accompanied by formation of proton gradients which are used for ATP production.Knowledge of the structure of photosynthetic reaction centres of bacteria and plants originates from crystal structure investigations. 4-7Crystal structure investigations revealed not only the spacial orientation but also that of the membrane protein environment in which the chlorophyll pigments are embedded by lipophilic interactions.For studying the complex photophysical/photochemical process of light-induced electron transfer in natural photosynthesis on a level of lower complexity, numerous artificial photosynthesis model systems were designed and synthesized. 8-11The majority of those model systems made use of porphyrin pigments; chlorin based systems are less widespread. 12-16Chlorin 2 the dihydroporphyrin chromophore of chlorophyll a 1 has different photophysical properties compared to the completely unsaturated porphyrins (Figure 1).The ubiquitous green colour of chlorophylls and the red of porphyrinoid blood pigment heme make this difference palpable. 17   To obtain more biomimetic photosynthesis models we aimed at the synthesis of chlorin type pigments with amino acid functionality.The chlorin subunits could then be covalently linked to peptide-like oligomers using established coupling methods from peptide chemistry (Figure 2).
Chlorin pigments arranged along the artificial peptide backbone could mimic the natural design in which chlorophylls are held together by lipophilic interactions with the protein environment.

Results and Discussion
The tricyclic nickel complex 9 (Scheme 2) which was used for several syntheses of chlorins in our laboratory is also an ideal intermediate for preparation of chlorins with the desired amino acid functionality. 22-28The task therefore was to connect 9 with pyrrole ring D building blocks which contain annuleted cycloketone moieties as masked amino acid functions.Pyrroles 3 and 6 were chosen as starting materials for ring D building blocks (Scheme 1).Preparation of 3 and 6 was achieved from cyclohept-4-ene-1-one and isocyanides according a general protocol for pyrrole synthesis developed in our laboratory. 29,30 Condensation of ring D building pyrroles with nickel tricycle 9 requires aldehyde functions.Therefore pyrrole benzyl ester 3 was subjected to Vilsmeier reaction conditions to yield 4. Debenzylation by catalytic hydrogenolysis and subsequent decarboxylative halogenations gave potential ring D building blocks 5 and 8. Bromide and iodide should function as leaving groups for the final cyclization step forming the chlorin.An alternative route started from cyano pyrrole 6 which yielded ring D building block directly by Vilsmeier formylation.The cyano group acts as leaving group for the final cyclization reaction.
With ring D building blocks in hand, synthesis of chlorin 12 could be achieved (Scheme 2).The sequence started with hydrolysis of the ester group of nickel complex 9 and condensation with ring D pyrrole aldehyde 7. Hydrolysis is facilitated by nickel complexation of the ethyl carboxylate group.Acid induced condensation proceeded with decarboxylation and decomplexation of nickel.The acidic reaction conditions also led to partial hydrolysis of the ketal function.© ARKAT USA, Inc Thus tetracyclic bilin was formed in good yield as mixture of ketone 10a and ketal 10b derivatives.Because keto chlorin 12 was envisaged as the final target, we did not make any attempts to separate ketone and ketal derivatives on a preparative scale.To perform cyclization of bilin 10a,b to chlorins 11a,b the bilin was recomplexed with zinc(II) diacetate.The zinc stabilizes the quite sensitive bilin and, what is more important, it exercises an essential template effect for the cyclization process. 22,23Cyclization was initiated by base-induced elimination of HCN from the reduced pyrrole ring with formation of an enamine structure.The enamine attacks as a nucleophile at the cyano-substituted position of pyrrole ring D. Thus a methine bridge between rings A and B is formed with loss of a second HCN fragment.The obtained zinc chlorin 11a,b existed again as mixture of ketone 11a and ketal 11b derivatives.
Treatment of the mixture of chlorin derivatives 11a,b with perchloric acid removes the central zinc(II) and hydrolysed the ketal function to yield single keto chlorin 12 in good overall yield.
With iodo pyrrole aldehyde 8 as ring D building block only negligibly lower overall yields for the entire reaction sequence were achieved, but here reproducibility suffered due to the sensitivity of the bilin intermediates.With bromo pyrrole aldehyde 5, synthesis of bilins/chlorins failed completely.
Using keto chlorin 12 a Beckmann rearrangement for formation of lactam targets was performed (Scheme 3).O-Mesityl sulfonyl hydroxylamine (Tamura reagent) was reported as a reagent that allows very gentle reaction conditions (temperatures around 0 o C) for Beckmann rearrangements. 31,32Another advantage of this hydroxylamine derivative could be its sterical strain with possible preferred formation of one constitutional lactam isomer.Indeed, the rearrangement reaction of keto chlorin 12 could be achieved with good yields under very gentle reaction conditions.
Analytical HPLC and 1 H NMR spectroscopy revealed that a mixture of constitutionally isomeric lactams 13a and 13b was formed.Though constitutional isomer 13a was slightly preferred (13a:13b = 1.5:1), the observed selectivity cannot be attributed to sterical strain of the Tamura reagent.Possible less favorable orientation of the mesityl residue in the oxime intermediate towards ring A with bulky geminal dimethyl substitution should favor constitutional isomer 13b and not the observed isomer 13a.The constitutions of 13a and 13b were tentatively assigned by 2D-NOESY-and 2D-NOESY-HH-COSY experiments.Assignment was facilitated by the fact that the isomers have different proportions in the mixture.

Conclusions
Condensation of tricyclic nickel complex 9 and cyanopyrrole aldehyde 7 provided a facile synthetic access to ketochlorin 12. Subsequent cyclization of bilin intermediates 10 formed the macrocyclic chlorin in a 48% yield.The desired lactams were obtained by Beckmann rearrangement, also in good yields.Lactams 13a,b as protected amino acid like subunits should open an access to artificial photosynthesis models with a peptide/polyamide backbone.

Figure 2 .
Figure 2. Schematic representation of chlorin subunits arranged along an artificial peptide backbone.